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"abstract": "Voriconazole is an antifungal agent that is commonly used in immunocompromised patients who develop fungal infections. We report a case of severe recurrent hyperkalemia that developed after starting voriconazole for the treatment of histoplasmosis in a kidney transplant patient who was maintained on tacrolimus-based immunosuppression. Hyperkalemia developed despite reducing the tacrolimus dose to maintain levels in a low therapeutic range. Although interactions between azoles and calcineurin inhibitors are widely recognized, this is the 1st report describing new-onset hyperkalemia following initiation of voriconazole in a kidney transplant patient receiving tacrolimus.",
"affiliations": "Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.;Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.;Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska. Electronic address: scott.westphal@unmc.edu.",
"authors": "Nazmul|M N|MN|;Miles|C D|CD|;Westphal|S G|SG|",
"chemical_list": "D000935:Antifungal Agents; D007166:Immunosuppressive Agents; D065819:Voriconazole; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2017.09.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "49(10)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D000935:Antifungal Agents; D006660:Histoplasmosis; D006801:Humans; D006947:Hyperkalemia; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D016559:Tacrolimus; D065819:Voriconazole",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "2372-2373",
"pmc": null,
"pmid": "29198681",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe Hyperkalemia Complicating Voriconazole Treatment in a Kidney Transplant Recipient With Histoplasmosis: A Case Report.",
"title_normalized": "severe hyperkalemia complicating voriconazole treatment in a kidney transplant recipient with histoplasmosis a case report"
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"companynumb": "US-ACCORD-061934",
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"activesubstancename": "MYCOPHENOLIC ACID"
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"abstract": "Hand-foot-and-mouth disease, a highly contagious viral infection, occurs more common in children than in adults. However, there was a recent outbreak of Coxsackievirus A6-induced infection with an atypical presentation among the adult population. Stevens-Johnson syndrome is a severe mucocutaneous disease characterized by extensive necrosis and detachment of the epidermis, and this condition is commonly caused by medications. Herein, we describe a 30-year-old male patient taking allopurinol for the management of gout. The patient presented with numerous erythematous papules, vesicles, and patches with mucosal eruptions on the whole body, oral mucositis, and fever, and he was finally diagnosed with hand-foot-and-mouth disease.",
"affiliations": "Division of Infectious Disease, Department of Internal Medicine, Inje University Haeundae Paik Hospital, Busan, Korea.;Division of Infectious Disease, Department of Internal Medicine, Inje University Haeundae Paik Hospital, Busan, Korea.;Department of Dermatology, Inje University Haeundae Paik Hospital, Busan, Korea.;Department of Otorhinolaryngology, Head and Neck Surgery, Inje University Haeundae Paik Hospital, Busan, Korea.;Department of Pathology, Inje University Haeundae Paik Hospital, Busan, Korea.;Division of Allergology, Department of Internal Medicine, Inje University Haeundae Paik Hospital, Busan, Korea. mdpcs00@hanmail.net.;Division of Infectious Disease, Department of Internal Medicine, Chungnam National University Sejong Hospital, Sejong, Korea. smkimkor@gmail.com.",
"authors": "No|Tae Hoon|TH|https://orcid.org/0000-0002-0112-0042;Jo|Kyeong Min|KM|https://orcid.org/0000-0002-0311-4463;Jung|So Young|SY|https://orcid.org/0000-0003-0155-5473;Kim|Mi Ra|MR|https://orcid.org/0000-0003-2875-0738;Kim|Joo Yeon|JY|https://orcid.org/0000-0002-4259-667X;Park|Chan Sun|CS|https://orcid.org/0000-0003-0113-8354;Kym|Sungmin|S|https://orcid.org/0000-0003-3518-966X",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.3947/ic.2020.52.4.634",
"fulltext": "\n==== Front\nInfect Chemother\nInfect Chemother\nIC\nInfection & Chemotherapy\n2093-2340 2092-6448 The Korean Society of Infectious Diseases; Korean Society for Antimicrobial Therapy; The Korean Society for AIDS \n\n32757503\n10.3947/ic.2020.52.4.634\nCase Report\nCoxsackievirus A6-induced Hand-Foot-and-Mouth Disease Mimicking Stevens-Johnson Syndrome in an Immunocompetent Adult\nhttps://orcid.org/0000-0002-0112-0042No Tae-Hoon 1 https://orcid.org/0000-0002-0311-4463Jo Kyeong Min 1 https://orcid.org/0000-0003-0155-5473Jung So Young 2 https://orcid.org/0000-0003-2875-0738Kim Mi Ra 3 https://orcid.org/0000-0002-4259-667XKim Joo Yeon 4 https://orcid.org/0000-0003-0113-8354Park Chan Sun 5* https://orcid.org/0000-0003-3518-966XKym Sungmin 6* 1 Division of Infectious Disease, Department of Internal Medicine, Inje University Haeundae Paik Hospital, Busan, Korea.\n2 Department of Dermatology, Inje University Haeundae Paik Hospital, Busan, Korea.\n3 Department of Otorhinolaryngology, Head and Neck Surgery, Inje University Haeundae Paik Hospital, Busan, Korea.\n4 Department of Pathology, Inje University Haeundae Paik Hospital, Busan, Korea.\n5 Division of Allergology, Department of Internal Medicine, Inje University Haeundae Paik Hospital, Busan, Korea.\n6 Division of Infectious Disease, Department of Internal Medicine, Chungnam National University Sejong Hospital, Sejong, Korea.\nCorresponding Authors: Chan Sun Park, MD. Division of Allergology, Department of Internal Medicine, Inje University Haeundae Paik Hospital, 875 Haeun-daero, Haeundae-gu, Busan 48108, Korea. Tel: +82-51-797-2210, Fax: +82-51-797-1341, mdpcs00@hanmail.netCorresponding Authors: Sungmin Kym, MD, PhD. Division of Infectious Disease, Department of Internal Medicine, Chungnam National University Sejong Hospital, 20, Bodeum 7-ro, Sejong 30099, Korea. Tel: +82-44-995-3350, Fax: +82-44-995-3359, smkimkor@gmail.com*Chan Sun Park and Sungmin Kym corresponded equally to the work.\n\n\n12 2020 \n27 7 2020 \n52 4 634 640\n31 3 2020 07 6 2020 Copyright © 2020 by The Korean Society of Infectious Diseases, Korean Society for Antimicrobial Therapy, and The Korean Society for AIDS2020The Korean Society of Infectious Diseases, Korean Society for Antimicrobial Therapy, and The Korean Society for AIDSThis 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.Hand-foot-and-mouth disease, a highly contagious viral infection, occurs more common in children than in adults. However, there was a recent outbreak of Coxsackievirus A6-induced infection with an atypical presentation among the adult population. Stevens–Johnson syndrome is a severe mucocutaneous disease characterized by extensive necrosis and detachment of the epidermis, and this condition is commonly caused by medications. Herein, we describe a 30-year-old male patient taking allopurinol for the management of gout. The patient presented with numerous erythematous papules, vesicles, and patches with mucosal eruptions on the whole body, oral mucositis, and fever, and he was finally diagnosed with hand-foot-and-mouth disease.\n\nAdultCoxsackievirus A6Hand-foot-and-mouth diseaseStevens–Johnson syndromeAllopurinol\n==== Body\nIntroduction\nHand-foot-and-mouth disease (HFMD) is a highly contagious viral infection commonly affecting children [1]. It is caused by several enteroviruses, primarily Coxsackievirus A16 and Enterovirus 71. HFMD is typically characterized by fever, malaise, sore mouth or throat, and characteristic cutaneous eruptions on the hands, feet, and mouth [2]. With the appearance of skin lesions, this condition must be distinguished from other skin diseases, including erythema multiforme (EM), and other viral infections such as chickenpox and measles. Currently, the occurrence of atypical adult HFMD caused by Coxsackievirus A6 (CVA6) is increasing worldwide [345]. HFMD caused by CVA6 affects a higher number of adult patients compared with that caused by conventional viruses.\n\nStevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) constitute a disease spectrum of the severe mucocutaneous hypersensitivity reaction commonly caused by drugs [6]. This spectrum is characterized by skin detachment and mucosal involvement. SJS is a severe type of reaction characterized by skin detachment of less than 10% of the body surface area (BSA), widespread macules, and flat, atypical target lesions. Further, TEN involves more than 30% of the BSA. The SJS/TEN overlap syndrome is defined as skin detachment of 10 – 30% of the BSA [7]. Allopurinol, a drug used for the treatment of gout, has been well known to be associated with SJS [8]. Herein, we present a case of an adult male patient with an atypical presentation of CVA6-induced HFMD, which mimicked SJS caused by allopurinol.\n\nCase report\nA 30-year-old male patient visited the emergency room due to fever for 5 days and whole-body skin eruption for 3 days. The skin eruption started in both hands and then spread to the whole body within 3 days. Moreover, he had labial vesicles, painful scrotal skin eruption, odynophagia, and dysphagia\n\nThe patient presented with acute ill-looking appearance upon check-up, and his vital signs were as follows: blood pressure, 110/70 mmHg; pulse rate, 100 beats/min; body temperature, 38.3°C; and respiration rate, 20 cycles/min.\n\nNumerous erythematous papules were observed on the patient's torso, palms, perioral area, and scrotum. The lips were covered with crusts, and blisters were found around the area (Fig. 1A-1C). The patient also presented with oral mucosal lesions. There were three round-shaped non-tender lymph nodes measuring 0.5 cm on the left side of the neck. The patient claimed that he had been taking drugs for gout for 3 weeks before the visit, as well as vitamins and lutein supplements. Moreover, he had no close contact with any ill child or adult.\n\nFigure 1 Skin lesions observed during the emergency room visit. (A) (left upper) Crusts covered lips, perioral viscles were shown. (B) (middle upper) Torso, and (C) (right upper) hands showing numerous erythematous papules.\nSkin lesions on the third day of hospitalization. (D) (left lower) Labial crusts went worse. (E) (middle lower) Erythematous papules enlarged and merged with each other. (F) (right lower) Erythematous papules of the dorsum of the hands.\n\nLaboratory test results were as follows: blood test (white blood cell [WBC] count: 8,190 x106/L, neutrophil count: 79.9%, lymphocyte count: 11%, eosinophil count: 0.0%, hemoglobin level: 15.5 g/dL, and platelet count: 148x109/L), liver function test (aspartate aminotransferase level: 26 U/L, alanine aminotransferase level: 37 U/L, alkaline phosphate level: 73 U/L, and gamma-glutamyl transpeptidase level: 16 U/L), and kidney function test (blood urea nitrogen level: 12.3 mg/dL and creatinine level: 1.15 mg/dL). Only the C-reactive protein level was elevated at 2.1 mg/dL. The human immunodeficiency virus (HIV) and syphilis tests had negative results. . Based on the Epstein-Barr virus test, the patient tested positive for IgG and negative for IgM. Antipyretics (ketorolac, propacetamol) and antihistamines (hydroxyzine, levocetirizine) were administered, and ceftriaxone was provided as an empirical therapy. The fever persisted until the third day, and the skin lesions, including those on the dorsum of the hands, progressed with a merging pattern, and the lip and oral mucosal lesions were worse that the patient could not even drink water (Fig. 1D-1F).\n\nThe patient was then admitted on the third day of the emergency room visit, with consideration of viral infection and SJS caused by allopurinol. After 60 mg of methylprednisolone was administered in accordance with the treatment guidelines for SJS, the fever improved. A skin biopsy was performed on the second day of admission. On microscopic examination, superficial perivascular dermatitis and papillary dermal edema with epidermal necrosis (Fig. 2A), intra-epidermal vesicles containing neutrophils and epidermal necrosis of the upper third layer of the skin (Fig. 2B, 2C), scattered apoptotic keratinocytes and ballooning leading to reticular degeneration, and neutrophil dominant infiltration (about 10/high-power field) in the dermal interstitium (Fig. 2D) were shown. These findings are not suitable for diagnose SJS. Laboratory tests for measles and Varicella Zoster virus revealed that the patient tested positive for IgG but negative for IgM. Laryngoscopic examination showed that mucosal erosion and inflammation were noted in the epiglottis, aryepiglottic fold, and pyriform sinus, causing swelling and airway obstruction. On the eighth day, the laryngoscopic examination revealed bleeding, discharge, and blood clots around the lips, and the mucosal lesions in the larynx improved (Fig. 3A-3C). On the eleventh day, only focal lesions were observed on the lips. However, the lesions in the larynx were improved (Fig 3D-3F). He was then discharged after 14 days and was prescribed with oral antihistamines only.\n\nFigure 2 Pathologic findings of skin biopsy (hematoxylin and eosin stain).\n(A) (left upper) Superficial perivascular dermatitis with spongiosis was predominantly noted. (x 100). (B) (right upper) Intraepidermal vesicle with neutrophils. (C) (left lower) Epidermal necrosis and reticular degeneration. (D) (right lower image) Superficial perivascular infiltrates comprising lymphocytes and neutrophils (arrow) were predominantly observed in the dermis.\n\nFigure 3 Laryngoscopic examination findings on the 8th day of admission. Lips (A) (left upper) Bleeding, discharge, and blood clots around the lips. (B) (middle upper) Palatine mucosal ulceration. (C) (right upper) Laryngeal mucosal ulceration.\nLaryngoscopic examination findings on the 11th day of admission. (D) (left lower) Perioral discharge and blood clots were improved. (E) (middle lower) Buccal mucosal ulceration. (F) (right lower) Laryngeal mucosal ulceration were improved.\n\nHe visited the hospital eight days after discharge, and the skin lesions and mucosal lesions improved. The result of the HLA-B*58:01 test for allopurinol-induced severe cutaneous adverse drug reactions (SCARs) was negative. Ten days after discharge, we found that the CVA6 neutralization test result was positive (1:32). The patient's sample was sent to LSI Medience Corporation, Tokyo, Japan, and tested. Moreover, the allopurinol patch test conducted 5 weeks after discharge was negative. Thus, the patient was finally diagnosed with adult HFMD. This case report had been approved by the Institutional Review Board of Inje University Haeundae Paik Hospital. (no. 2020-01-010).\n\nDiscussion\nHFMD is a rare disease in adults. Only 11% of the adults exposed to the infection and less than 1% of infected adults develop HFMD [9]. In recent years, several cases of HFMD in adults were reported worldwide [34]. Adult HFMD cases are often associated with CVA6, and the first case was identified in Finland after a major outbreak of HFMD in 2008 [4]. This strain caused outbreaks among both children and adults in Europe and Asia [34].\n\nThe clinical manifestations of adult HFMD are quite different from those of the typical HFMD in children. Adult HFMD has atypical and more severe characteristics such as higher fever and gastrointestinal and catarrhal symptoms [5]. It often resembles EM or a disseminated herpetic eruption, indicating extensive cutaneous involvement and targetoid macules and papulo-vesicles. Thus, the clinical course of the condition is worse than that of classic cases [2310]. Moreover, it is characterized by more widespread distribution of skin lesion in areas, including the perioral region, dorsum of the hands and feet, trunk, calves, forearms, and neck, and onychomadesis can occur [310]. The rash in atypical HFMD often presents with ulcerations and scabs, and bullae can be observed [10].\n\nSJS/TEN is a disease spectrum of severe hypersensitivity reaction involving the mucous membrane and epidermal tissue, causing the formation of bullae. It is commonly associated with drugs such as allopurinol, sulfamethoxazole, carbamazepine, phenytoin, sulfasalazine, sulfonamides, oxicam (non-steroidal anti-inflammatory drugs [NSAIDs]), and phenobarbital [68]. The differential diagnosis of SJS/TEN includes EM, generalized bullous fixed drug eruption (GBFDE), and other cutaneous bullous diseases. EM is characterized by typical target lesions, bullae, and epidermal detachment. However, it is strongly associated with herpes simplex virus and rarely with drugs [11]. EM with severe mucosal involvement is referred to as erythema multiforme major, and it is often associated with systemic symptoms such as fever and arthralgias. Skin lesions of mild EM are limited to the arms, hands, and feet, but in severe cases it can spread to the mouth, genitalia, and mucocutaneous junction of the anus [12].\n\nAllopurinol is a xanthine oxidase inhibitor used for gout management, as it reduces the production of uric acid. It is widely used despite the development of alternative agents such as febuxostat and probenecid [13]. Allopurinol can induce SCARs, including SJS/TEN, with an incidence rate of 0.69 per 1,000 person-years [14]. Allopurinol-induced SCARs are strongly associated with the HLA-B*58:01 allele and are relatively common among Asian populations [15]. In this case, with the patient's past medication history of allopurinol for gout, allopurinol-induced SCARs can be considered a major differential diagnosis in Korea. So, HLA-B*58:01 test can be meaningful although it is not a confirmatory test, drug provocation test (DPT) for excluding allopurinol-induced SCARs.\n\nBecause adult HFMD is quite uncommon and shows atypical presentations, it is often hardly distinguishable from SJS or EM. Therefore, skin biopsy with histopathologic analysis could be a useful diagnostic tool for differential diagnosis [16]. Adult HFMD and EM have similar histopathologic features such as epidermal necrosis and superficial perivascular lymphocytic infiltration. However, HFMD has quite distinct microscopic findings and clinical presentation, which are different from those of EM. For example, neutrophilic infiltration of both the epidermis and the dermis is significantly more common in HFMD than in EM. On the one hand, intraepidermal necrosis in HFMD is commonly localized in the upper third of the epidermis. On the other hand, EM is typically characterized by lymphocyte predominant interface dermatitis with necrosis in the lower third of the epidermis [17].\n\nIn this case, SJS was the primary clinical differential diagnosis. However, the patient was not diagnosed with the condition due to the presence of atypical features, which were as follows: (1) different patterns of skin lesions, including erythematous papules starting from the hands and feet to the thorax, unlike in SJS, which starts from the thorax to the extremities [18]; (2) severe erythematous papules and skin detachment in the hands and feet; (3) oral, pharyngeal, and laryngeal mucosal lesions that are significantly more severe than skin lesions on the same day; (4) enlarged cervical lymph nodes in the early phase; and (5) lack of abnormal laboratory results indicative of organ involvement in SJS, such as hematologic abnormalities, elevated aminotransferase levels, and decreased renal function [19]. Although we could not detect the virus in blood and tissue, clinical symptoms that were suitable for acute virus infection, and the serology test was positive, and the pathologic findings were more favorable to HFMD than SJS. Taken together, it was believed that this case was appropriate to diagnose HFMD. It is not possible to completely confirm the Coxsackievirus infection by pathologic findings, it is considered appropriate to diagnose HFMD if such pathological findings are confirmed in the context of the patient's clinical features and Coxsackievirus neutralization test result as in the case of this patient. Plus, as described above, histopathologic features were more suitable for HFMD than SJS [17].\n\nIn Korea, several cases of HFMD in immunocompetent adult patients were recorded [20]. However, this is the first case of CVA6-induced HFMD in an immunocompetent adult. The patient was initially diagnosed with SJS because he was taking a common causative drug and presented with vesiculobullous skin rash. However, he was eventually diagnosed with HFDM. This case showed that the diagnosis of adult HFDM is challenging. In addition, HFMD should be included in the differential diagnosis of patients with vesicular skin lesions with severe oral mucosal involvement.\n\nConflict of Interest: No conflicts of interest.\n\nAuthor Contributions:\nConceptualization: CSP.\n\nData curation: THN.\n\nInvestigation: THN, SYJ, MRK, JYK, CSP, SMK.\n\nSupervision: CSP, SMK.\n\nValidation: CSP, SMK.\n\nWriting - original draft: THN, KMJ.\n\nWriting - review & editing: THN, CSP.\n==== Refs\n1 Wong SS Yip CC Lau SK Yuen KY Human enterovirus 71 and hand, foot and mouth disease Epidemiol Infect 2010 138 1071 1089 20056019 \n2 Laga AC Shroba SM Hanna J Atypical hand, foot and mouth disease in adults associated with coxsackievirus A6: a clinico-pathologic study J Cutan Pathol 2016 43 940 945 27445155 \n3 Merzel Šabović EK Točkova O Uršič T Žgavec B Dolenc-Voljč M Atypical hand, foot, and mouth disease in an adult patient: a case report and literature review Acta Dermatovenerol Alp Pannonica Adriat 2019 28 85 88 31233173 \n4 Osterback R Vuorinen T Linna M Susi P Hyypiä T Waris M Coxsackievirus A6 and hand, foot, and mouth disease, Finland Emerg Infect Dis 2009 15 1485 1488 19788821 \n5 Horsten HH Kemp M Fischer TK Lindahl KH Bygum A Atypical hand, foot, and mouth disease caused by Coxsackievirus A6 in Denmark: a diagnostic mimicker Acta Derm Venereol 2018 98 350 354 29182793 \n6 Stern RS Divito SJ Stevens-Johnson syndrome and toxic epidermal necrolysis: associations, outcomes, and pathobiology-thirty years of progress but still much to be done J Invest Dermatol 2017 137 1004 1008 28411832 \n7 Schneider JA Cohen PR Stevens-Johnson syndrome and toxic epidermal necrolysis: a concise review with a comprehensive summary of therapeutic interventions emphasizing supportive measures Adv Ther 2017 34 1235 1244 28439852 \n8 Mockenhaupt M Viboud C Dunant A Naldi L Halevy S Bouwes Bavinck JN Sidoroff A Schneck J Roujeau JC Flahault A Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study J Invest Dermatol 2008 128 35 44 17805350 \n9 Galen WK Cutaneous manifestations of enterovirus infections Tyring SK Mucocutaneous manifestations of viral diseases NewYork Marcel Dekker 2002 455 467 \n10 Feder HM Jr Bennett N Modlin JF Atypical hand, foot, and mouth disease: a vesiculobullous eruption caused by Coxsackie virus A6 Lancet Infect Dis 2014 14 83 86 24287184 \n11 Huff JC Weston WL Tonnesen MG Erythema multiforme: a critical review of characteristics, diagnostic criteria, and causes J Am Acad Dermatol 1983 8 763 775 6345608 \n12 Kang JH Febrile illness with skin rashes Infect Chemother 2015 47 155 166 26483989 \n13 Terkeltaub R Gout. Novel therapies for treatment of gout and hyperuricemia Arthritis Res Ther 2009 11 236 19664185 \n14 Kim SC Newcomb C Margolis D Roy J Hennessy S Severe cutaneous reactions requiring hospitalization in allopurinol initiators: a population-based cohort study Arthritis Care Res (Hoboken) 2013 65 578 584 22899369 \n15 Hung SI Chung WH Liou LB Chu CC Lin M Huang HP Lin YL Lan JL Yang LC Hong HS Chen MJ Lai PC Wu MS Chu CY Wang KH Chen CH Fann CS Wu JY Chen YT HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol Proc Natl Acad Sci U S A 2005 102 4134 4139 15743917 \n16 Kimmis BD Downing C Tyring S Hand-foot-and-mouth disease caused by coxsackievirus A6 on the rise Cutis 2018 102 353 356 30566537 \n17 Böer-Auer A Metze D Histopathology of hand-foot-mouth disease in adults and criteria for differentiation from erythema multiforme Am J Dermatopathol 2019 41 273 280 30211734 \n18 Roujeau JC Chosidow O Saiag P Guillaume JC Toxic epidermal necrolysis (Lyell syndrome) J Am Acad Dermatol 1990 23 1039 1058 2273103 \n19 Revuz J Penso D Roujeau JC Guillaume JC Payne CR Wechsler J Touraine R Toxic epidermal necrolysis. Clinical findings and prognosis factors in 87 patients Arch Dermatol 1987 123 1160 1165 3632000 \n20 Shin JU Oh SH Lee JH A case of hand-foot-mouth disease in an immunocompetent adult Ann Dermatol 2010 22 216 218 20548919\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1598-8112",
"issue": "52(4)",
"journal": "Infection & chemotherapy",
"keywords": "Adult; Allopurinol; Coxsackievirus A6; Hand-foot-and-mouth disease; Stevens-Johnson syndrome",
"medline_ta": "Infect Chemother",
"mesh_terms": null,
"nlm_unique_id": "101531537",
"other_id": null,
"pages": "634-640",
"pmc": null,
"pmid": "32757503",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports",
"references": "24287184;20056019;19664185;30566537;3632000;22899369;27445155;31233173;29182793;28439852;17805350;15743917;19788821;20548919;28411832;26483989;30211734;6345608;2273103",
"title": "Coxsackievirus A6-induced Hand-Foot-and-Mouth Disease Mimicking Stevens-Johnson Syndrome in an Immunocompetent Adult.",
"title_normalized": "coxsackievirus a6 induced hand foot and mouth disease mimicking stevens johnson syndrome in an immunocompetent adult"
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"abstract": "Macrolide antibiotics, erythromycin, clarithromycin and azithromycin are commonly prescribed for upper respiratory infection, and their use has recently been further linked to immunomodulatory effects. With the widespread and expanded use of macrolides, special attention should be paid to their potential adverse effects. We reported two cases of end-stage renal disease (ESRD) patients who developed hallucinations such as vivid images of worms after taking clarithromycin. Similar to previous case reports of clarithromycin neurotoxicity, the visual hallucination resolved upon cessation of clarithromycin. Furthermore, we discussed the pharmacokinetic properties and other toxicities of macrolide antibiotics in patients with chronic kidney disease and ESRD.",
"affiliations": "Carol and Richard Yu Peritoneal Dialysis Research Centre, Department of Medicine & Therapeutics, Prince of Wales Hospital , The Chinese University of Hong Kong , Shatin, Hong Kong , China.;Carol and Richard Yu Peritoneal Dialysis Research Centre, Department of Medicine & Therapeutics, Prince of Wales Hospital , The Chinese University of Hong Kong , Shatin, Hong Kong , China.;Carol and Richard Yu Peritoneal Dialysis Research Centre, Department of Medicine & Therapeutics, Prince of Wales Hospital , The Chinese University of Hong Kong , Shatin, Hong Kong , China.;Carol and Richard Yu Peritoneal Dialysis Research Centre, Department of Medicine & Therapeutics, Prince of Wales Hospital , The Chinese University of Hong Kong , Shatin, Hong Kong , China.;Carol and Richard Yu Peritoneal Dialysis Research Centre, Department of Medicine & Therapeutics, Prince of Wales Hospital , The Chinese University of Hong Kong , Shatin, Hong Kong , China.;Carol and Richard Yu Peritoneal Dialysis Research Centre, Department of Medicine & Therapeutics, Prince of Wales Hospital , The Chinese University of Hong Kong , Shatin, Hong Kong , China.",
"authors": "Ma|Terry King-Wing|TK|;Chow|Kai-Ming|KM|;Choy|Agnes Shin Man|AS|;Kwan|Bonnie Ching-Ha|BC|;Szeto|Cheuk-Chun|CC|;Li|Philip Kam-Tao|PK|",
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"country": "England",
"delete": false,
"doi": "10.1093/ckj/sfu098",
"fulltext": "\n==== Front\nClin Kidney JClin Kidney JckjndtplusClinical Kidney Journal2048-85052048-8513Oxford University Press 2585936510.1093/ckj/sfu098sfu098Original ContributionsCkj ReviewsClinical manifestation of macrolide antibiotic toxicity in CKD and dialysis patients Ma Terry King-Wing Chow Kai-Ming Choy Agnes Shin Man Kwan Bonnie Ching-Ha Szeto Cheuk-Chun Li Philip Kam-Tao Carol and Richard Yu Peritoneal Dialysis Research Centre, Department of Medicine & Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, ChinaCorrespondence and offprint requests to: Chow Kai Ming; E-mail: Chow_Kai_Ming@alumni.cuhk.net12 2014 18 9 2014 18 9 2014 7 6 507 512 8 7 2014 21 8 2014 © The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For permissions, please email: journals.permissions@oup.com.2014This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comMacrolide antibiotics, erythromycin, clarithromycin and azithromycin are commonly prescribed for upper respiratory infection, and their use has recently been further linked to immunomodulatory effects. With the widespread and expanded use of macrolides, special attention should be paid to their potential adverse effects. We reported two cases of end-stage renal disease (ESRD) patients who developed hallucinations such as vivid images of worms after taking clarithromycin. Similar to previous case reports of clarithromycin neurotoxicity, the visual hallucination resolved upon cessation of clarithromycin. Furthermore, we discussed the pharmacokinetic properties and other toxicities of macrolide antibiotics in patients with chronic kidney disease and ESRD.\n\nazithromycinclarithromycincolchicineneurotoxicityperitoneal dialysis\n==== Body\nIntroduction\nIn the past decade, macrolide antibiotics have been increasingly prescribed, and more so for the treatment of community-acquired respiratory tract infection. The recent interest of macrolides linked to its anti-inflammatory effect on airway diseases (notably obstructive airway disease and non-cystic fibrosis bronchiectasis) has brought renewed attention to this class of drugs [1–3]. The prototype macrolide erythromycin has been used since 1952; other commonly used macrolides include clarithromycin and azithromycin. Despite their difference in pharmacologic properties and chemical structures, the three macrolide antibiotics share similar adverse event profiles. Some of the macrolide toxicities are of particular concern among patients with chronic kidney disease.\n\nThis in-focus review of macrolide toxicity covers those that have more significant clinical manifestation of chronic kidney disease patients, including those on dialysis. Patients who are at risk of or who have known kidney disease are also included in the discussion.\n\nDrug properties of macrolides\nAs a class, macrolides act via the same mechanism, namely, binding to the 50S subunit of the bacterial ribosome and blocking initiation of protein synthesis [4]. They all consist of a large lactone ring. Erythromycin and clarithromycin have 14-membered lactone ring, whereas azithromycin has a 15-membered ring. Minor structural changes prevent the metabolism of clarithromycin and azithromycin to an inactive compound, improve the acid stability, and provide a broader spectrum of antibacterial activity than erythromycin.\n\nErythromycin is metabolized by cytochrome P450 (CYP) enzyme CYP3A4 and eliminated primarily by faeces. Since only a small fraction (less than 7.5%) appears in urine as unchanged drug [5], kidney disease has theoretically minimal impact on the pharmacokinetics of erythromycin. However, clinical observation of elevated serum erythromycin concentrations and prolonged half-life in patients with end-stage renal disease (ESRD), associated with reversible hearing loss, led to speculation of altered drug clearance [6, 7]. These results have important clinical implications on drug dosing of erythromycin in ESRD patients. It is now believed that hepatic CYP3A4 metabolic activity, one of the most important enzymes in human drug metabolism, is decreased in uraemia and acutely improved by haemodialysis therapy. Specifically, CYP3A4 activity and elimination of erythromycin is increased by 27% after 2 h of conventional haemodialysis, presumably via removal of a rapid-acting and dialyzable byproduct of uraemia that can inhibit hepatic intrinsic clearance mediated by CYP3A4 [8]. A mounting body of experimental and clinical evidence indicates altered nonrenal clearance, namely, impaired hepatic clearance, of erythromycin in ESRD patients. Reduced hepatic clearance is attributed to downregulation of cytochrome P450 enzymes and alterations in the transporter system (of drugs into or out of the liver) [9, 10].\n\nClarithromycin is metabolized by CYP 3A4 to its 14-hydroxy active metabolite, both of which require renal excretion [11]. Because the metabolite 14-hydroxy derivative is primarily excreted in the urine, an increase in area under the plasma concentration-time curve, peak plasma concentrations and elimination half-life are expected in patients with kidney disease (but not those with hepatic impairment). The need to adjust clarithromycin dose for patients with kidney disease is supported by pharmacokinetic studies showing a prolonged elimination half-life of clarithromycin and its metabolite 14-hydroxyclarithromycin when the creatinine clearance is <30 mL/min [11, 12]. Clarithromycin has high lipid solubility which renders it poorly dialyzable.\n\nAzithromycin is excreted in bile and then faeces. Unlike clarithromycin, very little unchanged azithromycin appears in the urine, and there are no biologically active metabolites. Thus, azithromycin dosing modification is not needed in patients with kidney disease. It is also not substantially removed by peritoneal dialysis [13].\n\nNeurotoxicity of macrolides\nAntibiotic-induced neurotoxicity is a well-known complication in patients with chronic kidney disease and ESRD. Common examples include penicillins, cephalosporins, carbapenems and quinolones [14, 15]. Clarithromycin [16], and much less for erythromycin [17, 18], have been reported to cause neurotoxicity, mostly in the form of acute delirium or psychosis. Although uncommon, visual hallucination was the predominant presenting symptom of clarithromycin-induced neurotoxicity in some patients, including both dialysis [19, 20] and non-dialysis populations [21, 22]. Most patients improved spontaneously upon cessation of clarithromycin. Box 1 and Box 2 outline two patients with ESRD and clarithromycin neurotoxicity.\n\nBox 1. A 55-year-old male patient suffered from ESRD secondary to hypertensive nephrosclerosis and was started on continuous ambulatory peritoneal dialysis (CAPD) for 5 years. He was admitted to hospital because of a history of insomnia, tinnitus and visual hallucination for 3 days. He reported seeing worms crawling in his surrounding environment, rendering him unable to perform CAPD. Five days before admission, he was diagnosed to have Helicobacter pylori-related gastritis and started on amoxicillin 1 g twice daily, clarithromycin 500 mg twice daily and esomeprazole 20 mg twice daily. Concurrent medications included allopurinol, atenolol, nifedipine sustained release, spironolactone and calcium carbonate. He had no focal neurological deficit or fever. Computed tomography of the brain and electrolytes were unremarkable. He was managed conservatively and symptoms completely subsided after 4 days. There was no recurrence of symptoms in the subsequent 7 years of follow-up. Causality assessment of adverse drug reaction suggested possible (Naranjo probability scale score 4) clarithromycin toxicity; we cannot exclude the alternative explanation by the concurrent use of relatively high-dose amoxicillin.\n\nBox 2. A 71-year-old female patient had ESRD due to IgA nephropathy, for which she had received dialysis treatment for >20 years. Due to progressive cognitive impairment, she required assisted CAPD by a domestic helper. Other medical comorbidities included bilateral cataract, ischaemic heart disease and atrial fibrillation. Three weeks before admission, she was admitted to hospital because of CAPD peritonitis due to coagulase-negative staphylococcus and Moraxella catarrhalis. She was initially treated with intraperitoneal cefazolin and ceftazidime, without clinical response. Antibiotic regime was switched to intraperitoneal vancomycin 1 g once every 5 days and oral clarithromycin 250 mg twice daily was added to cover Moraxella infection based on sensitivity results. She responded well with that regime. Her other medications included aspirin, famotidine, bisoprolol, isosorbide dinitrate, valsartan, alfacalcidol and nystatin. She developed unsteady gait after 10 days of clarithromycin. She then reported seeing worms over her body and in her surrounding environment after 16 days of clarithromycin. She was subsequently admitted to hospital because of a fall, minor head injury and scalp laceration. She had no focal neurological deficit or cerebellar signs. Computed tomography of the brain showed cerebral atrophy but no evidence of acute stroke. Electrolytes were unremarkable. Clarithromycin was stopped and symptoms completely subsided after 1 week. She had no recurrence of symptoms in her subsequent follow-up and remained well on CAPD. Naranjo criteria suggested probable clarithromycin adverse event (score 7).\n\nSteinman and Steinman [19] first reported clarithromycin-induced visual hallucination in a 56-year-old ESRD patient on CAPD. The patient had acute onset of visual hallucination within 24 h after taking clarithromycin 500 mg twice daily for acute bronchitis. His visual hallucination was described as a ‘constantly evolving landscape of sharks, priests, red lines and other Technicolor’. Symptoms subsided 3 days after drug cessation. Tse et al. [20] reported another case of visual hallucination in the form of delusion of worms in a 49-year-old male peritoneal dialysis patient after taking clarithromycin 250 mg three times a day for 1 week. This particular patient also had history of acyclovir-induced encephalopathy. He was treated with haloperidol and symptoms completely subsided after 3 weeks. Similarly, both of our patients had visual hallucination in the form of parasitosis.\n\nThe mechanism of clarithromycin-induced neurotoxicity remains largely unknown. Proposed neurotoxicity mechanisms include direct toxicity of the lipid-soluble active metabolite of 14-hydroxyclarithromycin on the central nervous system, alterations of cortisol and prostaglandin metabolism, inhibitory action on glutaminergic neurotransmission [23].\n\nIn our second patient (Box 2) who received a reduced dose of clarithromycin, neurotoxicity developed after 10 days. This might reflect the gradual accumulation of clarithromycin and its metabolite even with adjusted dose. Of note, our second patient had been anuric for years and had no residual renal function. Altered blood–brain barrier in the setting of uraemia may be associated with increased concentration of clarithromycin and its metabolite in the central nervous system, which may be another contributing factor in the development of neurotoxicity.\n\nBandettini et al. [16] analysed 38 patients who developed neurotoxicity after clarithromycin. Most patients had a history of psychiatric illness and only 2 patients had renal insufficiency. This implies that elevated serum drug level secondary to reduced renal excretion is only one possible mechanism of neurotoxicity. In fact, hallucination had been reported in patients taking therapeutic doses of clarithromycin [21, 22]. Clarithromycin has been linked to the development of many acute psychotic manifestations, including the phenomenon of ‘antibiomania’, the feeling of ‘leaving the planet’, and cat-like screeching and movements [24]. According to previous World Health Organization and the Food and Drug Administration, clarithromycin and ciprofloxacin are the most frequent causes linked to antibiotic-induced manic episodes or antibiomania [23]. Other neurotoxic manifestations of clarithromycin include non-convulsive status epilepticus, depersonalization, semi-catatonic behaviour, paranoid ideation, delirium and insomnia [16, 25–29]. On the other hand, prolonged duration of treatment may not necessarily result in neurotoxicity. In two series of atypical mycobacterium exit site infection in peritoneal dialysis patients, 10 out of 15 patients received prolonged clarithromycin therapy ranging from 6 to 42 weeks. None of them developed neurotoxicity, although the exact dosages of clarithromycin were not mentioned in either study [30, 31].\n\nCardiotoxicity of macrolides\nAll three macrolides, erythromycin, clarithromycin and azithromycin, have been associated with QT interval prolongation. The single most important concern with drug-induced QT prolongation is risk of fatal polymorphic ventricular tachycardia, or torsades de pointes (characterized by QRS complexes of progressively changing amplitude and contour that seem to twist around the isoelectric line from beat to beat).\n\nThe mechanism of QT prolongation after macrolides is blockage of the outward potassium current or channel in myocyte membranes [32]. Although QT interval lengthening is not infrequent after clarithromycin, reports of torsades de pointes after clarithromycin appear to be primarily linked to simultaneous administration of other drugs that prolong the QT interval. Analysis of torsades de pointes associated with macrolide also highlighted the risk factors of concomitant drugs, female gender and increasing age [33]. At least three case reports of torsades de pointes after clarithromycin have been published in patients with creatinine clearance below 30 mL/min when they received clarithromycin at 500 mg twice daily [34, 35]. Such an observation implies the dose effectness of clarithromycin, which can accumulate to the high-risk level in the presence of renal failure (when the dose is not adjusted accordingly). Similarly, a dose-response effect of erythromycin has been reported; the effect on the QT interval is directly related to the rate of intravenous infusion of erythromycin [36]. Azithromycin metabolism is not affected by kidney function. For unknown reasons, on the other hand, acute kidney injury has been suggested to be a risk factor for azithromycin-induced torsades de pointes [37].\n\nThe observation that prolonged QT interval increased the all-cause mortality and the risk of sudden cardiac death in ESRD patients [38, 39] suggests the possibility of a further increased propensity to macrolide cardiac toxicity in this population.\n\nIndirect kidney injury after macrolides\nMacrolides do not cause direct nephrotoxicity in general [40], but erythromycin and clarithromycin can influence kidney function secondary to interactions with other drugs. These two macrolides are strong inhibitors of CYP3A4 enzymes, and thus lead to accumulation of drugs that require CYP3A4 for their metabolism, potentially causing toxicity. In other words, the potential mechanisms whereby macrolides are linked to adverse kidney events are the indirect effect of increased concentration of concurrent drugs such as statins and calcium-channel blockers.\n\nA recent Canadian population-based cohort study involving 144 336 users of erythromycin, clarithromycin or azithromycin together with statins found a 2-fold increased risk of hospitalization (relative risk 2.17, 95% CI 1.04–4.53) with rhabdomyolysis among those taking statin and coprescription of erythromycin or clarithromycin [41]. The absolute risk increase was 0.02%, 95% CI 0.01–0.03%. The results also confirmed an increased risk of hospitalization with acute kidney injury, hyperkalaemia and all-cause mortality after concurrent use of statins with erythromycin or clarithromycin. This study evaluated statins (atorvastatin, simvastatin or lovastatin) metabolized by CYP3A4 isoenzyme, and confirmed a significantly lower risk of myopathy with concurrent use of azithromycin which does not inhibit CYP3A4. Although only older adults (older than 65 years) were included in the study, it appears prudent to consider a different antibiotic or temporarily stop the CYP3A4-metabolized statin during erythromycin or clarithromycin administration in all patients [41, 42]. Current warnings and recommendations are avoidance of lovastatin and simvastatin with erythromycin or clarithromycin, whereas atorvastatin dose adjustment may be required. Increased monitoring for toxicity is warranted for any such combination.\n\nA much less commonly recognized mechanism by which clarithromycin may cause kidney injury indirectly is via an increase in concentrations of calcium-channel blockers and thus hypotensive insult to the kidneys. This has been shown by two Canadian groups evaluating the use of macrolide and calcium-channel blocker in elderly subjects [43, 44]. The first signal of hypotension risk came from a population-based nested, case-crossover study that included patients who required hospital admission for the treatment of shock or hypotension within 7 days after co-prescription of macrolide antibiotics and calcium-channel blockers (amlodipine, felodipine, nifedipine, verapamil, diltiazem, all of them being metabolized by CYP3A4 enzyme) [43]. This study did not look into nephrotoxicity but confirmed the strongest association of hypotension with concurrent erythromycin (the strongest inhibitor of CYP3A4), followed by clarithromycin. No such association with azithromycin was reported [43]. The second population-based cohort study studied concurrent use of clarithromycin and the previously mentioned calcium-channel blockers [44]. Using azithromycin as a comparator to minimize confounding by indication, the population-based cohort study showed a small but statistically significant greater 30-day risk of hospitalization with acute kidney injury (absolute risk increase 0.22%, 95% CI 0.16–0.27%). The risks of hospitalization with hypotension and all-cause mortality were both increased. The most pronounced effect was observed with concurrent use of clarithromycin and nifedipine [44]. Collectively, these studies indicate a small but significant risk of combined use of macrolide and calcium-channel blockers among older patients. What are the implications for patients with chronic kidney disease? We suspect chronic kidney disease patients represent another at-risk group given the widespread use of calcium-channel blockers among them and the susceptibility of the injured kidney to hypotensive insults. Nevertheless, this needs to be substantiated in further analysis because <10% of the subjects were suffering from chronic kidney disease in the two Canadian studies [43, 44].\n\nDrug toxicity after macrolides interaction\nIn addition to the inhibition of CYP3A4 enzyme, macrolides are also known to inhibit the P-glycoprotein transport system [45]. P-glycoprotein, also known as multidrug transporter 1 and ATP-binding cassette B1 transporter, is located in the apical membrane of the enterocytes and functions as the intestinal drug efflux pump, reducing the absorption of orally administered drugs [46]. Consequently, P-glycoprotein inhibitor may increase the bioavailability of those drugs which are substrate for the P-glycoprotein transport system. P-glycoprotein is also present on the canalicular aspect of the hepatocyte (biliary excretion), as well as an important component of the blood–brain barrier.\n\nTwo clinically important P-glycoprotein substrates relevant to kidney disease are colchicine and digoxin.\n\nColchicine is not uncommonly used in patients with chronic kidney disease and acute gout, when nonsteroidal anti-inflammatory drugs are considered undesirable. Ten per cent or more of colchicine undergoes excretion by the kidneys, besides the metabolism by the cytochrome P450 system. Colchicine accumulation occurs in patients with renal or hepatic dysfunction, and even more so when there is concomitant use of erythromycin or clarithromycin (both of which inhibit the P-glycoprotein transport). This underappreciated but fatal drug interaction is exemplified by a classic case of colchicine toxicity in Box 3.\n\nBox 3. An 85-year-old elderly with chronic kidney disease, diabetes and gout was admitted from an aged care home for symptomatic anaemia. Her estimated glomerular filtration rate was 28 mL/min/1.73 m2 and haemoglobin level was low (7.7 g/dL). An upper endoscopy showed mild gastritis and Helicobacter pylori. She was transfused and given eradication therapy which included clarithromycin 500 mg twice daily. Three days later, she developed acute gouty arthritis and was treated with oral colchicine 0.5 mg four times daily. Four days after colchicine use, her platelet count decreased from 230 to 127 × 109/L. She developed sudden cardiac arrest 2 days afterward, when her complete blood count showed a platelet count of 32 × 109/L and white cell count 0.8 × 109/L.\n\nA retrospective analysis of 116 Chinese patients who were prescribed colchicine and clarithromycin during the same hospital admission confirmed a high risk of fatalities (10.2%). Independent predictors of death were renal impairment (defined as serum creatinine level above 140 µmol/L at baseline), longer overlapping therapy of colchicine and clarithromycin, and the development of pancytopenia [47]. Reported manifestations of colchicine toxicity with concurrent clarithromycin include haematological (pancytopenia, hypocellular bone marrow), gastrointestinal (vomiting, diarrhoea, abdominal pain), neuromyopathy (including rhabdomyolysis), multi-organ dysfunction and death [47, 48]. Although a specific recommendation for colchicine dose reduction (when macrolide such as clarithromycin is coprescribed) has been published [49], the safeguards need to be substantiated in larger clinical trials. In this regard, avoiding combined use of colchicine and P-glycoprotein inhibitor remains the best strategy to prevent drug interaction, and especially among patients with chronic kidney disease.\n\nDigoxin toxicity after macrolide use in patients with chronic kidney disease or ESRD has been characterized more in the literature [50, 51], and continues to be one of the most prevalent adverse drug reactions in clinical practice. This should come as no surprise after considering the pharmacokinetics of digoxin. Over 70% of the body load of digoxin is eliminated unchanged in the urine. Furthermore, patients with chronic kidney disease have decreased extravascular volume of digoxin distribution. These account for the prolonged half-life of digoxin in patients with chronic kidney disease, as well as the need to reduce the loading and maintenance digoxin dose. When macrolides (erythromycin, clarithromycin and azithromycin) are administered together with digoxin, the inhibition of P-glycoprotein will further increase the digoxin levels because digoxin is a substrate for P-glycoprotein.\n\nA study comparing digoxin concentration before and (four to seven days) after clarithromycin treatment in seven elderly found that digoxin level increased significantly; the digoxin clearance and elimination rate constants were 56–60% lower and elimination half-life was 82% longer [52]. Moreover, only one out of the seven patients developed an electrocardiographic sign of digoxin toxicity when she developed acute kidney injury, which further reduced the digoxin clearance [52].\n\nThe observation is consistent with the finding of a 15-year population-based nested case-control study evaluating digoxin toxicity after recent macrolide antibiotic use. Indeed, the risk of digoxin toxicity is highest for recent use of clarithromycin (adjusted odds ratio 14.83, 95% CI 7.89–27.86), followed by erythromycin and azithromycin. There was no significant risk for the neutral comparator of cefuroxime [53]. The risk of digoxin toxicity after clarithromycin is 4-fold higher than erythromycin or azithromycin. This is consistent with in vitro data showing the highest inhibitory capacity of P-glycoprotein for clarithromycin [45]. Thus, it should be emphasized that use of azithromycin might avoid drug interaction via CYP3A4 inhibition, but azithromycin might still lead to clinically important drug interaction (such as digoxin) by inhibiting P-glycoprotein [54]. Risk of concomitant use of macrolide with digoxin also applies to ESRD patients. Specifically, adding clarithromycin to six ESRD patients taking oral digoxin (on haemodialysis or haemofiltration) was shown to cause 1.8–4.0-fold increase in their serum digoxin levels [51].\n\nAnother potential and interesting mechanism of drug interaction between macrolide and digoxin is mediated by human intestinal bacteria. There is evidence that inactivation of digoxin by the gut actinobacterium Eggerthella lenta to its inactive metabolite, dihydrodigoxin, contributes to around 10% of digoxin metabolism [55, 56]. Macrolides including azithromycin can kill off a large fraction of Eggerthella lenta bacteria and therefore increase the serum digoxin concentration.\n\nConclusion\nThe mode of action is similar for all macrolides, but their pharmacokinetics and adverse events differ slightly, as summarized in Table 1. Patients with chronic kidney disease and ESRD are prone to drug-induced neurotoxicity. In particular, visual hallucination in the form of parasitosis should raise the clinical suspicion of clarithromycin neurotoxicity. Drug interaction with statins, calcium-channel blockers and colchicine is another concerning complication of macrolides. Close monitoring is warranted, and even more so in the setting of chronic kidney disease, ESRD or acute kidney injury.\nTable 1. Summary of three macrolides with reference to kidney disease\n\n\tErythromycin\tClarithromycin\tAzithromycin\t\nKidney excretion\tMinimal (<7.5% unchanged in urine)\tActive metabolites excreted unchanged in urine\tMinimal\t\nRecommended dose reduction with kidney disease\tNo need for dose adjustment but altered nonrenal clearance suggested in ESRD\tDecrease by 50% if creatinine clearance <30 mL/min\tNo need for dose adjustment\t\nDialyzable\tSlightly (5% to 20%)\tMinimal\tMinimal\t\nCYP3A4 inhibition\t+++\t+++\t−\t\nP-glycoprotein inhibition\t+\t++++\t+\t\nReported neurotoxicity\t+\t++\t−\t\n\n\nConflict of interest statement\nNone declared.\n==== Refs\nReferences\n1 Albert RK Connett J Bailey WC Azithromycin for prevention of exacerbations of COPD N Engl J Med 2011 365 689 698 21864166 \n2 Brusselle GG Joos G Is there a role for macrolides in severe asthma? 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"keywords": "azithromycin; clarithromycin; colchicine; neurotoxicity; peritoneal dialysis",
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"nlm_unique_id": "101579321",
"other_id": null,
"pages": "507-12",
"pmc": null,
"pmid": "25859365",
"pubdate": "2014-12",
"publication_types": "D016428:Journal Article",
"references": "6117714;23778904;15544496;11587409;18490798;11110120;10208196;18558792;6860057;11587400;21269833;11799346;23725229;20142454;23532242;7266632;19494544;11463936;11158222;21480191;9576415;1355971;24346990;20556806;17591517;18027988;19606089;8222460;7274053;21864166;12356809;24028838;8546130;23869020;9292575;15164960;23032088;16007523;21907534;11837378;17208955;21242274;16899515;12087527;3963982;15704612;23284142;3781679;19473602;20090676;9819955;24247040;17546486;10589373;22855656",
"title": "Clinical manifestation of macrolide antibiotic toxicity in CKD and dialysis patients.",
"title_normalized": "clinical manifestation of macrolide antibiotic toxicity in ckd and dialysis patients"
} | [
{
"companynumb": "HK-LUPIN PHARMACEUTICALS INC.-2016-04756",
"fulfillexpeditecriteria": "1",
"occurcountry": "HK",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ALFACALCIDOL"
},
"drugadditio... |
{
"abstract": "A case of fatal invasion of Scopulariopsis brevicaulis to the bronchus in an acute monocytic leukemia (M(5)) patient is described. This infection leads to mediastinal emphysema, bronchial bleeding, and bronchial obstruction before finally spreading to the entire lung. The patient was initially diagnosed with pulmonary aspergillosis based on clinical signs and morphological examination. However, S. brevicaulis was finally identified by 18S rDNA sequencing. The patient failed lipid amphotericin B therapy and voriconazole plus caspofungin combination therapy. To the best of our knowledge, this is the first report on S. brevicaulis affecting the bronchus and resulting in a fatal prognosis in an M(5) patient.",
"affiliations": "State Key Laboratory for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, PR China.",
"authors": "Yang|Qing|Q|;Wei|Juying|J|;Chen|Zhenjing|Z|",
"chemical_list": "D004271:DNA, Fungal; D004275:DNA, Ribosomal; D054714:Echinocandins; D055666:Lipopeptides; D011743:Pyrimidines; D012331:RNA, Fungal; D012337:RNA, Ribosomal, 18S; D014230:Triazoles; D000666:Amphotericin B; D000077336:Caspofungin; D065819:Voriconazole",
"country": "United States",
"delete": false,
"doi": "10.1016/j.diagmicrobio.2012.04.010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-8893",
"issue": "73(4)",
"journal": "Diagnostic microbiology and infectious disease",
"keywords": null,
"medline_ta": "Diagn Microbiol Infect Dis",
"mesh_terms": "D000328:Adult; D000666:Amphotericin B; D001980:Bronchi; D000077336:Caspofungin; D004271:DNA, Fungal; D004275:DNA, Ribosomal; D004359:Drug Therapy, Combination; D054714:Echinocandins; D017809:Fatal Outcome; D005260:Female; D020459:Genes, rRNA; D006651:Histocytochemistry; D006801:Humans; D007948:Leukemia, Monocytic, Acute; D055666:Lipopeptides; D008168:Lung; D008172:Lung Diseases, Fungal; D008969:Molecular Sequence Data; D011743:Pyrimidines; D012331:RNA, Fungal; D012337:RNA, Ribosomal, 18S; D013902:Radiography, Thoracic; D060645:Scopulariopsis; D017422:Sequence Analysis, DNA; D014057:Tomography, X-Ray Computed; D017211:Treatment Failure; D014230:Triazoles; D065819:Voriconazole",
"nlm_unique_id": "8305899",
"other_id": null,
"pages": "369-71",
"pmc": null,
"pmid": "22633337",
"pubdate": "2012-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fatal bronchial invasion of Scopulariopsis brevicaulis in an acute monocytic leukemia patient.",
"title_normalized": "fatal bronchial invasion of scopulariopsis brevicaulis in an acute monocytic leukemia patient"
} | [
{
"companynumb": "CN-PFIZER INC-2019252731",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VORICONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "Alemtuzumab (a drug highly active in multiple sclerosis) is a humanized monoclonal antibody targeting the surface molecule CD52. It causes a rapid depletion of innate and adaptive immune cells with a peak during the first month after infusion. Infection rates in alemtuzumab-treated patients with multiple sclerosis in clinical trials were higher in than in interferon beta-treated patients. Cytomegalovirus (CMV) primary infections and reactivations have been reported in this setting of patients. We describe the case of a patient that developed both viral (CMV) and bacterial pneumonia one month after alemtuzumab infusion for multiple sclerosis. Physicians dealing with this drug should be aware of this serious but treatable complication.",
"affiliations": "Department of Clinical Medicine and Surgery - Section of Infectious Diseases. University of Naples Federico II. Electronic address: antonioriccardobuonomo@gmail.com.;Department of Neurological Sciences, Reproductive and Odontostomatological Sciences, University of Naples Federico II.;Department of Clinical Medicine and Surgery - Section of Infectious Diseases. University of Naples Federico II.;Department of Clinical Medicine and Surgery - Section of Infectious Diseases. University of Naples Federico II.;Department of Neurological Sciences, Reproductive and Odontostomatological Sciences, University of Naples Federico II.;Department of Clinical Medicine and Surgery - Section of Infectious Diseases. University of Naples Federico II.;Department of Neurological Sciences, Reproductive and Odontostomatological Sciences, University of Naples Federico II.;Department of Clinical Medicine and Surgery - Section of Infectious Diseases. University of Naples Federico II.;Department of Neurological Sciences, Reproductive and Odontostomatological Sciences, University of Naples Federico II.",
"authors": "Buonomo|Antonio Riccardo|AR|;Saccà|Francesco|F|;Zappulo|Emanuela|E|;De Zottis|Federico|F|;Lanzillo|Roberta|R|;Gentile|Ivan|I|;Carotenuto|Antonio|A|;Borgia|Guglielmo|G|;Russo|Cinzia Valeria|CV|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074323:Alemtuzumab",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.msard.2018.09.031",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2211-0348",
"issue": "27()",
"journal": "Multiple sclerosis and related disorders",
"keywords": "Alemtuzumab; CMV; Multiple sclerosis; Opportunistic infections",
"medline_ta": "Mult Scler Relat Disord",
"mesh_terms": "D000074323:Alemtuzumab; D061067:Antibodies, Monoclonal, Humanized; D003586:Cytomegalovirus Infections; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis; D018410:Pneumonia, Bacterial; D011024:Pneumonia, Viral",
"nlm_unique_id": "101580247",
"other_id": null,
"pages": "44-45",
"pmc": null,
"pmid": "30316174",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bacterial and CMV pneumonia in a patient treated with alemtuzumab for multiple sclerosis.",
"title_normalized": "bacterial and cmv pneumonia in a patient treated with alemtuzumab for multiple sclerosis"
} | [
{
"companynumb": "IT-FRESENIUS KABI-FK201811252",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ACYCLOVIR SODIUM"
},
"drugadditional": n... |
{
"abstract": "Optimal upfront therapy for posttransplant lymphoproliferative disease (PTLD) arising after solid organ transplant remains contentious. Rituximab monotherapy (R-Mono) in unselected patients has shown a lack of durable remissions. Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)-based chemotherapy confers improved response rates, although concerns exist about toxicity.\n\n\n\nThis multicenter retrospective study reports outcomes for adults with biopsy-proven B-cell PTLD treated initially with R-Mono or Rituximab plus CHOP (R-CHOP). Selection of therapy was made according to physician preference.\n\n\n\nAmong 101 patients, 41 received R-Mono and 60 had R-CHOP. Most (93%) had undergone renal or liver transplantation. R-CHOP showed a trend toward improved complete (53% versus 71%; P = 0.066) and overall (75% versus 90%; P = 0.054) response rates. In the R-Mono group, 13 of 41 (32%) subsequently received chemotherapy, while 25 of 41 (61%) remained progression-free without further therapy. With median follow-up of 47 months, overall survival (OS) was similar for R-Mono and R-CHOP, with 3-year OS of 71% and 63%, respectively (P = 0.722). Non-PTLD mortality was 3 of 41 (7%) and 4 of 60 (7%) within 12 months of R-Mono or R-CHOP, respectively. The International Prognostic Index was statistically significant, with low- (0-2 points) and high-risk (≥3 points) groups exhibiting 3-year OS of 78% and 54%, respectively (P = 0.0003). In low-risk PTLD, outcomes were similar between therapies. However, in high-risk disease R-Mono conferred an inferior complete response rate (21% versus 68%; P = 0.006), albeit with no impact on survival.\n\n\n\nOur data support R-Mono as initial therapy for PTLD arising after renal or liver transplantation. However, upfront R-CHOP may benefit selected high-risk cases in whom rapid attainment of response is desirable.",
"affiliations": "Centre for Clinical Haematology, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom.;Department of Haematology, University College London Hospital, London, United Kingdom.;Department of Haematology, Nottingham City Hospital, Nottingham, United Kingdom.;Department of Haematology, Royal Hallamshire Hospital, Sheffield, United Kingdom.;Department of Clinical Haematology, St James's University Hospital, Leeds, United Kingdom.;Department of Haematology, Freeman Hospital, Newcastle upon Tyne, United Kingdom.;Department of Haematology, Freeman Hospital, Newcastle upon Tyne, United Kingdom.;Department of Haematology, University College London Hospital, London, United Kingdom.;Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.;Department of Haematology, County Hospital Hereford, Hereford, United Kingdom.;Department of Renal Medicine, Nottingham City Hospital, Nottingham, United Kingdom.;Department of Haematology, University College London Hospital, London, United Kingdom.;Department of Histopathology, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom.;Department of Haematology, Freeman Hospital, Newcastle upon Tyne, United Kingdom.;Department of Haematology, Guy's and Saint Thomas' Hospital, London, United Kingdom.;Department of Clinical Haematology, St James's University Hospital, Leeds, United Kingdom.;Department of Haematology, Royal Hallamshire Hospital, Sheffield, United Kingdom.;Department of Haematology, Nottingham City Hospital, Nottingham, United Kingdom.;Department of Haematology, University College London Hospital, London, United Kingdom.;Centre for Clinical Haematology, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom.",
"authors": "Burns|David M|DM|;Clesham|Katherine|K|;Hodgson|Yan A|YA|;Fredrick|Lynsey|L|;Haughton|Joanna|J|;Lannon|Michelle|M|;Hussein|Hayder|H|;Shin|Jin-Sup|JS|;Hollows|Robert J|RJ|;Robinson|Lisa|L|;Byrne|Catherine|C|;McNamara|Christopher|C|;Vydianath|Bindu|B|;Lennard|Anne L|AL|;Fields|Paul|P|;Johnson|Rod|R|;Wright|Josh|J|;Fox|Christopher P|CP|;Cwynarski|Kate|K|;Chaganti|Sridhar|S|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1097/TP.0000000000003183",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1337",
"issue": "104(12)",
"journal": "Transplantation",
"keywords": null,
"medline_ta": "Transplantation",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000074322:Antineoplastic Agents, Immunological; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D004317:Doxorubicin; D004739:England; D005260:Female; D006801:Humans; D008232:Lymphoproliferative Disorders; D008297:Male; D008875:Middle Aged; D016377:Organ Transplantation; D011241:Prednisone; D000077982:Progression-Free Survival; D012189:Retrospective Studies; D012307:Risk Factors; D000069283:Rituximab; D013997:Time Factors; D014750:Vincristine; D055815:Young Adult",
"nlm_unique_id": "0132144",
"other_id": null,
"pages": "2582-2590",
"pmc": null,
"pmid": "33104308",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Real-world Outcomes With Rituximab-based Therapy for Posttransplant Lymphoproliferative Disease Arising After Solid Organ Transplant.",
"title_normalized": "real world outcomes with rituximab based therapy for posttransplant lymphoproliferative disease arising after solid organ transplant"
} | [
{
"companynumb": "GB-CELLTRION INC.-2021GB004933",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Osteonecrosis is a well-recognized complication in patients treated with corticosteroids. The incidence of osteonecrosis in children treated for Hodgkin lymphoma is unknown because prospective whole-body magnetic resonance imaging (MRI) studies are lacking in this patient population. Paediatric patients with newly diagnosed Hodgkin lymphoma who were treated according to a uniform paediatric Hodgkin protocol were eligible for inclusion in this prospective study. Whole-body MRI was performed in all 24 included patients (mean age 15·1 years, 12 girls) both before treatment and after 2 cycles of chemotherapy, and in 16 patients after completion of chemotherapy. Osteonecrosis was identified in 10 patients (41·7%, 95% confidence interval: 22·0-61·4%), with a total of 56 osteonecrotic sites. Osteonecrosis was detected in 8 patients after 2 cycles of OEPA (vincristine, etoposide, prednisone, doxorubicin), and in 2 additional patients after completion of chemotherapy. Epiphyseal involvement of long bones was seen in 4 of 10 children. None of the patients with osteonecrosis had any signs of bone collapse at the times of scanning. Whole-body MRI demonstrates osteonecrosis to be a common finding occurring during therapy response assessment of paediatric Hodgkin lymphoma. Detection of early epiphyseal osteonecrosis could allow for treatment before bone collapse and joint damage may occur.",
"affiliations": "Department of Radiology, University Medical Centre Utrecht-Princess Maxima Centre for Paediatric Oncology, Utrecht, the Netherlands.;Department of Radiology, University Medical Centre Utrecht-Princess Maxima Centre for Paediatric Oncology, Utrecht, the Netherlands.;Department of Paediatric Radiology, Hospital Materno-Infantil Vall d'Hebron, Barcelona, Spain.;Department of Radiology, VU University Medical Centre, Amsterdam, the Netherlands.;Department of Radiology, IRCCS Giannina Gaslini Hospital, Genoa, Italy.;Department of Paediatric Oncology/Haematology, Erasmus MC University Medical Centre-Sophia's Children's Hospital, Rotterdam, the Netherlands.;Department of Diagnostic Imaging and Intervention, Oslo University Hospital, Rikshospitalet, Oslo, Norway.;Department of Paediatric Radiology, Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy.;Princess Maxima Centre for Paediatric Oncology, Utrecht, the Netherlands.;Department of Radiology, University Medical Centre Utrecht-Princess Maxima Centre for Paediatric Oncology, Utrecht, the Netherlands.",
"authors": "Littooij|Annemieke S|AS|;Kwee|Thomas C|TC|;Enríquez|Goya|G|;Verbeke|Jonathan I M L|JI|;Granata|Claudio|C|;Beishuizen|Auke|A|;de Lange|Charlotte|C|;Zennaro|Floriana|F|;Bruin|Marrie C A|MC|;Nievelstein|Rutger A J|RA|",
"chemical_list": "D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D011241:Prednisone",
"country": "England",
"delete": false,
"doi": "10.1111/bjh.14452",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1048",
"issue": "176(4)",
"journal": "British journal of haematology",
"keywords": "Osteonecrosis; late effects; paediatric Hodgkin Lymphoma; whole-body MRI",
"medline_ta": "Br J Haematol",
"mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D004317:Doxorubicin; D004838:Epiphyses; D005047:Etoposide; D005260:Female; D006689:Hodgkin Disease; D006801:Humans; D015994:Incidence; D008279:Magnetic Resonance Imaging; D008297:Male; D010020:Osteonecrosis; D011241:Prednisone; D011446:Prospective Studies; D014750:Vincristine",
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "637-642",
"pmc": null,
"pmid": "27891588",
"pubdate": "2017-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Whole-body MRI reveals high incidence of osteonecrosis in children treated for Hodgkin lymphoma.",
"title_normalized": "whole body mri reveals high incidence of osteonecrosis in children treated for hodgkin lymphoma"
} | [
{
"companynumb": "NL-JNJFOC-20170215189",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": "3",
"d... |
{
"abstract": "Perioperative vision loss in non-ocular surgery represents a rare but devastating complication and multiple causes have been proposed. Any portion of the visual system may be involved and several authors have tried to relate that complication with deliberate hypotension anaesthetic technique, used to control intraoperative bleeding. We report a patient operated for orthognathism who suffered unilateral blindness. After review of similar cases, we can state that the transmission of forces generated during Le fort I osteotomy is related to the complication. This osteotomy technique is regularly performed in our hospital using a curved osteotome to achieve the pterygomaxillary disjunction and the adverse transmission of forces via the sphenoid bone is the main reason for indirect damage to the optic nerve and its vascular structures causing the neuropathy and blindness. Hypotensive anaesthesia may certainly lead to transient ischaemia but only in specific cases because of decreased ocular perfusion pressured.",
"affiliations": "Department of Anaesthesia and Critical Care, Reina Sofia General University Hospital, Murcia, Spain.;Department of Surgery, University of Murcia, Reina Sofia General University Hospital, Murcia, Spain. Electronic address: migova67@gmail.com.",
"authors": "Rodríguez-Navarro|Á|Á|;Gonzalez-Valverde|F M|FM|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1016/j.ijom.2017.07.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0901-5027",
"issue": "47(1)",
"journal": "International journal of oral and maxillofacial surgery",
"keywords": "anaesthesia and controlled hypotensive complications; orthognathism surgery complications; orthognatic surgery ophthalmic complications; perioperative visual loss",
"medline_ta": "Int J Oral Maxillofac Surg",
"mesh_terms": "D000328:Adult; D000768:Anesthesia, General; D001766:Blindness; D005260:Female; D006801:Humans; D008310:Malocclusion; D056948:Orthognathic Surgical Procedures; D019340:Osteotomy, Le Fort; D011183:Postoperative Complications; D013705:Temporomandibular Joint Disorders; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8605826",
"other_id": null,
"pages": "79-82",
"pmc": null,
"pmid": "28751182",
"pubdate": "2018-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Unilateral blindness after orthognathic surgery: hypotensive anaesthesia is not the primary cause.",
"title_normalized": "unilateral blindness after orthognathic surgery hypotensive anaesthesia is not the primary cause"
} | [
{
"companynumb": "ES-BIODELIVERY SCIENCES INTERNATIONAL-2018BDSI0504",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FENTANYL CITRATE"
},
... |
{
"abstract": "BACKGROUND\nThis study aimed to investigate the efficacy of abatacept for arthritis in patients with rhupus, an overlap syndrome between rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).\n\n\nMETHODS\nPatients who fulfilled both the 2010 ACR/EULAR criteria for RA classification and the 1997 ACR revised criteria for classification of SLE and received abatacept treatment for arthritis were retrospectively studied.\n\n\nRESULTS\nSix rhupus patients who fulfilled the inclusion criteria above were identified. All patients had active arthritis despite receiving antirheumatic drugs including methotrexate when abatacept was initiated. Clinical Disease Activity Index (CDAI) significantly decreased between baseline and 12 weeks (P = 0.028) and remained low through 24 weeks. All patients achieved either a good or moderate response according to the EULAR response criteria at 24 weeks. Health Assessment Questionnaire-Disability Index (HAQ-DI) also significantly decreased between baseline and 24 weeks (P = 0.043). In addition, the levels of immunoglobulin G and anti-DNA antibody significantly decreased between baseline and 24 weeks (P = 0.028 and P = 0.043, resp.).\n\n\nCONCLUSIONS\nTreatment with abatacept is likely to be efficacious in patients with rhupus whose arthritis is refractory to methotrexate. In addition, abatacept may have a moderate effect on abnormal antibody production in rhupus patients.",
"affiliations": "Department of Allergy and Clinical Immunology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8670, Japan.",
"authors": "Ikeda|Kei|K|;Sanayama|Yoshie|Y|;Makita|Sohei|S|;Hosokawa|Junichi|J|;Yamagata|Mieko|M|;Nakagomi|Daiki|D|;Takabayashi|Katsuhiko|K|;Nakajima|Hiroshi|H|",
"chemical_list": "D018501:Antirheumatic Agents; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D000069594:Abatacept",
"country": "Egypt",
"delete": false,
"doi": "10.1155/2013/697525",
"fulltext": "\n==== Front\nClin Dev ImmunolClin. Dev. ImmunolCDIClinical and Developmental Immunology1740-25221740-2530Hindawi Publishing Corporation 10.1155/2013/697525Research ArticleEfficacy of Abatacept for Arthritis in Patients with an Overlap Syndrome between Rheumatoid Arthritis and Systemic Lupus Erythematosus http://orcid.org/0000-0003-0574-9611Ikeda Kei *Sanayama Yoshie Makita Sohei Hosokawa Junichi http://orcid.org/0000-0002-2426-8736Yamagata Mieko Nakagomi Daiki Takabayashi Katsuhiko http://orcid.org/0000-0001-8595-9381Nakajima Hiroshi Department of Allergy and Clinical Immunology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8670, Japan*Kei Ikeda: k.ikeda@faculty.chiba-u.jpAcademic Editor: T. Nakayama\n\n2013 14 11 2013 2013 6975251 9 2013 1 10 2013 Copyright © 2013 Kei Ikeda et al.2013This 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.\nIntroduction. This study aimed to investigate the efficacy of abatacept for arthritis in patients with rhupus, an overlap syndrome between rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Methods. Patients who fulfilled both the 2010 ACR/EULAR criteria for RA classification and the 1997 ACR revised criteria for classification of SLE and received abatacept treatment for arthritis were retrospectively studied. Results. Six rhupus patients who fulfilled the inclusion criteria above were identified. All patients had active arthritis despite receiving antirheumatic drugs including methotrexate when abatacept was initiated. Clinical Disease Activity Index (CDAI) significantly decreased between baseline and 12 weeks (P = 0.028) and remained low through 24 weeks. All patients achieved either a good or moderate response according to the EULAR response criteria at 24 weeks. Health Assessment Questionnaire-Disability Index (HAQ-DI) also significantly decreased between baseline and 24 weeks (P = 0.043). In addition, the levels of immunoglobulin G and anti-DNA antibody significantly decreased between baseline and 24 weeks (P = 0.028 and P = 0.043, resp.). Conclusions. Treatment with abatacept is likely to be efficacious in patients with rhupus whose arthritis is refractory to methotrexate. In addition, abatacept may have a moderate effect on abnormal antibody production in rhupus patients.\n==== Body\n1. Introduction\nThe clinical coexistence of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) is a rare occurrence frequently referred to as “rhupus syndrome” [1]. Increasing evidence suggests that arthritis in patients with rhupus can cause joint damage indistinguishable from that of RA, requiring aggressive treatment [2–5]. However, TNF antagonists, which are the most potent agents in preventing joint damage in RA when used in combination with methotrexate (MTX), can induce production of autoantibodies characteristic to SLE such as antinuclear antibodies (ANA) or anti-DNA antibodies [6, 7]. Less frequently but more importantly, TNF antagonists can cause lupus manifestations in RA [6–10] and rhupus syndrome [11].\n\nAbatacept is a fully human, soluble fusion protein that consists of the extracellular domain of human cytotoxic T-lymphocyte antigen 4 (CTLA-4) and the Fc portion of IgG1, which selectively modulates the CD80/CD86:CD28 costimulatory signals and interactions between activated T cells and antigen presenting cells (APCs). The use of abatacept in patients with RA is associated with sustained efficacy both in disease activity and in radiographic progression without inducing autoantibody production [12–16]. Abatacept treatment has been explored for its efficacy in other T cell-mediated diseases such as ankylosing spondylitis [17, 18]. Moreover, a recent phase IIb randomized, double-blind, placebo-controlled trial showed modest but significant efficacy of abatacept against polyarthritis in patients with non-life-threatening SLE [19]. However, abatacept treatment in rhupus patients has not been reported.\n\nIn this study, we retrospectively assessed the efficacy of abatacept in six rhupus patients with active arthritis but not with life-threatening lupus manifestations.\n\n2. Materials and Methods\n2.1. Patients\nMedical records in the Department of Allergy and Clinical Immunology, Chiba University Hospital were thoroughly reviewed to identify patients who received abatacept treatment for arthritis and also fulfilled both the 2010 ACR/EULAR criteria for RA classification and the 1997 ACR revised criteria for classification of SLE. In order to ensure the inclusion of patients with genuine overlap, patients were excluded when the arthritis was better explained by SLE than by RA, and arthritis was not counted when SLE was classified. All patients gave a written consent for their clinical information to be published and the study procedures were approved by the Ethics Committee of Chiba University.\n\n2.2. Statistical Analysis\nStatistical analysis was performed using SPSS version 16.0J (IBM Japan, Tokyo, Japan). As all data were not normally distributed, data were summarized with medians and were analyzed using nonparametric tests (Wilcoxon's signed-rank test). P values less than 0.05 were considered significant.\n\n3. Results\n3.1. Demographics and Disease Characteristics of RA\nSix patients who fulfilled the above mentioned inclusion criteria were identified. Demographics and disease characteristics of RA before abatacept administration of these patients are summarized in Table 1. All patients were Japanese females with a median age of 57.5 years. Four patients had an onset of arthritis symptoms which preceded the diagnosis of SLE. Three patients were seronegative (i.e., both rheumatoid factor [RF] and anticitrullinated protein antibody [ACPA] were negative) at baseline although one of them (Case 5) was positive for RF at the time of the diagnosis of SLE. Five patients had at least one erosive lesion on radiograph that was typical of RA. Median level of C-reactive protein (CRP) at baseline was relatively low (11.5 mg/L) as compared to median Clinical Disease Activity Index (CDAI) (23.55) (Figure 1). All patients underwent musculoskeletal ultrasonography for the assessment of synovial inflammation before abatacept treatment. All patients had increased PD signals within intra-articular synovium (i.e., active intra-articular synovitis) in at least one joint region, and five out of six patients had increased PD signals within tenosynovium as well (i.e., active tenosynovitis) in at least one joint region. \n\n3.2. Disease Characteristics of SLE\nDisease characteristics of SLE before abatacept treatment are summarized in Table 2. No patient had previously experienced severe organ manifestations of SLE such as nephritis or neuropsychiatric lupus, and arthritis was the major disease manifestation when abatacept was introduced. Sjogren's syndrome was the most common concomitant autoimmune disease other than RA or SLE (n = 4), followed by chronic thyroiditis (n = 2) and scleroderma (n = 1). All patients were positive for antinuclear antibody and five patients were positive for anti-DNA antibody at the baseline. Antidouble stranded DNA antibody in Case 6 was positive when the patient was diagnosed with SLE but turned negative under treatment. Other autoantibodies, which, were positive at baseline were anti-Ro antibody (n = 4), anti-U1-RNP antibody (n = 3), anti-La antibody (n = 2), anti-thyroid peroxidase antibody (n = 2), anti-cardiolipin antibody (n = 1), and lupus anticoagulant (n = 1). Reflecting the lack of severe organ manifestations, clinically significant hypocomplementemia was only present in one patient (Case 3).\n\n3.3. Previous Treatment\nFive patients were receiving a small dose of prednisolone (median 4.5 mg/day), whereas one patient (Case 1) was not because the patient did not agree to receive corticosteroid therapy. All patients were receiving treatment with MTX although half of them (n = 3) discontinued MTX due to either cytopenia, elevation of liver enzymes, or lack of efficacy when abatacept therapy was initiated. Three patients were receiving a calcineurin inhibitor such as tacrolimus (n = 2) or cyclosporine A (n = 1), effectiveness of which was insufficient. Two patients had previously received a TNF antagonist, which was not effective in either case. One patient (Case 1) received adalimumab before the diagnosis of SLE. Although the patient had already tested positive for anti-nuclear antibody (ANA) and anti-DNA antibody before receiving adalimumab and it was discontinued after only four injections 7 months before the development of her major lupus symptoms; the TNFα blockade could have been the trigger for the onset of SLE in her case. No patient had received rituximab because the use of rituximab has been approved for neither RA nor SLE in Japan.\n\n3.4. Efficacy of Abatacept for Arthritis\nAs shown in Figure 1, CDAI and CRP significantly decreased after 12 weeks of abatacept treatment (median CDAI 23.55 versus 7 and P = 0.028; median CRP 11.5 mg/L versus 1.5 mg/L and P = 0.046) and remained low through 24 weeks (median CDAI 5.95; median CRP 2.0 mg/L). Four patients achieved a good or moderate response according to EULAR response criteria at 12 weeks (three good and one moderate) and all patients achieved a good or moderate response at 24 weeks (two good and four moderate). Health Assessment Questionnaire-Disability Index (HAQ-DI) also significantly decreased from median of 2.13 at baseline to median of 0.87 at 12 weeks (P = 0.046) and median of 0.5 at 24 weeks (P = 0.043). In addition, matrix metalloproteinase 3 (MMP-3) also significantly decreased from median of 132 ng/mL at baseline to median of 88 ng/mL at 12 weeks (P = 0.028) and median of 76.7 ng/mL at 24 weeks (P = 0.028) (data not shown). Prednisolone dose was decreased slightly but successfully by 1 mg/day in Case 3 and 6 before 24 weeks. These results suggest that abatacept is efficacious in the treatment of arthritis for patients with rhupus.\n\n3.5. Efficacy of Abatacept on Nonarticular Lupus Manifestations\nAs shown in Figure 1, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) significantly decreased from median of 7 at baseline to median of 6 at 12 and 24 weeks (P = 0.039 and 0.042, resp.), mostly reflecting the remission induction of arthritis in Cases 5 and 6. Other major symptoms which, upon improvement, decreased SLEDAI were fever in Case 1 and rash in Case 5. Among laboratory tests for lupus activity, hemoglobin significantly increased from median of 11.6 g/dL to median of 12.3 g/dL at 12 and 24 weeks (P = 0.028). None of the six patients had thrombocytopenia and only one had leukocytopenia at baseline, which did not improve with abatacept treatment. The serum levels of immunoglobulin G (IgG) and anti-DNA antibody also significantly decreased from baseline to 24 weeks (IgG, median 1,782 mg/dL to 1,609.5 mg/dL, and P = 0.028; anti-DNA antibody, median 22.55 U/mL to 11.85 U/mL, and P = 0.043). However, changes in C3 levels and CH50 were variable and were not statistically significant. These data suggest that the efficacy of abatacept on nonarticular lupus manifestation at low disease activity states may be absent but abatacept may have moderate effect on abnormal antibody production in rhupus patients.\n\n3.6. Adverse Events\nOne patient (Case 5) experienced mild olecranon bursitis in the elbow after 2nd administration of abatacept. The bursitis was considered to be self-limiting or infectious, since swelling in the other joints was improving and the symptom subsided after 1-week treatment with oral antibiotics. The 3rd administration was postponed for a week, but abatacept was restarted without relapse. No other adverse events, including exacerbation of any lupus manifestations or concomitant autoimmune conditions, have been reported for a median follow-up period of 15 months (range 7–22).\n\n3.7. Case Report (Case 3)\nA 60-year-old woman was admitted to the Department of Allergy and Clinical Immunology, Chiba University Hospital, on 13th of November, 2009, for the treatment of RA and SLE. She had been diagnosed with RA since 1996, when she had arthritis in hands and tested positive for RF, but had only received Chinese herbal medicine since the diagnosis. She was diagnosed with duodenal cancer and SLE in August, 2009, when she was admitted to another hospital for the investigation of intermittent fever, pancytopenia, multiple lymphadenopathy, and congestive heart failure. After receiving treatment for anemia and congestive heart failure with blood transfusion and diuretics, the patient underwent distal gastrectomy and proximal duodenectomy, on 28th of October, 2009 at the Department of Frontier Surgery, Chiba University Hospital, without any complication. The histopathological diagnosis was papillary adenocarcinoma. \n\nOn admission to our department, the patient had a low grade fever, lymphadenopathy in the neck and bilateral inguinal areas, and markedly swollen but only slightly tender fingers and wrists (Figures 2(a) and 2(b)). Blood tests revealed bicytopenia (white blood cell count 1,900/mm3, hemoglobin 10.2 g/dL, platelet count 405 × 103/mm3), acute inflammatory response (CRP 32 mg/L, erythrocyte sedimentation rate [ESR] 48 mm/h), hypergammaglobulinemia (IgG 2,395 mg/dL), abnormal coagulation (prothrombin time-international normalized ratio [PT-INR] 1.14, activated partial thromboplastin time [APTT] 40.1 sec, D-Dimer 23.2 μg/mL), decreased levels of complements (C3 29 mg/dL, C4 5 mg/dL, CH50 7 U/mL), and the presence of autoantibodies (ANA x320 speckled pattern, IgG anti-DNA antibody 20.3 U/mL, β2-glycoprotein 1-dependent IgG anti-cardiolipin antibody 16 U/mL, RF 188 U/mL, and ACPA >100 U/mL). Antibodies to extractable nuclear antigens such as Sm, U1-RNP, Ro/SS-A, and La/SS-B were all negative. \n\nHand radiographs showed soft tissue swelling, joint space narrowing, and bone erosions (Figure 3). Musculoskeletal ultrasound of the left hand revealed both intra-articular and tenosynovitis with increased PD signals (Figures 4(a)–4(d), [see also webvideo 1, 2] see Supplementary Material available online at http://dx.doi.org/10.1155/2013/697525). Echocardiogram and computed tomography (CT) scan of chest showed a small amount of pericardial effusion. CT scan of abdomen and magnetic resonance imaging of brain were unremarkable.\n\nThe patient fulfilled both the 2010 ACR/EULAR Criteria for the Classification of RA (arthritis in more than ten joints, elevated levels of ESR and CRP, highly positive RF and ACPA, and disease duration of longer than 6 months) and the 1997 ACR Revised Classification Criteria of SLE (Pericarditis, leukocytopenia/lymphocytopenia, anti-DNA antibody/anti-phospholipid antibody, and anti-nuclear antibody). Because she did not have severe organ involvement due to SLE, the treatment for RA was initiated with a small dose of MTX (4 mg/week) given the presence of bicytopenia. CDAI gradually decreased from 35 to 23 with an increase to 6 mg/week of MTX and she was discharged although low grade fever, bicytopenia, and serological activity of lupus persisted (Figure 5). \n\nA small dose of prednisolone (10 mg/day) was added to the treatment in July 2010 because of a gradual worsening of arthritis, persistent fever, and increased levels of anti-DNA antibody. Although the lupus-like manifestations, including fever, bicytopenia, and increased levels of anti-DNA antibody, improved after corticosteroid therapy; severe joint swelling persisted even after tacrolimus was added to the regimen and MTX was increased to 10 mg/week.\n\nDue to insufficient effectiveness, along with concerns regarding elevated liver enzymes, MTX was replaced by abatacept, in April 2011. Joint swelling markedly improved (Figures 2(c) and 2(d)) and the patient achieved CDAI/SDAI/DAS28 remission after 12 weeks of abatacept treatment (Figure 1, Case 3). Intra-articular and tenosynovitis on ultrasound also improved markedly during the 24 weeks of abatacept treatment (Figures 4(e)–4(h)). Corticosteroid dose was reduced successfully to 6 mg/day in February 2012 and the patient has remained in remission for 14 months.\n\n4. Discussion\nThis is the first report of rhupus patients treated with abatacept for arthritis. All rhupus patients whose arthritis was refractory to MTX and other antirheumatic agents such as TNF antagonists and calcineurin inhibitors achieved a moderate or better response after receiving abatacept treatment. Although this result cannot be directly compared with data from clinical trials, the efficacy of abatacept for arthritis in rhupus patients seems to be at least as good as that in MTX-resistant and biologics-naive RA patients [12, 15]. Considering the potentially detrimental effect of TNF antagonists on lupus manifestation, our data support the preferential choice of abatacept in a patient with rhupus syndrome whose arthritis is refractory to MTX. Whether this also applies to RA patients with positive ANA or anti-DNA antibody without clinical lupus manifestation is a matter of interest, and a comparison between different agents in this subpopulation is needed to address this question.\n\nThe relatively safe profile of abatacept as compared to other biological agents for infection in RA patients has been shown in clinical trials and a meta-analysis [12, 20]. Although the bursitis which Case 5 developed in this study could have been due to infection, this event required neither hospitalization nor intravenous administration of antibiotics and did not recur after readministration of abatacept. We think this nonserious adverse event, which could have been infectious, does not necessarily raise a concern about the relative safety of abatacept as compared to other biological agents, but further investigation is nonetheless needed for rhupus patients.\n\nUltrasound revealed active intra-articular synovitis in all cases and active tenosynovitis in the majority of our cases. The latter lesions may represent the pathology characteristic to SLE rather than RA according to the previous studies which showed high prevalence of tenosynovitis in lupus patients [4, 5, 21]. Although the absence of tenosynovitis did not influence the efficacy of abatacept in our small number of rhupus patients, the discrimination between intra-capsular- and extra-capsular-dominant patients using ultrasound may be informative in the prediction of effectiveness of antirheumatic and immunosuppressive agents for arthritis in RA and SLE. A large-scale prospective study, however, would be necessary to prove this hypothesis.\n\nIn contrast to the efficacy of abatacept on arthritis, its efficacy on non-articular lupus manifestations was marginal in our case series, which is consistent with the previous study in patients with non-life-threatening SLE [19]. However, the statistically significant decrease in the levels of IgG and anti-DNA antibody in our cases may reflect the effect of abatacept on autoantibody production in SLE. Because T cell-APC interaction is an attractive target in the pathogenesis of SLE [22–25], more severe cases may respond to abatacept treatment. Accumulation of such cases may justify future trials to identify the subset of SLE patients who may benefit from abatacept treatment. \n\n5. Conclusions\nTreatment with abatacept is likely to be efficacious in patients with rhupus whose arthritis is refractory to methotrexate. In addition, abatacept may have a moderate effect on abnormal antibody production in rhupus patients.\n\nSupplementary Material\nUltrasound images of extensor carpi ulnaris in the right hand before abatacept treatment show severe tenosynovial hypertrophy accompanied by moderate Doppler signals both in the longitudinal view (webvideo 1) and in the transverse view (webvideo 2).\n\nClick here for additional data file.\n\n Click here for additional data file.\n\n Conflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 Changes in clinical indices and laboratory tests reflecting disease activity of RA and/or SLE in each case during 24 weeks after abatacept treatment. *P < 0.05, Wilcoxon's signed-rank test. Comparisons were made against baseline values. RA: rheumatoid arthritis; SLE: systemic lupus erythematosus; CDAI: Clinical Disease Activity Index; HAQ-DI: Health Assessment Questionnaire-Disability Index; SLEDAI: systemic lupus erythematosus disease activity index; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; RF, rheumatoid factor; IgG: immunoglobulin G; Anti-DNA Ab: anti-DNA antibody.\n\nFigure 2 Joint swelling of hands in Case 3 before and after treatment. Dorsal aspects (a, c) and palmer aspects (b, d) of the hand are shown. Swelling in fingers and wrists before treatment (a, b) markedly improved after 24 weeks of abatacept treatment (c, d), leaving swan-neck deformity.\n\nFigure 3 Plain radiographs of hands in Case 3. Plain radiographs of hands before treatment in the anterior-posterior view (a) and the oblique view (b). Arrows indicate small erosions in the heads of left 2nd and 3rd metacarpal bones and right proximal phalanx. Markedly thickened soft tissues are demonstrated (asterisks).\n\nFigure 4 Ultrasound images of hands in Case 3 before and after treatment. Shown are the representative ultrasound images of the left hand before treatment (a–d) and after 24 weeks of abatacept treatment (e–h). Ultrasound images before treatment reveal moderate synovial hypertrophy with moderate Doppler signals in the 3rd proximal interphalangeal joint (a) and severe synovial hypertrophy with moderate Doppler signals in the flexor tendon of the 3rd finger (b) and extensor carpi ulnaris longitudinal view (c) (see also webvideo 1) and transverse view (d) (see also webvideo 2). Corresponding ultrasound images after abatacept treatment demonstrate marked improvement (e–h). PP: proximal phalanx; MP: middle phalanx; FD: flexor digitorum; ECU: extensor carpi ulnaris.\n\nFigure 5 Treatment summary and clinical course of Case 3. MTX: methotrexate; CDAI: Clinical Disease Activity Index; CRP: C-reactive protein; WBC: white blood cell count; IgG: immunoglobulin G; RF: rheumatoid factor; Anti-DNA Ab: anti-DNA antibody; C3: complement component 3; CH50: 50% hemolytic complement activity of serum.1. Panush et al. [1].\n\nTable 1 Patient demographics and disease characteristics of RA before abatacept treatment.\n\nCase number\tSex\tAge (year)\tDuration of arthritis (month)\tRF (U/mL)\tACPA (U/mL)\tErosion on X-ray typical for RA\tTJC (/28)\tSJC (/28)\tPatient global VAS (mm)\tPhysician global VAS (mm)\tDAS28\n-ESR\tMMP-3 (ng/mL)\tIntra-articular\nsynovitis with PD signals\tTeno-synovitis with PD signals\tPredni-solone (mg/day)\tDMARD/\nimmunosuppressant in combination\tPrevious DMARD/\nimmunosuppressant\t\n1\tF\t29\t38\t459\t110\t(+)\t16\t10\t60\t73\t7.02\t116\t(+)\t(+)\t0\tMTX\tAdalimumab\t\n2\tF\t66\t85\t<5\t<0.6\t(+)\t0\t5\t77\t65\t3.64\t175\t(+)\t(−)\t7\tTacrolimus\tMTX\t\n3\tF\t60\t183\t40\t>100\t(+)\t5\t11\t48\t49\t4.11\t87.6\t(+)\t(+)\t8\tTacrolimus\tMTX\t\n4\tF\t58\t163\t<5\t<0.6\t(+)\t0\t12\t51\t43\t4.11\t106\t(+)\t(+)\t5\tMTX\tNone\t\n5\tF\t53\t23\t<5\t0.7\t(+)\t0\t2\t25\t40\t3.08\t148\t(+)\t(+)\t4\tMTX\tEtanercept\t\n6\tF\t57\t108\t25\t>100\t(−)\t9\t17\t66\t73\t6.42\t160\t(+)\t(−)\t2\tCyclosporin A\tMTX\t\nRA: rheumatoid arthritis; RF: rheumatoid factor; ACPA: anticitrullinated peptide antibody; TJC: tender joint count; SJC: swollen joint count; VAS: visual analogue scale; DAS: Disease Activity Score; ESR: erythrocyte sedimentation rate; MMP: matrix metalloproteinase; PD: power Doppler; SLE: systemic lupus erythematosus; DMARD: disease-modifying antirheumatic drug; F: female; MTX: methotrexate.\n\nTable 2 Disease characteristics of SLE before abatacept treatment.\n\nCase number\tDuration of SLE (month)\tMajor current disease manifestations other than arthritis\tMajor previous disease manifestations other than arthritis\tCTD other than RA or SLE\tANA\tAnti-DNA antibody (U/mL)\tOther autoantibodies\tIgG (mg/dL)\tC3 (mg/dL)\tC4 (mg/dL)\tCH50 (U/mL)\tSLEDAI\t\n1\t2\tLow grade fever, rash, anemia, leukocytopenia\tFever, rash, anemia, leukocytopenia\tSS, chronic thyroiditis\t>1280\t29.5\tRo, LA, TPO\t2285\t81\t14\t36.8\t7\t\n2\t565\tRash\tRash, leukocytopenia, pericarditis, pleuritis\tSS\t>1280\t47.8\tRo, La\t1265\t87\t12\t31.1\t12\t\n3\t20\tNone\tFever, anemia, leukocytopenia\tNone\t320\t28.3\tU1-RNP, Cardiolipin\t1939\t27\t3\t<5.0\t8\t\n4\t151\tRash\tRash, leukocytopenia\tScleroderma, chronic thyroiditis\t>1280\t16.8\tSm, U1-RNP, TPO\t1625\t111\t41\t47.5\t6\t\n5\t420\tNone\tFever, rash, severe thrombocytopenia\tSS\t160\t10.1\tRo, La\t2285\t66\t4\t17.4\t6\t\n6\t96\tNone\tFever, rash, myositis, ILD\tSS\t320\t4.0\tU1-RNP, Ro\t1598\t152\t40\t45.1\t4\t\nSLE: systemic lupus erythematosus; CTD: connective tissue disease; ANA: antinuclear antibody; IgG: immunoglobulin G; SLEDAI: systemic lupus erythematosus disease activity index; ILD: interstitial lung disease; SS: Sjogren's syndrome; APS: antiphospholipid syndrome; LA: lupus anticoagulant; TPO: thyroid peroxidase; RNP: ribonucleoprotein.\n==== Refs\n1 Panush RS Edwards L Longley S Webster E ‘Rhupus’ syndrome Archives of Internal Medicine 1988 148 7 1633 1636 2-s2.0-0023762899 3382309 \n2 van Vugt RM Derksen RH Kater L Bijlsma JWJ Deforming arthropathy or lupus and rhupus hands in systemic lupus erythematosus Annals of the Rheumatic Diseases 1998 57 9 540 544 2-s2.0-0031691764 9849313 \n3 Chan MT Owen P Dunphy J Associations of erosive arthritis with anti-cyclic citrullinated peptide antibodies and MHC class II alleles in systemic lupus erythematosus Journal of Rheumatology 2008 35 1 77 83 2-s2.0-38149021391 18085741 \n4 Ball EM Bell AL Lupus arthritis-do we have a clinically useful classification? Rheumatology 2012 51 5 771 779 2-s2.0-84860261622 ker381 22179731 \n5 Gabba A Piga M Vacca A Joint and tendon involvement in systemic lupus erythematosus: an ultrasound study of hands and wrists in 108 patients Rheumatology 2012 51 12 2278 2285 22956550 \n6 Eriksson C Engstrand S Sundqvist K-G Rantapää-Dahlqvist S Autoantibody formation in patients with rheumatoid arthritis treated with anti-TNFα \n Annals of the Rheumatic Diseases 2005 64 3 403 407 2-s2.0-14144256349 15297281 \n7 Charles PJ Smeenk RJ De Jong J Assessment of antibodies to double-stranded DNA induced in rheumatoid arthritis patients following treatment with infliximab, a monoclonal antibody to tumor necrosis factor alpha: findings in open-label and randomized placebo-controlled trials Arthritis and Rheumatism 2000 43 11 2383 2390 11083258 \n8 Costa MF Said NR Zimmermann B Drug-induced lupus due to anti-tumor necrosis factor alpha agents Seminars in Arthritis and Rheumatism 2008 37 6 381 387 2-s2.0-44349171691 17977585 \n9 De Bandt M Sibilia J Le Loët X Systemic lupus erythematosus induced by anti-tumour necrosis factor alpha therapy: a French national survey Arthritis Research & Therapy 2005 7 3 R545 R551 2-s2.0-21744446004 15899041 \n10 Debandt M Vittecoq O Descamps V Le Loët X Meyer O Anti-TNF-α -induced systemic lupus syndrome Clinical Rheumatology 2003 22 1 56 61 2-s2.0-0038460243 12605321 \n11 Chogle AR Shah CV Murthy AK Role of anti-tumor necrosis factor-α blockers in inducing lupus erythematosus tumidus in ‘rhupus syndrome’ Journal of Rheumatology 2011 38 6 1218 1219 2-s2.0-79957849753 21632691 \n12 Schiff M Keiserman M Codding C Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate Annals of the Rheumatic Diseases 2008 67 8 1096 1103 2-s2.0-47949106400 18055472 \n13 Westhovens R Robles M Ximenes AC Clinical efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis and poor prognostic factors Annals of the Rheumatic Diseases 2009 68 12 1870 1877 2-s2.0-65349176911 19124524 \n14 Genovese MC Becker J Schiff M Abatacept for rheumatoid arthritis refractory to tumor necrosis factor α inhibition New England Journal of Medicine 2005 353 11 1114 1123 2-s2.0-24944498854 16162882 \n15 Kremer JM Genant HK Moreland LW Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: a randomized trial Annals of Internal Medicine 2006 144 12 865 876 2-s2.0-33745291091 16785475 \n16 Westhovens R Kremer JM Moreland LW Safety and efficacy of the selective costimulation modulator abatacept in patients with rheumatoid arthritis receiving background methotrexate: a 5-year extended phase IIB study Journal of Rheumatology 2009 36 4 736 742 2-s2.0-66149093043 19273451 \n17 Lekpa FK Farrenq V Canouï-Poitrine F Lack of efficacy of abatacept in axial spondylarthropathies refractory to tumor-necrosis-factor inhibition Joint Bone Spine 2012 79 1 47 50 2-s2.0-84855661105 21497538 \n18 Song IH Heldmann F Rudwaleit M Treatment of active ankylosing spondylitis with abatacept: an open-label, 24-week pilot study Annals of the Rheumatic Diseases 2011 70 6 1108 1110 2-s2.0-79955868460 21415053 \n19 Merrill JT Burgos-Vargas R Westhovens R The efficacy and safety of abatacept in patients with non-life-threatening manifestations of systemic lupus erythematosus: results of a twelve-month, multicenter, exploratory, phase IIb, randomized, double-blind, placebo-controlled trial Arthritis and Rheumatism 2010 62 10 3077 3087 2-s2.0-77957682858 20533545 \n20 Singh JA Wells GA Christensen R Adverse effects of biologics: a network meta-analysis and Cochrane overview Cochrane Database of Systematic Reviews 2011 2 CD008794 2-s2.0-79953018875 \n21 Delle Sedie A Riente L Scirè CA Ultrasound imaging for the rheumatologist XXIV. Sonographic evaluation of wrist and hand joint and tendon involvement in systemic lupus erythematosus Clinical and Experimental Rheumatology 2009 27 6 897 901 2-s2.0-76649093587 20149302 \n22 Tsokos GC Mechanisms of disease: systemic lupus erythematosus New England Journal of Medicine 2011 365 22 2110 2121 2-s2.0-82555196095 22129255 \n23 Lee YH Harley JB Nath SK CTLA-4 polymorphisms and systemic lupus erythematosus (SLE): a meta-analysis Human Genetics 2005 116 5 361 367 2-s2.0-17144378972 15688186 \n24 Takeuchi T Suzuki K Kondo T Yoshimoto K Tsuzaka K CD3 zeta defects in systemic lupus erythematosus Annals of the Rheumatic Diseases 2012 71 supplement 2 i78 i81 2-s2.0-84859506368 22460144 \n25 Dörner T Giesecke C Lipsky PE Mechanisms of B cell autoimmunity in SLE Arthritis Research and Therapy 2011 13 5 p. 243 2-s2.0-81255146464\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1740-2522",
"issue": "2013()",
"journal": "Clinical & developmental immunology",
"keywords": null,
"medline_ta": "Clin Dev Immunol",
"mesh_terms": "D000069594:Abatacept; D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents; D001168:Arthritis; D001172:Arthritis, Rheumatoid; D005260:Female; D006801:Humans; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D008180:Lupus Erythematosus, Systemic; D008875:Middle Aged; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "101183692",
"other_id": null,
"pages": "697525",
"pmc": null,
"pmid": "24324510",
"pubdate": "2013",
"publication_types": "D016428:Journal Article",
"references": "18055472;15297281;22179731;20533545;21632691;20149302;3382309;11083258;15688186;16785475;19273451;22129255;9849313;21415053;22956550;22460144;19124524;12605321;17977585;18085741;21497538;15899041;16162882;21328309;22078750",
"title": "Efficacy of abatacept for arthritis in patients with an overlap syndrome between rheumatoid arthritis and systemic lupus erythematosus.",
"title_normalized": "efficacy of abatacept for arthritis in patients with an overlap syndrome between rheumatoid arthritis and systemic lupus erythematosus"
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"abstract": "BACKGROUND\nThis study evaluated the anterior ocular segment in a pseudophakic eye with angle closure due to a plateau-like iris associated with Soemmering's ring, using ultrasound biomicroscopy (UBM) and anterior segment optical coherence tomography (AS-OCT).\n\n\nMETHODS\nA 60-year-old woman was referred from a local clinic due to sudden-onset ocular pain and uncontrolled intraocular pressure (IOP) in the left eye, which was 56 mmHg after treatment with latanoprost, timolol, and dorzolamide eye drops. Fourteen years earlier, she developed acute primary angle closure. At that time, because the IOP remained elevated after a peripheral iridectomy, cataract extraction combined with goniosynechialysis was added. After the IOP decreased to within the normal range, a secondary intraocular lens was implanted outside the bag. On this admission, UBM and AS-OCT images showed angle closure caused by the combination of a plateau-like iris and contact between the mydriatic pupillary margin and enlarged Soemmering's ring. After adding 2 % pilocarpine four times a day, the mydriasis resolved slightly, and the IOP decreased to the normal range between 8 and 18 mmHg. AS-OCT images showed re-opening of the angle structure after treatment with 2 % pilocarpine.\n\n\nCONCLUSIONS\nThe intraocular pressure and angle structure in eyes with a plateau iris after cataract extraction should be followed carefully.",
"affiliations": "Department of Ophthalmology, Faculty of Life Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan.;Department of Ophthalmology, Faculty of Life Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan. noel@da2.so-net.ne.jp.;Department of Ophthalmology, Faculty of Life Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan.;Department of Ophthalmology, Faculty of Life Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan.",
"authors": "Kitamura|Fumika|F|;Inoue|Toshihiro|T|;Kuroda|Utako|U|;Tanihara|Hidenobu|H|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12886-016-0226-0",
"fulltext": "\n==== Front\nBMC OphthalmolBMC OphthalmolBMC Ophthalmology1471-2415BioMed Central London 22610.1186/s12886-016-0226-0Case ReportAngle closure caused by a plateau-like iris associated with an enlarged Soemmering’s ring: a case report Kitamura Fumika Inoue Toshihiro +81-96-373-5247+81-96-373-5249noel@da2.so-net.ne.jp Kuroda Utako Tanihara Hidenobu Department of Ophthalmology, Faculty of Life Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto Japan 4 5 2016 4 5 2016 2016 16 4916 9 2015 27 4 2016 © Kitamura et al. 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nThis study evaluated the anterior ocular segment in a pseudophakic eye with angle closure due to a plateau-like iris associated with Soemmering’s ring, using ultrasound biomicroscopy (UBM) and anterior segment optical coherence tomography (AS-OCT).\n\nCase presentation\nA 60-year-old woman was referred from a local clinic due to sudden-onset ocular pain and uncontrolled intraocular pressure (IOP) in the left eye, which was 56 mmHg after treatment with latanoprost, timolol, and dorzolamide eye drops. Fourteen years earlier, she developed acute primary angle closure. At that time, because the IOP remained elevated after a peripheral iridectomy, cataract extraction combined with goniosynechialysis was added. After the IOP decreased to within the normal range, a secondary intraocular lens was implanted outside the bag. On this admission, UBM and AS-OCT images showed angle closure caused by the combination of a plateau-like iris and contact between the mydriatic pupillary margin and enlarged Soemmering’s ring. After adding 2 % pilocarpine four times a day, the mydriasis resolved slightly, and the IOP decreased to the normal range between 8 and 18 mmHg. AS-OCT images showed re-opening of the angle structure after treatment with 2 % pilocarpine.\n\nConclusion\nThe intraocular pressure and angle structure in eyes with a plateau iris after cataract extraction should be followed carefully.\n\nKeywords\nAngle closure glaucomaPilocarpineSoemmering’s ringissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nAcute angle closure has various causes, including pupillary block, plateau iris, and secondary mechanisms (e.g., neovascularization, iris tumor, and aqueous misdirection) [1]. In pseudophakic eyes, some investigators have reported the occurrence of angle closure caused by Soemmering’s ring [2, 3]. Soemmering’s ring is a doughnut-like structure that results from the proliferation of lens epithelial cells in the peripheral part of the capsular bag remaining after cataract extraction. However, the causative mechanism of angle closure differs from case to case. Kobayashi et al. reported a case of pupillary block related to enlargement of Soemmering’s ring, in which a laser iridotomy overcame the pupillary block, reducing the intraocular pressure (IOP) [2]. Kung et al. reported a non-pupillary block mechanism in which progressive synechial angle closure was induced by enlargement of Soemmering’s ring [3]. Here, we report another non-pupillary block mechanism, involving a combination of a plateau-like iris and enlarged Soemmering’s ring in an eye with a mydriatic pupil.\n\nCase presentation\nA 60-year-old woman was referred from a local clinic with sudden-onset ocular pain and uncontrolled IOP in the left eye, which was 56 mmHg after treatment with latanoprost, timolol, and dorzolamide eye drops. Fourteen years earlier, she developed acute primary angle closure in both eyes. At that time, a peripheral iridectomy was performed in both eyes to relieve the pupillary block, resulting in controlled IOP levels in the right eye, but not in the left. Subsequently, cataract extraction combined with goniosynechialysis (GSL) was performed in the left eye and the IOP levels normalized. Secondary implantation of an intraocular lens (IOL) was performed, resulting in out-of-the-bag fixation of the implanted IOL. The detail of the cataract surgery is unknown, because the medical record is not available.\n\nAt the first examination in our department, slit lamp examination of the left eye showed corneal edema, a markedly dilated pupil, a patent iris coloboma created by the previous peripheral iridectomy, and the presence of Soemmering’s ring in the peripheral part of the remaining capsular bag (Fig. 1a, b). The anterior chamber of the right eye was somewhat shallow due to anterior positioning of the crystalline lens (Fig. 1c, d), while in the left eye, it was deep in the central region, but very shallow in the periphery (Fig. 1b). Ultrasound biomicroscopy (UBM) showed that the iris had been displaced anteriorly by the enlarged Soemmering’s ring (Fig. 1e). The IOP was 8 mm Hg in the right eye and 50 mm Hg in the left (Fig. 2). Gonioscopic observation showed a narrow angle (Shaffer grade 1) in the right eye, and total closure of the angle structure in the left eye. Anterior segment optical coherence tomography (AS-OCT) showed a short, thick iris with a plateau-like iris configuration and angle closure due to the crowded angle structure in the left eye (Fig. 3). Despite treatment with a carbonic anhydrase inhibitor, β-blocker, prostaglandin analogue, and α2-agonist eye drops, the IOP remained elevated at 48–50 mmHg. After adding 2 % pilocarpine four times a day, the mydriasis resolved slightly, and IOP decreased to 8–18 mmHg, in the normal range (Fig. 2). AS-OCT images showed re-opening of the angle structure after treatment with 2 % pilocarpine.Fig. 1 Slit lamp photographs. In the left eye, the pupil was markedly dilated, and a patent peripheral iridectomy and Soemmering’s ring were found (a, b). In the right eye, the anterior chamber was shallow despite a patent iridectomy. In the left eye, the anterior chamber was deep in the central region, but very shallow in the periphery, with a plateau-like iris configuration (c, d). Ultrasound biomicroscopy (UBM) showed a plateau-like iris and co-localized dilated pupil margin (between yellow arrow heads) with an enlarged Soemmering’s ring (yellow arrow) and anterior insertion of ciliary process (white arrow) (e)\n\nFig. 2 Intraocular pressure (IOP) changes and medical treatments\n\nFig. 3 Anterior segment optical coherence tomography (AS-OCT) and UBM images. AS-OCT showed re-opening of the angle structure after medical treatment. The insets correspond to slices at the red lines\n\n\n\nPrimary angle closure can be induced by pupillary block or a plateau iris (non-pupillary block). In our case, the angle closure did not result from a pupillary block mechanism, due to the patent (surgical) peripheral iridectomy and flat iris seen on AS-OCT and UBM. In addition, the UBM image showed a plateau-like iris and a crowded angle structure in the left eye. Clinically, the IOP can increase after the relief of pupillary block mechanisms in some eyes with narrow or closed angles, especially in Asians [4]. However, residual angle closure can be inhibited by lens extraction, as shown by UBM [5]. In some cases, iridociliary apposition in a plateau iris can persist after cataract extraction [6]. Even with a patent laser peripheral iridotomy, which relieves the pupillary block, about 30 % of the eyes with primary angle closure glaucoma had a plateau iris on UBM in Asian patients [7]. Furthermore, a secondary plateau iris configuration is often found after relief of synechial closure by GSL, although it is difficult to differentiate a surgically induced plateau iris configuration from a plateau iris that existed before the angle closure developed [8]. In our case, UBM demonstrated the anterior insertion of ciliary processes in the left eye (Fig. 1e) and a shallow anterior chamber in the right eye (data not shown), suggesting a pre-existing plateau-like iris before GSL. There was no history or UBM finding of secondary angle closure mechanisms, such as neovascularization, uveitis, iridociliary tumor, a dislocated IOL, iridovitreal block, or aqueous misdirection (malignant glaucoma). Therefore, it is quite likely that the plateau-like iris contributed to the episode of acute angle closure, although 14 years had passed since the GSL and cataract extraction. Therefore, additional factors may have contributed to the angle closure in our case. An enlarged Soemmering’s ring was noted in contact with the posterior surface of the iris in the dilated pupil margin, resulting in anterior displacement of the iris plane. It is possible that anterior swelling of Soemmering’s ring pushed the iris tissue causing deterioration of the plateau-like iris and closing the angle structure. This hypothesis is supported by the fact that the angle re-opened and the IOP fell after treatment with pilocarpine eye drops.\n\nIn conclusion, our case suggests that swelling of Soemmering’s ring can contribute to angle closure in eyes with a plateau-like iris. To our knowledge, this is the first report in which enlargement of Soemmering’s ring contributed to angle closure in addition to non-pupillary block mechanisms (plateau iris).\n\nConclusion\nThe intraocular pressure and angle structure in eyes with a plateau iris configuration after cataract extraction should be followed carefully.\n\nEthics and consent to participate\nNot Applicable.\n\nConsent to publish\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the consent is available for review by the Editor of this journal. All procedures conformed to the Declaration of Helsinki.\n\nAvailability of data and materials\nAll the data supporting our findings is contained within the manuscript.\n\nAbbreviations\nAS-OCTanterior segment optical coherence tomography\n\nGSLgoniosynechialysis\n\nIOLintraocular lens\n\nIOPintraocular pressure\n\nUBMultrasound biomicroscopy\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nFK, TI, and UK conceived of the study, examined the patient, and drafted the manuscript. HT participated in the study design, interpreted the patient data, and helped to draft the manuscript. All authors read and approved the final manuscript.\n\nFunding\nThe case report has no funding involved.\n==== Refs\nReferences\n1. Aslanides IM Libre PE Silverman RH Reinstein DZ Lazzaro DR Rondeau MJ Harmon GK Coleman DJ High frequency ultrasound imaging in pupillary block glaucoma Br J Ophthalmol 1995 79 972 6 10.1136/bjo.79.11.972 8534666 \n2. Kobayashi H Hirose M Kobayashi K Ultrasound biomicroscopic analysis of pseudophakic pupillary block glaucoma induced by Soemmering’s ring Br J Ophthalmol 2000 84 1142 6 10.1136/bjo.84.10.1142 11004100 \n3. Kung Y Park SC Liebmann JM Ritch R Progressive synechial angle closure from an enlarging Soemmering ring Arch Ophthalmol 2011 129 1631 2 10.1001/archophthalmol.2011.344 22159689 \n4. Ang LP Aung T Chew PT Acute primary angle closure in an Asian population: long-term outcome of the fellow eye after prophylactic laser peripheral iridotomy Ophthalmology 2000 107 2092 6 10.1016/S0161-6420(00)00360-2 11054339 \n5. Nonaka A Kondo T Kikuchi M Yamashiro K Fujihara M Iwawaki T Yamamoto K Kurimoto Y Cataract surgery for residual angle closure after peripheral laser iridotomy Ophthalmology 2005 112 974 9 10.1016/j.ophtha.2004.12.042 15885784 \n6. Tran HV Liebmann JM Ritch R Iridociliary apposition in plateau iris syndrome persists after cataract extraction Am J Ophthalmol 2003 135 40 3 10.1016/S0002-9394(02)01842-1 12504695 \n7. Kumar RS Baskaran M Chew PT Friedman DS Handa S Lavanya R Sakata LM Wong HT Aung T Prevalence of plateau iris in primary angle closure suspects an ultrasound biomicroscopy study Ophthalmology 2008 115 430 4 10.1016/j.ophtha.2007.07.026 17900691 \n8. Tanihara H Nagata M Argon-laser gonioplasty following goniosynechialysis Graefes Arch Clin Exp Ophthalmol 1991 229 505 7 10.1007/BF00203310 1765287\n\n",
"fulltext_license": "CC BY",
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"issue": "16(1)",
"journal": "BMC ophthalmology",
"keywords": "Angle closure glaucoma; Pilocarpine; Soemmering’s ring",
"medline_ta": "BMC Ophthalmol",
"mesh_terms": "D005260:Female; D015812:Glaucoma, Angle-Closure; D006801:Humans; D007499:Iris Diseases; D007905:Lens Diseases; D008875:Middle Aged; D019591:Pseudophakia",
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"title": "Angle closure caused by a plateau-like iris associated with an enlarged Soemmering's ring: a case report.",
"title_normalized": "angle closure caused by a plateau like iris associated with an enlarged soemmering s ring a case report"
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"abstract": "BACKGROUND\nDantrolene is neuroprotective in animal models and may attenuate cerebral vasospasm (cVSP) in human aneurysmal subarachnoid haemorrhage (aSAH). We evaluated safety, feasibility and tolerability of intravenous dantrolene (IV-D) in patients with aSAH.\n\n\nMETHODS\nIn this single-centre, randomised, double blind, placebo-controlled trial, 31 patients with aSAH were randomised to IV-D 1.25 mg every 6 h for 7 days (n=16) or equiosmolar free water/5% mannitol (placebo; n=15). Primary safety end points were incidence of hyponatraemia (sNa≤132 mmol/L) and liver toxicity (proportion of patients alanine transaminase, aspartate aminotransferase and AlkPhos >5× upper-limit-of-normal). Secondary end points included tolerability, systemic hypotension and intracranial hypertension. Efficacy was explored for clinical/radiological cVSP, delayed cerebral ischaemia (DCI), and 3-month functional outcomes. Quantitative analyses of angiograms and daily transcranial Doppler (TCD) were performed.\n\n\nRESULTS\nBetween IV-D versus placebo, no differences were observed in the primary outcomes (hyponatremia 44% vs 67% (p=0.29); liver toxicity 6% vs 0% (p=1.0)). Three patients in the IV-D versus two in the placebo group had severe adverse events possibly attributable to infusion and reached stop criteria: one IV-D patient developed liver toxicity; two patients in each group developed brain oedema requiring osmotherapy. The majority of adverse events were not related to infusion (17 vs 5 (RR 2.2; 95% CI 0.7 to 6.7; p=0.16) in IV-D vs placebo). No differences in any categorical cVSP outcomes, DCI, 3-month outcomes or quantitative angiogram and TCD analyses were seen in this small safety trial not powered to detect efficacy.\n\n\nCONCLUSIONS\nIn this small trial, IV-D after aSAH was feasible, tolerable and safe.\n\n\nBACKGROUND\nhttp://clinicaltrials.gov NCT01024972.",
"affiliations": "Departments of Neurology (Neurocritical Care), University of Massachusetts Medical School, Worcester, Massachusetts, USA Department of Anesthesia/Critical Care, University of Massachusetts Medical School, Worcester, Massachusetts, USA Department of Surgery, University of Massachusetts Medical School, Worcester, Massachusetts, USA.;Departments of Neurology (Neurocritical Care), University of Massachusetts Medical School, Worcester, Massachusetts, USA Department of Surgery, University of Massachusetts Medical School, Worcester, Massachusetts, USA.;Departments of Neurology (Neurocritical Care), University of Massachusetts Medical School, Worcester, Massachusetts, USA Department of Surgery, University of Massachusetts Medical School, Worcester, Massachusetts, USA.;Department of Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, Massachusetts, USA.;Departments of Neurology (Neurocritical Care), University of Massachusetts Medical School, Worcester, Massachusetts, USA.;Departments of Neurology (Neurocritical Care), University of Massachusetts Medical School, Worcester, Massachusetts, USA.;Departments of Neurology (Neurocritical Care), University of Massachusetts Medical School, Worcester, Massachusetts, USA.;Department of Radiology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.;Department of Radiology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.;Department of Radiology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.;Department of Neurosurgery, University of Massachusetts Medical School, Worcester, Massachusetts, USA.;Department of Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, Massachusetts, USA.;Departments of Neurology (Neurocritical Care), University of Massachusetts Medical School, Worcester, Massachusetts, USA Department of Radiology, University of Massachusetts Medical School, Worcester, Massachusetts, USA Department of Neurosurgery, University of Massachusetts Medical School, Worcester, Massachusetts, USA.",
"authors": "Muehlschlegel|Susanne|S|http://orcid.org/0000-0002-5717-9246;Carandang|Raphael|R|;Hall|Wiley|W|;Kini|Nisha|N|;Izzy|Saef|S|;Garland|Bridget|B|;Ouillette|Cynthia|C|;van der Bom|Imramsjah M J|IM|;Flood|Thomas F|TF|;Gounis|Matthew J|MJ|;Weaver|John P|JP|;Barton|Bruce|B|;Wakhloo|Ajay K|AK|",
"chemical_list": "D009125:Muscle Relaxants, Central; D003620:Dantrolene",
"country": "England",
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"journal": "Journal of neurology, neurosurgery, and psychiatry",
"keywords": "INTENSIVE CARE; STROKE; SUBARACHNOID HAEMORRHAGE",
"medline_ta": "J Neurol Neurosurg Psychiatry",
"mesh_terms": "D000328:Adult; D000368:Aged; D003620:Dantrolene; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009125:Muscle Relaxants, Central; D013345:Subarachnoid Hemorrhage; D016896:Treatment Outcome; D020301:Vasospasm, Intracranial",
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"references": null,
"title": "Dantrolene for cerebral vasospasm after subarachnoid haemorrhage: a randomised double blind placebo-controlled safety trial.",
"title_normalized": "dantrolene for cerebral vasospasm after subarachnoid haemorrhage a randomised double blind placebo controlled safety trial"
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"abstract": "Heparin-induced thrombocytopenia (HIT) is the most important and the most frequent drug-induced, immune-mediated type of thrombocytopenia. It is associated with significant mortality and morbidity if unrecognized. We describe a patient with a giant thrombus on the apical wall of the left ventricle that occurred due to HIT syndrome after anterior myocardial infarction.",
"affiliations": "Department of Cardiology, Istanbul University Institute of Cardiology, Haseki, Aksaray , 34350, Istanbul, Turkey, drumityasar@hotmail.com.",
"authors": "Sinan|U Y|UY|;Coskun|U|U|;Balaban Kocas|B|B|;Gultekin|N|N|;Gurmen|T|T|;Kucukoglu|S|S|",
"chemical_list": "D000925:Anticoagulants; D017984:Enoxaparin",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00059-013-3908-x",
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"mesh_terms": "D000925:Anticoagulants; D017984:Enoxaparin; D006352:Heart Ventricles; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction; D013921:Thrombocytopenia; D013927:Thrombosis; D016896:Treatment Outcome; D014463:Ultrasonography",
"nlm_unique_id": "7801231",
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"references": "15886823;12480713;7715641;10378620;12901146;16634744;21929685;15520327;21159704;16391169;1689564;16202170",
"title": "Giant thrombus on apical wall of left ventricle due to HIT syndrome after anterior MI.",
"title_normalized": "giant thrombus on apical wall of left ventricle due to hit syndrome after anterior mi"
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"abstract": "Several retrospective studies have shown that the antitumor efficacy of capecitabine-containing chemotherapy decreases when co-administered with a proton pump inhibitor (PPI). Although a reduction in capecitabine absorption by PPIs was proposed as the underlying mechanism, the effects of PPIs on capecitabine pharmacokinetics remain unclear. We prospectively examined the effects of rabeprazole on the pharmacokinetics of capecitabine and its metabolites.\n\n\n\nWe enrolled patients administered adjuvant capecitabine plus oxaliplatin (CapeOX) for postoperative colorectal cancer (CRC) patients and metastatic CRC patients receiving CapeOX with/without bevacizumab. Patients receiving a PPI before registration were allocated to the rabeprazole group, and the PPI was changed to rabeprazole (20 mg/day) at least 1 week before the initiation of capecitabine treatment. On day 1, oral capecitabine (1000 mg/m2) was administered 1 h after rabeprazole intake. Oxaliplatin (and bevacizumab) administration on day 1 was shifted to day 2 for pharmacokinetic analysis of the first capecitabine dose. Plasma concentrations of capecitabine, 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine, and 5-fluorouracil were analyzed by high-performance liquid chromatography. Effects of rabeprazole on inhibition of cell proliferation by each capecitabine metabolite were examined with colon cancer cells (COLO205 and HCT116).\n\n\n\nFive and 9 patients enrolled between September 2017 and July 2018 were allocated to rabeprazole and control groups, respectively. No significant effects of rabeprazole on area under the plasma concentration-time curve divided by capecitabine dose for capecitabine and its three metabolites were observed. Rabeprazole did not affect the proliferation inhibition of colon cancer cells by the respective capecitabine metabolites.\n\n\n\nRabeprazole does not affect capecitabine pharmacokinetics.",
"affiliations": "Division of Cancer Cell Biology, Department of Pharmaceutical Science, Showa University School of Pharmacy, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan.;Division of Cancer Cell Biology, Department of Pharmaceutical Science, Showa University School of Pharmacy, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan. k.fujita@med.showa-u.ac.jp.;Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan.;Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan.;Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan.;Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan.;Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan.;Division of Cancer Cell Biology, Department of Pharmaceutical Science, Showa University School of Pharmacy, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan.;Division of Cancer Cell Biology, Department of Pharmaceutical Science, Showa University School of Pharmacy, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan.;Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan.",
"authors": "Sekido|Masae|M|;Fujita|Ken-Ichi|KI|;Kubota|Yutaro|Y|;Ishida|Hiroo|H|;Takahashi|Takehiro|T|;Ohkuma|Ryotaro|R|;Tsunoda|Takuya|T|;Ishikawa|Fumihiro|F|;Shibanuma|Motoko|M|;Sasaki|Yasutsuna|Y|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D054328:Proton Pump Inhibitors; D005467:Floxuridine; D003841:Deoxycytidine; D064750:Rabeprazole; D000069287:Capecitabine; C418208:5'-deoxy-5-fluorocytidine; D005472:Fluorouracil; C025034:doxifluridine",
"country": "Germany",
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"doi": "10.1007/s00280-019-03837-y",
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"issue": "83(6)",
"journal": "Cancer chemotherapy and pharmacology",
"keywords": "Capecitabine; Capecitabine metabolites; Colorectal cancer; Pharmacokinetics; Proton pump inhibitor; Rabeprazole",
"medline_ta": "Cancer Chemother Pharmacol",
"mesh_terms": "D000368:Aged; D000964:Antimetabolites, Antineoplastic; D000971:Antineoplastic Combined Chemotherapy Protocols; D019540:Area Under Curve; D000069287:Capecitabine; D049109:Cell Proliferation; D002851:Chromatography, High Pressure Liquid; D015179:Colorectal Neoplasms; D003841:Deoxycytidine; D004347:Drug Interactions; D005260:Female; D005467:Floxuridine; D005472:Fluorouracil; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D054328:Proton Pump Inhibitors; D064750:Rabeprazole",
"nlm_unique_id": "7806519",
"other_id": null,
"pages": "1127-1135",
"pmc": null,
"pmid": "30972456",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Rabeprazole intake does not affect systemic exposure to capecitabine and its metabolites, 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine, and 5-fluorouracil.",
"title_normalized": "rabeprazole intake does not affect systemic exposure to capecitabine and its metabolites 5 deoxy 5 fluorocytidine 5 deoxy 5 fluorouridine and 5 fluorouracil"
} | [
{
"companynumb": "JP-ROCHE-2320051",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": "3",
"drug... |
{
"abstract": "The impact of SARS-CoV-2 infection in patients with autoimmune/auto-inflammatory rheumatic diseases (AARD) under immunomodulatory treatment has been a focus of interest during the COVID-19 pandemic. In this observational study, demographic data, disease related features and comorbidities, COVID-19 manifestations and outcome as well as antibody responses to SARS-CoV-2 were recorded among 77 consecutive patients with underlying AARD infected by SARS-CoV-2. Analysis of data was performed using univariate and multivariate models. Most patients (68.8%) had a mild COVID-19 course. The predominant clinical manifestations were fatigue (58.4%), low grade fever (45.4%) and upper respiratory tract symptoms (68.8%). About a quarter of patients required hospitalization (23.3%) and the mortality rate was 1.3%. Regarding COVID-19 severity, prior treatment with corticosteroids, mycophenolate mofetil or rituximab was more common in patients who developed a more serious disease course (60.0 vs 29.9%, p = 0.003, 40.0 vs 7.5%, p = 0.003, 10.0 vs 0.0%, p = 0.009, respectively). When disease related features and comorbidities were considered in multivariate models, older age and lung disease in the context of the AARD were found to be independent predictive factors for hospitalization (OR [95%]: 1.09 [1.03-1.15] and 6.43 [1.11-37.19]). Among COVID-19 related features, patients with shortness of breath and high-grade fever were more likely to get hospitalized (OR [95%]: 7.06 [1.36-36.57], 12.04 [2.96-48.86]), while anosmia was independently associated with lower hospitalization risk (OR [95%]: 0.09 [0.01-0.99]). Though the majority of AARD patients displayed a mild COVID-19 course, certain underlying disease features and COVID-19 related manifestations should prompt alertness for the physician to identify patients with AARD at high risk for severe COVID-19 and need for hospitalization.",
"affiliations": "Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.;Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; Department of Physiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; Institute for Autoimmune Systemic and Neurologic Diseases, Athens, Greece. Electronic address: kmauragan@med.uoa.gr.;Rheumatology Unit, Sismanoglio General Hospital, Athens, Greece.;Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; Institute for Autoimmune Systemic and Neurologic Diseases, Athens, Greece.;Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; Institute for Autoimmune Systemic and Neurologic Diseases, Athens, Greece.;Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.;Department of Nutrition and Clinical Dietetics, Harokopio University of Athens, Athens, Greece; Department of Medicine and Clinical Immunology, Euroclinic of Athens, Athens, Greece.;Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; Medical Sciences/Immunology, Academy of Athens, Athens, Greece.",
"authors": "Bakasis|Athanasios-Dimitrios|AD|;Mavragani|Clio P|CP|;Boki|Kyriaki A|KA|;Tzioufas|Athanasios G|AG|;Vlachoyiannopoulos|Panayiotis G|PG|;Stergiou|Ioanna E|IE|;Skopouli|Fotini N|FN|;Moutsopoulos|Haralampos M|HM|",
"chemical_list": "D000914:Antibodies, Viral; D007074:Immunoglobulin G; D007155:Immunologic Factors; D007166:Immunosuppressive Agents",
"country": "England",
"delete": false,
"doi": "10.1016/j.jaut.2021.102687",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0896-8411",
"issue": "123()",
"journal": "Journal of autoimmunity",
"keywords": "Autoimmunity; COVID-19; Immunosuppression; Rheumatic disease; SARS-CoV-2",
"medline_ta": "J Autoimmun",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000914:Antibodies, Viral; D058345:Asymptomatic Infections; D001327:Autoimmune Diseases; D000086382:COVID-19; D015897:Comorbidity; D003240:Connective Tissue Diseases; D016638:Critical Illness; D005260:Female; D006115:Greece; D006760:Hospitalization; D006801:Humans; D007037:Hypothyroidism; D016867:Immunocompromised Host; D007074:Immunoglobulin G; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D007249:Inflammation; D008171:Lung Diseases; D008297:Male; D008875:Middle Aged; D064887:Observational Studies as Topic; D012196:Review Literature as Topic; D012216:Rheumatic Diseases; D000086402:SARS-CoV-2; D012720:Severity of Illness Index; D063189:Symptom Assessment",
"nlm_unique_id": "8812164",
"other_id": null,
"pages": "102687",
"pmc": null,
"pmid": "34311142",
"pubdate": "2021-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "COVID-19 infection among autoimmune rheumatic disease patients: Data from an observational study and literature review.",
"title_normalized": "covid 19 infection among autoimmune rheumatic disease patients data from an observational study and literature review"
} | [
{
"companynumb": "GR-CELLTRION HEALTHCARE HUNGARY KFT-2021GR017308",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadd... |
{
"abstract": "Knowledge of the molecular basis of acute myeloid leukaemia has increased considerably in the past few years, and therapies targeting specific molecular defects of this disease are intensively investigated. Patients with both NPM1 and FLT3-ITD mutations encompass 20% of cytogenetically normal AML. The multikinase and FLT3 inhibitor, sorafenib, has shown some efficacy in patients with relapsed FLT3-ITD(+) AML. In addition, it is suggested that all-trans retinoic acid (ATRA) used in combination with chemotherapy has shown to improve outcome of patients harbouring NPM1 mutations. We report here the clinical course of three patients with refractory or relapsed FLT3-ITD(+) /NPM1(+) AML who achieved significant response upon sorafenib and ATRA combination.",
"affiliations": "Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Hôpital Purpan, Toulouse, France.",
"authors": "Guenounou|Sarah|S|;Delabesse|Eric|E|;Récher|Christian|C|",
"chemical_list": "C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D010671:Phenylurea Compounds; D000090243:Nucleophosmin; D009536:Niacinamide; D014212:Tretinoin; D000077157:Sorafenib; D051941:fms-Like Tyrosine Kinase 3",
"country": "England",
"delete": false,
"doi": "10.1111/ejh.12334",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-4441",
"issue": "93(6)",
"journal": "European journal of haematology",
"keywords": "Acute myeloid leukemia; FLT3-ITD mutation; NPM1 mutation; all trans retinoid acid; sorafenib; targeted therapy",
"medline_ta": "Eur J Haematol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009536:Niacinamide; D009687:Nuclear Proteins; D000090243:Nucleophosmin; D010671:Phenylurea Compounds; D000077157:Sorafenib; D016896:Treatment Outcome; D014212:Tretinoin; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3",
"nlm_unique_id": "8703985",
"other_id": null,
"pages": "533-6",
"pmc": null,
"pmid": "24689895",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Sorafenib plus all-trans retinoic acid for AML patients with FLT3-ITD and NPM1 mutations.",
"title_normalized": "sorafenib plus all trans retinoic acid for aml patients with flt3 itd and npm1 mutations"
} | [
{
"companynumb": "FR-MYLANLABS-2017M1054609",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nFetal arrhythmias characteristic of long QT syndrome (LQTS) include torsades de pointes (TdP) and/or 2° atrioventricular block, but sinus bradycardia, defined as fetal heart rate<3% for gestational age, is most common. We hypothesized that prenatal rhythm phenotype might predict LQTS genotype and facilitate improved risk stratification and management.\n\n\nRESULTS\nRecords of subjects exhibiting fetal LQTS arrhythmias were reviewed. Fetal echocardiograms, neonatal ECG, and genetic testing were evaluated. We studied 43 subjects exhibiting fetal LQTS arrhythmias: TdP±2° atrioventricular block (group 1, n=7), isolated 2° atrioventricular block (group 2, n=4), and sinus bradycardia (group 3, n=32). Mutations in known LQTS genes were found in 95% of subjects tested. SCN5A mutations occurred in 71% of group 1, whereas 91% of subjects with KCNQ1 mutations were in group 3. Small numbers of subjects with KCNH2 mutations (n=4) were scattered in all 3 groups. Age at presentation did not differ among groups, and most subjects (n=42) were live-born with gestational ages of 37.5±2.8 weeks (mean±SD). However, those with TdP were typically delivered earlier. Prenatal treatment in group 1 terminated (n=2) or improved (n=4) TdP. The neonatal heart rate-corrected QT interval (mean±SE) of group 1 (664.7±24.9) was longer than neonatal heart rate-corrected QT interval in both group 2 (491.2±27.6; P=0.004) and group 3 (483.1±13.7; P<0.001). Despite medical and pacemaker therapy, postnatal cardiac arrest (n=4) or sudden death (n=1) was common among subjects with fetal/neonatal TdP.\n\n\nCONCLUSIONS\nRhythm phenotypes of fetal LQTS have genotype-suggestive features that, along with heart rate-corrected QT interval duration, may risk stratify perinatal management.",
"affiliations": "Department of Pediatrics, Rosalind Franklin School of Medicine and Science, North Chicago, IL.",
"authors": "Cuneo|Bettina F|BF|;Etheridge|Susan P|SP|;Horigome|Hitoshi|H|;Sallee|Denver|D|;Moon-Grady|Anita|A|;Weng|Hsin-Yi|HY|;Ackerman|Michael J|MJ|;Benson|D Woodrow|DW|",
"chemical_list": "D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human",
"country": "United States",
"delete": false,
"doi": "10.1161/CIRCEP.113.000618",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1941-3084",
"issue": "6(5)",
"journal": "Circulation. Arrhythmia and electrophysiology",
"keywords": "arrhythmias, cardiac; atrioventricular block; fetal; long-QT syndrome; sinus bradycardia torsade de pointes",
"medline_ta": "Circ Arrhythm Electrophysiol",
"mesh_terms": "D054537:Atrioventricular Block; D001919:Bradycardia; D000072237:ERG1 Potassium Channel; D004452:Echocardiography; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D005820:Genetic Testing; D005838:Genotype; D006339:Heart Rate; D006801:Humans; D007231:Infant, Newborn; D051657:KCNQ1 Potassium Channel; D008133:Long QT Syndrome; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010641:Phenotype; D011247:Pregnancy; D011256:Pregnancy Outcome; D011296:Prenatal Diagnosis; D018570:Risk Assessment",
"nlm_unique_id": "101474365",
"other_id": null,
"pages": "946-51",
"pmc": null,
"pmid": "23995044",
"pubdate": "2013-10",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "11710892;19996378;11854117;19695463;19731233;14676229;12767447;23124029;7484750;19808432;16432067;9742063;10716483;14998624;9495298;23388215;10419620;22064211;15840476;8521555;15051644;22370247;1884444;17210839",
"title": "Arrhythmia phenotype during fetal life suggests long-QT syndrome genotype: risk stratification of perinatal long-QT syndrome.",
"title_normalized": "arrhythmia phenotype during fetal life suggests long qt syndrome genotype risk stratification of perinatal long qt syndrome"
} | [
{
"companynumb": "US-ROXANE LABORATORIES, INC.-2014-BI-50803GD",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MEXILETINE"
},
"drugadditi... |
{
"abstract": "We evaluated pomalidomide with prednisone for myelofibrosis (MF) with significant anemia (hemoglobin < 10 g/dL). Patients (n = 29; 18 RBC-transfusion dependent) received 0.5mg pomalidomide daily in continuous 28-day cycles with prednisone given for the first 3 cycles only. Six (21%) patients responded (median response duration 11.4 months), including four who achieved RBC-transfusion-independence per the Delphi criteria and two who achieved clinical improvement (in platelets and spleen, respectively) per the International Working Group for Myelofibrosis Research and Treatment criteria. Grade 3 toxicity occurred in 1 patient (fatigue). Pomalidomide with prednisone is safe therapy with modest activity in patients with MF and anemia. ClinicalTrials.gov Identifier: NCT00946270.",
"affiliations": "Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 428, Houston, TX 77030, USA.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 428, Houston, TX 77030, USA.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 428, Houston, TX 77030, USA.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 428, Houston, TX 77030, USA.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 428, Houston, TX 77030, USA.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 428, Houston, TX 77030, USA.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 428, Houston, TX 77030, USA.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 428, Houston, TX 77030, USA.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 428, Houston, TX 77030, USA.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 428, Houston, TX 77030, USA.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 428, Houston, TX 77030, USA. Electronic address: sverstov@mdanderson.org.",
"authors": "Daver|Naval|N|;Shastri|Aditi|A|;Kadia|Tapan|T|;Newberry|Kate|K|;Pemmaraju|Naveen|N|;Jabbour|Elias|E|;Zhou|Linghsa|L|;Pierce|Sherry|S|;Cortes|Jorge|J|;Kantarjian|Hagop|H|;Verstovsek|Srdan|S|",
"chemical_list": "D013792:Thalidomide; C467566:pomalidomide; D011241:Prednisone",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0145-2126",
"issue": "38(9)",
"journal": "Leukemia research",
"keywords": "Anemia; Myelofibrosis; Pomalidomide",
"medline_ta": "Leuk Res",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011241:Prednisone; D055728:Primary Myelofibrosis; D016019:Survival Analysis; D013792:Thalidomide; D016896:Treatment Outcome",
"nlm_unique_id": "7706787",
"other_id": null,
"pages": "1126-9",
"pmc": null,
"pmid": "25047979",
"pubdate": "2014-09",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "19366369;20843246;18988864;19720904;12517815;17123268;16675707;19652059;20052748;21052089;20692036;15953003;23071245;23890523;15190515;22375971;16609064;12903007;22081489;16583431;14752066",
"title": "Phase II study of pomalidomide in combination with prednisone in patients with myelofibrosis and significant anemia.",
"title_normalized": "phase ii study of pomalidomide in combination with prednisone in patients with myelofibrosis and significant anemia"
} | [
{
"companynumb": "US-CELGENEUS-163-C4047-13042859",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "POMALIDOMIDE"
},
"drugadditional": nul... |
{
"abstract": "Chronic daily headache is a group of headache syndromes including most commonly chronic migraine and chronic tension-type headache, which often overlap, are complicated by medication overuse and are disabling, costly, and variable responsive to western pharmacotherapeutic interventions. There is growing research and awareness of integrative health approaches and therapies to address patients with chronic headache, yet limited examples of how to deliver this approach. This article reviews a commonly seen challenging case of a patient with overlapping chronic migraine and chronic tension-type headache complicated by medication overuse managed with an integrative east-west medicine intervention. This included person-centered biopsychosocial history taking, traditional Chinese medicine informed acupuncture, trigger point injections, and contributing factors modifications. A narrative review of the literature is presented to demonstrate an evidence-informed rationale for incorporating nonpharmacologic approaches to effectively help reduce the symptom burden of this patient population.",
"affiliations": "UCLA Center for East-West Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.;UCLA Center for East-West Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.;UCLA Center for East-West Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.",
"authors": "Laube|Justin G|JG|https://orcid.org/0000-0002-1483-0609;Salles Araujo|Thais|T|;Taw|Lawrence B|LB|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/2164956120905817",
"fulltext": "\n==== Front\nGlob Adv Health MedGlob Adv Health MedGAMspgamGlobal Advances in Health and Medicine2164-957X2164-9561SAGE Publications Sage CA: Los Angeles, CA 10.1177/216495612090581710.1177_2164956120905817Feature ArticleIntegrative East–West Medicine Intervention for Chronic Daily\nHeadache: A Case Report and Care Perspective https://orcid.org/0000-0002-1483-0609Laube Justin G MD12Salles Araujo Thais MD1Taw Lawrence B MD, FACP12\n1 UCLA Center for East-West Medicine, Department of Medicine, David\nGeffen School of Medicine at UCLA, Los Angeles, California\n2 Division of General Internal Medicine and Health Service Research,\nDepartment of Medicine, University of California, Los Angeles, Los Angeles,\nCaliforniaJustin G Laube, University of California,\nLos Angeles, 2336 Santa Monica Boulevard, Suite 301, Los Angeles, CA 90404, USA.\nEmail: jlaube@mednet.ucla.edu13 2 2020 2020 9 216495612090581729 10 2019 20 1 2020 © The Author(s) 20202020Academic Consortium for Integrative\nMedicine & Health, unless otherwise noted. Manuscript content on this site\nis licensed under Creative Commons LicensesCreative Commons Non Commercial CC BY-NC: This article is distributed\nunder the terms of the Creative Commons Attribution-NonCommercial 4.0\nLicense (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 pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Chronic daily headache is a group of headache syndromes including most commonly\nchronic migraine and chronic tension-type headache, which often overlap, are\ncomplicated by medication overuse and are disabling, costly, and variable\nresponsive to western pharmacotherapeutic interventions. There is growing\nresearch and awareness of integrative health approaches and therapies to address\npatients with chronic headache, yet limited examples of how to deliver this\napproach. This article reviews a commonly seen challenging case of a patient\nwith overlapping chronic migraine and chronic tension-type headache complicated\nby medication overuse managed with an integrative east–west medicine\nintervention. This included person-centered biopsychosocial history taking,\ntraditional Chinese medicine informed acupuncture, trigger point injections, and\ncontributing factors modifications. A narrative review of the literature is\npresented to demonstrate an evidence-informed rationale for incorporating\nnonpharmacologic approaches to effectively help reduce the symptom burden of\nthis patient population.\n\nchronic daily headacheintegrative medicinemigraineacupuncturetrigger pointcover-dateJanuary-December 2020typesetterts2\n==== Body\nIntroduction\nChronic daily headache (CDH) is a group of headache syndromes characterized by\nheadache symptoms ≥15 days per month over at least 3 months.1 The prevalence of CDH is estimated to be ∼4% of the US adult population.2 The 2 most common subtypes are chronic migraine (CM) and chronic tension-type\nheadache (CTTH), estimated to be ∼58% and 40% of CDH patients, respectively.3 CDH contributes significantly to patients’ overall disability, impaired\nquality of life, and higher health-care resource utilization compared to less\nfrequent headache syndromes.4 CM is particularly insidious; the WHO ranked CM among the top 5 conditions\ncontributing to disability worldwide.5 Determining treatment plans for CDH patients is complicated due to the\nconsiderable overlap between CM and CTTH in regards to symptoms and their medication\noveruse patterns. In patient surveys, 58% of migraine patients reported tension-type\nsymptoms and 68% of tension-headache patients reported migraine-type symptoms.6 CDH patients also commonly overuse acute headache medications. At least\ntwo-thirds of CDH patients report that they have used abortive medications ≥14 days\nper month and meet criteria for a dual diagnosis of medication overuse headache (MOH).7,8 Despite a variety of oral pharmacologic therapies used for the prophylaxis of\nCDH, many patients continue to suffer with unacceptable symptom burden and\ndisability.1,9\n\nThere is an inherent tension between the dominant conventional biomedical model that\nemphasizes a specific reductionist diagnosis and pharmacologic therapies and\npatients with chronic headaches that do not fall neatly into this paradigm. Many\npatients with CDH are dissatisfied with a purely pharmacotherapy-based approach and\nseek complementary and alternative medicine (CAM) therapies to combine with their\ncare. One large online survey of chronic migraineurs found that only 30% were\nsatisfied or very satisfied with their medical treatment for their migraines, and\n75% reported that they incorporated nonpharmacological therapies “most of the time”\nor “always” into their migraine care.10 The rates of CAM use by headache sufferers are reported to be as high as 50%\nin primary care and ∼80% in tertiary care headache clinics and suggest the desire\nfor more holistic treatment options.11 We present a patient case with refractory CDHs, specifically, intermittent\nmigraines without aura, daily tension-type headaches, and medication overuse. The\npatient’s symptoms were successfully managed through a person-centered, integrative\neast–west medicine approach which incorporates an integrative medical health history\nand assessment both from traditional Chinese medicine (TCM) and western biomedical\nmodel. The individualized treatment methods included acupuncture, trigger point\ninjections (TPIs), lifestyle modifications, and self-care prescriptions to modify\nrisk factors for perpetuating headache symptoms.12 This case demonstrates the potential value of a multimodality, integrative\nmedicine, CAM, and patient empowering approach to help complex CDH patients.\n\nCase Presentation\nPresenting Concerns\nA 61-year-old male business executive with a medical history of anxiety and\nobstructive sleep apnea (OSA) presented to our integrative medicine consultative\nclinic with a chief complaint of CDHs. He recalls having headaches since\nchildhood, and both his mother and sister had CMs. He described his headaches as\na “tension” sensation radiating from his shoulders and base of the skull to his\neyes bilaterally that was worse in the afternoon and upon awakening. His\nsymptoms improved with massage therapy and avoidance of work-related stress. A\nminimum of 3 times per week, his headaches worsened and were accompanied by\nmigrainous symptoms of unilateral blurry vision, nausea, vomiting, photophobia,\nand scalp/shoulder touch sensitivity that would last for 3 to 12 hours. His\nmigraines were precipitated by alcohol intake and changes in the temperature. He\ndenied any persistent visual changes, hearing loss, numbness, or weakness.\n\nHe was previously evaluated by a neurologist and a brain magnetic resonance\nimaging was unremarkable. He tried daily propranolol and amitriptyline for\n3 months each, but did not notice a change in his symptom burden and was\nintolerant of the central nervous system side effects. He had been managed\nprimarily by his primary care physician (PCP) for >10 years through\nprescriptions of oxycodone-acetaminophen and sumatriptan (average 12 and 9\ntablets each month, respectively) which he used together to treat each migraine\nheadache. He also used an acetaminophen–aspirin–caffeine (Excedrin) combination\npill to address his tension-type headache symptoms an average of 12 tablets per\nmonth.\n\nClinical Findings and Integrative Diagnosis\nA biopsychosocial history was obtained, and he reported frequent and chronic\nstress from his work and often felt pervasive anxious thoughts. He slept poorly\nand sparingly used his continuous positive airway pressure (CPAP) because of\nmask fitting issues. He had significant daytime sleepiness and attempted to\nmanage this through prescription stimulants (modafinil, prescribed by his PCP)\nand consumed 4 to 5 cups of coffee per day. He spent the majority of his day at\nhis desk and typing on his computer. He felt easily irritable and had a\npropensity to have outbursts of anger. He ate large amounts of red meat with\nlimited fruit and vegetable intake. He had the habit of eating in a hurry at his\nwork desk or during lunch meetings.\n\nOn examination, he was obese, with a body mass index of 30 kg/m2. He\nexhibited a head forward posture, limited neck range of motion, and exquisite\nsensitivity to the upper trapezius muscles and base of occiput with palpation,\nwhich radiated to his temples and orbit. His neurologic examination was\nunremarkable. According to TCM examination, his tongue was slightly red around\nthe edges, without coating and the pulse bilaterally wiry.\n\nHis east–west integrative assessment and diagnosis includes CDH that is an\noverlap of CM and CTTH with MOH, and TCM pattern diagnosis of liver yang rising\nwith liver yin deficiency. Contributing factors likely include cervical\npredominant myofascial pain, unmanaged OSA, chronic over work, and psychological\nstress (Table\n1).\n\nTable 1. Therapeutic Plan.\n\nDiagnosis and Factors\tTreatments and Medical Care\tSelf-Care/Lifestyle Homework\t\n • Chronic daily headache • Chronic migraine • Chronic\ntension-type headache • Medication overuse headache • TCM\ndiagnosis—liver yang rising with liver yin deficiency\t • Acupuncture • Trigger point injections • Referral for\nsleep specialist for CPAP mask re-fitting • Recommendation\nto reduce opiate and Excedrin use\t • Neck stretching\nroutine • Self—acupressure/massage • Transcutaneous\nelectrical nerve stimulator • Mindfulness guided MP3s • Diet\nmodification with increased fruits and vegetables intake and\nreduction of red meat and coffee\t\nContributing factors: • Chronic stress • Sedentary\nlifestyle • Obesity • OSA unmanaged • Low intake of fruits\nand vegetables • Stimulant overuse\t\t\t\nAbbreviations: CPAP, continuous positive airway pressure; OSA,\nobstructive sleep apnea; TCM, traditional Chinese medicine.\n\nTherapeutic Focus and Assessment\nA treatment plan was created with a goal to reduce his headache symptom burden\nand overall disability (Table 1). He was seen every 2 weeks for a total of 5 visits. Each\nvisit included an acupuncture treatment session that lasted for 25 minutes of\nneedle time. This was preceded by atleast 15 minutes of a medical visit to\nreview his progress and care plan, and TPIs with 25-gauge × ½ in. needle with\n0.2 mL of 1% lidocaine to each active trigger point noted on the initial\nexamination. This was performed with the patient in a seated position and into\nhis bilateral trapezius, rhomboid, and suboccipital musculature (total of 6\ninjections per session—Figure\n1). Both procedures were performed by a licensed integrative medicine\nphysician trained in internal medicine and certified to provide acupuncture\nthrough a physician fellowship (>200 h of acupuncture clinical training).\nAcupuncture points for each session included Yintang, Du-20, and bilateral\nplacement at Lv-3, LI-4, LI-10, ST-36, GB-34, SP-6, KI-3, and SJ-3. Acupuncture\nwas performed using 34-gauge needle, without attention to the De Qi sensation to\na depth of 0.2 to 1 cm, retained without further manual or electrical\nstimulation (Figure 1).\nPoint selection was based on TCM pattern diagnosis and common points utilized\nfor headache from the medical literature and our clinical experience.13\n\nFigure 1. Acupoint and TPI Locations. TPI locations: a, sub-occipital; b,\ntrapezius; c, rhomboid. Acupoint locations: 1, Du-20; 2, Yintang; 3,\nLI-10; 4, LI-4; 5, SJ-3; 6, GB-34; 7, ST-36; 8, SP-6; 9, LV-3.\n\nSelf-care plan\nThe patient was given a homework prescription of alternating between applying\nself-acupressure and an over-the-counter transcutaneous electrical nerve\nstimulator (TENS) to acupoints LI-4, SJ-3, GB-20, and GB-21 (Figure 2) for 15 to\n20 minutes twice daily to help address head and neck pain (Table 1). He was\nadvised to follow a generic neck and shoulder stretch routine handout for 10\nto 15 minutes twice daily (build from the website hep2go.com). Given his\nanxiety and high subjective stress, we utilized a motivational interviewing\napproach to explore potential mind–body interventions to improve his stress\nmastery, and he decided on a goal to regularly walk outdoors while listening\nto the free guided mindfulness mp3 file from our affiliated UCLA Mindful\nAwareness Reseach Center (see https://www.uclahealth.org/marc/mindful-meditations). He was\nadvised to reduce alcohol and caffeine use, increase his intake of\nvegetables with a goal of weight loss, to take frequent stretch breaks from\nhis computer at work, and eat lunch mindfully. A referral was placed to\nfollow-up with his sleep team to discuss his CPAP mask fitting issues.\n\nFigure 2. Acupressure Self-Care Handout.\n\nFollow-up and Outcomes\nShort term\nOver the following 2 weeks after his initial visit and treatment, he had no\nmigraine headaches and did not require any medications for headache (Table 2). He had a\nstable reduction of his tension-type headache frequency and severity at each\nsubsequent visit. By his third visit, his tension-type headache frequency\nhad reduced to twice per week and migraine headache occurred once every\n2 weeks. He reported the overall headache severity was characterized as\n“mild.” After the initial follow-up, he reported using oxycodone a maximum\nof ½ tablet per week and was not using any other abortive medications. He\nreported feeling an overall improvement in his quality of life and feeling\nof more control of his headache symptoms. During his treatment, he reported\nbeing adherent to the dietary recommendations, acupressure/self-massage,\nTENS unit use, stretching, and beach walking meditation activities more than\n5 days per week.\n\nNo adverse effects were noted during or after his needle-based treatments or\nself-care homework.\n\nLong term\nAt 3 months after his last treatment visit, he continued to have a more\nmanageable headache symptom burden with mild tension-type headaches 2 days\nper week (Table\n2). These headaches would progress to a migraine headache a\nmaximum of once every 2 weeks. He continued to walk outside regularly and\nmeditate daily. He had seen his pulmonologist and was treated for allergic\nrhinitis to improve his CPAP tolerance and was using the machine nightly.\nPatient reported being able to function in a higher level at work with a\nrelatively small amount of analgesics along with stretching, TENS use, and\nwalking meditation.\n\nTable 2. Summary of the Patient’s Treatment Course and Improvements Noted Over\nTime.\n\n\tInitial Consult\t2 Weeks\t4 Weeks\t6 Weeks\t8 Weeks\t5 Months\t\nAcupuncture\tX\tX\tX\tX\tX\tNA\t\nTPI\tX\tX\tX\tX\tX\tNA\t\nAssessment of self-care/lifestyle changes\tX\tX\tX\tX\tX\tX\t\nOxycodone use\t3×/week\t0\t½ tablet every other week\t½ tablet every other week\t½ tablet every other week\t½ tablet every other week\t\nSumatriptan use\t2×/week\t0\t0\t0\t0\t0\t\nAcetaminophen–aspirin–caffeine use\t3×/week\t0\t0\t0\t0\t0\t\nMigraine HA episodes\t3×/week\t0\t1× every other week\t1× every other week\t1× every other week\t1× every other week\t\nTension HA episodes\tDaily\t2×/week\t2×/week\t2×/week\t2×/week\t2×/week\t\nAbbreviations: HA, headache; TPI, trigger point injection.\n\nCase Discussion and Care Perspective\nThis case study shows the potential benefits of using a person-centered, integrative\neast–west medicine approach to reduce the symptom burden, and debility for patients\nwith CDH. The patient presented with a lifelong burden of daily intractable\nheadaches. He met the International Classification of Headache Disorders (ICHD)\ncriteria for the diagnosis of CM without aura and MOH, yet as is commonly found, the\ndiagnosis did not tell the full story.14 He also had multiple modifiable perpetuating behavioral risk factors and\nactive myofascial trigger points.\n\nFrom our clinical experience, these are commonly missed or overlooked features on\nhistory and physical examinations by neurologists and PCPs. Recognition of these\nrisk factors could be used to create customized treatment plans to help patients\nmodify behavioral factors that may be contributing to their headache syndrome\nchronicity and perpetuation. This patient was found to have unmanaged OSA with\nsevere daytime sleepiness and morning headaches. Unfortunately, this was primarily\naddressed at a symptom level with prescription stimulants and patient administered\nhigh doses of caffeine. Patients with CDH are more likely to be habitual snorers and\nhave more morning headaches compared to episodic headache suffers.15 High caffeine use is also associated with an increased risk of developing CDH\ncompared to episodic headache controls.16 The patient is also obese, which is a modifiable risk factor for progression\nof migraine, and is also associated with an increased frequency and intensity of\nmigraine symptoms.17 A review from 2008 emphasized the link between obesity and CDH and encouraged\nweight loss intervention for overweight patients with chronic headaches including\nbehavioral nutritional education, dietary intervention, and exercise counseling.18\n\nFrom a TCM viewpoint, the patient fits into the pattern diagnosis of liver yang\nrising which is an imbalance of liver yin (deficient) and liver yang (in excess)\nleading to a relative rise of liver yang. Simplified, this would be a relative\nexcess of heat in the body. It is the most common pattern diagnosis for chronic\nheadaches13,19 and according to TCM theory has a root cause in emotional\ndistress over long periods of time, specially anger, frustration, and resentment.20 Eating meals while working and in a hurry can also contribute as causing this\npattern, as well as poor sleep, and stimulant medications. The principle of TCM\ntreatment is to nourish yin and quieten liver yang. In this case, the stress\nmanagement tools and eating habits modification in a TCM perspective were treating\nthe root cause of his liver yang rising, together with the acupuncture\ntreatments.\n\nOur patient struggled with significant psychological stress, anger, and poor coping\nwhich were triggers for his headache symptoms. He implemented a regular meditation\nprogram that he felt was supportive of his treatments in clinic. Mind–body\napproaches for CM and CTTH have been increasingly studied and supported,\nspecifically cognitive behavioral therapy, stress management training, and\nbiofeedback.21,22 The efficacy of these approaches may be because many CDH\npatients also suffer from psychiatric comorbid diagnoses including anxiety,\ndepression, and posttraumatic stress disorder, and mind–body interventions commonly\nfocus on reducing the effects of stress and reduce central nervous system reactivity.23\n\nMany of our patients with chronic stress and headaches are found to have a head\nforward posture and exhibit multiple palpable myofascial trigger points. We utilized\nTPIs with this patient because they are a safe and effective adjunctive treatment\nfor tension-type and migraine headache to address the myofascial pain syndrome content.24 Active myofascial trigger points and cutaneous nociceptive units contribute\nto the symptom burden of both CM and CTTH. Two contributing factors are forward head\nposture and reduced neck mobility, which put excessive strain on the neck\nmusculature and are strongly associated with CM and CTTH.25,26 Multiple studies have\ndemonstrated a benefit with treatment of trigger points using lidocaine and other\nsimilar anesthetizing injections to the active myofascial trigger points for both CM\nand CTTH patients.27–29\n\nFor our patient, we combined TPIs along with acupuncture at each visit. Acupuncture\nis the most evidence supported CAM therapy for chronic headache. A Cochrane\nmeta-analysis in 2009 investigating the use of acupuncture for migraine prophylaxis\nconcluded acupuncture “is at least as effective as, or possibly more effective, than\nprophylactic drug treatment, and has fewer adverse effects.”30 In the same issue, a companion review concluded acupuncture could be a\nvaluable option to treat frequent episodic or chronic TTH.31 Acupuncture is one cost-effective, low-risk intervention that shows many\npotential benefits to CDH patients and is underutilized by many allopathic\npractitioners and patients.10,32\n\nAside from passively received needle treatments, there is evidence for noninvasive\ntherapies to address dysfunctional posture and myofascial contributions to headache\nand can be performed independently by patients. A 2017 review from Neurology\nencouraged utilizing a multidisciplinary team approach to manage CDH including\noccupational and physical therapists teaching patients self-management tools such as\nfocusing on postural awareness, stretching, supportive exercises, and body mechanics.33 In addition, a Cochrane review found some evidence of benefit from randomized\ncontrolled trials investigating the use of TENS for CM, and a combination of TENS,\nself-massage, and stretching for CTTH. Although the evidence was “weak,” there was\nlittle risk of serious adverse effects.34 Our clinical experience with CDH patients is they are often receptive to\nreceiving self-care homework.\n\nPrior to our first visit, the patient’s care included a purely pharmacologic approach\nthat included primarily abortive medications. This likely contributed to our patient\ndeveloping CDH. An estimated 3% to 14% of episodic migraine patients that frequently\nuse acute headache medication will transform to CM.1 The risk is highest with regular use of opioid (odds ratio [OR], 1.4) and\nbutalbital combination (OR, 1.73) medications compared to triptans (OR, 1.07), and\nnonsteroidal anti-inflammatory drugs (OR, 0.97).9 Opiate class medications have previously been overly prescribed for recurrent\nheadache, and newer recommendations from the Centers for Disease Control, the\nneurology community and the American Board of Internal Medicine strongly argue that\nfor most patients, the risks of opiates outweigh the benefits for treating acute and\nchronic headache syndromes.35,36 Botox or the newest pharmacological approach for chronic\nheadaches could have also been considered in this patient. Erenumab is the first\ndrug of this new class called calcitonin gene-related peptide inhibitors approved by\nthe U.S. Food and Drug Administration as a preventive treatment option for patients\nwith episodic or CM.37 The limiting aspects are the high cost, need for chronic use, and the unknown\nlong-term effects, since it has only been tested in short trials of 12 to 24 weeks.38\n\nIt is unclear as to which part or parts of the intervention account for his rapid\nimprovement. This could include, for example, effects from the physical treatments,\nplacebo, nonspecific therapeutic effects (therapeutic setting, provider–patient\nrelationship), homework activities, and lifestyle modifications. In our clinical\nopinion, this is a tolerable limitation in order to create effective personalized\ntherapies for an often-incurable complex chronic medical syndrome.\n\nFinal Thoughts\nIt takes patience, inquisitiveness, and sufficient clinical visit time to conduct a\nthorough history that includes both medical investigation and exploration into the\nmultiple potential contributing factors to CDH patients’ debility.\n\nGiven the complex medical, personal, and lifestyle issues at play in many CDH\npatients who have suffered long-term limiting symptoms, we advocate for exploring\nmore integrative approaches. This favors CAM and nonpharmacologic options to be used\nconcurrently with the lowest risk, low cost, and most evidence supported mainstream\npharmacologic treatments and therapies.39 Eastern philosophies, specifically TCM, are holistically oriented and have\nsimilar goals to support a patient’s inherent healing capacities.13 In addition to the proven needle effects, repeated acupuncture procedure\nvisits provide the opportunity to build a therapeutic relationship, support\nlifestyle changes, and encourage self-care practices.13 TPIs are a low risk and effective needle-based intervention that could easily\nbe used along with an integrative approach in a primary care setting.\n\nWe advocate for further research into the clinical application of integrative,\ncomprehensive, multidisciplinary approaches in the routine, and compassionate care\nof CDH patients.\n\nDeclaration of Conflicting Interests\nThe author(s) declared no potential conflicts of interest with respect to the\nresearch, authorship, and/or publication of this article.\n\nFunding\nThe author(s) received no financial support for the research, authorship, and/or\npublication of this article.\n\nORCID iD\nJustin G Laube https://orcid.org/0000-0002-1483-0609\n==== Refs\nReferences\n1 Sheikh HU. \nApproach to chronic daily headache. \nCurr Neurol Neurosci Rep . 2015 ;\n15 :4 .25637288 \n2 Garza I Schwedt T. \nDiagnosis and management of CDH . Semin\nNeurol . 2010 ;\n30 (2 ):154 –166 .20352585 \n3 Cha MJ Moon HS Sun JH et al\nChronic daily headache and\nmedication overuse headache in first-visit headache patients in Korea: a\nmulticenter clinic-based study. \nJ Clin Neurol . 2016 ;\n12 (3 ):316 –322 .27449912 \n4 Blumenfeld AM Varon SF Wilcox TK et al\nDisability, HRQoL and resource\nuse among chronic and episodic migraineurs: results from the International\nBurden of Migraine Study (IBMS). \nCephalalgia . 2011 ;\n31 (3 ):301 –315 .20813784 \n5 Mathers C Fat DM Boerma JT. \nThe Global Burden of Disease: 2004 Update .\nGeneva, Switzerland : World\nHealth Organization , 2008 .\n6 Turkdogan D Cagirici S Soylemez D et al\nCharacteristics and\noverlapping features of migraine and TTH .\nHeadache . 2006 ;\n46 :461 –468 .16618264 \n7 Yancey JR Sheridan R Koren KG. \nChronic daily headache: diagnosis and management .\nAm Fam Physician . 2014 ;\n15 :89(8 ):642 –648 .\n8 Silberstein SD Blumenfeld AM Cady RK et al\nOnabotulinumtoxinA for\ntreatment of chronic migraine: PREEMPT 24-week pooled subgroup analysis of\npatients who had acute headache medication overuse at\nbaseline. \nJ Neurol Sci . 2013 ;\n15:331 (1–2 ):48 –56 .\n9 Ahmed F Parthasarathy R Khalil M. \nChronic daily headache . Ann Indian Acad\nNeurol . 2012 ; 15 (Suppl\n1 ):S40 –S50 .23024563 \n10 Wachholtz A Malone C Bhowmick A. \nThe chronic migraineur and health services: national survey\nresults . J Pain Manag Med .\n2015 ;\n1 (1 ):103 .26807447 \n11 Adams J Barbery G Lui CW. \nComplementary and alternative medicine use for headache and\nmigraine: a critical review of the literature. \nHeadache . 2013 ;\n53 (3 ):459 –473 .23078346 \n12 Pritzker S Katz M Hui KK. \nPerson-centered medicine at the intersection of East and\nWest . Eur J Pers Cent Healthc .\n2012 ;\n1 (1 ):209 –215 .\n13 Schiapparelli P Allais G Rolando S et al\nAcupuncture in primary\nheadache treatment. \nNeurol Sci . 2011 ; 32 \nSuppl 1 :S15 –S18 .21533705 \n14 Headache Classification Committee\nof the International Headache Society . The\nInternational Classification of Headache Disorders, 3rd edition (beta\nversion) . Cephalalgia . 2013 ;\n33 (9 ):629 –808 .23771276 \n15 Stark CD Stark RJ. \nSleep and chronic daily headache. \nCurr Pain Headache Rep . 2015 ;\n19 :468 .25416461 \n16 Scher AI Stewart WF Lipton RB. \nCaffeine as a risk factor for chronic daily headache: a\npopulation-based study. \nNeurology . 2004 ;\n63 (11 ):2022 –2027 15596744 \n17 Bigal ME Rapoport AM. \nObesity and chronic daily headache. \nCurr Pain Headache Rep . 2012 ;\n16 (1 ):101 –109 .22076673 \n18 Nicholson R Bigal M. \nScreening and behavioral management: obesity and weight\nmanagement. \nHeadache . 2008 ;\n48 (1 ):51 –57 .18184286 \n19 Böwing G Zhou J Endres HG Coeytaux RR Diener HC Molsberger AF. \nDifferences in Chinese diagnoses for migraine and tension-type\nheadache: an analysis of the German acupuncture trials (GERAC) for\nheadache. \nCephalalgia . 2010 ;\n30 (2 ):224 –232 .19614709 \n20 Maciocia G. \nThe Foundations of Chinese Medicine, A Comprehensive Text for\nAcupuncturists and Herbalists . London,\nEngland : Churchill\nLivingstone ; 2005 .\n21 Sierpina V Astin J Giordano J. \nMind-body therapies for headache. \nAm Fam Physician . 2007 ;\n76 :1518 –1524 .18052018 \n22 Nicholson R Buse DC Andrasik F et al\nNonpharmacologic treatments\nfor migraine and tension-type headache: how to choose and when to\nuse. \nCurr Treat Options Neurol . 2011 ;\n13 (1 ):28 –40 .21080124 \n23 Smitherman TA Black AK Davis CN. \nTreatment of PTSD and chronic daily headache. \nCurr Treat Options Neurol . 2014 ;\n16 (10 ):312 .25129572 \n24 Robbins MS Kuruvilla D Blumenfeld A et al\nTrigger point injections for\nheadache disorders: expert consensus methodology and narrative\nreview. \nHeadache . 2014 ;\n54 (9 ):1441 –1459 .25168295 \n25 Fernández-de-las-Peñas C Cuadrado ML Pareja JA. \nMyofascial trigger points, neck mobility and forward head posture\nin unilateral migraine. \nCephalalgia . 2006 ;\n26 :1061 –1070 .16919056 \n26 Fernández-de-las-Peñas C Cuadrado ML Pareja JA et al\nTrigger points in the\nsuboccipital muscles and forward head posture in tension-type\nheadache. \nHeadache . 2006 ;\n46 :454 –460 .16618263 \n27 Karadaş O Gül HL İnan LE. \nLidocaine injection of pericranial myofascial trigger points in\nthe treatment of frequent episodic tension-type headache. \nJ Headache Pain . 2013 ;\n14 :44 .23698019 \n28 Alonso-Blanco C De-la-Llave-Rincón AI , Fernándezde-las-Peñas C. Muscle trigger point\ntherapy in tension-type headache. \nExpert Rev Neurother . 2014 ;\n12 (3 ):315 –322 .\n29 García-Leiva JM Hidalgo J Rico-Villademoros F et al\nEffectiveness of ropivacaine\ntrigger points inactivation in the prophylactic management of patients with\nsevere migraine. \nPain Med . 2007 ;\n8 (1 ):65 –70 .17244105 \n30 Linde K Allais G Brinkhaus B et al\nAcupuncture for migraine\nprophylaxis. \nCochrane Database Syst Rev . 2009 ;\n21 (1 ):CD001218 .\n31 Linde K Allais G Brinkhaus B et al\nAcupuncture for the prevention\nof tension-type headache . Cochrane Database Syst\nRev . 2016;(4).\n32 Wonderling D Vickers AJ Grieve R et al\nCost effectiveness analysis of\na randomized trial of acupuncture for chronic headache in primary\ncare. \nBMJ . 2004 ;\n328 (7442 ):747 .15023830 \n33 Sahai-Srivastava S Sigman E Uyeshiro Simon A et al\nMultidisciplinary team\ntreatment approaches to chronic daily headaches. \nHeadache . 2017 ;\n57 (9 ):1482 –1491 .28742242 \n34 Brønfort G Nilsson N Haas M et al\nNon-invasive physical\ntreatments for chronic/recurrent headache . Cochrane\nDatabase Syst Rev .\n2004 ;(3 ):CD001878 .\n35 Dowell D Haegerich TM Chou R. \nCDC guideline for prescribing opioids for chronic pain—United\nStates, 2016. \nMMWR Recomm Rep . 2016 ;\n65 (1 ):1 –49 .\n36 Loder E Weizenbaum E Frishberg B et al\nChoosing wisely in headache\nmedicine: The American Headache Society’s list of five things physicians and\npatients should question. \nHeadache . 2013 ;\n53 :1651 –1659 .24266337 \n37 Lipton R Tepper S Reuter U et al (2019 ). Erenumab\nin chronic migraine . Neurology .\n92 (19 ):e2250 –e2260 .30996060 \n38 ICER Staff and\nConsultants . Calcitonin gene-related peptide (CGRP) inhibitors as\npreventive treatments for patients with episodic or chronic migraine:\neffectiveness and value. Evidence report. [online] Institute for Clinical and\nEconomic Review. https://icer-review.org/wp-content/uploads/2017/11/ICER_Migraine_Evidence_Report_053118.pdf.\nPublished 2018. Accessed October 27, 2019.\n39 Rosenthal B Lisi AJ. \nA qualitative analysis of various definitions of integrative\nmedicine and health. \nTop Integr Health Care . 2014 ;\n5 (4 ):9 .\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2164-9561",
"issue": "9()",
"journal": "Global advances in health and medicine",
"keywords": "acupuncture; chronic daily headache; integrative medicine; migraine; trigger point",
"medline_ta": "Glob Adv Health Med",
"mesh_terms": null,
"nlm_unique_id": "101584936",
"other_id": null,
"pages": "2164956120905817",
"pmc": null,
"pmid": "32110474",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "20813784;19160193;22364330;23078346;24784123;23024563;27092807;15266458;26807447;16618263;23771276;15023830;25129572;25416461;22076673;23790235;23698019;18184286;21080124;20352585;24266337;16618264;25637288;19614709;26987082;21533705;15596744;30996060;17244105;25168295;18052018;16919056;27449912;28742242",
"title": "Integrative East-West Medicine Intervention for Chronic Daily Headache: A Case Report and Care Perspective.",
"title_normalized": "integrative east west medicine intervention for chronic daily headache a case report and care perspective"
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"activesubstance": {
"activesubstancename": "PROPRANOLOL HYDROCHLORIDE"
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"abstract": "Calcineurin and mTOR inhibitors are commonly used immunosuppressive agents with narrow therapeutic range. As the drugs are mainly metabolized by the P450 cytochrome system, the interaction between food and herbs are also commonly seen and affect the drug levels. We present a case of a kidney transplant recipient with toxic therapeutic levels of cyclosporine A and sirolimus due to interaction between the immunosuppressive agents and Chinese herbal tea. Ingredients within the herbal tea were reported to have inhibitory effect on cytochrome CYP3A4 in-vitro studies. Transplant recipients should be alert that there may be potent interaction between the immunosuppressive drugs and herbs resulting in adverse effect on allograft function.",
"affiliations": "Division of Nephrology, Department of Medicine, Queen Mary Hospital , Hong Kong , China.",
"authors": "Kwan|Lorraine P Y|LP|;Mok|Maggie M Y|MM|;Ma|Maggie K M|MK|;Lam|Man-Fai|MF|",
"chemical_list": "D065692:Cytochrome P-450 CYP3A Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D020123:Sirolimus",
"country": "England",
"delete": false,
"doi": "10.3109/0886022X.2013.846864",
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"issn_linking": "0886-022X",
"issue": "36(2)",
"journal": "Renal failure",
"keywords": null,
"medline_ta": "Ren Fail",
"mesh_terms": "D001628:Beverages; D001682:Biological Availability; D016572:Cyclosporine; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D006801:Humans; D007166:Immunosuppressive Agents; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D020123:Sirolimus",
"nlm_unique_id": "8701128",
"other_id": null,
"pages": "309-12",
"pmc": null,
"pmid": "24180243",
"pubdate": "2014-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute drug toxicity related to drinking herbal tea in a kidney transplant recipient.",
"title_normalized": "acute drug toxicity related to drinking herbal tea in a kidney transplant recipient"
} | [
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"companynumb": "HK-JNJFOC-20140308846",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
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"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
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{
"abstract": "Mesenchymal stromal cells (MSC) hold promise as a novel immune-modulatory therapy in organ transplantation. First clinical studies have used autologous MSCs; however, the use of allogeneic \"off-the-shelf\" MSCs is more sustainable for broad clinical implementation, although with the risk of causing sensitization. We investigated safety and feasibility of allogeneic MSCs in renal transplantation, using a matching strategy that prevented repeated mismatches. Ten patients received two doses of 1.5 × 106 /kg allogeneic MSCs 6 months after transplantation in a single-center nonrandomized phase Ib trial, followed by lowering of tacrolimus (trough level 3 ng/mL) in combination with everolimus and prednisone. Primary end point was safety, measured by biopsy proven acute rejection (BPAR) and graft loss 12 months after transplantation. Immune monitoring was performed before and after infusion. No BPAR or graft loss occurred and renal function remained stable. One patient retrospectively had DSAs against MSCs, formed before infusion. No major alterations in T and B cell populations or plasma cytokines were observed upon MSC infusion. Administration of HLA selected allogeneic MSCs combined with low-dose tacrolimus 6 months after transplantation is safe at least in the first year after renal transplantation. This sets the stage to further explore the efficacy of third-party MSCs in renal transplantation.",
"affiliations": "Department of Internal Medicine (Nephrology) and Transplant Center, Leiden University Medical Center, Leiden, the Netherlands.;Department of Internal Medicine (Nephrology) and Transplant Center, Leiden University Medical Center, Leiden, the Netherlands.;Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.;Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.;Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.;Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.;Department of Transplant Surgery and Transplant Center, Leiden University Medical Center, Leiden, the Netherlands.;Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands.;Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, the Netherlands.;Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.;Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.;Department of Internal Medicine (Nephrology) and Transplant Center, Leiden University Medical Center, Leiden, the Netherlands.;Department of Internal Medicine (Nephrology) and Transplant Center, Leiden University Medical Center, Leiden, the Netherlands.;Department of Internal Medicine (Nephrology) and Transplant Center, Leiden University Medical Center, Leiden, the Netherlands.;Department of Internal Medicine (Nephrology) and Transplant Center, Leiden University Medical Center, Leiden, the Netherlands.",
"authors": "Dreyer|Geertje J|GJ|0000-0001-6166-7819;Groeneweg|Koen E|KE|0000-0001-9077-1471;Heidt|Sebastiaan|S|0000-0002-6700-188X;Roelen|Dave L|DL|;van Pel|Melissa|M|;Roelofs|Helene|H|;Huurman|Volkert A L|VAL|;Bajema|Ingeborg M|IM|;Moes|Dirk Jan A R|DJAR|;Fibbe|Willem E|WE|;Claas|Frans H J|FHJ|;van Kooten|Cees|C|;Rabelink|Rabelink J|RJ|;de Fijter|Johan W|JW|;Reinders|Marlies E J|MEJ|0000-0001-9543-567X",
"chemical_list": "D006680:HLA Antigens",
"country": "United States",
"delete": false,
"doi": "10.1111/ajt.15910",
"fulltext": "\n==== Front\nAm J Transplant\nAm J Transplant\n10.1111/(ISSN)1600-6143\nAJT\nAmerican Journal of Transplantation\n1600-6135 1600-6143 John Wiley and Sons Inc. Hoboken \n\n10.1111/ajt.15910\nAJT15910\nBrief Communication\nBrief Communications\nHuman leukocyte antigen selected allogeneic mesenchymal stromal cell therapy in renal transplantation: The Neptune study, a phase I single‐center study\nDREYER et al.Dreyer Geertje J. https://orcid.org/0000-0001-6166-7819\n1\ng.j.dreyer@lumc.nl Groeneweg Koen E. https://orcid.org/0000-0001-9077-1471\n1\n Heidt Sebastiaan https://orcid.org/0000-0002-6700-188X\n2\n Roelen Dave L. \n2\n van Pel Melissa \n2\n Roelofs Helene \n2\n Huurman Volkert A. L. \n3\n Bajema Ingeborg M. \n4\n Moes Dirk Jan A. R. \n5\n Fibbe Willem E. \n2\n Claas Frans H. J. \n2\n van Kooten Cees \n1\n Rabelink Rabelink J. \n1\n de Fijter Johan W. \n1\n Reinders Marlies E. J. https://orcid.org/0000-0001-9543-567X\n1\n \n1 \nDepartment of Internal Medicine (Nephrology) and Transplant Center\nLeiden University Medical Center\nLeiden\nthe Netherlands\n\n\n2 \nDepartment of Immunohematology and Blood Transfusion\nLeiden University Medical Center\nLeiden\nthe Netherlands\n\n\n3 \nDepartment of Transplant Surgery and Transplant Center\nLeiden University Medical Center\nLeiden\nthe Netherlands\n\n\n4 \nDepartment of Pathology\nLeiden University Medical Center\nLeiden\nthe Netherlands\n\n\n5 \nDepartment of Clinical Pharmacy and Toxicology\nLeiden University Medical Center\nLeiden\nthe Netherlands\n\n* Correspondence\n\nGeertje J. Dreyer\n\nEmail: g.j.dreyer@lumc.nl\n\n06 5 2020 \n10 2020 \n20 10 10.1111/ajt.v20.102905 2915\n15 1 2020 10 3 2020 29 3 2020 © 2020 The Authors. American Journal of Transplantation published by Wiley Periodicals Inc. on behalf of The American Society of Transplantation and the American Society of Transplant SurgeonsThis is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Mesenchymal stromal cells (MSC) hold promise as a novel immune‐modulatory therapy in organ transplantation. First clinical studies have used autologous MSCs; however, the use of allogeneic \"off‐the‐shelf\" MSCs is more sustainable for broad clinical implementation, although with the risk of causing sensitization. We investigated safety and feasibility of allogeneic MSCs in renal transplantation, using a matching strategy that prevented repeated mismatches. Ten patients received two doses of 1.5 × 106/kg allogeneic MSCs 6 months after transplantation in a single‐center nonrandomized phase Ib trial, followed by lowering of tacrolimus (trough level 3 ng/mL) in combination with everolimus and prednisone. Primary end point was safety, measured by biopsy proven acute rejection (BPAR) and graft loss 12 months after transplantation. Immune monitoring was performed before and after infusion. No BPAR or graft loss occurred and renal function remained stable. One patient retrospectively had DSAs against MSCs, formed before infusion. No major alterations in T and B cell populations or plasma cytokines were observed upon MSC infusion. Administration of HLA selected allogeneic MSCs combined with low‐dose tacrolimus 6 months after transplantation is safe at least in the first year after renal transplantation. This sets the stage to further explore the efficacy of third‐party MSCs in renal transplantation.\n\nThe authors report that administration 6 months after kidney transplantation of allogeneic bone marrow–derived mesenchymal stromal cells selected to have no repeated HLA mismatches with the kidney donor was safe 1 year after transplantation with no instances of biopsy‐proven acute rejection, graft loss, or de novo antibodies against either donor.\n\nclinical research/practiceclinical trialimmune regulationimmunosuppression/immune modulationkidney transplantation/nephrologymonitoring: immunestem cells source-schema-version-number2.0cover-dateOctober 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.3 mode:remove_FC converted:26.10.2020\n\n\nDreyer \nGJ \n, \nGroeneweg \nKE \n, \nHeidt \nS \n, et al. Human leukocyte antigen selected allogeneic mesenchymal stromal cell therapy in renal transplantation: The Neptune study, a phase I single‐center study\n. Am J Transplant . 2020 ;20 :2905 –2915\n. 10.1111/ajt.15910 \n32277568\n==== Body\nAbbreviations\n(dn)DSA(de novo) donor specific anti‐HLA antibodies\n\n(s)AE(serious) adverse event\n\nBKVBK viremia\n\nBMbone marrow\n\nBPARbiopsy proven acute rejection\n\nCCMOCentral Committee on Research involving Human Subjects\n\nCMVcytomegalovirus\n\nCNIcalcineurin inhibitor\n\neGFRestimated glomerular filtration rate\n\nHLAhuman leukocyte antigen\n\nIFTAinterstitial fibrosis and tubular atrophy\n\nMedDRA©Medical Dictionary for Regulatory Activities\n\nMFImean fluorescence intensity\n\nMSCmesenchymal stromal cell\n\nNKnatural killer\n\nSABsingle antigen bead\n\nSRSirius Red\n\nTregregulatory T cell\n\n1 INTRODUCTION\nSince the late 1980s short‐term kidney graft survival improved due to the prevention of acute rejection; however, improvement in long‐term survival was hampered.\n1\n An important cause of late graft failure is interstitial fibrosis and tubular atrophy (IFTA) due to nonimmunological (eg, drug toxicity) and immunological mechanisms\n2\n, \n3\n and therefore new immunosuppressive protocols aim to reduce calcineurin inhibitors (CNI). However, this in turn has been shown to promote the formation of de novo donor specific antihuman leukocyte antigen (HLA) antibodies (dnDSAs) and rejection, which increases the chance of graft loss.\n4\n\n\n\nIn order to improve graft survival, cellular therapy has gained interest. Mesenchymal stromal cells (MSCs) have anti‐inflammatory, immune‐regulatory, and reparative properties, which make them a promising therapy in transplantation.\n5\n, \n6\n Most clinical studies in renal transplantation have used autologous MSCs\n7\n, \n8\n, \n9\n but for acute treatment indications, allogeneic MSCs are more feasible due to standardized quality control and the possibility to use \"off‐the‐shelf\" products.\n10\n However, they potentially can elicit an antidonor immune response against the kidney allograft or the MSCs.\n11\n In renal transplantation only a few studies have been performed with allogeneic MSCs\n12\n, \n13\n and the use of unmatched MSCs resulted in dnDSA formation in the study of Erpicum et al.\n13\n\n\n\nIn contrast to previous studies, where MSCs were administered early after renal transplantation with the aim to induce tolerance, we infused the MSCs 6 months after transplantation. This later timepoint could give the opportunity to lower CNI levels in order to reverse or stabilize IFTA and retain long‐term renal function.\n14\n Therefore, the primary aim of this phase Ib study is to prove safety and feasibility of infusion of third‐party MSCs where a matching strategy prevented repeated mismatches with the kidney allograft to minimize the risk of an antidonor immune response against the allograft.\n\n2 MATERIAL AND METHODS\n2.1 Study design and patients\nThis is a 12‐month, nonrandomized, prospective, single‐center, phase Ib study where 10 patients received a first solitary renal transplant from a living (unrelated) donor and fulfilled the study criteria as described.\n15\n\n\n\nAll patients received alemtuzumab (anti‐CD52) induction and prednisone, tacrolimus (Advagraf®), and everolimus (Certican®) as maintenance therapy (Figure 1). Tacrolimus was reduced to trough levels of 1.5‐3 ng/mL after the second MSC infusion. Details of target levels and comedication have been described previously.\n15\n Primary end point was safety assessed by the occurrence of biopsy proven acute rejection (BPAR) or graft loss with a target of <3 patients, based on an occurrence of <25% BPAR/graft loss in the overall renal transplant population. Peripheral lymphocyte subsets, anti‐HLA antibodies, and serum cytokine and chemokine levels before and after MSC infusion were measured.\n16\n, \n17\n Secondary end points were adverse events including infections, renal function, and fibrosis measured by Sirius Red (SR) scoring.\n\nWritten informed consent was obtained from all participants. The protocol was approved by the local ethics committee and by the Central Committee on Research involving Human Subjects (CCMO) (EudraCT: 2013‐005407‐14; Clinical‐Trials.gov: NCT02387151).\n\nFIGURE 1 Schematic presentation of study interventions and immunosuppressive regimen. Patients received induction therapy with alemtuzumab (Campath®) 15 mg on day 0 and day 1 after transplantation [Tx]). Prednisolone started on day 0 with 500 mg, 250 mg on day 1, 125 mg on day 2, 100 mg on day 3, 50 mg on day 4, and 10 mg/day from day 5, then reduced to 7.5 mg after 3 months (week 12) and to 5 mg at 6 months (week 26). Target trough level of everolimus (Certican®) was 3‐8 ng/mL. The tacrolimus (Advagraf®) target was 8‐10 ng/mL the first 6 weeks post Tx, 4‐7 ng/mL from 6 to 24 weeks, and lowered to 1.5‐3 ng/mL at week 26. A renal biopsy was performed 24 weeks after transplantation, before MSC infusion, and 52 weeks after transplantation. In week 25 and week 26 1‐2 × 106/kg allogeneic MSC were infused. W, weeks; Tx, transplantation; MSC, mesenchymal stromal cells; C0, trough level\n\n2.2 MSC products\nBone marrow (BM)‐derived MSCs were obtained from healthy independent third‐party donors.\n15\n The protocol was approved by the local ethics committee (P11.089) and by the CCMO. Details of BM donors, processing and expansion of the MSCs is described in the Supporting Information and Table S1.\n\nThe MSC product was infused via peripheral infusion within 30 minutes. Patients received two doses of 1‐2 × 106 MSCs per kg body weight at week 25 and 26 after transplantation.\n\n2.3 Monitoring\nPatients were monitored according to the assessment schedule (Table S2).\n\n(Serious) adverse events (SAE) were documented according to MedDRA® (Medical Dictionary for Regulatory Activities), the international medical terminology developed under the auspices of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use.\n\nRenal function was measured by estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration (CKD‐EPI) formula.\n15\n In addition, iohexol clearance at week 24 and week 52 was done retrospectively. Iohexol was measured with a validated High Performance Liquid Chromatography with Diode Array Detector assay.\n18\n Validation was performed according to European Medicines Agency Guidelines on bioanalytical method validation (2011). Iohexol GFR was calculated, based on samples at T = 5 minutes, T = 1, T = 2, T = 3 and T = 4 hours after iohexol administration, with nonlinear regression.\n\nRenal biopsy was performed 6 months after transplantation (1 week before the first MSC infusion) and 6 months after the second MSC infusion. Biopsies were scored using the Banff classification from 2018\n19\n by a pathologist from our center after completion of the study and stained for SR to quantify the extent of interstitial fibrosis, which correlates with long‐term graft failure.\n20\n The amount of collagen I and III deposition was measured in multiple slices per biopsy by computerized image analysis and expressed as percentage of positivity per region of the kidney.\n20\n\n\n\nDuring the study cytomegalovirus (CMV)‐, Epstein‐Barr virus, and BK‐virus (BKV) were detected through polymerase chain reaction testing as indicated (Table S2) and on clinical indication.\n\nQuantification of tacrolimus and everolimus was performed using a previously validated liquid chromatography–mass spectrometry (LC–MS)/MS assay.\n21\n\n\n\n2.4 HLA typing and HLA antibody detection\nRecipients, kidney donors and MSC donors were typed for HLA class I by Luminex SSO (Lifecodes, ImmuCor, Peachtree Corners, GA) and HLA‐DRB1, ‐DRB3, 4, 5, and ‐DQB1 by rSSO.\n22\n MSCs were selected specifically for each patient without repeated HLA mismatches on the split antigen level for HLA‐A, ‐B, ‐DR, and ‐DQ (Figure 2).\n\nFIGURE 2 MSC selection procedure regarding HLA matching. This figure shows the method of MSC selection for patient 3. In this patient the HLA mismatch with the kidney donor was 1‐2‐1 (and 1 for HLA DQ). MSC1 has three repeated mismatches, HLA‐B, HLA‐DR, and HLA‐DQ, therefore the product was not selected. MSC2 has mismatches with the recipient (1‐2‐0, 0) but no repeated mismatches between the mismatches with the kidney donor, so this product was selected for infusion. HLA, human leukocyte antigen; MSC, mesenchymal stromal cells\n\nThe presence of serum HLA antibodies was determined as indicated (Table S2). Samples were screened using Luminex assay (ImmuCor) and analyzed with a Luminex 100 reader. Provider suggested definitions of the negative/positive discriminations were used. When positive, a single antigen bead (SAB) assay (Lifecodes, ImmuCor) was performed as standard of care. After completion of the study all samples before MSC infusion and 26 weeks after the second MSC infusion were tested using this SAB assay (Lifecodes, ImmuCor). Assignment of positivity was assessed according to manufacturer's instructions.\n\n2.5 Immunological monitoring\nPhenotypical analysis of leukocyte subpopulations was performed according to the One study protocol at several timepoints (Table S2).\n16\n Absolute cell counts were obtained by using the BD Multitest kit (BD Biosciences, San Jose, CA).\n\nLevels of 29 systemic proinflammatory and anti‐inflammatory cytokines and chemokines, summarized in the Supporting information, were measured before and 4 hours after MSC infusion using multiplex assays (Biorad, Hercules, CA).\n17\n\n\n\n2.6 Statistical analysis\nComparisons between measurements before and after MSC infusion were done using paired t tests in SPSS version 25.0. P values < .05 were considered statistically significant.\n\n3 RESULTS\n3.1 Clinical course of MSC treated patients\nTen patients, aged 24 to 68 years, were included and received MSC infusions between March 2015 and May 2018. Four of 10 patients received a kidney from a related donor, stated as the type of transplant in Table 1. All patients received the target MSC dose and had stable vital signs before and after infusion monitored using Modified Early Warning Scores (Table S3).\n\nTABLE 1 Baseline characteristics\n\nPatient\t1\t2\t3\t4\t5\t6\t7\t8\t9\t10\t\nRecipient\t\nAge (y)\t24\t59\t56\t46\t68\t47\t59\t59\t39\t44\t\nGender\t♂\t♀\t♂\t♀\t♀\t♂\t♂\t♂\t♂\t♀\t\nWeight (kg)\t70\t69\t75\t75\t62\t79\t90\t83\t85\t83\t\nPrimary diagnosis\tHT\tAnti‐GBM\tTIN\tADPKD\tADPKD\tIgA\tADPKD\tIgA\tUnknown\tSLE\t\nPRA (%)*\t4\t36\t4\t4\t0\t4\t4\t5\t4\t5\t\nDonor\t\nAge (y)\t56\t61\t69\t49\t63\t43\t60\t59\t49\t63\t\nGender\t♂\t♂\t♂\t♀\t♀\t♂\t♀\t♀\t♀\t♀\t\nTransplant\t\nType\tLR\tLUR\tLUR\tLR\tLUR\tLR\tLUR\tLUR\tLUR\tLR\t\nCold ischemia time (h:min)\t2:39\t2:51\t3:15\t4:40\t2:57\t3:19\t2:52\t3:04\t3:22\t3:12\t\nWarm ischemia time (min)\t25\t33\t26\t45\t22\t27\t26\t33\t33\t27\t\nCytomegalovirus IgG status\tD−/R−\tD−/R+\tD−/R−\tD−/R−\tD+/R+\tD−/R−\tD−/R−\tD+/R+\tD−/R+\tD−/R−\t\nEpstein‐Barr virus IgG status\tD+/R+\tD+/R+\tD+/R+\tD+/R+\tD+/R+\tD+/R+\tD+/R+\tD+/R+\tD−/R+\tD+/R+\t\nNote\nCharacteristics of 10 renal recipients and their kidney donors. The second warm ischemia time is given. For cytomegalovirus and Epstein‐Barr virus, the IgG status of the donor (D) and recipient (R) were given positive or negative.\n\nAbbreviations: ADPKD, autosomal dominant polycystic kidney disease; GBM, glomerular basement membrane; HT, hypertension; L(U)R, living (un) related; PRA, panel reactive antibody; SLE, systemic lupus erythematosus; TIN, tubulointerstitial nephritis.\n\nJohn Wiley & Sons, LtdAll patients had a functioning kidney graft at the end of the study and no BPAR occurred. Banff classification (Table S4) showed some changes between the first and second biopsy in six patients. In two patients the IFTA score was higher in the second biopsy and two patients developed nonspecific changes. In two patients, the second biopsy showed a small focus of borderline rejection; however, renal function remained stable and no signs of rejection were observed during the study. In patient 10 the second renal biopsy was cancelled because of a vital anticoagulation indication due to a transient ischemic attack 5 months after MSC infusion.\n\nIn total 10 infectious events occurred before MSC infusion and 11 events occurred afterwards. Three patients had BKV with stable renal function and no signs of BK nephropathy. In one patient this occurred two months after transplantation and it resolved after lowering immunosuppression. Two BKV reactivations occurred both 5 months after MSC infusion and resolved spontaneously within several weeks. Six couples were both CMV IgG negative (Table 1). From the patients with a positive CMV IgG, one had a CMV reactivation (1.5 log) 1 month after the first MSC infusion that decreased to zero within 1 month. Patient 3 had a herpes zoster reactivation 3 months after MSC infusion. The other infectious adverse events were mainly viral upper respiratory tract infections (10/21) and three urinary tract infections. One viral infection occurred the week after MSC infusion, five viral infections and one urinary tract infections occurred several months after MSC infusion.\n\nRenal function remained stable in five patients during the study follow‐up (Figure 3). Patient 9 had a slight decrease in both eGFR and iohexol clearance. Four patients had an improved renal function between 6 and 12 months after transplantation. In most patients eGFR and iohexol clearance were comparable; however, two patients had an improvement of their iohexol clearance that was not reflected in eGFR. Mean eGFR at week 24, before MSC infusion, was 47 mL/min (±13) and mean eGFR at week 52 was 50 mL/min (±13; P = .289).\n\nFIGURE 3 Kidney function before and after MSC infusion. The table on the left shows the values of the Chronic Kidney Disease Epidemiology Collaboration (CKD‐EPI) compared to the iohexol clearance in mL/min measured 24 and 52 weeks after kidney transplantation. In patient 3 iohexol clearance at week 24 is missing due to 1 missing laboratory measurement. Mean renal function is the mean of all patients. The figure on the right shows the eGFR calculated with CKD‐EPI formula for all 10 patients during study follow‐up. Week 0 is calculated just before transplantation, week 24 is the moment of renal biopsy, before MSC infusions (week 25 and 26). W, week; eGFR, estimated glomerular filtration rate; MSC, mesenchymal stromal cells\n\nMost immunosuppressive drug levels were within or slightly out of the target range (Table S5). Tacrolimus trough levels decreased after MSC infusion as meant per protocol from a mean of 6.1 (±1.7) ng/mL before infusion to 3.0 (±0.9) ng/mL afterwards. Mean everolimus trough level was 5.7 ng/mL before and after MSC infusion. Prednisone was tapered to 5 mg in all patients according to the protocol.\n\n3.2 SR staining before and after MSC infusion\nComparing SR scores in the renal biopsies 6 and 12 months after transplantation, an obvious rise was observed in the first two patients (Figure 4) and patient 8 had a marked improvement of the SR score. Other values were comparable and there was no significant difference in mean SR score before and after MSC infusion (P = .949). Regarding the improvement in patient 8, this patient experienced perioperative bleeding, requiring a second operation. Renal function improved very slowly afterwards and a kidney biopsy 9 days after transplantation showed acute tubular necrosis without signs of rejection. Renal function improved further until 12 months after transplantation (Figure 3), which could reflect the improvement of the SR score.\n\nFIGURE 4 Sirius Red scores. This figure shows in the table on the left the Sirius Red score in percentages scored for the first biopsy at 6 months after transplantation (before MSC infusion) and the second biopsy 12 months after transplantation. The last patient had a vital anticoagulation indication (transient ischemic attack) so no renal biopsy was performed and therefore this value is missing. Two biopsies were shown as example, the biopsy of patient 8 had an important improvement of Sirius Red score, which is also seen in the picture. The second example from patient 9 had a stable Sirius Red score. MSC, mesenchymal stromal cells.\n\n3.3 HLA mismatches and DSAs\nAll kidney donors and MSC products had HLA mismatches with the patients (Table 2). As meant per protocol there were no repeated HLA mismatches with the kidney graft in nine patients. In patient 2 it was not possible to find a suitable MSC product and a repeated mismatch on HLA‐DQ was accepted. Patient 2 had class I (HLA‐B) antibodies before transplantation, after previous pregnancy, which were not directed against the kidney donor or the selected MSCs. None of the patients had dnDSAs using Luminex screening before and after MSC infusion. After completion of the study, SAB assays showed no dnDSAs against the kidney graft. Retrospectively, patient 4 happened to have a class II DSA (DQ8) directed against the MSCs with an mean fluorescence intensity (MFI) of 1696, already formed before MSC infusion in week 24, which was also measurable at the end of the study with an MFI of 1936.\n\nTABLE 2 HLA mismatches on split level between patient, kidney donor and MSCs\n\n\tPatient/kidney/MSC\tHLA‐A\t\tHLA‐B\t\tHLA‐DR\t\tHLA‐DQ\t\t\n1\tPatient\tA68\t\t\tB60\tB44\t\tDR4\tDR11\t\tDQ7\t\t\t\nKidney\tA68\tA31\t1\tB27\tB44\t1\tDR4\tDR11\t0\tDQ7\tDQ8\t1\t\nMSC\tA2\tA32\t2\tB51\t\t1\tDR8\tDR12\t2\tDQ7\tDQ4\t1\t\n2\tPatient\tA2\tA68\t\tB44\tB53\t\tDR15\t\t\tDQ6\t\t\t\nKidney\tA29\tA66\t2\tB35\tB39\t2\tDR1\tDR11\t2\tDQ7\tDQ5\t2\t\nMSC\tA2\t\t0\tB44\tB62\t1\tDR4\tDR7\t2\tDQ7\tDQ9\t2\t\n3\tPatient\tA2\tA31\t\tB7\tB52\t\tDR13\tDR17\t\tDQ2\tDQ6\t\t\nKidney\tA3\tA31\t1\tB51\tB62\t2\tDR13\tDR4\t1\tDQ8\tDQ6\t1\t\nMSC\tA1\tA2\t1\tB8\tB60\t2\tDR13\tDR17\t0\tDQ2\tDQ6\t0\t\n4\tPatient\tA2\t\t\tB39\tB44\t\tDR4\tDR8\t\tDQ2\tDQ4\t\t\nKidney\tA2\t\t0\tB62\tB44\t1\tDR4\tDR1\t1\tDQ2\tDQ5\t1\t\nMSC\tA2\tA68\t1\tB35\tB60\t2\tDR4\tDR17\t1\tDQ2\tDQ8\t1\t\n5\tPatient\tA2\tA29\t\tB44\tB51\t\tDR7\tDR11\t\tDQ2\tDQ7\t\t\nKidney\tA2\tA74\t1\tB72\tB27\t2\tDR17\tDR11\t1\tDQ2\tDQ6\t1\t\nMSC\tA2\tA32\t1\tB51\t\t0\tDR8\tDR12\t2\tDQ4\tDQ7\t1\t\n6\tPatient\tA1\tA24\t\tB7\tB27\t\tDR4\tDR17\t\tDQ2\tDQ7\t\t\nKidney\tA1\tA2\t1\tB8\tB62\t2\tDR4\tDR17\t0\tDQ2\tDQ8\t1\t\nMSC\tA24\tA25\t1\tB18\tB39\t2\tDR8\tDR15\t2\tDQ4\tDQ6\t2\t\n7\tPatient\tA2\tA32\t\tB44\t\t\tDR7\tDR11\t\tDQ2\tDQ7\t\t\nKidney\tA2\tA32\t0\tB44\tB18\t1\tDR7\tDR16\t1\tDQ2\tDQ5\t1\t\nMSC\tA2\tA32\t0\tB51\t\t1\tDR8\tDR12\t2\tDQ4\tDQ7\t1\t\n8\tPatient\tA2\tA32\t\tB44\tB51\t\tDR11\tDR12\t\tDQ7\t\t\t\nKidney\tA3\tA24\t2\tB44\t\t0\tDR11\tDR7\t1\tDQ7\tDQ2\t1\t\nMSC\tA2\t\t0\tB7\tB8\t2\tDR11\tDR15\t1\tDQ7\tDQ6\t1\t\n9\tPatient\tA2\tA24\t\tB8\tB35\t\tDR17\tDR14\t\tDQ2\tDQ5\t\t\nKidney\tA3\t\t1\tB7\tB65\t2\tDR13\tDR15\t2\tDQ6\t\t1\t\nMSC\tA2\t\t0\tB44\tB62\t2\tDR4\tDR7\t2\tDQ7\tDQ9\t2\t\n10\tPatient\tA1\tA2\t\tB8\tB62\t\tDR15\t\t\tDQ6\t\t\t\nKidney\tA1\t\t0\tB8\t\t0\tDR15\tDR17\t1\tDQ6\tDQ2\t1\t\nMSC\tA2\tA31\t1\tB7\tB60\t2\tDR4\tDR14\t2\tDQ7\tDQ5\t2\t\nThis table shows the HLA mismatches for A‐, B‐, DR‐ and DQ‐locus on split level between the patient and kidney donor and between the patient and MSC donor. For HLA‐DR only DRB1 was taken into account.\n\nAbbreviations: HLA, human leucocyte antigen; MSC, mesenchymal stromal cell.\n\nJohn Wiley & Sons, Ltd3.4 Cellular response and cytokine levels after MSC infusion reflect safety\nAbsolute numbers of CD45+ leukocytes remained stable after transplantation (P = .088 between week 0‐52; Figure 5). Monocytes increased after transplantation (P = .034 between week 0‐52) although the level before and after the two MSC infusions did not differ significantly (P = .228; Figure 5). CD19+ B cells and CD 56+ NK cells decreased after induction therapy and an increase was seen from week 25; however, no statistically significant change was measured after MSC infusions (Figure 5). CD8+ T cells, CD4+ T cells as well as naïve and memory regulatory T cells (Tregs) demonstrated a decrease after induction therapy and T cell numbers did not return to baseline levels at week 52, 12 months, after transplantation (Figure 6). In CD4+ T cells a significant increase after two MSC infusions was seen (P = .028). The percentages of naïve and memory Tregs within CD4+ T cells did not change after MSC infusions (Figure S1).\n\nFIGURE 5 Leukocytes before and after MSC infusion. Absolute numbers of (A) CD45+ leukocytes, (B) CD19+ B cells, (C) CD14+ monocytes, and (D) CD56+ NK cells are shown at baseline before transplantation, so before induction therapy, before the first MSC infusion (week 25) and before the second MSC infusion (week 26) and three time points after both infusions (week 27, week 34, and week 52). Median values are given for every time point (horizontal bars). The y‐axis is a logarithmic scale. P values are given for the differences between week 25‐26 (after the first infusion), week 26‐27 (after the second infusion), and for week 25‐27 (before MSC infusion and after both infusions). The P value given at week 52 is the difference before transplantation (week 0) and week 52. MSC, mesenchymal stromal cells; NK, natural killer\n\nFIGURE 6 T cell subsets before and after MSC infusions. Absolute numbers of (A) CD8+ T cells, (B) CD4+ T cells, (C) naïve Tregs, and (D) memory Tregs are shown at baseline before transplantation, so before induction therapy, before the first MSC infusion (week 25) and before the second MSC infusion (week 26) and three time points after both infusions (week 27, week 34, and week 52). In the population of naïve Treg cells there were one and two patients respectively with a value of 0 cells in week 26 and week 27, these values were not plotted. Median values are given for every time point (horizontal bars). The y‐axis is a logarithmic scale. P values are given for the differences between week 25‐26 (after the first infusion), week 26‐27 (after the second infusion), and for week 25‐27 (before MSC infusion and after both infusions). The P value given at week 52 is the difference before transplantation (week 0) and week 52. MSC, mesenchymal stromal cells; Treg, regulatory T cell\n\nCytokine levels before and 4 hours after both MSC infusions are shown in Figure 7. Tumor necrosis factor alpha (TNFα) showed a consistent decrease in all patients 4 hours after the first MSC infusion (P = .000), although this effect was not seen after the second infusion (P = .977) levels remained lower for at least 6 months after the first infusion (P = .008; data not shown). Anti‐inflammatory cytokine IL4 showed significant differences after the first and second infusion; however, the effect did not sustain and levels returned to the value before infusion. Anti‐inflammatory cytokine interleukin (IL)10 showed a significant decrease after the second infusion and this effect remained (P = .018 between week 25 T0 and week 52, data not shown). Proinflammatory cytokine interferon gamma (IFNγ) did not show significant differences. Levels of other cytokines (supporting information) and chemokines were within physiological range and no major changes were observed 4 hours after MSC infusions (data not shown).\n\nFIGURE 7 Cytokine levels of TNFα, IL4, IL10, and IFNγ and before and after MSC infusion. Levels of (A) TNFα, (B) IL4, (C) IL10, and (D) IFNγ, measured by multiplex assays before and 4 hours after the first and second MSC infusion (week 25 and week 26 after transplantation). IL, interleukin; IFN, interferon; MSC, mesenchymal stromal cells; TNF, tumor necrosis factor\n\n3.5 (Serious) adverse events during study follow‐up\nIn total, 117 AEs were reported (Figure 8). All SAEs occurred in 6 patients and 11 of the 12 events occurred before MSC infusion. The SAE after MSC infusion was a second pneumoniae several months after the infusion. The SAEs were classified as serious due to (prolonged) admission. There were no AEs directly related to the MSC infusions.\n\nMost AEs (72%) occurred before MSC infusions. Of the AEs after MSC infusion, 45% was related to comedication, 10% to the primary disease, and 34% were uncomplicated infections.\n\nFIGURE 8 All (serious) adverse events were classified according to MedDRA® (Medical Dictionary for Regulatory Activities). During follow‐up 12 serious adverse events and 105 adverse events occurred. Most frequent reported adverse events are infectious problems. There were no adverse events directly related to the MSC infusions. MSC, mesenchymal stromal cells\n\n4 DISCUSSION\nThis clinical study, with a follow‐up of 12 months, demonstrates safe infusion of HLA selected allogeneic BM‐derived MSCs 6 months after renal transplantation in combination with low‐dose tacrolimus. All 10 patients had a functioning kidney graft and no BPAR or MSC‐related adverse events were observed. MSC trials in renal transplantation reported different outcomes regarding renal function after infusion.\n7\n, \n23\n In our study renal function was stable after MSC infusion.\n\nUnselected allogeneic MSCs bore a risk of dnDSA development.\n11\n In renal transplantation, only one study determined DSAs and 4 of the 10 patients developed dnDSAs against the single dose of unmatched third‐party MSCs, one of which was also directed against the kidney graft.\n13\n However, only one DSA had an MFI > 1500 and renal function remained stable rendering clinical relevance of the dnDSAs in this trial unclear. In our study no dnDSAs were formed against the allograft and retrospectively one patient happened to have DSAs against the MSCs, formed before infusion. Of importance, after MSC infusion the MFI of the antibody was comparable to the level before infusion. The low occurrence of DSA formation in our study might also have been influenced by the time of infusion, 6 months after transplantation, when there is relative immunological and inflammatory quiescence as compared to the perioperative phase. It should also be noted that in this study we used alemtuzumab as a relatively strong induction therapy to allow comparability to our ongoing cell therapy studies\n24\n and due to a possible higher immunological risk with the use of third‐party MSCs and the lowering of CNI.\n25\n\n\n\nSeveral studies in the transplant setting have demonstrated that MSCs could skew the immune system toward a more tolerogenic response, which is even sustained 4 years after renal transplantation.\n9\n, \n26\n However, our first clinical study demonstrated no change in total numbers and subsets of T cells, B cells, NK cells, and monocytes after autologous MSCs 6 months after transplantation,\n8\n which we confirm in the current study. Only CD4+ T cells increased during the infusion; however, this could be due to repopulation after induction therapy.\n\nIn vitro studies demonstrate that MSCs can act pro‐ or anti‐inflammatory after infusion, depending on the milieu reflected by cytokines.\n26\n, \n27\n In a mouse study an increase of pro‐inflammatory cytokines was found 2 hours after the MSC infusion.\n17\n In renal transplantation, TNFα, IFNγ, IL4, and IL10 are studied before and no significant differences were found between groups treated with or without MSCs.\n12\n In the current study, TNFα and IL10 were consistently lower in all patients after MSC infusions and this effect remained. However, the implication of this observation is unclear because we can compare levels only within the patient but not with a control group.\n\nA tacrolimus trough level of 3 ng/mL at 6 months after transplantation, as reached in our study, is a risk factor for dnDSA development.\n4\n Although the design of our study does not allow conclusions on efficacy, the fact that there was no dnDSA formation against the kidney or after MSC infusion is suggestive of a potential immune‐modulatory effect of MSC therapy for example via suppression of B cell terminal differentiation.\n28\n Alternatively, the induction with alemtuzumab may also play a role in this observation. However, previous studies suggested rather an increased risk on dnDSA development after alemtuzumab induction.\n29\n\n\n\nSo far, clinical trials using MSCs in renal transplantation have reported differences in infectious complications compared to control populations.\n8\n, \n13\n We report no increased risk of infectious complications, including BKV and CMV, compared to renal recipients with standard immunosuppression.\n30\n However, we have to take into account that the risk of CMV in this study was low due to 6 CMV negative donors and recipients.\n\nIn the current study we observed slight changes in Banff scores before and after MSC infusion. To address the potential role of MSCs in these observations, future studies with a control group receiving a comparable immunosuppressive regimen would be of interest.\n\nIn conclusion, our study proves safety of infusion of HLA selected allogeneic MSCs 6 months after transplantation. Our current design also underlines the feasibility of the strategy used to develop and implement MSCs as immunomodulatory therapy in the setting of renal transplantation.\n\nDISCLOSURE\nThe authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.\n\n\nSupporting information\nFig S1\n\nClick here for additional data file.\n\n Supplementary Material\n\nClick here for additional data file.\n\n Supplementary Material\n\nClick here for additional data file.\n\n ACKNOWLEDGMENTS\nMedDRA® trademark is registered by International Federation of Pharmaceutical Manufacturers & Associations on behalf of International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. We thank the research department of the Leiden University Medical Center for their help with the study visits. We thank the research technicians from the Transplant Immunology lab for technical assistance with the immune monitoring and cytokine and chemokine assays.\n\nDATA AVAILABILITY STATEMENT\nThe data that support the findings of this study are available from the corresponding author upon reasonable request.\n==== Refs\nREFERENCES\n1 \n\nCoemans \nM \n, \nSüsal \nC \n, \nDöhler \nB \n, et al. Analyses of the short‐ and long‐term graft survival after kidney transplantation in Europe between 1986 and 2015\n. Kidney Int . 2018 ;94 (5 ):964 ‐973\n.30049474 \n2 \n\nEl‐Zoghby \nZM \n, \nStegall \nMD \n, \nLager \nDJ \n, et al. Identifying specific causes of kidney allograft loss\n. Am J Transplant . 2009 ;9 (3 ):527 ‐535\n.19191769 \n3 \n\nWekerle \nT \n, \nSegev \nD \n, \nLechler \nR \n, \nOberbauer \nR \n. Strategies for long‐term preservation of kidney graft function\n. Lancet . 2017 ;389 (10084 ):2152 ‐2162\n.28561006 \n4 \n\nSüsal \nC \n, \nAykut \nG \n, \nMorath \nC \n, et al. Relevance of donor‐specific antibody monitoring after kidney transplantation: findings from the collaborative transplant study and the Heidelberg transplant center\n. HLA . 2019 ;94 :11 ‐15\n.\n5 \n\nReinders \nME \n, \nde Fijter \nJW \n, \nRabelink \nTJ \n. Mesenchymal stromal cells to prevent fibrosis in kidney transplantation\n. Curr Opin Organ Transplant . 2014 ;19 (1 ):54 ‐59\n.24275894 \n6 \n\nCasiraghi \nF \n, \nRemuzzi \nG \n, \nPerico \nN \n. Mesenchymal stromal cells to promote kidney transplantation tolerance\n. Curr Opin Organ Transplant . 2014 ;19 (1 ):47 ‐53\n.24257324 \n7 \n\nPerico \nN \n, \nCasiraghi \nF \n, \nGotti \nE \n, et al. Mesenchymal stromal cells and kidney transplantation: pretransplant infusion protects from graft dysfunction while fostering immunoregulation\n. Transpl Int . 2013 ;26 (9 ):867 ‐878\n.23738760 \n8 \n\nReinders \nMEJ \n, \nde Fijter \nJW \n, \nRoelofs \nH \n, et al. Autologous bone marrow‐derived mesenchymal stromal cells for the treatment of allograft rejection after renal transplantation: results of a phase I study\n. Stem Cells Transl Med . 2013 ;2 (2 ):107 ‐111\n.23349326 \n9 \n\nMudrabettu \nC \n, \nKumar \nV \n, \nRakha \nA \n, et al. Safety and efficacy of autologous mesenchymal stromal cells transplantation in patients undergoing living donor kidney transplantation: a pilot study\n. Nephrology . 2015 ;20 (1 ):25 ‐33\n.25230334 \n10 \n\nStolzing \nA \n, \nJones \nE \n, \nMcGonagle \nD \n, \nScutt \nA \n. Age‐related changes in human bone marrow‐derived mesenchymal stem cells: consequences for cell therapies\n. Mech Ageing Dev . 2008 ;129 (3 ):163 ‐173\n.18241911 \n11 \n\nAvivar‐Valderas \nA \n, \nMartín‐Martín \nC \n, \nRamírez \nC \n, et al. Dissecting allo‐sensitization after local administration of human allogeneic adipose mesenchymal stem cells in perianal fistulas of Crohn's disease patients\n. Front Immunol . 2019 ;10 :1244 .31258526 \n12 \n\nPeng \nY \n, \nKe \nM \n, \nXu \nLU \n, et al. Donor‐derived mesenchymal stem cells combined with low‐dose tacrolimus prevent acute rejection after renal transplantation: a clinical pilot study\n. Transplantation . 2013 ;95 (1 ):161 ‐168\n.23263506 \n13 \n\nErpicum \nP \n, \nWeekers \nL \n, \nDetry \nO \n, et al. Infusion of third‐party mesenchymal stromal cells after kidney transplantation: a phase I‐II, open‐label, clinical study\n. Kidney Int . 2019 ;95 (3 ):693 ‐707\n.30528263 \n14 \n\nAlagesan \nS \n, \nGriffin \nMD \n. Autologous and allogeneic mesenchymal stem cells in organ transplantation: what do we know about their safety and efficacy?\n\nCurrent Opinion in Organ Transplantation . 2014 ;19 (1 ):65 ‐72\n.24370985 \n15 \n\nReinders \nMEJ \n, \nDreyer \nGJ \n, \nBank \nJR \n, et al. Safety of allogeneic bone marrow derived mesenchymal stromal cell therapy in renal transplant recipients: the neptune study\n. J Transl Med . 2015 ;13 :344 .26537851 \n16 \n\nStreitz \nM \n, \nMiloud \nT \n, \nKapinsky \nM \n, et al. Standardization of whole blood immune phenotype monitoring for clinical trials: panels and methods from the ONE study\n. Transplant Res . 2013 ;2 (1 ):17 .24160259 \n17 \n\nHoogduijn \nMJ \n, \nRoemeling‐van Rhijn \nM \n, \nEngela \nAU \n, et al. Mesenchymal stem cells induce an inflammatory response after intravenous infusion\n. Stem Cells Dev . 2013 ;22 (21 ):2825 ‐2835\n.23767885 \n18 \n\nSoman \nRS \n, \nZahir \nH \n, \nAkhlaghi \nF \n. Development and validation of an HPLC‐UV method for determination of iohexol in human plasma\n. J Chromatogr B Analyt Technol Biomed Life Sci . 2005 ;816 (1–2 ):339 ‐343\n.\n19 \n\nRoufosse \nC \n, \nSimmonds \nN \n, \nClahsen‐van Groningen \nM \n, et al. A 2018 reference guide to the Banff classification of renal allograft pathology\n. 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Autologous mesenchymal stromal cells and kidney transplantation: a pilot study of safety and clinical feasibility\n. Clin J Am Soc Nephrol . 2011 ;6 (2 ):412 ‐422\n.20930086 \n24 \n\nReinders \nMEJ \n, \nBank \nJR \n, \nDreyer \nGJ \n, et al. Autologous bone marrow derived mesenchymal stromal cell therapy in combination with everolimus to preserve renal structure and function in renal transplant recipients\n. J Transl Med . 2014 ;12 :331 .25491391 \n25 \n\nHaynes \nR \n, \nHarden \nP \n, \nJudge \nP \n, et al. Alemtuzumab‐based induction treatment versus basiliximab‐based induction treatment in kidney transplantation (the 3C Study): a randomised trial\n. Lancet (London, UK) . 2014 ;384 (9955 ):1684 ‐1690\n.\n26 \n\nPerico \nN \n, \nCasiraghi \nF \n, \nTodeschini \nM \n, et al. Long‐term clinical and immunological profile of kidney transplant patients given mesenchymal stromal cell immunotherapy\n. Front Immunol . 2018 ;9 :1359 .29963053 \n27 \n\nLuk \nF \n, \nde Witte \nSF \n, \nBramer \nWM \n, \nBaan \nCC \n, \nHoogduijn \nMJ \n. Efficacy of immunotherapy with mesenchymal stem cells in man: a systematic review\n. Expert Rev Clin Immunol . 2015 ;11 (5 ):617 ‐636\n.25817052 \n28 \n\nAsari \nS \n, \nItakura \nS \n, \nFerreri \nK \n, et al. Mesenchymal stem cells suppress B‐cell terminal differentiation\n. Exp Hematol . 2009 ;37 (5 ):604 ‐615\n.19375651 \n29 \n\nTodeschini \nM \n, \nCortinovis \nM \n, \nPerico \nN \n, et al. In kidney transplant patients, alemtuzumab but not basiliximab/low‐dose rabbit anti‐thymocyte globulin induces B cell depletion and regeneration, which associates with a high incidence of de novo donor‐specific anti‐HLA antibody development\n. J Immunol . 2013 ;191 (5 ):2818 ‐2828\n.23913968 \n30 \n\nEkberg \nH \n, \nTedesco‐Silva \nH \n, \nDemirbas \nA \n, et al. Reduced exposure to calcineurin inhibitors in renal transplantation\n. N Engl J Med . 2007 ;357 (25 ):2562 ‐2575\n.18094377\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1600-6135",
"issue": "20(10)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "clinical research/practice; clinical trial; immune regulation; immunosuppression/immune modulation; kidney transplantation/nephrology; monitoring: immune; stem cells",
"medline_ta": "Am J Transplant",
"mesh_terms": "D006680:HLA Antigens; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016030:Kidney Transplantation; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells; D018541:Neptune; D012189:Retrospective Studies",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "2905-2915",
"pmc": null,
"pmid": "32277568",
"pubdate": "2020-10",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article",
"references": "8376188;19375651;25078310;25817052;23738760;18241911;25491391;24370985;26521259;23263506;18094377;20930086;30528263;24160259;30049474;26537851;28561006;32277568;25230334;23349326;29963053;23767885;24275894;24257324;19191769;31403240;12761269;31258526;15664368;23913968;30028786",
"title": "Human leukocyte antigen selected allogeneic mesenchymal stromal cell therapy in renal transplantation: The Neptune study, a phase I single-center study.",
"title_normalized": "human leukocyte antigen selected allogeneic mesenchymal stromal cell therapy in renal transplantation the neptune study a phase i single center study"
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"companynumb": "NL-MYLANLABS-2020M1050032",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EVEROLIMUS"
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{
"abstract": "Primary brain tumors, both benign and malignant, pose a high risk of perioperative venous thromboembolism (VTE) due to the development of a prothrombotic state. Perioperative pharmacologic thromboprophylaxis with subcutaneous (SC) unfractionated heparin (UFH) has significantly reduced VTE associated morbidity. Recent reports suggest an association between prolonged activated partial thromboplastin time (aPTT) due to prophylactic SC UFH and increased bleeding risk. We present three patients with normal baseline coagulation parameters in whom pharmacologic thromboprophylaxis with SC UFH resulted in a marked prolongation of the aPTT, leading to adverse outcomes in two patients. These cases demonstrate the uncertain kinetics of SC UFH and effect on aPTT, suggesting the significance of routine aPTT monitoring in high-risk settings. Given the wide variation in presentations of therapeutic or supratherapeutic values of aPTT in the perioperative neurosurgical setting, we propose a practical standardized approach to the evaluation and management of aPTT prolongation following prophylactic SC UFH administration.",
"affiliations": "Division of Hematology - Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA. mis9277@nyp.org.;Division of Hematology - Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA.;Department of Pharmacy, New York-Presbyterian Hospital - Weill Cornell Medical Center, New York, NY, USA.;Division of Hematology - Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA. mtd2002@med.cornell.edu.",
"authors": "Shusterman|Michael|M|http://orcid.org/0000-0003-2899-7714;Grassl|Niklas|N|;Berger|Karen|K|;De Sancho|Maria T|MT|",
"chemical_list": "D000925:Anticoagulants; D006493:Heparin",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s11239-019-01936-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0929-5305",
"issue": "49(1)",
"journal": "Journal of thrombosis and thrombolysis",
"keywords": "Activated partial thromboplastin time; Neurosurgery; Prophylaxis; Venous thromboembolism",
"medline_ta": "J Thromb Thrombolysis",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D001932:Brain Neoplasms; D005260:Female; D006493:Heparin; D006801:Humans; D019635:Neurosurgical Procedures; D010314:Partial Thromboplastin Time; D011183:Postoperative Complications; D020246:Venous Thrombosis",
"nlm_unique_id": "9502018",
"other_id": null,
"pages": "153-158",
"pmc": null,
"pmid": "31456167",
"pubdate": "2020-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "7572796;26714677;3710290;18574264;22315261;946507;4082105;21482849;16512825;27555191;28890040;17296655;29192859;20178528;11345711;7667826;30779530;22315264;17154163;28632418;28085682;28431186;23370827",
"title": "Prolonged activated partial thromboplastin time after prophylactic-dose unfractionated heparin in the post-operative neurosurgical setting: case series and management recommendations.",
"title_normalized": "prolonged activated partial thromboplastin time after prophylactic dose unfractionated heparin in the post operative neurosurgical setting case series and management recommendations"
} | [
{
"companynumb": "US-PFIZER INC-2019390478",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": "1",
... |
{
"abstract": "Purpose: To report a case of posterior reversible encephalopathy syndrome (PRES) in a 75 year-old patient who was taking concomitant ciprofloxacin and metronidazole. Method: Case report Results: A patient had been prescribed ciprofloxacin and metronidazole during a recent hospitalization and continued this regimen outpatient. Two weeks after discharge and 3 weeks after initiation of her regimen, she was brought to the emergency department after developing acute weakness and lightheadedness. After admission, the patient declined more rapidly and began seizing with subsequent intubation. Initial computed tomographic (CT) imaging showed no acute neurological abnormalities, and a sepsis workup was initiated. After negative CT, a magnetic resonance imaging scan was performed that showed a T2 flair and hyperdensity consistent with PRES. The final diagnosis was considered to be PRES secondary to ciprofloxacin/metronidazole utilization. Conclusion: Antibiotic induced PRES is a condition that needs to be explored more thoroughly.",
"affiliations": "Wesley Medical Center, Wichita, KS, USA.;Wesley Medical Center, Wichita, KS, USA.;Wesley Medical Center, Wichita, KS, USA.",
"authors": "Gilbert|Brian Wesley|BW|https://orcid.org/0000-0002-1385-7500;Gabriel|Ali|A|;Velazquez|Laura|L|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/0018578719844706",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0018-5787",
"issue": "55(5)",
"journal": "Hospital pharmacy",
"keywords": "adverse drug reactions; adverse drug reactions reporting/monitoring; critical care; infectious diseases",
"medline_ta": "Hosp Pharm",
"mesh_terms": null,
"nlm_unique_id": "0043175",
"other_id": null,
"pages": "338-341",
"pmc": null,
"pmid": "32999504",
"pubdate": "2020-10",
"publication_types": "D016428:Journal Article",
"references": "25596288;17502475;23585504;18403560;23212858;17885234;27537580;10954269;27572434;26935366;21996645;28761402;29531864",
"title": "A Case of Antibiotic-Induced Posterior Reversible Encephalopathy Syndrome.",
"title_normalized": "a case of antibiotic induced posterior reversible encephalopathy syndrome"
} | [
{
"companynumb": "US-TEVA-2020-US-1851399",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN"
},
"drugadditional": "1",
... |
{
"abstract": "Necrotizing enterocolitis (NEC) is the most common gastrointestinal (GI) emergency that primarily affects premature infants. In the last decade, there have been significant advances to our understanding of neonatal NEC. The exact etiology of NEC remains unclear, but it is widely considered a multifactorial disease; prematurity, enteral feeding, intestinal hypoxia-ischemia, and bacterial colonization are considered major risk factors. We report a case of a 35 week preterm infant with recurrent episodes of supraventricular tachycardia who developed NEC in the second week of life. This case underscores the importance of being appropriately cautious in the feeding of these high-risk premature infants.",
"affiliations": "Department of Pediatrics, University of Kentucky, Lexington, KY, USA.",
"authors": "Hanna|M H|MH|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.3233/NPM-1372013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-4429",
"issue": "6(4)",
"journal": "Journal of neonatal-perinatal medicine",
"keywords": "Necrotizing enterocolitis; supraventricular tachycardia",
"medline_ta": "J Neonatal Perinatal Med",
"mesh_terms": "D020345:Enterocolitis, Necrotizing; D006801:Humans; D007081:Ileostomy; D007231:Infant, Newborn; D007234:Infant, Premature; D008297:Male; D012008:Recurrence; D013617:Tachycardia, Supraventricular",
"nlm_unique_id": "101468335",
"other_id": null,
"pages": "359-61",
"pmc": null,
"pmid": "24441095",
"pubdate": "2013-01-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Necrotizing enterocolitis after recurrent supraventricular tachycardia.",
"title_normalized": "necrotizing enterocolitis after recurrent supraventricular tachycardia"
} | [
{
"companynumb": "US-APOTEX-2017AP017758",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ESMOLOL HYDROCHLORIDE"
},
"drugadditional": "3",... |
{
"abstract": "To evaluate the impact of cisplatin-based neoadjuvant chemotherapy (NAC) in patients who underwent nephroureterectomy for high-grade (HG) upper tract urothelial carcinoma (UTUC).\n\n\n\nRetrospective review was conducted of patients with HG UTUC from 2011 to 2017 who underwent nephroureterectomy at 2 institutions. Patients with eGFR >50 mL/min/1.73 m2 were considered eligible for NAC and were referred for evaluation of NAC prior to nephroureterectomy. Patient demographics, kidney function, clinical and pathologic response rates, and outcomes were analyzed.\n\n\n\nOf 95 patients with HG UTUC meeting inclusion criteria (mean age 72.3 years, mean preop eGFR 57.0 mL/min/1.73 m2), 61 patients were considered eligible for NAC with eGFR >50 mL/min/1.73 m2, of which 25 (41%) received NAC. Of the patients who received NAC, 80% (20/25) of the patients had clinical response on imaging and 80% (20/25) had pathologic response (<pT2N0 disease) on nephroureterectomy. On final pathology, only 20% of the NAC group had ≥pT2 disease compared to 64% of patients who proceeded directly to surgery (P = .001). Patients who received NAC had significantly longer progression free survival (P = .051) and overall survival (P = .052) compared to patients who proceeded directly to surgery. No patients progressed or were deemed ineligible for surgery due to NAC.\n\n\n\nCisplatin-based NAC demonstrated a high clinical and pathologic response rate in patients with HG UTUC without compromising definitive surgical treatment. Since nephroureterectomy significantly reduces kidney function and eligibility for cisplatin-based chemotherapy after surgery, patients with HG UTUC should be considered for NAC.",
"affiliations": "Department of Urology, NYU Langone Health, New York, NY.;Department of Urology, NYU Langone Health, New York, NY.;Department of Urology, NYU Langone Health, New York, NY.;Department of Urology, NYU Langone Health, New York, NY.;Department of Urology, Columbia University Medical Center, New York, NY.;Department of Medical Oncology, NYU Langone Health, New York, NY.;Department of Urology, NYU Langone Health, New York, NY.;Department of Urology, Columbia University Medical Center, New York, NY.;Department of Urology, NYU Langone Hospital - Brooklyn, Brooklyn, NY.;Department of Urology, Columbia University Medical Center, New York, NY.;Department of Urology, NYU Langone Health, New York, NY. Electronic address: William.Huang@nyulangone.org.",
"authors": "Meng|Xiaosong|X|;Chao|Brian|B|;Vijay|Varun|V|;Silver|Hayley|H|;Margolin|Ezra J|EJ|;Balar|Arjun|A|;Taneja|Samir S|SS|;Shah|Ojas|O|;Bjurlin|Marc A|MA|;Anderson|Christopher B|CB|;Huang|William C|WC|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "United States",
"delete": false,
"doi": "10.1016/j.urology.2019.01.058",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0090-4295",
"issue": "129()",
"journal": "Urology",
"keywords": null,
"medline_ta": "Urology",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D002295:Carcinoma, Transitional Cell; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D000074682:Nephroureterectomy; D009518:New York; D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome; D014571:Urologic Neoplasms",
"nlm_unique_id": "0366151",
"other_id": null,
"pages": "146-152",
"pmc": null,
"pmid": "30930207",
"pubdate": "2019-07",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "High Response Rates to Neoadjuvant Chemotherapy in High-Grade Upper Tract Urothelial Carcinoma.",
"title_normalized": "high response rates to neoadjuvant chemotherapy in high grade upper tract urothelial carcinoma"
} | [
{
"companynumb": "US-HQ SPECIALTY-US-2019INT000177",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "Differentiation therapy based on all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) for the treatment of acute promyelocytic leukemia (APL) is complicated by the development of differentiation syndrome (DS), which can be fatal. We examined the role of HMGB1 (high-mobility group box 1) in DS using both in vitro and in vivo models. HMGB1 and the pro-inflammatory cytokines IL-1β and TNF-α were gradually released from NB4 and HL-60 cells treated with ATRA and/or ATO. Similarly, higher serum HMGB1 levels positively correlated with the clinical status of DS patients. Exogenous HMGB1 promoted rapid release of IL-1β and TNF-α as well as elevated expression of ICAM-1, without altering cell differentiation. Exogenous HMGB1 also enhanced pulmonary infiltration and up-regulated ICAM-1 expression in the ATRA-treated DS mouse. Pharmacological inhibition or depletion of MEK1/2 reduced the cytokine levels and suppressed expression of ICAM-1 and the adhesion of HMGB1-treated NB4 cells to endothelial cells, implicating MEK/ERK signaling in the response to HMGB1 during DS. Treatment with a HMGB1-neutralizing antibody reduced secretion of TNF-α and IL-1β, arrested the elevation of ICAM-1 and blunted the activation of ERK1/2 in ATRA-induced NB4 cells. The HMGB1-neutralizing antibody also decreased ICAM-1 expression and reduced mortality in ATRA-treated DS model mice. These findings demonstrate that released HMGB1 is central to DS, and that targeting HMGB1 may be of therapeutic value in the treatment of DS.",
"affiliations": "Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People's Republic of China.;Department of Nuclear Medicine, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410008, People's Republic of China.;Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People's Republic of China.;Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People's Republic of China.;Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People's Republic of China.;Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People's Republic of China.;Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People's Republic of China.;Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People's Republic of China.",
"authors": "Tang|Lanlan|L|;Chai|Wenwen|W|;Ye|Fanghua|F|;Yu|Yan|Y|;Cao|Lizhi|L|;Yang|Minghua|M|;Xie|Min|M|;Yang|Liangchun|L|",
"chemical_list": "D015815:Cell Adhesion Molecules; D016207:Cytokines; D024243:HMGB1 Protein; D018836:Inflammation Mediators",
"country": "United States",
"delete": false,
"doi": "10.18632/oncotarget.15432",
"fulltext": "\n==== Front\nOncotargetOncotargetOncotargetImpactJOncotarget1949-2553Impact Journals LLC 284048911543210.18632/oncotarget.15432Research PaperHMGB1 promotes differentiation syndrome by inducing hyperinflammation via MEK/ERK signaling in acute promyelocytic leukemia cells Tang Lanlan 1Chai Wenwen 2Ye Fanghua 1Yu Yan 1Cao Lizhi 1Yang Minghua 1Xie Min 1Yang Liangchun 11 Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People's Republic of China2 Department of Nuclear Medicine, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410008, People's Republic of ChinaCorrespondence to:Liangchun Yang,yangliangchung@163.com18 4 2017 17 2 2017 8 16 27314 27327 23 9 2016 24 1 2017 Copyright: © 2017 Tang et al.2017This 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.Differentiation therapy based on all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) for the treatment of acute promyelocytic leukemia (APL) is complicated by the development of differentiation syndrome (DS), which can be fatal. We examined the role of HMGB1 (high-mobility group box 1) in DS using both in vitro and in vivo models. HMGB1 and the pro-inflammatory cytokines IL-1β and TNF-α were gradually released from NB4 and HL-60 cells treated with ATRA and/or ATO. Similarly, higher serum HMGB1 levels positively correlated with the clinical status of DS patients. Exogenous HMGB1 promoted rapid release of IL-1β and TNF-α as well as elevated expression of ICAM-1, without altering cell differentiation. Exogenous HMGB1 also enhanced pulmonary infiltration and up-regulated ICAM-1 expression in the ATRA-treated DS mouse. Pharmacological inhibition or depletion of MEK1/2 reduced the cytokine levels and suppressed expression of ICAM-1 and the adhesion of HMGB1-treated NB4 cells to endothelial cells, implicating MEK/ERK signaling in the response to HMGB1 during DS. Treatment with a HMGB1-neutralizing antibody reduced secretion of TNF-α and IL-1β, arrested the elevation of ICAM-1 and blunted the activation of ERK1/2 in ATRA-induced NB4 cells. The HMGB1-neutralizing antibody also decreased ICAM-1 expression and reduced mortality in ATRA-treated DS model mice. These findings demonstrate that released HMGB1 is central to DS, and that targeting HMGB1 may be of therapeutic value in the treatment of DS.\n\nHMGB1differentiation syndromecytokinesadhesive moleculeMEK/ERK\n==== Body\nINTRODUCTION\nAcute promyelocytic leukemia (APL) is characterized by a reciprocal balanced translocation between chromosomes 15 and 17 [t (15; 17)] leading to a fusion between the promyelocytic leukemia (PML) and the retinoic acid receptor-α (RARα) gene [1]. Morphologically, APL is categorized as AML-M3 based on the French-American-British (FAB) classification scheme. All-trans retinoic acid (ATRA) and arsenic trioxide (ATO) are used for APL therapy since they degrade the PML-RARα oncoprotein and differentiate the leukemic cells resulting in clinical remission of APL patients [2]. However, long-term exposure of ATRA and ATO results in hyper-inflammation and development of the differentiation syndrome (DS) [3, 4].\n\nThe DS involves the cytokine storm that coincides with the differentiation of blasts [3]. Yet the underlying pathogenic mechanisms for DS, which was previously called the retinoic acid syndrome that can be fatal to APL patients are unknown. The classic symptoms of DS include respiratory distress, unexplained fever, weight gain, interstitial pulmonary infiltration, pleural or pericardial effusion, hypotension and acute renal failure [5]. Complications that occurred during induction therapy with ATRA and/or ATO when leukemic blasts were abundant were rare during consolidation or maintenance therapy [6, 7]. Either alone or in combination with cytotoxic drugs, induction therapy with ATRA or ATO induced DS in 2-30% of APL patients [8]. Treatment with corticosteroids and close monitoring of symptoms has reduced DS associated mortality from historical high of 30% to about 2–10% [9]. Therefore, mechanistic understanding of the differentiation-related hyper-inflammation is necessary to identify novel therapeutic targets for DS.\n\nAs a highly conserved nuclear protein, HMGB1 (high-mobility group box 1) is a highly conserved nuclear protein that acts as a chromatin-binding factor for bending DNA and promoting access to transcriptional protein assemblies on specific DNA targets [10]. Additionally, it functions as a prototypic damage-associated molecular pattern (DAMP) molecule that is released from various cancer cells after chemotherapy or radiotherapy and is implicated in many cancer associated inflammation disorders [11]. The release of HMGB1 was identified as a trigger for acute anti-neoplastic inflammation that was initiated against tumor cells during chemotherapy [12]. Tumor-derived HMGB1 inhibited the cytotoxic anti-tumor CD8+ cells by potentiating regulatory IL-10-producing T cells [13]. Also, exogenous HMGB1 positively correlated with the clinical status in childhood leukemia and stimulated leukemic cells to secrete TNF-α [14]. However, the role of HMGB1 including its impact on hyper-inflammation during the development of DS in APL patients is unknown.\n\nTherefore, in this study we explored the relationship between exogenous HMGB1 and the clinical status of DS patients by examining its effects on NB4 cell differentiation, pro-inflammatory cytokine secretion and expression of cell adhesive molecules. Further, we investigated the signaling pathway activated by HMGB1 that regulates the pathological mechanisms in DS using both the in vitro and in vivo DS mouse model.\n\nRESULTS\nHMGB1 release and correlation with clinical stage of DS patients\nDuring induction treatment for APL, DS manifests between 2 to 46 days with the predominant symptoms being fever, respiratory failure and fluid retention resulting in weight gain [3, 4]. The criteria for definitive DS diagnosis included appearance of three or more symptoms and signs [15]. The most severe clinical outcome of DS during ATRA treatment of APL is hyper-inflammation that involves excessive cytokine secretions and induction of cell surface adhesive molecules [3]. Therefore, to study DS and the causative factors, we enrolled 38 patients from January 2012 to December 2015 that were newly diagnosed with APL and aged between 1-13 years. These patients received 25 mg/m2/day ATRA plus cytarabine and daunorubicin chemotherapy as induction treatment. Firstly, we quantified the serum levels of IL-1β, TNF-α and HMGB1 from 1 case of newly diagnosed APL patient developed DS on the eighth day after ATRA treatment using ELISA. We observed a gradual increase suggesting that HMGB1 was linked to inflammatory response during induction treatment of APL (Figure 1A).\n\nFigure 1 HMGB1 and pro-inflammtory cytokines are released from cells during DS\nA. Quantification of serum TNF-α, IL-1β and HMGB1 levels after ATRA treatment (25 mg/m2/day) in one patient for 0-8 day by ELISA (n=3, *P<0.05 versus untreated group); B. Quantification of serum HMGB1 and cytokines after ATRA treatment (25 mg/m2/day) in 10 DS patients with different clinical status. The serum amounts of TNF-α, IL-1β and HMGB1 in the DS patients at different time points during DS was analyzed by ELISA. Each dot represents the level of TNF-α, IL-1β or HMGB1 in each sample. Group a represents time point before ATRA treatment; Group b represents time point when DS developed; Group c represents time point with DS complete remission (n=3, *P<0.05 versus group a/c). C. Quantification of HMGB1 protein and mRNA in the sera of DS and non-DS patients after ATRA treatment. A total of 38 patients with newly diagnosed APL received ATRA were analyzed. The serum samples of DS patients were collected range from day 3 to 16. If patients didn't demonstrate DS in 2 weeks, serum samples of non-DS patients were collected at day 14. HMGB1 protein and mRNA in sera were detected by ELISA and real-time quantitative PCR, respectively. Each dot represents HMGB1 levels in each sample. Control, normal healthy subjects; DS, patients with differentiation syndrome; non-DS, patients without differentiation syndrome (n=3, *P<0.05 versus non-DS group).\n\nFurther, we observed that ten of the 38 patients developed DS, of which 4 were severe [≥4 symptoms of DS] and 6 were moderate [3 symptoms of DS]. The median time for development of DS from the start of ATRA administration was 9 days (range: 3-16). Eight of the ten DS patients (80%) achieved remission under close observation and prompt administration of corticosteroids, whereas two others (20%) died. To investigate the plausible reasons for DS in these patients, cytokine levels were measured at various clinical stages. Our data suggested that the serum concentrations of IL-1β, TNF-α and HMGB1 were elevated in DS patients compared to primary and DS remission stages (Figure 1B) and hence were closely linked to the clinical status of the disease.\n\nTo further characterize the role of HMGB1 in DS, its release was evaluated in the 38 APL patients after chemotherapy using ELISA. As shown in Figure 1C, the serum levels of HMGB1 protein and mRNA were elevated in DS patients compared to normal healthy controls and non-DS patients. Moreover, leukocytosis correlated with higher HMGB1 secretion at diagnosis (a median WBC count of 8.6×109/l). These data suggested that HMGB1 was a prognostic indicator for DS (Table 1).\n\nTable 1 Clinical variables of DS patients*\nVariables at diagnosis\tDS group\tNon-DS group\tP-valuea\t\nHMGB1 (ng/ml)\t94.2 (63-154.1)b\t35.7 (10.5-79.4)\t0.000\t\nWBCs (×109/l)\t8.6 (1.5-54.7)\t3.4 (0.5-22.6)\t0.021\t\nHb (g/l)\t76 (29-114)\t81.5 (65-95)\t0.289\t\nPlatelet (×109/l)\t33(5-86)\t29.5 (5-321)\t0.829\t\nAge (years)\t8.5(3-13)\t6(1-13)\t0.147\t\nDS, differentiation syndrome; WBCs, white blood cells; Hb, hemoglobin; *patients having DS (≥3 symptoms of DS); aP-value in Mann-Whitney U test; bmedian values (minimum-maximum).\n\nInduction therapeutic agents, ATRA and ATO promote HMGB1 and cytokine release in human myeloid cells\nTo gain investigate the mechanisms underlying DS, we treated human myeloid cells, HL-60 and NB4 with ATRA and/or ATO for 24–72 h and quantified the supernatant concentrations of HMGB1, IL-1β and TNF-α by ELISA. We observed that HMGB1 levels gradually increased, especially in the ATRA plus ATO group compared to non-treated cells (Figure 2A). Further, ATRA and/or ATO treatments resulted in elevated levels of IL-1β and TNF-α in the supernatant of both the cell types, 48 h after treatment (Figure 2B). This suggested that the release of HMGB1 and the cytokines was a universal event upon treatment with ATRA and/or ATO.\n\nFigure 2 All-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) promote release of HMGB1 and cytokine release in human myeloid cells\nA. HL-60 and NB4 cells were treated with either ATRA (1 μM) or ATO (5 mM) for 24-72 h or ATRA plus ATO for 48 h and the amount of HMGB1 released into the supernatant was analyzed by ELISA. (n=3, *P<0.05 versus untreated group; #P<0.05 versus ATRA or HMGB1 group). B. HL-60 and NB4 cells were treated with ATRA (1 μM) or/and ATO (5 mM) for 48 h and the levels of TNF-α and IL-1β released into the supernatant were analyzed by ELISA. (n=3, *P<0.05 versus untreated group; #P<0.05 versus ATRA or HMGB1 group).\n\nExogenous HMGB1 has no effect on cell differentiation\nTo determine if DS was induced by the exogenous HMGB1, the effect of recombinant HMGB1 protein on cell viability was determined at various concentrations (10, 20 & 50 μg/ml) for 6-72 h (Figure 3A). At 10 and 20 μg/ml, HMGB1 did not inhibit growth between 6-48 h (inhibitory percentage <10%). However, treatment with 50 μg/ml HMGB1 resulted in significant growth inhibition between 6-72 h (Figure 3A). Further, as shown in Figure 3B, we observed time-dependent increase in LDH in the supernatant of NB4 cells treated with 10 μg/ml HMGB1 suggesting compromised cell membrane integrity in accordance with previous studies [18, 32].\n\nFigure 3 Effects of exogenous HMGB1 on ATRA-induced differentiation\nA. Viability of NB4 cells that were treated with exogenous HMGB1 (10, 20 & 50 μg/ml) for 6-72 h was determined by the CCK-8 assay. Viability of control cells (DMSO) was set as 100%. (n=3, *P <0.05 versus control group). B. LDH released by NB4 cells that were treated with HMGB1 (10 μg/ml) for 6-48 h was detected by LDH assay kit and expressed as percentage of control (n=3, *P>0.05 versus untreated group). C. Morphological features of NB4 cells that were treated with ATRA (1 μM) or HMGB1 (1 μg/ml) was determined by Wright-Giemsa staining and visualized by light microscopy (100X magnification). D. Differentiation of NB4 cells treated with ATRA (1 μM) or HMGB1 (10 μg/ml) for 6-48 h was examined by NBT reduction and surface CD11b expression in comparison to the control (DMSO) (n=3, *P<0.05 versus ATRA group). E. Expression of PML-RARα, P62 and LC3-I/II in NB4 cells treated with ATRA (1 μM) or HMGB1 (10 μg/ml) for 48 h was assayed by western blotting and co-immunoprecipitation in comparison to control (DMSO).\n\nTo determine the role of exogenous HMGB1 in differentiation of APL cells, the morphology of recombinant HMGB1 protein-treated NB4 cells was assessed. Aggregation of NB4 cells with irregular nuclei was observed at 48 h after incubation with ATRA, but no morphological differences were observed in cells treated with HMGB1 (Figure 3C). Further, enhanced expression of myeloid differentiation cell surface marker CD11b and the functional differentiation as determined by NBT reduction was observed only upon ATRA treatment and HMGB1 treatment had no effect (Figure 3D).\n\nThe direct molecular target of ATRA in human myeloid cells is the PML-RARα oncoprotein that mediates differentiation. Previously, we demonstrated that up-regulated endogenous HMGB1 promoted autophagy and induced NB4 cell differentiation via ubiquitin-binding adaptor protein p62/SQSTM1-mediated degradation of PML-RARα oncoprotein [16]. However, in this study, the exogenous treatment of cells with the recombinant HMGB1 protein failed to induce degradation of PML-RARα and conversion of LC3-I to LC3-II in comparison to ATRA treatment (Figure 3E). Further, P62 and PML-RARα did not co-IP in cells treated with exogenous HMGB1 compared to ATRA (Figure 3E). This suggested that exogenous HMGB1 did not induce cell differentiation.\n\nHMGB1 induced cytokine secretion, adhesive molecule expression and enhanced endothelial adhesion\nMounting evidence suggests that hyper-inflammation is critical for the development of DS [3, 4]. To determine if exogenous HMGB1 directly induced inflammatory response in NB4 cells, we observed its effects on pro-inflammatory molecules involved in DS, including TNF-α, IL-1β and ICAM-1. Treatment of recombinant HMGB1 (10 μg/ml) protein resulted in the release of TNF-α (from 2 h to 16 h) and IL-1β (from 2 h to 8 h) in a time-dependent manner (Figure 4A). Moreover, ICAM-1 expression was significantly elevated with ATRA and/or recombinant HMGB1 protein treatment based on FACS, western blot and qRT-PCR data (Figure 4B & 4C). Combination of ATRA and HMGB1 lead to greater ICAM-1 expression than ATRA alone (Figure 4B & 4C). These data suggested a potential pro-inflammatory role for exogenous HMGB1 in ATRA-induced differentiation. Endothelial adhesion of activated leukocytes is a critical step during inflammation [17]. Therefore, when NB4 cells treated with ATRA and HMGB1 were co-incubated with EA.hy926 endothelial cells, increased endothelial adhesion was observed (Figure 4D) suggesting that HMGB1 was involved in inflammation.\n\nFigure 4 Exogenous HMGB1 induced cytokine secretion, up-regulated expression of ICAM-1 and enhanced endothelial adhesion in NB4 cells\nA. Levels of TNF-α and IL-1β secreted by NB4 cells that were treated with HMGB1 (10 μg/ml) for 2-32 h were detected by ELISA. (n=3, *P<0.05 versus control group). B. and C. Levels of ICAM-1 expressed in NB4 cells that were treated with ATRA (1 μM) for 48 h, HMGB1 (10 μg/ml) for 8 h or ATRA (1 μM) for 48 h followed by HMGB1 (10 μg/ml) for 8 h were determined by flow cytometry, western blot and qRT-PCR. ICAM-1 levels were expressed as a percentage of control (DMSO) (n=3, *P<0.05 versus control group; #P<0.05 versus ATRA or HMGB1 group). D. Determination of cell adhesiveness of NB4 cells after treatment with ATRA (1 μM) for 48 h, HMGB1 (10 μg/ml) for 8 h or ATRA (1 μM) for 48 h followed by HMGB1 (10 μg/ml) for 8 h. Towards this, NB4 cells were fluorescently tagged by CM-Dil. Then, the fluorescent NB4 cells were co-incubated with EA.hy926 endothelial cells (transfected with pEGFP-N1 vector) and observed microscopically (100X magnification) and quantified fluorometrically. The data were expressed as a percentage of the DMSO control (n=3, *P<0.05 versus control group; #P<0.05 versus ATRA or HMGB1 group).\n\nExogenous HMGB1 promotes lung infiltration in the DS model\nSimilar to a previous study [18], we created a NOD/SCID mouse model of DS by injecting ATRA-treated NB4 cells followed by continuous administration of ATRA. The study design is summarized in Figure 5A. We evaluated the effect of HMGB1 on the histology of lung based on hematoxylin & eosin (HE) staining. Mice that received a tail vein injection of ATRA-untreated NB4 cells followed by a 6-day oral administration of PBS and an abdominal injection of DMSO or recombinant HMGB1 protein did not show any cellular infiltration in the lungs (Figure 5B, groups 1 & 2). However, mice that received ATRA-treated NB4 and subsequent six-day oral administration of ATRA and abdominal injection of DMSO (HMGB1's control) demonstrated severe cellular infiltration, widened lung intervals, highly congested pulmonary interstitial space and fractured alveolar walls (Figure 5B, group 3). Moreover, the DS model mice that were injected abdominally with recombinant HMGB1 protein showed significant changes in lung tissue compared to group 3 (Figure 5B, group 4). Furthermore, immunohistochemistry revealed that ICAM-1 was highly expressed in the lung vascular endothelial cells (CD31 positive) of ATRA-treated DS model mice (Figure 5C, group 3). Since co-treatment of exogenous HMGB1 and ATRA (group 4) significantly increased the expression of ICAM-1 compared to group 3 (Figure 5C), we concluded that HMGB1 effectively promoted lung infiltration in the DS model.\n\nFigure 5 Effects of HMGB1 on pulmonary infiltration in mice\nA. Experimental scheme shows twenty-four mice divided into four groups that received different treatments. Note: i.p. = intraperitoneal injection. B. Hematoxylin & Eosin staining of lung tissue sections. After 6-days of treatments, the mice from the four groups were sacrificed, the lungs were removed and tissue sections were prepared as described in the methods. After staining with hematoxylin & eosin, the specimens were examined microscopically under high power field (400X magnification). C. Immunohistochemistry of ICAM-1 in lung tissue sections of mice from the four treatments was performed as described in the methods. The specimens were examined microscopically under 400X magnification. The lung vascular endothelial cells were marked by CD31 antibody. The arrows indicate positive immunoreactivity of ICAM-1 and/or CD31.\n\nRequirement of MEK/ERK pathway for HMGB1-mediated cytokine secretion and ICAM-1 elevation\nThe cytokines and ICAM-1 are up-regulated by a variety of intracellular signaling pathways, including mitogen-activated protein kinases (MAPKs) and nuclear transcriptional factors-κB (NF-κB) [19]. To determine if exogenous HMGB1 directly regulated these pathways, we analyzed the activation of ERK, JNK, p38 MAPKs and NF-κB in ATRA and/or HMGB1-treated NB4 cells. We observed that ERK1/2, JNK1/2, p38 and NF-κB (p65) were activated as suggested by their phosphorylation in response to treatment with ATRA and/or recombinant HMGB1 protein (Figure 6A). Further, combination of ATRA and exogenous HMGB1 showed greater activation compared to ATRA alone (Figure 6A). These results suggested that ERK1/2, JNK1/2, p38 and NF-κB (p65) were primary candidates for exogenous HMGB1-mediated inflammation. To further confirm this, ICAM-1 expression was analyzed in HMGB1 and ATRA-treated NB4 cells in presence of MEK, JNK, p38 and NF-κB inhibitors were used. Only MEK inhibitor partially inhibited ICAM-1 elevation (Figure 6B & 5C). Furthermore, transfection of target-specific shRNAs against MEK1/2 that depleted MEK1/2 expression inhibited both ICAM-1 and p-ERK1/2 (Figure 6C). This suggested that MEK/ERK was necessary for exogenous HMGB1-mediated ICAM-1 elevation in ATRA-induced NB4 cells.\n\nFigure 6 Role of MEK/ERK pathway in HMGB1-mediated cytokine secretion and ICAM-1 elevation\nA. The MAPK signaling pathway was analyzed in NB4 cells that were treated with ATRA (1 μM) for 48 h or/and HMGB1 (10 μg/ml) for 8 h by western blot analysis of phosphorylated and non-phosphorylated p38, Jnk and Erk kinases. Also, NF-kB pathway was analyzed by detecting the levels of p65 and IkB-α proteins for the same treatments described above along with PCNA. Actin was used as control. B. ICAM-1 levels were determined by FACS analysis of NB4 cells that were treated with ATRA (1 μM) for 48 h followed by HMGB1 (10 μg/ml) for 8 h with or without pre-treatment of the p38, Jnk, NF-kB or MEK inhibitors for 30 min (n=3, *P<0.05 versus MEK ATRA+HMGB1 group; #P>0.05 versus P38, JNK or NF-κB ATRA+HMGB1 group). C. The requirement for MEK/ERK signaling in DS was analyzed by detecting the levels of ICAM-1, MEK1/2 and p-ERK by western blot in NB4 cells that after pre-treatment with U0126 (20 μM) for 30 min or transfection with MEK1/2 siRNA for 48 h were induced by ATRA (1μM) for 48h followed by HMGB1 (10 μg/ml) for 8 h. D. Adhesion property of NB4 cells that were transfected with MEK1/2 or control siRNA for 48 h and treated with ATRA (1 μM) for 48 h followed by HMGB1 (10 μg/ml) for 8 h was analyzed as described in the methods. Briefly, the treated cells were fluorescence-labeled with CM-Dil and then co-incubated with EA.hy926 endothelial cells (transfected with pEGFP-N1 vector) to monitor cell-cell adhesion. Fluorescent NB4 cells adherent on endothelial cells were observed microscopically and quantified fluorometrically (100X magnification). The data were expressed as percentages relative to the control group (n=3, *P<0.05 versus control siRNA group).\n\nTo further characterize the role of the MEK/ERK pathway in exogenous HMGB1-mediated inflammation, cytokine secretion and cell adhesion molecules were analyzed in ATRA and HMGB1-treated cells in presence of either MEK1/2 inhibitor (U0126) or MEK1/2 depletion. U0126 significantly diminished the secretion of TNF-α and IL-1β upon HMGB1 and ATRA co-induction (Table 2). Moreover, knockdown of MEK1/2 attenuated the adhesion of exogenous HMGB1 and ATRA co-treated NB4 cells in the endothelial adhesion assay (Figure 6D). This suggested that HMGB1 mediated inflammation through the MEK/ERK signaling pathway in the ATRA-induced NB4 cells.\n\nTable 2 Effects of U0126 on the secretion of cytokines in HMGB1-mediated NB4 cells\n\tTime\tControl\tU0126\tHMGB1+ATRA\tHMGB1+ATRA+U0126\t\nIL-1β (pg/ml)\t24h\t2.8±0.6\t2.4±0.7\t6.9±0.8\t3.0±1.2\t\n\t48h\t5.9±0.7\t5.7±0.8\t25.3±1.2*\t9.2±0.7**\t\n\t72h\t6.5±1.1\t8.2±1.1\t72.6±3.0 *\t30.5±2.9**\t\nTNF-α (pg/ml)\t24h\t11.3±2.3\t12.8±2.7\t42.1±8.4\t12.9±2.3\t\n\t48h\t21.1±2.0\t20.2±1.4\t128.9±18.0*\t71.0±14.8**\t\n\t72h\t50.9±7.5\t43.3±7.6\t539.7±51.1*\t293.2±44.7**\t\nNote: *P <0.01, vs control group; **P<0.05, vs HMGB1 group\n\nHMGB1 neutralizing antibody reduced the inflammatory response to ATRA treatment\nTo further find conclusive evidence regarding the regulation of HMGB1 in pro-inflammatory function after chemotherapy, ATRA-induced NB4 cells that were incubated with 10 μg/ml neutralizing antibody against HMGB1 [20] showed partial reduction of TNF-α and IL-1β secretion compared to the negative control (Figure 7A). In addition, treatment of HMGB1-neutralizing antibody partially inhibited ICAM-1 elevation (Figure 7B) and reduced ERK1/2 phosphorylation compared to the ATRA-treated group (Figure 7C). Moreover, the ATRA-treated DS mouse model with an abdominal injection of HMGB1-neutralizing antibody showed a significant decrease of ICAM-1 expression (Figure 7D, group c) and mice death (Supplementary Figure 2). These data conclusively supported the pro-inflammatory function of exogenous HMGB1 in ATRA chemotherapy that lead to DS.\n\nFigure 7 Inhibition of HMGB1 level blunted HMGB1-mediated inflammatory response\nA. The levels of TNF-α and IL-1β in the supernatant of NB4 cells that were treated with ATRA (1 μM) for 24-72 h with or without HMGB1-neutralizing antibody (10 μg/ml) were analyzed by ELISA (n=3, *P<0.05 versus control IgG group). B. ICAM-1 levels in NB4 cells that were treated with ATRA (1 μM) for 48 h with or without co-incubation with HMGB1-neutralizing antibody (10 μg/ml) was determined by flow cytometry (left, surface expression), western blot (center, total protein) and qRT-PCR (right, mRNA). Incremental production of ICAM-1 was expressed as a percentage of control (n=3, *P<0.05 versus ATRA + control IgG group). C. The activation of the MEK/ERK signaling pathway was analyzed in NB4 cells that were treated with ATRA (1μM) for 48 h with or without co-incubation with HMGB1-neutralizing antibody (10 μg/ml) by western blot analysis of ERK1/2 and p-ERK1/2. D. Immunohistochemistry of ICAM-1. Lung tissue sections were prepared from the mice that were sacrificed 6-days after treatment and immunohistochemical staining of ICAM-1 was performed as described in the methods. The lung vascular endothelial cells were marked by the CD31 antibody with the arrows indicating positive immunoreactivity of ICAM-1 and CD31. Group a, non-DS model receiving DMSO; Group b: DS model receiving DMSO; Group c: DS model receiving HMGB1-neutralizing antibody. (400X magnification).\n\nDISCUSSION\nThe pathogenesis of DS is not well understood. Mounting evidence suggests that sustained hyperinflammation is critical for the development of DS [3, 4]. Emigration of ATRA-treated APL cells into lungs and other tissues recapitulates the molecular events during inflammation and immune responses [21]. The major molecular mediators of inflammation during ATRA-induced APL are pro-inflammatory cytokines and ICAM-1 [20, 22]. ATRA induces release of early pro-inflammatory cytokines such as TNF-α and IL-1β [22, 23], which promote endothelial adhesion in NB4 cells [24, 25]. In comparison to IL-1β and TNF-α, exogenous HMGB1 is released in a delayed manner and functions as a late inflammation mediator. As a potential therapeutic target, it provides a broader time window for clinical interventions [26]. In our study, we demonstrated elevated TNF-α and IL-1β levels in the cell supernatant and patient sera after chemotherapy. Also, similar to the cytokine secretions, ATRA induced HMGB1 release into the cell supernatants and patient sera. Therefore, the expression of HMGB1 positively correlated with the clinical status of DS suggesting that it is involved in the mechanism leading to DS.\n\nHMGB1 contributes to the pathogenesis of various human diseases including leukemia and maybe relevant for understanding the mechanisms underlying DS and its therapy [27, 28]. Previous studies have shown that exogenous HMGB1 of levels reach as high as 200 ng/ml during anti-neoplastic immunity of leukemia chemotherapy and induce TNF-α and IL-1β secretion [14, 29]. However, at lower doses, HMGB1 failed to trigger inflammasome activation [29]. Consistent with previous studies, 10 μg/ml HMGB1 induced a time-dependent increase in TNF-α and IL-1β secretion. Moreover, HMGB1 dosing had no obvious effects on cell differentiation suggesting that suppressed release of HMGB1 may be a novel way of blunting differentiation-associated hyper-inflammation.\n\nIn addition to inducing the secretion of cytokines, HMGB1 promoted ATRA-induced ICAM-1 expression. Widely expressed at basal levels on the surface of endothelial cells, leukocytes and the APL cell line NB4, ICAM-1 is up-regulated by pro-inflammatory cytokines and ATRA [30, 31]. Association between ICAM-1 polymorphism and DS exists in ATRA-treated patients [32]. This is further reiterated by the fact that knockout of the ICAM-1 gene abolished inflammation-related syndrome in mice [33]. Furthermore, the interaction between endothelial cells and the extracellular matrix during leukocytic transmigration from the bloodstream into the tissues is critical for inflammation during the development of DS [24] and ICAM-1 is a principal mediator of leukocyte adhesion [34]. In this study, ATRA and/or exogenous HMGB1 significantly enhanced ICAM-1 elevation and endothelial adhesion in the in vitro assays as well as in the animal model of the DS [18]. Most DS patients manifest pulmonary changes due to leukemic pulmonary infiltration, granulocytic transmigration and endothelial leakage [20]. In our study, co-treatment of HMGB1 led to the classic manifestations of DS, i.e. severe cellular infiltration, widened pulmonary intervals, highly congested pulmonary interstitial space and fractured alveolar walls. Also, high upregulation of ICAM-1 was observed in the alveolar epithelial cells and pulmonary perivascular space. Thus both in vitro and in vivo data suggested that HMGB1 promoted hyperinflammation during ATRA treatment of APL.\n\nThe expression of cytokines and ICAM-1 is regulated by intracellular signaling pathways as MAPKs and NF-κB [35]. The ERK, JNK and p38 MAP kinases participate in cell proliferation, differentiation and inflammation [36]. The ubiquitous pleiotropic transcription factor, NF-κB activation plays vital roles in inflammation, immunity and survival [37]. As a late inflammation mediator, extracellular HMGB1 has been shown to mediate the release of TNF-α, IL-1β and other inflammatory mediators, endothelial cell activation, stromagenesis, recruitment and activation of innate immune cells and maturation of dendritic cells, thereby leading to chronic inflammatory response and activation of protein kinase B (AKT), MAPKs and NF-κB [38]. In the present study, exogenous HMGB1 enhances ATRA-induced phosphorylation of ERK, JNK, p38 and NF-κB, thereby implicating the MAPKs and NF-κB in the pro-inflammatory function of HMGB1.\n\nThe MEK/ERK pathway is a key diagnostic and therapeutic target for leukemia due to its extensive involvement in cell proliferation, differentiation, survival and apoptosis [39]. Extracellular signal-regulated kinase (MEK) functions as an immediate upstream activator of ERK [40]. It is well established that exogenous HMGB1 induces MEK/ERK activation in immune and cancer cells including leukemic cells [14, 41, 42]. Previously, the MEK/ERK pathway was shown to be essential for ATRA-induced ICAM-1 elevation in NB4 cells [23]. In this study, knockdown or pharmacological inhibition of MEK attenuated HMGB1-mediated ICAM-1 elevation, reduced IL-1β/TNF-α secretion and lowered cell adhesion. This suggested that MEK/ERK signaling was necessary for exogenous HMGB1-mediated inflammatory response. Furthermore, dose dependent treatment with anti-HMGB1 antibody significantly inhibited the secretion of cytokines, expression of cell surface adhesive molecules and activation of ERK1/2. In addition, the HMGB1-neutralizing antibody also decreased ICAM-1 expression and reduced ATRA-treated DS mouse model death further supporting the pro-inflammatory function of exogenous HMGB1 during DS.\n\nIn conclusion, HMGB1 plays a key role in the development of DS by inducing inflammation through the MEK/ERK signaling pathway. Therefore, HMGB1 is a potential target for DS therapy.\n\nMATERIALS AND METHODS\nReagents and antibodies\nRARα (sc-773), MEK1/2 (sc-436), NF-κB-p65 (sc-109), IκB-α (sc-1643), p62 (sc-28359) and actin (sc-47778) antibodies were obtained from Santa Cruz Biotechnology (TX, USA); The antibodies to CD11b (C0551) and ICAM-1 (C2969) were from Sigma(St. Louis, MO, USA); Antibody to LC3 (#NB600-1384) was from Novus (Littleton, CO, USA); The p-ERK1/2 (#9101), ERK1/2 (#4695), p-JNK (#9251), JNK (#9252), p-P38 (#9215), P38 (#9212) and PCNA (#2586) antibodies were from Cell Signaling Technology (MA, USA); ATRA, ATO, DMSO, JNK inhibitor (SP600125), p38 inhibitor (SB203580) and ERK inhibitor (U0126) were from Cell Signaling Technology (MA, USA); p65 inhibitor (BAY11-7802) was from Merck Millipore (Darmstadt, Germany); The recombinant HMGB1 protein was kindly provided by Dr. Rui Kang (University of Pittsburgh, USA).\n\nCell culture\nNB4 and HL-60 cells (Xiangya School of Medicine Type Culture Collection, China) were cultured in RPMI 1640 medium supplemented with 10% heat-inactivated FBS (Life Technologies, NY, USA) in 5% CO2. NB4 is a promyelocytic leukemia cell line, whereas HL-60 represents a discrete stage of differentiation between the late myeloblasts and the promyelocyte [43]. The human endothelial cell line, EA.hy926 (ATCC, VA, USA) was cultured in DMEM (Gibco BRL, NY, USA) supplemented with 10% FBS (Gibco BRL, NY, USA), penivilin (100ug/mL) and streptomycin (100ug/mL). All cells were incubated at 37°C in a humidified atmosphere of 5% CO2 and 95% air.\n\nMouse model of DS\nSeven- to 8-week male NOD/SCID (non-obese diabetic/severe combined immunodeficient) mice that weighed about 20g were purchased in 2 batches of 24 mice each from the National Rodent Laboratory Animal Resources (Shanghai, China) and maintained at the Shanghai Shilaike Laboratory Animal Co, Ltd. The animal raising and experimental procedures were approved by the Shanghai Animal Welfare & Research Ethics Committee, Science & Technology Committee of Shanghai Municipal Government, China. The animals were raised in pathogen-free conditions with a 12-hour light-dark cycle with water and food provided ad libitum. For each experiment, 24 mice were randomly divided into the following 4 groups: (1) non-DS model receiving DMSO; (2) non-DS model receiving HMGB1; (3) DS model receiving DMSO and (4) DS model receiving HMGB1 treatment (Figure 5A). The DS mice model was established as previously described [18]. Briefly, at Day 1, mice were intravenously injected via a tail vein with 1×107 NB4 cells that were induced by 1mM ATRA. From days 1 to 6, the mice were orally administered with 100 μl ATRA (1 mg/ml) daily. The non-DS model mice received an intravenous injection via tail vein with 1×107 NB4 that were not induced by ATRA and were orally administered with 100 μl of phosphate buffered saline (PBS) every day from days 1 to 6. The HMGB1 or HMGB1-neutralizing antibody (or control DMSO) was administered in the control or model mice by a single intraperitoneal injection of 100 μl PBS containing 10 μg/ml HMGB1 or anti- HMGB1 antibody (or DMSO equivalent) from days 1 to 6. All the mice were sacrificed at day 7 after anesthesia. Their body weights were measured, organs extracted followed by peripheral white blood count and examination of the peripheral blood smear (Supplementary Figure 1). The lung specimens were fixed with 10% formalin followed by cutting 4-μm sections by microtome (Leica, Germany) that were further mounted on slides and stained with hematoxylin and eosin.\n\nCell viability assay\nCell viability assays after different treatments were conducted with the Cell Counting Kit-8 (CCK8) kit (Tokyo, Japan) according to the manufacturer's instructions.\n\nHMGB1, IL-1β and TNF-α quantification by ELISA\nThe levels of HMGB1, IL-1β and TNF-α in the cell supernatant or patient sera were quantified with the ELISA kits from Shino-Test Corporation (Kanagawa, Japan) or R&D Systems Inc (Minneapolis, MN, USA) according to the manufacturer's instructions.\n\nLactate dehydrogenase quantification assay\nCell membrane integrity was determined by assaying the lactate dehydrogenase (LDH) amounts in the supernatant using TOX-7 LDH assay kit (Sigma, MO, USA) [44]. Absorbance at 490nm wavelength was measured using a Wallace 1420 micro-plate reader (PerkinElmer, Waltham, MA, USA). The background optical absorbance at 690 nm was subtracted from the primary measurements for each well. LDH content in medium was calculated by extrapolation from a standard curve and expressed as units/L.\n\nRNAi and gene transfection\nHuman MEK1 siRNA (sc-35898: Sense: 5’-GAACCACAUUGAUAUUCUATT-3’; Antisense: 5’-UA GAAUAUCAAUGUGGUUCTT-3’), Human MEK2 siRNA (sc-35905: Sense: 5’-AGAGGCCAAGAGGAUUCCCTT-3’; Antisense: 5’-GGGAAUCCUCUUGGCCUCUTT-3’) and scrambled siRNA were obtained from Santa Cruz Biotechnology (TX, USA). Human MEK1/2 siRNA or pEGFP-N1 control plasmid (a gift from Dr Rui Kang, Hillman Cancer Center, University of Pittsburgh, USA) were performed with FuGENE HD Transfection Reagent (Roche Applied Science, Stockholm, Sweden) according to the manufacturer's instructions.\n\nFlow cytometry\nAfter culturing under various experimental conditions, the NB4 cells were collected by centrifugation and re-suspended in 50 μl BS-0.5% BSA solution containing adequate concentrations for cell surface adhesion molecules (20 μg/ml ICAM-1) or differentiation markers (10 μg/ml CD11b). Appropriate isotypic antibodies were used as controls. After 30-minute incubation at 4°C in darkness, the cells were washed twice with PBS and resuspended in 600 μl PBSA. Flow cytometry was performed in a BD FACS Calibur. Data acquisition was processed by the Cell Quest software.\n\nMorphologic observation of differentiation\nCellular morphology was assessed by light microscopy of Wright's-stained cyto-smear preparations as follows: after treatment, NB4 cells were pelleted at 1000 rpm for 5 minutes and the supernatant discarded. Cyto-smear for microscopic examination was prepared by spreading a small drop of cell pellet on a glass microscope slide and air-drying. The smears were subjected to Wright's staining and observed by microscope under high power field. Wright's staining solution solution was from Sigma-Aldrich.\n\nNitro blue tetrazolium reduction assay\nNB4 cells after specific treatments were centrifuged at 1500 rpm for 5 minutes and re-suspended in equal volumes of RPMI-1640 medium containing 0.2% Nitro Blue Tetrazolium (NBT; Sigma, St.Louis, MO, USA) and 2 μg/ml 12-O-tetradecanoylphorbol-13-acetate (TPA; Sigma, St.Louis, MO, USA) followed by incubation in darkness for 30 minutes at 37°C. The cells were further loaded with 100 μL DMSO into a 96-well plate and after gentle vortexing for 20 minutes, the absorbance of each well was measured at 570 nm in a Thermo Scientific Multiskan Ascent plate reader. The data are representative of three independent experiments.\n\nWestern blot analysis\nProteins in whole-cell lysate or subcellular fractions were resolved on a 10% SDS-PAGE and transferred onto PVDF membrane. After blocking for 3 h at room temperature, the membranes were incubated with various primary antibodies in TBST at 4°C overnight. Further, the membranes were incubated with peroxidase-conjugated secondary antibodies (1:5000) for 1 h at 25°C, followed by visualization of signals based on enhanced chemiluminescence (Pierce Biotechnology, Inc, Rockford, IL, USA.). Membranes were exposed to radiographic film and the expression of targeted proteins was quantified by detecting specific radiographic bands using the BandScan 5.0 system. The experiments were conducted in triplicate.\n\nImmunoprecipitation\nFor immunoprecipitation, cells were lysed at 4°C in ice-cold lysis buffer (50 mM Tris-HCl, pH 7.4, containing 150 mM NaCl, 1% NP-40, 0.5% Na-deoxycholate, 0.1% SDS, protease inhibitor cocktail) followed by centrifugation (12000xg,10min) to pellet the cell debris. The protein concentration in the supernatant was determined by bicinchoninic acid (BCA) assay. For immunoprecipitation, equal amounts of protein samples were first pre-cleared with protein A or protein G agarose / sepharose (Santa Cruz, CA, USA) at 4°C for 3h followed by incubation with various specific antibodies (5mg/mL) or control IgG in the presence of protein A or G agarose / sepharose beads for 2h or overnight at 4°C with gentle vortexing. After incubation, the agarose / sepharose beads were thoroughly rinsed with PBS and the proteins eluted by boiling in 2x SDS sample buffer prior to SDS-PAGE.\n\nQuantitative RT-PCR (qRT-PCR)\nTotal ribonucleic acid (RNA) was isolated from cells using Trizol reagent (Invitrogen, Carlsbad, CA, USA) according to the manufacturer's protocol. Reverse transcription of 1 μg total RNA was performed using 50 U murine leukemia virus reverse transcriptase, 50 μM random hexamers, and 10 mM deoxynucleoside triphosphates (dNTP) mix (Applied Biosystems, Foster City, CA, USA) in a total reaction volume of 20 μl. Afterwards, qRT-PCR was performed in duplicate with preoptimized primer/probe mixture (TaqMan Gene Expression Assay, Applied Biosystems, Foster City, CA, USA) and TaqMan universal PCR Master Mix (Applied Biosystems, Foster City, CA, USA) on a StepOnePlus Real-Time PCR System (Applied Biosystems, Foster City, CA, USA). The sequences of primers used for qRT-PCR were as follows: (1) ICAM-1 forward 5’-CACAAG CCACGCCTCCCTGAACCTA-3’ and reverse 5’-TGTGGGCCTTTGTGTTTTGATGCTA-3’; (2) HMGB1 forward 5’-TTGGGTCACATGGATTATTAGTGT-3’ and reverse 5’ -CAGGGCATGTGGACAAAAG-3’;(3) β-actin forward 5’-TGGCACCCAGCACAATGAA-3’ and reverse 5’-CTAAGTCATAGTCCGCCTAGAAGCA-3’. The following cycling protocol was used: polymerase activation, 50°C for 2 min, denaturation, 95°C for 10 min, and 35 to 44 cycles of 15 s denaturation at 95°C followed by 1 min of annealing and elongation at 60°C. Data were normalized against the β-actin internal control transcript and were analyzed according to the comparative threshold cycle method. The experiments were performed in triplicates.\n\nImmunohistochemistry\nThe lung tissues were fixed in 10% formalin for 24 h followed by dehydration and, paraffin embedding. Then, the paraffin embedded specimens were sliced into 5 μm thick sections by microtome (Leica, Germany) and placed on glass slides. Further, the specimens were deparaffinized, stained with hematoxylin and eosin (H&E) and evaluated under an optical microscope (Olympus BX51, Japan). The pulmonary expression of ICAM-1 and CD31 was determined by immunostaining. After deparaffinization and rehydrating, sections were pressure cooked in antigen retrieval buffer (0.01 M citrate buffer, pH 6.0) for 2 min to unmask antigens. Then, they were incubated with murine anti-rat ICAM-1 and CD31 monoclonal antibodies (1:200, Abcam, MA) at 4°C overnight, followed by biotinylated anti-mouse IgG secondary antibody (ZSGB-bio, China) for 1h at 37°C and streptavidin-HRP (ZSGB-bio, China) for 30 min at 37°C. Further, the HRP substrate, DAB (3, 3-diaminobenzidine; ZSGB-bio, China) was used to develop and visualize the immunostaining, whereas the cell nuclei were counter-stained with hematoxylin. Images were acquired with the Olympus BX51 microscope and the proportion of positive staining cells was determined with the Image-Pro plus 5.1 software.\n\nCell adhesion assay\nTo quantify the cell adhesion ability, the NB4 cells were first loaded in 12-well tissue culture plates at a concentration of 1×106 cells per well in RPMI 1640 medium. After different treatments, the cells were centrifuged at 1000 rpm for 3 minutes and washed twice with PBS. Further, 5×106 cells/mL were resuspended in PBS containing 5 μg/mL CM-Dil (chloromethyl-1,1-dioctadecyl-3,3,3′,3′-tetramethyl- indocarbocyanine perchlorate; Molecular Probes, CA, USA) for fluorescence labeling, incubated at 37°C for 5 minutes followed by additional incubation at 4°C for 15 minutes. The cell pellets were collected by centrifugation, washed twice with PBS and resuspended in RPMI 1640 medium prior to adding the cells onto the endothelial cell culture.\n\nThe EA.hy926 endothelial cells were seeded at 2×105 cells/cm2 in DMEM onto 6-well tissue culture plates and cultured for 2 days. Then, the culture medium was replaced by RPMI 1640 medium followed by addition of the fluorescence-labeled NB4 cells at a ratio of 1:1. After co-incubation in the RPMI1640 medium for 2 h, the non-adherent NB4 cells were washed off twice with PBS gently so that the endothelial cell monolayer was not disturbed. Fresh RPMI 1640 medium was then added for the remaining cells on the culture plates and the fluorescence-labeled NB4 cells adhering to the endothelial cell monolayer were observed under a Nikon eclipse TE2000-U fluorescence microscope (Tokyo, Japan). For quantification, adherent cells were lysed in 200 μL 0.1 M Tris-HCl containing 0.1% Triton X-100 and centrifuged at 13,000 rpm for 15 minutes. The fluorescent intensity of supernatant was determined at an excitation wavelength of 556nm and an emission wavelength of 573 nm in a LS55 fluorescent spectrometer (PerkinElmer, Waltham, MA, USA) and normalized for endothelial cells.\n\nStatistical analyses\nThe data were expressed as mean ±standard error. Statistical significance of differences between treatments was determined by a two-tailed Student's t-test or Mann-Whitney U test. P<0.05 was deemed as statistically significant.\n\nSUPPLEMENTARY FIGURES\n This project was supported by the grants of National Natural Science Foundation of China (Nos. 81400138, 81601528, 81270616 & 81370648) and Hunan Provincial Natural Science Foundation of China (No. 2015J-J6110).\n\nCONFLICTS OF INTEREST\n\nThe authors declare no potential conflicts of interest.\n==== Refs\nREFERENCES\n1 Mistry AR Pedersen EW Solomon E Grimwade D The molecular pathogenesis of acute promyelocytic leukaemia: implications for the clinical management of the disease Blood Rev 2003 17 71 97 12642121 \n2 Nasr R Lallemand-Breitenbach V Zhu J Guillemin M de The H Therapy-induced PML/RARA Proteolysis and Acute Promyelocytic Leukemia Cure Clin Cancer Res 2009 15 6321 6326 19808868 \n3 Luesink M Pennings JL Wissink WM Linssen PC Muus P Pfundt R de Witte TJ van der Reijden BA Jansen JH Chemokine induction by all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia: triggering the differentiation syndrome Blood 2009 114 5512 5521 19828696 \n4 Larson RS Tallman MS Retinoic acid syndrome: manifestations, pathogenesis, and treatment Best Practice & Research Clinical Hematology 2003 16 453 461 \n5 Rego EM De Santis GC Differentiation syndrome in promyelocytic leukemia: clinical presentation, pathogenesis and treatment Mediterranean journal of hematology and infectious diseases 2011 3 e2011048 22110898 \n6 Rust DM Soignet SL Risk/benefit profile of arsenic trioxide Oncologist 2001 62 29 32 \n7 Gupta V Yi QL Brandwein J Lipton JH Messner HA Schuh AC Wells RA Minden MD Role of all-trans-retinoic acid (ATRA) in the consolidation therapy of acute promyelocytic leukaemia (APL) Leukemia Res 2005 29 113 114 15541484 \n8 Montesinos P Bergua JM Vellenga E Rayon C Parody R de la Serna J Leon A Esteve J Milone G Deben G Rivas C Gonzalez M Tormo M Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors Blood 2009 113 775 783 18945964 \n9 Rogers JE Yang D Differentiation syndrome in patients with acute promyelocytic leukemia Journal of oncology pharmacy practice 2012 18 109 114 21364078 \n10 Harris HE Andersson U Pisetsky DS HMGB1: A multifunctional alarmin driving autoimmune and inflammatory disease Nature Reviews Rheumatology 2012 8 195 202 22293756 \n11 Tang D Kang R Zeh HR Lotze MT High-mobility group box 1 and cancer Biochim Biophys Acta 2010 1799 131 140 20123075 \n12 Apetoh L Ghiringhelli F Tesniere A Obeid M Ortiz C Criollo A Mignot G Maiuri MC Ullrich E Saulnier P Yang H Amigorena S Ryffel B Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy Nat Med 2007 13 1050 1059 17704786 \n13 Liu Z Falo LJ You Z Knockdown of HMGB1 in tumor cells attenuates their ability to induce regulatory T cells and uncovers naturally acquired CD8 T cell-dependent antitumor immunity J Immunol 2011 187 118 125 21642542 \n14 Kang R Tang D Cao L Yu Y Zhang G Xiao X [High mobility group box 1 is increased in children with acute lymphocytic leukemia and stimulates the release of tumor necrosis factor-alpha in leukemic cell]. [Article in Chinese] Zhonghua er ke za zhi 2007 45 329 333 17697615 \n15 Cardinale L Asteggiano F Moretti F Torre F Ulisciani S Fava C Rege-Cambrin G Pathophysiology, clinical features and radiological findings of differentiation syndrome/all-trans-retinoic acid syndrome World journal of radiology 2014 6 583 588 25170395 \n16 Yang L Chai W Wang Y Cao L Xie M Yang M Kang R Yu Y Reactive oxygen species regulate the differentiation of acute promyelocytic leukemia cells through HMGB1-mediated autophagy Am J Cancer Res 2015 5 714 725 25973309 \n17 Gonzalez-amaro R Cell adhesion, inflammation and therapy: old ideas and a significant step forward Acta Pharmacol Sin 2011 32 1431 1432 22036864 \n18 Ninomiya M Kiyoi H Ito M Hirose Y Ito M Naoe T Retinoic acid syndrome in NOD/scid mice induced by injecting an acute promyelocytic leukemia cell line Leukemia 2004 18 442 448 14749706 \n19 Hopkins PN Molecular biology of Atherosclerosis Physiol Rev 2013 93 1317 1542 23899566 \n20 Pandolfi F Altannura S Frosali S Conti P Key Role of DAMP in Inflammation, Cancer, and Tissue Repair Clin Ther 2016 38 1017 1028 27021609 \n21 Brown DC Tsuji H Larson RS All-trans retinoic acid regulates adhesion mechanism and transmigration of the acute promyelocytic leukaemia cell line NB-4 under physiologic flow Brit J Haematol 1999 107 86 98 10520028 \n22 Dubois C Schlageter MH de Gentile A Balitrand N Toubert ME Krawice I Fenaux P Castaigne S Najean Y Degos L Modulation of IL-8, IL-1 beta, and G-CSF secretion by all-trans retinoic acid in acute promyelocytic leukemia Leukemia 1994 8 1750 1757 7523800 \n23 Xu L Zheng Y Wang Y Yang Y Cao F Peng B Xu X An H Zheng A Zhang D Uzan G Yu Y Celastrol Inhibits Lung Infiltration in Differential Syndrome Animal Models by Reducing TNF-α and ICAM-1 Levels while Preserving Differentiation in ATRA-Induced Acute Promyelocytic Leukemia Cells PLoS ONE 2014 9 e105131 25116125 \n24 Di Noto R Schiavone EM Ferrara F Manzo C Lo Pardo C Del Vecchio L Expression and ATRA-driven modulation of adhesion molecules in acute promyelocytic leukemia Leukemia 1994 8 Suppl 2 S71 S76 \n25 Shibakura M Niiya K Kiguchi T Shinagawa K Ishimaru F Ikeda K Namba M Nakata Y Harada M Tanimoto M Simultaneous induction of matrix metalloproteinase-9 and interleukin 8 by all-trans retinoic acid in human PL-21 and NB4 myeloid leukaemia cells Brit J Haematol 2002 118 419 425 12139725 \n26 Wang HH Yang H Czura CJ Sama AE Tracey KJ HMGB1 as a late mediator of lethal systemic inflammation Am J Resp Crit Care 2001 164 1768 1773 \n27 Lotze MT Tracey KJ High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal Nat Rev Immunol 2005 5 331 342 15803152 \n28 Bae J Role of high mobility group box 1 in inflammatory disease: Focus on sepsis Arch Pharm Res 2012 35 1511 1523 23054707 \n29 Liu L Yang M Kang R Dai Y Yu Y Gao F Wang H Sun X Li X Li J Wang H Cao L Tang D HMGB1-DNA complex-induced autophagy limits AIM2 inflammasome activation through RAGE Biochem Bioph Res Co 2014 450 851 856 \n30 Larson RS Brown DC Sklar LA Retinoic acid induces aggregation of the acute promyelocytic leukemia cell line NB-4 by utilization of LFA-1 and ICAM-2 Blood 1997 90 2747 2756 9326242 \n31 Hordijk PL Endothelial signalling events during leukocyte transmigration FEBS journal 2006 273 4408 4415 16956370 \n32 Dore AI Santana-Lemos BA Coser VM Santos FL Dalmazzo LF Lima AS Jacomo RH Elias JJ Falcao RP Pereira WV Rego EM The association of ICAM-1 Exon 6 (E469K) but not of ICAM-1 Exon 4 (G241R) and PECAM-1 Exon 3 (L125V) polymorphisms with the development of differentiation syndrome in acute promyelocytic leukemia J Leukoc Biol 2007 82 1340 1343 17704297 \n33 Cunha De Santis G Tamarozzi MDB Sousa RB Moreno SE Secco D Garcia AB Lima ASG Faccioli LH Falcao RP Cunha FQ Rego EM Adhesion molecules and Differentiation Syndrome: phenotypic and functional analysis of the effect of ATRA, As2O3, phenylbutyrate, and G-CSF in acute promyelocytic leukemia Haematologica 2007 92 1615 1622 18055984 \n34 Ley K Laudanna C Cybulsky MI Nourshargh S Getting to the site of inflammation: the leukocyte adhesion cascade updated Nat Rev Immunol 2007 7 678 689 17717539 \n35 Hopkins PN Molecular Biology of Atherosclerosis Physiol Rev 2013 93 1317 23899566 \n36 Cobb MH MAP kinase pathways Prog Biophys Mol Bio 1999 71 479 500 10354710 \n37 Panday A Inda ME Bagam P Sahoo MK Osorio D Batra S Transcription Factor NF-kappaB: An Update on Intervention Strategies Arch Immunol Ther Exp (Warsz) 2016 \n38 Tang D Kang R Zeh HR Lotze MT High-mobility group box 1 and cancer Biochim Biophys Acta 2010 1799 131 140 20123075 \n39 Lee JJ McCubrey JA The Raf/MEK/ERK signal transduction cascade as a target for chemotherapeutic intervention in leukemia Leukemia 2002 16 486 507 11960326 \n40 Crews CM Alessandrini A Erikson RL The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product Science 1992 258 478 480 1411546 \n41 Liu L Yang M Kang R Wang Z Zhao Y Yu Y Xie M Yin X Livesey KM Lotze MT Tang D Cao L HMGB1-induced autophagy promotes chemotherapy resistance in leukemia cells Leukemia 2011 25 23 31 20927132 \n42 Tang D Kang R Xiao W Zhang H Lotze MT Wang H Xiao X Quercetin Prevents LPS-Induced High-Mobility Group Box 1 Release and Proinflammatory Function Am J Resp Cell Mol 2009 41 651 660 \n43 Drexler HG Quentmeier H MacLeod RA Uphoff CC Hu ZB Leukemia cell lines: in vitro models for the study of acute promyelocytic leukemia Leukemia Res 1995 19 681 691 7500643 \n44 Laughlin AM Welsh TH Jr Love CC Varner DD Parrish AR Forrest DW Ing NH In vitro culture of precision-cut testicular tissue as a novel tool for the study of responses to LH In Vitro Cell Dev-An 2010 46 45 53\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1949-2553",
"issue": "8(16)",
"journal": "Oncotarget",
"keywords": "HMGB1; MEK/ERK; adhesive molecule; cytokines; differentiation syndrome",
"medline_ta": "Oncotarget",
"mesh_terms": "D000293:Adolescent; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D015815:Cell Adhesion Molecules; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002470:Cell Survival; D002648:Child; D002675:Child, Preschool; D016207:Cytokines; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D024243:HMGB1 Protein; D006801:Humans; D007223:Infant; D018836:Inflammation Mediators; D015473:Leukemia, Promyelocytic, Acute; D020935:MAP Kinase Signaling System; D008297:Male; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D012074:Remission Induction; D023041:Xenograft Model Antitumor Assays",
"nlm_unique_id": "101532965",
"other_id": null,
"pages": "27314-27327",
"pmc": null,
"pmid": "28404891",
"pubdate": "2017-04-18",
"publication_types": "D016428:Journal Article",
"references": "14749706;12139725;19915939;17697615;24971542;17704786;23054707;11734424;15541484;20927132;15803152;19828696;1411546;7500643;23899566;20123075;18055984;16956370;7815843;10354710;21364078;11331438;27236331;19808868;21642542;7523800;17717539;27021609;18945964;9326242;17704297;22110898;19265175;12935962;22036864;10520028;25973309;22293756;12642121;11960326;25116125;25170395",
"title": "HMGB1 promotes differentiation syndrome by inducing hyperinflammation via MEK/ERK signaling in acute promyelocytic leukemia cells.",
"title_normalized": "hmgb1 promotes differentiation syndrome by inducing hyperinflammation via mek erk signaling in acute promyelocytic leukemia cells"
} | [
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"companynumb": "CN-CHEPLA-C20170212",
"fulfillexpeditecriteria": "2",
"occurcountry": "CN",
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"activesubstancename": "TRETINOIN"
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"abstract": "BACKGROUND\nCisplatin is one of the key drugs that is frequently used for treating various types of malignancies. Although renal and digestive toxicities are well-known cisplatin-related toxicities, attention should also be paid to acute aortic thrombosis, a relatively rare but potentially fatal disorder caused by cisplatin. Additionally, D-dimer is mainly measured to detect venous thromboembolism or disseminated intravascular coagulation, whereas its usefulness for detecting aortic thrombosis remains unclear. Here, we report a case of squamous cell lung cancer treated with cisplatin-based chemotherapy, wherein acute aortic thrombosis was diagnosed based on elevated D-dimer levels.\nA 65-year-old man with stage IV squamous cell lung cancer presented with elevated D-dimer levels during treatment with second-line chemotherapy with cisplatin and S-1. Contrast-enhanced computed tomography (CT) revealed an intramural thrombus, which had not been previously identified, extending from the abdominal aorta to the common iliac artery.\nWe diagnosed the patient as having acute aortic thrombosis caused by cisplatin.\n\n\nMETHODS\nThe patient received intravenous administration of unfractionated heparin for 9 days followed by oral warfarin.\n\n\nRESULTS\nOne month after initiating treatment, the patient's D-dimer levels decreased to the normal range, and contrast-enhanced CT revealed that the thrombi had nearly completely disappeared without any sequelae or organ damage.\n\n\nCONCLUSIONS\nOur findings revealed that cisplatin can cause acute aortic thrombosis and that regular measurements of D-dimer levels before and during chemotherapy may contribute to the early detection of acute aortic thrombosis.",
"affiliations": "Department of Respiratory Medicine, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, Japan.",
"authors": "Matsumoto|Yu|Y|0000-0002-6066-0014;Horimasu|Yasushi|Y|;Yamaguchi|Kakuhiro|K|;Sakamoto|Shinjiro|S|;Masuda|Takeshi|T|;Nakashima|Taku|T|;Miyamoto|Shintaro|S|;Iwamoto|Hiroshi|H|;Fujitaka|Kazunori|K|;Hamada|Hironobu|H|;Hattori|Noboru|N|",
"chemical_list": "D000925:Anticoagulants; D000970:Antineoplastic Agents; D005338:Fibrin Fibrinogen Degradation Products; C036309:fibrin fragment D; D014859:Warfarin; D006493:Heparin; D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000024695",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974\n1536-5964\nLippincott Williams & Wilkins Hagerstown, MD\n\n33607810\nMD-D-20-10535\n10.1097/MD.0000000000024695\n24695\n5700\nResearch Article\nClinical Case Report\nD-dimer can be a diagnostic marker for cisplatin-related aortic thrombosis\nA case report\nMatsumoto Yu MD\nHorimasu Yasushi MD, PhD ∗\nYamaguchi Kakuhiro MD, PhD\nSakamoto Shinjiro MD, PhD\nMasuda Takeshi MD, PhD\nNakashima Taku MD, PhD\nMiyamoto Shintaro MD, PhD\nIwamoto Hiroshi MD, PhD\nFujitaka Kazunori MD, PhD\nHamada Hironobu MD, PhD\nHattori Noboru MD, PhD\nSaranathan. Maya\nDepartment of Respiratory Medicine, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, Japan.\n∗ Correspondence: Yasushi Horimasu, Department of Respiratory Medicine, Hiroshima University Hospital, Hiroshima, Japan (e-mail: yasushi17@hiroshima-u.ac.jp).\n19 2 2021\n19 2 2021\n100 7 e2469530 10 2020\n8 1 2021\n21 1 2021\nCopyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0\n\nAbstract\n\nRationale:\n\nCisplatin is one of the key drugs that is frequently used for treating various types of malignancies. Although renal and digestive toxicities are well-known cisplatin-related toxicities, attention should also be paid to acute aortic thrombosis, a relatively rare but potentially fatal disorder caused by cisplatin. Additionally, D-dimer is mainly measured to detect venous thromboembolism or disseminated intravascular coagulation, whereas its usefulness for detecting aortic thrombosis remains unclear. Here, we report a case of squamous cell lung cancer treated with cisplatin-based chemotherapy, wherein acute aortic thrombosis was diagnosed based on elevated D-dimer levels.\n\nPatient concerns:\n\nA 65-year-old man with stage IV squamous cell lung cancer presented with elevated D-dimer levels during treatment with second-line chemotherapy with cisplatin and S-1. Contrast-enhanced computed tomography (CT) revealed an intramural thrombus, which had not been previously identified, extending from the abdominal aorta to the common iliac artery.\n\nDiagnoses:\n\nWe diagnosed the patient as having acute aortic thrombosis caused by cisplatin.\n\nInterventions:\n\nThe patient received intravenous administration of unfractionated heparin for 9 days followed by oral warfarin.\n\nOutcomes:\n\nOne month after initiating treatment, the patient's D-dimer levels decreased to the normal range, and contrast-enhanced CT revealed that the thrombi had nearly completely disappeared without any sequelae or organ damage.\n\nLessons:\n\nOur findings revealed that cisplatin can cause acute aortic thrombosis and that regular measurements of D-dimer levels before and during chemotherapy may contribute to the early detection of acute aortic thrombosis.\n\nKeywords\n\nacute aortic thrombosis\ncisplatin\nD-dimer\nOPEN-ACCESSTRUE\n==== Body\npmc1 Introduction\n\nCisplatin is one of the most commonly used drugs in the treatment of various types of malignancies, including lung cancer. Renal and digestive toxicities are well-known cisplatin-related toxicities, and it has been reported that 18.1% of cisplatin-treated cancer patients develop thromboembolic events (TEEs).[1] However, most of these TEEs are venous thrombosis, and cisplatin-induced acute aortic thrombosis is a rare and adverse event.[1] Nonetheless, it is clinically important to promptly and accurately detect aortic thrombosis because it may cause a fatal ischemic event.\n\nD-dimer, a marker of fibrin degradation, is mainly measured to detect venous thromboembolism or to diagnose and monitor disseminated intravascular coagulation. However, the efficacy of measuring D-dimer levels to detect aortic thrombosis remains unclear.[2] Herein, we report a case of squamous cell lung cancer treated with cisplatin-based chemotherapy, wherein elevated D-dimer levels led us to the diagnosis of acute aortic thrombosis.\n\n2 Case report\n\nA 62-year-old man with a 75 pack-year smoking history was diagnosed with squamous cell lung carcinoma in June 2018. A chest computed tomography (CT) scan revealed a 42 × 50-mm-sized lesion in the upper lobe of the left lung, and whole-body 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) revealed metastasis in the right iliac bone. Following the clinical stage assessment (stage IVA [cT3N1M1b]), the patient underwent first-line chemotherapy with pembrolizumab. The treatment was discontinued after administering 4 cycles of pembrolizumab, even though its efficacy was determined as partial response. This was because the patient developed oral mucosal disorder and hypothyroidism that were considered to be immune-related adverse events caused by pembrolizumab. In May 2019, after the patient remained in remission for over 8 months, disease progression was detected using FDG-PET, which showed an abnormal uptake in the left lung tumor, left hilar lymph node, and left adrenal gland.\n\nThe patient was in a good condition with an Eastern Cooperative Oncology Group performance status of 0. He had no medical history of TEE, however, he had dyslipidemia and hyperuricemia. He had no family history of thromboembolic disease, and physical examination revealed no abnormal findings. Blood test results showed no abnormalities, including normal D-dimer levels (0.6 μg/mL). Echocardiography showed normal left ventricular systolic function without any mural thrombus.\n\nThe patient was then treated with second-line chemotherapy comprising 60 mg/m2 cisplatin intravenously, which was administered on day 8, and 100 mg S-1 was orally administered daily from days 1 to 21. On day 14, the patient collapsed due to syncope after defecation, however, he recovered quickly without any sequelae. The patient was diagnosed with orthostatic hypotension based on a positive head-up tilt test; however, no abnormal findings, besides elevated D-dimer levels up to 8.1 μg/mL, were noted on electrocardiography or blood test results. On day 21, although no significant clinical symptoms were noted, contrast-enhanced CT performed to identify the causative lesion of elevated D-dimer levels revealed an intramural thrombus extending from the abdominal aorta to the common iliac artery without any occlusive lesion or progression of cancer (Fig. 1). Based on the patient's clinical course, he was diagnosed as having acute aortic thrombosis caused by cisplatin. To prevent further complications, he immediately received 10,000 to 20,000 U/d unfractionated heparin intravenously for 9 days and 3 mg warfarin orally. The D-dimer levels normalized on day 34, and follow-up contrast-enhanced CT performed on day 44 revealed that the thrombi in the abdominal aorta and common iliac artery had nearly completely disappeared (Fig. 2). Following this, he has been treated with chemotherapy comprising various anti-cancer agents, except for cisplatin, and no recurrence of thrombosis has been identified ever since.\n\nFigure 1 Contrast-enhanced CT on day 21: thrombotic deposits (arrows) were identified in the abdominal aorta and common iliac artery without any occlusive lesion or progression of cancer. CT = computed tomography.\n\nFigure 2 Contrast-enhanced CT on day 44: thrombus nearly completely disappeared. CT = computed tomography.\n\n3 Discussion\n\nWe report the case of a man with squamous cell lung cancer who developed acute aortic thrombosis during chemotherapy with cisplatin. Although thrombosis-related symptoms were not remarkable, elevated D-dimer levels led us to perform contrast-enhanced CT, which in turn led to the diagnosis of aortic thrombosis. We consider 2 clinical observations to be crucial in this case report: first, cisplatin-based chemotherapy can cause acute aortic thrombosis, and second, regular measurements of D-dimer levels before and during chemotherapy may contribute to the early detection of acute aortic thrombosis.\n\nCisplatin-based chemotherapy can cause acute aortic thrombosis. Moore et al[1] reported that among 932 patients treated with cisplatin, 169 (18.1%) experienced TEEs during treatment or within 4 weeks after the last dose. Among the 169 patients, 150 (88.8%) had deep venous thrombosis and/or pulmonary embolism, whereas only 19 (11.2%) patients had arterial thrombosis including acute aortic thrombosis.[1] In the present case, we observed the aortic thrombus without any other causative factors including occlusive lesion or progression of cancer. Therefore, we diagnosed him as having acute aortic thrombosis caused by cisplatin.\n\nAcute aortic thrombosis, which occurred during cisplatin-based chemotherapy, has previously been reported in 13 cases (9 with lung cancer,[3–8] 2 with gastrointestinal cancer,[3,9] 1 with testicular seminoma,[10] and 1 with cervical cancer[11]) (Table 1).[11] Eight of the 13 previous cases, as well as our case, presented with thrombi in the abdominal aorta, whereas in 4 cases, thrombi were limited to the thoracic aorta. In previous cases, thrombi were detected between 12 days and 5 months after initiating cisplatin-based chemotherapy. In our case, we identified thrombi on a CT scan on day 21, which is relatively early in the treatment course as compared with the average of the previous cases. Furthermore, etoposide or vinorelbine was used in combination with cisplatin in most of the previous cases, whereas S-1 was administered to only 1 patient besides the one in our case report.\n\nTable 1 Reported cases of cisplatin-related aortic thrombosis.\n\nCase\tAuthor\tAge/sex\tCancer type\tChemotherapy\tLocation of thrombi\tD-dimer\tDetection opportunity\tDetection time\tManagement\t\n1\tHahn et al[5]\t74/M\tLung cancer (adenocarcinoma)\tCDDP/VP16\tAscending aorta\t1077 μg/L (0–324 μg/L)\tSymptom (dyspnea on exertion and chest discomfort)\tN/A\tAnticoagulant\t\n2\tIto et al[9]\t66/F\tGastric cancer\tCDDP/S-1\tDescending arch of the thoracic aorta\t(FDP: 3.4 μg/mL)\tAccidental (follow-up CT)\tFollow up after the first cycle of chemotherapy\tAnticoagulant\t\n3\tHahn et al[5]\t50/M\tLung cancer (small cell carcinoma)\tCDDP/VP16\tAortic arch\t3.2 μg/mL\tAccidental (follow-up CT)\tApproximately 6 weeks after cisplatin was first administered\tAnticoagulant\t\n4\tDieckmann et al[10]\t49/M\tTesticular seminoma\tCDDP/VP16/BLM\tDescending arch of the thoracic aorta and infrarenal abdominal aorta\tN/A\tAccidental (follow-up CT)\tFollow up after the second cycle of chemotherapy\tAnticoagulant\t\n5\tFernandes et al[3]\t60/F\tRectosigmoid adenocarcinoma\tCDDP/5-FU/FLO\tProximal abdominal aorta and extending to the right common iliac artery\tN/A\tAccidental (follow-up CT)\tSix days after completion of the 3rd cycle\tAnticoagulant\t\n6\tFernandes et al[3]\t53/M\tLung cancer (small-cell lung adenocarcinoma)\tCDDP/VP16\tAbdominal aorta, extending from the level of the celiac artery to the right common iliac artery\tN/A\tSymptom (vomiting and abdominal pain)\tApproximately 3 months after cisplatin was first administered\tAnticoagulant\t\n7\tFernandes et al[3]\t53/M\tLung cancer (adenocarcinoma)\tCDDP/VNR\tAbdominal aorta, extending from the level of the celiac plexus to the left common iliac artery\tN/A\tAccidental (follow-up CT)\tApproximately 4.5 months after cisplatin was first administered\tAnticoagulant\t\n8\tFernandes et al[3]\t50/F\tNon-small cell lung cancer\tCDDP/VNR\tAbdominal aorta, extending from the level of the superior mesenteric artery to the level above the origin of the common iliac arteries.\tN/A\tAccidental (follow-up CT)\tApproximately 4.5 months after cisplatin was first administered\tAnticoagulant\t\n9\tSato et al[6]\t68/M\tLung cancer (adenocarcinoma)\tCDDP/VNR\tFrom the thoracic artery to the abdominal aorta\t5.7 μg/mL\tSymptom (acute pain in his right leg and intermittent claudication)\tThirteen days after cisplatin was first administered\tAnticoagulant\t\n10\tMathews et al[7]\t54/M\tLung cancer (adenocarcinoma)\tCDDP/VP16\tAbdominal artery below the renal artery\tN/A\tSymptom (discomfort in his right leg)\tTwelve days after cisplatin was first administered\tAmputation (below the knee)\t\n11\tMathews et al[7]\t54/F\tLung cancer (large cell type)\tCDDP/VP16\tAbdominal artery at the level of the renal artery\tN/A\tSymptom (leg paresthesia and low back pain)\tHalfway through the second cycle of chemotherapy\tThrombectomy aortobifemoral graft\t\n12\tAoki et al[8]\t64/M\tLung cancer (adenocarcinoma)\tCDDP/PEM\tAortic arch\t2.9 μg/mL\tAccidental (follow-up CT)\tFollow up after the first cycle of chemotherapy\tAnticoagulant\t\n13\tAbdel-Razeq et al[12]\t59/F\tCervical cancer\tCDDP/5-FU\tAortic arch, descending aorta, and popliteal artery\tN/A\tSymptom (acute pain in his right leg, nausea, and vomiting)\tN/A\tThrombectomy of the popliteal artery\t\n14\tMatsumoto et al (present case)\t65/M\tLung cancer (squamous cell carcinoma)\tCDDP/S-1\tFrom the abdominal aorta to the common iliac artery\t8.1 μg/mL\tAccidental (D-dimer increase)\tThirteen days after cisplatin was first administered\tAnticoagulant\t\n\nAlthough the exact mechanism by which cisplatin causes TEE remains unknown, it has been reported that cisplatin induces damage to vascular endothelial cells via hypomagnesemia, increased activity of von Willebrand factor, and increased formation of procoagulant endothelial microparticles.[1] Furthermore, platelet activation and upregulation of prothrombotic factors are implicated in cisplatin-related thrombosis.[12]\n\nD-dimer is a product generated by plasmin-induced degradation of stabilized fibrin and is a generic term for mixtures having a D-dimer structure. An increase in D-dimer levels may be a marker for thrombus formation and the enhanced state of secondary fibrinolysis, and thus, is widely used in clinical settings as an important marker for thrombosis detection. As shown in Table 1, 6 of the 13 reported cases were diagnosed while investigating the source of a symptom; however, others were asymptomatic and were diagnosed based on follow-up CT, which evaluates the response to chemotherapy. These findings suggest that aortic thrombosis may follow an asymptomatic course for a period of time; however, there is a high need for its early detection because it may be exacerbated by organ embolism. In our case, D-dimer levels before initiating chemotherapy were normal and increased only after cisplatin was administered. This apparent change encouraged us to perform contrast-enhanced CT, which resulted in the diagnosis of aortic thrombosis relatively early in the treatment course compared to previous cases.\n\nAlthough many studies have reported the usefulness of D-dimer in cases of intravenous thrombus and aortic aneurysm, its utility in the detection of intra-aortic thrombus remains uncertain. Nevertheless, as shown in Table 1, D-dimer levels were elevated in all 4 previous cases as well as in our case. These results suggest that D-dimer can be a potential diagnostic marker of cisplatin-related aortic thrombosis. Importantly, elevated D-dimer is commonly observed in presence of cancer no matter with or without thrombus. Therefore, regular measurements of D-dimer levels started from before the initiation of cisplatin-based chemotherapy can be useful to distinguish the elevation of D-dimer caused by the chemotherapy from that caused by the cancer itself, and it may helpful for the early detection of aortic thrombosis, especially before the appearance of thrombus-induced symptom. However, we should note that the elevation of D-dimer in patients with cancer can be caused by various factors including cancer itself or intravenous thrombus, thus the further examination such as contrast-enhanced CT is required to investigate the cause of the elevation of D-dimer.\n\nIn conclusion, we report a case of acute aortic thrombosis caused by cisplatin. Cisplatin-related arterial thrombus is a relatively rare but important complication that can cause life-threatening ischemic events. Regular measurements of D-dimer levels during chemotherapy with cisplatin may help in the early detection of acute aortic thrombosis.\n\nAuthor contributions\n\nConceptualization: Yu Matsumoto, Yasushi Horimasu.\n\nData curation: Yasushi Horimasu, Kakuhiro Yamaguchi, Shinjiro Sakamoto, Takeshi Masuda, Taku Nakashima, Shintaro Miyamoto, Hiroshi Iwamoto, Kazunori Fujitaka, Hironobu Hamada, Noboru Hattori.\n\nInvestigation: Yu Matsumoto, Yasushi Horimasu.\n\nMethodology: Yu Matsumoto, Yasushi Horimasu.\n\nSupervision: Hiroshi Iwamoto, Kazunori Fujitaka, Hironobu Hamada, Noboru Hattori.\n\nWriting – original draft: Yu Matsumoto.\n\nWriting – review & editing: Yu Matsumoto, Yasushi Horimasu, Kakuhiro Yamaguchi, Shinjiro Sakamoto, Takeshi Masuda, Taku Nakashima, Shintaro Miyamoto, Hiroshi Iwamoto, Kazunori Fujitaka, Hironobu Hamada, Noboru Hattori.\n\nAbbreviations: CT = computed tomography, FDG-PET = fluorodeoxyglucose-positron emission tomography, TEE = thromboembolic event.\n\nHow to cite this article: Matsumoto Y, Horimasu Y, Yamaguchi K, Sakamoto S, Masuda T, Nakashima T, Miyamoto S, Iwamoto H, Fujitaka K, Hamada H, Hattori N. D-dimer can be a diagnostic marker for cisplatin-related aortic thrombosis: a case report. Medicine. 2021;100:7(e24695).\n\nInformed Consent: The patient provided written informed consent for publishing his clinical information.\n\nThe authors have no funding and conflicts of interest to disclose.\n\nData sharing not applicable to this article as no datasets were generated or analyzed during the current study.\n\n5-FU = 5-fluorouracil; BLM = bleomycin hydrochloride; CDDP = cisplatin; CT = computed tomography; FDP = fibrinogen/fibrin degradation products; FLO = folinic acid; N/A = not applicable, PEM = pemetrexed sodium hydrate, VNR = vinorelbine detartrate, VP16 = etoposide.\n==== Refs\nReferences\n\n[1] Moore RA Adel N Riedel E . High incidence of thromboembolic events in patients treated with cisplatin-based chemotherapy: a large retrospective analysis. J Clin Oncol 2011;29 :3466–73.21810688\n[2] Adam SS Key NS Greenberg CS . D-dimer antigen: current concepts and future prospects. Blood 2009;113 :2878–87.19008457\n[3] Fernandes DD Louzada ML Souza CA . Acute aortic thrombosis in patients receiving cisplatin-based chemotherapy. Curr Oncol 2011;18 :e97–100.21505594\n[4] Chin SO Lee JJ Hwang YH . Aortic thrombosis resolved with enoxaparin in a patient treated with cisplatin-based regimen for small cell lung cancer. Int J Hematol 2010;91 :892–6.20428980\n[5] Hahn SJ Oh JY Kim JS . A case of acute aortic thrombosis after cisplatin-based chemotherapy. Int J Clin Oncol 2011;16 :732–6.21455627\n[6] Sato C Okuda K Tamiya H . Acute arterial thrombosis during postoperative adjuvant cisplatin-based chemotherapy for completely resected lung adenocarcinoma. Intern Med 2018;57 :557–61.29225246\n[7] Mathews J Goel R Evans WK . Arterial occlusion in patients with peripheral vascular disease treated with platinum-based regimens for lung cancer. Cancer Chemother Pharmacol 1997;40 :19–22.9137524\n[8] Aoki R Kashiwabara K Fujii S . Acute aortic thrombosis in pulmonary adenocarcinoma patients receiving cisplatin-based chemotherapy. Nihon Kokyuki Gakkai Zasshi 2015;4 :288–92. (in Japanese).\n[9] Ito S Nakamura Y Noumi T . Acute aortic thrombosis during cisplatin based chemotherapy for gastric cancer. Intern Med 2013;52 :973–5.23648716\n[10] Dieckmann KP Gehrckens R . Thrombosis of abdominal aorta during cisplatin-based chemotherapy of testicular seminoma - a case report. BMC Cancer 2009;9 :459.20028501\n[11] Apiyasawat S Wongpraparut N Jacobson L . Cisplatin induced localized aortic thrombus. Echocardiography 2003;20 :199–200.12848689\n[12] Abdel-Razeq H Mansour A Abdulelah H . Thromboembolic events in cancer patients on active treatment with cisplatin-based chemotherapy: another look!. Thromb J 2018;16 :2.29507532\n\n",
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"mesh_terms": "D061605:Administration, Intravenous; D000284:Administration, Oral; D000368:Aged; D000925:Anticoagulants; D000970:Antineoplastic Agents; D001018:Aortic Diseases; D002294:Carcinoma, Squamous Cell; D002945:Cisplatin; D005338:Fibrin Fibrinogen Degradation Products; D006493:Heparin; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D009367:Neoplasm Staging; D013927:Thrombosis; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D014859:Warfarin",
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"pubdate": "2021-02-19",
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"title": "D-dimer can be a diagnostic marker for cisplatin-related aortic thrombosis: A case report.",
"title_normalized": "d dimer can be a diagnostic marker for cisplatin related aortic thrombosis a case report"
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"abstract": "BACKGROUND\nThere is increasing concern about the risk of latent tuberculosis infection (LTBI) reactivation during the use of biologics for psoriasis. Although ustekinumab had been documented with low risk of tuberculosis, the long-term follow-up of LTBI as determined by QuantiFERON-TB Gold (QFT-G) testing in patients treated with ustekinumab is limited.\n\n\nOBJECTIVE\nThis study aims to use serial QFT-G testing as a screening method for detecting LTBI in patients with psoriasis from an intermediate tuberculosis burden country.\n\n\nMETHODS\nThis retrospective review investigated 134 psoriatic patients in whom ustekinumab was prescribed for at least one year between 2010 and 2016 in National Taiwan University Hospital. All patients underwent annular QFT-G testing during ustekinumab therapy.\n\n\nRESULTS\nAmong the 134 enrolled patients, baseline LTBI rate was 13.4% (18/134). Indeterminate QFT-G result was noted in 5.2% (7/134) of patients and 71.4% (5/7) of them turn to be QFT-G negative during the next testing. 81.3% (109/134) of patients had a negative QFT-G at baseline and the seroconversion rate was 7.3% (8/109) in the serial QFT-G. All the patients in the conversion group were referred to a pulmonologist for evaluation and 81.5% (22/27) of them underwent chemoprophylactic therapy while on ustekinumab. No active TB infection was noted during further follow-up with or without chemoprophylaxis.\n\n\nCONCLUSIONS\nThis study revealed that psoriatic patients receiving long-term ustekinumab therapy had a low QFT-G conversion rate (7.3%). The clinical significance of QFT-G conversion remains controversial and needs larger scale trials to investigate.",
"affiliations": "Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.;Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.;Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.;Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.",
"authors": "Hsiao|Chuan-Yu|CY|http://orcid.org/0000-0002-7871-8480;Chiu|Hsien-Yi|HY|;Wang|Ting-Shun|TS|;Tsai|Tsen-Fang|TF|",
"chemical_list": "D003879:Dermatologic Agents; D007371:Interferon-gamma; D000069549:Ustekinumab",
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"doi": "10.1371/journal.pone.0184178",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 2888609910.1371/journal.pone.0184178PONE-D-17-07058Research ArticleMedicine and Health SciencesInfectious DiseasesBacterial DiseasesTuberculosisMedicine and Health SciencesTropical DiseasesTuberculosisMedicine and Health SciencesClinical MedicineClinical ImmunologyAutoimmune DiseasesPsoriasisBiology and Life SciencesImmunologyClinical ImmunologyAutoimmune DiseasesPsoriasisMedicine and Health SciencesImmunologyClinical ImmunologyAutoimmune DiseasesPsoriasisPeople and PlacesGeographical LocationsAsiaTaiwanMedicine and Health SciencesPublic and Occupational HealthPreventive MedicineProphylaxisMedicine and Health SciencesPulmonologyMedicine and Health SciencesPharmacologyDrugsMethotrexateMedicine and Health SciencesInfectious DiseasesOpportunistic InfectionsMedicine and Health SciencesDiagnostic MedicineSigns and SymptomsNecrosisMedicine and Health SciencesPathology and Laboratory MedicineSigns and SymptomsNecrosisSerial QuantiFERON-TB Gold testing in patients with psoriasis treated with ustekinumab QTF-TB Gold testing in ustekinumab treated patientshttp://orcid.org/0000-0002-7871-8480Hsiao Chuan-Yu ConceptualizationData curationFormal analysisFunding acquisitionInvestigationMethodologyProject administrationResourcesSoftwareValidationVisualizationWriting – original draftWriting – review & editing1Chiu Hsien-Yi ConceptualizationData curationFormal analysisFunding acquisitionInvestigationMethodologyProject administrationResourcesSoftwareSupervisionValidationVisualizationWriting – review & editing12Wang Ting-Shun ConceptualizationData curationFormal analysisFunding acquisitionInvestigationMethodologyProject administrationResourcesSoftwareSupervisionValidationVisualizationWriting – review & editing13Tsai Tsen-Fang ConceptualizationData curationFormal analysisFunding acquisitionInvestigationMethodologyProject administrationResourcesSoftwareSupervisionValidationVisualizationWriting – review & editing1*1 \nDepartment of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan2 \nDepartment of Dermatology, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, Taiwan3 \nDepartment of Dermatology, National Taiwan University Hospital, Yun-Lin Branch, Dou-Liou, TaiwanProost Paul EditorKatholieke Universiteit Leuven Rega Institute for Medical Research, BELGIUMCompeting Interests: T-F Tsai has conducted clinical trials or received honoraria for serving as a consultant for AbbVie, Boehringer Ingelheim, Celgene, Eli Lilly, Galderma, GSK-Stiefel, Janssen-Cilag, Leo Pharma, Merck, Novartis Pharmaceuticals, Pfizer Inc, and Serono International SA (now Merck Serono International). Dr Chiu has received speaking fees from AbbVie, Janssen-Cilag Pharmaceutical, and Pfizer. Dr. Hsiao had received funding from Pfizer, Serono International SA (now Merck Serono International), UniPharma/Biogen Idec, Galderma, Celgene, Novartis Pharmaceuticals, Janssen-Cilag Pharmaceutica and AbbVie. Dr. Wang has received speaking fee from Abbvie, Pfizer, Novartis International AG and Janssen-Cilag Pharmaceuticals. This does not alter our adherence to PLOS ONE policies on sharing data and materials.\n\n* E-mail: tftsai@yahoo.com8 9 2017 2017 14 9 2017 12 9 e018417811 3 2017 19 8 2017 © 2017 Hsiao et al2017Hsiao et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background\nThere is increasing concern about the risk of latent tuberculosis infection (LTBI) reactivation during the use of biologics for psoriasis. Although ustekinumab had been documented with low risk of tuberculosis, the long-term follow-up of LTBI as determined by QuantiFERON-TB Gold (QFT-G) testing in patients treated with ustekinumab is limited.\n\nObjectives\nThis study aims to use serial QFT-G testing as a screening method for detecting LTBI in patients with psoriasis from an intermediate tuberculosis burden country.\n\nMethods\nThis retrospective review investigated 134 psoriatic patients in whom ustekinumab was prescribed for at least one year between 2010 and 2016 in National Taiwan University Hospital. All patients underwent annular QFT-G testing during ustekinumab therapy.\n\nResults\nAmong the 134 enrolled patients, baseline LTBI rate was 13.4% (18/134). Indeterminate QFT-G result was noted in 5.2% (7/134) of patients and 71.4% (5/7) of them turn to be QFT-G negative during the next testing. 81.3% (109/134) of patients had a negative QFT-G at baseline and the seroconversion rate was 7.3% (8/109) in the serial QFT-G. All the patients in the conversion group were referred to a pulmonologist for evaluation and 81.5% (22/27) of them underwent chemoprophylactic therapy while on ustekinumab. No active TB infection was noted during further follow-up with or without chemoprophylaxis.\n\nConclusions\nThis study revealed that psoriatic patients receiving long-term ustekinumab therapy had a low QFT-G conversion rate (7.3%). The clinical significance of QFT-G conversion remains controversial and needs larger scale trials to investigate.\n\nNo funding was received that supported this specific study. Data AvailabilityAll relevant data are within the paper and its Supporting Information files.Data Availability\nAll relevant data are within the paper and its Supporting Information files.\n==== Body\nIntroduction\nBiologics have been increasingly used in the treatment of moderate to severe psoriasis due to their efficacy and safety compared to pre-existing treatment modalities. Anti-tumor necrosis factors (TNF), and ustekinumab (a monoclonal antibody against the p40 subunit of IL-12 and IL-23) are currently the most commonly used biologics for psoriasis. Biologics are also considered to be safer than conventional systemic agents except for increased granulomatous infections, mainly tuberculosis (TB). Screening and monitoring for both active and latent TB infection (LTBI) before and during treatment with TNF-blockers are considered to be the standard of care [1–6]. Among the different methods of LTBI detection, whole blood interferon-γ release assays (IGRAs) offer better sensitivity and specificity than tuberculin skin test (TST) in detecting LTBI (sensitivity 89% vs. 74%; specificity 98% vs. 81%) [7, 8], especially in subjects who had received Bacilli Calmette-Guerin (BCG) vaccination previously [9,10]. There are two commercially available IGRAs, T-Spot and QuantiFERON-TB Gold In-Tube test (QFT-GIT; Cellestis Limited, Carnegie, Victoria, Australia), and the latter test is more commonly used due to its lower cost and ease to perform.\n\nThe validity of IGRAs in screening LTBI before initiating TNF-α antagonists had been well documented [11–14]. The prevalence of LTBI varies according to countries, and was 12/110 (11%) [15] and 10/101 (10%) [16] in Taiwan among TNF-blockers users for psoriasis. The optimal timing or need of IGRAs retest has not been standardized in otherwise asymptomatic biologic users, and seroconversion rate may be affected by the background TB prevalence, frequency of IGRAs retest, patient demographics, types of underlying diseases, types of biologics and concomitant medications. Serial QFT tests have revealed annual seroconversion rate between 7%~ 18% in TNF-blockers users in psoriasis [17–20], and it was 14.29% in Taiwan [16]. Risks of TB and TBLI reactivation are considered to be lower for using ustekinumab compared to TNF-blockers. However, there are limited studies regarding the serial IGRAs results among patients who received ustekinumab therapy. This study aimed to evaluate the serial QFT-GIT results in patients receiving long-term ustekinumab treatment in Taiwan, a country with an intermediate prevalence of tuberculosis.\n\nMaterials and methods\nPatients\nThe study was approved by the local investigational research bureau of National Taiwan University Hospital. Screening for LTBI is mandatory before and during biologics use for psoriasis in Taiwan. According to local risk management requirement of all biologics used for psoriasis, QFT-GIT has to be performed once a year in routine practice. Both serial IGRA testing and regular chest X-ray examination were performed. We retrospectively enrolled all psoriatic patients treated with ustekinumab from May 2010 to September 2016 in National Taiwan University Hospital, Taipei and Hsin-Chu, Taiwan. All patients who used ustekinumab and have received quantiferon test at least twice separated by at least one year during the study period were included. The time span between serial QFT for a single patient was at least 12 months respectively. We reviewed the medial records of these patients to evaluate clinical diagnosis, demographic information, medical history and laboratory data.\n\nQuantiFERON-TB Gold In-Tube assay for latent tuberculosis infection\nQFT-GIT was performed in all patients with ustekinumab use. Antigen with peptide cocktail simulating the proteins ESAT-6, CFP-10 and TB7.7 were used in the test. The interferon-γ (IFN-γ) values were calculated by subtracting the obtained value with nil antigens. A positive result was defined as IFN-γ≥ 0.35 IU/ml and positive control value (IFN-γ of mitogen minus nil antigens) ≥ 0.5 IU/ml. A negative result was defined as 0 < IFN-γ< 0.35 IU/ml and positive control (mitogen) value ≥ 0.5 IU/ml. Indeterminate result was defined as IFN-γ of nil antigen >8 IU/ml or positive control value < 0.5 IU/ml. Conversion of IGRA was defined as a negative IGRA at baseline and a positive IGRA at follow-up, while reversion of IGRA was defined as a positive IGRA at baseline and negative IGRA at follow-up.\n\nTreatment and follow-up of LTBI\nThe diagnosis of LTBI in our study was defined as a positive QFT-GIT result and a negative chest X-ray or microbiological assay. All patients diagnosed with LTBI were referred to pulmonologists for evaluation and underwent further survey and chemoprophylactic therapy if recommended. The recommendation of tuberculosis screening and treatment in Taiwan was originally based on anti-TNF agents. However, no modification was made after the introduction of ustekinumab. For anti-TNF agents, an at least 4-week treatment with isoniazid (INH) before anti-TNF agent use was suggested in cases of latent TB detected by either IRGAs or tuberculin skin test. A 9-month INH is needed for latent TB. Since the tuberculosis risk of ustekinumab is supposed to be much lower than anti-TNF agents, and there is a risk of INH resistance for tuberculosis, the infection specialists will decide the appropriateness of INH prophylaxis according to their risk assessment results based on clinical symptoms, chest X ray findings, exposure sources, and sputum culture results. In clinical practice, ustekinumab is usually prescribed at the same time as INH initiation in cases without any other evidence of latent tuberculosis. In fact, in the registration trial of ustekinumab for psoriasis in Taiwan, ustekinumab was approved to be given at the same day as INH initiation [21].\n\nStatistical analysis\nStatistical analysis and graphs were done with standard spreadsheet software program using Microsoft Excel 2010 (Microsoft Corporation, Seattle, WA, USA) and Fisher exact test. Statistical significant was defined as p value < 0.05.\n\nResults\nPatient characteristics\nWe enrolled 134 patients to this study in total. Of these patients, the mean age was 47.16 years (standard deviation((SD)) 13.14 years) and the male-to female ratio was 101/33. The mean follow-up months were 20.5 (SD 10.52) and 42 patients (32.1%) also had psoriatic arthritis. Most patients were biologics naïve, 24 patients (17.9%) had received at least 6 months of etanercept and 23 patients (17.2%) had received at least 6 months of adalimumab. During ustekinumab treatment, 17 patients (12.7%) also received concomitant immunosuppressant therapy or other biological agents. Among these agents, methotrexate was the most commonly used drug (n = 12, 9%). The demographic features are presented in Table 1.\n\n10.1371/journal.pone.0184178.t001Table 1 Dermographic features.\nAge (years)\t47.16 ± 13.14a\t\nSex, n (%)\tMan: 101 (75.4)\t\nWoman: 33 (24.6)\t\nWith psoriatic arthritis, n (%)\t42 (32.1)\t\nMean follow-up months\t20.5 ± 10.52a\t\nPrevious biological treatment, n (%)\tEtanercept: 24 (17.9)\t\nAdalimumab: 23 (17.2)\t\nCombined treatment, n (%)\tMethotrexate: 12 (9)\t\nEtanercept: 4 (3)\t\nAdalimumab: 1(0.7)\t\naStandard deviation\n\nSerial QuantiFERON-TB Gold In-Tube assay results\nThe serial QFT-GIT assay results are summarized in the study flowchart (Fig 1) and histogram (Fig 2). All the patients had received baseline QFT and 2nd QFT at least 12 months later. 39 patients (29.1%) had undergone 3rd QFT and 7 patients (5.2%) had received 4th QFT. The initial IGRA result was positive in 18 patients (13.4%), negative in 109 patients (81.4%) and indeterminate in 7 patients (5.2%). The conversion rate was 7.3% (8/109) in the serial QFT. Six patients had QFT seroconversion at the 2nd QFT follow-up while 2 patients had seroconversion at the 3rd QFT follow-up. The longitudinal IFN-γ level changes before and after ustekinumab treatment in the seroconversion group were shown in Fig 3.\n\n10.1371/journal.pone.0184178.g001Fig 1 Flowchart distribution of QantiFERON Gold In-Tube test results.\n10.1371/journal.pone.0184178.g002Fig 2 Results of serial QuantiFERON-TB Gold In-Tube tests.\n10.1371/journal.pone.0184178.g003Fig 3 IFN-γ level before and after ustekinumab treatment in the conversion group.\nWe divided patient data according to (I) patients receiving only ustekinumab (n = 117) and (II) patients receiving another treatment as well (n = 17). The seroconversion patient number in each group was 7 and 1 respectively and showed no statistically significant difference (Table 2).\n\n10.1371/journal.pone.0184178.t002Table 2 Seroconversion patient number from (I) patients receiving only ustekinumab(II) patients receiving ustekinumab along with other treatment.\n\tPatients receiving only ustekinumab (number = 117)\tPatients receiving ustekinumab along with other treatment as well (number = 17)\tp value\t\nSeroconversion patient number\t7\t1\t1\t\nPatients were also divided into two subgroups: (I) biologic-naïve group who had never received biologics agents before using ustekinumab (n = 97) (II) non-biologic-naïve group (n = 37). The seroconversion patient number in each group was 5 and 2 respectively and revealed no statistically significant difference (Table 3).\n\n10.1371/journal.pone.0184178.t003Table 3 Seroconversion patient number from (I) biologics-naïve patients (II) non-biologics-naïve patients.\n\tBiologics-naïve patients (number = 97)\tNon-biologics-naïve patients (number = 37)\tp value\t\nSeroconversion patient number\t5\t2\t1\t\nTotally 27 patients were diagnosed with LTBI in our study. All were referred to pulmonologists for evaluation. Among them, one patient had poor compliance and was lost to follow-up afterwards. 16 patients (59.2%) had received 9-month course of prophylactic therapy with 300 mg of daily isoniazid (INH) and had been follow-up for an average of 17.2 months. 5 patients (18.5%) had only received 1~3 months of INH prophylactic due to nausea, vomiting and elevated liver enzyme and received follow-up for an average of 11.4 months. The rest 5 patients (18.5%) didn’t receive prophylactic therapy after pulmonologists’ evaluation and had been followed up for an average of 29.2 months. During follow-up, no active TB infection was detected in our study.\n\nDiscussion\nBiologic agents had become increasingly used in treating moderate to severe psoriasis and psoriatic arthritis since 2002. Opportunistic infections were one of the most important adverse effects during usage of biologic agents. Patients treated with TNF-blockers have increased risk of LTBI reactivation and need to undergo regular TB screening [1]. Regular screening for LTBI during TNF-blockers or ustekinumab treatment had been listed into guidance in many professional dermatologic associations including American Academy of Dermatology (AAD), the Japanese Dermatology Association (JDA) and the European Academy of Dermatology and Venereology (EADV) [5]. Among the screening methods, IGRA such as QFT-GIT was preferred due to higher sensitivity and specificity [7, 8]. Risks of TB and LTBI reactivation are generally considered lower for ustekinumab compared to TNF-blockers. While previous studies indicate that patients with inborn errors of IL-12/ 23- IFN-γ-mediated immunity area are at higher risk for developing TB infection [22], cases of TB reactivation or infection during ustekinumab use remain limited. Across five phase III clinical trials of ustekinumab-treated patients with psoriasis, no cases of LTBI reactivation was observed in patients receiving concomitant INH prophylaxis [23]. However, reactivation of LTBI during ustekinumab and low dose oral steroid treatment had been reported in a patient who underwent prophylactic therapy with isoniazid [24].\n\nThe seroconversion rate from our study was 7.3%, which is lower than previous study (14.29%) conducted among psoriasis patients treated with anti-tumor necrosis factors in Taiwan [16]. Accuracy of IGRAs during biological therapy has been disputed, especially for patients undergoing anti-TNF blockers. For example, it was found that the development of positive QFT-GIT, observed in 8% of patients treated with infliximab, was not associated with pulmonary or extra-pulmonary tuberculosis [25]. In the other study, adalimumab (a TNF blocker) was found to significantly reduce the IFN-γ levels, potentially causing false negative QF results in a dose-dependent manner [26]. As for ustekinumab, an IL12/IL23 blocker, there are no prior reports of serial quantiferon results in patients receiving ustekinumab for psoriasis. Although, a prior study showed that treatment with ustekinumab resulted in no changes of serum TNF levels [27], maintenance of pulmonary Th1 effector function in chronic tuberculosis requires persistent IL-12 production [28]. Thus, we suspect the QFT seroconversion rate might reflect either a background tuberculosis exposure or from a prior false negative QFT test result at baseline before ustekinumab treatment, such as in the case report of latent tuberculosis reactivation with quantiferon conversion [29]. Weather the fluctuation of IFN-γ level correlated with clinical significance still remained controversial. Some reported that there is a biphasic emergence of TB infection in patients receiving TNF-blockers. Persistently high levels of released IFN-γ (during the first 3 months) or QFT conversion (after 20–24 months) strongly indicate the development of active tuberculosis in patients undergoing long-term anti-TNFα therapy [30]. Some advocate that dynamic changes occurring with serial IFN-γ release assay testing in patients treated with biologic therapy do not correlate with clinical outcome [31]. Scrivo et al proposed a concept of “zone of uncertainty” and re-defined the cut off value of QFT positive result. The zone of uncertainty was defined in the range of 0.2–0.5 IU/mL IFN-γ levels. Any results fluctuate within the uncertainty zone during repeated testing were considered doubtful conversions or doubtful reversions. As seen in Fig 3, some IFN-γ levels did fluctuate within the uncertainty zone. After excluding these doubtful conversions, seroconversion rate would be decreased to 3.7% in our study. In further study, Mancuso et al found that patients with negative TB responses near the cutoff (i.e., ≥0.25 but <0.35 IU/ml) were, 30 times more likely to convert to positive than those with responses further from the cutoff [32]. As the IGRAs are complicated laboratory tests that may require at least 126 measurements for a single test [33], the in-test variability may contribute to the zone of uncertainty. Use of this borderline zone may reduce the conversion numbers but would increase the number of patients with uncertain results. Further evaluation of risk, serial duplicate testing and long-term follow-up in clinical practice are needed to clarify the usefulness of the concept of “zone of uncertainty”.\n\nThe QF seroconversion rate might reflect either a background tuberculosis exposure or from a prior false negative QFT test result at baseline. A background tuberculosis exposure may differ significantly in different areas and diseases. Taiwan is an intermediate tuberculosis burden country. Although the prior reports show QF conversion rate to be between 7%~ 18% in TNF-blockers users in psoriasis [17–20], the 7.3% percent is still lower than the experience of TNF blockers for psoriasis in Taiwan [16]. Moreover, the LTBI rate in our study was 13.4% (18/134), similar to previous studies: 12/110 (11%) [15] and 10/101 (10%) [16] in Taiwan among TNF-blockers users for psoriasis. All the patients with LTBI were referred to pulmonologists for evaluation and most patients had underwent 1~9-month course of INH prophylactic therapy while 5 patients (18.5%) didn’t. During further follow-up, no patients from either INH prophylactic or non-prophylactic group developed active tuberculosis. Although chemoprophylactic therapy can efficiently decrease the LTBI reactivation rate in patients who underwent ustekinumab therapy [23], adverse effect such as liver toxicity and increased drug resistance had also been proposed. The possibility of pre-existing or newly emergent INH resistant Mycobacterium tuberculosis strains has also been considered. Thus INH monotherapy, although recommended, is not always prescribed by all referral pulmonologists, especially in low risk patients. Apart from IGRA, clinical vigilance which incorporates careful evaluation of the clinical symptoms and signs, the contact and exposure history, and the TB prevalence rate of the endemic area are needed to guide the final treatment decision.\n\nThere are several limitations in the study. First, this is a non-prospective study, which results in some variation in the exact QF retest time. However, most patients received annual tests according to the risk management requirement. Second, some patients received concomitant systemic therapy. However, methotrexate is mainly used and methotrexate has not been found to increase TB risk in prior study when used alone in psoriasis. Additionally, even with concomitant use of TNF blockers, none of the subjects developed tuberculosis in the study [34]. Third, the subjects who had long term follow-up beyond two years are still limited.\n\nIn summary, our study revealed that psoriatic patients had a lower QFT-GIT seroconversion rate (7.3%) after ustekinumab therapy compared to anti-tumor necrosis factors therapy. No active tuberculosis was detected during serial follow-up. However, a larger sample size with longer follow-up is still needed to fully assess the TB risks associated with ustekinumab therapy.\n\nSupporting information\nS1 Dataset Primay data of enrolled patients.\n(XLSX)\n\nClick here for additional data file.\n\n S1 Checklist STROBE checklist.\n(DOC)\n\nClick here for additional data file.\n==== Refs\nReferences\n1 Keane J , Gershon S , Wise RP , Mirabile-Levens E , Kasznica J , Schwieterman WD , et al (2001 ) Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent . N Engl J Med \n345 : 1098 –1104 . doi: 10.1056/NEJMoa011110 \n11596589 \n2 Gómez-Reino JJ , Carmona L , Valverde VR , Mola EM , Montero MD . (2003 ) Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report . Arthritis Rheum \n48 : 2122 –2127 . doi: 10.1002/art.11137 \n12905464 \n3 Mohan AK , Coté TR , Block JA , Manadan AM , Siegel JN , Braun MM . (2004 ) Tuberculosis following the use of etanercept, a tumor necrosis factor inhibitor . Clin Infect Dis \n39 : 295 –299 . doi: 10.1086/421494 \n15306993 \n4 Bongartz T , Sutton AJ , Sweeting MJ , Buchan I , Matteson EL , Montori V . (2006 ) Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials . JAMA \n295 : 2275 –2285 . doi: 10.1001/jama.295.19.2275 \n16705109 \n5 Ahn CS , Dothard EH , Garner ML , Feldman SR , Huang WW . (2015 ) To test or not to test? An updated evidence-based assessment of the value of screening and monitoring tests when using systemic biologic agents to treat psoriasis and psoriatic arthritis . J Am Acad Dermatol \n73 : 420 –428.e1 . doi: 10.1016/j.jaad.2015.06.004 \n26184440 \n6 Sivamani RK , Goodarzi H , Garcia MS , Raychaudhuri SP , Wehrli LN , Ono Y , et al (2013 ) Biologic therapies in the treatment of psoriasis: a comprehensive evidence-based basic science and clinical review and a practical guide to tuberculosis monitoring . Clin Rev Allergy Immunol \n44 : 121 –140 . doi: 10.1007/s12016-012-8301-7 \n22311162 \n7 Mori T , Sakatani M , Yamagishi F , Takashima T , Kawabe Y , Nagao K , et al (2004 ) Specific detection of tuberculosis infection: an interferon-gamma-based assay using new antigens . Am J Respir Crit Care Med \n170 : 59 –64 . doi: 10.1164/rccm.200402-179OC \n15059788 \n8 Lein AD , von Reyn CF , Ravn P , Horsburgh CR Jr, Alexander LN , Andersen P . (1999 ) Cellular immune responses to ESAT-6 discriminate between patients with pulmonary disease due to Mycobacterium avium complex and those with pulmonary disease due to Mycobacterium tuberculosis . Clin Diagn Lab Immunol \n6 : 606 –609 . 10391871 \n9 Diel R , Loddenkemper R , Meywald-Walter K , Niemann S , Nienhaus A . (2008 ) Predictive value of a whole blood IFN-gamma assay for the development of active tuberculosis disease after recent infection with Mycobacterium tuberculosis . Am J Respir Crit Care Med \n177 : 1164 –1170 . doi: 10.1164/rccm.200711-1613OC \n18276940 \n10 Gisondi P , Cazzaniga S , Chimenti S , Maccarone M , Picardo M , Girolomoni G , et al (2014 ) Latent tuberculosis infection in patients with chronic plaque psoriasis who are candidates for biological therapy . Br J Dermatol \n171 : 884 –890 . doi: 10.1111/bjd.13130 \n24863903 \n11 Chen DY , Shen GH , Hsieh TY , Hsieh CW , Lan JL . (2008 ) Effectiveness of the combination of a whole-blood interferon-gamma assay and the tuberculin skin test in detecting latent tuberculosis infection in rheumatoid arthritis patients receiving adalimumab therapy . Arthritis Rheum \n59 : 800 –806 . doi: 10.1002/art.23705 \n18512714 \n12 Pratt A , Nicholl K , Kay L . (2007 ) Use of the QuantiFERON TB Gold test as part of a screening programme in patients with RA under consideration for treatment with anti-TNF-alpha agents: the Newcastle (UK) experience . Rheumatology (Oxford) \n46 : 1035 –1036 . doi: 10.1093/rheumatology/kem064 \n17409126 \n13 Ponce de Leon D , Acevedo-Vasquez E , Alvizuri S , Gutierrez C , Cucho M , Alfaro J , et al (2008 ) Comparison of an interferon-gamma assay with tuberculin skin testing for detection of tuberculosis (TB) infection in patients with rheumatoid arthritis in a TB-endemic population . J Rheumatol \n35 : 776 –781 . 18398944 \n14 Matulis G , Jüni P , Villiger PM , Gadola SD . (2008 ) Detection of latent tuberculosis in immunosuppressed patients with autoimmune diseases: performance of a Mycobacterium tuberculosis antigen-specific interferon gamma assay . Ann Rheum Dis \n67 : 84 –90 . doi: 10.1136/ard.2007.070789 \n17644549 \n15 Chiu HY , Hsueh PR , Tsai TF . (2011 ) Clinical experience of QuantiFERON® -TB Gold testing in patients with psoriasis treated with tumor necrosis factor blockers in Taiwan . Br J Dermatol \n164 : 553 –559 . doi: 10.1111/j.1365-2133.2010.10137.x \n21083541 \n16 Cheng CY , Hui CY , Sindy Hu , Hsieh MH , Huang YH . (2015 ) Serial QuantiFERON-TB Gold In-Tube testing for psoriatic patients receiving antitumor necrosis factor-alpha therapy . Dermatol Sinica \n33 : 124 –129 .\n17 Kim KH , Lee SW , Chung WT , Kim BG , Woo KS , Han JY , et al (2011 ) Serial interferon-gamma release assays for the diagnosis of latent tuberculosis infection in patients treated with immunosuppressive agents . Korean J Lab Med \n31 : 271 –278 . doi: 10.3343/kjlm.2011.31.4.271 \n22016681 \n18 Garcovich S , Ruggeri A , D'Agostino M , Ardito F , De Simone C , Delogu G , et al (2012 ) Clinical applicability of Quantiferon-TB-Gold testing in psoriasis patients during long-term anti-TNF-alpha treatment: a prospective, observational study . J Eur Acad Dermatol Venereol \n26 : 1572 –1576 . doi: 10.1111/j.1468-3083.2011.04220.x \n21923840 \n19 Hatzara C , Hadziyannis E , Kandili A , Koutsianas C , Makris A , Georgiopoulos G , et al (2015 ) Frequent conversion of tuberculosis screening tests during anti-tumour necrosis factor therapy in patients with rheumatic diseases . Ann Rheum Dis \n74 : 1848 –1853 . doi: 10.1136/annrheumdis-2014-205376 \n24854354 \n20 Bartalesi F , Goletti D , Spinicci M , Cavallo A , Attala L , Mencarini J , et al (2013 ) Serial QuantiFERON TB-gold in-tube testing during LTBI therapy in candidates for TNFi treatment . J Infect \n66 : 346 –356 . doi: 10.1016/j.jinf.2012.10.017 \n23103667 \n21 Tsai TF , Ho JC , Song M , Szapary P , Guzzo C , Shen YK , et al (2011 ) Efficacy and safety of ustekinumab for the treatment of moderate-to-severe psoriasis: a phase III, randomized, placebo-controlled trial in Taiwanese and Korean patients (PEARL) . J Dermatol Sci \n63 : 154 –163 . doi: 10.1016/j.jdermsci.2011.05.005 \n21741220 \n22 Filipe-Santos O , Bustamante J , Chapgier A , Vogt G , de Beaucoudrey L , Feinberg J , et al (2006 ) Inborn errors of IL-12/23- and IFN-gamma-mediated immunity: molecular, cellular, and clinical features . Semin Immunol \n18 : 347 –361 . doi: 10.1016/j.smim.2006.07.010 \n16997570 \n23 Tsai TF , Ho V , Song M , Szapary P , Kato T , Wasfi Y , et al (2012 ) The safety of ustekinumab treatment in patients with moderate-to-severe psoriasis and latent tuberculosis infection . Br J Dermatol \n167 : 1145 –1152 . doi: 10.1111/j.1365-2133.2012.11142.x \n22803615 \n24 Errichetti E , Piccirillo A . (2014 ) Latent tuberculosis reactivation in a patient with erythrodermic psoriasis under treatment with ustekinumab and a low dose steroid, despite isoniazid chemoprophylaxis . Eur J Dermatol \n24 : 508 –509 . doi: 10.1684/ejd.2014.2386 \n25120233 \n25 Saraceno R , Specchio F , Chiricozzi A , Sarmati L , Amicosante M , Chimenti MS , et al (2014 ) Usefulness of QuantiFERON®-TB Gold test in psoriatic patients under treatment with tumour necrosis factor blockers . Expert Opin Biol Ther \n14 : 151 –156 . doi: 10.1517/14712598.2014.860441 \n24303977 \n26 Sauzullo I , Mengoni F , Marocco R , Potenza C , Skroza N , Tieghi T , et al (2013 ) Interferon-γ release assay for tuberculosis in patients with psoriasis treated with tumour necrosis factor antagonists: in vivo and in vitro analysis . Br J Dermatol \n169 : 1133 –1140 . doi: 10.1111/bjd.12544 \n23909256 \n27 Reddy M , Torres G , McCormick T , Marano C , Cooper K , Yeilding N , et al (2010 ) Positive treatment effects of ustekinumab in psoriasis: analysis of lesional and systemic parameters . J Dermatol \n37 : 413 –425 . doi: 10.1111/j.1346-8138.2010.00802.x \n20536646 \n28 Feng CG , Jankovic D , Kullberg M , Cheever A , Scanga CA , Hieny S , et al (2005 ) Maintenance of pulmonary Th1 effector function in chronic tuberculosis requires persistent IL-12 production . J Immunol \n174 : 4185 –4192 . 15778379 \n29 Tsai TF , Chiu HY , Song M , Chan D . (2013 ) A case of latent tuberculosis reactivation in a patient treated with ustekinumab without concomitant isoniazid chemoprophylaxis in the PEARL trial . Br J Dermatol \n168 : 444 –446 . doi: 10.1111/j.1365-2133.2012.11162.x \n22816505 \n30 Chen DY , Shen GH , Chen YM , Chen HH , Hsieh CW , Lan JL . (2012 ) Biphasic emergence of active tuberculosis in rheumatoid arthritis patients receiving TNFα inhibitors: the utility of IFNγ assay . Ann Rheum Dis \n71 : 231 –237 . doi: 10.1136/annrheumdis-2011-200489 \n22021896 \n31 Scrivo R , Sauzullo I , Mengoni F , Priori R , Coppola M , Iaiani G , et al (2013 ) Mycobacterial interferon-γ release variations during longterm treatment with tumor necrosis factor blockers: lack of correlation with clinical outcome . J Rheumatol \n40 : 157 –165 . doi: 10.3899/jrheum.120688 \n23204217 \n32 Mancuso JD , Bernardo J , Mazurek GH . (2013 ) The elusive \"gold\" standard for detecting Mycobacterium tuberculosis infection . Am J Respir Crit Care Med \n187 : 122 –124 . doi: 10.1164/rccm.201211-2033ED \n23322793 \n33 Powell RD 3rd, Whitworth WC , Bernardo J , Moonan PK , Mazurek GH . (2011 ) Unusual interferon gamma measurements with QuantiFERON-TB Gold and QuantiFERON-TB Gold In-Tube tests . PLoS One \n6 : e20061 \ndoi: 10.1371/journal.pone.0020061 \n21687702 \n34 Chen YJ , Wu CY , Shen JL , Chen TT , Chang YT . (2013 ) Association between traditional systemic antipsoriatic drugs and tuberculosis risk in patients with psoriasis with or without psoriatic arthritis: results of a nationwide cohort study from Taiwan . J Am Acad Dermatol \n69 : 25 –33 . doi: 10.1016/j.jaad.2012.12.966 \n23375515\n\n",
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"title": "Serial QuantiFERON-TB Gold testing in patients with psoriasis treated with ustekinumab.",
"title_normalized": "serial quantiferon tb gold testing in patients with psoriasis treated with ustekinumab"
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"abstract": "NC, with renal failure secondary to bilateral dysplastic kidneys, received an LRD renal transplant (tx) at 17 months of age. Her early post-tx course was complicated by persistently elevated blood polyoma BK virus DNA loads. A protocol biopsy at six months post-transplant revealed BKVAN. Blood viral loads did not respond to decreased immunosuppression or treatment with ciprofloxacin and leflunomide. Six months post-tx, her serum creatinine began to rise and we sought experimental therapy to prevent the loss of her graft. At seven months post-tx, with FDA approval under an eIND, the patient was started on a 36-wk course of treatment with the investigational drug. The patient is now more than 24 months after stopping treatment with CMX. BKV viral DNA loads remain at low, but still detectable levels. Urine viral loads have declined, but remain elevated. EBV DNA loads become undetectable. The patient's serum creatinine has declined back to a baseline of 0.5-0.7 mg/dL and has been stable for two yr. Renal function was preserved in association with the use of CMX001 to treat BKV nephropathy in a young pediatric kidney transplant recipient. There were no serious adverse events associated with the use of CMX001. This novel medication may be of value in the treatment of BKVAN in pediatric renal transplant recipients.",
"affiliations": "Section of Pediatric Nephrology, Department of Pediatrics, Louisiana State University Health Sciences Center - Shreveport, Shreveport, LA, USA.",
"authors": "Reisman|Lewis|L|;Habib|Sabeen|S|;McClure|Gloria B|GB|;Latiolais|Lisa S|LS|;Vanchiere|John A|JA|",
"chemical_list": "D004279:DNA, Viral; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D063065:Organophosphonates; D002939:Ciprofloxacin; C525733:brincidofovir; D003596:Cytosine; D003404:Creatinine; D000077339:Leflunomide",
"country": "Denmark",
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"doi": "10.1111/petr.12340",
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"issue": "18(7)",
"journal": "Pediatric transplantation",
"keywords": "BK virus; BKVAN; CMX001; nephropathy",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D000284:Administration, Oral; D001739:BK Virus; D001706:Biopsy; D002675:Child, Preschool; D002939:Ciprofloxacin; D003404:Creatinine; D003596:Cytosine; D004279:DNA, Viral; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D016030:Kidney Transplantation; D000077339:Leflunomide; D063065:Organophosphonates; D051437:Renal Insufficiency; D051436:Renal Insufficiency, Chronic; D019562:Viral Load",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "E227-31",
"pmc": null,
"pmid": "25174393",
"pubdate": "2014-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Treatment of BK virus-associated nephropathy with CMX001 after kidney transplantation in a young child.",
"title_normalized": "treatment of bk virus associated nephropathy with cmx001 after kidney transplantation in a young child"
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"companynumb": "PHHY2014US111102",
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"abstract": "Pancreatic cancer is an extremely lethal malignancy with the majority of patients presenting with advanced disease. Typically, fit patients with advanced unresectable disease are treated with chemotherapy, which comprises either first-line folfirinox (FNX) or gemcitabine/nab-paclitaxel (GNP) regimens based on level 1 evidence. To our knowledge, robust evidence for second-line GNP post FNX does not exist. We herein report four cases treated at our institute with second-line GNP. Amongst those were patients with durable responses lasting over a year, which is extremely rare in stage 4 pancreatic cancer.",
"affiliations": "Department of Medical Oncology, King Fahad Specialist Hospital, Dammam, SAU.;Department of Medical Oncology, King Fahad Specialist Hospital, Dammam, SAU.;Department of Medical Oncology, King Fahad Specialist Hospital, Dammam, SAU.;Department of Medical Oncology, King Fahad Specialist Hospital, Dammam, SAU.;Department of Radiation Oncology, King Fahad Specialist Hospital, Dammam, SAU.;Multiorgan Transplant Center, King Fahad Specialist Hospital, Dammam, SAU.",
"authors": "Bukhari|Nedal|N|;Abdalla|Khalda|K|;Ibnshamsa|Fahad|F|;Alselwi|Waleed|W|;Al-Shakir|Shakir|S|;Alqahtani|Mohammed|M|",
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"doi": "10.7759/cureus.18756",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.18756\nOncology\nExceptional Response to Second-Line Gemcitabine/Nab-Paclitaxel Chemotherapy in Patients With Metastatic Pancreatic Adenocarcinoma\nMuacevic Alexander\nAdler John R\nBukhari Nedal 12\nAbdalla Khalda 1\nIbnshamsa Fahad 1\nAlselwi Waleed 1\nAl-Shakir Shakir 3\nAlqahtani Mohammed 4\n1 Department of Medical Oncology, King Fahad Specialist Hospital, Dammam, SAU\n2 Department of Internal Medicine, Imam Abdulrahman Bin Faisal University, Dammam, SAU\n3 Department of Radiation Oncology, King Fahad Specialist Hospital, Dammam, SAU\n4 Multiorgan Transplant Center, King Fahad Specialist Hospital, Dammam, SAU\nNedal Bukhari nedal.bukhari36@gmail.com\n13 10 2021\n10 2021\n13 10 e1875613 10 2021\nCopyright © 2021, Bukhari et al.\n2021\nBukhari et al.\nhttps://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/74160-exceptional-response-to-second-line-gemcitabinenab-paclitaxel-chemotherapy-in-patients-with-metastatic-pancreatic-adenocarcinoma\nPancreatic cancer is an extremely lethal malignancy with the majority of patients presenting with advanced disease. Typically, fit patients with advanced unresectable disease are treated with chemotherapy, which comprises either first-line folfirinox (FNX) or gemcitabine/nab-paclitaxel (GNP) regimens based on level 1 evidence. To our knowledge, robust evidence for second-line GNP post FNX does not exist. We herein report four cases treated at our institute with second-line GNP. Amongst those were patients with durable responses lasting over a year, which is extremely rare in stage 4 pancreatic cancer.\n\nchemotherapy\nnab-paclitaxel\ngemcitabine\nfolfirinox\npancreatic cancer\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\npmcIntroduction\n\nPancreatic adenocarcinoma (PAC) is the eighth cause of cancer mortality and ranked the 14th in incidence worldwide in 2016 [1,2]. The current standard of care for resectable PAC is surgery followed by adjuvant chemotherapy. However, 15-20% of patients only present with potentially curative disease and the vast majority present with advanced unresectable disease, which is translated to a five-year survival rate of around 5% [3-5].\n\nOver the last decade, new lines of treatments for metastatic PAC have emerged. Folfirinox (5-fluorouracil, leucovorin, irinotecan and oxaliplatin; FNX) and gemcitabine/nab-paclitaxel (GNP) both extended survival when compared to gemcitabine in first-line setting [6,7]. Second-line chemotherapy post-FNX therapy remains controversial due to the lack of phase III clinical trials. The best evidence comes from a phase II trial by Portal et al. where the median number of GNP cycles given to patients was four, with a median overall survival of 8.8 months [8]. We report four cases of metastatic PAC with durable responses to second-line GNP post-FNX. Three of them experienced a durable response lasting for 12 months and beyond, which is extremely rare in metastatic pancreatic cancer patients on palliative chemotherapy [9]. Those patients were treated at a tertiary hospital in Dammam, Saudi Arabia.\n\nCase presentation\n\nCase 1\n\nA 59-year-old male underwent Whipple’s procedure for a mass involving the head of the pancreas. Pathology was remarkable for a T3N1 poorly differentiated pancreatic ductal adenocarcinoma. Preoperative cancer antigen 19-9 (CA19-9) level was read at 282 U/ml. The patient received adjuvant capecitabine and gemcitabine (cape/gem) protocol for six months and was placed on surveillance afterwards.\n\nSeven months after completion of the adjuvant treatment, his computed tomography (CT) scan revealed recurrent disease involving the liver. He was started on palliative FNX every two weeks. Disease progression to his liver and retroperitoneal lymphadenopathy was confirmed on his CT scan after six cycles of FNX (Figure 1). He was then switched to second-line GNP immediately afterwards.\n\nFigure 1 CT abdomen done prior to starting second-line gemcitabine/nab-paclitaxel (Case 1)\n\nThe arrow indicates liver metastasis.\n\nBefore initiation of second-line GNP, his CA19-9 was at 1642.39, with a nadir of 6.8 U/ml. His tumor was tested for mismatch repair proteins and was found to be low in microsatellite instability (MSI-L).\n\nHe received a total of 14 cycles of GNP with multiple interruptions in his treatment course due to recurrent hepatic abscesses requiring long courses of intravenous (IV) antibiotics. His performance status dropped significantly after cycle 14 with an interval CT scan that showed interval disease progression with extensive liver metastasis (Figure 2). Second-line GNP was discontinued, and he was placed on complete palliative measures and died a few weeks afterwards (Table 1).\n\nFigure 2 CT abdomen (Case 1)\n\nThe figure indicates disease stability post 14 months of second-line gemcitabine/nab-paclitaxel.\n\nTable 1 Clinical Characteristics of Patients (Cases 1-4)\n\n**All patients received GNP in a 28-day cycle, where both nab-paclitaxel and gemcitabine were given on days 1, 8 and 15.\n\nGNP: gemcitabine/nab-paclitaxel; FNX: folfirinox; CA19-9: cancer antigen 19-9; MSI: microsatellite instability; ECOG: Eastern Cooperative Oncology Group; PS: performance status\n\nPatients\tPS pre GNP (ECOG)\tCa 19-9 pre GNP U/ml\tPrior treatment and number of cycles\tNumber of GNP cycles*\tDuration of response in months (m) while on GNP\tCa 19-9 nadir while on GNP U/ml\tGrade III or higher side effects\tOther molecular characteristics\tSurvival\t\nCase 1\t1\t1642\tFNX 6 cycles\t14\t18 m (patient had breaks from chemotherapy)\t6.8\tNot reported. Chemotherapy was interrupted\tMSI-Low\t19 m\t\nCase 2\t1\t106\tFNX 18 cycles\t 6\t9 m \tN/A\tFatigue and peripheral neuropathy\tUnknown\t10 m\t\nCase 3\t1\t63.3\tFNX 3 cycles only\t 9\t12 m \t4.08\tTreatment interrupted\tMS-Stable\t12 m still alive on 3rd line Folfiri\t\nCase 4\t1\t662\tGemcitabine 4 cycles\t14\t14 m still receiving GNP with good clinical response\t13.85\tNil\tUnknown\t16 m\t\n\nCase 2\n\nA 58-year-old male patient presented with metastatic pancreatic ductal adenocarcinoma, primary originating from the body and tail of the pancreas with metastatic paraaortic and aortocaval lymphadenopathy, peritoneal and bilateral pulmonary metastasis. At the time of presentation, his CA19-9 was at 359.96 U/ml.\n\nHe was started on palliative FNX with very good response to it lasting for over a year through which he received a total of 18 cycles. Treatment delays occurred several times, each lasting one to two weeks, mainly due to grade III fatigue and neutropenia. His CT scan done after 13 months indicated interval progression of his peritoneal metastasis and a new right adrenal gland metastasis. \n\nHe was started on second-line GNP with a marked improvement in his disease reflected on interval CT scans done after three months. He received a total of six cycles of GNP over 10 months. \n\nTreatment delays occurred few times, mainly secondary to grade III fatigue and peripheral neuropathy. CA19-9 level prior to starting GNP was at 106.7 U/ml. His CA19-9 continued to climb up despite good clinical and radiological responses. The patient died of septic shock in ICU a few weeks after completion of cycle 6 (Table 1).\n\nCase 3\n\nA 47-year-old male patient was referred from a community hospital with advanced pancreatic ductal adenocarcinoma, initially thought to be borderline resectable disease where three cycles of FNX were given. Disease progression involving the liver was noted on CT scan and curative surgery was declined (Figure 3). At the time of admission, his CA19-9 level was at 63U/ml. Due to interval disease progression, GNP was started. CA 19-9 nadir after four cycles was at 4.08 U/ml.\n\nFigure 3 CT abdomen shows pancreatic mass prior to starting second-line GNP chemotherapy (Case 3)\n\nArrows indicate the pancreatic mass\n\nHis CT done after 12 months of GNP showed interval disease progression of the primary lesion involving the body and tail of the pancreas with newly developed liver metastasis (Figure 4). He received a total of nine cycles of GNP throughout 12 months. His Medical Oncologist placed him on third-line Folfiri (5-FU, folinic acid and irinotecan) protocol due to interval clinical and radiological progression and he continues to be on it (Table 1).\n\nFigure 4 CT abdomen shows newly developed lesions in the liver (red arrows) after 12 months of starting second-line GNP (Case 3).\n\nThe pancreatic mass showing interval regression (white arrow)\n\nCase 4\n\nAn 80-year-old male patient presented with pancreatic ductal adenocarcinoma with mediastinal lymphadenopathy and bilateral lung metastasis. His Eastern Cooperative Oncology Group (ECOG) performance status (PS) was borderline at 2. Therefore, he was started on single-agent gemcitabine with a marked improvement in his performance status after three cycles. However, his first reassessment CT scan done after cycle 3 revealed an interval progression of his pulmonary metastasis (Figure 5).\n\nFigure 5 CT scan revealing bilateral pulmonary metastasis (Case 4).\n\nArrows showing bilateral pulmonary metastatic lesions.\n\nHis clinical improvement and performance status implied adding nab-paclitaxel to gemcitabine. A CT scan was done after 12 cycles of second-line GNP and showed stable metastatic disease (Figure 6). To date, he has completed a total of 14 cycles of GNP with plans to proceed further (Table 1).\n\nFigure 6 A reassessment CT scan done after 12 cycles of chemotherapy showing stable metastatic disease (Case 4).\n\nCT chest showing response to treatment.\n\nDiscussion\n\nChemotherapy is the standard of care in metastatic PAC. FNX and GNP are both preferred, well-studied chemotherapeutic regimens in the first-line treatment of metastatic PAC.\n\nA phase III trial of first-line FNX by Conroy et al. was the first to demonstrate a survival advantage closer to six months [6,10,11]. This regimen constitutes 5-fluorouracil, oxaliplatin, irinotecan and leucovorin and is usually offered to patients with an ECOG performance status of 0 to 1 [6,12]. Respectively, The MPACT trial clearly proved the overall survival (OS) advantage of GNP. This trial included patients with an ECOG PS of 2.7.\n\nSecond-line nano-liposomal irinotecan and infusional 5-FU showed a survival advantage in patients who progressed on first-line gemcitabine-based treatments [13]. To date, there is no standardized second-line treatment for metastatic pancreatic cancer (PC) patients progressing on first-line FNX due to the lack of conclusive level 1 evidence. However, there are small-scale phase II trials and observational studies that indicated objective response to second-line GNP, its safety and also a modest increase in OS [14].\n\nWe herein report four cases with an exceptional response to second-line GNP (Table 1) with Case 1 experiencing an 18-month survival after starting second-line GNP. Cases 1 and 2 experienced a prolonged response and OS to second-line GNP despite receiving prolonged FNX treatment courses in first-line setting, exceeding a year in Case 1. Case 4 had single agent gemcitabine initially due to borderline ECOG PS, for three months, commenced on GNP after a significant improvement in his PS, has been on this combination for 14 months with good response.\n\nOver the last few years, extensive molecular and genomic research has been conducted to identify predictive and prognostic features in PC. Moffitt et al. identified two types of PC: classical, and basal-like type which carries the worst prognosis. The COMPASS trial showed that besides the typical histopathological characteristics, PC has different genomic and molecular subtypes with different responses to treatment classes [15,16]. The COMPASS trial clearly demonstrated that Moffit’s classical type expressed higher levels of GATA 6, responded better to first-line 5-FU-based chemotherapy, and also lived longer. Basal-like PC tumors were found to associate with low GATA 6 expression, resistance to adjuvant 5-FU based chemotherapy and demonstrated shorter OS. The predictive value of these classifications has not been investigated in adequately powered studies [15-17].\n\nApproximately 10% of pancreatic malignancies harbour breast cancer (BRCA) gene mutations, detected by germlines testing and gene profiling of the tumor tissue. Fifty percent of those patients have germline BRCA and BRCA-like mutations in whom olaparib can be used as maintenance treatment post first-line platinum-based first line. Olaparib, a polyadenosine diphosphate-ribose polymerase (PARP) inhibitor was proven to prolong progression free survival (PFS) in a randomized phase III trial [18,19].\n\nIt is expected that germline mutations will confer the greatest benefit. However, a recent study indicated that PC harbouring germline or somatic mutations involving the homologous recombination repair (HRR) genes like BRCA1/2, PALB2, ATM, BAP1, BARD1, BLM, CHEK2, FANCA, BRIP1, FAM175A, FANCC, NBN, RAD50, RAD51, RAD51C and RTEL 1, will experience an improved PFS when treated with first-line platinum-based chemotherapy [18].\n\nMicrosatellite instability (MSI), present in approximately 1% of patients with PC, serves as a predictive biomarker for the anti-PD1 immunotherapy, pembrolizumab [18]. The phase II open label nonrandomized trial Keynote-158 enrolled patients with microsatellite instability-high (MSI-H) cancers including metastatic PAC patients who progressed on first-line standard chemotherapy. This trial concluded the efficacy and safety of pembrolizumab in MSI-H metastatic PAC. The subgroup analysis of PAC patients in this study showed an objective response rate (ORR) of 18.2%, a patient with complete response, three patients with partial response (PR) and a median OS of four months [20].\n\nNTRK mutation is another good example of an actionable target, which is present in approximately 0.6% of patients with metastatic PC and may respond to anti-TRK agents like larotrectinib and entrectinib [21-23].\n\nThe main limitation of this series was the lack of information on molecular predictive and prognostic biomarkers, most of which are not routinely performed at our institute. Further studies are required to better understand the biology of pc and to identify and validate prognostic and predictive biomarkers that could help oncologists stratify and treat patients accordingly.\n\nConclusions\n\nThis case series with patients demonstrating an exceptional response to second-line GNP supports the use of this line of treatment in metastatic PC patients progressing on first-line FNX. We also believe that current standards of care should incorporate further personalized medicine-based approaches to select the most appropriate treatments.\n\nHuman Ethics\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 The global, regional, and national burden of pancreatic cancer and its attributable risk factors in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017 Lancet Gastroenterol Hepatol GBD 2017 Pancreatic Cancer Collaborators 0 5 2020\n2 Pancreatic cancer Lancet Kamisawa T Wood LD Itoi T Takaori K 73 85 388 2016 26830752\n3 Pancreatic cancer: a review of clinical diagnosis, epidemiology, treatment and outcomes World J Gastroenterol McGuigan A Kelly P Turkington RC Jones C Coleman HG McCain RS 4846 4861 24 2018 30487695\n4 A single center experience in resectable pancreatic ductal adenocarcinoma : the limitations of the surgery-first approach. Critical review of the literature and proposals for practice update Acta Gastroenterol Belg Dumont R Puleo F Collignon J 451 461 80 2017 https://pubmed.ncbi.nlm.nih.gov/29560639/ 29560639\n5 Impact of early disease progression and surgical complications on adjuvant chemotherapy completion rates and survival in patients undergoing the surgery first approach for resectable pancreatic ductal adenocarcinoma - a population-based cohort study Acta Oncol Labori KJ Katz MH Tzeng CW 265 277 55 2016 26213211\n6 FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer N Engl J Med Conroy T Desseigne F Ychou M 1817 1825 364 2011 21561347\n7 Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine N Engl J Med Von Hoff DD Ervin T Arena FP 1691 1703 369 2013 24131140\n8 Nab-paclitaxel plus gemcitabine for metastatic pancreatic adenocarcinoma after Folfirinox failure: an AGEO prospective multicentre cohort Br J Cancer Portal A Pernot S Tougeron D 989 995 113 2015 26372701\n9 Efficacy and safety of second-line nab-paclitaxel plus gemcitabine after progression on FOLFIRINOX for unresectable or metastatic pancreatic ductal adenocarcinoma: multicenter retrospective analysis Ther Adv Med Oncol Chae H Jeong H Cheon J 1758835920923424 12 2020 32523632\n10 Chronic oxaliplatin-based chemotherapy in a primary ampullary adenocarcinoma patient without significant peripheral neuropathy: case report and literature review Case Rep Oncol Bukhari N Winquist E 577 581 10 2017 28868015\n11 Early stage anaplastic sarcomatoid carcinoma of the pancreas, a case report Am J Case Rep Bukhari N Joudeh A 597 601 20 2019 31023997\n12 Performance status assessment by using ECOG (Eastern Cooperative Oncology Group) score for cancer patients by oncology healthcare professionals Case Rep Oncol Azam F Latif MF Farooq A Tirmazy SH AlShahrani S Bashir S Bukhari N 728 736 12 2019 31616281\n13 Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI- 1): a global, randomised, open-label, phase 3 trial Lancet Wang-Gillam A Li CP Bodoky G 545 557 387 2016 26615328\n14 Second-line gemcitabine plus nab-paclitaxel for patients with unresectable advanced pancreatic cancer after first-line FOLFIRINOX failure J Clin Med Mita N Iwashita T Uemura S 761 8 2019\n15 Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma Nat Genet Moffitt RA Marayati R Flate EL 1168 1178 47 2015 26343385\n16 Genomics-driven precision medicine for advanced pancreatic cancer: early results from the COMPASS trial Clin Cancer Res Aung KL Fischer SE Denroche RE 1344 1354 24 2018 29288237\n17 GATA6 regulates EMT and tumour dissemination, and is a marker of response to adjuvant chemotherapy in pancreatic cancer Gut Martinelli P Carrillo-de Santa Pau E Cox T 1665 1676 66 2017 27325420\n18 Genomic methods identify homologous recombination deficiency in pancreas adenocarcinoma and optimize treatment selection Clin Cancer Res Park W Chen J Chou JF 3239 3247 26 2020 32444418\n19 Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer N Engl J Med Golan T Hammel P Reni M 317 327 381 2019 31157963\n20 Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 study J Clin Oncol Marabelle A Le DT Ascierto PA 1 10 38 2020 31682550\n21 NTRK fusion detection across multiple assays and 33,997 cases: diagnostic implications and pitfalls Mod Pathol Solomon JP Linkov I Rosado A 38 46 33 2020 31375766\n22 Tumour response to TRK inhibition in a patient with pancreatic adenocarcinoma harbouring an NTRK gene fusion Ann Oncol O'Reilly EM Hechtman JF 0 40 30 2019\n23 Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children N Engl J Med Drilon A Laetsch TW Kummar S 731 739 378 2018 29466156\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "13(10)",
"journal": "Cureus",
"keywords": "chemotherapy; folfirinox; gemcitabine; nab-paclitaxel; pancreatic cancer",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e18756",
"pmc": null,
"pmid": "34796055",
"pubdate": "2021-10",
"publication_types": "D002363:Case Reports",
"references": "26830752;26372701;21561347;31616281;26213211;31682550;29288237;31146420;32444418;29560639;30487695;31375766;24131140;28868015;31605106;31023997;26615328;26343385;29466156;31157963;32523632;27325420;31648972",
"title": "Exceptional Response to Second-Line Gemcitabine/Nab-Paclitaxel Chemotherapy in Patients With Metastatic Pancreatic Adenocarcinoma.",
"title_normalized": "exceptional response to second line gemcitabine nab paclitaxel chemotherapy in patients with metastatic pancreatic adenocarcinoma"
} | [
{
"companynumb": "SA-Accord-246452",
"fulfillexpeditecriteria": "1",
"occurcountry": "SA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": "3",
"dru... |
{
"abstract": "Everolimus has important clinical activity in various malignancies, but its use can be complicated by respiratory adverse events. Important everolimus-induced respiratory adverse events are interstitial lung disease (ILD) and infections, either typical or opportunistic. Furthermore, non-everolimus-related respiratory events can occur. Due to the non-specific presentation of most of these respiratory disorders, it is often not possible to differentiate between these causes on clinical and radiological grounds only. Considering the potential fatal nature of opportunistic infections, these are especially important to recognize. To be able to distinguish between ILD and (opportunistic) infections as the underlying cause, an aggressive diagnostic workup, including bronchoalveolar lavage, should be performed in patients treated with everolimus who develop respiratory disease. We report three cases of severe opportunistic pulmonary infections during everolimus treatment, concerning two Pneumocystis jirovecii pneumonia infections. These cases illustrate the diagnostic challenges of respiratory adverse events and the importance of a thorough diagnostic workup for correct diagnosis and treatment.",
"affiliations": "Department of Medical Oncology (452), Radboud University Medical Centre, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands, annelieke.willemsen@Radboudumc.nl.",
"authors": "Willemsen|Annelieke E C A B|AE|;De Vos|Filip Y|FY|;Jansen|Anne|A|;de Boer|Maaike|M|;Tjan-Heijnen|Vivianne C G|VC|;van Herpen|Carla M L|CM|",
"chemical_list": "D000970:Antineoplastic Agents; D000068338:Everolimus; D020123:Sirolimus",
"country": "France",
"delete": false,
"doi": "10.1007/s11523-014-0310-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1776-2596",
"issue": "9(3)",
"journal": "Targeted oncology",
"keywords": null,
"medline_ta": "Target Oncol",
"mesh_terms": "D000970:Antineoplastic Agents; D000068338:Everolimus; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009894:Opportunistic Infections; D012141:Respiratory Tract Infections; D020123:Sirolimus",
"nlm_unique_id": "101270595",
"other_id": null,
"pages": "287-91",
"pmc": null,
"pmid": "24590692",
"pubdate": "2014-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16162203;19402072;26029507;17765042;23423809;23383366;22210429;20194812;21781947;18848473;23312829;19265086;21986616;22149876;20946413;15190141;23606919;20047487;21306238;20549832;21193785;23392213;2817582;8429048",
"title": "Diagnostic challenges of respiratory adverse events during everolimus treatment.",
"title_normalized": "diagnostic challenges of respiratory adverse events during everolimus treatment"
} | [
{
"companynumb": "NL-ROXANE LABORATORIES, INC.-2016-RO-00397RO",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "EXEMESTANE"
},
"drugadditi... |
{
"abstract": "A 6-year-old girl experienced nausea and vomiting for 3 weeks and double vision for 1 week prior to her first visit to our hospital. She had bilateral ophthalmoplegia from sixth cranial nerve palsy and papilledema. Her brain MRI showed normal brain parenchyma. The lumbar cerebrospinal fluid (CSF) opening pressure was 1000 mm of water measured with normal CSF contents. From these findings, she was diagnosed with idiopathic intracranial hypertension (IIH). Initial lumbar puncture (LP) immediately improved her symptoms, but acetazolamide, a first line drug for the treatment of IIH, failed to maintain the remission, and three more periodical LP were required to relieve her symptoms every 2 weeks. After the fourth LP, acetazolamide was switched to a second line drug for IIH, topiramate, which was found to be highly effective in controlling IIH in a short time period. The long process of IIH causes vision loss, therefore, its prompt treatment is vital. In cases refractory to medical treatment, surgical treatments such as CSF shunt are considered. Acetazolamide is used in most IIH cases after the initial diagnosis, but in this case, it was ineffective, and topiramate was highly effective. Both acetazolamide and topiramate are inhibitors of carbonic anhydrase isoforms involved in CSF secretion. Inhibition of choroid plexus carbonic anhydrase by these drugs leads to decreased CSF secretion and the consequent control of intracranial pressure. Higher isoform specificity and increased lipophilic nature of topiramate, which are advantageous for passing through the blood brain barrier, may be the reasons for better activity than acetazolamide, at least in the present case. Topiramate might be effective and should be considered for refractory IIH cases before surgical treatments.",
"affiliations": null,
"authors": "Noda|Marie|M|;Sonoda|Yuri|Y|;Takemoto|Megumi|M|;Kira|Ryutaro|R|",
"chemical_list": "D000086:Acetazolamide",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0029-0831",
"issue": "49(3)",
"journal": "No to hattatsu = Brain and development",
"keywords": null,
"medline_ta": "No To Hattatsu",
"mesh_terms": "D000086:Acetazolamide; D002648:Child; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D011559:Pseudotumor Cerebri; D016896:Treatment Outcome; D014786:Vision Disorders",
"nlm_unique_id": "0215224",
"other_id": null,
"pages": "207-10",
"pmc": null,
"pmid": "30113799",
"pubdate": "2017-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment with topiramate in a case of idiopathic intracranial hypertension refractory to acetazolamide.",
"title_normalized": "successful treatment with topiramate in a case of idiopathic intracranial hypertension refractory to acetazolamide"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2017R1-147027",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ACETAZOLAMIDE"
},
"d... |
{
"abstract": "Matched sibling donor hematopoietic stem cell transplantation is the standard of care for severe aplastic anemia, with an overall survival of 80% to 90%. Only 60% to 70% of patients respond to treatment with immunosuppressive therapy. The main life threatening complications are infections, graft failure, and graft versus host disease. A 10-year-old patient with severe aplastic anemia underwent matched sibling donor hematopoietic stem cell transplantation, but developed sudden onset of fatal multiorgan failure on day +12. The cause of death was found only after autopsy.",
"affiliations": "Department of Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, USA.",
"authors": "Rawlinson|Neil J|NJ|;Fung|Bonita|B|;Gross|Thomas G|TG|;Termuhlen|Amanda M|AM|;Skeens|Micah|M|;Garee|Amy|A|;Soni|Sandeep|S|;Pietryga|Daniel|D|;Bajwa|Rajinder P S|RP|",
"chemical_list": "D011743:Pyrimidines; D014230:Triazoles; C068538:liposomal amphotericin B; D000666:Amphotericin B; D065819:Voriconazole",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0b013e3182050a4f",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "33(3)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000666:Amphotericin B; D000741:Anemia, Aplastic; D002648:Child; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D009091:Mucormycosis; D009102:Multiple Organ Failure; D011743:Pyrimidines; D020103:Rhizomucor; D014230:Triazoles; D065819:Voriconazole",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "235-7",
"pmc": null,
"pmid": "21358340",
"pubdate": "2011-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Disseminated Rhizomucor pusillus causing early multiorgan failure during hematopoietic stem cell transplantation for severe aplastic anemia.",
"title_normalized": "disseminated rhizomucor pusillus causing early multiorgan failure during hematopoietic stem cell transplantation for severe aplastic anemia"
} | [
{
"companynumb": "US-PFIZER INC-2021136414",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FLUCONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe case of a central nervous system human herpes virus type 6 (HHV-6) and Toxoplasma gondii co-infection after an umbilical cord blood transplantation in a chronic myelomonocytic leukaemia patient is reported.\n\n\nMETHODS\nA 65-year-old Caucasian man underwent an umbilical cord blood transplantation within the context of chronic myelomonocytic leukaemia. On day 37 post-graft, he presented with a severe headache; PCRs of cerebrospinal fluid and blood were positive for T. gondii and HHV-6. The patient was treated with pyrimethamine and sulfadiazine associated with ganciclovir.\n\n\nCONCLUSIONS\nHHV-6 reactivation can trigger a reactivation of T. gondii. This case suggests that patients who are seropositive for T. gondii and who present with HHV-6 reactivation should be monitored closely for toxoplasmosis.",
"affiliations": "Laboratoire de Parasitologie-Mycologie, Centre de Biologie, CHU Gabriel Montpied, 58, rue Montalembert, F-63003 Clermont-Ferrand, France.;Service d'Hématologie clinique et Thérapie cellulaire, CHU Estaing, Clermont-Ferrand, France.;Service de Virologie, Centre National de Référence des Enterovirus-Parechovirus, Clermont-Ferrand, France; Université d'Auvergne, EA4843 « Epidémiologie et Pathogénie des Infections à Entérovirus », Faculté de Médecine, Clermont-Ferrand, France.;Laboratoire de Parasitologie-Mycologie, Centre de Biologie, CHU Gabriel Montpied, 58, rue Montalembert, F-63003 Clermont-Ferrand, France; Clermont Université, Université Blaise Pascal-Université d'Auvergne-CNRS, UMR 6023 Laboratoire Microorganismes: Génome et Environnement, Clermont-Ferrand, France.;Laboratoire de Parasitologie-Mycologie, Centre de Biologie, CHU Gabriel Montpied, 58, rue Montalembert, F-63003 Clermont-Ferrand, France; Clermont Université, Université Blaise Pascal-Université d'Auvergne-CNRS, UMR 6023 Laboratoire Microorganismes: Génome et Environnement, Clermont-Ferrand, France. Electronic address: c_nourrisson@chu-clermontferrand.fr.",
"authors": "Chapuis|Alexandra|A|;Chabrot|Cécile|C|;Mirand|Audrey|A|;Poirier|Philippe|P|;Nourrisson|Céline|C|",
"chemical_list": "D015774:Ganciclovir",
"country": "Canada",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1201-9712",
"issue": "46()",
"journal": "International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases",
"keywords": "Cerebral co-infection; Cord blood transplantation; Encephalitis; HHV-6; Toxoplasmosis",
"medline_ta": "Int J Infect Dis",
"mesh_terms": "D000368:Aged; D060085:Coinfection; D004660:Encephalitis; D005312:Fetal Blood; D015774:Ganciclovir; D018380:Hematopoietic Stem Cell Transplantation; D015654:Herpesvirus 6, Human; D006801:Humans; D008297:Male; D016133:Polymerase Chain Reaction; D019349:Roseolovirus Infections; D014122:Toxoplasma; D014123:Toxoplasmosis; D066027:Transplant Recipients",
"nlm_unique_id": "9610933",
"other_id": null,
"pages": "79-81",
"pmc": null,
"pmid": "27060193",
"pubdate": "2016-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Encephalitis caused by an unusual human herpes virus type 6 and Toxoplasma gondii co-infection in a cord blood transplant recipient.",
"title_normalized": "encephalitis caused by an unusual human herpes virus type 6 and toxoplasma gondii co infection in a cord blood transplant recipient"
} | [
{
"companynumb": "FR-CELGENEUS-FRA-20170401561",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,
... |
{
"abstract": "A 22-year-old Japanese woman consulted an endocrinologist due to persistent galactorrhea for the past 10 months. She had hyperprolacinemia and had previously been diagnosed with type 2 diabetes mellitus based on her glycohemoglobin level of 11.6%. After two months, she was admitted to our hospital and finally diagnosed with prolactinoma. For the treatment of prolactinoma, bromocriptine 2.5 mg/day was started. After seven days, her post-prandial blood glucose levels, homeostasis model assessment of insulin resistance and plasma C-peptide levels were significantly improved. These results indicate that traditional bromocriptine can be an effective therapeutic alternative in patients with prolactinoma complicated with type 2 diabetes.",
"affiliations": "Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Japan.;Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Japan.;Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Japan.;Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Japan.;Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Japan.;Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Japan.;Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Japan.;Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Japan.;Asakura Medical Association Hospital, Japan.;Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Japan.;Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Japan.;Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Japan.",
"authors": "Oshige|Tamami|T|;Nakamura|Yui|Y|;Sasaki|Yuko|Y|;Kawano|Seiko|S|;Ohki|Tsuyoshi|T|;Tsuruta|Munehisa|M|;Tokubuchi|Ichiro|I|;Nakayama|Hitomi|H|;Yamada|Kentaro|K|;Ashida|Kenji|K|;Tajiri|Yuji|Y|;Nomura|Masatoshi|M|",
"chemical_list": "D006727:Hormone Antagonists; D001971:Bromocriptine; D011388:Prolactin",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.2755-19",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 3124321410.2169/internalmedicine.2755-19Case ReportBromocriptine as a Potential Glucose-lowering Agent for the Treatment of Prolactinoma with Type 2 Diabetes Oshige Tamami 1Nakamura Yui 1Sasaki Yuko 1Kawano Seiko 1Ohki Tsuyoshi 1Tsuruta Munehisa 1Tokubuchi Ichiro 1Nakayama Hitomi 1Yamada Kentaro 2Ashida Kenji 1Tajiri Yuji 1Nomura Masatoshi 1\n1 Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Japan\n2 Asakura Medical Association Hospital, JapanCorrespondence to Dr. Tamami Oshige, ohshige_tamami@med.kurume-u.ac.jp\n\n27 6 2019 1 11 2019 58 21 3125 3128 27 1 2019 13 3 2019 Copyright © 2019 by The Japanese Society of Internal MedicineThe Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).A 22-year-old Japanese woman consulted an endocrinologist due to persistent galactorrhea for the past 10 months. She had hyperprolacinemia and had previously been diagnosed with type 2 diabetes mellitus based on her glycohemoglobin level of 11.6%. After two months, she was admitted to our hospital and finally diagnosed with prolactinoma. For the treatment of prolactinoma, bromocriptine 2.5 mg/day was started. After seven days, her post-prandial blood glucose levels, homeostasis model assessment of insulin resistance and plasma C-peptide levels were significantly improved. These results indicate that traditional bromocriptine can be an effective therapeutic alternative in patients with prolactinoma complicated with type 2 diabetes. \n\nprolactinomatype 2 diabetes mellitusbromocriptineinsulin resistance\n==== Body\nIntroduction\nBromocriptine, a dopamine 2 (D2) receptor agonist, is widely used to treat pituitary tumors, such as prolactinoma and acromegaly (1). It is already known that bromocriptine has effects of suppressing glucose production in the liver and improving peripheral insulin resistance by decreasing the plasma free fatty acid (FFA) and triglyceride (TG) levels (2,3) as well as inducing tumor regression. Quick-release-type bromocriptine, which is an enantiomer of the traditional type, was approved as a glucose-lowering agent by the U.S. Food and Drug Administration in 2010 and has been used to treat type 2 diabetes mellitus in the United States (1).\n\nWe herein report a patient with prolactinoma complicated with type 2 diabetes mellitus whose plasma glucose (PG) level was markedly improved by the administration of traditional bromocriptine.\n\nCase Report\nA 22-year-old Japanese woman consulted a gynecologic clinic complaining of galactorrhea for 10 months. Although 8 months before her visit to the clinic she had been diagnosed with type 2 diabetes mellitus based on her hemoglobin A1c (HbA1c) level of 8.5% at a periodic medical checkup, she failed to be treated for her diabetes. She had no obvious medical history. Her mother had type 2 diabetes mellitus with insulin therapy, and her maternal grandfather had type 2 diabetes mellitus as well. There was no family history of pituitary diseases. She reported having a normal menstrual cycle since 11 years of age.\n\nHer plasma prolactin (PRL) level was 46.48 ng/mL (normal range <20 ng/mL) at her first visit, and she was referred to an endocrinologist 8 months later. The plasma PRL level had increased to 63.54 ng/mL, and prolactinoma was suspected based on the findings of a pituitary magnetic resonance imaging (MRI) dynamic study. Due to her HbA1c level of 11.6%, she was recommended to undergo diabetes treatment while hospitalized. Because she rejected hospitalization, she was prescribed metformin (750 mg/day) and sitagliptin (50 mg/day) for the treatment of her diabetes. Two months later, however, her HbA1c level remained high at 8.5%, not showing any improvement, and her galactorrhea persisted. She was therefore referred to our hospital and admitted for the treatment of galactorrhea as well as hyperglycemia.\n\nOn a physical examination, her height was 160.2 cm, body weight was 75.6 kg, body mass index was 29.2 kg/m2, blood pressure was 116/74 mmHg, and her pulse rate was 78/min and regular. No abnormal findings were noted except for galactorrhea from both nipples. Her laboratory data at admission are shown in Table 1. HbA1c was 8.5%, fasting plasma glucose (FPG) level was 106 mg/dL, fasting plasma C-peptide (CPR) level was 2.0 ng/mL, and fasting plasma insulin level was 9.0 μU/mL, indicating that the capacity for insulin secretion was preserved. Homeostasis model assessment of insulin resistance (HOMA-IR) was 2.4, indicating her insulin sensitivity was somewhat impaired. She had no diabetic microvascular complication. Her plasma PRL level was 62.2 ng/mL, and pituitary MRI showed two microadenomas with diameters of approximately 5 mm (Fig. 1). Based on the disappearance of the PRL response after thyrotropin-releasing hormone loading (Table 2), she was finally diagnosed with prolactinoma.\n\nTable 1. Laboratory Findings at Admission.\n\nFactor\t\tValue\t\tNormal range\t\nFasting PG\t\t106\tmg/dL\t\t70-110\t\nHbA1c\t\t8.5\t%\t\t4.6-6.2\t\nFasting IRI\t\t9.0\tμU/mL\t\t2.0-10.0\t\nHOMA-IR\t\t2.4\t\t\t≤1.6\t\nUrine-Alb\t\t11.2\tmg/day\t\t<30.0\t\nPRL\t\t62.2\tng/mL\t\t1.6-21.9\t\nACTH\t\t19.5\tpg/mL\t\t7.2-63.3\t\nCortisol\t\t16.1\tμg/dL\t\t6.24-18.0\t\nLH\t\t3.9\tmIU/mL\t\t1.76-10.2\t\nFSH\t\t9.6\tmIU/mL\t\t3.01-14.7\t\nGH\t\t0.1\tng/mL\t\t≤2.10\t\nIGF-1\t\t246\tng/mL\t\t161-425\t\nTSH\t\t2.38\tμIU/mL\t\t0.21-3.85\t\nFree T3\t\t3.0\tpg/mL\t\t1.9-3.5\t\nFree T4\t\t1.34\tng/dL\t\t0.88-1.56\t\nPG: plasma glucose, HbA1c: hemoglobin A1c, IRI: immunoreactive insulin, HOMA-IR: homeostasis model assessment of insulin resistance, Alb: albumin, PRL: prolactin, ACTH: adrenocorticotropic hormone, LH: luteinizing hormone, FSH: follicle stimulating hormone, GH: growth hormone, IGF-1: insulin-like growth factor-1, TSH: thyroid stimulating hormone, T3: triiodo thyronine, T4: thyroxine\n\nFigure 1. Pituitary magnetic resonance imaging. There were two microadenomas in the pituitary gland (arrows).\n\nAfter admission, the administration of metformin (750 mg/day) and sitagliptin (50 mg/day) was continued with concomitant diet therapy (1,600 kcal/day). Although FPG remained stable at around 120 mg/dL, post-prandial PG levels were higher than 200 mg/dL after breakfast and after lunch, remaining around 200 mg/dL even after bedtime (Fig. 2). On the 13th hospital day, bromocriptine (2.5 mg/day after dinner) was started as the treatment for prolactinoma. Subsequently, the plasma PRL concentration decreased to 24.9 ng/mL after 7 days of administration. Furthermore, FPG decreased to 101 mg/dL, and the post-prandial PG levels markedly improved to 130-180 mg/dL after starting bromocriptine therapy (Fig. 2).\n\nFigure 2. Daily profile of plasma glucose (PG). Open triangles and solid lines indicate the daily profile at admission, open circles and dotted lines indicate that before bromocriptine administration (in 10 days after admission) and closed circles and solid lines indicate that after bromocriptine administration (in 17 days after admission). Closed inverted triangles indicate meal times.\n\nTable 2. TRH Loading Test.\n\nTime (min)\t\t0\t\t30\t\t60\t\t90\t\t120\t\nPRL (ng/mL)\t\t55.5\t\t62.5\t\t59.9\t\t56.6\t\t51.4\t\nTRH: thyrotropin-releasing hormone, PRL: prolactin\n\nWe compared the PG levels and M values (based on the glucose level of 100 mg/dL) at the time of admission, before bromocriptine administration (10 days after admission), and after bromocriptine administration (17 days after admission), using the paired t-test. The average daily PG levels at admission, before bromocriptine and after bromocriptine were 189±43, 182±45, and 147±26 mg/dL, and the average M values were 25±17.9, 23±19.9 and 6.3±6.3 mg/dL, respectively. There was no significant difference in the average daily PG and M values between admission and before bromocriptine administration (p=0.5197 and p=0.6881, respectively). However, a significant difference was observed in the daily PG (p=0.0097) and M values (p=0.0194) between before and after the administration of bromocriptine.\n\nThe fasting FFA value after taking bromocriptine for 7 days was almost the same as that before the administration. In the meal tolerance test, the ΔCPR 2 hours value (CPR value 2 hours after meal ingestion minus the value before the meal) improved from 2.3 ng/mL to 5.4 ng/mL with bromocriptine administration. To evaluate the insulin sensitivity of the peripheral tissues, a euglycemic hyperinsulinemic glucose clamp test (4) (insulin infusion rate: 1.25 mU/kg/min) was performed before and after bromocriptine treatment, and the glucose infusion rate (GIR; normal value: >8 mg/kg/min) was not improved by the administration of bromocriptine (3.58→2.99 mg/kg/min). However, the fasting immunoreactive insulin (IRI) decreased from 9.0 μU/mL to 7.8 μU/mL, and HOMA-IR, which mainly reflects insulin resistance in the liver (5), decreased from 2.4 to 1.9 after the administration of bromocriptine. Two days after the bromocriptine treatment started, dull headache, malaise and constipation were observed, but those symptoms were tolerated and disappeared after several more days. At the 5-year follow-up, her HbA1c level remained around 6%, and the plasma PRL value remained within the normal range, but the two microadenomas had not disappeared.\n\nThe patient has given her informed consent for the publication of her case findings, and the identity of the patient has been protected.\n\nDiscussion\nBromocriptine, a D2 receptor agonist, has been recognized to lower the plasma glucose level through the amelioration of insulin resistance (2,6). Bromocriptine is therefore approved as a therapeutic agent for diabetes in Europe and the United States as a quick-release type (QR) called CyclosetⓇ and is categorized as an insulin-sensitizing agent. In the phase III study of bromocriptine QR, it was reported that FPG and post-prandial PG were significantly improved in the bromocriptine QR-treated group compared to the placebo group (1,2). In Japan, however, only traditional bromocriptine, called ParodelⓇ, is approved, and its applications are limited to pituitary tumors, such as prolactinoma, acromegaly and Parkinson's disease, and not for the treatment of diabetes.\n\nCabergoline, another kind of D2 receptor agonist, is approved for use in treating these diseases along with traditional bromocriptine in Japan. Cabergoline works about 65 hours after its administration, so it is administrated once a week, and the frequency of side effects is lower than with bromocriptine. It has been reported that cabergoline also has glucose-improving effects (7,8); however, the international approval date of cabergoline is March 1992, about 17 years later than that of traditional bromocriptine. Therefore, there are few reports concerning the glucose-lowering effects of cabergoline, and it is not yet approach as a therapeutic agent for diabetes.\n\nIn the present report, we showed for the first time that traditional-type bromocriptine has a glucose-lowering effect in Japanese patients with type 2 diabetes mellitus. In diabetic patients, the hypothalamic dopamine level in the early morning is believed to be low, which leads to increased sympathetic activity and insulin resistance. Following the administration of bromocriptine, the hypothalamic dopamine level increases, resulting in the suppression of PRL and growth hormone (GH) secreted from the pituitary gland and the amelioration of glucose tolerance (2). Bromocriptine improves insulin resistance by suppressing lipolysis and decreasing the production of FFA in the periphery as well as glucose production in the liver (3). These effects of bromocriptine on glucose and lipid metabolisms are brought about through the activation of dopaminergic neurons and suppression of sympathetic nerves without mediating specific receptors (9).\n\nIt is known that an elevated prolactin level causes insulin resistance (7) in patients with prolactinoma. In our case, we selected conservative therapy using traditional-type bromocriptine to treat prolactinoma complicated by type 2 diabetes mellitus due to the presence of microadenomas of about 5 mm in diameter. Following this treatment, the FPG and post-prandial PG were improved, similar to the results obtained with bromocriptine QR. Although there was no change in the GIR, which mainly reflects peripheral insulin sensitivity, the HOMA-IR, which mainly reflects the hepatic insulin resistance, was improved by the administration of traditional bromocriptine. There was almost no change in the fasting FFA by traditional bromocriptine treatment, which is consistent with the fact that the insulin sensitivity in the peripheral tissues did not change.\n\nWhen taken within two hours after waking up, bromocriptine QR increases the hypothalamic dopamine tone in the early morning, which leads to the suppression of glucose release from the liver and FFA release from the adipose tissue, thus helping improve the insulin resistance. However, traditional-type bromocriptine has a lower bioavailability than the QR type (28% vs. 65-95%) (1), so this agent might not have sufficiently suppressed the FFA release throughout the day had it been taken in this manner. Traditional bromocriptine was taken after dinner in the present patient, explaining the sufficient supply of this agent in the early morning and the improvement of hepatic insulin resistance. These may explain the partial improvement of insulin resistance using this traditional agent. The improvement in insulin secretion observed in this case is presumed to be due to the mitigation of glucose toxicity by the effects of traditional bromocriptine on the amelioration of hepatic insulin resistance.\n\nAs mentioned above, because the traditional agent provides peak concentrations about three hours after administration, it works more slowly than the QR type (1) and has a relatively low bioavailability by comparison (1). Therefore, it is less suitable for the treatment of diabetes than the QR type. Bromocriptine QR is administered in the early morning, and the blood concentration of this drug increases to the maximum within one hour after ingestion, with a half-life of around six hours. Because 98% of metabolites are excreted into bile acid, the QR type can be used in patients with an impaired renal function (10,11). The administration of bromocriptine QR alone reduced the HbA1c by 0.65% without increasing hypoglycemia compared to placebo administration (2). Furthermore, in a randomized clinical trial, the QR type significantly suppressed the cardiovascular outcomes among patients with type 2 diabetes mellitus (12). While there is no report on the long-term safety and efficacy of the QR type and it is not yet approved in Japan, it is expected to be a viable alternative for the management of type 2 diabetes mellitus, which is becoming more and more complicated as time goes on.\n\nConclusion\nAlthough the glucose-lowering effect of bromocriptine is well known in Europe and the United States, few cases have been reported so far in Japan. While other therapeutic strategies, such as cabergoline administration and surgery, should also be considered for the treatment of prolactinoma, traditional-type bromocriptine may be an effective therapeutic alternative in Japanese patients with prolactinoma complicated with type 2 diabetes mellitus.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nHolt RI , Barnett AH , Bailey CJ \nBromocriptine: old drug, new formulation and new indication . Diabetes Obes Metab \n12 : 1048 -1057 , 2010 .20977575 \n2. \nDefronzo RA \nBromocriptine: a sympatholytic, D2-dopamine agonist for the treatment of type 2 diabetes . Diabetes Care \n34 : 789 -794 , 2011 .21447659 \n3. \nCincotta AH , Meier AH \nBromocriptine inhibits in vivo free fatty acid oxidation and hepatic glucose output in seasonally obese hamsters (Mesocricetus auratus) . Metabolism \n44 : 1349 -1355 , 1995 .7476296 \n4. \nDeFronzo RA , Tobin JD , Andres R \nGlucose clamp technique: a method for quantifying insulin secretion and resistance . Am J Physiol \n237 : 214 -223 , 1979 .\n5. \nMatthews DR , Hosker JP , Rudenski AS , et al \nHomeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man . Diabetologia \n28 : 412 -419 , 1985 .3899825 \n6. \nBarnett AH , Chapman C , Gailer K , Hayter CJ \nEffect of bromocriptine on maturity onset diabetes . Postgrad Med J \n56 : 11 -14 , 1980 .6992131 \n7. \nGibson CD , Karmally W , McMahon DJ , Wardlaw SL , Korner J \nRandomized pilot study of cabergoline, a dopamine receptor agonist: effects on body weight and glucose tolerance in obese adults . Diabetes Obes Metab \n14 : 335 -340 , 2012 .22074059 \n8. \nAdele B , Zahra K , Ezzatossadat D , Ozra A , Shahram A \nEffects of cabergoline on blood glucose levels in type 2 diabetic patients. A double-blind controlled clinical trial . Medicine (Baltimore) \n95 : e4818 , 2016 .27749534 \n9. \nCincotta AH \nHypothalamic role in the insulin resistance syndrome . In: Insulin resistance syndrome . Hansen B , Shaffrir E , Eds. Taylor and Francis , London , 2002 : 271 -312 .\n10. \nHahr AJ , Molitch ME \nManagement of diabetes mellitus in patients with chronic kidney disease . Clin Diabetes Endocrinol \n1 : 2 , 2015 .28702221 \n11. \nMejia-Rodriguez O , Herrera-Abarca JE , Ceballos-Reyes G , et al \nCardiovascular and renal effects of bromocriptine in diabetic patients with stage 4 chronic kidney disease . Biomed Res Int \n2013 : 104059 , 2013 .23984312 \n12. \nGaziano JM , Cincotta AH , O'Connor CM , et al \nRandomized clinical trial of quick-release bromocriptine among patients with type 2 diabetes on overall safety and cardiovascular outcomes . Diabetes Care \n33 : 1503 -1508 , 2010 .20332352\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "58(21)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "bromocriptine; insulin resistance; prolactinoma; type 2 diabetes mellitus",
"medline_ta": "Intern Med",
"mesh_terms": "D000568:Amenorrhea; D001971:Bromocriptine; D003924:Diabetes Mellitus, Type 2; D005260:Female; D005687:Galactorrhea; D006727:Hormone Antagonists; D006801:Humans; D008279:Magnetic Resonance Imaging; D010902:Pituitary Gland; D010911:Pituitary Neoplasms; D011388:Prolactin; D015175:Prolactinoma; D055815:Young Adult",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "3125-3128",
"pmc": null,
"pmid": "31243214",
"pubdate": "2019-11-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21447659;7476296;27749534;22074059;20332352;6992131;23984312;20977575;382871;28702221;3899825",
"title": "Bromocriptine as a Potential Glucose-lowering Agent for the Treatment of Prolactinoma with Type 2 Diabetes.",
"title_normalized": "bromocriptine as a potential glucose lowering agent for the treatment of prolactinoma with type 2 diabetes"
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"abstract": "BACKGROUND\nRhabdomyolysis is a widely recognized yet rare complication in statin use. Rhabdomyolysis might be triggered by the prescription of high doses of statins or by statin accumulation due to interactions with concomitant medication. Muscle cell destruction as evidenced by myoglobin elevation can induce potentially life-threatening acute renal failure.\n\n\nMETHODS\nWe report a case of a 70-year-old obese white man with sudden onset of severe rhabdomyolysis with consecutive renal failure. His medication included low-dose simvastatin, which he had taken for 6 years up until the event. The statin was withdrawn immediately. After 3 days of veno-venous hemofiltration his renal function was completely restored.\n\n\nCONCLUSIONS\nClinicians in both primary and special care might be unaware that side effects of statins do occur even after a long uneventful statin medication; they should be advised not to exclude that possibility upfront, even if a patient has tolerated the medication for years.",
"affiliations": "Department of Neuropathology, University Hospital Leipzig, Liebigstrasse 26, House G, 04103, Leipzig, Germany. clara.frydrychowicz@medizin.uni-leipzig.de.;Medical Intensive Care Unit, University Hospital Leipzig, Leipzig, Germany.;Medical Intensive Care Unit, University Hospital Leipzig, Leipzig, Germany.;Department of Neuropathology, University Hospital Leipzig, Liebigstrasse 26, House G, 04103, Leipzig, Germany.;Medical Intensive Care Unit, University Hospital Leipzig, Leipzig, Germany.;Medical Intensive Care Unit, University Hospital Leipzig, Leipzig, Germany.",
"authors": "Frydrychowicz|Clara|C|;Pasieka|Bastian|B|;Pierer|Matthias|M|;Mueller|Wolf|W|;Petros|Sirak|S|;Weidhase|Lorenz|L|",
"chemical_list": "D006074:Gout Suppressants; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin; D000069438:Ezetimibe; D003078:Colchicine",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-016-1169-z",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 116910.1186/s13256-016-1169-zCase ReportColchicine triggered severe rhabdomyolysis after long-term low-dose simvastatin therapy: a case report Frydrychowicz Clara +49 (0) 341/ 97 15025clara.frydrychowicz@medizin.uni-leipzig.de 1Pasieka Bastian bastian.pasieka@medizin.uni-leipzig.de 2Pierer Matthias matthias.pierer@medizin.uni-leipzig.de 2Mueller Wolf wolf.mueller@medizin.uni-leipzig.de 1Petros Sirak sirak.petros@medizin.uni-leipzig.de 2Weidhase Lorenz lorenz.weidhase@medizin.uni-leipzig.de 21 Department of Neuropathology, University Hospital Leipzig, Liebigstrasse 26, House G, 04103 Leipzig, Germany 2 Medical Intensive Care Unit, University Hospital Leipzig, Leipzig, Germany 4 1 2017 4 1 2017 2017 11 824 3 2016 5 12 2016 © The Author(s). 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nRhabdomyolysis is a widely recognized yet rare complication in statin use. Rhabdomyolysis might be triggered by the prescription of high doses of statins or by statin accumulation due to interactions with concomitant medication. Muscle cell destruction as evidenced by myoglobin elevation can induce potentially life-threatening acute renal failure.\n\nCase presentation\nWe report a case of a 70-year-old obese white man with sudden onset of severe rhabdomyolysis with consecutive renal failure. His medication included low-dose simvastatin, which he had taken for 6 years up until the event. The statin was withdrawn immediately. After 3 days of veno-venous hemofiltration his renal function was completely restored.\n\nConclusions\nClinicians in both primary and special care might be unaware that side effects of statins do occur even after a long uneventful statin medication; they should be advised not to exclude that possibility upfront, even if a patient has tolerated the medication for years.\n\nKeywords\nCase reportRhabdomyolysisStatin therapyAnti-HMGCR-antibodyStatin-associated myopathies (SAM)Colchicineissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nStatins are a common group of cholesterol-lowering pharmaceuticals, with the shared pharmacodynamical characteristic of 3-Hydroxy-3-Methylglutaryl-Coenzym-A-Reduktase (3-HMG-CoA) inhibition, the key enzyme in cholesterol synthesis. Inhibition of 3-HMG-CoA by statins is the most effective way of lowering low-density lipoprotein (LDL) cholesterol. Even though adverse effects are frequent, severe complications occur in less than one out of 10,000 patients [1]. Between 2005 and 2011 the US Food and Drug Administration (FDA) Adverse Event Reporting System identified 147,789 case reports with suspected statin-associated myopathy (SAM), including patients with rhabdomyolysis. Rhabdomyolysis as a major statin-associated adverse effect has been reported for all available statins [2] with the highest rate reported for simvastatin [2]. The incidence of clinically relevant rhabdomyolysis is not well defined, but large cohort studies showed incidences of 0.1% [3]. Rhabdomyolysis is defined by creatine kinase (CK) levels at least 10 times normal and reflects acute and massive muscle fiber necrosis accompanied by the release of muscle-related metabolites into the bloodstream [4]. Mortality in general is low with 0.15 deaths per 1 million [5]. Patients with rhabdomyolysis present with muscle weakness, myalgia and brown “tea-colored” urine. Concomitant statin medication in a patient with signs of rhabdomyolysis strongly suggests SAM. Clinical diagnosis without biopsy is possible and depends on multiple symptoms and signs, laboratory findings, and anamnestic characteristics. Rhabdomyolysis with histopathological confirmation has the strongest impact on the diagnosis of SAM. For reference see Table 1. Standard therapy for rhabdomyolysis consists of urine alkalization, aggressive intravenous administration of fluids, and in some cases short-term dialysis and immediate withdrawal of the statin. Here, we report a case of a sudden severe rhabdomyolysis with consecutive renal failure in a patient who received low-dose simvastatin therapy for 6 years without previous complications. This case highlights the difficulty of identifying potential causing or aggravating substances that can lead to SAM and provides high quality histopathological and immunohistochemical pictures of a typical toxic rhabdomyolysis in a patient with statin-induced rhabdomyolysis.Table 1 Diagnosis of statin-induced myopathy\n\nFeature\tPoints\t\nSymmetrical myalgia\t1\t\nOccurrence within 4 weeks from the start of statin therapy\t1\t\nSymptoms resolving with withdrawal of therapy\t1\t\nFamily history of statin-induced myopathy\t1\t\nElevation of creatine kinase\t2\t\nPositive re-challenge test\t2\t\nConfirmed rhabdomyolysis\t5\t\nHistological confirmation of statin-induced myopathy\t5\t\nCharacteristic features allow classification of patients who have a possible statin-induced myopathy (1–2 points), probable statin-induced myopathy (3–4 points), or definite statin-induced myopathy (>5 points) [9]\n\n\n\n\nCase presentation\nA 70-year-old obese white man presented with acute kidney failure after a 1-year history of progressive muscle weakness and severe generalized myalgia, with difficulty in walking and climbing stairs. His past medical history was significant for chronic renal dysfunction (Kidney Disease Outcomes Quality Initiative IV), chronic heart failure (New York Heart Association III), coronary heart disease with acute myocardial infarction and coronary artery bypass, chronic atrial fibrillation, diabetes type 2, hyperlipoproteinemia, gout, and obstructive sleep apnea syndrome. He had a 6-year history of low-dose simvastatin medication with a daily dose of 40 mg. Further medication included acetylsalicylic acid, rivaroxaban, metoprolol, ramipril, furosemide, molsidomine, isosorbide dinitrate, pantoprazole, and insulin. Colchicine was prescribed as required (0.5 to 1 mg). He had no past medical history of muscular toxicity with statin use.\n\nOn admission he was in poor general condition. A clinical examination revealed symmetric proximal muscle weakness of all extremities (level of strength 3/5). Electroneurographic and myographic diagnostics showed chronic myopathic alterations in all of the examined muscles of his upper and lower extremities. Alterations were more pronounced in proximal muscle groups of his lower extremities. He had dyspnea induced by light exercise, edema of lower extremities, no fever, and no rashes.\n\nHis CK was elevated with activities >334 μkat/l (Table 2). Antibody diagnostics provided no typical findings for classical antibody-positive autoimmune myositis: dermatomyositis, systemic lupus erythematosus (SLE), scleroderma-myositis overlap syndromes, and Sjögren’s (Sj) antibody-positive autoimmune myositis.Table 2 Patient laboratory data on hospitalization\n\nParameter\tValue\tReference\t\nCK\t>334 μkat/l\t0.63–2.91 μkat/l\t\nMyoglobin\t21896 μg/l\t28–72 μg/l\t\nASAT\t4.54 μkat/l\t0.17–0.85 μkat/l\t\nLDH\t22.54 μkat/l\t2.25–3.75 μkat/l\t\nCreatinine\t596 μmol/l\t59–104 μmol/l\t\nGFR MDRD\t8.7 ml/min\t\t\nUrea\t50.7 mmol/l\t<11.9mmol/l\t\nTSH\t0.928 mU/l\t0.4–3.77 mU/l\t\n\nASAT aspartate-aminotransferase, CK creatine kinase, GFR glomerular filtration rate, LDH lactate dehydrogenase, MDRD Modification of Diet in Renal Disease, TSH Thyrotropin\n\n\n\n\nBased on the combination of acute kidney failure with muscle weakness and severe generalized myalgia combined with an elevated CK, a muscle biopsy was performed to confirm the diagnosis of SAM and exclude possible differential diagnoses, such as polymyositis. Histology predominantly revealed single fiber necrosis. Necrotic muscle fibers were present throughout the biopsy in a scattered distribution. Some necrotic fibers were in a state of macrophage-mediated degradation (myophagocytosis). Despite widespread scattered muscle fiber necrosis, the tissue was devoid of an interstitial or endomysial inflammatory infiltrate. Immunohistochemistry highlighted a striking sarcolemmal and cytoplasmic upregulation of major histocompatibility complex (MHC) class I expression. Also, complement membrane attack complex (C5b-9)-positive deposits were detected on endothelial cells of endomysial capillaries and on the sarcolemma and in the cytoplasm of necrotic muscle fibers (Fig. 1). The histopathological diagnosis of SAM was made, followed by serum testing for the anti-HMGCR antibody. No anti-HMGCR antibody was detected.Fig. 1 \na Skeletal muscle with numerous scattered necrotic fibers (*) without signs of inflammation (hematoxylin and eosin, ×100). b Single skeletal muscle fiber in a state of myophagocytosis (hematoxylin and eosin, ×200); * marks another fresh single fiber necrosis. c Detection of membrane attack complex-positive immune complexes on small vessels (arrowheads), endomysial capillaries, sarcolemma, and cytoplasm in necrotic muscle fibers (*) (membrane attack complex, ×200). d Clear sarcolemmal and cytoplasmic upregulation of major histocompatibility complex class I (major histocompatibility complex-I, ×100)\n\n\n\n\nAcute renal failure, which was induced by muscle necrosis, necessitated a continuous veno-venous hemofiltration (CVVH). Simvastatin was withdrawn and replaced by Ezetrol (ezetimibe). After 3 days of CVVH, his renal function was completely restored. After 15 days his myoglobin and CK levels had normalized (Fig. 2). He was discharged without further complaints on day 18 after hospitalization.Fig. 2 Timely normalization of myoglobin and creatine kinase levels after initiating supportive therapy (continuous veno-venous hemofiltration) and cessation of simvastatin medication. CK creatine kinase, Myo myoglobin\n\n\n\n\nDiscussion\nIn clinical practice up to 10% of patients with statin medication develop at least mild forms of myopathy [6]. This constitutes an underestimated side effect as was underlined in the Primo Trial; an observational study of muscular symptoms in a randomized population of 7924 patients with hyperlipidemia [6]. In 2012, Germany registered more than 3.2 billion statin prescriptions, which leads to an expectation of a large number of affected or symptomatic patients [7]. For patients with long-term statin usage, a recently published meta-analysis by the Cholesterol Treatment Trialists’ Collaboration states the risk of myopathy to be as low as 0.5 per 1000 patients over 5 years of statin treatment [8]. Almost 30% of statin-associated incidences occur within the first year of treatment [9]. However, onset of muscular side effects has been documented between 2 months and up to 10 years after initiation of statin therapy [4]. Our case confirms and underscores these observations. Six years after well tolerated and uneventful simvastatin medication, our patient suddenly developed a severe statin-associated rhabdomyolysis, which was histologically compatible with the diagnosis of SAM. To date, however, the definition of SAM remains unclear; in particular, the diagnostic criteria of SAM are ill defined, which may explain different data concerning the prevalence and seriousness of SAM [10]. There is general consent that statin can cause several muscle-related complaints. These may range from mild myalgia, may lead to manifest myopathy and myositis-mimicking symptoms, and may culminate in severe rhabdomyolysis. The latter may – when not recognized early enough – induce crush kidney with consecutive renal failure and death [11].\n\nThe exact mechanism of SAM still remains elusive. Several theories exist ranging from membrane destabilization due to decreased cholesterol content of skeletal muscle plasma membrane, impaired mitochondrial function due to coenzyme Q10 depletion, disturbed calcium metabolism, and vitamin D deficiency [11]. Also, there are various co-medications that increase the risk of SAM, mostly by interference of the metabolizing cytochrome p450 system (CYP3A4, CYP2C). In particular, the fibric acid derivative gemfibrozil is known to aggravate the symptoms and severity of SAM [12]. The development of statin-associated muscle problems is dose-dependent [10]. However, severe cases of SAM have been reported in patients under low-dose statin medication and without interfering medication. Documented long-term co-medication in the presented case was devoid of potentially interfering drugs. However, personal communication with our patient’s family doctor revealed a newly introduced colchicine medication in close temporal vicinity of clinically manifest rhabdomyolysis. Colchicine was prescribed because muscle pain was misinterpreted as a potential gout attack. Colchicine itself can cause myopathy. Concomitant treatment of colchicine and simvastatin may exacerbate its myotoxic effect (Table 3) [12–15]. Reported case reports of concomitant use of statin and colchicine describe a development of muscle weakness within 8 to 20 days after initiation of colchicine [16–18]. Before excretion, colchicine is metabolized in the liver by demethylation. Statin metabolism may compete with colchicine for the CYP3A4 isoenzyme leading to higher serum concentrations of both medications, thereby increasing the risk of side effects.Table 3 Colchicine triggered simvastatin-induced myopathy: review of the literature\n\nCase reports\tAge in years\tSex\tMuscle symptoms\tSimvastatin\tColchicine\t\nHsu et al. 2002 [17]\t70\tM\tSymmetrical proximal muscle weakness 3–4/5\t\n–\n\t0.5 mg daily\t\nBaker et al. 2004 [18]\t79\tM\tSevere weakness\t40 mg daily\t0.6 mg daily\t\nJustiniano et al. 2007 [16]\t61\tF\tRhabdomyolysis\t40 mg daily\t0.6 mg daily\t\nSahin et al. 2008 [15]\t30\tM\tProximal muscle weakness upper and lower extremities 2–3/5\t20 mg daily\t1.5 mg daily\t\nOh et al. 2012 [13]\t84\tM\tSymmetrical proximal muscle weakness\t40 mg daily\t1 mg (first 3 days); 0.5 mg daily\t\nMedani and Wall 2016 [14]\t60\tM\tMuscle weakness 4/5 in all limbs except 5/5 in hip extensor\t\n–\n\t1.5 mg daily\t\nCurrent case\t70\tM\tRhabdomyolysis\t40 mg daily\t0.5–1 mg as required\t\nCase reports of concomitant simvastatin and colchicine treatment and development of muscle weakness, including rhabdomyolysis. F female, M male\n\n\n\n\nAdvanced age, female sex, presence of comorbidities, and alcohol consumption are further predisposing factors for SAM [9]. Given the high number of prescriptions, clinicians are in need of reliable risk evaluation methods for the identification of vulnerable patients.\n\nMore recently, a self-limiting statin-induced primarily toxic necrotizing myopathy can be distinguished from a persisting autoimmune-mediated statin-induced necrotizing myopathy. The latter persists even after cessation of statin therapy and immunosuppressive therapy [19]. In addition, anti-HMG-CoA reductase antibodies can be detected in the serum and muscle of affected patients [10]. Both SAM and immune-mediated necrotizing myopathy (IMNM) show extensive histopathological overlap and might not be distinguished based on biopsy only. In the present case, IMNM was excluded by antibody testing (anti-HMGCR antibody, negative). Neuropathologists should be aware of the possibility of autoimmune-mediated statin-induced necrotizing myopathy and should recommend anti-HMG-CoA reductase antibody testing in all patients with persistent muscle pathology after statin arrest. Clinical monitoring of SAM may include baseline CK levels of patients especially if there are risk factors such as impaired renal function, genetic myopathy in the past medical history, or significant alcohol abuse [9, 10]. Co-medication should be checked for potential interaction with statins, especially if a new medication is prescribed, including herbal cures. Patients with muscle-related symptoms and statin medication should immediately be checked for an increase in CK. Medication should be stopped immediately and CK levels monitored. In case of persistent elevated CK levels after cessation of statin medication other causes of elevated CK levels should be considered and investigated, including anti-HMGCR-associated SAM [9]. Patients should be informed about the risk of developing myopathy and symptoms. Despite the risk of SAM, statin therapy remains a useful and powerful tool in cardiovascular risk reduction and in reducing cardiovascular morbidity and mortality. Our case emphasizes the need for clinicians to be aware of statin-associated necrotizing myopathy even after long-term statin treatment. The presented patient received uneventful simvastatin therapy for a period of 6 years. In addition, we identified colchicine as a potential trigger of SAM in our patient based on its metabolism potentially competing with statin metabolism. Fast recognition of SAM is mandatory to rescue renal function and avoid life-threatening complications. The treatment of choice remains immediate cessation of statin medication and supportive care for renal function. If recognized early enough, the outcome is excellent.\n\nConclusions\nWe wish to alert clinicians to the fact that side effects of statins do occur even after a long uneventful statin medication; they should be advised not to exclude that possibility upfront, even if a patient has tolerated the medication for years. In particular, for patients with multiple drugs, clinicians should be aware of possible drug–drug interactions such as colchicine and statins. In cases in which colchicine is indicated, statins not metabolized via the CYP3A4 system should be preferred. Patients with muscle-related symptoms and statin medication should immediately be checked for an increase in CK and levels should be monitored after statin medication is stopped. In cases of persistent elevated CK levels after cessation of statin medication, other causes of elevated CK levels should be considered and investigated, including anti-HMGCR-associated SAM. Further studies are needed to clarify the different pathogeneses of statin-induced myopathies, as well as the optimal management of patients with this severe side effect.\n\nAcknowledgements\nNot applicable.\n\nFunding\nNot applicable.\n\nAvailability of data and materials\nNot applicable.\n\nAuthors’ contributions\nCF histopathological diagnosis and manuscript design. BP treatment of patient, patient investigation, screening laboratory data, and manuscript design. MP treatment of patient and treatment supervision. WM histopathological diagnosis and manuscript draft. SP manuscript draft. LW first-line treatment of patient, initiating manuscript work, and manuscript design. All authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n==== Refs\nReferences\n1. Armitage J The safety of statins in clinical practice Lancet (London, England) 2007 370 1781 90 10.1016/S0140-6736(07)60716-8 \n2. Hoffman KB Kraus C Dimbil M Golomb BA A survey of the FDA’s AERS database regarding muscle and tendon adverse events linked to the statin drug class PLoS One. 2012 7 10.1371/journal.pone.0042866 22936996 \n3. Finsterer J Fibrate and statin myopathy Nervenarzt. 2003 74 115 22 10.1007/s00115-002-1445-6 12596012 \n4. Albayda J Christopher-Stine L Identifying statin-associated autoimmune necrotizing myopathy Cleve Clin J Med. 2014 81 736 41 10.3949/ccjm.81a.13158 25452351 \n5. Staffa JA Chang J Green L Cerivastatin and reports of fatal rhabdomyolysis N Engl J Med. 2002 346 539 40 10.1056/NEJM200202143460721 11844864 \n6. Bruckert E Hayem G Dejager S Yau C Bégaud B Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients – the PRIMO study Cardiovasc Drugs Ther. 2005 19 403 14 10.1007/s10557-005-5686-z 16453090 \n7. Schwabe U, Paffrath D. Arzneiverordnungs-Report 2013 Aktuelle Daten, Kosten, Trends und Kommentare. Berlin, Heidelberg: Imprint: Springer; 2013.\n8. Abramson JD Rosenberg HG Jewell N Wright JM Should people at low risk of cardiovascular disease take a statin? BMJ. 2013 347 f6123 10.1136/bmj.f6123 24149819 \n9. Vrablik M Zlatohlavek L Stulc T Adamkova V Prusikova M Schwarzova L Hubacek JA Ceska R Statin-associated myopathy: from genetic predisposition to clinical management Physiol Res. 2014 63 Suppl 3 S327 334 25428737 \n10. Moßhammer D Schaeffeler E Schwab M Mörike K Mechanisms and assessment of statin-related muscular adverse effects Br J Clin Pharmacol. 2014 78 454 66 10.1111/bcp.12360 25069381 \n11. Shannon JA John SM Parihar HS Allen SN Ferrara JJ A clinical review of statin-associated myopathy J Pharm Technol. 2013 29 219 30 10.1177/8755122513500915 \n12. Goh XW How CH Tavintharan S Cytochrome P450 drug interactions with statin therapy Singapore Med J. 2013 54 131 5 10.11622/smedj.2013044 23546024 \n13. Oh DH Chan SQ Wilson AM Myopathy and possible intestinal dysfunction in a patient treated with colchicine and simvastatin Med J Aust. 2012 197 332 3 10.5694/mja12.10333 22994827 \n14. Medani S Wall C Colchicine toxicity in renal patients – Are we paying attention? Clin Nephrol. 2016 86 100 5 10.5414/CN108343 26249546 \n15. Sahin G Korkmaz C Yalcin AU Which statin should be used together with colchicine? Clinical experience in three patients with nephrotic syndrome due to AA type amyloidosis Rheumatol Int. 2008 28 289 91 10.1007/s00296-007-0435-1 17703308 \n16. Justiniano M Dold S Espinoza LR Rapid onset of muscle weakness (rhabdomyolysis) associated with the combined use of simvastatin and colchicine J Clin Rheumatol. 2007 13 266 8 10.1097/RHU.0b013e318156d977 17921794 \n17. Hsu WC Chen WH Chang MT Chiu HC Colchicine-induced acute myopathy in a patient with concomitant use of simvastatin Clin Neuropharmacol. 2002 25 266 8 10.1097/00002826-200209000-00008 12410059 \n18. Baker SK Goodwin S Sur M Tarnopolsky MA Cytoskeletal myotoxicity from simvastatin and colchicine Muscle Nerve. 2004 30 799 802 10.1002/mus.20135 15389652 \n19. Mammen AL Amato AA Statin myopathy: a review of recent progress Curr Opin Rheumatol. 2010 22 644 50 10.1097/BOR.0b013e32833f0fc7 20827205\n\n",
"fulltext_license": "CC BY",
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"keywords": "Anti-HMGCR-antibody; Case report; Colchicine; Rhabdomyolysis; Statin therapy; Statin-associated myopathies (SAM)",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D003078:Colchicine; D000069438:Ezetimibe; D006074:Gout Suppressants; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008297:Male; D009765:Obesity; D012206:Rhabdomyolysis; D019821:Simvastatin; D016896:Treatment Outcome",
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"title": "Colchicine triggered severe rhabdomyolysis after long-term low-dose simvastatin therapy: a case report.",
"title_normalized": "colchicine triggered severe rhabdomyolysis after long term low dose simvastatin therapy a case report"
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"abstract": "In this report we describe in detail a case from clinical practice of the most dangerous side effect of an antiarrhythmic agent amiodarone - amiodarone induced pulmonary toxicity.",
"affiliations": "Donetsk National Medical University named after M. Gorky, Donetsk, Ukraine.;Donetsk National Medical University named after M. Gorky, Donetsk, Ukraine.;Donetsk National Medical University named after M. Gorky, Donetsk, Ukraine.;Donetsk National Medical University named after M. Gorky, Donetsk, Ukraine.;Donetsk National Medical University named after M. Gorky, Donetsk, Ukraine.;Donetsk National Medical University named after M. Gorky, Donetsk, Ukraine.",
"authors": "Vatutin|N T|NT|;Shevelyok|A N|AN|;Degtiarova|A E|AE|;Taradin|G G|GG|;Gricenko|Yu P|YP|;Vasilenko|I V|IV|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D000638:Amiodarone",
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"doi": "10.18565/cardio.2016.8.93-96",
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"issue": "56(8)",
"journal": "Kardiologiia",
"keywords": "amiodarone; drug induced pulmonary toxicity; lipid laden macrophage; lung injury; side effects",
"medline_ta": "Kardiologiia",
"mesh_terms": "D000638:Amiodarone; D000889:Anti-Arrhythmia Agents; D005260:Female; D006801:Humans; D055370:Lung Injury; D008875:Middle Aged",
"nlm_unique_id": "0376351",
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"pages": "93-96",
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"pubdate": "2016-08",
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"references": null,
"title": "The Development of Pulmonary Damage When Receiving Amiodarone.",
"title_normalized": "the development of pulmonary damage when receiving amiodarone"
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"abstract": "BACKGROUND\nGrowing teratoma syndrome is defined as an increase in tumor size during or after systemic chemotherapy for germ cell tumors. These cases involve normal tumor maker levels and histological features of only mature teratoma. We report a rare case of an ovarian immature teratoma in a Japanese child that was diagnosed as growing teratoma syndrome.\nA 12-year-old girl presented a painful abdominal mass. She underwent left salpingo-oophorectomy for grade 1 immature teratoma in the left ovary. She did not undergo additional chemotherapy or radiotherapy. Four months later, she presented with grade 3 immature teratoma disseminated into the abdomen and pelvis. Chemotherapy resulted in the tumor maker levels returning to their normal ranges, although the tumors had grown slightly.\n\n\nMETHODS\nThe specimens resected by laparotomy after the chemotherapy consisted of mature tissue predominantly, although primitive neuroepithelium was observed in a small part of the specimen. The pathological diagnosis was grade 1 immature teratoma, notwithstanding the clinical diagnosis was growing teratoma syndrome based on the clinical features and pathogenesis.\n\n\nMETHODS\nLaparotomy was performed at 7 months after the first operation, with resection of various tumors as well as the rectum, sigmoid colon, residual left fallopian duct, and a small part of the ileum and omentum. Some small tumors at the parietal peritoneum were ablated, although many tiny tumors around the uterus were left untreated.\n\n\nRESULTS\nThe patient has been free from recurrence for 5 years.\n\n\nCONCLUSIONS\nGrowing teratoma syndrome can develop in children, and their tumor size is comparable to that in adolescents and adults. Furthermore, development of growing teratoma syndrome from a primary germ cell tumor is presumably faster in children than in adolescents and adults. Complete resection of all growing teratoma tissue is recommended, although fertility-sparing surgery should be considered when possible.",
"affiliations": "Department of Pediatric Surgery.;Department of Pediatric Surgery.;Department of Pediatrics, Okayama University Hospital, Okayama, Japan.;Department of Pediatrics, Okayama University Hospital, Okayama, Japan.",
"authors": "Oyama|Takanori|T|0000-0003-3063-1754;Noda|Takuo|T|;Washio|Kana|K|;Shimada|Akira|A|",
"chemical_list": "D001761:Bleomycin; D005047:Etoposide; D002945:Cisplatin",
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"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974 1536-5964 Lippincott Williams & Wilkins Hagerstown, MD \n\nMD-D-19-09079\n10.1097/MD.0000000000022297\n22297\n6200\nResearch Article\nClinical Case Report\nPediatric growing teratoma syndrome of the ovary\nA case report and review of the literatureOyama Takanori MD, PhDa∗ Noda Takuo MD, PhDa Washio Kana MD, PhDb Shimada Akira MD, PhDb Saranathan. Maya a Department of Pediatric Surgery\nb Department of Pediatrics, Okayama University Hospital, Okayama, Japan.\n∗ Correspondence: Takanori Oyama, Department of Pediatric Surgery, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan (e-mail: oyama@cc.okayama-u.ac.jp).\n18 9 2020 \n18 9 2020 \n99 38 e2229718 11 2019 7 8 2020 21 8 2020 Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.2020This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nRationale:\nGrowing teratoma syndrome is defined as an increase in tumor size during or after systemic chemotherapy for germ cell tumors. These cases involve normal tumor maker levels and histological features of only mature teratoma. We report a rare case of an ovarian immature teratoma in a Japanese child that was diagnosed as growing teratoma syndrome.\n\nPatient concerns:\nA 12-year-old girl presented a painful abdominal mass. She underwent left salpingo-oophorectomy for grade 1 immature teratoma in the left ovary. She did not undergo additional chemotherapy or radiotherapy. Four months later, she presented with grade 3 immature teratoma disseminated into the abdomen and pelvis. Chemotherapy resulted in the tumor maker levels returning to their normal ranges, although the tumors had grown slightly.\n\nDiagnosis:\nThe specimens resected by laparotomy after the chemotherapy consisted of mature tissue predominantly, although primitive neuroepithelium was observed in a small part of the specimen. The pathological diagnosis was grade 1 immature teratoma, notwithstanding the clinical diagnosis was growing teratoma syndrome based on the clinical features and pathogenesis.\n\nInterventions:\nLaparotomy was performed at 7 months after the first operation, with resection of various tumors as well as the rectum, sigmoid colon, residual left fallopian duct, and a small part of the ileum and omentum. Some small tumors at the parietal peritoneum were ablated, although many tiny tumors around the uterus were left untreated.\n\nOutcomes:\nThe patient has been free from recurrence for 5 years.\n\nLessons:\nGrowing teratoma syndrome can develop in children, and their tumor size is comparable to that in adolescents and adults. Furthermore, development of growing teratoma syndrome from a primary germ cell tumor is presumably faster in children than in adolescents and adults. Complete resection of all growing teratoma tissue is recommended, although fertility-sparing surgery should be considered when possible.\n\nKeywords\ngrowing teratoma syndromeimmature teratomaovarian tumorpediatricOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nGrowing teratoma syndrome (GTS) is defined as an increase in tumor size during or after systemic chemotherapy for germ cell tumors, with normal tumor markers and histological features of only mature teratoma. Logothetis et al[1] first used this term in 1982, although DiSaia et al[2] previously described a similar phenomenon as “chemotherapeutic retroconversion” in 1977. Amsalem et al[3] subsequently concluded that GTS and chemotherapeutic retroconversion were probably the same phenomenon.\n\nAlthough GTS is well known in male patients with germ cell tumors, ovarian GTS is less commonly reported. According to Li et al,[4] who reviewed 101 cases reported in the English literature, ovarian GTS typically occurs in adolescents and young adults (median age at diagnosis of primary immature teratoma: 22 years), and only 8 cases (7.9%) were diagnosed in children. Thus, we report a rare case of an ovarian immature teratoma that was diagnosed as GTS in a 12-year-old Japanese girl, and review the literature regarding ovarian GTS in children.\n\n2 Case report\nA 12-year-old girl was admitted to a local hospital with a painful abdominal mass. Abdominal computed tomography (CT) revealed a large cystic mass containing calcified tissues and fat in the pelvic cavity. Serum tumor marker levels were normal (alfa-fetoprotein [AFP]: 11.25 ng/mL, beta-human chorionic gonadotropin [beta-HCG]: <0.10 mg/mL), although serum CA125 levels were not measured. Left salpingo-oophorectomy was performed based on a suspicion of a teratoma in the left ovary. Interestingly, malignant cells were not observed in the ascites despite previous rupture of the tumor. Gross total resection was achieved and the pathological diagnosis was grade 1 immature teratoma. No additional chemotherapy or radiotherapy was performed.\n\nFour months after the operation, abdominal CT revealed multiple multinodular tumors with a maximum diameter of 9.0 cm in the pelvis, which contained calcified and fatty tissue (Fig. 1), although the lymph nodes were not enlarged. Open biopsy was used to obtain a specimen for histological evaluation, which supported a diagnosis of grade 3 immature teratoma with substantial primitive neuroepithelium. The patient was admitted to our hospital soon after the recurrence with lower abdominal distention and tenderness, and the elastic hard tumor was palpable. Serum tumor maker testing revealed that her CA125 level was elevated to 198.2 U/mL, but with normal levels of AFP (5.1 ng/mL) and beta-HCG (<0.40 mIU/mL), despite the tumor's immaturity. Treatment was started using 1 cycle of bleomycin, etoposide, and cisplatin (BEP) chemotherapy, which normalized the CA125 levels, but the tumor became slightly enlarged. The treatment was then changed to 1 cycle of ifosfamide, carboplatin, and etoposide (ICE) chemotherapy, although the tumor became further enlarged. After the ICE chemotherapy, positron emission tomography-computed tomography (PET-CT) revealed abnormal accumulation in the lower abdomen and pelvis, which was considered indicative of a recurrent lesion (Fig. 2).\n\nFigure 1 Abdominal computed tomography findings from 4 months after the first operation revealed multiple multinodular tumors containing calcified and fatty tissues (A). Invasion or lymph node swelling were not detected. Small amounts of ascites were observed around the liver and in the pelvic cavity (B).\n\nFigure 2 Post-chemotherapy findings from abdominal computed tomography (A) and positron emission tomography–computed tomography (B). The tumor had grown (A), and abnormal accumulation was observed (B).\n\nGiven the tumor growth, despite normalization of tumor markers after 2 chemotherapy cycles, we suspected GTS, which requires a pathological diagnosis and total resection even in asymptomatic cases. Thus, at 7 months after the first operation, we performed laparotomy (Fig. 3) and observed numerous disseminated tumors at the parietal and visceral peritoneum in the lower abdomen and pelvis. We resected the rectum and sigmoid colon because several disseminated tumors were firmly adherent to the ventral side of the rectum. We also resected the residual left fallopian duct and small parts of the ileum and omentum with the tumors. Some small tumors at the parietal peritoneum were ablated, although many tiny tumors around the uterus were not treated. The abdominal lymph nodes were not enlarged and the cytology results for the ascites were negative.\n\nFigure 3 The surgery revealed numerous disseminated tumors in the great omentum.\n\nPathological analysis of the resected specimens revealed that most of the specimen consisted of mature tissue, although primitive neuroepithelium was observed in a small part of the specimen (Fig. 4). The pathological diagnosis was grade 1 immature teratoma, which did not fulfill the pathological criteria for GTS (histological evidence of only mature teratoma). However, the pathogenesis agreed with that of GTS, and the use of additional chemotherapy could have converted the tumor into a mature teratoma. Thus, we considered the tumor to be GTS. The postoperative course was uneventful, and the patient was discharged 1 month after the operation with no additional chemotherapy or radiotherapy. The residual disseminated tumors have not enlarged during the 5-year follow-up.\n\nFigure 4 Pathological findings revealed mature tissue in almost all parts of the tumor (A), but a primitive neuroepithelium, represented by a slightly high cell density, in a small part of the tumor (B).\n\n3 Discussion\nOvarian immature teratoma is a relatively rare tumor that arises in young women, whose prognosis has been dramatically improved by BEP chemotherapy after fertility-preserving surgery. However, in the advanced cases with peritoneal metastasis, the prognosis remains poor even after appropriate treatment. In these cases, the diagnosis of GTS relies on 3 criteria:\n\n(1) germ cell tumor growth during or after systemic chemotherapy,\n\n(2) the normalization of previously elevated serum tumor markers, and\n\n(3) the absence of immature components, other than mature teratoma, in the resected specimen.\n\nIn this context, ovarian teratoma of any grade can induce peritoneal implantation of mature glial tissues, which are known as gliomatosis peritonei (GP), and GTS is considered a type of GP, as both GTS and GP are associated with benign peritoneal glial implants regardless of the original tumor's malignancy grade.[5]\n\nTwo different pathogenic mechanisms have been proposed for GTS:\n\n(1) chemotherapy induces the malignant differentiation of immature teratoma into a mature component[2] or\n\n(2) chemotherapy destroys only the immature malignant cells and spares the mature benign teratomatous elements.[1]\n\nIn the present case, the tumor had ruptured before the first operation, which might have been the cause of GTS development. Chemotherapy or radiotherapy was not performed after the first operation because there was no evidence of malignant ascites, dissemination was not detected using PET-CT, and the immature teratoma was histologically classified as grade 1. However, the disseminated tumor had enlarged at 4 months after the first surgery, and the histological classification was a grade 3 immature teratoma with an elevated CA125 level. Thus, the teratoma recurred as a higher-grade immature teratoma, rather than as GTS, which was induced by the BEP and ICE chemotherapy that was performed after the recurrence. Interestingly, the present case developed from a recurrent tumor, whereas the reported cases have developed from a primary tumor. In our case, the pathological diagnosis after the last surgery was grade 1 immature teratoma, and we suspect that further chemotherapy might have led to teratoma maturation that would ultimately have fulfilled the criteria for GTS. Therefore, we clinically diagnosed the tumor as GTS. Another important difference is that the only elevated tumor marker in the present case was CA125, while almost all reported cases have involved pre-treatment elevations of AFP and HCG, AFP and CA125, or only AFP.[4] Thus, although the cause for this discrepancy is unclear, the tumor marker profile from present case appears to be rare.\n\nThe incidence of GTS in non-seminomatous germ cell tumors of the testis is 1.9% to 7.6%.[1,6] In contrast, the incidence of ovarian GTS in ovarian immature teratomas is 12% to 19%,[7,8] with the GTS originating from the right ovary in 57% of cases and the left ovary in 43% of cases. The median primary tumor size was reportedly 18.7 cm (range: 6–45 cm) and median subsequent tumor size was 8.6 cm (range: 1–25 cm). During the interval between the primary treatment and the diagnosis of ovarian GTS, the median tumor growth was 0.94 cm/month (range: 0.3–4.3 cm/month) and the median interval to diagnosis was 26.6 months (range: 1–264 months).[4] While the GTS usually occurs at the primary site of the germ cell tumor, 13% of GTS cases involve metastatic sites.[9]\n\nOvarian GTS typically occurs in adolescents and young adults, with a median age of 22 years at the diagnosis of primary immature teratoma and only 7.9% of GTS cases being diagnosed during childhood.[4] We have identified 17 cases of ovarian GTS in children in the English literature (Table 1).[10–18] The youngest patient was 4 years old at the diagnosis of the primary germ cell tumor. The primary tumor size was 9 to 30 cm, which is comparable to in adolescent and adult patients, and our case involved the smallest reported primary tumor size (9 cm). The histology of the primary germ cell tumor was immature teratoma in 9 cases and mixed germ cell tumor in 5 cases. Eleven patients received chemotherapy, and the GTS diagnosis was made during the chemotherapy in 6 cases (including the present case), which suggests that GTS development is faster in children than in adolescents and adults. The GTS may cause obstruction or compression of abdominal structures, including the urinary tract, vascular structures, and gastrointestinal tract.[11] Another report described mesenteric compression with bowel necrosis, renal failure due to ureteral compression, bowel obstruction, and bile duct obstruction.[9] Fortunately, most children (including our patient) did not develop serious symptoms.\n\nTable 1 Ovarian growing teratoma syndrome in children: review of the literature.\n\nThe imaging-based diagnosis of GTS is supported by a mass with increasing size that contains fat, calcification, or cystic changes.[19] Thus, similar to in ovarian cancer, PET-CT provides more information than CT alone, although a positive PET-CT finding does not always reflect malignancy.[20] For example, positive PET-CT findings could be related to the high rate of glucose metabolism in brain tissues for cases of GTS (as in the present case).[21]\n\nThe GTS lesions are refractory to chemotherapy, which makes surgery the only curative treatment.[19] Complete resection of all GST tissue is recommended, as incomplete resection can lead to progression or malignant transformation. For example, Shigeta et al reviewed 55 cases of ovarian GTS and reported that GTS recurred in 12.7% of cases (7/55) and underwent malignant transformation in 5.4% of cases (3/55),[22] which can result in sarcoma, adenocarcinoma, or a primitive neuroectodermal tumor and carcinoid.[23] Thus, if the residual teratoma components are caused by chemotherapeutic retroconversion, it appears logical that they would retain a high level of histopathological genetic aneuploidy and their malignant potential.[24–26] Therefore, complete surgical resection is a highly desirable treatment,[27] although recurrence or malignant transformation have not been reported in children. Nevertheless, fertility-sparing surgery is recommended when possible based on the findings of 2 studies. Li et al reviewed 101 patients with ovarian GTS and found that 5 of these patients became pregnant during the interval between the primary disease and GTS, with 1 patient becoming pregnant after the diagnosis of ovarian GTS. Bentivegna et al[8] have also reported that 5 of 38 patients with ovarian GTS became pregnant after the diagnosis of ovarian GTS. Both studies mention that fertility-sparing surgery is recommended “when possible,” although the criteria for evaluating this possibility remain unclear. Further studies are needed to address this issue, as none of the reports regarding the children in Table 1 indicate whether they underwent fertility-sparing surgery, subsequently became pregnant, and relapsed.\n\nThe recurrence rate for ovarian GTS is up to 83% in cases with partial resection but only 0% to 4% in cases with complete resection.[4] Among the reported children, only 2 cases involved complete resection (Table 1), and the median recurrence-free interval (from the final treatment for GTS to recurrence) was 24 months. These findings strongly indicate that a prolonged follow-up is needed in cases with GTS.[22] Furthermore, several cases involved malignant transformation of GTS, which might be misdiagnosed as mature teratoma because the low-grade primitive neuroepithelium is only present in a small part of the specimen (as in the present case). Moreover, in the present case, we elected to leave many disseminated small immature tumors, and did not perform chemotherapy or radiotherapy because of the paucity of the primitive neuroepithelium, although close follow-up is necessary given the possibility of malignant transformation.\n\n4 Conclusions\nWe encountered a rare case of an ovarian immature teratoma that was diagnosed as GTS in a Japanese child. In similar cases, the GTS can develop during early childhood and the tumor size is comparable to that in adolescents and adults, although the development of the GTS from the primary germ cell tumor is presumably faster in children. Complete resection of all GST tissue is recommended based on the possibility of malignant transformation, although fertility-sparing surgery should be considered when possible.\n\nAcknowledgment\nThe authors thank Editage for English language editing.\n\nAuthor contributions\nConceptualization: Takanori Oyama, Takuo Noda, Akira Shimada.\n\nData curation: Takanori Oyama.\n\nInvestigation: Takanori Oyama, Takuo Noda, Kana Washio, Akira Shimada.\n\nProject administration: Takuo Noda, Akira Shimada.\n\nSupervision: Takuo Noda.\n\nVisualization: Takanori Oyama.\n\nWriting – original draft: Takanori Oyama.\n\nWriting – review & editing: Takanori Oyama, Takuo Noda, Kana Washio, Akira Shimada.\n\nAbbreviations: AFP = alfa-fetoprotein, BEP = bleomycin, etoposide and cisplatin, Beta-HCG = beta-human chorionic gonadotropin, CA125 = carbohydrate antigen 125, CT = computed tomography, GP = gliomatosis peritonei, GTS = growing teratoma syndrome, ICE = ifosfamide, carboplatin, etoposide, NSGSTs = non-seminomatous germ cell tumors, PET-CT = positron emission tomography-computed tomography.\n\nHow to cite this article: Oyama T, Noda T, Washio K, Shimada A. Pediatric growing teratoma syndrome of the ovary: A case report and review of the literature. Medicine. 2020;99:38(e22297).\n\nWritten informed consent was obtained from the patient's parents for the publication of this case report and the accompanying images.\n\nThe authors have no funding and conflicts of interest to disclose.\n\nData sharing not applicable to this article as no datasets were generated or analyzed during the current study.\n==== Refs\nReferences\n[1] Logothetis CJ Samuels ML Trindade A \nThe growing teratoma syndrome\n. Cancer \n1982 ;50 :1629 35\n.6288220 \n[2] DiSaia PJ Saltz A Kagan AR \nChemotherapeutic retroconversion of immature teratoma of the ovary\n. Obstet Gynecol \n1977 ;49 :346 50\n.65751 \n[3] Amsalem H Nadjari M Prus D \nGrowing teratoma syndrome vs chemotherapeutic retroconversion: case report and review of the literature\n. Gynecol Oncol \n2004 ;92 :357 60\n.14751185 \n[4] Li S Liu Z Dong C \nGrowing teratoma syndrome secondary to ovarian giant immature teratoma in an adolescent girl: a case report and literature review\n. Medicine (Baltimore) \n2016 ;95 :e2647 .26886604 \n[5] Umekawa T Tabata T Tanida K \nGrowing teratoma syndrome as an unusual cause of gliomatosis peritonei: a case report\n. Gynecol Oncol \n2005 ;99 :761 3\n.16125758 \n[6] Jeffery GM Theaker JM Lee AH \nThe growing teratoma syndrome\n. Br J Urol \n1991 ;67 :195 202\n.2004236 \n[7] Zagamé L Pautier P Duvillard P \nGrowing teratoma syndrome after ovarian germ cell tumors\n. Obstet Gynecol \n2006 ;108 :509 14\n.16946208 \n[8] Bentivegna E Azaïs H Uzan C \nSurgical outcomes after debulking surgery for intraabdominal ovarian growing teratoma syndrome: analysis of 38 cases\n. Ann Surg Oncol \n2015 ;22 : Suppl 3 : S964 70\n.26033179 \n[9] André F Fizazi K Culine S \nThe growing teratoma syndrome: results of therapy and long-term follow-up of 33 patients\n. Eur J Cancer \n2000 ;36 :1389 94\n.10899652 \n[10] Moskovic E Jobling T Fisher C \nRetroconversion of immature teratoma of the ovary: CT appearances\n. Clin Radiol \n1991 ;43 :402 8\n.2070582 \n[11] Inaoka T Takahashi K Yamada T \nThe growing teratoma syndrome secondary to immature teratoma of the ovary\n. Eur Radiol \n2003 ;13 :2115 8\n.12928961 \n[12] Nimkin K Gupta P McCauley R \nThe growing teratoma syndrome\n. Pediatr Radiol \n2004 ;34 :259 62\n.14551755 \n[13] Tangjitgamol S Manusirivithaya S Leelahakorn S \nThe growing teratoma syndrome: a case report and a review of the literature\n. Int J Gynecol Cancer \n2006 ;16 : Suppl 1 : 384 90\n.16515629 \n[14] Hsieh YL Liu CS \nProgression from an immature teratoma with miliary gliomatosis peritonei to growing teratoma syndrome with nodular gliomatosis peritonei\n. Pediatr Neonatol \n2009 ;50 :78 81\n.19453084 \n[15] Al-Jumaily U Al-Hussaini M Ajlouni F \nOvarian germ cell tumors with rhabdomyosarcomatous components and later development of growing teratoma syndrome: a case report\n. J Med Case Rep \n2012 ;6 :13 .22248255 \n[16] Daher P Riachy E Khoury A \nGrowing teratoma syndrome: first case report in a 4-year-old girl\n. J Pediatr Adolesc Gynecol \n2015 ;28 :e5 7\n.25256881 \n[17] Rentea RM Varghese A Ahmed A \nPediatric ovarian growing teratoma syndrome\n. Case Rep Surg \n2017 ;2017 :3074240 .28656118 \n[18] Frazer JL Hook CE Addley HC \nRecurrent ovarian immature teratoma in a 12-year-old girl: Implications for management\n. Gynecologic Oncology \n2019 ;154 :259 65\n.31176555 \n[19] Panda A Kandasamy D Sh C \nGrowing teratoma syndrome of ovary: avoiding a misdiagnosis of tumour recurrence\n. J Clin Diagn Res \n2014 ;8 :197 8\n.24596773 \n[20] Kikawa S Todo Y Minobe S \nGrowing teratoma syndrome of the ovary: a case report with FDG-PET findings\n. J Obstet Gynaecol Res \n2011 ;37 :926 32\n.21450035 \n[21] Hariprasad R Kumar L Janga D \nGrowing teratoma syndrome of ovary\n. Int J Clin Oncol \n2008 ;13 :83 7\n.18307026 \n[22] Shigeta N Kobayashi E Sawada K \nLaparoscopic excisional surgery for growing teratoma syndrome of the ovary: case report and literature review\n. J Minim Invasive Gynecol \n2015 ;22 :668 74\n.25620216 \n[23] Shibata K Kajiyama H Kikkawa F \nGrowing teratoma syndrome of the ovary showing three patterns of metastasis: a case report\n. Case Rep Oncol \n2013 ;6 :544 9\n.24348391 \n[24] Davey DD Ulbright TM Loehrer PJ \nThe significance of atypia within teratomatous metastases after chemotherapy for malignant germ cell tumors\n. Cancer \n1987 ;59 :533 9\n.3024806 \n[25] Castedo SM de Jong B Oosterhuis JW \nChromosomal changes in mature residual teratomas following polychemotherapy\n. Cancer Res \n1989 ;49 :672 6\n.2910486 \n[26] Molenaar WM Oosterhuis JW Meiring A \nHistology and DNA contents of a secondary malignancy arising in a mature residual lesion six years after chemotherapy for a disseminated nonseminomatous testicular tumor\n. Cancer \n1986 ;58 :264 8\n.3719520 \n[27] Homs MY Schreuder HW Jonges GN \nClinical and radiologic signs of relapsed ovarian germ cell tumor: tissue is the issue\n. Case Rep Obstet Gynecol \n2013 ;2013 :984524 .24222875\n\n",
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"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001761:Bleomycin; D002648:Child; D002945:Cisplatin; D005047:Etoposide; D005260:Female; D006801:Humans; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local; D010051:Ovarian Neoplasms; D000072078:Positron Emission Tomography Computed Tomography; D000074868:Salpingo-oophorectomy; D013577:Syndrome; D013724:Teratoma",
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"title": "Pediatric growing teratoma syndrome of the ovary: A case report and review of the literature.",
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"abstract": "OBJECTIVE\nTo retrospectively evaluate the failure patterns of multimodality bladder-preserving therapy in patients with muscle-invasive bladder cancer.\n\n\nMETHODS\nPatients with muscle-invasive bladder cancer underwent maximal transurethral resection of bladder tumor and induction chemotherapy, followed by concurrent chemoradiotherapy (CCRT). Radiotherapy was given with 45 Gy to the pelvis, 50.4 Gy to the bladder, and 64.8 Gy to the tumor bed. Three protocols of trimodality treatment were used: Protocol A, three cycles of cisplatin and fluorouracil (CF), followed by CCRT with 6 weekly cisplatin; Protocol B, three cycles of weekly paclitaxel plus CF, followed by CCRT with 6 weekly paclitaxel and cisplatin; Protocol C, three cycles of gemcitabine and cisplatin, followed by CCRT with 6 weekly cisplatin. Interval cystoscopy confirmed complete response (CR) after induction chemotherapy and 40-50 Gy of radiotherapy. Patients without CR were referred for salvage cystectomy.\n\n\nRESULTS\nA total of 60 patients were enrolled, including 11 patients with unfavorable factors defined as hydronephrosis and/or pelvic nodal involvement. After a median follow-up of 86.7 months, the 5-year overall, progression-free, and bladder preservation-specific survival rates were 76.3%, 62.9%, and 71.5%, respectively. Three patients underwent salvage cystectomy for invasive bladder recurrence. Of 45 surviving patients, 42 patients (93.3%) retained functioning bladders. Patients with unfavorable factors had significantly lower metastasis-free survival (p=0.002), but not bladder preservation-specific survival (p=0.25).\n\n\nCONCLUSIONS\nWith trimodality treatment involving visually complete transurethral resection of bladder tumor, cisplatin-based induction chemotherapy, and CCRT, patients with unfavorable factors maintained satisfactory bladder preservation but not systemic control.",
"affiliations": "Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.;Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.;Department of Urology, National Taiwan University Hospital, Taipei, Taiwan.;Division of Medical Oncology, Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.;Division of Medical Oncology, Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan. Electronic address: cclin1@ntu.edu.tw.;Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan; Division of Medical Oncology, Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.;Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan; Division of Medical Oncology, Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.;Department of Urology, National Taiwan University Hospital, Taipei, Taiwan.",
"authors": "Chiang|Yun|Y|;Cheng|Jason Chia-Hsien|JC|;Huang|Chao-Yuan|CY|;Tsai|Yu-Chieh|YC|;Lin|Chia-Chi|CC|;Hsu|Chih-Hung|CH|;Cheng|Ann-Lii|AL|;Pu|Yeong-Shiau|YS|",
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"keywords": "bladder cancer; chemotherapy; cystectomy; hydronephrosis; radiotherapy",
"medline_ta": "J Formos Med Assoc",
"mesh_terms": "D000328:Adult; D000368:Aged; D059248:Chemoradiotherapy; D003131:Combined Modality Therapy; D015653:Cystectomy; D005260:Female; D006801:Humans; D006869:Hydronephrosis; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D012189:Retrospective Studies; D001749:Urinary Bladder Neoplasms",
"nlm_unique_id": "9214933",
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"title": "A role of multimodality bladder-preserving therapy in patients with muscle-invasive bladder cancer plus hydronephrosis with or without pelvic nodal involvement.",
"title_normalized": "a role of multimodality bladder preserving therapy in patients with muscle invasive bladder cancer plus hydronephrosis with or without pelvic nodal involvement"
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"abstract": "Crizotinib is a standard treatment for advanced ALK-positive non-small-cell lung cancer (NSCLC). We undertook this study to investigate the pharmacokinetics of crizotinib and clinical and pharmacogenomic factors that may increase the risk of adverse events (AEs). We defined clinically significant AEs as grade 4 hematological toxicity, grade ≥3 non-hematological toxicity, and any grade of interstitial lung disease. Eight subjects with ALK-positive NSCLC scheduled to receive crizotinib 250 mg twice daily were studied. Six patients were female and two were male, and most of the patients had low body weight with a median body weight of 46.8 kg (range, 42.4-61.0 kg). All patients developed AEs, five developing six clinically significant AEs. Six patients required dose reduction. In pharmacokinetic analysis, blood samples were obtained on days 1 and 15. The mean area under the plasma concentration-time curve from 0-12 h (AUC0-12 ) on day 15 was significantly increased in patients with clinically significant AEs (n = 5) compared with those without (n = 3) (P = 0.04). Genetic polymorphisms of ABCB1 were analyzed. One patient with the ABCB1 1236TT-2677TT-3435TT genotype was an outlier, with an AUC0-12 and peak concentrations on day 15 of 2.84× and 2.61× the mean, respectively, compared with those with other genotypes. Our results suggest that some Japanese NSCLC patients treated with crizotinib developed clinically significant toxicities that were related to altered pharmacokinetics parameters due to genotype and body weight factors.",
"affiliations": "Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.;Division of Clinical Pharmacology and Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo, Japan.;Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.;Division of Clinical Pharmacology and Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo, Japan.;Division of Clinical Pharmacology and Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo, Japan.;Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.;Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.;Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.;Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.;Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.;Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.;Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.",
"authors": "Fujiwara|Yutaka|Y|;Hamada|Akinobu|A|;Mizugaki|Hidenori|H|;Aikawa|Hiroaki|H|;Hata|Toshiyuki|T|;Horinouchi|Hidehito|H|;Kanda|Shintaro|S|;Goto|Yasushi|Y|;Itahashi|Kota|K|;Nokihara|Hiroshi|H|;Yamamoto|Noboru|N|;Ohe|Yuichiro|Y|",
"chemical_list": "C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases",
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"fulltext": "\n==== Front\nCancer SciCancer Sci10.1111/(ISSN)1349-7006CASCancer Science1347-90321349-7006John Wiley and Sons Inc. Hoboken 10.1111/cas.12983CAS12983Original ArticleOriginal ArticlesClinical ResearchPharmacokinetic profiles of significant adverse events with crizotinib in Japanese patients with ABCB1 polymorphism Fujiwara et al.Fujiwara Yutaka \n1\n\n2\nHamada Akinobu \n3\nMizugaki Hidenori \n1\n\n4\nAikawa Hiroaki \n3\nHata Toshiyuki \n3\nHorinouchi Hidehito \n1\nKanda Shintaro \n1\nGoto Yasushi \n1\nItahashi Kota \n1\nNokihara Hiroshi \n1\nYamamoto Noboru \n1\n\n2\nOhe Yuichiro \n1\n1 Department of Thoracic OncologyNational Cancer Center HospitalTokyoJapan2 Department of Experimental TherapeuticsNational Cancer Center HospitalTokyoJapan3 Division of Clinical Pharmacology and Translational ResearchExploratory Oncology Research and Clinical Trial CenterNational Cancer CenterTokyoJapan4 First Department of MedicineHokkaido University School of MedicineSapporoJapan* Correspondence\n\nYutaka Fujiwara, Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5‐1‐1, Chuo‐ku, Tokyo 104‐0045, Japan.\n\nTel: +81‐3‐3542‐2511; Fax: +81‐3‐3542‐3815;\n\nE‐mail: yutakafu@ncc.go.jp\n21 7 2016 8 2016 107 8 10.1111/cas.2016.107.issue-81117 1123 14 3 2016 24 5 2016 06 6 2016 © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Crizotinib is a standard treatment for advanced ALK‐positive non‐small‐cell lung cancer (NSCLC). We undertook this study to investigate the pharmacokinetics of crizotinib and clinical and pharmacogenomic factors that may increase the risk of adverse events (AEs). We defined clinically significant AEs as grade 4 hematological toxicity, grade ≥3 non‐hematological toxicity, and any grade of interstitial lung disease. Eight subjects with ALK‐positive NSCLC scheduled to receive crizotinib 250 mg twice daily were studied. Six patients were female and two were male, and most of the patients had low body weight with a median body weight of 46.8 kg (range, 42.4–61.0 kg). All patients developed AEs, five developing six clinically significant AEs. Six patients required dose reduction. In pharmacokinetic analysis, blood samples were obtained on days 1 and 15. The mean area under the plasma concentration–time curve from 0–12 h (AUC\n0–12) on day 15 was significantly increased in patients with clinically significant AEs (n = 5) compared with those without (n = 3) (P = 0.04). Genetic polymorphisms of ABCB1 were analyzed. One patient with the ABCB1 1236TT‐2677TT‐3435TT genotype was an outlier, with an AUC\n0–12 and peak concentrations on day 15 of 2.84× and 2.61× the mean, respectively, compared with those with other genotypes. Our results suggest that some Japanese NSCLC patients treated with crizotinib developed clinically significant toxicities that were related to altered pharmacokinetics parameters due to genotype and body weight factors.\n\nCrizotinibEML4–ALK fusion proteinnon‐small‐cell lung cancerpharmacogenomicspharmacokineticsJapanese Society of Clinical Pharmacology and TherapeuticsJapan Society for the Promotion of ScienceKAKENHI 21590167 source-schema-version-number2.0component-idcas12983cover-dateAugust 2016details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:4.9.4 mode:remove_FC converted:12.08.2016\n\nCancer Sci \n107 (2016 ) 1117 –1123 \n\n\n\n\nFunding Information\n\n\nJapanese Society of Clinical Pharmacology and Therapeutics; Japan Society for the Promotion of Science.\n\nTrial registration ID: UMIN000009867; date of registration: January 1, 2013.\n==== Body\nIdentifying the molecular alterations that underlie the pathogenesis of lung cancer may allow dramatic progress in clinical outcomes. The echinoderm microtubule‐associated protein‐like 4 (EML‐4)–anaplastic lymphoma kinase (ALK) fusion gene, first described by Soda et al.1 is one of the driver oncogenes in non‐small‐cell lung cancer (NSCLC). It is known that approximately 5% of lung adenocarcinoma patients are ALK fusion gene‐positive (ALK‐positive).1, 2 Crizotinib (Pfizer, Mission, KS, USA), a multitarget tyrosine kinase inhibitor, showed favorable clinical activity in ALK‐positive NSCLC patients3, 4, 5, 6 and was approved for ALK‐positive NSCLC in 2011 in the USA and in March 2012 in Japan.\n\nIn phase 1 pharmacokinetic (PK) analyses of crizotinib carried out in the USA and Korea, the mean area under the plasma concentration–time curve (AUC) from 0 to 24 h and peak concentration (C\nmax) (% coefficient variance [CV]) were 589 ng h/mL (34%; n = 4) and 91.4 ng/mL (34%; n = 9) for a single dose of 250 mg and 3641 ng h/mL (37%; n = 4) and 368 ng/mL (30%; n = 6) for multiple doses, respectively. Mean half‐life of crizotinib at the terminal phase was 43–51 h, giving an estimated steady state within 15 days.4 Further exploratory population PK analysis was carried out to identify factors affecting the AUC of crizotinib at steady state, including body weight, sex, age, and race. The C\nmax, trough concentration (C\ntrough), and AUC values were higher in Asian patients (n = 13), including Japanese, than in non‐Asian patients (n = 11) (C\nmax, 506 vs 322 ng/mL, ratio 1.57 [90% confidence interval (CI), 1.16−2.13]; AUC, 4696 vs 3137 ng/h/mL, ratio 1.50 [90% CI, 1.10−2.04]). However, when adjusted for body weight or body surface area, these differences were not statistically significant, suggesting that ethnic/racial differences in the PK of crizotinib were unlikely.\n\nCrizotinib is reported to be primarily metabolized by cytochrome P450 3A4 (CYP3A4) and to be a substrate of P‐glycoprotein.7 Expression of P‐glycoprotein has been reported to be influenced by ATP‐binding cassette sub‐family B member 1 (ABCB1) single nucleoside polymorphisms (SNPs). Previous studies have revealed a significant association between ABCB1 SNPs and the functionality of P‐glycoprotein.8, 9, 10, 11, 12 There are known ethnic differences in ABCB1 SNPs. It is also known that the PK and pharmacodynamics (PD) of some anticancer agents such as erlotinib differ in patients of different ethnicities.13, 14 These factors may lead to differences in intracellular versus extracellular concentrations of crizotinib.\n\nThe most common adverse events (AEs) in these crizotinib studies have been vision abnormalities (most frequently visual impairment, photophobia, or blurred vision), diarrhea, nausea, vomiting, constipation, elevated transaminase levels, edema, upper respiratory infection, dysgeusia, and dizziness.5 Grade 3 or higher AEs including neutropenia, elevated transaminase levels, fatigue, interstitial lung disease, pneumonia, and electrocardiogram QTc prolongation occasionally occurred.\n\nHere, we investigated possible clinical and pharmacogenomic factors in the PK, PD, or pharmacogenomics (PGx) of crizotinib in Japanese patients with ALK‐positive NSCLC.\n\nPatients and Methods\nPatient selection criteria\nInclusion criteria were advanced ALK‐positive NSCLC scheduled for treatment with crizotinib therapy, age ≥20 years, and adequate organ function (serum total bilirubin ≤2.0 mg/dL, aspartate aminotransferase ≤150 IU/L, alanine aminotransferase ≤150 IU/L, serum creatinine ≤2.0 mg/dL, and SpO2 ≥90%). Exclusion criteria included: concomitant treatment with other anticancer agents, radiotherapy, or surgery; the inability to swallow tablets; gastrointestinal disorders that could affect the ingestion or absorption of crizotinib, such as watery diarrhea, intestinal paresis, ileus, or a history of gastrectomy or intestinal resection; intake of drugs or food that could act as potent cytochrome P450 3A4 or P‐glycoprotein inhibitors or inducers; and women of childbearing age unless using effective contraception.\n\nStudy design and outcome\nThe study was carried out under an open‐label observational design to evaluate the PK/PD/PGx of crizotinib in Japanese patients with ALK‐positive NSCLC. The primary objective was to characterize PK parameters of crizotinib in these patients. Secondary objectives were to investigate the relationship between PK parameters and PD, including toxicities and anticancer effects, and to explore any genetic factors, including ABCB1 SNPs.\n\nThis study (UMIN000009867) was designed and carried out at the National Cancer Center Hospital (Tokyo, Japan). The protocol was approved by the review board of the National Cancer Center Hospital on January 31, 2013, and the study was carried out in accordance with the ethical principles stated in the Declaration of Helsinki. All patients provided written informed consent.\n\nTreatment and assessments\nPatients received the standard crizotinib dose of 250 mg twice daily. Patients continued to receive therapy until disease progression, clinical deterioration, or intolerable AEs that did not improve with dose adjustment.\n\nThe ALK fusion gene was confirmed by real‐time RT‐PCR, immunohistochemistry staining with D5F3 antibody (Cell Signaling Technology, Danvers, MA, USA) or FISH. The ALK FISH testing was carried out using a Vysis ALK break‐apart probe set (Abbott Molecular, Abbott Park, IL, USA). The specimen was considered positive if more than 15% of scored tumor cells had split ALK 5′ and 3′ probe signals or had isolated 3′ signals.\n\nBlood samples for PK analysis were collected immediately before and 0.5, 1, 2, 4, 6, 8, and 12 h after administration of crizotinib on days 1 and 15. Serial electrocardiography (ECG) was carried out in triplicate immediately before and 4 and 12 h after treatment with crizotinib on days 1 and 15 to assess for QTc prolongation.\n\nAdverse events were evaluated using the Common Terminology Criteria for Adverse Events version 4.0. Objective tumor response according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) was evaluated in all eligible patients before treatment, 8 weeks after the start of treatment, and then every 3–4 months.15\n\n\nPharmacokinetic analysis\nAfter blood was collected in EDTA‐containing tubes, plasma was separated within 30 min by centrifugation at 1500g for 10 min at 4°C and stored at –80°C until analysis. Plasma concentrations of crizotinib were measured by liquid chromatography–tandem mass spectrometry. Chromatographic separation of crizotinib and the internal standard, erlotinib‐d6, was carried out using an XBridge C18 HPLC column (2.1 × 5.0 mm, 3.5 μm) (Waters Corp., Milford, MA, USA) maintained at 40°C. Mobile phases A and B consisted of 0.1% formic acid aqueous solution and acetonitrile containing 0.1% formic acid, respectively. Separation was carried out using a gradation elution (from B of 15–90% over 5 min, B of 99% for 2.5 min, B of 15% for 3 min) at a flow rate of 0.3 mL/min with Nexera X2 ultra‐HPLC (Shimadzu Co., Kyoto, Japan). Quantitation was undertaken by selected reaction monitoring on a QTRAP5500 mass spectrometer (AB SCIEX, Framingham, MA, USA) with electrospray ionization in the positive mode. The selected reaction monitoring transitions were m/z 451.1–261.1 for crizotinib and m/z 400.2–278.0 for erlotinib‐d6. All data were acquired and analyzed using Analyst version 1.6.1 software (AB SCIEX). All sample analyses were carried out according to the internal assay quality guidelines. The lower limit of quantification was 5 ng/mL.\n\nPharmacokinetic variables of crizotinib and its metabolites were determined using the Phoenix WinNonlin PK program (Pharsight, Mountain View, CA, USA). The C\nmax and time to maximum concentration were recorded directly from the data. The AUC with extrapolation to 12 h (AUC0–12h) was calculated by the trapezoidal rule. The linear trapezoidal rule was used for successively increasing concentration values, and the logarithmic trapezoidal rule for decreasing concentration values.\n\nGenotyping\nGenotyping assays were carried out for eligible patients who had sufficient DNA in their sample. DNA was extracted and the concentration was fixed at 10 ng/μL. Genotyping was undertaken using the i‐densy genetic testing platform (ARKRAY, Kyoto, Japan) and the QP‐system quenching probe system (J‐Bio 21, Tokyo, Japan) based on the principles of mutant detection. To detect the various genotypes, we used QProbe (Nippon Steel Kankyo Engineering, Tokyo, Japan).\n\nWe analyzed the SNPs ABCB1 1236C>T, 2677G>T/A, and 3435C>T (rs1128503, rs2032582, and rs1045642, respectively). The primers that we used were: ABCB1‐1236F, 5′‐cctgtgtctgtgaatYgccttgaag‐3′ (Y represents C or T); ABCB1‐1236R, 5′‐gtctgcccactctgcaccttc‐3′; ABCB1‐2677F, 5′‐aaatgttgtctggacaagcactg‐3′; ABCB1‐2677R, 5′‐aattaatcaatcatatttagtttgactcac‐3′; ABCB1‐3435F, 5′‐actgcagcattgctgagaac‐3′; and ABCB1‐3435R, 5′‐cagagaggctgccacatgctc‐3′. The probes that we used were: ABCB1‐1236, 5′‐ttcaggttcagacccttc‐TAMRA‐3′; ABCB1‐2677, 5′‐PACIFIC BLUE‐cccagaaccttctagttc‐3′; and ABCB1‐3435, 5′‐ ctgccctcacaatctcttc‐BODIPY FL‐3′.\n\nStatistical analysis\nData are expressed as the geometric mean ± SD. The statistical significance of PK parameters was analyzed using a Wilcoxon signed‐rank test, with P < 0.05 considered significant. Progression‐free survival was defined as the time from the first day of crizotinib therapy to detection of the earliest signs of disease progression or death from any cause. Overall survival (OS) was defined as the time from the first day of crizotinib therapy to the last day on which the patient was confirmed to be alive or dead from any cause. Median survival was calculated using the Kaplan–Meier method. All statistical analyses were carried out with spss Statistics version 23.0 (SPSS, Chicago, IL, USA).\n\nResults\nPatient group\nFrom March 2013 to June 2014, a total of eight patients were enrolled (Table 1, Fig. S1). All patients had adenocarcinoma. Six patients were female and two were male, with a median age of 59 years (range, 46–72 years). The median body weight was 46.8 kg (range, 42.4–61.0 kg), and the median body surface area was 1.47 m2 (range, 1.30–1.70 m2).\n\nTable 1 Characteristics of Japanese non‐small‐cell lung cancer patients with ABCB1 polymorphism (n = 8)\n\n\t\tNo. of patients\t\nSex\tMale/female\t2/6\t\nAge, years\tMedian (range)\t59 (46–72)\t\nECOG PS\t0/1/2/3\t2/4/1/1\t\nHistologic type\tAdenocarcinoma\t8\t\nClinical stage\tIV/recurrence\t7/1\t\nBrain metastasis\tYes/no\t5/3\t\nHeight, cm\tMedian (range)\t158.2 (143.5–168.6)\t\nWeight, kg\tMedian (range)\t46.8 (42.4–61)\t\nBSA, m2\n\tMedian (range)\t1.47 (1.30–1.70)\t\nSmoking status\tNever/ex‐smoker\t5/3\t\nPack‐years\tMedian (range)\t30 (1–40)\t\nT‐Bil, mg/dL\tMedian (range)\t0.6 (0.3–1.6)\t\nAST, IU/L\tMedian (range)\t19 (13–30)\t\nALT, IU/L\tMedian (range)\t15 (7–38)\t\nCr, mg/dL\tMedian (range)\t0.59 (0.38–0.67)\t\nCCr, mL/min\tMedian (range)\t120.4 (65.0–131.4)\t\nPrior chemotherapy\tYes/no\t4/4\t\nPrior ALK‐TKI\tYes/no\t1/7\t\nPrior radiotherapy\tYes/no\t6/2\t\nPrior surgery\tYes/no\t1/7\t\nALT, alanine aminotransferase; AST, aspartate aminotransferase; BSA, body surface area; Cr, creatinine; CCr, creatinine clearance by the Cockcroft–Gault method; ECOG‐PS, Eastern Cooperative Oncology Group performance status; T‐Bil, total bilirubin; TKI, tyrosine kinase inhibitor.\n\nJohn Wiley & Sons, LtdTreatment efficacy and toxicity\nSeven patients were positive for ALK with FISH and one was negative, but positive on immunohistochemistry. Five patients had a partial response, one had stable disease, and two had progressive disease as their best response. The overall response rate by RECIST was 62.5% (95% CI, 24.5–91.5) (Fig. S2). Of two patients with progressive disease, one developed a brain metastasis on day 60, and after treatment with stereotactic irradiation, she continued crizotinib treatment beyond progression. Another patient, who had a history of previous crizotinib treatment, developed liver metastasis on day 47. Seven patients eventually discontinued crizotinib treatment due to progressive disease, and one due to an AE. Six patients required dose reduction due to AEs. Median PFS was 9.8 (95% CI, 2.3–17.3) months and median OS was not applicable (Figs S3,S4).\n\nCommon hematological and non‐hematological AEs observed during crizotinib treatment are summarized in Table 2. All patients experienced at least one AE of any grade of toxicity, and five patients experienced clinically significant AEs: grade 3 or 4 alanine aminotransferase increased (n = 2), grade 3 aspartate aminotransferase increased (n = 1), grade 3 esophagitis (n = 1), grade 3 QTc prolongation (n = 1), and grade 3 interstitial nephritis (n = 1). We were able to manage these AEs with supportive care and reduced doses in seven patients.\n\nTable 2 Adverse events of any cause in Japanese non‐small‐cell lung cancer patients with ABCB1 polymorphism treated with crizotinib (n = 8)\n\nAdverse event\tAny grade, n\n\tGrade 3, n\n\tGrade 4, n\n\t\nDiarrhea\t8\t0\t0\t\nALT increased\t7\t1\t1\t\nAST increased\t7\t1\t0\t\nVisual disorder\t5\t0\t0\t\nAnorexia\t4\t0\t0\t\nNausea\t4\t0\t0\t\nVomiting\t4\t0\t0\t\nConstipation\t4\t0\t0\t\nFatigue\t3\t0\t0\t\nDysgeusia\t3\t0\t0\t\nQTc prolongation\t2\t1\t0\t\nAbdominal pain\t2\t0\t0\t\nDizziness\t2\t0\t0\t\nEsophagitis\t1\t1\t0\t\nInterstitial nephritis\t1\t1\t0\t\nSkin eruption\t1\t0\t0\t\nALT, alanine aminotransferase; AST, aspartate aminotransferase.\n\nJohn Wiley & Sons, LtdA female patient developed severe esophagitis with dysphagia and odynophagia 4 weeks after starting crizotinib. Gastrointestinal endoscopy revealed diffuse grade 3 esophagitis and the drug was discontinued. When her symptoms resolved 3 weeks after discontinuation, she was restarted at a reduced dose of 200 mg twice daily, but the esophagitis returned.\n\nAnother patient developed grade 3 QTc prolongation. Grade 2 nausea and anorexia developed shortly after starting crizotinib and the ECG 4 h after crizotinib was given on day 15 showed a QTc interval of 507 ms with an RR interval of 158 ms. After discontinuation of crizotinib for 5 days, her ECG normalized. She was restarted at a reduced dose of 200 mg twice daily until disease progression.\n\nPharmacokinetic analysis related to toxicity\nThe PK parameters of crizotinib on days 1 and 15 are presented in Table 3 and Figure S5. The geometric mean of AUC0–12 and C\nmax measured in the Japanese patients in this study were generally similar to those in Asian patients obtained in the previous phase 1 study (Table 4). The geometric mean of AUC0–12 on day 15 was significantly increased in patients with clinically significant AEs (n = 5) compared to those without (n = 3) (Table 3, Fig. 1a). There was also a significant increase in the geometric mean of C\nmax and C\ntrough on day 15 in the patients with significant AEs.\n\nTable 3 Pharmacokinetic parameters of crizotinib in Japanese non‐small‐cell lung cancer patients with ABCB1 polymorphism\n\n\tAll patients n = 8\tSignificant AE n = 5\tNo significant AE n = 3\t\nP‐value\t\nAUC0–12, ng h/mL\t\nDay 1\t872 ± 379\t1040 ± 264\t650 ± 519\t0.57\t\nDay 15\t5410 ± 3220\t6540 ± 3660\t3940 ± 277\t0.04\t\nRatio\t6.20 ± 3.55\t6.28 ± 3.75\t6.06 ± 4.01\t\t\n\nC\nmax, ng/mL\t\nDay 1\t129 ± 54.0\t156 ± 49.1\t94.6 ± 44.4\t0.14\t\nDay 15\t525 ± 279\t631 ± 312\t387 ± 28.7\t0.04\t\n\nC\ntrough on day 15\t422 ± 302\t512 ± 354\t305 ± 39.3\t0.04\t\nHalf‐life, min\t\nDay 1\t447 ± 522\t528 ± 645\t338 ± 117\t0.25\t\nDay 15\t2010 ± 3780\t1840 ± 1830\t2310 ± 6190\t1.00\t\n\nT\nmax, min\t\nDay 1\t304 ± 86.8\t323 ± 97.8\t275 ± 67.0\t0.57\t\nDay 15\t268 ± 198\t245 ± 246\t310 ± 68.9\t0.79\t\nAE, adverse event; AUC0–12, area under the plasma concentration–time curve from 0 to 12 h; C\nmax, peak concentration; C\ntrough, trough concentration; T\nmax, time to maximum concentration.\n\nJohn Wiley & Sons, LtdTable 4 Pharmacokinetic parameters (mean [coefficient of variation %]) of crizotinib on day 15 in this study of Japanese non‐small‐cell lung cancer patients with ABCB1 polymorphism compared with subjects in a global phase I study\n\n\tThis trial\tGlobal phase I trial\t\nJapanese\tNon‐Asian\tAsian (8 Korean, 5 Japanese)\t\n\nn = 8\t\nn = 11\t\nn = 13\t\nAUC0–12, ng h/mL\t5410 (60)\t3137 (55)\t4696 (11)\t\n\nC\nmax, ng/mL\t525 (53)\t322 (67)\t506 (23)\t\nAUC0–12, area under the plasma concentration–time curve from 0 to 12 h; C\nmax, peak concentration.\n\nJohn Wiley & Sons, LtdFigure 1 Mean area under the plasma concentration–time curve from 0–12 h (AUC\n0–12) of crizotinib in Japanese patients with non‐small‐cell lung cancer with ABCB1 polymorphism. (a) Comparison of those with clinically significant adverse events with those without. (b) Comparison of AUC\n0–12 of crizotinib by ABCB1 genotyping.\n\nGenotype related to PK and toxicity\nFigure 1(b) and Table 5 depict the genotype findings. For the ABCB1 1236C>T SNPs, we identified one CC, three CT, and four TT genotypes among all eight patients. One patient showed all TT alleles (TT‐TT‐TT, homozygous variant), and three patients had at least one TT allele. Regarding the relationship between ABCB1 genotype and PKs, one patient (#7) with all‐TT ABCB1 alleles was a pronounced outlier in AUC0–12 and C\nmax on day 15 (13 467 ng h/mL and 1216 μg/mL, respectively). This was the same patient who developed grade 3 QTc prolongation.\n\nTable 5 Polymorphisms in ABCB1 in Japanese non‐small‐cell lung cancer patients (n = 8) treated with crizotinib\n\n\tAge, years\tSex\tBW, kg\tDetection method for ALK\n\tShrinkage rate,‡ %\tPFS, days\tDose reduction\tReason for discontinuation\tClinically significant AE\t\nABCB1 polymorphism\t\nIHC\tFISH,† %\t3435\t2677\t1236\t\n#1\t50\tFemale\t53.0\t+\t40\t87\t60\tYes\tPD\tGr3 esophagitis\tCC\tGG\tCC\t\n#2\t56\tFemale\t42.8\t+\t70\t57\t302\tYes\tOngoing\tGr3 ALT increased\tCC\tGG\tCT\t\n#3\t72\tMale\t49.7\t+\t72\t76\t295\tNo\tPD\tNone\tCC\tGT or AT\tTT\t\n#4§\n\t46\tFemale\t45.0\t+\t31\t66\t47\tNo\tPD\tNone\tCC\tGG\tCT\t\n#5\t48\tMale\t61.0\tUntested\t33\t79\t374\tYes\tPD\tGr3 AST increased and Gr4 ALT increased\tCT\tGT or AT\tTT\t\n#6\t66\tFemale\t42.4\t+\t4\t43\t323\tYes\tAE\tGr3 interstitial nephritis\tCC\tGT or AT\tTT\t\n#7\t69\tFemale\t43.3\t+\t29\t67\t138\tYes\tPD\tGr3 QTc prolongation\tTT\tTT\tTT\t\n#8\t62\tFemale\t48.6\t+\t70\t36\t301\tYes\tOngoing\tNone\tCC\tGG\tCT\t\n†Rate of positive cells in FISH (%). ‡Percent change at maximum reduction from baseline according to Response Evaluation Criteria in Solid Tumors version 1.1. §This patient had a previous history of crizotinib treatment. AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BW, body weight; Gr, grade; IHC, immunohistochemistry; PD, progressive disease; PFS, progression‐free survival.\n\nJohn Wiley & Sons, LtdDiscussion\nIn this evaluation of the PKs of crizotinib in Japanese patients with ALK‐positive NSCLC, we found that patients appeared to develop toxicities of any grade, especially clinically significant toxicities, more frequently than in previous trials. Nevertheless, all AEs could be managed with appropriate supportive care and dose reduction, and only one patient required discontinuing of treatment due to an AE. These results suggest that the toxicity and PKs of crizotinib are related to the effects of body weight and ABCB1 SNPs.\n\nThe dose escalation phase I trial of 1001/NCT00585195 determined that the maximum tolerated dose of crizotinib was 250 mg twice daily.4, 16 Several later clinical studies reported the efficacy and safety of crizotinib in patients with malignant solid tumors, including advanced ALK‐positive NSCLC. Crizotinib is currently the standard of care for patients with advanced ALK‐positive NSCLC and is under development for ROS1‐rearranged NSCLC and MET mutated or amplified NSCLC.17, 18, 19, 20 Nevertheless, only a few PK studies of crizotinib have been reported, and most data were extracted primarily from documents submitted for drug approval.21, 22, 23 The phase I documents reported that that peak plasma concentration of crizotinib after a single oral dose of 50–300 mg was reached at approximately 4 h, followed by a multiexponential decline with a terminal half‐life of 43–51 h. After multiple doses, the steady state was reached within 15 days with a mean AUC of 3880 ng h/mL (CV 36%) and a mean C\nmax of 411 ng/mL (CV 44%). Steady‐state C\ntrough levels with a twice daily dose of 250 mg were stable with median C\ntrough ranging from 242 to 319 ng/mL.23\n\n\nIn this study, Japanese patients appeared to develop toxicities of all grades more frequently than patients in the previous trials. The PK parameters at steady state, with a mean AUC of 5410 ng h/mL and a mean C\nmax of 525 ng/mL, also appear to be higher than patients in the previous trials (Table 3). Moreover, the geometric mean of AUC0–12 on day 15 was significantly increased in the five patients with clinically significant AEs compared to the three without (6540 ± 3660 vs 3940 ± 277 ng h/mL respectively; P = 0.04). These results suggest a correlation between the toxicity and PK of crizotinib (Table 3). Potential reasons for the difference in toxicity and PK might include body weight, sex, race, and PGx. The previous population PK study compared parameters in 13 Asian (including eight Korean and five Japanese) and 11 non‐Asian (including white, black, and other) patients.24 Although mean values for crizotinib C\nmax and AUC in Asian patients were 1.57× and 1.50× those in non‐Asian patients, respectively, these differences were lost on correction for body weight, and the population PK study accordingly concluded that the PK differences between Asian and non‐Asian subjects were due to body weight rather than race. In our results, the differences in crizotinib C\nmax and AUC were lost on correction for body weight or body surface area (Table S1). However, the safety and efficacy profile suggested that no dose adjustment was required for Asian patients. The Japanese patients in that study also had mean C\nmax and AUC values of 1.63× and 1.72× those in the non‐Asian patients, respectively. Due to lack of data access, including individual PK data and body weight in the non‐Asian patients, we could not statistically analyze the difference between our Japanese subjects and the previous non‐Asian subjects. The differences in toxicity and PK in the present study may be due to the very low weights (42.4–61.0 kg) of all of our subjects.\n\nCrizotinib is reported to be a substrate of P‐glycoprotein.7 Expression of P‐glycoprotein has been shown to be influenced by ABCB1 SNPs. Previous studies have revealed a significant association between ABCB1 SNPs and the functionality of P‐glycoprotein.8, 9, 10, 11, 12 In particular, ABCB1 expression is largely influenced by three SNPs in the ABCB1 gene at positions 1236C>T, 2677G>T, and 3435C>T.12, 25, 26 These three SNPs occur frequently and are strongly linked, creating a common haplotype. Indeed, an increasing number of variant alleles, such as 1236TT‐2677TT‐3435TT, are known to be associated with lower expression.27 Interestingly, one patient with all‐TT ABCB1 alleles was a distinct outlier in AUC0–12 and C\nmax on day 15 (2.84× and 2.61×, respectively) compared with patients with other genotypes. This patient also had grade 3 QTc prolongation. Because we could not interpret this outlier as a consequence of this subject's low weight, we suggest that PK parameters may be increased in patients with all‐TT ABCB1 alleles, and that these patients may be at risk of severe toxicity.\n\nSeveral limitations of the study warrant mention. First, the sample size was very small because of the rarity of ALK‐positive NSCLC patients. Second, our results have not been validated in different patients. However, we consider that our speculations are valuable because of significant AEs to crizotinib in one patient with all‐TT ABCB1 alleles. Finally, because we could not access the individual PK data and body weight in non‐Asian patients in a previous study, we did not statistically analyze the difference between our Japanese subjects and non‐Asian subjects.\n\nIn conclusion, we evaluated the PK of crizotinib in Japanese patients with ALK‐positive NSCLC. Japanese patients in this study appeared to develop toxicities of any grade more frequently than patients in previous trials, especially clinically significant toxicities. Nevertheless, these could be managed with appropriate supportive care and dose reduction, and only one patient discontinued treatment due to an AE. These results suggest that the toxicity and PK of crizotinib are related to the effects of body weight and ABCB1 SNPs.\n\nDisclosure Statement\nNone of the authors have a direct conflict of interest regarding this study but disclose a potential conflict of interest outside the submitted work, in the form of research grants: Y.F. from AstraZeneca, Eli Lilly, and Chugai; A.H. from AstraZeneca, Chugai, and Shimadzu; H.H. from Taiho, Merk Serono, Novartis, Astellas, and MSD; S.K. from AstraZeneca and ONO; Y.G. from Pfizer, Eli Lilly, and Abbie GK; H.N. from Merck Serono, Pfizer, Taiho, Eisai, Chugai, Eli Lilly, Novartis, Daiichi Sankyo, GlaxoSmithKline, Yakult, Quintiles, Astellas, AstraZeneca, Boehringer Ingelheim, and ONO; N.Y. from Chugai, Eli Lilly, Taiho, Eisai, Quintiles, Astellas, BMS, Novartis, Daiichi‐Sankyo, Pfizer, and Boehringer Ingelheim and has received honoraria from AstraZeneca, Pfizer, Eli Lilly, and Chugai; Y.O. from AstraZeneca, Chugai, Eli Lilly, ONO, BMS, Kyorin, Dainippon‐ Sumitomo, Pfizer, Taiho, Novartis, and Merck Serono and has received honoraria from AstraZeneca, Chugai, Lilly, ONO, BMS, Daiichi‐Sankyo, Nipponkayaku, Boehringer Ingelheim, Bayer, Pfizer, MSD, Taiho, Clovis, and Sanofi. The other authors have no conflict of interest.\n\nSupporting information\n\nFig. S1. \nCONSORT diagram of this study.\n\nClick here for additional data file.\n\n \nFig. S2. Tumor responses to crizotinib from baseline in Japanese non‐small‐cell lung cancer patients with ABCB1 polymorphism.\n\nClick here for additional data file.\n\n \nFig. S3. Progression‐free survival in Japanese non‐small‐cell lung cancer patients with ABCB1 polymorphism treated with crizotinib.\n\nClick here for additional data file.\n\n \nFig. S4. Overall survival in Japanese non‐small‐cell lung cancer patients with ABCB1 polymorphism treated with crizotinib.\n\nClick here for additional data file.\n\n \nFig. S5. Mean plasma concentration–time curves of crizotinib on days 1 (■) and 15 (○) (mean ± standard deviation) in Japanese non‐small‐cell lung cancer patients with ABCB1 polymorphism.\n\nClick here for additional data file.\n\n \nTable S1. Pharmacokinetic parameters of crizotinib in Japanese non‐small‐cell lung cancer patients with ABCB1 polymorphism adjusted by (A) body weight and (B) body surface area.\n\nClick here for additional data file.\n\n Acknowledgments\nThis work was supported by the grant from the Japanese Society of Clinical Pharmacology and Therapeutics and in part by a Grant‐in‐Aid for Scientific Research from the Japan Society for the Promotion of Science (KAKENHI 21590167). We greatly appreciate the patients who participated in this study and their families, and the assistance of the staff of the Department of Thoracic Oncology, National Cancer Center Hospital.\n==== Refs\nReferences\n1 \n\nSoda \nM \n, \nChoi \nYL \n, \nEnomoto \nM \n\net al\nIdentification of the transforming EML4‐ALK fusion gene in non‐small‐cell lung cancer . Nature \n2007 ; 448 : 561 –6 .17625570 \n2 \n\nKris \nMG \n, \nJohnson \nBE \n, \nBerry \nLD \n\net al\nUsing multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs . JAMA \n2014 ; 311 : 1998 –2006 .24846037 \n3 \n\nShaw \nAT \n, \nYeap \nBY \n, \nSolomon \nBJ \n\net al\nEffect of crizotinib on overall survival in patients with advanced non‐small‐cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis . Lancet Oncol \n2011 ; 12 : 1004 –12 .21933749 \n4 \n\nCamidge \nDR \n, \nBang \nYJ \n, \nKwak \nEL \n\net al\nActivity and safety of crizotinib in patients with ALK‐positive non‐small‐cell lung cancer: updated results from a phase 1 study . Lancet Oncol \n2012 ; 13 : 1011 –9 .22954507 \n5 \n\nShaw \nAT \n, \nKim \nDW \n, \nNakagawa \nK \n\net al\nCrizotinib versus chemotherapy in advanced ALK‐positive lung cancer . N Engl J Med \n2013 ; 368 : 2385 –94 .23724913 \n6 \n\nBenjamin \nJS \n, \nTony \nMok \n, \nDong?Wan \nKim \n\net al\nFirst‐Line Crizotinib versus Chemotherapy in ALK‐Positive Lung Cancer . N Engl J Med \n2014 ; 371 : 2167 –2177 .25470694 \n7 \n\nJohnson \nTR \n, \nTan \nW \n, \nGoulet \nL \n\net al\nMetabolism, excretion and pharmacokinetics of [C]crizotinib following oral administration to healthy subjects . Xenobiotica \n2015 ; 45 : 45 –59 .25034009 \n8 \n\nHoffmeyer \nS \n, \nBurk \nO \n, \nvon Richter \nO \n\net al\nFunctional polymorphisms of the human multidrug‐resistance gene: multiple sequence variations and correlation of one allele with P‐glycoprotein expression and activity in vivo . Proc Natl Acad Sci USA \n2000 ; 97 : 3473 –8 .10716719 \n9 \n\nSakaeda \nT \n, \nNakamura \nT \n, \nOkumura \nK \n. Pharmacogenetics of MDR1 and its impact on the pharmacokinetics and pharmacodynamics of drugs . Pharmacogenomics \n2003 ; 4 : 397 –410 .12831320 \n10 \n\nMarzolini \nC \n, \nPaus \nE \n, \nBuclin \nT \n, \nKim \nRB \n. Polymorphisms in human MDR1 (P‐glycoprotein): recent advances and clinical relevance . Clin Pharmacol Ther \n2004 ; 75 : 13 –33 .14749689 \n11 \n\nAarnoudse \nAL \n, \nvan Schaik \nRH \n, \nDieleman \nJ \n\net al\nMDR1 gene polymorphisms are associated with neuropsychiatric adverse effects of mefloquine . Clin Pharmacol Ther \n2006 ; 80 : 367 –74 .17015054 \n12 \n\nFung \nKL \n, \nGottesman \nMM \n. A synonymous polymorphism in a common MDR1 (ABCB1) haplotype shapes protein function . Biochim Biophys Acta \n2009 ; 1794 : 860 –71 .19285158 \n13 \n\nHamada \nA \n, \nSasaki \nJ \n, \nSaeki \nS \n\net al\nAssociation of ABCB1 polymorphisms with erlotinib pharmacokinetics and toxicity in Japanese patients with non‐small‐cell lung cancer . Pharmacogenomics \n2012 ; 13 : 615 –24 .22462752 \n14 \n\nRudin \nCM \n, \nLiu \nW \n, \nDesai \nA \n\net al\nPharmacogenomic and pharmacokinetic determinants of erlotinib toxicity . J Clin Oncol \n2008 ; 26 : 1119 –27 .18309947 \n15 \n\nTherasse \nP \n, \nArbuck \nSG \n, \nEisenhauer \nEA \n\net al\nNew 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 \n2000 ; 92 : 205 –16 .10655437 \n16 \n\nKwak \nEL \n, \nBang \nYJ \n, \nCamidge \nDR \n\net al\nAnaplastic lymphoma kinase inhibition in non‐small‐cell lung cancer . N Engl J Med \n2010 ; 363 : 1693 –703 .20979469 \n17 \n\nDietrich \nMF \n, \nYan \nSX \n, \nSchiller \nJH \n. Response to crizotinib/erlotinib combination in a patient with a primary EGFR‐mutant adenocarcinoma and a primary c‐met‐amplified adenocarcinoma of the lung . J Thorac Oncol \n2015 ; 10 : e23 –5 .25902175 \n18 \n\nPaik \nPK \n, \nDrilon \nA \n, \nFan \nPD \n\net al\nResponse to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping . Cancer Discov \n2015 ; 5 : 842 –9 .25971939 \n19 \n\nShaw \nAT \n, \nOu \nSH \n, \nBang \nYJ \n\net al\nCrizotinib in ROS1‐rearranged non‐small‐cell lung cancer . N Engl J Med \n2014 ; 371 : 1363 –71 .\n20 \n\nYamazaki \nS \n, \nVicini \nP \n, \nShen \nZ \n\net al\nPharmacokinetic/pharmacodynamic modeling of crizotinib for anaplastic lymphoma kinase inhibition and antitumor efficacy in human tumor xenograft mouse models . J Pharmacol Exp Ther \n2012 ; 340 : 549 –57 .22129595 \n21 \nDocument of the United States Application for approval of crizotinib . Food and Drug Administration , 2011 .\n22 \nDocument of the European Medicines Agency for approval of crizotinib . European Medicines Agency , 2012 .\n23 \n\nHamilton \nG \n, \nRath \nB \n, \nBurghuber \nO \n. Pharmacokinetics of crizotinib in NSCLC patients . Expert Opin Drug Metab Toxicol \n2015 ; 11 : 835 –42 .25732197 \n24 \n\nOu \nSHI \n, \nSalgia \nR \n, \nClark \nJ \n. Comparison of crizotinib (PF‐02341066) pharmacokinetics between Asian and non‐Asian patients with advanced malignancies . J Thorac Oncol \n2010 ; 5 (suppl 5 ): S382 .\n25 \n\nKroetz \nDL \n, \nPauli‐Magnus \nC \n, \nHodges \nLM \n\net al\nSequence diversity and haplotype structure in the human ABCB1 (MDR1, multidrug resistance transporter) gene . Pharmacogenetics \n2003 ; 13 : 481 –94 .12893986 \n26 \n\nHodges \nLM \n, \nMarkova \nSM \n, \nChinn \nLW \n\net al\nVery important pharmacogene summary: ABCB1 (MDR1, P‐glycoprotein) . Pharmacogenet Genomics \n2011 ; 21 : 152 –61 .20216335 \n27 \n\nKimchi‐Sarfaty \nC \n, \nMarple \nAH \n, \nShinar \nS \n\net al\nEthnicity‐related polymorphisms and haplotypes in the human ABCB1 gene . Pharmacogenomics \n2007 ; 8 : 29 –39 .17187507\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1347-9032",
"issue": "107(8)",
"journal": "Cancer science",
"keywords": "Crizotinib; EML4-ALK fusion protein; non-small-cell lung cancer; pharmacogenomics; pharmacokinetics",
"medline_ta": "Cancer Sci",
"mesh_terms": "D018435:ATP Binding Cassette Transporter, Subfamily B; D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D044466:Asians; D001835:Body Weight; D002289:Carcinoma, Non-Small-Cell Lung; D000077547:Crizotinib; D005260:Female; D005838:Genotype; D006801:Humans; D007564:Japan; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011720:Pyrazoles; D011725:Pyridines; D020794:Receptor Protein-Tyrosine Kinases",
"nlm_unique_id": "101168776",
"other_id": null,
"pages": "1117-23",
"pmc": null,
"pmid": "27270784",
"pubdate": "2016-08",
"publication_types": "D016428:Journal Article",
"references": "19285158;12893986;14749689;17187507;25470694;22954507;27270784;10655437;25971939;20979469;12831320;20216335;25264305;25732197;10716719;18309947;25902175;22129595;25034009;24846037;23724913;17625570;17015054;21933749;22462752",
"title": "Pharmacokinetic profiles of significant adverse events with crizotinib in Japanese patients with ABCB1 polymorphism.",
"title_normalized": "pharmacokinetic profiles of significant adverse events with crizotinib in japanese patients with abcb1 polymorphism"
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"abstract": "BACKGROUND\nDevelopment of hypersensitivity pneumonitis has been reported in association with combination chemotherapy consisting of gemcitabine and paclitaxel. However, diagnosis of this condition is based on computed tomography imaging and correlative bronchoalveolar findings on bronchoscopy. Although transient elevation of the tumor marker CA 15-3 has been reported in patients with interstitial pneumonitis associated with collagen disease, elevation of this marker during drug-induced hypersensitivity pneumonitis has not been reported yet.\n\n\nMETHODS\nIn this report, we describe a 74-year-old metastatic schwannoma patient with drug-induced pneumonitis secondary to combined gemcitabine and paclitaxel treatment associated with transient elevation of CA 15-3.Management and outcome: The patient responded to steroid treatment with clinical and radiological improvement, and CA 15-3 levels returned to normal within four weeks.\n\n\nCONCLUSIONS\nThese findings suggest that blood CA 15-3 level has the potential to be used as a marker to monitor drug-induced pneumonitis.",
"affiliations": "Department of Anesthesiology and Reanimation, Gayrettepe 90790Florence Nightingale Hospital, Istanbul, Turkey.",
"authors": "Comlek|Savas|S|https://orcid.org/0000-0002-7741-8400",
"chemical_list": "D003841:Deoxycytidine; C056507:gemcitabine; D017239:Paclitaxel",
"country": "England",
"delete": false,
"doi": "10.1177/1078155220904994",
"fulltext": null,
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"issn_linking": "1078-1552",
"issue": "26(7)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "CA 15-3; drug-induced pneumonitis; gemcitabine; hypersensitivity pneumonitis; metastatic schwannoma; paclitaxel",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D003841:Deoxycytidine; D006801:Humans; D008297:Male; D017239:Paclitaxel; D011014:Pneumonia; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "1750-1753",
"pmc": null,
"pmid": "32075504",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Chemotherapy-induced pneumonitis associated with transient CA 15-3 elevation.",
"title_normalized": "chemotherapy induced pneumonitis associated with transient ca 15 3 elevation"
} | [
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"companynumb": "TR-TEVA-2020-TR-1856151",
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{
"abstract": "A 65-year-old woman with prolonged cough and presumed pulmonary hypertrophic osteoarthropathy was referred to our hospital. Computed tomography showed 2 tumors larger than 3 cm in size and massive hilar lymph node enlargement in the right lung. Pathological examination of the transbronchial lung biopsy specimen showed atypical malignant cells, presumed adenocarcinoma, with 1% positivity of programmed cell death 1 ligand (PD-L1). Three courses of chemoimmunotherapy with pembrolizumab (400 mg q3w), carboplatin (AUC 5 mg/mL · min q3w), and pemetrexed (500 mg/m2 q3w) were well tolerated and brought about a quasi-complete response both of the lung tumors and lymph nodes and complete symptom relief of the pulmonary hypertrophic osteoarthropathy, finally leading to the surgical intervention, that is, lobectomy and lymph node dissection. Postoperative pathological examination showed no viable cancer foci both in the lung tumors and lymph nodes. The patient recovered uneventfully. Physicians should note the combination chemoimmunotherapy including pembrolizumab, with curative intent, to optimally treat patients with locally advanced non-small cell lung cancer (NSCLC) even if the NSCLC bears a small amount of PD-L1.",
"affiliations": "Department of Surgery, Kishiwada Tokushukai Hospital, Kishiwada-city, Japan.;Department of Surgery, Kishiwada Tokushukai Hospital, Kishiwada-city, Japan.;Department of Surgery, Kishiwada Tokushukai Hospital, Kishiwada-city, Japan.;Department of Surgery, Kishiwada Tokushukai Hospital, Kishiwada-city, Japan.",
"authors": "Kataoka|Naoki|N|;Oura|Shoji|S|;Yamaguchi|Tomoyuki|T|;Makimoto|Shinichiro|S|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000512818",
"fulltext": "\n==== Front\nCase Rep Oncol\nCase Rep Oncol\nCRO\nCase Reports in Oncology\n1662-6575\nS. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com\n\n10.1159/000512818\ncro-0014-1380\nCase Report\nA Case of Lung Adenocarcinoma with Pulmonary Hypertrophic Osteoarthropathy Showing Pathological Complete Response to a Pembrolizumab-Containing Chemoimmunotherapy\nKataoka Naoki\nOura Shoji *\nYamaguchi Tomoyuki\nMakimoto Shinichiro\nDepartment of Surgery, Kishiwada Tokushukai Hospital, Kishiwada-city, Japan\n*Shoji Oura, shouji.oura@tokushukai.jp\nSep-Dec 2021\n21 9 2021\n21 9 2021\n14 3 13801386\n14 10 2020\n27 10 2020\n2021\nCopyright © 2021 by S. Karger AG, Basel\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This 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.\nA 65-year-old woman with prolonged cough and presumed pulmonary hypertrophic osteoarthropathy was referred to our hospital. Computed tomography showed 2 tumors larger than 3 cm in size and massive hilar lymph node enlargement in the right lung. Pathological examination of the transbronchial lung biopsy specimen showed atypical malignant cells, presumed adenocarcinoma, with 1% positivity of programmed cell death 1 ligand (PD-L1). Three courses of chemoimmunotherapy with pembrolizumab (400 mg q3w), carboplatin (AUC 5 mg/mL · min q3w), and pemetrexed (500 mg/m2 q3w) were well tolerated and brought about a quasi-complete response both of the lung tumors and lymph nodes and complete symptom relief of the pulmonary hypertrophic osteoarthropathy, finally leading to the surgical intervention, that is, lobectomy and lymph node dissection. Postoperative pathological examination showed no viable cancer foci both in the lung tumors and lymph nodes. The patient recovered uneventfully. Physicians should note the combination chemoimmunotherapy including pembrolizumab, with curative intent, to optimally treat patients with locally advanced non-small cell lung cancer (NSCLC) even if the NSCLC bears a small amount of PD-L1.\n\nKeywords\n\nImmune checkpoint inhibitor\nNon-small cell lung cancer\nPathological complete response\nPembrolizumab\nPulmonary hypertrophic osteoarthropathy\n==== Body\npmcIntroduction\n\nLung cancer is the leading cause of cancer-related mortality in men worldwide. Surgery has been the mainstay in the treatment of resectable non-small cell lung cancer (NSCLC) with curative intent. On the other hand, systemic therapy, especially chemotherapy, has played a major role in the treatment of inoperable NSCLCs. However, no effective systemic therapies, leading to a cure without local therapy, have been thus far established.\n\nImmune tolerance through the interaction between programmed cell death 1 (PD-1) and programmed cell death 1 ligand (PD-L1) has become the important therapeutic target in the treatment of locally advanced or metastatic NSCLCs [1]. The advent of immune checkpoint inhibitors has dramatically changed the strategy and clinical outcome of inoperable NSCLCs.\n\nWe herein report a case of locally advanced NSCLC with pulmonary hypertrophic osteoarthropathy [2] showing a complete pathological response to a pembrolizumab-containing chemoimmunotherapy.\n\nCase Report\n\nA 65-year-old woman, an ex-smoker with a Brinkman index of 800, with a past history of breast cancer, urothelial cancer, and ischemic heart disease presented cough for several months. Plain chest X-P showed a mass in the right lung field and enlargement of the right lung hilum (Fig. 1). Computed tomography (CT) showed well-defined oval masses in the lung with apparent hilar lymph node enlargement. Laboratory testing showed no significant tumor marker elevations. Pathological examination of the transbronchial lung biopsy specimen showed large oval atypical cells with mucin formation in some cells. Immunostaining showed that the atypical cells (Fig. 2) were TTF-1, napsin A, CK5/6, CD56, synaptophysin, and chromogranin negative, Alucian blue positive, p40 and p63 focally positive, and PD-L1 weakly, that is,1%, positive. Molecular testing showed that no molecular mutations were observed in epidermal growth factor receptor exons 18–21. Positron emission tomography (PET) showed maximum standard uptake values of 8.0 and 14.1 in the 2 tumors located in the right lower lobe and those of 6.3 and 5.3 in the hilar and mediastinal lymph nodes, respectively, but no significant accumulation in the bone (Fig. 3). The patient with digital clubbing and cortical and periosteal thickening of the tibias complained of polyarthralgia after the onset of cough, leading to the diagnosis of pulmonary hypertrophic osteoarthropathy. The presence of 2 lung cancers in the right lower lobe suggested the T category in this case as at least T2, that is, more than 3 cm in size, or T3 with possible pulmonary metastasis in the same lobe. In addition, bulky presumed hilar lymph node metastasis could lead to inevitable pneumonectomy when primary surgery was applied to the patient. We, therefore, treated the patient with primary chemoimmunotherapy using pembrolizumab (400 mg q3w), carboplatin (AUC 5 mg/mL/min q3w), and pemetrexed (500 mg/m2 q3w). The patient showed prompt symptom relief, that is, disappearance of the cough and polyarthralgia with manageable side effects. Due to the quasi-complete remission of the lung cancers and the marked shrinkage of the presumed lymph node metastases (Fig. 3) with 3 courses of the chemoimmunotherapy, the patient underwent lower lobe lobectomy and hilar and mediastinal lymph node dissection. Pathological examination showed no viable cancer remnants in the lung tumors and lymph nodes dissected (Fig. 2). The postoperative course was uneventful and the patient was discharged on the 9th day after operation.\n\nDiscussion\n\nVarious therapies, mainly chemotherapy and molecularly targeted drugs such as bevacizumab [3], have been employed to improve survival of the patients with metastatic or locally advanced NSCLC, resulting in certain but nominal survival benefit with considerable therapy-induced uncomfortable side effects. Unlike breast cancers, pathological complete response has been regarded as exceptional in the treatment of locally advanced NSCLCs [4]. This case, however, showed a complete pathological response both in the lung cancers and presumed metastatic lymph nodes.\n\nSingle or dual immune checkpoint inhibitor therapy, much less toxic than conventional chemotherapies, has become a preferred option in the treatment of chemonaive inoperable NSCLC with high PD-L1 expression [5]. Various studies have showed that high PD-L1 expression correlated well with the favorite efficacy of the single or dual immune checkpoint inhibitor therapy against NSCLC on one hand. This case had only 1% positivity of PD-L1 in the biopsy specimen but showed marked antitumor response clinically and pathologically on the other hand. A clinical trial, however, clearly showed that even though patients were limited to those with less than 1% PD-L1 positive squamous cell carcinoma, adding pembrolizumab to conventional calboplatin and paclitaxel could lead to a significant survival benefit [6]. Immune checkpoint inhibitors, therefore, may be possible enhancers of the chemotherapy with unproven mechanisms. In fact, the regimen used in this case has received US Food and Drug Administration approval for the frontline metastatic NSCLC irrespective of PD-L1 expression.\n\nPulmonary hyperplastic osteoarthropathy is defined as the syndrome which mainly consisted of clubbed fingers, periostitis of the long tubular bones, and arthritis [2]. Patients with pulmonary hyperplastic osteoarthropathy, therefore, usually present a painful arthropathy. In this case, in addition to the amelioration of the cough with the tumor regression, pain as a symptom of paraneoplastic syndrome disappeared completely during the administration of pembrolizumab-containing chemoimmunotherapy. The presence of paraneoplastic syndrome, more often observed in small cell carcinoma than in NSCLC [7], generally implies that a subset of cancer cells, releasing some kind of symptom-causing cytokine(s), predominates in the tumor. Therefore, some anticancer therapy, when being effective for cancer clones causing paraneoplastic syndrome, could lead to marked antitumor effects, occasionally leading to a pathological complete response like this case. Therefore, patients with paraneoplastic syndrome due to NSCLC should be good candidates for multidisciplinary therapy with curative intent.\n\nUnlike chemotherapy, immune checkpoint inhibitors generally develop unique adverse effects, so-called immune-related adverse effects, such as colitis, pneumonitis, hepatitis, neurotoxic effects, and myocarditis [8]. Fatal adverse effects were observed in approximately 0.4% of patients treated with an anti-PD-1/anti-PD-L1 agent and in over 1.0% of those treated with an anticytotoxic T-lymphocyte antigen-4 (CTLA-4) plus an anti-PD-1/anti-PD-L1 agent [9]. Much attention should be paid to immune-related adverse effects but without overweighing the benefits, that is, pathological complete response in this case.\n\nWith the remarkable clinical outcomes using various immune checkpoint inhibitors, the therapeutic strategy for inoperable NSCLC has diverged into two directions. When PD-L1 expression of the NSCLC is very high, that is, ≥50 percent expression, dual immune checkpoint inhibitor therapy without chemotherapy plays an important role in order both to maintain quality of life for the patients and to possibly prolong survival of the patients. On the other hand, in case of positive but weak PD-L1 expression, chemoimmunotherapy using platinum doublet and an immune checkpoint inhibitor, especially pembrolizumab, has become a standard therapeutic option for NSCLC not with curative intent but with palliative intent. However, the therapeutic goal of the locally advanced NSCLC should be changed from palliation to cure when the induction chemoimmunotherapy brings about a remarkable response.\n\nIn conclusion, physicians should take the induction therapy using platinum doublet and pembrolizumab into consideration to optimally treat the patients with advanced NSCLC, especially with low PD-L1 expression and paraneoplastic syndrome, followed by adequate local therapy. Further study with a pembrolizumab-containing chemoimmunotherapy should be done, with curative intent, in patients with locally advanced NSCLC.\n\nStatement of Ethics\n\nWe have reported this case in compliance with the Declaration of Helsinki. Written informed consent was obtained from the patient for the publication of this case report and any accompanying images.\n\nConflict of Interest Statement\n\nThe authors have no conflicts of interest to declare.\n\nFunding Sources\n\nNot applicable.\n\nAuthor Contributions\n\nN.K. contributed the design of the report and collected the data. S.O. drafted the manuscript. T.Y. developed the therapeutic strategy of the patient. S.M. revised the manuscript. All authors read and approved the final version of the manuscript.\n\nFig. 1 Chest X-ray. a Chest X-ray before chemoimmunotherapy shows an oval shadow approximately 3 cm in size in the right lower lung field (arrow) and enlargement of the lung hilum (arrowhead). b Chest X-ray after chemoimmunotherapy showed complete disappearance of the tumor and shrinkage of the lung hilum.\n\nFig. 2 Pathological examination. a Pathological examination of the transbronchial lung biopsy specimen showed the growth of large oval atypical cells in a sheet-like fashion. Some cells contain mucin in the cytoplasm. HE. ×200. b Low magnification view of the resected specimen showed marked hyalinization (arrows) just beneath the pleura. HE. ×40. c Higher magnification view of the resected specimen showed marked fibrosis and lymphocytic infiltrates with no viable cancer foci. HE. ×100. d Low magnification view showed marked fibrosis and no viable cancer foci in the subcarinal lymph nodes dissected. HE. ×40.\n\nFig. 3 PET/CT. a PET before chemoimmunotherapy showed 2 lung tumors (arrows) and hilar and mediastinal lymph nodes (arrowheads) with markedly increased avidity and no uptakes in the bone. b PET after chemoimmunotherapy showed no uptake in the lung tumors and lymph nodes. c PET/CT before chemoimmunotherapy showed increased avidity both in the lung tumor and the presumed hilar metastatic lymph node. d PET/CT after chemoimmunotherapy showed quasi-complete disappearance of the lung tumor and marked shrinkage of the hilar lymph node.\n==== Refs\nReferences\n\n1 Hanna NH Schneider BJ Temin S Baker JS Brahmer J Ellis PM Therapy for stage IV non–small-cell lung cancer without driver alterations: ASCO and OH (CCO) joint guideline update J Clin Oncol 2020 38 1608 32 31990617\n2 Ito T Goto K Yoh K Niho S Ohmatsu H Kubota K Hypertrophic pulmonary osteoarthropathy as a paraneoplastic manifestation of lung cancer J Thorac Oncol 2010 5 (7) 976 80 20453688\n3 Barlesi F Scherpereel A Gorbunova V Gervais R Vikström A Chouaid C Maintenance bevacizumab-pemetrexed after first-line cisplatin-pemetrexed-bevacizumab for advanced nonsquamous nonsmall-cell lung cancer: updated survival analysis of the AVAPERL (MO22089) randomized phase III trial Ann Oncol 2014 25 (5) 1044 52 24585722\n4 Hellmann MD Chaft JE William WNJ Rusch V Pisters KMW Kalhor N Pathologic response after neoadjuvant chemotherapy in resectable non-small cell lung cancers: proposal for the use of “major pathologic response” as a surrogate endpoint Lancet Oncol 2014 15 e42 e50 24384493\n5 Reck M Rodriguez-Abreu D Robinson AG Hui R Csoszi T Fulop A Updated analysis of KEY-NOTE-024: Pembrolizumab versus platinum-based chemotherapy for advanced non–small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater J Clin Oncol 2019 37 537 46 30620668\n6 Paz-Ares L Luft A Vicente D Tafreshi A Gümüş M Mazières J Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer N Engl J Med 2018 379 (21) 2040 51 30280635\n7 Ilias I Torpy DJ Pacak K Mullen N Wesley RA Nieman LK Cushing's syndrome due to ectopic corticotropin secretion: twenty years' experience at the national institutes of health J Clin Endcrinol 2005 90 4955 62\n8 Naidoo J Page DB Li BT Connell LC Schindler K Lacouture M Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies Ann Oncol 2015 26 (12) 2375 91 26371282\n9 Wang DY Salem JE Cohen JV Chandra S Menzer C Ye F Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis JAMA Oncol 2018 4 (12) 1721 8 30242316\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "14(3)",
"journal": "Case reports in oncology",
"keywords": "Immune checkpoint inhibitor; Non-small cell lung cancer; Pathological complete response; Pembrolizumab; Pulmonary hypertrophic osteoarthropathy",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "1380-1386",
"pmc": null,
"pmid": "34720945",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "30280635;24384493;20453688;31990617;26371282;24585722;15914534;30620668;30242316",
"title": "A Case of Lung Adenocarcinoma with Pulmonary Hypertrophic Osteoarthropathy Showing Pathological Complete Response to a Pembrolizumab-Containing Chemoimmunotherapy.",
"title_normalized": "a case of lung adenocarcinoma with pulmonary hypertrophic osteoarthropathy showing pathological complete response to a pembrolizumab containing chemoimmunotherapy"
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"abstract": "Objective: Neuroleptic malignant syndrome (NMS) is a rare but severe side effect of antipsychotic medication. Neutrophil-lymphocyte ratio (NLR) is a simple marker used to measure systemic inflammation. Method : In this case report we explore the relationship of inflammation in the etiology of NMS. In our case involving NMS, although there was no leukocytosis, the NLR was increased up to systemic infection levels. Conclusion: We hypothesized that systemic inflammation may take a role in developing NMS. If so, NLR could be a new marker of NMS that may be able to provide more sensitive results than leukocyte levels.",
"affiliations": "Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, Virginia, United States of America.;Department of Psychiatry, Bakırköy Mental Health Research and Teaching Hospital, Istanbul, Turkey.;Department of Psychiatry, Bakırköy Mental Health Research and Teaching Hospital, Istanbul, Turkey.;Department of Psychiatry, Bakırköy Mental Health Research and Teaching Hospital, Istanbul, Turkey.;Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, Virginia, United States of America.",
"authors": "Kalelioglu|Tevfik|T|;Celikel|Guler|G|;Balaban|Ozlem Devrim|OD|;Karamustafalioglu|Nesrin|N|;Penberthy|Jennifer Kim|JK|",
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"doi": "10.18502/ijps.v16i3.6264",
"fulltext": "\n==== Front\nIran J Psychiatry\nIran J Psychiatry\nIJPS\nIranian Journal of Psychiatry\n1735-4587\n2008-2215\nPsychiatry & Psychology Research Center, Tehran University of Medical Sciences Tehran, Iran\n\n10.18502/ijps.v16i3.6264\nIJPS-16-370\nCase Report\nCan Neutrophil-Lymphocyte Ratio Be a Useful Criterion for Neuroleptic Malignant Syndrome in the Absence of Leukocytosis?\nKalelioglu Tevfik 1*\nCelikel Guler 2\nBalaban Ozlem Devrim 2\nKaramustafalioglu Nesrin 2\nPenberthy Jennifer Kim 1\n1 Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, Virginia, United States of America.\n2 Department of Psychiatry, Bakırköy Mental Health Research and Teaching Hospital, Istanbul, Turkey.\n* Corresponding Author: Address: Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, Virginia, United States of America, Postal Code: 22903. Tel: 90-544834 6643, Email: tevfikkaleli@hotmail.com\n7 2021\n16 3 370373\n23 4 2019\n14 2 2021\n9 3 2021\nCopyright © 2021 Tehran University of Medical Sciences. Published by Tehran University of Medical Sciences.\nhttps://creativecommons.org/licenses/by-nc/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International license (https://creativecommons.org/licenses/by-nc/4.0/). Non-commercial uses of the work are permitted, provided the original work is properly cited.\nObjective: Neuroleptic malignant syndrome (NMS) is a rare but severe side effect of antipsychotic medication. Neutrophil-lymphocyte ratio (NLR) is a simple marker used to measure systemic inflammation.\n\nMethod: In this case report we explore the relationship of inflammation in the etiology of NMS. In our case involving NMS, although there was no leukocytosis, the NLR was increased up to systemic infection levels.\n\nConclusion: We hypothesized that systemic inflammation may take a role in developing NMS. If so, NLR could be a new marker of NMS that may be able to provide more sensitive results than leukocyte levels.\n\nKey Words\n\nAntipsychotic Agents\nInflammation\nLymphocyte\nNeuroleptic Malignant Syndrome\nNeutrophil\n==== Body\npmcNeuroleptic malignant syndrome (NMS) is a severe side effect of antipsychotic medication. Although mechanisms underlying NMS are not fully understood, hypodopaminergic state has been proposed as a potential triggering factor. The main symptoms of NMS are hyperthermia, muscle rigidity, autonomic imbalance, and changes in consciousness after initiation of antipsychotic treatment (1).\n\nLaboratory findings of NMS may include increased levels of creatinine phosphokinase (CPK), leukocyte, and liver enzymes. About 40% of cases demonstrate increase in leukocyte levels (2). In our case report we aimed to discuss the role of inflammation in NMS and the usefulness of neutrophil to lymphocyte ratio (NLR) as a potential criteria to utilize, even in the absence of leukocytosis.\n\nCase Report\n\nA 30-year-old woman with a 17-year history of bipolar affective disorder was transferred to acute care psychiatry service with acute exacerbation of symptoms of manic episode. She had no previous medical or substance abuse history. Before hospitalization, zuclopenthixol acuphase 50 mg IM, haloperidole 10 mg IM, biperiden five mg IM., chlorpromazine 100 mg IM. were applied as needed because of affective elevation at another hospital. At admission, the patient received treatment with clozapine 800 mg/day, amisulpirid 800 mg/day, and chlorpromazine 200 mg/day. She was treated with haloperidol 20 mg/day IM, and biperiden 10 mg/day IM. The dose of clozapine, chlorpromazine, and valproat were diminished gradually and amisulpride was stopped.\n\nOn the seventh day of hospitalization, the patient developed rigidity, tremor and incontinence without fever. Haloperidol was stopped for probability of NMS, and ECT was initiated on the eighth day of hospitalization. On day 11 and 12 of hospitalization, haloperidol IM was used for acute agitation. Rigidity, confusion, diaphoresis, tremor, tachycardia, and incontinence occurred at the following day. The patient’s temperature was 36.3 C°, heart rate was 110 per minute, respiratory rate was 15 to-20 per minute, blood pressure fluctuated between 90/70 and 110/70 mm/hg, and oxygen saturation was 97%. Laboratory findings revealed increased levels of CPK (> 2000 IU/L; normal range= 20-200), aspartate aminotransferase (AST) (188 U/L; normal range= 5-45), alanine transaminase (ALT) (66 U/L, normal range= 5-40), lactate dehydrogenase (LDH) (581 IU/L; normal range = 60-200), C-reactive protein (CRP) (1.84 mg/dL; normal range= 0-0.5), and erythrocyte sedimentation rate (ESR) (44 mm/hour; normal range= 0-20). Leukocyte count (6.35 103/µL; normal range= 4.1-11.2) was in normal range. Neuroimaging, EEG (electroencephalogram), and chest x-ray imaging showed no abnormalities. Urinalysis and thyroid hormones were in normal range. There was no focus for infection (pulmonary, urinary etc).\n\nOn day 19, a confusional state developed and by day 20 of the hospitalization, bromocriptin 5mg/day was initiated with the diagnosis of NMS according to DSM-5 (Diagnostic and Statistical Manual of Mental Disorders). On the 29th day of admission, all symptoms of NMS disappeared. Antipsychotic treatment was initiated with clozapine 12.5 mg/day because of agitation. The patient developed rigidity as cogwheel sign, dystonia, altered mental status, and autonomic dysregulation after 6 days of clozapine initiation and was admitted to the intensive care unit on the 37th day of admission. After 6 days of hospitalization in intensive care unit, she was transferred back to psychiatry service. On the 43th day of hospitalization, the patient’s bromocriptine was elevated to 10 mg/day to address rigidity and dystonia. At the 57th day, no symptom of NMS were observed (nearest NLR value mesasured on the 62nd day). The patient's informed consent was provided for the publication of this case presentation.\n\nDiscussion\n\nPrevious case reports suggest an association between systemic inflammatory response and developing NMS (3, 4). Increased levels of acute phase reactants such as α-1 antichymotrypsin and fibrinogen, elevated ESR, C-reactive protein, and IL-6 cytokine levels, decreased negative acute phase reactants as albumin, serum Fe indicate that an inflammatory reaction occurs in NMS (3, 4). Based on these findings, Anglin et al. (2010) speculate that there may be a neuroimmunological involvement in these cases. The authors argue that NMS and acute phase response have common findings of fever, tachycardia, diaphoresis, unstable blood pressure, tissue injury, altered consciousness, and leukocytosis (5).\n\nThe NLR is a relatively new and simple marker used to measure systemic inflammation (6). In previous studies, mean NLR levels of neuropsychiatric illness were reported in bipolar disorder manic episode as 3.09 ±1.9 (7), 2.8±1.67 (8), in euthymic episode as 2.8 ± 0.81 (7), and in schizophrenia as 2.6 ± 1.1 (9). NLR is a relatively new marker for psychiatric disorders; thus, no cut-off level or disease-specific values have been identified.\n\nA recent study, investigating the NLR values in healthy adults has shown that NLR has ranged from 0.78 to 3.53 (10). In another study conducted by Gurol et al. (11), NLR levels in a healthy group were 4.19 ± 4.36, a group with local infection had findings of 5.68 ± 8.99, and findings for systemic infection were 11.78 ± 14.04, with additional findings for sepsis as13.16 ± 6.38, and septic shock as 16.87 ± 9.55. The authors recommend a cut-off NLR value <5 for healthy group. Increasing levels of NLR indicates different levels of infections such as local infection (5 to 10), systemic infection (10 to 13), sepsis (13 to 15), and septic shock (≥15). (11) This study aimed to make a comparison and better understanding of NLR findings. In a recent study, it has been suggested that NLR levels above 4 may be useful for diagnosing NMS (12). In our case, the patient’s NLR level was above 9 at the time of NMS diagnosis before initiation of NMS treatment. We did not observe fever and leukocytosis during hospitalization. Although leukocyte levels were in a normal range, NLR levels were nearly as high as those found at a systemic infection level. In addition, the NMS development after starting clozapine showed a NLR level of >5, which is between the cut-off level of local infection levels. Strikingly, in our case we observed a connection between NMS treatment and NLR levels. Leukocyte, neutrophil, lymphocyte counts and NLR levels during hospitalization are presented in Table 1.\n\nTable 1 Laboratory Follow Up during Hospitalization\n\nDay of hospitalization\tClinical Status and Treatment\tWBC\n(103/µL)\tNEU\n(103/µL)\tLYM\n(103/µL)\tNLR\t\nDay 1\t-Clozapine 600 mg/day↓, valproat↓,\nclorpromazine 100mg/day↓,\namisulpirid stopped,\n-Haloperidol 20 mg/day IM. And biperiden 10 mg/day IM.\ninitiated\t\t\t\t\t\nDay 2\t-Clorpromazine 300 mg/day ↑\t\t\t\t\t\nDay 7\t-Rigidity, tremor, neck dystonia, incontinence (+)\n-Fever (-)\n-Haloperidol IM. stopped\t6.35\t5.13\t0.52\t9.73\t\nDay 8\t-Valproat stopped\n-ECT initiated\t\t\t\t\t\nDay 11-12\t-Haloperidol IM (p.r.n)\t\t\t\t\t\nDay 13\t-Rigidity, CPK↑, confusion, diaphoresis, tremor,\ntachycardia, incontinence (+)\n-Fever (-)\n-All medication stopped\n-i.v. hydration\t5.86\t4.62\t0.50\t9.13\t\nDay 15-19\t-i.v. hydration + biperiden\n-Bromocriptine was initially held because of differential\ndiagnosis\t4.93\n4.45\t3.88\n3.10\t0.49\n0.69\t7.88\n4.44\t\nDay 19\t-Confusion(+++)\t5.64\t4.60\t0.46\t9.82\t\nDay 20\t-Bromocriptin 5 mg/day initiated\n-Broncospasm(+)\t4.85\t3.82\t0.49\t7.66\t\nDay 24\t\t3.44\t2.60\t0.37\t7.01\t\nDay 26\t\t4.54\t3.36\t0.70\t4.74\t\nDay 29\t-No symptom of NMS\n-Excitation\n-Clozapine 12.5 mg/day initiated\t5.59\t3.93\t1.08\t3.63\t\nDay 33\t-Clozapine 50 mg/day\n-Dystonia at neck-biperiden i.m.\t\t\t\t\t\nDay 34\t-Rigidity, dystonia, cogwheel sign, altered mental status\n(+), autonomic dysregulation\n-Fever (-)\n-Clozapine stopped, i.v hydration\t5.1\t3.89\t0.71\t5.47\t\nDay 37\t-Confusion to stupor progression, vomiting, autonomic\ndysregulation\n-Transferred to intensive care unit.\t\t\t\t\t\nDay 37-42\t-Bromocriptine 5 mg/day, i.v. hydration\t3.86\n3.35\n4.38\t2.45\n2.27\n3.13\t0.95\n0.64\n0.66\t2.57\n3.50\n4.72\t\nDay 42\t-Interned to psychiatry service\t\t\t\t\t\nDay 43\t-Rigidity, dystonia, cogwheel sign (+)\n-Fever (-)\n-Bromocriptine 10 mg/day↑\t\t\t\t\t\nDay 51\t\t4.27\t2.98\t0.72\t4.1\t\nDay53\t-Added lorazepam for excitation\t\t\t\t\t\nDay 55\t-ECT was stopped at 15th session\t\t\t\t\t\nDay 57\t-No symptoms of NMS\n-Bromocriptine 2.5 mg/day ↓\t\t\t\t\t\nDay 62\t\t3.85\t2.81\t0.70\t3.96\t\nDay 75\t\t3.92\t2.65\t0.67\t3.95\t\nDay 82\t\t3.99\t2.74\t0.83\t3.30\t\nWBC; white blood cell, NEU; Neutrophil, LYM; Lymphocyte, NLR; Neutrophil-lymphocyte ratio.\n\nLimitation\n\nMethodologically, it is difficult to perform a clinical study regarding the relationship between inflammatory markers and NMS because of the rarity of cases and difficulties in storing blood specimens. It may be insufficient to support our hypothesis over one case.\n\nConclusion\n\nIn our case NLR level was as high as systemic infection levels, even though with the absence of leukocytosis. In our opinion, NLR could be a new criterion of NMS which would allow for more sensitive findings than leukocyte levels alone. Further studies are needed to support our hypothesis. Specifically, we propose that NLR may be a useful choice for a prospective study to test the neuro-inflammation hypothesis of NMS.\n\nAcknowledgment\n\nNone.\n\nConflict of Interest\n\nNone.\n==== Refs\nReferences\n\n1 Ananth J Aduri K Parameswaran S Gunatilake S Neuroleptic malignant syndrome: risk factors, pathophysiology, and treatment Acta Neuropsychiatr 2004 16 4 219 28 26984310\n2 Jahan MS Farooque AI Wahid Z Neuroleptic malignant syndrome J Natl Med Assoc 1992 84 11 966 70 1460685\n3 Rosebush PI Mazurek MF Serum iron and neuroleptic malignant syndrome Lancet 1991 338 149 51 1677067\n4 Rosebush PI Anglin RE Richards C Mazurek MF Neuroleptic malignant syndrome and the acute phase response J Clin Psychopharmacol 2008 28 4 459 61 18626278\n5 Anglin RE Rosebush PI Mazurek MF Neuroleptic malignant syndrome: a neuroimmunologic hypothesis Cmaj 2010 182 18 E834 8 20696799\n6 Zahorec R Ratio of neutrophil to lymphocyte counts--rapid and simple parameter of systemic inflammation and stress in critically ill Bratisl Lek Listy 2001 102 1 5 14 11723675\n7 Kalelioglu T Akkus M Karamustafalioglu N Genc A Genc ES Cansiz A Neutrophil-lymphocyte and platelet-lymphocyte ratios as inflammation markers for bipolar disorder Psychiatry Res 2015 228 3 925 7 26154814\n8 Mert DG Terzi H Mean platelet volume in bipolar disorder: the search for an ideal biomarker Neuropsychiatr Dis Treat 2016 12 2057 62 27578978\n9 Semiz M Yildirim O Canan F Demir S Hasbek E Tuman TC Elevated neutrophil/lymphocyte ratio in patients with schizophrenia Psychiatr Danub 2014 26 3 220 5 25191768\n10 Forget P Khalifa C Defour JP Latinne D Van Pel MC De Kock M What is the normal value of the neutrophil-to-lymphocyte ratio? BMC Res Notes 2017 10 1 12 28057051\n11 Gürol G Çiftci İ H Terizi HA Atasoy AR Ozbek A Köroğlu M Are there standardized cutoff values for neutrophil-lymphocyte ratios in bacteremia or sepsis? J Microbiol Biotechnol 2015 25 4 521 5 25341467\n12 Karamustafalioglu N Kalelioglu T Celikel G Genc A Emul M Clinical utility of neutrophil-lymphocyte ratio in the diagnosis of neuroleptic malignant syndrome Nord J Psychiatry 2019 73 4-5 288 92 31164025\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1735-4587",
"issue": "16(3)",
"journal": "Iranian journal of psychiatry",
"keywords": "Antipsychotic Agents; Inflammation; Lymphocyte; Neuroleptic Malignant Syndrome; Neutrophil ",
"medline_ta": "Iran J Psychiatry",
"mesh_terms": null,
"nlm_unique_id": "101302041",
"other_id": null,
"pages": "370-373",
"pmc": null,
"pmid": "34616472",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports",
"references": "28057051;1460685;18626278;25341467;26984310;27578978;11723675;20696799;31164025;26154814;25191768;1677067",
"title": "Can Neutrophil-Lymphocyte Ratio Be a Useful Criterion for Neuroleptic Malignant Syndrome in the Absence of Leukocytosis?",
"title_normalized": "can neutrophil lymphocyte ratio be a useful criterion for neuroleptic malignant syndrome in the absence of leukocytosis"
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"activesubstancename": "CHLORPROMAZINE HYDROCHLORIDE"
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"abstract": "METHODS\nThis is a case report.\n\n\nMETHODS\nThe setting is at a postoperative recovery area.\n\n\nMETHODS\nA 52-year-old woman with a history of migraine with unilateral motor symptoms developed hemiparesis after undergoing general anesthesia for total thyroidectomy.\n\n\nMETHODS\nNo interventions were performed.\n\n\nRESULTS\nHead computed tomography and magnetic resonance imaging were normal. Laboratory studies including basic metabolic panel and complete blood count were also within normal limits.\n\n\nCONCLUSIONS\nGeneral anesthesia may be a trigger for hemiplegic migraine syndromes; however, it behooves the practitioner to rule out acute neurologic and metabolic events before making this diagnosis.",
"affiliations": "Department of Anesthesiology and Critical Care, Hospital of the University of Pennsylvania, University of Pennsylvania Health System, 3400 Spruce St, Philadelphia, PA 19104. Electronic address: Rachel.hadler@uphs.upenn.edu.;Department of Anesthesiology and Critical Care, Hospital of the University of Pennsylvania, University of Pennsylvania Health System, 3400 Spruce St, Philadelphia, PA 19104.;Department of Anesthesiology and Critical Care, Hospital of the University of Pennsylvania, University of Pennsylvania Health System, 3400 Spruce St, Philadelphia, PA 19104.;Department of Anesthesiology and Critical Care, Hospital of the University of Pennsylvania, University of Pennsylvania Health System, 3400 Spruce St, Philadelphia, PA 19104.;Department of Anesthesiology and Critical Care, Hospital of the University of Pennsylvania, University of Pennsylvania Health System, 3400 Spruce St, Philadelphia, PA 19104.",
"authors": "Hadler|Rachel A|RA|;Schiffman|Joshua M|JM|;Augoustides|John G|JG|;Liu|Renyu|R|;Chen|Linda|L|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0952-8180",
"issue": "31()",
"journal": "Journal of clinical anesthesia",
"keywords": "Anesthesia, general; Disease management; Headache; Migraine disorders; Perioperative period",
"medline_ta": "J Clin Anesth",
"mesh_terms": "D000768:Anesthesia, General; D005260:Female; D006801:Humans; D008875:Middle Aged; D008881:Migraine Disorders; D010291:Paresis; D011183:Postoperative Complications; D013965:Thyroidectomy",
"nlm_unique_id": "8812166",
"other_id": null,
"pages": "142-4",
"pmc": null,
"pmid": "27185697",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hemiparesis after general anesthesia in a patient with migraine with unilateral motor symptoms.",
"title_normalized": "hemiparesis after general anesthesia in a patient with migraine with unilateral motor symptoms"
} | [
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"companynumb": "US-PURDUE PHARMA-GBR-2016-0036172",
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"activesubstancename": "LIDOCAINE"
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"abstract": "Enzalutamide, an androgen receptor antagonist, is a standard drug for the treatment of castrationresistant prostate cancer. A 77-year-old man developed a seizure after administration of enzalutamide. The patient presented with general fatigue and high fever approximately 5 weeks after oral administration of enzalutamide. Several days later, a seizure attack occurred at home, resulting in cardiopulmonary arrest. The patient was taken to the hospital emergency room but could not be resuscitated. We described a 63-year-old man who was diagnosed with clinical T1c prostate cancer, with a Gleason score of 6 (3＋3), and a preoperative prostate-specific antigen (PSA) level of 5. 27 ng/ml. Radical prostatectomy(RP) was performed and final pathologyshowed Gleason score 3＋4, pT2c with negative surgical margin. In spite of suggested surgical radicality, PSA was 3.32, 4.78, 5.93 ng/ml, at 1, 2, and 3 months after RP, respectively. However, radiological investigation revealed no metastasis. Because of this clinical discrepancy, we checked the PSA-α1-antichemotrypsin level and found it to be ≦0.1 ng/ml. From these results, false PSA elevation caused byinterference of positive heterophilic antibodies was suggested and demonstrated byseveral immunoassays.",
"affiliations": "The Department of Urology, Higashiosaka City Medical Center.;The Department of Urology, Higashiosaka City Medical Center.;The Department of Urology, Higashiosaka City Medical Center.;The Department of Urology, Higashiosaka City Medical Center.;The Department of Urology, Higashiosaka City Medical Center.;The Department of Urology, Higashiosaka City Medical Center.",
"authors": "Iwanishi|Toshichika|T|;Yumiba|Satoru|S|;Koida|Youhei|Y|;Kobayashi|Masao|M|;Komori|Kazuhiko|K|;Ono|Yutaka|Y|",
"chemical_list": "D001549:Benzamides; D009570:Nitriles; D010669:Phenylthiohydantoin; C540278:enzalutamide",
"country": "Japan",
"delete": false,
"doi": "10.14989/ActaUrolJap_63_10_431",
"fulltext": null,
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"issn_linking": "0018-1994",
"issue": "63(10)",
"journal": "Hinyokika kiyo. Acta urologica Japonica",
"keywords": "Prostate cancer; Seizure",
"medline_ta": "Hinyokika Kiyo",
"mesh_terms": "D000368:Aged; D001549:Benzamides; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D009570:Nitriles; D010669:Phenylthiohydantoin; D064129:Prostatic Neoplasms, Castration-Resistant; D012640:Seizures",
"nlm_unique_id": "0421145",
"other_id": null,
"pages": "431-433",
"pmc": null,
"pmid": "29103258",
"pubdate": "2017-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "A Case of Castration-Resistant Prostate Cancer with Fatal Convulsive Seizure after Administration of Enzalutamide.",
"title_normalized": "a case of castration resistant prostate cancer with fatal convulsive seizure after administration of enzalutamide"
} | [
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"companynumb": "JP-MYLANLABS-2018M1011648",
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"activesubstancename": "FERRIC SODIUM CITRATE"
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"abstract": "Fusarium species are ubiquitously present in environment and are well known as human pathogens with high mortality rate in immunocompromised patients. We report here two cases where immunocompromised patients developed fatal bloodstream infections by this organism. Isolates were further identified by ITS1 region sequencing which confirmed them as Fusarium solani. Antifungal susceptibility testing was done following CLSI M38-A2 guidelines to amphotericin B, fluconazole, itraconazole, voriconazole, posaconazole, caspofungin, and micafungin. Both patients had a fatal outcome and expired of septic shock. Therefore, identification up to species level is of utmost importance as that helps in directing the management of the patient thereby leading to a favourable outcome.",
"affiliations": "Department of Microbiology, All India Institute of Medical Sciences (AIIMS), New Delhi, India.;Department of Medical Oncology, BRA-IRCH, All India Institute of Medical Sciences (AIIMS), New Delhi, India.;Department of Microbiology, All India Institute of Medical Sciences (AIIMS), New Delhi, India. immaxess@gmail.com.",
"authors": "Dabas|Yubhisha|Y|;Bakhshi|Sameer|S|;Xess|Immaculata|I|",
"chemical_list": "D000935:Antifungal Agents; D021901:DNA, Intergenic; D000666:Amphotericin B; D015725:Fluconazole",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s11046-015-9960-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-486X",
"issue": "181(3-4)",
"journal": "Mycopathologia",
"keywords": "Antifungal susceptibility testing; Bloodstream infection; Fusarium solani; ITS1 DNA sequencing; India",
"medline_ta": "Mycopathologia",
"mesh_terms": "D000293:Adolescent; D000368:Aged; D000666:Amphotericin B; D000935:Antifungal Agents; D001483:Base Sequence; D021901:DNA, Intergenic; D015725:Fluconazole; D016469:Fungemia; D060585:Fusariosis; D005670:Fusarium; D006801:Humans; D016867:Immunocompromised Host; D007194:India; D008297:Male; D008826:Microbial Sensitivity Tests; D017422:Sequence Analysis, DNA; D012772:Shock, Septic",
"nlm_unique_id": "7505689",
"other_id": null,
"pages": "291-6",
"pmc": null,
"pmid": "26541869",
"pubdate": "2016-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "9071840;16207996;12234865;12872351;17934079;10759712;17058254;16772406;20161440;26407418;23703243;14532255;16619151;16495251;22205818;15545866;21482725;21777412;22659590;15956243;14648020;12627286;12354880;23935636;25253233;21177404;19665409;25234793;21200188;25210666;23076561;23762675",
"title": "Fatal Cases of Bloodstream Infection by Fusarium solani and Review of Published Literature.",
"title_normalized": "fatal cases of bloodstream infection by fusarium solani and review of published literature"
} | [
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"activesubstancename": "AMPHOTERICIN B"
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... |
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"abstract": "Diffuse melanosis cutis (DMC) is a rare presentation of metastatic melanoma associated with a particularly guarded prognosis. We report a case of a 35-year-old man with BRAF(V600E) metastatic melanoma treated with dabrafenib (as well as ipilimumab and whole brain radiotherapy), who is alive, 25 months after the onset of his DMC. This is significantly longer than the reported mean survival of 4 months, highlighting the importance of BRAF mutation testing and the promising survival advantage of using targeted therapies compared with conventional chemotherapeutic regimens.",
"affiliations": "Department of Dermatology, Westmead Hospital, Westmead, New South Wales, Australia.",
"authors": "Minocha|Rashi|R|;Kefford|Richard|R|;Uribe|Pablo|P|;Sebaratnam|Deshan F|DF|;Fernández-Peñas|Pablo|P|",
"chemical_list": "D000911:Antibodies, Monoclonal; D007093:Imidazoles; D000074324:Ipilimumab; D010091:Oximes; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib",
"country": "Australia",
"delete": false,
"doi": "10.1111/ajd.12187",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0004-8380",
"issue": "56(2)",
"journal": "The Australasian journal of dermatology",
"keywords": "BRAF; case; cutis; diffuse; melanosis; mutation; positive; therapy; treatment",
"medline_ta": "Australas J Dermatol",
"mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D001932:Brain Neoplasms; D006801:Humans; D007093:Imidazoles; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma; D008548:Melanosis; D058990:Molecular Targeted Therapy; D009154:Mutation; D010091:Oximes; D048493:Proto-Oncogene Proteins B-raf; D012878:Skin Neoplasms",
"nlm_unique_id": "0135232",
"other_id": null,
"pages": "128-30",
"pmc": null,
"pmid": "25159853",
"pubdate": "2015-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Diffuse melanosis cutis in the setting of BRAF(V600E) mutant melanoma and treatment with targeted therapies.",
"title_normalized": "diffuse melanosis cutis in the setting of braf v600e mutant melanoma and treatment with targeted therapies"
} | [
{
"companynumb": "PHHY2015AU163405",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IPILIMUMAB"
},
"drugadditional": null,
"drug... |
{
"abstract": "BACKGROUND\nWe report 2 cases of medulloblastoma maturing into gangliocytoma after receiving multimodal therapy. Here we present 2 cases of diagnosed medulloblastoma which on re-resection were noted to be gangliocytoma without heterogeneity, which is an extremely rare occurrence.\n\n\nMETHODS\nThe first patient, an 11-year-old boy diagnosed with high-risk (non-WNT, non-SHH) medulloblastoma, was treated with near-total surgical resection followed by craniospinal radiation therapy with weekly vincristine. He then received maintenance chemotherapy with vincristine, cyclophosphamide, and cisplatin. On surveillance MR imaging studies residual tumor in the lateral aspect of the tumor bed was noted to be slowly growing, eliciting gross-total resection of the residual tumor. Histopathology showed benign gangliocytoma without residual medulloblastoma. The second patient, a 3-year-old girl, was diagnosed with medulloblastoma, desmoplastic nodular variant. She was initially treated with gross total resection and chemotherapy with etoposide, carboplatin, and high-dose methotrexate. At 4 months off therapy, she was noted to have local recurrence along the resection cavity. Second-line therapy was started with irinotecan and temozolomide, but MRI assessment during treatment showed further disease progression. She then received craniospinal radiation. Eleven months off therapy, further radiographic progression was noted, and the patient underwent second-look surgery, with pathology showing gangliocytoma and treatment-related gliosis.\n\n\nCONCLUSIONS\nThe maturation of medulloblastoma into a ganglion cell-rich lesion is very rare, with few well-characterized previous reports. Given the rare nature of this entity, it would be of great value to understand the process of posttreatment maturation and the genetic and treatment factors which contribute to this phenomenon.",
"affiliations": "Department of Neurosurgery, The University of Texas Health Science Center at Houston, Houston, Texas, USA.;Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Pathology, The University of Texas Health Science Center at Houston, Houston, Texas, USA.;Department of Pathology, The University of Texas Health Science Center at Houston, Houston, Texas, USA.;Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Pediatric Surgery, Division of Pediatric Neurosurgery, The University of Texas Health Science Center at Houston, Houston, Texas, USA.;Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Pediatric Surgery, Division of Pediatric Neurosurgery, The University of Texas Health Science Center at Houston, Houston, Texas, USA, David.I.Sandberg@uth.tmc.edu.",
"authors": "Mullarkey|Matthew P|MP|;Nehme|Grace|G|;Mohiuddin|Sana|S|;Ballester|Leomar Y|LY|;Bhattacharjee|Meenakshi B|MB|;Trivedi|Darshan|D|;Shah|Manish N|MN|;Fuller|Gregory N|GN|;Zaky|Wafik|W|;Sandberg|David I|DI|",
"chemical_list": "D014750:Vincristine",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000509520",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1016-2291",
"issue": "55(4)",
"journal": "Pediatric neurosurgery",
"keywords": "Gangliocytoma; Maturation; Medulloblastoma",
"medline_ta": "Pediatr Neurosurg",
"mesh_terms": "D002528:Cerebellar Neoplasms; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D005260:Female; D005729:Ganglioneuroma; D006801:Humans; D008297:Male; D008527:Medulloblastoma; D009364:Neoplasm Recurrence, Local; D014750:Vincristine",
"nlm_unique_id": "9114967",
"other_id": null,
"pages": "222-231",
"pmc": null,
"pmid": "32882694",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Posttreatment Maturation of Medulloblastoma into Gangliocytoma: Report of 2 Cases.",
"title_normalized": "posttreatment maturation of medulloblastoma into gangliocytoma report of 2 cases"
} | [
{
"companynumb": "US-TEVA-2020-US-1865138",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "Docetaxel is a taxane, which is a class of chemotherapy agent used in the treatment of multiple malignancies. It is known to have gastrointestinal side effects which can range from mild symptoms such as nausea and diarrhea to more severe complications such as neutropenic enterocolitis. In the current literature, taxanes have not been described to cause upper gastrointestinal bleeding and melena. Here, we present a case of a 54-year-old woman with breast cancer who developed dizziness, fatigue, and melena after receiving chemotherapy. Esophagogastroduodenoscopy revealed diffuse gastric erosions as well as ulceration and linear superficial lesions in the duodenum; biopsies from these sites showed taxane-induced toxicity. Her bleeding resolved with medical therapy and subsequent removal of docetaxel from her chemotherapy regimen. This case identifies upper gastrointestinal bleeding as a previously undescribed side effect of docetaxel therapy. Recent docetaxel use should be included in the differential diagnosis for upper gastrointestinal bleed, and diagnosis should lead to consideration of cessation of docetaxel or substitution with another chemotherapeutic agent.",
"affiliations": "Department of Internal Medicine, University of Southern California ‒ Internal Medicine Residency, Los Angeles, California, USA.;Department of Internal Medicine, University of Southern California ‒ Internal Medicine Residency, Los Angeles, California, USA.;Division of Gastrointestinal and Liver Disease, Department of Internal Medicine, University of Southern California ‒ Keck School of Medicine, Los Angeles, California, USA.;Department of Pathology, University of Southern California ‒ Keck School of Medicine, Los Angeles, California, USA.;Department of Pathology, University of Southern California ‒ Keck School of Medicine, Los Angeles, California, USA.;Division of Oncology, Department of Internal Medicine, University of Southern California ‒ Keck School of Medicine, Los Angeles, California, USA.;Division of Gastrointestinal and Liver Disease, Department of Internal Medicine, University of Southern California ‒ Keck School of Medicine, Los Angeles, California, USA.",
"authors": "Liu|Yao|Y|;Hiramoto|Brent|B|;Kwok|Janet|J|;Ibrahim|Ahmad|A|;Tatishchev|Sergei|S|;Kang|Irene|I|;Modi|Rushabh|R|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000517818",
"fulltext": "\n==== Front\nCase Rep Oncol\nCase Rep Oncol\nCRO\nCase Reports in Oncology\n1662-6575\nS. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com\n\n10.1159/000517818\ncro-0014-1373\nCase Report\nTaxane-Induced Upper Gastrointestinal Bleeding\nLiu Yao a *\nHiramoto Brent a\nKwok Janet b\nIbrahim Ahmad c\nTatishchev Sergei c\nKang Irene d\nModi Rushabh b\naDepartment of Internal Medicine, University of Southern California ‒ Internal Medicine Residency, Los Angeles, California, USA\nbDivision of Gastrointestinal and Liver Disease, Department of Internal Medicine, University of Southern California ‒ Keck School of Medicine, Los Angeles, California, USA\ncDepartment of Pathology, University of Southern California ‒ Keck School of Medicine, Los Angeles, California, USA\ndDivision of Oncology, Department of Internal Medicine, University of Southern California ‒ Keck School of Medicine, Los Angeles, California, USA\n*Yao Liu, yaoliu90@gmail.com\nSep-Dec 2021\n21 9 2021\n21 9 2021\n14 3 13731379\n17 5 2021\n9 6 2021\n2021\nCopyright © 2021 by S. Karger AG, Basel\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This 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.\nDocetaxel is a taxane, which is a class of chemotherapy agent used in the treatment of multiple malignancies. It is known to have gastrointestinal side effects which can range from mild symptoms such as nausea and diarrhea to more severe complications such as neutropenic enterocolitis. In the current literature, taxanes have not been described to cause upper gastrointestinal bleeding and melena. Here, we present a case of a 54-year-old woman with breast cancer who developed dizziness, fatigue, and melena after receiving chemotherapy. Esophagogastroduodenoscopy revealed diffuse gastric erosions as well as ulceration and linear superficial lesions in the duodenum; biopsies from these sites showed taxane-induced toxicity. Her bleeding resolved with medical therapy and subsequent removal of docetaxel from her chemotherapy regimen. This case identifies upper gastrointestinal bleeding as a previously undescribed side effect of docetaxel therapy. Recent docetaxel use should be included in the differential diagnosis for upper gastrointestinal bleed, and diagnosis should lead to consideration of cessation of docetaxel or substitution with another chemotherapeutic agent.\n\nKeywords\n\nGastrointestinal bleed\nChemotherapy\nBreast cancer\nTaxane\n==== Body\npmcBackground\n\nTaxanes are chemotherapeutic agents whose use is widespread in treating malignancies of the esophagus, stomach, breast, lung, bladder, prostate, and ovary. The gastrointestinal toxicities commonly associated with taxane therapy include nausea, vomiting, mucositis, and diarrhea. Rarely, lower gastrointestinal bleeding and colonic perforation secondary to neutropenic enterocolitis and ischemic colitis have both been reported as complications of taxane-based chemotherapy [3]. Here, we present a case of upper gastrointestinal bleeding secondary to taxane toxicity diffusely involving the stomach and the second portion of the duodenum in the absence of neutropenia. To the best of our knowledge, this complication has not been previously reported to be associated with taxane toxicity in the literature.\n\nCase Report\n\nA 54-year-old woman with recently diagnosed early-stage breast invasive ductal carcinoma presents with recurrent episodes of melena following her chemotherapy infusions. She was diagnosed after a routine mammogram picked up microcalcifications in her right breast, and subsequent biopsy revealed invasive ductal carcinoma which was estrogen receptor positive, progesterone receptor positive, and human epidermal growth factor receptor 2 positive. She was initiated on the chemotherapy regimen of docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) planned every 3 weeks for 6 cycles; she additionally received dexamethasone for premedication and granulocyte colony stimulating factor to reduce the risk of developing febrile neutropenia. She initially tolerated her first cycle well but developed persistent diarrhea 7 days after her first infusion. Five days later, she developed melenic diarrhea that was associated with dizziness for which she presented to a local emergency department; she denied any vomiting, fevers, chills, or abdominal pain during this time. Her medical history was negative for peptic ulcer disease and alcohol abuse. However, she had been intermittently taking ibuprofen for the past 3 months, which had increased recently to approximately 400 mg of ibuprofen a day. On admission, she was afebrile and normotensive, and her abdominal exam was negative for any tenderness, but her hemoglobin was noted to drop from 11.7 g/dL to 8.4 g/dL (reference range 12.0 g/dL–15.5 g/dL) in the first 18 h of her inpatient stay. Her white blood cell count was elevated to 17.5 × 103 cells/mcL (reference range 4.1 × 103 cells/mcL–10.9 × 103 cells/mcL) with a neutrophilic predominance. The patient had been started on intravenous proton-pump inhibitor (PPI) therapy at 40 mg twice a day empirically in the emergency department, and she underwent inpatient esophagogastroduodenoscopy which revealed a nonbleeding post-bulbar ulcer in the duodenum. The ulcer was subsequently biopsied and was negative for H. pylori. Her melena resolved by hospital day 2 and was discharged on oral PPI therapy. She stopped taking NSAIDs, and she remained asymptomatic aside from developing some alopecia until her second cycle of TCHP chemotherapy.\n\nLess than 24 h after her second chemotherapy infusion, she had several episodes of black stools that were initially well formed in consistency that progressively became loose and concurrently experienced dizziness and palpitations; she did not experience any abdominal pain, nausea, nor did she have any emesis. She was compliant with her PPI therapy since discharge. She was then directly admitted to our hospital, where physical exam was notable for conjunctival pallor and frank melena on digital rectal exam, but her abdominal exam elicited no tenderness with palpation and was otherwise unremarkable. On laboratory studies, her hemoglobin was critically low at 6.5 g/dL (reference range 12.0 g/dL–15.5 g/dL), trending down from 8.2 g/dL in the oncology clinic the day before despite being transfused 2 units of packed red blood cells during that visit. She additionally had a leukocytosis to 19.91 × 103 cells/mcL (reference range 4.1 × 103 cells/mcL–10.9 × 103 cells/mcL) with a normal differential distribution. Another urgent inpatient esophagogastroduodenoscopy was performed which showed scattered gastric erosions (Fig. 1) as well as the previously characterized clean-based ulcer in the superior aspect of the post-bulbar area (Fig. 2) and furthermore showed multiple oozing linear superficial mucosal breaks that circumferentially involved the majority of the second portion of the duodenum (Fig. 3). The source of the patient's melena was deemed to be from these prominent mucosal lesions in the second portion of the duodenum which exhibited signs of recent bleeding, as the ulcer in the first portion of the duodenum had a stable appearance with no high-risk stigmata. Biopsies were obtained at all 3 sites and underwent review by pathology. At low magnification, the cells in the proliferative compartment appeared hyperchromatic with numerous mitotic arrest results in several readily apparent mitoses, many seen as ring forms. However, these histologic changes are confined to the proliferative compartment, and the biopsy displays epithelial surface maturation (Fig. 4). On a higher microscopic magnification, the main striking histologic features were ring mitoses and prominence in apoptosis (Fig. 5 A, B). These findings, seen in all 3 biopsies, were compatible with taxane toxicity. Focal hemorrhaging was observed with the mucosal breaks seen on the duodenal biopsies (Fig. 6). No evidence of Helicobacter pylori infection was seen.\n\nThe patient's melena resolved on PPI therapy alone. Subsequent stool culture did not grow any pathogenic organisms, and stool studies were negative for Shigella, E. coli O157, Salmonella, and Campylobacter. Docetaxel was removed from her next chemotherapy infusion which she tolerated well. She subsequently had taxanes re-introduced into her chemotherapy regimen at her next cycle in the form of weekly paclitaxel. She did not report any further GI bleeding and completed her adjuvant chemotherapy successfully. The patient underwent surveillance endoscopy approximately 1.5 weeks after completing paclitaxel therapy, almost 4 months after the previous endoscopy. It showed a normal appearing esophagus and duodenum; however, multiple dispersed erosions were seen in the gastric body with stigmata of recent bleeding. Her hemoglobin was stable at 10.9 g/dL 9 days after the surveillance endoscopy, and she has not required any blood transfusions since docetaxel was removed from her chemotherapy regimen.\n\nDiscussion\n\nTaxanes are thought to induce changes in the gastrointestinal epithelium by binding to microtubules, which promotes their polymerization [1]. These microtubule polymers can be visualized under electron microscopy as ringed mitoses, as seen in the biopsies from our patient. The gastrointestinal toxicities commonly associated with taxane therapy include nausea (34–42%), vomiting (22–23%), stomatitis (26–53%), and diarrhea, and there have been several case reports of neutropenic enterocolitis and ischemic colitis. Common skin manifestations include alopecia (56–76%) and nail changes (11–41%) and like gastrointestinal toxicities are also due to the direct cytotoxic effects of taxanes [5]. With regard specifically to combination therapy of docetaxel with carboplatin, trastuzumab, and pertuzumab as per the TCHP protocol, the most common side effects are neutropenia (25.1%), diarrhea (15.5%), febrile neutropenia (15.1%), and anemia (11%). Other side effects of docetaxel include infusion reactions, fluid retention, pneumonitis, fatigue, lacrimal duct stenosis, and peripheral neuropathy [4]. Taxane toxicities typically resolve following cessation or dose reduction of the medication except for peripheral neuropathy, which can persist long following discontinuation of chemotherapy. These toxicities are dose dependent and may have a delayed presentation in patients following infusion. For example, neutropenic enterocolitis can present 2–13 days following docetaxel infusion. There are emerging data suggesting that patients with gene variants in proteins involved in the metabolism of taxanes such as ABCB1, CYP3A4, and CYP3A5 are at higher risk of developing taxane toxicities; however, data are still inconclusive [2]. Within administration regimens of taxanes, weekly administered paclitaxel is associated with less toxicity than docetaxel administered at 3-week intervals [6]. Furthermore, the purported mechanism of docetaxel-induced GI toxicity is p53 independent, whereas paclitaxel appears to induce apoptosis in the GI epithelia [1, 7]. For these reasons, the patient presented in this report was switched to weekly paclitaxel.\n\nSince there have been no previously described cases of upper gastrointestinal bleeding secondary to taxane-induced duodenitis, this patient received the standard of care for nonvariceal upper gastrointestinal bleeding which comprised packed red blood cell resuscitation, PPI therapy, and upper endoscopy, although docetaxel was omitted from her next chemotherapy cycle. Appropriate PPI therapy, which is typically 12 weeks in duration, generally heals over 90% of peptic ulcers given that their aggravating factors such as nonsteroidal anti-inflammatory drug use and H. pylori are removed or treated, respectively. Regarding conventional duodenal ulcers and duodenitis, repeat surveillance endoscopy is typically not performed due to their low risk of association with enteric malignancy. The abdominal pain, nausea, emesis, and other symptoms associated with duodenal ulcers resolve with successful treatment with appropriate acid suppressive therapy, and persistence of symptoms may be suggestive of refractory disease. In patients with refractory peptic ulcer disease, the risk for complications such as gastrointestinal bleeding, perforation, and gastric outlet obstruction is approximately 2–3% yearly. With continued PPI therapy and re-introduction of weekly paclitaxel in lieu of docetaxel, she has had no further episodes of gastrointestinal bleeding.\n\nThis case illustrates a previously undescribed side effect of gastropathy and duodenopathy causing gastrointestinal hemorrhage associated with docetaxel administration. Our findings will help expand our understanding of the potential complications that can occur with docetaxel therapy. Prompt diagnosis obtained through endoscopic biopsy and medical intervention followed by adjustment of the chemotherapy regimen helped this patient receive successful treatment of her breast cancer without further complication from gastrointestinal bleeding.\n\nStatement of Ethics\n\nThe study is exempt from ethics committee approval as it is a report of a single case; no special protocol was followed, and the patient received the standard of medical care. The subject of the case report has given her written informed consent to publish this case.\n\nConflict of Interest Statement\n\nDr. Irene Kang discloses Bristol Myers Squibb (consulting fee) and Puma Biotechnology (consulting fees and speakers bureau) as potential conflicts of interest.\n\nFunding Sources\n\nNo funding was received nor utilized in the production of this publication.\n\nAuthor Contributions\n\nYao Liu and Brent Hiramoto wrote and revised the manuscript; they contributed equally and share first authorship. Janet Kwok reviewed and revised the manuscript and holds second authorship. Ahmad Ibrahim and Sergei Tatsichev performed the pathology figures and analysis; they share third authorship. Irene Kang and Rushabh Modi reviewed and revised the manuscript; they share senior authorship.\n\nData Availability Statement\n\nAll data relevant to the case presentation are available as part of the article and no additional source data are required.\n\nAcknowledgments\n\nWe would like to recognize all the contributors in this case report. In addition, special thanks are due to all the patients at the Norris Comprehensive Cancer Center, especially the subject of this case report, who have privileged us with their care.\n\nFig. 1 Stomach, scattered gastral erosions.\n\nFig. 2 Clean-based ulcer in the first part of the duodenum.\n\nFig. 3 Linear superficial lesions in the second portion of the duodenum.\n\nFig. 4 H&E low-power view of biopsy from mucosal break from the second portion of the duodenum shows hyperchromatic nuclei and numerous mitotic figures at the proliferative compartment (➝); however, the surface epithelium shows complete maturation (➧).\n\nFig. 5 A, B H&E high-power view of the biopsy from the oozing lesions of the second portion of the duodenum shows numerous ring mitosis (➧) and apoptotic bodies (★).\n\nFig. 6 H&E high-power view of the biopsy from the second portion of the duodenum showing mucosal breaks/ulceration (➧) in the setting of taxane toxicity with focal erosion and hemorrhage (➝).\n==== Refs\nReferences\n\n1 Daniels JA Gibson MK Xu L Sun S Canto MI Heath E Gastrointestinal tract epithelial changes associated with taxanes: marker of drug toxicity versus effect Am J Surg Pathol 2008 32 (3) 473 7 18300801\n2 Frederiks CN Lam SW Guchelaar HJ Boven E Genetic polymorphisms and paclitaxel- or docetaxel-induced toxicities: a systematic review Cancer Treat Rev 2015 41 (10) 935 50 26585358\n3 Ho MY Mackey JR Presentation and management of docetaxel-related adverse effects in patients with breast cancer Cancer Manag Res 2014 6 253 9 24904223\n4 Hurvitz SA Martin M Jung KH Huang CS Harbeck N Valero V Neoadjuvant trastuzumab emtansine and pertuzumab in human epidermal growth factor receptor 2-positive breast cancer: three-year outcomes from the phase III KRISTINE Study J Clin Oncol 2019 37 (25) 2206 16 31157583\n5 Marks DH Qureshi A Friedman A Evaluation of prevention interventions for taxane-induced dermatologic adverse events: a systematic review JAMA Dermatol 2018 154 (12) 1465 72 30383138\n6 Mauri D Kamposioras K Tsali L Bristianou M Valachis A Karathanasi I Overall survival benefit for weekly vs. three-weekly taxanes regimens in advanced breast cancer: a meta-analysis Cancer Treat Rev 2010 36 (1) 69 74 19945225\n7 Schimming R Mason KA Hunter N Weil M Kishi K Milas L Lack of correlation between mitotic arrest or apoptosis and antitumor effect of docetaxel Cancer Chemother Pharmacol 1999 43 165 72 9923824\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "14(3)",
"journal": "Case reports in oncology",
"keywords": "Breast cancer; Chemotherapy; Gastrointestinal bleed; Taxane",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "1373-1379",
"pmc": null,
"pmid": "34720944",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "31157583;30383138;26585358;24904223;18300801;19945225;9923824",
"title": "Taxane-Induced Upper Gastrointestinal Bleeding.",
"title_normalized": "taxane induced upper gastrointestinal bleeding"
} | [
{
"companynumb": "US-MLMSERVICE-20211008-3155102-1",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nWe retrospectively assessed the initial clinical impact of the locally administered bacteriostatic antibiotic, powder minocycline, during surgery for active infective endocarditis (AIE).\n\n\nMETHODS\nAmong 38 surgical AIE patients, 36 patients who underwent surgical intervention for AIE using local administration of powder minocycline between January 2008 and August 2017 in our institute were enrolled. During surgery, the local administration and dispersion of powder minocycline at not only the valvular annulus and perivalvular cavity, but also the prosthetic cuff and ring were performed following the complete resection and aggressive debridement of infectious tissues. Early clinical outcomes, including survival, postoperative co-morbidities, and freedom from re-intervention or significant paravalvular leakage (PVL), were assessed.\n\n\nRESULTS\nEarly mortality within 30 days was 5.6% and hospital death was 13.9%. There was no reoperation within 30 days and only one patient (3.8%) developed recurrent infection, which improved with additional antibiotic treatments. More than moderate PVL within 30 days was detected in one patient only (3.8%). Over a median follow-up period of 38.3 ± 35.5 months, a Kaplan-Meier analysis revealed that 1- and 5-year survival rates were 75.7 and 66.8%, respectively, and freedom from reoperation was 100% at 5 years. Freedom from significant PVL at 5 years was 91.0%.\n\n\nCONCLUSIONS\nThe local administration of powder minocycline may be a simple and effective manipulation during surgical intervention for AIE without extensive reconstruction; however, the surgical management of AIE remains challenging.",
"affiliations": "Department of Cardiovascular Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan. hfurukawa@med.kawasaki-m.ac.jp.;Department of Cardiovascular Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan.;Department of Cardiovascular Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan.;Department of Cardiovascular Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan.;Department of Cardiovascular Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan.;Department of Cardiovascular Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan.",
"authors": "Furukawa|Hiroshi|H|;Yamane|Naoki|N|;Honda|Takeshi|T|;Yamasawa|Takahiko|T|;Kanaoka|Yuji|Y|;Tanemoto|Kazuo|K|",
"chemical_list": "D000900:Anti-Bacterial Agents; D011208:Powders; D008911:Minocycline",
"country": "Japan",
"delete": false,
"doi": "10.1007/s11748-020-01294-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1863-6705",
"issue": "68(9)",
"journal": "General thoracic and cardiovascular surgery",
"keywords": "Active infective endocarditis; Bacteriostatic antibiotic; Minocycline; Paravalvular leakage; Perivalvular abscess",
"medline_ta": "Gen Thorac Cardiovasc Surg",
"mesh_terms": "D000287:Administration, Topical; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D003646:Debridement; D004697:Endocarditis, Bacterial; D005260:Female; D017052:Hospital Mortality; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D008911:Minocycline; D011208:Powders; D012008:Recurrence; D012086:Reoperation; D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome",
"nlm_unique_id": "101303952",
"other_id": null,
"pages": "943-950",
"pmc": null,
"pmid": "31983052",
"pubdate": "2020-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Local administration of the powder minocycline during surgical intervention for active infective endocarditis.",
"title_normalized": "local administration of the powder minocycline during surgical intervention for active infective endocarditis"
} | [
{
"companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2020-05917",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MINOCYCLINE HYDROCHLORIDE"
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... |
{
"abstract": "BACKGROUND\nPregnancy among patients with congenital myasthenic syndrome (CMS) is a rare occurrence. Since most of the patients with CMS reach adulthood, questions regarding clinical outcome with pregnancy arise.\n\n\nMETHODS\nWe describe a 38-year-old Portuguese female who presented in the second trimester of pregnancy with proximal fluctuating limb-girdle weakness, hyperlordosis, waddling gait, dysphagia, dysphonia and ptosis, with no ophthalmoparesis. Initial diagnosis of seronegative myasthenia, supported by neurophysiology findings, led to unsuccessful treatment with intravenous immunoglobulin, pyridostigmine, prednisolone and plasmapheresis, and the patient slowly progressed to a severe tetraparesis with facial and bulbar involvement. Genetic testing for CMS identified a novel compound heterozygous mutation (c.1124_1127dupTGCC and c.935_936del) in the DOK7 gene. Subsequent treatment with salbutamol resulted in substantial clinical benefit.\n\n\nCONCLUSIONS\nThis case underlines the importance of considering the diagnosis of CMS in patients with fluctuating weakness during pregnancy. Patients of child-bearing potential diagnosed with CMS, particularly due to DOK7 mutations, should be counseled in advance and closely followed during pregnancy.",
"affiliations": "Department of Neurology, Hospital de Egas Moniz, Centro Hospitalar de Lisboa Ocidental, Rua da Junqueira 126, 1349-019, Lisbon, Portugal. Electronic address: marcoa.fernandes91@gmail.com.;Department of Neurology, Hospital de Egas Moniz, Centro Hospitalar de Lisboa Ocidental, Rua da Junqueira 126, 1349-019, Lisbon, Portugal; CEDOC Chronic Diseases Research Centre, Nova Medical School / Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal.;Department of Neurology, Hospital de Egas Moniz, Centro Hospitalar de Lisboa Ocidental, Rua da Junqueira 126, 1349-019, Lisbon, Portugal.;Department of Neurology, Hospital de Egas Moniz, Centro Hospitalar de Lisboa Ocidental, Rua da Junqueira 126, 1349-019, Lisbon, Portugal; CEDOC Chronic Diseases Research Centre, Nova Medical School / Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal.;Department of Neurology, Hospital de Egas Moniz, Centro Hospitalar de Lisboa Ocidental, Rua da Junqueira 126, 1349-019, Lisbon, Portugal; CEDOC Chronic Diseases Research Centre, Nova Medical School / Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal.",
"authors": "Fernandes|Marco|M|;Caetano|André|A|;Pinto|Miguel|M|;Medeiros|Elmira|E|;Santos|Luís|L|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.clineuro.2021.106591",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0303-8467",
"issue": "203()",
"journal": "Clinical neurology and neurosurgery",
"keywords": "Congenital myasthenic syndrome; DOK7; Neuromuscular junction; Pregnancy",
"medline_ta": "Clin Neurol Neurosurg",
"mesh_terms": null,
"nlm_unique_id": "7502039",
"other_id": null,
"pages": "106591",
"pmc": null,
"pmid": "33714798",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Diagnosis of DOK7 congenital myasthenic syndrome during pregnancy: A case report and literature review.",
"title_normalized": "diagnosis of dok7 congenital myasthenic syndrome during pregnancy a case report and literature review"
} | [
{
"companynumb": "PT-ALVOGEN-2021-ALVOGEN-116816",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HUMAN IMMUNOGLOBULIN G"
},
"drugaddition... |
{
"abstract": "Studies have documented AKI with high-grade proteinuria in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In some patients, biopsies have revealed collapsing glomerulopathy, a distinct form of glomerular injury that has been associated with other viruses, including HIV. Previous patient reports have described patients of African ancestry who developed nephrotic-range proteinuria and AKI early in the course of disease.\n\n\n\nIn this patient series, we identified six patients with coronavirus disease 2019 (COVID-19), AKI, and nephrotic-range proteinuria. COVID-19 was diagnosed by a positive nasopharyngeal swab RT-PCR for SARS-CoV-2 infection. We examined biopsy specimens from one transplanted kidney and five native kidneys. Three of the six patients underwent genetic analysis of APOL1, the gene encoding the APOL1 protein, from DNA extracted from peripheral blood. In addition, we purified genomic DNA from paraffin-embedded tissue and performed APOL1 genotype analysis of one of the native biopsies and the donor kidney graft.\n\n\n\nAll six patients were of recent African ancestry. They developed COVID-19-associated AKI with podocytopathy, collapsing glomerulopathy, or both. Patients exhibited generally mild respiratory symptoms, and no patient required ventilator support. Genetic testing performed in three patients confirmed high-risk APOL1 genotypes. One APOL1 high-risk patient developed collapsing glomerulopathy in the engrafted kidney, which was transplanted from a donor who carried a low-risk APOL1 genotype; this contradicts current models of APOL1-mediated kidney injury, and suggests that intrinsic renal expression of APOL1 may not be the driver of nephrotoxicity and specifically, of podocyte injury.\n\n\n\nGlomerular disease presenting as proteinuria with or without AKI is an important presentation of COVID-19 infection and may be associated with a high-risk APOL1 genotype.",
"affiliations": "Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, Illinois aneesha.shetty@northwestern.edu.;Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, Illinois.;Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, Illinois.;Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, Illinois.;Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, Illinois.;Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, Illinois.;Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, Illinois.;Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.;Division of Nephrology, Columbia University Vagelos College of Physicians and Surgeons, New York, New York.;Division of Nephrology, Columbia University Vagelos College of Physicians and Surgeons, New York, New York.;Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, Illinois.;Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, Illinois.",
"authors": "Shetty|Aneesha A|AA|;Tawhari|Ibrahim|I|;Safar-Boueri|Luisa|L|;Seif|Nay|N|;Alahmadi|Ameen|A|;Gargiulo|Richard|R|;Aggarwal|Vikram|V|;Usman|Irtaza|I|0000-0002-7870-8792;Kisselev|Sergey|S|;Gharavi|Ali G|AG|;Kanwar|Yahspal|Y|;Quaggin|Susan E|SE|0000-0002-3706-5727",
"chemical_list": "C108666:APOL1 protein, human; D000075944:Apolipoprotein L1",
"country": "United States",
"delete": false,
"doi": "10.1681/ASN.2020060804",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1046-6673",
"issue": "32(1)",
"journal": "Journal of the American Society of Nephrology : JASN",
"keywords": "APOL1; COVID-19; collapsing glomerulopathy",
"medline_ta": "J Am Soc Nephrol",
"mesh_terms": "D058186:Acute Kidney Injury; D001741:African Americans; D000075944:Apolipoprotein L1; D001706:Biopsy; D000086382:COVID-19; D003928:Diabetic Nephropathies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006417:Hematuria; D006801:Humans; D006973:Hypertension; D007678:Kidney Glomerulus; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D050199:Podocytes; D011507:Proteinuria; D012306:Risk; D000086402:SARS-CoV-2; D056189:Viral Tropism",
"nlm_unique_id": "9013836",
"other_id": null,
"pages": "33-40",
"pmc": null,
"pmid": "33214201",
"pubdate": "2021-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "24173214;32346659;32371536;17021266;32713123;25788523;25168832;29531077;20668430;31558683;32292867;32775990;32154449;20647424;32402155;32649078;25993319;32345702;32680910;32561682;18391591;28218918;32187552;32247631;27445167;32427098;21997397;16541018;32327202;32221937;23438974;32437769;21997394;26699492;25100047;32775989;30287079;22257798",
"title": "COVID-19-Associated Glomerular Disease.",
"title_normalized": "covid 19 associated glomerular disease"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2021SP001449",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugaddition... |
{
"abstract": "To test whether the use of rituximab (RTX) is effective and safe as a rescue therapy add-on treatment to mycophenolate (MMF) in patients with progressive systemic sclerosis-associated interstitial lung disease (SSc-ILD) in whom conventional immunosuppressants (IS) have failed.\n\n\n\nLongitudinal retrospective observational study of a cohort of patients with SSc-ILD that started treatment with RTX due to ongoing lung function impairment despite treatment with glucocorticoids and IS (cyclophosphamide and/or MMF). All patients were treated with 2 or more cycles of RTX and evaluated for at least 12 months.\n\n\n\nTwenty-four patients were included. Before initiation of RTX the mean decline in%pFVC and %pDLCO during the previous 2 years (delta) was -12.9% and -12.5%, respectively. After 1 year of treatment with RTX, a significant improvement in %pFVC (∆+8.8% compared to baseline, 95% CI: -13.7 to -3.9; p = 0.001) and%pDLCO (∆+4.6%, 95% CI: -8.2 to -0.8; p = 0.018) was observed. In addition, there was a significant reduction in the median dose of prednisone and it could be suspended in 25% of patients. At 2 years of treatment, RTX had been discontinued in 9 patients (due to adverse events in 3 cases and inefficacy in 6). In the 15 patients (62.5%) that completed 24 months of therapy, the statistically significant amelioration in pulmonary function test parameters was maintained: ∆%pFVC: +11.1% (95% CI: -17.6 to -4.5; p = 0.003) and ∆%pDLCO: +8.7% (95% CI: -13.9 to -8.3; p = 0.003).\n\n\n\nBased on our results, RTX's use as an add-on treatment to MMF appears to be effective as a rescue therapy in patients with a more aggressive SSc-ILD phenotype.",
"affiliations": "Department of Rheumatology, Hospital Universitario de Bellvitge. Barcelona, Spain. Electronic address: fjnarvaez@bellvitgehospital.cat.;Department of Rheumatology, Hospital Universitario de Bellvitge. Barcelona, Spain.;Department of Pneumology (Unit of Interstitial Lung Diseases), Hospital Universitario de Bellvitge, Barcelona, Spain.;Department of Pneumology (Unit of Interstitial Lung Diseases), Hospital Universitario de Bellvitge, Barcelona, Spain.;Department of Radiology, Hospital Universitario de Bellvitge, Barcelona, Spain.;Department of Rheumatology, Hospital Universitario de Bellvitge. Barcelona, Spain; Department of Radiology, Hospital Altos de Salta, Salta, Argentina.;Department of Rheumatology, Hospital Universitario de Bellvitge. Barcelona, Spain.",
"authors": "Narváez|Javier|J|;LLuch|Judit|J|;Molina-Molina|Maria|M|;Vicens-Zygmunt|Vanesa|V|;Luburich|Patricio|P|;Yañez|Marcos Anibal|MA|;Nolla|Joan M|JM|",
"chemical_list": "D007166:Immunosuppressive Agents; D000069283:Rituximab; D009173:Mycophenolic Acid",
"country": "United States",
"delete": false,
"doi": "10.1016/j.semarthrit.2020.08.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0049-0172",
"issue": "50(5)",
"journal": "Seminars in arthritis and rheumatism",
"keywords": "Interstial lung disease; Rituximab; Systemic sclerosis; Treatment",
"medline_ta": "Semin Arthritis Rheum",
"mesh_terms": "D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D017563:Lung Diseases, Interstitial; D009173:Mycophenolic Acid; D064887:Observational Studies as Topic; D000069283:Rituximab; D045743:Scleroderma, Diffuse; D016896:Treatment Outcome",
"nlm_unique_id": "1306053",
"other_id": null,
"pages": "977-987",
"pmc": null,
"pmid": "32911289",
"pubdate": "2020-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Rituximab as a rescue treatment added on mycophenolate mofetil background therapy in progressive systemic sclerosis associated interstitial lung disease unresponsive to conventional immunosuppression.",
"title_normalized": "rituximab as a rescue treatment added on mycophenolate mofetil background therapy in progressive systemic sclerosis associated interstitial lung disease unresponsive to conventional immunosuppression"
} | [
{
"companynumb": "ES-MYLANLABS-2020M1088940",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
... |
{
"abstract": "We report a case of Clostridium difficile infection in a patient with hidradenitis suppurativa who was taking clindamycin and rifampin. Clostridium difficile infection treatment prompted discontinuation of the medication. Clostridium difficile infection is known to develop after antibiotic treatment, such as clindamycin, but has rarely been associated with anti-tuberculosis agents, such as rifampin. Clinicians should be aware of the risk of Clostridium difficile infection in patients with hidradenitis suppurativa, even in those receiving rifampin.",
"affiliations": "Department of Dermatology, Weil Cornell Medical College, New York, New York. Scheinfeld@earthlink.net.",
"authors": "Bessaleli|Elicia|E|;Scheinfeld|Noah|N|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002981:Clindamycin; D012293:Rifampin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2108",
"issue": "24(5)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D000900:Anti-Bacterial Agents; D002981:Clindamycin; D016360:Clostridioides difficile; D003015:Clostridium Infections; D005260:Female; D017497:Hidradenitis Suppurativa; D006801:Humans; D008875:Middle Aged; D012293:Rifampin",
"nlm_unique_id": "9610776",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30142743",
"pubdate": "2018-05-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Clostridium difficile arising in a patient with hidradenitis suppurativa on clindamycin and rifampin.",
"title_normalized": "clostridium difficile arising in a patient with hidradenitis suppurativa on clindamycin and rifampin"
} | [
{
"companynumb": "US-SA-2018SA220542",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ATENOLOL"
},
"drugadditional": "3",
"druga... |
{
"abstract": "The aim of this study is to report the results of a second cycle audit of the use of subcutaneous levetiracetam (Keppra®) and an updated literature review of management of seizures in palliative care patients. A comprehensive literature review on the use of subcutaneous levetiracetam performed in 2016 was updated. A retrospective audit of the use of subcutaneous levetiracetam for inpatients at Sir Michael Sobell House Hospice during the period of 2019-2020 was performed. Ethical approval was not required and was therefore not sought. We report an additional 66 cases identified through an updated literature review and our audit. Fourteen articles were identified from the literature review, reporting a total of 120 cases where subcutaneous levetiracetam was administered. We report 19 further cases of subcutaneous levetiracetam administration between April 2019 and April 2020. Doses ranged from 500 mg to 4000 mg daily. Doses above 2000 mg were administered using a T60 syringe driver. The oral-to-subcutaneous conversion ratio was 1:1 in all but one case where the dose had to be reduced to fit a T34 syringe driver, after which the T60s were purchased. Levetiracetam was not mixed with other medications, but administered alone using water as the diluent for injection. Where necessary, the dose was appropriately adjusted for renal function. No site reactions were reported. Combined analysis of the 139 cases of subcutaneous levetiracetam administration suggests that this treatment continues to have a role in management of seizures at the end of life. Clinical outcomes suggest that therapeutic levels may be achieved, although there are only very limited data available with a few cases worldwide to support this. Randomized controlled trials are urgently needed to establish the efficacy and tolerability of subcutaneous levetiracetam administration.",
"affiliations": "Department of Palliative Medicine, Michael Sobell House Hospice, Churchill Hospital, Oxford, United Kingdom.;Department of Palliative Medicine, Michael Sobell House Hospice, Churchill Hospital, Oxford, United Kingdom.;Department of Palliative Medicine, Michael Sobell House Hospice, Churchill Hospital, Oxford, United Kingdom.;Department of Palliative Medicine, Michael Sobell House Hospice, Churchill Hospital, Oxford, United Kingdom.",
"authors": "Sutherland|Anna|A|;Meldon|Charlotte|C|;Harrison|Timothy|T|;Miller|Mary|M|",
"chemical_list": "D000927:Anticonvulsants; D000077287:Levetiracetam; D010889:Piracetam",
"country": "United States",
"delete": false,
"doi": "10.1089/jpm.2020.0414",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1557-7740",
"issue": "24(7)",
"journal": "Journal of palliative medicine",
"keywords": "pharmacology; symptom control (other than pain)",
"medline_ta": "J Palliat Med",
"mesh_terms": "D000927:Anticonvulsants; D003643:Death; D006801:Humans; D000077287:Levetiracetam; D010889:Piracetam; D012189:Retrospective Studies; D012640:Seizures",
"nlm_unique_id": "9808462",
"other_id": null,
"pages": "976-981",
"pmc": null,
"pmid": "33296254",
"pubdate": "2021-07",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Subcutaneous Levetiracetam for the Management of Seizures at the End of Life: An Audit and Updated Literature Review.",
"title_normalized": "subcutaneous levetiracetam for the management of seizures at the end of life an audit and updated literature review"
} | [
{
"companynumb": "GB-LUPIN PHARMACEUTICALS INC.-2021-21776",
"fulfillexpeditecriteria": "2",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditio... |
{
"abstract": "Purpose To test for measurable visual enhancement of the dentate nucleus (DN) on unenhanced T1-weighted magnetic resonance (MR) images in a cohort of patients with a primary brain tumor who had not received linear gadolinium-based contrast agents (GBCAs) but had received many injections of macrocyclic GBCAs. Materials and Methods Seventeen patients with high-grade gliomas who had received 10-44 administrations of the macrocyclic GBCA gadobutrol (0.1 mmol/kg of body weight) were retrospectively included in this regional ethics committee-approved study. Two neuroradiologists inspected T1-weighted MR images with optimized window settings to visualize small differences in contrast at the baseline and at the last examination for the presence of visual DN signal enhancement. Signal intensity (SI) in the DN was normalized to the SI of the pons, and a one-sample t test was used to test for differences between baseline normalized SI (nSI) in the DN (nSIDN) and the average change in nSIDN of all postbaseline MR imaging sessions (ΔnSIDNavg) or the change in nSIDN from baseline to the last MR imaging session (ΔnSIDN). Linear and quadratic correlation analyses were used to examine the association between the number of macrocyclic GBCA administrations and ΔnSIDN or ΔnSIDNavg. Results The mean ± standard deviation number of macrocyclic GBCA administrations was 22.2 ± 10.6 administered throughout 706 days ± 454. Visually appreciable signal enhancement was observed in two patients who had received 37 and 44 macrocyclic GBCA injections. Mean ΔnSIDN was greater than zero (0.03 ± 0.05; P = .016), and there was a significant linear association between the number of macrocyclic GBCA injections and ΔnSIDN (r = 0.69, P = .002) and ΔnSIDNavg (r = 0.77, P < .001). Conclusion A small but statistically significant dose-dependent T1-weighted signal enhancement was observed in the DN after multiple macrocyclic GBCA injections. Visually appreciable enhancement in the DN was observed on contrast-optimized images in two patients who had received 37 and 44 standard doses of macrocyclic GBCAs. © RSNA, 2017 Online supplemental material is available for this article.",
"affiliations": "From the Department of Diagnostic Physics (A.B., C.L., I.R.G.), Intervention Centre (S.A.S.V., P.K.H.), and Department of Radiology (P.D.T.), Oslo University Hospital, Rikshospitalet, Sognsvannsveien 20, N-0372 Oslo, Norway; Faculty of Mathematics and Natural Sciences, Institute of Physics (A.B) and Faculty of Medicine, Institute of Clinical Medicine (P.K.H, C.L.), University of Oslo, Oslo, Norway.;From the Department of Diagnostic Physics (A.B., C.L., I.R.G.), Intervention Centre (S.A.S.V., P.K.H.), and Department of Radiology (P.D.T.), Oslo University Hospital, Rikshospitalet, Sognsvannsveien 20, N-0372 Oslo, Norway; Faculty of Mathematics and Natural Sciences, Institute of Physics (A.B) and Faculty of Medicine, Institute of Clinical Medicine (P.K.H, C.L.), University of Oslo, Oslo, Norway.;From the Department of Diagnostic Physics (A.B., C.L., I.R.G.), Intervention Centre (S.A.S.V., P.K.H.), and Department of Radiology (P.D.T.), Oslo University Hospital, Rikshospitalet, Sognsvannsveien 20, N-0372 Oslo, Norway; Faculty of Mathematics and Natural Sciences, Institute of Physics (A.B) and Faculty of Medicine, Institute of Clinical Medicine (P.K.H, C.L.), University of Oslo, Oslo, Norway.;From the Department of Diagnostic Physics (A.B., C.L., I.R.G.), Intervention Centre (S.A.S.V., P.K.H.), and Department of Radiology (P.D.T.), Oslo University Hospital, Rikshospitalet, Sognsvannsveien 20, N-0372 Oslo, Norway; Faculty of Mathematics and Natural Sciences, Institute of Physics (A.B) and Faculty of Medicine, Institute of Clinical Medicine (P.K.H, C.L.), University of Oslo, Oslo, Norway.;From the Department of Diagnostic Physics (A.B., C.L., I.R.G.), Intervention Centre (S.A.S.V., P.K.H.), and Department of Radiology (P.D.T.), Oslo University Hospital, Rikshospitalet, Sognsvannsveien 20, N-0372 Oslo, Norway; Faculty of Mathematics and Natural Sciences, Institute of Physics (A.B) and Faculty of Medicine, Institute of Clinical Medicine (P.K.H, C.L.), University of Oslo, Oslo, Norway.;From the Department of Diagnostic Physics (A.B., C.L., I.R.G.), Intervention Centre (S.A.S.V., P.K.H.), and Department of Radiology (P.D.T.), Oslo University Hospital, Rikshospitalet, Sognsvannsveien 20, N-0372 Oslo, Norway; Faculty of Mathematics and Natural Sciences, Institute of Physics (A.B) and Faculty of Medicine, Institute of Clinical Medicine (P.K.H, C.L.), University of Oslo, Oslo, Norway.",
"authors": "Bjørnerud|Atle|A|;Vatnehol|Svein Are Sirirud|SAS|;Larsson|Christopher|C|;Due-Tønnessen|Paulina|P|;Hol|Per Kristian|PK|;Groote|Inge Rasmus|IR|",
"chemical_list": "D003287:Contrast Media; D009942:Organometallic Compounds; C090600:gadobutrol",
"country": "United States",
"delete": false,
"doi": "10.1148/radiol.2017170391",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0033-8419",
"issue": "285(2)",
"journal": "Radiology",
"keywords": null,
"medline_ta": "Radiology",
"mesh_terms": "D000328:Adult; D000368:Aged; D002529:Cerebellar Nuclei; D003287:Contrast Media; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009942:Organometallic Compounds; D012189:Retrospective Studies",
"nlm_unique_id": "0401260",
"other_id": null,
"pages": "434-444",
"pmc": null,
"pmid": "28885891",
"pubdate": "2017-11",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Signal Enhancement of the Dentate Nucleus at Unenhanced MR Imaging after Very High Cumulative Doses of the Macrocyclic Gadolinium-based Contrast Agent Gadobutrol: An Observational Study.",
"title_normalized": "signal enhancement of the dentate nucleus at unenhanced mr imaging after very high cumulative doses of the macrocyclic gadolinium based contrast agent gadobutrol an observational study"
} | [
{
"companynumb": "NO-BAYER-2017-214298",
"fulfillexpeditecriteria": "1",
"occurcountry": "NO",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GADOBUTROL"
},
"drugadditional": null,
"... |
{
"abstract": "Phenytoin was administered intravenously in large doses (mean = 16.6 mg per kilogram) for prevention and treatment of seizures on 159 occasions to 139 patients aged 17 to 94 years (mean = 52 years) and weighing 37 to 113 kg (mean = 65 kg). Hypotension was more frequent among older patients. No deaths were attributable to phenytoin. Volumes of distribution were relatively constant (mean = 0.78 +/- 0.11 liters per kilogram), but half-lives varied considerably and were prolonged (mean = 51 +/- 32 hours) because of the large doses administered. A dose of 18 mg per kilogram was effective in maintaining phenytoin serum levels above 10 microgram per milliliter for 24 hours.",
"affiliations": null,
"authors": "Cranford|R E|RE|;Leppik|I E|IE|;Patrick|B|B|;Anderson|C B|CB|;Kostick|B|B|",
"chemical_list": "D010672:Phenytoin",
"country": "United States",
"delete": false,
"doi": "10.1212/wnl.28.9.874",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3878",
"issue": "28(9 Pt 1)",
"journal": "Neurology",
"keywords": null,
"medline_ta": "Neurology",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D005260:Female; D006207:Half-Life; D006801:Humans; D007022:Hypotension; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D010672:Phenytoin",
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"references": null,
"title": "Intravenous phenytoin: clinical and pharmacokinetic aspects.",
"title_normalized": "intravenous phenytoin clinical and pharmacokinetic aspects"
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"abstract": "A patient with valproate-induced hyperammonemic encephalopathy presented with altered mental status and hyperammonemia in the context of normal liver functions. Fortunately, altered mental status and elevated plasma ammonia level normalized 1 day after discontinuation of divalproex sodium (Depakote). The case analysis suggests a possible synergistic interaction of valproic acid and topiramate with respect to the emergence of hyperammonemic encephalopathy in the context of normal liver functions. Possible mechanisms of the encephalopathy and hyperammonemia are discussed. For example, valproate has diverse metabolic effects that include regulating levels of ammonia by altering activity of the urea cycle, whose first step uses HCO3 in the synthesis of carbamoylphosphate. Topiramate's inhibition of carbonic anhydrase activity may be the basis of its possible synergy with valproate by affecting levels of HCO3.",
"affiliations": "Mental Health Service Line, Department of Veterans Affairs Medical Center, 50 Irving Street NW, Washington, DC 20422, USA. Stephen.deutsch@med.va.gov",
"authors": "Deutsch|Stephen I|SI|;Burket|Jessica A|JA|;Rosse|Richard B|RB|",
"chemical_list": "D000927:Anticonvulsants; D000077236:Topiramate; D005632:Fructose; D014635:Valproic Acid",
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"issue": "32(6)",
"journal": "Clinical neuropharmacology",
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"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D001927:Brain Diseases; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004827:Epilepsy; D005260:Female; D005632:Fructose; D006801:Humans; D022124:Hyperammonemia; D008111:Liver Function Tests; D000077236:Topiramate; D014635:Valproic Acid",
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"title": "Valproate-induced hyperammonemic encephalopathy and normal liver functions: possible synergism with topiramate.",
"title_normalized": "valproate induced hyperammonemic encephalopathy and normal liver functions possible synergism with topiramate"
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"abstract": "Trisomy 3 has been previously reported in association with T-cell lymphomas and less commonly in different types of non-Hodgkin B-cell lymphomas. Trisomy 3 has also been reported in two cases of pediatric post-transplant lymphoproliferative disorder (PTLD). We present comprehensive clinicopathologic review of two pediatric patients with cardiac and liver/intestinal allografts that developed polymorphic PTLD characterized by trisomy 3. Both patients had Epstein-Barr virus (EBV) viremia and EBV was positive in tissue by EBER in situ hybridization. Using karyotype analysis and fluorescence in situ hybridization, we identified trisomy 3 in both patients. Both patients responded to treatment and are now free of the PTLD. Trisomy 3, an uncommon cytogenetic finding in pediatric polymorphic PTLD, may be a recurrent cytogenetic aberration if confirmed in a larger study of pediatric PTLDs. Further clinical follow up might help stratify significance of trisomy 3 as a prognostic factor.",
"affiliations": "Department of Pathology and Laboratory Medicine, University of California, Irvine, UCIMC, Bldg. 1, Rm. 3426, Mail Code: 4805, Orange, CA 92868, USA. Electronic address: gshestak@uci.edu.;Advanced Dermatology of Colorado, 1100 Poudre River Dr ste a, Fort Collins, CO 80524, USA.;Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA , USA.;Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA , USA.;Department of Pathology and Laboratory Medicine, University of California, Irvine, UCIMC, Bldg. 1, Rm. 3426, Mail Code: 4805, Orange, CA 92868, USA. Electronic address: fabiolaq@hs.uci.edu.",
"authors": "Shestakova|Anna|A|;Grove|Narina|N|;Said|Jonathan|J|;Song|Sophie|S|;Quintero-Rivera|Fabiola|F|",
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"doi": "10.1016/j.cancergen.2020.09.006",
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"issue": "248-249()",
"journal": "Cancer genetics",
"keywords": "Cytogenetics; Pediatric PTLD; Recurrent; Transplantation; Trisomy 3",
"medline_ta": "Cancer Genet",
"mesh_terms": "D000293:Adolescent; D002311:Cardiomyopathy, Dilated; D002648:Child; D002869:Chromosome Aberrations; D002893:Chromosomes, Human, Pair 3; D020031:Epstein-Barr Virus Infections; D005260:Female; D016027:Heart Transplantation; D004854:Herpesvirus 4, Human; D006801:Humans; D007410:Intestinal Diseases; D007422:Intestines; D007621:Karyotyping; D008107:Liver Diseases; D016031:Liver Transplantation; D008232:Lymphoproliferative Disorders; D012008:Recurrence; D014314:Trisomy",
"nlm_unique_id": "101539150",
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"pubdate": "2020-10",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Trisomy 3, a sole recurrent cytogenetic abnormality in pediatric polymorphic post-transplant lymphoproliferative disorder (PTLD).",
"title_normalized": "trisomy 3 a sole recurrent cytogenetic abnormality in pediatric polymorphic post transplant lymphoproliferative disorder ptld"
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"abstract": "Myocarditis, arrhythmia, and cardiomyopathy are the most reported acute cardiotoxicities in cancer patients receiving immune checkpoint inhibitor (ICI) therapy. But it is not clear whether ICI can cause acute coronary occlusive disease. We reported acute coronary artery occlusion in an 83-year-old male non-small cell lung cancer (NSCLC) patient after 2 days of pembrolizumab infusion. This patient had a server-underlying three-vessel coronary artery disease without symptoms. The patient was discharged from the hospital two weeks after percutaneous coronary intervention. Pembrolizumab may cause destabilization of severely stenosed atherosclerotic plaques, which contributes to acute myocardial infarction. We should take more caution about lung cancer patients with baseline coronary disease when treat with ICI. CRP may be a useful predictor factor of early-onset coronary events in these patients.",
"affiliations": "Department of Respiratory and Critical Care Medicine, Peking University First Hospital, 8 Xi Shi Ku Street, Xi Cheng District, Beijing, 100034, China. softsnake@bjmu.edu.cn.;Department of Respiratory and Critical Care Medicine, Peking University First Hospital, 8 Xi Shi Ku Street, Xi Cheng District, Beijing, 100034, China.;Department of Cardiology, Peking University First Hospital, 8 Xi Shi Ku Street, Xi Cheng District, Beijing, 100034, China.;Department of Cardiology, Peking University First Hospital, 8 Xi Shi Ku Street, Xi Cheng District, Beijing, 100034, China.",
"authors": "Cheng|Yuan|Y|0000-0002-9763-7424;Nie|Ligong|L|;Ma|Wei|W|;Zheng|Bo|B|",
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"doi": "10.1007/s12012-021-09664-z",
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"issue": "21(8)",
"journal": "Cardiovascular toxicology",
"keywords": "Cardiotoxicitiy; Coronary artery occlusion; Early onset; Immune checkpoint inhibitor",
"medline_ta": "Cardiovasc Toxicol",
"mesh_terms": null,
"nlm_unique_id": "101135818",
"other_id": null,
"pages": "683-686",
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"title": "Early Onset Acute Coronary Artery Occlusion After Pembrolizumab in Advanced Non-Small Cell Lung Cancer: A Case Report.",
"title_normalized": "early onset acute coronary artery occlusion after pembrolizumab in advanced non small cell lung cancer a case report"
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"abstract": "Pulmonary veno-occlusive disease (PVOD) is a rare but devastating cause of pulmonary hypertension (PH) characterized by preferential remodeling of the pulmonary venules. Mitomycin-C (MMC) is an alkylating agent commonly used in chemotherapy with documented lung toxicity as well as PVOD adverse effect. The incidence of PVOD in patients with anal cancer is much higher than in those with idiopathic PVOD, especially following treatment with MMC. An accurate diagnosis of PVOD can be made based on noninvasive investigations utilizing oxygen parameters, low diffusing capacity for carbon monoxide and characteristic signs on high-resolution computed tomography of the chest. No evidence-based medical therapy exists for PVOD at present and lung transplant remains the preferred definitive therapy for eligible patients. We present a case of autopsy confirmed MMC induced PVOD in a patient with metastatic anal cancer.",
"affiliations": "Division of Pulmonary, Critical Care and Sleep Medicine, USA.;Department of Pathology, East Carolina University, Greenville, North Carolina 27858, USA.;Division of Pulmonary, Critical Care and Sleep Medicine, USA.;Department of Pathology, East Carolina University, Greenville, North Carolina 27858, USA.;Department of Pathology, East Carolina University, Greenville, North Carolina 27858, USA.;Division of Pulmonary, Critical Care and Sleep Medicine, USA.",
"authors": "Kunadu|Afua|A|;Stalls|J Stephen|JS|;Labuschagne|Heloise|H|;Thayyil|Abdullah|A|;Falls|Randall|R|;Maddipati|Veeranna|V|",
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"doi": "10.1016/j.rmcr.2021.101437",
"fulltext": "\n==== Front\nRespir Med Case Rep\nRespir Med Case Rep\nRespiratory Medicine Case Reports\n2213-0071\nElsevier\n\nS2213-0071(21)00099-X\n10.1016/j.rmcr.2021.101437\n101437\nCase Report\nMitomycin induced pulmonary veno-occlusive disease\nKunadu Afua totezee@yahoo.com\na∗\nStalls J. Stephen b\nLabuschagne Heloise a\nThayyil Abdullah b\nFalls Randall b\nMaddipati Veeranna a\na Division of Pulmonary, Critical Care and Sleep Medicine, USA\nb Department of Pathology, East Carolina University, Greenville, North Carolina 27858, USA\n∗ Corresponding author. 3E-149E Brody Medical Sciences Building, 600 Moye Blvd, Mail stop 628, East Carolina University, Greenville, NC 27834-4354, USA. totezee@yahoo.com\n01 6 2021\n2021\n01 6 2021\n34 10143731 1 2021\n24 5 2021\n27 5 2021\n© 2021 The Authors\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nPulmonary veno-occlusive disease (PVOD) is a rare but devastating cause of pulmonary hypertension (PH) characterized by preferential remodeling of the pulmonary venules.\n\nMitomycin-C (MMC) is an alkylating agent commonly used in chemotherapy with documented lung toxicity as well as PVOD adverse effect. The incidence of PVOD in patients with anal cancer is much higher than in those with idiopathic PVOD, especially following treatment with MMC. An accurate diagnosis of PVOD can be made based on noninvasive investigations utilizing oxygen parameters, low diffusing capacity for carbon monoxide and characteristic signs on high-resolution computed tomography of the chest. No evidence-based medical therapy exists for PVOD at present and lung transplant remains the preferred definitive therapy for eligible patients. We present a case of autopsy confirmed MMC induced PVOD in a patient with metastatic anal cancer.\n\nKeywords\n\nPulmonary veno-occlusive disease\nPulmonary arterial hypertension\nPulmonary hypertension\nPulmonary vasodilators\nMitomycin-C\nRespiratory failure\nAnal cancer\n==== Body\n1 Introduction\n\nPulmonary veno-occlusive disease (PVOD) is a rare but devastating cause of pulmonary hypertension (PH) characterized by preferential remodeling of pulmonary venules. In the current PH classification based on the 6th world symposium on PH, PVOD and pulmonary capillary hemangiomatosis (PCH) are considered to be a common entity and represent varied expressions of the same disease [1]. Incidence of PVOD in the general population is estimated at 0.5/million persons per year while the estimated incidence in patients with anal cancer based off a French registry was 3.9/1000 patients per year. This is significantly higher than in those with idiopathic PVOD, especially following treatment with Mitomycin-C (MMC) [2]. We present a case of MMC induced PVOD in a patient with metastatic anal cancer, confirmed on autopsy.\n\n2 Case presentation\n\nPatient was a 50-year-old man who initially presented to the emergency department (ED) with painful peri-anal mass and was later diagnosed with locally advanced invasive anal squamous cell cancer. He received 6 weeks of concomitant radiation and chemotherapy with 5-fluoro-uracil and MMC. His treatment course was complicated by poor wound healing in his right groin and recurrent hospital admissions for hypoxic respiratory failure thought to be from multifactorial etiologies including right heart failure, recurrent pleural effusions and pneumonia. Echo initially only showed left ventricular diastolic dysfunction and he improved with diuresis and antibiotics on different admissions. Chest computed tomography (CT) revealed smooth interlobular septal thickening, ground-glass opacities (GGOs), mediastinal lymphadenopathy (LAD), pleural effusions and enlarged central pulmonary arteries. Thoracentesis of the effusions and endoscopic bronchial ultrasound fine needle aspirates of mediastinal LAD were negative for malignancy.\n\nA year after his initial cancer diagnosis, he received systemic chemotherapy with carboplatin and paclitaxel as well as local radiation for recurrent metastatic disease but ended up on admission shortly after. He presented with worsening shortness of breath and increasing oxygen requirements and was found to be in cardiogenic shock requiring multiple pressors. Echo showed dilated right ventricle (RV) with systolic and diastolic septal flattening consistent with RV pressure and volume overload (Fig. 1).Fig. 1 Echo showing dilated RV with systolic and diastolic septal flattening consistent with RV pressure and volume overload.\n\nFig. 1\n\nChest computed tomography angiography (CTA) ruled out pulmonary embolism but again, had nonspecific findings of interlobular septal thickening, patchy GGOs, bilateral pleural effusions, mediastinal LAD and enlarged central pulmonary arteries (Fig. 2, Fig. 3, Fig. 4).Fig. 2 Mediastinal view of Chest CTA showing mediastinal LAD and enlarged central pulmonary artery.\n\nFig. 2\n\nFig. 3 Lung window of CTA showing interlobular septal thickening and pleural effusions.\n\nFig. 3\n\nFig. 4 Lung window of CTA showing patchy GGOs (albeit not in classic centrilobular fashion) and pleural effusions.\n\nFig. 4\n\nHe was admitted to the intensive care unit (ICU) in cardiogenic shock requiring multiple pressors and had pulmonary artery catheter (PAC) placed which showed elevated pulmonary artery and wedge pressures, increased pulmonary vascular resistance (PVR) and decreased cardiac index (CI).\n\nHe was aggressively diuresed and put on inhaled epoprostenol but later had to be switched to intravenous epoprostenol. After volume optimization, PAC numbers showed hemodynamics suggestive of pre-capillary PH with normal wedge pressure (Table 1). These findings, along with his extreme hypoxia, radiographic imaging and timeline from exposure to MMC raised concerns for possible MMC induced PVOD. Lung biopsy was not an option given his markedly elevated pulmonary artery pressures and hypoxemia. Despite our high clinical suspicion for PVOD, an informed and shared decision was made to try pulmonary vasodilators as the only other option was comfort measures. He fortunately responded well. His shock resolved with reduced oxygen requirements and after closely monitoring him in the ICU for a few more days, he was discharged home on supplemental oxygen, sildenafil, furosemide and intravenous epoprostenol. He unfortunately got re-admitted a week later in cardiogenic shock and succumbed to his disease. Genetic studies were negative for eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4) and bone morphogenetic protein receptor type II (BMPR2).Table 1 Shows pulmonary artery catheter readings on admission and after volume optimization but while still on a small dose of norepinephrine.\n\nTable 1PAC Variables (Normal PAC Values)\tAdmission PAC readings\tPAC numbers after volume optimization\t\nRight atrial pressure (mmHg)\t10\t0\t\nPulmonary artery pressure (mmHg)\t\t\t\nSystolic\t97\t54\t\nDiastolic\t48\t18\t\nMean\t63\t30\t\nPulmonary capillary wedge pressure\t17\t12\t\nCardiac output\t2.65\t3.69\t\nCardiac index\t1.62\t2.27\t\nPulmonary vascular resistance-calculated (dyn/sec/cm−5)\t1389\t390\t\nSystemic vascular resistance (dyn/sec/cm−5)\t1680\t2081\t\nMixed venous oxygen saturation\t20\t57\t\n\nPostmortem autopsy done showed slight cardiomegaly, dilated hypertrophy of right ventricle, left ventricular dilatation and pericardial effusion. Histopathologic findings of the lungs showed extensive interstitial fibrosis and organizing pneumonia involving both lungs as well as centrilobular emphysema, alveolar edema, pleural effusions, organizing bronchopneumonia, subpleural infarcts and thrombotic microangiopathy (small vessel thromboemboli). Based on the clinical history and autopsy findings his cardiac arrest was deemed to be secondary to right heart failure from pulmonary hypertension and PVOD secondary to MMC.\n\n3 Discussion\n\nPVOD is a rare form of pulmonary hypertension characterized by obliteration of small pulmonary veins by fibrous intimal thickening and patchy capillary proliferation [3]. It is often misclassified as pulmonary arterial hypertension (PAH) in about 10% of cases as they share similar clinical presentation with features of severe precapillary PH. It is however important to differentiate these two conditions as PVOD carries a much worse prognosis [1].\n\nPVOD may be idiopathic, heritable, drug/toxin induced, or it may develop in association with connective tissue diseases among other causes. Eyries et al., in 2013, discovered biallelic mutations in the EIF2AK4 gene as the cause of heritable PVOD and PCH(4). Current evidence therefore supports the concept that PVOD and PCH are in fact varied expressions of the same disorder(1). Regardless of etiology, PVOD tends to have poor prognosis and poor response to typical PAH therapies. Certain et al., in a small retrospective study, looked at characteristics and long-term outcomes of PVOD induced by MMC and came to the conclusion that ‘like other forms of PVOD, prognosis remains dismal despite MMC withdrawal and PAH-specific therapy’. However, they noted that whereas sporadic PVOD is male predominant and may be associated with mutations in EIF2AK4, MMC-PVOD is female predominant and has no association with EIF2AK4 mutations [4,5].\n\nClinical findings suggestive of PVOD are similar to PAH and include insidious onset of fatigue and breathlessness progressing to symptoms of right heart failure in end-stage disease, out-of-proportion dyspnea, hypoxemia, and low diffusion capacity of carbon monoxide (DLCO) on pulmonary function tests [6]. Definitive diagnosis of PVOD, regardless of etiology requires lung biopsy which carries a high risk of life-threatening complications in these patients. A noninvasive diagnostic approach is therefore favored. Decreased diffusing capacity of the lung for carbon monoxide, severe hypoxemia, radiological abnormalities on high-resolution chest CT, and the occurrence of pulmonary edema after starting pulmonary vasodilator therapy strongly argue for PVOD. The presence of two or three radiological abnormalities including mediastinal lymph node enlargement, interlobular septal thickening (Kerley B lines), and centrilobular ground-glass opacities had a sensitivity of 75% and a specificity of 84.6% for the detection of PVOD in a retrospective study by Montani et al., 2008 [6]. Ogawa et al., in 2018, based off a small retrospective study, also published a novel scoring system designed to clinically help diagnose PVOD/PCH: male sex, smoking history, 6-minute walk distance <285 m, minimum SpO2 < 92% during the 6-minute walk test (6MWT), %DLCO < 34%, GGO plus thickening of the interlobular septa on high-resolution CT, defects in the perfusion lung scan, and pulmonary edema due to vasodilators. They predicted a score of ≥5 points had 95% sensitivity and 98% specificity to predict PVOD/PCH (area under the curve: 0.991; 95% CI: 0.976–1.000) [7]. By their criteria, our patient had a score of 5 even though we did not have some of these variables like DLCO and 6MWT due to the patient presenting with such acuity in shock.\n\nOther suggestive CT findings include enlarged central pulmonary arteries and pleural effusions [8,9]. Bronchoalveolar lavage (BAL) may show increased hemosiderin-laden macrophages as occult alveolar hemorrhage tends to occur in these patients due to the presence of post-capillary block [10].\n\nMMC is an alkylating agent commonly used in chemotherapy. Lung toxicity and PVOD are documented in patients taking MMC [[11], [12], [13]] and the incidence of PVOD in patients with anal cancer is higher than in those with idiopathic PVOD, especially following treatment with MMC [2]. To confirm a causal link between MMC and human PVOD, Perros et al., in 2015 found that in rats, intraperitoneal administration of MMC induced PVOD, as demonstrated by pulmonary hypertension at right-heart catheterization at days 21–35 and major remodeling of small pulmonary veins associated with foci of intense microvascular endothelial-cell proliferation of the capillary bed. They also evaluated 7 cases of PVOD induced by MMC therapy from the French Pulmonary Hypertension Registry. These patients had received 2 to 4 cycles of chemotherapy except for one who also received 8 cycles of 5-fluorouracil plus oxaliplatin [2]. The average interval between the end of chemotherapy with MMC and the diagnosis of PVOD was four months (range: 2–12 months). It was about 11 months in the case of our patient. They also demonstrated in a follow up publication that MMC exposed lungs displayed areas of exuberant microvascular endothelial cell proliferation which mimics pulmonary capillary hemangiomatosis, one of the pathologic hallmarks of human PVOD.\n\nHistopathological features of PVOD include prominent alveolar septa, which are thickened secondary to capillary congestion. Evidence of old hemorrhage may be found in intra-alveolar hemosiderin-laden macrophages and interstitial hemosiderin. Interstitial fibrosis and focal interstitial lymphocytic infiltrates may be seen. These findings give the appearance of a chronic fibrosing interstitial process at low power. At higher power, examination of small and medium-sized veins shows fibrous intimal thickening by dense collagen or by edematous, loose connective tissue within the intima and media. Venous lumina are greatly narrowed or show total fibrous occlusion (Slide 1). Additional associated features include arterial hypertrophy, arterial thrombi, venous infarcts, and lymphatic dilation [14].Slide 1 Postmortem histopathology section from our patient showing a vein with its lumen significantly narrowed by fibrous intimal thickening.\n\nSlide 1\n\nFor our patient, extensive interstitial fibrosis was reported in the lung microscopic sections on the autopsy report. Additionally, subpleural infarcts, thrombotic microangiopathy, and small vessel thromboemboli were noted. Fibrous intimal thickening of veins was shown with an elastin stain (Slide 2). Elastin stains are crucial in diagnosing PVOD as they highlight the single external elastic membranes of veins and the internal and external elastic membranes of arteries. This is important as completely obliterated veins can sometimes only be appreciated with these special stains. This helps to distinguish PVOD from usual interstitial pneumonia (UIP) and other hemorrhagic and fibrosing processes [14].Slide 2 Elastin stain outlining the external elastic laminae of this vein in black. Fibrous intimal thickening is present. Red arrow: external elastic laminae of vessel.\n\nSlide 2\n\nNo evidence-based medical therapy exists for PVOD at present and lung transplant remains the preferred definitive therapy for eligible patients. The mean time from diagnosis to death or lung transplantation was 11.8 months, and the mean time from the first reported symptom to death or lung transplantation was 24.4 months in a study by Montani et al., 2008 [5]. Exposure to pulmonary vasodilators used to treat PAH may precipitate acute pulmonary edema in patients with PVOD but can be used with extreme caution and close monitoring [15]. The alveolar edema seen on our patient's autopsy could have been due to the pulmonary vasodilator he was on (edema can occur weeks or even months after treatment initiation) or more likely because he received a significant amount of fluid bolus for shock when he presented to the outside hospital the second time.\n\n4 Conclusion\n\nPVOD is an uncommon form of PH that is usually difficult to diagnose and is refractory to treatment with poor prognosis. It should be considered in cancer patients with PH, extreme hypoxemia, and suggestive CT findings in the setting of exposure to MMC. It is equally important to differentiate PVOD from other causes of PAH as standard therapy for PAH can be detrimental in PVOD if not used with caution. Lung transplant is the recommended treatment. Our case is particularly challenging because the patient presented to our center in such acuity and we could not get some tests that we would otherwise get when patients are more stable. There are very few reported cases of mitomycin induced PVOD (possibly under recognized) and we hope to increase the awareness with this report to facilitate diagnosis and expedite management because of the poor outcomes.\n\nDeclaration of competing interest\n\nNone.\n\nAuthors have no conflicts of interest to declare.\n==== Refs\nReferences\n\n1 Montani D. Lau E. Dorfmüller P. Girerd B. Jaïs X. Savale L. Pulmonary veno-occlusive disease Eur. Respir. J. 47 5 2016 1518 1534 10.1183/13993003.00026-2016 27009171\n2 Perros F. Günther S. Ranchoux B. Godinas L. Antigny F. Chaumais M. Mitomycin-induced pulmonary veno-occlusive disease Circulation 132 9 2015 834 847 10.1161/circulationaha.115.014207 26130118\n3 Mandel J. Mark E. Hales C. Pulmonary veno-occlusive disease Am. J. Respir. Crit. Care Med. 162 5 2000 1964 1973 10.1164/ajrccm.162.5.9912045 11069841\n4 Eyries M. Montani D. Girerd B. Perret C. Leroy A. Lonjou C. EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension Nat. Genet. 46 1 2013 65 69 10.1038/ng.2844 24292273\n5 Certain M. Chaumais M. Jaïs X. Savale L. Seferian A. Parent F. Characteristics and long-term outcomes of pulmonary veno-occlusive disease induced by mitomycin C Chest 159 3 2021 1197 1207 10.1016/j.chest.2020.09.238 32979348\n6 Montani D. Achouh L. Dorfmüller P. Le Pavec J. Sztrymf B. Tchérakian C. Pulmonary veno-occlusive disease Medicine 87 4 2008 220 233 10.1097/md.0b013e31818193bb 18626305\n7 Ogawa A. Takahashi Y. Matsubara H. Clinical prediction score for identifying patients with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis J. Cardiol. 72 3 2018 255 260 10.1016/j.jjcc.2018.02.009 29548663\n8 Pulmonary hypertension: CT of the chest in pulmonary veno-occlusive disease AJR Am. J. Roentgenol. 183 2004 65 70 15208112\n9 Frazier A. Franks T. Mohammed T. Ozbudak I. Galvin J. Pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis Radiographics 27 3 2007 867 882 10.1148/rg.273065194 17495297\n10 Rabiller A. Occult alveolar hemorrhage in pulmonary veno-occlusive disease Eur. Respir. J. 27 2013 108 113 2006\n11 Botros L. Van Nieuw Amerongen G. Noordegraaf A. Bogaard H. Recovery from mitomycin-induced pulmonary arterial hypertension Annals of The American Thoracic Society 11 3 2014 468 470 10.1513/annalsats.201312-426le 24673706\n12 Khalid H. Damjanov I. Latham H. Mitomycin induced pulmonary veno-occlusive disease in a patient with carcinoma of the breast Kansas Journal of Medicine 6 1 2013 31 33 10.17161/kjm.v6i1.11433\n13 Joselson R. Warnock M. Pulmonary veno-occlusive disease after chemotherapy Hum. Pathol. 14 1 1983 88 91 10.1016/s0046-8177(83)80052-5 6187654\n14 Hoda S. D'Alfonso T. Sternberg's diagnostic surgical Pathology Adv. Anat. Pathol. 22 3 2015 225 10.1097/pap.0000000000000070\n15 Montani D. O'Callaghan D. Pulmonary veno-occlusive disease: recent progress and current challenges Respir. Med. 2010\n\n",
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"title": "Mitomycin induced pulmonary veno-occlusive disease.",
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"abstract": "In a prospective case series of patients with Blau-Jabs syndrome (BJS) conducted in the Ophthalmology Department/Federal University of Sao Paulo, seven patients with clinical and ophthalmologic manifestations of the disease and a positive genetic test result for the presence of a mutation in the CARD15/NOD2 gene were followed for a minimal period of 1 year. All patients had uveitis, five had nummular corneal subepithelial opacities, and four had multifocal choroiditis. Oral prednisolone was administered to all patients; inflammation was controlled in six patients with at least one immunosuppressive drug. Infliximab (Remicade; Janssen Pharmaceuticals, Beerse, Belgium) and etanercept (Enbrel; Amgen, Thousand Oaks, CA) were used to treat two cases refractory to the anti-inflammatory drugs. A subconjunctival dexamethasone implant (Ozurdex; Allergan, Irvine, CA) and a periocular injection of triamcinolone were used in one case to achieve inflammation control. Six patients achieved a visual acuity of 20/25 or better. The authors conclude that periocular treatment with steroid injections might be effective adjuvant therapy to control ocular inflammation. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:70-75.].",
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"authors": "Nascimento|Heloisa|H|;Sousa|Jacqueline M|JM|;Fernández|Délia González|DG|;Salomão|Gustavo H A|GHA|;Sato|Elcio H|EH|;Muccioli|Cristina|C|;Belfort|Rubens|R|",
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"mesh_terms": "D000293:Adolescent; D000328:Adult; D000869:Anterior Eye Segment; D001168:Arthritis; D002648:Child; D004247:DNA; D003937:Diagnosis, Differential; D005260:Female; D005500:Follow-Up Studies; D005820:Genetic Testing; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D033401:Microscopy, Acoustic; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein; D011446:Prospective Studies; D012507:Sarcoidosis; D013585:Synovitis; D062606:Tertiary Care Centers; D014605:Uveitis; D055815:Young Adult",
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"abstract": "The case of an infant girl with severe congenital sideroblastic anemia associated with a novel molecular defect in mitochondrial transporter SLC25A38 is presented. Her transfusion dependence was fully reversed following allogeneic hematopoietic stem cell transplantation using a modified reduced-intensity conditioning regimen, and she remains healthy 5 years posttransplant.",
"affiliations": "Blood and Marrow Transplantation and Cellular Therapies Children's Hospital of Pittsburgh Pittsburgh PA USA.;Center for Cancer and Blood Disorders Phoenix Children's Hospital Phoenix AZ USA.;Department of Medicine Hematology-Oncology Section University of Oklahoma College of Medicine Oklahoma City OK USA.;Pediatric Blood and Marrow Transplantation Yale New Haven Children's Hospital New Haven CT USA.",
"authors": "Kim|Min Hee|MH|0000-0002-3487-7746;Shah|Sanjay|S|0000-0001-7762-598X;Bottomley|Sylvia S|SS|;Shah|Niketa C|NC|",
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"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.1667CCR31667Case ReportCase ReportsReduced‐toxicity allogeneic hematopoietic stem cell transplantation in congenital sideroblastic anemia KIM et al.Kim Min Hee http://orcid.org/0000-0002-3487-7746minheekim.mini@gmail.com \n1\nShah Sanjay http://orcid.org/0000-0001-7762-598X\n2\nBottomley Sylvia S. \n3\nShah Niketa C. \n4\n\n1 \nBlood and Marrow Transplantation and Cellular Therapies\nChildren's Hospital of Pittsburgh\nPittsburgh\nPA\nUSA\n\n2 \nCenter for Cancer and Blood Disorders\nPhoenix Children's Hospital\nPhoenix\nAZ\nUSA\n\n3 \nDepartment of Medicine\nHematology‐Oncology Section\nUniversity of Oklahoma College of Medicine\nOklahoma City\nOK\nUSA\n\n4 \nPediatric Blood and Marrow Transplantation\nYale New Haven Children's Hospital\nNew Haven\nCT\nUSA\n* Correspondence\n\nMin Hee Kim, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.\n\nEmail: minheekim.mini@gmail.com\n01 8 2018 9 2018 6 9 10.1002/ccr3.2018.6.issue-91841 1844 23 1 2018 18 4 2018 11 6 2018 © 2018 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Key Clinical Message\nThe case of an infant girl with severe congenital sideroblastic anemia associated with a novel molecular defect in mitochondrial transporter SLC25A38 is presented. Her transfusion dependence was fully reversed following allogeneic hematopoietic stem cell transplantation using a modified reduced‐intensity conditioning regimen, and she remains healthy 5 years posttransplant.\n\nhematopoietic stem cell transplantationsideroblastic anemiaSLC25A38 source-schema-version-number2.0component-idccr31667cover-dateSeptember 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.7.1 mode:remove_FC converted:11.09.2018\n\n\nKim \nMH \n, \nShah \nS \n, \nBottomley \nSS \n, \nShah \nNC \n. Reduced‐toxicity allogeneic hematopoietic stem cell transplantation in congenital sideroblastic anemia . Clin Case Rep . 2018 ;6 :1841 –1844 . 10.1002/ccr3.1667\n==== Body\n1 INTRODUCTION\nSideroblastic anemia is identified by the unique presence of erythroid precursors in the bone marrow aspirate smear that contain pathologic deposits of iron in mitochondria and are called ring sideroblasts. Occurring as a broad spectrum of erythropoietic disorders, in adults they are most often acquired conditions (eg, in association with a myelodysplastic syndrome, exposure to certain drugs and alcohol, and copper deficiency), while in early life a congenital or inherited sideroblastic anemia (CSA) is most frequent and its molecular basis can be established in over 50% of cases.1, 2 Recognized defects reside in the pathways of heme synthesis, iron‐sulfur cluster biogenesis, and mitochondrial protein translation. The most common CSA forms are X‐linked sideroblastic anemia due to mutations affecting the erythroid heme synthesis enzyme 5‐aminolevulinate synthase 2 (ALAS2) and the autosomal recessive sideroblastic anemia due to mutations affecting the erythroid‐specific mitochondrial inner membrane protein SLC25A38. Associated ineffective erythropoiesis leads to variably severe anemia and usually systemic iron overload.\n\nFor severe, transfusion‐dependent sideroblastic anemia, treatment with hematopoietic stem cell transplantation (HSCT) had been reported in the limited number of six cases with apparent CSA although their molecular basis was not known.3, 4, 5, 6 More recently, a few anecdotal cases having identified molecular defects in SLC25A38 who were treated with HSCT were briefly annotated.7, 8 Here, we describe a patient with CSA associated with novel mutations in the SLC25A38 gene and her treatment with HSCT using a novel preparative regimen consisting of busulfan, fludarabine, and alemtuzumab with the aim to reduce toxicity.\n\n2 CASE REPORT\nWe present the case of a Hispanic girl who was noted to be pale since birth in 2009 and at 2.5 months of age exhibited severe microcytic anemia with hemoglobin at 3.3 g/dL and mean red cell volume (MCV) of 57 fl; the red blood cell (RBC) relative distribution width (RDW) was 31%, and reticulocytes, 2.3%, and leukocyte and platelet counts were normal. The blood smear showed marked microcytosis, hypochromia, anisocytosis, and nucleated RBCs. At age 5 months, the marrow aspirate revealed mild erythroid hyperplasia and numerous ring sideroblasts (Figure 1). Serum iron data were said to be normal as also erythrocyte protoporphyrins, blood chemistries, and various hematologic studies. Her clinical phenotype was highly suggestive of autosomal recessive CSA. In 2010, Sanger sequencing, targeting the coding and flanking intronic regions of the SLC25A38 gene,7 disclosed a novel homozygous c.832C>T change resulting in a stop codon at arginine 278 (Arg278X) of the protein (Figure 2). Both parents and a sister are carriers (heterozygous) for the mutation. Only distant consanguinity in the family was evident in that the paternal grandmothers of the patient's parents were cousins.\n\nFigure 1 The patient's bone marrow aspirate stained with Prussian blue, showing two ring sideroblasts\n\nFigure 2 Identification of the mutation in SLC25A38 by direct sequencing. The patient (A) is homozygous for c.832C>T, and the sister (B), mother (C), and father (D) are heterozygous for the c832C>T change\n\nThe patient received RBC transfusions every 4‐6 weeks since infancy, and after age 15 months, when the serum ferritin had reached 1700 ng/mL, deferasirox was also administered. At age 4, when the liver iron by MRI was 5.3 mg/g dry tissue and cardiac MRI T2‐star was normal (41.5 ms), she received a 6/6 matched sibling donor bone marrow infusion with a nucleated cell dose of 5.43 × 108/kg. The conditioning regimen consisted of busulfan (1.2 mg/kg every 6 hours for 4 days), fludarabine (40 mg/m2/day for 4 days), and an intermediate dose of alemtuzumab (0.2 mg/kg/day for 5 days from day ‐14 to day ‐10). Methotrexate (days +1, +3, and +6) and tacrolimus were given for graft‐vs‐host disease (GVHD) prophylaxis. She tolerated the transplant very well without major complications. Leukocyte engraftment was present on day +17 and a 100% donor chimerism on day +30. RBC transfusion was no longer required after 1 month posttransplant. Subsequently, monthly phlebotomy was performed for 6 months to reduce residual iron overload. At present, nearly 5 years posttransplant, she is healthy with a hemoglobin of 12‐14 g/dL.\n\n3 DISCUSSION\nAmong the nonsyndromic types of CSA so far characterized, the autosomal recessive form due to molecular defects in the glycine transporter SLC25A38 is most common in occurrence after X‐linked sideroblastic anemia.2 To date, biallelic mutations in the SLC25A38 gene associated with CSA have been reported in at least 40 probands or families.7, 8, 9, 10, 11, 12 Most mutations are severe or complete loss‐of‐function mutations. Severe anemia is typically found at birth or in early childhood and requires lifelong transfusions. The burden of supportive care includes iron chelation and avoidance of alloimmunization and infection.\n\nAt present, definitive cure for this CSA form may be attempted with allogeneic HSCT, but to date this therapeutic option remains anecdotal.7, 8 HSCT has become an established treatment for a variety of genetic diseases in childhood, namely thalassemia major, sickle cell anemia, Wiskott‐Aldrich syndrome, Fanconi's constitutional hypoplastic anemia, lysosomal storage diseases, and severe combined immunodeficiency.13 The major consideration in this procedure is to provide effective immunosuppression while creating a sufficient degree of donor bone marrow engraftment. Among the previously described six patients with CSA of undefined cause who were treated with HSCT, five received myeloablative conditioning with busulfan and cyclophosphamide +/− antithymocyte globulin (ATG) as the preparative regimen.3, 4, 5 One patient, who could not receive conventional myeloablative conditioning due to underlying comorbidities, received fludarabine, low‐dose total body irradiation, and ATG.6 Despite full engraftment, he succumbed to GVHD and prior iron overload on day +190.\n\nThe conditioning regimen in our patient, consisting of busulfan, fludarabine, and alemtuzumab, was chosen over traditional myeloablation to decrease transplant‐related toxicities while achieving stable engraftment, which is not seen with very low‐intensity regimens.14, 15 Fludarabine, a strongly immunosuppressive purine analogue, replaced cyclophosphamide that is known to have increased hepatic toxicity in the presence of busulfan, cardiac toxicity with high doses, and a risk of hemorrhagic cystitis.16 Serotherapy with rabbit‐derived antithymocyte globulin (ATG) has been used for many years as prophylaxis for GVHD. However, in recent years it has been replaced by alemtuzumab, a humanized monoclonal antibody directed against CD52, which has had less graft failure and less chronic GVHD in comparison with ATG.17, 18 In the pediatric age group, single‐center studies using a similar approach have evaluated ATG or alemtuzumab with busulfan and fludarabine for both malignant and nonmalignant diseases. The busulfan/fludarabine/ATG regimen had excellent overall survival; however, graft failure occurred in the majority of children with nonmalignant disorders undergoing mismatched unrelated donor transplants.18 The same group reported improved engraftment and decreased GVHD rates using alemtuzumab instead of ATG with busulfan and fludarabine conditioning for malignant and nonmalignant disorders.19 Our patient also benefited from this reduced‐toxicity regimen. She continues to have 100% donor chimerism posttransplant without a need for RBC transfusion, signs of iron overload, or GVHD. At nearly 5 years posttransplant, she has no long‐term side effects and is living a healthy life.\n\nIn conclusion, this case illustrates that allogeneic bone marrow transplantation using busulfan, fludarabine, and alemtuzumab as the conditioning regimen can be a curative therapy for severe CSA. As the genetic knowledge of CSA becomes extended, we hope to further classify CSAs and tailor each SCT process to aim for continued successful outcomes.\n\nAUTHORSHIP\nMHK, SS, and NCS: involved in patient management. SSB: suggested the diagnosis, facilitated molecular analysis of samples, and provided review and editing of the manuscript. MHK, SS, and NCS: wrote the manuscript.\n\nCONFLICT OF INTEREST\nNone declared.\n\nACKNOWLEDGMENT\nWe thank Dr. Mark Fleming and Dean Campagna at Boston Children's Hospital, Boston, MA, for performing the DNA analysis of the family.\n==== Refs\nREFERENCES\n1 \n\nBottomley \nSS \n, \nFleming \nMD \n. Sideroblastic anemia diagnosis and management . Hematol Oncol Clin N Am . 2014 ;28 :653 ‐670 .\n2 \n\nBergmann \nAK \n, \nCampagna \nDR \n, \nMcLoughlin \nEM \n, et al. Systemic molecular genetic analysis of congenital sideroblastic anemia: evidence for genetic heterogeneity and identification of novel mutations . Pediatr Blood Cancer . 2010 ;54 :273 ‐278 .19731322 \n3 \n\nUrban \nC \n, \nBinder \nB \n, \nHauer \nC \n, \nLanzer \nG \n. Congenital sideroblastic anemia successfully treated by allogeneic bone marrow transplantation . Bone Marrow Transplant . 1992 ;10 :373 ‐375 .1422494 \n4 \n\nGonzalez \nMI \n, \nCaballero \nD \n, \nVazquez \nL \n, et al. Allogeneic peripheral stem cell transplantation in a case of hereditary sideroblastic anemia . Br J Haematol . 2000 ;109 :658 ‐660 .10886220 \n5 \n\nAyas \nM \n, \nAl‐Jefri \nA \n, \nMustafa \nMM \n, \nAl‐Mahr \nM \n, \nShalaby \nL \n, \nSolh \nH \n. Congenital sideroblastic anemia successfully treated using allogeneic stem cell transplantation . Br J Haematol . 2001 ;113 :938 ‐939 .11442487 \n6 \n\nMedeiros \nBC \n, \nKolhouse \nJF \n, \nCagnoni \nPJ \n, et al. Nonmyeloablative allogeneic hematopoietic stem cell transplantation for congenital sideroblastic anemia . Bone Marrow Transplant . 2003 ;31 :1053 ‐1055 .12774059 \n7 \n\nGuernsey \nDL \n, \nJiang \nH \n, \nCampagna \nDR \n, et al. Mutations in mitochondrial carrier family gene SLC25A38 cause nonsyndromic autosomal recessive congenital sideroblastic anemia . Nat Genet . 2009 ;41 :651 ‐653 .19412178 \n8 \n\nKannengiesser \nC \n, \nSanchez \nM \n, \nSweeney \nM \n, et al. Missense SLC25A38 variations play an important role in autosomal recessive inherited sideroblastic anemia . Haematologica . 2011 ;96 :808 ‐813 .21393332 \n9 \n\nLiu \nG \n, \nGuo \nS \n, \nKang \nH \n, et al. Haematologica . 2013 ;98 :e158 ‐e160 .24323989 \n10 \n\nWong \nWS \n, \nWong \nHF \n, \nCheng \nCK \n, et al. Congenital sideroblastic anaemia with a novel frameshift mutation in SLC25A38 . J Clin Pathol . 2015 ;68 :249 ‐251 .25512395 \n11 \n\nAn \nW \n, \nZhang \nJ \n, \nChang \nL \n, et al. Mutation analysis of Chinese sporadic congenital sideroblastic anemia by targeted capture sequencing . J Hematol Oncol . 2015 ;8 :55 .25985931 \n12 \n\nMehri \nM \n, \nZarin \nM \n, \nArdalani \nF \n, \nNajmabadi \nH \n, \nAzarkeivan \nA \n, \nNeishabury \nM \n. Novel mutations in mitochondrial carrier family gene SLC25A38, causing congenital sideroblastic anemia in Iranian families, identified by whole exome sequencing . Blood Cell Mol Dis . 2018 ;71 :39 ‐44 .\n13 \n\nNeumann \nKB \n, ed. Hematopoietic stem cell transplantation research advances . New York : Nova Science Publishers ; 2008 .\n14 \n\nde Lima \nM \n, \nCouriel \nD \n, \nThall \nPF \n, et al. Once‐daily intravenous busulfan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced‐toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS . Blood . 2004 ;104 :857 ‐864 .15073038 \n15 \n\nBornhauser \nM \n, \nStrorer \nB \n, \nSlattery \nJT \n, et al. Conditioning with fludarabine and targeted busulfan for transplantation of allogeneic hematopoietic stem cells . Blood . 2003 ;102 :820 ‐826 .12676781 \n16 \n\nMcDonald \nGB \n, \nSlattery \nJT \n, \nBouvier \nME \n, et al. Cyclophosphamide metabolism, liver toxicity, and mortality following hematopoietic stem cell transplantation . Blood . 2003 ;101 :2043 ‐2048 .12406916 \n17 \n\nHo \nAY \n, \nPagliuca \nA \n, \nKenyon \nM \n, et al. Reduced‐intensity allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome and acute myeloid leukemia with multilineage dysplasia using fludarabine, busulphan, and alemtuzumab (FBC) conditioning . Blood . 2004 ;104 :1616 ‐1623 .15059843 \n18 \n\nHorn \nB \n, \nBaxter‐Lowe \nLA \n, \nEnglert \nL \n, et al. Reduced intensity conditioning using intravenous busulfan, fludarabine and rabbit ATG for children with nonmalignant disorders and CML . Bone Marrow Transplant . 2006 ;37 :263 ‐269 .16327813 \n19 \n\nLaw \nJ \n, \nCowan \nMJ \n, \nDvorak \nCC \n, et al. Busulfan, fludarabine, and alemtuzumab as a reduced toxicity regimen for children with malignant and nonmalignant diseases improves engraftment and graft‐versus‐host disease without delaying immune reconstitution . Biol Blood Marrow Transplant . 2012 ;18 :1656 ‐1663 .22609040\n\n",
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"title": "Reduced-toxicity allogeneic hematopoietic stem cell transplantation in congenital sideroblastic anemia.",
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"abstract": "Recent molecular advances have identified a novel sarcoma defined molecularly by oncogenic fusion of the genes CIC and DUX4 termed CIC-DUX4 sarcomas. The most common site of involvement was the trunk but some cases have been described in the head and neck and extremities. We report one of the first cases of primitive renal CIC-DUX4 sarcoma: a 12-year-old boy who presented a renal tumor, a vena cava thrombus, and lung metastases. The morphological and immunohistochemical analysis showed an undifferentiated sarcoma. Molecular analysis demonstrated a CIC-DUX4 translocation, confirmed by fluorescence in situ hybridization. Despite treatment with chemotherapy, the evolution was unfavorable and the patient died 17 months after the diagnosis in a context of brain metastases. The diagnosis of sarcoma with CIC-DUX4 gene fusion is difficult in lack of specific pathological characteristics emphasizing the need for molecular analysis. Treatment has not yet been codified for these very aggressive tumors.",
"affiliations": "1 Département D'oncologie Pédiatrique, CHU de Grenoble, Grenoble, France.;2 Département de Pathologie, CHU de Grenoble, Grenoble, France.;1 Département D'oncologie Pédiatrique, CHU de Grenoble, Grenoble, France.;1 Département D'oncologie Pédiatrique, CHU de Grenoble, Grenoble, France.;3 INSERM U830, Laboratoire de Génétique et Biologie des Cancers, Institut Curie, Paris, France.;3 INSERM U830, Laboratoire de Génétique et Biologie des Cancers, Institut Curie, Paris, France.;2 Département de Pathologie, CHU de Grenoble, Grenoble, France.;2 Département de Pathologie, CHU de Grenoble, Grenoble, France.;2 Département de Pathologie, CHU de Grenoble, Grenoble, France.;4 Département de Chirurgie, CHU de Grenoble, Grenoble, France.;5 Département de Radiologie, CHU de Grenoble, Grenoble, France.;1 Département D'oncologie Pédiatrique, CHU de Grenoble, Grenoble, France.;2 Département de Pathologie, CHU de Grenoble, Grenoble, France.",
"authors": "Camille|Allirot|A|;Anne-Sophie|Bidaut|B|;Cécile|Perret|P|;Severine|Bobillier-Chaumont|BC|;Gaelle|Pierron|P|;Olivier|Delattre|D|;Geraldine|Saada-Sebag|SS|;Leer-Florin|Anne Mc|AM|;Eleni|Nika|N|;Christian|Piolat|P|;Chantal|Durand|D|;Dominique|Plantaz|P|;Hervé|Sartelet|S|",
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"title": "Sarcoma With CIC-DUX4 Gene Fusion: Case Report of Kidney Tumor Location in a 12-year-old Boy.",
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"abstract": "Infants with low-grade glioma (LGG) have a poor survival. BRAFV600E mutation has been identified in pediatric LGG; however, the use of BRAF inhibitors in infants has never been reported. A 2-month-old with V600E mutant hypothalamic/chiasmatic glioma progressed on chemotherapy resulting in profound visual loss, massive ascites, and diencephalic syndrome. Initiation of dabrafenib resulted in rapid and sustained disappearance of clinical symptoms and a profound sustained cytoreduction. BRAF inhibition was safely tolerated with dramatic clinicoradiological response, suggesting early targeted therapy is a viable option in infants with LGG. A re-evaluation of current management paradigms in this population is warranted to leverage the potential benefit of upfront-targeted therapies.",
"affiliations": "Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.;Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.;Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.;Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.;Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.;The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.;Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.;Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada. uri.tabori@sickkids.ca.",
"authors": "Lassaletta|Alvaro|A|;Guerreiro Stucklin|Ana|A|;Ramaswamy|Vijay|V|;Zapotocky|Michal|M|;McKeown|Tara|T|;Hawkins|Cynthia|C|;Bouffet|Eric|E|;Tabori|Uri|U|",
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"doi": "10.1002/pbc.26086",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "63(11)",
"journal": "Pediatric blood & cancer",
"keywords": "dabrafenib; glioma; hypothalamic-chiasmatic; infant; low grade",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D001932:Brain Neoplasms; D005260:Female; D005910:Glioma; D006801:Humans; D007027:Hypothalamic Diseases; D007223:Infant; D008279:Magnetic Resonance Imaging; D048493:Proto-Oncogene Proteins B-raf",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "2038-41",
"pmc": null,
"pmid": "27398937",
"pubdate": "2016-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Profound clinical and radiological response to BRAF inhibition in a 2-month-old diencephalic child with hypothalamic/chiasmatic glioma.",
"title_normalized": "profound clinical and radiological response to braf inhibition in a 2 month old diencephalic child with hypothalamic chiasmatic glioma"
} | [
{
"companynumb": "CA-FRESENIUS KABI-FK201609102",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VINBLASTINE"
},
"drugadditional": null,
... |
{
"abstract": "Kounis Syndrome is a rare allergic reaction that results in coronary vasospasm and may occur in patients with and without coronary artery disease. A 57-year-old man receiving pre-operative vancomycin for osteomyelitis and gangrene of the foot experienced an episode of anginal symptoms associated with transient ischemic 12-lead electrocardiogram (ECG) changes. The patient's symptoms and ECG changes abated with discontinuation of vancomycin and subsequent coronary angiography revealed no evidence of coronary artery disease. Treatment of Kounis Syndrome begins with cessation of the causative agent. Consensus guidelines for the management of Kounis Syndrome have not been established but treatment should both dilate the coronary vessels and suppress the allergic response. Coronary vasospasm after administration of antibiotics, including vancomycin, is a rare but serious reaction. It is important that Emergency Physicians recognize Kounis Syndrome as an uncommon yet dramatic and consequential reaction to such a commonly-administered antibiotic.",
"affiliations": "The Johns Hopkins University School of Medicine, Department of Emergency Medicine, 1830 E. Monument Street - Suite 6-100, Baltimore, MD 21287, United States of America. Electronic address: cleibee1@jhmi.edu.;The Johns Hopkins University School of Medicine, Department of Emergency Medicine, 1830 E. Monument Street - Suite 6-100, Baltimore, MD 21287, United States of America. Electronic address: bgetach2@jhmi.edu.;The Johns Hopkins University School of Medicine, Department of Emergency Medicine, 1830 E. Monument Street - Suite 6-100, Baltimore, MD 21287, United States of America. Electronic address: mehmann1@jhmi.edu.",
"authors": "Leibee|Caleb|C|;Getachew|Bahrenegash|B|;Ehmann|Michael R|MR|",
"chemical_list": "D000900:Anti-Bacterial Agents; D014640:Vancomycin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajem.2019.06.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": "37(9)",
"journal": "The American journal of emergency medicine",
"keywords": "Allergens; Coronary vasospasm; Kounis Syndrome; Vancomycin",
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D061605:Administration, Intravenous; D000900:Anti-Bacterial Agents; D003329:Coronary Vasospasm; D004562:Electrocardiography; D005734:Gangrene; D006801:Humans; D000074962:Kounis Syndrome; D008297:Male; D008875:Middle Aged; D010019:Osteomyelitis; D014640:Vancomycin",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "1806.e3-1806.e5",
"pmc": null,
"pmid": "31182359",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Vancomycin-induced Kounis Syndrome.",
"title_normalized": "vancomycin induced kounis syndrome"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK201910035",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CLONIDINE"
},
"drugadditional": null,
... |
{
"abstract": "Background Previous observational studies have shown that telemedicine is feasible and safe to deliver intravenous (IV) recombinant tissue plasminogen activator (rt-PA). However, implementation of telemedicine may be challenging. To illustrate this fact, we report a study showing that telemedicine failed to improve clinical outcome and analyze the reasons for this shortcoming. Methods We established a tele-stroke network of 10 emergency rooms (ERs) of community hospitals connected to a stroke center to perform a randomized, open-label clinical trial with blinded outcome evaluation. Eligible patients were randomly assigned to either a usual care arm (i.e. immediate transfer to the stroke center and administration of IV rt-PA if indication was confirmed upon stroke arrival) or tele-thrombolysis arm (i.e. immediate administration of IV rt-PA in ER and transfer to the stroke center). The primary efficacy outcome was an excellent outcome (modified Rankin scale (mRS) 0-1 at 90 days). Secondary endpoints included favorable outcome (90-day mRS 0-2) and early neurological improvement (NIHSS score 0-1 at 24 hours or a decrease of ≥ 4 points within 24 hours). Safety outcomes included symptomatic intracerebral hemorrhage (ICH) per ECASS II definition, any ICH and all-cause mortality. Results During an accrual time of 48 months, because of a slow enrollment rate, only 49 of 270 patients initially planned for inclusion were randomized into usual care ( n = 23) and tele-thrombolysis ( n = 26). Despite random assignment, patients allocated to tele-thrombolysis were older and had more severe stroke than patients allocated to usual care. The median duration of video-conference was 23 minutes in the usual care arm and 73 minutes in the tele-thrombolysis arm. Eighty-four percent of patients in the tele-thrombolysis arm were treated by IV rt-PA in comparison to 18% in the usual care arm. In univariate analysis but not after adjustment for age and baseline NIHSS, patients allocated in the usual care arm had a higher rate of excellent or favorable outcome. There were no differences in safety outcomes, with only one symptomatic ICH occurring in the tele-thrombolysis arm. Conclusions Stroke patients included in the telemedicine arm of the TRUST-tPA trial increased their rt-PA eligibility five-fold. However, the efficacy and safety remains to be determined (ClinicalTrials.org, NCT00279149).",
"affiliations": "1 Department of Neurology and Stroke Centre, Bichat University Hospital, France.;1 Department of Neurology and Stroke Centre, Bichat University Hospital, France.;1 Department of Neurology and Stroke Centre, Bichat University Hospital, France.;3 Emergency Department, Compiègne Hospital, France.;4 Emergency Department, Argenteuil Hospital, France.;5 Emergency Department, Provins Hospital, Provins, France.;6 APHP, Département D'Epidémiologie et Recherche Clinique, Hôpital Bichat, France; Univ Paris Diderot, Sorbonne Paris Cité, UMR 1123, France; INSERM, CIC-EC 1425, UMR 1123, France.;1 Department of Neurology and Stroke Centre, Bichat University Hospital, France.",
"authors": "Mazighi|Mikael|M|;Meseguer|Elena|E|;Labreuche|Julien|J|;Miroux|Patrick|P|;Le Gall|Catherine|C|;Roy|Patricia|P|;Tubach|Florence|F|;Amarenco|Pierre|P|",
"chemical_list": "D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator",
"country": "England",
"delete": false,
"doi": "10.1177/1357633X15615762",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1357-633X",
"issue": "23(1)",
"journal": "Journal of telemedicine and telecare",
"keywords": "Telemedicine; teleneurology",
"medline_ta": "J Telemed Telecare",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003299:Cooperative Behavior; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D008297:Male; D008875:Middle Aged; D009422:Nervous System Diseases; D017063:Outcome Assessment, Health Care; D020521:Stroke; D017216:Telemedicine; D010959:Tissue Plasminogen Activator; D055815:Young Adult",
"nlm_unique_id": "9506702",
"other_id": null,
"pages": "174-180",
"pmc": null,
"pmid": "26656722",
"pubdate": "2017-01",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "TRUST-tPA trial: Telemedicine for remote collaboration with urgentists for stroke-tPA treatment.",
"title_normalized": "trust tpa trial telemedicine for remote collaboration with urgentists for stroke tpa treatment"
} | [
{
"companynumb": "FR-ROCHE-1684473",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": null,
"druga... |
{
"abstract": "We report a 58-year-old man presenting with acute paraplegia. MRI showed a haematoma within a well-defined epidural lesion at C7-D1. Intraoperatively, organised epidural haematoma surrounded by tumour tissue was found. The final histopathology report was angiolipoma. The patient had dramatic recovery. Angiolipomas should be considered in the differential diagnosis of acute paraplegia when imaging shows well-circumscribed haematoma.",
"affiliations": "Department of Neurosurgery, Seth G.S. Medical College & KEM Hospital, Mumbai, Maharashtra, India.;Department of Neurosurgery, Seth G.S. Medical College & KEM Hospital, Mumbai, Maharashtra, India.;Department of Neurosurgery, Seth G.S. Medical College & KEM Hospital, Mumbai, Maharashtra, India.;Department of Medicine, Seth G.S. Medical College & KEM Hospital, Mumbai, Maharashtra, India.",
"authors": "Ramdasi|Raghvendra Vijayrao|RV|;Avinasha|K M|KM|;Mahore|Amit|A|;Kawale|Juhi|J|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2014()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000208:Acute Disease; D018206:Angiolipoma; D001707:Biopsy, Needle; D003937:Diagnosis, Differential; D038524:Diffusion Magnetic Resonance Imaging; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D007796:Laminectomy; D008297:Male; D008875:Middle Aged; D010264:Paraplegia; D020127:Recovery of Function; D018570:Risk Assessment; D013117:Spinal Cord Compression; D013125:Spinal Neoplasms; D020521:Stroke; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "24842366",
"pubdate": "2014-05-19",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "8421211;21435880;16370284;19127373;18228054;2201098;17823050;20874452;10492682;9346153;742436;3982624",
"title": "Spinal angiolipoma manifesting with apoplexy.",
"title_normalized": "spinal angiolipoma manifesting with apoplexy"
} | [
{
"companynumb": "IN-SUN PHARMACEUTICAL INDUSTRIES LTD-2017R1-131944",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadd... |
{
"abstract": "Tumor lysis syndrome is a potentially lethal complication of chemotherapy, usually associated with aggressive hematologic malignancies. We describe the case of a young patient with metastatic hepatocellular cancer who developed rapid and fatal tumor lysis syndrome following initiation of sorafenib therapy. Although rare with sorafenib therapy for hepatocellular carcinoma, tumor lysis syndrome is serious complication. Patients with a high burden of disease at therapy initiation should have their metabolic parameters measured prior to starting therapy and closely followed for the first 1-2 weeks while being treated.",
"affiliations": "Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA; San Juan Oncology Associates, Farmington, NM, USA.;Department of Internal Medicine, Temple University Hospital, Philadelphia, PA, USA. Electronic address: mohammad.zahid@tuhs.temple.edu.;Medical College, Aga Khan University, Karachi, Pakistan.",
"authors": "Imam|Sardar Zakariya|SZ|;Zahid|Mohammad Faizan|MF|;Maqbool|Muhammad Asad|MA|",
"chemical_list": "D000077157:Sorafenib",
"country": "England",
"delete": false,
"doi": "10.1016/j.hemonc.2018.03.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "13(3)",
"journal": "Hematology/oncology and stem cell therapy",
"keywords": "Hepatocellular carcinoma; Sorafenib; Tumor lysis syndrome",
"medline_ta": "Hematol Oncol Stem Cell Ther",
"mesh_terms": "D006528:Carcinoma, Hepatocellular; D017809:Fatal Outcome; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D000077157:Sorafenib; D015275:Tumor Lysis Syndrome",
"nlm_unique_id": "101468532",
"other_id": null,
"pages": "168-170",
"pmc": null,
"pmid": "29684339",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Sorafenib-induced tumor lysis syndrome in a patient with metastatic hepatocellular carcinoma.",
"title_normalized": "sorafenib induced tumor lysis syndrome in a patient with metastatic hepatocellular carcinoma"
} | [
{
"companynumb": "US-BAYER-2018-093584",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SODIUM POLYSTYRENE SULFONATE"
},
"drugadditional"... |
{
"abstract": "Nivolumab exerts antitumor effects by inhibiting binding of PD-L1 to PD-1, and offers proven effectiveness in various disease areas, including cancers of the head and neck. The mechanisms of action lead nivolumab to induce immune-related adverse events (irAE). We report a case of pituitary-adrenal dysfunction to isolated adrenocorticotropic hormone (ACTH) deficiency as an irAE of nivolumab in a patient treated for head and neck cancer. This is the first report of an irAE of nivolumab in the field of head and neck squamous cell cancer. The patient was a man in his 50s with cancer of the tongue and hypopharynx that recurred after chemoradiotherapy, surgery and chemotherapy. After starting nivolumab, irAEs developed after 8 courses. The case was managed from the early stages in collaboration with the endocrinology department. Pituitary-adrenal hypofunction due to isolated ACTH deficiency was diagnosed on the basis of endocrine tests. The patient responded to hydrocortisone replacement therapy and has been able to continue treatment with nivolumab while continuing oral hydrocortisone. Although irAEs involving pituitary gland disorders are rare, these events can become life-threatening when severe. Early diagnosis and treatment are essential and require regular blood sampling and collaboration with specialists from an early stage.",
"affiliations": "Department of Otorhinolaryngology, Head and Neck Surgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.;Department of Otorhinolaryngology, Head and Neck Surgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.;Department of Otorhinolaryngology, Head and Neck Surgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.;Department of Otorhinolaryngology, Head and Neck Surgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.;Department of Otorhinolaryngology, Head and Neck Surgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.;Department of Otorhinolaryngology, Head and Neck Surgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.;Department of Otorhinolaryngology, Head and Neck Surgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.;Department of Otorhinolaryngology, Head and Neck Surgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan. Electronic address: tsuka@tokyo-med.ac.jp.",
"authors": "Hihara|Kosuke|K|;Sato|Hiroki|H|;Okamoto|Isaku|I|;Katsube|Yasuaki|Y|;Maruyama|Ryo|R|;Tomioka|Ryota|R|;Tanaka|Hideki|H|;Tsukahara|Kiyoaki|K|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000077594:Nivolumab; D000324:Adrenocorticotropic Hormone",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.anl.2019.02.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-8146",
"issue": "46(6)",
"journal": "Auris, nasus, larynx",
"keywords": "Hypopharyngeal cancer; Nivolumab; Pituitary-adrenal dysfunction; Tongue cancer; irAE",
"medline_ta": "Auris Nasus Larynx",
"mesh_terms": "D000303:Adrenal Cortex Diseases; D000324:Adrenocorticotropic Hormone; D000074322:Antineoplastic Agents, Immunological; D059248:Chemoradiotherapy; D006801:Humans; D007012:Hypopharyngeal Neoplasms; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D000077594:Nivolumab; D013517:Otorhinolaryngologic Surgical Procedures; D010900:Pituitary Diseases; D010913:Pituitary-Adrenal System; D000077195:Squamous Cell Carcinoma of Head and Neck; D014062:Tongue Neoplasms",
"nlm_unique_id": "7708170",
"other_id": null,
"pages": "896-901",
"pmc": null,
"pmid": "31350019",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pituitary-adrenal dysfunction caused by nivolumab for head and neck cancer.",
"title_normalized": "pituitary adrenal dysfunction caused by nivolumab for head and neck cancer"
} | [
{
"companynumb": "JP-ACCORD-151299",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "BACKGROUND\nDocetaxel-cisplatin and 5-fluorouracil (TPF) chemotherapy (days 1-21) represents a standard but toxic regimen for advanced head and neck cancer (HNC). We report a retrospective monocentric study evaluating the safety and the efficacy of a dose-dense modified TPF (mTPF) regimen (days 1-14) in patients with stage III-IV HNC.\n\n\nMETHODS\nThirty-seven patients retrospectively included from May 2011 to May 2014 were treated with a bimonthly dose-dense mTPF regimen (40 mg/m(2) docetaxel, 40 mg/m(2) cisplatin or AUC2 carboplatin, folinic acid 400 mg/m(2) for 2 h, bolus 5-FU 400 mg/m(2) for 10 min and 5-FU 1,000 mg/m(2)/day) by continuous infusion over 46 h).\n\n\nRESULTS\nChemotherapy was used as induction or palliative treatment in 12 and 25 patients, respectively, with a median age of 60 years (range 46-83). Median follow-up time was 7.4 months (2.53-16.7 months). There was no intestinal toxicity in 25 patients (68 %). Grade 3-4 hematological toxicity was noticed for 5 (13.5 %) patients. Granulocyte-colony stimulating factor was used as primary prophylaxis in 30 patients (81 %). After at least 4 delivered cycles, complete responses, partial responses and stable diseases were reported in 5 (15 %), 13 (39 %) and 5 (15 %) of the 33 evaluable patients, respectively, yielding an objective response rate of 54.5 % (39 % for palliative chemotherapy and 90 % for induction chemotherapy).\n\n\nCONCLUSIONS\nDose-dense mTPF (days 1-14) is safe and seems to be as effective as TPF (days 1-21). Future prospective trials are required to confirm our results.",
"affiliations": "Department of Oncopharmacology-Pharmacogenetics, Integrated Center of Oncology (ICO) Paul Papin, 2 rue Moll, 49033, Angers Cedex 9, France. senyo@wanadoo.fr.;Department of Oncopharmacology-Pharmacogenetics, Integrated Center of Oncology (ICO) Paul Papin, 2 rue Moll, 49033, Angers Cedex 9, France.;Department of Oncopharmacology-Pharmacogenetics, Integrated Center of Oncology (ICO) Paul Papin, 2 rue Moll, 49033, Angers Cedex 9, France.;Head and Neck Surgery Department, Centre Hospitalier Universitaire, 4 Rue Larrey, 49100, Angers, France.;Head and Neck Surgery Department, Centre Hospitalier Universitaire, 4 Rue Larrey, 49100, Angers, France.;Department of Oncopharmacology-Pharmacogenetics, Integrated Center of Oncology (ICO) Paul Papin, 2 rue Moll, 49033, Angers Cedex 9, France.",
"authors": "Yossi|Séna|S|;Linot|Benjamin|B|;Peyraga|Guillaume|G|;Breheret|Renaud|R|;Laccourreye|Laurent|L|;Capitain|Olivier|O|",
"chemical_list": "D043823:Taxoids; D016179:Granulocyte Colony-Stimulating Factor; D000077143:Docetaxel; D016190:Carboplatin; D002945:Cisplatin; D002955:Leucovorin; D005472:Fluorouracil",
"country": "Japan",
"delete": false,
"doi": "10.1007/s10147-015-0836-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-9625",
"issue": "20(6)",
"journal": "International journal of clinical oncology",
"keywords": "5-fluorouracil; Cisplatin; Docetaxel; Dose-dense chemotherapy; Head and neck cancer; Quality of life",
"medline_ta": "Int J Clin Oncol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D002945:Cisplatin; D000077143:Docetaxel; D005240:Feasibility Studies; D005260:Female; D005472:Fluorouracil; D016179:Granulocyte Colony-Stimulating Factor; D006258:Head and Neck Neoplasms; D006801:Humans; D060828:Induction Chemotherapy; D002955:Leucovorin; D008297:Male; D008875:Middle Aged; D010166:Palliative Care; D012074:Remission Induction; D012189:Retrospective Studies; D043823:Taxoids; D016896:Treatment Outcome",
"nlm_unique_id": "9616295",
"other_id": null,
"pages": "1086-92",
"pmc": null,
"pmid": "25931315",
"pubdate": "2015-12",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "23818349;17075117;17327856;16585868;18715812;19446902;19318632;17960012;17960013;12115384;22020564;19639668;11896109;19557750;18784101;23086560;22161550",
"title": "Feasibility and safety of dose-dense modified docetaxel-cisplatin or carboplatin and 5-fluorouracil regimen (mTPF) in locally advanced or metastatic head and neck cancers: a retrospective monocentric study.",
"title_normalized": "feasibility and safety of dose dense modified docetaxel cisplatin or carboplatin and 5 fluorouracil regimen mtpf in locally advanced or metastatic head and neck cancers a retrospective monocentric study"
} | [
{
"companynumb": "FR-CIPLA LTD.-2015FR09356",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nFludarabine, cyclophosphamide, and rituximab (FCR) result in durable responses in patients with previously untreated chronic lymphocytic leukemia (CLL). Previous reports have suggested that in patients with relapsed CLL, a dose-intensified rituximab regimen increases response rates in comparison with standard-dose rituximab. It is unknown whether rituximab intensification of the FCR regimen will result in improved response rates and patient outcomes in patients with previously untreated CLL.\n\n\nMETHODS\nA single-arm study was conducted to evaluate the safety and efficacy of a modified FCR regimen with multiple-dose rituximab (FCR3) in 65 patients with previously untreated CLL. The results were compared with those for a historical cohort treated with FCR.\n\n\nRESULTS\nThe overall response rate to FCR3 was 97%, with 75% of the patients achieving a complete remission. Minimal residual disease negativity was achieved for 62% of the patients according to flow cytometry. The median time to progression (TTP) was 81 months, and the median overall survival (OS) was not reached, with 58% of the patients still alive at a median survivor follow-up of 9.7 years. Grade 3 or 4 neutropenia, grade 3 or 4 thrombocytopenia, and major infections were observed with 45%, 5%, and 1.9% of the FCR3 courses, respectively. Therapy-related myelodysplastic syndrome (t-MDS) or therapy-related acute myelogenous leukemia (t-AML) developed in 7 patients (11%; P < .01 vs the historical FCR cohort).\n\n\nCONCLUSIONS\nIn patients with previously untreated CLL, FCR3 resulted in response rates, TTP, and OS similar to those of a historical cohort of patients treated with FCR. FCR3 was associated with an increased incidence of t-MDS/t-AML.",
"affiliations": "Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Division of Leukemia, Hackensack University Medical Center, Hackensack, New Jersey.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Chao Family Comprehensive Cancer Center, University of California Irvine, Orange, California.",
"authors": "Short|Nicholas J|NJ|;Keating|Michael J|MJ|;Wierda|William G|WG|;Faderl|Stefan|S|;Ferrajoli|Alessandra|A|;Estrov|Zeev|Z|;Smith|Susan C|SC|;O'Brien|Susan M|SM|",
"chemical_list": "D000069283:Rituximab; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine",
"country": "United States",
"delete": false,
"doi": "10.1002/cncr.29605",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0008-543X",
"issue": "121(21)",
"journal": "Cancer",
"keywords": "and rituximab (FCR); chemoimmunotherapy; chronic lymphocytic leukemia; cyclophosphamide; fludarabine; rituximab; therapy-related acute myelogenous leukemia; therapy-related myelodysplastic syndrome",
"medline_ta": "Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003520:Cyclophosphamide; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008297:Male; D008875:Middle Aged; D000069283:Rituximab; D015996:Survival Rate; D016896:Treatment Outcome; D014740:Vidarabine",
"nlm_unique_id": "0374236",
"other_id": null,
"pages": "3869-76",
"pmc": null,
"pmid": "26218678",
"pubdate": "2015-11-01",
"publication_types": "D017427:Clinical Trial, Phase II; D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "20888994;19667089;21690573;22080061;22331940;24124086;23808813;11304767;11062708;24705492;11304768;11520778;11564066;11801463;12721250;1380203;8652811;9704735;15767648;16219797;17283364;17361231;17658394;18411418;21189387",
"title": "Fludarabine, cyclophosphamide, and multiple-dose rituximab as frontline therapy for chronic lymphocytic leukemia.",
"title_normalized": "fludarabine cyclophosphamide and multiple dose rituximab as frontline therapy for chronic lymphocytic leukemia"
} | [
{
"companynumb": "US-ROCHE-1656372",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
"drug... |
{
"abstract": "BACKGROUND\nGemcitabine is the only approved cytotoxic agent for the treatment of pancreatic cancer by the Food and Drug Administration. In addition, gemcitabine is also commonly used for the management of breast, ovarian, and non-small cell lung cancer. Myelosuppression is the most common toxicity of gemcitabine therapy. Pulmonary toxicities due to gemcitabine have, however, been reported. Dyspnea occurs in approximately 25% of patients treated with gemcitabine, whereas serious pulmonary toxicities are much less common, approximately 0.3%. Here, we present a case of gemcitabine-induced pneumonitis, encountered during treatment of pancreatic cancer, and review the literature of this rare, but dangerous complication.\n\n\nMETHODS\nA 56-year old male being treated for stage IV pancreatic cancer developed progressive dyspnea on exertion, chest tightness, and palpitations. Oxygen saturation was 82-84%. Computerized-tomography (CT) angiography of the chest demonstrated new diffuse groundglass opacities in the bilateral lower lobes when compared to the CT of the chest without intravenous contrast, 5 weeks prior. Mild to moderate emphysema was also seen, but no pulmonary emboli were detected. Myocardial infraction was ruled-out by normal electrocardiogram and normal cardiac biomarkers.\n\n\nCONCLUSIONS\nWe report another case of gemcitabine-induced pneumonitis. Physicians seeing such patients should be aware of this rare but real pulmonary toxicity. A delay in diagnosis and treatment can lead to potentially fatal outcomes.",
"affiliations": "Tufts Medical Center, Boston, MA 02111, USA.",
"authors": "Chi|Dow-Chung|DC|;Brogan|Frances|F|;Turenne|Ithamar|I|;Zelonis|Sarah|S|;Schwartz|Lawrence|L|;Saif|Muhammad Wasif|MW|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; C056507:gemcitabine",
"country": "Greece",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "32(9)",
"journal": "Anticancer research",
"keywords": null,
"medline_ta": "Anticancer Res",
"mesh_terms": "D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms; D011014:Pneumonia",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "4147-9",
"pmc": null,
"pmid": "22993376",
"pubdate": "2012-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Gemcitabine-induced pulmonary toxicity.",
"title_normalized": "gemcitabine induced pulmonary toxicity"
} | [
{
"companynumb": "ES-SUN PHARMACEUTICAL INDUSTRIES LTD-2016RR-121536",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
... |
{
"abstract": "Malignant pleural mesothelioma (MPM) is an aggressive malignancy with few long-term survivors. Despite the dismal prognosis, hyperthermic intrathoracic chemoperfusion (HITHOC) was shown to improve survival in a selective group of patients. We analyzed the influence of HITHOC following pleurectomy and decortication on postoperative morbidity and overall survival for patients suffering from localized mesothelioma.\nFrom 2009 until 2013, 71 patients with localized pleural mesothelioma underwent pleurectomy and decortication followed by HITHOC with cisplatin and doxorubicin. We analyzed postoperative morbidity, age, overall survival and influence of macroscopic resection on survival.\nMedian patient age was 70 years (range, 65-73 years). Patients having the sarcomatoid subtype of mesothelioma showed a poor median survival of 9.2 months. In contrast, patients having the epithelioid subtype had a median survival of 17.9 months. Patients following macroscopic complete resection had a significantly better survival with 28.2 months compared to 13.1 months in patients with incomplete resection of the mesothelioma (P<0.0001). HITHOC was performed in all patients after tumor resection using cisplatin and doxorubicin.\nTaken together, HITHOC following pleurectomy and decortication is supposed to be a safe therapeutic option for selected patients with localized epithelial pleural mesothelioma.",
"affiliations": "Center for Thoracic Surgery Munich, Ludwig-Maximilians-University of Munich/Asklepios Lung Clinic Gauting, Gauting, Germany.;Center for Thoracic Surgery Munich, Ludwig-Maximilians-University of Munich/Asklepios Lung Clinic Gauting, Gauting, Germany.;Department of Thoracic Surgery, Thoraxklinik, University of Heidelberg, Heidelberg, Germany.;Center for Thoracic Surgery Munich, Ludwig-Maximilians-University of Munich/Asklepios Lung Clinic Gauting, Gauting, Germany.;Center for Thoracic Surgery Munich, Ludwig-Maximilians-University of Munich/Asklepios Lung Clinic Gauting, Gauting, Germany.;Department of Thoracic Surgery, Thoraxklinik, University of Heidelberg, Heidelberg, Germany.;Center for Thoracic Surgery Munich, Ludwig-Maximilians-University of Munich/Asklepios Lung Clinic Gauting, Gauting, Germany.;Department of Pneumology, Asklepios Lung Clinic Gauting, Gauting, Germany.;Center for Thoracic Surgery Munich, Ludwig-Maximilians-University of Munich/Asklepios Lung Clinic Gauting, Gauting, Germany.",
"authors": "Klotz|Laura V|LV|;Lindner|Michael|M|;Eichhorn|Martin E|ME|;Grützner|Uwe|U|;Koch|Ina|I|;Winter|Hauke|H|;Kauke|Teresa|T|;Duell|Thomas|T|;Hatz|Rudolf A|RA|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.21037/jtd.2019.04.93",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2072-1439",
"issue": "11(5)",
"journal": "Journal of thoracic disease",
"keywords": "Pleural mesothelioma; chemoperfusion, decortication; cisplatin; hyperthermic intrathoracic chemoperfusion (HITHOC)",
"medline_ta": "J Thorac Dis",
"mesh_terms": null,
"nlm_unique_id": "101533916",
"other_id": null,
"pages": "1963-1972",
"pmc": null,
"pmid": "31285889",
"pubdate": "2019-05",
"publication_types": "D016428:Journal Article",
"references": "11834661;12544259;12620914;15273542;15511473;15677623;16101199;16575008;17638057;18398658;18647189;19699913;19717482;22290929;22885228;22929121;23434448;24360321;24868442;25124472;25534527;25726878;26319490;26611742;26660351;26845118;27687963;27825687;27903668;30293239",
"title": "Pleurectomy/decortication and hyperthermic intrathoracic chemoperfusion using cisplatin and doxorubicin for malignant pleural mesothelioma.",
"title_normalized": "pleurectomy decortication and hyperthermic intrathoracic chemoperfusion using cisplatin and doxorubicin for malignant pleural mesothelioma"
} | [
{
"companynumb": "DE-JNJFOC-20190742038",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SODIUM CHLORIDE"
},
"drugadditional": null,
... |
{
"abstract": "Cytopathic effects and local immune response were analyzed histologically in prostatic cancer (PCa) with in situ herpes simplex virus-thymidine kinase (HSV-tk)/ganciclovir (GCV) gene therapy (GT).\nFour high-risk PCa patients who received HSV-tk/GCV GT were investigated. After two cycles of intraprostatic injection of HSV-tk and administration of GCV, radical prostatectomy was performed. Formalin-fixed, paraffin-embedded sections were evaluated using immunohistochemistry. PCa with hormone therapy (HT, n=3) or without neoadjuvant therapy (NT, n=4) that were equivalent in terms of risk were also examined as reference. Immunoreactively-positive cells were counted in at least three areas in cancer tissue. Labeling indices (LI) were calculated as percentage values.\nssDNA LI in GT increased, indicating apoptosis, as well as tumor-infiltrating lymphocytes and CD68-positive macrophages, compared with their biopsies. GT cases showed significantly higher numbers of single-stranded DNA (ssDNA) LI, CD4/CD8-positive T cells and CD68-positive macrophages including M1/M2 macrophages than HT or NT cases. However, there was no significant difference in CD20-positive B cells among the types of case. There were strong correlations between CD8+ T cells and CD68+ macrophages (ρ=0.656, p<0.0001) as well as CD4+ T cells and CD20+ B cells (ρ=0.644, p<0.0001) in PCa with GT.\nEnhanced cytopathic effect and local immune response might be indicated in PCa patients with HSV-tk/GCV gene therapy.",
"affiliations": "Department of Pathology, St. Marianna University School of Medicine Yokohama-City Seibu Hospital, Yokohama, Kanagawa, Japan.;Department of Urology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.;Department of Urology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.;Department of Urology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.;Department of Urology, Okayama University, Okayama, Japan.;Department of Urology, Okayama University, Okayama, Japan.;Department of Genitourinary Medical Oncology - Research, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.;Department of Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.;Department of Urology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.;Department of Urology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.",
"authors": "Yanagisawa|Nobuyuki|N|;Satoh|Takefumi|T|;Tabata|Ken-Ichi|KI|;Tsumura|Hideyasu|H|;Nasu|Yasutomo|Y|;Watanabe|Masami|M|;Thompson|Timothy C|TC|;Okayasu|Isao|I|;Murakumo|Yoshiki|Y|;Baba|Shiro|S|;Iwamura|Masatsugu|M|",
"chemical_list": null,
"country": "Singapore",
"delete": false,
"doi": "10.1016/j.ajur.2020.06.004",
"fulltext": "\n==== Front\nAsian J Urol\nAsian J Urol\nAsian Journal of Urology\n2214-3882\n2214-3890\nSecond Military Medical University\n\nS2214-3882(20)30043-6\n10.1016/j.ajur.2020.06.004\nOriginal Article\nCytopathic effects and local immune responses in repeated neoadjuvant HSV-tk + ganciclovir gene therapy for prostate cancer\nYanagisawa Nobuyuki czp05616@nifty.com\nab∗\nSatoh Takefumi cd\nTabata Ken-ichi c\nTsumura Hideyasu c\nNasu Yasutomo e\nWatanabe Masami ef\nThompson Timothy C. g\nOkayasu Isao bh\nMurakumo Yoshiki b\nBaba Shiro c\nIwamura Masatsugu c\na Department of Pathology, St. Marianna University School of Medicine Yokohama-City Seibu Hospital, Yokohama, Kanagawa, Japan\nb Department of Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan\nc Department of Urology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan\nd Takefumi Satoh Prostate Clinic, Machida, Tokyo, Japan\ne Department of Urology, Okayama University, Okayama, Japan\nf Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan\ng Department of Genitourinary Medical Oncology - Research, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA\nh Division of Nutrition, School of Health Care, Kiryu University, Midori-City Gunma, Japan\n∗ Corresponding author. Department of Pathology, St. Marianna University School of Medicine Yokohama-City Seibu Hospital, Yokohama, Kanagawa, Japan. czp05616@nifty.com\n16 6 2020\n7 2021\n16 6 2020\n8 3 280288\n10 4 2019\n27 1 2020\n17 3 2020\n© 2021 Editorial Office of Asian Journal of Urology. Production and hosting by Elsevier B.V.\n2021\nEditorial Office of Asian Journal of Urology\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nObjective\n\nCytopathic effects and local immune response were analyzed histologically in prostatic cancer (PCa) with in situ herpes simplex virus-thymidine kinase (HSV-tk)/ganciclovir (GCV) gene therapy (GT).\n\nMethods\n\nFour high-risk PCa patients who received HSV-tk/GCV GT were investigated. After two cycles of intraprostatic injection of HSV-tk and administration of GCV, radical prostatectomy was performed. Formalin-fixed, paraffin-embedded sections were evaluated using immunohistochemistry. PCa with hormone therapy (HT, n=3) or without neoadjuvant therapy (NT, n=4) that were equivalent in terms of risk were also examined as reference. Immunoreactively-positive cells were counted in at least three areas in cancer tissue. Labeling indices (LI) were calculated as percentage values.\n\nResults\n\nssDNA LI in GT increased, indicating apoptosis, as well as tumor-infiltrating lymphocytes and CD68-positive macrophages, compared with their biopsies. GT cases showed significantly higher numbers of single-stranded DNA (ssDNA) LI, CD4/CD8-positive T cells and CD68-positive macrophages including M1/M2 macrophages than HT or NT cases. However, there was no significant difference in CD20-positive B cells among the types of case. There were strong correlations between CD8+ T cells and CD68+ macrophages (ρ=0.656, p<0.0001) as well as CD4+ T cells and CD20+ B cells (ρ=0.644, p<0.0001) in PCa with GT.\n\nConclusions\n\nEnhanced cytopathic effect and local immune response might be indicated in PCa patients with HSV-tk/GCV gene therapy.\n\nKeywords\n\nSuicide gene therapy\nProstate carcinoma\nHSV-tk\nGanciclovir\nImmunohistochemistry\n==== Body\n1 Introduction\n\nProstatic cancer (PCa) was the most common cancer worldwide in men, accounting for 17% of all cancer cases among men, with 1.6 million cases in 2015 [1]. The incidence of PCa and its mortality rates have increased throughout the world [2]. Currently available therapies—potentially curative localized therapy (radical prostatectomy or irradiation) for PCa are limited [3] or palliative androgen ablation therapy for advanced disease [4]. Despite significant progress in the detection and treatment of PCa, the problem of high relapse rates following radical prostatectomy remains unsolved; for example, a large number of PCa patients undergoing hormone therapy (HT) often show disease progression with castration-resistant status. Because combined radical prostatectomy with adjuvant or neoadjuvant treatment may improve the relapse rate in PCa patients, various adjuvant/neoadjuvant treatments have been examined, and novel therapeutic options are strongly needed.\n\nSuicide gene therapy (GT) is an innovative approach that can kill tumor cells by inserting suicide genes into cancer cells. To date, suicide GT using herpes simplex virus-tyrosine kinase (HSV-tk) gene transduction followed by the systemic administration of ganciclovir (GCV) is one of the novel therapeutic strategies against human malignancies including PCa [5]. GCV phosphorylated by HSV-tk is incorporated into DNA, which inhibits DNA synthesis, leading to cell death [6]. As phase I/II clinical trials, several protocols of GT for PCa have shown biochemical or histological responses [[7], [8], [9], [10], [11], [12], [13]], indicating the effectiveness of GT against PCa. However, because the previous reports of HSV-tk/GCV GT for PCa were usually limited to advanced or refractory cases [10,11], almost no published studies reported histological analysis with HSV-tk/GCV GT, especially in radical prostatectomy specimens. In addition, a single intraprostatic vector injection was performed in previous reports, in contrast with our two cycles of HSV-tk/GCV treatments [7,8].\n\nIn the present study, we confirmed the safety of repeated in situ HSV-tk/GCV GT and demonstrated the histological analysis of PCa using radical prostatectomy specimens to shed light on the histological effect of HSV-tk/GCV GT against PCa cells.\n\n2 Patients and methods\n\n2.1 Patient eligibility\n\nFive patients with biopsy-proven, clinically localized PCa were analyzed. All the patients had a Kattan preoperative nomogram score of 115 (high risk of recurrence) [14], and submitted informed consents prior to enrollments in this phase I/II clinical trial. Normal hematopoietic function (platelet count >100 000/mL, neutrophil count >2000/mL and hemoglobin >6.5 mmol/L), a normal coagulation profile, and normal kidney and liver functions (serum creatinine <1.5 mg/dL, bilirubin <2.5 mg/dL, liver enzymes and alkaline phosphatase <2× normal) were required. No androgen deprivation, immunosuppressive drug or corticosteroid were accepted. The protocol used in our study was approved by the Biosafety Committees and the Institutional Review Boards of the participating institutions of the Kitasato University School of Medicine, the Ministry of Health, Labor and Welfare, and Ministry of Education, Culture, Sports, Science and Technology in Japan (Registration number, 07-36V-0001). Informed consents were obtained from all individual participants included in the study.\n\n2.2 Vector and therapy administration\n\nThe vector used was a serotype Ad5 adenovirus that contained the HSV-tk gene and Rous sarcoma virus long terminal repeat promoter in the region of the excised E1/E2 wild-type adenoviral genes. This replication-defective adenoviral vector was constructed as described previously [12]. A clinical-grade preparation was made by the Baylor Center for Cell and Gene Therapy, Gene Vector Laboratory (Houston, TX, USA) under good manufacturing practice conditions. On Day 0, a transrectal ultrasound (TRUS) guided single intraprostatic injection of Ad5 HSV-tk vector was delivered in the target lesion mapped by template-guided three-dimensional mapping biopsy [15]. All patients received a total dose of 2×1011 viral particles of the vector. Thereafter patients received an intravenous infusion of 5 mg/kg of GCV (Mitsubishi Tanabe Pharma Corp., Osaka, Japan) twice daily from Day 1 to Day 14 for one course. The intraprostatic vector injection was repeated on Day 14 and patients received same dose of CGV twice daily from Day 15 to Day 28 for second course. Patients underwent an extended pelvic lymph node dissection and a retro-pubic radical prostatectomy on Day 56 (Fig. 1).Figure 1 Serum PSA levels in prostatic cancer patients treated with HSV-tk/GCV gene therapy. The PSA levels decreased after increasing temporarily at HSV-tk injections. PSA, prostate-specific antigen; GCV, ganciclovir; HSV-tk, herpes-simplex virus-tyrosine kinase.\n\nFigure 1\n\n2.3 Monitoring viral DNA detection and neutralizing antibody\n\nAdenoviral DNA in blood was determined by real-time PCR on Days 0, 2, 7, 14, 16, 21, 28, 42 and 56. Gene expression in urine was measured with PCR/real-time PCR as in the above schedule. PCR and real-time PCR were analyzed in a commercial based laboratory (SRL, Tokyo, Japan). Neutralizing antibody titers were determined by neutralization tests in a commercial-based laboratory (SRL) on Days 0, 14, 28, 42 and 56.\n\n2.4 Cytopathic effects and local immune response\n\nAll of the resected specimens were fixed in 10% buffered formalin and were step-sliced at 4-mm thickness and processed for embedding in paraffin as a whole mount. Then, 4 μm-thick sections were cut and used for hematoxylin-eosin (H.E.) staining and immunohistochemical analyses. Briefly, tissue sections were deparaffinized and endogenous peroxidase was blocked with 1% hydrogen peroxide in methanol for 30 min. The sections were incubated with primary antibodies, anti-CD20 for B-cells (clone L26, 1/400 diluted, Dako, Carpinteria, CA, USA), CD4 for helper T-cells (1F6, 1/40, Leica Biosystems, Newcastle Upon Tyne, UK), CD8 for cytotoxic T-cells (C8/144B, 1/100, Dako), CD68 for macrophages (PG-M1, 1/200, Dako), anti-CD11c (ab52632, 1/500, Abcam, Cambridge, UK) for M1 macrophages, anti-CD163 (sc-20066, 1/100, Santa Cruz Biotechnology, Dallas, TX, USA) for M2 macrophages and anti-Ki-67 (1/100, Dako) at 4 °C overnight, with or without microwave oven pretreatment to retrieve antigenic reactivity. After incubation with peroxidase-labeled polymer (ChemMate EnVision kit, Dako) for 30 min, 3,3′-diaminobenzidine (DAB) was applied as the chromogen. Nuclei were counterstained with Mayer's hematoxylin to facilitate histological assessment.\n\nTo evaluate apoptotic cells, single-stranded DNA (ssDNA) immunostaining was performed using anti-ssDNA antibody (1/400, IBL Co. Ltd., Gunma, Japan), as described above. Anti-Cytokeratin (CAM5.2, BD Biosciences, San Jose, CA, USA) and anti-prostate-specific antigen (anti-PSA) antibodies (Dako) were also used to evaluate cellular viability with 3-amino-9-ethylcarbazole (AEC, for the chromogen).\n\n2.5 Evaluation of the immunohistochemical staining\n\nEvaluation of immunohistochemical staining was performed in each cancer lesion in the all whole-mount slides. CD20, CD4, CD8, CD68, CD11c and CD163-positive cells per 1 mm2 were counted. The ssDNA and Ki-67-positive cells were counted in at least 1 000 of epithelial cells, and labeling indices (LIs) were calculated as percentage values. At least five lesions of carcinoma and two of non-cancerous lesions in prostatectomy specimens were analyzed. The biopsy samples of two GT cases (Case 1 and 2, two cores each) were also evaluated. PCa with HT (n=3) or without neoadjuvant therapy (NT, n=4) that were equivalent to in risk were also examined, as a reference. Affected areas within the tumors were outlined on whole-mount slides and quantified using ImageJ software (U. S. National Institutes of Health, Bethesda, Maryland, USA).\n\n2.6 Statistical analysis\n\nData were given as the mean±standard deviation values. Comparisons between groups were conducted with the Mann-Whitney U test or the Fisher protected least significant difference test. Relations between each values and ssDNA LI were analyzed using the Spearman's rank correlation coefficient test. StatView software (version 5.0, Abacus Concepts, Inc. Berkeley, CA, USA) was employed for all statistical analyses, and a p-value less than 0.05 was considered to indicate statistical significance.\n\n2.7 Ethical approval\n\nAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards (approval number: ITI04-1).\n\n3 Results\n\n3.1 Patient characteristics\n\nThe patients’ characteristics are shown in Table 1. One patient (Case 3) was switched to HT instead of radical prostatectomy because of prolonged activated partial thromboplastin time. Thus, histological analyses were performed in four patients. After prostatectomy, one patient (Case 2) died as a result of pulmonary thrombus. Fig. 1 shows the serum PSA levels in GT cases. The PSA levels decreased after increasing temporarily after HSV-tk injections. The average PSA reduction rate (PSAR) at prostatectomy (56 days) was 23.1% (range, 1.7%–32.0%). The interferon responses were observed in the GT patients, which were described previously [9]. No biochemical recurrence has been observed in the four alive patients (the average follow-up period was 114 months).Table 1 Clinicopathologic characteristics of prostatic cancer patients treated with HSV-tk/GCV gene therapy.\n\nTable 1Patient No.\tEntry age\tBaseline PSA, ng/mL\tBiopsy Gleason Score\tPositive Cores\tcStage\tKattan Score\tTherapy\tpStage\tTumor affected, %\tPSA reduction rate, %\tFever\tLiver dysfunction (AST)\tLiver dysfunction (ALT)\tThrombo-cytopenia\tProlonged APTT\tDetection of ADV (Day 0, 2, 7, 16, 21, 28, 42, 56)\tMaximum anti-ADV antibody titer (days)\t\nBlood\tUrine\tNasal cavity\t\n1\t70\t13.6\t3+3=6\t6/8\tT2c\t117\tRP\tT2c\t15.6\t24.1\tGrade 2\tGrade 1\tGrade 1\t\t\t–\t–\t–\tx512 (28)\t\n2\t63\t5.89\t3+5=8\t6/22\tT2b\t116\tRP\tT2a\t9.5\t30.0\tGrade 2\tGrade 3\tGrade 3\tGrade 1\t\t–\t–\t–\tx256 (28)\t\n3\t60\t42.1\t4+3=7\t3/6\tT2c\t166\tHT\t–\t–\t32.0\tGrade 1\tGrade 1\t\t\tGrade 1\t–\t–\t–\tx16 (42)\t\n4\t68\t7.43\t4+3=7\t6/10\tT2b\t123\tRP\tT2b\t52.7\t27.7\tGrade 1\tGrade 1\tGrade 1\tGrade 1\t\t–\t–\t–\tx32 (14)\t\n5\t71\t17.76\t3+3=6\t2/8\tT2b\t125\tRP\tT3a\t22.8\t1.7\tGrade 2\tGrade 1\t\t\t\t–\t–\t–\tx1024 (14)\t\nAST, aspartate sminotransferase; ALT, alanine aminotransferase; APTT, activated partial thromboplastin time; ADV, adenovius; cStage, clinical stage; HT, hormone therapy; pStage, pathological stage; RP, radical prostatectomy; PSA, prostate-specific antigen; –, not determined.\n\n3.2 Safety and feasibility\n\nNo adenoviral DNA was detected in the blood, in the urine and in the nasal cavity by real-time polymerase chain reaction (PCR) on Day 0, Day 2, Day 7, Day 16, Day 21, Day 28, Day 42 and Day 56. Patients experienced clinical grade 1 toxicity (five patients, six events) and clinical grade 2 toxicity (three patients, three events) with fever within the 24 h following the viral injection. The increase in body temperature never lasted longer than 72 h. Elevation of C-reactive protein values was observed at the four of vector injection in five patients. Temporary elevation of AST was seen as clinical grade 1 toxicity (four patients, five events) and clinical grade 3 toxicity (one patient, one event) following the viral injection, that spontaneously returned to normal level. Temporary elevation of ALT was seen as clinical grade 1 toxicity (two patients, three events) and clinical grade 3 toxicity (one patient, one event) following the viral injection that spontaneously returned to normal level. An asymptomatic grade 1 thrombocytopenia was seen in two patients that spontaneously returned to normal level. Asymptomatic prolonged activated partial thromboplastin time was seen as clinical grade 1 toxicity (one patient, one event) that spontaneously returned to normal level. No patient developed urinary obstruction. As for symptomatic adverse events, one patient showed grade 2 complications with pollakiuria on Day 4. Grade 1 hematuria was observed in one patient on Day 1. Grade 1 constipation was observed in one patient on Day 3, and grade 1 diarrhea was observed in one patient on Day 16.\n\n3.3 Histology\n\nGenerally, moderate to severe chronic inflammation was observed in the cases of prostate treated with GT, predominantly in their peripheral zone. Inflammatory cell infiltration into periprostatic fat was also observed. Neuritis and venulitis were found occasionally. An injection site with small coagulative necrotic focus was identified in one case. In addition, inflammatory cell infiltration was also observed in the tumor. The cancer cells partially lost glandular structure and had pyknotic nuclei (Fig. 2A). Apoptotic bodies were scattered (Fig. 2A, arrows). These findings were thought of as a cytopathic effect. Volumetric analyses with the cytopathic effect were shown as tumor affected area (%) in Table 1 (range, 9.5%–52.7%).Figure 2 Histological results of prostatic cancer patients with HSV-tk gene therapy. (A) The cancer cells showed glandular dissolution, nuclear pyknosis and apoptotic bodies (arrows). Inflammatory cell infiltration was also observed. (B) The cancer cells almost lost PSA positivity. (C) Cytokeratin (CAM5.2) was still focally positive. (D) ssDNA indicating apoptosis was scattered positive in cancer cells. (E–I) Increased CD8+ T cells (E), CD68+ (F) and CD11c+ M1 macrophages (H) were observed in tumor, while CD20+ B cells (G) and CD163+ M2 macrophages (I) were a few. Original magnification, ×400. Scale bars, 50 μm. PSA, prostate-specific antigen; HSV-tk, herpes-simplex virus-tyrosine kinase.\n\nFigure 2\n\nImmunohistochemically, cancer cells with cytopathic effects were still weak and partially positive for cytokeratin (CAM5.2); however, they were mostly negative for PSA (Fig. 2B and 2C). ssDNA-positive cells were also observed (Fig. 2D). Many CD8+ T cells (Fig. 2E) and CD68+ macrophages (Fig. 2F) were observed in tumor tissue, while CD20+ B cells were scant (Fig. 2G). In addition, CD11c+ M1 macrophages were mainly observed rather than CD163+ M2 macrophages (Fig. 2H and I). ssDNA in cancer cells tended to be high compared with that in non-cancerous epithelial cells (Fig. 3). In contrast, the number of inflammatory cells such as CD20+ B cells were significantly increased in non-cancerous lesions compared with in intratumoral lesions (Fig. 3). Other markers including CD4+, CD8+ T cells and CD68+ macrophages also tended to increase more in non-cancerous lesions than in tumor lesions (Fig. 3).Figure 3 Comparison of cytopathic effects and local immune responses between prostatic cancer and non-cancerous lesions in patients with HSV-tk/GCV gene therapy. The cancer cells (T) increased ssDNA labelling index compared with non-cancerous lesions (N). In contrast, the non-cancerous legions (N) tended to show more inflammatory cell infiltration than intratumoral legions (T). Comparisons between groups were conducted with the Manne-Whitney U test. p-Value <0.05 was considered significant. HSV-tk, herpes-simplex virus-tyrosine kinase; ssDNA, single-stranded DNA.\n\nFigure 3\n\nThe prostatic biopsy samples (two cores each) of two GT patients (Cases 1 and 2) were also analyzed. The ssDNA LI and intratumoral inflammatory cells in prostatectomy (RP) samples of GT patients increased compared with their biopsies (BP) (ssDNA, 0.1±0.1 vs. 4.9±5.2; CD4, 30.0±13.4 vs. 49.9±39.0; CD8, 36.5±7.9 vs. 246.7±132.4; CD68, 21.5±7.7 vs. 58.6±37.2; CD20, 0.0±0.0 vs. 14.9±38.4, respectively. Fig. 4).Figure 4 Comparison of cytopathic effects and local immune responses between biopsy and radical prostatectomy specimens in prostatic cancer patients with HSV-tk/GCV gene therapy. ssDNA labelling index and intratumoral CD8+ T cells, CD68+ macrophages and CD20+ B cells in the radical prostatectomy specimens (RP) treated with gene therapy were significantly increased compared with their biopsies (BP) before the treatment. p-Value <0.05 was considered significant. HSV-tk, herpes-simplex virus-tyrosine kinase.\n\nFigure 4\n\n3.4 Comparison among PCas with or without neoadjuvant therapies\n\nFig. 5 shows cytopathic effects and local immune responses in PCa with GT, HT and without NT. Intratumoral CD4+ (GT, 49.9±39.0; HT, 11.1±11.2; NT, 47.5±55.7, respectively. Fig. 5A), CD8+ (GT, 246.7±132.4; HT, 136.4±73.4; NT, 112.7±106.6) T cells and CD68+ macrophages (GT, 58.6±37.2; HT, 14.6±12.2; NT, 6.2±7.0) also increased in GT cases compared with in other groups. However, no significant differences were found in CD20+ B cells among the groups (GT, 14.9±38.4; HT, 14.3±22.4; NT, 17.0±44.7). These results indicate that GT induced apoptosis in the cancer cells and enhanced local immune response with CD8+ T cells and CD68+ macrophages. In addition, both CD11c+ (M1) and CD163+ (M2) macrophages increased significantly in GT cases compared with that in other groups (CD11c, GT, 109.9±32.3; HT, 48.3±9.2; NT, 41.9±18.0. CD163, GT, 4.5±6.2; HT, 0.5±0.8; NT, 2.1±2.6. Fig. 5B). ssDNA LI was higher in GT than the other groups (GT, 4.9±5.2; HT, 0.9±1.0; NT, 1.8±3.0, respectively. Fig. 5B), although Ki-67 LI in GT was not significant (GT, 3.0±2.0; HT, 1.6±1.3; NT, 4.7±2.6).Figure 5 Cytopathic effects and local immune responses in prostatic cancer with or without neoadjuvant treatment. (A) CD4, CD8, CD68-positive cells significantly increased in the prostatic cancers of patients with HSV-tk/GCV gene therapy (GT) compared with hormone therapy (HT) or no neoadjuvant therapy (NT) patients. (B) ssDNA labelling index (LI) also increased, while Ki-67 LI was not significant in GT patients. Both CD11c+ (M1 macrophages) and CD163+ (M2 macrophages) cells also increased, and M1 macrophages were predominant in GT tumors. Statistical analysis was done using Fisher protected least significant difference test. p-Value<0.05 was considered significant.\n\nFigure 5\n\n3.5 Correlation of intratumoral inflammatory cells in PCa with gene therapy\n\nThere were strong correlations between CD8+ T cells and CD68+ macrophages (ρ=0.656, p<0.0001) as well as CD4+ T cells and CD20+ B cells (ρ=0.644, p<0.0001) in PCa with GT (Table 2). However, no significant positive correlations were found between ssDNA LI and the inflammatory cells. In addition, no significant correlations like in GT were found neither in NT nor HT cases (data not shown).Table 2 Correlation coefficients for ssDNA and intratumoral inflammatory cells in prostatic cancer patients with HSK-tk/GCV gene therapy.\n\nTable 2marker\tρa\tp-Valueb\t\nssDNA/CD4\t−0.322\t0.0271\t\nssDNA/CD8\t−0.084\t0.5642\t\nssDNA/CD68\t−0.193\t0.1853\t\nssDNA/CD20\t−0.474\t0.0012\t\nCD4/CD8\t0.466\t0.0014\t\nCD4/CD68\t0.483\t0.0009\t\nCD4/CD20\t0.644\t<0.0001\t\nCD8/CD68\t0.656\t<0.0001\t\nCD8/CD20\t0.381\t0.0091\t\nCD68/CD20\t0.392\t0.0072\t\nssDNA, single strand DNA; HSK-tk/GCV, herpes-simplex virus-tyrosine kinase/ganciclovir.\n\na Statistical analysis was done using Spearman's rank correlation coefficient test.\n\nb p-Value <0.05 was considered significant.\n\n4 Discussion\n\nIn the present study, we proposed a new protocol of HSV-tk/GCV GT for high-risk PCa patients. The characteristics of our protocol were two cycles of HSV-tk/GCV treatments in patients with localized PCa with a high risk of recurrence. We adopted the repeat treatments because a single HSV-tk/GCV cycle was insufficient to induce a histological cytopathic effect, according to previous reports [7,13]. Therefore, we tested two cycles and tried confirming their histologic effects in prostatectomy specimens. Although some GT cases had side effects including mild fever and liver dysfunction, our clinical trial confirmed the safety profile of repeated cycles of HSV-tk/GCV treatment.\n\nSerum PSA reduction at radical prostatectomy (56 days) was observed in all GT cases (Fig. 1). However, some authors previously reported that PCa patients with HSV-tk/GCV GT did not always show PSA reduction. For example, Miles et al. [10] demonstrated that 28 of 36 (77.8%) PCa patients with unsuccessful radiotherapy had a mean 28% PSAR (range, 4.0%–84.8%). Nasu et al. [11] found that six of nine (67%) PCa patients with local recurrence after hormonal therapy had a median 24.1% PSAR (6.7%–43.9%). These PSAR values were almost equal to our result (mean 23.1%), in spite of repeated HSV-tk/GCV treatment against non-refractory localized PCa. Unexpectedly, our new protocol could not confirm further effects, at least in the PSAR data. In the present study, we first demonstrated histological analyses using the radical prostatectomy specimens in PCa with repeated HSV-tk/GCV GT; however, further study is needed because no histological comparison between single and repeated HSV-tk injection has been reported.\n\nWe found a cytopathic effect using H.E. slides and ssDNA LI in radical prostatectomy specimens with HSV-tk/GCV GT, in line with the previous reports [7,8]. However, the authors of one study reported that no viral cytopathic effect was observed in four PCa patients with GT [13]. Our PSA data and histological result including affected tumor area also indicated individual differences among the patients, suggesting that HSV-tk/GCV GT is not always effective in PCa patients. We focused on Case 4, in whom strong cytopathic effect, large affected tumor area (52.7%) and increased ssDNA LI were observed compared with other GT cases. However, a significantly increased PSAR was not observed (27.7%) compared with other GT cases. Although the reason for this is unclear, it may be possible that Cases 3 and 4 had lower anti-adenovirus neutralizing antibody responses (16 and 32, respectively, Table 1), suggesting that the injected vector may still retain effectiveness against PCa.\n\nWe hypothesized that GT caused both cytopathic effects including apoptosis and local immune responses. However, we could not find a significant close correlation between ssDNA LI (apoptosis) and local immune response. To our knowledge, our study is the first to describe this result. Although the reason is still unclear, the increasing apoptosis induced by HSV-tk vector may be a different phenomenon from the local immune response caused mainly by intraprostatic viral injection. Our results showed that ssDNA LIs were higher in the carcinoma cells than in the non-cancerous cells (Fig. 3), in the radical prostatectomy specimens than the biopsy (Fig. 4) and in the GT cases than NT and HT (Fig. 5B). Taking into consideration that HSV-tk/GCV GT induces suicide in vector-transfected cells, we confirmed the “direct” cytopathic effect in carcinoma cells in the GT cases. Local immune responses may indicate the “indirect” effects caused by HSV-tk/GCV GT.\n\nA close correlation between CD8+ T cells and CD68+ macrophages in PCa with GT was observed (Table 2). The previous report also pointed out that CD8+ and CD68+ cells increased in PCa with GT compared with controls [7]. In other tumors, CD8+ cells that are functionally characterized as cytotoxic T lymphocytes have been most often associated with favorable prognosis [16,17]. However, intratumoral CD68+ cells including tumor-associated macrophages (TAM) have been reported as both promoting and preventing tumor progression [18]. CD8+ cytotoxic T cells kill their targets by programming them to induce apoptosis [19]. Classically activated macrophages are known to have a high bactericidal and tumoricidal capacity [18]. Considering these facts, it seems reasonable that the positive correlation between CD8+ and CD68+ cells indicates the elimination of tumor cells. Furthermore, a correlation between CD20+ and CD4+ cells was also observed. B lymphocytes are associated with a humoral immune reaction including antibody production. The production of neutralizing antibodies by plasma cells and memory B cells is dependent on sequential CD4+ T cell to drive antibody affinity maturation and memory formation [20]. This may be one of the reasons for the close correlation between CD20+ and CD4+ cells. However, GT Case 5 with high anti-adenovirus antibody titer (1024) did not significantly increase CD20+ B cells compared with others. Further study is needed.\n\nPCa with GT showed increased ssDNA LI as well as CD8+ T cells and CD68+ macrophages (predominantly CD11c+ M1 macrophages) compared with NT or HT patients with significance (Fig. 5), indicating that GT treatment strongly induced cytopathic effect and local immune response in the PCa. Interestingly, a previous report also demonstrated that PCa patients with androgen-deprived HT had significantly increased CD3+/CD8+ T lymphocytes and CD68+ macrophages compared with controls [21]. Although these therapeutic mechanisms are thought to be different, it is interesting that both GT and HT showed partly similar tendencies with respect to local immune responses. As a local immune response, we investigated tumor-infiltrating lymphocytes (TIL) and M1/M2 macrophages in PCa. TIL has been believed to be one of the host-mediated anti-cancer responses in the microenvironment and has been reported to be a prognostic factor in malignancies. In addition, the presence of TIL also influenced the neoadjuvant chemotherapeutic response in breast cancers [22,23]. Similarly, GT using intraprostatic viral injection was thought to induce the forced recruitment of CD8+ lymphocytes and CD68+ macrophages into PCa. We confirmed that the local immune responses and cytopathic effect were increased in the prostatectomy specimens after GT compared with the biopsy specimens (Fig. 4). Thus, GT may enhance cytotoxic response, resulting in anti-tumor immunity.\n\nWe found that ssDNA LI was high in cancer cells compared with non-cancerous prostatic epithelial cells in GT despite their inflammatory cell infiltration (Fig. 3). GCV inhibits DNA synthesis mainly in cells having high proliferative activities such as cancer cells [24], supporting their enhanced apoptosis. In addition, this GT effect may be more selectively caused by the adenovirus vector localization; no vector was detected in all of the GT patients’ peripheral blood, urine and nasal mucosae. This might be an advantage of GT in terms of selective cytopathic effect against PCa.\n\nPrevious reports indicated a “bystander effect” of HSV-tk/GCV GT [25]. This was an additional cytopathic effect that occurred in tumor cells expressing the HSV gene as well as their adjacent cells without HSV-tk induction. Because of the high cellularity of tumor cells, this phenomenon may cause increased cytopathic effect, especially in high-grade malignancies. In addition, we also demonstrated a clear increase of central memory CD8+ T cells and tumor antigen-specific T cells in peripheral blood following HSV-tk/GCV treatment [9]. This was expected given the systemic immune response effects against the PCa as well as the metastatic cancer foci. Therefore, HSV-tk/GCV GT has potential as a new treatment, especially against unresectable malignancies such as advanced cancer with metastasis or high-grade brain tumors. Indeed, some clinical GT trials using HSV-tk/GCV have been reported against high-grade gliomas [26].\n\nHSV-tk/GCV GT may also have some disadvantages. First, some authors found differing effectiveness among patients, as was the case in this study. PSA recurrence occurred in seven of 18 (39%) patients, and no PSA reduction was observed in three of eight (38%) PCa patients treated with GT [10,11]. Although all of our GT cases showed PSA reduction, a wide range of PSARs from 1.7% to 32.0% were observed, consistent with previous reports [10,11]. Furthermore, Case 4 showed a strong cytopathic effect, large affected tumor area and high ssDNA LI compared with the other cases (Fig. 3, Table 1), indicating individual variation in their responses to GT. Second, the expected duration of the vector's action in vivo remains unclear. According to the PSA reduction data, it seems to be about 30–50 days after a single HSV-tk injection [11]. To date, the safety of more than two cycles of HSV-tk/GCV treatment has not been confirmed. Therefore, it is a problem that GT still requires stronger and longer-range medication.\n\nThe limitations of this study include its small sample size, the setting of the control cases that did not allow adequate assessment of their effects.\n\n5 Conclusion\n\nIn summary, we proposed a new protocol of repeated HSV-tk/GCV gene therapy in patients with localized PCa. Our results demonstrated cytopathic effects and local immune response consistent with some previous reports, indicating that the HSV-tk/GCV GT could be a novel gene therapy against PCa, especially in high-risk patients.\n\nAuthor contributions\n\nStudy concept and design: Nobuyuki Yanagisawa, Takefumi Satoh.\n\nData acquisition: Nobuyuki Yanagisawa, Takefumi Satoh.\n\nData analysis: Nobuyuki Yanagisawa.\n\nDrafting of manuscript: Nobuyuki Yanagisawa, Takefumi Satoh.\n\nCritical revision of the manuscript: Isao Okayasu, Yoshiki Murakumo, Shiro Baba, Masatsugu Iwamura.\n\nPerforming the clinical treatments: Takefumi Satoh.\n\nProviding the clinical information: Ken-ichi Tabata, Hideyasu Tsumura.\n\nDeveloping the vector for HSV-tk Gene therapy: Yasutomo Nasu, Masami Watanabe, Timothy C. Thompson.\n\nConflicts of interest\n\nThe authors have no conflict of interest.\n\nAcknowledgements\n\nThis work was supported by Grants-in-Aid for Scientific Research (JSPS KAKENHI) grant (number 21592060). We thank Dr. M. Ichinoe, E. Satoh and Y. Numata for expert technical assistance.\n\nPeer review under responsibility of Second Military Medical University.\n==== Refs\nReferences\n\n1 Fitzmaurice C. Allen C. Barber R.M. Barregard L. Bhutta Z.A. Brenner H. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the global burden of disease study JAMA Oncol 3 2017 524 548 27918777\n2 Center M.M. Jemal A. Lortet-Tieulent J. Ward E. Ferlay J. Brawley O. International variation in prostate cancer incidence and mortality rates Eur Urol 61 2012 1079 1092 22424666\n3 Keyes M. Crook J. Morton G. Vigneault E. Usmani N. Morris W.J. Treatment options for localized prostate cancer Can Fam Physician 59 2013 1269 1274 24336537\n4 Westdorp H. Benoist G.E. Schers H.J. van Erp P.H. Gerritsen W.R. Mulders P.F. Hormone therapy in prostate cancer; a pharmacotherapeutic challenge Ned Tijdschr Geneeskd 159 2015 A9250 [Article in Dutch] https://pubmed.ncbi.nlm.nih.gov/26246066/ 26246066\n5 Hassan W. Sanford M.A. Woo S.L. Chen S.H. Hall S.J. Prospects for herpes-simplex-virus thymidine-kinase and cytokine gene transduction as immunomodulatory gene therapy for prostate cancer World J Urol 18 2000 130 135 10854148\n6 Moolten F.L. Wells J.M. Curability of tumors bearing herpes thymidine kinase genes transferred by retroviral vectors J Natl Cancer Inst 82 1990 297 300 2299679\n7 Ayala G. Satoh T. Li R. Shalev M. Gdor Y. Aguilar-Cordova E. Biological response determinants in HSV-tk + ganciclovir gene therapy for prostate cancer Mol Ther 13 2006 716 728 16480930\n8 Ayala G. Wheeler T.M. Shalev M. Thompson T.C. Miles B. Aguilar-Cordova E. Cytopathic effect of in situ gene therapy in prostate cancer Hum Pathol 31 2000 866 870 10923926\n9 Kubo M. Satoh T. Tabata K.I. Tsumura H. Iwamura M. Baba S. Enhanced central memory cluster of differentiation 8+ and tumor antigen-specific T cells in prostate cancer patients receiving repeated in situ adenovirus-mediated suicide gene therapy Mol Clin Oncol 3 2015 515 521 26137259\n10 Miles B.J. Shalev M. Aguilar-Cordova E. Timme T.L. Lee H.M. Yang G. Prostate-specific antigen response and systemic T cell activation after in situ gene therapy in prostate cancer patients failing radiotherapy Hum Gene Ther 12 2001 1955 1967 11686937\n11 Nasu Y. Saika T. Ebara S. Kusaka N. Kaku H. Abarzua F. Suicide gene therapy with adenoviral delivery of HSV-tK gene for patients with local recurrence of prostate cancer after hormonal therapy Mol Ther 15 2007 834 840 17327829\n12 Satoh T. Teh B.S. Timme T.L. Mai W.Y. Gdor Y. Kusaka N. Enhanced systemic T-cell activation after in situ gene therapy with radiotherapy in prostate cancer patients Int J Radiat Oncol Biol Phys 59 2004 562 571 15145177\n13 van der Linden R.R. Haagmans B.L. Mongiat-Artus P. van Doornum G.J. Kraaij R. Kadmon D. Virus specific immune responses after human neoadjuvant adenovirus-mediated suicide gene therapy for prostate cancer Eur Urol 48 2005 153 161 15967266\n14 Kattan M.W. Eastham J.A. Stapleton A.M. Wheeler T.M. Scardino P.T. A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer J Natl Cancer Inst 90 1998 766 771 9605647\n15 Satoh T. Matsumoto K. Fujita T. Tabata K. Okusa H. Tsuboi T. Cancer core distribution in patients diagnosed by extended transperineal prostate biopsy Urology 66 2005 114 118\n16 Galon J. Costes A. Sanchez-Cabo F. Kirilovsky A. Mlecnik B. Lagorce-Pages C. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome Science 313 2006 1960 1964 17008531\n17 Mahmoud S.M. Paish E.C. Powe D.G. Macmillan R.D. Grainge M.J. Lee A.H. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer J Clin Oncol 29 2011 1949 1955 21483002\n18 Sica A. Schioppa T. Mantovani A. Allavena P. Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy Eur J Canc 42 2006 717 727\n19 Chavez-Galan L. Arenas-Del Angel M.C. Zenteno E. Chavez R. Lascurain R. Cell death mechanisms induced by cytotoxic lymphocytes Cell Mol Immunol 6 2009 15 25 19254476\n20 Kerfoot S.M. Yaari G. Patel J.R. Johnson K.L. Gonzalez D.G. Kleinstein S.H. Germinal center B cell and T follicular helper cell development initiates in the interfollicular zone Immunity 34 2011 947 960 21636295\n21 Gannon P.O. Poisson A.O. Delvoye N. Lapointe R. Mes-Masson A.M. Saad F. Characterization of the intra-prostatic immune cell infiltration in androgen-deprived prostate cancer patients J Immunol Methods 348 2009 9 17 19552894\n22 Denkert C. Loibl S. Noske A. Roller M. Muller B.M. Komor M. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer J Clin Oncol 28 2010 105 113 19917869\n23 Yamaguchi R. Tanaka M. Yano A. Tse G.M. Yamaguchi M. Koura K. Tumor-infiltrating lymphocytes are important pathologic predictors for neoadjuvant chemotherapy in patients with breast cancer Hum Pathol 43 2012 1688 1694 22516244\n24 Ezzeddine Z.D. Martuza R.L. Platika D. Short M.P. Malick A. Choi B. Selective killing of glioma cells in culture and in vivo by retrovirus transfer of the herpes simplex virus thymidine kinase gene N Biol 3 1991 608 614\n25 Freeman S.M. Abboud C.N. Whartenby K.A. Packman C.H. Koeplin D.S. Moolten F.L. The \"bystander effect\": tumor regression when a fraction of the tumor mass is genetically modified Canc Res 53 1993 5274 5283\n26 Immonen A. Vapalahti M. Tyynela K. Hurskainen H. Sandmair A. Vanninen R. AdvHSV-tk gene therapy with intravenous ganciclovir improves survival in human malignant glioma: a randomised, controlled study Mol Ther 10 2004 967 972 15509514\n\n",
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"issue": "8(3)",
"journal": "Asian journal of urology",
"keywords": "Ganciclovir; HSV-tk; Immunohistochemistry; Prostate carcinoma; Suicide gene therapy",
"medline_ta": "Asian J Urol",
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"nlm_unique_id": "101699720",
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"pages": "280-288",
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"pubdate": "2021-07",
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"references": "17327829;10923926;16520032;19917869;1655012;15145177;24336537;15992910;21636295;22424666;19552894;21483002;16480930;26246066;26137259;9605647;17008531;10854148;2299679;15509514;8221662;22516244;11686937;15967266;19254476;27918777",
"title": "Cytopathic effects and local immune responses in repeated neoadjuvant HSV-tk + ganciclovir gene therapy for prostate cancer.",
"title_normalized": "cytopathic effects and local immune responses in repeated neoadjuvant hsv tk ganciclovir gene therapy for prostate cancer"
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"abstract": "This case report discusses a suspected case of lithium toxicity following the administration of topiramate (TPM). Our patient is a 47-year-old man who has been an inpatient for the past year and was diagnosed with schizoaffective disorder bipolar type 1 for the past 20 years according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5). He manifested symptoms of lithium toxicity following administration of TPM to ameliorate the compulsive consumption of food and liquids. The patient was already being treated with lithium carbonate for mania, labile mood, and aggressive behavior for the past year. The patient developed symptoms of lithium toxicity on the fourth day of the TPM treatment. We transferred the patient to the emergency department where he was diagnosed and treated for renal insufficiency due to lithium toxicity. After halting the TPM and reintroducing lithium carbonate, the patient's laboratory results improved. This case illustrates the potential toxic interaction of medications with a narrow therapeutic index like lithium.",
"affiliations": "Psychiatry, Heartland Behavioral Healthcare, Department of Mental Health and Addiction, State of Ohio, Northeast Ohio Medical University.;Public Health, Uthealth University of Texas Health Science Center at Houston/utsw (dallas).",
"authors": "Khan|Afaque H|AH|;Shah|Shazia Q|SQ|",
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"doi": "10.7759/cureus.1804",
"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.1804PsychiatryEmergency MedicineInternal MedicinePsychiatryTopiramate-Induced Lithium Toxicity Muacevic Alexander Adler John R Khan Afaque H 1Shah Shazia Q 2\n1 \nPsychiatry, Heartland Behavioral Healthcare, Department of Mental Health and Addiction, State of Ohio, Northeast Ohio Medical University \n2 \nPublic Health, Uthealth University of Texas Health Science Center at Houston/utsw (dallas) \nAfaque H. Khan hassan.khan@mha.ohio.gov26 10 2017 10 2017 9 10 e180417 10 2017 26 10 2017 Copyright © 2017, Khan et al.2017Khan et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/9493-topiramate-induced-lithium-toxicityThis case report discusses a suspected case of lithium toxicity following the administration of topiramate (TPM). Our patient is a 47-year-old man who has been an inpatient for the past year and was diagnosed with schizoaffective disorder bipolar type 1 for the past 20 years according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5). He manifested symptoms of lithium toxicity following administration of TPM to ameliorate the compulsive consumption of food and liquids. The patient was already being treated with lithium carbonate for mania, labile mood, and aggressive behavior for the past year. The patient developed symptoms of lithium toxicity on the fourth day of the TPM treatment. We transferred the patient to the emergency department where he was diagnosed and treated for renal insufficiency due to lithium toxicity. After halting the TPM and reintroducing lithium carbonate, the patient’s laboratory results improved. This case illustrates the potential toxic interaction of medications with a narrow therapeutic index like lithium. \n\ncompulsive urge of food intaketopiramatelithium toxicitiybinge eating disorderschizoaffective disorder bipolar type 1The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nNumerous studies have shown the mechanism of action of topiramate (TPM) has a wide spectrum of pharmacological properties. TPM has been used as a mood stabilizer in patients with bipolar and schizoaffective disorders and has been used to treat anorexia, bulimia, epilepsy, migraines, essential tremors, and cluster headaches. It is also effective in treatment-resistant bipolar disorder by augmenting the effects of lithium. Recent literature has also documented TPM use in treating binge eating disorder (BED) and as an aid for weight loss [1]. TPM reduces the frequency of the voltage-sensitive sodium channels, which plays a key role in the treatment of epilepsy. TPM potentiates the inhibitory effects of gamma-aminobutyric acid-(GABA)-A in the brain and enhances the effects of GABA-stimulated chloride influx in the cerebellar and cortical neurons, increasing the frequency of activation of the GABA-A receptor in the brain, and exhibits anticonvulsant action. TPM also inhibits the excitatory pathways of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and glutamate receptors. TPM inhibits high-voltage activated calcium channels and reduces their neurotransmitter release, inhibiting the calcium-dependent second messenger system. TPM also has an inhibitory action of carbonic anhydrase at the proximal tubular level. TPM has been considered a weak carbonic anhydrase (CA) inhibitor, which offers no therapeutic value in the treatment of epilepsy and other conditions, but does determine some of its side effects, such as hyponatremia, metabolic acidosis, and increased risk of nephrolithiasis [2].\n\nCase presentation\nA 47-year-old African American man was admitted to the psychiatric state hospital from a group home, as he had become increasingly aggressive, violent, and threatening toward other residents and staff. He became noncompliant with his treatment prior to this relapse. Upon admission to the hospital, the patient was hyperverbal and presented with pressured speech and flight of ideas. He had manifested aggressive, threatening behavior, and insomnia for the past seven days. The patient was started on lithium carbonate to stabilize his mood and paliperidone to ameliorate his symptoms of mania and psychosis. The results of his comprehensive metabolic panel, thyroid panel, complete blood chemistry, and HbA1c tests were within reference ranges. He responded rapidly to the above combination and stabilized. His schizoaffective bipolar type 1 condition was in remission. We monitored his lithium levels weekly with a comprehensive metabolic panel (CMP) and thyroid panel every six months. During hospitalization, the patient developed a compulsive urge to drink an excessive amount of fluids which was managed by daily weight monitoring and water restriction. For the past eight months, the patient developed a compulsive urge to eat excessive amounts of food and had a rapid gain of 40 lbs. Despite various trials of behavioral modifications and therapies, we were unable to control above this compulsive consumption behavior. The patient urgently needed pharmacological intervention to prevent further weight gain, comorbidities, and metabolic syndrome. He was started on TPM for mood stabilization and compulsive excessive food intake. His lithium levels, HBA1c, thyroid panels, CMP, and complete blood count (CBC) all were within reference ranges prior to the TPM administration (Table 1).\n\nTable 1 Laboratory test results with lithium carbonate prior to TPM administration for compulsive excessive food intake\nNA: not applicable; TPM: topiramate\n\n\nAnalyte \n\t\nPatient Values \n\t\nReference Range \n\t\n\nLithium \n\t\n0.47 mEq/L \n\t\n0.4-1.3 mEq/L \n\t\n\nSodium \n\t\n141 mEq/L \n\t\n135-145 mEq/L \n\t\n\nCreatinine \n\t\n1.1 mg/dL \n\t\n0.50-1.20 mg/dL \n\t\n\nBlood Urea Nitrogen \n\t\n15 mg/dL \n\t\n8.0-22.0 mg/dL \n\t\n\nCreatinine/Blood Urea Nitrogen Ratio \n\t\n17 \n\t\n10.0-22.0 \n\t\n\nWeight Change \n\t\n0 lbs \n\t\nNA \n\t\n\nPotassium \n\t\n3.8 mEq/L \n\t\n3.5-5.0 mEq/L \n\t\nHis kidneys were functioning within reference levels. On the fourth day of treatment, the patient appeared disoriented, increasingly confused, and delirious. He had slurred speech, tremors in both hands, and an unsteady gait. He presented with rapid and shallow breathing. He had concerns of nausea, vomiting, inability to eat, and increased urinary frequency. We suspected lithium toxicity, and treatment with TPM and lithium carbonate were stopped immediately. We ordered an immediate evaluation of laboratory values including CMP, lithium level, thyroid panel, and CBC. His lithium levels were in the toxic range; his creatinine and blood urea nitrogen (BUN) were above the reference ranges (Table 2).\n\nTable 2 Laboratory test results following TPM administration for compulsive excessive food intake\nNA: not applicable; TPM: topiramate\n\n\nAnalyte \n\t\nPatient Values \n\t\nReference Range \n\t\n\nLithium level \n\t\n1.46 mEq/L \n\t\n0.4-1.3 mEq/L \n\t\n\nSodium \n\t\n131 mEq/L \n\t\n135-145 mEq/L \n\t\n\nCreatinine \n\t\n3.4 mg/dL \n\t\n0.50-1.20 mg/dL \n\t\n\nBlood Urea Nitrogen \n\t\n47 mg/dL \n\t\n8.0-22.0 mg/dL \n\t\n\nCreatinine/Blood Urea Nitrogen Ratio \n\t\n23 \n\t\n10.0-22.0 \n\t\n\nWeight Change \n\t\n-6 lbs \n\t\nNA \n\t\n\nPotassium \n\t\n2.9 mEq/L \n\t\n3.5-5.0 mEq/L \n\t\nHe was transferred to the emergency department where he was diagnosed and treated for renal insufficiency secondary to lithium toxicity. Later, the patient showed significant improvement with conservative and supportive treatment, including rehydration and correction of electrolytes imbalance. The results from his final laboratory assessment are presented in Table 3.\n\nTable 3 Laboratory test results following halted TPM treatment and reintroduction of lithium carbonate regimen\nNA: not applicable; TPM: topiramate\n\n\nAnalyte \n\t\nPatient Values \n\t\nReference Range \n\t\n\nLithium level \n\t\n0.79 mEq/L \n\t\n0.4-1.3 mEq/L \n\t\n\nSodium \n\t\n141 mEq/L \n\t\n135-145 mEq/L \n\t\n\nCreatinine \n\t\n1.1 mg/dL \n\t\n0.50-1.20 mg/dL \n\t\n\nBlood Urea Nitrogen \n\t\n15 mg/dL \n\t\n8.0-22.0 mg/dL \n\t\n\nCreatinine/Blood Urea Nitrogen Ratio \n\t\n17 \n\t\n10.0-22.0 \n\t\n\nWeight Change \n\t\n0 lbs \n\t\nNA \n\t\n\nPotassium \n\t\n3.8 mEq/L \n\t\n3.5-5.0 mEq/L \n\t\nDiscussion\nWeight gain and BED are ongoing problems associated with psychotropic medications. Management of these associated conditions is both hectic and time-consuming. After the failure of behavioral and lifestyle modifications, physicians have little choice but to utilize pharmacological interventions. TPM is a useful mood stabilizer in addition to its recent use in affecting weight loss. Currently, no psychotropic medications available include efficacy for weight loss. Multiple case studies indicate long-term effectiveness and tolerability of topiramate in patients with a binge eating disorder and obesity. Treatment with TPM has shown improvement in patients with symptoms of binge eating disorder and obesity [3]. In a randomized controlled trial, TPM was found effective and well tolerated in the short-term treatment of binge eating disorder with obesity. A small number of patients presented with side effects of headache and paresthesias [4]. Our patient had been on lithium for the past year without any significant adverse effects. TPM can increase plasma lithium levels significantly, by five-fold [5]. He developed lithium toxicity due to the pharmacokinetic interaction of TPM with lithium, affecting renal excretion. TPM may increase the lithium level by increasing the excretion of sodium. The potential mechanisms of TPM-induced lithium toxicity appear to be both pharmacokinetic (i.e., the competition for renal excretion) and pharmacodynamic (i.e., the weight-loss-induced decrease in sodium-lithium countertransport activity). TPM also reportedly increases plasma lithium levels by 140%, along with increasing plasma lithium clearance by 36%, decreasing the area under the curve by 12%. Both effects are due to TPM's inhibitory action on carbonic anhydrase in the proximal tubule of the kidneys, and this consequently affects lithium renal clearance [2].\n\nConclusions\nAs healthcare providers, we do not recommend TPM for use as a weight-loss aid, but we also need to prevent patients from developing conditions like coronary heart disease, diabetes, hypertension, and metabolic syndrome—conditions that often develop due to the drastic weight gain associated with psychotropic medications. Unfortunately, our patient developed lithium toxicity due to the pharmacokinetic interaction between TPM and lithium. Our patient made a rapid recovery with conservative treatment, including rehydration and correcting his electrolyte imbalance. Behavioral modifications were reinitiated for the binge eating disorder since TPM is not recommended in this case. More research is required to explore a therapeutic approach for patients with binge eating disorders. Our case report underscores the importance of psychopharmacology; psychiatrists should be aware of the potentially hazardous interactions of psychotropic medications with a narrow therapeutic index such as lithium.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Lithium augmentation of topiramate for bipolar disorder with comorbid binge eating disorder and obesity Hum Psychopharmacol Kotwal R Guerdjikova A McElroy SL Keck PE Jr 425 431 21 2006 16941522 \n2 Psychopharmacology of topiramate: from epilepsy to bipolar disorder Neuropsychiatr Dis Treat Mula M Cavanna AE Monaco F 475 478 2 2006 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2671954/ 19412496 \n3 Topiramate in the long-term treatment of binge-eating disorder associated with obesity J Clin Psychiatry McElroy SL Shapira NA Arnold LM 1463 1469 65 2005 \n4 Topiramate in the treatment of binge eating disorder associated with obesity: a randomized, placebo-controlled trial Am J Psychiatry McElroy SL Arnold LM Shapira NA 255 261 160 2003 12562571 \n5 Does topiramate elevate serum lithium levels? J Clin Psychopharmacol Pinninti NR Zelinski G 340 22 2002 http://journals.lww.com/psychopharmacology/Citation/2002/06000/Does_Topiramate_Elevate_Serum_Lithium_Levels_.20.aspx 12006910\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "9(10)",
"journal": "Cureus",
"keywords": "binge eating disorder; compulsive urge of food intake; lithium toxicitiy; schizoaffective disorder bipolar type 1; topiramate",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e1804",
"pmc": null,
"pmid": "29308332",
"pubdate": "2017-10-26",
"publication_types": "D002363:Case Reports",
"references": "16941522;12006910;12562571;15554757;19412496",
"title": "Topiramate-Induced Lithium Toxicity.",
"title_normalized": "topiramate induced lithium toxicity"
} | [
{
"companynumb": "US-HETERO CORPORATE-HET2018US00042",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drugadditional": "1"... |
{
"abstract": "BACKGROUND\nVascular complications following anterior cervical spine surgery are rare but potentially devastating. Complications associated with the carotid artery are even more disastrous but largely anecdotal, with no more than 4 reported cases.\n\n\nMETHODS\nWe report 3 new cases of carotid artery-related perioperative stroke following anterior cervical spine surgery. All 3 patients had carotid artery atherosclerosis and the time of intraoperative carotid artery retraction was longer than 1 hour. One patient underwent hypotension during surgery. Risk factors as well as prevention and management protocols of carotid artery-related perioperative stroke based on the literature review and our clinical experience are discussed.\n\n\nCONCLUSIONS\nCarotid artery-related perioperative stroke following anterior cervical spine surgery is extremely rare. Prolonged traction, carotid artery atherosclerosis, and intraoperative hypotension can produce cerebral hypoperfusion and cause ischemic stroke. Preoperative risk assessment, adequate perioperative manipulation, and postoperative management can minimize overall morbidity and mortality.",
"affiliations": "Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, China.;Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, China.;Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, China.;Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, China.;Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, China. Electronic address: fengzengjian@hotmail.com.",
"authors": "Du|Yue-Qi|YQ|;Duan|Wan-Ru|WR|;Chen|Zan|Z|;Wu|Hao|H|;Jian|Feng-Zeng|FZ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jstrokecerebrovasdis.2018.10.024",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1052-3057",
"issue": "28(2)",
"journal": "Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association",
"keywords": "Cervical spine; anterior surgery; carotid artery; ischemic stroke; vascular complication",
"medline_ta": "J Stroke Cerebrovasc Dis",
"mesh_terms": "D000369:Aged, 80 and over; D016893:Carotid Stenosis; D002533:Cerebral Angiography; D002574:Cervical Vertebrae; D000072226:Computed Tomography Angiography; D038524:Diffusion Magnetic Resonance Imaging; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D061646:Operative Time; D019637:Orthopedic Procedures; D012307:Risk Factors; D020521:Stroke; D013997:Time Factors",
"nlm_unique_id": "9111633",
"other_id": null,
"pages": "458-463",
"pmc": null,
"pmid": "30413291",
"pubdate": "2019-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Carotid Artery-Related Perioperative Stroke Following Anterior Cervical Spine Surgery: A Series of 3 Cases and Literature Review.",
"title_normalized": "carotid artery related perioperative stroke following anterior cervical spine surgery a series of 3 cases and literature review"
} | [
{
"companynumb": "CN-PFIZER INC-2019032951",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMLODIPINE BESYLATE"
},
"drugadditional": "3",... |
{
"abstract": "Richter syndrome (RS) is associated with chemotherapy resistance and a poor historical median overall survival (OS) of 8-10 months. We conducted a phase II trial of standard CHOP-21 (cyclophosphamide, doxorubicin, vincristine, prednisolone every 21 d) with ofatumumab induction (Cycle 1: 300 mg day 1, 1000 mg day 8, 1000 mg day 15; Cycles 2-6: 1000 mg day 1) (CHOP-O) followed by 12 months ofatumumab maintenance (1000 mg given 8-weekly for up to six cycles). Forty-three patients were recruited of whom 37 were evaluable. Seventy-three per cent were aged >60 years. Over half of the patients received a fludarabine and cyclophosphamide-based regimen as prior CLL treatment. The overall response rate was 46% (complete response 27%, partial response 19%) at six cycles. The median progression-free survival was 6·2 months (95% confidence interval [CI] 4·9-14·0 months) and median OS was 11·4 months (95% CI 6·4-25·6 months). Treatment-naïve and TP53-intact patients had improved outcomes. Fifteen episodes of neutropenic fever and 46 non-neutropenic infections were observed. There were no treatment-related deaths. Seven patients received platinum-containing salvage at progression, with only one patient obtaining an adequate response to proceed to allogeneic transplantation. CHOP-O with ofatumumab maintenance provides minimal benefit beyond CHOP plus rutuximab. Standard immunochemotherapy for RS remains wholly inadequate for unselected RS. Multinational trials incorporating novel agents are urgently needed.",
"affiliations": "Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Oxford, UK.;Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Oxford, UK.;Department of Haematology, The Christie Hospital NHS Trust, Wimslow Road, Manchester, UK.;OCTO - Oncology Clinical Trials Office, Department of Oncology, University of Oxford, Oxford, UK.;Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology & Musculoskeletal Sciences, University of Oxford, Oxford, UK.;NIHR BRC Oxford Molecular Diagnostic Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK.;Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Oxford, UK.;Department of Haematology, Kings College Hospital, London, UK.;Department of Haematology, Addenbrooke's Hospital NHS Trust, Cambridge, UK.;Department of Haematology, Nottingham University Hospitals NHS Trust, Nottingham, UK.;Institute of Cancer, Barts & the London School of Medicine & Dentistry, London, UK.;St James's Institute of Oncology; Dena Cohen, University of Leeds, Leeds, UK.;Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Oxford, UK.;Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Oxford, UK.;Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK.;Department of Haematology, Queen Elizabeth Hospital, Birmingham, UK.;Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, Merseyside, UK.;Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.;NIHR BRC Oxford Molecular Diagnostic Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK.;Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology & Musculoskeletal Sciences, University of Oxford, Oxford, UK.;Laboratory of Clinical Cell Therapy, Jules Bordet Institute, Université Libre de Bruxelles (ULB), Brussels, Belgium.;Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Oxford, UK. anna.schuh@oncology.ox.ac.uk.",
"authors": "Eyre|Toby A|TA|;Clifford|Ruth|R|;Bloor|Adrian|A|;Boyle|Lucy|L|;Roberts|Corran|C|;Cabes|Maite|M|;Collins|Graham P|GP|;Devereux|Stephen|S|;Follows|George|G|;Fox|Christopher P|CP|;Gribben|John|J|;Hillmen|Peter|P|;Hatton|Chris S|CS|;Littlewood|Tim J|TJ|;McCarthy|Helen|H|;Murray|Jim|J|;Pettitt|Andrew R|AR|;Soilleux|Elizabeth|E|;Stamatopoulos|Basile|B|;Love|Sharon B|SB|;Wotherspoon|Andrew|A|;Schuh|Anna|A|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; C527517:ofatumumab; D011241:Prednisone",
"country": "England",
"delete": false,
"doi": "10.1111/bjh.14177",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1048",
"issue": "175(1)",
"journal": "British journal of haematology",
"keywords": "CHOP; Chronic lymphocytic leukaemia; Ofatumumab; Richter syndrome; TP53",
"medline_ta": "Br J Haematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D015415:Biomarkers; D003520:Cyclophosphamide; D018450:Disease Progression; D004317:Doxorubicin; D005260:Female; D006801:Humans; D060828:Induction Chemotherapy; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008223:Lymphoma; D060046:Maintenance Chemotherapy; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D000072078:Positron Emission Tomography Computed Tomography; D011241:Prednisone; D016019:Survival Analysis; D013577:Syndrome; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "43-54",
"pmc": null,
"pmid": "27378086",
"pubdate": "2016-10",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "NCRI phase II study of CHOP in combination with ofatumumab in induction and maintenance in newly diagnosed Richter syndrome.",
"title_normalized": "ncri phase ii study of chop in combination with ofatumumab in induction and maintenance in newly diagnosed richter syndrome"
} | [
{
"companynumb": "GB-JNJFOC-20160929519",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": "... |
{
"abstract": "BACKGROUND\nSayana Press (SP), a subcutaneous formulation of depot medroxyprogesterone acetate (DMPA) prefilled in a Uniject injection system, could potentially improve and expand contraceptive injection services, but acceptability of SP is unknown. HIV-positive women need contraception to avoid unintended pregnancy and risk of vertical HIV transmission. We assessed acceptability of SP versus intramuscular DMPA (DMPA-IM) among HIV-positive women and their care providers in Rakai, Uganda.\n\n\nMETHODS\nWomen were randomized to DMPA-IM or SP at baseline, received the alternate product at 3 months, and chose their preferred method at 6 months. We determined preferences among new and experienced contraceptive injectable users who had tried both types of injection during the trial, and from providers before and after providing both types of injectables to clients.\n\n\nRESULTS\nAmong 357 women randomized, 314 were followed up at 6 months (88%). Although SP caused more skin irritation than DMPA-IM (3.8% vs. 0% at 6 months, p=.03), it was associated with marginally fewer side effects (30.4% vs. 40.4% at 6 months, p=.06). Participants reported high levels of willingness to recommend the DMPA contraception to a friend and satisfaction with the injection received, and these did not differ by injection type. Sixty-four percent of women and 73% of providers preferred SP to DMPA-IM at 6 months; women's preferences did not differ by previous experience with injectable contraception.\n\n\nCONCLUSIONS\nSP is acceptable to HIV-positive women and health care providers in this rural Ugandan population.\n\n\nCONCLUSIONS\nSP appears to be acceptable to HIV-positive women and their care providers in Rakai, Uganda, and strategies for appropriate rollout of this innovative technology should be explored.",
"affiliations": "Office of Population and Reproductive Health, United States Agency for International Development (USAID), Washington, D.C., 20004, USA; Johns Hopkins Bloomberg School of Public Health, Department of Epidemiology, Baltimore, MD, 21205, USA. Electronic address: cpolis@usaid.gov.;Rakai Health Sciences Program, Kalisizo, Uganda.;Rakai Health Sciences Program, Kalisizo, Uganda.;Rakai Health Sciences Program, Kalisizo, Uganda.;Makerere University, College of Health Sciences, School of Public Health, Kampala, Uganda.;Johns Hopkins Bloomberg School of Public Health, Department of Epidemiology, Baltimore, MD, 21205, USA.",
"authors": "Polis|Chelsea B|CB|;Nakigozi|Gertrude F|GF|;Nakawooya|Hadijja|H|;Mondo|George|G|;Makumbi|Fredrick|F|;Gray|Ronald H|RH|;|||",
"chemical_list": "D003271:Contraceptive Agents, Female; D017258:Medroxyprogesterone Acetate",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0010-7824",
"issue": "89(5)",
"journal": "Contraception",
"keywords": "Acceptability; Contraception; Injectable; Intramuscular; Subcutaneous",
"medline_ta": "Contraception",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D003271:Contraceptive Agents, Female; D018592:Cross-Over Studies; D005260:Female; D015658:HIV Infections; D006801:Humans; D007273:Injections, Intramuscular; D007279:Injections, Subcutaneous; D017258:Medroxyprogesterone Acetate; D008875:Middle Aged; D057240:Patient Preference; D014454:Uganda; D055815:Young Adult",
"nlm_unique_id": "0234361",
"other_id": null,
"pages": "385-95",
"pmc": null,
"pmid": "24332432",
"pubdate": "2014-05",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Preference for Sayana® Press versus intramuscular Depo-Provera among HIV-positive women in Rakai, Uganda: a randomized crossover trial.",
"title_normalized": "preference for sayana press versus intramuscular depo provera among hiv positive women in rakai uganda a randomized crossover trial"
} | [
{
"companynumb": "UG-PFIZER INC-2012176280",
"fulfillexpeditecriteria": "1",
"occurcountry": "UG",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
"drugadditional": null,
... |
{
"abstract": "The role for PD-1/PD-L1 and CTLA-4 targeted immunotherapy is well outlined in the treatment of metastatic NSCLC. Increased survival benefit supports the use of these medications and the development of next-generation agents with improved efficacy and favorable side-effect profiles. The prevalence of immunotherapy-associated cardiotoxicity (IAC) has grown significantly over the past two years as awareness of this toxicity class has emerged. High-grade conduction disorders comprise a subset of cardiotoxicities with a high case fatality rate. We presented a case of suspected combination ipilimumab-nivolumab associated 3rd degree heart block. The onset of this event was 16 days after immunotherapy initiation. A literature review has suggested that over 75% of cases of cardiotoxicity are observed within the first 6 weeks. We present findings from an interrogation of the FDA Adverse Event Reporting System (FAERS) and provide clinical guidance for the early identification of high-risk patients.",
"affiliations": "Department of Medicine, University of Connecticut School of Medicine, 263 Farmington Avenue L2104, Farmington, CT, 06030, USA.;Department of Medicine, University of Connecticut School of Medicine, 263 Farmington Avenue L2104, Farmington, CT, 06030, USA.;Department of Medicine, University of Connecticut School of Medicine, 263 Farmington Avenue L2104, Farmington, CT, 06030, USA.;Department of Medicine, Hospital of Central Connecticut, 100 Grand Street, New Britain, CT, 06052, USA.;Department of Medicine, University of Connecticut School of Medicine, 263 Farmington Avenue L2104, Farmington, CT, 06030, USA.;Department of Medical Oncology, Hartford Healthcare, 201 North Mountain Road Suite 202, Plainville, CT, 06062, USA.",
"authors": "Vartanov|Alexander|A|;Kalotra|Aditi|A|;Varughese|Jasmine|J|;Gautam|Shovendra|S|;Kandel|Sean|S|;Hosmer|Wylie|W|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.rmcr.2021.101390",
"fulltext": "\n==== Front\nRespir Med Case Rep\nRespir Med Case Rep\nRespiratory Medicine Case Reports\n2213-0071\nElsevier\n\nS2213-0071(21)00052-6\n10.1016/j.rmcr.2021.101390\n101390\nCase Report\nImmunotherapy-associated complete heart block in a patient with NSCLC: A case report and literature review\nVartanov Alexander vartanov@uchc.edu\na∗\nKalotra Aditi kalotra@uchc.edu\na\nVarughese Jasmine varughese@uchc.edu\na\nGautam Shovendra shovendra@gmail.com\nb\nKandel Sean sean.kandel@hhchealth.org\nab\nHosmer Wylie wylie.hosmer@hhchealth.org\nc\na Department of Medicine, University of Connecticut School of Medicine, 263 Farmington Avenue L2104, Farmington, CT, 06030, USA\nb Department of Medicine, Hospital of Central Connecticut, 100 Grand Street, New Britain, CT, 06052, USA\nc Department of Medical Oncology, Hartford Healthcare, 201 North Mountain Road Suite 202, Plainville, CT, 06062, USA\n∗ Corresponding author. vartanov@uchc.edu\n18 3 2021\n2021\n18 3 2021\n33 1013906 11 2020\n10 3 2021\n15 3 2021\n© 2021 The Author(s)\n2021\nThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nThe role for PD-1/PD-L1 and CTLA-4 targeted immunotherapy is well outlined in the treatment of metastatic NSCLC. Increased survival benefit supports the use of these medications and the development of next-generation agents with improved efficacy and favorable side-effect profiles. The prevalence of immunotherapy-associated cardiotoxicity (IAC) has grown significantly over the past two years as awareness of this toxicity class has emerged. High-grade conduction disorders comprise a subset of cardiotoxicities with a high case fatality rate. We presented a case of suspected combination ipilimumab-nivolumab associated 3rd degree heart block. The onset of this event was 16 days after immunotherapy initiation. A literature review has suggested that over 75% of cases of cardiotoxicity are observed within the first 6 weeks. We present findings from an interrogation of the FDA Adverse Event Reporting System (FAERS) and provide clinical guidance for the early identification of high-risk patients.\n\nKeywords\n\nImmunotherapy\nCardiotoxicity\nLung cancer\nConduction disorder\nMyocarditis\n==== Body\n1 Introduction\n\nImmune checkpoint inhibitors (ICIs) are transformative agents in the field of immunotherapy. These medications have redefined treatment strategies for multiple indications, most notably for NSCLC. In 2015, Pembrolizumab was the first approved antibody targeting the programmed cell death protein 1 (PD-1) receptor in the treatment of NSCLC [1,2]. In subsequent years, atezolizumab, nivolumab, and ipilimumab were approved. Multiple studies have shown extended survival benefit with these new agents; most recently demonstrated with combination ipilimumab and nivolumab in CheckMate-227, independent of PD-L1 expression [[3], [4], [5]]. While effective therapeutically, a new toxicity class has emerged.\n\nImmune-related adverse events (irAEs), notably pneumonitis, colitis, and endocrinopathies were first observed in clinical trials, but the recent recognition of immunotherapy-associated cardiotoxicity (IAC) is of growing concern [6,7]. Both myocarditis and supraventricular arrhythmia have been reported with increased prevalence in patients receiving immunotherapy, and infrequent reports of high-grade conduction disorders are associated with increased mortality [[8], [9], [10], [11], [12], [13]]. Here, we present a rare case of complete heart block in a patient receiving combination ipilimumab and nivolumab.\n\n2 Case presentation\n\nA 78-year-old man with recently diagnosed metastatic ALK-negative, BRAF-positive NSCLC with histopathologic adenocarcinoma and 2% PD-L1 expression presented with subacute onset shortness of breath and feeling “shaky.” His medical comorbidities included, coronary artery disease (CAD), prior coronary artery bypass grafting (CABG), hypertension, diabetes mellitus (DM), chronic kidney disease (CKD), rheumatoid arthritis, and hypothyroidism. He underwent aortic valve replacement and CABG ten years prior. Home medications were valsartan, amlodipine, metoprolol tartrate, metformin, levothyroxine, aspirin, atorvastatin, and as-needed alprazolam. Although both metoprolol and amlodipine could affect atrioventricular (AV) node conduction, the patient was on these medications for over three years.\n\nThe patient was started on combination ipilimumab and nivolumab 15 days prior to admission and tolerated cycle one well. In addition, he reported worsening lower extremity swelling on presentation but denied lightheadedness, orthopnea, chest pain, or palpitations. The patient attributed these symptoms to underlying anxiety.\n\nOn examination, the patient was afebrile, normotensive, with a regular pulse of 63 bpm. He was anxious and tachypneic and was placed on 2 L supplemental oxygen. An EKG (Fig. 1A) showed sinus rhythm, left bundle branch block, and a gradually prolonging PR interval consistent with evolving heart block. There was no EKG for comparison. He had bilateral lower extremity edema and JVD with diminished breath sounds in the left lower lung field. There were no skin changes or new lesions. Initial laboratory studies were notable for neutrophilic leukocytosis of 31.1 x109/L, stable normocytic anemia, potassium 5.9 mmol/L, BUN 52 mg/dL, and creatinine 1.8 mg/dL, at baseline. Initial troponin I was 1.36 (laboratory normal <0.30 ng/mL) and proBNP was 14,180 pg/mL. This was discussed with the cardiology service and attributed to type II NSTEMI complicated by known renal disease. A CT angiogram was negative for pulmonary embolism.Fig. 1 EKG tracing captures evolving complete heart block\n\nFig. 1. Sequential electrocardiogram (EKG) tracings in our patient with likely immunotherapy-associated cardiotoxicity as manifested by a complete heart block. The first tracing is from admission (K = 5.9 mmol/L) and captures atrioventricular dissociation (A), the second at the time of potassium level = 6.0 mmol/L with a 3rd degree heart block with an escape rhythm and new right axis deviation (B), and last on the following day showing persistence of the 3rd degree AV block despite lower potassium (K = 5.6 mmol/L)(C). Atrial impulses identified with thin black arrows, ventricular complex with thick black arrows, and new right axis deviation circled.\n\nFig. 1\n\nThe troponin I remained elevated on the second day (range 1.10–2.18 ng/mL). He was asymptomatic but hyperkalemic to 6.0 mmol/L. Prior potassium levels during this hospitalization were serially between 5 and 6 mmol/L. At this point, an EKG was repeated (Fig. 1B) which revealed a new complete 3rd degree heart block and a junctional versus ventricular escape rhythm. A new right axis deviation was present. This was seen on two subsequent EKGs despite improvement of hyperkalemia. An echocardiogram performed the next day showed a left ventricular ejection fraction (LVEF) of 45% with hypokinesis of mid-anteroseptal and anterior wall segments. There was no valvulopathy or pericardial effusion.\n\nThe patient was deemed a poor surgical candidate due to his metastatic disease and comorbidities. He remained asymptomatic and, through shared decision-making, the patient and medical teams elected not to pursue emergent pacemaker placement. He was scheduled for an outpatient event monitor.\n\nOn hospital day three the patient was found in asystole. Despite several rounds of cardiopulmonary resuscitation, he unfortunately did not achieve return of spontaneous circulation. His family requested to stop further efforts and he expired.\n\n3 Discussion\n\nThe exact prevalence of IACs remains unclear although compounding evidence suggests increased awareness of cardiotoxicity. A review of the WHO VigiBase found cardiac toxicities comprise 2,215 (2.09%) of 106,025 adverse drug reactions (ADRs) for six commonly used ICIs. Of these, nearly 7% were conduction disorders [13,14]. Our own interrogation of the FDA Adverse Event Reporting System (FAERS) is shown in Table 1. This demonstrates the high case fatality rate associated with high-grade heart block and myocarditis, which may present with conduction abnormalities as well.Table 1 Cardiac toxicities in setting of immunotherapy\n\nTable 1. Overall cardiac adverse events by treatment regimen with overall conduction disorders, complete heart block, and myocarditis events. Data secured from the FDA AERS updated through 6/30/2020. Both complete heart block and myocarditis events carry a high case fatality rate particularly for pembrolizumab containing regimens and combination ipilimumab/nivolumab.\n\nTable 1Cardiac\nAdverse Event\tImmunotherapeutic Agent/Regimen\t\nPembrolizumab\tIpilimumab + Nivolumab\tAtezolizumab\tDurvalumab\tBevacizumab\t\nCardiac Disorder, Total n\t1203\t3217\t586\t198\t4881\t\nDeathan (%)\t420 (35%)\t1121 (35%)\t163 (28%)\t76 (38%)\t1458 (30%)\t\nConduction Disorderbn\t56\t105\t15\t5\t38\t\nDeath n (%)\t18 (32%)\t39 (37%)\t2 (13%)\t0\t7 (18%)\t\nComplete Heart Block n\t37\t49\t8\t4\t13\t\nDeath n (%)\t13 (35%)\t18 (37%)\t1 (13%)\t0\t3 (23%)\t\nMyocarditis n\t234\t506\t74\t23\t32\t\nDeath n (%)\t103 (44%)\t216 (43%)\t20 (27%)\t12 (52%)\t13 (41%)\t\na Cases resulting in patient death without investigator assessment of association to immunotherapy.\n\nb Database search terms: atrioventricular block complete, atrioventricular block second degree, atrioventricular block, conduction disorder.\n\nThe clinical significance is also in the time of onset of IAC from initiation of therapy. For immunotherapy associated myocarditis in particular, one study showed median onset of 17 days; another reported 34 days after starting ICI [10,15]. In a review of 101 cases reported to the VigiBase, 76% occurred in the first 6 weeks of therapy [16]. The onset of conduction disorders is less well defined but appears to follow a similar trend. Our case shows rapid onset of complete heart block on day 16 after starting combination ipilimumab-nivolumab. This therapeutic combination was recently found to have a 4.5-fold increase in cardiotoxicity compared with nivolumab alone [10]. A systematic literature review identified 99 cases of ICI-associated cardiotoxicity with mean age of 65 years. Of these, 45% were diagnosed with myocarditis and 12% with conduction disorders - this group carrying the highest case fatality rate, 55% in this series [17].\n\nThis case demonstrates the complexity of managing high-grade conduction disorders that develop in the setting of immune checkpoint inhibitor therapy. The nonspecific clinical manifestations of myocarditis make it difficult, in the absence of an endomyocardial biopsy, to rule out this inflammatory process as contributing to the heart block. The presence of several comorbid conditions should be considered. Hyperkalemia could have caused complete heart block. Our patient had low-grade hyperkalemia throughout the hospital course although this value did not reach greater than 6.0 mmol/L. In the absence of peaked T waves, sine waves, and normal P wave morphology on EKG it is less likely, though not impossible, that this mild hyperkalemia would cause a high-grade heart block particularly in a patient with CKD. The patient's history of CAD requiring CABG supported the working diagnosis of type II NSTEMI as the etiology of the mild troponin elevation. Any direct cardiac tissue damage or inflammation was likely mild given the patient's co-existent renal dysfunction with impaired renal clearance. It is possible that the patient had myocarditis-induced heart block, particularly given the propensity of myocarditis to affect the AV node. However, we hypothesize that the conduction disorder was a direct toxicity of the immunotherapeutic regimen given the time of onset relative to ICI therapy initiation. The low troponin elevation in the setting of CKD and CAD and the lack of characteristics hyperkalemic EKG changes making the other possible etiologies less likely.\n\nIn our patient's case, emergent intervention with pacemaker placement was not absolutely indicated. His presenting symptoms of dyspnea and restlessness were non-specific and appeared incongruent with episodes of complete heart block. From a cardiac perspective, he was asymptomatic, and multiple advanced comorbidities precluded aggressive intervention during his hospitalization.\n\nThis case highlights three particular elements of surveillance and identification of IACs, specifically, conduction disorders. Complete atrioventricular dissociation, as with 3rd degree heart block, carries the highest morbidity and early identification of this sinister event is vital in management. This however remains a clinical challenge.\n\nFirst, it is imperative to acquire a comprehensive history of cardiac risk-factors. The focus should be on ischemic injury, CAD or its equivalents (e.g. DM, CKD), arrhythmia, cardiomyopathy, pericardial disease, and, but not limited to, medication review with attention on nodal-blocking agents and duration of therapy. This further includes a history of primary, or drug-induced, infiltrative and autoimmune disorders contributing to pro-inflammatory states as was observed in our patient with mild rheumatoid arthritis [12,18]. Secondly, we advocate for consideration of serial biomarkers and EKG testing in the early weeks of therapy for high-risk patients. In one study, in cases reporting cardiac biomarkers, serum troponin I, creatine kinase (CK), and brain natriuretic peptide were elevated in 93%, 100%, and 100% of cases, respectively [17]. A second study identified elevated troponin in 94% of cases of myocarditis [15], at times in the absence of symptoms. Coupled with data regarding event onset and given increasing incidence and high case fatality rate of IACs, weekly troponin I, CK, and EKG may prove cost-effective and instrumental in early recognition of at-risk patients. Lastly, early evaluation with advanced diagnostic strategies may be helpful to identify early cardiotoxicity. This can be pursued if a positive biomarker or EKG evaluation is identified. An initial screen could be performed with a 2D-echocardiogram, a test that is sufficiently sensitive for the identification of wall-motion abnormalities and decreased systolic function, findings that may suggest asymptomatic myocarditis. If inconclusive, cardiac MRI may assist in the identification of tissue edema, hyperemia, or fibrosis albeit with variable sensitivity [19].\n\n4 Conclusion\n\nImmunotherapy-associated cardiac adverse events are more prevalent with the increased use of immunotherapeutic agents. Conduction disorders in particular often develop within 6 weeks of therapy initiation. Our case of an elderly gentleman with multiple cardiac risk factors developing complete heart block 16 days after starting ipilimumab-nivolumab combination therapy supports increased clinical vigilance for IAC. Future studies directed at the prospective identification of high-risk patients for IACs may be beneficial.\n\nDeclaration of competing interest\n\nThe authors have no competing financial interests to disclose.\n\nAbbreviations\n\nADR adverse drug reactions\n\nAV atrioventricular\n\nCD conduction disorder\n\nCTLA-4 cytotoxic T-lymphocyte-associated antigen 4\n\nIAC immunotherapy-associated cardiotoxicity\n\nICI immune checkpoint inhibitors\n\nirAEs immune-related adverse events\n\nMACE major adverse cardiac events\n\nNSCLC non-small cell lung cancer\n\nNSTEMI non-ST segment elevation myocardial infarction\n\nPD-1 programmed cell death protein 1\n\nWHO World Health Organization\n\nAuthor contributions\n\nAlexander Vartanov: Conceptualization, Writing – Original Draft, Visualization Aditi Kalotra: Data Curation, Writing – Review & Editing Jasmine Varughese: Data Curation, Writing – Review & Editing Shovendra Gautam: Supervision Sean Kandel: Visualization, Writing – Review & Editing, Supervision Wylie Hosmer: Supervision, Writing – Review & Editing.\n\nFunding\n\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nInformed consent\n\nThis case report was written in accordance with the Declaration of Helsinki. Informed consent was obtained from the patient's next of kin for publication.\n\nAcknowledgements\n\nNot applicable.\n==== Refs\nReferences\n\n1 Sul J. Blumenthal G.M. Jiang X. He K. Keegan P. Pazdur R. FDA approval summary: pembrolizumab for the treatment of patients with metastatic non-small cell lung cancer whose tumors express programmed death-ligand 1 Oncol. 21 5 2016 643 650 10.1634/theoncologist.2015-0498\n2 Garon E.B. Rizvi N.A. Hui R. Pembrolizumab for the treatment of non-small-cell lung cancer N. Engl. J. Med. 372 21 2015 2018 2028 10.1056/NEJMoa1501824 25891174\n3 Hellmann M.D. Paz-Ares L. Bernabe Caro R. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer N. Engl. J. Med. 381 21 2019 2020 2031 10.1056/NEJMoa1910231 31562796\n4 Antonia S.J. Borghaei H. Ramalingam S.S. Four-year survival with nivolumab in patients with previously treated advanced non-small-cell lung cancer: a pooled analysis Lancet Oncol. 20 10 2019 1395 1408 10.1016/S1470-2045(19)30407-3 31422028\n5 Bironzo P. Passiglia F. Novello S. Five-year overall survival of pembrolizumab in advanced non-small cell lung cancer: another step from care to cure? Ann. Transl. Med. 7 Suppl 6 2019 S212 10.21037/atm.2019.08.91 31656791\n6 Naidoo J. Page D.B. Li B.T. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies Ann. Oncol. 26 12 2015 2375 2391 10.1093/annonc/mdv383 26371282\n7 Khunger M. Rakshit S. Pasupuleti V. Incidence 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 152 2 2017 271 281 10.1016/j.chest.2017.04.177 28499515\n8 Heinzerling L. Ott P.A. Hodi F.S. Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy J Immunother Cancer 4 2016 50 10.1186/s40425-016-0152-y 27532025\n9 Varricchi G. Marone G. Mercurio V. Galdiero M.R. Bonaduce D. Tocchetti C.G. Immune checkpoint inhibitors and cardiac toxicity: an emerging issue Curr. Med. Chem. 25 11 2018 1327 1339 10.2174/0929867324666170407125017 28403786\n10 Johnson D.B. Balko J.M. Compton M.L. Fulminant myocarditis with combination immune checkpoint blockade N. Engl. J. Med. 375 18 2016 1749 1755 10.1056/NEJMoa1609214 27806233\n11 Escudier M. Cautela J. Malissen N. Clinical features, management, and outcomes of immune checkpoint inhibitor-related cardiotoxicity Circulation 136 21 2017 2085 2087 10.1161/CIRCULATIONAHA.117.030571 29158217\n12 Lyon A.R. Yousaf N. Battisti N.M.L. Moslehi J. Larkin J. Immune checkpoint inhibitors and cardiovascular toxicity Lancet Oncol. 19 9 2018 e447 e458 10.1016/S1470-2045(18)30457-1 30191849\n13 Salem J.-E. Manouchehri A. Moey M. Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study Lancet Oncol. 19 12 2018 1579 1589 10.1016/S1470-2045(18)30608-9 30442497\n14 Upadhrasta S. Elias H. Patel K. Zheng L. Managing cardiotoxicity associated with immune checkpoint inhibitors Chronic Dis Transl Med 5 1 2019 6 14 10.1016/j.cdtm.2019.02.004 30993259\n15 Mahmood S.S. Fradley M.G. Cohen J.V. Myocarditis in patients treated with immune checkpoint inhibitors J. Am. Coll. Cardiol. 71 16 2018 1755 1764 10.1016/j.jacc.2018.02.037 29567210\n16 Moslehi J.J. Salem J.-E. Sosman J.A. Lebrun-Vignes B. Johnson D.B. Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis Lancet 391 10124 2018 933 10.1016/S0140-6736(18)30533-6\n17 Mir H. Alhussein M. Alrashidi S. Cardiac complications associated with checkpoint inhibition: a systematic review of the literature in an important emerging area Can. J. Cardiol. 34 8 2018 1059 1068 10.1016/j.cjca.2018.03.012 29980467\n18 Chopra A. Nautiyal A. Kalkanis A. Drug-induced sarcoidosis-like reactions Chest 154 3 2018 Sep 664 677 10.1016/j.chest.2018.03.056 29698718\n19 Zhou Y.-W. Zhu Y.-J. Wang M.-N. Immune checkpoint inhibitor-associated cardiotoxicity: current understanding on its mechanism, diagnosis and management Front. Pharmacol. 10 2019 1350 10.3389/fphar.2019.01350 31849640\n\n",
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"keywords": "Cardiotoxicity; Conduction disorder; Immunotherapy; Lung cancer; Myocarditis",
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"title": "Immunotherapy-associated complete heart block in a patient with NSCLC: A case report and literature review.",
"title_normalized": "immunotherapy associated complete heart block in a patient with nsclc a case report and literature review"
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"abstract": "BACKGROUND\nStrong immunosuppression, including chemotherapy and immune-depleting antibodies followed by autologous haemopoietic stem-cell transplantation (aHSCT), has been used to treat patients with multiple sclerosis, improving control of relapsing disease. We addressed whether near-complete immunoablation followed by immune cell depleted aHSCT would result in long-term control of multiple sclerosis.\n\n\nMETHODS\nWe did this phase 2 single-arm trial at three hospitals in Canada. We enrolled patients with multiple sclerosis, aged 18-50 years with poor prognosis, ongoing disease activity, and an Expanded Disability Status Scale of 3.0-6.0. Autologous CD34 selected haemopoietic stem-cell grafts were collected after mobilisation with cyclophosphamide and filgrastim. Immunoablation with busulfan, cyclophosphamide, and rabbit anti-thymocyte globulin was followed by aHSCT. The primary outcome was multiple sclerosis activity-free survival (events were clinical relapse, appearance of a new or Gd-enhancing lesion on MRI, and sustained progression of Expanded Disability Status Scale score). This study was registered at ClinicalTrials.gov, NCT01099930.\n\n\nRESULTS\nBetween diagnosis and aHSCT, 24 patients had 167 clinical relapses over 140 patient-years with 188 Gd-enhancing lesions on 48 pre-aHSCT MRI scans. Median follow-up was 6.7 years (range 3.9-12.7). The primary outcome, multiple sclerosis activity-free survival at 3 years after transplantation was 69.6% (95% CI 46.6-84.2). With up to 13 years of follow-up after aHSCT, no relapses occurred and no Gd enhancing lesions or new T2 lesions were seen on 314 MRI sequential scans. The rate of brain atrophy decreased to that expected for healthy controls. One of 24 patients died of transplantation-related complications. 35% of patients had a sustained improvement in their Expanded Disability Status Scale score.\n\n\nCONCLUSIONS\nWe describe the first treatment to fully halt all detectable CNS inflammatory activity in patients with multiple sclerosis for a prolonged period in the absence of any ongoing disease-modifying drugs. Furthermore, many of the patients had substantial recovery of neurological function despite their disease's aggressive nature.\n\n\nBACKGROUND\nMultiple Sclerosis Scientific Research Foundation.",
"affiliations": "Ottawa Hospital Research Institute, Ottawa, ON, Canada; The Ottawa Hospital Blood and Marrow Transplant Program, Ottawa, ON, Canada; Department of Medicine, University of Ottawa, Ottawa, ON, Canada. Electronic address: hatkins@ohri.ca.;Ottawa Hospital Research Institute, Ottawa, ON, Canada; The Ottawa Hospital MS Clinic, Ottawa, ON, Canada.;Ottawa Hospital Research Institute, Ottawa, ON, Canada; The Ottawa Hospital Blood and Marrow Transplant Program, Ottawa, ON, Canada; Department of Medicine, University of Ottawa, Ottawa, ON, Canada.;The Ottawa Hospital Blood and Marrow Transplant Program, Ottawa, ON, Canada.;Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada; NeuroRx Research, Montreal, QC, Canada.;Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada; Neuroimmunology Unit, Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada.;The Ottawa Hospital Blood and Marrow Transplant Program, Ottawa, ON, Canada; Department of Medicine, University of Ottawa, Ottawa, ON, Canada.;Ottawa Stem Cell Program, Canadian Blood Services, Ottawa, ON, Canada.;Ottawa Hospital Research Institute, Ottawa, ON, Canada; The Ottawa Hospital Blood and Marrow Transplant Program, Ottawa, ON, Canada; Department of Medicine, University of Ottawa, Ottawa, ON, Canada.;Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada; Department of Neurosciences, Cleveland Clinic, Cleveland, OH, USA.;Ottawa Hospital Research Institute, Ottawa, ON, Canada; Department of Medicine, University of Ottawa, Ottawa, ON, Canada.;Ottawa Stem Cell Program, Canadian Blood Services, Ottawa, ON, Canada.;The Ottawa Hospital Blood and Marrow Transplant Program, Ottawa, ON, Canada.;The Ottawa Hospital Blood and Marrow Transplant Program, Ottawa, ON, Canada; Department of Medicine, University of Ottawa, Ottawa, ON, Canada.;Ottawa Hospital Research Institute, Ottawa, ON, Canada.;McGill University Health Center, Montreal, QC, Canada; Division of Oncology, Department of Medicine, McGill University, Montreal, QC, Canada.;Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada.;Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada.;Ottawa Stem Cell Program, Canadian Blood Services, Ottawa, ON, Canada.;The Ottawa Hospital Blood and Marrow Transplant Program, Ottawa, ON, Canada.;Division of Neurology, St Michael's Hospital, University of Toronto, Toronto, ON, Canada.;Ottawa Hospital Research Institute, Ottawa, ON, Canada; Department of Medicine, University of Ottawa, Ottawa, ON, Canada.;The Ottawa Hospital Blood and Marrow Transplant Program, Ottawa, ON, Canada; Department of Medicine, University of Ottawa, Ottawa, ON, Canada.;School of Psychology, University of Ottawa, Ottawa, ON, Canada; The Ottawa Hospital MS Clinic, Ottawa, ON, Canada.;Ottawa Hospital Research Institute, Ottawa, ON, Canada; Department of Medicine, University of Ottawa, Ottawa, ON, Canada; The Ottawa Hospital MS Clinic, Ottawa, ON, Canada.",
"authors": "Atkins|Harold L|HL|;Bowman|Marjorie|M|;Allan|David|D|;Anstee|Grizel|G|;Arnold|Douglas L|DL|;Bar-Or|Amit|A|;Bence-Bruckler|Isabelle|I|;Birch|Paul|P|;Bredeson|Christopher|C|;Chen|Jacqueline|J|;Fergusson|Dean|D|;Halpenny|Mike|M|;Hamelin|Linda|L|;Huebsch|Lothar|L|;Hutton|Brian|B|;Laneuville|Pierre|P|;Lapierre|Yves|Y|;Lee|Hyunwoo|H|;Martin|Lisa|L|;McDiarmid|Sheryl|S|;O'Connor|Paul|P|;Ramsay|Timothy|T|;Sabloff|Mitchell|M|;Walker|Lisa|L|;Freedman|Mark S|MS|",
"chemical_list": "D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D002066:Busulfan",
"country": "England",
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"mesh_terms": "D000293:Adolescent; D000328:Adult; D000961:Antilymphocyte Serum; D002066:Busulfan; D003520:Cyclophosphamide; D018450:Disease Progression; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis; D019172:Transplantation Conditioning; D014182:Transplantation, Autologous; D055815:Young Adult",
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"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial.",
"title_normalized": "immunoablation and autologous haemopoietic stem cell transplantation for aggressive multiple sclerosis a multicentre single group phase 2 trial"
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"abstract": "Legionella pneumophila is an important cause of community-acquired and nosocomial pneumonia. We describe an immunocompromised patient with severe pneumonia from whom Legionella species were isolated from sputum samples by culture for 30 days, despite administration of treatment with appropriate antimicrobial agents. However, clear improvement in the patient's respiratory condition was evident, and he subsequently recovered completely.",
"affiliations": "Department of Medicine and Therapeutics, St. Vincent's University Hospital, Dublin, Ireland.",
"authors": "O'Reilly|Katherine M A|KM|;Urban|Marguerite A|MA|;Barriero|Timothy|T|;Betts|Robert F|RF|;Trawick|David R|DR|",
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"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D006801:Humans; D016867:Immunocompromised Host; D007877:Legionnaires' Disease; D008297:Male; D011014:Pneumonia; D013183:Sputum; D013997:Time Factors",
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"title": "Persistent culture-positive Legionella infection in an immunocompromised host.",
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"abstract": "Prolonged oligohydramnios following extreme preterm prelabour rupture of membranes (EPPROM) is traditionally associated with a high morbidity and mortality to both the mother and the baby. The clinical maternal evaluation and fetal ultrasound assessment may provide important prognostic information for the clinicians and should be taken into account when counselling the patients so as to provide them with enough information to make decision of continuing or interrupting the pregnancy. Current financial constraints on the National Healthcare Service (NHS) resources make it imperative for clinical decision-makers and budgetary planners to make the right decision of continuing or terminating a second trimester pre-viability amniorrhexis for desperate parents. To assess the economic consequences following EPPROM, the risk of infection to both baby and mother, psychological impact on the parents and associated complications and further disability after delivery on this fragile group of patients to the NHS resources. We review the clinical course, outcome, and the challenges to parents and health care professionals on three pregnancies complicated by EPPROM, occurring before 24 weeks' gestation with a membrane rupture to delivery interval (latent period) of 14 days or more. The anticipated birth of an extremely premature infant poses many challenges for parents and health care professionals. As parents are faced with difficult decisions that can have a long-term impact on the infant, family and country's resources, it is critical to provide the type of information and support that is needed by them. Taking all these into consideration with the period of ventilation and respiratory assistance in Neonatal Intensive Care Unit (NICU) is essential to provide maximum chances for survival, minimizing the risk for long term sequelae of the neonate and provides the parents enough time to decide on making the right decision with the associated guidance of the healthcare provider.",
"affiliations": "Department of Obstetrics and Gynecology, Leicester Royal Infirmary, University Hospitals of Leicester NHS Trust, Leicester LE1 5WW, UK. engemisesam@doctors.org.uk.;Department of Child Health, Northampton General Hospital NHS Trust, Northampton NN1 5BD, UK. fiona.thompson@ngh.nhs.uk.;Department of Obstetrics and Gynecology, Northampton General Hospital NHS Trust, Northampton NN1 5BD, UK. william.davies@ngh.nhs.uk.",
"authors": "Engemise|Samuel|S|;Thompson|Fiona|F|;Davies|William|W|",
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"doi": "10.3390/jcm3010025",
"fulltext": "\n==== Front\nJ Clin MedJ Clin MedjcmJournal of Clinical Medicine2077-0383MDPI 10.3390/jcm3010025jcm-03-00025ReviewEconomical Analysis of Different Clinical Approaches in Pre-Viability Amniorrhexis—A Case Series Engemise Samuel 1*Thompson Fiona 2Davies William 31 Department of Obstetrics and Gynecology, Leicester Royal Infirmary, University Hospitals of Leicester NHS Trust, Leicester LE1 5WW, UK2 Department of Child Health, Northampton General Hospital NHS Trust, Northampton NN1 5BD, UK; E-Mail: fiona.thompson@ngh.nhs.uk3 Department of Obstetrics and Gynecology, Northampton General Hospital NHS Trust, Northampton NN1 5BD, UK; E-Mail: william.davies@ngh.nhs.uk* Author to whom correspondence should be addressed; E-Mail: engemisesam@doctors.org.uk; Tel./Fax: +44-1162-764-099. 09 1 2014 3 2014 3 1 25 38 19 11 2013 18 12 2013 30 12 2013 © 2014 by the authors; licensee MDPI, Basel, Switzerland.2014This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).Prolonged oligohydramnios following extreme preterm prelabour rupture of membranes (EPPROM) is traditionally associated with a high morbidity and mortality to both the mother and the baby. The clinical maternal evaluation and fetal ultrasound assessment may provide important prognostic information for the clinicians and should be taken into account when counselling the patients so as to provide them with enough information to make decision of continuing or interrupting the pregnancy. Current financial constraints on the National Healthcare Service (NHS) resources make it imperative for clinical decision-makers and budgetary planners to make the right decision of continuing or terminating a second trimester pre-viability amniorrhexis for desperate parents. To assess the economic consequences following EPPROM, the risk of infection to both baby and mother, psychological impact on the parents and associated complications and further disability after delivery on this fragile group of patients to the NHS resources. We review the clinical course, outcome, and the challenges to parents and health care professionals on three pregnancies complicated by EPPROM, occurring before 24 weeks’ gestation with a membrane rupture to delivery interval (latent period) of 14 days or more. The anticipated birth of an extremely premature infant poses many challenges for parents and health care professionals. As parents are faced with difficult decisions that can have a long-term impact on the infant, family and country’s resources, it is critical to provide the type of information and support that is needed by them. Taking all these into consideration with the period of ventilation and respiratory assistance in Neonatal Intensive Care Unit (NICU) is essential to provide maximum chances for survival, minimizing the risk for long term sequelae of the neonate and provides the parents enough time to decide on making the right decision with the associated guidance of the healthcare provider.\n\namniorrhexisEPPROMPPROMNational Healthcare Services (NHS) resources\n==== Body\n1. Introduction\nPreterm prelabour rupture of the membranes (PPROM), particularly at very early gestations, presents a management problem for obstetricians and neonatologists alike with inherent risks to both mother and foetus. About six in 1000 pregnancies are complicated by PPROM in the second trimester [1]. The management of this group of patients in obstetrics is one of “watchful waiting”, involving monitoring for signs of developing infection, the administration of antibiotics and antenatal corticosteroids, the use of tocolytics and the delivery of the infant once there is any sign of infection or an acceptable maturity is reached [2,3,4].\n\nOverall, there has been traditionally poor outcome in neonatal survival following second trimester PPROM with a number of published series quoting figures of between 20% and 55% [5,6]. Mortality outcomes of >90% have been recorded in infants following rupture of membranes prior to 25 weeks, with a latency period to delivery of over 14 days with persistently confirmed severe oligohydramnios [7]. Parents need to be aware of this when termination is discussed as one of the management options in severe cases of PPROM. More recent studies have showed an improved neonatal outcome following the increased use of antenatal corticosteroids, improvements in antenatal care and monitoring, postnatal surfactant therapy, and general improvement in neonatal intensive care [8,9]. The risks to the infant following EPPROM are associated with the gestation at amniorhexis and gestation at delivery with added risks of infection, limb contractures, cord compression during labour, and pulmonary hypoplasia. These adverse sequelae combined with preterm birth impose a considerable burden on finite National Healthcare Service (NHS) resources. Assessments of the economic consequences following EPPROM, the risk of infection to both baby and mother, psychological impact on the parents, associated complications, and disability of the baby after delivery could provide an invaluable resource for clinical decision-makers and budgetary or service planners on the NHS.\n\nWe review the clinical course, outcome, and the challenges to parents and health care professionals on three pregnancies complicated by EPPROM, the first published by Engemise et al. [10] occurring before 24 weeks’ gestation with a membrane rupture to delivery interval (latent period) of 14 days or more.\n\n1.1. Case 1\nA 34-year-old woman with severe Crohn’s disease, grade IV endometriosis, and bilateral tubal obstruction, booked for antenatal care at 13 weeks gestation. This was her first pregnancy following four attempts of in vitro fertilization and embryo transfer (IVF). Routine antenatal blood investigations were unremarkable. Her blood group was A-negative. Pregnancy was uncomplicated until 17 weeks gestation when she presented with spontaneous PPROM. This was confirmed by the presence of a pool of clear liquor in the vagina and a positive nitrazine test. High vaginal swab cultures for bacteria were negative. Ultrasound scans confirmed a singleton pregnancy with oligohydramnios. There was complete anhydramnion at 19 weeks gestation, and this rendered assessment of foetal anatomy difficult.\n\nThe couple was counselled on the poor outcome and risks of infection to the mother and foetus but expressed the wish to continue with the pregnancy. The risks of significant perinatal mortality and neonatal morbidity associated with chronic anhydramnios and the poor outcome associated with extreme prematurity was fully discussed by the neonatal team. The risks were based on the risk of infection to both mother and the foetus, up to date evidence and the ultrasound findings.\n\nShe was commenced on erythromycin 250 mg eight hourly, and managed expectantly as an outpatient with twice daily temperature checks at home, as well as serial full blood counts (FBC), serum C-reactive protein (CRP) and weekly low vaginal swabs. Two weekly growth scan showed a normally growing foetus, with visible breathing movements, and chest circumference growing along the 50th centile. Abdominal circumference (AC) measurement in foetuses with oligohydramnios may be technically difficult and less reproducible as the abdominal profile may be significantly deformed due to compression, thus, it is probably more reproducible to use ratios based upon head circumference rather than AC as the fetal head is more rigid, even in such conditions [11]. Liquor volume was never measurable due to continuous amniotic fluid leak and anhydramnios.\n\nShe remained well until 24 weeks gestation when she was admitted into hospital following a painful antepartum bleed. There was no clinical or laboratory evidence of chorioamnionitis. She was managed conservatively, with bed rest in hospital, and prophylactic antibiotics. Two doses of 12 mg intra-muscular. Betamethasone were given at 24 weeks, 24 h apart, in order to facilitate foetal lung maturity, and minimise neonatal respiratory distress syndrome (NRDS). Anti D immunoglobulin was also administered to prevent rhesus isoimmunization. She remained in hospital and pregnancy continued largely uneventful until 28 weeks gestation when she had a major placenta abruption; associated with foetal heart decelerations on the cardiotocogram. A live male infant weighing 1100 g was delivered by emergency caesarean section, with an Apgar score of 4 at 1 min. He was electively intubated immediately and given a dose of surfactant. A diagnosis of pulmonary hypoplasia was made on the basis of immediate onset of severe respiratory distress syndrome (RDS) requiring high ventilator pressures (MAP = 18) and no improvement in oxygenation or lung compliance after two doses of surfactant. Plain chest X-ray showed small lung fields with elevated diaphragms and a bell shaped thorax; highly suggestive of the diagnosis of pulmonary hypoplasia.\n\nApart from his compressed ears and mildly depressed tip of the nose, (mild degree of Potter’s features), there were no other gross skeletal deformities. The second day of life was complicated by pneumothorax probably secondary to the high-pressure ventilation. This resolved with no sequelae following chest tube drainage. He was extubated after 14 days of ventilation but required nasal continuous positive airway pressure ventilation for another 80 days. He tolerated bilateral inguinal herniotomy at the age of 130 days and was discharged home, self-ventilating in air and in good health; with a follow-up appointment for developmental assessment.\n\n1.2. Case 2\nA 33-year-old woman para 4 (two term and two preterm at 34 and 28 weeks) all normal deliveries, one miscarriage, and one termination booked for antenatal care at eight weeks and five days gestation. Routine antenatal blood investigations were unremarkable. Her blood group was A Rhesus positive. The patient developed a urinary tract infection at 15 weeks and three days and was treated with antibiotics. At 22 weeks of gestation she presented with a history suggestive of spontaneous PPROM. This was confirmed by the presence of trickling of clear liquor through the cervix on speculum examination. High vaginal swab cultures taking at the time for infection were negative. Ultrasound scans confirmed a singleton pregnancy with complete oligohydramnios which made assessment of foetal anatomy difficult.\n\nThe couple was counselled on the outcome and risks of infection to the mother and foetus but expressed the wish to continue with the pregnancy. The risks of significant perinatal mortality and neonatal morbidity associated with chronic oligohydramnios and the outcome associated with extreme prematurity was also fully discussed with the couple.\n\nShe was commenced on erythromycin 250 mg, six hourly, and managed expectantly as inpatient with twice daily temperature checks, twice weekly FBC and serum CRP. Two weekly growth scan showed a normal growing foetus, oligohydramnios with visible breathing movements, and chest and abdominal circumference growing along the 50th centile. Abdominal circumference (AC) measurement in foetuses with oligohydramnios may be technically difficult and less reproducible as the abdominal profile may be significantly deformed due to compression so it is probably more reproducible to use ratios based upon head circumference rather than AC as the fetal head is more rigid, even in such conditions [11].\n\nTwo doses of 12 mg intra-muscular betamethasone were given 24 h apart at 23 weeks in order to facilitate foetal lung maturity, and minimise NRDS. Liquor volume was never measurable due to continuous amniotic fluid leak and anhydramnios. While in hospital at 25 weeks and six days gestation she developed mild lower abdominal pain with minimal vaginal bleeding with no clinical or laboratory evidence of chorioamnionitis. At 27 weeks and 6 days, the bleeding was severe with moderate to severe intermittent lower abdominal pain. On bimanual vaginal examination the presentation was breech and cervix was 9 cm dilated with adequate contraction.\n\nCardiotocogram was normal and patient was delivered by breech extraction of a male infant weighing 1126 g with Apgar of 4, 7, and 10 at 1, 5, and 10 min respectively. He was electively intubated at 10 min of life and given a dose of surfactant and then transferred to the special baby care unit (SCBU).\n\nIn SCBU he was treated for presumed sepsis and briefly ventilated for 10 h for RDS and required nasal continuous positive airway pressure (CPAP) for 29 days, and oxygen until day 41. Echocardiography revealed a small patent ductus arteriosus (PDA) and ultrasound of the liver showed an abnormality, which was presumed to be a haemangioma. The patient was treated with diuretics and for gastro-oesophageal reflux disease and was discharged home, self-ventilating on air after 69 days in SCBU weighing 2250 g; with a follow-up appointment for developmental assessment in six weeks.\n\n1.3. Case 3\nA 42-year-old A rhesus negative woman with minimal endometriosis, multiple uterine surgeries for removal of uterine fibroids, MTHFR—(methylene-tetra-hydro-folate-reductase) homozygous mutation with factor V Leiden deficiency booked for antenatal care at six weeks gestation following three embryo transfers. She was a para (Never carried a pregnancy beyond the viability stage is the 0 and the 3 is the three miscarriages as indicated) 0 + 3, three miscarriages with the fourth attempt of IVF. This was a triplet pregnancy with a monochorionic diamniotic (MCDA) twins’ and a singleton. The patient was placed on daily 60 mg of subcutaneous clexane and 75 mg of oral aspirin until 24 weeks gestation when her aspirin was stopped. Routine antenatal blood investigations were unremarkable.\n\nOn routine scan at 15 weeks, the MCDA twins’ were found to have developed severe Twin-to-Twin Transfusion (TTTs) with a 17.3% growth discrepancy and a velamentous cord insertion of the recipient twin. The couple was counselled on the condition, as well as the chances of survival of the MCDA twins’ either by expectant management or surgery. The later was agreed and performed at 16 weeks gestation with laser ablation of the communicating vessels.\n\nAt 18 weeks of gestation the patient presented into gynecology emergency clinic (GEAC) with history suggestive of PPROM, which was later confirmed by the presence of clear liquor in the vagina. High vaginal swab for cultures were negative for infection. Ultrasound scans confirmed a reduced liquor of maximum amniotic fluid index (AFI) of 3 cm in the MCDA donor twin, 11 cm of the recipient twin, and normal liquor volume in the singleton, with the later lying at the basal end of the uterus. Baseline FBC and CRP were taken and their results showed no sign of infection.\n\nThe couple was counselled on the poor outcome and risks of infection to the mother and foetus but expressed their desire to continue with the pregnancy. The risks of significant perinatal mortality and neonatal morbidity associated with persistent reduced liquor and extreme prematurity were also discussed by the neonatal team.\n\nShe was commenced on clindamycin 150 mg, six hourly throughout her stay in hospital, as she was allergy to penicillin, erythromycin, and metronidazole, and managed expectantly while in hospital as inpatient with routine daily vital signs, twice weekly FBC and serum CRP, as well as weekly low vaginal swabs. A weekly growth, liquor, and viability scan showed normal growing foetuses and maximum AFI depth of 3 cm in the MCDA twins with normal liquor in the singleton, with visible breathing movements and chest circumference of all three foetuses growing along the 50th centile.\n\nAt 23 weeks and four days gestation, two doses of 12 mg intra-muscular betamethasone were given, 24 h apart, to facilitate foetal lung maturity and minimise NRDS. She also had anti D immunoglobulin administered to prevent rhesus isoimmunization. At 27 weeks and three days the vagina liquor was blood stained with intermittent abdominal pain and ultrasound scan revealed a minor placenta abruption. She remained in hospital and pregnancy continued until 28 weeks and five days gestation when she had an elective caesarean section for worsening vaginal bleeding and lower abdominal pain with the delivery of three live female infants weighing 1350 g, 1165 g, and 1038 g, respectively, with cord blood and base excess (Table 1). Her estimated blood loss (EBL) during the procedure was 2 L. They were electively intubated immediately and each given a dose of surfactant and transferred to SCBU.\n\njcm-03-00025-t001_Table 1Table 1 Birth weight and venous and arterial cord bloods of the triplets.\n\nBabies weight (g)\tCord blood arterial “A”\tCord blood venous “V”\tBase excess “A”\tBase excess “V”\t\n1350 “A”\t7.31\t7.38\t−5.1\t−1.9\t\n1165 “B”\t7.29\t7.40\t−4.1\t−3.7\t\n1038 “C”\t7.20\t7.31\t−6.6\t−2.5\t\n1.4. Triplet A\nShe was the singleton of the triplet with Apgar score of 9 and 10, in 1 and 5 min, respectively, at delivery. She was immediately electively ventilated due to prematurity with a dose of surfactant given at 9 min of life and transferred to SCBU. In SCBU she was treated for presumed sepsis and developed RDS for possible pulmonary hypoplasia requiring CPAP and oxygen until day 85. She developed chronic lung disease (CLD) in the process and has been treated for gastro-oesophageal reflux disease (GORD). She also developed grade IV intraventricular haemorrhage on day eight and later developed a parencephalic cyst which did not progress to hydrocephalus during her stay in SCBU. Echocardiography revealed a small PDA, which had closed by the 21st day of life. She has been discharged home, self-ventilating on air after 98 days in SCBU, weighing 3.260 g; with a follow-up appointment for developmental assessment in six weeks.\n\n1.5. Triplet B\nShe was the MCDA recipient twin with triplet C with Apgar scores of 7 and 9, at 1 and 5 min, after delivery. She was immediately electively ventilated due to prematurity and given a dose of surfactant and then transfer to SCBU. In SCBU she was treated for presumed sepsis and developed RDS. However, she developed pulmonary hypertension and hypotension, which was not responding to maximal con ventilation and inotropes but had a good response with nitric oxide and high frequency ventilation following transfer to the tertiary centre. Following the RDS, she developed CLD and was treated with diuretics and erythromycin from days 47 to 57 and for GORD. She has been discharged home, self-ventilating on air from day 85 after 98 days in SCBU, weighing 3.210 g; with a follow-up appointment for developmental assessment in six weeks.\n\n1.6. Triplet C\nShe was the MCDA donor twin with triplet B with Apgar scores of 6 and 8, at 1 and 5 min, after delivery. As noticed above (Table 1) this triplet revealed signs of fetal distressed as evidence by the cord arterial PH. She was immediately electively ventilated due to prematurity and given a dose of surfactant and then transferred to the SCBU. In SCBU she was treated for presumed sepsis and developed RDS and possible pulmonary hypoplasia requiring CPAP and oxygen. She then developed CLD and was treated with diuretics and erythromycin from day 43 to 53 and for GORD. She was discharged home, self-ventilating on air from day 85 after 98 days in SCBU, weighing 3.082 g; with a follow-up appointment for developmental assessment in six weeks.\n\n2. Discussion\nEPPROM before 24 weeks occurs in less than 1% of pregnancies [12]. Most cases deliver spontaneously before one week [13,14] with expectant management not applicable. The optimal management of the remaining pregnancies is still controversial because pulmonary hypoplasia and extreme prematurity limit survival and increase perinatal morbidity. The decision to continue or terminate a pregnancy complicated by EPPROM prior to foetal viability is fraught with difficulties due to the medical, socioeconomics, and emotional problems associated with it. The adverse sequelae resulting from EPPROM impose a considerable burden on finite NHS resources and the country. Over the past few years, advances in neonatal intensive care have led to a dramatic increase in neonatal survival at early gestation; therefore termination of second trimester pre-viability amniorrhexis in a desperate family situation needs some consideration.\n\nAssessments of the economic consequences of preterm birth with parents’ involvement could provide an invaluable resource for clinical decision-makers and budgetary or service planners on the NHS. The risk of infection to both baby and mother, psychological impact on the parents’ lives and the associated complications and disability on the baby following delivery at extreme prematurity further weighs on the fragile economy system.\n\nThe current financial constraints on NHS resources make it imperative to define better health care outcomes achieved and the costs of achieving these outcomes. In the last decade, there has been an increase in aggressive obstetric management and neonatal resuscitation for threatened preterm births [15]. According to American College of Obstetricians and Gynecologists (ACOG) there is sufficient evidence to inform parents that the survival rate for newborns increases from 0% at 21 weeks to 75% at 25 weeks, with or without major disability [16]. Associated costs impose a significant burden on multiple sectors of the US economy and include long-term hospital, outpatient medical, developmental, and educational expenses. A full characterization of all costs is necessary when evaluating the cost-effectiveness of preterm delivery, prevention therapies and when estimating the impact that increasing preterm birth rates and extreme preterm survivorship will have on future expenditures.\n\nNeonatal and postneonatal hospital and outpatient costs that are associated with preterm birth and, related, low birth weight, have been well characterized. Estimates of neonatal inpatient costs for children who are born preterm range from approximately $11,000 to $18,000 (2,003 dollars) per birth, compared with $1,300 to $1,900 (2,003 dollars) per term birth [17,18,19]. Rogowski et al., in [20], estimated the cost of rehospitalizations and outpatient care during the first year for preterm infants who are born <1500 g to be approximately $8,000 (1,987 dollars) per child. Lewett et al. [21] estimated that each low birth weight child costs an average of approximately $290 more than a higher birth weight child for inpatient medical care during the preschool years. These are even higher in pregnancies complicated by EPPROM prior to foetal viability, as these patients have extremely long hospital admission as in these cases with continuous use of the health care resources and expertise. Accommodation and other resources are allocated to the infants according to the need.\n\nAmongst infants with disability, mean health service costs for the entire follow-up period were estimated at £14,510 for the lowest birth weight group (<1000 g), £12,051 for the intermediate birth weight group (1000–1500 g) and £7,178 for the highest birth weight group (>1500 g). Relatively little is known about the economic impact of preterm birth outside of the health sector [22]. Moreover, there is no empirical evidence that focuses on the economic impact of extreme preterm birth, which is of increasing relevance in the modern perinatal care context.\n\nCounselling may produce confusion and ambiguity for parents. While this is a very real and stressful event for them, the physicians talks about hypothetical situations and uncertainty. The fear of what may happen to the baby in terms of morbidity and suffering is often mixed with a fear of losing the baby. As a result, many women will wax and wane on their decision to continue the pregnancy. Given the confusion and stress that parents may be experiencing there are many things that healthcare providers need to consider. First, it is the parents who will have to accept the ramifications of their decisions for the rest of their lives although the life time financial burden of a disable child rests in the nation’s economy. The medical and obstetrics history of the mother, as well as the risk of chorioamnionitis to the mother and the foetus, up to date literature evidence, and the ultrasound findings will help both the healthcare provider and the couple in deciding on either terminating or continuing the pregnancy.\n\nTaking these into consideration render the management of pregnancies complicated by EPPROM controversial and either option has risks for the mother and baby. Parents need to be counselled on the benefits and burdens either decision (termination or continuation) will have on their future life. This is so as the most critical interval in fetal lung development, the canalicular phase, which occurs between 16 and 28 weeks’ gestation, is delayed following EPPROM, thus, causing the likes of pulmonary hypoplasia. Pulmonary hypoplasia poses a serious threat to the live of the fetus with the mortality rate estimated to be 70% (55%–100%) [23]. The lethal form of pulmonary hypoplasia is only proven by autopsy as there is poor sensitivity and specificity of imaging techniques to predict this condition is poor [24]. Vergani, in 2012, proposed that the most accurate prediction of lethal pulmonary hypoplasia in utero might be achieved by different combinations of clinical, ultrasound, and MRI parameters as there is no single test to achieve that at the moment [25]. The spirituality and support from both the parents and family may also help them to cope at this difficult time [26]. In a study that explored the effects of high risk pregnancies on families, it was found that family support had a positive impact on the mothers’ ability to manage their current situation [26]. The fragility of the parent’s condition, both physiologically and psychologically at this point need’s consideration by the healthcare provider with the experienced team members giving the leading role. Despite the best care, adverse outcomes occur and should be anticipated by all involved with the possibility that the infant may die in utero or may not be viable at birth.\n\nMicrobial invasion of the amniotic cavity is present in one third of patients with PPROM and is strongly associated with impending preterm delivery, adverse pregnancy, and neonatal outcome [27,28,29]. The risk of infection to the mother and the unborn baby should be anticipated with the babies more susceptible. This susceptibility is more pronounced in preterm babies who have been potentially exposed to maternal flora following a breach in the amniotic membrane secondary to prolonged PPROM. This has made the prognosis for a normal pregnancy where the membranes rupture at 14 weeks dismal primarily due to the risk of miscarriage secondary to infection. Even with appropriate antibiotic treatment, approximately 50% of pregnancies are delivered each subsequent week following PPROM. Therefore parent should be aware that, when the membranes rupture before 20 weeks of gestation the probability of reaching viability is <5% [30], hence, the need for good decision in this stressful situation.\n\nChorioamnionitis, when present, regardless of its infectious aetiology, challenges the functional integrity of the membranes, making them vulnerable to other environmental insults with pathologic consequences during the pregnancy. Bacteria from the vagina can access foetal membranes by ascending the cervical canal and, then, infect amniotic fluid and foetal blood resulting in inflammation. This inflammation will cause the release of inflammatory markers like cytokines. Normal level of cytokines and their receptors, found in central nervous system cells, are important for brain development and function. They influence inflammatory response as well as neuron and glial cell development. Elevated levels of proinflammatory cytokines in amniotic fluid, cord blood, or neonatal blood indicate the presence of a systemic foetal inflammatory response. A persistent neuroinflammatory response may result when the inflammation signal is transmitted across the blood-brain barrier [31]. This is associated with intraventricular haemorrhage, white matter damage, and cerebral palsy [32,33]. When associated with hypoxic events, cytokines negatively affect functional outcome, such as early psychomotor development [34]. High concentrations of specific cytokines, such as interleukin-1β, interleukin-6, and interleukin-8, have been associated with abnormal neurodevelopment at 6, 12, and 30 months of age [35,36,37]. These cytokines are not routinely determined in patients with EPPROM as persistence high level in the maternal blood and amniotic fluid may indicate a possible abnormal psychomotor development in later life [35,36,37]. White matter injury appears to be the most common brain abnormality in preterm infants with PPROM, and a major predictor of smaller volumes along with gestational age [38].\n\nA second reason for dismal prognosis is the risk of neonatal death secondary to pulmonary hypoplasia when pregnancy becomes viable. The chance of pulmonary hypoplasia is lessened if the fluid re-accumulates before 24 weeks of gestation. One study using a multivariate analysis suggested that the likelihood for neonate survival increases by 2.7 (95% CI 1.45 to 4.65) for every 5-mm increase in the depth of amniotic fluid during the follow up from rupture up to the 24th week of gestation [39]. Despite dismal prognosis, however, expectant management for EPPROM at 14 weeks may be appropriate if the parents are well-informed and aware of the risks in both the mother and the unborn baby. In time of decision making the healthcare provider need to consider the emotional attachment to the unborn baby and the psychological impact this will have on the parents’ future lives.\n\nPreterm infants are at increased risk of other range of adverse neonatal outcomes including retinopathy of prematurity [40], necrotizing enterocolitis, and neonatal sepsis [41]. In later life, they are at increased risk of motor and sensory impairment [42,43], learning difficulties [44,45,46,47,48], and behavioural problems [49,50,51,52]. These should be borne in mind when counselling the couple as this helps them to make the right decision with no future regret.\n\nThe maternal morbidity and mortality risk of chorioamnionitis, retained placenta, postpartum hemorrhage, placental abruption, and classical caesarean section also increases in this group of patients. These risks need to be explained to the parents with their complications (such as endoparametrities, septic pelvic thrombophlebitis, and the possibility of hysterectomy in very rare cases). The risk of chorioamnionitis is up to 30% in some studies [53,54], which may reflect to a more widespread use of antibiotics in recent years in this group of patient. The overall frequency of placental abruption of 4.0%–6.8% as reported by several authors [55,56,57,58], occurred in two of these patients. Scar dehiscence in future pregnancies following a classical caesarean need not be ignored.\n\n3. Conclusions\nOur small series of three treated successfully cases without recourse to the complication associated with EPPROM may be the subject to publication bias and may not represent widespread medical opinion. This makes the acceptable outcome individually determined and parents should be aware that the mortality for infants with rupture of membranes prior to 25 weeks and a latency period of over 14 days with severe oligohydramnios is in excess of 90% in some studies [7]. The limit; expectancy; risks of infections to the mother, and chances of infant survival is always a consensus for debate in EPPROM. Thus, the clinical maternal evaluation and the fetal ultrasound assessment, as well as other risks, such as chorioamnionitis may provide important prognostic information for the clinicians and should be taken into account when counselling the patients so as to provide them with enough information to make decision of continuing or interrupting the pregnancy.\n\nThe anticipated birth of an extremely premature infant also poses many challenges for the parents, government and health care professionals. As parents are faced with difficult decisions that can have a long-term impact on the infant and family, it is critical to provide the type of information and support that is needed by them. Taking all these into consideration parents should be given enough time to decide on making the right decision with the associated guidance of the healthcare provider without forgetting all the risks involved to both the mother and the premature infant.\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n==== Refs\nReferences\n1. Locatelli A. Ghidini A. Verderio M. Andreani M. Strobelt N. Pezzullo J. Vergani P. Predictors of perinatal survival in a cohort of pregnancies with severe oligohydramnios due to premature rupture of membranes at <26 weeks managed with serial amnioinfusions Eur. J. Obstet. Gynecol. Reprod. Biol. 2006 128 97 102 10.1016/j.ejogrb.2006.02.003 16530921 \n2. Schucker J.L. Mercer B. Mid trimester premature rupture of the membranes Semin. 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The fetal lung 2: Pulmonary hypoplasia Ultrasound Obstet. Gynecol. 2000 16 482 494 10.1046/j.1469-0705.2000.00252.x 11169336 \n24. Van Teeffelen A.S.P. van der Heijden J. Oei S.G. Porath M.M. Willekes C. Opmeer B. Mol B.W.J. Accuracy of imaging parameters in the prediction of lethal pulmonary hypoplasia secondary to mid-trimester prelabour rupture of fetal membranes: A systematic review and meta-analysis Ultrasound Obstet. Gynecol. 2012 39 495 499 10.1002/uog.10047 21793083 \n25. Vergani P. Prenatal diagnosis of pulmonary hypoplasia Curr. Opin. Obstet. Gynecol. 2012 24 89 94 10.1097/GCO.0b013e3283505a86 22249145 \n26. Sittner B.J. DeFrain J. Hudson D.B. Effects of high-risk pregnancies on families Am. J. Matern. Child Nurs. 2005 30 121 126 10.1097/00005721-200503000-00010 \n27. Romero R. Quintero R. Oyarzun E. Wu Y.K. Sabo V. Mazor M. Hobbins J.C. Intra-amniotic infection and the onset of labour in preterm premature rupture of the membranes Am. J. Obstet. Gynecol. 1988 159 661 666 10.1016/S0002-9378(88)80030-9 3421266 \n28. Gibbs R.S. Romero R. Hillier S.L. Eschenbach D.A. Sweet R.L. A review of premature birth and subclinical infection Am. J. Obstet. Gynecol. 1992 166 1515 1528 10.1016/0002-9378(92)91628-N 1595807 \n29. Shim S.S. Romero R. Hong J.S. Park C.W. Jun J.K. Kim B.I. Yoon B.H. Clinical significance of intra-amniotic inflammation in patients with preterm premature rupture of membranes Am. J. Obstet. Gynecol. 2004 191 1339 1345 10.1016/j.ajog.2004.06.085 15507963 \n30. Mercer B. Milluzzi C. Collin M. Periviable birth at 20 to 26 weeks of gestation: Proximate causes, previous obstetric history and recurrence risk Am. J. Obstet. Gynecol. 2005 193 1175 1180 10.1016/j.ajog.2005.05.040 16157133 \n31. Malaeb S. Dammann O. Fetal inflammatory response and brain injury in the preterm newborn J. Child Neurol. 2009 24 1119 1126 10.1177/0883073809338066 19605775 \n32. Tauscher M.K. Berg D. Brockmann M. Seidenspinner S. Speer C.P. Groneck P. Association of histologic chorioamnionitis, increased levels of cord blood cytokines, and intracerebral hemorrhage in preterm neonates Biol. Neonate 2003 83 166 170 10.1159/000068924 12660432 \n33. Yoon B.H. Jun J.K. Romero R. Park K.H. Gomez R. Choi J.H. Kim I.O. Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-1beta, and tumour necrosis factor alpha), neonatal brain white matter lesions, and cerebral palsy Am. J. Obstet. Gynecol. 1997 177 19 26 10.1016/S0002-9378(97)70432-0 9240577 \n34. Hansen-Pupp I. Hallin A.L. Hellstrom-Westas L. Cilio C. Berg A.C. Stjernqvist K. Fellman V. Ley D. Inflammation at birth is associated with subnormal development in very preterm infants Pediatr. Res. 2008 64 183 188 10.1203/PDR.0b013e318176144d 18391842 \n35. Bartha A.I. Foster-Barber A. Miller S.P. Vigneron D.B. Glidden D.V. Barkovich A.J. Ferriero D.M. Neonatal encephalopathy: Association of cytokines with MR spectroscopy and outcome Pediatr. Res. 2004 56 960 966 10.1203/01.PDR.0000144819.45689.BB 15496611 \n36. Okazaki K. Nishida A. Kato M. Kozawa K. Uga N. Kimura H. Elevation of cytokine concentrations in asphyxiated neonates Biol. Neonate 2006 89 183 189 10.1159/000089180 16244469 \n37. Rezaie P. Dean A. Periventricular leukomalacia, inflammation and white matter lesions within the developing nervous system Neuropathology 2002 22 106 132 10.1046/j.1440-1789.2002.00438.x 12416551 \n38. Martinussen M. Flanders D.W. Fischl B. Busa E. Lohaugen G.C. Skranes J. Vangberg T.R. Brubakk A.M. Haraldseth O. Dale A.M. Segmental brain volumes and cognitive and perceptual correlates in 15-year-old adolescents with low birth weight J. Pediatr. 2009 155 848 853 10.1016/j.jpeds.2009.06.015 19683725 \n39. Palacio M. Cobo T. Figueras F. Gómez O. Coll O. Cararach V. Gratacós E. Previable rupture of membranes: Effect of amniotic fluid on pregnancy outcome Eur. J. Obstet. Gynecol. Reprod. Biol. 2008 138 158 163 10.1016/j.ejogrb.2007.08.014 17920752 \n40. Msall M.E. Phelps D.L. Hardy R.J. Dobson V. Quinn G.E. Summers C.G. Tremont M.R. Educational and social competencies at 8 years in children with threshold retinopathy of prematurity in the CRYO-ROP multicenter study Paediatrics 2004 113 790 799 10.1542/peds.113.4.790 \n41. Stoll B.J. Hansen N.I. Bell E.F. Shankaran S. Laptook A.R. Walsh M.C. Hale E.C. Newman N.S. Schibler K. Carlo W.A. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network Paediatrics 2010 126 443 456 10.1542/peds.2009-2959 \n42. Hack M. Fanaroff A. Outcome of extremely low birth weight and gestational age in the 1990s Early Hum. Dev. 1999 53 193 218 10.1016/S0378-3782(98)00052-8 10088988 \n43. Wood N. Marlow N. Costeloe K. Gibson A. Wilkinson A. Neurologic and developmental disability after extremely preterm birth N. Engl. J. Med. 2000 343 378 384 10.1056/NEJM200008103430601 10933736 \n44. Hall A. McLeod A. Counsell C. Thomson L. Mutch L. School attainment, cognitive ability and motor function in a total Scottish very low birth weight population at 8 years—A controlled study Dev. Med. Child Neurol. 1995 37 1037 1050 8566462 \n45. Botting N. Powls A. Cooke R.W.I. Marlow N. Cognitive and educational outcome of very low birthweight children in early adolescence Dev. Med. Child Neurol. 1998 40 652 660 9851233 \n46. Saigal S. Szatmari P. Rosenbaum P. Campbell D. King S. Cognitive abilities and school performance of extremely low birthweight children and matched term control children at age 8 years: A regional study J. Paediatr. 1991 118 751 760 10.1016/S0022-3476(05)80043-5 \n47. Buck G. Msall M. Schisterman E. Lyon N. Rogers B. Extreme prematurity and school outcomes Paediatr. Perinat. Epidemiol. 2000 14 324 331 10.1046/j.1365-3016.2000.00276.x 11101019 \n48. Saigal S. Hoult L. Streiner D. Stoskopf B.L. Rosenbaum P. School difficulties at adolescence in a regional cohort of children who were extremely low birth weight Pediatrics 2000 105 325 331 10.1542/peds.105.2.325 10654950 \n49. Scottish Low Birthweight Study Group The Scottish low birthweight study: II. Language attainment, cognitive status and behavioural impairment at 4 years Arch. Dis. Child. 1992 67 682 689 10.1136/adc.67.6.682 1626984 \n50. Pharoah P.O.D. Stevenson C.J. Cooke R.W. Stevenson R.C. Prevalence of behaviour disorders in low birth weight infants Arch. Dis. Child. 1994 70 271 274 10.1136/adc.70.4.271 8185358 \n51. Botting N. Powls A. Cooke R.W.I. Marlow N. Attention deficit hyperactivity disorders and other psychiatric outcomes in very low birthweight children at age 12 years J. Child. Psychol. Psychiatry 1997 38 931 941 10.1111/j.1469-7610.1997.tb01612.x 9413793 \n52. Horwood L.J. Mogridge N. Darlow B. Cognitive, educational and behavioural outcomes at 7–8 years in a national very low birthweight cohort Arch. Dis. Child. 1998 79 12 20 10.1136/fn.79.1.F12 9771245 \n53. Farooqi A. Holmgren P.A. Engberg S. Serenius F. Survival and 2-year outcome with expectant management of second-trimester rupture of membranes Obstet. Gynecol. 1998 92 895 901 10.1016/S0029-7844(98)00287-7 9840545 \n54. Dinsmoor M.J. Bachman R. Haney E.I. Goldstein M. Mackendrick W. Outcomes after expectant management of extremely preterm premature rupture of the membranes Am. J. Obstet. Gynecol. 2004 190 183 187 10.1016/S0002-9378(03)00926-8 14749657 \n55. Vintzileos A.M. Campbell W.A. Nochimson D.J. Weinbaum P.J. Preterm premature rupture of the membranes: A risk factor for the development of abruptio placentae Am. J. Obstet. Gynecol. 1987 156 1235 1238 10.1016/0002-9378(87)90153-0 3495181 \n56. Gonen R. Hannah M.E. Milligan J.E. Does prolonged preterm premature rupture of the membranes predispose to abruptio placentae? Obstet. Gynecol. 1989 74 347 350 2668817 \n57. Major C.A. de Veciana M. Lewis D.F. Morgan M.A. Preterm premature rupture of membranes and abruptio placentae: Is there an association between these pregnancy complications? Am. J. Obstet. Gynecol. 1995 172 672 676 10.1016/0002-9378(95)90591-X 7856704 \n58. Ananth C.V. Oyelese Y. Srinivas N. Yeo L. Vintzileos A.M. Preterm premature rupture of membranes, intrauterine infection, and oligohdramnios: Risk factors for placental abruption Obstet. Gynecol. 2004 104 71 77 10.1097/01.AOG.0000128172.71408.a0 15229003\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2077-0383",
"issue": "3(1)",
"journal": "Journal of clinical medicine",
"keywords": "EPPROM; National Healthcare Services (NHS) resources; PPROM; amniorrhexis",
"medline_ta": "J Clin Med",
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"pages": "25-38",
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"pmid": "26237250",
"pubdate": "2014-01-09",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "12660432;11169336;15507972;14749657;7856704;16446024;15715592;3421266;15775808;17219157;11101019;18391842;8566462;2403164;17920752;9413793;19605775;2668817;16244469;20732945;10871491;10654950;8185358;15496611;3495181;8912993;8828433;19683725;11758532;9840545;15060229;12415047;16157133;21793083;12763106;17400872;9651411;9851233;9240577;16530921;12732862;2019932;9797619;10088988;12962929;7633866;22249145;10933736;15507963;22539491;1595807;10649175;11865268;16396873;15229003;1626984;12416551;17660215",
"title": "Economical Analysis of Different Clinical Approaches in Pre-Viability Amniorrhexis-A Case Series.",
"title_normalized": "economical analysis of different clinical approaches in pre viability amniorrhexis a case series"
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"abstract": "Aggressive pituitary tumors that have progressed following temozolomide have limited treatment options. Peptide receptor radionuclide therapy and immunotherapy may have a complementary role in the management of these tumors.\nWe provide follow-up data on a previously reported patient with a hypermutated recurrent tumor. The patient in this report provided written informed consent for tumor sequencing and review of medical records on an institutional review board-approved research protocol (NCT01775072).\nThis patient with a corticotroph pituitary carcinoma with alkylator-induced somatic hypermutation has remained on treatment with ipilimumab and nivolumab for 3.5 years and remains clinically well. After an initial partial response to checkpoint inhibitors, she has had several recurrences that have undergone immunoediting of subclonal mutations, which have been effectively treated with continuation of immunotherapy, surgery, external beam radiation, and 177Lu-DOTATATE. Following external beam radiotherapy (RT), she had radiographic evidence of an abscopal response at a distant site of disease suggesting a synergism between checkpoint inhibitors and RT. Following treatment with 177Lu-DOTATATE, the patient had a partial response with a 61% reduction in volume of the target lesion.\nIn patients with aggressive pituitary tumors, treatment with checkpoint inhibitors may trigger an abscopal response from RT. With appropriate selection, an additional efficacious treatment, 177Lu-DOTATATE, may be available for a limited number of patients with aggressive pituitary tumors, including patients who have progressed on temozolomide and exhibit increased somatostatin receptor expression on 68Ga-DOTATATE positron emission tomography.",
"affiliations": "Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.;Weill Cornell Medical College, New York, New York 10065, USA.;Weill Cornell Medical College, New York, New York 10065, USA.;Weill Cornell Medical College, New York, New York 10065, USA.;Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.;Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.;Weill Cornell Medical College, New York, New York 10065, USA.;Marie-Josée and Henry R. Kravis Center for Molecular Oncology Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.;Weill Cornell Medical College, New York, New York 10065, USA.;Weill Cornell Medical College, New York, New York 10065, USA.",
"authors": "Lin|Andrew L|AL|https://orcid.org/0000-0003-0659-261X;Tabar|Viviane|V|;Young|Robert J|RJ|;Cohen|Marc|M|;Cuaron|John|J|;Yang|T Jonathan|TJ|;Rosenblum|Marc|M|;Rudneva|Vasilisa A|VA|;Geer|Eliza B|EB|;Bodei|Lisa|L|",
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"doi": "10.1210/jendso/bvab133",
"fulltext": "\n==== Front\nJ Endocr Soc\nJ Endocr Soc\njes\nJournal of the Endocrine Society\n2472-1972\nOxford University Press US\n\n10.1210/jendso/bvab133\nbvab133\nCase Reports\nAcademicSubjects/MED00250\nSynergism of Checkpoint Inhibitors and Peptide Receptor Radionuclide Therapy in the Treatment of Pituitary Carcinoma\nhttps://orcid.org/0000-0003-0659-261X\nLin Andrew L 1234lina1@mskcc.org\n\nTabar Viviane 234\nYoung Robert J 25\nCohen Marc 2346\nCuaron John 7\nYang T Jonathan 7\nRosenblum Marc 248\nRudneva Vasilisa A 9\nGeer Eliza B 23410\nBodei Lisa 25\n1 Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA\n2 Weill Cornell Medical College, New York, New York 10065, USA\n3 Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA\n4 Multidisciplinary Pituitary and Skull Base Tumor Center, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA\n5 Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA\n6 Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA\n7 Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA\n8 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA\n9 Marie-Josée and Henry R. Kravis Center for Molecular Oncology Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA\n10 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA\nCorrespondence: Andrew L. Lin, Department of Neurology, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065, USA. Email: lina1@mskcc.org.\nE.G.B. and L.B. are co-senior authors of this work.\n\n01 10 2021\n07 8 2021\n07 8 2021\n5 10 bvab13325 6 2021\n02 8 2021\n28 8 2021\n© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com\n\nAbstract\n\nContext\n\nAggressive pituitary tumors that have progressed following temozolomide have limited treatment options. Peptide receptor radionuclide therapy and immunotherapy may have a complementary role in the management of these tumors.\n\nMethods\n\nWe provide follow-up data on a previously reported patient with a hypermutated recurrent tumor. The patient in this report provided written informed consent for tumor sequencing and review of medical records on an institutional review board–approved research protocol (NCT01775072).\n\nResults\n\nThis patient with a corticotroph pituitary carcinoma with alkylator-induced somatic hypermutation has remained on treatment with ipilimumab and nivolumab for 3.5 years and remains clinically well. After an initial partial response to checkpoint inhibitors, she has had several recurrences that have undergone immunoediting of subclonal mutations, which have been effectively treated with continuation of immunotherapy, surgery, external beam radiation, and 177Lu-DOTATATE. Following external beam radiotherapy (RT), she had radiographic evidence of an abscopal response at a distant site of disease suggesting a synergism between checkpoint inhibitors and RT. Following treatment with 177Lu-DOTATATE, the patient had a partial response with a 61% reduction in volume of the target lesion.\n\nConclusion\n\nIn patients with aggressive pituitary tumors, treatment with checkpoint inhibitors may trigger an abscopal response from RT. With appropriate selection, an additional efficacious treatment, 177Lu-DOTATATE, may be available for a limited number of patients with aggressive pituitary tumors, including patients who have progressed on temozolomide and exhibit increased somatostatin receptor expression on 68Ga-DOTATATE positron emission tomography.\n\ncheckpoint inhibitor\nimmunotherapy\nPRRT\npituitary carcinoma\nNational Institutes of Health 10.13039/100000002 National Cancer Institute Cancer Center P30 CA008748\n==== Body\nWhile there are retrospective data supporting the use of temozolomide in the treatment of aggressive pituitary adenomas and carcinomas, there remains a significant unmet need for effective treatments.\n\nThe largest cohort of patients receiving temozolomide in the literature is an electronic survey of the European Society of Endocrinology, which captured 166 individual patients and reported an objective response (complete or partial) in 37%—implying that a significant subset of patients failed to demonstrate a benefit [1]. Of patients who responded, the average time to progression after cessation of therapy was short, only 12 months, and these patients rarely reresponded to temozolomide when rechallenged. Of 18 patients who were rechallenged in this situation for whom there are data, only 2 of 18 had a partial response.\n\nRecently, there has been interest in the use of checkpoint inhibitors in the management of patients with aggressive pituitary tumors, based on an earlier report describing the present patient’s dramatic response to immunotherapy [2]. There are now additional examples in the literature of patients who responded to checkpoint inhibitors [3, 4] and preclinical evidence supporting its use [5].\n\nPeptide receptor radionuclide therapy (PRRT) with radiolabeled octreotide derivatives, such as 177Lu-DOTATATE, is an efficacious and approved therapy for gastroenteropancreatic neuroendocrine tumors [6]. 177Lu-DOTATATE delivers a cytotoxic dose of radiation to tumors with overexpression of somatostatin receptors. The requisite somatostatin density can be established with radiolabeled diagnostic tracers, such as 68Ga-DOTATATE, when tumoral uptake is equal to or higher than the normal liver. PRRT is generally well tolerated with mild and reversible toxicity. Toxicity can be short term, such as moderate fatigue, nausea (more rarely vomiting), abdominal pain, or exacerbation of hormonal syndrome such as diarrhea in carcinoid syndrome; mid term, such as hematological toxicity and transaminitis, which is mild in the large majority; and long term, such as the rare occurrence of myeloproliferative diseases and the almost exceptional occurrence of renal failure. PRRT has been tested in a few cases of treatment-refractory pituitary adenomas naive to temozolomide, with therapeutic efficacy [7, 8]. None of the reported patients who were previously treated with temozolomide and subsequently challenged with PRRT have had reported benefit [9].\n\nIn this report, we provide long-term follow-up on this previously reported patient, who remains clinically well without a new neurologic deficit and a Karnofsky Performance Score of 80, after 3.5 years on immunotherapy. Though this patient has had multiple additional recurrences, she has remained on checkpoint inhibitors, has had an abscopal response to external beam radiotherapy (RT) mediated by immunotherapy, and is the first patient with a partial response to PRRT following progression on temozolomide.\n\nCase Description\n\nThe patient is a 45-year-old woman with an adrenocorticotropic hormone (ACTH)-secreting pituitary carcinoma described previously [2]. She initially presented with a sixth nerve palsy, facial fulness, and hirsutism. Imaging revealed an invasive pituitary macroadenoma, for which she underwent resection September 12, 2011, revealing an ACTH-secreting adenoma. Owing to rapid regrowth, she underwent reresection in 2012, followed by fractionated RT. She underwent 2 additional transsphenoidal resections in 2014 and 2015. Because of tumor growth and inadequate biochemical control on pasireotide, ketoconazole, and cabergoline, treatment with temozolomide and capecitabine (CAPTEM) was initiated in March 2016. She received 3 cycles of CAPTEM with a radiographic response; however, treatment had to be discontinued because of multiple complications including pulmonary embolus and acute renal failure. She continued to suffer from the sequelae of hypercortisolemia and was referred for adrenalectomy. As a part of preoperative testing, she received a computed tomography scan of the abdomen in May 2017, which revealed a hepatic mass. She underwent bilateral adrenalectomy and biopsy of this liver lesion June 15, 2017, which revealed a high-grade neuroendocrine neoplasm with focal positivity for ACTH. Next-generation sequencing of the temozolomide-naive pituitary adenoma and the liver metastasis revealed MSH6 inactivation and the development of alkylator-induced somatic hypermutation in the liver metastasis, as previously reported [2]. This prior report demonstrated that the mutagenesis induced by alkylator therapy led to pathway activation of the PI3K pathway through the development of a subclonal PIK3CA G1050D hot spot mutation. It was also demonstrated that the majority of the mutations in this hypermutated liver metastasis were subclonal [2, 10].\n\nFollowing identification of the liver metastasis, the patient was fully restaged and found to have progressive disease within the right cavernous sinus, right Meckel cave, and right tentorium. The rapid progression of disease following bilateral adrenalectomy was consistent with Nelson syndrome. At this time, the patient was rechallenged with 2 cycles of CAPTEM; subsequent imaging demonstrated growth of the known metastasis and the development of new liver metastases, and, therefore, treatment with carboplatin and etoposide was initiated. Because of further progression after 2 cycles of carboplatin and etoposide, she received palliative RT to the tentorial component of her intracranial disease, and then was challenged with the checkpoint inhibitors, ipilimumab and nivolumab December 15, 2017. She received a 5-dose course of ipilimumab (3 mg/kg) and nivolumab (1 mg/kg), with a reduction in her plasma ACTH from a peak of 45 551 to 451 pg/mL (Fig. 1). By June 2018, her ACTH had decreased to 41.5 pg/mL and she had a dramatic reduction in disease burden both intracranially and extracranially on single-agent nivolumab.\n\nFigure 1. Adrenocorticotropin (ACTH) levels over the course of treatment with immunotherapy, surgery, and radiotherapy.\n\nBy July 2018, all lesions demonstrated marked improvement. At this time, her plasma ACTH increased from a nadir of 37 to 75.3 pg/mL, and there was a slight increase in the primary site of her disease (the small residual within the cavernous sinus). At this time, she was treated with a course of proton RT 25.09 cobalt Gray equivalent in 5 fractions. Unfortunately, her ACTH continued to rise to a level of 3680.7 pg/mL in the setting of a negative 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography scan that showed a subtle focus of FDG uptake at the primary site in the sella but no other concerning sites of abnormal FDG uptake (uptake in the left adnexa was believed to be physiologic). Owing to this unexplained rise in plasma ACTH, a 68Ga-DOTATATE PET/magnetic resonance (MR) scan was performed that identified abnormal uptake in the left adnexa consistent with recurrent tumor. A salpingo-oophorectomy was performed revealing a high-grade malignant neuroendocrine neoplasm, with patchy ACTH staining and following surgery, her plasma ACTH level dropped down to 76.2 pg/mL. Sequencing of the recurrent tumor was performed using the US Food and Drug Administration–authorized, Clinical Laboratory Improvement Amendments–certified next-generation sequencing platform, Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT), showing a decrease in the tumor mutational burden to 3.5 mutations/megabase (in contrast to 93 mutations/megabase in the hypermutated liver metastasis that responded to checkpoint inhibitors). She was then rechallenged with another 4-dose course of ipilimumab and nivolumab followed by single-agent nivolumab. With this rechallenge of dual checkpoint inhibitors, followed by single-agent nivolumab, her ACTH stabilized/downtrended (60.4-51.0 pg/mL; see Fig. 1), shrinkage of the disease in her skull base was observed, and no new disease was noted until August 2019.\n\nIn August 2019, a new left parietal metastasis appeared and the patient’s plasma ACTH rose to 129.3 pg/mL. She received stereotactic radiosurgery to this isolated recurrence in the left parietal lobe (21 Gy in 1 fraction) September 17, 2019, that was complicated almost immediately by severe fatigue and orthostasis (seated: heart rate 112, blood pressure 104/66 and standing: heart rate 154, blood pressure undetectable). She was started on stress dose steroids with improvement in these symptoms and her ACTH unexpectedly dropped from 129.3 to 19.3 pg/mL on a physiologic dose of steroids (see Fig. 1). Notably, the component of her pituitary tumor in the cavernous sinus, which was outside the radiation field, regressed in the setting of being stable in size since the beginning of the year (Fig. 2). This is consistent with an abscopal effect as radiation induced an immunologic response that led to regression of a tumor that was distant to the site of radiation.\n\nFigure 2. Abscopal response in the cavernous sinus disease following radiotherapy to the left parietal metastasis September 17, 2019.\n\nFrom November 5, 2019 to April 21, 2020, she received 4 additional doses of ipilimumab and nivolumab (doses 10-13). In December 2019, while on ipilimumab and nivolumab, there was transient enlargement and then shrinkage of a segment 2 liver metastasis. Unfortunately, on the magnetic resonance imaging (MRI) scan in April 2020, there was growth of the tumor in the right cavernous sinus and she was found to have a progressive left occipital lobe metastasis, while her systemic disease remained stable. She underwent stereotactic radiosurgery to this left occipital lobe metastasis in May 2020 (21 Gy in 1 fraction). Because she had already received 2 courses of RT to the skull base, she was not felt to be a candidate for further external beam RT at this site. For that reason, a repeat 68Ga-DOTATATE PET/MR was performed that revealed high avidity of the recurrent skull base tumor for the radiotracer (maximal standardized uptake value of 24.3) and low-grade uptake in the treated left parietal and left occipital brain metastases (standardized uptake value of 4.8 and 5.8, respectively). There was no focal uptake in the liver.\n\nA decision was made to hold checkpoint inhibitors and treat the patient with 4 cycles of 177Lu-DOTATATE. She received 7.05 GBq (190.5 mCi) June 4, 2020; 6.92 GBq (187 mCi) July 27, 2020; 6.97 GBq (188.42 mCi) September 22, 2020; and 7.13 GBq (192.8 mCi) November 17, 2020, for a cumulative activity of 28.07 GBq (758.7 mCi). She tolerated treatment well without side effects; she did not experience gastrointestinal side effects, myelosuppression, transaminitis, or changes in kidney function. In fact, she felt less fatigued during treatment with 177Lu-DOTATATE, while off checkpoint inhibitors.\n\nWhereas the volume of disease in her right cavernous sinus increased from 2.14 cm3 to 2.66 cm3 in the 4 months before the initiation of 177Lu-DOTATATE (as determined by a board-certified neuroradiologist through manual segmentation using iNtuition 4.4.13, TeraRecon), the volume of disease in her cavernous sinus stabilized during treatment with a final volume of 2.64 cm3 immediately following the fourth dose of 177Lu-DOTATATE. Following the fourth dose of 177Lu-DOTATATE, in the brain adjacent to the cavernous sinus, the patient did develop a small asymptomatic hemorrhage, which improved on subsequent MRI scans (Fig. 3, arrow). During treatment with 177Lu-DOTATATE from May 2020 to December 2020, a biochemical response was noted with a decrease in the plasma ACTH level from 280.5 to 171.6 pg/mL. Following the completion of 177Lu-DOTATATE, nivolumab was resumed and after 6 months further shrinkage was observed with a calculated volume of 1.03 cm3 on the MRI scan from June 5, 2021 (a volume reduction of 61% from the pre-PRRT baseline; see Fig. 3) and the plasma ACTH has declined further to 75.4 pg/mL (Fig. 1). No new sites of disease have developed.\n\nFigure 3. Partial response to 177Lu-DOTATATE following the initiation of treatment in June 2020 complicated by a small asymptomatic hemorrhage into the right mesiotemporal lobe (arrow).\n\nDiscussion\n\nThis case suggests that treatment response of pituitary carcinomas to checkpoint inhibitors may be associated with high tumor mutational burden, that recurrence following treatment with checkpoint inhibitor may be due to the immunoediting of subclonal mutations, and that radiation and checkpoint inhibitors can be complementary in the treatment of aggressive pituitary tumors. In this patient, an abscopal response was observed within this patient’s skull base disease following treatment of a distant brain metastasis with external beam radiation. It is less clear whether the checkpoint inhibitor mediated this patient’s treatment response to PRRT, but notably, this is the first patient to demonstrate a response to PRRT after progressing on temozolomide [7, 9]. In a recent review of the literature, among the 20 patients with aggressive pituitary tumors who received PRRT, the only patients who derived a clinical benefit from PRRT were temozolomide naive [9]. Among the 7 patients in this cohort of 20 who were temozolomide naive, 3 had a partial response and 3 had stable disease.\n\nIt is well known that the response to PRRT is mediated by overexpression of somatostatin receptors on the tumor cells, which serve as intracellular transporters for the radioactivity [11]. In this patient with a high density of somatostatin receptors at the only site of active disease as determined by 68Ga-DOTATATE PET/MR, it is possible that radiation-related cell lysis uncovered antigenic sites that then augmented the activity of immunotherapy, as has been previously demonstrated for external and internal RTs [12, 13]. It is also possible that the benefit this patient received from PRRT is directly attributable to the high dose of radiation that was administered, and that the limited activity that has been previously reported in patients with aggressive pituitary tumors who were previously treated with temozolomide is in large part due to patient selection.\n\nFinally, this case suggests that patients who have derived a benefit from ipilimumab and nivolumab may derive continued benefit from immunotherapy (with the addition of RT and surgery) following progression in part due to abscopal effects, and possibly may benefit from a rechallenge of dual checkpoint inhibitors, as there was evidence of immune activation when this patient was retreated with combination therapy.\n\nAcknowledgments\n\nFinancial Support: This work was supported in part by the National Institutes of Health/National Cancer Institute Cancer Center Support Grant P30 CA008748.\n\nAbbreviations\n\nACTH adrenocorticotropic hormone\n\nCAPTEM temozolomide and capecitabine\n\nFDG 18F-fluorodeoxyglucose\n\nMRI magnetic resonance imaging\n\nPRRT peptide receptor radionuclide therapy\n\nRT radiotherapy\n\nAdditional Information\n\nDisclosures: A.L.L. reports research funding to institution from Bristol Myers Squibb. V.T., M.C., J.C., T.J.Y., M.R., V.A.R., and E.B.G. have nothing to disclose. R.J.Y. has consulted for Agios, Puma, NordicNeuroLab, and ICON plc, and has research funding to his institution from Agios. L.B. has been an unpaid consultant/speaker for AAA-Novartis, Ipsen, ITM, Clovis Oncology, IBA, and has received a grant from AAA-Novartis.\n\nData Availability\n\nData sharing is not applicable to this article because no data sets were generated or analyzed during the present study.\n==== Refs\nReferences\n\n1. McCormackA, DekkersOM, PetersennS, et al ; ESE survey collaborators. Treatment of aggressive pituitary tumours and carcinomas: results of a European Society of Endocrinology (ESE) survey 2016. Eur J Endocrinol. 2018;178 (3 ):265-276.29330228\n2. LinAL, JonssonP, TabarV, et al. Marked response of a hypermutated ACTH-secreting pituitary carcinoma to ipilimumab and nivolumab. J Clin Endocrinol Metab. 2018;103 (10 ):3925-3930.30085142\n3. MajdN, WaguespackSG, JankuF, et al. Efficacy of pembrolizumab in patients with pituitary carcinoma: report of four cases from a phase II study. J Immunother Cancer. 2020;8 (2 ):e001532.33427689\n4. DuhamelC, IlieMD, SalleH, et al. Immunotherapy in corticotroph and lactotroph aggressive tumors and carcinomas: two case reports and a review of the literature. J Pers Med. 2020;10 (3 ):88.\n5. KemenyHR, ElsamadicyAA, FarberSH, et al. Targeting PD-L1 initiates effective antitumor immunity in a murine model of Cushing disease. Clin Cancer Res. 2020;26 (5 ):1141-1151.31744830\n6. HopeTA, BodeiL, ChanJA, et al. NANETS/SNMMI consensus statement on patient selection and appropriate use of 177Lu-DOTATATE peptide receptor radionuclide therapy. J Nucl Med. 2020;61 (2 ):222-227.32015164\n7. GiuffridaG, FerraùF, LaudicellaR, et al. Peptide receptor radionuclide therapy for aggressive pituitary tumors: a monocentric experience. Endocr Connect. 2019;8 (5 ):528-535.30939449\n8. NovruzovF, AliyevJA, JaunmuktaneZ, BomanjiJB, KayaniI. The use of (68)Ga DOTATATE PET/CT for diagnostic assessment and monitoring of (177)Lu DOTATATE therapy in pituitary carcinoma. Clin Nucl Med. 2015;40 (1 ):47-49.25275413\n9. IlieMD, LasolleH, RaverotG. Emerging and novel treatments for pituitary tumors. J Clin Med. 2019;8 (8 ):1107.\n10. LinAL, DonoghueMTA, WardlawSL, et al. Approach to the treatment of a patient with an aggressive pituitary tumor. J Clin Endocrinol Metab. 2020;105 (12 ):3807-3820.\n11. BodeiL, FeroneD, GranaCM, et al. Peptide receptor therapies in neuroendocrine tumors. J Endocrinol Invest. 2009;32 (4 ):360-369.19636207\n12. PrasadV, ZengerlingF, SteinackerJP, et al. First experiences with 177Lu-PSMA therapy in combination with pembrolizumab or after pretreatment with olaparib in single patients. J Nucl Med. 2021;62 (7 ):975-978.33246977\n13. AzghadiS, DalyME. Radiation and immunotherapy combinations in non-small cell lung cancer. Cancer Treat Res Commun. 2021;26 :100298.33387868\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2472-1972",
"issue": "5(10)",
"journal": "Journal of the Endocrine Society",
"keywords": "PRRT; checkpoint inhibitor; immunotherapy; pituitary carcinoma",
"medline_ta": "J Endocr Soc",
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"nlm_unique_id": "101697997",
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"pages": "bvab133",
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"pmid": "34466766",
"pubdate": "2021-10-01",
"publication_types": "D016428:Journal Article",
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"title": "Synergism of Checkpoint Inhibitors and Peptide Receptor Radionuclide Therapy in the Treatment of Pituitary Carcinoma.",
"title_normalized": "synergism of checkpoint inhibitors and peptide receptor radionuclide therapy in the treatment of pituitary carcinoma"
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"abstract": "Complete surgical resection remains the only curative treatment option in locally advanced gastric cancer (GC). Several studies were conducted to prevent local recurrence and to increase the chance of cure. The aim of this study was to summarize our experience in locally advanced GC patients treated with adjuvant chemoradiotherapy (CRT) and to evaluate overall survival (OS), disease-free survival (DFS), toxicity rate and compliance to treatment.\nLocally advanced GC stage IB-III were included. Adjuvant CRT consisted of 45-50.4 Gy (1.8 Gy/day, 5 days/week) with concomitant Macdonald regimen (Mcd) or Epirubicin, Cisplatin and 5-Fluorouracil (ECF) scheme. Univariate and multivariate analysis of several prognostic factors for OS was conducted.\nFourty-nine GC patients were treated: 24 received Mcd and 25 received ECF. Median follow up was 48 months. Acute grade 3-4 toxicity was observed in 6 patients. The 2-year and 5-year OS rates were 65.3% and 41.5%, respectively. The 2-year and 5-year DFS were 59.2% and 41.2%, respectively. No prognostic factors were significantly associated with OS.\nAdjuvant CRT is a feasible strategy in locally advanced GC. It has an acceptable toxicity rate and it is able to increase both DFS and OS.",
"affiliations": "Department of Radiotherapy, Policlinico Umberto I, Sapienza University of Rome, Rome 155, Italy.;Department of Radiotherapy, Policlinico Umberto I, Sapienza University of Rome, Rome 155, Italy.;Department of Radiotherapy, Policlinico Umberto I, Sapienza University of Rome, Rome 155, Italy.;Department of Radiotherapy, Policlinico Umberto I, Sapienza University of Rome, Rome 155, Italy.;Department of Surgical Sciences, Policlinico Umberto I, Sapienza University of Rome, Rome 155, Italy.;Department of Radiotherapy, Policlinico Umberto I, Sapienza University of Rome, Rome 155, Italy.",
"authors": "Benevento|Ilaria|I|;Bulzonetti|Nadia|N|;De Felice|Francesca|F|;Musio|Daniela|D|;Vergine|Massimo|M|;Tombolini|Vincenzo|V|",
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"doi": "10.18632/oncotarget.26106",
"fulltext": "\n==== Front\nOncotargetOncotargetOncotargetImpactJOncotarget1949-2553Impact Journals LLC 2610610.18632/oncotarget.26106Clinical Research PaperThe role of different adjuvant therapies in locally advanced gastric adenocarcinoma Benevento Ilaria 1Bulzonetti Nadia 1De Felice Francesca 1Musio Daniela 1Vergine Massimo 2Tombolini Vincenzo 11 Department of Radiotherapy, Policlinico Umberto I, Sapienza University of Rome, Rome 155, Italy2 Department of Surgical Sciences, Policlinico Umberto I, Sapienza University of Rome, Rome 155, ItalyCorrespondence to:Ilaria Benevento,ilaria.benevento@uniroma1.it21 9 2018 21 9 2018 9 74 34022 34029 29 5 2018 27 8 2018 Copyright: © 2018 Benevento 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.Background and Purpose\nComplete surgical resection remains the only curative treatment option in locally advanced gastric cancer (GC). Several studies were conducted to prevent local recurrence and to increase the chance of cure. The aim of this study was to summarize our experience in locally advanced GC patients treated with adjuvant chemoradiotherapy (CRT) and to evaluate overall survival (OS), disease-free survival (DFS), toxicity rate and compliance to treatment.\n\nMaterials and Methods\nLocally advanced GC stage IB-III were included. Adjuvant CRT consisted of 45–50.4 Gy (1.8 Gy/day, 5 days/week) with concomitant Macdonald regimen (Mcd) or Epirubicin, Cisplatin and 5-Fluorouracil (ECF) scheme. Univariate and multivariate analysis of several prognostic factors for OS was conducted.\n\nResults\nFourty-nine GC patients were treated: 24 received Mcd and 25 received ECF. Median follow up was 48 months. Acute grade 3–4 toxicity was observed in 6 patients. The 2-year and 5-year OS rates were 65.3% and 41.5%, respectively. The 2-year and 5-year DFS were 59.2% and 41.2%, respectively. No prognostic factors were significantly associated with OS.\n\nConclusions\nAdjuvant CRT is a feasible strategy in locally advanced GC. It has an acceptable toxicity rate and it is able to increase both DFS and OS.\n\nadjuvant therapychemoradiotherapyradiotherapygastric cancer\n==== Body\nINTRODUCTION\nComplete surgical resection represents the only curative treatment option in locally advanced gastric cancer (GC). Clinical outcomes are still strongly influenced by the high percentage of both local recurrence (LR) and distant metastases rates. Approximately 60% of GC patients presented locally advanced disease at diagnosis. Although a complete tumor resection with negative margins (R0) can be achieved in 40–60% of these cases, about 70–90% of patients will subsequently relapse. An extended lymph node dissection might improve local control rate, but its optimal extent remains unresolved.\n\nIn order to reduce LR rate and increase cure rate of GC patients, several studies have tested different treatment strategies after surgery. US Intergroup Study INT-0116 [1] was the first large randomized trial that compared adjuvant chemoradiotherapy (CRT) versus surgery alone in patients with locally advanced disease. This study demonstrated a significant impact on progression free survival (PFS) and overall survival (OS), although mainly the benefit appeared to be derived from a reduction in LR rather than in distant metastases rate.\n\nThe aim of this study was to report our data concerning patients with locally advanced GC treated with adjuvant CRT, in order to analyze treatment compliance, toxicity rate and survival outcomes.\n\nMATERIALS AND METHODS\nPatient selection\nPatients with locally advanced GC treated at our Department from 2000 to 2011 were retrospectively reviewed. All patients were assessed in a multidisciplinary clinic board by radiation oncologist, gastrointestinal surgeon and medical oncologist. The study was approved by the Institutional Reviewed Board and patients signed an informed consent.\n\nEligibility criteria included histologically confirmed gastric adenocarcinoma; stage IB-III disease; lack of involvement of esophagus; no distant metastases; a performance status of 0–2 according to the criteria of the Eastern Cooperative Oncology Group (ECOG); age greater than 18 years; adequate liver, renal and bone-marrow function.\n\nTreatment\nAll patients underwent surgery: gastrectomy or gastric resection with limited (D1) or extended (D2) lymph node dissection was performed at least 3 months before starting adjuvant CRT. Prior to CRT, all patients were subjected to post-surgical revaluation with clinical examination and total-body computed tomography scan.\n\nAll patients were treated with a concomitant adjuvant treatment.\n\nRadiotherapy (RT) consisted of 45 Gy in 25 fractions (1.8 Gy/fraction, 5 days/week). In patients with resection margin microscopically involved (R1) the total dose was 50.4 Gy, with boost of 5.4 Gy.\n\nFrom 2000 to 2004, external beam RT was delivered with a two-dimensional technique (2DRT) with anterior-posterior opposing fields and in the next years using three-dimensional RT (3DRT) with a multiple field technique.\n\nThe planning target volume (PTV) included tumor bed, as defined by preoperative imaging, residual stomach or anastomosis site with a safety margin of at least 2 cm and regional lymph nodes, based on the location of the primary tumor and the type of surgical procedure carried out. Regional lymph nodes included the perigastric, the periesophageal, the celiac axis, the para-aortic, the hepato-duodenal and pancreatic-duodenal lymph nodes as well as the nodes along the splenic artery to the splenic hilum and along the hepatic artery to the hepatic hilum. The dose planning for PTV and organs at risk (OAR) were performed according to the ICRU 50 [2] and 62 [3] guidelines.\n\nA central venous access was placed for the administration of concomitant chemotherapy (CT). According to medical oncologist, two CT regimens were used: Macdonald scheme (Mcd) and Epirubicin, Cisplatin and 5-Fluorouracil scheme (ECF). Mcd consisted of continuous infusion of 5-Fluorouracil (5-FU, 425 mg/mq per day) plus Leucovorin (LV, 20 mg/mq per day) for 5 days, given every 3 weeks for two cycles, followed by continuous infusion of 5-FU (400/mg/mq/day) and LV (20 mg/mq/day) on days 1–4 and 23–25 during concomitant RT, and an additional cycles of 5-FU (425 mg/mq/day) and LV (20 mg/mq/day). The ECF scheme consisted of Epirubicin (50 mg/mq), Cisplatin (60 mg/mq) and 5-FU (200 mg/mq/day) before (1 cycle) and after (2 cycle) concurrent CRT.\n\nToxicity\nDuring CRT patients were evaluated daily. Toxicity was graded according to the Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.0 [4].\n\nFollow-up\nAfter adjuvant therapy, post-treatment surveillance was performed every 3 months for the first 2 years, every 6 months for the subsequent 3 years and then annually. Follow-up consisted of physical examination, a complete blood cell count, liver and renal function tests, level of tumour markers (CEA, Ca 19.9), abdominal ultrasound, total body computed tomography scan and PET/CT as clinically indicated.\n\nStatistical analysis\nStandard descriptive statistics were used to evaluate the distribution of each factor. Continuous data were given as median (range), and categorical data as the number of observations and ratios.\n\nOS and DFS were calculated in months from the date of the end of treatment to the first event, including date of the last follow-up or death (OS), and/or relapse (DFS).\n\nOS and DFS were estimated using the Kaplan–Meier method and survival curves were compared using the log-rank test.\n\nThe following variables were investigated: sex (male versus female), age in years at diagnosis (< 65 versus ≥ 65), tumor grading (G1-2 versus G3), tumor site (cardia versus body-pylorus), CT regimen (Mcd versus ECF) and type of lymph node dissection (D1 versus D2). Variables associated with a p-value < 0.25 would be included in a multivariate survival analysis performed using Cox proportional hazard model. All reported p values are two-sided, and p-values lower than 0.05 were considered significant. Statistical analysis was performed using RStudio-0.98.1091 software.\n\nRESULTS\nBaseline characteristics\nBetween 2000 and 2011, 49 locally advanced GC patients were treated at our institution. Baseline patient and tumour characteristics are shown in Table 1. Median age was 59 years (35–78) and 23 patients (46.9%) were male. Median follow up was 48 months (3–129).\n\nTable 1 Baseline patients' and tumours' characteristics\nPatients' characteristic\tN (%)\tTumours' characteristic\tN (%)\t\nSex:\t\tAdenocarcinoma\t49 (100)\t\n Male\t23 (46.9)\t\t\t\n Female\t26 (53.1)\t\t\t\nAge:\t\tGrading:\t\t\n Median\t59\tG2\t12 (24.5)\t\n Range\t35–78\tG3\t35 (71.4)\t\n\t\tG4\t2 (4.1)\t\nPS ECOG:\t\tAnatomical Site:\t\t\n 0\t19 (38.8)\tCardia\t22 (45)\t\n 1\t24 (49)\tBody/pylorus\t27 (55)\t\n 2\t6 (12.2)\t\t\t\nSurgery:\t\tpT Stage:\t\t\n Gastrectomy\t30 (61.2)\tpT1\t3 (6.1)\t\n Gastroresection:\t19 (38.7)\tpT2\t5 (10.2)\t\n Billroth I\t3 (15.8)\tpT2a\t1 (2)\t\n Billroth II\t16 (84.2)\tpT2b\t18 (36.7)\t\n\t\tpT3\t15 (30.6)\t\n\t\tpT4\t7 (14.3)\t\nLymphadenectomy:\t\tpN Stage:\t\t\n D1\t13 (26.5)\tN0\t6 (12.2)\t\n D2\t36 (73.5)\tN1\t19 (38.8)\t\n\t\tN2\t15 (30.6)\t\n\t\tN3\t9 (18.4)\t\n\t\tpM Stage:\t\t\n\t\tMx\t46 (93.9)\t\n\t\tM0\t3 (6.1)\t\n\t\tTNM:\t\t\n\t\tIB\t7 (14.3)\t\n\t\tII\t10 (20.4)\t\n\t\tIIIA\t17 (34.7)\t\n\t\tIIIB\t8 (16.3)\t\n\t\tIV\t7 (14.3)\t\nThirty-six patients (73.5%) received D2 lymph node dissection and 13 patients (26.5%) received D1 dissection. Patients with R1 surgical margins were 16 (32.6%).\n\nTwenty-four patients (49%) received Mcd regimen and 25 patients (51%) received ECF scheme. All patients completed RT as planned: 45 Gy in 33 patients (67.4%); 50.4 Gy in 16 patients (32.6%).\n\nAcute grade 3–4 toxicities were observed in 6 patients (12.1%) (Table 2). No patients required hospital recovery for acute toxicity during adjuvant treatment.\n\nTable 2 Toxicity grade sec CTCAE V4.0\n\tNumber of patients (%)\t\nToxicity\tGrade 2\tGrade 3\tGrade G4\t\nGastrointestinal\t3 (6)\t1 (2)\t-\t\nWeight loss\t3 (6)\t2 (4)\t1 (2)\t\nThrombocytopenia\t2 (4)\t-\t-\t\nAnaemia\t2 (4)\t1 (2)\t-\t\nMucositis\t2 (4)\t1 (2)\t-\t\nNeurological\t2 (4)\t-\t-\t\nSkin reaction\t1 (2)\t-\t-\t\nOverall, 46 patients (94%) receive full dose of CT. Three patients (6%) were unable to complete CT: 1 patient due to G3 gastrointestinal toxicity and 2 patients due to reduced compliance. No patient had treatment interruption for progressive disease.\n\nOverall survival and disease-free survival analysis\nOverall, median OS and DFS were 46 months and 39 months, respectively. Thirty-one patients (63.3%) had died. The 2-year and 5-year OS rates for the entire population were 65.3% (95% CI 0.503–0.768) and 41.5% (95% CI 0.268–0.545), respectively. The 2-year and 5-year DFS were 59.2% (95% CI 0.442–0.714) and 41.2% (95% 0.271–0.548), respectively. The prognostic analysis is shown in Table 3. No prognostic factors were significantly associated with OS.\n\nTable 3 Univariate and multivariate analysis of prognostic factor for overall survival\n\tUnivariate analysis\tMultivariate analysis\t\nPrognostic factor\tHR (95% CI)\tp value\tHR (95% CI)\tp value\t\nSex (male vs female)\t0.59 (0.82–3.42)\t0.15\t0.55 (0.88–3.79)\t0.10\t\nAge (< 65 vs ≥ 65)\t1.10 (0.43–1.88)\t0.79\t\t\t\nGrading (G1-2 vs G3)\t1.59 (0.28–1.41)\t0.25\t1.81 (0.24–1.27)\t0.16\t\nTumour location (cardia vs body/pylorus)\t0.95 (0.52–2.12)\t0.89\t\t\t\nChemotherapy regimen (Mcd vs ECF)\t0.81 (0.59–2.54)\t0.56\t\t\t\nLymph node dissection (D1 vs D2)\t0.78 (0.54–2.96)\t0.57\t\t\t\nAbbreviation: Mcd: Macdonald.\n\nOverall, 30 patients (61.2%) relapsed. Most of these patients (n = 28, 93.3%) had distant metastases, in 8 cases (28.6%) associated with loco-regional failures. Only 2 patients (6.7%) had local recurrences and both within the first year after the end of treatment (1-year DFS = 69.4%, 95% CI 0.544–0.803).\n\nSubgroup survival analysis\nThe 2-year OS for Mcd group versus ECF group was 70.8% (95% CI 0.484–0.849) versus 60.0% (95% CI 0.384–0.761); the 5-year OS for Mcd group versus ECF group was 48.7% (95% CI 0.276–0.669) versus 34.3% (95% CI 0.166–0.528) (p = 0.568) (Figure 1).\n\nFigure 1 Overall survival in Macdonald (Mcd) patients and ECF patients\nThe 2-year and 5-year DFS in Mcd group versus ECF group were 66.7% (95% CI 0.443–0.817) versus 52% (95% CI 0.313–0.692) and 48.9% (95% CI 0.278–0.67) versus 33.4% (95% CI 0.156–0.523) (p = 0.404), respectively (Figure 2).\n\nFigure 2 Disease free survival in Macdonald (Mcd) patients and ECF patients\nDISCUSSION\nGC is usually diagnosed in locally advanced stage. Prognosis is poor, with 5-year OS of 5–20% [5]. Surgery is considered the current standard recommendation. However, survival rates remain quite low despite tumor curative resection and therefore different adjuvant strategies were extensively tested. At present, no standard CT regimens have been defined and the role of adjuvant RT after an adequate lymph node dissection is unclear.\n\nIt is well established that survival outcomes significantly differ between Asian and Western cohort studies [6]. Thus it is difficult to compare their results mainly due to differences in disease natural history, diagnostic approach and treatment strategy.\n\nFor instance, Japanese and other Asian surgeons routinely perform a D2 lymph node dissection to remove the nodes along the mains branches of the celiac axis. Whereas the vast majority of Western surgeons perform a D1 dissection, including only lymph nodes close to surgical stomach bed, in order to reduce morbidity and mortality rates.\n\nBoth Dutch trial [7] and MRC (Medical Research Council) trial [8] registered high postoperative complications and mortality rates following D2 dissection without a significant improvement in survival outcomes compared to D1 dissection. The update data of Dutch trial showed a lower LR rate and cancer-related deaths in D2 lymphadenectomy [9]. However, it should be emphasized that in more advanced stages even with an adequate lymphadenectomy the results of surgery in Western patients are still unsatisfactory [10]. In this setting of patients, additional treatments should be planned to improve patients' long-term survival.\n\nBased on MAGIC trial results [11], nowadays the neoadjuvant approach is recommended. The aim of neoadjuvant CT (NACT) is to downstage and downsize primary tumor and to treat potential micro-metastasis.\n\nDifferent studies demonstrated a significant improvement in OS rates of NACT versus surgery alone. Schuhmacher et al. [12] reported that NACT improved R0 resection rate without impact on OS rate. Similarly, Stahl et al. [13] showed a higher rate of complete responders and Van Hagen et al. [14] reported an improved OS. A recent meta-analysis of 1820 patients with advanced GC confirmed NACT survival benefit (OR: 1.32; 95% CI: 1.07–1.64; p < 0.01), 3-year PFS (OR: 1.85; 95% CI: 1.39–2.46; p < 0.0001), tumor down-staging rate (OR: 1.71; 95% CI: 1.26–2.33; p < 0.0006) and R0 resection rate (OR: 1.38; 95% CI: 1.08–1.78; p < 0.01) [15].\n\nThe aim of this study was to investigate OS, DFS, toxicity rate and treatment compliance in patients with locally advanced GC treated with postoperative CRT. Two CT regimens were analysed: Mcd and ECF. Mcd group achieved higher DFS and OS rates then ECF group.\n\nIn the Intergroup trial INT-0116 [1] a significant OS improvement resulted in those patients who received adjuvant CRT versus surgery alone. Authors reported that 19% of patients in the CRT arm had LR versus 29% in the control arm. However, the high LR rate should be related to limited lymph node dissection. Our median OS in Mcd regimen was higher than INT 0116 trial (46 months versus 36 months). It should be noted that 73.5% of our patients underwent D2 dissection versus 10% in the INT 0116 trial. In our study, all patients with D1 dissection developed LR.\n\nIn the Korean ARTIST study [16], after gastrectomy with D2 dissection, patients were randomized to adjuvant CT or adjuvant CRT. There were no differences in DFS and OS between the two groups, but a subgroup analysis showed an improvement in DFS in the CRT group (p = 0.0365).\n\nThe European CRITICS trial [17] evaluated the clinical outcome for adjuvant CT versus adjuvant CRT after 3 cycles of NACT. The results are expected.\n\nOur patients completed planned RT and 94% of patients received CT at full dose. The optimal toxicity rate (mainly gastrointestinal) was probably related to modern RT technique. In fact, since 2004, RT was delivered with 3DRT that allows to conform the radiation dose on the PTV and to reduce the volume and the dose to the surrounding OARs. Whereas, literature data still refers to a 2DRT technique, using two fields AP and PA. Maybe, in our study, premedication to CRT, including metoclopramide, ondansetron and dexamethasone, contributed to lower toxicity rates, too.\n\nIn the INT 0116 trial, 36% of patients did not complete the treatment, mainly due to G3-4 toxicities (17% of cases). In a retrospective study of Kundel et al. [18] higher toxicity rates were registered: 46.4% of patients presented severe adverse events, 32% were hospitalized and 1.8% died.\n\nIn this analysis, sex, age, tumor grading, tumor site, CT regimen and type of lymph node dissection were no significantly associated with OS. However, in several retrospective studies some prognostic factors were demonstrated [19–21]. N-category and N-ratio interaction, perineural invasion and extended resections were prognostic factors for survival in GC patients treated with D2 dissection in a retrospective study by Costa et al. [21]. Therefore, it seems that a category of patients may benefit from an intensified therapy. This setting of patients may be treated with NACT, surgery and adjuvant treatment, while other types of patients may benefit from a radical surgery followed by adjuvant therapy.\n\nIn conclusion, adjuvant CRT was a feasible strategy in locally advanced GC. It had an acceptable toxicity rate and it was able to increase both DFS and OS, even after extended lymph node dissection. Modern 3DRT reduced toxicity effects.\n\nAs a future perspective, it is desirable to find prognostic factors to select patients in order to provide a personalized therapy.\n\nCONFLICTS OF INTEREST\n\nThe authors declare that they have no conflicts of interest.\n==== Refs\nREFERENCES\n1 Macdonald JS Smalley SR Benedetti J Hundahl SA Estes NC Stemmermann GN Haller DG Ajani JA Gunderson LL Jessup JM Martenson JA Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastoeophageal junction N Engl J Med 2001 345 725 730 11547741 \n2 Landberg T Chavaudra J Dobbs J Hanks G Johansson KA Möller T Purdy J Report 50 Journal of the International Commission on Radiation Units and Measurements 1993 26 10.1093/jicru/os26.1.Report50 \n3 Landberg T Chavaudra J Dobbs J Gerard JP Hanks G Horiot JC Johansson KA Möller T Purdy J Suntharalingam N Svensson H Report 62 Journal of the International Commission on Radiation Units and Measurement 1999 32 10.1093/jicru/os32.1.Report62 \n4 U.S. Department Of Health And Human Services, National Institutes of Health, National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 Published: May 28, 2009 (v4.03: June 14, 2010) \n5 Ochenduszko S Puskulluoglu M Konopka K Fijorek K Slowik AJ Pędziwiatr M Budzyński A Clinical effectiveness and toxicity of second-line irinotecan in advanced gastric and gastroesophageal junction adenocarcinoma: a single-center observational study Ther Adv Med Oncol 2017 9 223 233 28491144 \n6 Kim J Sun CL Mailey B Prendergast C Artinyan A Bhatia S Pigazzi A Ellenhorn JD Race and ethnicity correlate with survival in patients with gastric adenocarcinoma Ann Oncol 2010 21 152 6 19622590 \n7 Bonenkamp JJ Hermans J Sasako M van de Velde CJ Welvaart K Songun I Meyer S Plukker JT Van Elk P Obertop H Gouma DJ van Lanschot JJ Taat CW Extended lymph-node dissection for gastric cancer N Engl J Med 1999 340 908 14 10089184 \n8 Cuschieri A Weeden S Fielding J Bancewicz J Craven J Joypaul V Sydes M Fayers P Patient survival after D1 and D2 resections for gastric cancer: long-term results of the MRC randomized surgical trial. Surgical Co-operative Group Br J Cancer 1999 79 1522 30 10188901 \n9 Songun I Putter H Kranenbarg EM Sasako M van de Velde CJ Surgical treatment of gastric cancer: 15–year follow-up results of the randomised nationwide Dutch D1D2 trial Lancet Oncol 2010 11 439 449 20409751 \n10 Tanizawa Y Terashima M Lymph node dissection in the resection of gastric cancer: review of existing evidence Gastric Cancer 2010 13 137 148 20820982 \n11 Cunningham D Allum WH Stenning SP Thompson JN Van de Velde CJ Nicolson M Scarffe JH Lofts FJ Falk SJ Iveson TJ Smith DB Langley RE Verma M MAGIC Trial Participants Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer N Engl J Med 2006 355 11 20 16822992 \n12 Schuhmacher C Gretschel S Lordick F Reichardt P Hohenberger W Eisenberger CF Haag C Mauer ME Hasan B Welch J Ott K Hoelscher A Schneider PM Neoadjuvant chemotherapy compared with surgery alone for locally advanced cancer of the stomach and cardia: European Organisation for Research and Treatment of Cancer randomized trial 40954 J Clin Oncol 2010 28 5210 5218 21060024 \n13 Stahl M Walz MK Stuschke M Lehmann N Meyer HJ Riera-Knorrenschild J Langer P Engenhart-Cabillic R Bitzer M Königsrainer A Budach W Wilke H Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction J Clin Oncol 2009 27 851 856 19139439 \n14 Van Hagen P Hulshof MC van Lanschot JJ Steyerberg EW van Berge Henegouwen MI Wijnhoven BP Richel DJ Nieuwenhuijzen GA Hospers GA Bonenkamp JJ Cuesta MA Blaisse RJ Busch OR Preoperative chemoradiotherapy for esophageal or junctional cancer N Engl J Med 2012 366 2074 84 22646630 \n15 Xiong BH Cheng Y Ma L Zhang CQ An updated meta-analysis of randomized controlled trial assessing the effect of neoadjuvant chemotherapy in advanced gastric cancer Cancer Invest 2014 32 272 84 24800782 \n16 Lee J Lim DH Kim S Park SH Park JO Park YS Lim HY Choi MG Sohn TS Noh JH Bae JM Ahn YC Sohn I Phase III trial comparing capecitabine plus cisplatin versus capecitabine plus cisplatin with concurrent capecitabine radiotherapy in completely resected gastric cancer with D2 lymph node dissection: the ARTIST trial J Clin Oncol 2012 30 268 273 22184384 \n17 Dikken JL van Sandick JW Maurits Swellengrebel HA Lind PA Putter H Jansen EP Boot H van Grieken NC van de Velde CJ Verheij M Cats A Neo-adjuvant chemotherapy followed by surgery and chemotherapy or by surgery and chemoradiotherapy for patients with resectable gastric cancer (CRITICS) BMC Cancer 2011 11 329 21810227 \n18 Kundel Y Purim O Idelevich E Lavrenkov K Man S Kovel S Karminsky N Pfeffer RM Nisenbaum B Fenig E Sulkes A Brenner B Postoperative chemoradiation for resected gastric cancer–is Macdonald Regimen Tolerable? A retrospective multi-istitutional study Radiation Oncology 2011 6 127 21958692 \n19 Bilici A Uygun K Seker M Ustaalioglu BB Aliustaoglu M Temiz S Aksu G Gezen C Yavuzer D Kaya S Salepci T Mayadagli A Gumus M The effect of tumor size on overall survival in patients with pT3 gastric cancer: experiences from 3 centers Onkologie 2010 33 676 682 21124038 \n20 Kim DH Yun HY Ryu DH Han HS Han JH Yoon SM Youn SJ Preoperative CA 125 is significant indicator of curative resection in gastric cancer patients World J Gastroenterol 2015 21 1216 1221 25632195 \n21 Costa WL Coimbra FJ Fogaroli RC Ribeiro HS Diniz AL Begnami MD Mello CA Fanelli MF Silva MJ Fregnani JH Montagnini AL Adjuvant chemoradiotherapy after d2-lymphadenectomy for gastric cancer: the role of n-ratio in patient selection. results of a single cancer center Radiat Oncol 2012 7 169 23068190\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1949-2553",
"issue": "9(74)",
"journal": "Oncotarget",
"keywords": "adjuvant therapy; chemoradiotherapy; gastric cancer; radiotherapy",
"medline_ta": "Oncotarget",
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"pages": "34022-34029",
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"pmid": "30338043",
"pubdate": "2018-09-21",
"publication_types": "D016428:Journal Article",
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"title": "The role of different adjuvant therapies in locally advanced gastric adenocarcinoma.",
"title_normalized": "the role of different adjuvant therapies in locally advanced gastric adenocarcinoma"
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"abstract": "A 5-year-old patient treated for acute lymphoblastic leukaemia (ALL) developed proven pulmonary invasive fungal disease (IFD) due to Actinomucor elegans. While completing ALL treatment according to AIEOP ALL protocol 2009 for further 15 months, antifungal treatment with liposomal amphotericin B and intermittent additional posaconazole was continued until immune reconstitution 7 months after the end of ALL treatment. Repeated imaging guided treatment decisions. Twenty-six and 19 months after the end of ALL treatment and antifungal treatment, respectively, the patient is still in the first complete remission and shows no signs of active invasive fungal disease (IFD).",
"affiliations": "Department of Paediatrics and Adolescent Medicine, Division of Paediatric Haematology/Oncology, Medical University, Graz, Austria.;Department of Radiology, Division of Paediatric Radiology, Medical University Graz, Graz, Austria.;Diagnostic & Research Institute of Pathology, Medical University, Graz, Austria.;Department of Paediatrics, Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria.;Department of Paediatrics and Adolescent Medicine, Division of Paediatric Haematology/Oncology, Medical University, Graz, Austria.;Department of Paediatrics and Adolescent Medicine, Division of Paediatric Haematology/Oncology, Medical University, Graz, Austria.;Department of Paediatrics and Adolescent Medicine, Division of Paediatric Haematology/Oncology, Medical University, Graz, Austria.;Department of Paediatrics and Adolescent Medicine, Division of Paediatric Haematology/Oncology, Medical University, Graz, Austria.;Department of Paediatrics and Adolescent Medicine, Division of Paediatric Haematology/Oncology, Medical University, Graz, Austria.;Department of Paediatrics and Adolescent Medicine, Division of Paediatric Pulmonology and Allergology, Medical University, Graz, Austria.;Department of Paediatrics and Adolescent Medicine, Division of Paediatric Haematology/Oncology, Medical University, Graz, Austria.;Department of Paediatrics and Adolescent Medicine, Division of Paediatric Haematology/Oncology, Medical University, Graz, Austria.;Department of Paediatrics and Adolescent Medicine, Division of Paediatric Haematology/Oncology, Medical University, Graz, Austria. volker.strenger@medunigraz.at.",
"authors": "Trobisch|Andreas|A|http://orcid.org/0000-0003-2679-1173;Marterer|R|R|;Gorkiewicz|G|G|;Flaschberger|S|S|;Lackner|H|H|;Seidel|M|M|;Sperl|D|D|;Karastaneva|A|A|;Kohlmaier|B|B|;Egger|M|M|;Urban|C|C|;Benesch|M|M|;Strenger|V|V|",
"chemical_list": "D000935:Antifungal Agents; D014230:Triazoles; C068538:liposomal amphotericin B; D003561:Cytarabine; D014750:Vincristine; C101425:posaconazole; D000666:Amphotericin B; D003520:Cyclophosphamide; D015122:Mercaptopurine; D001215:Asparaginase; D011241:Prednisone; D008727:Methotrexate; D003630:Daunorubicin",
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"doi": "10.1007/s00520-019-04962-3",
"fulltext": "\n==== Front\nSupport Care Cancer\nSupport Care Cancer\nSupportive Care in Cancer\n0941-4355 1433-7339 Springer Berlin Heidelberg Berlin/Heidelberg \n\n31410599\n4962\n10.1007/s00520-019-04962-3\nOriginal Article\nInvasive mucormycosis during treatment for acute lymphoblastic leukaemia—successful management of two life-threatening diseases\nhttp://orcid.org/0000-0003-2679-1173Trobisch Andreas 12 Marterer R. 3 Gorkiewicz G. 4 Flaschberger S. 5 Lackner H. 1 Seidel M. 1 Sperl D. 1 Karastaneva A. 1 Kohlmaier B. 1 Egger M. 6 Urban C. 1 Benesch M. 1 Strenger V. volker.strenger@medunigraz.at 167 1 grid.11598.340000 0000 8988 2476Department of Paediatrics and Adolescent Medicine, Division of Paediatric Haematology/Oncology, Medical University, Graz, Austria \n2 grid.11598.340000 0000 8988 2476Department of Paediatrics and Adolescent Medicine, Division of Neonatology, Medical University, Graz, Austria \n3 grid.11598.340000 0000 8988 2476Department of Radiology, Division of Paediatric Radiology, Medical University Graz, Graz, Austria \n4 grid.11598.340000 0000 8988 2476Diagnostic & Research Institute of Pathology, Medical University, Graz, Austria \n5 grid.415431.60000 0000 9124 9231Department of Paediatrics, Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria \n6 grid.11598.340000 0000 8988 2476Department of Paediatrics and Adolescent Medicine, Division of Paediatric Pulmonology and Allergology, Medical University, Graz, Austria \n7 grid.11598.340000 0000 8988 2476Research Unit Infectious Diseases in the Immunocompromised Host, Medical University, Graz, Austria \n14 8 2019 \n14 8 2019 \n2020 \n28 5 2157 2161\n16 3 2019 11 6 2019 © The Author(s) 2019Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.A 5-year-old patient treated for acute lymphoblastic leukaemia (ALL) developed proven pulmonary invasive fungal disease (IFD) due to Actinomucor elegans. While completing ALL treatment according to AIEOP ALL protocol 2009 for further 15 months, antifungal treatment with liposomal amphotericin B and intermittent additional posaconazole was continued until immune reconstitution 7 months after the end of ALL treatment. Repeated imaging guided treatment decisions. Twenty-six and 19 months after the end of ALL treatment and antifungal treatment, respectively, the patient is still in the first complete remission and shows no signs of active invasive fungal disease (IFD).\n\nKeywords\nALLMucormycosisIFDAntimycotic treatmentChemotherapyMedical University of GrazOpen access funding provided by Medical University of Graz.\n\nissue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2020\n==== Body\nIntroduction\nInvasive mould diseases remain an important cause of death in immunocompromised patients [1, 2]. While invasive diseases with Aspergillus sp. have mortality rates of 20–50%, mortality rates in mucormycosis range from 50 to 100% [3–5]. Differentiation between mucormycoses and other mould infections remains challenging, since these pathogens are difficult to culture and show similar radiological and clinical features leading from 4% to up to 90% of suspected mucormycosis cases not being confirmed until post-mortem examination [1, 4, 5]. Moreover, mucormycetes lack susceptibility to many antifungal agents and need higher dosages of amphotericin B [6, 7]. A mainstay of the successful management is the reversal of the underlying condition [4]. On the other hand, treatment of (haematologic) malignancies often leads to enhanced susceptibility for mucormycosis necessitating sophisticated management of these infections with concurrent further sufficient treatment of the malignant disease.\n\nWe describe the successful management of mucormycosis during ALL treatment.\n\nCase description\nA 5-year-old patient was treated for precursor B cell acute lymphoblastic leukaemia (ALL) according to AIEOP BFM ALL 2009 protocol for 7 months in the non-high-risk arm. For digestive decolonisation, he continuously received oral amphotericin B. Overall, he had received antileukaemic treatment for 25 weeks and 3 weeks of restarted steroid therapy in protocol IIA with dexamethasone (10 mg/m2/day), before he developed fever and CRP levels with a maximum of 200 mg/L during neutropenia (neutrophilic leucocyte count < 500/μL); thus, ALL treatment was stopped. Chest X-ray performed 15 days after admission showed a diffuse spread infiltrate of up to 3 cm in the right middle to lower field and treatment with meropenem and clarithromycin was initiated and later switched to ceftazidim and linezolid. Furthermore, antimycotic treatment with caspofungin (1 mg/kg/d) was initiated. Bronchoalveolar lavage (BAL) was sent for microbiological evaluation including auramine staining for mycobacteria and calcofluor-white staining for fungus and revealed hyphae and weak growth of Aspergillus fumigatus. Neither fungal PCR from BAL fluid nor lung biopsy was performed at that time. Antifungal treatment was switched to liposomal amphotericin B (AmBisome®, 1 mg/kg/day) and voriconazole (8 mg/kg/day). Due to clinical and radiologic deterioration (Fig. 1), the patient was transferred to our University Hospital. Beta-d-glucan and galactomannan were both unremarkable, whereas CRP was still slightly elevated with 9.3 mg/L. Uncomplicated thoracoscopic biopsy and subsequent histopathological examination revealed fungal hyphae, which were identified as Actinomucor elegans via fungal ITS PCR and sequencing (GenBank acc. no.: gb|FJ176396.1|; Identities: 312/313 bp (99%)) representing proven invasive mucormycosis according to the EORTC criteria [8, 9]. Therefore, voriconazole was switched to posaconazole suspension (15 mg/kg/day) and dosage of AmBisome® was increased to 10 mg/kg/day, with AmBisome®-induced hypopotassaemia being substituted intravenously. Cranial magnet resonance imaging (MRI) did not show any signs of central nervous involvement of mucormycosis neither did the nasal sinuses show signs of obliteration. After 4 weeks without ALL treatment, an interval therapy with methotrexate (0.5–0.7 mg/kg once weekly) and 6-mercaptopurine (1.5 mg/kg daily) was administered for another month. Under continued antifungal treatment, we reinitiated therapy according to the AIEOP BFM ALL 2009 protocol, completed block IIB and started maintenance therapy. Five weeks after the start of maintenance therapy, AmBisome® dosages were reduced to 10 mg/kg/day every 2nd day. Another 8 weeks later, AmBisome® was reduced to 2.5 mg/kg/day every 3rd day due to practicability while posaconazole had to be discontinued due to lacking compliance (Fig. 2). The pulmonary mucormycosis was monitored every 2–6 months, either by thoracic CT or by MRI. Four months after the start of antifungal treatment, we additionally performed a PET-CT scan still showing multifocal metabolically active consolidations in both lungs. After 12 months of antifungal therapy with slight radiologic improvement, CT scan again showed an increase of infiltrates, leading to an increase in AmBisome® dosages to 5 mg/kg/day every 3rd day and reinitiation of posaconazole at an increased dosage of 20 mg/kg/day. The patient again refused posaconazole intake, so we had to stop combination therapy after only 2 weeks while continuing AmBisome® at 5 mg/kg/day every 3rd day. ALL treatment was terminated 22 months after diagnosis (2 months earlier than required) in order to improve the immune system. Flow cytometry further showed diminished B and T cell fractions after the termination of ALL treatment and CT/MRI as well as PET-CT scans still indicated infiltrates with reduced but still recognisable activity. Therefore, AmBisome® was given for another 7 months, until immunologic reconstitution (indicated by flow cytometry) and imaging showed significant improvement. Thirty months after the end of antileukaemic treatment and 23 months after the end of antifungal treatment, the patient is still in the first remission of ALL and recent thoracic CT and chest X-ray indicate further improvement with only signs of tissue scarring. An overview of our management is depicted in Fig. 2.Fig. 1 Initial (a) CT scan of the chest and at last follow-up (b). Soft tissue windowing images are displayed in the left and corresponding lung windowing images in the right rows. In the initial series (a), multiple, partly enhancing nodules in both lungs with a maximum diameter of 2.1 cm, predominantly in the lung periphery were detected. Furthermore, two consolidations with a maximum extent of 4.7 cm were present in the lingula and the right lower lobe. At last follow-up (b), only a few subtle residual changes in the lingula and the right lower lobe were seen\n\nFig. 2 Treatment timeline\n\n\n\nDiscussion\nWe report the successful management of a 5-year-old patient treated for ALL, complicated by an opportunistic infection with Actinomucor elegans representing the first paediatric patient with this pathogen.\n\nActinomucor elegans belongs to the genus Actinomucor in the order Mucorales. So far, only 5 cases of infection with Actinomucor elegans in humans have been described in adults [2, 10, 11]. Two patients (1 immunocompetent, 1 recipient of an allogeneic stem cell transplantation for lymphoma) were described with sinusitis and were cured with debridement, irrigation and antifungal treatment [2, 12]. Two patients were described with soft tissue infections. One of them with underlying refractory aplastic anaemia died despite debridement and antifungal treatment [11]. In the other patient, treatment and outcome were not reported [13]. Another patient developed disseminated disease after extensive wounds and died despite extensive debridement and antifungal treatment [14].\n\nWhile mucormycosis in patients with diabetes mainly causes rhinocerebral and sino-orbital infections, patients with malignancy typically develop pulmonary infections. The extensive angioinvasive properties result in vessel thrombosis, tissue necrosis and haematogenous dissemination. Furthermore, ischaemic necrosis prevents leukocyte and drug penetration [4].\n\nIn our case, host factors and imaging (representing possible IFD [8, 15]) led to the initiation of antifungal treatment. The growth of Aspergillus fumigatus from BAL fluid retrospectively most likely represents airway colonisation, reflecting the low specificity of cultivation of moulds from BAL fluid [1]. The detection of hyphae from otherwise sterile material and molecular analyses led to the diagnosis of proven mucormycosis [9].\n\nCurrently no indirect methods are available facilitating the diagnosis [16], since cell walls of Mucorales spp. are lacking (1–3)-beta-d-glucan and galactomannan, which therefore cannot be used to diagnose invasive mucormycosis [1, 4, 17].\n\nInitial empiric antifungal therapy comprising caspofungin, conventional doses of liposomal amphotericin B and voriconazole did not prevent deterioration. After proof of mucormycosis, therapy was switched to a combination of high-dose liposomal amphotericin B and posaconazole; despite lacking clear evidence, we decided for combination therapy due to the extent of the pulmonary lesions and the poor prognosis of invasive mucormycoses. Due to the widespread diffuse character of the infiltrates, we abandoned thoracotomy and surgical debridement. Mucorales spp. are considered to be resistant against echinocandins as well as against most azoles like voriconazole, fluconazole and itraconazole [7, 18] and require higher doses of amphotericin B usually administered in the liposomal formulation (AmBisome®) [6, 19]. Early treatment with high doses of amphotericin B is important since a delay results in a twofold increase in mortality leading to an overall mortality of up to 100% for patients with disseminated disease [4]. The optimal dosage has still not been determined. Many clinicians use the maximum tolerable dosages, condoning nephrotoxicity, while efficacy results from a phase II clinical trial of high-dose therapy with 10 mg/kg/day i.v. are still pending (http://clinicaltrials.gov/show/NCT00467883) [4]. Furthermore, posaconazole monotherapy is not recommended due to several reports on breakthrough mucormycoses under posaconazole prophylaxis [20].\n\nIn addition to antifungal treatment, the elimination of risk factors such as immunosuppressive therapies is essential for successful management of mucormycosis [4, 21]. As in our patient, a common risk factor is the treatment of haematologic and other malignancies, which on the other hand is vital to be cured. Therefore, it was crucial to continue treatment of ALL as soon as possible, despite invasive pulmonary mucormycosis. After initiation of adequate therapy for mucormycosis, we also reinitiated antileukaemic treatment with an interval treatment aligned to the ALL maintenance therapy and switched to the reinduction according to protocol 7 weeks later. The duration of treatment for mucormycosis remains unclear. ECIL recommends duration on an individual basis, but should continue for at least 6–8 weeks [22]. We gradually reduced dosages and prolonged intervals of AmBisome® infusions during ALL maintenance therapy to minimise side effects and to enable ambulatory parenteral therapy during several months of treatment. Intermittent AmBisome® administration is considered to be an effective alternative to the standard regimen in preventing and possibly treating invasive fungal diseases, since it appears to accumulate in tissue [23, 24]. We used this approach for a long time therapy of 1.5 years. However, after 1 year of antifungal treatment and 10 months of ALL maintenance therapy, again progression of the infiltrates was seen, which underlines the importance of radiologic monitoring and constant adequate treatment until immune reconstitution clearly has been achieved. We reintensified and successfully continued antifungal treatment with intermittent AmBisome® until numerical immune reconstitution had been indicated by flow cytometry 7 months after the end of ALL treatment. We monitored our patient via intermittent thoracic MRI in addition to CT scans to reduce radiation. To discriminate active infection from tissue scarring, we also used FDG-PET imaging, which has been described to have valuable sensitivity in detecting fungal lesions [25]. To gain immune reconstitution, one might be misled to extensively shorten maintenance therapy. However, we shortened ALL therapy by only 2 months, since it had been clearly shown that shortening therapy for ALL from 18 to 12 months leads to significantly worse outcome [26].\n\nIn conclusion, proof of mucormycetes from otherwise sterile material is essential for adequate diagnostics and therapy. Continued treatment of ALL is as important as concurrent adequate (long-term) antifungal treatment, alongside radiologic and immunologic monitoring which are essential in managing these both potentially fatal diseases.\n\nAbbreviations\nAIEOPAssociazione Italiana Ematologia Oncologia Pediatrica\n\nALLAcute lymphoblastic leukaemia\n\nCNSCentral nervous system\n\nCRPC-reactive protein\n\nCTComputed tomography\n\nECILEuropean Conference on Infections in Leukaemia\n\nEORTCEuropean Organisation for Research and Treatment of Cancer\n\nFDGFluoro-2-deoxyglucose\n\nIFDInvasive fungal disease\n\nIMIInvasive mould infection\n\nMRIMagnetic resonance imaging\n\nPCRPolymerase chain reaction\n\nPETPositron emission tomography\n\nPublisher’s note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nFunding Information\nOpen access funding provided by Medical University of Graz.\n\nCompliance with ethical standards\nConflict of interest\nThe authors declare that they have no conflict of interest.\n\nThe authors have full control of all primary data and allow the journal to review this data if requested.\n==== Refs\nReferences\n1. Lamoth F Calandra T Early diagnosis of invasive mould infections and disease J Antimicrob Chemother 2017 72 suppl_1 i19 i28 10.1093/jac/dkx030 28355464 \n2. Dorin J D’Aveni M Debourgogne A Cuenin M Guillaso M Rivier A Gallet P Lecoanet G Machouart M Update on Actinomucor elegans, a mucormycete infrequently detected in human specimens: how combined microbiological tools contribute efficiently to a more accurate medical care Int J Med Microbiol 2017 307 8 435 442 10.1016/j.ijmm.2017.10.010 29108709 \n3. Roden MM Epidemiology and outcome of zygomycosis: a review of 929 reported cases Clin Infect Dis 2005 41 5 634 653 10.1086/432579 16080086 \n4. Katragkou A Walsh TJ Roilides E Why is mucormycosis more difficult to cure than more common mycoses? Clin Microbiol Infect 2014 20 Suppl 6 74 81 10.1111/1469-0691.12466 \n5. Skiada A, Pagano L, and Groll AEA 2010 Zygomycosis in Europe - analysis of 230 cases accrued by the registry of the European Confederation of Medical Mycology (ECMM) working group on zygomycosis between 2005 and 2007. Clin Microbiol Infect\n6. Walsh TJ Goodman JL Pappas P Bekersky I Buell DN Roden M Barrett J Anaissie EJ Safety, tolerance, and pharmacokinetics of high-dose liposomal amphotericin B (AmBisome) in patients infected with Aspergillus species and other filamentous fungi: maximum tolerated dose study Antimicrob Agents Chemother 2001 45 12 3487 3496 10.1128/AAC.45.12.3487-3496.2001 11709329 \n7. Dannaoui E In vitro susceptibilities of zygomycetes to conventional and new antifungals J Antimicrob Chemother 2002 51 1 45 52 10.1093/jac/dkg020 \n8. Hoenigl M Strenger V Buzina W Valentin T Koidl C Wolfler A Seeber K Valentin A Strohmeier AT Zollner-Schwetz I Raggam RB Urban C Lass-Florl C Linkesch W Krause R European Organization for the Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) host factors and invasive fungal infections in patients with haematological malignancies J Antimicrob Chemother 2012 67 8 2029 2033 10.1093/jac/dks155 22566591 \n9. De Pauw B Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group Clin Infect Dis 2008 46 12 1813 1821 10.1086/588660 18462102 \n10. Gomes MZ Lewis RE Kontoyiannis DP Mucormycosis caused by unusual mucormycetes, non-Rhizopus, -Mucor, and -Lichtheimia species Clin Microbiol Rev 2011 24 2 411 445 10.1128/CMR.00056-10 21482731 \n11. Mahmud A Actinomucor elegans as an emerging cause of mucormycosis J Clin Microbiol 2012 50 3 1092 1095 10.1128/JCM.05338-11 22205785 \n12. Davel G Featherston P Fernandez A Abrantes R Canteros C Rodero L Sztern C Perrotta D Maxillary sinusitis caused by Actinomucor elegans J Clin Microbiol 2001 39 2 740 742 10.1128/JCM.39.2.740-742.2001 11158140 \n13. Khan ZU Ahmad S Mokaddas E Chandy R Cano J Guarro J Actinomucor elegans var. kuwaitiensis isolated from the wound of a diabetic patient Antonie Van Leeuwenhoek 2008 94 3 343 352 10.1007/s10482-008-9251-1 18496764 \n14. Tully CC Romanelli AM Sutton DA Wickes BL Hospenthal DR Fatal Actinomucor elegans var. kuwaitiensis infection following combat trauma J Clin Microbiol 2009 47 10 3394 3399 10.1128/JCM.00797-09 19675213 \n15. Groll AH Castagnola E Cesaro S Dalle JH Engelhard D Hope W Roilides E Styczynski J Warris A Lehrnbecher T Fourth European Conference on Infections in Leukaemia (ECIL-4): guidelines for diagnosis, prevention, and treatment of invasive fungal diseases in paediatric patients with cancer or allogeneic haemopoietic stem-cell transplantation Lancet Oncol 2014 15 8 e327 e340 10.1016/S1470-2045(14)70017-8 24988936 \n16. Dornbusch HJ Strenger V Kerbl R Lackner H Schwinger W Sovinz P Urban C Procalcitonin--a marker of invasive fungal infection? Support Care Cancer 2005 13 5 343 346 10.1007/s00520-004-0721-3 15657690 \n17. Egger M False positive serum levels of (1-3)—ß-D-glucan after infusion of intravenous immunoglobulins and time to normalisation J Inf Secur 2018 76 2 206 210 \n18. Strenger V Farowski F Müller C Hofer N Dornbusch HJ Sperl D Lackner H Benesch M Urban C Low penetration of caspofungin into cerebrospinal fluid following intravenous administration of standard doses Int J Antimicrob Agents 2017 50 2 272 275 10.1016/j.ijantimicag.2017.02.024 28527634 \n19. Strenger V Meinitzer A Donnerer J Hofer N Dornbusch HJ Wanz U Seidel MG Sperl D Lackner H Schwinger W Sovinz P Benesch M Urban C Amphotericin B transfer to CSF following intravenous administration of liposomal amphotericin B J Antimicrob Chemother 2014 69 9 2522 2526 10.1093/jac/dku148 24891430 \n20. Spellberg B Ibrahim AS Recent advances in the treatment of mucormycosis Curr Infect Dis Rep 2010 12 6 423 429 10.1007/s11908-010-0129-9 21308550 \n21. Danion F Aguilar C Catherinot E Alanio A DeWolf S Lortholary O Lanternier F Mucormycosis: new developments into a persistently devastating infection Semin Respir Crit Care Med 2015 36 5 692 705 10.1055/s-0035-1562896 26398536 \n22. Skiada A Lanternier F Groll AH Pagano L Zimmerli S Herbrecht R Lortholary O Petrikkos GL on behalf of the third European Conference on Infections in Leukemia* Diagnosis and treatment of mucormycosis in patients with hematological malignancies: guidelines from the 3rd European Conference on Infections in Leukemia (ECIL 3) Haematologica 2013 98 4 492 504 10.3324/haematol.2012.065110 22983580 \n23. Ellis M New dosing strategies for liposomal amphotericin B in high-risk patients Clin Microbiol Infect 2008 14 Suppl 4 55 64 10.1111/j.1469-0691.2008.01982.x \n24. Bochennek K Tramsen L Liposomal amphotericin B twice weekly as antifungal prophylaxis in paediatric haematological malignancy patients Clin Microbiol Infect 2011 17 1868 1874 10.1111/j.1469-0691.2011.03483.x 21895857 \n25. Hot A Maunoury C Poiree S Lanternier F Viard JP Loulergue P Coignard H Bougnoux ME Suarez F Rubio MT Mahlaoui N Dupont B Lecuit M Faraggi M Lortholary O Diagnostic contribution of positron emission tomography with [18F]fluorodeoxyglucose for invasive fungal infections Clin Microbiol Infect 2011 17 3 409 417 10.1111/j.1469-0691.2010.03301.x 20636432 \n26. Schrappe M Reiter A Zimmermann M Harbott J Ludwig WD Henze G Gadner H Odenwald E Riehm H Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM study group from 1981 to 1995. Berlin-Frankfurt-Munster Leukemia 2000 14 12 2205 2222 10.1038/sj.leu.2401973 11187912\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0941-4355",
"issue": "28(5)",
"journal": "Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer",
"keywords": "ALL; Antimycotic treatment; Chemotherapy; IFD; Mucormycosis",
"medline_ta": "Support Care Cancer",
"mesh_terms": "D000666:Amphotericin B; D000935:Antifungal Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D001215:Asparaginase; D002675:Child, Preschool; D003520:Cyclophosphamide; D003561:Cytarabine; D003630:Daunorubicin; D006801:Humans; D000072742:Invasive Fungal Infections; D008172:Lung Diseases, Fungal; D008297:Male; D015122:Mercaptopurine; D008727:Methotrexate; D009090:Mucorales; D009091:Mucormycosis; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011241:Prednisone; D012074:Remission Induction; D014230:Triazoles; D014750:Vincristine",
"nlm_unique_id": "9302957",
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"pages": "2157-2161",
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"pmid": "31410599",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21199154;24891430;11158140;22205785;11709329;29108709;26398536;16080086;21895857;24988936;15657690;18462102;20636432;28355464;21308550;12493786;18430130;22983580;19675213;21482731;29174967;28527634;18496764;22566591;24279587;11187912",
"title": "Invasive mucormycosis during treatment for acute lymphoblastic leukaemia-successful management of two life-threatening diseases.",
"title_normalized": "invasive mucormycosis during treatment for acute lymphoblastic leukaemia successful management of two life threatening diseases"
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"abstract": "We present a 71-year old woman treated with 14 days of 5 mg intraventricular caspofungin for Scedosporium apiospermum complex meningoencephalitis diagnosed after spinal fusion and instrumentation. Cerebrospinal fluid studies improved during therapy and intraventricular administration was well tolerated. Within weeks of discontinuation, the patient experienced clinical deterioration with disease progression. There are sparse data on the efficacy and safety of administering intraventricular caspofungin. While apparently safe, intraventricular caspofungin was insufficient for disease control in this case.",
"affiliations": "Department of Neurological Surgery, University of Washington School of Medicine, Seattle, WA, USA.;Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.;Department of Pharmacy, Harborview Medical Center, Seattle, WA, USA.;Department of Neurological Surgery, University of Washington School of Medicine, Seattle, WA, USA.;Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA; Department of Global Health, University of Washington School of Medicine, Seattle, WA, USA; Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA.",
"authors": "Williams|John R|JR|;Tenforde|Mark W|MW|;Chan|Jeannie D|JD|;Ko|Andrew|A|;Graham|Susan M|SM|",
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"doi": "10.1016/j.mmcr.2016.07.003",
"fulltext": "\n==== Front\nMed Mycol Case RepMed Mycol Case RepMedical Mycology Case Reports2211-7539Elsevier S2211-7539(16)30040-910.1016/j.mmcr.2016.07.003Case ReportSafety and clinical response of intraventricular caspofungin for Scedosporium apiospermum complex central nervous system infection Williams John R. Jrwneur0@uw.edua⁎Tenforde Mark W. bChan Jeannie D. cKo Andrew aGraham Susan M. bdea Department of Neurological Surgery, University of Washington School of Medicine, Seattle, WA, USAb Department of Medicine, University of Washington School of Medicine, Seattle, WA, USAc Department of Pharmacy, Harborview Medical Center, Seattle, WA, USAd Department of Global Health, University of Washington School of Medicine, Seattle, WA, USAe Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA⁎ Corresponding author. Jrwneur0@uw.edu09 7 2016 9 2016 09 7 2016 13 1 4 20 5 2016 25 6 2016 8 7 2016 © 2016 The Authors2016This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).We present a 71-year old woman treated with 14 days of 5 mg intraventricular caspofungin for Scedosporium apiospermum complex meningoencephalitis diagnosed after spinal fusion and instrumentation. Cerebrospinal fluid studies improved during therapy and intraventricular administration was well tolerated. Within weeks of discontinuation, the patient experienced clinical deterioration with disease progression. There are sparse data on the efficacy and safety of administering intraventricular caspofungin. While apparently safe, intraventricular caspofungin was insufficient for disease control in this case.\n\nKeywords\nIntraventricularCaspofunginScedosporium apiospermum complexScedosporium apiospermum\n==== Body\n1 Introduction\nScedosporium apiospermum complex, Scedosporium apiospermum and Scedosporium minutisporum, is a ubiquitous saprophytic fungus found in soil, sewage, and polluted waters [1]. Exposure through cutaneous breach or inhalation can result in skin and soft tissue infection or sinopulmonary disease, although Scedosporium apiospermum complex can disseminate widely, including to the central nervous system (CNS) [1], [2]. Most disseminated infections occur in association with immunocompromised states, such as malignancy, use of immunosuppressive agents, or advanced HIV, although this is not prerequisite for disease [1], [2], [3]. We describe a case of Scedosporium apiospermum complex infection in an immunocompetent woman who developed meningoencephalitis following spinal surgery. After failure of conventional therapies, intraventricular administration of caspofungin was attempted as part of a salvage treatment regimen.\n\n2 Case\nA fully independent 71-year old female with a history of encephalomalacia from remote traumatic brain injury presented to clinic with progressive neurogenic claudication and radiculopathy associated with magnetic resonance imaging (MRI) findings of lateral recess stenosis at L2–L3, L3–L4, and L4–L5 and central canal stenosis from L4 to L5 anterolisthesis. She underwent elective surgical decompression and instrumentation from L2 to L5 with placement of an allograft interbody spacer and multi-level autograft (day 0). The procedure took place sterilely using an institutional protocol for prophylactic antibiotics including perioperative cefazolin and powdered vancomycin administered to the wound cavity before closure. Her post-surgical course was complicated by displacement of the L4–L5 interbody spacer and ongoing L4 radiculopathy. The surgical site was re-explored and the interbody spacer replaced (day 22). The construct was augmented with bone morphogenic protein.\n\nThe patient had resolution of radicular symptoms in the month following the second surgery, but began to experience cognitive decline, decreased mobility, and incontinence over several weeks. She was readmitted after a ground level fall (day 92). During this admission, she developed bradykinesia, right-sided hemiparesis, hypophonia, and disorientation. An MRI revealed diffuse ventriculomegaly with possible hydrocephalus as well as two areas of nodular enhancement in the region of the left cerebellopontine angle (CPA) [Fig. 1]. A right frontal extraventricular drain (EVD) was placed (day 96) and her mental status improved.\n\nDuring this hospitalization, an extensive infectious work-up including cerebrospinal fluid (CSF) bacterial, fungal, AFB, and Nocardia stains and cultures; CSF Mycobacterium tuberculosis, non-tuberculous Mycobacterium, Mycoplasma, Tropheryma whipplei, bacterial, and fungal polymerase chain reaction (PCR) studies; CSF cryptococcal antigen; CSF herpes simplex virus, cytomegalovirus and Epstein-barr virus PCRs; serum Coccidioides, Blastomyces, and Brucella antibody testing; Leptospira titer, Lyme serology, and HIV testing was unrevealing. She had an elevated angiotensin converting enzyme (ACE) level and was treated empirically with high-dose steroids for possible neurosarcoidosis but continued to decline clinically. She ultimately underwent bilateral suboccipital craniectomy for biopsy of the CPA mass with placement of a right ventriculoperitoneal shunt (VPS) for hydrocephalus (day 137). Specimens were sent for frozen section and permanent section pathology and microbiological studies, including bacterial, fungal, and mycobacterial stains and culture and broad-range fungal PCR. The frozen section pathology showed tissue necrosis, neutrophilic infiltrate and focal giant cell reaction. Multiple tissue fungal cultures and fungal PCR were positive for Scedosporium apiospermum complex with the following susceptibilities reported by the University of Texas San Antonio Department of Pathology: amphotericin minimum inhibitory concentration (MIC) 16 mcg/mL, posaconazole MIC 2 mcg/mL, voriconazole MIC 1 mcg/mL, caspofungin MIC 1 mcg/mL, and terbinafine MIC >2 mcg/mL. Of note, molecular testing was not conducted to differentiate between Scedosporium apiospermum or Scedosporium minutisporum.\n\nIntravenous voriconazole, often considered first-line therapy, was initiated day 139 with gradual clinical improvement [4]. After two weeks, however, the patient developed shock-like sensations down her upper extremities and progressively worsening bilateral weakness. Repeat MRI showed progression of the initial CPA lesion further into the basal cisterns, diffuse leptomeningeal enhancement, and enhancement of the cervical and superior thoracic CSF space. Given disease progression, intravenous terbinafine was added to her regimen at 250 mg PO daily (day 154), as synergy between terbinafine and azoles may inhibit the growth of Scedosporium isolates [5]. She had a percutaneous endoscopic gastrostomy (PEG) tube placed for feeding and at discharge had only limited residual motor function of her left extremities.\n\nFollowing discharge home with home health care, she remained on intravenous voriconazole and terbinafine with plan to continue for an undefined course given severity of the infection, lack of experience base to guide treatment duration, and anticipation of difficulty definitively eradicating the infection with retention of the VPS. Serum voriconazole level was maintained in a therapeutic range (1.0 mg/mL and 5.5 mg/mL) apart from a single subtherapeutic concentration of 0.7 mg/mL 6 months into the treatment course.\n\nEight months into therapy, she was readmitted for two days of increasing somnolence and lethargy (day 366). Her VPS was malpositioned with the distal portion seen intrahepatically on imaging and she underwent shunt adjustment (day 229). After re-positioning, the VPS ceased functioning and a second VPS was placed in the right 4th ventricle (day 367). Voriconazole was transitioned to tablet form through PEG tube and terbinafine was discontinued during admission (day 367). Following shunt adjustment, her mental status condition improved and she was discharged (day 381). After discharge, fungal CSF cultures from day 370 returned positive for Scedosporium apiospermum complex (day 399). Fungal susceptibility testing was not performed and no changes were made to her antifungal regimen.\n\nThe patient remained on voriconazole for over two months before being readmitted for unresponsiveness and fevers (day 467). Both of her shunts were exchanged for EVDs. Specimens from the removed shunt systems grew Scedosporium apiospermum complex. She was restarted on terbinafine 250 mg twice daily by PEG tube with continued voriconazole treatment. Scedosporium apiospermum complex susceptibilities were re-tested with the following results: amphotericin MIC 16 mcg/mL, posaconazole MIC 4 mcg/mL, voriconazole MIC 2 mcg/mL, caspofungin MIC 2 mcg/mL, terbinafine MIC >2 mcg/mL, and isavuconazole MIC >16 mcg/mL.\n\nGiven the protracted failure of conventional therapy, more aggressive treatment approaches were considered. A successful case of intraventricular caspofungin administration in curing Scedosporium apiospermum complex meningoencephalitis was identified in the literature [6]. In this reported case of a 2-year old near-drowning victim, intraventricular caspofungin in combination with terbinafine and voriconazole was successful in treating multiple Scedosporium apiospermum complex intracerebral abscesses. Although other clinical data on efficacy were lacking, intraventricular caspofungin was considered a viable option for the patient given her disease progression on usual therapy and the increasing MIC for voriconazole. The patient and her family were counseled on the treatment, its risks and potential benefits, available alternatives, and the experimental nature of the plan and consented to treatment.\n\nA preparation of 5 mg/mL caspofungin was prepared for daily administration, using CANCIDAS® (Merck and Co.) which contains a sterile, lyophilized product of caspofungin acetate (50 mg). Following CANCIDAS® package insert instructions, we aseptically added 10.8 mL of preservative-free 0.9% sodium chloride injection into a CANCIDAS® 50 mg vial, reconstituting to a final concentration of 5 mg/mL [7]. The vial was mixed gently until a clear solution was obtained. We then aseptically transferred 1 mL of reconstituted CANCIDAS®, equivalent to a 5 mg dose, into a syringe. This 5 mg caspofungin dose was administered intraventricularly by the neurosurgeon.\n\nAdministration was carried out as follows: The proximal port of the patient's right frontal EVD was prepped with betadine each day. Five mL of sterile, preservative-free normal saline was injected into the port as a primer, followed by 1 mL of the 5 mg/mL caspofungin preparation, which was then followed by an additional 5 mL of sterile, preservative-free normal saline. Both the right frontal and right occipital EVDs were then occluded proximally for approximately 30 min to allow for dissemination and absorption of the drug more directly into the CNS. The patient was also given intravenous anti-emetics and narcotic pain medication to help with symptoms from increased intracranial pressure and potential drug-related cerebritis. This routine was continued daily for 14 days total (days 480–493). CSF samples were sent roughly every other day to monitor for trends in cell counts.\n\nIntraventricular caspofungin was well-tolerated. The patient experienced some nausea and headaches temporally associated with intraventricular drug administration and EVD clamping, but these symptoms were well-controlled with IV pain medications and anti-emetics. The patient also experienced transient somnolence during administration, but remained easily arousable with no changes from the pre-admission neurological exam. Repeat computed tomography showed no new lesions or signs of cerebral edema. Her intracranial pressures remained stable on ICP monitoring throughout the caspofungin treatment course. Semi-daily CSF studies showed an oscillatory damping pattern over the course of intraventricular treatment with a decrease in inflammatory cells, although a relative increase in percent eosinophils was noted [Table 1]. The patient's shunts were re-internalized (day 497) and she was discharged on voriconazole and terbinafine through her PEG tube.\n\nUnfortunately, the patient's condition deteriorated five weeks after discharge with development of sixth and seventh cranial nerve palsies (day 530). An MRI of the brain and cervical spine were obtained demonstrated interval development of a new right frontal lobe focus of enhancement measuring 1.0 cm×0.4 cm, along with thickened enhancement of the right occipital horn and increased diffuse pachymeningeal enhancement concerning for progression of intracranial infection. Paradoxically, CSF obtained at the time was within normal limits in its nucleated cell count, glucose, and protein measures. In addition, cultures from that sample and the distal catheter did not grow bacteria or fungi after 4 weeks, and a CSF fungal PCR was negative. The patient and her family did not want additional aggressive treatment maneuvers and she was discharged home to continue voriconazole and terbinafine. The patient ultimately expired within 4 months of discharge (day 648).\n\n3 Discussion\nWe describe the case of a woman with post-surgical Scedosporium apiospermum complex infection that failed to resolve with usual antifungal therapies. Scedosporium apiospermum complex characteristically exhibits excellent in vitro susceptibility to voriconazole, which is typically selected as initial therapy [8]. After our patient failed voriconazole therapy, terbinafine was added to her regimen. While MICs of terbinafine for Scedosporium apiospermum complex are characteristically high, terbinafine exhibits in vitro synergy with other antifungal agents used to treat Scedosporium and has been used in combination regimens to successfully treat CNS disease [6], [9], [10]. Unfortunately, our patient did not respond to combination treatment options.\n\nAfter treatment failure on voriconazole and terbinafine, we hoped to obtain high antifungal concentrations in the CNS in order to improve the chance of complete fungal eradication after externalization of both CNS shunts. Decades of experience exist in the use of intraventricular amphotericin and, to a lesser extent, miconazole, for the treatment of serious CNS fungal diseases [11]. The MIC of amphotericin for the initial Scedosporium apiospermum complex isolate was characteristically high (MIC 16 mcg/mL) and we instead opted to use intraventricular caspofungin administered through a clamped EVD. Only 1 case report describes intraventricular administration of an echinocandin for treatment of CNS fungal disease [6]. A 2-year old boy with multiple Scedosporium apiospermum complex brain abscesses after a near-drowning event was treated for 3 weeks with a combination of intravenous voriconazole, terbinafine, and caspofungin. Intraventricular caspofungin was added at a dose of 1–2 mg daily for 20 days after a brain MRI demonstrated new intraventricular, ependymal reaction. Following intraventricular caspofungin therapy, MRI revealed diminution of the brain abscesses but also showed massive cerebral edema and ventriculitis. It is unclear whether these latter findings were a result of treatment or instead related to the underlying disease. The patient ultimately survived, albeit with intellectual deficiency. Our case provides further insight into the safety and clinical and laboratory response to caspofungin administered intraventricularly for the treatment of serious CNS Scedosporium apiospermum complex infections.\n\nCaspofungin is a semisynthetic compound derived from a fermentation product of Glarea lozoyensis. It is a water soluble lipopeptide with a molecular weight of 1213 kDa that is highly protein bound in plasma (approximately 96%) [12]. It is an echinocandin antifungal that inhibits the synthesis of β (1,3)-D-glucan. Mechanistically, disruption of cell wall permeability results in osmotic stress, lysis and cell death. The clinical role of caspofungin in CNS infections is somewhat limited due to its large molecular weight, high plasma protein binding, and water solubility, precluding its ability to penetrate across the blood brain barrier and achieve therapeutic CSF concentration during conventional intravenous therapy [12]. In principle, intraventricular or intrathecal administration of caspofungin can overcome this problem by enhancing distribution of the drug into brain parenchymal tissue [6].\n\nWhile the single published case suggested that intraventricular caspofungin could be effective treatment for CNS Scedosporium apiospermum complex infection [6], results of use for our patient were mixed. Treatment was well-tolerated, did not cause apparent ventriculitis, and led to initial CSF culture clearance in our patient, but clinical and radiographic evidence of disease progression emerged in the post-treatment phase. It is not clear if intrathecal antifungal therapy produced high drug concentrations in brain parenchyma. In future applications of intraventricular caspofungin to treat Scedosporium apiospermum complex-related meningoencephalitis, it is worth considering higher doses or longer courses as typical for management of invasive fungal disease. Ultimately, alternative antifungal agents with an acceptable CNS safety profile and better CNS penetration may be needed.\n\nConflict of interest\nAll authors report no potential conflicts of interest.\n\nAcknowledgments\nWe thank MM (our patient's husband) for his extremely well-organized data and timeline of the patient's medical course, and David Fredricks and Jill Gersh for manuscript review.\n\nFig. 1 MRI showing enhancing lesion at the left cerebellopontine angle before biopsy confirmation of Scedosporium apiospermum complex infection.\n\nFig. 1Table 1 Cerebrospinal fluid profile during intraventricular caspofungin therapy.a\n\nTable 1Day intraventricular caspofungin\t2\t3\t5\t7\t9\t11\t13\t\nCSF WBC (cells/μL)\t39\t40\t14\t32\t10\t29\t14\t\n% neutrophils\t39\t16\t14\t4\t4\t0\t0\t\n% lymphocytes\t26\t14\t13\t13\t17\t13\t28\t\n% macrophages\t30\t67\t62\t70\t57\t74\t43\t\n% eosinophils\t5\t3\t11\t13\t22\t13\t29\t\nRBC (cells/μL)\t653\t475\t41\t132\t205\t93\t152\t\nProtein (mg/dL)\t29\t22\t28\t32\t37\t28\t31\t\nGlucose (mg/dL)\t88\t73\t80\t75\t74\t86\t79\t\na Values from first sample if multiple cerebrospinal fluid samples were collected on the same day.\n==== Refs\nReferences\n1 Cortez K.J. Roilides E. Quiroz-Telles F. Meletiadis J. Antachopoulos C. Knudsen T. Infections caused by Scedosporium spp Clin. Microbiol. Rev. 21 1 2008 157 197 18202441 \n2 Nesky M.A. McDougal E.C. Peacock J.E. Jr Scedosporium apiospermum complex brain abscess successfully treated with voriconazole and surgical drainage: case report and literature review of central nervous system pseudallescheriasis Clin. Infect. Dis. 31 3 2000 673 677 11017814 \n3 Castiglioni B. Sutton D.A. Rinaldi M.G. Fung J. Kusne S. Scedosporium apiospermum complex (Anamorph Scedosporium apiospermum ). Infection in solid organ transplant recipients in a tertiary medical center and review of the literature Medicine 81 5 2002 333 348 12352630 \n4 Troke P. Aguirrebengoa K. Arteaga C. Ellis D. Heath C.H. Lutsar I. Treatment of scedosporiosis with voriconazole: clinical experience with 107 patients Antimicrob. Agents Chemother. 52 5 2008 1743 1750 18212110 \n5 Meletiadis J. Mouton J.W. Meis J.F. Verweij P.E. In vitro drug interaction modeling of combinations of azoles with terbinafine against clinical Scedosporium prolificans isolates Antimicrob. Agents Chemother. 47 1 2003 106 117 12499177 \n6 Mursch K. Trnovec S. Ratz H. Hammer D. Horré R. Klinghammer A. Successful treatment of multiple Scedosporium apiospermum complex brain abscesses and ventriculitis/ependymitis in a 2-year-old child after a near-drowning episode Childs Nerv. Syst. 22 2 2006 189 192 15864705 \n7 Cancidas(R), [package insert]. Whitehouse Station NMCI, 2001.\n8 Lackner M. de Hoog G.S. Verweij P.E. Najafzadeh M.J. Curfs-Breuker I. Klaassen C.H. Species-specific antifungal susceptibility patterns of Scedosporium and Pseudallescheria species Antimicrob. Agents Chemother. 56 5 2012 2635 2642 22290955 \n9 Henao-Martínez A.F. Castillo-Mancilla J.R. Barron M.A. Nichol A.C. Combination antifungal therapy in the treatment of Scedosporium apiospermum central nervous system infections Case Rep. Infect. Dis. 2013 589490 23738164 \n10 Meletiadis J. Meis J.F. Mouton J.W. Rodriquez-Tudela J.L. Donnelly J.P. Verweij P.E. In vitro activities of new and conventional antifungal agents against clinical Scedosporium isolates Antimicrob. Agents Chemother. 46 1 2002 62 68 11751112 \n11 Wen D.Y. Bottini A.G. Hall W.A. Haines S.J. Infections in neurologic surgery. The intraventricular use of antibiotics Neurosurg. Clin. N. Am. 3 2 1992 343 354 1633464 \n12 Dodds Ashley E.S. Lewis R. Martin C. Andes D. Pharmacology of Systemic Antifungal Agents 43 2006 S28 S39 osaaCID\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2211-7539",
"issue": "13()",
"journal": "Medical mycology case reports",
"keywords": "Caspofungin; Intraventricular; Scedosporium apiospermum; Scedosporium apiospermum complex",
"medline_ta": "Med Mycol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101598259",
"other_id": null,
"pages": "1-4",
"pmc": null,
"pmid": "27656356",
"pubdate": "2016-09",
"publication_types": "D016428:Journal Article",
"references": "1633464;11017814;12499177;11751112;23738164;18212110;18202441;15864705;22290955;12352630",
"title": "Safety and clinical response of intraventricular caspofungin for Scedosporium apiospermum complex central nervous system infection.",
"title_normalized": "safety and clinical response of intraventricular caspofungin for scedosporium apiospermum complex central nervous system infection"
} | [
{
"companynumb": "US-PFIZER INC-2016448973",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VORICONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "We report here a case of rocuronium-induced anaphylactic shock in a 41-year-old woman. She was scheduled for partial hepatectomy due to liver metastasis of a pheochromocytoma. Anesthesia was induced with propofol, remifentanil, and rocuronium. Bag-mask ventilation was difficult, and her blood pressure fell to around 40 mmHg just after induction. Subsequently, her trachea was intubated and adrenaline was injected. However, due to the subsequent persistence of severe hypotension and hypoxia, cardiopulmonary resuscitation was necessary. Suspecting the development of pulmonary embolism or anaphylaxis, we performed transesophageal echography; however, no evidence of right heart dilatation was observed, indicating a low possibility of pulmonary embolism. Although her general condition was stabilized, surgery was canceled. Blood tests showed high serum histamine and tryptase levels, suggesting an Ig-E mediated allergic reaction. A skin test performed five weeks after anesthesia suggested that she had suffered from rocuronium-induced anaphylaxis. A skin test also showed cross-reactivity between rocuronium and vecuronium. Therefore, we did not use any neuromuscular agent for the subsequent surgery, which was completed uneventfully. Determining the drug responsible for anaphylaxis helps to prevent recurrence of anaphylaxis.",
"affiliations": null,
"authors": "Horiuchi|Tatsuo|T|;Takazawa|Tomonori|T|;Saito|Shigeru|S|",
"chemical_list": "D000732:Androstanols; D009466:Neuromuscular Blocking Agents; D010880:Piperidines; D053802:Tryptases; D000077208:Remifentanil; D000077123:Rocuronium; D015742:Propofol",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-4892",
"issue": "65(3)",
"journal": "Masui. The Japanese journal of anesthesiology",
"keywords": null,
"medline_ta": "Masui",
"mesh_terms": "D000328:Adult; D000707:Anaphylaxis; D000732:Androstanols; D000768:Anesthesia, General; D005260:Female; D006801:Humans; D009364:Neoplasm Recurrence, Local; D009466:Neuromuscular Blocking Agents; D010880:Piperidines; D015742:Propofol; D011655:Pulmonary Embolism; D000077208:Remifentanil; D000077123:Rocuronium; D012882:Skin Tests; D053802:Tryptases",
"nlm_unique_id": "0413707",
"other_id": null,
"pages": "299-303",
"pmc": null,
"pmid": "27097513",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Rocuronium-induced Anaphylaxis in Which Surgery was Subsequently Performed under General Anesthesia without Neuromuscular Blocking Agents.",
"title_normalized": "a case of rocuronium induced anaphylaxis in which surgery was subsequently performed under general anesthesia without neuromuscular blocking agents"
} | [
{
"companynumb": "JP-PFIZER INC-2016280008",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "NOREPINEPHRINE\\NOREPINEPHRINE BITARTRATE"
},
... |
{
"abstract": "BACKGROUND\nHypersensitivity reactions to beta-lactams (BLs) are often reported in children, with amoxicillin and, to a lesser extent, cephalosporins being the most frequent drugs involved. Although many of these children are considered to be allergic, a careful evaluation only confirms a low percentage.\n\n\nOBJECTIVE\nTo analyse the clinical data, sensitization profile and diagnostic methods used in a large group of children with a clinical history of hypersensitivity reactions to BLs.\n\n\nMETHODS\nThe study included children aged 1-14 yr with symptoms suggestive of hypersensitivity to BLs from January 2006-December 2012. Diagnosis was confirmed from a clinical history, specific IgE determination, skin testing and, if necessary, a drug provocation test (DPT).\n\n\nRESULTS\nOf a total of 783 patients studied, only 62 (7.92%) were confirmed as being allergic, 9 (14.52%) with immediate and 53 (85.48%) with non-immediate reactions. In those with immediate reactions, 2 (22.22%) were diagnosed by in vitro test, 2 (22.22%) by skin testing and 5 (55.56%) by DPT; in those with non-immediate reactions, 2 (3.77%) were diagnosed by skin testing and 51 (96.23%) by DPT. In all cases, DPT was positive to the culprit drug (29 AX-CLV, 26 AX, 1 cefixime and 1 cefaclor), and the most usual symptoms were exanthema in 43 cases, urticaria in 12, urticaria-angio-oedema in 1 and erythema in 1 case.\n\n\nCONCLUSIONS\nAfter an allergological work-up, over 90% of the children evaluated were finally confirmed as tolerant to BLs. Most reactions were of the non-immediate type, and DPT was an essential tool for diagnosis.",
"affiliations": "Paediatric Service, Carlos Haya Hospital, Málaga, Spain.",
"authors": "Zambonino|Maria A|MA|;Corzo|Jose Luis|JL|;Muñoz|Candelaria|C|;Requena|Gloria|G|;Ariza|Adriana|A|;Mayorga|Cristobalina|C|;Urda|Antonio|A|;Blanca|Miguel|M|;Torres|M J|MJ|",
"chemical_list": "D002511:Cephalosporins; D047090:beta-Lactams; D007073:Immunoglobulin E; D000658:Amoxicillin",
"country": "England",
"delete": false,
"doi": "10.1111/pai.12155",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0905-6157",
"issue": "25(1)",
"journal": "Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology",
"keywords": "IgE; beta-lactams; children; drug provocation test; hypersensitivity; skin test",
"medline_ta": "Pediatr Allergy Immunol",
"mesh_terms": "D000293:Adolescent; D000658:Amoxicillin; D002511:Cephalosporins; D002648:Child; D002675:Child, Preschool; D004342:Drug Hypersensitivity; D005076:Exanthema; D005260:Female; D006801:Humans; D006968:Hypersensitivity, Delayed; D007114:Immunization; D007073:Immunoglobulin E; D007223:Infant; D008297:Male; D044382:Population Groups; D012882:Skin Tests; D047090:beta-Lactams",
"nlm_unique_id": "9106718",
"other_id": null,
"pages": "80-7",
"pmc": null,
"pmid": "24329898",
"pubdate": "2014-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Diagnostic evaluation of hypersensitivity reactions to beta-lactam antibiotics in a large population of children.",
"title_normalized": "diagnostic evaluation of hypersensitivity reactions to beta lactam antibiotics in a large population of children"
} | [
{
"companynumb": "ES-LUPIN PHARMACEUTICALS INC.-2015-00005",
"fulfillexpeditecriteria": "2",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CEFIXIME"
},
"drugadditional":... |
{
"abstract": "BACKGROUND\nPrevious studies have shown a modest impact of tyrosine kinase inhibitors on primary renal tumors. Those studies were mostly retrospective or heterogeneous in their eligibility criteria with regard to histology, disease stage, duration of therapy, and time off therapy prior to surgery.\n\n\nOBJECTIVE\nTo prospectively investigate the safety and efficacy of axitinib in downsizing tumors in patients with nonmetastatic biopsy-proven clear cell renal cell carcinoma (ccRCC).\n\n\nMETHODS\nThis was a single-institution, single-arm phase 2 clinical trial. Patients with locally advanced nonmetastatic biopsy-proven ccRCC were eligible.\n\n\nMETHODS\nPatients received axitinib 5mg for up to 12 wk. Axitinib was continued until 36h prior to surgery. Patients underwent partial or radical nephrectomy after axitinib therapy.\n\n\nMETHODS\nThe primary outcome was objective response rate prior to surgery. Secondary outcomes included safety, tolerability, and quality of life. A dedicated radiologist independently reviewed all computed tomography scans to evaluate for response using Response Evaluation Criteria in Solid Tumors (RECIST).\n\n\nCONCLUSIONS\nA total of 24 patients were treated. Twenty-two patients continued axitinib for 12 wk; 1 patient continued axitinib for 11 wk and underwent surgery as planned. One patient stopped treatment at 7 wk due to adverse events (AEs). Median reduction of primary renal tumor diameter was 28.3%. Eleven patients experienced a partial response per RECIST; 13 had stable disease. There was no progression of disease while on axitinib. The most common AEs were hypertension, fatigue, oral mucositis, hypothyroidism, and hand-foot syndrome. Postoperatively, 2 grade 3 and 13 grade 2 complications were noted. No grade 4 or 5 complications occurred. Functional Assessment of Cancer Therapy-Kidney Specific Index-15 changed over time, with quality of life worsening while on therapy, but by week 19, it was not statistically different from screening. Limitations include single-arm design and small patient numbers.\n\n\nCONCLUSIONS\nAxitinib was clinically active and reasonably well tolerated in the neoadjuvant setting in patients with locally advanced nonmetastatic ccRCC.\n\n\nRESULTS\nIn this prospective clinical trial, we found that axitinib, when given prior to surgery, results in significant shrinking of kidney cancers. Larger studies are needed prior to further clinical use.\n\n\nBACKGROUND\nThis clinical trial was registered with clinicaltrials.gov (NCT01263769).",
"affiliations": "Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: CGWood@mdanderson.org.",
"authors": "Karam|Jose A|JA|;Devine|Catherine E|CE|;Urbauer|Diana L|DL|;Lozano|Marisa|M|;Maity|Tapati|T|;Ahrar|Kamran|K|;Tamboli|Pheroze|P|;Tannir|Nizar M|NM|;Wood|Christopher G|CG|",
"chemical_list": "D000970:Antineoplastic Agents; D007093:Imidazoles; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D000077784:Axitinib",
"country": "Switzerland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0302-2838",
"issue": "66(5)",
"journal": "European urology",
"keywords": "Clinical trial; Clinically localized; Neoadjuvant; Renal cell carcinoma; Targeted therapy",
"medline_ta": "Eur Urol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D000077784:Axitinib; D001706:Biopsy; D002292:Carcinoma, Renal Cell; D017024:Chemotherapy, Adjuvant; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007093:Imidazoles; D007191:Indazoles; D007680:Kidney Neoplasms; D010535:Laparoscopy; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D009392:Nephrectomy; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors; D011788:Quality of Life; D013781:Texas; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D047368:Tumor Burden",
"nlm_unique_id": "7512719",
"other_id": null,
"pages": "874-80",
"pmc": null,
"pmid": "24560330",
"pubdate": "2014-11",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "19097774;16669463;20105087;20394613;22397650;19652060;18410444;24140184;15273542;19145434;17959415;19616232;20643461;21258806;7165009;22425095;20159822;21612860;19636008;24140182;21367518;20952123;18413834;22056247;18684493",
"title": "Phase 2 trial of neoadjuvant axitinib in patients with locally advanced nonmetastatic clear cell renal cell carcinoma.",
"title_normalized": "phase 2 trial of neoadjuvant axitinib in patients with locally advanced nonmetastatic clear cell renal cell carcinoma"
} | [
{
"companynumb": "US-PFIZER INC-2013058028",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AXITINIB"
},
"drugadditional": "1",
... |
{
"abstract": "The purpose of this case report is to describe a new surgical method for sutureless placement of the amniotic membrane with a symblepharon ring in a pediatric patient with acute toxic epidermal necrolysis (TEN). A 1-year-old girl developed severe ocular surface inflammation with large corneal and conjunctival epithelial defects secondary to TEN. She was treated by applying a large (4 cm x 4 cm) amniotic membrane graft and non-sterile symblepharon ring under sedoanalgesia at bedside in the intensive care unit. The ocular surface was completely epithelized by post-treatment week 6 in the right and week 8 in the left eye. Two years after amniotic membrane transplantation, both eyes were quiet with no symblepharon, scar formation, or limbal stem cell deficiency. Performing bilateral amniotic membrane transplantation under a symblepharon ring at bedside provided sufficient acute coverage of the ocular surface and led to excellent clinical outcomes by reducing inflammation and protecting the ocular surface.",
"affiliations": "Ankara University, Faculty of Medicine, Department of Ophthalmology, Ankara, Turkey;Ankara University, Faculty of Medicine, Department of Ophthalmology, Ankara, Turkey",
"authors": "Baş|Zeynep|Z|0000-0002-8172-0477;Uçakhan Gündüz|Ömür|Ö|0000-0002-3447-7785",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.4274/tjo.galenos.2019.13333",
"fulltext": "\n==== Front\nTurk J OphthalmolTurk J OphthalmolTJOTurkish Journal of Ophthalmology2149-86952149-8709Galenos Publishing 3189359210.4274/tjo.galenos.2019.1333334580Case ReportSutureless Amniotic Membrane Transplantation in a Pediatric Patient with Acute Toxic Epidermal Necrolysis Baş Zeynep 1*https://orcid.org/0000-0002-8172-0477Uçakhan Gündüz Ömür 1https://orcid.org/0000-0002-3447-7785\n1 Ankara University, Faculty of Medicine, Department of Ophthalmology, Ankara, Turkey* Address for Correspondence: Ankara University, Faculty of Medicine, Department of Ophthalmology, Ankara, Turkey Phone: +90 543 449 88 97 E-mail:zeynepbs2003@yahoo.com12 2019 31 12 2019 49 6 356 360 20 6 2018 10 9 2019 © Copyright 2019 by Turkish Ophthalmological Association | Turkish Journal of Ophthalmology, published by Galenos Publishing House.2019This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.The purpose of this case report is to describe a new surgical method for sutureless placement of the amniotic membrane with a symblepharon ring in a pediatric patient with acute toxic epidermal necrolysis (TEN). A 1-year-old girl developed severe ocular surface inflammation with large corneal and conjunctival epithelial defects secondary to TEN. She was treated by applying a large (4 cm x 4 cm) amniotic membrane graft and non-sterile symblepharon ring under sedoanalgesia at bedside in the intensive care unit. The ocular surface was completely epithelized by post-treatment week 6 in the right and week 8 in the left eye. Two years after amniotic membrane transplantation, both eyes were quiet with no symblepharon, scar formation, or limbal stem cell deficiency. Performing bilateral amniotic membrane transplantation under a symblepharon ring at bedside provided sufficient acute coverage of the ocular surface and led to excellent clinical outcomes by reducing inflammation and protecting the ocular surface.\n\nAmniotic membrane transplantationdry eyeocular surfacetoxic epidermal necrolysis\n==== Body\nIntroduction\nToxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are severe adverse drug reactions that predominantly involve the skin and mucous membranes. They are considered to be two ends of the same spectrum, differing only by their extent of skin detachment. Both are rare diseases, with an approximate incidence of 1 to 2 per 1,000,000 annually.1 SJS and TEN are both immune-mediated diseases caused by cytotoxic CD8+T lymphocyte response. The histopathology of SJS/TEN lesions shows that T cells respond via interferong and Fas ligand pathway, leading to keratinocyte apoptosis. Drugs are identified as the main cause of SJS and TEN in most cases, but Mycoplasma pneumoniae and herpes simplex virus infections are also well documented causes. Genetic background may also have an impact on risk of developing SJS/TEN. Recently, associations between HLA genotypes and drug hypersensitivity have been demonstrated in various ethnic groups.2 Chung et al.3 described strong relationships between HLA-B1502 and carbamazepine, HLA-B5801, and allopurinol.\n\nSJS and TEN are severe and life-threatening diseases with an estimated mortality rate of 1-5% for SJS and 25-35% for TEN.4 Clinical findings include a prodromal symptom of fever and malaise, followed by the development of generalized, tender cutaneous eruptions. Common ocular manifestations of TEN include conjunctivitis, as well as conjunctival and corneal epithelial defects and ulcerations secondary to conjunctival inflammation. Goblet cells, lacrimal ducts, and meibomian glands may be damaged.5 If left untreated, these acute changes may ultimately lead to recurrent or persistent corneal epithelial defects and symblepharon formation. Severe dry eye and limbal stem cell deficiency may subsequently develop in the chronic stage.6 The ongoing inflammatory process on the ocular surface tends to be relentless and prolonged even after the patients are discharged from the hospital.7 Although intervention in the acute stage has more favorable ocular outcomes, treatments also exist for the chronic sequelae of SJS and TEN. Patients with SJS/TEN are poor candidates for traditional penetrating keratoplasty due to the development of cicatrizing lid disorders and severe ocular surface diseases. For these patients, limbal allografting and Boston keratoprosthesis may provide some visual recovery despite limbal stem cell deficiency and corneal conjunctivalization.8\n\nEarly evaluation and treatment of patients with SJS and TEN are critical. Recent literature data show that amniotic membrane transplantation (AMT) can suppress inflammation and facilitate healing if done in the acute phase of TEN.7,9,10 The amnion has immunomodulatory effects and promotes epithelialization. The amnion’s anti-inflammatory mechanism of action may be due to downregulation of inflammatory cytokines released by activated lymphocytes and promotion of leukocyte apoptosis.11\n\nVarious AMT techniques have been described previously, as traditional AMT is a time-consuming and a laborious surgery that is difficult to perform on patients who are unstable for surgical interventions because of systemic complications. It should also be taken into account that extensive eyelid sloughing in these patients makes the surgical area unfit for traditional AMT, and multiple surgeries are needed. Recently, a sutureless amniotic membrane fixation method was described, which utilized different materials to secure the membrane in the fornices. Ma et al.12 described a technique for sutureless application of amniotic membrane in SJS patients using sterile intravenous tubing. Kara.13 utilized a feeding tube to make a modified ocular surface ring in a chemical ocular surface burn patient.\n\nIn this case report, we describe a method for sutureless placement of amniotic membrane on the bulbar and palpebral conjunctiva that has been previously used for acute ocular burns but is novel in the setting of ocular TEN.14 To the best of our knowledge this is the first report documenting the use of this novel technique in a TEN patient.\n\nCase Report\nA 1-year-old girl was admitted to the Ankara University Pediatric Emergency Department with the suspicion of TEN. Her history revealed that she had received a measles, mumps, and rubella vaccine 13 days before admission. The day after vaccination, she developed seizures and was transferred to another pediatric emergency department. Under suspicion of febrile convulsion, she was treated with phenobarbital, levetiracetam, and cefuroxime. Seizure did not recur, and on day 9 she was discharged from the hospital. Three days after initiation of treatment, the patient developed a raised, maculopapular rash on her body, together with mucosal involvement. She was admitted to the Ankara University Pediatric Infection Unit with suspected Stevens-Johnson Syndrome. Upon admission, the anticonvulsant medications were discontinued and she was started on intravenous (IV) prednisolone 2 mg/kg/day and IV immunoglobulin 2 g/kg/day. On her second day in hospital, she was evaluated by the ophthalmology unit. On examination at bedside, the patient was observed to have severe bilateral bulbar and palpebral conjunctival inflammation, desquamation, and epithelial defects. The corneal epithelial defects measured 1x1 mm in the right eye and 7x8 mm in the left eye (Figure 1). The patient was started on aggressive lubrication with preservative-free artificial tears, as well as cyclosporine ophthalmic emulsion 0.05% (Restasisâ, Allergan, Ireland) and loteprednol ophthalmic suspension 0.5% (Lotemaxâ, Bausch&Lomb, USA) 4 times a day to both eyes.\n\nThe patient remained in critical condition, which prevented her from leaving the pediatric unit for surgery. During this period, it was noted that her systemic condition was worsening despite systemic treatment, so she was treated with infliximab (Remicadeâ, Essex GmbH, Germany) 5 mg/kg as single-shot therapy. The patient’s severe clinical condition, intense laryngeal desquamation, and edema precluded her from receiving general anesthesia. On post-admission day 3, it was decided to perform AMT at bedside under sedoanalgesia. The placenta was retrieved intact and processed under sterile conditions. The chorioamnion was stripped from the placenta, and following antibiotic decontamination, the amniotic membrane was separated from the chorion, cut into 4-cm squares and mounted on nitrocellulose backing paper as previously described.15 After instilling 1 drop of proparacaine (Alcaine®, Alcon, USA), the amniotic membrane was spread onto the ocular surface epithelial side up. Since there was severe epidermal desquamation, we had difficulty even holding the eyelids open and instead of securing the amniotic membrane with sutures, a symblepharon ring was gently placed on the ocular surface in the superior and inferior fornix. The symblepharon ring (open fornix conformer) was chosen according to the height of palpebral apertures and was big enough to safely sit in the fornices. It was made of polymethyl methacrylate and had a diameter of 18 mm (IMKA, Ankara, Turkey) (Figure 2). The rest of the membrane was tucked into the palpebral conjunctiva using forceps and the excess was trimmed with Westcott scissors. The same procedure was performed on the contralateral eye. Postoperatively, moxifloxacin 0.5% (Vigamox®, Alcon, USA) 4 times a day and tacrolimus ointment 0.03% (Protopic®, Astellas, USA) 2 times a day were added to topical treatment.\n\nOn postoperative day 3, the amniotic membranes and symblepharon rings were still in place (Figure 3). Disintegration of the amniotic membrane was noticed and the procedure was repeated on both eyes on day 7 (Figure 4). The patient was seen 1 month later. Her systemic condition was stable, so she was examined under general anesthesia. Examination of her right eye on day 37 showed the corneal defect was healed and the tarsal conjunctiva was epithelized, and a bandage contact lens (Pure Vision, Bausch & Lomb, USA) was applied. In the left eye, the symblepharon ring and the old disintegrated membrane were removed, and a 7x7 mm persistent corneal epithelial defect was observed. Peripheral keratectomy was performed and a new amniotic membrane was sutured onto the cornea using 10-0 nylon sutures, and a bandage contact lens was placed (Figure 5). The corneal defect in the left eye was healed on day 53 and remained that way through the remainder of the follow-up. The patient was kept on cyclosporine, tacrolimus, artificial tears and ointments for 3 months, followed by tapering of all medications. At postoperative 6 months, there was no ectropion and the conjunctival fornices were preserved without residual inflammation in both eyes. There was mild corneal haze in left eye (Figure 6). At 2-year follow-up, both corneas were clear with no residual scars (Figure 7). No other scarring sequelae occurred.\n\nDiscussion\nToxic epidermal necrolysis is a severe immunologic dermatobullous condition with high morbidity and mortality. It is characterized by widespread erythema, necrosis, and bullous detachment of the epidermis and mucous membranes. It exists on the same spectrum as SJS, but is characterized by more than 30% body surface area detachment.16 It is believed that drugs or metabolites, acting as receptors, bind to surface of keratinocytes and cause them to become antigenic and stimulate cytotoxic CD8+T cell response.17 In our case, the immune reaction was considered to be triggered by the use of phenobarbital. SJS and TEN have long been associated with the administration of barbiturates, with the greatest risk occurring within the first two months of treatment.4\n\nThe incidence of TEN is very low but the ocular sequelae can be blinding. Rapid recognition and prompt withdrawal of the offending drug is essential. The main clinical presentations are conjunctival inflammation, keratinization of the ocular surface, and symblepharon formation. Recent literature data indicate that early intervention with AMT in the hyperacute phase gives better long-term results in terms of ocular surface and forniceal stability.7,10 Amniotic membrane suppresses inflammation, prevents ulcer formation, and promotes healing of the ocular surface.11 A delay in the treatment may result in corneal stem cell deficiency and sight-threatening cicatricial complications.18 However, securing the amniotic membrane onto the ocular surface with sutures at bedside in intensive care units is technically difficult and poses several challenges.7 Anchoring the amniotic membrane requires complex and time-consuming suturing of multiple amnion pieces to the eyelids, fornix, and limbus that requires bolsters and stitch removal from the patient’s eyelids and ocular surface. In order to address some of these problems, sutureless techniques in SJS patients have been published recently by Shay et al.7, Pruet et al.9, Cheung et al.,10 and Ma et al.12 Cheung et al.10 used specially made symblepharon rings that are not commercially available and hard to find, possibly causing operations to be delayed. Shay et al.7 utilized ProKera rings, but the diameter of the ProKera only covers the cornea and perilimbal conjunctiva, thus making the fornices vulnerable to symblepharon formation.19 Ma et al.12 employed an intravenous tube, but the circular shape of the tube may not be an adequate fit for the oval contour of the fornices.\n\nOur technique minimized symblepharon formation because of increased coverage of the amnion membrane thanks to the broad shape of the symblepharon rings. Symblepharon rings are effective in keeping the fornices intact in conjunctival cicatricial diseases. The ring prevents adhesions and forniceal contractures without touching the cornea. Liang et al.14 used a similar sutureless technique on burn patients and reported higher reepithelialization rates, shorter operation time, and lower symblepharon rates in the sutureless AMT group. To our knowledge, this technique was never performed in patients with SJS/TEN.\n\nPatients with acute TEN often do not receive AMT during the hyperacute phase because of the lack of standardized protocol, high mortality risk associated with general anesthesia, and difficulty in performing this extensive surgery. Our technique can be performed at the bedside without the need for general anesthesia or operating room conditions. This minimizes the delay in AMT and is less invasive for the patient. In addition, amniotic membrane coverage of the entire conjunctival surface is crucial to maximizing benefit; therefore, patients undergoing traditional AMT only to the bulbar conjunctiva may still develop chronic sequelae of SJS and TEN. A possible disadvantage is that the amniotic membrane and ring may come loose from the fornices. However, the simplicity of the method allows easy manipulation of the membrane.\n\nIn the absence of banked cryopreserved amnion and due to the pressing nature of the patient’s condition, we decided to use fresh amniotic membrane. There may be a number of disadvantages to this, the most important being the theoretical risk of disease transmission. Another difficulty is the need to find a suitable donor fast enough in advance of surgery to allow processing and testing and coordination with the obstetrics and gynecology department.15 No such problems arose in our case.\n\nThe use of a symblepharon ring with amniotic membrane to cover the ocular surface and fornices without the use of sutures or tissue glue as described herein is fast, nontraumatic, technically easy, and seems to yield final outcomes comparable to those achieved with conventional AMT methods. The results of this study are in agreement with recently published reports that AMT performed in the acute phase of TEN is vital to prevent sight-threatening cicatrizing sequelae associated with ocular manifestations of the disease.\n\nEthics\n\nInformed Consent: Obtained.\n\nPeer-review: Externally peer-reviewed.\n\nAuthorship Contributions\n\nSurgical and Medical Practices: Zeynep Baş, Ömür Uçakhan Gündüz, Concept: Zeynep Baş, Ömür Uçakhan Gündüz, Design: Zeynep Baş, Ömür Uçakhan Gündüz, Data Collection or Processing: Zeynep Baş, Ömür Uçakhan Gündüz, Analysis or Interpretation: Zeynep Baş, Ömür Uçakhan Gündüz, Literature Search: Zeynep Baş, Ömür Uçakhan Gündüz, Writing: Zeynep Baş, Ömür Uçakhan Gündüz.\n\nConflict of Interest: No conflict of interest was declared by the authors.\n\nFinancial Disclosure: The authors declared that this study received no financial support.\n\nFigure 1 Ocular manifestations of acute toxic epidermal necrolysis: A) Sloughing and erythema on eyelid skin; B) Fluorescein-stained corneal epithelial defect; C) Eyelid margin sloughing and conjunctival injection\n\nFigure 2 Small non-sterile symblepharon ring, size 18 mm, polymethyl methacrylate (IMKA, Ankara, Turkey)\n\nFigure 3 Postoperative day 3: Amniotic membranes wrapped around a symblepharon ring in the A) Right eye and B) Left eye\n\nFigure 4 Postoperative day 7: A) Amniotic membrane has begun to erode on the left side; B) Amniotic membrane transplantation was repeated at bedside with the same procedure on both eyes\n\nFigure 5 Postoperative 1 month, examination under general anesthesia: Epithelization has begun on the A) left and B) right palpebral conjunctiva. In the left eye, C) peripheral keratectomy was performed and D) amniotic membrane transplantation was repeated for the third time, this time under general anesthesia\n\nFigure 6 At 6-month follow up, the patient had grade 1 corneal haze in her left eye\n\nFigure 7 At 2-year follow-up, the patient exhibited no corneal haze or other sequelae\n==== Refs\nReferences\n1 Harr T French LE Toxic epidermal necrolysis and Stevens-Johnson syndrome Orphanet J Rare Dis. 2010 5 39 21162721 \n2 Lonjou C Borot N Sekula P Ledger N Thomas L Halevy S Naldi L Bouwes- Bavinck JN Sidoroff A de Toma C Schumacher M Roujeau JC Hovnanian A Mockenhaupt M; RegiSCAR study group A European study of HLA-B in Stevens-Johnson syndrome and toxic epidermal necrolysis related to five highrisk drugs Pharmacogenet Genomics. 2008 18 99 107 18192896 \n3 Chung WH Hung SI Hong HS Hsih MS Yang LC Ho HC Wu JY Chen YT Medical genetics: a marker for Stevens-Johnson syndrome Nature. 2004 428 486 \n4 Roujeau JC Stern RS Severe adverse cutaneous reactions to drugs N Engl J Med. 1994 331 1272 1285 7794310 \n5 Di Pascuale MA Espana EM Liu DT Kawakita T Li W Gao YY Baradaran- Rafii A Elizondo A Raju VK Tseng SC Correlation of corneal complications with eyelid cicatricial pathologies in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis syndrome. Ophthalmology 2005 112 904 912 15878074 \n6 Catt CJ Hamilton GM Fish J Mireskandari K Ali A Ocular Manifestations of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Children Am J Ophthalmol. 2016 166 68 75 27018234 \n7 Shay E Khadem JJ Tseng SC Efficacy and limitation of sutureless amniotic membrane transplantation for acute toxic epidermal necrolysis Cornea. 2010 29 359 361 20098313 \n8 Sayegh RR Ang LP Foster CS Dohlman CH The Boston keratoprosthesis in Stevens-Johnson syndrome Am J Ophthalmol. 2008 145 438 444 18207122 \n9 Pruet CM Queen JH Kim G Amnion doughnut: a novel method for sutureless fixation of amniotic membrane to the bulbar and palpebral conjunctiva in acute ocular-involving Stevens-Johnson syndrome Cornea. 2014 33 1240 1244 25222004 \n10 Cheung CS Ali A Chew HF Successful Treatment of Acute Ocular-Involving Toxic Epidermal Necrolysis Using Amniotic Membrane Suture Fixated to Custom Designed Symblepharon Rings Cornea. 2016 35 578 581 26863497 \n11 Park CY Kohanim S Zhu L Gehlbach PL Chuck RS Immunosuppressive property of dried human amniotic membrane. Ophthalmic Res. 2009 41 112 113 19122474 \n12 Ma KN Thanos A Chodosh J Shah AS Mantagos IS A Novel Technique for Amniotic Membrane Transplantation in Patients with Acute Stevens-Johnson Syndrome Ocul Surf. 2016 14 31 36 26387869 \n13 Kara N Sutureless amniotic membrane transplantation with a modified ocular surface ring Can J Ophthalmol. 2018 53 46 48 \n14 Liang X Liu Z Lin Y Li N Huang M Wang Z A modified symblepharon ring for sutureless amniotic membrane patch to treat acute ocular surface burns J Burn Care Res. 2012 33 32 38 \n15 Adds PJ Hunt CJ Dart JK Amniotic membrane grafts, «fresh» or frozen? A clinical and in vitro comparison Br J Ophthalmol. 2001 85 905 907 11466241 \n16 French LE Toxic epidermal necrolysis and Stevens Johnson syndrome: our current understanding Allergol Int. 2006 55 9 16 17075281 \n17 Abe R Immunological response in Stevens-Johnson syndrome and toxic epidermal necrolysis J Dermatol. 2015 42 42 48 25355273 \n18 Tomlins PJ Parulekar MV Rauz S «Triple-TEN» in the treatment of acute ocular complications from toxic epidermal necrolysis. Cornea 2013 32 365 369 22677638 \n19 Gregory DG Treatment of acute Stevens-Johnson syndrome and toxic epidermal necrolysis using amniotic membrane: a review of 10 consecutive cases Ophthalmology. 2011 118 908 914 21440941\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2149-8709",
"issue": "49(6)",
"journal": "Turkish journal of ophthalmology",
"keywords": "Amniotic membrane transplantation; dry eye; ocular surface; toxic epidermal necrolysis",
"medline_ta": "Turk J Ophthalmol",
"mesh_terms": "D000208:Acute Disease; D000650:Amnion; D003229:Conjunctival Diseases; D003316:Corneal Diseases; D004847:Epithelial Cells; D005260:Female; D006801:Humans; D007223:Infant; D013262:Stevens-Johnson Syndrome; D000071062:Sutureless Surgical Procedures",
"nlm_unique_id": "101686048",
"other_id": null,
"pages": "356-360",
"pmc": null,
"pmid": "31893592",
"pubdate": "2019-12-31",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "26863497;15878074;7794310;20098313;25222004;22210078;17075281;19122474;27018234;11466241;18192896;21440941;22677638;18207122;21162721;25355273;29631837;26387869;15057820",
"title": "Sutureless Amniotic Membrane Transplantation in a Pediatric Patient with Acute Toxic Epidermal Necrolysis",
"title_normalized": "sutureless amniotic membrane transplantation in a pediatric patient with acute toxic epidermal necrolysis"
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"abstract": "Diffuse panbronchiolitis (DPB) is a chronic diffuse airway inflammatory disease, which is strongly associated with the class I human leukocyte antigen (HLA) alleles. Here, we report a pair of sisters who have been suffering from chronic cough, expectoration and wheezing for many years. They were previously misdiagnosed as chronic bronchitis and bronchial asthma, and were recently diagnosed as diffuse panbronchiolitis. The 36-year-old elder sister suffered from diffuse panbronchiolitis complicated with pulmonary tuberculosis. The 30-year-old younger sister suffered from diffuse panbronchiolitis complicated with bronchial asthma and bronchiectasis. We have performed HLA genotyping research on the two sisters, their parents and younger brother. The results showed that all family members were positive for HLA-A24 and HLA-B13. The younger sister and mother were positive for HLA-A2. The younger brother and father were positive for HLA-A11. We suspect that the two sisters' disease susceptibility may be caused by their parents' consanguineous marriage. In this study, we reported the clinical characteristics of the two sisters with diffuse panbronchiolitis and shared the associated HLA genotyping results of this family cluster, hoping to provide reference for the etiology, diagnosis and treatment of this disease.",
"affiliations": "Department of Respiratory and Critical Care Medicine, 117913Affiliated Hospital of North Sichuan Medical College, Nanchong, China.;Department of Respiratory and Critical Care Medicine, 117913Affiliated Hospital of North Sichuan Medical College, Nanchong, China.;Department of Respiratory and Critical Care Medicine, 117913Affiliated Hospital of North Sichuan Medical College, Nanchong, China.;Department of Respiratory and Critical Care Medicine, 117913Affiliated Hospital of North Sichuan Medical College, Nanchong, China.;74655North Sichuan Medical College, Nanchong, China.;Department of Respiratory and Critical Care Medicine, 117913Affiliated Hospital of North Sichuan Medical College, Nanchong, China.",
"authors": "He|Fang|F|;Gong|Hai-Ying|HY|;Jiang|Guo-Lu|GL|;Chen|Xiao-Ju|XJ|;Yao|Qian-Jing|QJ|;Jiang|Li|L|0000-0003-0891-8775",
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"doi": "10.1177/1479973120961847",
"fulltext": "\n==== Front\nChron Respir Dis\nChron Respir Dis\nCRD\nspcrd\nChronic Respiratory Disease\n1479-9723 1479-9731 SAGE Publications Sage UK: London, England \n\n33063535\n10.1177/1479973120961847\n10.1177_1479973120961847\nCase Report\nDiffuse panbronchiolitis: A case report from a Chinese consanguineous marriage family and literature review\nHe Fang 12 Gong Hai-ying 12 Jiang Guo-lu 1 Chen Xiao-ju 1 Yao Qian-jing 2 https://orcid.org/0000-0003-0891-8775Jiang Li 12 \n1 Department of Respiratory and Critical Care Medicine, 117913Affiliated Hospital of North Sichuan Medical College, Nanchong, China\n\n2 74655North Sichuan Medical College, Nanchong, China\nLi Jiang, Department of Respiratory and Critical Care Medicine, Affiliated Hospital of North Sichuan Medical College, No. 63 Wenhua Road, Shunqing District, Nanchong, China. Email: lanqilily@163.com\n16 10 2020 \nJan-Dec 2020 \n17 147997312096184729 6 2020 26 8 2020 1 9 2020 © The Author(s) 20202020SAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons LicensesThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (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).Diffuse panbronchiolitis (DPB) is a chronic diffuse airway inflammatory disease, which is strongly associated with the class I human leukocyte antigen (HLA) alleles. Here, we report a pair of sisters who have been suffering from chronic cough, expectoration and wheezing for many years. They were previously misdiagnosed as chronic bronchitis and bronchial asthma, and were recently diagnosed as diffuse panbronchiolitis. The 36-year-old elder sister suffered from diffuse panbronchiolitis complicated with pulmonary tuberculosis. The 30-year-old younger sister suffered from diffuse panbronchiolitis complicated with bronchial asthma and bronchiectasis. We have performed HLA genotyping research on the two sisters, their parents and younger brother. The results showed that all family members were positive for HLA-A24 and HLA-B13. The younger sister and mother were positive for HLA-A2. The younger brother and father were positive for HLA-A11. We suspect that the two sisters’ disease susceptibility may be caused by their parents’ consanguineous marriage. In this study, we reported the clinical characteristics of the two sisters with diffuse panbronchiolitis and shared the associated HLA genotyping results of this family cluster, hoping to provide reference for the etiology, diagnosis and treatment of this disease.\n\nDiffuse panbronchiolitisDPBclinical characteristicsHLA genotypingconsanguineous marriageScience and Technology Project of Sichuan Province2018JY0416cover-dateJanuary-December 2020typesetterts3\n==== Body\nIntroduction\nDiffuse panbronchiolitis (DPB) is a distinctive chronic progressive pulmonary disease with unknown pathogenesis and characterized by chronic inflammation in respiratory bronchioles and sinobronchial infection.1 It is a rare complex genetic disease that mainly affects East Asians and is strongly associated with the class I human leukocyte antigen (HLA)-B54 in Japanese and HLA-A11 in Koreans.2 This uneven distribution is suspected to be highly associated with genetic predisposition located between HLA-A and HLA-B loci. More than 80% of the patients have chronic sinusitis, which usually precedes the lower respiratory tract symptoms by years.3 If left untreated, DPB will progress to bronchiectasis, respiratory failure, and eventually death.4 Here, we have reported a pair of sisters with diffuse panbronchiolitis and conducted HLA-A and HLA-B genotyping on them and their families. We hope that our cases report can provide reference for the diagnosis and treatment of this disease, and hope that our HLA high-resolution genotyping research will also be helpful to clarify its etiology and pathogenesis.\n\nMethods\nThe study was performed in Affiliated Hospital of North Sichuan Medical College. The written informed consent from all cases involved was obtained before enrollment. 5 ml of whole blood (EDTA anticoagulant) was collected from all cases. Genomic DNA from whole blood samples was used for next generation sequencing (NGS) HLA typing. DNA concentration greater than 50 ng/ul. The ratio of OD260/OD280 was between 1.7 and 1.9.\n\nThe NGSgo-AmpX kit was used to amplify the HLA-A and HLA-B loci. Amplicons were pooled and fragmented enzymatically using NGSgo-LibrX kit. Then “barcode” adapters were ligated on specimen with NGSgo-IndX kit, according to the NGSgo workflow. The pooled library was sequenced by a MiniSEQ instrument (Illumina), using paired-end sequencing. FASTQ files were assembled and analyzed with NGSengine (version 2.10, GenDx). The operation steps were carried out according to reagent instructions. Genomic DNA kit, NGSgo-AmpX kit, NGSgo-LibrX kit, and NGSgo-IndX kit were purchased from GenDx Company, USA.\n\nCase presentation\nCase 1\nA 36-year-old female patient was admitted to our hospital due to chronic cough, expectoration, chest tightness and wheezing. She is a never smoker. She had experienced chronic sinusitis since the age of 12 and started experiencing cough and purulent sputum at the age of 20. The symptoms progressively worsened, presenting with exertional dyspnea and constant wheezing. At the age of 25, the patient underwent “thoracotomy drainage and biopsy” in the local hospital due to “empyema and pleural effusion.” Physical examination on admission revealed diffuse expiratory wheezes and coarse crackles in both lungs. Pulmonary function test showed that the ratio of the forced expiratory volume in 1 second to the forced vital capacity (FEV1/FVC) was 43.39% (Table 1). Blood gas analysis showed hypoxemia with an oxygen partial pressure (PaO2) of 62 mmHg and oxygenation index of 155 mmHg. Chest high-resolution computed tomography (HRCT) scan showed well-defined multiple centrilobular nodules and diffuse tree-in-bud pattern (Figure 1A). No obvious abnormalities were found in routine blood tests, procalcitonin, sputum smear microscopy, sputum culture, tuberculosis bacili gamma interferon release test, rheumatoid factors, humoral immunity, connective tissue related antibodies, anti-neutrophil cytoplasmic antibody, etc. On the first admission, the patient’s symptoms improved after symptomatic treatment such as antitussive, expectorant and antiasthmatic treatment and discharged from the hospital automatically.\n\nTable 1. Pulmonary function results of the case 1 and case 2.\n\nCase NO.\tTime\tFEV1 (%Pre)\tFVC (%Pre)\tFEV1/FVC (%)\tFeNO\t\n1\tFirst admission\t0.61 L (23.5%)\t1.41 L (47.0%)\t43.39\tNA\t\n\t17 months later\t0.66 L (25.8%)\t1.35 L (45.3%)\t49.09\tNA\t\n\t26 months later\t0.59 L (22.3%)\t1.42 L (46.3%)\t41.49\tNA\t\n2\tFirst admission\t1.42 L (53.0%)\t2.60 L (84.0%)\t63.00\t13 ppb\t\n\t25 months later\t1.51 L (56.7%)\t2.76 L (89.6%)\t54.78\tNA\t\n%Pre, Percentage of reference value to predicted value. FeNO, fractional exhaled nitric oxide. NA, not available.\n\nFigure 1. Chest CT findings of the case 1. Chest CT showed bilateral diffuse small nodular shadows which presented with typical tree-in-bud pattern. Figure 1(A), 1(B), 1(C), 1(D), 1(E), 1(F) are the chest CT of the patient at the first diagnosis, 2 months, 4 months, 16 months, 18 months and 26 months later, respectively.\n\nHowever, the patient presented with the above symptoms repeatedly and was hospitalized in our hospital again after 1 month. On this admission, we performed further investigations on this patient. Paranasal sinus CT showed bilateral maxillary sinus inflammation (Figure 2A, 2B). Cold agglutinin level was in the normal range. A diagnosis of diffuse panbronchiolitis was made given the symptoms, signs, history of sinusitis, radiological, pulmonary function and laboratory findings. In this hospitalization, we treated the patient with azithromycin (500 mg per day), and the respiratory symptoms of the patient were obviously improved. However, dyspnea symptoms of the case 1 were not well controlled, so we treated the patient with prednisone acetate for 12 months. The dose was gradually reduced from 30 mg to 10 mg per day and finally stopped.\n\nFigure 2. Paranasal sinus CT findings of case 1 and case 2. Figure 2A and 2B are sinus CT of case 1. Figure 2C and 2D are sinus CT of case 2. Inflammatory lesion of maxillary sinus (red arrows). Inflammatory lesion of ethmoid sinus (blue arrow).\n\nSince then, the patient has been followed up at our hospital for 2 years, sometimes hospitalized for deterioration of her condition. Sixteen months after the definite diagnosis, the patient was hospitalized again in our hospital for cough, expectoration and dyspnea. Chest CT showed a small nodule at the upper tip of the right lung (Figure 3D). Sputum culture showed a small amount of Pseudomonas aeruginosa growth (++). Fiberoptic bronchoscopy revealed abundant purulent secretions in the left and right main bronchi and all levels of bronchi (Figure 4). Bronchoalveolar lavage fluid culture showed that Pseudomonas aeruginosa was 300 colony-forming units per milliliter (CFU/ml). The second bronchoscope lavage fluid smear revealed 1 root of acid-fast bacilli/300 visual field, and the culture showed a small amount of fusarium. Mycobacterium tuberculosis complex group DNA was positive. The patient was diagnosed as secondary pulmonary tuberculosis and received anti-tuberculosis treatment with isoniazid, rifapentine, ethambutol and moxifloxacin. Since then, the patient has received anti-tuberculosis treatment for up to 12 months. The patient’s condition gradually improved and the nodule in the right lung showed significant shrinkage (Figure 3E, 3F) after anti-tuberculosis treatment.\n\nFigure 3. Dynamic chest CT changes of pulmonary tuberculosis lesions in case 1. Figure 3(A), 3(B), 3(C), 3(D), 3(E), 3(F) are the chest CT of case 1 at the first diagnosis, 2 months, 4 months, 16 months, 18 months and 26 months later, respectively. Figure 3(D) shows the pulmonary tuberculosis lesion of the patient (green arrows).\n\nFigure 4. The bronchoscopy findings of case 1. There were abundant purulent secretions in the bronchi.\n\nCase 2\nThis patient is the younger sister of the above patient. She is a 30-year-old female who was admitted to our hospital due to persistent cough, expectoration, hemoptysis and dyspnea. The patient began to suffer from recurrent cough and hemoptysis at the age of 15. She started experiencing productive purulent sputum at the age of 20, and the amount of sputum increased year by year. The above-mentioned symptoms occurred repeatedly and progressively worsened, presenting with exertional dyspnea at the age of 24. Case 2 had recurrent episodes of wheezing, chest tightness and cough, especially after exposure to cold air, pungent odor and exercise. The wheezing sound can be heard in both lungs during an attack. Pulmonary function result from a local hospital showed an FEV1/FVC ratio of 63% and a positive bronchodilation test (FEV1 increased by ≥12% and ≥200 ml in absolute value after inhalation of β2 agonists such as salbutamol). In 2010, she was diagnosed with bronchiectasis and asthma in the local hospital. Treatment with budesonide and formoterol fumarate powder for inhalation (160 ug, twice a day) did not lead to any improvement, thus leading to admission to our hospital for further examination and treatment.\n\nLike her elder sister, she suffered from chronic sinusitis from childhood. Physical examination on admission revealed diffuse expiratory wheezes and coarse crackles in both lungs. Pulmonary function test showed that FEV1/FVC was 63.0% (Table 1). Blood gas analysis showed hypoxemia with PaO2 of 75 mmHg and oxygenation index of 187.5 mmHg. Chest CT showed bronchiectasis and diffuse small nodules in both lungs (Figure 5). Paranasal sinus CT showed bilateral maxillary sinusitis and ethmoid sinusitis (Figure 2C, 2D). Cold agglutinin level was in the normal range. Other relevant examinations such as routine blood tests, procalcitonin, sputum smear, sputum culture, bronchoscopy, tuberculosis screening, etc. showed no obvious abnormalities. In view of her symptoms, signs, history of sinusitis, chest imaging, pulmonary function and laboratory findings, we have confirmed her diagnosis of diffuse panbronchiolitis. We treated the case 2 with azithromycin (500 mg per day) and prednisone acetate (30 mg per day), and the respiratory symptoms of her were obviously improved. However, the case 2 developed diarrhea during the use of azithromycin and did not take macrolide drugs regularly, resulting in her repeated condition and difficulty in recovery.\n\nFigure 5. Chest CT findings of the case 2. Chest CT showed bilateral diffuse small nodular shadows and bronchiectasis. Figure 5(A, G), 5(B, H), 5(C, I), 5(D, J), 5(E, K), 5(F, L) are the chest CT of the patient at the first diagnosis, 1 months, 3 months, 8 months, 16 months and 25 months later, respectively.\n\nThe two sisters grew up in different living environments, but they had similar manifestations of diffuse panbronchiolitis. More importantly, we learned that their parents are cousins, and their disease susceptibility may be attributed to their parents’ consanguineous marriage. Therefore, we conducted HLA genotyping tests on the two sisters, their parents and brother. The results revealed that the case 1 and case 2 were negative for HLA-A11 and HLA-B54, but the father and younger brother were positive for HLA-A11 (Table 2). Therefore, we performed chest CT and sinus CT examination on the father and brother. The results showed no obvious abnormalities in their chest CT, but father’s sinus CT showed bilateral maxillary sinus inflammation (Figure 6B).\n\nTable 2. General characteristics and HLA genotyping results of the family.\n\nCase NO.\tGender\tAge\tFamily relationships\tHistory of sinusitis\tHLA-A*\tHLA-B*\t\n1\tF\t37\tElder sister\t25 years\t24:02:01\t13:01\t\n\t\t\t\t\t24:02:01\t40:01\t\n2\tF\t31\tYounger sister\t11 years\t02:07:01:01\t13:01:01:01\t\n\t\t\t\t\t24:02:01\t46:01:01:01\t\n3\tM\t29\tYounger brother\tNo\t11:01\t13:01\t\n\t\t\t\t\t24:02\t40:01\t\n4\tF\t66\tMother\tNo\t02:07\t13:01\t\n\t\t\t\t\t24:02\t46:01\t\n5\tM\t64\tFather\tNA\t11:01\t13:01\t\n\t\t\t\t\t24:02\t40:01\t\nNA, not available.\n\nFigure 6. Sinus CT of the younger brother (figure 6A) and the father (figure 6B). Inflammatory lesion of maxillary sinus (red arrows).\n\nDiscussion\nDPB is a progressive inflammatory airway disease characterized clinically by a chronic cough, sputum, exertional dyspnea and chronic sinusitis, radiologically by diffuse small nodules, and histologically by chronic inflammatory lesions around respiratory bronchioles. The current DPB diagnostic criteria still refers to the guidelines proposed by a working group of the Ministry of Health and Welfare of Japan.5 The diagnostic criteria are: (i) persistent cough, sputum and exertional dyspnea; (ii) a history of, or current chronic sinusitis; (iii) bilateral diffuse small nodular shadows on a plain chest X-ray or centrilobular micronodules on chest CT. (iv) coarse crackles; (v) FEV1/FVC <70% and PaO2 <80 mmHg; and (vi) titer of cold haemagglutinin ≥64. Definite cases should fulfill criteria 1, 2 and 3, and at least two of criteria 4, 5 and 6.\n\nHerein, we report two cases whose typical clinical manifestations and auxiliary examinations meet the above diagnostic criteria 1 to 5, but they are different in onset, clinical manifestations and disease progression. Below, we will summarize the similarities and differences of this two cases.\n\nThe case 1 (elder sister) had onset symptoms of chest tightness and wheezing. The dyspnea symptoms were earlier than those of cough and expectoration. Her sinusitis symptoms predate respiratory symptoms for about 8 years. Case 1 was characterized by recurrent respiratory tract infection in the early stage of the disease and infected with Pseudomonas aeruginosa and Mycobacterium tuberculosis infection in the late stage. The case 2 (younger sister) had onset symptoms of cough and hemoptysis. The symptoms of dyspnea were later than those of cough and expectoration. Her sinusitis symptoms were 5 years later than respiratory symptoms. Case 2 was characterized by paroxysmal wheezing. Before being admitted to our hospital, the case 2 received asthma medication for 8 years, but the symptom of paroxysmal wheezing were not well controlled.\n\nThere are many similarities in the clinical manifestations of the two cases. They all got sick from adolescence and suffered from chronic sinusitis for many years. They all had progressive aggravation of exertional dyspnea. Hypoxemia was found in the early stage of the disease, which was aggravated by repeated infections in the later stage. Before being diagnosed with DPB, case 1 had been misdiagnosed with chronic bronchitis for many years, while case 2 had been only diagnosed with bronchial asthma for many years. Because of misdiagnosis or missed diagnosis, they all missed the opportunity of early treatment, leading to further aggravation of their condition. They were all in the advanced stage of DPB at the time of diagnosis. They had diarrhea adverse reactions during azithromycin treatment and did not use macrolide antibiotics regularly for a long course.\n\nThey had similar clinical manifestations and were finally diagnosed as DPB despite living in different environments since childhood. Genetic factors may be the main influencing factors. We suspect that the disease susceptibility of the two sisters may be caused by their parents’ consanguineous marriage. At present, China lacks large-scale epidemiological data of DPB and its own diagnostic criteria, and the pathogenesis is still unclear. The influence of consanguineous marriage on this disease remains to be further studied.\n\nDPB is often complicated with Pseudomonas aeruginosa, Haemophilus influenzae, Klebsiella pneumoniae and other infections.1 Pseudomonas aeruginosa is a pathogen that can provoke an intense inflammatory response leading to persistent airway inflammation and airway structural damage.6,7 It was more frequently detected in DPB patients with bronchiectasis, which was partly responsible for the poor therapeutic outcomes. The case 1 was infected with Pseudomonas aeruginosa in the advanced stage of the disease. The patient’s pulmonary function was worse than before. It was considered that the chronic colonization of Pseudomonas aeruginosa is associated with a greater decline in pulmonary function, and more frequent deterioration, hospitalization as well as increased mortality rate.8 In addition, pulmonary dysfunction may be a natural consequence of long-term chronic airway inflammation and recurrent infectious episodes.9 The case 2 was complicated with bronchiectasis, but no P. aeruginosa infection has yet occurred. Further follow-up is required for the occurrence of P. aeruginosa infection in the following course of disease.\n\nSecondary tuberculosis infection in DPB patients is very rare. Case 1 developed tuberculosis infection after long-term corticosteroid use (12 months). We know that corticosteroid has anti-inflammatory and immunosuppressive effects in DPB treatment. Corticosteroid can quickly relieve the dyspnea symptoms and accelerate the absorption of chronic airway inflammation. It is mainly suitable for those who still have obvious dyspnea after treatment with macrolides, or patients with slow absorption of small pulmonary nodules. The treatment course of corticosteroids should be shorter than that of macrolides, which varies from person to person. However, long-term use of corticosteroids has a progressive destructive effect on human immune function, reducing the autoimmune defense mechanism and increasing the risk of various infectious diseases, especially tuberculosis infection.10 Long-term use of corticosteroids is likely to induce tuberculosis or lead to the deterioration of the original tuberculosis. Therefore, we should guard against the occurrence of pulmonary tuberculosis for DPB patients who use corticosteroids for a long time. Case 1 is currently in the advanced stage of the disease and has just finished anti-tuberculosis treatment. The prognosis of this patient needs further follow-up.\n\nDPB has a very well-established relationship with bronchiectasis. DPB can occur simultaneously with bronchiectasis or progress to bronchiectasis in its advanced stage. The coexistence of DPB and bronchiectasis has been assumed a more severe syndrome, which predicts a poor outcome of maintenance macrolide therapy and an increased exacerbation risk in DPB patients.9 In our case 2, the patient’s condition was repeated, persistent, and diarrhea adverse reaction occurred during azithromycin treatment. The poor prognosis may be associated with the coexistence of DPB and bronchiectasis.\n\nDPB and asthma are obstructive airway diseases, which are difficult to make a clear diagnosis when they co-exist. The cough, expectoration and chest imaging changes of the case 2 improved obviously after the treatment with DPB, but the paroxysmal wheezing symptom was not well controlled, and the symptom could be obviously relieved after using antispasmodic drug such as tiotropium bromide powder inhalant. And the patient had been diagnosed with bronchial asthma before the diagnosis of DPB. This is consistent with the diagnostic criteria of DPB combined with bronchial asthma (Table 3).\n\nTable 3. Diagnostic criteria of DPB complicated with bronchial asthma.\n\n1. Childhood onset\t\n2. Family history of asthma\t\n3. History of allergy or positive for allergens\t\n4. On the basis of shortness of breath after activity, there is paroxysmal wheezing different from DPB\t\n5. Cough, expectoration and imaging changes were obviously improved after DPB treatment, but the symptoms of paroxysmal wheezing were not well controlled, which could be obviously relieved by adding β2 receptor agonist.\t\nDefinite cases should fulfill criteria 4 and 5, and at least one of criteria 1, 2 and 3.\n\nDPB is a complex pulmonary disease that can be associated with many diseases, such as myasthenia gravis with thymoma,11 rheumatoid arthritis,12,13 lung cancer,14 IgA nephropathy,15 asthma16–18 etc. To date, one case report of DPB complicated with asthma and bronchiectasis in a 48-year-old Irish woman on PubMed,19 and one case report of DPB complicated with tuberculosis in a 12-year-old Chinese child on CNKI20 have been published. The co-existence of DPB and pulmonary tuberculosis, and the co-existence of DPB with both asthma and bronchiectasis are rare. However, the co-existence of DPB with either asthma or bronchiectasis has been reported relatively frequently. Similarly, there are few reports of DPB family clustering.21–24\n\n\nIn our report, the case 1 was complicated with tuberculosis and pseudomonas aeruginosa infection in the course of DPB, accompanied by respiratory failure. The case 2 suffered from DPB complicated with bronchial asthma and bronchiectasis. They were all in advanced stage of DPB and presented with poor therapeutic effects. The complexity of the disease contributed to their recurrent, persistent and difficult recovery. The two sisters was treated with azithromycin for 2 years but showed no signs of recovery. The duration of treatment remains unclear. Their prognosis needs further follow-up evaluation.\n\nDPB is strongly associated with an HLA class I gene. Studies have shown that DPB is closely related to HLA-A11 and HLA-B54.2 However, the two sisters with DPB were both negative for HLA-A11 and HLA-B54, but positive for HLA-A24 and HLA-B13. Interestingly, their father and younger brother were positive for HLA-A11, but there was no evidence of diffuse panbronchiolitis. Besides, the case 2 (the younger sister) and the mother were both positive for HLA-A2. It was reported that HLA-A2 may be a genetic factor contributing to the relatively low incidence of DPB in Chinese population and may be involved in the process of presentation and recognition.25,26 However, there was no significant difference in the expression of HLA-A2 between DPB population and non-DPB population in Japan and South Korea. In our report, DPB patient was positive for HLA-A2, while non-DPB patients were positive for HLA-A11, which is different from previous literature reports. Further studies are needed to confirm the results and to identify the action of the HLA-A2 and HLA-A11 allele in DPB patients at the nucleotide sequence level. There are few reports about HLA-A24, HLA-B13, HLA-B40 and HLA-B46 in diffuse panbronchiolitis,25 and due to the small number of cases, its pathogenesis mechanism in DPB was not elaborated. Future research needs to be further clarified.\n\nDPB was first detected and reported in Japan,1 and cases have been reported in South Korea, China, and other East Asian countries. Genetic predisposition to the disease has been assumed in Asians. To date, studies on DPB are mostly case reports, and the etiology and pathogenesis of DPB are still unclear. With the development of a series of molecular genes and immunological studies, it is generally considered that DPB is a disease involving a variety of factors, including genetic, immune abnormalities, environmental and infectious factors. Until the establishment of long-term macrolide therapy, the prognosis was generally poor.27 It is a treatable disease if detected early and treated correctly. Because it is responsive and reversible to long-term (at least 6 months) macrolide drug therapy, especially when administered early in the course. However, the clinical manifestations of DPB lack specificity, which is easy to be confused with chronic obstructive pulmonary disease, bronchial asthma, bronchiectasis, pulmonary tuberculosis and other chronic airway diseases. Most cases are misdiagnosed or missed and cannot be effectively treated for many years. It requires our clinicians to carefully assess the condition and make a differential diagnosis.\n\nDPB is not rare in China, but under-diagnosis seems likely. Due to the lack of large sample study on DPB, its etiology, pathological mechanism and treatment criteria are not clear. Clinicians generally lack understanding of DPB and reports on this disease are not enough. Therefore, it is necessary for researchers and clinicians to make unremitting study in the future to clarify the etiology and pathogenesis of DPB and formulate a scientific and reasonable diagnosis and treatment standard.\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) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was partly supported by operating research grants from the Science and Technology Project of Sichuan Province (grant no: 2018JY0416), Nanchong City-school Cooperation Project (grant no: 18SXHZ0470).\n\nORCID iD: Li Jiang \nhttps://orcid.org/0000-0003-0891-8775\n==== Refs\nReferences\n1 \nHomma H Yamanaka A Tanimoto S , et al.\nDiffuse panbronchiolitis: a disease of the transitional zone of the lung\n. Chest \n1983 ; 83 (1 ): 63 –69\n.6848335 \n2 \nChen Y Kang J Wu M , et al.\nDifferential association between HLA and diffuse panbronchiolitis in Northern and Southern Chinese\n. Intern Med \n2012 ; 51 (3 ): 271 –276\n.22293801 \n3 \nKudoh S Keicho N \nDiffuse panbronchiolitis\n. Clin Chest Med \n2012 ; 33 (2 ): 297 –305\n.22640847 \n4 \nPoletti V Chilosi M Casoni G , et al.\nDiffuse panbronchiolitis\n. Sarcoidosis Vasc Diffuse Lung Dis \n2004 ; 21 (2 ): 94 –104\n.15281430 \n5 \nNakata K \nDiffuse panbronchiolitis (DPB)\n. Ryoikibetsu Shokogun Shirizu \n1999 ; 23 (1 ): 423 –427\n.\n6 \nFaure E Kwong K Nguyen D \nPseudomonas aeruginosa in chronic lung infections: How to adapt within the host?\n\nFront Immunol \n2018 ; 9 : 2416 .30405616 \n7 \nFlume PA Chalmers JD Olivier KN \nAdvances in bronchiectasis: endotyping, genetics, microbiome, and disease heterogeneity\n. The Lancet \n2018 ; 392 (10150 ): 880 –890\n.\n8 \nFinch S McDonnell MJ Abo-Leyah H , et al.\nA comprehensive analysis of the impact of Pseudomonas aeruginosa colonization on prognosis in adult bronchiectasis\n. Ann Am Thorac Soc \n2015 ; 12 (11 ): 1602 –1611\n.26356317 \n9 \nXu B Mao Y Wan X , et al.\nPrognostic value of concomitant bronchiectasis in newly diagnosed diffuse panbronchiolitis patients on a maintenance therapy with macrolides\n. Can Respir J \n2019 ; 2019 : 4913814 .30984318 \n10 \nLai CC Lee MT Lee SH , et al.\nRisk of incident active tuberculosis and use of corticosteroids\n. Int J Tuberc Lung Dis \n2015 ; 19 (8 ): 936 –942\n.26162360 \n11 \nMaekawa R Shibuya H Hideyama T , et al.\nA case of myasthenia gravis with invasive thymoma associated with diffuse panbronchiolitis, alopecia, dysgeusia, cholangitis and myositis\n. Rinsho Shinkeigaku \n2014 ; 54 (9 ): 703 –708\n.25283823 \n12 \nSugiyama Y Ohno S Kano S , et al.\nDiffuse panbronchiolitis and rheumatoid arthritis: a possible correlation with HLA-B54\n. Intern Med \n1994 ; 33 (10 ): 612 –614\n.7827377 \n13 \nHomma S Kawabata M Kishi K , et al.\nDiffuse panbronchiolitis in rheumatoid arthritis\n. Eur Respir J \n1998 ; 12 (2 ): 444 –452\n.9727799 \n14 \nIshioka S Hiyama K Nishisaka T , et al.\nAn autopsy case of diffuse panbronchiolitis associated with lung cancer\n. Intern Med \n2000 ; 39 (5 ): 404 –406\n.10830183 \n15 \nTossier C Pilette C Guilleminault L , et al.\nDiffuse panbronchiolitis and IgA nephropathy\n. Am J Respir Crit Care Med \n2014 ; 189 (1 ): 106 –109\n.24381993 \n16 \nFujita S Suzuki R Sagara N , et al.\nThree cases of diffuse panbronchiolitis in children with a past history of difficult-to-treat bronchial asthma: a case report from a single medical facility\n. Allergol Int \n2020 ; 69 (3 ): 468 –470\n.\n17 \nPark KH Park HJ Lee JH , et al.\nSingle center experience of five diffuse panbronchiolitis patients clinically presenting as severe asthma\n. J Korean Med Sci \n2015 ; 30 (6 ): 823 –828\n.26028938 \n18 \nPark KH Lee JH Hong CS , et al.\nAsthma diagnosis and treatment—1014. Single center experience of 4 cases of diffuse panbronchiolitis clinically presented as treatment resistant asthma\n. World Allergy Organ J \n2013 ; 6 (Suppl 1 ): P14 .23819501 \n19 \nMcGrath EE McLaughlin AM Fitzgerald MX \nDiffuse panbronchiolitis: East meets West\n. Eur Respir J \n2007 ; 29 (4 ): 817 –818\n.17400883 \n20 \nChen WF Qu YE Lu WZ \nDiffuse panbronchiolitis complicated with pulmonary tuberculosis in a child: a case report\n. J Clin Pulm Med \n2012 ; 17 (12 ): 2323 –2324\n.\n21 \nDanbara T Matsuoka R Nukiwa T , et al.\nFamilial occurrence of diffuse panbronchiolitis accompanied with elevation of cold agglutinin titer in a father and his two daughters\n. Nihon Kyobu Shikkan Gakkai Zasshi \n1982 ; 20 (5 ): 597 –603\n.7131981 \n22 \nSuzuki M Usui K Tamura N , et al.\nFamilial cases of diffuse panbronchiolitis (Author’s Transl.)\n. Nihon Kyobu Shikkan Gakkai Zasshi \n1981 ; 19 (9 ): 645 –651\n.7328954 \n23 \nSugiyama Y Kitamura S \nChronic sinusitis among family members of patients with diffuse panbronchiolitis\n. Nihon Kyobu Shikkan Gakkai Zasshi \n1995 ; 33 (2 ): 140 –143\n.7731117 \n24 \nSugiyama Y Kudoh S Maeda H , et al.\nAnalysis of HLA antigens in patients with diffuse panbronchiolitis\n. Am Rev Respir Dis \n1990 ; 141 (6 ): 1459 –1462\n.2350086 \n25 \nShe J Sun Q Fan L , et al.\nAssociation of HLA genes with diffuse panbronchiolitis in Chinese patients\n. Respir Physiol Neurobiol \n2007 ; 157 (2–3 ): 366 –373\n.17350353 \n26 \nShen C She J \nHuman leukocyte antigen genes to genetic predisposition in diffuse panbronchiolitis\n. Zhonghua Jie He He Hu Xi Za Zhi \n2008 ; 31 (4 ): 272 –276\n.18846964 \n27 \nKudoh S Azuma A Yamamoto M , et al.\nImprovement of survival in patients with diffuse panbronchiolitis treated with low-dose erythromycin\n. Am J Respir Crit Care Med \n1998 ; 157 : 1829 –1832\n.9620913\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1479-9723",
"issue": "17()",
"journal": "Chronic respiratory disease",
"keywords": "DPB; Diffuse panbronchiolitis; HLA genotyping; clinical characteristics; consanguineous marriage",
"medline_ta": "Chron Respir Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D001988:Bronchiolitis; D002681:China; D003241:Consanguinity; D020022:Genetic Predisposition to Disease; D006192:Haemophilus Infections; D006801:Humans; D008297:Male",
"nlm_unique_id": "101197408",
"other_id": null,
"pages": "1479973120961847",
"pmc": null,
"pmid": "33063535",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "18846964;25283823;26028938;24381993;7731117;9727799;15281430;30215383;17400883;26162360;9620913;23819501;7131981;30405616;2350086;32217024;7328954;10088434;6848335;17350353;10830183;26356317;22293801;30984318;22640847;7827377",
"title": "Diffuse panbronchiolitis: A case report from a Chinese consanguineous marriage family and literature review.",
"title_normalized": "diffuse panbronchiolitis a case report from a chinese consanguineous marriage family and literature review"
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"abstract": "With post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis, nonmyeloablative (NMA) HLA-haploidentical (haplo) and HLA-matched blood or marrow transplantation (BMT) have comparable outcomes. Previous reports have shown that discontinuation of immunosuppression (IS) as early as day 60 after infusion of a bone marrow (BM) haplo allograft with PTCy is feasible. There are certain diseases in which peripheral blood (PB) may be favored over BM, but given the higher rates of GVHD with PB, excessive GVHD is of increased concern. We report a completed, prospective single-center trial of stopping IS at days 90 and 60 after NMA PB stem cell transplantation (PBSCT). Between 12/2015-7/2018, 117 consecutive patients with hematologic malignancies associated with higher rates of graft failure after NMA conditioned BMT and PTCy, received NMA PB allografts on trial. The primary objective of this study was to evaluate the safety and feasibility of reduced-duration IS (from day 5 through day 90 in the D90 cohort and through day 60 in the D60 cohort). Of the 117 patients (median age, 64 years; range, 22 to 78 years), the most common diagnoses were myelodysplastic syndrome (33%), acute myelogenous leukemia (with minimal residual disease or arising from an antecedent disorder) (32%), myeloproliferative neoplasms (19%), myeloma (9%), and chronic lymphoblastic leukemia (7%). Shortened IS was feasible in 75 patients (64%) overall. Ineligibility for shortened IS resulted most commonly from GVHD (17 patients), followed by early relapse (11 patients), nonrelapse mortality (NRM) (7 patients), patient/ physician preference (4 patients) or graft failure (3 patients). Of the 57 patients in the D90 cohort, 33 (58%) stopped IS early as planned, and among the 60 patients in the D60 cohort, 42 (70%) stopped IS early as planned. The graft failure rate was 2.6%. After IS cessation, the median time to diagnosis of grade II-IV acute GVHD was 21 days in the D90 cohort and 32 days in the D60 cohort, with almost all cases developing within 40 days. Approximately one-third of these patients resumed IS. All outcome measures were similar in the 2 cohorts and our historical outcomes with 180 days of IS. The cumulative incidence of grade III-IV acute GVHD was low, 2% in the D90 cohort and 7% in the D60 cohort. The incidence of severe chronic GVHD at 2 years was 9% in the D90 cohort and 5% in the D60 cohort. The 2-year overall survival was 67% for both the D90 and D60 cohorts. The 2-year progression-free survival was 47% for the D90 cohort and 52% for the D60 cohort, and the GVHD-free, relapse-free survival was <35% for both cohorts. These data suggest that reduced-duration IS in patients undergoing NMA PBSCT with PTCy is feasible and has an acceptable safety profile. © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.",
"affiliations": "Department of Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland; Division of Hematology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland; Division of Pediatric Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland. Electronic address: adezern1@jhmi.edu.;Division of Pediatric Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland; Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, Florida.;Department of Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland; Department of Oncology Biostatistics, Sidney Kimmel Cancer Center, Baltimore, Maryland; Division of Pediatric Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland.;Department of Oncology Biostatistics, Sidney Kimmel Cancer Center, Baltimore, Maryland; Division of Pediatric Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland.;Department of Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland; Division of Pediatric Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland.;Department of Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland; Division of Pediatric Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland.;Department of Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland; Division of Pediatric Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland.;Department of Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland; Division of Pediatric Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland.;Department of Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland; Division of Pediatric Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland.;Department of Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland; Division of Pediatric Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland.;Department of Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland; Division of Pediatric Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland.;Department of Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland; Division of Pediatric Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland.;Department of Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland; Division of Hematology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland; Division of Pediatric Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland.;Department of Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland; Division of Pediatric Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland.;Department of Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland; Division of Pediatric Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland.;Department of Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland; Division of Pediatric Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland.;Department of Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland; Division of Pediatric Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland.;Department of Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland; Division of Hematology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland; Division of Pediatric Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland.",
"authors": "DeZern|Amy E|AE|;Elmariah|Hany|H|;Zahurak|Marianna|M|;Rosner|Gary L|GL|;Gladstone|Douglas E|DE|;Ali|Syed Abbas|SA|;Huff|Carol Ann|CA|;Swinnen|Lode J|LJ|;Imus|Phil|P|;Borrello|Ivan|I|;Wagner-Johnston|Nina D|ND|;Ambinder|Richard F|RF|;Brodsky|Robert A|RA|;Cooke|Kenneth|K|;Luznik|Leo|L|;Fuchs|Ephraim J|EJ|;Bolaños-Meade|Javier|J|;Jones|Richard J|RJ|",
"chemical_list": "D003520:Cyclophosphamide",
"country": "United States",
"delete": false,
"doi": "10.1016/j.bbmt.2020.07.037",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-8791",
"issue": "26(11)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": "Cyclophosphamide; Disease Risk Index; Haploidentical; Nonmyeloablative; Peripheral blood",
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D016026:Bone Marrow Transplantation; D003520:Cyclophosphamide; D006086:Graft vs Host Disease; D006801:Humans; D008875:Middle Aged; D011446:Prospective Studies; D019172:Transplantation Conditioning",
"nlm_unique_id": "9600628",
"other_id": null,
"pages": "2075-2081",
"pmc": null,
"pmid": "32818556",
"pubdate": "2020-11",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": null,
"title": "Shortened-Duration Immunosuppressive Therapy after Nonmyeloablative, Related HLA-Haploidentical or Unrelated Peripheral Blood Grafts and Post-Transplantation Cyclophosphamide.",
"title_normalized": "shortened duration immunosuppressive therapy after nonmyeloablative related hla haploidentical or unrelated peripheral blood grafts and post transplantation cyclophosphamide"
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"activesubstancename": "FLUDARABINE PHOSPHATE"
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"abstract": "The prognosis of biliary tract cancer (BTC) is poor. Standard treatment for advanced BTC is a chemotherapy (CT) with gemcitabine and cisplatin. Phase III evidence for a second-line (2L) CT is lacking. We aimed to investigate the feasibility of a 2L CT, to estimate the outcome and to identify prognostic markers.\n\n\n\nPatients of our institution with advanced BTC between 2000 and 2015 receiving CT were included. Data were analysed in univariate and multivariate analysis.\n\n\n\nThree-hundred and fifteen and 144 patients (45.7%) received first-line (1L) and 2L CT respectively. The OS of patients receiving 2L CT was 16.67 and 9.9 months from the beginning of 1L and 2L CT respectively. The overall response rate and the disease control rate after 3 months were 9.7% and 33.6% respectively. Adverse events of grade 3 or more were observed in 26.1%. One patient died of gemcitabine-related haemolytic uraemic syndrome. Age of more than 70 years was not associated with a poor outcome. In multivariate analysis, CEA levels of >3 µg/L (P = 0.004, hazard ratio [HR] 1.89, 95% CI 1.22, 2.91), cholinesterase (CHE) levels of <5 kU/L (P = 0.001, HR 2.11, 95% CI 1.34, 3.31) and leukocytosis (P = 0.001, HR 2.90, 95% CI 1.51, 5.56) were associated with poor survival.\n\n\n\nDespite a relevant toxicity, our data suggest that 2L CT may be feasible in fit BTC patients. CEA elevation, leukocytosis and low CHE levels are unfavourable prognostic markers. Results from prospective randomized trials are urgently awaited.",
"affiliations": "Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.;Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.;Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.;Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.;Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.;Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.;Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.",
"authors": "Schweitzer|Nora|N|0000-0002-4687-3582;Kirstein|Martha M|MM|0000-0001-9415-4083;Kratzel|Anna-Maria|AM|;Mederacke|Young-Seon|YS|;Fischer|Mareike|M|;Manns|Michael P|MP|;Vogel|Arndt|A|",
"chemical_list": "D003841:Deoxycytidine; C056507:gemcitabine; D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": "10.1111/liv.14063",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1478-3223",
"issue": "39(5)",
"journal": "Liver international : official journal of the International Association for the Study of the Liver",
"keywords": "biliary tract cancer; chemotherapy; cholangiocarcinoma; second line",
"medline_ta": "Liver Int",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D001661:Biliary Tract Neoplasms; D018281:Cholangiocarcinoma; D002945:Cisplatin; D002986:Clinical Trials as Topic; D003841:Deoxycytidine; D005260:Female; D005706:Gallbladder Neoplasms; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011379:Prognosis; D011446:Prospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome",
"nlm_unique_id": "101160857",
"other_id": null,
"pages": "914-923",
"pmc": null,
"pmid": "30716200",
"pubdate": "2019-05",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Second-line chemotherapy in biliary tract cancer: Outcome and prognostic factors.",
"title_normalized": "second line chemotherapy in biliary tract cancer outcome and prognostic factors"
} | [
{
"companynumb": "DE-ROCHE-2335475",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": "3",
"dru... |
{
"abstract": "Postmortem blood samples may not accurately reflect antemortem drug concentrations, as the levels of some drugs increase due to postmortem redistribution (PMR). The brain has been suggested as an alternative sampling site. The anatomically secluded site of the brain limits redistribution and prolongs the detection window, thereby enabling sampling from deceased individuals where blood is no longer suitable for analysis. We report concentrations in brain tissue and blood from 91 cases for the four antidepressants citalopram, duloxetine, mirtazapine and sertraline. The cases were classified according to their role in the cause of death, as follows: (A) concentrations where the drug was the sole cause of fatal intoxication; (B) concentrations where the drug contributed to a fatal outcome; and (C) concentrations where the drug was not related to the cause of death. The analytical method was successfully validated in brain tissue in terms of linearity, process efficiency, precision and accuracy. Quantification of analytes was performed by ultra-performance liquid chromatography with tandem mass spectrometry. Correlations between blood and brain concentrations were achieved with R2-values between 0.67 and 0.91. The following median brain-blood ratios were obtained: 3.71 for citalopram (range: 1.4-5.9), 11.0 for duloxetine (range: 5.0-21.6), 1.53 for mirtazapine (range: 1.02-4.71) and 7.38 for sertraline (range: 3.2-14.2). The S/R ratio of racemic citalopram was the same in brain (0.80) and blood (0.85), whereas the median citalopram/N-desmethylcitalopram ratio was higher in brain (9.1) than blood (4.1). The results of this study may serve as reference concentrations in brain for forensic cases.",
"affiliations": "Department of Forensic Medicine, University of Copenhagen, Frederik V's vej 11, 3. Floor, 2100 Copenhagen Ø, Denmark.;Department of Forensic Medicine, University of Copenhagen, Frederik V's vej 11, 3. Floor, 2100 Copenhagen Ø, Denmark.;Department of Forensic Medicine, University of Copenhagen, Frederik V's vej 11, 3. Floor, 2100 Copenhagen Ø, Denmark.",
"authors": "Nedahl|Michael|M|;Johansen|Sys Stybe|SS|;Linnet|Kristian|K|",
"chemical_list": "D000928:Antidepressive Agents; D015283:Citalopram; D008803:Mianserin; D000068736:Duloxetine Hydrochloride; D000078785:Mirtazapine; D020280:Sertraline",
"country": "England",
"delete": false,
"doi": "10.1093/jat/bkx098",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0146-4760",
"issue": "42(3)",
"journal": "Journal of analytical toxicology",
"keywords": null,
"medline_ta": "J Anal Toxicol",
"mesh_terms": "D000928:Antidepressive Agents; D001921:Brain; D002138:Calibration; D002423:Cause of Death; D002853:Chromatography, Liquid; D015283:Citalopram; D062787:Drug Overdose; D000068736:Duloxetine Hydrochloride; D053593:Forensic Toxicology; D006801:Humans; D016014:Linear Models; D008803:Mianserin; D000078785:Mirtazapine; D012015:Reference Standards; D015203:Reproducibility of Results; D020280:Sertraline; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry",
"nlm_unique_id": "7705085",
"other_id": null,
"pages": "149-156",
"pmc": null,
"pmid": "29244076",
"pubdate": "2018-04-01",
"publication_types": "D016428:Journal Article; D023361:Validation Study",
"references": null,
"title": "Reference Brain/Blood Concentrations of Citalopram, Duloxetine, Mirtazapine and Sertraline.",
"title_normalized": "reference brain blood concentrations of citalopram duloxetine mirtazapine and sertraline"
} | [
{
"companynumb": "US-CIPLA (EU) LIMITED-2018US10673",
"fulfillexpeditecriteria": "1",
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SERTRALINE HYDROCHLORIDE"
},
"drugadd... |
{
"abstract": "Raynaud's phenomenon is a recurrent vasospastic condition with reducing in peripheral blood flow due to cold, or emotional stress. White, blue and red discolorations occur during the attacks. Serotonin reuptake inhibitors, psychostimulants, and aripiprazole are reported to be related with Raynaud's phenomenon. Risperidone is an atypical antipsychotic drug with dopaminergic and serotonergic effects. In children and adolescents, risperidone is used for bipolar disorder, tic disorders, conduct disorder, schizophrenia, symptoms of irritability and self-mutilation. Here we report a case of Raynaud's phenomenon associated with risperidone in a 12-year-old boy. Raynaud's phenomenon occurred two weeks after starting risperidone and disappeared after stopping risperidone.",
"affiliations": "Department of Child and Adolescent Psychiatry, Hatay State Hospital, Hatay, Turkey.;Department of Child and Adolescent Psychiatry, Mersin University School of Medicine, Mersin, Turkey.;Department of Child and Adolescent Psychiatry, Mersin University School of Medicine, Mersin, Turkey.;Department of Child and Adolescent Psychiatry, Mersin University School of Medicine, Mersin, Turkey.",
"authors": "Güneş|Serkan|S|;Ekinci|Özalp|Ö|;Teke|Halenur|H|;Yıldırım|Veli|V|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.9758/cpn.2018.16.1.118",
"fulltext": "\n==== Front\nClin Psychopharmacol NeurosciClin Psychopharmacol NeurosciClinical Psychopharmacology and Neuroscience1738-10882093-4327Korean College of Neuropsychopharmacology 2939767510.9758/cpn.2018.16.1.118cpn-16-118Case ReportRisperidone Related Raynaud’s Phenomenon: An Adolescent Case Güneş Serkan 1Ekinci Özalp 2Teke Halenur 2Yıldırım Veli 2\n1 Department of Child and Adolescent Psychiatry, Hatay State Hospital, Hatay, \nTurkey\n2 Department of Child and Adolescent Psychiatry, Mersin University School of Medicine, Mersin, \nTurkeyAddress for correspondence: Serkan Güneş, MD, Department of Child and Adolescent Psychiatry, Hatay State, Hospital, Hatay, Turkey, Tel: +90-5542587368, Fax: +90-3262272440, E-mail: dr_sgunes@hotmail.com2 2018 28 2 2018 16 1 118 121 18 4 2016 14 5 2016 15 6 2016 Copyright © 2018, Korean College of Neuropsychopharmacology2018This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Raynaud’s phenomenon is a recurrent vasospastic condition with reducing in peripheral blood flow due to cold, or emotional stress. White, blue and red discolorations occur during the attacks. Serotonin reuptake inhibitors, psychostimulants, and aripiprazole are reported to be related with Raynaud’s phenomenon. Risperidone is an atypical antipsychotic drug with dopaminergic and serotonergic effects. In children and adolescents, risperidone is used for bipolar disorder, tic disorders, conduct disorder, schizophrenia, symptoms of irritability and self-mutilation. Here we report a case of Raynaud’s phenomenon associated with risperidone in a 12-year-old boy. Raynaud’s phenomenon occurred two weeks after starting risperidone and disappeared after stopping risperidone.\n\nRaynaud’s phenomenonRisperidoneAdolescentChildCase report\n==== Body\nINTRODUCTION\nRisperidone is an atypical antipsychotic drug that combines dopamine D2 and serotonin 5HT2 receptor antagonism.1) It is a widely prescribed agent effective in bipolar disorder, tic disorders, schizophrenia, conduct disorder, irritability, self-mutilation, and behavioral problems due to autism spectrum disorder or mental retardation.2) In children and adolescents, many studies have shown the effectiveness of risperidone in treating disruptive and aggressive behaviors.3) Sedation, weight gain, hyperprolactinemia, parkinsonism, akathisia, dyskinesia, and dystonia are side effects that occur during risperidone use.1) Vascular side effects such as orthostatic hypotension can also be seen with risperidone.4)\n\nRaynaud’s phenomenon (RP) is a common vascular disease, characterized by white, blue, or red discoloration of effected body part due to cold, or emotional stress. The extremities are usually affected bilaterally when exposed to triggers. Whereas the pathophysiological mechanisms of RP are unclear, investigators have indicated that the phenomenon is caused by vasoconstriction, increased blood viscosity, and disturbance in microcirculation.5) Several drugs including beta blockers, ergot alkaloids, selective serotonin reuptake inhibitors, psychostimulants, atomoxetine, and aripiprazole have been reported to induce RP.6–11)\n\nHereby, we report the emergence of RP with risperidone use in a 12-year-old boy. Informed consent was taken from the patient’s parents for publication of this case report.\n\nCASE\nA 12-year-old boy was evaluated in child and adolescent psychiatry clinic for irritability and aggression. He had been a hyperactive and irritable boy since early childhood. He exhibited aggressive behaviors such as property damage, setting fire, and fighting with friends. No problem with attention in classroom was evident, however he was reported not to study enough, therefore his academic performance was not good. His mental examination revealed normal perception, orientation, and memory functions. His affect was dysphoric, anxious, and irritable. There was no substance and another drug use, physical illness, drug allergy, trauma, or family history of RP.\n\nThe patient was diagnosed with conduct disorder according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-V), and risperidone 1 mg/day was initiated gradually for behavioral problems and impulse control. Two weeks after starting risperidone, the patient communicated with our clinic, he was describing cyanosis following pallor in his right and left fingers. During the clinical evaluation, we observed cyanosis in his right and left hands that was limited to the fingers (Fig. 1). His fingers were cold with palpation, we didn’t observe necrosis, ulceration and the patient didn’t describe pain. The patient was consulted to the general pediatrician and dermatologist for further evaluation. Neurological and rheumatological examinations were normal, and the dermatologist evaluated the patient’s symptoms as RP. To examine RP etiology, common blood and urine count, routine biochemical tests, thyroid function tests, coagulation factors, sedimentation, CRP, rheumatoid factor, and antinuclear anticores were tested and all of them were normal. Risperidone dose was reduced to 0.5 mg/day, but the patient’s RP symptoms continued. So, we stopped risperidone therapy and suggested a periodic follow-up. One month after stopping risperidone, the patient didn’t experience any pallor, or cyanosis in fingers and we started aripiprazole 5 mg/day for behavioral problems. Six months later, the patient reported that he was free of RP symptoms.\n\nIn this case, we excluded other seconder causes of RP with anamnesis, physical examination, and laboratory tests. Risperidone therapy was the only potential cause for RP. Therefore, we accepted the patient as a RP secondary to risperidone.\n\nDISCUSSION\nRP is defined as periodical vasospasms of peripheral vessels. It usually occurs with episodic and tri-phasic discoloration white, blue-purple, or red respectively. White discoloration represents ischemia, blue or purple discoloration shows deoxygenation, and red discoloration is a sign of reperfusion. Although our patient didn’t describe any pain or paresthesia, in some cases, pain or paresthesia may accompany discoloration.5)\n\nPrevalence of RP is known to be between 1–20% and it is common in young females. Other risk factors can be sorted as; family history, migraine, cardiovascular diseases, estrogen treatment, smoking, alcohol, and low body mass index. However our case didn’t represent these risk factors. On the contrary, our case was a medically healthy male, was not smoking or drinking alcohol, and had no family history of RP.12)\n\nRP is classified as primary and secondary. Primary RP, in other terms Raynaud’s Disease or idiopathic RP, is the term to define the absence of any etiological cause. Secondary RP is known as Raynaud’s syndrome, and this term is used to define an underlying pathology that causes RP.5) The most common cause of secondary RP is connective tissue diseases. In addition, trauma, hematological, neurological or arterial diseases, toxins, and drugs may also cause seconder RP.11) Several psychotropic drugs inluding fluoxetine, citalopram, aripiprazole, atomoxetine, methylphenidate, and dextroamphetamine have been reported to cause secondary RP.7–10,13)\n\nAlthough pathophysiology of RP isn’t clearly understood, vasospasm of digital arterioles is thought to be a potential mechanism. Endothelial damage and following perivascular changes could be resulting with arteriolar spasm. Spasm of arterioles as a response to alpha-beta adrenergic and serotonergic receptors is the other potential mechanism.5) Consistent with these mechanisms, there are case reports of RP due to serotonergic drugs.7,8) Rudnick et al.7) reported a 54-year-old woman who developed RP after increasing fluoxetine dose and the patient recovered five days after switching back to the previous dose. Another case of RP reported due to initiating citalopram in a 43-year-old women and the patient recovered a month after discontinuation.8) On the other hand, there are several reports that selective serotonin reuptake inhibitors could be used in the treatment of RP.14,15) Bolte and Avery15) reported complete remission of RP in a 31-year-old nondepressed woman treated with fluoxetine. In addition, Skop and Brown16) reported that peripheral serotonin causes vasodilation in a healthy vascular bed, and vasoconstriction in damaged endothelium. So, it can be considered that the peripheral vascular effects of serotonin are complex, and this discrepancy may be related to endothelial damage. In another case presentation, Camkurt et al.9) reported a case of RP with aripiprazole which is an atypical antipsychotic with a partial agonism for D2 and 5HT1a receptors, and an antagonism for 5HT2a. In this paper, it was suggested that RP could be associated with dopaminergic agonism or serotonergic effects of aripiprazole. In our case, risperidone, which has a 5HT2 receptor antagonism, might cause RP symptoms through the serotonin receptors.\n\nGökçen et al.13) reported a dose-dependent RP developing from use of atomoxetine, which is a presynaptic norepinephrine transportation inhibitor. In this case report, it was suggested that atomoxetine might increase levels of norepinephrine in peripheral and central synapses, stimulate peripheral α1 and α2 receptors, and lead to prolonged vasoconstriction. In addition, Syed and Moore10) reported four RP case due to methylphenidate and dextroamphetamine that have noradrenergic and dopaminergic effects. It is known that risperidone has a high affinity to α1-adrenergic receptors, and it may increase the plasma norepinephrine levels and sympathetic activity.4) In this context, these mechanisms could also be a potential cause of RP in our case. Furthermore, a study suggests that risperidone worsens vascular endothelial function in diabetic rats, which may be mediated by upregulation of VCAM-1, ICAM-1, and E-selectin.17) Endothelial dysfunction and upregulation of the adhesion molecules might be another mechanism that induced RP in our case.\n\nAs far as we know, this is the first case of RP reported in the literature to occur because of risperidone use. We hope this paper will be a warning for clinicians who follow up the patients using risperidone. In addition, further investigations are needed to clarify the characteristics, risk factors, dose dependence, and potential mechanisms of risperidone-related RP.\n\nAcknowledgments\nThis article was conducted at the Mersin University School of Medicine.\n\nFig. 1 Cyanosis in the patient’s right and left fingers.\n==== Refs\nREFERENCES\n1 Conley RR Risperidone side effects J Clin Psychiatry 2000 61 Suppl 8 20 23 discussion 24–25 10811239 \n2 Güneş S Ekinci Ö Direk MÇ Yıldırım V Okuyaz Ç Toros F Risperidone induced Pisa syndrome in a male adolescent Clin Psychopharmacol Neurosci 2016 14 104 106 10.9758/cpn.2016.14.1.104 26792048 \n3 Hosseini SH Ahmadi A Peripheral edema occurring during treatment with risperidone combined with citalopram Case Rep Med 2012 2012 540732 10.1155/2012/540732 23251178 \n4 Leung JY Barr AM Procyshyn RM Honer WG Pang CC Cardiovascular side-effects of antipsychotic drugs: the role of the autonomic nervous system Pharmacol Ther 2012 135 113 122 10.1016/j.pharmthera.2012.04.003 22565090 \n5 O'connor CM Raynaud's phenomenon J Vasc Nurs 2001 19 87 92 10.1067/mvn.2001.117786 11533581 \n6 Zenone T Durieu I Nagnoug F Castell P Levrat R Raynaud phenomenon with organic microangiopathy and prolonged treatment with bromocriptine Rev Med Interne 1996 17 948 950 10.1016/0248-8663(96)88128-8 8977979 \n7 Rudnick A Modai I Zelikovski A Fluoxetine-induced Raynaud's phenomenon Biol Psychiatry 1997 41 1218 1221 10.1016/S0006-3223(97)00188-1 9171912 \n8 Peiró AM Margarit C Torra M Citalopram-induced Raynaud's phenomenon Rheumatol Int 2007 27 599 601 10.1007/s00296-006-0254-9 17103176 \n9 Camkurt MA Gunes S Tecimer E Aripiprazole-induced Raynaud's phenomenon: An adolescent case J Child Adolesc Psychopharmacol 2016 26 953 954 10.1089/cap.2015.0153 26784283 \n10 Syed RH Moore TL Methylphenidate and dextroamphetamineinduced peripheral vasculopathy J Clin Rheumatol 2008 14 30 33 10.1097/RHU.0b013e3181639aaa 18431096 \n11 Ratchford EV Evans NS Raynaud's phenomenon Vasc Med 2015 20 269 271 10.1177/1358863X15579122 25878215 \n12 Garner R Kumari R Lanyon P Doherty M Zhang W Prevalence, risk factors and associations of primary Raynaud's phenomenon: systematic review and meta-analysis of observational studies BMJ Open 2015 5 e006389 10.1136/bmjopen-2014-006389 25776043 \n13 Gökçen C Kutuk MO Coşkun Ş Dose-dependent Raynaud's phenomenon developing from use of atomoxetine in a girl J Child Adolesc Psychopharmacol 2013 23 428 430 10.1089/cap.2012.0131 23952193 \n14 Coleiro B Marshall SE Denton CP Howell K Blann A Welsh KI Treatment of Raynaud's phenomenon with the selective serotonin reuptake inhibitor fluoxetine Rheumatology (Oxford) 2001 40 1038 1043 10.1093/rheumatology/40.9.1038 11561116 \n15 Bolte MA Avery D Case of fluoxetine-induced remission of Raynaud's phenomenon--a case report Angiology 1993 44 161 163 10.1177/000331979304400213 8434812 \n16 Skop BP Brown TM Potential vascular and bleeding complications of treatment with selective serotonin reuptake inhibitors Psychosomatics 1996 37 12 16 10.1016/S0033-3182(96)71592-X 8600488 \n17 Aboul-Fotouh S Elgayar N Atypical antipsychotics such as risperidone, but not paliperidone, worsen vascular endothelial function via upregulation of adhesion molecules VCAM-1, ICAM-1, and E-selectin in diabetic rats Can J Physiol Pharmacol 2013 91 1119 1126 10.1139/cjpp-2013-0185 24289084\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1738-1088",
"issue": "16(1)",
"journal": "Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology",
"keywords": "Adolescent; Case report; Child; Raynaud's phenomenon; Risperidone",
"medline_ta": "Clin Psychopharmacol Neurosci",
"mesh_terms": null,
"nlm_unique_id": "101207332",
"other_id": null,
"pages": "118-121",
"pmc": null,
"pmid": "29397675",
"pubdate": "2018-02-28",
"publication_types": "D002363:Case Reports",
"references": "25776043;9171912;18431096;26784283;17103176;11561116;23952193;8977979;8434812;26792048;8600488;25878215;11533581;22565090;23251178;24289084;10811239",
"title": "Risperidone Related Raynaud's Phenomenon: An Adolescent Case.",
"title_normalized": "risperidone related raynaud s phenomenon an adolescent case"
} | [
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"companynumb": "TR-CIPLA LTD.-2018TR11984",
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"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nStaphylococcus lugdunensis (S. lugdunensis) is a coagulase-negative, Gram-positive bacterium that can be isolated as a component of normal skin flora in humans. However, more recently, it has also been documented as a culprit in skin and soft tissue infections. We describe the clinical features of five individuals with S. lugdunensis-associated skin infections. We review the characteristics of other patients that were previously described with this organism as the causative agent of skin infection.\n\n\nMETHODS\nStaphylococcus lugdunensis was correlated with the development of significant skin and soft tissue infections in five patients. The Pubmed database was used to search for the following terms: \"abscess,\" \"cellulitis,\" \"cutaneous,\" \"lugdunensis,\" \"paronychia,\" \"skin,\" \"soft,\" \"staphylococcus,\" and \"tissue.\" The relevant and reference papers generated by the search were reviewed.\n\n\nRESULTS\nOne woman and four men developed S. lugdunensis-related skin infections from February 19, 2015 to May 30, 2017. The patients' ages at the onset of the infection ranged from 30 to 82 years; the median age was 70 years. Four patients were older than 65 years. The back was the most common location for the infection, followed by digits. The infection presented as cystic lesions with cellulitis or periungual abscesses. The lesions were incised or spontaneously ruptured. Patients were empirically treated with oral antibiotics; if necessary, the management was adjusted based on the culture-derived sensitivities of the organisms. The infections resolved within 10-30 days after commencing treatment.\n\n\nCONCLUSIONS\nStaphylococcus lugdunensis has previously been considered as a nonpathogenic organism and to be a component of normal skin flora. However, S. lugdunensis can result in significant skin and soft tissue infections, perhaps more frequently in older individuals. Its antibiotic sensitivities appear to be similar to those of methicillin-susceptible Staphylococcus aureus.",
"affiliations": "John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA. manica@hawaii.edu.;Department of Dermatology, University of California San Diego, La Jolla, CA, USA. mitehead@gmail.com.",
"authors": "Heldt Manica|Lucas A|LA|;Cohen|Philip R|PR|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1007/s13555-017-0202-5",
"fulltext": "\n==== Front\nDermatol Ther (Heidelb)\nDermatol Ther (Heidelb)\nDermatology and Therapy\n2193-8210\n2190-9172\nSpringer Healthcare Cheshire\n\n29022273\n202\n10.1007/s13555-017-0202-5\nCase Report\nStaphylococcus lugdunensis Infections of the Skin and Soft Tissue: A Case Series and Review\nHeldt Manica Lucas A. manica@hawaii.edu\n\n1\nCohen Philip R. mitehead@gmail.com\n\n2\n1 0000 0001 2188 0957 grid.410445.0 John A. Burns School of Medicine, University of Hawaii, Honolulu, HI USA\n2 0000 0001 2107 4242 grid.266100.3 Department of Dermatology, University of California San Diego, La Jolla, CA USA\n11 10 2017\n11 10 2017\n12 2017\n7 4 555562\n1 8 2017\n© The Author(s) 2017\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial 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.\nIntroduction\n\nStaphylococcus lugdunensis (S. lugdunensis) is a coagulase-negative, Gram-positive bacterium that can be isolated as a component of normal skin flora in humans. However, more recently, it has also been documented as a culprit in skin and soft tissue infections. We describe the clinical features of five individuals with S. lugdunensis-associated skin infections. We review the characteristics of other patients that were previously described with this organism as the causative agent of skin infection.\n\nMethods\n\nStaphylococcus lugdunensis was correlated with the development of significant skin and soft tissue infections in five patients. The Pubmed database was used to search for the following terms: “abscess,” “cellulitis,” “cutaneous,” “lugdunensis,” “paronychia,” “skin,” “soft,” “staphylococcus,” and “tissue.” The relevant and reference papers generated by the search were reviewed.\n\nResults\n\nOne woman and four men developed S. lugdunensis-related skin infections from February 19, 2015 to May 30, 2017. The patients’ ages at the onset of the infection ranged from 30 to 82 years; the median age was 70 years. Four patients were older than 65 years. The back was the most common location for the infection, followed by digits. The infection presented as cystic lesions with cellulitis or periungual abscesses. The lesions were incised or spontaneously ruptured. Patients were empirically treated with oral antibiotics; if necessary, the management was adjusted based on the culture-derived sensitivities of the organisms. The infections resolved within 10–30 days after commencing treatment.\n\nConclusion\n\nStaphylococcus lugdunensis has previously been considered as a nonpathogenic organism and to be a component of normal skin flora. However, S. lugdunensis can result in significant skin and soft tissue infections, perhaps more frequently in older individuals. Its antibiotic sensitivities appear to be similar to those of methicillin-susceptible Staphylococcus aureus.\n\nKeywords\n\nAbscess\nCellulitis\nCutaneous\nLugdunensis\nParonychia\nSkin\nSoft\nStaphylococcus\nTissue\nissue-copyright-statement© Springer Healthcare Ltd., part of Springer Nature 2017\n==== Body\nIntroduction\n\nStaphylococcus lugdunensis (S. lugdunensis) is a coagulase-negative staphylococcus organism. It is typically considered to be a component of the normal flora of the skin. However, more recently, it has also been identified as a pathogen in a variety of infections, particularly in skin and soft tissue [1]. We describe five patients who developed significant skin and soft tissue infections due to S. lugdunensis and review their clinical features and treatments.\n\nCase Series\n\nCase 1\n\nA 70-year-old woman presented for evaluation of a tender lesion on her left lower back in April 2017 (Fig. 1). There was no fever or associated systemic symptoms. Her past medical history was significant for basal cell carcinoma, melanoma in situ, and seronegative rheumatoid arthritis. She was currently being treated with methotrexate.Fig. 1 Distant view of Staphylococcus lugdunensis skin and soft tissue infection presenting as a tender cystic lesion with surrounding cellulitis on the left lower back of a 70-year-old woman\n\nNine days prior to presentation, she was at the beach and felt her back being bitten by an insect. The affected area became red and painful and increased in size over the next few days.\n\nCutaneous examination showed an erythematous patch—the presumed bite site—with an underlying cystic component on the left lower back (Fig. 2). A small amount of pus was expressed from the lesion and cultured. The bacterial culture grew S. lugdunensis (Table 1) and antibiotic susceptibility testing was performed (Table 2).Fig. 2 Closer view of Staphylococcus lugdunensis cutaneous infection of the back of a 70-year-old woman; the infection occurred at a presumed bite site\n\nTable 1 Characteristics of patients with S. lugdunensis infections\n\nCase\tAge\nSex\tLocation\tMorphologya\tBacterial culture\tTreatment\t\n1\t70 years\n\nW\n\n\tLeft lower back\tInflamed cyst\tS. lugdunensis\t1—Cephalexin 500 mg QID for 10 days, then\n\n2—Five days later, doxycycline 100 mg BID for 10 days was added to the antibiotic regimen\n\n\t\n2\t30 years\n\nM\n\n\tRight great toe nail fold\tAbscess\t1—S. lugdunensis\n\n2—S. aureus\n\n3—S. agalactiae\n\n\tCephalexin 500 mg QID for 30 days\t\n3\t67 years\n\nM\n\n\tLeft upper back\tInflamed cyst\tS. lugdunensis\t1—Cefdinir 300 mg BID for 1 day, then\n\n2—Doxycycline 100 mg BID for 10 days\n\n\t\n4\t80 years\n\nM\n\n\tRight index finger nail fold\tAbscess\t1—S. lugdunensis\n\n2—S. intermedius\n\n\t1—Cephalexin 500 mg QID for 10 days concurrent with\n\n2—Sulfamethoxazole-trimethoprim 800–160 mg BID for 10 days\n\n\t\n5\t82 years\n\nM\n\n\tLeft lower back\tInflamed cyst\tS. lugdunensis\t1—Cephalexin 500 mg QID daily for 30 days\t\nBID, twice daily; M, man; mg, milligrams; QID, four times daily; S. aureus, Staphylococcus aureus; S. lugdunensis, Staphylococcus lugdunensis; S. agalactiae, Streptococcus agalactiae; S. intermedius, Streptococcus intermedius; W, woman\n\naAll of the sites of infection clinically presented as cellulitis. Some had an underlying infected cystic lesion, whereas others had an abscess of the nail fold\n\nTable 2 Susceptibility results from bacterial cultures of patients with S. lugdunensis cutaneous infection\n\nAntibiotic\tCase 1\tCase 2\tCase 3\tCase 4\tCase 5\t\nCefazolin\tSusceptible\tSusceptible\tSusceptible\tSusceptible\tSusceptible\t\nClindamycin\tSusceptible\tNot tested\tNot tested\tNot tested\tNot tested\t\nDaptomycin\tSusceptible\tSusceptible\tSusceptible\tSusceptible\tSusceptible\t\nErythromycin\tSusceptible\tNot tested\tNot tested\tNot tested\tNot tested\t\nGentamicin\tSusceptible\tNot tested\tNot tested\tNot tested\tNot tested\t\nLinezolid\tSusceptible\tSusceptible\tSusceptible\tSusceptible\tSusceptible\t\nMinocycline\tSusceptible\tNot tested\tNot tested\tNot tested\tNot tested\t\nMoxifloxacin\tSusceptible\tNot tested\tNot tested\tNot tested\tNot tested\t\nOxacillin\tSusceptible\tSusceptible\tSusceptible\tSusceptible\tSusceptible\t\nPenicillin G\tResistant\tResistant\tResistant\tResistant\tNot tested\t\nRifampin\tSusceptible\tSusceptible\tSusceptible\tSusceptible\tSusceptible\t\nTetracycline\tSusceptible\tSusceptible\tSusceptible\tSusceptible\tSusceptible\t\nTrimethoprim/sulfamethoxazole\tSusceptible\tNot tested\tNot tested\tNot tested\tNot tested\t\nVancomycin\tSusceptible\tSusceptible\tSusceptible\tSusceptible\tSusceptible\t\nS. lugdunensis, Staphylococcus lugdunensis\n\nShe was treated with incision and drainage; empiric treatment with cephalexin 500 mg, four times daily for 10 days, was also initiated. A wound check performed 5 days later did not show any significant improvement. Therefore, doxycycline 100 mg, twice daily for 10 days, was added. The infection resolved during the subsequent 3 weeks. There was no recurrence of the infection within 60 days following treatment.\n\nCase 2\n\nA 30-year-old man presented for evaluation of a tender lesion on his right great toe in September 2015. There was no fever or associated systemic symptoms. His past medical history was significant for psoriasis and psoriatic arthritis. He was currently being treated with adalimumab and methotrexate.\n\nCutaneous examination showed erythema of the medial right great toe nail fold with an underlying abscess. A small amount of pus was expressed from the abscess and cultured. The bacterial culture grew S. lugdunensis, Staphylococcus aureus (S. aureus), and Streptococcus agalactiae (S. agalactiae) as the pathogens (Table 1). Antibiotic susceptibility panels were performed (Table 2).\n\nHe was treated with incision and drainage. Empiric oral antibiotic treatment with cephalexin 500 mg, four times daily for 10 days, was initiated. Six days after starting the antibiotic, the patient mentioned that the infection had improved by 70%. The cephalexin treatment was extended for another 20 days, for a total of 30 days of treatment. One month after the initiation of antibiotic therapy, the patient presented to the office for a wound check; the infection had resolved. After an additional 30 days, there were no signs of infection.\n\nCase 3\n\nA 67-year-old man presented for the evaluation of a tender lesion on his left upper back in February 2015. There was no fever or associated systemic symptoms. His medical history was significant for elevated fasting glucose levels. The lesion initially appeared a few months earlier.\n\nCutaneous examination showed an inflamed cystic lesion with surrounding erythema on the left upper back. A small amount of pus was expressed from the lesion and cultured. Bacterial culture grew S. lugdunensis (Table 1) and antibiotic susceptibility tests were performed (Table 2).\n\nHe was treated with incision and drainage; empiric oral antibiotic treatment with cefdinir 300 mg, twice daily for 10 days, was initiated. Two days later, the patient reported that he experienced severe diarrhea. Therefore, the cefdinir was stopped and doxycycline 100 mg, twice daily for 10 days, was initiated. The infection resolved within the 10 days of treatment. There was no clinical evidence of recurrent infection 2 months after completion of treatment.\n\nCase 4\n\nA healthy 80-year-old man presented with right index finger pain and swelling in March 2016. There was no fever or associated systemic symptoms. His past medical history was significant for nodular basal cell carcinoma.\n\nThe patient stated that a few days prior to the presentation he was doing some gardening and scraped his finger on a plant. He subsequently developed a large blister with localized throbbing, numbness, and redness.\n\nCutaneous examination showed an abscess with surrounding erythema on the nail fold of the radial aspect of the right index finger. The finger was cleaned and a small amount of pus was expressed from the abscess and cultured. The bacterial culture grew S. lugdunensis and Streptococcus intermedius (S. intermedius) (Table 1). Antibiotic susceptibility tests were performed (Table 2).\n\nHe was treated with incision and drainage; empiric oral antibiotic treatment was initiated with cephalexin 500 mg, four times daily, and sulfamethoxazole–trimethoprim 800–160 mg, twice daily, for 10 days. The infection resolved within 10 days of treatment. Sixty days following completion of treatment, there were no clinical signs of recurrent infection.\n\nCase 5\n\nAn 82-year-old man presented for evaluation of a tender lesion on his left lower back in May 2017. There was no fever or associated systemic symptoms. His past medical history was significant for diabetes mellitus and metastatic lentigo maligna melanoma. He was being treated with pembrolizumab.\n\nCutaneous examination showed an inflamed cyst with surrounding erythema on the left lower back (Fig. 3). A small amount of pus from the cyst was expressed and cultured. Bacterial culture grew S. lugdunensis (Table 1) and antibiotic susceptibility tests were performed (Table 2).Fig. 3 Close-up view of an inflamed cystic lesion with surrounding erythema from which Staphylococcus lugdunensis was cultured on the left lower back of an 82-year-old man\n\nHe was treated with incision and drainage. Empiric oral antibiotic treatment with cephalexin 500 mg, four times daily for 30 days, was initiated. The infection cleared within the 30 days of the antibiotic regimen (Figs. 4, 5). There was no recurrence of the infection 60 days after completion of treatment.Fig. 4 Distant view of the complete resolution of the cutaneous Staphylococcus lugdunensis skin and soft tissue infection on the back of an 82-year-old man that resolved after 30 days of treatment with cephalexin 500 mg four times daily\n\nFig. 5 Close-up view of the healed site of a Staphylococcus lugdunensis skin infection on the left lower back of an 82-year-old man after 30 days of cephalexin 500 mg, four times daily\n\nInformed consent was obtained from the patients who were included in the study.\n\nDiscussion\n\nStaphylococcus organisms can be coagulase-positive or coagulase-negative. Coagulase is an enzyme produced by many bacteria that allows the conversion of prothrombin to staphylothrombin, which in turn activates the protease activity of thrombin. Activated thrombin catalyzes the conversion of fibrinogen to fibrin and other coagulation-related reactions resulting in the clotting of the blood [2, 3]. Although controversial, it has been postulated that the localized clotting elicited by coagulase can serve as a shield that protects the microorganism from the patient’s immune and phagocytic defenses [3].\n\nCoagulase-positive microorganisms tend to be considered pathogens and are traditionally associated with S. aureus, including methicillin-resistant and methicillin-susceptible strains. Coagulase-negative staphylococci are not able to produce coagulase and are typically considered a component of the normal flora of the skin; they are not usually considered to be pathogens.\n\nStaphylococcus lugdunensis is a coagulase-negative staphylococcus. It was first described by Freney et al. [4]. It is typically considered part of the normal skin flora. Recently, S. lugdunensis has been implicated as the main pathogen in a variety of infections, including central nervous system infections, endocarditis, endophthalmitis, osteomyelitis, peritonitis, prosthetic joint infections, urinary tract infections, and systemic infections [1, 5, 6]. In addition, an increasing number of the infections caused by S. lugdunensis are skin and soft tissue infections [1, 6, 7].\n\nHerchline and Ayers [7] performed a study involving 143 patients over a period of 63 months; they examined the occurrence of S. lugdunensis in cultures originating from 155 specimens isolated from all parts of the body. The skin and skin structures represented about 55% of the clinical diagnosis of S. lugdunensis infections, and most of those samples originated from patients’ abscesses, cellulitis, or wounds.\n\nFive patients (one woman and four men) developed S. lugdunensis related-skin infections from February 19, 2015 to May 30, 2017 (Table 1). The patients’ ages during the onset of the infection ranged from 30 to 82 years; the median age was 70 years. Four of the patients were older than 65 years.\n\nThe bacterial cultures from the five patients grew S. lugdunensis. In addition to S. lugdunensis, the bacterial culture from the 30-year-old man grew two other organisms: S. aureus and S. agalactiae (Streptococcus group B). Also, the bacterial culture of the 80-year-old woman grew one additional organism: S. intermedius. Similar to our two patients whose infections contained not only S. lugdunensis but also other organisms, Herchline and Ayers [7] noted that 60% of the cultures of specimens from their patients infected with S. lugdunensis also grew other microorganisms. Some of these organisms were pathogenic bacteria that can be associated with mixed infections, whereas others were bacteria that reflected the location of the lesion and included some common components of the skin flora [7].\n\nThe back was the most common location for the S. lugdunensis infection, followed by the digits. All of the sites of infection clinically presented as cellulitis. Some had an underlying infected cyst, whereas others had abscess of the nail fold. The lesions were incised or spontaneously ruptured. The initial clinical impression for all of the patients favored an infection caused by S. aureus, which is a prevalent pathogen in our practice. Therefore, all patients were initially treated with antibiotics that would cover methicillin-sensitive S. aureus. Similar to our patients, Bocher et al. [1] also observed that skin and soft tissue infections caused by S. lugdunensis are clinically indistinguishable from those caused by S. aureus.\n\nStaphylococcus lugdunensis can also causes infection in patients with intact immunity. However, three patients were receiving immunosuppressive therapy when their infections occurred. Similarly, the studies provided by Herchline and Ayers [7] also noted that 50% of S. lugdunensis infections occurred in patients who were immunosuppressed or had a prior history of trauma to the site.\n\nThe susceptibilities of the cultured strains of S. lugdunensis demonstrated that all of the organisms were sensitive to cefazolin, which is similar to observations made in patients with methicillin-sensitive S. aureus infections. Two patients were treated with cephalexin only. The other patients were treated with the following antibiotics: cephalexin and doxycycline or cefdinir and doxycycline or cephalexin and sulfamethoxazole–trimethoprim (Table 1). The patients were treated from 10 to 30 days until complete healing. There was no recurrence of the infection 2 months following treatment.\n\nOne limitation of our case series of S. lugdunenesis skin and soft tissue infections is that our methodology is prone to selection bias. The cases were retrospectively selected from among the patients evaluated by bacterial culture during a time period of 27 months. A prospective study in which all patients with suspected skin and soft tissue infections are consecutively screened for inclusion during a predefined time period could provide information on the incidence of skin and soft tissue infections of S. lugdunenesis as compared to those of other pathogenic bacteria.\n\nConclusions\n\nStaphylococcus lugdunensis was previously considered a nonpathogenic organism and a component of the normal skin flora. However, S. lugdunensis can cause significant skin and soft tissue infections, and these may be more prevalent in older individuals. We observed S. lugdunensis skin and soft tissue infections in five individuals, four of whom were over 65 years. Three of the five patients were receiving immunosuppressive therapy. The antibiotic sensitivities of S. lugdunensis appear to be similar to those of methicillin-susceptible S. aureus. Prolonged treatment was necessary for two individuals, and therapy ranged from 10 to 30 days. In summary, this case series and relevant previous studies demonstrate that S. lugdunensis can cause skin and soft tissue infections which can be clinically analogous to those caused by S. aureus. Therefore, when S. lugdunensis is detected, it should be considered a potential cutaneous pathogen, especially in wounds occurring in older individuals.\n\nAcknowledgements\n\nNo funding or sponsorship was received for this study or the publication of this article. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval of the version to be published.\n\nDisclosures\n\nLucas A. Heldt Manica, BS, and Philip R. Cohen, MD, have nothing to disclose.\n\nCompliance with Ethics Guidelines\n\nInformed consent was obtained from the patients before they were included in the study.\n\nOpen Access\n\nThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial 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.\n\nEnhanced content\n\nTo view enhanced content for this article go to http://www.medengine.com/Redeem/31BCF06046EA9476.\n==== Refs\nReferences\n\n1. Bocher S Tonning B Skov R Prag J Staphylococcus lugdunensis, a common cause of skin and soft tissue infections in the community J Clin Microbiol 2009 47 946 950 10.1128/JCM.01024-08 19244465\n2. Cheng A McAdow M Kim H Bae T Missiakas D Schneewind O Contribution of coagulases towards Staphylococcus aureus disease and protective immunity PLoS Pathog 2010 6 8 e1001036 10.1371/journal.ppat.1001036 20700445\n3. Guo H Hall J Yang J Ji Y The SaeRS two-component system controls survival of Staphylococcus aureus in human blood through regulation of coagulase Front Cell Infect Microbiol 2017 7 204 10.3389/fcimb.2017.00204 28611950\n4. Freney J Brun Y Bes M Meugnier H Grimont F Grimont P Nervi C Fleurette J Staphylococcus lugdunensis sp. nov. and Staphylococcus schleiferi sp. nov., two species from human clinical specimens Int J Syst Evol Microbiol 1988 38 168 172\n5. Haile DT Hughes J Vetter E Kohner P Snyder R Patel R Cockerill FR 3rd Frequency of isolation of Staphylococcus lugdunensis in consecutive urine cultures and relationship to urinary tract infection J Clin Microbiol 2002 40 654 656 10.1128/JCM.40.2.654-656.2002 11825988\n6. Frank K Del Pozo J Patel R From clinical microbiology to infection pathogenesis: how daring to be different works for Staphylococcus lugdunensis Clin Microbiol Rev 2008 21 111 133 10.1128/CMR.00036-07 18202439\n7. Herchline T Ayers L Occurrence of Staphylococcus lugdunensis in consecutive clinical cultures and relationship of isolation to infection J Clin Microbiol 1991 29 419 421 2037657\n\n",
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"issue": "7(4)",
"journal": "Dermatology and therapy",
"keywords": "Abscess; Cellulitis; Cutaneous; Lugdunensis; Paronychia; Skin; Soft; Staphylococcus; Tissue",
"medline_ta": "Dermatol Ther (Heidelb)",
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"title": "Staphylococcus lugdunensis Infections of the Skin and Soft Tissue: A Case Series and Review.",
"title_normalized": "staphylococcus lugdunensis infections of the skin and soft tissue a case series and review"
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"abstract": "BACKGROUND\nSpinal atypical teratoid/rhabdoid tumour (AT/RT) is exquisitely rare and constitutes 2% of all AT/RTs.\n\n\nMETHODS\nA 6-year-old boy presented with low backache for the last 5 months. MRI of the spine showed a 1.5 × 1.5 × 4.7 cm intradural extramedullary mass extending from D10 to D12, causing compression of the conus medullaris. With a preoperative diagnosis of ependymoma, a gross total resection (GTR) of tumour was performed. Post-operative histopathology showed AT/RT. The tumour cells were immunopositive for cytokeratin, epithelial membrane antigen, smooth muscle actin, and p53 and immunonegative for MIC2, desmin, glial fibrillary acidic protein, and INI1. Post-operative neuraxis MRI revealed post-operative changes (D10-D12) with a 9 mm enhancing lesion at L5-S1 junction suggesting drop metastasis. There was no lesion in brain. Cerebrospinal fluid cytology did not show any malignant cell. The metastatic work-up was normal. He received 3 cycles of chemotherapy with ICE regimen (ifosfamide, carboplatin, and etoposide). Subsequently, he received craniospinal irradiation (CSI)-36 Gy/20 fractions/4 weeks followed by focal boost to primary tumour bed and spinal drop metastasis-14.4 Gy/8 fractions/1.5 weeks. Thereafter, he received 3 more cycles of ICE regimen. End-of-treatment MRI spine showed post-op changes (D10-D12) and 38.9% reduction of the L5-S1 lesion suggesting partial response. Six monthly spinal MRI showed serial reduction of the metastatic lesion leading to complete response (CR) 1 year after completion of treatment. On last follow-up (30 months from the initial diagnosis), he was neurologically intact and in CR.\n\n\nCONCLUSIONS\nMultimodality management comprising GTR of tumour, CSI followed by focal boost, and multiagent chemotherapy (ICE) can lead to successful outcome in patients with this rare and aggressive spinal tumour.",
"affiliations": "Department of Radiotherapy & Oncology, All India Institute of Medical Sciences, New Delhi, India, dr_ahitagni@yahoo.co.in.;Department of Radiotherapy & Oncology, All India Institute of Medical Sciences, New Delhi, India.;Department of Radiotherapy & Oncology, All India Institute of Medical Sciences, New Delhi, India.;Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.;Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.;Institute of Spine, Jaypee Hospital, Noida, India.;Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India.",
"authors": "Biswas|Ahitagni|A|;Velu|Umesh|U|;Sharma|Seema|S|;Kumari|Kalpana|K|;Sharma|Mehar Chand|MC|;Gupta|Ankit|A|;Bakhshi|Sameer|S|",
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"journal": "Pediatric neurosurgery",
"keywords": "Atypical teratoid/rhabdoid tumour; Craniospinal irradiation; Gross total resection; Paediatric spine",
"medline_ta": "Pediatr Neurosurg",
"mesh_terms": "D016543:Central Nervous System Neoplasms; D002648:Child; D004806:Ependymoma; D006801:Humans; D008297:Male; D018335:Rhabdoid Tumor; D013131:Spine; D013724:Teratoma",
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"pubdate": "2021",
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"references": null,
"title": "Successful Multimodality Management of Atypical Teratoid/Rhabdoid Tumour of the Lower Dorsal Spine with Spinal Drop Metastasis: Illustrated Review.",
"title_normalized": "successful multimodality management of atypical teratoid rhabdoid tumour of the lower dorsal spine with spinal drop metastasis illustrated review"
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"abstract": "As a consequence of its consistent safety profile and the low incidence of side effects, paracetamol is one of the most widely used analgesics, both in adults and children. However, paracetamol has the potential for hepatotoxicity, usually as a result of deliberate self-poisoning or, to a much lesser extent, accidental overdose. A variety of factors is thought to influence hepatotoxicity, including dose, concomitant use of microsome-inducing agents and other drugs, underlying disease, malnutrition, fasting, acute and chronic alcohol intake, ethnicity, and age. Unfortunately, none of these factors has been properly studied in humans. From a physiological standpoint, acute paracetamol hepatotoxicity at therapeutic doses is extremely unlikely despite reports of so-called therapeutic misadventure. It is clear that, in many of these cases, grossly excessive doses of paracetamol have been taken. Analyzing the various reports is difficult as the data are often incomplete. In summary, although hepatic toxicity is recognized in patients taking a major paracetamol overdose, the incidence of adverse events with its proper use is very low, particularly when considering with the enormous volume of drug use. Therapeutic misadventure is extremely uncommon and the facts are often misrepresented.",
"affiliations": "Clinical Pharmacology, University of Edinburgh, Edinburgh, Scotland, United Kingdom.",
"authors": "Prescott|L F|LF|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen",
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"issue": "7(2)",
"journal": "American journal of therapeutics",
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"medline_ta": "Am J Ther",
"mesh_terms": "D000082:Acetaminophen; D000328:Adult; D018712:Analgesics, Non-Narcotic; D002648:Child; D062787:Drug Overdose; D006801:Humans; D008099:Liver",
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"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Therapeutic misadventure with paracetamol: fact or fiction?",
"title_normalized": "therapeutic misadventure with paracetamol fact or fiction"
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"abstract": "Eosinophilic pustular folliculitis (EPF) (Ofuji disease) is a chronic, noninfectious pruritic cutaneous disorder of unknown etiology. No official guidelines are available for its treatment. Herein we present the case of a 59-year-old Caucasian man admitted to our outpatient clinic due to a generalized itchy skin rash characterized by papulo-pustules involving the face, trunk, and limbs. Histological examination supported the clinical diagnosis of EPF (Ofuji disease). The combination of low-dose oral indomethacin and topical tacrolimus ointment once a day led to a complete resolution of the lesions as well as associated symptoms in 8 weeks.",
"affiliations": "Section of Dermatology, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.;Section of Dermatology, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.;Section of Dermatology, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.;Section of Dermatology, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.",
"authors": "Marasca|Claudio|C|;Ruggiero|Angelo|A|;Fabbrocini|Gabriella|G|;Megna|Matteo|M|",
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"country": "Switzerland",
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"fulltext": "\n==== Front\nCase Rep Dermatol\nCase Rep Dermatol\nCDE\nCase Reports in Dermatology\n1662-6567 S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com \n\n10.1159/000509176\ncde-0012-0155\nSingle Case\nA Case of Ofuji Disease Successfully Treated with the Combination of Low-Dose Indomethacin and Topical Tacrolimus\nMarasca Claudio * Ruggiero Angelo Fabbrocini Gabriella Megna Matteo Section of Dermatology, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy\n*Claudio Marasca, Section of Dermatology, Department of Clinical Medicine and Surgery, University of Naples Federico II, Via Pansini 5, IT–80131 Naples (Italy), Claudio.marasca@gmail.com\nMay-Aug 2020 \n18 8 2020 \n18 8 2020 \n12 2 155 158\n27 3 2020 4 6 2020 2020 Copyright © 2020 by S. Karger AG, Basel2020This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Eosinophilic pustular folliculitis (EPF) (Ofuji disease) is a chronic, noninfectious pruritic cutaneous disorder of unknown etiology. No official guidelines are available for its treatment. Herein we present the case of a 59-year-old Caucasian man admitted to our outpatient clinic due to a generalized itchy skin rash characterized by papulo-pustules involving the face, trunk, and limbs. Histological examination supported the clinical diagnosis of EPF (Ofuji disease). The combination of low-dose oral indomethacin and topical tacrolimus ointment once a day led to a complete resolution of the lesions as well as associated symptoms in 8 weeks.\n\nKeywords\nOfuji diseaseEosinophilic pustular folliculitisIndomethacinTacrolimus\n==== Body\nIntroduction\nEosinophilic pustular folliculitis (EPF) is a chronic, noninfectious pruritic cutaneous disorder of unknown etiology. It was originally described by Ise and Ofuji [1] in 1965 as a variant of “superficial pustular dermatosis” in a Japanese female patient with recurrent follicular pustules on the trunk and the face accompanied by peripheral eosinophilia. The eruption of EPF consists of papulo-pustules which tend to form annular plaques. Histologically, EPF is characterized by an eosinophil-dominated infiltrate within and around the pilosebaceous units, often accompanied by eosinophilic microabscess formation [2, 3]. This type of EPF is currently called Ofuji disease or classic EPF. Herein, we describe the case of an immunocompetent male patient with the classic form of EPF who was successfully treated with low-dose oral indomethacin combined with topical tacrolimus.\n\nCase Report\nA 59-year-old Caucasian man was admitted at our outpatient Clinic in December 2019 presenting a severe and generalized skin rash characterized by papulo-pustules involving the face, trunk, and limbs. These manifestations were strongly itchy and not responsive to topical steroids and systemic antihistamine drugs, showing a high impact on quality of life. His medical history was positive for hypertension, arthrosis, anxiety, and depression; he also presented a percutaneous nephrostomy for a previous obstructive uropathy (2018) and a percutaneous ileostomy for a previous intestinal obstruction (2017). The patient said that the skin rash began 2 months ago, involving the face and subsequently expanding to the trunk and upper limbs. Dermatologic examination showed follicular papules and pustules, coalescing to form plaques on the face, trunk, and limbs (Fig. 1a). Routine blood tests were within normal ranges except for peripheral eosinophilia which represented 24.3% of the leukocyte formula, with a 1.91 × 103/μL count of eosinophils (normal value: 0–6%; 0.0–0.45 × 103/μL). An HIV screening was performed with negative results. A 3-mm skin biopsy was sent for histology showing skin with a rich representation of the pilosebaceous appendages, site of severe lympho-granulocytic infiltrate, with an impressive amount of eosinophilic granulocytes, which involved the annexes both superficially and deeply supporting the diagnosis of EPF (Ofuji disease). As shown by the therapeutic algorithm for EPF proposed by Takashi Nomura et al. [4], we started oral indomethacin (50 mg). Despite an initial improvement, the patient discontinued the therapy after only 1 week due to gastrointestinal events (diarrhea), manifesting an aggravation of the facial manifestations, with the appearance of new papulo-pustules. We decided to reduce the dosage of oral indomethacin from 50 to 25 mg combining it with topical tacrolimus ointment once a day, observing the spontaneous disappearance of the gastrointestinal symptoms and an excellent response especially on the itch symptom. During the last follow-up (week 8), the patient showed a total absence of itching and an important reduction of facial manifestations (Fig. 1b).\n\nDiscussion and Conclusion\nEPF is a chronic, noninfectious pruritic cutaneous disorder of unknown etiology. The eruption of EPF consists of papulo-pustules which tend to form annular plaques. Histologically, EPF is characterized by an eosinophil-dominated infiltrate within and around the pilosebaceous units, often accompanied by eosinophilic microabscess formation [1, 2, 3]. Apart from the classic EPF (Ofuji disease), which affects otherwise healthy individuals, additional variants of this disorder have been recognized: immunosuppression-associated EPF (IS-EPF) and infancy-associated EPF (I-EPF) are variants of EPF, both of which have been constantly reported since the 1980s [5]. There is also a rare drug-induced variant, which is associated with the administration of medications such as carbamazepine, minocycline, indeloxazine hydrochloride, and allopurinol [6, 7, 8]. The clinical features of the present case were compatible with the classic form of EPF. The diagnosis of EPF is occasionally difficult and problematic as EPF may share clinical and/or histological appearance overlapping with other diseases [5]. Because of the non-specific clinical features, histology is mandatory for the final diagnosis. Follicles must be included and studied carefully through serial sectioning. The presence of microabscesses containing eosinophil-dominant granulocytes in the upper portion of the outer root sheath is the hallmark of EPF [9]. The etiopathogenesis of EPF still remains unknown. It has been suggested that EPF most likely represents a multifactorial immunological reaction pattern to antigenic stimuli of diverse origin, which may cause an alteration of the immunological balance in the microenvironment of sebocytes leading to the production of prostaglandin D2 [4]. Many treatments have been used for classic EPF therapy (topical and systemic steroids, topical tacrolimus, systemic dapsone, sulfonamides, macrolides, tetracyclines, cyclosporine, retinoids, and systemic and topical antifungals) with variable results [4]. To our knowledge, only 1 case has been reported so far describing the efficacy of a low dose of systemic indomethacin in combination with topical tacrolimus ointmentfor the classic EPF [10]. To our experience, this combination could be an effectiveness and safe therapy for the Ofuji disease, reducing the dosage of oral indomethacin and its gastrointestinal adverse events. To date, no official guidelines are available for the treatment of the Ofuji disease. According to our experience, we can confirm the use of low dose of oral indomethacin (25 mg) in combination with topical tacrolimus once a day as a first-line safe and very promising option for patients with classic EPF.\n\nStatement of Ethics\nInformed consent for the study and for the publication of the photos was obtained from the patient. The study complied with the Declaration of Helsinki. Internal board review number was not required since we present a case report that does not need to be approved by the local ethics committee; it is not an experimental or an observational study.\n\nConflict of Interest Statement\nThe authors declare no conflict of interest.\n\nFunding Sources\nNone of the authors received any financial support for the present study.\n\nAuthor Contributions\nAll named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of the manuscript, take responsibility for the integrity of the work as a whole, and gave final approval of the version to be published.\n\nFig. 1 Patient at baseline (week 0) (a) and after 8 weeks of low dose of oral indomethacin in combination with topical tacrolimus once a day (b).\n==== Refs\nReferences\n1 Ise S Ofuji S Subcorneal pustular dermatosis; a follicular variant? [PMID: 11850921] Arch Dermatol 1965 92 (2) 169 71 \n2 Ofuji S Ogino A Horio T Oseko T Uehara M Eosinophilic pustular folliculitis Acta Derm Venereol 1970 50 (3) 195 203 4193219 \n3 Ofuji S Eosinophilic pustular folliculitis Dermatologica 1987 174 (2) 53 6 3556698 \n4 Nomura T Katoh M Yamamoto Y Miyachi Y Kabashima K Eosinophilic pustular folliculitis: A proposal of diagnostic and therapeutic algorithms J Dermatol 2016 11 43 (11) 1301 6 27028427 \n5 Nervi SJ Schwartz RA Dmochowski M Eosinophilic pustular folliculitis: a 40 year retrospect J Am Acad Dermatol 2006 8 55 (2) 285 9 16844513 \n6 Mizoguchi S Setoyama M Higashi Y Hozumi H Kanzaki T Eosinophilic pustular folliculitis induced by carbamazepine [PMID:9555813] J Am Acad Dermatol 1998 4 38 (4) 641 3 9555813 \n7 Kimura K Ezoe K Yokozeki H Katayama I Nishioka K A case of eosinophilic pustular folliculitis (Ofuji's disease) induced by patch and challenge tests with indeloxazine hydrochloride [PMID:8772029] J Dermatol 1996 7 23 (7) 479 83 8772029 \n8 Ooi CG Walker P Sidhu SK Gordon LA Marshman G Allopurinol induced generalized eosinophilic pustular folliculitis [PMID:17034470] Australas J Dermatol 2006 11 47 (4) 270 3 17034470 \n9 Fujiyama T Tokura Y Clinical and histopathological differential diagnosis of eosinophilic pustular folliculitis J Dermatol 2013 6 40 (6) 419 23 23488969 \n10 Hara D Kuroda K Mieno H Tajima S Treatment of eosinophilic pustular folliculitis with tacrolimus ointment J Am Acad Dermatol 2004 11 51 (5 Suppl) S143 5 15577754\n\n",
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"keywords": "Eosinophilic pustular folliculitis; Indomethacin; Ofuji disease; Tacrolimus",
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"title": "A Case of Ofuji Disease Successfully Treated with the Combination of Low-Dose Indomethacin and Topical Tacrolimus.",
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"abstract": "Pancreatic neuroendocrine neoplasms (PNENs) are rare, but their incidence has increased in recent years. Curative surgery is recommended in several global guidelines for resectable PNENs. Lymph node recurrence after R0 resection for PNENs is infrequent, and global guidelines recommend surgical resection for recurrence, if resectable. However, data on the prognosis after surgical resection for nodal recurrence of PNENs are limited. We herein report two cases in which long-term survival was achieved after repetitive lymphadenectomy for nodal recurrence of PNENs. In both cases, the pathological findings for primary PNEN showed well-differentiated neuroendocrine neoplasms and R0 resection was successfully performed. The Ki-67 index increased with each resection in both cases. Both patients showed long-term survival (10 and 14 years, respectively). Repetitive lymphadenectomy for nodal recurrence of PNENs may improve patient prognosis.",
"affiliations": "Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan.;Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan.;Department of Medical Oncology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.;Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan.;Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan.;Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan.;Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan.;Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan.;Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan.;Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan.;Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan.;Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan.;Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan.;Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan.",
"authors": "Hane|Yuma|Y|https://orcid.org/0000-0002-8449-0398;Tsuchikawa|Takahiro|T|https://orcid.org/0000-0002-3847-280X;Takeuchi|Satoshi|S|;Tanaka|Kimitaka|K|;Nakanishi|Yoshitsugu|Y|;Asano|Toshimichi|T|;Noji|Takehiro|T|;Kurashima|Yo|Y|;Ebihara|Yuma|Y|;Murakami|Soichi|S|;Nakamura|Toru|T|;Okamura|Keisuke|K|;Shichinohe|Toshiaki|T|;Hirano|Satoshi|S|",
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"fulltext": "\n==== Front\nJ Surg Case Rep\nJ Surg Case Rep\njscr\nJournal of Surgical Case Reports\n2042-8812\nOxford University Press\n\n10.1093/jscr/rjab446\nrjab446\nAcademicSubjects/MED00910\njscrep/080\nCase Series\nLong-term survival after repetitive lymphadenectomy for nodal recurrence of pancreatic neuroendocrine neoplasms: a report of two cases\nhttps://orcid.org/0000-0002-8449-0398\nHane Yuma Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan\n\nhttps://orcid.org/0000-0002-3847-280X\nTsuchikawa Takahiro Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan\n\nTakeuchi Satoshi Department of Medical Oncology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan\n\nTanaka Kimitaka Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan\n\nNakanishi Yoshitsugu Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan\n\nAsano Toshimichi Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan\n\nNoji Takehiro Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan\n\nKurashima Yo Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan\n\nEbihara Yuma Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan\n\nMurakami Soichi Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan\n\nNakamura Toru Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan\n\nOkamura Keisuke Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan\n\nShichinohe Toshiaki Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan\n\nHirano Satoshi Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan\n\nCorrespondence address. Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan. Tel: +81-11-706-7714; Fax: +81-11-706-7158; E-mail: tsuchi-t@med.hokudai.ac.jp\n10 2021\n13 10 2021\n13 10 2021\n2021 10 rjab44627 7 2021\n14 9 2021\n15 9 2021\nPublished by Oxford University Press and JSCR Publishing Ltd. © The Author(s) 2021.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com\n\nAbstract\n\nPancreatic neuroendocrine neoplasms (PNENs) are rare, but their incidence has increased in recent years. Curative surgery is recommended in several global guidelines for resectable PNENs. Lymph node recurrence after R0 resection for PNENs is infrequent, and global guidelines recommend surgical resection for recurrence, if resectable. However, data on the prognosis after surgical resection for nodal recurrence of PNENs are limited. We herein report two cases in which long-term survival was achieved after repetitive lymphadenectomy for nodal recurrence of PNENs. In both cases, the pathological findings for primary PNEN showed well-differentiated neuroendocrine neoplasms and R0 resection was successfully performed. The Ki-67 index increased with each resection in both cases. Both patients showed long-term survival (10 and 14 years, respectively). Repetitive lymphadenectomy for nodal recurrence of PNENs may improve patient prognosis.\n==== Body\npmcINTRODUCTION\n\nPancreatic neuroendocrine neoplasms (PNENs) are rare tumors with a reported incidence of 0.48 in 100 000 persons, but the number of cases has been increasing recently [1]. PNENs have a better prognosis compared with pancreatic cancer, 5-year survival rate of PNENs is reported 54% by SEER data base. However, PNENs with distant metastases have a poor prognosis, with a reported 5-year survival rate of 25% by SEER data base. In 2017, the World Health Organization classified PNENs into well-differentiated and poorly differentiated neuroendocrine neoplasms (NENs) from a morphological point of view, with the former being further subdivided into neuroendocrine tumors G1, G2 and G3 based on the status of cell proliferation [2]. Resectable PNENs have been reported to have a good prognosis [3–5]. Therefore, curative surgical resection is recommended by several guidelines for well-differentiated NENs, with regional lymphadenectomy in cases in which the tumor size is >2 cm, according to the therapeutic strategy for pancreatic ductal adenocarcinoma.\n\nRecurrence after R0 resection for PNENs is uncommon, with a reported incidence of 9.7% [6]. The National Comprehensive Cancer Network and Japanese Neuroendocrine Tumors Society guidelines recommend curative surgical resection for recurrence, if resectable [7]. However, data on the prognosis of PNEN recurrence after surgical resection are limited. Here, we focused on nodal recurrences and reported two cases in which long-term survival was achieved after repetitive lymphadenectomy for nodal recurrence of PNENs.\n\nCASE SERIES\n\nCase 1\n\nA 71-year-old woman underwent distal pancreatectomy with prophylactic local lymph node resection, left adrenal resection and partial gastric resection for PNEN. The pathological findings of the resected specimen were as follows: well-differentiated NEN, tumor size of 36 mm, negative resection margins, positive vascular invasion, no lymph node metastases and a Ki-67 index of 4%. Four years after the pancreatectomy, abdominal computed tomography (CT) revealed a regional lymph node recurrence located dorsal to the left renal vein (Fig. 1A); therefore, regional lymphadenectomy was performed. The pathological finding was metachronous nodal recurrence of PNEN (Ki-67 index: unknown). Five years after the first surgery, regional lymph node recurrence occurred, with invasion of the left kidney (Fig. 1B); therefore, left nephrectomy with lymphadenectomy was performed. The pathological finding was metachronous nodal recurrence of PNEN (Ki-67 index: 20%) with renal invasion. Five years after the pancreatectomy, follow-up CT and gadoxetic acid–enhanced magnetic resonance imaging (MRI) revealed local recurrence and multiple liver metastases (Fig. 1C and D). Daily oral sunitinib (37.5 mg) was initiated 5 years and 5 months after pancreatectomy; however, the patient developed fever and joint pain 2 weeks after initiating sunitinib. Therefore, sunitinib was switched to daily oral everolimus (10 mg). She maintained stable disease for 1 year and 3 months after the initiation of everolimus; however, follow-up CT revealed enlargement of multiple liver metastases. Therefore, everolimus was switched to weekly streptozocin (800 mg/m2). She maintained stable disease for 1 year and 6 months after the initiation of streptozocin. Streptozocin was switched to sunitinib with lanreotide because of the enlargement of multiple liver metastases. Sunitinib with lanreotide was administered for 1 year and was switched to amrubicin (30 mg/m2) 3 days per week due to the enlargement of multiple liver metastases. The patient died of liver metastases 10 years after pancreatectomy.\n\nFigure 1 Selected abdominal computed tomography and gadoxetic acid–enhanced magnetic resonance images: Case 1. (A) Recurrence for the first time: para-aortic mass measuring 28 mm located dorsal to the left renal vein (arrowhead). (B) Recurrence for the second time: mass measuring 40 mm invading the left kidney (arrow). (C, D) Recurrence for the third time: mass measuring 12 mm at the same site as that of the second recurrence (c; arrowhead) and multiple liver metastases in the bilateral lobe (d).\n\nCase 2\n\nAn 80-year-old woman underwent distal pancreatectomy with lymphadenectomy for PNEN. The pathological findings were as follows: well-differentiated NEN, tumor size of 80 mm, negative resection margins, negative lymphovascular invasion, no lymph node metastases and a Ki-67 index <1%. Five years after the pancreatectomy, nodal metastasis was noted near the abdominal aorta on positron emission tomography and CT (Fig. 2A). A para-aortic lymphadenectomy was performed. The pathological finding was metachronous nodal recurrence of PNEN and a Ki-67 index of 10%. Nine years after the pancreatectomy, nodal metastasis recurred near the abdominal aorta (Fig. 2B). We performed a second para-aortic lymphadenectomy, and the pathological finding was metachronous nodal recurrence of PNEN, with a Ki-67 index of 15%. Eleven years after the pancreatectomy, a third metachronous nodal recurrence appeared near the abdominal aorta (Fig. 2C). A third para-aortic lymphadenectomy was not performed because of severe aortic stenosis. Since somatostatin receptor scintigraphy revealed positive SSTR-2, 120 mg of lanreotide was administered. She complained of diarrhea as a side effect. The patient maintained stable disease for 14 years after pancreatectomy.\n\nFigure 2 Selected abdominal computed tomography and positron emission tomography–computed tomography images: Case 2. (A) Recurrence for the first time: para-aortic mass measuring 24 mm with accumulation on positron emission tomography (SUVmax: 5.1). (B) Recurrence for the second time: para-aortic mass measuring 15 mm (arrowhead). (C) Recurrence for the third time: para-aortic mass measuring 24 mm (arrow).\n\nDISCUSSION\n\nIn this report, we describe the cases of two patients who underwent repetitive lymphadenectomy for nodal recurrence after curative surgical resection of PNENs and achieved long-term survival.\n\nIn both cases, para-aortic lymph node recurrence occurred despite the absence of lymph node metastases in the pathological findings of the first surgery, which was caused by skip metastasis. Li et al. [8] reported that the mechanisms of skip metastasis are the following: occult metastasis or micrometastasis to N1 nodes may have been missed during dissection or routine histopathological examination; aberrant lymphatic drainage patterns may have been present in patients with gastric cancer through which metastasis bypasses the lymphatic vessels; lymphatic flow to the N1 nodes may have been blocked by cancer tissue and free cancer cells may diffuse through regional nodes to distant nodes because the microenvironment in N1 nodes is unsuitable for the development of metastasis [8]. Recurrence after R0 resection for PNEN is rare, with a reported incidence of 9.7% (43/462) and a reported nodal recurrence rate after R0 resection of 1.3% [9]. In a previous study, patients who underwent resection for metachronous local recurrence and liver metastases after R0/1 resection of PNENs had a better prognosis than those who did not [3]; therefore, global guidelines allow curative surgical resection of recurrence sites, including nodal recurrence, if it appears to be resectable on several imaging modalities [7]. However, due to its slow growing nature and recent advance in multimodal therapeutic modalities, it is difficult to clarify whether the surgical intervention alone separately contributed to the patients prognosis [10]. Moreover, there is a lack of data on the location of lymph node recurrence and prognosis with lymph node recurrence after surgical resection of PNENs. In our cases, repetitive lymphadenectomy for nodal recurrences resulted in long-term survival for 10 and 14 years.\n\nIn our department, all candidates for surgical resection are principally observed for at least 3 months after systemic treatment, if indicated. If a new metastatic lesion was found during this window period, surgical resection was not performed, suggesting systemic disease. To detect new metastatic lesions, cross-sectional imaging studies, such as CT, ultrasound, MRI and stereotactic radiosurgery (SRS) are used. In particular, MRI is useful for the detection of liver metastases, whereas SRS is useful for detecting lymph node and bone metastases [9, 11].\n\nIn the present cases, the Ki-67 index was elevated for each metastasis. Recently, some studies have reported that the Ki-67 index may increase throughout the disease course in NENs due to genetic intramural heterogeneity or therapy resistance [12, 13]. Moreover, the duration to the next recurrence was shortened over the course of the disease, with an increase in the Ki-67 index. This could be interpreted as a change in tumor pathology during disease progression. Re-biopsy, functional imaging modalities and an appropriate window period are required to make a decision on the operative indication for lymph node recurrence in rapidly progressive cases.\n\nIn conclusion, repetitive lymphadenectomy for resectable nodal recurrence of PNENs with multidisciplinary treatment may contribute to improved prognosis.\n\nACKNOWLEDGEMENTS\n\nWe would like to thank Editage (www.editage.jp) for English language editing.\n\nCONSENT FOR PUBLICATION\n\nWritten informed consent was obtained from the patients for publication of this case report and the accompanying images.\n\nCONFLICT OF INTEREST STATEMENT\n\nThe authors declare that they have no competing interests relevant to this article.\n\nFUNDING\n\nNone.\n==== Refs\nReferences\n\n1. Dasari A, Shen C, Halperin D, Zhao B, Zhou S, Xu Y, et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol 2017;3 :1335–42.28448665\n2. Lloyd RV, Osamura RY, Klöppel G, Rosai J. WHO Classification of Tumours of Endocrine Organs, 4th edn. Lyon, France: WHO, 2017.\n3. Schurr PG, Strate T, Rese K, Kaifi J, Reichelt U, Petri S, et al. Aggressive surgery improves long-term survival in neuroendocrine pancreatic tumors: an institutional experience. Ann Surg 2007;245 :273–81.17245182\n4. Cherenfant J, Stocker SJ, Gage MK, Du H, Thurow TA, Odeleye M, et al. Predicting aggressive behavior in nonfunctioning pancreatic neuroendocrine tumors. Surgery 2013;154 :785–91.24074416\n5. Ricci C, Partelli S, Ingaldi C, Valentina A, Campana D, Muffati F, et al. Disease-free survival as a measure of overall survival in resected pancreatic endocrine neoplasms. Endocr Relat Cancer 2020;27 :275–83.32053492\n6. Marchegiani G, Landoni L, Andrianello S, Masini G, Cingarlini S, D'Onofrio M, et al. Patterns of recurrence after resection for pancreatic neuroendocrine tumors: who, when, and where? Neuroendocrinology 2019;108 :161–71.30481765\n7. Manisha HS, Whitney SG, Benson III AB, Emily B, Lawrence SB, Pamela B, et al. Neuroendocrine and adrenal tumors, version 2. 2021. J Natl Compr Canc Netw 2021;19 :839–68.\n8. Li C, Kim S, Lai JF, Oh SJ, Hyung WJ, Choi WH, et al. Solitary lymph node metastasis in gastric cancer. J Gastrointest Surg 2008;12 :550–4.17786527\n9. Frilling A, Malago M, Martin H, Broelsch CE. Use of somatostatin receptor scintigraphy to image extrahepatic metastases of neuroendocrine tumors. Surgery 1998;124 :1000–4.9854575\n10. Kim H, Song KB, Hwang DW, Lee JH, Alshammary S, Kim SC. Time-trend and recurrence analysis of pancreatic neuroendocrine tumors. Endocr Connect 2019;8 :1052–60.31252400\n11. Dromain C, de Baere T, Lumbroso J, Caillet H, Laplanche A, Boige V, et al. Detection of liver metastases from endocrine tumors: a prospective comparison of somatostatin receptor scintigraphy, computed tomography, and magnetic resonance imaging. J Clin Oncol 2005;23 :70–8.15625361\n12. Singh S, Hallet J, Rowsell C, Law CH. Variability of Ki67 labeling index in multiple neuroendocrine tumors specimens over the course of the disease. Eur J Surg Oncol 2014;40 :1517–22.25088936\n13. Shi H, Zhang Q, Han C, Zhen D, Lin R. Variability of the Ki-67 proliferation index in gastroenteropancreatic neuroendocrine neoplasms—a single-center retrospective study. BMC Endocr Disord 2018;18 :51.30055596\n\n",
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"pubdate": "2021-10",
"publication_types": "D002363:Case Reports",
"references": "30055596;32053492;28448665;17786527;15625361;31252400;30481765;25088936;24074416;9854575;17245182",
"title": "Long-term survival after repetitive lymphadenectomy for nodal recurrence of pancreatic neuroendocrine neoplasms: a report of two cases.",
"title_normalized": "long term survival after repetitive lymphadenectomy for nodal recurrence of pancreatic neuroendocrine neoplasms a report of two cases"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2022RR-333235",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SUNITINIB"
},
"druga... |
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