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"abstract": "Objective. We report a rare case of keloidal scleroderma and provide an analysis of similar cases. Results. A 41 year-old woman presented with dark brown, indurated, exophytic nodules over the chest along with smaller hyperpigmented plaques scattered over the abdomen, with concomitant sclerodactyly. The clinical, laboratory, and pathological findings were consistent with a diagnosis of keloidal scleroderma. The patient was treated with methotrexate, resulting in reduced firmness of her plaques and no new lesions. A literature review of previously reported cases was performed using keywords including keloidal morphea, keloidal scleroderma, nodular morphea, and nodular scleroderma. In our review, the majority of patients were African American and female. 91% of cases had nodular lesions with distribution on the trunk. The majority of patients exhibited sclerodactyly and pulmonary involvement was reported in 28%1. The majority of patients were ANA positive (63%) and only 10% demonstrated anti-SCL-70 positivity. Conclusion. Keloidal scleroderma is a rare presentation, which can often be clinically confused with keloid and scar formation. Due to this being a rare variant, our knowledge of treatment options and efficacy is limited. Methotrexate could be considered as an initial treatment option for patients with progressive keloidal scleroderma.",
"affiliations": "Department of Dermatology, University of Alabama at Birmingham, EFH 414, 1530 3rd Avenue S, Birmingham, AL 35294, USA.;Department of Dermatology, University of Alabama at Birmingham, EFH 414, 1530 3rd Avenue S, Birmingham, AL 35294, USA.;Department of Dermatology, University of Alabama at Birmingham, EFH 414, 1530 3rd Avenue S, Birmingham, AL 35294, USA.;Department of Dermatology, University of Alabama at Birmingham, EFH 414, 1530 3rd Avenue S, Birmingham, AL 35294, USA.",
"authors": "Kassira|Sama|S|;Jaleel|Tarannum|T|;Pavlidakey|Peter|P|;Sami|Naveed|N|",
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"fulltext": "\n==== Front\nCase Rep Dermatol MedCase Rep Dermatol MedCRIDMCase Reports in Dermatological Medicine2090-64632090-6471Hindawi Publishing Corporation 10.1155/2015/635481Case ReportKeloidal Scleroderma: Case Report and Review Kassira Sama Jaleel Tarannum Pavlidakey Peter Sami Naveed \n*\nDepartment of Dermatology, University of Alabama at Birmingham, EFH 414, 1530 3rd Avenue S, Birmingham, AL 35294, USA*Naveed Sami: nsami@uab.eduAcademic Editor: Jacek Cezary Szepietowski\n\n2015 30 11 2015 2015 6354819 9 2015 9 11 2015 18 11 2015 Copyright © 2015 Sama Kassira et al.2015This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nObjective. We report a rare case of keloidal scleroderma and provide an analysis of similar cases. Results. A 41 year-old woman presented with dark brown, indurated, exophytic nodules over the chest along with smaller hyperpigmented plaques scattered over the abdomen, with concomitant sclerodactyly. The clinical, laboratory, and pathological findings were consistent with a diagnosis of keloidal scleroderma. The patient was treated with methotrexate, resulting in reduced firmness of her plaques and no new lesions. A literature review of previously reported cases was performed using keywords including keloidal morphea, keloidal scleroderma, nodular morphea, and nodular scleroderma. In our review, the majority of patients were African American and female. 91% of cases had nodular lesions with distribution on the trunk. The majority of patients exhibited sclerodactyly and pulmonary involvement was reported in 28%1. The majority of patients were ANA positive (63%) and only 10% demonstrated anti-SCL-70 positivity. Conclusion. Keloidal scleroderma is a rare presentation, which can often be clinically confused with keloid and scar formation. Due to this being a rare variant, our knowledge of treatment options and efficacy is limited. Methotrexate could be considered as an initial treatment option for patients with progressive keloidal scleroderma.\n==== Body\n1. Introduction\nKeloidal scleroderma is a very rare diagnosis, which has been also reported with alternate nomenclature including keloidal morphea, nodular morphea, and nodular scleroderma. Keloidal scleroderma presents as multiple keloid-like lesions that occur in the absence of preceding trauma or injury and can be associated with localized or systemic symptoms of scleroderma. This is in contrast to the flat and/or depressed plaques with associated tightening of the skin that is seen in classical cutaneous scleroderma. Histopathological findings in keloidal scleroderma can be variable. We report a 41-year-old woman with keloidal scleroderma and provide a review of 43 reported cases of this variant of scleroderma.\n\n2. Case\nA 41-year-old African American woman presented with initial symptoms of burning and stinging of the upper body for over 4 weeks, progressing to dark firm painful areas on her chest, neck, and abdomen with concomitant sclerodactyly. She denied tightening around her mouth, dry eyes or mouth, arthritis, dysphagia, or signs of Raynaud's phenomenon.\n\nPhysical examination revealed dark brown indurated nodules with a slightly violaceous border over the chest and breasts along with smaller hyperpigmented plaques scattered over the abdomen (Figure 1). There was also extensive hyperpigmentation and skin tightening over the anterior neck, chest, axillae, and abdomen. A hypertrophic, exophytic papule overlying a hyperpigmented plaque was present over the center of the chest. Examination of the hands showed a contracture of the left hand 4th and 5th digits with slight tapering of the fingertips. There was sparing of the face and telangiectasias were absent.\n\nComplete blood count, metabolic panel, and hepatitis serologies did not reveal any abnormalities. Serum ANA (antinuclear antibody) titer was elevated (1 : 1280). Anti-SSA and anti-SSB serum antibodies were both elevated, while SCL70 and anti-Smith autoantibody titers were within normal limits.\n\nHistologic sections show an acanthotic epidermis with overlying basilar hyperpigmentation. Within the dermis there is a proliferation of myofibroblasts and thickened collagen bundles. There is a lack of vertically oriented blood vessels and a lack of atrophy of the overlying epidermis speaking against that of a keloid or scar. At low power biopsy has a barrel-shaped appearance. The dermal component is expansile and extends beyond that of the epidermal component (Figure 2). A tissue elastic stain shows preserved elastic fibers within areas of scleroderma (Figure 3). In areas of keloid these elastic fibers are typically absent, thus supporting the diagnosis of keloidal scleroderma and not that of a keloid.\n\nThe clinical and pathological findings were consistent with a diagnosis of keloidal scleroderma. The patient was treated with methotrexate (17.5 mg/week) for six weeks resulting in reduced firmness of her plaques and no new lesions.\n\n3. Discussion\nKeloidal scleroderma is a rare presentation, which can often be clinically confused with keloid and scar formation. Although there have been some reports suggesting that keloidal scleroderma may represent two distinct processes with keloid formation causally unrelated to sclerosis, others suggest that there is a combined mechanism with a dermal inflammatory process of sclerosis forming keloidal lesions [1]. High levels of tenascin have been histologically observed in keloidal scleroderma lesions as well as increased levels of TFG-beta cytokines [1, 2]. Tenascin has been shown to have distinct mid-dermal distribution in sclerodermal lesions, reflecting active fibrosis [1]. A strikingly different tenascin distribution in the nodular lesions of a single case as compared to sclerotic tissue has been shown, suggesting a differing pathological course between the nodular and sclerotic lesions [1]. However, keloidal scleroderma lesions have shown increased levels of TGF-beta and connective tissue growth factor (CTF), which is similarly seen in fibroblasts of classic sclerodermal lesions suggesting analogous pathogenesis of collagen synthesis [1, 2].\n\nWe performed a literature review for previously reported cases using keywords, which have been used to describe similar clinical presentations, including keloidal morphea, keloidal scleroderma, nodular morphea, and nodular scleroderma. All cases where the clinical presentation was confirmed by a histopathological diagnosis were included. Clinical data of 43 patients from 29 different publications is presented in Table 1.\n\nIn our review, the majority of patients were African American and female. Ages ranged from 3 to 70 years (median 41). 91% of cases had nodular lesions with distribution on the trunk, while one case had lesions in the intertriginous areas. The majority of patients presented with sclerodactyly as well as extracutaneous manifestations of systemic scleroderma (Table 1). Pulmonary involvement was reported in 28% and renal involvement in 5% [1]. Ten percent of cases noted an external trigger prior to the onset of keloidal plaques, including infection, D-penicillamine, tetanus vaccine, and environmental exposures. One patient, who already had a diagnosis of keloidal scleroderma, did not have any involvement at a recent surgical site [1].\n\nLaboratory values demonstrated the majority of patients were ANA positive (63%) and only 10% demonstrated anti-SCL-70 positivity. A single case noted positive anti-Borrelia antibodies and two cases were seropositive for anti-SSB [1].\n\nCurrent treatments for cutaneous and systemic sclerosis include topical or intralesional corticosteroids, a topical vitamin D analog, topical tacrolimus or imiquimod, UV light therapy, methotrexate, and systemic steroids [3–5].\n\nThirteen out of 22 cases were treated with local and/or systemic steroids. The majority reported no response to treatment. Only three cases showed partial response with local and/or systemic steroid therapy and one case showed complete response to systemic steroids. D-penicillamine was used in 6 patients and only one patient had full resolution with 5 years of oral D-penicillamine in combination with topical steroids. However, one patient showed progression while on therapy [1, 6–9]. Both patients who showed complete response to D-penicillamine and systemic steroids had systemic scleroderma with pulmonary involvement [1]. Azathioprine (100 mg daily) was also used in a case for an unknown duration with no resolution. Surgical removal of several large nodules showed complete resolution in one patient [1, 10]. Multiple studies using PUVA showed partial response. However, one case using PUVA in combination with methotrexate and systemic steroids reported no response [2]. Our patient reported a partial response with six weeks of methotrexate with a decrease in firmness of the keloidal plaques and no new active lesions.\n\nIn conclusion, diagnosis of scleroderma should be considered in a patient with extensive keloids. Due to this being a rare variant, our knowledge of treatment options and efficacy is limited. Methotrexate could be considered as an initial treatment option for patients with progressive keloidal scleroderma. Further research is still needed to understand the pathogenesis and treatment of this rare variant of scleroderma.\n\nAcknowledgments\nAll authors have contributed equally to this work and are in agreement with the content of this paper.\n\nAbbreviations \nANA:Antinuclear antibody\n\nSSA:Anti-Ro antibody\n\nSSB:Anti-La antibody\n\nTGF:Transforming growth factor\n\nCTF:Connective tissue factor\n\nUV:Ultraviolet\n\nPUVA:Psoralen plus Ultraviolet-A treatment.\n\nConflict of Interests\nThe authors have no conflict of interests to declare.\n\nFigure 1 Keloidal scleroderma. Multiple, scattered, and hyperpigmented nodules overlying plaques along the trunk and upper extremities.\n\nFigure 2 Keloidal scleroderma. Histologic sections show an acanthotic epidermis with overlying basilar hyperpigmentation. Within the dermis there is a proliferation of myofibroblasts and thickened collagen bundles. There is a lack of vertically oriented blood vessels and a lack of atrophy of the overlying epidermis speaking against that of a keloid or scar. At low power (2x) biopsy has a barrel-shaped appearance. The dermal component is expansile and extends beyond that of the epidermal component.\n\nFigure 3 A tissue elastic stain shows preserved elastic fibers within areas of scleroderma. In areas of keloid these elastic fibers are typically absent, thus supporting the diagnosis of keloidal scleroderma and not that of a keloid.\n\nTable 1 Patient characteristics, clinical manifestations, and laboratory findings in keloidal scleroderma.\n\nPatient characteristics\t% of total patients \t\nGender\t \t\n Female\t70\t\n Male\t30\t\nRace\t \t\n African American\t59\t\n Caucasian\t30\t\n Hispanic\t7\t\n Middle Eastern\t4\t\nClinical manifestation\t58\t\n Sclerodactyly\t58\t\n Raynaud's\t47\t\n Arthritis\t30\t\n Pulmonary involvement\t28\t\n Esophageal dysmotility\t23\t\n Renal involvement\t5\t\nDistribution\t \t\n Trunk\t91\t\n Acral\t60\t\n Head/neck\t35\t\n Intertriginous\t2\t\nExternal trigger\t10\t\nLaboratory results\t \t\n ANA\t63\t\n Elevated ESR\t15\t\n Anti-Scl-70\t10\n==== Refs\n1 Labandeira J. León-Mateos A. Suárez-Peñaranda J. M. Garea M. T. Toribio J. What is nodular-keloidal scleroderma? Dermatology 2003 207 2 130 132 10.1159/000071780 2-s2.0-0042508789 12920359 \n2 Stadler B. Fontana M. T. Somacal A. P. B. Skare T. L. Weingraber E. Systemic sclerosis with keloidal nodules Anais Brasileiros de Dermatologia 2013 88 6 supplement 1 75 77 10.1590/abd1806-4841.20132245 2-s2.0-84890616801 24346885 \n3 Zwischenberger B. A. Jacobe H. T. A systematic review of morphea treatments and therapeutic algorithm Journal of the American Academy of Dermatology 2011 65 5 925 941 10.1016/j.jaad.2010.09.006 2-s2.0-80054115914 21645943 \n4 van den Hoogen F. H. J. Boerbooms A. M. T. Swaak A. J. G. Rasker J. J. van Lier H. J. J. van de Putte L. B. A. Comparison of methotrexate with placebo in the treatment of systemic sclerosis: a 24 week randomized double-blind trial, followed by a 24 week observational trial British Journal of Rheumatology 1996 35 4 364 372 10.1093/rheumatology/35.4.364 2-s2.0-0029867337 8624641 \n5 Pope J. E. Bellamy N. Seibold J. R. A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma Arthritis and Rheumatism 2001 44 6 1351 1358 10.1002/1529-0131(200106)44:6<1351::AID-ART227>3.0.CO;2-I 2-s2.0-0034970031 11407694 \n6 Melani L. Caproni M. Cardinali C. A case of nodular scleroderma The Journal of Dermatology 2005 32 12 1028 1031 10.1111/j.1346-8138.2005.tb00895.x 2-s2.0-32944476257 16471471 \n7 Mizutani H. Taniguchi H. Sakakura T. Shimizu M. Nodular scleroderma: focally increased tenascin expression differing from that in the surrounding scleroderma skin Journal of Dermatology 1995 22 4 267 271 10.1111/j.1346-8138.1995.tb03384.x 2-s2.0-0029044721 7541812 \n8 Santiago M. de Castro D. O. Jr. Costa C. A. Passos E. S. Paixão A. Keloidal scleroderma Clinical Rheumatology 2004 23 1 50 51 10.1007/s10067-003-0823-1 2-s2.0-1342326613 14749984 \n9 Sasaki T. Denpo K. Ono H. Nakajima H. Nodular scleroderma in systemic sclerosis under D-penicillamine therapy The Journal of Dermatology 1992 19 12 968 971 10.1111/j.1346-8138.1992.tb03814.x 2-s2.0-0027070649 1293190 \n10 Le E. N. Junkins-Hopkins J. M. Sherber N. S. Wigley F. M. Nodular/keloidal scleroderma: acquired collagenous nodules in systemic sclerosis The Journal of Rheumatology 2012 39 3 660 661 10.3899/jrheum.111057 2-s2.0-84857888299 22383359\n\n",
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"abstract": "Despite the theoretical risk of serotonin toxicity (ST) with linezolid, \"real-world\" clinical evaluations of the risk of ST in patients receiving linezolid have been limited to case reports and noncomparator studies. An observational, matched-cohort study was conducted to evaluate the risk of ST among hospitalized patients who received linezolid or vancomycin at the Upstate New York Veterans Affairs Healthcare Network (Veterans Integrated Service Network 2 [VISN-2]). Matching criteria included VISN-2 hospital, hospital ward, prior hospital length of stay, age, and baseline platelet counts. The patients' electronic medical records were evaluated for symptoms consistent with ST and the Hunter serotonin toxicity criteria (HSTC) using an intensive, natural word search algorithm. The study included 251 matched pairs. Demographics and comorbidities were similar between groups. Over half of the study population received at least one concurrent medication with serotonergic activity. Receipt of agents with serotonergic activity was more pronounced in the vancomycin group, and the higher frequency was due to concomitant antihistamine and antiemetic use. Antidepressant use, including selective serotonin reuptake inhibitors (SSRIs), was similar between groups. No patients in either group were found to meet the criteria using the word search algorithm for ST. Fewer linezolid patients than vancomycin patients met the HSTC overall (3.2% versus 8.8%) and when stratified by receipt of a concurrent serotonergic agent (4.3% versus 12.4%). Of the patients meeting the HSTC, most had past or present comorbidities that may have contributed to or overlapped the HSTC. This study of hospitalized patients revealed comparably low frequencies of adverse events potentially related to ST among patients who received linezolid or vancomycin.",
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"abstract": ": Kaposi sarcoma Herpesvirus (KSHV)-associated inflammatory cytokine syndrome (KICS) is an uncommon but aggressive human Kaposi sarcoma herpesvirus associated disorder that is mostly reported in people living with HIV. The diagnosis of KICS is based on clinical criteria, and, in contrast to other KSHV-related malignancies, characteristic pathological features have not yet been described. We report novel clinical and pathological features in an HIV-1 infected patient diagnosed with KICS.",
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"abstract": "Daptomycin, a cyclic lipopeptide antibiotic, has bactericidal activity against Gram-positive organisms and is especially effective against methicillin-resistant Staphylococcus aureus. Although daptomycin causes unique adverse drug reactions such as elevation of creatine phosphokinase or rhabdomyolysis, the detailed mechanisms underlying these adverse drug reactions in skeletal muscle are unclear. This study aimed to elucidate whether daptomycin causes direct skeletal muscle cell toxicity and investigate the relationship between daptomycin exposure and musculoskeletal toxicity. First, we evaluated the relationship between daptomycin exposure and skeletal muscle toxicity. Of the 38 patients who received daptomycin intravenously, an elevation in creatine phosphokinase levels was observed in five. The median plasma trough concentration of daptomycin in patients with elevated creatine phosphokinase levels was significantly higher than that in patients whose creatine phosphokinase levels were within the normal range, suggesting that increased exposure to daptomycin is related to elevation in creatine phosphokinase levels. In an in vitro study using human rhabdomyosarcoma cells, daptomycin reduced cell viability and increased membrane damage. These effects were more marked under hypoxic conditions. A necroptotic pathway seemed to be involved because phosphorylated mixed lineage kinase domain-like protein expression was enhanced following daptomycin exposure, which was significantly enhanced under hypoxic conditions. These findings indicate that daptomycin elicits cytotoxic effects against skeletal muscle cells via the necroptotic pathway, and the extent of toxicity is enhanced under hypoxic conditions.",
"affiliations": "Department of Pharmacy, Hokkaido University Hospital.;Department of Pharmacy, Hokkaido University Hospital.;Department of Infection Control and Prevention, Hokkaido University Hospital.;Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Laboratory of Clinical Pharmaceutics and Therapeutics, Hokkaido University.;Department of Pharmacy, Hokkaido University Hospital.",
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"abstract": "Allogeneic hematopoietic cell transplantation (allo-HCT) in a CCR5∆32 homozygous donor resulted in HIV cure. Understanding how allo-HCT impacts the HIV reservoir will inform cure strategies.\nA 12-year-old with perinatally acquired, CCR5-tropic HIV and acute lymphoblastic leukemia underwent myeloablative conditioning and umbilical cord blood (UCB) transplantation from a CCR5∆32 homozygous donor. Peripheral blood mononuclear cells (PBMCs) and the rectum were sampled pre- and post-transplant. The brain, lung, lymph node (LN), stomach, duodenum, ileum, and colon were sampled 73 days after transplantation (day +73), when the patient died from graft-vs-host disease. Droplet digital polymerase chain reaction (ddPCR) and in situ hybridization (ISH) were used detect the HIV reservoir in tissues. CCR5 and CD3 expression in the LN was assessed using immunohistochemistry (IHC).\nHIV DNA (vDNA) was detected in PBMCs by ddPCR pretransplant but not post-transplant. vDNA was detected by ISH in the rectum at days -8 and +22, and in the LN, colon, lung, and brain day +73. vDNA was also detected in the lung by ddPCR. IHC revealed CCR5+CD3+ cells in the LN postmortem.\nHIV was detected in multiple tissues 73 days after CCR5∆32 homozygous UCB allo-HCT despite myeloablative conditioning and complete donor marrow engraftment. These results highlight the importance of analyzing tissue during HIV cure interventions and inform the choice of assay used to detect HIV in tissue reservoirs.",
"affiliations": "Department of Medicine, University of Minnesota, Minneapolis, Minnesota.;Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.;Department of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota.;Veteran's Affairs (VA) San Diego Healthcare System, San Diego, California.;Center for AIDS Research, University of California San Diego, La Jolla, California.;Veteran's Affairs (VA) San Diego Healthcare System, San Diego, California.;Department of Pathology and Lab Medicine, University of Minnesota, Minneapolis, Minnesota.;AIDS and Cancer Virus Program and Laboratory Animal Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland.;College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska.;College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska.;Department of Medicine, University of Minnesota, Minneapolis, Minnesota.;Department of Medicine, University of Minnesota, Minneapolis, Minnesota.;Department of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota.;Department of Medicine, University of Minnesota, Minneapolis, Minnesota.;Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.",
"authors": "Rothenberger|Meghan|M|;Wagner|John E|JE|;Haase|Ashley|A|;Richman|Douglas|D|;Grzywacz|Bartosz|B|;Strain|Matthew|M|;Lada|Steven|S|;Estes|Jacob|J|;Fletcher|Courtney V|CV|;Podany|Anthony T|AT|;Anderson|Jodi|J|;Schmidt|Thomas|T|;Wietgrefe|Steve|S|;Schacker|Timothy|T|;Verneris|Michael R|MR|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1093/ofid/ofy090",
"fulltext": "\n==== Front\nOpen Forum Infect Dis\nOpen Forum Infect Dis\nofid\nOpen Forum Infectious Diseases\n2328-8957 Oxford University Press US \n\n29868623\n10.1093/ofid/ofy090\nofy090\nMajor Article\nEditor's Choice\nTransplantation of CCR5∆32 Homozygous Umbilical Cord Blood in a Child With Acute Lymphoblastic Leukemia and Perinatally Acquired HIV Infection\nRothenberger Meghan 1 Wagner John E 2 Haase Ashley 3 Richman Douglas 56 Grzywacz Bartosz 4 Strain Matthew 5 Lada Steven 6 Estes Jacob 7 Fletcher Courtney V 8 Podany Anthony T 8 Anderson Jodi 1 Schmidt Thomas 1 Wietgrefe Steve 3 Schacker Timothy 1 Verneris Michael R 2 1 \nDepartment of Medicine, University of Minnesota, Minneapolis, Minnesota\n\n2 \nDepartment of Pediatrics, University of Minnesota, Minneapolis, Minnesota\n\n3 \nDepartment of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota\n\n6 \nDepartment of Pathology and Lab Medicine, University of Minnesota, Minneapolis, Minnesota\n\n4 \nCenter for AIDS Research, University of California San Diego, La Jolla, California\n\n5 \nVeteran’s Affairs (VA) San Diego Healthcare System, San Diego, California\n\n7 \nAIDS and Cancer Virus Program and Laboratory Animal Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland\n\n8 \nCollege of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska\n\nCorrespondence: M. Rothenberger, MD, Department of Medicine, University of Minnesota, Medicine Education Office, MMC 284 Mayo, 8284A, 420 Delaware St SE, Minneapolis, MN 55455 (roth0134@umn.edu).Present affiliation: Pediatrics-Heme/Onc and Bone Marrow Transplantation, University of Colorado, Aurora, Colorado\n\nCo-senior authors\n\n\n5 2018 \n22 5 2018 \n22 5 2018 \n5 5 ofy09018 12 2017 09 5 2018 © The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases Society of America.2018This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nBackground\nAllogeneic hematopoietic cell transplantation (allo-HCT) in a CCR5∆32 homozygous donor resulted in HIV cure. Understanding how allo-HCT impacts the HIV reservoir will inform cure strategies.\n\nMethods\nA 12-year-old with perinatally acquired, CCR5-tropic HIV and acute lymphoblastic leukemia underwent myeloablative conditioning and umbilical cord blood (UCB) transplantation from a CCR5∆32 homozygous donor. Peripheral blood mononuclear cells (PBMCs) and the rectum were sampled pre- and post-transplant. The brain, lung, lymph node (LN), stomach, duodenum, ileum, and colon were sampled 73 days after transplantation (day +73), when the patient died from graft-vs-host disease. Droplet digital polymerase chain reaction (ddPCR) and in situ hybridization (ISH) were used detect the HIV reservoir in tissues. CCR5 and CD3 expression in the LN was assessed using immunohistochemistry (IHC).\n\nResults\nHIV DNA (vDNA) was detected in PBMCs by ddPCR pretransplant but not post-transplant. vDNA was detected by ISH in the rectum at days –8 and +22, and in the LN, colon, lung, and brain day +73. vDNA was also detected in the lung by ddPCR. IHC revealed CCR5+CD3+ cells in the LN postmortem.\n\nConclusions\nHIV was detected in multiple tissues 73 days after CCR5∆32 homozygous UCB allo-HCT despite myeloablative conditioning and complete donor marrow engraftment. These results highlight the importance of analyzing tissue during HIV cure interventions and inform the choice of assay used to detect HIV in tissue reservoirs.\n\nallogeneic bone marrow transplantationCCR5∆32HIV cureHIV reservoirsNational Institutes of Health10.13039/100000002P01 CA65493AI100879U19AI096109P01AI074340TWS RO1AI124965HHSN261200800001E\n==== Body\nDespite great advances in HIV treatment, cure remains elusive. The Berlin Patient, who underwent myeloablative, allogeneic hematopoietic cell transplantation (allo-HCT) from an human leukocyte antigen (HLA)-matched, CCR5∆32 homozygous donor, is the only individual in whom a cure has been achieved [1, 2]. Mechanistically, it is postulated that “cure” was achieved through a combination of myeloablative conditioning and eradication of HIV-infected host cells by graft-vs-host (GVH) immune responses and establishment of donor cells resistant to infection by the patient’s R5 virus. Subsequent allo-HCT transplants in HIV-infected patients using wild-type CCR5 donor cells have not resulted in lasting HIV remission [3].\n\nWe describe a case of a child with congenitally acquired HIV who developed acute lymphoblastic leukemia (ALL) with characteristics that were unlikely to be cured with traditional chemotherapy and whose odds for survival was best with an allo-HCT. We chose to use banked 3/6 HLA-matched umbilical cord blood (UCB) because of the lack of a matched sibling donor and because we previously demonstrated that 3/6 matched UCB has equivalent outcomes in children with leukemia, relative to better-matched UCB units [4]. Given the patient’s HIV status and CCR5-tropic virus, we searched for a suitably HLA-matched CCR5∆32 homozygous donor in the unrelated donor registries [5].\n\nPublished reports on CCR5∆32 homozygous UCB allo-HCT include a 53-year-old male with HIV and myelodysplastic syndrome who died of recurrent disease 2 months after allo-HCT and a 37-year-old male with HIV and aggressive lymphoma who died 3 months after transplant from progressive disease [6, 7]. Although no virologic studies have been reported from the first patient, HIV DNA was cleared from the peripheral blood (PB) of the second patient. However, virologic studies were not performed in secondary lymphatic tissues (LTs), which harbor the majority of latently infected cells [8–12]. As demonstrated by the Boston Patients, both of whom developed virologic rebound after allo-HCT despite clearing HIV DNA from PB and losing detectable cellular immune responses to HIV, PB analyses cannot reliably predict cure after allo-HCT [3].\n\nHerein, we report our experience using myeloablative conditioning followed by transplantation of a CCR5∆32 homozygous UCB unit in a child with perinatally acquired HIV and ALL and show the impact of this procedure on the HIV reservoir in multiple tissues using both polymerase chain reaction (PCR) and in situ hybridization (ISH) 73 days after transplantation, when the patient died from complications of graft-vs-host disease (GVHD). Our results describe the timing of viral clearance after transplantation, the management of HIV-infected patients undergoing allo-HCT, and the utility of different methods of detecting HIV when evaluating cure strategies.\n\nCASE REPORT\nThe patient was diagnosed with perinatally acquired HIV at age 1 and was started on antiretroviral therapy (ART). However, given difficulties tolerating multiple oral regimens and issues with clinic follow-up, the patient had detectable viremia and marked immune suppression with absolute CD4 T cell counts consistently <100 cells/mm3 throughout childhood, with several opportunistic infections including presumed Pneumocystis jirovecii pneumonia at age 7 years. In September 2012, at the age of 11 years, the patient underwent evaluation of pancytopenia and was found to have hypodiploid ALL. After induction using protocol COG AALL1131, the patient had persistent minimal residual disease (MRD; 0.3% using COG reference flow cytometry laboratory). Given the high-risk features of the leukemia and poor response to induction therapy, the patient was referred for consideration of allo-HCT. Because the patient’s HIV was CCR5-tropic, a search for a CCR5∆32 homozygous UCB unit commenced.\n\nBefore transfer to the University of Minnesota (UMN) Bone Marrow Transplant Center, the patient had been treated with raltegravir and tenofovir/emtricitabine but had a difficult time tolerating oral medications due to gastrointestinal (GI) issues. He developed a detectable HIV viral load (VL) and a new M184V mutation. His antiretrovirals (ARVs) were therefore changed to raltegravir, tenofovir, and abacavir several weeks before transfer to UMN. Immediately after transfer, his HIV VL was 63 800 copies/mL and absolute CD4 count was 1 cell/mm3. A gastrostomy tube was placed, tenofovir and raltegravir were continued, abacavir was stopped, and ritonavir-boosted darunavir was started in an attempt to rapidly suppress the VL before allo-HCT. Four weeks later, his VL had improved to 74 copies/mL. Transplant conditioning was initiated and consisted of cyclophosphamide (50 mg/kg × 2), fludarabine (25 mg/m2 × 3), and total body irradiation (1320 cGy); GVHD prophylaxis was with cyclosporine A (CSA) and mycophenolic acid mofetil (MMF). Inhaled pentamidine, micafungin, and azithromycin were used for infectious disease prophylaxis. During conditioning with cyclophosphamide, tenofovir and raltegravir were continued, but ritonovir and darunavir were held, and abacavir was substituted given drug/drug interactions. Abacavir was stopped and boosted darunavir was restarted after cyclophosphamide was completed. At day 0, the patient underwent UCB transplant from an HLA 3/6 matched donor. The patient’s HIV PB VL was suppressed (<48 copies/mL) at the time of transplant. All ARVs were held for 3 days after transplant given concern that they might interfere with engraftment, but they were then restarted. ARV drug levels were checked weekly, and several dose adjustments were required, although HIV VL remained suppressed. The patient demonstrated neutrophil recovery in the peripheral blood on day 14, and whole-blood chimerism studies demonstrated 100% donor engraftment based on short tandem repeat analysis; the margin of error of this clinical assay is ±5%. On day 21, the bone marrow also demonstrated 100% donor engraftment and 10% cellularity, tri-lineage hematopoiesis, and no evidence of leukemia. Chimerism studies on purified CD3 and CD15 isolated from the peripheral blood on days 35 and 59 also revealed 100% donor engraftment. Thirty-six days after transplant, the patient was transitioned from intravenous to oral CSA. Concurrent with this, there was a drop in the systemic CSA levels, and the patient developed grade IV lower gastrointestinal GVHD at day 38 that was refractory to corticosteroid treatment. He was subsequently treated with antithymocyte globulin, MMF, budesonide, and infliximab. Given drug/drug interactions and concern for toxicity, all ARVs were stopped at day 62. Despite aggressive supportive care, the patient developed multi-organ failure and died 73 days after allo-HCT. The patient’s clinical course is outlined in Figure 1.\n\nFigure 1.\n The patient’s clinical course, including HIV viral load (VL), timing of myeloablative allogeneic umbilical cord blood hematopoietic cell transplant (UCB-allo-HCT), immune suppressant therapy, and tissue sampling time points, is shown from time of transfer to our institution to time of death 73 days after transplantation. Abbreviations: ABC, abacavir; ARVs, antiretrovirals; GVHD, graft-vs-host disease; RAL, raltegravir; r/DRV, ritonavir-boosted darunavir; TBI, total body irradiation; TDF, tenofovir.\n\nMETHODS\nClinical and Study Laboratory Procedures\nInformed consent from the patient’s guardian was obtained in accordance with the Declaration of Helsinki. The work was approved by the Institutional Review Board of the University of Minnesota, and the clinical treatment protocol was registered with the US Food and Drug Administration (as an amendment to IND 14797) before study initiation. HIV tropism was determined using the Monogram Biosciences phenotypic viral RNA assay. HIV VL was measured twice weekly using the Roche COBAS Ampliprep/COBAS Taqman HIV-1 Test, version 2.0.\n\nPlasma Antiretroviral Drug Levels\nTrough plasma concentrations of ARVs were measured weekly from the time of transplant in the Antiviral Pharmacology Laboratory at the University of Nebraska Medical Center using quality-controlled, liquid chromatography/tandem mass spectrometry methods, as previously described [13–15].\n\nTissue Collection and Processing\nRelative to the day of transplant (day 0), PBMCs were obtained at days –61, –20, and –8 and +35 and +49. Rectal biopsies were obtained via flexible sigmoidoscopy at days –8 and +22. Samples of the brain, lung, lymph node (LN), stomach, duodenum, ileum, and colon were obtained at autopsy. PBMCs and tissues were processed as previously described [12].\n\nRadiolabeled RNA In Situ Hybridization\nRadiolabeled RNA ISH (rISH) was performed on tissues as previously described [12]. Five-micrometer-thick sections from the paraffin-embedded tissue were cut through the entire tissue block. Twenty sections from each block were analyzed using every fourth section to measure vRNA+ cells in 20-μm intervals. Photographic images using epifluorescence were taken with a digital camera, and the tif images were analyzed for the area of the sections and the area occupied by silver grains using Photoshop with Fovea Pro. Section weights were estimated from their 5-μm thickness and area and density of fixed tissues. Image analyses were repeated by a blinded expert at an outside institution.\n\nNext-Generation DNA In Situ Hybridization (DNAScope)\nAfter processing as above, next-generation DNA in situ hybridization (DNAscope) was used to detect vDNA as previously described [16]. Image analyses were also repeated by a blinded expert at an outside institution.\n\nDroplet Digital PCR\nDroplet digital PCR (ddPCR) was performed at the University of California San Diego as previously described [17, 18]. Two primers, skGag and joPol, were used as described [19, 20].\n\nImmunohistochemistry\nStaining was completed using the Opal 4-color Fluorescent IHC Kit (PerkinElmer). Briefly, slides were dewaxed and hydrated. Antigen retrieval was performed with AR6 buffer in the microwave. After washing, slides were blocked with the PerkinElmer antibody diluent/block for 10 minutes. Slides were drained, and CD3 (clone SP7, Thermo Scientific) was added for 1 hour at room temperature. Following TBST buffer rinses, the Polymer HRP Ms+Rb was added for 10 minutes and washed again. The Opal 520 working solution was added to the slides for 10 minutes. Slides were rinsed. To strip the antibody off, the slides were microwaved again in the AR6 buffer. The staining process was repeated, this time using the CCR5 antibody (Lifespan Biosciences, Inc.) as the primary antibody and the Opal 570 for the fluorophore. Slides were washed, counterstained with DAPI, and mounted in Aqua-Poly/Mount (Polysciences, Inc.).\n\nRole of Funding Sources\nThe funders of this study had no role in the design of the study, the data collection, analysis, or interpretation, the writing of the report, or the decision to submit for publication.\n\nRESULTS\nViral load results and ART regimens used throughout the transplant course are detailed in Figure 1. At time of transplant, the trough plasma raltegravir concentration was low at 67.2 ng/mL, so the dose was increased to three 100-mg chewable tablets twice daily. The goal trough (approximately 100 ng/mL) was reached the following week and remained stable (median, 89 ng/mL; interquartile range, 85–155 ng/mL) until discontinued. Tenofovir levels were below the limit of detection (10 ng/mL) at the time of transplant; this was felt to be due to adherence and the difficulties of use of oral tenofovir powder. Shortly after transplant, the appropriate strength (250 mg) of tenofovir tablets was obtained, and tenofovir was given as a crushed tablet via a G tube. Levels increased but did not reach the target range until day +42. Darunavir levels (median, 772 ng/mL) were in the target range from time of transplant and remained there until the onset of GI GVHD on day +38, when levels decreased; darunavir remained below target level until it was discontinued on day 57. HIV VL remained suppressed from the time of transplant until death.\n\nHIV DNA was detectable in PBMCs using ddPCR targeting Pol and Gag genes at all time points before transplant (days –61, –20, and –8), with a frequency ranging from 140 to nearly 500 copies of HIV DNA per 106 cells; HIV DNA was also detected at a lower frequency in rectal tissues at day –8 (Table 1). At the time these pretransplant samples were obtained, HIV RNA was detectable in the PB as the patient did not develop a suppressed HIV VL until 5 days before transplant. Following allo-HCT, HIV DNA was not detected by ddPCR in PBMCs at +35 and +49 days, nor was it present in rectal tissues obtained at day +22. Similarly, ddPCR targeting Pol and Gag genes was negative in the brain, LN, stomach, duodenum, ileum, and colon tissues collected at autopsy on day +73. However, ddPCR using a skGag probe was positive in lung tissue at the time of autopsy, with a frequency of 22 copies/106 cells (Table 1).\n\nTable 1. Results of HIV Reservoir Assessment\n\nTime Pointa\tTissue\tAssay\t\t\nddPCR Polb\tddPCR Gagc\tNo. of Cells Assayed by ddPCR\tISH DNAd\tISH RNAe\t\nPretransplant\t\n–60\tPBMCs\t211.26\t146.11\t74 600\t-\t-\t\n–20\tPBMCs\t496.43\t140.89\t112 000\t-\t-\t\n–8\tPBMCs\t260.10\t152.33\t193 000\t-\t-\t\n\tRectum\t71.75\t35.80\t53 800\t2.58 × 105\t0\t\nPost-transplant\t\n+22\tRectum\t0\t0\t16 100\t2.60 × 104\t0\t\n+35\tPBMCs\t0\t0\t135 000\t-\t-\t\n+49\tPBMCs\t0\t0\t70 000\t-\t-\t\n+73 (autopsy)\tBrain\t0\t0\t22 600\t7.35 × 102\t0\t\n\tLung\t0\t22.57\t101 000\t1.57 × 104\t0\t\n\tLymph node\t0\t0\t85 900\t1.06 × 105\t0\t\n\tDuodenum\t0\t0\t233 000\t0\t0\t\n\tIleum\t0\t0\t84 600\t0\t0\t\n\tColon\t0\t0\t166 000\t4.16 × 103\t0\t\n\tStomach\tND\tND\t\t0\t0\t\nAbbreviations: ddPCR, droplet digital polymerase chain reaction; ISH, in situ hybridization; ND, not done; PBMC, peripheral blood mononuclear cell. \n\n\naDays in relationship to transplant (date of transplant = day 0). \n\n\nbDigital droplet polymerase chain reaction (PCR) using joPol primer; results reported in DNA copy per 106 cells. \n\n\ncDigital droplet PCR using skGag primer; results reported in DNA copy per 106 cells. \n\n\ndCopies of HIV DNA per gram of tissue; assay performed on tissue only. \n\n\neCopies of HIV RNA per gram of tissue; assay performed on tissue only. \n\nNo HIV RNA (vRNA) was detected by rISH in rectal tissues obtained at days –8 and +22, or in the brain, lung, LN, stomach, duodenum, ileum, and colon at autopsy. However, 2.58 × 105 copies of vDNA/gram of tissue were detected in rectal samples obtained at day –8 and 2.60 × 104 copies/gram at day +22 using DNAscope. At autopsy, 1.06 × 105 copies of vDNA/gram were detected in the LN, 1.57 × 104 copies/gram in the lung, 4.16 × 103 copies/gram in the colon, and 7.35 × 102 copies/gram in the brain (Table 1 and Figure 2). No vDNA was noted in the duodenum, ileum, or stomach.\n\nFigure 2. HIV DNA detected by next-generation in situ hydridization (DNAScope) in rectal tissue (A) obtained 22 days after transplantation and in the rectum (B), lymph node (C), and lung (D) obtained at autopsy 73 days after transplantation. HIV DNA appears red and is highlighted by arrows.\n\nAnalysis of postmortem LN using IHC demonstrated loss of normal lymph node architecture with large areas of necrosis and depleted CD3-positive T cells. Some of the cells stained with CCR5 were consistent with persistence of rare cells of recipient origin, most of which represented CD68-positive macrophages; however, rare CD3-positive cells co-staining with CCR5 were also seen (Figure 3).\n\nFigure 3. Lymph node obtained at autopsy 73 days after transplantation. CD3-positive T cells (green), CCR5-expressing cells (red) and double-positive cells (yellow; denoted by white arrow).\n\nDISCUSSION\nEradication of the reservoir of vDNA+ cells had not occurred 73 days after allo-HCT, despite myeloablative conditioning, grade IV acute GVHD, and the use of CCR5∆32 homozygous donor cells. This not only informs the clinical management of HIV-infected patients undergoing allo-HCT, but more importantly, highlights the challenges of clearing HIV from tissue reservoirs and provides insight into the utility of ddPCR and ISH in detecting the HIV reservoirs in tissues.\n\nAlthough the kinetics of donor engraftment in the PB and BM are well characterized after allo-HCT, little is known about the turnover of recipient cells and the engraftment of donor cells in secondary LT, including LN and GI-associated LT (GALT). These tissues serve as the primary reservoir of HIV vDNA+ and vRNA+ cells and appear to be the source of viral recrudescence after treatment interruption [21]. In the Berlin Patient, CCR5+-expressing macrophages were detected in rectal tissue more than 5 months after transplant, although no HIV was detected [2]. In our patient, we detected presumed recipient cells (CCR5+CD68+ macrophages and CCR5+CD3+ T cells) in the LN 73 days post-transplant despite full donor engraftment in the PB and BM; we also detected vDNA in the colon and LN at this time point. These findings suggest that (1) the turnover of recipient hematopoietic cells in secondary LT is a protracted process, (2) engraftment in PB and BM may not predict engraftment status in the secondary LTs, and (3) these long-lived, radiation- and chemotherapy-resistant recipient cells can harbor HIV for months after transplantation.\n\nWe also found vDNA in our patient’s lung tissue postmortem, which is consistent with evidence that alveolar macrophages (AMs) can harbor HIV DNA [22–24]. There is also evidence that AMs repopulate slowly and remain of recipient origin for at least weeks after allo-HCT, likely explaining the detection of vDNA in this tissue [25].\n\nAlthough we detected vDNA in multiple tissues, we were unable to assess replication competency. However, we readily detected vDNA despite sampling only a fraction of our patient’s tissues, suggesting that the total number of vDNA+ cells was substantial at the time of death. Given evidence that up to 5% of vDNA+ cells harbor replication competent provirus, it seems likely that withdrawing ART in this individual would have resulted in recrudescence of virus replication [26, 27]. Furthermore, in the Boston Patients, viral rebound after allo-HCT resulted from activation of only 1 or a few latently infected cells, demonstrating that even a very small HIV reservoir post-transplant has the potential to avert cure [3].\n\nThere were also differences between measures of HIV DNA by ddPCR and direct visualization by ISH, highlighting the challenge of reservoir measures in tissues. The results of these 2 assays varied, with vDNA being detected in only the rectum and lung post-transplant by ddPCR but in multiple tissues using DNAscope. After processing and disaggregating each tissue, only limited, unsorted cell populations could be assessed by ddPCR. The sensitivity of ddPCR was also likely further impacted by proviral sequence variation as only 2 PCR primers were used. On the other hand, DNAScope utilizes intact tissue, thereby minimizing cellular loss, and has high sensitivity through the use of a combination of ZZ probes in a cocktail probe mixture (40–85 ZZ pairs with approximately 2 to 4.2 kb of genome coverage) and an amplification cascade via sequential hybridization that allows for the visualization of individual virions or vDNA within the nuclei of infected cells [16]. HIV DNA extracted from tissues can be readily quantitated, but the number of CD4 lymphocytes or macrophages being interrogated cannot be measured at present. However, these results highlight the need for multiple measures of vRNA and vDNA to assess the impact of cure interventions, as was done with the Berlin Patient [1].\n\nFinally, our results have implications for the clinical management of HIV+ patients undergoing allo-HCT. First, given our tissue results, we believe that post-transplant ART should be used, even though ART dosing is complex and requires careful attention to drug/drug interactions and an understanding of ARV pharmacokinetics [28]. In our patient, multiple ARV dose adjustments were required due to subtherapeutic plasma drug concentrations, presumably related to impaired GI absorption in the setting of HCT, suggesting that ARV monitoring should be routine for HIV patients undergoing allo-HCT. Furthermore, in this patient, the conversion from intravenous to oral CSA corresponded with the development of GVHD, and drug/drug interactions could have exacerbated this. We were not able to determine the optimal duration of ARVs post-transplant using treatment interruption or additional tissue sampling given our patient’s untimely death, but this will need to be addressed in the future.\n\nSecond, in our patient, only the commercially available phenotypic CCR5 trophile assay was used to determine HIV tropism. However, this assay may miss minority CXCR4 variants that can be selected for by CCR5∆32 allo-HCT, leading to virologic rebound, as has been reported [28, 29]. Although it is unknown if these variants existed in our patient or if they would have emerged post-transplant after stopping ARVs, in the future, consideration should be given to using next-generation sequencing techniques to assess for X4 variants before pursuing CCR5∆32 allo-HCT.\n\nThird, our case illustrates the risks of a curative approach using allogeneic transplantation in HIV-infected patients. At present, it is unclear whether the use of a biallelic mutated CCR5 donor increases the risk of transplant-related mortality. Individuals with this genetic variation have no overt medial problems [30]. However, cure approaches using transplantation and CCR5∆32 hematopoietic stem cell grafts in HIV+ individuals have resulted in a higher than expected mortality.\n\nIn summary, we present evidence that HIV can persist in tissues months after myeloablative UCB allo-HCT with CCR5∆32 donor cells despite clearance of measurable HIV DNA from PBMCs. Our experience provides insight into the optimal management of HIV-infected patients with hematologic malignancies undergoing allo-HCT with CCR5∆32 donor cells and also provides new information about the optimal tools to use when assessing new cure strategies.\n\nAcknowledgments\n\nFinancial support. This work was supported by the following grants: National Institutes of Health grant numbers P01 CA65493 to M.R.V. and J.S.M., AI100879 to M.R.V., U19AI096109 and P01AI074340 to TWS RO1AI124965 to C.V.F. This work was also funded in part with federal funds from the National Cancer Institute, National Institutes of Health (Contract No. HHSN261200800001E to J.E.). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.\n\n\nPotential conflicts of interest. D.R. receives personal fees from Gilead, Antiva, Merck, and Monogram. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.\n==== Refs\nReferences\n1. \nYukl SA , Boritz E , Busch M et al \nChallenges in detecting HIV persistence during potentially curative interventions: a study of the Berlin Patient\n. PLoS Pathog 2013 ; 9 :e1003347 .23671416 \n2. \nHütter G , Nowak D , Mossner M et al \nLong-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation\n. N Engl J Med 2009 ; 360 :692 –8\n.19213682 \n3. \nHenrich TJ , Hanhauser E , Marty FM et al \nAntiretroviral-free HIV-1 remission and viral rebound after allogeneic stem cell transplantation: report of 2 cases\n. Ann Intern Med 2014 ; 161 :319 –27\n.25047577 \n4. \nKurtzberg J , Prasad VK , Carter SL et al ; COBLT Steering Committee \nResults of the Cord Blood Transplantation Study (COBLT): clinical outcomes of unrelated donor umbilical cord blood transplantation in pediatric patients with hematologic malignancies\n. 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Nature 1993 ; 362 :359 –62\n.8096068 \n9. \nHaase AT \nPopulation biology of HIV-1 infection: viral and CD4+ T cell demographics and dynamics in lymphatic tissues\n. Annu Rev Immunol 1999 ; 17 :625 –56\n.10358770 \n10. \nHaase AT , Henry K , Zupancic M et al \nQuantitative image analysis of HIV-1 infection in lymphoid tissue\n. Science 1996 ; 274 :985 –9\n.8875941 \n11. \nReinhart TA , Rogan MJ , Huddleston D et al \nSimian immunodeficiency virus burden in tissues and cellular compartments during clinical latency and AIDS\n. J Infect Dis 1997 ; 176 :1198 –208\n.9359719 \n12. \nSchacker T , Little S , Connick E et al \nProductive infection of T cells in lymphoid tissues during primary and early human immunodeficiency virus infection\n. J Infect Dis 2001 ; 183 :555 –62\n.11170980 \n13. \nDelahunty T , Bushman L , Robbins B , Fletcher CV \nThe simultaneous assay of tenofovir and emtricitabine in plasma using LC/MS/MS and isotopically labeled internal standards\n. J Chromatogr B Analyt Technol Biomed Life Sci 2009 ; 877 :1907 –14\n.\n14. \nSandkovsky U , Swindells S , Robbins BL et al \nMeasurement of plasma and intracellular concentrations of raltegravir in patients with HIV infection\n. AIDS 2012 ; 26 :2257 –9\n.22948265 \n15. \nPodany AT , Winchester LC , Robbins BL , Fletcher CV \nQuantification of cell-associated atazanavir, darunavir, lopinavir, ritonavir, and efavirenz concentrations in human mononuclear cell extracts\n. Antimicrob Agents Chemother 2014 ; 58 :2866 –70\n.24614370 \n16. \nDeleage C , Wietgrefe SW , Del Prete G et al \nDefining HIV and SIV reservoirs in lymphoid tissues\n. Pathog Immun 2016 ; 1 :68 –106\n.27430032 \n17. \nStrain MC , Lada SM , Luong T et al \nHighly precise measurement of HIV DNA by droplet digital PCR\n. PLoS One 2013 ; 8 :e55943 .23573183 \n18. \nMassanella M , Gianella S , Lada SM et al \nQuantification of total and 2-LTR (long terminal repeat) HIV DNA, HIV RNA and herpesvirus DNA in PBMCs\n. Bio Protoc 2015 ; 5 :pii: e1492 .\n19. \nRousseau CM , Nduati RW , Richardson BA et al \nAssociation of levels of HIV-1-infected breast milk cells and risk of mother-to-child transmission\n. J Infect Dis 2004 ; 190 :1880 –8\n.15499546 \n20. \nMulder J , McKinney N , Christopherson C et al \nRapid and simple PCR assay for quantitation of human immunodeficiency virus type 1 RNA in plasma: application to acute retroviral infection\n. J Clin Microbiol 1994 ; 32 :292 –300\n.8150937 \n21. \nRothenberger MK , Keele BF , Wietgrefe SW et al \nLarge number of rebounding/founder HIV variants emerge from multifocal infection in lymphatic tissues after treatment interruption\n. Proc Natl Acad Sci U S A 2015 ; 112 :E1126 –34\n.25713386 \n22. \nYearsley MM , Diaz PT , Knoell D , Nuovo GJ \nCorrelation of HIV-1 detection and histology in AIDS-associated emphysema\n. Diagn Mol Pathol 2005 ; 14 :48 –52\n.15714064 \n23. \nCribbs SK , Lennox J , Caliendo AM et al \nHealthy HIV-1-infected individuals on highly active antiretroviral therapy harbor HIV-1 in their alveolar macrophages\n. AIDS Res Hum Retroviruses 2015 ; 31 :64 –70\n.25134819 \n24. \nJambo KC , Banda DH , Kankwatira AM et al \nSmall alveolar macrophages are infected preferentially by HIV and exhibit impaired phagocytic function\n. Mucosal Immunol 2014 ; 7 :1116 –26\n.24472847 \n25. \nNakata K , Gotoh H , Watanabe J et al \nAugmented proliferation of human alveolar macrophages after allogeneic bone marrow transplantation\n. Blood 1999 ; 93 :667 –73\n.9885229 \n26. \nHo YC , Shan L , Hosmane NN et al \nReplication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure\n. Cell 2013 ; 155 :540 –51\n.24243014 \n27. \nBruner KM , Murray AJ , Pollack RA et al \nDefective proviruses rapidly accumulate during acute HIV-1 infection\n. Nat Med 2016 ; 22 :1043 –9\n.27500724 \n28. \nKordelas L , Verheyen J , Beelen DW et al ; Essen HIV AlloSCT Group \nShift of HIV tropism in stem-cell transplantation with CCR5 Delta32 mutation\n. N Engl J Med 2014 ; 371 :880 –2\n.\n29. \nHütter G \nMore on shift of HIV tropism in stem-cell transplantation with CCR5 delta32/delta32 mutation\n. N Engl J Med 2014 ; 371 :2437 –8\n.\n30. \nGalvani AP , Novembre J \nThe evolutionary history of the CCR5-Delta32 HIV-resistance mutation\n. Microbes Infect 2005 ; 7 :302 –9\n.15715976\n\n",
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"keywords": "CCR5∆32; HIV cure; HIV reservoirs; allogeneic bone marrow transplantation",
"medline_ta": "Open Forum Infect Dis",
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"title": "Transplantation of CCR5∆32 Homozygous Umbilical Cord Blood in a Child With Acute Lymphoblastic Leukemia and Perinatally Acquired HIV Infection.",
"title_normalized": "transplantation of ccr5 32 homozygous umbilical cord blood in a child with acute lymphoblastic leukemia and perinatally acquired hiv infection"
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"abstract": "Kidney transplantation is the best treatment modality for patients with end-stage renal disease. Wound healing is impaired in these patients, and factors such as immunosuppression, older age and comorbidities have a negative impact on wound healing. Recently, negative pressure wound therapy has become an important wound management technique. We present two patients with wound healing issues in the early posttransplant period. In both patients, an imrnunosup- pressive treatment was administered, which included tacrolimus, mycophenolate mophetil and high-dose corticosteroids with anti-IL-2 induction therapy. Postoperatively, the wounds became inflamed with dehiscence. Negative pressure wound therapy was successfully applied to aid the wound healing. The treatment duration period was two weeks for one patient and three weeks for the other. After the treatment period, the wounds were significantly improved and were closed. After the secondary wound closures, the posttransplant course was uneventful in both patients. Presently, one and three years after the transplantations, both patients have well functioning kidneys. According to our limited experience, negative pressure wound therapy is a feasible and effective dehiscence wound treatment following kidney transplantation.",
"affiliations": null,
"authors": "Markić|Dean|D|;Marinović|Marin|M|;Sotosek|Stanislav|S|;Spanjol|Josip|J|;Ivancić|Aldo|A|;Anton|Maricić|M|;Fuckar|Zeljko|Z|",
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"issue": "38(4)",
"journal": "Collegium antropologicum",
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"mesh_terms": "D005260:Female; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D054843:Negative-Pressure Wound Therapy; D016896:Treatment Outcome; D014947:Wounds and Injuries",
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"title": "The role of negative pressure wound therapy in patients with kidney transplantation.",
"title_normalized": "the role of negative pressure wound therapy in patients with kidney transplantation"
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"abstract": "Conventional treatment of Bulimia Nervosa is long term, expensive, and often ineffective. Neural therapy holds promise for treating Bulimia Nervosa in a shorter term, lower cost, and more effective manner. Much of neural therapy involves the superficial injection of local anesthetic injections. Implementation into current practice would be feasible.",
"affiliations": "Psychiatry and Integrative Medicine 997 Glen Cove Avenue Glen Head New York 11545.;Cooper Medical School of Rowan University Chung Institute of Integrative Medicine 110 Marter Avenue, Suite 507 Moorestown New Jersey 08057.;Center for Clinical Epidemiology and Biostatistics Perlman School of Medicine University of Pennsylvania Philadelphia Pennsylvania.",
"authors": "Gurevich|Michael I|MI|0000-0002-2867-6171;Chung|Myung Kyu|MK|;LaRiccia|Patrick J|PJ|",
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"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 2944546310.1002/ccr3.1326CCR31326Case ReportCase ReportsResolving bulimia nervosa using an innovative neural therapy approach: two case reports M. I. Gurevich et al.Gurevich Michael I. http://orcid.org/0000-0002-2867-6171migurevich@gmail.com \n1\nChung Myung Kyu \n2\nLaRiccia Patrick J. \n3\n\n4\n\n1 \nPsychiatry and Integrative Medicine\n997 Glen Cove Avenue\nGlen Head\nNew York\n11545\n\n2 \nCooper Medical School of Rowan University\nChung Institute of Integrative Medicine\n110 Marter Avenue, Suite 507\nMoorestown\nNew Jersey\n08057\n\n3 \nCenter for Clinical Epidemiology and Biostatistics\nPerlman School of Medicine\nUniversity of Pennsylvania\nPhiladelphia\nPennsylvania\n\n4 \nPenn‐Presbyterian Medical Center\nWon Sook Chung Foundation\n51 N. 39th St.\nPhiladelphia\nPennsylvania\n19104\n* Correspondence\n\nMichael I. Gurevich, Psychiatry and Integrative Medicine, 997 Glen Cove Avenue, Glen Head, New York 11545.\n\nTel: 516‐6749489; Fax: 516‐7595946;\n\nE‐mail: migurevich@gmail.com\n22 12 2017 2 2018 6 2 10.1002/ccr3.2018.6.issue-2278 282 01 9 2017 26 10 2017 20 11 2017 © 2017 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Key Clinical Message\nConventional treatment of Bulimia Nervosa is long term, expensive, and often ineffective. Neural therapy holds promise for treating Bulimia Nervosa in a shorter term, lower cost, and more effective manner. Much of neural therapy involves the superficial injection of local anesthetic injections. Implementation into current practice would be feasible.\n\nBulimia nervosainjectionslocal anesthesianeural therapy source-schema-version-number2.0component-idccr31326cover-dateFebruary 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.3.2.2 mode:remove_FC converted:19.02.2018\n\nClinical Case Reports \n2018 ; 6 (2 ): 278 –282 \n29445463 \n\n\nEthical Approval: Our study does not require ethical approval.\n\nSignificant Outcomes: The symptoms of BN were rapidly resolved in two patients using neural therapy.\n\nLimitations: This was a case study of two patients who had simultaneously received other treatments that may have confounded the results.\n==== Body\nIntroduction\nBulimia Nervosa (BN) is characterized by binge eating and compensatory behavior such as frequent self‐induced vomiting 1. Lifetime prevalence is 1% worldwide 2, affecting women at 1.5% and men at 0.5% 2. BN is often accompanied by additional psychopathology, suicidal behavior 3, and physical complications 2, 4. Treatment for BN is complex: involving teams of practitioners 5 including group, family 6, and individual psychotherapists; dietary consultations; medical management of complications; psycho‐pharmacotherapy; hospitalizations and day treatment programs 7, 8. However, treatment efficacy remains limited, with high dropout rates, frequent relapses, and long‐lasting morbidity 5, 6, 7, 8.\n\nWe present two case reports of patients with BN who had failed conventional medical treatment. Their treatment regime included an innovative component called neural therapy (NT). This approach appears to have provided rapid recovery of cases in my practice (MG) and a possible new outlook on the pathophysiology of the condition.\n\nNeural therapy 9 (NT) is a method that uses injections of local anesthetic into trigger points, scars, peripheral nerves, autonomic ganglia, tendon and ligament insertions, the epidural space, and tissues. The determination of injection site(s) depends on the findings of a conventional medical evaluation in the context of referred pain, dermatomes, regional influence of autonomic ganglia, and identified interference fields (IFs). IFs can be generated by any damaged tissue via chronic stimulation of afferent neurons in the autonomic nervous system resulting in chronic autonomic reflex activity such as nausea, vomiting, and pain. Scars are often sources of interference fields.\n\nNT was developed in Germany and the former USSR in the first half of the 1900s. It is commonly used in German‐ and Spanish‐speaking countries, but poorly known in the English‐speaking world. It has been used for the treatment of multiple medical conditions, injuries, and pain 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21. However, its application in the treatment of psychiatric conditions is largely unexplored. The research from VA hospitals to treat veterans suffering from PTSD using Stellate Ganglion injections 22, 23 (which is a NT technique) shows very promising results. It has been used as an adjunct therapy for bipolar disorder patients with good results 24, 25. A literature search in PubMed (which includes MEDLINE), EMBASE, AMED, and CINAHL found no prior report of the use of NT in the treatment of BN. Both patients mentioned herein have provided signed written consent for publication of this report.\n\nCase Presentations\nA 48‐year‐old married female executive presented with persistent daily vomiting for the last 20 years. She self‐induced vomiting nightly. It was a compulsive habit which she accepted to maintain stable weight, reduce guilt from eating large portions at night, and relieve uncomfortable sensations in her stomach. She had suffered from bulimia and anorexia since age 16. At that time, she required extensive therapy managing distorted body images, excessive and compulsive food consumption, and vomiting to control her weight. Over the last several years, her weight had been stable on a highly restricted diet. But any significant bending forward caused her to vomit. She reported an inability to feel emotions and cry. She was sexually abused at age 11 and abused drugs and alcohol in her late teens. Her father committed suicide when she was 6 years old. He suffered from alcoholism and depression. She tried multiple conventional therapies but felt limited or no improvement. Despite her psychiatric issues, she excelled academically and professionally.\n\nHer past medical history included insomnia, depression, hypothyroidism, gastro‐esophageal reflux, and other digestive problems. She received multiple courses of antibiotics due to frequent infections and food poisonings. She ingested two glasses of wine nightly to cope with insomnia. She was taking medications: Escitalopram, Ambien, Levothyroxine, Famotidine, Omeprazole, and Calcium Carbonate. Her initial DSM5 psychiatric diagnoses were as follows: Anorexia Nervosa in full remission, Bulimia Nervosa, moderate; PTSD; substance use disorder in full remission; and major depression, and mild. Her Clinical Global Impression‐Severity (CGI‐S) score was 5.\n\nNeural therapy injections using a total of 10 mL of preservative‐free 1% procaine were injected into the following locations: scar on the right side of the face—1 mL; the umbilical scar—2 mL; intracutaneous blebs over the area of the esophagus—2 mL; xyphoid process—1 mL; upper abdomen—2 mL; and periosteal injections into the sternum—2 mL. During injections, she was asked to focus on her emotional traumas, losses in her life, and her compulsion to vomit resulting in strong emotional relief with a lot of tears.\n\nAlso, a modified form of EMDR (eye movement desensitization and reprocessing) was performed to facilitate processing of emerging emotions. She was asked to follow with her eyes MG's hand making figure eights in the air, while focusing on stressful events resulting in further emotional release. That night she did not vomit.\n\nThe patient's follow‐up appointment occurred 2 weeks later. She had discontinued Famotidine, Omeprazole, and Calcium Carbonate, and later tapered off Escitalopram. There has not been a single episode of self‐induced vomiting or vomiting associated with bending forward for the last 23 months of follow‐up. Her CGI‐S score is 1. She has had at minimum monthly follow‐up visits for other health concerns and prevention. Currently, she has weekly to bi‐weekly appointments with an acupuncturist/naturopathic physician in MG's office.\n\nCase #2\nA 25‐year‐old white male presented with a chief complaint of 5 months of self‐induced vomiting and 30‐pound weight loss. Six months prior, he had discontinued a gluten‐free diet and began to indulge in rapidly consuming large amounts of junk food, and hiding this behavior from his family. He felt guilty and fearful of gaining weight and becoming fat. He resolved his fear and guilt by self‐induced vomiting after each binging episode. The number of vomiting episodes quickly progressed to several times per day, becoming compulsive and unavoidable.\n\nDuring vomiting episodes, he experienced emotional relief and almost sexual‐like pleasure akin to a drug addiction. Initially, he felt gratified for controlling his weight during binging episodes but soon lost control, being unable to resist urges to vomit. This compulsion reminded him of the struggle he experienced earlier in his life coping with drug abuse. Compulsive behavior escalated over the preceding 2 months. He was anxious and preoccupied with the need to vomit, which he induced after each meal. He began to lose weight rapidly. His parents, concerned about unexplained weight loss, consulted a gastroenterologist. Gastroscopy revealed esophagitis. He was started on Omeprazole with some relief of heartburn and vomiting, but he developed severe constipation.\n\nThe patient had long‐standing issues with anxiety and substance abuse. At age 23, he developed psychosis, depression, and suicidal ideations, diagnosed by a consulting psychiatrist as schizophrenia. Several psychotropic medications were prescribed, but his parents refused medication treatment. MG was consulted, changing the diagnosis to drug‐induced psychosis. He was treated using supplements, energetically based psychotherapy, dietary modifications, meditation, and neural therapy. Keeping with the parents’ desires, psychotropic medications were avoided. The patient had 27 office visits over a period of 28 months. He responded well but stopped follow‐up a year and a half before the current visit. His DSM‐5 diagnoses were Bulimia Nervosa, extreme, multiple substance use disorder in full remission, substance‐induced psychotic disorder, in full remission, and generalized anxiety disorder. His Clinical Global Impression‐Severity (CGI‐S) score was 6.\n\nOn this current visit, NT injections were applied to the skin overlying the stomach and esophagus ventrally and dorsally; the periosteum of the sternum; and the thyroid gland. Twelve injections were given using 0.5 to 1 cc of preservative‐free 1% procaine, in addition, 3 cc of preservative‐free 1% procaine was given intravenously as an IV push of 1 to 3 min. The patient was also placed on multivitamins, minerals, and omega 3 oils for general support; St. John's Wort and Avena Sativa for symptoms of depression; Soluna™ homeopathic‐phytotherapy remedies # 3,8,17 and 20 for detoxification; and Biotonic™Adaptogenic Tonic for adrenal support, to improve his digestion, decrease inflammation, and assist with anxiety and depression. On a visit 1 month later, he reported cessation of bulimic episodes after the NT injections. His desire to compulsively vomit stopped. However, he could eat only small doses of food, experienced constipation, and indigestion, but was able to gain 2 lb. He continued Omeprazole for another month.\n\nNeural therapy with localizations similar to the initial visit was repeated four times over the next 2 months in visits spaced 2–3 weeks apart. For the following 9 months, the patient was then seen monthly with the main therapeutic emphasis placed on persistent digestive issues, which resolved after a therapeutic trial of antiparasitic medications, a gluten‐free diet, and use of a mindful eating approach. In a total of 18 months of follow‐up, the patient has been free of self‐induced vomiting for 12 months. He had two episodes of self‐induced vomiting at month six related to stress at work and persistent indigestion. At 9 months of follow‐up, his CGI‐S score was 1 and Clinical Global Impression‐Improvement (CGI‐I) score was 1.\n\nDiscussion\nTwo adult cases of BN responded very quickly to outpatient therapy which included NT. A 48‐year‐old female responded after one NT treatment session and has been free of BN for the last 23 months. A 29‐year‐old male's self‐induced vomiting was eliminated after the first visit. He had two vomiting episodes at the 6‐month mark and has had no vomiting episodes the past 12 months.\n\nThe main limitations of this report are the small sample size, its retrospective nature with the possibility of selection bias, and the lack of controlled replication. Case reports sit on the bottom of evidence‐based medicine's hierarchy of study designs. One cannot generalize from such a small sample. Also, other treatments such as EMDR, food supplements, and gluten restriction were administered, thus there is the problem of confounding which includes the possibility that the whole treatment package rather than NT alone was responsible for the therapeutic benefit. Based on our clinical experience and training, we feel that NT contributed the most to the positive outcomes. More vigorously designed future studies are needed to determine the contributions of the individual components and the entire regime as a whole.\n\nOur total experience with BN includes seven cases. The other five cases were treated with psychotherapy, medications, and food supplements without success. Our positive experiences of NT after addition to our practices across all encountered medical problems prompt us to think that NT was a major contributor to the successful outcome of these two reported cases of BN.\n\nBN treatment approaches encompass the application of behavioral modification, dietary changes, and medication management for patients who are often reluctant to accept any extended therapy. Treatment strategies require long‐term management, efforts of multispecialty treatment teams, expensive hospitalizations, and day treatment program management. High dropout rates are common, and full recovery remains problematic. There are no tactics that can offer speedy symptom resolution, are inexpensive, and do not require long‐term compliance or patient commitment.\n\nNT may offer a fresh understanding of BN's pathophysiological mechanisms and a highly effective treatment. It presents the possibility of a rapid resolution of compulsive vomiting and obsessive food behavior.\n\nThe pathophysiological mechanism of BN is complicated. A psychologically vulnerable population distressed by substance abuse, sexual and emotional traumas looks for relief from pain and suffering. Indulging in food offers a short‐lasting pleasure. It is our hypothesis that self‐induced vomiting coupled with food ingestion creates a Pavlovian conditioned response. After a number of repetitions, vomiting can become an independent provider of endorphin release, creating a vicious cycle. Part of this cycle is localized in the autonomic nervous system (ANS) within ganglions controlling the stomach and esophagus. Vulnerable tissue becomes part of an interference field (IF). The IF in the damaged esophagus and stomach has a memory of its own: Vomiting creates a pleasure experience. Thus a vicious cycle, akin to narcotic seeking behavior, is formed and maintained by the IF.\n\nThe IF concept was developed to explain some of the of the NT effects. Scars, fractures, and dental lesions can create ANS disturbances that can affect other organs. Signals from them can provide nonlinear and nonanatomically connected interference with affected organs. Over the past 90 years, several reports have documented clinical experience suggesting that injecting an IF such as a scar can resolve pain, organ dysfunction, or other symptoms near or at a distance from the IF 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25.\n\nLocal anesthetic injections, like procaine, have the capacity to repolarize the nerve cell membrane resulting in restoration of organ function 9. Nerve cell repolarization is posited to be the crucial mechanism 9 in contrast to endorphin release in acupuncture.\n\nThe rationale for using NT to treat BN is based on the hypothesis that BN is associated with an IF in autonomic nervous system ganglions affecting the esophagus and stomach. The ectodermal layer of the skin is connected to the ANS ganglions controlling those organs. By injecting the ectodermal layer of the skin, the organ function becomes restored. Thus symptoms of compulsive vomiting are eliminated or significantly reduced. “Lightening reaction” a term developed by NT founders denotes an immediate healing reaction. It was observed in both presented cases. Compulsive vomiting stopped immediately in both cases; however, in the second case, there were two additional episodes of vomiting reported 6 months after the treatment.\n\nNT can be convenient for psychiatric patients: It does not require conscious patient participation, examination of underlying psychodynamic mechanisms, or long‐term medication use. Interactions between physician and patient can be relatively brief, and frequent long‐term follow‐up visits are not required. Materials used in NT are inexpensive. Training to learn superficial injections is relatively brief. The method is remarkably safe with very rare side effects. It can be easily incorporated into any treatment program. In my (MG) psychiatric practice, I have witnessed profound effects in treatment‐resistant patients 24, 25.\n\nSummary\nThe effectiveness of conventional BN treatment has been problematic. The two reported cases of successfully treated BN patients point to the possibility of NT being an effective therapeutic agent in the treatment of BN. In both cases, patients were able to rapidly halt vomiting. There were no reported adverse events. Future rigorously designed studies are indicated. We are open to collaboration in this endeavor.\n\nAuthorship\nMichael I Gurevich, MD: wrote the first draft as the treating physician. Myung Kyu Chung, MD: critically reviewed all aspects of the manuscript with special attention to the description of the basic mechanism of action of NT in the introduction; the description of the neural therapy techniques used in the case presentations; and the proposed mechanisms of action described in the discussion section as a collaborating colleague, neural therapy practitioner, and lecturer. Patrick J LaRiccia, MD, MSCE: engaged in the development of the discussion section, the literature review directly related to NT, content development of the introduction, and editing and formatting the content of the case presentations.\n\nConflict of Interest\nNone declared.\n\nAcknowledgment\nWe extend our appreciation to Karl Kjer, PhD for his manuscript editing and formatting.\n==== Refs\nReferences\n1 \nAmerican Psychiatric Association \n. 2013 \nDiagnostic and statistical manual of mental disorders, Fifth Edition (DSM‐5) . American Psychiatric Association , Arlington, TX .\n2 \n\nHudson , J. I. \n, \nE. \nHiripi \n, \nH. G. J. R. \nPope \n, and \nR. C. \nKessler \n. 2007 \nThe prevalence and correlates of eating disorders in the National Comorbidity Survey Replication . Biol. Psychiatry \n61 :348 –358 .16815322 \n3 \n\nPaul , T. \n, \nK. \nSchroeter \n, \nB. \nDahme \n, and \nD. O. \nNutzinger \n. 2002 \nSelf‐injurious behavior in woman with eating disorders . Am. J. Psychiatry \n159 :408 –411 .11870004 \n4 \n\nCrow , S. \n, and \nS. \nSwigart \n. 2005 \nMedical assessment P. 120 in Mitchel J. E. and Peterson C. B. , eds. Assessment of eating disorders . Guilford Publications , New York, NY .\n5 \n\nMcintosh , V. V. W. \n, \nJ. \nJordan \n, and \nC. M. \nBuilic \n. 2010 \nSpecialist supportive clinical management in Grilo C. M. and Mitchel J. E. , eds. The treatment of eating disorders: a clinical handbook . The Guilford Press , New York, NY .\n6 \n\nCouturier , J. \n, \nM. \nKimber \n, and \nP. \nSzatmari \n. 2013 \nEfficacy of family‐based treatment for adolescents with eating disorders: a systemic review and meta‐analysis . Int. J. Eat. Disord. \n46 :3 –11 .22821753 \n7 \n\nWhittal , M. L. \n, \nW. S. \nAgras \n, and \nR. A. \nGould \n. 1999 \nBulimia nervosa: a meta‐ analysis of psychosocial and pharmacological treatments . Behav. Ther. \n30 :117 –135 .\n8 \n\nShapiro , J. R. \n, \nN. D. \nBerkman \n, \nK. A. \nBrownley \n, \nJ. A. \nSedway \n, \nK. N. \nLohr \n, and \nC. M. \nBulik \n. 2007 \nBulimia nervosa treatment: a systemic review of randomized control trials . Int. J. Eat. Disorder. \n40 :321 –336 .\n9 \n\nDosch , P. \n, and \nM. P. \nDosch \n. 2007 \nManual of neural therapy according to Huneke . Thieme , New York, NY .\n10 \n\nBrobyn , T. L. \n, \nM. K. \nChung \n, and \nP. J. \nLaRiccia \n. 2015 \nNeural therapy: an overlooked game changer for patients suffering chronic pain? \nPain Relief. \n4 :1 –4 .\n11 \n\nWeinschenk , S. \n\n2012 \nNeural therapy—a review of the therapeutic use of local anesthetics . Acupunct. Relat. Therap. \n1 :5 –9 .\n12 \n\nHui , F. \n, \nE. \nBoyle \n, and \nE. \nVayda \n. 2012 \nA randomized controlled trial of a multifaceted integrated complementary‐alternative therapy for chronic herpes zoster‐related pain . Altern. Med. Rev. \n17 :57 –68 .22502623 \n13 \n\nChung , M. K. \n, \nD. \nChung \n, and \nP. J. \nLaRiccia \n. 2015 \nTongue piercing and chronic abdominal pain with nausea and vomiting – two cases . Explore \n11 :59 –62 .25457444 \n14 \n\nChung , M. K. \n, and \nP. J. \nLaRiccia \n. 2015 \nSuccessful treatment of chronic nausea and vomiting related to body piercing and tattooing with integrative medicine interventions . Holist. Nurs. Pract. \n29 :33 –36 .25470478 \n15 \n\nMermod , J. \n, \nL. \nFischer \n, and \nL. \nStabu \n. 2008 \nPatient satisfaction of primary care for musculoskeletal diseases: a comparison between neural therapy and conventional medicine . BMC Complem. Altern. Med. \n8 :33 .\n16 \n\nFischer , L. \n, \nS. M. \nLudin \n, \nK. \nPuente de la Vega \n, and \nM. \nSturzenegger \n. 2015 \nNeuralgia of the glossopharyngeal nerve in a patient with posttonsillectomy scarring: recovery after local infiltration of procaine—case report and pathophysiologic discussion . Case Rep. Neurol. Med. \n2015 :5 .\n17 \n\nWeinschenk , S. \n, \nK. \nBrocker \n, \nL. \nHotz \n, \nT. \nStrowitzski \n, and \nS. \nJoos \n. 2013 \nSuccessful therapy of vulvodynia with local anesthetics. A case report . Forsch. Komplementmed. \n20 :138 –143 .23636033 \n18 \n\nSahaa , F. J. \n, \nK. \nKomhard \n, and \nJ. \nLanghorsta \n. 2014 \nSuccessful endoscopic neural therapy of a patient with chronic pain syndrome after rectum gunshot injury . Forsch. Komplementmed. \n21 :310 –313 .25427522 \n19 \n\nChung , M. K. \n, and \nP. J. \nLaRiccia \n. 2017 \nSuccessful integrative medicine assessment and treatment of chronic pain associated with breast surgery: a report of 3 cases . Holist. Nurs. Pract. \n31 :21 –29 .27782920 \n20 \n\nFischer , L. \n, and \nM. \nPfister \n. 2007 \nWirksamkeit der Neuraltherapie bei überwiesenen Patienten mit therapieresistenten chronischen Schmerzen . Schweiz. Zschr. GanzheitsMedizin. \n19 :30 –35 .\n21 \n\nEgli , S. \n, \nM. \nPfister \n, \nM. \nSabina \n, \nS. M. \nLudin \n, \nK. \nPuente de la Vega \n, \nA. \nBusato \n, et al. 2015 \nLong‐term results of therapeutic local anesthesia (neural therapy) in 280 referred refractory chronic pain patients . BMC Complement Altern. Med. \n15 :200 .26115657 \n22 \n\nLipov , G. \n, \nJ. R. \nJoshi \n, \nS. \nSanders \n, \nK. V. \nSlavin \n\n2009 \nA unifying theory linking the prolonged efficacy of the stellate ganglion block for the treatment of chronic regional pain syndrome (CRPS), hot flashes, and posttraumatic stress disorder (PTSD) . Med. Hypotheses \n72 :657 –661 .19237252 \n23 \n\nHicky , A. \n, \nS. \nHandling \n, \nE. \nPevney \n, \nR. \nAllen \n, \nR. N. \nMcLay \n\n2012 \nStellate ganglion block for PTSD . Am. J. Psychiatry \n169 :760 .22760192 \n24 \n\nGurevich , M. I. \n, and \nC. L. \nRobinson \n. 2016 \nAn individualized approach to treatment‐resistant bipolar disorder: a case series . Explore \n12 :237 –245 .27179557 \n25 \n\nGurevich , M. I. \n, and \nC. L. \nRobinson \n. 2015 \nMedication‐free alternatives for long‐term maintenance of bipolar disorder: a case series . Glob. Adv. Health Med. \n4 :53 –60 .25984407\n\n",
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"issn_linking": "2050-0904",
"issue": "6(2)",
"journal": "Clinical case reports",
"keywords": "Bulimia nervosa; injections; local anesthesia; neural therapy",
"medline_ta": "Clin Case Rep",
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"pages": "278-282",
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"pubdate": "2018-02",
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"references": "22821753;11870004;18573222;26115657;25960898;27782920;25427522;27179557;25457444;29445463;23636033;22502623;22760192;19237252;16815322;17370288;25470478;25984407",
"title": "Resolving bulimia nervosa using an innovative neural therapy approach: two case reports.",
"title_normalized": "resolving bulimia nervosa using an innovative neural therapy approach two case reports"
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"abstract": "Cardio-oncology is a growing interdisciplinary field which aims to improve cardiological care for cancer patients in order to reduce morbidity and mortality. The impact of cardiac biomarkers, echocardiographic parameters, and cardiological assessment regarding risk stratification is still unclear. We aimed to identify potential parameters that allow an early risk stratification of cancer patients.\n\n\n\nIn this cohort study, we evaluated 930 patients that were admitted to the cardio-oncology outpatient clinic of the University Hospital Heidelberg from January 2016 to January 2019. We performed echocardiography, including Global Longitudinal Strain (GLS) analysis and measured cardiac biomarkers including N-terminal pro brain-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T levels (hs-cTnT). Most patients were suffering from breast cancer (n = 450, 48.4%), upper gastrointestinal carcinoma (n = 99, 10.6%) or multiple myeloma (n = 51, 5.5%). At the initial visit, we observed 86.7% of patients having a preserved left ventricular ejection fraction (LVEF >50%). At the second follow up, still 78.9% of patients showed a preserved LVEF. Echocardiographic parameters or elevation of NT-proBNP did not significantly correlate with all-cause mortality (ACM) (logistic regression LVEF <50%: P = 0.46, NT-proBNP: P = 0.16) and failed to identify high-risk patients. In contrast, hs-cTnT above the median (≥7 ng/L) was an independent marker to determine ACM (multivariant logistic regression, OR: 2.21, P = 0.0038) among all included patients. In particular, hs-cTnT levels before start of a chemotherapy were predictive for ACM.\n\n\n\nBased on our non-selected cohort of cardio-oncological patients, hs-cTnT was able to identify patients with high mortality by using a low cutoff of 7 ng/L. We conclude that measurement of hs-cTnT is an important tool to stratify the risk for mortality of cancer patients before starting chemotherapy.",
"affiliations": "Department of Internal Medicine III: Cardiology, Angiology & Pulmonology, Heidelberg University Hospital, Heidelberg, Germany.;Department of Internal Medicine III: Cardiology, Angiology & Pulmonology, Heidelberg University Hospital, Heidelberg, Germany.;Department of Internal Medicine III: Cardiology, Angiology & Pulmonology, Heidelberg University Hospital, Heidelberg, Germany.;Department of Internal Medicine III: Cardiology, Angiology & Pulmonology, Heidelberg University Hospital, Heidelberg, Germany.;Clinical Cancer Registry, National Centre for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany.;Department of Cardiology, University Hospital Frankfurt am Main, Frankfurt am Main, Germany.;Department of Internal Medicine III: Cardiology, Angiology & Pulmonology, Heidelberg University Hospital, Heidelberg, Germany.;Department of Cardiology, University Hospital Kiel, Kiel, Germany.;Department of Internal Medicine III: Cardiology, Angiology & Pulmonology, Heidelberg University Hospital, Heidelberg, Germany.;Department of Internal Medicine III: Cardiology, Angiology & Pulmonology, Heidelberg University Hospital, Heidelberg, Germany.;Department of Internal Medicine III: Cardiology, Angiology & Pulmonology, Heidelberg University Hospital, Heidelberg, Germany.",
"authors": "Finke|Daniel|D|;Romann|Sebastian W|SW|;Heckmann|Markus B|MB|;Hund|Hauke|H|;Bougatf|Nina|N|;Kantharajah|Ajith|A|;Katus|Hugo A|HA|;Müller|Oliver J|OJ|;Frey|Norbert|N|;Giannitsis|Evangelos|E|;Lehmann|Lorenz H|LH|",
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"doi": "10.1002/ehf2.13515",
"fulltext": "\n==== Front\nESC Heart Fail\nESC Heart Fail\n10.1002/(ISSN)2055-5822\nEHF2\nESC Heart Failure\n2055-5822\nJohn Wiley and Sons Inc. Hoboken\n\n34396713\n10.1002/ehf2.13515\nEHF213515\nESCHF-20-01230\nOriginal Research Article\nOriginal Research Articles\nHigh‐sensitivity cardiac troponin T determines all‐cause mortality in cancer patients: a single‐centre cohort study\nHigh‐sensitivity cardiac troponin T determines all‐cause mortality in cancer patients: a single‐centre cohort study\nD. Finke et al.\nFinke Daniel 1 2\nRomann Sebastian W. 1 2\nHeckmann Markus B. 1 2\nHund Hauke 1\nBougatf Nina 3 4 5\nKantharajah Ajith 6\nKatus Hugo A. 1 2\nMüller Oliver J. 7\nFrey Norbert 1 2\nGiannitsis Evangelos 1 2\nLehmann Lorenz H. 1 2 4 lorenz.lehmann@med.uni-heidelberg.de\n\n1 Department of Internal Medicine III: Cardiology, Angiology & Pulmonology Heidelberg University Hospital Heidelberg Germany\n2 DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim Heidelberg Germany\n3 Clinical Cancer Registry, National Centre for Tumor Diseases (NCT) Heidelberg Heidelberg Germany\n4 German Cancer Research Center (DKFZ) Heidelberg Germany\n5 Department of Radiation Oncology and Radiotherapy Heidelberg University Hospital Heidelberg Germany\n6 Department of Cardiology University Hospital Frankfurt am Main Frankfurt am Main Germany\n7 Department of Cardiology University Hospital Kiel Kiel Germany\n* Correspondence to: Lorenz Lehmann, Department of Internal Medicine III: Cardiology, Angiology & Pulmonology, Cardio‐Oncology Unit, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. Tel: +49 6221 56‐8676; Fax: +49 6221 56‐5515. Email: lorenz.lehmann@med.uni-heidelberg.de\n15 8 2021\n10 2021\n8 5 10.1002/ehf2.v8.5 37093719\n27 4 2021\n07 1 2021\n05 7 2021\n© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.\n\nAbstract\n\nAims\n\nCardio‐oncology is a growing interdisciplinary field which aims to improve cardiological care for cancer patients in order to reduce morbidity and mortality. The impact of cardiac biomarkers, echocardiographic parameters, and cardiological assessment regarding risk stratification is still unclear. We aimed to identify potential parameters that allow an early risk stratification of cancer patients.\n\nMethods and results\n\nIn this cohort study, we evaluated 930 patients that were admitted to the cardio‐oncology outpatient clinic of the University Hospital Heidelberg from January 2016 to January 2019. We performed echocardiography, including Global Longitudinal Strain (GLS) analysis and measured cardiac biomarkers including N‐terminal pro brain‐type natriuretic peptide (NT‐proBNP) and high‐sensitivity cardiac troponin T levels (hs‐cTnT). Most patients were suffering from breast cancer (n = 450, 48.4%), upper gastrointestinal carcinoma (n = 99, 10.6%) or multiple myeloma (n = 51, 5.5%). At the initial visit, we observed 86.7% of patients having a preserved left ventricular ejection fraction (LVEF >50%). At the second follow up, still 78.9% of patients showed a preserved LVEF. Echocardiographic parameters or elevation of NT‐proBNP did not significantly correlate with all‐cause mortality (ACM) (logistic regression LVEF <50%: P = 0.46, NT‐proBNP: P = 0.16) and failed to identify high‐risk patients. In contrast, hs‐cTnT above the median (≥7 ng/L) was an independent marker to determine ACM (multivariant logistic regression, OR: 2.21, P = 0.0038) among all included patients. In particular, hs‐cTnT levels before start of a chemotherapy were predictive for ACM.\n\nConclusions\n\nBased on our non‐selected cohort of cardio‐oncological patients, hs‐cTnT was able to identify patients with high mortality by using a low cutoff of 7 ng/L. We conclude that measurement of hs‐cTnT is an important tool to stratify the risk for mortality of cancer patients before starting chemotherapy.\n\nCardio‐oncology\nCardiac biomarkers\nHeart failure\nCardiotoxicity\nCancer survivors\nRisk stratification\nBundesministerium für Bildung und Forschung 10.13039/501100002347 01KC2006B Deutsche Forschungsgemeinschaft 10.13039/501100001659 LE 3570/2‐1; 3570/3‐1 German Centre for Cardiovascular Research 10.13039/100010447 source-schema-version-number2.0\ncover-dateOctober 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.8 mode:remove_FC converted:07.10.2021\nFinke, D. , Romann, S. W. , Heckmann, M. B. , Hund, H. , Bougatf, N. , Kantharajah, A. , Katus, H. A. , Müller, O. J. , Frey, N. , Giannitsis, E. , and Lehmann, L. H. (2021) High‐sensitivity cardiac troponin T determines all‐cause mortality in cancer patients: a single‐centre cohort study. ESC Heart Failure, 8 : 3709–3719. 10.1002/ehf2.13515.\n==== Body\npmcIntroduction\n\nThe importance of cardiologic care for cancer patients has emerged over the last years. Three major reasons account for that: improved survival rates of cancer patients due to early detection, personalized treatment options with novel therapies, 1 , 2 and common risk factors for cancer and cardiovascular disease. 3 Moreover, there is evidence that cardiovascular diseases can promote the occurrence of cancer and vice versa. 4 , 5 In general, cardiovascular events such as thrombosis, pulmonary embolism, heart failure, arrhythmia or pericardial effusion have higher incidences in patients suffering from cancer, due to the malignant disease itself or in response to its therapy. 6\n\nSo far, there are only a few studies dedicated to oncologic patients and their specific cardiovascular assessment. This is why the role of cardiac biomarkers or cardiac therapies are still not well defined for the care of cancer patients. 3 , 7 , 8 It is further unclear which surveillance algorithms to use in order to fulfil the specific needs of cancer patients treated with certain kinds of chemotherapy/radiotherapy or who are suffering from multiple oncological diseases.\n\nThe life expectancy of patients suffering from potentially curable cancer entities such as breast cancer is frequently limited by non‐oncological complications. 9 In fact, cardiovascular events are the main cause for death in breast cancer patients who have survived their malignant disease for over 10 years. 10\n\nThese cardiovascular events require special treatment with regard to the medical history of the patients. One critical aim of cardio‐oncological care is to accompany cancer patients throughout their systemic therapy, so that cardiac high‐risk patients can endure potential cardiotoxic drug regimens. Therefore, early detection and subsequent treatment of cardiovascular adverse effects are a cornerstone to improve outcome of cancer patients. 9 , 10\n\nTo date, there is a lack of knowledge, how cardiac parameters can predict the mortality of cancer patients. In order to diagnose cardiotoxicity, many studies concentrated on functional alterations in cardiac imaging, especially in echocardiography. 11 , 12 , 13 , 14 Apart from oncological patients, high‐sensitivity cardiac troponin T (hs‐cTnT) has been shown to be a determining factor for all‐cause mortality (ACM) in patient cohorts with stable coronary heart disease. 15 More recently, cardiotoxicity was classified in three categories: higher grades showed a significantly reduced survival. The grading was distinguished by a combination of biomarkers and echocardiographic parameter including the left ventricular ejection fraction (LVEF), the diastolic function (E/E′), and the global longitudinal strain (GLS). The authors did not focus on the role of single factors, whereas the left ventricular function played a predominant role. 16\n\nThe primary objective of our study was to determine cardiac factors which help to risk stratify cancer patients in a cardio‐oncological setting. We hypothesize that functional impairments in cardiac function and cardiac biomarkers correlate with the patients' mortality.\n\nIn the current cardio‐oncological study cohort, an elevated plasma concentration of hs‐cTnT was associated with increased ACM. This allowed a prediction of the patients' outcome superior to NT‐proBNP or functional cardiac parameters.\n\nMethods\n\nPatients\n\n930 patients attended the cardio‐oncology unit at the University Hospital Heidelberg in the context of systemic therapies at the oncology departments from January 2016 to January 2019. Patient data were collected within the HEidelberg Cardio‐Oncology REgistry (HEartCORE). The study protocol was approved by the Ethics Committee of the Medical Faculty, University Heidelberg (S‐286/2017, 390/2011). The investigation conforms with the principles outlined in the Declaration of Helsinki.\n\nPatients were admitted to the cardio‐oncology unit according to the current guidelines of the American Heart Association (AHA) and European Society of Cardiology (ESC). We did not exclude patients with prior heart failure or reduction in LVEF before the first presentation.\n\nEvery patient was examined prospectively by 12‐lead‐ECG, echocardiography including GLS, if technically applicable, and cardiac biomarkers [hs‐cTnT, N‐terminal pro brain‐type natriuretic peptide (NT‐proBNP)] were assessed, if applicable. In 810 patients, hs‐cTnT was measured at the first or second presentation. These patients were included in the following analysis regarding cardiac biomarkers.\n\nIf no cardiac alterations were found at the first presentation, we monitored the patients every 12 weeks as long as the oncological therapy was continued. Patients with a terminated regimen presented once. In case of reduction of LVEF, hs‐cTnT or NT‐proBNP‐elevation or symptoms of heart failure or acute coronary syndrome, we assessed the patients more frequently, in general every 4 weeks. Further cardiac assessment via cardiac computer tomography (CT), cardiac magnet resonance tomography (MRI), or cardiac catherization were based on clinical presentation, echocardiographic parameter, and cardiovascular risk factors.\n\nData acquisition\n\nPatient specific data were extracted from electronic medical records including ECG, laboratory results, echocardiographic measurements, cardiac MRI/CT results, and angiographic results using the cardiac Research Data Warehouse (RWH).\n\nMeasurement of hs‐cTnT in plasma samples was performed using the Elecsys® Troponin T high sensitive hs‐cTnT assay (Roche Diagnostics) on a Cobas® e411 immunoassay analyser in the central laboratory at Heidelberg University Hospital. On Cobas e411, limit of blank (LoB), limit of detection (LoD), 10% coefficient of variation (CV), and 99th percentile cutoff values for the hs‐cTnT assay were 3, 5, 13, and 14 ng/L. 17 , 18 N‐terminal pro brain‐type natriuretic peptide was measured by the Stratus® CS Acute Care™ NT‐proBNP assay (Siemens AG, Berlin and Munich, Germany). The glomerular filtration rate (GFR) was measured in the central laboratory at Heidelberg University Hospital according to the Modification of Diet in Renal Disease (MDRD) method. Outcome data, including ACM, the date of the initial cancer diagnosis, and tumour grading, were acquired from the Clinical Cancer Registry of the National Centre for Tumour Diseases (NCT) Heidelberg. Tumour grading was performed via pathological evaluation. If there was no pathological material present, we used the clinical staging data.\n\nEchocardiography was performed on a General Electrics (GE) Vivid E9 machine. Images were acquired ECG‐triggered with at least three beads per image. LVEF was measured by a physician who is experienced in echocardiography using the biplanar calculation (2‐ and 4‐chamber view). GLS was determined by use of a vendor‐dependent analysis software (GE). The endocardial surface was detected automatically with manual adjustments, if necessary.\n\nStatistical analysis\n\nPie charts and graphs were illustrated in GraphPad Prism, version 6.0. In order to compare continuous variables, we used the Mann–Whitney test. Dichotomic data were compared using the binomial distribution model. A confidence interval of 95% was considered significant.\n\nLogistic regression analyses were performed in R, version 3.6.2. with the use of the packages safeBinaryRegression (version: 0.1–3), MASS (version 7.3) and in‐house‐scripting. The ggplot2 package (version: 3.2.1) was used to illustrate forest plots.\n\nROC curves and AUC analysis were calculated by the use of the pROC package (version 1.16.2). Kaplan–Meier curves were generated with the survival package (version: 3.1‐8). The observational range was set to 5 years. Patients with shorter follow‐ups were censored. The follow‐up for ACM was defined as the time difference between the initial cancer diagnosis and the date of death or the date of the last reported medical presentation, respectively. Adjustments of hs‐cTnT were performed to left ventricular function, the occurrence of diabetes or arterial hypertension, body mass index (BMI), NT‐proBNP levels, GFR, age, and gender. The log rank test was used to determine differences in survival. A P‐value <0.05 was considered significant.\n\nElevated hs‐cTnT was determined as levels above the 99th percentile (14 ng/L) 19 and elevated NT‐proBNP as levels above the rule‐out criterion of heart failure (300 ng/L). 20 Median laboratory values in our cohort were used for further analysis in order to predict ACM.\n\nImpairments in the systolic left ventricular function were defined as previously published and recommended in the current guidelines of the European Society of Cardiology (ESC). A drop in LV‐function was defined as a LVEF deterioration of above 5% or below 50%. 21\n\nResults\n\nWe examined 930 patients before, during or after their systemic therapies between January 2016 and January 2019. These patients were mainly diagnosed with breast cancer (48.4%), upper gastrointestinal carcinoma (10.6%), multiple myeloma (5.5%), or melanoma (4.1%). Most of the patients were graded T1 or T2 (34.0%) and had no metastasis (M0, 49.8%) or affected lymph nodes (N0, 49.8%).\n\nThe majority of patients in the outpatient clinic was seen during an adjuvant or neoadjuvant setting (415 patients, 44.6%). 138 patients (14.8%) attended after terminated oncological therapies or during palliative regimes (228 patients, 24.5%). 318 patients (34.2%) were treated with radiation, 547 patients (58.8%) underwent surgery and 870 patients (93.5%) received chemotherapy (Table 1 ). Among those patients, 413 patients with available data for outcome and hs‐cTnT were seen before the start of their first chemotherapeutic regimen. 123 patients presented initially in the cardio‐oncology unit during chemotherapy and 109 patients after a terminated chemotherapy. Regarding the cardiovascular risk factors (arterial hypertension, diabetes, adiposity, smoking and hyperlipidemia), there were no significant differences between the groups (Table 2 ). Patients were seen again after 98 days at median (IQR: 58, 153 days, n = 392) and after 191 days (IQR: 127, 287 days, n = 191). Follow‐ups of the outcome were obtained for 553 days at median (IQR: 288; 1,213 days, n = 846). The median time between the initial cancer diagnosis and the blood draw of the cardiac biomarkers was 263 days (IQR: 35; 1,758 days, n = 810). All patients received a cardiological assessment including anamnesis, physical examination, echocardiography including GLS and cardiac biomarkers (hs‐cTnT and NT‐proBNP), if applicable. Based on clinical decisions, 15 patients (1.6%) underwent CT scans to rule out any significant coronary heart disease (CHD). In 113 patients (12.1%) a cardiac catheterization and in 129 patients (13.8%) a cardiac MRI was performed. A more detailed description of the patients' characteristics and demographics can be found in Table 1 .\n\nTable 1 Baseline characteristics\n\n\tTotal (n = 930)\tTotal hs‐cTnT (n = 810)\tHs‐cTnT <7 ng/L (n = 374)\tHs‐cTnT ≥7 ng/L (n = 436)\tP‐value\t\nAge (years)\t61 (52, 70)\t60 (52, 70)\t54 (46, 62)\t67 (58, 75)\t<0.001\t\nMale gender\t287 (30.9%)\t240 (29.6%)\t51 (13.6%)\t189 (43.3%)\t<0.001\t\nRisk factors\t\nArterial hypertension\t222 (23.9%)\t196 (24.2%)\t56 (15%)\t140 (32.1%)\t<0.001\t\nDiabetes\t94 (10.1%)\t85 (10.5%)\t23 (6.1%)\t62 (14.2%)\t<0.001\t\nBMI > 35 kg/m2\t49 (5.3%)\t46 (5.7%)\t21 (5.6%)\t25 (5.7%)\t1.0\t\nSmoking\t272 (30.8%)\t256 (32.7)\t112 (30.7)\t144 (33.0)\t0.522\t\nHyperlipidemia\t135 (15.3%)\t126 (16.1)\t39 (10.7)\t87 (20.0)\t0.001\t\nCancer diagnosis\t\nBreast cancer\t450 (48.4%)\t404 (49.9%)\t258 (69.0%)\t146 (33.5%)\t<0.001\t\nUpper GI tumour\t99 (10.6%)\t90 (11.1%)\t25 (6.7%)\t65 (14.9%)\t<0.001\t\nMultiple myeloma\t51 (5.5%)\t41 (5.1%)\t8 (2.1%)\t33 (7.6%)\t<0.001\t\nMelanoma\t38 (4.1%)\t36 (4.4%)\t15 (4.0%)\t21 (4.8%)\t0.70\t\nOvarian cancer\t35 (3.8%)\t31 (3.8%)\t9 (2.4%)\t22 (5.0%)\t0.08\t\nNET\t34 (3.7%)\t28 (3.5%)\t12 (3.2%)\t16 (3.7%)\t0.87\t\nLymphoma\t31 (3.3%)\t29 (3.6%)\t7 (1.9%)\t22 (5.0%)\t0.03\t\nAML\t29 (3.1%)\t18 (2.2%)\t8 (2.1%)\t10 (2.3%)\t1.0\t\nSarkoma\t19 (2.0%)\t15 (1.9%)\t2 (0.5%)\t13 (3.0%)\t0.02\t\nOther\t144 (15.5%)\t118 (14.6%)\t30 (8.0%)\t88 (20.2%)\t<0.001\t\nOncologic staging\t\nTis\t2 (0.2%)\t1 (0.1%)\t1 (0.1%)\t0 (0.0%)\t0.93\t\nT1\t166 (17.8%)\t152 (18.8%)\t104 (27.8%)\t48 (11.0%)\t<0.001\t\nT2\t151 (16.2%)\t134 (16.5%)\t84 (22.5%)\t50 (11.5%)\t<0.001\t\nT3\t125 (13.4%)\t114 (14.1%)\t35 (9.4%)\t79 (18.1%)\t<0.001\t\nT4\t60 (6.5%)\t54 (6.7%)\t24 (6.4%)\t30 (6.9%)\t0.90\t\nN0\t270 (29.0%)\t252 (31.1%)\t160 (42.8%)\t92 (21.1%)\t<0.001\t\nN1\t212 (22.8%)\t188 (23.2%)\t90 (24.1%)\t98 (22.5%)\t0.65\t\nN2\t39 (4.2%)\t35 (4.3%)\t8 (2.1%)\t27 (6.2%)\t0.007\t\nNx\t13 (1.4%)\t31 (3.8%)\t11 (2.9%)\t20 (4.6%)\t0.30\t\nM0\t463 (49.8%)\t423 (52.2%)\t236 (63.1%)\t187 (42.9%)\t<0.001\t\nM1\t99 (10.6%)\t87 (10.7%)\t28 (7.5%)\t59 (13.5%)\t0.008\t\nMx\t37 (4.0%)\t34 (4.2%)\t19 (5.1%)\t15 (3.4%)\t0.32\t\nOncologic therapy\t\nTherapy setting\t\nPalliative\t228 (24.5%)\t174 (21.5%)\t47 (12.6%)\t127 (29.1%)\t<0.001\t\nAdjuvant\t153 (16.5%)\t125 (15.4%)\t58 (15.5%)\t67 (15.4%)\t1.0\t\nNeoadjuvant\t262 (28.2%)\t237 (29.3%)\t141 (37.7%)\t96 (22.0%)\t<0.001\t\nTerminated\t138 (14.8%)\t136 (16.8%)\t90 (24.1%)\t46 (10.6%)\t<0.001\t\nOther\t149 (16.0%)\t138 (17.0%)\t38 (10.2%)\t100 (22.9%)\t<0.001\t\nChemotherapy\t870 (93.5%)\t752 (92.8%)\t339 (90.6%)\t413 (94.7%)\t0.03\t\nBefore CTx\t504 (54.2%)\t445 (54.9%)\t215 (57.5%)\t230 (52.8%)\t0.20\t\nDuring CTx\t186 (20.0%)\t142 (17.5%)\t42 (11.2%)\t100 (22.9%)\t<0.001\t\nAfter CTx\t130 (14.0%)\t122 (15.1%)\t68 (18.2%)\t54 (12.4%)\t0.028\t\nAnthracyclines\t229 (26.3%)\t195 (25.1%)\t118 (32.4%)\t77 (18.7%)\t<0.001\t\nTrastuzumab\t139 (16.0%)\t118 (15.2%)\t67 (18.4%)\t51 (12.4%)\t0.016\t\nTKI\t37 (4.2%)\t25 (3.2%)\t9 (2.5%)\t16 (3.9%)\t0.41\t\nICI\t76 (8.7%)\t63 (8.1%)\t26 (7.1%)\t37 (9.0%)\t0.50\t\nPI (Carfilzomib)\t11 (1.3%)\t9 (1.2%)\t0 (0.0%)\t9 (2.2%)\t0.014\t\nOther drugs\t242 (26.0%)\t215 (26.5%)\t69 (18.4%)\t146 (33.5%)\t<0.001\t\nRadiation\t318 (34.2%)\t280 (36.1%)\t141 (38.7%)\t139 (33.7%)\t0.10\t\nChest radiation\t241 (25.9%)\t214 (27.6%)\t120 (33.0%)\t94 (22.8%)\t0.001\t\nSurgery\t547 (58.8%)\t489 (63.0%)\t239 (65.7%)\t250 (60.7%)\t0.07\t\nNumber of visits\t\n1 visit\t930 (100%)\t810 (100%)\t374 (100%)\t436 (100%)\t1.0\t\n2 visits\t392 (42.2%)\t341 (42.1%)\t152 (40.6%)\t189 (43.3%)\t0.43\t\n3 visits\t191 (20.5%)\t167 (20.6%)\t86 (23.0%)\t81 (18.6%)\t0.14 s\t\nClinical chemistry\t\nTimepoint (days)\t263 (35, 1758)\t239 (33, 1884)\t137 (30, 1971)\t267 (39, 1490)\t0.738\t\nHs‐cTnT (ng/L)\t7 (4, 12)\t7 (4, 12)\t4 (3, 5)\t11 (9, 17)\t<0.001\t\nNT‐proBNP (ng/L)\t141 (70, 293.5)\t140 (70, 291)\t96 (58, 174)\t210 (101, 533)\t<0.001\t\nCreatinine (mg/dL)\t0.75 (0.65, 0.88)\t0.74 (0.65, 0.87)\t0.70 (0.63, 0.77)\t0.82 (0.69, 1.03)\t<0.001\t\nGFR (mL/min)\t90.67 (76.4, 105.8)\t90.84 (76.75, 105.7)\t94.14 (84.52, 111.03)\t84.36 (69.68, 99.54)\t<0.001\t\nEchocardiography\t\nLVEF (%)\t60.0 (55, 60)\t60 (55, 60)\t60 (60, 60)\t60 (55, 60)\t<0.001\t\nGLS (−%)\t17.9 (16.0, 20.0)\t18.0 (16.0, 20.1)\t18.5 (16.4, 20.4)\t17.6 (15.2, 19.8)\t0.002\t\nE/E′\t7.00 (5.00, 9.00)\t7.00 (5.00, 8.95)\t6.00 (5.00, 8.00)\t7.00 (6.00, 9.00)\t<0.001\t\nCardiac catheterization\t110 (11.8%)\t96 (11.9%)\t22 (5.9%)\t74 (17.0%)\t<0.001\t\nStenosis ≥75%\t27 (2.9%)\t27 (3.3%)\t1 (0.2%)\t26 (6.0%)\t<0.001\t\nCardiac CT\t15 (1.6%)\t15 (1.9%)\t4 (1.1%)\t11 (2.5%)\t0.21\t\nCardiac MRI\t129 (13.9%)\t120 (14.8%)\t40 (10.7%)\t80 (18.3%)\t0.003\t\nAll‐cause mortality\t120 (12.9%)\t99 (12.2%)\t24 (6.4%)\t75 (17.2%)\t0.002\t\nMedian follow‐up survival (days)\t553 (288, 1213)\t541 (287, 1128)\t518 (283, 1245)\t557 (289, 1079)\t0.13\t\nCauses of death\t\nCancer\t58 (6.2%)\t50 (6.2%)\t14 (3.7%)\t36 (8.3%)\t0.01\t\nInfection\t11 (1.2%)\t9 (1.1%)\t0 (0.0%)\t9 (2.1%)\t0.014\t\nUnknown\t51 (5.5%)\t40 (4.9%)\t10 (2.7%)\t30 (6.9%)\t0.01\t\nAML, acute myeloid leukaemia; BMI, body mass index; CT, computer tomography; CTx, chemotherapy; E, early ventricular filling velocity; E′, peak mitral annular velocity during early filling; GFR, glomerular filtration rate; GI, gastrointestinal; GLS, global longitudinal strain; hs‐cTnT, high‐sensitivity cardiac troponin T; ICI, immune checkpoint inhibitor; LVEF, left ventricular ejection fraction; MRI, magnetic resonance imaging; NET, neuroendocrine tumour; NT‐proBNP, N‐terminal pro brain‐type natriuretic peptide; PI, proteasome inhibitor; Timepoint, median time between cancer diagnosis and blood draw (days); TKI, tyrosin kinase inhibitor.\n\nTable 2 Characteristics of patients with chemotherapy\n\n\tTotal patients with CTx (n = 707)\tPresentation before CTx (n = 413)\tPresentation during CTx (n = 123)\tPresentation after CTx (n = 109)\tOther (n = 62)\tP‐value\t\nAge (year)\t60 (51, 70)\t60 (50, 69)\t59 (48.5, 70)\t60 (53, 67)\t63 (56, 71)\t0.310\t\nMale gender\t214 (30.3%)\t137 (33.2%)\t44 (35.8%)\t14 (12.8%)\t19 (30.6%)\t0.056\t\nRisk factors\t\nArterial hypertension\t169 (23.9%)\t91 (22.0%)\t40 (32.5%)\t19 (17.4%)\t19 (30.6%)\t0.196\t\nDiabetes\t73 (10.3%)\t46 (11.1%)\t18 (14.6%)\t3 (2.8%)\t6 (9.7%)\t0.471\t\nBMI > 35 kg/m2\t40 (5.7%)\t27 (6.5%)\t5 (4.0%)\t5 (4.6%)\t3 (4.8%)\t0.301\t\nSmoking\t228 (33.2%)\t134 (33.5%)\t38 (30.4%)\t38 (34.9%)\t20 (33.9%)\t1.0\t\nHyperlipidemia\t104 (15.1%)\t66 (16.5%)\t19 (15.2%)\t15 (13.8%)\t6 (10.2%)\t0.444\t\nCancer diagnosis\t\nBreast cancer\t351 (49.6%)\t194 (47.0%)\t43 (35.0%)\t88 (80.7%)\t26 (41.9%)\t0.108\t\nUpper GI tumour\t86 (12.2%)\t74 (17.9%)\t8 (6.5%)\t3 (2.8%)\t1 (1.6%)\t<0.001\t\nMultiple myeloma\t31 (4.4%)\t23 (5.6%)\t2 (1.6%)\t0 (0.0%)\t6 (9.7%)\t0.102\t\nMelanoma\t27 (3.8%)\t16 (3.9%)\t7 (5.7%)\t1 (0.9%)\t3 (4.8%)\t1.0\t\nOvarial cancer\t31 (4.4%)\t18 (4.4%)\t6 (4.9%)\t1 (0.9%)\t6 (9.7%)\t1.0\t\nNET\t25 (3.5%)\t5 (1.2%)\t13 (10.6%)\t3 (2.8%)\t4 (6.5%)\t0.648\t\nLymphoma\t27 (3.8%)\t17 (4.1%)\t5 (4.1%)\t2 (1.8%)\t3 (4.8%)\t0.772\t\nAML\t17 (2.4%)\t12 (2.9%)\t1 (0.8%)\t3 (2.8%)\t1 (1.6%)\t0.434\t\nSarkoma\t12 (1.7%)\t6 (1.5%)\t2 (1.6%)\t0 (0.0%)\t4 (6.5%)\t0.763\t\nOther\t100 (14.1%)\t48 (11.6%)\t36 (29.3%)\t8 (7.3%)\t8 (12.9%)\t0.030\t\nChemotherapy\t\nAnthracyclines\t177 (25.0%)\t76 (18.4%)\t35 (28.5%)\t45 (41.3%)\t21 (33.9%)\t<0.001\t\nTrastuzumab\t112 (5.8%)\t66 (16.0%)\t23 (18.7%)\t17 (15.6%)\t6 (9.7%)\t0.336\t\nTKI\t19 (2.7%)\t4 (1.0%)\t12 (9.8%)\t1 (0.9%)\t2 (3.2%)\t0.002\t\nICI\t55 (7.8%)\t26 (6.3%)\t22 (17.9%)\t2 (1.8%)\t5 (8.1%)\t0.109\t\nPI (Carfilzomib)\t8 (1.1%)\t5 (1.2%)\t2 (1.6%)\t0 (0.0%)\t1 (1.6%)\t1.0\t\nOther\t194 (27.4%)\t105 (25.4%)\t43 (35.0%)\t22 (20.2%)\t24 (38.7%)\t0.181\t\nClinical chemistry\t\nHs‐cTnT (ng/L)\t7 (4, 11)\t9 (6, 15.5)\t6 (4, 9)\t8 (4, 12)\t7 (4, 11)\t<0.001\t\nEchocardiography\t\nLVEF (%)\t60 (55, 60)\t60 (60, 60)\t60 (55, 60)\t60 (60, 60)\t60 (60, 60)\t0.002\t\nAll‐cause mortality\t\nMedian follow‐up survival (days)\t541 (284.5, 1151.5)\t391 (235, 610)\t715 (323, 1409)\t1095 (823, 1688)\t1492 (745, 1763.25)\t<0.001\t\nCauses of death\t\nCancer\t50 (7.1%)\t35 (8.4%)\t13 (10.6%)\t0 (0.0%)\t2 (3.2%)\t0.115\t\nInfection\t9 (1.3%)\t8 (1.9%)\t0 (0.0%)\t0 (0.0%)\t1 (1.6%)\t0.127\t\nUnknown\t40 (5.7%)\t23 (5.6%)\t11 (8.9%)\t3 (2.8%)\t3 (4.8%)\t1.0\t\nAML, acute myeloid leukaemia; BMI, body mass index; CTx, chemotherapy; hs‐cTnT, high‐sensitivity cardiac troponin T; ICI, immune checkpoint inhibitor; LVEF, left ventricular ejection fraction; NET, neuroendocrine tumour; PI, proteasome inhibitor; TKI, tyrosin kinase inhibitor.\n\nFunctional cardiac assessments\n\n806 patients (86.7%) showed a preserved systolic left ventricular ejection fraction (LVEF >50%) on their first admission to the cardio‐oncology unit. 50.3% of patients (n = 282/561) with data for GLS showed reduced values (GLS > −18%) and 26.7% (n = 174/652) had a reduced diastolic function (E/E′ > 8).\n\nA total of 78.9% of patients still showed a preserved systolic LV function at second follow‐up. However, 17.2% of these patients showed elevated levels of N‐terminal pro brain‐type natriuretic peptide (NT‐proBNP) (above rule‐out, >300 ng/L) and 11.4% of these patients elevated hs‐cTnT (above 99th percentile, >14 pg/mL) (Supporting Information, Figure S1 )\n\nIn terms of diastolic function, we saw fewer patients with diastolic dysfunction during follow‐ups (E/E′ > 8: 20.8% of patients at second follow up, n = 192).\n\nHowever, neither a reduced systolic LV‐function (LVEF <50%, univariate logistic regression, P = 0.46) nor reduced GLS (univariate logistic regression, P = 0.33) did correlate significantly with ACM (Figure 1 ). Consequently, patients with a preserved LVEF >50% did not benefit with regard to survival in Kaplan–Meier analysis (Figure 2 A ).\n\nFigure 1 Univariate logistic regression analysis on all‐cause mortality (ACM). Odds ratios (OR) and 95% confidence interval are shown as forest plot. Male gender, upper gastrointestinal (GI) tumours, and hs‐cTnT levels ≥7 ng/L were associated with increased mortality. Breast cancer patients showed reduced mortality rates. P‐values as indicated. BMI, body mass index; GFR, glomerular filtration rate; GI, gastrointestinal; GLS, global longitudinal strain; Hs‐cTnT, high sensitivity cardiac troponin T; LVEF, left ventricular ejection fraction; NT‐proBNP, N‐terminal pro brain‐type natriuretic peptide.\n\nFigure 2 Kaplan–Meier curves on all‐cause mortality (ACM). Patients are divided into two groups according to their (A) left ventricular systolic function (LVEF ≥/< median of 60%), (B) NT‐proBNP levels (≥/< median of 141 ng/L) and (C) hs‐cTnT level (≥/< median of 7 ng/L). Log rank test P‐value as indicated. Hs‐cTnT, high sensitivity cardiac troponin T; LVEF, left ventricular ejection fraction; NT‐proBNP, N‐terminal pro brain‐type natriuretic peptide.\n\nCardiac biomarkers and all‐cause mortality\n\nOverall, 120 patients (14.2%) died of any cause, but no deaths due to cardiovascular events were documented (Table 1 ). We included LVEF, GLS, and the cardiac biomarkers NT‐proBNP and hs‐cTnT in addition to demographic parameters and oncological diseases in logistic regression analysis in order to test determination of ACM (Figure 1 ). NT‐proBNP levels above the median (141 ng/L) were not found to be significantly related with the patients' outcome (univariate logistic regression, P = 0.16; log rank test: P = 0.4) (Figure 2 B ).\n\nHowever, hs‐cTnT above the median of 7 ng/L was associated with ACM (univariate logistic regression, P < 0.001). A multivariate analysis of the significant factors from the univariate approach confirmed hs‐cTnT as an independent marker for the prediction of ACM (P = 0.0038) (Supporting Information, Figure S2B ). Furthermore, in Kaplan–Meier curves, there were significantly fewer deaths of patients with hs‐cTnT levels <7 ng/L (log rank test: P < 0.001) (Figures 1 and 2 C ). Univariate logistic regression analysis of factors which might be correlated with hs‐cTnT ≥7 ng/L is shown in the Supporting Information, Figure S2A . Apart from obesity, breast cancer, and GLS analysis, all tested factors did correlate with hs‐cTnT levels above the median of 7 ng/L.\n\nIn clinical use, commonly utilized hs‐cTnT ranges (<5, 5–14, and >14 ng/L) suggest a concentration‐dependent association of plasma hs‐cTnT levels and ACM (log rank test, P = 0.0002). The analysis was adjusted to age, gender, renal function (GFR), NT‐proBNP, the BMI, diabetes, arterial hypertension, and LVEF (Supporting Information, Figure S3 ).\n\nThe combined use of NT‐proBNP and LVEF did not improve the prediction of hs‐cTnT for ACM (AUC hs‐cTnT: 0.64, AUC Hs‐cTnT + NT‐proBNP + LVEF: 0.60) (Supporting Information, Figure S4 ). Of note, the proportion of patients with hs‐cTnT levels above 7 ng/L is significantly higher in the group of patients with a LVEF ≤50% (P < 0.001, χ 2 test, Supporting Information, Figure S1 ). In addition, there have been more relevant coronary stenoses (≥75% in any segment) in the patients of the higher hs‐cTnT group (hs‐cTnT <7 ng/L: 4.5%; hs‐cTnT ≥7 ng/L: 35.1%, P < 0.001). Regarding oncological therapy, there are no significant differences in radiations or surgery rates between the hs‐cTnT groups. Interestingly, anthrazyclines and trastuzumab were less frequently used in patients with hs‐cTnT values above 7 ng/L. There is a higher percentage of patients with use of Carfilzomib, and by trend of immune checkpoint inhibitors or tyrosine kinase inhibitors with elevated hs‐cTnT (Table 1 ).\n\nHigh‐sensitivity cardiac troponin T levels correlate with left ventricular‐dysfunction and all‐cause mortality\n\nWe correlated hs‐cTnT with LV‐dysfunction and ACM, as well as with a combined endpoint of both, a drop in LV‐function and ACM. Given the area under the curve (AUC), hs‐cTnT has a good predictive value for a drop in left ventricular function (AUC: 0.82). The correlation with ACM and the combined endpoint is less pronounced (ACM AUC: 0.61, Drop in LV function ACM: 0.66). Nevertheless, we observed high values of the sensitivity at the identified cutoff of hs‐cTnT ≥7 ng/L for the three endpoints. The sensitivity regarding a drop in LV‐function is 92%, regarding ACM 80% and for the combined endpoint 84%, respectively (Figure 3 ).\n\nFigure 3 ROC curves showing the predictive value of hs‐cTnT on the endpoints all‐cause mortality (ACM), drop in left ventricular (LV) function and the combined endpoint (ACM and drop in LV function). Area under the curve (AUC) as indicated. Hs‐cTnT, high sensitivity cardiac troponin T.\n\nHigh‐sensitivity cardiac troponin T levels at the start of chemotherapy are associated with higher all‐cause mortality rates\n\nFurther, we compared the predictive value of hs‐cTnT on ACM at different stages in the chemotherapeutic regimen. Patients who presented before the start of their first chemotherapy in the cardio‐oncology unit and whose hs‐cTnT measurement was below our identified cutoff showed a significantly better outcome (log rank test: P‐value: 0.01). The patients of the given cardio‐oncological cohort who presented already during treatment did not differ in survival (log rank test: P‐value: 0.8). Patients who survived their oncological disease showed a lower rate of ACM in general. Hs‐cTnT still distinguishes the survival using the cutoff of 7 ng/L (Figure 4 ). Concentrating on palliative patients, who have a higher mortality than the non‐palliative patients in our cohort, hs‐cTnT with the cutoff of 7 ng/L did not significantly subdivide those patients' ACM (P = 0.1) (Supporting Information, Figure S5 ).\n\nFigure 4 Kaplan–Meier curves on all‐cause mortality (ACM). Patients are divided according to the hs‐cTnT cutoff (7 ng/L), and results are shown for patients before starting chemotherapy, patients with initial presentation during chemotherapy and patients with terminated chemotherapy. Log rank test P‐value as indicated. Hs‐cTnT, high sensitivity cardiac troponin T.\n\nApart from the baseline hs‐cTnT, we reevaluated the hs‐cTnT of a number of patients during follow‐up. Patients with any increase of hs‐cTnT over time showed a tendency towards an increased ACM (log rank test: P = 0.4; data not shown). Patients with hs‐cTnT levels below the 99th percentile at the first and above the 99th percentile at the second visit showed a significantly increased ACM (log rank test: P = 0.04; Supporting Information, Figure S6 ).\n\nDiscussion\n\nCardiological management of cancer patients\n\nIn this single‐centre approach, we report a 3‐year experience of the cardio‐oncology unit of University Hospital Heidelberg. Our primary aim was to determine parameters which might be able to stratify cancer patients regarding their mortality. The cardiological assessment of those patients revealed hs‐cTnT to be the best predictor for mortality next to the oncological parameters.\n\nIn recent years, cardio‐oncology focused on cancer therapy‐related side effects and cardiotoxicity of chemotherapies. The detection of cardiotoxicity and cardiological surveillance strategies mainly relied on echocardiographic parameters such as the systolic and diastolic left ventricular function. 11 , 12 , 13 , 14 GLS analysis was further suggested to be a sensitive predictor of early cardiotoxicity. 22 , 23 This notion is underlined by the statements of the European Society of Cardiology (ESC), 24 the German Society of Cardiology (DGK), 25 and practical guidelines of the American Society of Clinical Oncology (ASCO) 1 that highlight the use of functional cardiac parameters. According to the current European Society of Medical Oncology (ESMO) consensus recommendations, cardiac biomarkers may be evaluated before and during chemotherapy for risk stratification in addition to measurements of the systolic LV function. The exact benefit in the daily clinical routine still needs to be determined by prospective clinical trials. 26 There are a few studies that focus on hs‐cTnT and NT‐proBNP and their specific use in cardio‐oncological patients. 27 For example, in breast cancer patients who received trastuzumab, elevated baseline troponin levels were linked to the risk of a drop in LVEF. 28 The authors could not link biomarkers to relevant clinical events or mortality, presumably due to the limited number of patients.\n\nHigh‐sensitivity cardiac troponin T levels are an independent predictor of all‐cause mortality in cancer patients\n\nA reduced ejection fraction and worsening of left ventricular function predicts the patients' outcome in oncological 16 and non‐oncological patients. 29 In stable 15 and unstable 30 coronary heart disease (CHD), patients whose hs‐cTnT‐levels are above the 99th percentile (14 ng/L) show a significantly higher ACM. In the present cardio‐oncological cohort, increased mortality rates were already seen above 7 ng/L. Considering the clinically used hs‐cTnT‐cutoffs of <5 ng/L (not detectable), 5–14 ng/L (normal), and >14 ng/L (elevated), the oncological patients showed a similar pattern in mortality at generally higher mortality rates in comparison with CHD patients.\n\nThese analyses were adjusted to known influencing factors of hs‐cTnT including GFR and cardiac risk factors (age, gender, hypertension, diabetes, and adiposity). Deterioration in renal function, measured via GFR, does not only correlate with elevated levels of hs‐cTnT in our data but was previously depicted as an independent cardiac risk factor as well. 31 Logistic regression analysis to test for co‐appearance of these factors and elevated hs‐cTnT levels (≥7 ng/L) revealed strong correlations, except for adiposity. The cardiac parameters, reduced LVEF and elevated NT‐proBNP, did also correlate with elevated hs‐cTnT. GLS did not correlate with elevated hs‐cTnT.\n\nTo our surprise, in our cohort a reduced ejection fraction was not associated with an increase of ACM. This might be explained by the limited number of patients with reductions of LVEF. On the other hand, hs‐cTnT levels correlated well with a drop in LVEF. In ROC‐curves, we found a particularly high sensitivity rate at the identified hs‐cTnT cutoff (≥7 ng/L) to predict worsening of the left ventricular function. Using hs‐cTnT as a risk stratification for cardio‐oncological patients, hardly any patients who experience a drop in LV function are overlooked. Among the patients which were further examined by cardiac catheterization, there has been hardly any stenosis in the low hs‐cTnT group.\n\nThus, at least in the present study cohort, echocardiography results correlated well with hs‐cTnT. Hs‐cTnT, however, used as a single marker, was superior to identify a high risk patient cohort.\n\nNeither reduced GLS, nor elevated levels of NT‐proBNP were able to predict ACM. Further, neither age, diabetes, arterial hypertension, adiposity, nor reduced GFR correlated significantly with unfavourable outcome.\n\nIdentification of patients at risk and follow‐up\n\nAccording to the current guidelines of the cardiological and oncological societies, the main method to keep cancer patients under cardiac surveillance is echocardiography. As proposed by current results from the CARDIOvascular TOXicity induced by cancer‐related therapies (CARDIOTOX) registry, outcome‐relevant cardiotoxic events include the occurrence of a reduced systolic left ventricular function. 16 These data excluded patients with history of heart failure (HF) or current occurrence of HF. The registry contained a higher number of female patients (84%), higher rates of breast cancer (64%) and lymphoma (20.5%) and lower rates of gastrointestinal tumours (2%) than the present cohort. In our cohort, the diagnosis of breast cancer was associated with a lower mortality whereas gastrointestinal tumours showed higher mortality. This might explain the low predictive value of echocardiographic parameters. Breast cancer and gastrointestinal tumours were depicted as independent predictors for ACM in multivariant logistic regression analysis. Nonetheless, patients with gastrointestinal tumours showed higher levels of hs‐cTnT (66.7% of patients with hs‐cTnT >7 ng/L) than breast cancer patients (28.2% of patients with hs‐cTnT >7 ng/L). A stronger association of baseline hs‐cTnT values to cardiovascular events and mortality has been shown for females and further supports the possible impact of hs‐cTnT in female patients with cancer. 32\n\nACM was higher in the present study (14.2% compared with 6.2% in the CARDIOTOX registry). The percentage of patients who experienced a drop in left ventricular function (4.3% in the present study, 5% in the CARDIOTOX registry) was comparable between both studies. Due to the differences in the patient characteristics as mentioned above and the observance intervals, we may see differences in the predicting factors.\n\nIn contrast to the approach of the CARDIOTOX registry that aimed to identify relevant cardiotoxic events during chemotherapies, we found that hs‐cTnT levels are valuable for a risk stratification before the start of chemotherapy. It might be the case that reductions in left ventricular function appear in advanced cases of cardiotoxicity, whereas elevations in cardiac biomarkers are suitable for early risk stratification. In patients without prior cardiotoxic therapy and without prior cardiac disease, a low cutoff of 5 ng/L was already shown to be associated with ACM. 33\n\nThe herewith presented real‐world data with the enrolment of patients with prior cardiovascular diseases highlight the general role of hs‐cTnT in risk‐stratification of cardio‐oncological patients and the potential impact of the plasma concentration of hs‐cTnT as a critical determinant for the prediction of mortality. Particularly, baseline hs‐cTnT values in patients before starting chemotherapy were predictive. The first evaluation of hs‐cTnT during or after chemotherapy played a minor role in HEartCORE patients. Of note, in a subgroup of patients we observed a prognostic value of an elevation of hs‐cTnT >14 ng/L in the follow‐up.\n\nConclusions\n\nBased on the present data, measurement of cardiac hs‐cTnT can possibly be used for the risk stratification of cancer patients. In particular, hs‐cTnT values which were measured before starting chemotherapy showed a predictive value. Patients with higher hs‐cTnT plasma concentration (≥7 ng/L) should be considered for a more detailed cardiac surveillance strategy. Hs‐cTnT might additionally be implemented in cancer studies to early identify high‐risk patients.\n\nFurther prospective, randomized, multi‐centre trials need to confirm these findings in other clinical cohorts. It further needs to be determined, if functional measurements including echocardiography might be dispensable in low‐risk patients characterized by hs‐cTnT levels <7 ng/L.\n\nStudy limitations\n\nPatients were evaluated in the context of a cancer‐related therapy. The study cohort describes a real‐world collective without patient selection according to specific oncological or cardiological parameters.\n\nDuring follow‐up consultations, there is an additional selection bias that needs to be noted, because patients with pathological findings (e.g. elevated cardiac biomarker or reduction of LVEF) were admitted to a more stringent follow‐up regimen. Patients who presented themselves after a terminated therapy can be considered as cancer survivors and showed a considerably lower overall mortality rate.\n\nData of the all‐cause mortality were retrieved from the Clinical Cancer Registry of the National Centre for Tumour Diseases (NCT) Heidelberg. The causes of death could be linked to the oncological disease in most cases. Nevertheless, 51/120 cases had an unknown cause of death and were not able to be linked to specific, e.g. cardiovascular complications.\n\nConflict of interest\n\nH.A.K. received honoraria for lecturers from Roche Diagnostics, AstraZeneca, Bayer Vital, Daiichi‐Sankyo, and held a patent on cTnT that has expired. E.G. received honoraria for lectures from Roche Diagnostics, AstraZeneca, Bayer Vital, Daiichi‐Sankyo, Eli Lilly Deutschland. He serves as a consultant for Roche Diagnostics, BRAHMS Thermo Fisher, Boehringer Ingelheim, and has received research funding from BRAHMS Thermo Fisher, Roche Diagnostics, Bayer Vital and Daiichi Sankyo. L.H.L. has served on the advisory board for Daiichi Sankyio, Senaca and Servier and received speakers' honoraria from MSD. The remaining authors have nothing to disclose.\n\nFunding\n\nM.H. is recipient of the rotation grant of the German Centre for Cardiovascular Research (DZHK). L.H.L. is supported by the Deutsche Forschungsgemeinschaft (DFG; LE 3570/2‐1; 3570/3‐1) and the Bundesministerium für Forschung (BMBF; 01KC2006B).\n\nSupporting information\n\nFigure S1. (A) Pie charts of LV‐function, measured via echocardiography at the first three consultations. Patients numbers and distribution of preserved LVEF (LVEF > 50%), mid‐range reduced LVEF (LVEF 40–50%) und reduced LVEF (LVEF < 40%) as indicated. (B) Distribution of elevated NT‐proBNP (> rule out criterion, 300 ng/l) in patients with preserved and reduced LVEF (LVEF >/≤50%). (C) Distribution of elevated hs‐cTnT (> 99 percentile, 14 ng/l) in patients with preserved and reduced LVEF. (D) Distribution of elevated hs‐cTnT with a cutoff of 7 ng/l in patients with preserved and reduced LVEF.\n\nFigure S2. (A) Univariate logistic regression analysis of elevated hs‐cTnT (≥ 7 ng/l). Odds Ratio (OR), confidential interval and p‐value as indicated. (B) Multivariate logistic regression analysis for all‐cause mortality including the significant factors (Gender, Breast cancer, Upper GI Tumour, hs‐cTnT ≥ 7 ng/l) from the univariate analysis. Odds Ratio (OR), confidential interval and p‐value as indicated.\n\nFigure S3. Kaplan Meier curves on all‐cause mortality (ACM). Patients are divided into three groups according to their hs‐cTnT level (< 5 ng/l, 5‐14 ng/l, > 14 ng/l). Adjustments of hs‐cTnT were performed to left ventricular function, the occurrence of diabetes or arterial hypertension, body mass index (BMI), NT‐proBNP levels, GFR, age and gender. Logrank‐Test p‐value as indicated.\n\nFigure S4. ROC curves to test for the prediction of all‐cause mortality. Single curves are shown for hs‐cTnT, NT‐proBNP, LVEF as continuous variables and hs‐cTnT, NT‐proBNP, LVEF together. Area under the curve (AUC) as indicated.\n\nFigure S5. Kaplan Meier curves on all‐cause mortality (ACM). Patients are divided into four groups according to a palliative and non‐palliative treatment and their hs‐cTnT level (</≥ 7 ng/l), respectively. Patient numbers per group as indicated. Logrank‐Test p‐value for the comparison of ACM in non‐palliative and palliative patients as indicated.\n\nFigure S6. Kaplan Meier curves on all‐cause mortality (ACM). Patients are divided into two groups according to the change of hs‐cTnT between the first and the second measurement (n = 213). Patients whose hs‐cTnT was below 14 ng/l at the first visit and above 14 ng/l at the second visit are shown in turquoise. Patients with no increase from below to above 14 ng/l are shown in red. Logrank‐Test p‐value as indicated.\n\nClick here for additional data file.\n==== Refs\nReferences\n\n1 Armenian SH , Lacchetti C , Barac A , Carver J , Constine LS , Denduluri N , Dent S , Douglas PS , Durand JB , Ewer M , Fabian C , Hudson M , Jessup M , Jones LW , Ky B , Mayer EL , Moslehi J , Oeffinger K , Ray K , Ruddy K , Lenihan D . Prevention and Monitoring of Cardiac Dysfunction in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2017; 35 : 893–911.27918725\n2 Witteles RM , Telli M . Underestimating cardiac toxicity in cancer trials: lessons learned? J Clin Oncol 2012; 30 : 1916–1918.22454419\n3 Cardinale D , Colombo A , Lamantia G , Colombo N , Civelli M , De Giacomi G , Pandini C , Sandri MT , Cipolla CM . Cardio‐oncology: a new medical issue. Ecancermedicalscience. 2008; 2 : 126.22275992\n4 Hasin T , Gerber Y , Weston SA , Jiang R , Killian JM , Manemann SM , Cerhan JR , Roger VL . 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The role of cardiac biomarkers in cardio‐oncology. Curr Probl Cancer 2018; 42 : 375–385.30126650\n9 Ammon M , Arenja N , Leibundgut G , Buechel RR , Kuster GM , Kaufmann BA , Pfister O . Cardiovascular management of cancer patients with chemotherapy‐associated left ventricular systolic dysfunction in real‐world clinical practice. J Card Fail 2013; 19 : 629–634.24054339\n10 Darby SC , McGale P , Taylor CW , Peto R . Long‐term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: prospective cohort study of about 300,000 women in US SEER cancer registries. Lancet Oncol 2005; 6 : 557–565.16054566\n11 Ewer MS , Lippman SM . Type II chemotherapy‐related cardiac dysfunction: time to recognize a new entity. J Clin Oncol 2005; 23 : 2900–2902.15860848\n12 Suter TM , Ewer MS . Cancer drugs and the heart: importance and management. Eur Heart J 2013; 34 : 1102–1111.22789916\n13 Seidman A , Hudis C , Pierri MK , Shak S , Paton V , Ashby M , Murphy M , Stewart SJ , Keefe D . Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 2002; 20 : 1215–1221.11870163\n14 Alexander J , Dainiak N , Berger HJ , Goldman L , Johnstone D , Reduto L , Duffy T , Schwartz P , Gottschalk A , Zaret BL . Serial assessment of doxorubicin cardiotoxicity with quantitative radionuclide angiocardiography. N Engl J Med 1979; 300 : 278–283.759880\n15 Biener M , Giannitsis E , Lamerz J , Mueller‐Hennessen M , Vafaie M , Katus HA . Prognostic value of elevated high‐sensitivity cardiac troponin T levels in a low risk outpatient population with cardiovascular disease. Eur Heart J Acute Cardiovasc Care 2016; 5 : 409–418.26450785\n16 Lopez‐Sendon J , Alvarez‐Ortega C , Zamora Aunon P , Buno Soto A , Lyon AR , Farmakis D , Cardinale D , Canales Albendea M , Feliu Batlle J , Rodriguez Rodriguez I , Rodriguez Fraga O , Albaladejo A , Mediavilla G , Gonzalez‐Juanatey JR , Martinez Monzonis A , Gomez Prieto P , Gonzalez‐Costello J , Serrano Antolin JM , Cadenas Chamorro R , Lopez FT . Classification, prevalence, and outcomes of anticancer therapy‐induced cardiotoxicity: the CARDIOTOX registry. Eur Heart J 2020; 41 : 1720–1729.32016393\n17 Giannitsis E , Kurz K , Hallermayer K , Jarausch J , Jaffe AS , Katus HA . Analytical validation of a high‐sensitivity cardiac troponin T assay. Clin Chem 2010; 56 : 254–261.19959623\n18 Saenger AK , Beyrau R , Braun S , Cooray R , Dolci A , Freidank H , Giannitsis E , Gustafson S , Handy B , Katus H , Melanson SE , Panteghini M , Venge P , Zorn M , Jarolim P , Bruton D , Jarausch J , Jaffe AS . 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Use of myocardial strain imaging by echocardiography for the early detection of cardiotoxicity in patients during and after cancer chemotherapy: a systematic review. J Am Coll Cardiol 2014; 63 : 2751–2768.24703918\n24 Eschenhagen T , Force T , Ewer MS , de Keulenaer GW , Suter TM , Anker SD , Avkiran M , de Azambuja E , Balligand JL , Brutsaert DL , Condorelli G , Hansen A , Heymans S , Hill JA , Hirsch E , Hilfiker‐Kleiner D , Janssens S , de Jong S , Neubauer G , Pieske B , Ponikowski P , Pirmohamed M , Rauchhaus M , Sawyer D , Sugden PH , Wojta J , Zannad F , Shah AM . Cardiovascular side effects of cancer therapies: a position statement from the Heart Failure Association of the European Society of Cardiology. 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Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations. Ann Oncol 2020; 31 : 171–190.31959335\n27 Michel L , Rassaf T , Totzeck M . Biomarkers for the detection of apparent and subclinical cancer therapy‐related cardiotoxicity. J Thorac Dis 2018; 10 : S4282–S4295.30701097\n28 Zardavas D , Suter TM , Van Veldhuisen DJ , Steinseifer J , Noe J , Lauer S , Al‐Sakaff N , Piccart‐Gebhart MJ , de Azambuja E . Role of Troponins I and T and N‐Terminal Prohormone of Brain Natriuretic Peptide in Monitoring Cardiac Safety of Patients With Early‐Stage Human Epidermal Growth Factor Receptor 2‐Positive Breast Cancer Receiving Trastuzumab: A Herceptin Adjuvant Study Cardiac Marker Substudy. J Clin Oncol 2017; 35 : 878–884.28199174\n29 Steinberg BA , Fang JC . Long‐Term Outcomes of Acute Heart Failure: Where Are We Now? J Am Coll Cardiol 2017; 70 : 2487–2489.29141782\n30 Giannitsis E , Biener M , Hund H , Mueller‐Hennessen M , Vafaie M , Gandowitz J , Riedle C , Lohr J , Katus HA , Stoyanov KM . Management and outcomes of patients with unstable angina with undetectable, normal, or intermediate hsTnT levels. Clin Res Cardiol 2020; 109 : 476–487.31325044\n31 Chesnaye NC , Szummer K , Barany P , Heimburger O , Magin H , Almquist T , Uhlin F , Dekker FW , Wanner C , Jager KJ , Evans M , dagger ESI, Investigatorsdagger ES . Association Between Renal Function and Troponin T Over Time in Stable Chronic Kidney Disease Patients. J Am Heart Assoc. 2019; 8 : e013091.31662068\n32 Suthahar N , Meems LMG , van Veldhuisen DJ , Walter JE , Gansevoort RT , Heymans S , Schroen B , van der Harst P , Kootstra‐Ros JE , van Empel V , Mueller C , Bakker SJL , de Boer RA . High‐Sensitivity Troponin‐T and Cardiovascular Outcomes in the Community: Differences Between Women and Men. 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"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2055-5822",
"issue": "8(5)",
"journal": "ESC heart failure",
"keywords": "Cancer survivors; Cardiac biomarkers; Cardio-oncology; Cardiotoxicity; Heart failure; Risk stratification",
"medline_ta": "ESC Heart Fail",
"mesh_terms": "D015331:Cohort Studies; D006801:Humans; D009369:Neoplasms; D013318:Stroke Volume; D020107:Troponin T; D016277:Ventricular Function, Left",
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"title": "High-sensitivity cardiac troponin T determines all-cause mortality in cancer patients: a single-centre cohort study.",
"title_normalized": "high sensitivity cardiac troponin t determines all cause mortality in cancer patients a single centre cohort study"
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"abstract": "Thirty-seven anaemic subjects with low-to-intermediate risk myelodysplastic syndrome (MDS) received the highly glycosylated, long-acting erythropoiesis-stimulating molecule darbepoetin-alpha (DPO) at the single, weekly dose of 150 microg s.c. for at least 12 weeks. Fifteen patients (40.5%) achieved an erythroid response (13 major and two minor improvements, respectively, according to International Working Group criteria). Such results are currently maintained after 7-22 months in 13 of the responders, one of whom required iron substitutive therapy during the treatment. One patient relapsed after 4 months. Another responder died after 5 months because of causes unrelated to the treatment. No relevant side-effects were recorded. At multivariate analysis, significant predictive factors of response were baseline serum levels of endogenous erythropoietin <100 IU/l, absent or limited transfusional needs, no excess of blasts and hypoplastic bone marrow. This study suggests that DPO, at the dose and schedule used, can be safely given in low-intermediate risk MDS and may be effective in a significant proportion of these patients.",
"affiliations": "Hematology and Stem Cell Transplantation Unit, IRCCS Casa Sollievo della Sofferenza Hospital, S. Giovanni Rotondo, Italy. p.musto@tin.it",
"authors": "Musto|Pellegrino|P|;Lanza|Francesco|F|;Balleari|Enrico|E|;Grossi|Alberto|A|;Falcone|Antonietta|A|;Sanpaolo|Grazia|G|;Bodenizza|Carlo|C|;Scalzulli|Potito Rosario|PR|;La Sala|Antonio|A|;Campioni|Diana|D|;Ghio|Riccardo|R|;Cascavilla|Nicola|N|;Carella|Angelo Michele|AM|",
"chemical_list": "D004921:Erythropoietin; D000068256:Darbepoetin alfa",
"country": "England",
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"doi": "10.1111/j.1365-2141.2004.05288.x",
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"issue": "128(2)",
"journal": "British journal of haematology",
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"mesh_terms": "D000368:Aged; D000740:Anemia; D000068256:Darbepoetin alfa; D004906:Erythrocyte Count; D004921:Erythropoietin; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009190:Myelodysplastic Syndromes; D010865:Pilot Projects",
"nlm_unique_id": "0372544",
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"pages": "204-9",
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"pubdate": "2005-01",
"publication_types": "D016428:Journal Article",
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"title": "Darbepoetin alpha for the treatment of anaemia in low-intermediate risk myelodysplastic syndromes.",
"title_normalized": "darbepoetin alpha for the treatment of anaemia in low intermediate risk myelodysplastic syndromes"
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"companynumb": "IT-AMGEN-ITASP2019169470",
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{
"abstract": "The general aim of this study was to evaluate the disease spectrum in patients presenting with a pure polymyositis (pPM) phenotype. Specific objectives were to characterize clinical features, autoantibodies (aAbs), and membrane attack complex (MAC) in muscle biopsies of patients with treatment-responsive, statin-exposed necrotizing autoimmune myositis (NAM). Patients from the Centre hospitalier de l'Université de Montréal autoimmune myositis (AIM) Cohort with a pPM phenotype, response to immunosuppression, and follow-up ≥3 years were included. Of 17 consecutive patients with pPM, 14 patients had a NAM, of whom 12 were previously exposed to atorvastatin (mean 38.8 months). These 12 patients were therefore suspected of atorvastatin-induced AIM (atorAIM) and selected for study. All had aAbs to 3-hydroxy-3-methylglutaryl coenzyme A reductase, and none had overlap aAbs, aAbs to signal recognition particle, or cancer. Three stages of myopathy were recognized: stage 1 (isolated serum creatine kinase [CK] elevation), stage 2 (CK elevation, normal strength, and abnormal electromyogram [EMG]), and stage 3 (CK elevation, proximal weakness, and abnormal EMG). At diagnosis, 10/12 (83%) patients had stage 3 myopathy (mean CK elevation: 7247 U/L). The presenting mode was stage 1 in 6 patients (50%) (mean CK elevation: 1540 U/L), all of whom progressed to stage 3 (mean delay: 37 months) despite atorvastatin discontinuation. MAC deposition was observed in all muscle biopsies (isolated sarcolemmal deposition on non-necrotic fibers, isolated granular deposition on endomysial capillaries, or mixed pattern). Oral corticosteroids alone failed to normalize CKs and induce remission. Ten patients (83%) received intravenous immune globulin (IVIG) as part of an induction regimen. Of 10 patients with ≥1 year remission on stable maintenance therapy, IVIG was needed in 50%, either with methotrexate (MTX) monotherapy or combination immunosuppression. In the remaining patients, MTX monotherapy or combination therapy maintained remission without IVIG. AtorAIM emerged as the dominant entity in patients with a pPM phenotype and treatment-responsive myopathy. Isolated CK elevation was the mode of presentation of atorAIM. The new onset of isolated CK elevation on atorvastatin and persistent CK elevation on statin discontinuation should raise early suspicion for atorAIM. Statin-induced AIM should be included in the differential diagnosis of asymptomatic hyperCKemia. Three patterns of MAC deposition, while nonpathognomonic, were pathological clues to atorAIM. AtorAIM was uniformly corticosteroid resistant but responsive to IVIG as induction and maintenance therapy.",
"affiliations": "Divisions of Rheumatology, Department of Medicine Internal Medicine, Hôpital du Sacré-Coeur Division of Rheumatology, Department of Medicine, Centre Hospitalier de l'Université de Montréal, University of Montreal Faculty of Medicine, Montreal, QC Mitogen Advanced Diagnostics Laboratory, Cumming School of Medicine, University of Calgary, Calgary, AB Department of Pathology, Hôpital Maisonneuve-Rosemont, University of Montreal Faculty of Medicine, Montreal, QC, Canada Veterans Affairs Medical Center, University of Oklahoma Health Sciences Center Oklahoma Medical Research Foundation, Oklahoma City, OK Department of Pathology, Hôpital Sainte-Justine Department of Pathology and Cell Biology, University of Montreal Faculty of Medicine Division of Rheumatology, Department of Medicine, Centre hospitalier affilié universitaire régional de Trois-Rivières, University of Montreal Faculty of Medicine, Montreal Division of Rheumatology, Centre Hospitalier de l'Université Laval, Laval University Faculty of Medicine, Québec, QC, Canada.",
"authors": "Troyanov|Yves|Y|;Landon-Cardinal|Océane|O|;Fritzler|Marvin J|MJ|;Ferreira|José|J|;Targoff|Ira N|IN|;Rich|Eric|E|;Goulet|Michelle|M|;Goulet|Jean-Richard|JR|;Bourré-Tessier|Josiane|J|;Robitaille|Yves|Y|;Drouin|Julie|J|;Albert|Alexandra|A|;Senécal|Jean-Luc|JL|",
"chemical_list": "D001323:Autoantibodies; D015938:Complement Membrane Attack Complex; D005938:Glucocorticoids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000069059:Atorvastatin; D008775:Methylprednisolone",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000005694",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 28099331MD-D-16-0453410.1097/MD.0000000000005694056946900Research ArticleObservational StudyAtorvastatin-induced necrotizing autoimmune myositis An emerging dominant entity in patients with autoimmune myositis presenting with a pure polymyositis phenotypeTroyanov Yves MD, FRCPCacLandon-Cardinal Océane MD, FRCPCcFritzler Marvin J. PhD, MDdFerreira José MD, FRCPCeTargoff Ira N. MDfgRich Eric MD, FRCPCcGoulet Michelle MD, FRCPCbGoulet Jean-Richard MSc, MD, FRCPCcBourré-Tessier Josiane MSc, MD, FRCPCcRobitaille Yves MD, FRCPChiDrouin Julie MD, FRCPCjAlbert Alexandra PhD, MD, FRCPCkSenécal Jean-Luc MD, FRCPCc∗Louthrenoo. Worawit a Divisions of Rheumatology, Department of Medicineb Internal Medicine, Hôpital du Sacré-Coeurc Division of Rheumatology, Department of Medicine, Centre Hospitalier de l’Université de Montréal, University of Montreal Faculty of Medicine, Montreal, QCd Mitogen Advanced Diagnostics Laboratory, Cumming School of Medicine, University of Calgary, Calgary, ABe Department of Pathology, Hôpital Maisonneuve-Rosemont, University of Montreal Faculty of Medicine, Montreal, QC, Canadaf Veterans Affairs Medical Center, University of Oklahoma Health Sciences Centerg Oklahoma Medical Research Foundation, Oklahoma City, OKh Department of Pathology, Hôpital Sainte-Justinei Department of Pathology and Cell Biology, University of Montreal Faculty of Medicinej Division of Rheumatology, Department of Medicine, Centre hospitalier affilié universitaire régional de Trois-Rivières, University of Montreal Faculty of Medicine, Montrealk Division of Rheumatology, Centre Hospitalier de l’Université Laval, Laval University Faculty of Medicine, Québec, QC, Canada.∗ Correspondence: Jean-Luc Senécal, MD, Division of Rheumatology, Centre Hospitalier de l’Université de Montréal, Laval University Faculty of Medicine, 1560 Sherbrooke Street East (M-4243), Montreal, QC, Canada H2L 4M1 (e-mail: dr.j.l.senecal.md@gmail.com)1 2017 20 1 2017 96 3 e569430 6 2016 8 10 2016 29 11 2016 Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc.2017This is an open access article distributed under the Creative Commons Attribution-NoDerivatives License 4.0, which allows for redistribution, commercial and non-commercial, as long as it is passed along unchanged and in whole, with credit to the author. http://creativecommons.org/licenses/by-nd/4.0Abstract\nThe general aim of this study was to evaluate the disease spectrum in patients presenting with a pure polymyositis (pPM) phenotype. Specific objectives were to characterize clinical features, autoantibodies (aAbs), and membrane attack complex (MAC) in muscle biopsies of patients with treatment-responsive, statin-exposed necrotizing autoimmune myositis (NAM). Patients from the Centre hospitalier de l’Université de Montréal autoimmune myositis (AIM) Cohort with a pPM phenotype, response to immunosuppression, and follow-up ≥3 years were included. Of 17 consecutive patients with pPM, 14 patients had a NAM, of whom 12 were previously exposed to atorvastatin (mean 38.8 months). These 12 patients were therefore suspected of atorvastatin-induced AIM (atorAIM) and selected for study. All had aAbs to 3-hydroxy-3-methylglutaryl coenzyme A reductase, and none had overlap aAbs, aAbs to signal recognition particle, or cancer. Three stages of myopathy were recognized: stage 1 (isolated serum creatine kinase [CK] elevation), stage 2 (CK elevation, normal strength, and abnormal electromyogram [EMG]), and stage 3 (CK elevation, proximal weakness, and abnormal EMG). At diagnosis, 10/12 (83%) patients had stage 3 myopathy (mean CK elevation: 7247 U/L). The presenting mode was stage 1 in 6 patients (50%) (mean CK elevation: 1540 U/L), all of whom progressed to stage 3 (mean delay: 37 months) despite atorvastatin discontinuation. MAC deposition was observed in all muscle biopsies (isolated sarcolemmal deposition on non-necrotic fibers, isolated granular deposition on endomysial capillaries, or mixed pattern). Oral corticosteroids alone failed to normalize CKs and induce remission. Ten patients (83%) received intravenous immune globulin (IVIG) as part of an induction regimen. Of 10 patients with ≥1 year remission on stable maintenance therapy, IVIG was needed in 50%, either with methotrexate (MTX) monotherapy or combination immunosuppression. In the remaining patients, MTX monotherapy or combination therapy maintained remission without IVIG. AtorAIM emerged as the dominant entity in patients with a pPM phenotype and treatment-responsive myopathy. Isolated CK elevation was the mode of presentation of atorAIM. The new onset of isolated CK elevation on atorvastatin and persistent CK elevation on statin discontinuation should raise early suspicion for atorAIM. Statin-induced AIM should be included in the differential diagnosis of asymptomatic hyperCKemia. Three patterns of MAC deposition, while nonpathognomonic, were pathological clues to atorAIM. AtorAIM was uniformly corticosteroid resistant but responsive to IVIG as induction and maintenance therapy.\n\nKeywords\nanti-HMGCR autoantibodiesatorvastatinautoimmune myositisnecrotizing autoimmune myopathypolymyositisstatinOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nThe spectrum and classification of autoimmune myositis (AIM) is evolving rapidly. The existence of the polymyositis (PM) entity as defined by Bohan and Peter[1] has been challenged. A recent clinicoserological classification of 100 consecutive French Canadians with AIM found that overlap myositis and pure dermatomyositis (DM) were the dominant entities, whereas pure PM emerged as an uncommon entity.[2] Furthermore, the original pathological definition of an endomysial mononuclear cell infiltrate with invasion of non-necrotic fibers is actually strongly suggestive of inclusion-body myositis rather than PM.[3] The current clinical definition of PM is therefore a phenotype of muscle disease at high risk for mimicry with other myopathies.[4]\n\nRecently, new pathological descriptions of immune myopathy were suggested, including necrotizing AIM (NAM), which is synonymous with immune-mediated necrotizing myopathy (IMNM) and is now recognized as an entity distinct from PM.[5,6] NAM is associated in particular with autoantibodies (aAbs) to signal recognition particle (anti-SRP), cancer, and with a novel aAb, aAbs to 3-hydroxy-3-methylglutaryl coenzyme A reductase (anti-HMGCR) linked most often to statin exposure.[5,6] Identification of NAM, therefore, further expands the differential diagnosis of pure PM.\n\nThe deposition of membrane attack complex components (MAC) was originally described in DM, with localization of MAC on endomysial capillaries.[7] More recently, sarcolemmal deposition of MAC was reported in other myopathies, including NAM associated with anti-SRP and anti-HMGCR.[8,9] Interestingly, sarcolemmal MAC deposition detected on muscle biopsies was considered an exclusion criterion for PM at the 119th European Neuromuscular Center international workshop.[10]\n\nIn light of these observations, the objective of the present study was to further characterize the disease spectrum in patients presenting with an apparent pure PM phenotype. Specifically, clinical features, serum aAbs, and MAC in muscle biopsies of patients with statin-exposed, treatment-responsive NAM were evaluated.\n\n2 Patients and methods\n2.1 Patients\nA patient cohort with a diagnosis of AIM between 2005 and 2014 was longitudinally followed at Centre Hospitalier de l’Université de Montréal (CHUM) and Hôpital du Sacré-Coeur in Montreal, Quebec, Canada. All patients fulfilled 7 inclusion criteria. First, patients were 18 years or older at the time of myositis diagnosis. Second, the presence of a myopathy was defined by elevated serum creatine kinase (CK) plus at least one of the following: proximal muscle weakness, an abnormal electromyogram (EMG), and/or an abnormal muscle biopsy. If CKs were normal, the presence of a myopathy was defined as an abnormal magnetic resonance imaging (MRI) of the thigh muscles. Third, patients had to present with a pure PM clinicoserological phenotype, that is, absence of DM rash, overlap connective tissue disease features, and overlap aAbs, as described.[2] Fourth, serum had to be available for further analysis. Fifth, at least 1 skeletal muscle biopsy had to be available. Sixth, follow-up of at least 3 years from the initial CK elevation to last visit was required. The last inclusion criterion was a documented clinical response to immunosuppressive treatment (as established by expert opinion) or clear improvement on statin discontinuation. The rationale for excluding treatment-refractory patients is that the PM phenotype and refractory PM are at high risk for AIM mimickers, such as muscular dystrophies.\n\n2.2 Data collection\nData on history, physical findings, and investigations were collected by retrospective medical record review using a standardized protocol. Data collection was focused on demographics, myopathic features, chronology of events preceding diagnosis (statin use, CKs, and clinical manifestations), treatment strategies (induction vs maintenance) and muscle pathological characteristics. This study was in compliance with the Declaration of Helsinki. Patients provided written informed consent for clinical data and serum collection. Biobank and clinical data collection procedures were approved by the CHUM Ethical Review Board.\n\n2.3 Definitions\n(1) Pure PM clinicoserological phenotype: absence of DM rash, overlap features, and overlap aAbs.[2,11]\n\n(2) NAM is synonymous with IMNM or necrotizing myopathy.[5,6] Three individual subsets are recognized: anti-SRP-related NAM, anti-HMGCR-related NAM, and paraneoplastic NAM. In the present study, the pathological features on muscle biopsy necessary for an AIM to be classified as NAM were the absence of significant inflammation and the presence of necrosis and/or regenerating fibers.\n\n(3) Overlap connective tissue disease features were as described[2,11]: polyarthritis, Raynaud phenomenon, sclerodactyly, scleroderma proximal to metacarpophalangeal joints, systemic sclerosis-type calcinosis in the fingers, lower esophageal, and/or small bowel hypomotility, carbon monoxide lung diffusing capacity <70% of the normal predicted value, interstitial lung disease on chest radiogram and/or computerized tomography scan, discoid lupus, antinative deoxyribonucleic acid antibodies plus hypocomplementemia, 4 or more of 11 American College of Rheumatology criteria for systemic lupus erythematosus,[12] and antiphospholipid syndrome.\n\n(4) Overlap aAbs included aAbs to Jo-1 and all other synthetases, scleroderma-associated, as well as scleroderma-specific aAbs and anti-nup aAbs.[2,11,13]\n\n(5) Abnormal EMG: presence of myopathic abnormalities, with or without fibrillations or complex repetitive discharges.[1]\n\n(6) Atorvastatin-induced AIM (atorAIM) is an AIM induced by atorvastatin exposure.\n\n(7) Definitions for assessment of atorAIM treatment were described as follows[2]:Adequate initial corticosteroid therapy: a daily prednisone dose of at least 40 mg during at least 1 month, followed by a steroid taper that was neither too rapid (based on clinical judgment) nor done in alternate-day fashion;\n\nInduction: therapeutic strategy to induce remission;\n\nMaintenance: after induction, therapeutic strategy to maintain remission; remission: sustained serum CK levels below 500 U/L with improved proximal muscle strength; corticosteroid resistance, or refractory myositis (as opposed to responsive myositis): myositis where adequate initial corticosteroid therapy failed to induce remission;\n\nResponsive myositis: decreasing serum CK to normal or below 500 U/L with improving proximal muscle strength.\n\n\n\n\n\n2.4 Serum autoantibodies\nCoded serum samples were biobanked at −80 °C, and all studies for aAbs were done without knowledge of clinical data or diagnosis. Antinuclear antibodies (ANA) were determined by indirect immunofluorescence on HEp-2 cells at 1:40 serum screening dilution (Antibodies Inc.; Davis, CA).[14]\n\nAnti-HMGCR were detected by addressable laser bead immunoassay (ALBIA) using purified human recombinant HMGCR (Sigma Aldrich; St. Louis, MO: Catalogue #H7309) and performed on the Luminex 200 platform (MJF, Mitogen Advanced Diagnostics Laboratory; Calgary, AB, Canada). Control positive sera containing anti-HMGCR used to establish the ALBIA were kindly provided by Andrew Mammen, MD (Johns Hopkins University, Baltimore, MD). Briefly, the cutoff values for the anti-HMGCR assay were validated by testing serum samples from 45 apparently healthy adults, 45 adults with osteoarthritis of age >60 years, 50 hemodialysis patients on statin therapy (with chronic renal insufficiency secondary to diabetic or hypertensive nephropathy), 45 patients with rheumatoid arthritis and positive anti-cyclic citrullinated peptide aAbs, 45 patients with systemic lupus erythematosus, and 100 French Canadian patients with AIM.[2] Cutoff values were set as follows: normal range, <250 mean fluorescence units (MFU); low positive, 251 to 500 MFU; moderate positive, 501 to 999 MFU; and high positive, >1000 MFU.\n\n2.5 Protein A–assisted immunoprecipitation\nSera were analyzed for aAbs by protein A–assisted immunoprecipitation, both for nucleic acid analysis (ribonucleic acid silver stain) and for proteins (metabolically labeled with 35S-methionine), along with double immunodiffusion (INT).[15–17] These immunoassays detect anti-SRP, all of the described antisynthetases (Jo-1, PL-7, PL-12, OJ, EJ, KS, Tyr, and Zo), anti-PM-Scl, anti-SumoAE, anti-RNA polymerase III, anti-Th/To, anti-U2RNP, anti-U3RNP, anti-U5RNP, anti-Mi-2, anti-p155/140, and anti-MJ. Immunoprecipitation of anti-p155/140 and anti-MJ was confirmed by an immunoblotting method.\n\n2.6 Pathology\nSeventeen skeletal muscle biopsies were performed on the 12 index patients and were analyzed by 2 myopathologists (JF and YR). The following pathological features on muscle biopsy were evaluated: presence and location of mononuclear cell inflammation; muscle fiber size, for the presence of perifascicular atrophy, hypertrophy, and muscle fiber size variation; muscle fiber pathologic features of focal invasion of non-necrotic fibers by lymphocytes, necrosis, regeneration, and presence of mitochondrial changes; presence of macrophages, by acid phosphatase staining and anti-CD68 testing; major histocompatibility complex class I (MHC-I) expression on muscle fibers; MHC-I expression on capillaries, to assess capillary loss; and presence and location of MAC (C5b-9) deposition. MAC was detected by immunocytochemistry using a mouse monoclonal anti-human C5b-9 antibody (code no. M0777, DakoCytomation; Glostrup, Denmark).\n\n2.7 Statistical analysis\nThe Wilcoxon rank-sum test was used for comparison of serum CK group means (Prism 6.0 software, GraphPad Software Inc.; San Diego, CA).\n\n3 Results\nBetween 2005 and 2014, we identified 17 consecutive patients followed for at least 3 years with an AIM associated with a pure PM clinicoserological phenotype (Fig. 1). All patients were followed by a rheumatologist with expertise in AIM, either as the primary treating physician or as part of a multidisciplinary team.\n\nFigure 1 Flow diagram showing how patients with statin-exposed necrotizing autoimmune myositis/immune-mediated necrotizing myopathy were identified. ∗As described in Section 2. †As defined in Ref. [10]. ‡Serum creatine kinase at diagnosis, U/L. F = female, M = male.\n\nOf these 17 patients, 3 patients were excluded because of prominent inflammatory infiltrates on muscle biopsy (Fig. 1). One patient had an HIV infection and endomysial inflammation (not tested for anti-SRP and anti-HMGCR). The second patient (negative for anti-SRP and anti-HMGCR) had endomysial inflammation without other pathological features of inclusion body myositis, whereas the last patient (negative for anti-SRP, not tested for anti-HMGCR) had significant perimysial and perivascular inflammation. The remaining 14 patients had necrosis and/or regeneration on muscle biopsy consistent with NAM. None had positive anti-SRP or cancer-associated NAM. Of these 14 patients, 12 had previously been exposed to a statin and 2 had not (of the latter 2 patients, 1 was anti-HMGCR-positive and 1 was negative). The statin used was atorvastatin in all patients, and they were therefore suspected of atorAIM (Fig. 1). This dominant patient subset with atorAIM, representing 70.6% (n = 12/17) of the cohort, is the focus of the present study.\n\n3.1 Demographics, statin use, and myopathic symptoms of atorAIM\nThe demographics and myopathic symptoms of these 12 patients are shown in Table 1. There were 6 women and 6 men with a mean age of 66 years (range 43–81 years) at diagnosis. Two patients received atorvastatin for isolated hypercholesterolemia, whereas most patients had either type 2 diabetes mellitus (75%) and/or atherosclerotic disease (50%). The highest daily atorvastatin dose was 20 mg in 6 patients, 40 mg in 5 patients, and 80 mg in 1 patient. The mean duration of atorvastatin therapy before first CK elevation was 38.8 months (range 15–84 months). The mean interval between atorvastatin initiation and the diagnosis of atorAIM was 59.3 months (range 17–127 months).\n\nTable 1 Demographics, myopathic features, and staging of 12 patients with atorvastatin necrotizing autoimmune myositis.\n\nIn all patients, suspicion of atorAIM eventually led to discontinuation of atorvastatin. The mean interval between atorvastatin discontinuation and the diagnosis of atorAIM was 17.8 months (range 0–79 months). Specifically, 4 out of 12 patients discontinued atorvastatin either at diagnosis (n = 2) or within 3 months of diagnosis (n = 2). Interestingly, the remaining 8 (67%) patients had discontinued atorvastatin for a mean of 26 months (range 8–79 months) at the time the diagnosis of atorAIM was made.\n\nMyalgias were noted in 8 patients (67%) before diagnosis of atorAIM. In 4 of these 8 patients (50%), myalgias occurred within 4 months of the diagnosis of atorAIM, whereas in the other 4 patients myalgias were present during 12 to 50 months before diagnosis. Nine (75%) patients reported subjective proximal skeletal muscle weakness on average within 12 months of diagnosis. Objective moderate oropharyngeal dysphagia was present in 3 patients (25%). Patients 2, 8, and 9 had dysphagia respectively for 12, 3, and 1 month(s) before the diagnosis of atorAIM. In all patients, dysphagia resolved within a year of treatment of atorAIM.\n\n3.2 Staging and chronology of myopathic features leading to atorAIM diagnosis\nThree distinctive and dynamic clinical stages of myopathy were recognized:Stage 1: serum CK elevation, normal muscle strength, and normal EMG.\n\nStage 2: CK elevation, normal muscle strength, and abnormal EMG.\n\nStage 3: CK elevation, proximal muscle weakness, and abnormal EMG.\n\n\n\nAt diagnosis, 10 out of 12 patients (83%) had stage 3 myopathy (mean CK elevation: 7661 U/L), whereas the remaining 2 patients had stage 1 myopathy (Table 1). However, examination at presentation revealed a markedly different staging distribution. Thus, whereas 5 of 12 (42%) patients presented in stage 3 myopathy, 6 of 12 patients (50%) presented with stage 1 myopathy (mean CK elevation: 1540 U/L) and a single patient (patient 1) presented in stage 2. Four of the 6 patients (67%) with stage 1 myopathy later progressed to stage 3 myopathy after a mean delay of 38 months (range 14–95 months) despite atorvastatin discontinuation, whereas the remaining 2 patients remained in stage 1 (Table 1).\n\nThe chronology of dynamic events leading to diagnosis in patients presenting in stage 1 myopathy is shown in Table 2, whereas patients presenting in stage 2 or 3 are shown in Table 3. In these tables, the time of atorAIM diagnosis and treatment initiation is identified as T0.\n\nTable 2 Chronology of events leading to diagnosis of atorvastatin autoimmune myositis in 12 patients presenting in stage 1 myopathy.\n\nTable 3 Chronology of events leading to diagnosis of atorvastatin autoimmune myositis in 12 patients presenting in stage 2 or 3 myopathy.\n\nIn Table 2, taking patient 3 as an example, it can be seen that the serum CK level was normal (86 U/L) at the time of atorvastatin initiation 41 months before diagnosis of atorAIM. An isolated CK elevation (1454 U/L, i.e., stage 1 myopathy) was noted 26 months before diagnosis of atorAIM, leading to statin discontinuation 3 months later. After atorvastatin discontinuation, CK levels which had initially decreased by 60% (from 1680 to 702 U/L) later fluctuated in the abnormal range until T0, where they reached 8300 U/L. At that time, the patient had developed proximal muscle weakness and an abnormal EMG and was therefore in stage 3 myopathy. Similarly, patient 2 had an improved yet persistent CK elevation following atorvastatin discontinuation and was diagnosed 79 months later with a stage 3 myopathy.\n\nOverall, in patients presenting with stage 1 myopathy, statin discontinuation led either to initial 45% to 90% CK lowering (but never to normal levels) with subsequent elevation rebound, or persistent CK elevation eventually leading to diagnosis of atorAIM (Table 2). Thus, CK levels never completely normalized following statin discontinuation.\n\nIn Table 3, taking patient 1 as an example, the serum CK level was normal (135 U/L) at the time of atorvastatin initiation 51 months before diagnosis of atorAIM. However, 11 months before diagnosis, CK was elevated (5613 U/L), and an EMG was myopathic despite normal muscle strength (i.e., stage 2 myopathy), leading to statin discontinuation. Nevertheless, patient 1 progressed 11 months later to stage 3 myopathy. Overall, Table 3 shows that discontinuation of atorvastatin before T0 was followed either by CK stabilization, CK lowering with subsequent elevation rebound, or persistent CK elevation (Table 3). Thus, as in the case of stage 1 myopathy, CK levels never normalized following statin discontinuation in patients presenting in stage 2 or 3.\n\nAt the time of first documented CK elevation, CK levels were significantly higher in patients presenting in stage 2 or 3 myopathy versus those in stage 1 myopathy (mean 5834 standard deviation (SD) 3652 U/L vs 1539 SD 1386 U/L, P = 0.015 by Wilcoxon rank-sum test). Similarly, CK levels were greater at the time of statin discontinuation in patients presenting in stage 2 or 3 versus those in stage 1 (mean 6070 SD 3279 U/L vs 2267 SD 1111 U/L, P = 0.016). However, when compared at T0, CK levels were similar between the 2 groups (mean 8173 SD 3763 U/L vs 5911 SD 3834 U/L, P = 0.48). The highest CK level observed in stage 3 myopathy was 11,755 U/L.\n\nEMG testing was abnormal at any time in 9 patients. At diagnosis, EMG testing showed an abnormal myopathy of the lower extremities in 7 patients and was normal in patient 7. Patients 1 and 2 had an abnormal EMG testing 11 and 8 months before diagnosis, respectively (Table 1). Two additional patients (patients 3 and 10) had a normal EMG done, respectively, 20 and 48 months before diagnosis.\n\nMRI of the thigh muscles was abnormal in 4 of 7 patients tested: either significant short tau inversion recovery inflammation (i.e., muscle edema) or T1 atrophy and fat replacement was noted (Table 1).\n\n3.3 Treatment of atorAIM: induction therapy\nAll but one of the patients (92%) were treated with corticosteroids. In the 9 (75%) patients treated with adequate oral corticosteroids alone as induction therapy, this approach was unable to normalize CKs and induce remission of the myopathy (Table 4). Weekly intravenous pulse methylprednisolone (500 mg) was also attempted in 5 patients (42%). However, because of the corticoresistance of atorAIM, intravenous immunoglobulins (IVIG) were used as second-line agent in 8 patients (67%). AtorAIM was notably responsive to IVIG as part of induction therapy.\n\nTable 4 Treatment of atorvastatin autoimmune myositis in 12 patients—induction therapy.\n\nFour patients did not need pulse methylprednisolone or IVIG therapy as induction therapy (Table 4). Of these, 2 patients were treated in stage 3 myopathy (patients 6 and 11) and 2 patients were treated in stage 1 myopathy (patients 7 and 10). Patient 6 responded, albeit slowly, to the combination of oral prednisone and methotrexate (MTX) as induction therapy, while patient 11 responded rapidly to the same induction therapy but subsequently needed IVIG as maintenance therapy in order to taper corticosteroids. Patient 7 responded slowly over 17 months to a combination of oral corticosteroids and MTX and never developed stage 3 myopathy with overt weakness. Finally, patient 10 was diagnosed in stage 1 myopathy, while previous statin discontinuation had initially substantially lowered his serum CK levels from 3793 to 429 U/L, this was followed by rebound CK elevation to 1232 U/L as shown in Table 2, and he was started on MTX monotherapy shortly before the end of follow-up.\n\n3.4 Treatment of atorAIM: maintenance therapy\nOf 10 patients with evaluable maintenance therapy (defined as a remission of at least 1 year on stable maintenance therapy), IVIG was needed in 5 patients (50%), either with MTX monotherapy (n = 3) or with combination immunosuppression (n = 2) (Table 5). In the remaining 5 patients, MTX monotherapy (n = 3) and combination therapy (n = 2) maintained remission without IVIG. Patient 3 successfully stopped IVIG therapy after 2 years, patient 2 is being slowly tapered off IVIG therapy, but 3 patients are still on IVIG therapy because of unsuccessful attempts at discontinuation.\n\nTable 5 Treatment of atorvastatin autoimmune myositis in 12 patients - maintenance therapy.\n\nCombination of at least 2 drugs, including MTX, either with IVIG, azathioprine (AZA), or mycophenolate mofetil (MMF), was needed in 7 patients (70%) with atorAIM. This myopathy proved to be particularly refractory to treatment. For example, 4 unsuccessful combination therapies were attempted in patient 1 before achieving remission with a combination of MMF, abatacept, and IVIG (Table 5). Similarly, patient 5 needed a combination of 4 drugs to maintain remission. This aggressive therapy combination strategy allowed complete tapering of corticosteroids in most patients (n = 9), while 3 patients remained on low-dose prednisone 5 mg daily. Patient 3, who was on combination MTX, AZA, and IVIG to induce corticosteroid-free remission and resolution of proximal weakness, then stopped IVIG successfully and then MTX, followed in the last year by AZA. The other patients on combination therapy could not be tapered off (Table 5).\n\n3.5 Anti-HMGCR autoantibodies\nAnti-HMGCR antibodies as determined by ALBIA were present in sera from all 12 patients (mean 4328.75 MFU, range 357.5–7095 MFU). Anti-HMGCR were highly positive in 10 patients, moderately positive (778.5 MFU) in patient 4, and low positive in patient 11 (357.5 MFU).\n\n3.6 Other autoantibodies\nBy indirect immunofluorescence on HEp-2 cells, ANA were negative in 11 of 12 samples and weakly positive in a single sample (diffuse granular pattern, endpoint titer 1:80). None of the sera displayed cytoplasmic fluorescence.\n\nImmunoprecipitation analysis, performed in sera from the 12 index patients, was negative for AIM aAbs, including for anti-SRP and the various anti-synthetases.\n\n3.7 Muscle pathological characteristics of atorAIM\nSkeletal muscle biopsy was performed in all 12 patients and was repeated in 5 patients (n = 17 biopsies). MAC (C5b-9) deposition was observed in all tested muscle biopsies (n = 14) (Table 6). Three patterns of MAC distribution were observed: isolated sarcolemmal deposition on non-necrotic fibers, isolated granular deposition on endomysial capillaries, and a mixed pattern.\n\nTable 6 Pathologic characteristics at skeletal muscle biopsy in 12 patients with atorvastatin autoimmune myositis.\n\nNecrosis and regeneration without inflammation was seen in all biopsies except in a biopsy performed 12 months before diagnosis in patient 3 (Fig. 2). Interestingly, at that time, patient 3 was in stage 1 myopathy, and MAC deposition on endomysial capillaries was the only abnormal pathological finding. At diagnosis, myopathy had progressed to stage 3, and a repeat muscle biopsy revealed abundant necrosis and regeneration as well as MAC deposition on endomysial capillaries (Fig. 2, Table 6). No capillary loss was found in patients showing MAC deposition in endomysial capillaries.\n\nFigure 2 Histopathological and immunohistochemical analysis of sequential skeletal muscle biopsies from patient 3, who presented in stage 1 atorvastatin autoimmune myositis (first biopsy) followed by progression to stage 3 myopathy (second biopsy 15 months later). (A) Normal histologic findings in stage 1 myopathy (biopsy 1, hematoxylin and eosin, H&E; original magnification 30×). (B) Histologic findings of myofiber necrosis and regeneration (inset) in stage 3 myopathy (biopsy 2, H&E, 63×). (C) and (D) Switch from negative (stage 1, biopsy 1) to positive (stage 3, biopsy 2) major histocompatibility complex class I staining by immunohistochemistry (40×). (E) and (F) Increasing granular endomysial capillary membrane attack complex staining by immunohistochemistry on biopsies 1 and 2 from patient 3 (40×).\n\nMHC-I expression on muscle fibers was noted in 8 (57%) of 14 tested biopsies. Thus, overall, MHC-I staining was absent in 43% of tested biopsies (n = 6/14). In stage 3 biopsies, MHC-I staining was absent in 27% of tested samples (n = 3/11), whereas in stage 1, it was absent in 2 out of 3 biopsies.\n\n4 Discussion\nThe objective of the present study was to further characterize the disease spectrum in patients presenting with a pure PM clinicoserological phenotype. Seventeen patients followed for at least 3 years with such a pure PM phenotype and treatment-responsive myopathy were identified. Of these patients, 82% (n = 14/17) had NAM on biopsy, of which 86% (n = 12/14) had previously been exposed to atorvastatin, leading to the diagnosis of atorAIM. Thus, atorAIM broadens the differential diagnosis of PM and, furthermore, emerges as a dominant entity in patients presenting with a pure PM phenotype.\n\nVarious investigators have described statin-induced AIM, most commonly related with atorvastatin use, and its place as a distinct subset of AIM can now be affirmed based on strong clinical, pathological, and serological arguments.[18–20] As several conclusions stem from the data presented herein, this study sheds light on the natural history of statin-induced AIM and further expands the spectrum of associated features.\n\nFirst, the distinct modes of presentation of atorAIM observed herein led to introduce the concept of staging of statin-induced AIM, as 3 clinical stages were recognized: stage 1—serum CK elevation, normal muscle strength, and normal EMG; stage 2—serum CK elevation, normal muscle strength, and myopathic EMG; and stage 3—serum CK elevation, proximal muscle weakness, and myopathic EMG. Thus, at diagnosis, 83% of patients had stage 3 myopathy, whereas the remaining 17% patients had stage 1 myopathy. However, at presentation, 50% of patients were in stage 1, 9% were in stage 2, whereas only 40% presented in stage 3. Interestingly, several patients with statin-associated IMNM described by Grable-Esposito et al[19] initially presented with high CK serum and normal strength and were likely in stage 2. In contrast, previous studies have essentially described patients at diagnosis in stage 3 myopathy, with high CK, abnormal EMG and MRI, and a treatment-refractory myopathy despite discontinuation of statin therapy.[21] Thus, clinicians should be aware of the various clinical stages of statin-induced AIM.\n\nSecond, statin-induced AIM should now be included specifically in the differential diagnosis of asymptomatic hyperCKemia. As shown in this study, CK elevation with preserved strength, defined as stage 1 myopathy, is the initial mode of presentation of statin-induced AIM.\n\nThird, stage 1 myopathy most commonly progresses to stage 3, despite discontinuation of atorvastatin therapy. In this cohort, only 2 patients with stage 1 (patients 7 and 10) did not progress to stage 3. Patient 7 was treated in a timely fashion when serum CK was at 6600 U/L and never got weak, whereas patient 10 was observed for 48 months, before treatment with MTX was considered at last follow-up because of a rebound in serum CK. Progression to stage 3 was typically slow, with a mean delay of 38 months. Similarly, 9 out of 25 (36%) patients with statin-induced AIM described by Grable-Esposito et al,[19] all of whom had normal strength at presentation developed proximal muscle weakness in the following months, despite discontinuation of statin therapy. Similar disease progression was noted by Needham et al.[21] Taken altogether, these shifts in staging emphasize the progressive nature of atorAIM despite discontinuation of statin therapy. Moreover, documented progression from stage 2 to stage 3 in patient 1 suggests that in an atorvastatin-treated patient with hyperCKemia but normal strength, an abnormal EMG may predict a high risk of progression to stage 3.\n\nFourth, isolated and persistent CK elevation following statin discontinuation should raise early suspicion for statin-induced AIM. Importantly, complete CK normalization was never seen in the present study after atorvastatin discontinuation. Isolated and progressive CK elevation is an uncommon mode of presentation of AIM and it was not seen as a presenting feature in a cohort of 100 French Canadians with AIM.[2] The slowly progressive presentation of statin-induced AIM is consequently at high risk for mimicking nonautoimmune myopathies and eventually delaying treatment. A diagnosis of statin-induced AIM should therefore be evoked in any patient who was previously exposed to statin therapy and in whom isolated but persistent CK elevation is documented.\n\nFifth, the deceptive nature of atorAIM is indicated by the initial decrease in serum CK levels that suggested improvement in several patients with stage 1 myopathy after atorvastatin discontinuation and by the shifting CK dynamics shown in Tables 2 and 3 that may suggest a relatively stable condition, thus delaying the introduction of definitive treatment. Furthermore, regardless of staging at presentation, not only did CK levels never normalize following statin discontinuation in all patients reported herein, but in all cases CK levels eventually rose to significantly higher levels than at baseline as atorAIM progressed to stage 3. Thus, even mild but persistent CK elevation following statin discontinuation may later progress clinically and justify introduction of treatment.\n\nSixth, atorAIM is uniformly corticosteroid resistant but responsive to IVIG as induction and maintenance therapy. Combination therapy is frequently needed to maintain remission. However, this study was observational and cannot answer definitively the question of the recommended treatments for atorAIM. No trials thus far have defined the optimal treatments for this condition. As shown in Table 4, in all patients treated with oral corticosteroids alone as induction therapy, this approach was unable to normalize CK levels and induce remission of the myopathy. Thus, the precise role of corticosteroids and the necessity, if any, to include them in the treatment of atorAIM are yet to be defined. However, atorAIM was clearly responsive to IVIG for induction and maintenance therapy. Therefore, the authors suggest MTX therapy (without or with corticosteroids) or combination MTX and IVIG therapy as the initial approach for treating atorAIM. If remission is not attained with this initial approach, or if remission is not sustained on tapering of either corticosteroids or IVIG, early addition of AZA or MMF may be contemplated. With this aggressive therapeutic approach, most patients (n = 8) were successfully tapered off corticosteroids and normal or near-normal strength could be restored at last follow-up. The need for combination therapy is supported by a recent trial of IVIG monotherapy in 3 patients with statin-induced AIM. While associated with improved strength, IVIG monotherapy failed to normalize serum CK in 2 patients.[22]\n\nSeventh, MAC deposition on non-necrotic fibers and endomysial capillaries, while non pathognomonic, is an important pathological clue to atorAIM. MAC deposition was observed in all 13 muscle biopsies in 3 patterns: isolated sarcolemmal deposition on non-necrotic fibers, isolated granular deposition on endomysial capillaries and a mixed pattern. Such MAC deposition represents a new feature of atorAIM. MAC deposition on capillaries, although initially thought of as a specific feature of dermatomyositis, has also been documented in anti-SRP (with capillary loss)[23] and in anti-HMGCR-associated myopathies,[24] suggesting that the latter myopathies are microangiopathies. The present report confirms the study by Chung et al,[24] where MAC deposition was noted in 85.7% of cases either on endomysial capillaries or on non-necrotic muscle fibers or a combination of both.\n\nEight, the pathophysiological sequence in atorAIM may be characterized first by MAC deposition in the capillaries followed later by necrosis. This is suggested by sequential muscle biopsies in patient 3 (Fig. 2 and Table 6), which revealed MAC deposition in the capillaries as the only pathological abnormality in stage 1, whereas a subsequent biopsy 15 months later in stage 3 demonstrated necrosis, regeneration, and MHC-I staining on non-necrotic muscle fibers, in addition to MAC deposition. However, since this conclusion is based only on 2 biopsies in a single patient, it cannot be generalized, and sequential biopsies from additional patients will be of interest. Necrosis and regeneration without significant inflammation were also noted in muscle biopsies of most of atorAIM patients (Table 6). The efficacy of IVIG therapy to induce and maintain remission in atorAIM adds weight to the pathophysiological importance of MAC deposition. An effort should be made to routinely document pathology in the capillaries, as well as MAC deposition on capillaries and non-necrotic muscle fibers, to fully appreciate the spectrum of NAM.\n\nNinth, MHC-I staining is not a sensitive marker for atorAIM. Overall, MHC-I staining was absent in 43% of tested biopsies. Similarly, MHC-I staining on non-necrotic fibers was seen in only 50% of patients in the study by Christopher-Stine et al.[9] Although the sample size in the present study is small, not only was MHC-I staining not present in several patients with stage 3 myopathy, it might very well be absent in many patients with stage 1 myopathy. Thus, treating stage 1 myopathy could be considered in individual patients without MHC-I staining at muscle biopsy if the clinical, serological, and, possibly, pathological manifestations (i.e., capillary MAC deposition at muscle biopsy, with or without necrosis and regeneration) suggest a statin-induced AIM.\n\nTenth, anti-HMGCR aAb testing demonstrated excellent (100%) sensitivity for the clinicopathological phenotype of atorAIM as defined herein. Anti-HMGCR aAbs were present in all 12 patients suspected of having atorAIM. All patients had a negative or weakly positive ANA, without cytoplasmic staining. No additional aAbs were detected. Previous studies by Mammen et al[25,26] found anti-HMGCR aAbs to be highly specific for NAM, with only 0% to 4% of false positives.\n\nLast, whether atorvastatin-exposed patients are more at risk for the development of NAM, and whether the natural history of NAM is worst with atorvastatin than with other statins are important questions. The former question is raised given that all patients in the present study were treated only with atorvastatin. Statins prescribed in the Province of Quebec are not restricted to atorvastatin and include simvastatin, pravastatin, and rosuvastatin. However, atorvastatin is locally the most commonly prescribed statin. Therefore, the association between NAM and atorvastatin reported herein may simply reflect prescription frequency. No dose–response effect was noted, as half of the patients were on a low dose (20 mg) of atorvastatin. That being said, statin-associated NAM is not restricted to atorvastatin. For example, in the report by Needham et al,[21] 4 of 8 patients with NAM had been treated with simvastatin, 3 with atorvastatin, and 1 with a combination of these drugs. In the report by Grable-Esposito et al,[19] although 21 of 25 patients had received atorvastatin, 4 were exposed to simvastatin or pravastatin. Importantly, Basharat et al recently used multiple regression analysis to identify independent variables that may be associated with the risk for the development of anti-HMGCR-positive NAM in statin-exposed patients. After adjusting for age and sex, type 2 diabetes mellitus and atorvastatin use (vs rosuvastatin and simvastatin) were significantly associated with anti-HMGCR NAM.[27] In support of the data of Basharat et al, 75% of patients with atorAIM in the present study had type 2 diabetes mellitus. Thus, atorvastatin-exposed patients with type 2 diabetes mellitus appear more at-risk for atorAIM.\n\nThis study had some limitations, including a small sample size and a retrospective design. In addition, patient recruitment was restricted to 2 academic hospitals (although such patients are typically seen in such institutions) from the same city. As indicated, these limitations may limit the generalizability of the results. Restriction of patients to the pure PM phenotype may have underestimated the full clinical spectrum of atorAIM. Additional multicenter studies with a larger number of patients and serial muscle biopsies will be of interest to confirm that atorAIM is becoming the leading cause of pure PM phenotype and to define the optimal treatment for this condition.\n\nIn conclusion, in the present study, atorAIM emerged as the dominant entity in patients with a pure PM phenotype and treatment-responsive myopathy. Isolated CK elevation, that is, stage 1 myopathy, was the initial mode of presentation of atorAIM. Thus, the new onset of isolated CK elevation on atorvastatin and persistent CK elevation on statin discontinuation should raise early suspicion for atorAIM. Three patterns of MAC deposition were seen and, while nonpathognomonic, were pathological clues to atorAIM. AtorAIM was uniformly corticosteroid resistant but responsive to IVIG as induction and maintenance therapy.\n\nAcknowledgments\nThe authors thank Martin Ladouceur, PhD, biostatistician, CHUM Research Center, for statistical advice, and Gemma Pérez, Meifeng Zhang, and Haiyan Hou for laboratory assistance.\n\nAbbreviations: aAbs = autoantibodies, AIM = autoimmune myositis, ANA = antinuclear antibodies, anti-HMGCR = aAbs to 3-hydroxy-3-methylglutaryl coenzyme A reductase, anti-SRP = aAbs to signal recognition particle, atorAIM = atorvastatin-induced AIM, AZA = azathioprine, CHUM = Centre hospitalier de l’Université de Montréal, CK = creatine kinase, DM = dermatomyositis, EMG = electromyogram, IMNM = immune-mediated necrotizing myopathy, IVIG = intravenous immunoglobulins, MAC = membrane attack complex, MHC-I = major histocompatibility complex class I, MMF = mycophenolate mofetil, MRI = magnetic resonance imaging, NAM = necrotizing AIM, PM = polymyositis, SD = standard deviation.\n\nDr Yves Robitaille is deceased.\n\nFunding/support: This work was supported in part by grant MOP-142211 from the Canadian Institutes of Health Research (to J-LS), by Department of Veterans Affairs Medical Research Funds (to INT), and by donations from Sclérodermie Québec (J-LS) and Mrs Gisèle Sarrazin-Locas (J-LS) in support of The Laboratory for Research in Autoimmunity, Centre Hospitalier de l’Université de Montréal. MJF holds the Arthritis Society Research Chair at the University of Calgary. J-LS holds the University of Montreal Scleroderma Research Chair.\n\nAuthors YT, OL-C, JF, ER, MG, J-RG, JB-T, YR, JD, AA, and J-LS have no conflicts of interest to disclose. The authors listed below have received financial support (personal or institutional) from the listed institutions, unrelated to the present work. INT: Oklahoma Medical Research Foundation Clinical Immunology Laboratory, UpToDate; MJF: EUROIMMUN, ImmunoConcepts, Inova Diagnostics.\n==== Refs\nReferences\n[1] Bohan A Peter JB \nPolymyositis and dermatomyositis (parts 1 and 2) . N Engl J Med \n1975 ;292 :344 –7 . 403–407 .1090839 \n[2] Troyanov Y Targoff I Tremblay JL \nNovel classification of idiopathic inflammatory myopathies based on overlap clinical features and autoantibodies: analysis of 100 French Canadian patients with myositis . Medicine (Baltimore) \n2005 ;84 :231 –49 .16010208 \n[3] van de Vlekkert J Hoogendijk JE de Visser M \nMyositis with endomysial cell invasion indicates inclusion body myositis even if other criteria are not fulfilled . Neuromusc Disord \n2015 ;25 :451 –6 .25817837 \n[4] van der Meulen MF Bronner IM Hoogendijk JE \nPolymyositis: an overdiagnosed entity . Neurology \n2003 ;61 :316 –21 .12913190 \n[5] Dalakas MC \nInflammatory muscle diseases . N Engl J Med \n2015 ;372 :1734 –47 .25923553 \n[6] Quinn C Salameh JS Smith T \nNecrotizing myopathies: an update . J Clin Neuromusc Disord \n2015 ;16 :131 –40 .\n[7] Kissel JT Mendell JR Rammohan KW \nMicrovascular deposition of complement membrane attack complex in dermatomyositis . N Engl J Med \n1986 ;314 :329 –34 .3945256 \n[8] Dimitri D Andre C Roucoules J \nMyopathy associated with anti-signal recognition peptide antibodies: clinical heterogeneity contrasts with stereotyped histology . Muscle Nerve \n2007 ;35 :389 –95 .17143889 \n[9] Christopher-Stine L Casciola-Rosen LA Hong G \nA novel autoantibody recognizing 200-kd and 100-kd proteins is associated with an immune-mediated necrotizing myopathy . Arthritis Rheum \n2010 ;62 :2757 –66 .20496415 \n[10] Hoogendijk JE Amato AA Lecky BR \n119th ENMC International Workshop: Trial design in adult idiopathic inflammatory myopathies, with the exception of inclusion body myositis, 10–12 October 2003, Naarden, The Netherlands . Neuromuscul Disord \n2004 ;14 :337 –45 .15099594 \n[11] Koenig M Fritzler MJ Targoff IN \nHeterogeneity of autoantibodies in 100 patients with autoimmune myositis: insights into clinical features and outcomes . Arthritis Res Ther \n2007 ;9 :1 –3 .\n[12] Hochberg MC \nUpdating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus . Arthritis Rheum \n1997 ;40 :1725 .\n[13] Senécal JL Isabelle C Fritzler MJ \nAn autoimmune myositis-overlap syndrome associated with autoantibodies to nuclear pore complexes. Description and long-term follow-up of the anti-nup syndrome . Medicine (Baltimore) \n2014 ;93 :361 –72 .\n[14] Troyanov Y Targoff IN Payette MP \nRedefining dermatomyositis: a description of new diagnostic criteria that differentiate pure dermatomyositis from overlap myositis with dermatomyositis features . Medicine (Baltimore) \n2014 ;93 :296 –310 .\n[15] Arnett FC Targoff IN Minori T \nInterrelationship of major histocompatibility complex class II alleles and autoantibodies in four ethnic groups with various forms of myositis . Arthritis Rheum \n1996 ;39 :1507 –18 .8814062 \n[16] Targoff IN \nAutoantibodies to aminoacyl-transfer RNA synthetases for isoleucine and glycine: two additional synthetases are antigenic in myositis . J Immunol \n1990 ;144 :1737 –43 .2307838 \n[17] Targoff IN Trieu EP Miller FW \nReaction of anti-OJ autoantibodies with components of the multi-enzyme complex of aminoacyl-tRNA synthetases in addition to isoleucyl-tRNA synthetase . J Clin Invest \n1993 ;91 :2556 –64 .8514867 \n[18] Albayda J Christopher-Stine L \nIdentifying statin-associated autoimmune necrotizing myopathy . Cleve Clin J Med \n2014 ;81 :736 –41 .25452351 \n[19] Grable-Esposito P Katzberg HD Greenberg SA \nImmune-mediated necrotizing myopathy associated with statins . Muscle Nerve \n2010 ;41 :185 –90 .19813188 \n[20] Mammen AL \nStatin-associated autoimmune myopathy . N Engl J Med \n2016 ;374 :664 –9 .26886523 \n[21] Needham M Fabian V Knezevic W \nProgressive myopathy with up-regulation of MHC-I associated with statin therapy . Neuromuscul Disord \n2007 ;17 :194 –200 .17241784 \n[22] Mammen AL \nIntravenous immune globulin for statin-triggered autoimmune myopathy . N Engl J Med \n2016 ;373 :1680 –1 .\n[23] Miller T Al-Lozi MT Lopate G \nMyopathy with antibodies to the signal recognition particle: clinical and pathological features . J Neurol Neurosurg Psychiatry \n2002 ;73 :420 –8 .12235311 \n[24] Chung T Christopher-Stine L Paik JJ \nThe composition of cellular infiltrates in anti-HMG-CoA reductase-associated myopathy . Muscle Nerve \n2015 ;52 :189 –95 .25737145 \n[25] Mammen AL Chung T Christopher-Stine L \nAutoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy . Arthritis Rheum \n2011 ;63 :713 –21 .21360500 \n[26] Mammen AL Pak K Williams EK \nRarity of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibodies in statin users, including those with self-limited musculoskeletal side effects . Arthritis Care Res (Hoboken) \n2012 ;64 :269 –72 .21972203 \n[27] Basharat P Lahouti AH Paik JJ \nStatin-induced anti-HMGCR-associated myopathy . J Am Coll Cardiol \n2016 ;68 :234 –5 .27386780\n\n",
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"issue": "96(3)",
"journal": "Medicine",
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"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000069059:Atorvastatin; D001323:Autoantibodies; D001327:Autoimmune Diseases; D015938:Complement Membrane Attack Complex; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D060828:Induction Chemotherapy; D008137:Longitudinal Studies; D008297:Male; D008775:Methylprednisolone; D008875:Middle Aged; D018482:Muscle, Skeletal; D017285:Polymyositis",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e5694",
"pmc": null,
"pmid": "28099331",
"pubdate": "2017-01",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "3945256;26488714;27386780;17688695;25737145;12235311;19813188;25500708;21360500;17241784;25817837;15099594;25500701;20496415;25923553;21972203;2307838;25695918;8814062;12913190;16010208;17143889;9324032;1090839;8514867;25452351;26886523",
"title": "Atorvastatin-induced necrotizing autoimmune myositis: An emerging dominant entity in patients with autoimmune myositis presenting with a pure polymyositis phenotype.",
"title_normalized": "atorvastatin induced necrotizing autoimmune myositis an emerging dominant entity in patients with autoimmune myositis presenting with a pure polymyositis phenotype"
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"abstract": "BACKGROUND\nPancytopenia has only rarely been reported with Levetiracetam use. It is a potentially life threatening adverse effect that requires cessation of therapy.\n\n\nMETHODS\nWe describe a case of an otherwise well thirty-two-year-old man who underwent an emergent craniotomy for evacuation of a traumatic extra-dural haematoma. Post-operatively, he developed pancytopenia which corrected with cessation of levetiracetam.\n\n\nCONCLUSIONS\nThis report aims to increase awareness of this rare side effect and reiterates the judicious use of prophylactic levetiracetam in brain trauma.",
"affiliations": "Department of Neurosurgery, Sir Charles Gairdner Hospital (SCGH), Perth, WA, Australia.;Department of Neurosurgery, Sir Charles Gairdner Hospital (SCGH), Perth, WA, Australia. Electronic address: alexandresimonin21@gmail.com.;Department of Neurosurgery, Sir Charles Gairdner Hospital (SCGH), Perth, WA, Australia.;Department of Neurosurgery, Sir Charles Gairdner Hospital (SCGH), Perth, WA, Australia.;Department of Neurosurgery, Sir Charles Gairdner Hospital (SCGH), Perth, WA, Australia.",
"authors": "Bangash|Omar|O|;Simonin|Alexandre|A|;Tsimiklis|Chrisovalantis|C|;Ramakonar|Hari|H|;Honeybul|Stephen|S|",
"chemical_list": "D000927:Anticonvulsants; D000077287:Levetiracetam",
"country": "Scotland",
"delete": false,
"doi": "10.1016/j.jocn.2020.08.004",
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"issue": "80()",
"journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia",
"keywords": "Craniotomy; Levetiracetam; Pancytopenia; Prophylaxis; Seizures",
"medline_ta": "J Clin Neurosci",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D000070642:Brain Injuries, Traumatic; D003399:Craniotomy; D006407:Hematoma, Epidural, Cranial; D006801:Humans; D000077287:Levetiracetam; D008297:Male; D010198:Pancytopenia; D056990:Post-Exposure Prophylaxis",
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"other_id": null,
"pages": "264-266",
"pmc": null,
"pmid": "33099358",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Prophylactic levetiracetam-induced pancytopenia with traumatic extra-dural hematoma: Case report.",
"title_normalized": "prophylactic levetiracetam induced pancytopenia with traumatic extra dural hematoma case report"
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"abstract": "BACKGROUND\nDirect-acting antivirals have been used for decompensated cirrhotic patients with hepatitis C virus (HCV) infection. However, the benefits in Chinese patients with decompensated cirrhosis are unclear.\n\n\nMETHODS\nThirty patients with HCV infection and decompensated cirrhosis were administered sofosbuvir-containing regimens at our hospital between April and December 2015. The efficacy and safety of the treatments was determined by sustained virological response at week 12 (SVR 12), change of liver function and adverse events.\n\n\nRESULTS\nThe cohort included 13 treatment-experienced and 17 treatment-naïve patients. A total of 27 patients (90%) achieved SVR 12. No baseline characteristics (sex, age, treatment-experience, genotype, viral load, liver function or splenectomy) was association with achievement of SVR 12. Patients achieved SVR 12 had significantly improved liver function by post-treatment week 12 (P < 0.05). Of the 30 patients, six developed anemia, one developed hepatic decompensation, two developed impaired renal function and one developed a severe upper respiratory tract infection during the treatment. There was no death or HCC development during 12 months of follow-up off-therapy. Two patients (7.4%) with SVR 12 experienced new decompensated episodes during the follow-up.\n\n\nCONCLUSIONS\nSofosbuvir-containing regimens are effective in Chinese HCV patients with decompensated cirrhosis, regardless of baseline characteristics, as demonstrated by a high rate of SVR 12, as well as improvement in liver function. Although antiviral therapy is generally well tolerated, a vigilant monitoring of anemia and renal function should be mandatory.",
"affiliations": "Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xi Wu Road, Xi'an, 710004 Shaanxi Province People's Republic of China.;Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xi Wu Road, Xi'an, 710004 Shaanxi Province People's Republic of China.;Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xi Wu Road, Xi'an, 710004 Shaanxi Province People's Republic of China.;Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xi Wu Road, Xi'an, 710004 Shaanxi Province People's Republic of China.;Department of Clinical Laboratory, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.;Department of Biochemistry and Molecular Biology, Medical College of Xi'an Jiaotong University, Xi'an, China.;Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xi Wu Road, Xi'an, 710004 Shaanxi Province People's Republic of China.;Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xi Wu Road, Xi'an, 710004 Shaanxi Province People's Republic of China.;Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xi Wu Road, Xi'an, 710004 Shaanxi Province People's Republic of China.;Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.",
"authors": "Ji|Fanpu|F|0000-0002-1463-8035;Wang|Wenjun|W|;Dang|Shuangsuo|S|;Wang|Shengbang|S|;Li|Burong|B|;Bai|Dan|D|;Zhao|Wenxue|W|;Deng|Hong|H|;Tian|Changyin|C|;Li|Zongfang|Z|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s13027-017-0158-1",
"fulltext": "\n==== Front\nInfect Agent CancerInfect. Agents CancerInfectious Agents and Cancer1750-9378BioMed Central London 15810.1186/s13027-017-0158-1Research ArticleOutcomes after sofosbuvir-containing regimens for hepatitis C virus in patients with decompensated cirrhosis: a real-world study http://orcid.org/0000-0002-1463-8035Ji Fanpu +86-29 87679275jifanpu1979@163.com 12Wang Wenjun alargo@163.com 1Dang Shuangsuo dang212@126.com 1Wang Shengbang 1462275997@qq.com 1Li Burong liburong@126.com 3Bai Dan danbai@xjtu.edu.cn 4Zhao Wenxue zhaowenxue888@126.com 1Deng Hong ganran@163.com 1Tian Changyin +86-29 87679273lbdtcyty@163.com 1Li Zongfang lzf2568@gmail.com 251 grid.452672.0Department of Infectious Diseases, Second Affiliated Hospital of Xi’an Jiaotong University, 157 Xi Wu Road, Xi’an, 710004 Shaanxi Province People’s Republic of China 2 grid.452672.0Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China 3 grid.452672.0Department of Clinical Laboratory, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China 4 0000 0001 0599 1243grid.43169.39Department of Biochemistry and Molecular Biology, Medical College of Xi’an Jiaotong University, Xi’an, China 5 grid.452672.0National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China 13 9 2017 13 9 2017 2017 12 4822 12 2016 5 9 2017 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nDirect-acting antivirals have been used for decompensated cirrhotic patients with hepatitis C virus (HCV) infection. However, the benefits in Chinese patients with decompensated cirrhosis are unclear.\n\nMethods\nThirty patients with HCV infection and decompensated cirrhosis were administered sofosbuvir-containing regimens at our hospital between April and December 2015. The efficacy and safety of the treatments was determined by sustained virological response at week 12 (SVR 12), change of liver function and adverse events.\n\nResults\nThe cohort included 13 treatment-experienced and 17 treatment-naïve patients. A total of 27 patients (90%) achieved SVR 12. No baseline characteristics (sex, age, treatment-experience, genotype, viral load, liver function or splenectomy) was association with achievement of SVR 12. Patients achieved SVR 12 had significantly improved liver function by post-treatment week 12 (P < 0.05). Of the 30 patients, six developed anemia, one developed hepatic decompensation, two developed impaired renal function and one developed a severe upper respiratory tract infection during the treatment. There was no death or HCC development during 12 months of follow-up off-therapy. Two patients (7.4%) with SVR 12 experienced new decompensated episodes during the follow-up.\n\nConclusion\nSofosbuvir-containing regimens are effective in Chinese HCV patients with decompensated cirrhosis, regardless of baseline characteristics, as demonstrated by a high rate of SVR 12, as well as improvement in liver function. Although antiviral therapy is generally well tolerated, a vigilant monitoring of anemia and renal function should be mandatory.\n\nKeywords\nHepatitis C virusSofosbuvirChild-Pugh scoreDecompensated cirrhosisRenal dysfunctionAnemiahttp://dx.doi.org/10.13039/501100001809National Natural Science Foundation of China81300322Ji Fanpu Personnel training special funds of the Second Affiliated Hospital of Xi’an Jiaotong UniversityRC(GG)201501Ji Fanpu issue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nHepatitis C virus (HCV) infection is a global health problem with an estimated disease burden affecting 130–170 million people. China, with a prevalence of 0.6–2.0%, has the most people (more than 10 million) with chronic HCV infection worldwide [1, 2]. Chronic hepatitis C (CHC) represents a life-threatening condition, especially if left untreated, as it is leads to development of cirrhosis, a liver disease that is accompanied by high risk of progression to hepatic decompensation and hepatocellular carcinoma (HCC) [1–3]. Despite advances in screening strategies and effective antiviral therapy, the number of patients with HCV-related decompensated cirrhosis is projected to rise over the next decade or more [2, 4, 5].\n\nHCV eradication in compensated and decompensated cirrhotic patients after interferon (IFN)-based antiviral therapy is associated with improvement of liver metabolic activity, prevention of HCV recurrence after transplantation, and removal of some patients from the waiting list for liver transplant, as well as reduced risk of HCC development [6–12]. Unfortunately, IFN-based antiviral therapy for cirrhotic patients with advanced disease is also associated with poor tolerability, serious infections and increased risk of death [10–13]. The advent of direct-acting antiviral agents (DAAs) promises to overcome these disadvantages in safety while increasing efficacy.\n\nSofosbuvir is a nucleotide analogue inhibitor of the HCV-encoded NS5B polymerase, and has been approved for treatment of genotypes 1–4 [14]. Sofosbuvir in combination with other DAAs (such as ledipasvir, daclatasvir, velpatasvir, simeprevir) with or without ribavirin has been reported to attain a sustained virologic response (SVR) rate of over 90% when administered as a 12- to 24-week course, while being well-tolerated in cirrhotic patients with advanced disease as well as in liver transplant patients through both clinical trials and real-world evidence [15–24]. Moreover, the sofosbuvir-based therapy also has been shown to improve liver function and halt liver disease progression in cirrhotic patients with advanced disease [15, 19, 20]. Despite of the impact of DAAs treatments on the risk of HCC occurrence in patients without HCC or on the risk of tumor recurrence after curative treatment of HCC remains controversial [25–29].\n\nTo date, few report of DAAs treatment of Chinese patients with HCV infection and decompensated cirrhosis exists in available literature without the data of follow-up off-therapy [30, 31]. Therefore, the objective of present study was to share our real-world experience of effectiveness and safety of sofosbuvir-containing regimens for HCV in patients with decompensated cirrhosis in a tertiary hospital in northwest China.\n\nMethods\nStudy design and patients\nThis study complied with the Declaration of Helsinki. The institutional review board of the Second Affiliated Hospital of Xi’an Jiaotong University waived the requirement for approval of this retrospective study. Patients were offered study enrollment upon meeting the following inclusion criteria: positive anti-HCV and HCV RNA at last 3 months; on admission, Child-Pugh score ≥ 7 or ≤6 points and at least one pre-admission event signifying hepatic decompensation, including ascites, variceal bleeding, spontaneous bacterial peritonitis (SBP) or hepatic encephalopathy. Patients with HCC, chronic renal failure, unstable cardiovascular disease, severe chronic obstructive lung disease, co-infection with human immunodeficiency virus, or Child-Pugh class C after the decompensated event who had been treated with appropriate therapy were denied study enrollment. Among those patients who met the criteria for study enrollment, only those who were willing to accept and adhere to the prescribed drug and regimen were included in the final study population.\n\nIn total 84 HCV related decompensated cirrhotic patients were screened for treatment in our hospital from April to December 2015. Fifteen of them were excluded for negative HCV RNA (14 of 15 patients with successful HCV treatment by IFN-based regimens), 13 were excluded for HCC, 12 for refusing to be treated with sofosbuvir-containing regimens, ten for Child-Pugh class C and four for severe complications including chronic kidney disease (n = 2), cardiovascular disease (n = 1) and severe chronic obstructive lung disease (n = 1). The remaining 30 patients were enrolled into the study (Fig. 1) included 13 treatment-experienced patients [8, 11, 32, 33] and 17 treatment-naïve patients.Fig. 1 Antiviral therapy regimens and virologic response in patients with decompensated cirrhosis. COPD, chronic obstructive lung disease\n\n\n\n\nTreatment schedules\nAntiviral treatment started 1- to 2-weeks after the decompensated event had been treated with appropriate therapy such as antibiotic treatment for SBP, diuretics for ascites and edema, etc. Prior to initiation of the sofosbuvir-containing therapeutic regimens, each patient underwent electrocardiogram, endoscopy, liver computed tomography (CT)/B ultrasound, α-fetoprotein and virus genotyping (Da An Gene Co. Ltd. of Sun Yat-Sen University, China). Twenty-one (70%) of the patients were infected with HCV genotype 1b. Among these patients, two were treated with sofosbuvir (400 mg/d) + ledipasvir (90 mg/d) for 16 weeks, three were treated with sofosbuvir (400 mg/d) + daclatasvir (60 mg/d) for 12–16 weeks, 15 were treated with sofosbuvir (400 mg/d) + ribavirin (900–1200 mg/d) for 24 weeks, and one was treated with triple-combination therapy of sofosbuvir (400 mg/d) + pegylated interferon alpha-2b (Peg-IFN α-2b) (80 μg/wk) + ribavirin (1000 mg/d) for 12 weeks. All of the nine patients with HCV genotype 2a infection were treated with sofosbuvir (400 mg/d) + ribavirin (900 mg/d) for 16–24 weeks. For patient showed decrease in hemoglobin to 9.0–10.0 g/dL required closely monitored, to 8.0–9.0 g/dL required ribavirin dose reductions, to less than 8.0 g/dL required ribavirin discontinuations and received erythropoietin treatment, which was referred to our previous studies of IFN-based treatment for this population [8, 11, 33]. The treatment regimens and effectiveness were presented in Fig. 1.\n\nTreatment monitoring and follow-up\nPatients receiving therapy were reviewed at treatment weeks 2, 4 and 12 and/or end of treatment, and at post-treatment weeks 4 and 12, and then once every 3 months subsequently. Partial patients underwent HCV RNA testing at days 3, and 7 of treatment. The blood cell count, HCV RNA and serum markers including total bilirubin (TBIL), alanine aminotransferase (ALT), albumin (ALB), urea nitrogen and serum creatinine, prothrombin activity (PTA) were checked in each review routinely. All patients received liver B ultrasound and α-fetoprotein test every 3 months after DAAs treatment for HCC screening. And patient also received liver computed tomography with or without contrast enhancement scan when it is necessary to rule out HCC development. HCV RNA was measured using the 7300 real-time PCR system (Applied Biosystems Inc., USA) and reagents from the Da An Gene Co. Ltd. of Sun Yat-Sen University, China. However, the Cobas TaqMan quantitative detection kit, with a detection limit <25 IU/mL, was used to measure HCV RNA at end-of-treatment and post-treatment week 12. Serious adverse events (SAEs), decompensation events, severe infections, HCC development and death were recorded. Other common adverse events (AEs), such as palpitation, dizziness, nausea, fatigue etc., were also recorded.\n\nOutcome measures\nThe primary end point of our study was sustained virological response at 12 weeks post-treatment (SVR 12), which was defined as undetectable HCV RNA measured with a detection limit of quantification <25 IU/mL. The secondary end points included undetectable HCV RNA at treatment week 1, 2 or 4, change in liver function (serum TBIL, ALT, ALB, PTA and Child-Pugh score) at post-treatment week 12, AEs including liver decompensation and HCC development during the treatment and follow-up period. The length of the follow-up period was calculated from the end of the antiviral treatment to the last follow-up visit.\n\nStatistical analysis\nData are represented as the mean and standard deviation or as absolute and relative frequencies. Statistical comparisons were carried out using the chi-square test or Fisher’s exact test for baseline characteristics, and the two-sided paired t-test for the change in liver function at baseline and post-treatment week 12. The following baseline characteristics were examined in relation to SVR 12: patient age > 60 years, sex, treatment-experienced, HCV genotype, baseline viral load ≥1.0 × 106 IU/mL, Child-Pugh score ≥ 7, and splenectomy. Analyses were carried out using SPSS statistical software, version 17.0 (IBM, Chicago, IL, USA). A p-value of <0.05 was set as the threshold for statistical significance.\n\nResults\nPatient demographics and clinical characteristics\nThe 30-patient cohort consisted of 8 males and 22 females, with a mean age of 58.57 ± 8.06 years-old (range: 42–73 years-old). Among the 30 patients, 13 (43.3%) had previously been administered an IFN-based regimen and showed treatment failure including relapse and non-virological response; the remaining 17 patients were treatment-naïve. The collective characteristics are presented in Table 1.Table 1 Patient demographics and clinical characteristics\n\nCharacteristic\tTreatment-naïve patients (n = 17)\tTreatment-experienced patients (n = 13)\tAll patients, (n = 30)\t\nSex, n (%)\t\n Male\n Female\t4 (23.5)\n13 (76.5)\t4 (30.8)\n9 (69.2)\t8 (26.7)\n22 (73.3)\t\nAge, n (%)\t\n ≥ 60 years-old\n < 60 years-old\t7 (41.2)\n10 (58.8)\t7 (53.8)\n6 (46.2)\t14 (46.7)\n16 (53.3)\t\nGenotypea, n (%)\t\n 1b\n 2a\t9 (52.3)\n8 (47.7)\t12 (92.3)\n1 (7.7)\t21 (70.0)\n9 (30.0)\t\nHCV RNA, n (%)\t\n ≥ 1.0 × 106 IU/mL\n < 1.0 × 106 IU/mL\t7 (41.2)\n10 (58.8)\t9 (69.2)\n4 (30.8)\t16 (53.3)\n14 (46.7)\t\nChild-Pugh scorea, n (%)\t\n ≥ 7\n < 7\t7 (41.2)\n10 (58.8)\t2 (15.4)\n11 (84.6)\t9 (30.0)\n21 (70.0)\t\nSplenectomy, n (%)\t\n Yes\n No\t6 (35.3)\n11 (64.7)\t3 (23.1)\n10 (76.9)\t9 (30.0)\n21 (70.0)\t\n\naCompared with the treatment-naïve patients, a lower proportion of treatment- experienced patients is genotype 2 and Child-Pugh score ≥ 7; p < 0.05\n\n\n\n\nVirological outcome\nSVR 12 was achieved in 27/30 (90%) for this population of HCV decompensated cirrhotic patients. For the various treatment regimens administered (Fig. 1), two of the patients infected with genotype 1b who received the sofosbuvir + ribavirin therapy experienced relapse at weeks 4 and 12 after end-of-treatment respectively, and one of them was treatment-naïve. Another treatment-naïve patient infected with genotype 2a who received sofosbuvir + ribavirin for 16 weeks experienced HCV recurrence at post-treatment week 12.\n\nNo baseline factors, including sex (SVR in males, 100% vs. in females, 86.3%), age (SVR in ≥60 years-old, 92.9% vs. <60 years-old, 87.5%), previous IFN-based therapy experience (SVR in treatment-experienced, 92.3% vs. treatment-naïve, 88.2%), virus genotype (SVR in 1b–infected, 90.5% vs. 2a–infected, 88.9%), baseline viral load (SVR in ≥106 IU/mL, 87.5% vs. <106 IU/mL, 92.9%), Child-Pugh score (SVR in ≥7, 88.9% vs. <7, 90.5%) and previous splenectomy treatment (SVR in splenectomy, 88.9% vs. no splenectomy, 90.5%) was associated with the achievement of SVR 12 (all p > 0.05) (Fig. 2).Fig. 2 SVR 12 by baseline factor\n\n\n\n\nSerum HCV RNA was detected in 12 patients 3 days after receiving antiviral treatment with sofosbuvir-containing regimens. There was an average reduction in HCV RNA viral load by 3.34 log10 (baseline, 6.06 ± 0.62 vs. treatment day 3, 2.72 ± 1.33). The rates of undetectable HCV during treatment were 54.8% (7/13) at week 1, 83.3% (15/18) at week 2, 100% (30/30) at week 4 and 100% (30/30) at end-of-treatment.\n\nEffects of sofosbuvir-containing regimens on liver function and safety\nThe sofosbuvir-containing treatment led to significant improvements in liver function (baseline vs. post-treatment week 12; Table 2). Totally, 14 patients (46.7%) experienced at least one AEs, four patients (13.3%) experienced SAEs. Of these SAEs, two patients experienced increase in serum urea nitrogen and/or serum creatinine to levels above the upper limit of normal. Another one patient developed severe anemia (5.6 g/dL in hemoglobin) accompanied by liver decompensation, massive ascites, and lower extremity edema; the complications were severe enough to require hospitalization and a 3-week discontinuation of the ribavirin therapy. The remains patient developed a severe upper respiratory tract infection, which was resolved with cefatriaxone treatment, administered for 5 days.Table 2 Liver function markers pre- and post-treatment week 12 (n = 30)\n\n\tTBIL, in μmol/L\tALT, in IU/L\tALB, in g/L\tPTA, in %\tChild-Pugh score\t\nBaseline\t23.48 ± 12.54\t50.17 ± 32.93\t39.52 ± 5.73\t76.17 ± 16.80\t6.30 ± 1.60\t\nPost-treatment week 12\t18.98 ± 9.24\t25.70 ± 10.67\t42.96 ± 6.17\t79.85 ± 14.62\t5.87 ± 1.14\t\n\nt-value\t3.371\t3.973\t4.214\t2.544\t2.642\t\n\np-value\t0.002\t0.000\t0.000\t0.017\t0.013\t\n\nALB albumin, ALT alanine aminotransferase, PTA prothrombin activity, TBIL total bilirubin\n\n\n\n\nAnemia (20%) was the most common AEs, all of the six patients experienced a more than 2.0 g/dL decrease in hemoglobin, who received a treatment regimen containing ribavirin (n = 25). Among them, four and two patients showed decrease in hemoglobin to less than 10.0 g/dL and 8.0 g/dL, respectively. The former responded to a reduction in the ribavirin dosage, while the other two required to interrupted ribavirin and received erythropoietin treatment. Of the 25 patients received ribavirin-containing regimens treatment, the hemoglobin was significantly reduced at the end-of-treatment, compare to those at baseline (11.5 ± 1.08 vs. 10.7 ± 0.96 g/dL, P = 0.013). Despite the hemoglobin re-elevated to a level of similar to baseline at 12 weeks post-treatment (11.5 ± 1.08 vs. 11.6 ± 0.99 g/dL, P = 0.546). There were no different of hemoglobin at baseline, end-of-treatment and 12 week post-treatment for five patients treated with ribavirin-free regimens. Other AEs included nausea, fatigue, palpitation, pruritus/rash, dizziness/headache, shortness of breath, and sleep disorders (Table 3).Table 3 Summary of adverse event during the treatment period (n = 30)\n\nPatients with adverse event\tNumber (%)\t\nAny adverse event\t14(46.7)\t\nSerious adverse event\t4(13.3)\t\n Renal dysfunction\t2(6.7)\t\n Hepatic decompensation\t1(3.3)\t\n Upper respiratory tract infection\t1(3.3)\t\nDiscontinuation due to adverse event\t3(10)\t\nDeath\t0(0)\t\nCommon adverse event\t\n Anemia\t6(20)\t\n Nausea\t3(10)\t\n Fatigue\t2(6.7)\t\n Palpitation\t2(6.7)\t\n Pruritus/rash\t2(6.7)\t\n Dizziness/headache\t2(6.7)\t\n Shortness of breath\t1(3.3)\t\n Sleep disorders\t1(3.3)\t\n\n\n\nOutcome of follow-up off-therapy\nThere was no death or HCC development during antiviral therapy and the median 12 (range 8–15) months of follow-up off-therapy. And none of the patients need for liver transplant, although two of the 27 patients with SVR 12 experienced new decompensated episodes of encephalopathy and ascites in 4 and 9 month after end-of-treatment, respectively.\n\nDiscussion\nOverall estimates indicate that up to 15% of patients with chronic HCV infection progress to cirrhosis within 20 years. Liver cirrhosis progression to the decompensated stage has an annual incidence of about 3–4% [1, 2]. Once decompensated HCV-related cirrhosis is established, patients have a poor prognosis, and are characterized by a very high frequency of readmission, development of decompensation different from the initial one, a generally low quality of life, and high risk of mortality [1, 2, 34, 35]. Thus, a highly safe and effective regimen for all genotypes of HCV infection in patients with decompensated liver disease would address a significant unmet medical need.\n\nStudies have shown that more than 90% patients achieve SVR 12 after DAAs treatment with or without ribavirin, and the treatment led to early improvements in hepatic function [15, 16, 18–20]. Therefore, the European Association for Study of Liver (EASL) does not recommend IFN-based regimens for patients with decompensated cirrhosis; instead, patients with genotype 2 infections are recommend to be treated with sofosbuvir + ribavirin for 16–20 weeks, and patients with genotype 1 infections are recommend to be treated with sofosbuvir + ledipasvir or sofosbuvir + daclatasvir with or without ribavirin for 12 or 24 weeks [36]. The treatment combination of sofosbuvir + velpatasvir has also been shown to have excellent efficacy and safety profiles in patients with decompensated cirrhosis [15]. In general, however, studies of DAAs in Chinese populations are lacking, due to the slow approval process and high cost of DAAs drugs. And our findings presented herein provide the clinical experience of sofosbuvir-containing regimens for Chinese patients with hepatitis C and decompensated cirrhosis.\n\nOur results show that the sofosbuvir-containing treatment regimens are well tolerated in this patient population, and provide a very good efficacy, regardless of baseline characteristics. All of the 27 patients in our study who achieved SVR 12 continued to show undetectable levels of HCV RNA up to post-treatment week 24. These results are in agreement with the recently reported multi-center clinical research study from China and Korea that showed that patients with genotype 1b infection who are ineligible/intolerant to IFN therapies respond well to daclatasvir + asunaprevir combination therapy [37]. In our study, patients who achieved SVR 12 showed significant improvements in liver function, including TBIL, ALT, ALB, PTA and Child-Pugh score post-treatment week 12, which was consistent with the previous studies [15, 16, 18–20]. However, the longer term impact of DAAs treatment in patients with decompensated cirrhosis remains unknown. Sustained virologic response to IFN-based antiviral therapy decreases the incidence of HCC and the risk of hepatic decompensation in patients with HCV cirrhosis [6–11]. SVR after DAAs treatment reduces the incidence of HCC in patients with CHC and compensated cirrhosis had been reported recently [26]. For patients with decompensated cirrhosis, Cheung et al. suggested antiviral therapy led to prolonged improvement in liver function without evidence of an increased risk of HCC development after 15 months follow-up off-therapy [19]. However, other studies showed unexpected high incidence of HCC in cirrhotic patients with SVR following IFN-free DAAs treatment [25, 27, 28]. None of our patients occurred HCC or death, and only 7.4% of patients with SVR 12 experienced new decompensated episodes during the median 12 (range 8–15) months of follow-up off-therapy. Thus, patient with decompensated cirrhosis can benefit from antiviral therapy with DAAs.\n\nAlthough ribavirin treatment was not associated with hepatic decompensation, 30.4% and 5.4% patients with compensated and decompensated cirrhosis need ribavirin dose reductions and discontinuations respectively [38]. Anemia was the most common AEs, and all of them presented in patients with ribavirin-containing regimen in our study. Thus, it appears that the ribavirin component may be responsible for the side effect of anemia. However, all of the six patients with ribavirin dose reductions and/or discontinuations achieved SVR 12, which add further evidence of ribavirin dose adjustment in cirrhotic patients with advanced disease should not reduce efficacy of antiviral treatment by Saxena et al. [38].\n\nTwo additional patients experienced renal adverse reaction, as evidenced by increased serum urea nitrogen/creatinine and decreased glomerular filtration rate (GFR). Both of them responded to a 2-week discontinuation of antiviral treatment, along with management using benazepril and prostaglandin E1. Re-initiation of the sofosbuvir + ribavirin treatment, after the patients showed improvement of renal dysfunction, were well tolerated. Ultimately, both of the patients completed the antiviral treatment and achieved SVR 12. Sofosbuvir is primarily metabolized by the kidney. Studies have shown that patients with HCV infection and decompensated cirrhosis and who underwent liver transplantation can experience reduced GFR or even acute renal failure during pre- and post-transplantation therapy with a sofosbuvir-based regimens [15, 18, 38]. However, studies also had shown that sofosbuvir-based regimen using dosage of 400 mg is effective and safe in patients with end-stage renal disease undergoing hemodialysis or who have GFR < 30 mL/min [39, 40].\n\nConsidering the potential risk of hepatorenal syndrome or acute kidney injury in patients with end-stage liver disease, and both sofosbuvir and ribavirin are mainly through kidney metabolism, patients with hepatitis C infection and decompensated cirrhosis who are administered a sofosbuvir-containing regimen with or without ribavirin require close monitoring of renal function. If renal damage occur or aggravate, treatments should be given to improve renal function, and short interruption or dose reductions of antiviral treatment may be necessary [38], as was evidenced in cases in our study.\n\nLimits of this retrospective study include heterogeneity of antiviral treatments, a relatively small number of cases, limited length of follow-up and possible selection bias. In particular, due to the urgency of treatment, the accessibility of drugs during the study period, as well as the rapid movement in the field of anti-HCV treatment and the dramatic improvement in efficacy and safety of DAAs, not all patients received the antiviral therapy program recommended by current guidelines [36, 41, 42], such as 15 GT 1-infected patients received sofosbuvir + ribavirin treatment for 24 weeks. Again, due to the nature of retrospective study, there were different sofosbuvir-containing regimens with or without ribavirin, which potential preclude useful comparison in the statistical analysis. Furthermore, we enrolled only patients with mild to moderate liver decompensation, so our results cannot be generalized to patients with more severe liver disease. Finally, these results also cannot be extrapolated widely to all patients with mild to moderate liver decompensation. Despite these limitations, several conclusions can be drawn based upon careful consideration of the available data.\n\nConclusions\nSofosbuvir-containing regimens produced high rates of SVR 12 in decompensated cirrhotic patients, regardless of baseline characteristics. Antiviral treatment was associated with improvement in liver function, and was generally well tolerated in this Chinese population. However, a vigilant monitoring of anemia and renal dysfunction should be mandatory. Results from currently ongoing large and well-designed long-term study (ClinicalTrials.gov number, NCT01457755) [15] is awaited to verify the benefit and safety of sofosbuvir-containing regimens for decompensated cirrhotic patients with HCV infection including the risk of HCC development and long-term survival.\n\nAbbreviations\nALBAlbumin\n\nALTAlanine aminotransferase\n\nCHCChronic hepatitis C\n\nDAAsDirect-acting antiviral agents\n\nGFRGlomerular filtration rate\n\nHCCHepatocellular carcinoma\n\nHCVHepatitis C virus\n\nPTAProthrombin activity\n\nSBPSpontaneous bacterial peritonitis\n\nSVR 12Sustained virological response at week 12\n\nTBILTotal bilirubin\n\nNot applicable.\n\nFunding\nThis work was supported by the National Natural Science Foundation of China (No. 81300322) and Personnel training special funds of the Second Affiliated Hospital of Xi’an Jiaotong University [RC(GG)201,501]. The funding source had no involvement in writing the report.\n\nAvailability of data and materials\nA majority of data generated or analyzed during this study are included in this published article. The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.\n\nGrant support\nThis work was supported by the National Natural Science Foundation of China (No. 81300322) and Personnel training special funds of the Second Affiliated Hospital of Xi’an Jiaotong University [RC(GG)201,501]. The funding source had no involvement in writing the report.\n\nAuthors’ contributions\nAll authors collaborated in the study design; FPJ, SSD, WXZ, HD, and CYT participated in diagnosing and managing these patients; FPJ, WJW, SBW, BRL, DB and CYT extracted and analyzed the clinical data; FPJ, WJW, BRL, DB and ZFL elucidated the data and carried out statistical analysis; FPJ prepared the first manuscript draft; CYT and ZFL modified the manuscript subsequently; all authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nThe institutional review board of the Second Affiliated Hospital of Xi’an Jiaotong University waived the requirement for approval of this retrospective study.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. 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Ji FP Dang SS Cai ZF Xue HA Huang N Liu LY Antiviral treatment and long-term clinical outcome of decompensated cirrhotic patients with hepatitis C virus infection Zhonghua Gan Zang Bing Za Zhi 2015 23 647 652 26524356 \n12. Iacobellis A Siciliano M Perri F Annicchiarico BE Leandro G Caruso N Peginterferon alfa-2b and ribavirin in patients with hepatitis C virus and decompensated cirrhosis: a controlled study J Hepatol 2007 46 206 212 10.1016/j.jhep.2006.08.020 17125876 \n13. Silva GF Villela-Nogueira CA Mello CE Soares EC Coelho HS Ferreira PR Peginterferon plus ribavirin and sustained virological response rate in HCV-related advanced fibrosis: a real life study Braz J Infect Dis 2014 18 48 52 10.1016/j.bjid.2013.05.007 24055310 \n14. Sovaldi (sofosbuvir) United States prescribing information. Foster City, CA: Gilead Sciences; 2013. http://www.gilead.com/~/media/Files/pdfs/medicines/liverdisease/sovaldi/sovaldi_pi.pdf. Accessed 12 Apr 2016.\n15. Curry MP O'Leary JG Bzowej N Muir AJ Korenblat KM Fenkel JM Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis N Engl J Med 2015 373 2618 2628 10.1056/NEJMoa1512614 26569658 \n16. Modi AA Nazario H Trotter JF Gautam M Weinstein J Mantry P Safety and efficacy of simeprevir plus sofosbuvir with or without ribavirin in patients with decompensated genotype 1 hepatitis C cirrhosis Liver Transpl 2016 22 281 286 10.1002/lt.24324 26335142 \n17. Bourlière M Bronowicki JP de Ledinghen V Hézode C Zoulim F Mathurin P Ledipasvir-sofosbuvir with or without ribavirin to treat patients with HCV genotype 1 infection and cirrhosis non-responsive to previous protease-inhibitor therapy: a randomised, double-blind, phase 2 trial (SIRIUS) Lancet Infect Dis 2015 15 397 404 10.1016/S1473-3099(15)70050-2 25773757 \n18. Charlton M Everson GT Flamm SL Kumar P Landis C Brown RS Jr Ledipasvir and sofosbuvir plus ribavirin for treatment of HCV infection in patients with advanced liver disease Gastroenterology 2015 149 649 659 10.1053/j.gastro.2015.05.010 25985734 \n19. Cheung MC Walker AJ Hudson BE Verma S McLauchlan J Mutimer DJ Outcomes after successful direct-acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis J Hepatol 2016 65 741 747 10.1016/j.jhep.2016.06.019 27388925 \n20. Foster GR Irving WL Cheung MC Walker AJ Hudson BE Verma S Impact of direct acting antiviral therapy in patients with chronic hepatitis C and decompensated cirrhosis J Hepatol 2016 64 1224 1231 10.1016/j.jhep.2016.01.029 26829205 \n21. Gane E Kowdley KV Pound D Stedman CA Davis M Etzkorn K Efficacy of sofosbuvir, velpatasvir, and GS-9857 in patients with HCV genotype 2, 3, 4, or 6 infections in an open-label, phase 2 trial Gastroenterology 2016 151 902 909 10.1053/j.gastro.2016.07.038 27486033 \n22. Nappi A Perrella A Bellopede P Lanza A Izzi A Spatarella M Safety of new DAAs for chronic HCV infection in a real life experience: role of a surveillance network based on clinician and hospital pharmacist Infect Agent Cancer 2017 12 12 10.1186/s13027-017-0119-8 28191032 \n23. Chang CY Nguyen P Le A Zhao C Ahmed A Daugherty T Real-world experience with interferon-free, direct acting antiviral therapies in Asian Americans with chronic hepatitis C and advanced liver disease Medicine (Baltimore) 2017 96 e6128 10.1097/MD.0000000000006128 28178174 \n24. Lutchman G Nguyen NH Chang CY Ahmed A Daugherty T Garcia G Effectiveness and tolerability of simeprevir and sofosbuvir in nontransplant and post-liver transplant patients with hepatitis C genotype 1 Aliment Pharmacol Ther 2016 44 738 746 10.1111/apt.13761 27506182 \n25. Kozbial K Moser S Schwarzer R Laferl H Al-Zoairy R Stauber R Unexpected high incidence of hepatocellular carcinoma in cirrhotic patients with sustained virologic response following interferon-free direct-acting antiviral treatment J Hepatol 2016 65 856 858 10.1016/j.jhep.2016.06.009 27318327 \n26. Kobayashi M Suzuki F Fujiyama S Kawamura Y Sezaki H Hosaka T Sustained virologic response by direct antiviral agents reduces the incidence of hepatocellular carcinoma in patients with HCV infection J Med Virol 2017 89 476 483 10.1002/jmv.24663 27531586 \n27. Reig M Mariño Z Perelló C Iñarrairaegui M Ribeiro A Lens S Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy J Hepatol 2016 65 719 726 10.1016/j.jhep.2016.04.008 27084592 \n28. Conti F Buonfiglioli F Scuteri A Crespi C Bolondi L Caraceni P Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals J Hepatol 2016 65 727 733 10.1016/j.jhep.2016.06.015 27349488 \n29. ANRS collaborative study group on hepatocellular carcinoma (ANRS CO22 HEPATHER, CO12 CirVir and CO23 CUPILT cohorts) Lack of evidence of an effect of direct-acting antivirals on the recurrence of hepatocellular carcinoma: Data from three ANRS cohorts J Hepatol 2016 65 734 740 10.1016/j.jhep.2016.05.045 27288051 \n30. Ji D Chen GF Wang C Wang YD Shao Q Li B Twelve-week ribavirin-free direct-acting antivirals for treatment-experienced Chinese with HCV genotype 1b infection including cirrhotic patients Hepatol Int 2016 10 789 798 10.1007/s12072-016-9755-0 27443347 \n31. Zeng QL Xu GH Zhang JY Li W Zhang DW Li ZQ Generic ledipasvir-sofosbuvir for patients with chronic hepatitis C: A real-life observational study J Hepatol 2017 66 1123 1129 10.1016/j.jhep.2017.01.025 28189754 \n32. Ji FP Zhang S Huang N Deng H Li ZF Splenectomy prior to antiviral therapy in patients with HCV related decompensated cirrhosis Braz J Infect Dis 2013 17 601 605 10.1016/j.bjid.2013.02.004 23830054 \n33. Ji FP Zhou R Wang WJ Bai D He CN Cai ZF High post-treatment α-fetoprotein levels and aspartate aminotransferase-to-platelet ratio index predict hepatocellular carcinoma in hepatitis C virus decompensated cirrhotic patients with sustained virological response after antiviral therapy J Interf Cytokine Res 2017 37 362 368 10.1089/jir.2017.0040 \n34. Planas R Balleste B Alvarez MA Rivera M Montoliu S Galeras JA Natural history of decompensated hepatitis C virus-related cirrhosis. A study of 200 patients J Hepatol 2004 40 823 830 10.1016/j.jhep.2004.01.005 15094231 \n35. Lawson A Hagan S Rye K Taguri N Ratib S Zaitoun AM The natural history of hepatitis C with severe hepatic fibrosis J Hepatol 2007 47 37 45 10.1016/j.jhep.2007.02.010 17400322 \n36. European Association for Study of Liver EASL recommendations on treatment of hepatitis C 2015 J Hepatol 2015 63 199 236 10.1016/j.jhep.2015.03.025 25911336 \n37. Wei L Zhang M Xu M Chuang WL Lu W Xie W A phase 3, open-label study of daclatasvir plus asunaprevir in Asian patients with chronic hepatitis C virus genotype 1b infection who are ineligible for or intolerant to interferon alfa therapies with or without ribavirin J Gastroenterol Hepatol 2016 31 1860 1867 10.1111/jgh.13379 27003037 \n38. Saxena V Nyberg L Pauly M Dasgupta A Nyberg A Piasecki B Safety and efficacy of simeprevir/sofosbuvir in hepatitis C-infected patients with compensated and decompensated cirrhosis Hepatology 2015 62 715 725 10.1002/hep.27922 26033798 \n39. Desnoyer A Pospai D Lê MP Gervais A Heurgué-Berlot A Laradi A Pharmacokinetics, safety and efficacy of a full dose sofosbuvir-based regimen given daily in hemodialysis patients with chronic hepatitis C J Hepatol 2016 65 40 47 10.1016/j.jhep.2016.02.044 26952005 \n40. Nazario HE Ndungu M Modi AA Sofosbuvir and simeprevir in hepatitis C genotype 1 patients with end-stage renal disease on hemodialysis or GFR <30mL/min Liver Int 2016 36 798 801 10.1111/liv.13025 26583882 \n41. AASLD/IDSA HCV Guidance Panel Hepatitis C guidance: AASLD-IDSA recommendations for testing, managing, and treating adults infected with hepatitis C virus Hepatology 2015 62 932 954 10.1002/hep.27950 26111063 \n42. Omata M Kanda T Wei L Yu ML Chuang WL Ibrahim A APASL consensus statements and recommendation on treatment of hepatitis C Hepatol Int 2016 10 702 726 10.1007/s12072-016-9717-6 27130427\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1750-9378",
"issue": "12()",
"journal": "Infectious agents and cancer",
"keywords": "Anemia; Child-Pugh score; Decompensated cirrhosis; Hepatitis C virus; Renal dysfunction; Sofosbuvir",
"medline_ta": "Infect Agent Cancer",
"mesh_terms": null,
"nlm_unique_id": "101276559",
"other_id": null,
"pages": "48",
"pmc": null,
"pmid": "28924449",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": "23268517;27506182;17125876;26829205;27003037;26628566;27822295;27818234;23395693;25773757;25911336;27443347;28191032;27130427;28731786;27349488;28178174;26524356;27486033;26335142;27531586;27288051;27084592;27318327;26033798;27388925;23830054;26569658;24055310;19861128;26111063;24780302;26739465;26583882;15094231;28189754;17400322;21092761;25985734;26952005;23817321",
"title": "Outcomes after sofosbuvir-containing regimens for hepatitis C virus in patients with decompensated cirrhosis: a real-world study.",
"title_normalized": "outcomes after sofosbuvir containing regimens for hepatitis c virus in patients with decompensated cirrhosis a real world study"
} | [
{
"companynumb": "CN-GILEAD-2017-0296418",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SOFOSBUVIR"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nSingle-dose pegylated filgrastim (pegfilgrastim) after autologous hematopoietic stem cell transplantation (AHSCT) showed similar efficacy compared to daily lenograstim. To address the question of the optimal application time, we randomly assigned patients (pts) to pegfilgrastim on day + 1 (Peg1) or day + 4 (Peg4) after AHSCT.\n\n\nMETHODS\nFifty-three pts with different hematological malignancies were included in this prospective randomized multicenter study. Primary endpoint of this study was time to neutrophil recovery (>500 Gpt/l), and secondary endpoint was time to neutrophil recovery (>1,000 Gpt/l), platelet recovery (>20,000 Gpt/l), number and duration of febrile episodes, i.v. antibiotics, and number of transfusions. Time to engraftment endpoints were estimated according to Kaplan-Meier.\n\n\nRESULTS\nMedian time to neutrophil recovery (>500 Gpt/l) was 10 days (95% CI: 10-11) in Peg1 versus 10 days (95% CI: 10-11) in Peg4 (P = 0.68, logrank test; hazard ratio: 0.93). The corresponding mean values were 10.2 and 10.4 days. Median time to platelet recovery (>20,000 Gpt/l) was 10 (95% CI: 10-11) in Peg1 versus 10 (95% CI: 9-11) in Peg4, again not significantly different (P = 0.54). There was no difference regarding the incidence (67% vs. 60%, P = 0.77, Fisher's exact test) or duration of febrile neutropenia episodes in both groups (median: 1 vs. 1; mean: 2.8 vs. 2.4 days; P = 0.73, Wilcoxon test).\n\n\nCONCLUSIONS\nIn terms of neutrophil or platelet recovery after AHSCT, number and duration of febrile episodes, the use of i.v. antibiotics, early and late administration of pegfilgrastim are equally effective.",
"affiliations": "Department of Hematology and Oncology, Klinikum Magdeburg, Birkenallee 34, 39130 Magdeburg, Germany. christoph.kahl@klinikum-magdeburg.de",
"authors": "Kahl|C|C|;Sayer|H G|HG|;Hinke|A|A|;Freund|M|M|;Casper|J|J|",
"chemical_list": "D000900:Anti-Bacterial Agents; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; C455861:pegfilgrastim; D011092:Polyethylene Glycols; D000078224:Lenograstim; D000069585:Filgrastim",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00432-011-1116-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0171-5216",
"issue": "138(3)",
"journal": "Journal of cancer research and clinical oncology",
"keywords": null,
"medline_ta": "J Cancer Res Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D001803:Blood Transfusion; D004334:Drug Administration Schedule; D005260:Female; D005334:Fever; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor; D019337:Hematologic Neoplasms; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007262:Infusions, Intravenous; D053208:Kaplan-Meier Estimate; D000078224:Lenograstim; D008297:Male; D008875:Middle Aged; D009503:Neutropenia; D011092:Polyethylene Glycols; D011446:Prospective Studies; D011994:Recombinant Proteins; D014182:Transplantation, Autologous; D016896:Treatment Outcome",
"nlm_unique_id": "7902060",
"other_id": null,
"pages": "513-7",
"pmc": null,
"pmid": "22198675",
"pubdate": "2012-03",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": "12679729;21292644;12040470;9579836;15489865;15880129;9509976;12123336;9432046;17320951;11821454;20062102;7538556;12199792;7538555",
"title": "Early versus late administration of pegfilgrastim after high-dose chemotherapy and autologous hematopoietic stem cell transplantation.",
"title_normalized": "early versus late administration of pegfilgrastim after high dose chemotherapy and autologous hematopoietic stem cell transplantation"
} | [
{
"companynumb": "DE-AMGEN-DEUSP2021177611",
"fulfillexpeditecriteria": "2",
"occurcountry": "DE",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEGFILGRASTIM"
},
"drugadditional": "3",
... |
{
"abstract": "Hemophagocytic lymphohistiocytosis (HLH) is an immune-mediated syndrome resulting in cytokine storm. The uncontrolled cytokine storm leads to significant tissue damage and potentially life-threatening multiorgan failure. Conventional first-line treatment for HLH included HLH-94 protocol or HLH-2004 protocol. However, up to 30% of patients do not respond to first-line therapy. We reported 3 cases of secondary HLH/macrophage activation syndrome which were caused by lymphoma (2 cases) and adult-onset still's disease. They received low dose ruxolitinib plus HLH-94 protocol, and had rapid response to treatment without obvious adverse effects. Following the treatment, there was improvement seen in several disease markers, including fever, fibrinogen, serum ferritin, and liver function tests. Our report indicated that treatment with low dose ruxolitinib plus HLH-94 protocol might be a potential choice for secondary HLH, and clinical trials warrants to be further investigated in this treatment regimen.",
"affiliations": "Department of Hematology, Tongji Hospital, Tongji Medical College, Hua Zhong University of Science and Technology, Wuhan, Hubei, China; Department of Hematology, Hubei TCM hospital, Wuhan, Hubei, China.;Department of Hematology, Tongji Hospital, Tongji Medical College, Hua Zhong University of Science and Technology, Wuhan, Hubei, China.;Department of Hematology, Tongji Hospital, Tongji Medical College, Hua Zhong University of Science and Technology, Wuhan, Hubei, China.;Department of Hematology, Tongji Hospital, Tongji Medical College, Hua Zhong University of Science and Technology, Wuhan, Hubei, China.;Department of Hematology, Tongji Hospital, Tongji Medical College, Hua Zhong University of Science and Technology, Wuhan, Hubei, China.;Department of Hematology, Tongji Hospital, Tongji Medical College, Hua Zhong University of Science and Technology, Wuhan, Hubei, China. Electronic address: 2896607051@qq.com.",
"authors": "Wang|Han|H|;Gu|Jia|J|;Liang|Xue|X|;Mao|Xiao|X|;Wang|Zhiqiong|Z|;Huang|Wei|W|",
"chemical_list": "D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; C540383:ruxolitinib",
"country": "United States",
"delete": false,
"doi": "10.1053/j.seminhematol.2018.07.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0037-1963",
"issue": "57(1)",
"journal": "Seminars in hematology",
"keywords": "HLH-94 protocol; Ruxolitinib; Secondary HLH",
"medline_ta": "Semin Hematol",
"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D051359:Lymphohistiocytosis, Hemophagocytic; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; D055815:Young Adult",
"nlm_unique_id": "0404514",
"other_id": null,
"pages": "26-30",
"pmc": null,
"pmid": "32690141",
"pubdate": "2020-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Low dose ruxolitinib plus HLH-94 protocol: A potential choice for secondary HLH.",
"title_normalized": "low dose ruxolitinib plus hlh 94 protocol a potential choice for secondary hlh"
} | [
{
"companynumb": "CN-PFIZER INC-2020343827",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MEROPENEM"
},
"drugadditional": "3",
... |
{
"abstract": "Posttransplant lymphoproliferative disorder (PTLD) is a rare complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with poor prognosis. We report a patient with PTLD involved central nervous system (CNS) who treated with zanubrutinib, a second-generation Bruton tyrosine kinase (BTK) inhibitor. Our report supports the efficacy of bruton tyrosine kinase inhibitor zanubrutinib in the treatment of CNS-PTLD, which provides a new therapeutic option.",
"affiliations": "Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.;Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.;Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.;Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.;Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.;Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.",
"authors": "Yang|Ting-Ting|TT|;Chen|Wei-Hao|WH|;Zhao|Yan-Min|YM|;Fu|Hua-Rui|HR|;Huang|He|H|;Shi|Ji-Min|JM|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fonc.2021.672052",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X\nFrontiers Media S.A.\n\n10.3389/fonc.2021.672052\nOncology\nCase Report\nZanubrutinib Treatment of Central Nervous System Posttransplant Lymphoproliferative Disorder After Allogeneic Hematopoietic Stem Cell Transplantation: A Case Report\nYang Ting-Ting 1 2 3\nChen Wei-Hao 1 2 3\nZhao Yan-Min 1 2 3\nFu Hua-Rui 1 2 3\nHuang He 1 2 3\n\nShi Ji-Min 1 2 3 *\n\n1 Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China\n2 Institute of Hematology, Zhejiang University, Hangzhou, China\n3 Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China\nEdited by: Michele Malagola, University of Brescia, Italy\n\nReviewed by: Elisa Sala, Ulm University Medical Center, Germany; Teresa Calimeri, San Raffaele Hospital (IRCCS), Italy\n\n*Correspondence: Ji-Min Shi, shijimin@zju.edu.cn\nThis article was submitted to Hematologic Malignancies, a section of the journal Frontiers in Oncology\n\n29 4 2021\n2021\n11 67205225 2 2021\n12 4 2021\nCopyright © 2021 Yang, Chen, Zhao, Fu, Huang and Shi\n2021\nYang, Chen, Zhao, Fu, Huang and Shi\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nPosttransplant lymphoproliferative disorder (PTLD) is a rare complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with poor prognosis. We report a patient with PTLD involved central nervous system (CNS) who treated with zanubrutinib, a second-generation Bruton tyrosine kinase (BTK) inhibitor. Our report supports the efficacy of bruton tyrosine kinase inhibitor zanubrutinib in the treatment of CNS-PTLD, which provides a new therapeutic option.\n\nhematopoietic stem cell transplantation\nEBV-negative\nposttransplant lymphoproliferative disorder\nlymphoma\nzanubrutinib\n==== Body\nIntroduction\n\nPost-transplantation lymphoproliferative disorder (PTLD) is a spectrum of unregulated lymphoid expansion ranging from polyclonal hyperplasia to monoclonal malignant lymphoma, which normally presents with nonspecific signs such as prolonged fever and lymphadenopathy (1). Most PTLDs originate from B cells, associated with Epstein-Barr virus (EBV) reactivation. Compared with PTLD in solid organ transplantation, PTLD after hematopoietic stem-cell transplantation (HSCT) is characteristic of high invasion, early dissemination and high mortality. Currently, there is no consensus regarding the treatment of PTLD.\n\nCase Presentation\n\nA 39-year-old Chinese man was diagnosed with BCR-ABL-positive acute lymphoblastic leukemia in November 2018. He was treated with 8 cycles of chemotherapy combined with imatinib, resulting in complete remission (CR). He received haploidentical hematopoietic stem cell transplantation (HSCT) from his daughter on September 25, 2019 during the first CR under a myeloablative conditioning regimen (cytarabine, busulfan, cyclophosphamide, methyl-N-2-chloroethyl-N-cyclohexyl-N-nitrosourea, and anti-thymocyte globulin). Prophylaxis against graft-versus-host disease comprised mycophenolate mofetil (MMF), cyclosporine (CsA), and short-course methotrexate (MTX). Neutrophils and platelets were engrafted on days +13 and +14, respectively. Cytogenetic studies showed complete donor chimerism on day +30. The EBV-DNA loads in the blood measured by real-time quantitative polymerase chain reaction were monitored weekly for the first 3 months after transplantation, every 2 weeks from the fourth month posttransplant. Acyclovir was used to prevent virus infection. Once EBV-DNA in the blood was positive, ganciclovir was administered until EBV-DNA turned negative on 2 consecutive measurements.\n\nHe was admitted to our center owing to headache, dizziness, and vomiting on day +90. Lumbar puncture revealed that the intracranial pressure exceeded 400 mmH2O. Cerebrospinal fluid (CSF) next generation sequencing (NGS) was positive for Toxoplasma gondii (T. gondii). Toxoplasma serology tests were positive for IgG (16.72 IU/mL), but negative for IgM. Contrast-enhanced brain magnetic resonance imaging (MRI) demonstrated multiple enhancing hyperintense lesions surrounded by edema in bilateral cerebellar and cerebral hemispheres ( Supplementary Figures 1A–C ). He was diagnosed with cerebral toxoplasmosis based on these findings. Oral sulfamethoxazole (SMZ, 1.44 g, thrice daily) and intravenous clindamycin (400 mg, 4 times daily) were administered. His clinical signs resolved completely after 1 week of treatment. After 2 weeks, brain MRI showed a marked decrease in the size of the lesions and perifocal edema. Hence, he was discharged and switched to maintenance therapy with oral azithromycin (500 mg, once daily) and SMZ (0.96 g, twice weekly). Brain MRI performed 1 month after discharge (on day +153 after HSCT) indicated near resolution of the multiple lesions and perifocal edema ( Supplementary Figures 1D–F ).\n\nThe patient presented with a recurring headache, accompanied by reducing right-sided power and binocular diplopia on day + 203 after HSCT, which underwent gradual exacerbation. He was readmitted to our center on day +223. Physical examination revealed grade IV muscle strength in the right limb and a positive Babinski sign on the right side. Brain MRI revealed a thalamic ring-enhancing lesion surrounded by edema on the left side ( Figure 1A ). CSF analyses demonstrated elevated cerebrospinal pressure (230 mmH2O) and elevated protein levels (1.280 g/L, reference <0.5 g/L). NGS of CSF was negative for bacterial, fungal, viral, or parasitic organisms. The serum Epstein-Barr virus (EBV)-DNA titer monitored twice a week ranged from 1.61×103 to 4.0×104copies/ml, with the treatment of ganciclovir. The distribution of T-cell subsets was examined: CD3+ T-cell count was 69 cells/μL, CD4+/CD8+ T cell was 0.57 and CD19+ B-cell count was 2 cells/μL, indicating that the patient was in a state of immunodeficiency. Systemic GVHD was not observed in the patient. Empirical treatment against Toxoplasma infection was implemented for 2 weeks but was ineffective. His clinical condition progressed on day +244 with grade II right-sided muscle strength, recurrent seizures, urinary incontinence, lethargy, memory loss, and transient consciousness disturbance. MRI was repeated, which revealed further enlargement of the lesion in the left thalamus, with a maximum diameter of approximately 53 mm ( Figure 1B ). We performed magnetic resonance spectroscopy (MRS), which depicted significant elevated lipid (Lip) and choline compounds (Cho) peaks, suggestive of lymphoma ( Figures 2A, B ). Brain biopsy, which was performed to confirm the diagnosis, identified monomorphic diffuse large B-cell lymphoma with EBV infection. The tumor cells stained positive for CD19, CD20, PAX-5, Ki-67 (approximately 65%), CD30, Bcl-2 (approximately 100%), MUM1, c-myc (approximately 25%), CD79a, and CD43 ( Figures 3A–C ). The results of EBV-encoded RNA in situ hybridization were positive ( Figure 3D ). Lung CT, abdominal B-ultrasound examination and bone marrow biopsy showed no evidence of systemic PTLD. Positron emission tomography-computed tomography (PET/CT) was not performed considering that the patient was critical with unstable conditions at that time. Based on these findings, the diagnosis of EBV-PTLD in central nervous system was made.\n\nFigure 1 Brain MRI of CNS-PTLD. (A) Emergence of CNS-PTLD on day +225. MRI revealed a hypointensity lesion in the left thalamus with ring enhancement (red arrow) on contrast-enhanced T1-weighted imagining. (B) Day +255 (before treatment): the enlarged lesion surrounded by significant edema with the longest diameter of about 53mm (T2 Flair). (C) Day +280 (three weeks after the use of rituximab and MTX): reduction in the size of the lesion and edema with the longest diameter of 36.4mm (T2 Flair). (D) Day +363 (after whole-brain radiotherapy completed): further reduction in the size of the lesion with the longest diameter of 29mm (T2 Flair). (E) Day +477(three months after the start of zanubrutinib): the reduced lesion with the longest diameter of 24mm (T2 Flair). MRI, magnetic resonance imaging; CNS-PTLD, central nervous system post-transplant lymphoproliferative disorder.\n\nFigure 2 Single-voxel 1H-magnetic resonance spectroscopy of the tumor area in the left thalamus showing elevated Cho peak in 3.2 ppm and Lip peak in 1.3ppm with decreased NAA in 2.0 ppm, with corresponding short echo time spectra (A, TE=35ms) and long echo time spectra (B, TE=144ms). Cho, choline compounds; Lip, lipid; NAA, N-acetyl-aspartate.\n\nFigure 3 Photomicrographs of the brain biopsy demonstrating a monomorphic diffuse large B-cell lymphoma with EBV infection. [hematoxylin and eosin (H&E) stain; original magnification (A) ×50; (B) ×200]. Immunohistochemical stains showed that the infiltrating lymphocytes were positive for CD20 (C). EBV-encoded RNA in situ hybridization was positive in the infiltrating cells (D).\n\nThus, CsA administration (50mg daily) was discontinued at the diagnosis of PTLD on day +250. A single dose of rituximab 375 mg/m2 was administrated on day +252, followed by high-dose methotrexate (MTX, 6 g) on day +256. After MTX+ rituximab, his consciousness improved and the seizure disappeared, although he still had a headache with a numerical rating scale (NRS) score of 3. Brain MRI indicated a reduction in lesion size, with the longest diameter of 36mm ( Figure 1C ). Serum EBV-DNA load decreased to 2 log10 within three weeks after administration of chemotherapy. The response to MTX+rituximab was stable disease. During the treatment of MTX+rituximab, the WBC and platelet counts decreased to a minimum of 0.9×109/L and 28×109/L, respectively. The patient also developed pulmonary infection. Considering that the patient’s inability to tolerate chemotherapy, whole-brain radiotherapy (WBRT) was implemented on day + 280 (30 times, total dose of 30 Gy) for 47 days. During radiotherapy, the platelet and white blood cell (WBC) counts decreased to a minimum of 34 x 109/L and 0.9 x 109/L, respectively, but gradually recovered to normal. At the end of radiotherapy, his headaches were alleviated (NRS score=2) and the language impairment and dyskinesia also recovered gradually. Brain MRI showed the remained lesion with the longest diameter of 29mm ( Figure 1D ) and the serum EBV DNA load in the blood reduced to an undetectable level. After radiotherapy, the patient achieved partial response (PR) and his condition was stable, but there were still residual intracranial lesions. The patient refused further systemic chemotherapy. Considering the therapeutic activity of bruton tyrosine kinase (BTK) inhibitors for CNS lymphomas, the patient was administered oral zanubrutinib 80 mg daily (given the concurrent administration of posaconazole for preventing fungal infection) on day +382. He developed transient systemic migrating muscle soreness on the first day during zanubrutinib therapy, which was ameliorated 1 day after discontinuation of the drug. Oral administration of zanubrutinib was subsequently continued without any other side-effects. Blood counts were monitored regularly: the lowest WBC count was 2.9 x 109/L, and the hemoglobin and platelet counts were within the normal range. After starting zanubrutinib, His dizziness and headache had resolved, and the findings of neurological examination were normal. The serum EBV-DNA loads remained negative during the treatment of zanubrutinib. Follow-up brain MRI revealed that the lesion’s size decreased to 24 x 24 x 21 mm ( Figure 1E ) with a response of PR. Until the last follow-up in February 2021(day +516), he was alive without and clinical symptom and continued to take zanubrutinib. The treatment process and changes of serum EBV-DNA titer are summarized in Figure 4 .\n\nFigure 4 The clinical treatment process of posttransplant lymphoproliferative disorder (PTLD) after transplantation and the changes of serum EBV-DNA titers. HSCT, hematopoietic stem cell transplantation; CsA, cyclosporine; MTX, methotrexate; WBRT, whole-brain radiotherapy.\n\nDiscussion\n\nTo date, there has been no definite guideline or consensus for the optimal treatment for CNS-PTLD after HSCT. The available therapeutic options include the withdrawal of immunosuppressive agents, high-dose MTX and cytarabine, WBRT and adoptive immunotherapy with EBV-specific cytotoxic T lymphocytes (2, 3). Although the patient achieved a PR with significant improvement of clinical symptoms after chemotherapy+ rituximab and WBRT, his headache remained, and MRI showed apparent residual lesions. Subsequent systemic chemotherapy was not considered because the patient refused chemotherapy. EBV-specific cytotoxic T lymphocytes(CTLs) derived from EBV-seropositive transplantation donors or the third party is effective in treat EBV- induced lymphoproliferative diseases through attacking EBV-infected cells, with durable response (4). Doubrovina et al. reviewed 19 EBV-PTLD patients who received EBV-specific CTL infusion after HSCT; in this study, 13 patients (85%) achieved CR and GVHD didn’t occur in any patients (5). However, EBV-specific CTLs was unavailable in our center.\n\nBTK, which is a tyrosine-protein kinase, is critical to B-cell maturation and proliferation, has emerged as a significant therapeutic target for various B-cell malignancies (6, 7). The first-generation BTK inhibitor ibrutinib has shown promising results for CNS lymphoma (8, 9). A phase I clinical trial conducted by Grommes et al. reported that ibrutinib showed a 77% (10/13) clinical response in patients with relapsed or refractory CNS lymphoma, including CR and partial response in 5 patients each (9). Zanubrutinib (BGB-3111), a highly-specific, irreversible second generation BTK inhibitor developed in China, has greater selectivity and higher anti-tumor activity for BTK compared to ibrutinib. It shows more restricted off-target activity for a series of kinases, such as interleukin-2-induced kinases (ITK), Scr family kinases, and epidermal growth factor receptor (EGFR), thereby limiting the toxicity and side-effects (10). It has been approved for relapsed/refractory mantle cell lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma. Moreover, its utility for the treatment of other B-cell malignancies is also being investigated worldwide. In our case, a further decrease in the size of lesions was observed 3 months after the use of zanubrutinib, suggesting its efficacy in treating CNS PTLD. The drug is well-tolerated, and no obvious hematological toxicity or infection was observed during the period of treatment. The patient should take zanubrutinib consistently until treatment failure or the occurrence of unacceptable toxicities. To the best of our knowledge, this was the first report to describe treatment of CNS-PTLD with zanubrutinib. However, it is not sure whether the response of zanubrutinib for PTLD is durable or further improved. Longer follow-up is needed to evaluate its effect.\n\nConclusion\n\nOur case shows that the novel BTK inhibitor zanubrutinib exhibit specific activity for CNS lymphomas. It provides a potential therapeutic option for CNS-PTLD when other attempted measures are judged to be ineffective or inappropriate.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by the ethics review committee of the First Affiliated Hospital of Zhejiang University School of Medicine. The patients/participants provided their written informed consent to participate in this study.\n\nAuthor Contributions\n\nT-TY wrote the manuscript. W-HC, Y-MZ, H-RF and HH contributed to the patient’s medical care. J-MS edited and approved the manuscript. All authors contributed to the article and approved the submitted version.\n\nFunding\n\nThis work was funded by the National Natural Science Foundation of China (Grant no. 82070179).\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nAcknowledgments\n\nThe authors gratefully acknowledge the contribution of the patient involved in this case report.\n\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2021.672052/full#supplementary-material\n\nSupplementary Figure 1 Brain Magnetic resonance imaging of cerebral toxoplasmosis. Multiple hyperintense enhancing lesions in bilateral cerebral hemispheres and cerebellar before treatment (on day +94 after transplantation) were observed (A–C). Two months after initiation of anti-toxoplasma therapy (on day +153 after transplantation), lesions had nearly disappeared (D, E). Red arrow indicated enhancing lesions on contrast-enhanced T1-weighted imaging.\n\nClick here for additional data file.\n==== Refs\nReferences\n\n1 Romero S Montoro J Guinot M Almenar L Andreu R Balaguer A . Post-transplant lymphoproliferative disorders after solid organ and hematopoietic stem cell transplantation. Leuk Lymphoma (2019) 60 (1 ):142–50. 10.1080/10428194.2018.1474462\n2 Singavi AK Harrington AM Fenske TS . Post-transplant lymphoproliferative disorders. Cancer Treat Res (2015) 165 :305–27. 10.1007/978-3-319-13150-4_13\n3 Styczynski J van der Velden W Fox CP Engelhard D de la Camara R Cordonnier C . Management of Epstein-Barr Virus infections and post-transplant lymphoproliferative disorders in patients after allogeneic hematopoietic stem cell transplantation: Sixth European Conference on Infections in Leukemia (ECIL-6) guidelines. Haematologica (2016) 101 (7 ):803–11. 10.3324/haematol.2016.144428\n4 Kaeuferle T Krauss R Blaeschke F Willier S Feuchtinger T . Post-transplant lymphoproliferative disorders after solid organ and hematopoietic stem cell transplantation. J Hematol Oncol (2019) 12 (1 ):13. 10.1186/s13045-019-0701-1 30728058\n5 Doubrovina E Oflaz-Sozmen B Prockop SE Kernan NA Abramson S Teruya-Feldstein J . Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. Blood (2012) 119 (11 ):2644–56. 10.1182/blood-2011-08-371971\n6 Advani RH Buggy JJ Sharman JP Smith SM Boyd TE Grant B . Post-transplant lymphoproliferative disorders after solid organ and hematopoietic stem cell transplantation. J Clin Oncol (2013) 31 (1 ):88–94. 10.1200/JCO.2012.42.7906 23045577\n7 Honigberg LA Smith AM Sirisawad M Verner E Loury D Chang B . The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci USA (2010) 107 (29 ):13075–80. 10.1073/pnas.1004594107\n8 Lionakis MS Dunleavy K Roschewski M Widemann BC Butman JA Schmitz R . Inhibition of B Cell Receptor Signaling by Ibrutinib in Primary CNS Lymphoma. Cancer Cell (2017) 31 (6 ):833–43.e5. 10.1016/j.ccell.2017.04.012 28552327\n9 Grommes C Pastore A Palaskas N Tang SS Campos C Schartz D . Ibrutinib Unmasks Critical Role of Bruton Tyrosine Kinase in Primary CNS Lymphoma. Cancer Discovery (2017) 7 (9 ):1018–29. 10.1158/2159-8290.CD-17-0613\n10 Guo YH Liu Y Hu N Yu DS Zhou CY Shi GY . Discovery of Zanubrutinib (BGB-3111), a Novel, Potent, and Selective Covalent Inhibitor of Bruton's Tyrosine Kinase. Journal of Medicinal Chemistry. J Med Chem (2019) 62 (17 ):7923–40. 10.1021/acs.jmedchem.9b00687\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2234-943X",
"issue": "11()",
"journal": "Frontiers in oncology",
"keywords": "EBV-negative; hematopoietic stem cell transplantation; lymphoma; posttransplant lymphoproliferative disorder; zanubrutinib",
"medline_ta": "Front Oncol",
"mesh_terms": null,
"nlm_unique_id": "101568867",
"other_id": null,
"pages": "672052",
"pmc": null,
"pmid": "33996600",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "27365460;20615965;28619981;31381333;22138512;25655616;23045577;28552327;29966464;30728058",
"title": "Zanubrutinib Treatment of Central Nervous System Posttransplant Lymphoproliferative Disorder After Allogeneic Hematopoietic Stem Cell Transplantation: A Case Report.",
"title_normalized": "zanubrutinib treatment of central nervous system posttransplant lymphoproliferative disorder after allogeneic hematopoietic stem cell transplantation a case report"
} | [
{
"companynumb": "CN-PFIZER INC-2021892792",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
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"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE"
},
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... |
{
"abstract": "Aflibercept has been listed on the Australian Pharmaceutical Benefit Scheme for the past year for neovascular age-related macular degeneration. Since that time there have not been any reports of delayed onset panuveitis. We present two cases of anterior and posterior uveitis that have occurred 4 weeks or more after first intravitreal injection of aflibercept. Both patients had received other vascular endothelial growth factor inhibitors prior to aflibercept administration without signs of inflammation and both cases had sterile endophthalmitis. On resolution of the inflammation the patients were recommenced on ranibizumab without further incident.",
"affiliations": "Department of Ophthalmology, Flinders Medical Centre, Bedford Park, South Australia, Australia.;Department of Ophthalmology, Flinders Medical Centre, Bedford Park, South Australia, Australia Department of Ophthalmology, Flinders University, Bedford Park, South Australia, Australia.;Department of Ophthalmology, Flinders Medical Centre, Bedford Park, South Australia, Australia Department of Ophthalmology, Flinders University, Bedford Park, South Australia, Australia.;Department of Ophthalmology, Flinders Medical Centre, Bedford Park, South Australia, Australia.",
"authors": "Glading|Jodi A|JA|;Lake|Stewart R|SR|;Craig|Jamie E|JE|;Supramaniam|Devaraj|D|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D011993:Recombinant Fusion Proteins; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor",
"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": "D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors; D005260:Female; D006801:Humans; D058449:Intravitreal Injections; D008268:Macular Degeneration; D008297:Male; D015864:Panuveitis; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "24920511",
"pubdate": "2014-06-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17021318;20384590;9117151;22927728;23642742;19287287;18672291;21526923;17031286;19033289;7387284;20559156;17021319;23522744;7893899",
"title": "Delayed onset panuveitis following intravitreal aflibercept injection.",
"title_normalized": "delayed onset panuveitis following intravitreal aflibercept injection"
} | [
{
"companynumb": "AU-SA-2014SA089803",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RANIBIZUMAB"
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"... |
{
"abstract": "Daclizumab is a monoclonal antibody that binds the high-affinity interleukin-2 receptor and was approved for the treatment of relapsing multiple sclerosis. Due to severe inflammatory brain disorders, the approval was suspended in March 2018.\n\n\n\nThis retrospective cohort study summarizes clinical, laboratory, radiological, and histological findings of seven patients who developed meningo-/encephalitis after daclizumab therapy.\n\n\n\nPatients presented with encephalitis and/or meningitis and suffered from systemic symptoms such as fever (5/7), exanthema (5/7), or gastrointestinal symptoms (4/7). Secondary autoimmune diseases developed. Blood analysis revealed an increase in eosinophils (5/7). Six patients fulfilled the diagnostic criteria for a drug reaction with eosinophilia and systemic symptoms (DRESS). Magnetic resonance imaging (MRI) showed multiple contrast-enhancing lesions, and enhancement of the ependyma (6/7), meninges (5/7), cranial or spinal nerves (2/7), and a vasculitic pattern (3/7). Histology revealed a pronounced inflammatory infiltrate consisting of lymphocytes, plasma cells and eosinophils, and densely infiltrated vessels. Most patients showed an insufficient therapeutic response and a high disability at last follow-up (median Expanded Disability Status Scale (EDSS) 8). Two patients died.\n\n\n\nMeningoencephalitis and DRESS may occur with daclizumab therapy. This potential lethal side effect is characterized by a dysregulated immune response. Our findings underline the importance of postmarketing drug surveillance.",
"affiliations": "Institute of Neuropathology, University Medical Center Göttingen, Göttingen, Germany.;Institute of Neuropathology, University Medical Center Göttingen, Göttingen, Germany.;Institute of Neuroradiology, University Medical Center Göttingen, Göttingen, Germany.;Department of Neurology, Imland Hospital, Rendsburg, Germany.;Department of Neurology, Imland Hospital, Rendsburg, Germany.;Institute of Neuropathology, University Hospital Hamburg Eppendorf, Hamburg, Germany.;Department of Neurology, University Medical Center Freiburg, Freiburg, Germany.;Department of Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany.;Institute of Neuropathology, Charité-Universitätsmedizin Berlin, Berlin, Germany.;Department of Neurology, Marienkrankenhaus, Hamburg, Germany.;Department of Neurology, University Hospital Schleswig-Holstein, Kiel, Germany.;Department of Neurology, University Hospital Hamburg Eppendorf, Hamburg, Germany; Institute of Neuroimmunology and Multiple Sclerosis, University Hospital Hamburg Eppendorf, Hamburg, Germany.;Department of Neurology, University Hospital Hamburg Eppendorf, Hamburg, Germany; Institute of Neuroimmunology and Multiple Sclerosis, University Hospital Hamburg Eppendorf, Hamburg, Germany.;Department of Neurology, Martha-Maria Hospital, Halle, Germany.;Department of Neurology, Martha-Maria Hospital, Halle, Germany.;Department of Neurology, University Medical Center, Otto von Guericke University, Magdeburg, Germany.;Institute for Immunology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.;Institute of Neuropathology, University Medical Center Göttingen, Göttingen, Germany.",
"authors": "Stork|Lidia|L|;Brück|Wolfgang|W|;von Gottberg|Phillip|P|;Pulkowski|Ulrich|U|;Kirsten|Florian|F|;Glatzel|Markus|M|;Rauer|Sebastian|S|;Scheibe|Franziska|F|;Radbruch|Helena|H|;Hammer|Eckhard|E|;Stürner|Klarissa H|KH|;Kaulen|Barbara|B|;Heesen|Christoph|C|0000-0001-8131-9467;Hoffmann|Frank|F|;Brock|Sebastian|S|;Pawlitzki|Marc|M|;Bopp|Tobias|T|;Metz|Imke|I|",
"chemical_list": "D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D000077561:Daclizumab",
"country": "England",
"delete": false,
"doi": "10.1177/1352458518819098",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1352-4585",
"issue": "25(12)",
"journal": "Multiple sclerosis (Houndmills, Basingstoke, England)",
"keywords": "Daclizumab; autoimmune diseases; meningoencephalitis; multiple sclerosis; natural killer cells; regulatory T cells",
"medline_ta": "Mult Scler",
"mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D001327:Autoimmune Diseases; D001921:Brain; D000077561:Daclizumab; D004660:Encephalitis; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008214:Lymphocytes; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis; D012189:Retrospective Studies",
"nlm_unique_id": "9509185",
"other_id": null,
"pages": "1618-1632",
"pmc": null,
"pmid": "30657420",
"pubdate": "2019-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Severe meningo-/encephalitis after daclizumab therapy for multiple sclerosis.",
"title_normalized": "severe meningo encephalitis after daclizumab therapy for multiple sclerosis"
} | [
{
"companynumb": "DE-AUROBINDO-AUR-APL-2019-104033",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CORTISONE"
},
"drugadditional": "3",
... |
{
"abstract": "Limited orbital granulomatosis with polyangiitis (GPA) is uncommon and its diagnosis may be delayed, especially when isolated lacrimal involvement is the initial presentation, because clinical manifestations are non-specific and systemic diagnostic criteria are not applicable. Making an early diagnosis despite the absence of systemic progression is extremely important because in some cases the disease is locally destructive, with irreversible visual and functional loss, and it can be refractory to corticosteroids and conventional immunosuppressive drugs to induce remission. The authors report an unusual limited form of orbital GPA in a 35-year-old woman presenting with bilateral dacryoadenitis, evolving later to locally aggressive bilateral orbital pseudotumour leading to proptosis, extraocular myositis, diplopia and medial deviation of the nasal septum. She had never had systemic manifestations but her disease was persistently active and unresponsive to corticosteroids and immunosuppressors. The aim of this paper is to provide further evidence of aggressive and refractory limited forms of GPA.",
"affiliations": "Department of Internal Medicine, Hospital Pedro Hispano, Matosinhos, Portugal.;Department of Internal Medicine, Hospital Pedro Hispano, Matosinhos, Portugal.;Department of Ophthalmology, Hospital Pedro Hispano, Matosinhos, Portugal.;Department of Internal Medicine, Hospital Pedro Hispano, Matosinhos, Portugal.",
"authors": "Lopes Caçola|Rute|R|;Morais|Sandra Alves|SA|;Carvalho|Rui|R|;Môço|Rui|R|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2016()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D003607:Dacryocystitis; D003937:Diagnosis, Differential; D019468:Disease Management; D005260:Female; D014890:Granulomatosis with Polyangiitis; D006801:Humans; D008279:Magnetic Resonance Imaging; D009916:Orbital Diseases",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "27170605",
"pubdate": "2016-05-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22730028;18604579;11535446;25352843;25047592;25076302;1782785;25595914;18569819;20647198;9204342;23237994;18163506;20647199;24485158;26233627;2202308;16616151;16052573;21372195;23203643;12113573;22422012;25149391;24560566;24315515;20638092;19335842;25413843;22927039;22808956",
"title": "Bilateral dacryoadenitis as initial presentation of a locally aggressive and unresponsive limited form of orbital granulomatosis with polyangiitis.",
"title_normalized": "bilateral dacryoadenitis as initial presentation of a locally aggressive and unresponsive limited form of orbital granulomatosis with polyangiitis"
} | [
{
"companynumb": "PT-BAUSCH-BL-2016-018486",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nAlthough imatinib is the first-line of therapy for Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML), in Japan, it is recommended by the manufacturer that lactating women treated with imatinib mesylate for CML should discontinue breastfeeding their infants.\n\n\nMETHODS\nA 32-year-old pregnant patient was diagnosed with Ph-positive CML at 13 weeks of gestation. She received imatinib (400 mg/day) after 28 weeks of gestation. A female infant was delivered at a gestational age of 35 weeks and 3/7 days after preterm premature rupture of membranes. It was decided to feed only colostrum to the infant and formula feeding was done subsequently because of the risk of the transfer of imatinib to breast milk. The milk/plasma (M/P) ratio and the relative infant dose (RID) for imatinib were calculated to be 0.35 and 1.4%, respectively at 5 days of life. Moreover, the serum level of imatinib in the child of age 5 days was 27 ng/mL, which was much lower than the target trough value for CML (1000 ng/mL).\n\n\nCONCLUSIONS\nThe M/P ratio and RID values for maternally administered imatinib were within the safe range for breastfeeding, as reported in previous studies. In addition, it was found that the serum concentration of imatinib in the child was relatively low during short-term breastfeeding.",
"affiliations": "Center for Maternity and Infant Care, 38051Asahikawa Medical University, Asahikawa, Japan.;Center for Maternity and Infant Care, 38051Asahikawa Medical University, Asahikawa, Japan.;Center for Maternity and Infant Care, 38051Asahikawa Medical University, Asahikawa, Japan.;Center for Maternity and Infant Care, 38051Asahikawa Medical University, Asahikawa, Japan.;Center for Maternity and Infant Care, 38051Asahikawa Medical University, Asahikawa, Japan.;Center for Maternity and Infant Care, 38051Asahikawa Medical University, Asahikawa, Japan.;Center for Maternity and Infant Care, 38051Asahikawa Medical University, Asahikawa, Japan.",
"authors": "Terao|Ryuta|R|https://orcid.org/0000-0001-6113-8626;Nii|Mitsumaro|M|;Asai|Hiroko|H|;Nohara|Fumikatsu|F|;Okamoto|Toshio|T|;Nagaya|Ken|K|;Azuma|Hiroshi|H|",
"chemical_list": "D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate",
"country": "England",
"delete": false,
"doi": "10.1177/1078155220948942",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "27(3)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Breastfeeding; CML; imatinib; infant",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D001942:Breast Feeding; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D007223:Infant; D007231:Infant, Newborn; D007564:Japan; D007774:Lactation; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D047428:Protein Kinase Inhibitors",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "756-760",
"pmc": null,
"pmid": "32787559",
"pubdate": "2021-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Breastfeeding in a patient with chronic myeloid leukemia during tyrosine kinase inhibitor therapy.",
"title_normalized": "breastfeeding in a patient with chronic myeloid leukemia during tyrosine kinase inhibitor therapy"
} | [
{
"companynumb": "NVSC2020JP228742",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IMATINIB MESYLATE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nCytomegalovirus (CMV) remains an important pathogen in solid organ transplant patients.\n\n\nOBJECTIVE\nWe executed a hybrid prophylactic and pre-emptive valganciclovir (VGCV) prophylaxis to prevent CMV infection in heart transplant patients with anti-thymocyte globulin (ATG) induction and retrospectively evaluated the efficacy and safety of this regimen.\n\n\nMETHODS\nHundred adult heart transplant patients between 2004 and 2010 were included. Recipients with CMV serostatus D+/R- received VGCV 900 mg OD for 6 months and 94.2% (81/86) of R+ recipients received a low-dose 450 mg OD for 3 months. Blood CMV was monitored until 3 months after cessation of the prophylaxis.\n\n\nRESULTS\nAll patients accomplished the prophylaxis. The overall incidence of CMV disease was 4% (4/100) and it was more frequent in D+/R- patients (P = .001). Three of eighty-six (3.5%) of R+ patients had CMV infection (one CMV disease) while on prophylaxis, 2/3 were still on the original significantly reduced renal dose though. There was one late CMV disease in both D+/R- and R+ groups. Ganciclovir/VGCV treatment was successful in all patients.\n\n\nCONCLUSIONS\nThe hybrid strategy with low-dose VGCV in R+ patients with ATG was efficient and safe. The good treatment results indicate that the regimen did not lead to a clinically relevant resistance. Optimal renal dosage is essential throughout prophylaxis.",
"affiliations": "Department of Medicine, Division of Infectious Diseases, Helsinki University Hospital, Helsinki, Finland.;Heart and Lung Transplantion Program, Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland.;Heart and Lung Center, Helsinki University Central Hospital and Research Programs'unit, Diabetes and Obesity Research Program, Helsinki, Finland.;Heart and Lung Transplantion Program, Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland.;Heart and Lung Transplantion Program, Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland.;Heart and Lung Transplantion Program, Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland.",
"authors": "Eriksson|Mari|M|http://orcid.org/0000-0002-5307-9096;Jokinen|Janne J|JJ|;Söderlund|Sanni|S|;Hämmäinen|Pekka|P|;Lommi|Jyri|J|;Lemström|Karl|K|",
"chemical_list": "D000961:Antilymphocyte Serum; D000998:Antiviral Agents; D007166:Immunosuppressive Agents; D000077562:Valganciclovir; D015774:Ganciclovir",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12868",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "20(3)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "cytomegalovirus; heart transplant; prophylaxis; valganciclovir",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D000961:Antilymphocyte Serum; D000998:Antiviral Agents; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D005260:Female; D015774:Ganciclovir; D006084:Graft Rejection; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D015994:Incidence; D008297:Male; D008499:Medical Records; D008875:Middle Aged; D065129:Pre-Exposure Prophylaxis; D012189:Retrospective Studies; D016896:Treatment Outcome; D000077562:Valganciclovir; D055815:Young Adult",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e12868",
"pmc": null,
"pmid": "29512249",
"pubdate": "2018-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Low-dose valganciclovir prohylaxis is efficacious and safe in cytomegalovirus seropositive heart transplant recipients with anti-thymocyte globulin.",
"title_normalized": "low dose valganciclovir prohylaxis is efficacious and safe in cytomegalovirus seropositive heart transplant recipients with anti thymocyte globulin"
} | [
{
"companynumb": "FI-TEVA-2018-FI-993711",
"fulfillexpeditecriteria": "1",
"occurcountry": "FI",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "3",... |
{
"abstract": "In the present study, the immune response to Wilms tumor gene 1 (WT1) peptide-pulsed dendritic cell (DC) vaccination combined with docetaxel (DCDOC) in advanced esophageal cancer patients who had already received first-line chemotherapy was investigated. Ten HLA-A*2402 patients were treated with docetaxel (50 mg/m2) on day 1 and WT1 peptide-pulsed DC vaccination (1×107 cells) on days 15 and 22 (repeated every 4 weeks for 3 cycles). The delayed-type hypersensitivity skin test, HLA tetramer assay and interferon-γ enzyme-linked immunospot (ELISPOT) assay were used to evaluate the induction of a WT1-specific immune response. Median overall survival was 5 months (range, 1.1-11.6). The clinical effect of DCDOC therapy was not observed and only 1 patient could complete the protocol therapy. Disease progression was observed in 9 patients and 1 patient succumbed to fatality during the second cycle of therapy. As a pilot study, it was not possible to evaluate the safety of WT1 peptide-pulsed DCDOC therapy for esophageal squamous cell cancer. However, a WT1-specific response in 6 patients, as indicated by the ELISPOT or HLA/WT1-tetramer assay, was demonstrated. The results suggested that the positive immune response had significant relevance on the low percentage of CD11b+ and CD66b+ granulocytic myeloid-derived suppressor cells in CD15+ cells. Furthermore, DCDOC elicited a WT1-specific immune response regardless of the myelosuppression associated with docetaxel. The present findings support future studies and further work to assess DCDOC as an adjuvant therapy for esophageal cancer will be performed. The present clinical trial was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry on November 11th, 2011, no. UMIN000006704.",
"affiliations": "Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.;Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.;Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan.;Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.;Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.;Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan.;Department of Gastroenterological Chemotherapy, International University of Health and Welfare, Mita Hospital, Tokyo 108-8329, Japan.;Tokyo Midtown Clinic, Midtown Tower 6F, Tokyo 107-6206, Japan.;Keio Cancer Center, Keio University School of Medicine, Tokyo 160-8582, Japan.;Keio Cancer Center, Keio University School of Medicine, Tokyo 160-8582, Japan.;Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.;Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan.;Department of Digestive Tract Surgery and Transplantation Surgery, Hachioji Medical Center, Tokyo Medical University, Tokyo 193-0998, Japan.;Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan.;Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.",
"authors": "Matsuda|Tatsuo|T|;Takeuchi|Hiroya|H|;Sakurai|Toshiharu|T|;Mayanagi|Shuhei|S|;Booka|Eisuke|E|;Fujita|Tomonobu|T|;Higuchi|Hajime|H|;Taguchi|Junichi|J|;Hamamoto|Yasuo|Y|;Takaishi|Hiromasa|H|;Kawakubo|Hirofumi|H|;Okamoto|Masato|M|;Sunamura|Makoto|M|;Kawakami|Yutaka|Y|;Kitagawa|Yuko|Y|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.3892/ol.2018.8734",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1792-1074",
"issue": "16(1)",
"journal": "Oncology letters",
"keywords": "WT1; dendritic cell vaccination; docetaxel; esophageal cancer; immunotherapy; peptide",
"medline_ta": "Oncol Lett",
"mesh_terms": null,
"nlm_unique_id": "101531236",
"other_id": null,
"pages": "1348-1356",
"pmc": null,
"pmid": "29963201",
"pubdate": "2018-07",
"publication_types": "D016428:Journal Article",
"references": "19410661;15151954;18519787;15122249;16281937;15510596;22735809;21792083;23160854;27793882;25625346;24199700;14657432;12681462;20702612;19723653;22437871;12439606;19097774;25178937;22641661;25863743;25056373;20818862;23374478;26657650;25620903;25614082",
"title": "Pilot study of WT1 peptide-pulsed dendritic cell vaccination with docetaxel in esophageal cancer.",
"title_normalized": "pilot study of wt1 peptide pulsed dendritic cell vaccination with docetaxel in esophageal cancer"
} | [
{
"companynumb": "JP-PFIZER INC-2018234710",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": "3",
... |
{
"abstract": "A 32-year-old primigravid woman developed pre-eclampsia after delivery of twins along with left fifth, sixth, and seventh cranial neuropathies. She also had evidence of hepatic and renal involvement. Results of patient evaluation were otherwise unremarkable, and the palsies completely resolved over 3 months after treatment with valacyclovir and systemic corticosteroids.",
"affiliations": "Department of Ophthalmology (MG, KL), CHUM Notre-Dame Hospital (Centre Hospitalier Universitaire de l'Université Montréal), Montreal, Québec, Canada; and Department of Ophthalmology (MG, KL), University of Montreal, Québec, Canada.",
"authors": "Gilca|Marina|M|;Luneau|Katie|K|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/WNO.0000000000000230",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1070-8022",
"issue": "35(2)",
"journal": "Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society",
"keywords": null,
"medline_ta": "J Neuroophthalmol",
"mesh_terms": "D000328:Adult; D003389:Cranial Nerve Diseases; D005260:Female; D006801:Humans; D011225:Pre-Eclampsia; D011247:Pregnancy",
"nlm_unique_id": "9431308",
"other_id": null,
"pages": "179-81",
"pmc": null,
"pmid": "25768245",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Multiple concomitant cranial nerve palsies secondary to preeclampsia.",
"title_normalized": "multiple concomitant cranial nerve palsies secondary to preeclampsia"
} | [
{
"companynumb": "PHHY2015CA073619",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LETROZOLE"
},
"drugadditional": null,
"druga... |
{
"abstract": "Purpose To report a case of bilateral cavernous sinus thrombosis (CST) in a patient with tacrolimus-associated posttransplant thrombotic microangiopathy. Methods Case report. Results An 8-year-old boy with a medical history of orthotopic heart transplant, posttransplant lymphoproliferative disease, and recurrent infections was hospitalized for nausea, vomiting, and diarrhea. His ocular history included accommodative esotropia, hyperopia with astigmatism, Molluscum contagiosum lid lesions, and idiopathic intracranial hypertension. Shortly after presentation, he developed increased intraocular pressure, an afferent pupillary defect, a layered hyphema, and tense proptosis of the left globe requiring an emergent canthotomy and cantholysis. Over the next month, the patient's hospital course included subdural and subarachnoid hemorrhage, temporal lobe stroke, serotonin syndrome, bilateral CST, and systemic microangiopathy. After an extensive workup, a diagnosis of tacrolimus-associated thrombotic microangiopathy was made. At this point, vision was 20/20 in the right eye and light perception in the left eye. Eight months after the canthotomy and cantholysis, the patient's vision in the left eye deteriorated to no light perception and remained so after 13 months of follow-up. Conclusions An idiosyncratic drug reaction should be considered in the differential diagnosis of CST, especially in a patient on calcineurin inhibitors after solid organ transplant without sinus disease or orbital cellulitis.",
"affiliations": "Department of Ophthalmology, Eye and Ear Institute, University of Pittsburgh Medical Center, Pittsburgh, PA - USA.;Department of Ophthalmology, Eye and Ear Institute, University of Pittsburgh Medical Center, Pittsburgh, PA - USA.;Department of Ophthalmology, Eye and Ear Institute, University of Pittsburgh Medical Center, Pittsburgh, PA - USA.",
"authors": "Kolomeyer|Anton M|AM|;Nischal|Ken K|KK|;Mitchell|Ellen|E|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.5301/ejo.5000889",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1120-6721",
"issue": "27(1)",
"journal": "European journal of ophthalmology",
"keywords": "Cavernous sinus thrombosis; Tacrolimus; Thrombotic microangiopathy",
"medline_ta": "Eur J Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "9110772",
"other_id": null,
"pages": "22-24",
"pmc": null,
"pmid": "27739559",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Bilateral Cavernous Sinus Thrombosis in a Patient with Tacrolimus-Associated Posttransplant Thrombotic Microangiopathy.",
"title_normalized": "bilateral cavernous sinus thrombosis in a patient with tacrolimus associated posttransplant thrombotic microangiopathy"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/16/0084805",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nTo investigate the utility of recombinant activated Factor VII (rFVIIa) for severe post-partum hemorrhage (PPH) in Japan.\n\n\nMETHODS\nWe studied 69 patients treated with rFVIIa for severe PPH; 44 patients were from the registry of Japan Society of Obstetrical, Gynecological and Neonatal Hematology, and 25 were identified by a survey of the Japan Society of Obstetrics and Gynecology.\n\n\nRESULTS\nOverall, the mean and median blood loss were 11 835 mL and 8639 mL, respectively. Treatment before rFVIIa included transarterial embolization in 23 patients and hysterectomy in 38. Forty-two patients had a single dose, 17 had two doses, and four had three doses. The mean (± SD) single dose was 81.60 ± 16.25 µg/kg. Sixty-five patients survived, and four died. The cause of PPH in patients who died was uterine rupture plus amniotic fluid embolism in two patients, uterine cervical laceration in one, and placental abruption in one. The amount of blood loss in cases of death was 6428-43 810 mL. This suggested that whether a patient survives or not was more dependent on her general condition before and after rFVIIa treatment than on the amount of blood loss. Four patients had thromboembolic events after rFVIIa treatment (deep vein thrombosis; deep vein thrombosis plus pulmonary embolism; acute myocardial infarction; and pulmonary embolism); all of these patients recovered.\n\n\nCONCLUSIONS\nThe present promising results may support the utility of rFVIIa for severe PPH in Japan.",
"affiliations": "Department of Obstetrics and Gynecology, Aiwa Hospital, Kawagoe, Saitama.;Department of Obstetrics and Gynecology, Hamamatsu Medical Center, Hamamatsu.;Division of Obstetrics, Center of Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development.;Perinatology Committee, Japan Society of Obstetrics and Gynecology, Tokyo.;Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine.;Perinatology Committee, Japan Society of Obstetrics and Gynecology, Tokyo.",
"authors": "Murakami|Maki|M|;Kobayashi|Takao|T|;Kubo|Takahiko|T|;Hata|Toshiyuki|T|;Takeda|Satoru|S|;Masuzaki|Hideaki|H|",
"chemical_list": "D011994:Recombinant Proteins; C103587:recombinant FVIIa; D015942:Factor VIIa",
"country": "Australia",
"delete": false,
"doi": "10.1111/jog.12712",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-8076",
"issue": "41(8)",
"journal": "The journal of obstetrics and gynaecology research",
"keywords": "critical bleeding in obstetrics; patient registry; post-partum hemorrhage; recombinant activated Factor VII; thromboembolism",
"medline_ta": "J Obstet Gynaecol Res",
"mesh_terms": "D000328:Adult; D001803:Blood Transfusion; D015942:Factor VIIa; D005260:Female; D006801:Humans; D006473:Postpartum Hemorrhage; D011247:Pregnancy; D011994:Recombinant Proteins; D013923:Thromboembolism",
"nlm_unique_id": "9612761",
"other_id": null,
"pages": "1161-8",
"pmc": null,
"pmid": "26013425",
"pubdate": "2015-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Experience with recombinant activated factor VII for severe post-partum hemorrhage in Japan, investigated by Perinatology Committee, Japan Society of Obstetrics and Gynecology.",
"title_normalized": "experience with recombinant activated factor vii for severe post partum hemorrhage in japan investigated by perinatology committee japan society of obstetrics and gynecology"
} | [
{
"companynumb": "JP-MYLANLABS-2016M1042138",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRANEXAMIC ACID"
},
"drugadditional": "3",
... |
{
"abstract": "Infliximab, an antitumour necrosis factor alpha (TNF-alpha)agent, is a cornerstone of treatment of inflammatory bowel disease with a favourable and well-tolerated side effect profile. While the majority of side effects associated with infliximab have been well established, the pathophysiology of infliximab-associated thrombosis remains controversial and poorly defined. We present a case of a young woman with ulcerative colitis who presented with a right ventricular thrombus and bilateral pulmonary emboli after initiation of infliximab and was subsequently found to have underlying factor V Leiden and prothrombin gene mutation. Clinicians should be aware of this potential adverse event associated with anti-TNF agents, especially in individuals with predisposing prothrombotic mutations such as factor V Leiden or prothrombin gene mutation.",
"affiliations": "Medicine, MedStar Union Memorial Hospital, Baltimore, Maryland, USA jennifer.a.ogilvie@medstar.net.;Medicine, MedStar Union Memorial Hospital, Baltimore, Maryland, USA.;MedStar Franklin Square Medical Center, Baltimore, Maryland, USA.;Medicine, MedStar Union Memorial Hospital, Baltimore, Maryland, USA.",
"authors": "Ogilvie|Jennifer Ann|JA|http://orcid.org/0000-0002-8925-1484;Iraqi|Ahmed|A|;Haas|Christopher|C|;Bharaj|Raman|R|",
"chemical_list": "D000079424:Tumor Necrosis Factor Inhibitors; D005165:Factor V; D000069285:Infliximab",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-243337",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(6)",
"journal": "BMJ case reports",
"keywords": "gastrointestinal system; immunological products and vaccines; inflammatory bowel disease; pulmonary embolism; venous thromboembolism",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D003093:Colitis, Ulcerative; D005165:Factor V; D005260:Female; D006801:Humans; D000069285:Infliximab; D011655:Pulmonary Embolism; D013927:Thrombosis; D000079424:Tumor Necrosis Factor Inhibitors",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34183315",
"pubdate": "2021-06-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Right ventricular thrombus and pulmonary embolism after infliximab therapy for ulcerative colitis.",
"title_normalized": "right ventricular thrombus and pulmonary embolism after infliximab therapy for ulcerative colitis"
} | [
{
"companynumb": "US-MYLANLABS-2021M1044348",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "BALSALAZIDE"
},
"drugadditional": null,
... |
{
"abstract": "Nitroprusside was used with intermittent hemodialysis over a 26-day period in a 6-year-old boy with intractable hypertension. Hemodialysis effectively removed thiocyanate from the blood, thus preventing its accumulation and subsequent toxic manifestations. Prolonged nitroprusside infusion maintained arterial blood pressure at acceptable levels until the patient became responsive to other antihypertensive therapy.",
"affiliations": null,
"authors": "Elberg|A J|AJ|;Gorman|H M|HM|;Baker|R|R|;Wenger|A J|AJ|;Strauss|J|J|",
"chemical_list": "D005292:Ferricyanides; D013861:Thiocyanates; D009599:Nitroprusside",
"country": "United States",
"delete": false,
"doi": "10.1001/archpedi.1978.02120350052009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-922X",
"issue": "132(10)",
"journal": "American journal of diseases of children (1960)",
"keywords": null,
"medline_ta": "Am J Dis Child",
"mesh_terms": "D002648:Child; D005292:Ferricyanides; D006801:Humans; D006973:Hypertension; D008297:Male; D009599:Nitroprusside; D006435:Renal Dialysis; D013861:Thiocyanates",
"nlm_unique_id": "0370471",
"other_id": null,
"pages": "988-9",
"pmc": null,
"pmid": "717310",
"pubdate": "1978-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Prolonged nitroprusside and intermittent hemodialysis as therapy for intractable hypertension.",
"title_normalized": "prolonged nitroprusside and intermittent hemodialysis as therapy for intractable hypertension"
} | [
{
"companynumb": "US-PFIZER INC-2019405853",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SODIUM NITROPRUSSIDE"
},
"drugadditional": "1"... |
{
"abstract": "BACKGROUND\nBrain death guidelines should be used with caution in patients with drug intoxication. It is often suggested that physicians use five half-lives of a drug when observing a patient with an overdose. We report two cases of baclofen intoxication where brain death was entertained as an explanation for prolonged coma, with arousal seen days later, suggesting that routine use of a 5-half-life observation period is insufficient with baclofen intoxication.\n\n\nMETHODS\nA 40-year-old woman was found unresponsive by her family. Baclofen was found to be the responsible overdose. The patient had absent brain stem reflexes and was intubated and in the ICU for several days. Although EEG and Apnea test were inconclusive, the patient was thought to be brain dead and organ procurement was arranged. On hospital day 5, the patient started having purposeful movements. The patient had progressive arousal and was eventually transferred without neurologic sequelae to psychiatry. The second patient also had a massive baclofen overdose, had absence of almost all brain stem reflexes and was also intubated and in the ICU. Brain death was felt to be imminent, but the patient began to awake on hospital day 7.\n\n\nCONCLUSIONS\nOur two cases suggest that baclofen intoxication may result in very prolonged and profound coma and may, in fact, mimic brain death. Conclusion. The determination of brain death in the comatose overdose patient must proceed with caution. An adequate period of time to allow drug clearance must be allowed.",
"affiliations": "SUNY Upstate Medical University, Department of Emergency Medicine, Syracuse, USA. sullivar@upstate.edu",
"authors": "Sullivan|Ross|R|;Hodgman|Michael J|MJ|;Kao|Louise|L|;Tormoehlen|Laura M|LM|",
"chemical_list": "D001418:Baclofen",
"country": "England",
"delete": false,
"doi": "10.3109/15563650.2011.654209",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": "50(2)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": null,
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D000328:Adult; D001418:Baclofen; D001926:Brain Death; D062787:Drug Overdose; D004569:Electroencephalography; D005260:Female; D006801:Humans; D008875:Middle Aged",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "141-4",
"pmc": null,
"pmid": "22292975",
"pubdate": "2012-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Baclofen overdose mimicking brain death.",
"title_normalized": "baclofen overdose mimicking brain death"
} | [
{
"companynumb": "US-PFIZER INC-2019167800",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NABUMETONE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nBiologics targeting interleukin 17A (IL-17A) allow for rapid clearance of psoriatic plaques, with a clinically favorable safety profile.\n\n\nOBJECTIVE\nTo compare the safety and efficacy of ixekizumab, an IL-17A antagonist, with the safety and efficacy of the IL-12/23 inhibitor ustekinumab through 52 weeks of treatment in the head-to-head trial IXORA-S.\n\n\nMETHODS\nPatients were randomized to ixekizumab (n = 136) or ustekinumab (n = 166) and dosed per the approved labels. After 1 year, efficacy was assessed via improvements in Psoriasis Area and Severity Index (PASI) score (with PASI 90 indicating a 90% or greater improvement from baseline PASI score) and a static Physician's Global Assessment (sPGA) response of either 0 or 0 or 1, with dropouts counted as nonresponders. Safety analyses included treatment-emergent adverse events (AEs).\n\n\nRESULTS\nAt week 52, significantly more ixekizumab-treated patients (P < .01) reported PASI 90 (104 [76.5%]), an sPGA response of 0 (72 [52.9%]), or an sPGA response of 0 or 1 (110 [82.1%]) responses than did ustekinumab-treated patients (PASI 90, 98 [59.0%]; sPGA response of 0, 60 [36.1%]; and sPGA response of 0 or 1, 108 [65.1%]). Treatment-emergent AEs, serious AEs, and discontinuation rates were not different between the treatment groups. Injection site reactions occurred more frequently in the ixekizumab-treated group (ixekizumab, 22 [16.3%]; ustekinumab, 2 [1.2%]) (P < .001).\n\n\nCONCLUSIONS\nThis study was not designed to compare safety end points related to rare events.\n\n\nCONCLUSIONS\nCompared with ustekinumab, ixekizumab showed superior efficacy and comparable safety outcomes through 52 weeks of treatment.",
"affiliations": "Dermatology Department, CHU, Paul Sabatier University, Toulouse, France. Electronic address: paul.c@chu-toulouse.fr.;Dermatology Centre, Salford Royal Hospital, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.;Department of Dermatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.;Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.;Eli Lilly and Company, Indianapolis, Indiana.;Eli Lilly and Company, Indianapolis, Indiana.;Eli Lilly and Company, Indianapolis, Indiana.;Eli Lilly and Company, Indianapolis, Indiana.;Dermatologikum Berlin and Georg-August-University Göttingen, Göttingen, Germany.",
"authors": "Paul|Carle|C|;Griffiths|Christopher E M|CEM|;van de Kerkhof|Peter C M|PCM|;Puig|Lluís|L|;Dutronc|Yves|Y|;Henneges|Carsten|C|;Dossenbach|Martin|M|;Hollister|Kristin|K|;Reich|Kristian|K|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D003879:Dermatologic Agents; C549079:ixekizumab; D000069549:Ustekinumab",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jaad.2018.06.039",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0190-9622",
"issue": "80(1)",
"journal": "Journal of the American Academy of Dermatology",
"keywords": "IXORA-S; biologic; clinical trial; efficacy; ixekizumab; psoriasis; safety; ustekinumab",
"medline_ta": "J Am Acad Dermatol",
"mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D003879:Dermatologic Agents; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D011565:Psoriasis; D013997:Time Factors; D016896:Treatment Outcome; D000069549:Ustekinumab",
"nlm_unique_id": "7907132",
"other_id": null,
"pages": "70-79.e3",
"pmc": null,
"pmid": "29969700",
"pubdate": "2019-01",
"publication_types": "D017428:Clinical Trial, Phase III; D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Ixekizumab provides superior efficacy compared with ustekinumab over 52 weeks of treatment: Results from IXORA-S, a phase 3 study.",
"title_normalized": "ixekizumab provides superior efficacy compared with ustekinumab over 52 weeks of treatment results from ixora s a phase 3 study"
} | [
{
"companynumb": "FR-JNJFOC-20190431831",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "USTEKINUMAB"
},
"drugadditional": "1",
... |
{
"abstract": "Management of bone and joint infection commonly includes 4-6 weeks of intravenous (IV) antibiotics, but there is little evidence to suggest that oral (PO) therapy results in worse outcomes.\n\n\n\nTo determine whether or not PO antibiotics are non-inferior to IV antibiotics in treating bone and joint infection.\n\n\n\nParallel-group, randomised (1 : 1), open-label, non-inferiority trial. The non-inferiority margin was 7.5%.\n\n\n\nTwenty-six NHS hospitals.\n\n\n\nAdults with a clinical diagnosis of bone, joint or orthopaedic metalware-associated infection who would ordinarily receive at least 6 weeks of antibiotics, and who had received ≤ 7 days of IV therapy from definitive surgery (or start of planned curative treatment in patients managed non-operatively).\n\n\n\nParticipants were centrally computer-randomised to PO or IV antibiotics to complete the first 6 weeks of therapy. Follow-on PO therapy was permitted in either arm.\n\n\n\nThe primary outcome was the proportion of participants experiencing treatment failure within 1 year. An associated cost-effectiveness evaluation assessed health resource use and quality-of-life data.\n\n\n\nOut of 1054 participants (527 in each arm), end-point data were available for 1015 (96.30%) participants. Treatment failure was identified in 141 out of 1015 (13.89%) participants: 74 out of 506 (14.62%) and 67 out of 509 (13.16%) of those participants randomised to IV and PO therapy, respectively. In the intention-to-treat analysis, using multiple imputation to include all participants, the imputed risk difference between PO and IV therapy for definitive treatment failure was -1.38% (90% confidence interval -4.94% to 2.19%), thus meeting the non-inferiority criterion. A complete-case analysis, a per-protocol analysis and sensitivity analyses for missing data each confirmed this result. With the exception of IV catheter complications [49/523 (9.37%) in the IV arm vs. 5/523 (0.96%) in the PO arm)], there was no significant difference between the two arms in the incidence of serious adverse events. PO therapy was highly cost-effective, yielding a saving of £2740 per patient without any significant difference in quality-adjusted life-years between the two arms of the trial.\n\n\n\nThe OVIVA (Oral Versus IntraVenous Antibiotics) trial was an open-label trial, but bias was limited by assessing all potential end points by a blinded adjudication committee. The population was heterogenous, which facilitated generalisability but limited the statistical power of subgroup analyses. Participants were only followed up for 1 year so differences in late recurrence cannot be excluded.\n\n\n\nPO antibiotic therapy is non-inferior to IV therapy when used during the first 6 weeks in the treatment for bone and joint infection, as assessed by definitive treatment failure within 1 year of randomisation. These findings challenge the current standard of care and provide an opportunity to realise significant benefits for patients, antimicrobial stewardship and the health economy.\n\n\n\nFurther work is required to define the optimal total duration of therapy for bone and joint infection in the context of specific surgical interventions. Currently, wide variation in clinical practice suggests significant redundancy that likely contributes to the excess and unnecessary use of antibiotics.\n\n\n\nCurrent Controlled Trials ISRCTN91566927.\n\n\n\nThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 38. See the NIHR Journals Library website for further project information.",
"affiliations": "Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, UK.;Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, UK.;MRC Clinical Trials Unit, University College London, London, UK.;Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;Nuffield Department of Medicine, University of Oxford, Oxford, UK.;Green Templeton College, University of Oxford, Oxford, UK.;Department of Microbiology and Public Health, University Hospital of Wales, Public Health Wales, Cardiff, Wales.;Department of Orthopaedic Surgery, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.;Infectious Diseases and Microbiology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, UK.;Infectious Diseases and Microbiology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, UK.;Department of Microbiology, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK.;Infectious Diseases and Microbiology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.;Infectious Diseases, Heart of England NHS Foundation Trust, Birmingham, UK.;Infectious Diseases and Microbiology, Royal Free London NHS Foundation Trust, London, UK.;Infectious Diseases and Microbiology, Gartnaval General Hospital, NHS Greater Glasgow and Clyde, Glasgow, UK.;Department of Microbiology and Infectious Diseases, Guy's and St Thomas' NHS Foundation Trust, London, UK.;Department of Microbiology, Leeds Teaching Hospitals NHS Trust, Leeds, UK.;Department of Microbiology and Infectious Diseases, Ninewells Hospital, NHS Tayside, Dundee, UK.;Infectious Diseases, Northumbria Healthcare NHS Foundation Trust, Cramlington, UK.;Infectious Diseases Unit, Regional Infectious Diseases Unit, Western General Hospital, NHS Lothian, Edinburgh, UK.;Health Economics and Health Technology Assessment, University of Glasgow, Glasgow, UK.;Health Economics and Health Technology Assessment, University of Glasgow, Glasgow, UK.;Nuffield Department of Medicine, University of Oxford, Oxford, UK.;National Infection Service, Public Health England, Horsham, UK.;Division of Infectious Diseases, Imperial College London, London, UK.;Patient and Public Representative, Division of Health and Social Care Research, King's College London, , London, UK.;Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;Nuffield Department of Medicine, University of Oxford, Oxford, UK.;Nuffield Department of Medicine, University of Oxford, Oxford, UK.",
"authors": "Scarborough|Matthew|M|0000-0002-0455-0785;Li|Ho Kwong|HK|0000-0002-8149-5943;Rombach|Ines|I|0000-0003-3464-3867;Zambellas|Rhea|R|0000-0002-0909-2920;Walker|A Sarah|AS|0000-0002-0412-8509;McNally|Martin|M|0000-0003-2003-9044;Atkins|Bridget|B|0000-0001-8778-0633;Kümin|Michelle|M|0000-0003-4618-6528;Lipsky|Benjamin A|BA|0000-0001-9886-5114;Hughes|Harriet|H|0000-0002-6405-0731;Bose|Deepa|D|0000-0001-6936-2438;Warren|Simon|S|0000-0001-6857-6303;Mack|Damien|D|0000-0001-6837-6467;Folb|Jonathan|J|0000-0002-1413-7118;Moore|Elinor|E|;Jenkins|Neil|N|0000-0001-6967-5709;Hopkins|Susan|S|0000-0001-5179-5702;Seaton|R Andrew|RA|0000-0002-2509-0597;Hemsley|Carolyn|C|0000-0002-0558-3984;Sandoe|Jonathan|J|0000-0003-0193-8677;Aggarwal|Ila|I|0000-0002-4565-2411;Ellis|Simon|S|0000-0003-2502-3818;Sutherland|Rebecca|R|0000-0001-5214-9630;Geue|Claudia|C|0000-0003-2243-0733;McMeekin|Nicola|N|0000-0003-2918-8820;Scarborough|Claire|C|0000-0002-4390-3598;Paul|John|J|0000-0002-0140-9153;Cooke|Graham|G|0000-0001-6475-5056;Bostock|Jennifer|J|0000-0001-9261-9350;Khatamzas|Elham|E|0000-0001-9253-1340;Wong|Nick|N|0000-0002-6325-8821;Brent|Andrew|A|0000-0002-5349-0723;Lomas|Jose|J|0000-0001-8092-805X;Matthews|Philippa|P|0000-0002-4036-4269;Wangrangsimakul|Tri|T|0000-0003-0430-5699;Gundle|Roger|R|0000-0002-2804-8853;Rogers|Mark|M|0000-0002-5858-2088;Taylor|Adrian|A|0000-0001-7521-8643;Thwaites|Guy E|GE|0000-0002-2858-2087;Bejon|Philip|P|0000-0002-2135-7549",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "England",
"delete": false,
"doi": "10.3310/hta23380",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1366-5278",
"issue": "23(38)",
"journal": "Health technology assessment (Winchester, England)",
"keywords": "ANTIBIOTIC; BONE AND JOINT INFECTION; INTRAVENOUS; NON-INFERIORITY; ORAL; RANDOMISED CONTROLLED TRIAL; TREATMENT FAILURE",
"medline_ta": "Health Technol Assess",
"mesh_terms": "D061605:Administration, Intravenous; D000284:Administration, Oral; D000328:Adult; D000900:Anti-Bacterial Agents; D001424:Bacterial Infections; D001850:Bone Diseases, Infectious; D002985:Clinical Protocols; D003362:Cost-Benefit Analysis; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007592:Joint Diseases; D008297:Male; D008875:Middle Aged; D019057:Quality-Adjusted Life Years; D013673:Technology Assessment, Biomedical; D016896:Treatment Outcome; D006113:United Kingdom",
"nlm_unique_id": "9706284",
"other_id": null,
"pages": "1-92",
"pmc": null,
"pmid": "31373271",
"pubdate": "2019-08",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Oral versus intravenous antibiotics for bone and joint infections: the OVIVA non-inferiority RCT.",
"title_normalized": "oral versus intravenous antibiotics for bone and joint infections the oviva non inferiority rct"
} | [
{
"companynumb": "GB-MYLANLABS-2019M1108622",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXYCYCLINE"
},
"drugadditional": "3",
... |
{
"abstract": "Drug-induced thrombocytopenia (DITP) has been described as a sudden and severe hematologic complication of piperacillin/tazobactam. The proposed mechanism by which piperacillin/tazobactam causes DITP involves the formation of a covalent bond to platelet membrane protein thereby inducing a humoral immune response. Given the immunogenic nature of this adverse event and the structural similarities across beta-lactam antibiotics, the potential for cross-reactivity between agents within the class should be considered. However, the structural moiety of piperacillin/tazobactam responsible for this immunogenic response has not been identified-the relationship between structure and activity for this phenomenon remains unknown. Data on the safety and cross-reactivity of other beta-lactam agents in this setting is lacking. We report the first case of piperacillin/tazobactam DITP successfully challenged by the use of cefepime for the treatment of aspiration pneumonia. Further studies are needed to determine the structural moiety of piperacillin/tazobactam responsible for this immunogenic response and evaluate the safety of other beta-lactam antibiotics in this clinical setting.",
"affiliations": "Department of Pharmacy, Virginia Commonwealth University Health, 401 North 12th Street, P.O. Box 980042, Richmond, VA, 23298-0042, USA. dr.carolinebeaulieu@gmail.com.;Department of Pharmacy, Virginia Commonwealth University Health, 401 North 12th Street, P.O. Box 980042, Richmond, VA, 23298-0042, USA.;Department of Anesthesiology, Virginia Commonwealth University Health/Medical College of Virginia Hospitals, 1200 E. Broad Street, 7th Floor, P.O. Box 980695, Richmond, VA, 23298-0695, USA.",
"authors": "Beaulieu|Caroline|C|;Kurczewski|Lisa|L|;Yajnik|Vishal|V|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000077725:Piperacillin, Tazobactam Drug Combination; D000077723:Cefepime; D000078142:Tazobactam; D010878:Piperacillin",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s11239-019-01848-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0929-5305",
"issue": "48(1)",
"journal": "Journal of thrombosis and thrombolysis",
"keywords": "Beta-lactams; Cefepime; Cross reactions; Piperacillin; Thrombocytopenia",
"medline_ta": "J Thromb Thrombolysis",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D000077723:Cefepime; D005260:Female; D006801:Humans; D056724:Immunity, Humoral; D008297:Male; D010878:Piperacillin; D000077725:Piperacillin, Tazobactam Drug Combination; D011015:Pneumonia, Aspiration; D000078142:Tazobactam; D013921:Thrombocytopenia",
"nlm_unique_id": "9502018",
"other_id": null,
"pages": "167-170",
"pmc": null,
"pmid": "30968302",
"pubdate": "2019-07",
"publication_types": "D016428:Journal Article",
"references": "10730685;12163790;17475637;17666285;17687133;18657075;19761734;21239783;23081819;25609660;26684560;27073426;27670947;27848200;29863943;7249508;9770174",
"title": "Cefepime challenge after piperacillin/tazobactam-induced thrombocytopenia.",
"title_normalized": "cefepime challenge after piperacillin tazobactam induced thrombocytopenia"
} | [
{
"companynumb": "PHHY2019US148593",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PIPERACILLIN SODIUM\\TAZOBACTAM SODIUM"
},
"drugadditi... |
{
"abstract": "BACKGROUND\nEsophageal achalasia is a rare disease with a high risk of aspiration during anesthesia induction. Here, we describe our experience involving a case of undiagnosed esophageal achalasia with profuse vomiting during anesthesia induction.\n\n\nMETHODS\nA 58-year-old woman was scheduled for orthopedic surgery under general anesthesia. She vomited a large amount of watery contents during anesthesia induction, and planned surgery was postponed. After recovery from anesthesia, she informed us that she usually had to drink a large amount of water to get food into her stomach and purged watery vomit every night before sleep. However, she attributed it to her constitutional problem, not to a specific disease. She was subsequently diagnosed with esophageal achalasia and underwent Heller myotomy with Dor fundoplication before her re-scheduled orthopedic surgery.\n\n\nCONCLUSIONS\nA detailed history of dysphagia and regurgitation should be taken in preoperative examinations to prevent unexpected aspiration due to undiagnosed achalasia.",
"affiliations": "Department of Anesthesia and Intensive Care Medicine, Akita University Hospital, Hondo 1-1-1, Akita city, Akita, 010-8543, Japan. abeky@doc.med.akita-u.ac.jp.;Department of Anesthesia and Intensive Care Medicine, Akita University Graduate School of Medicine, Akita, Japan.;Department of Anesthesia and Intensive Care Medicine, Akita University Graduate School of Medicine, Akita, Japan.",
"authors": "Abe|Kyoko|K|http://orcid.org/0000-0002-1122-6844;Kimura|Tetsu|T|;Niiyama|Yukitoshi|Y|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1186/s40981-021-00488-y",
"fulltext": "\n==== Front\nJA Clin Rep\nJA Clin Rep\nJA Clinical Reports\n2363-9024\nSpringer Berlin Heidelberg Berlin/Heidelberg\n\n488\n10.1186/s40981-021-00488-y\nCase Report\nEsophageal achalasia detected by vomiting during induction of general anesthesia: a case report\nhttp://orcid.org/0000-0002-1122-6844\nAbe Kyoko abeky@doc.med.akita-u.ac.jp\n\n1\nKimura Tetsu 2\nNiiyama Yukitoshi 2\n1 grid.411403.3 0000 0004 0631 7850 Department of Anesthesia and Intensive Care Medicine, Akita University Hospital, Hondo 1-1-1, Akita city, Akita 010-8543 Japan\n2 grid.251924.9 0000 0001 0725 8504 Department of Anesthesia and Intensive Care Medicine, Akita University Graduate School of Medicine, Akita, Japan\n10 12 2021\n10 12 2021\n12 2021\n7 841 10 2021\n25 11 2021\n26 11 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.\nBackground\n\nEsophageal achalasia is a rare disease with a high risk of aspiration during anesthesia induction. Here, we describe our experience involving a case of undiagnosed esophageal achalasia with profuse vomiting during anesthesia induction.\n\nCase presentation\n\nA 58-year-old woman was scheduled for orthopedic surgery under general anesthesia. She vomited a large amount of watery contents during anesthesia induction, and planned surgery was postponed. After recovery from anesthesia, she informed us that she usually had to drink a large amount of water to get food into her stomach and purged watery vomit every night before sleep. However, she attributed it to her constitutional problem, not to a specific disease. She was subsequently diagnosed with esophageal achalasia and underwent Heller myotomy with Dor fundoplication before her re-scheduled orthopedic surgery.\n\nConclusions\n\nA detailed history of dysphagia and regurgitation should be taken in preoperative examinations to prevent unexpected aspiration due to undiagnosed achalasia.\n\nKeywords\n\nEsophageal achalasia\nAspiration\nPreanesthetic examination\nissue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\nEsophageal achalasia is a rare disease (incidence, 1 in 100,000) associated with a high risk of aspiration during the induction of general anesthesia due to difficulties in passing food [1]. Here, we present a patient with undiagnosed esophageal achalasia who vomited profusely during the induction of general anesthesia.\n\nCase presentation\n\nA 58-year-old woman (height 163 cm, weight 52 kg, body mass index 19.6) with a diagnosis of spinal canal stenosis was admitted to an orthopedic hospital to undergo posterior lumbar interbody fusion. Her medical history included anterior cervical fusion 12 years previously without any anesthetic complications such as allergy or bronchial asthma. No full-time anesthesiologist was on staff at the hospital, so a part-time anesthesiologist was in charge of the anesthesia.\n\nThe patient had been fasting for 15 h, from dinner the night before surgery until entering the operating room (OR). Four hours before entering the OR, an intravenous infusion was started. The patient was administered ranitidine (150 mg orally) with a small amount of water 180 min before entering the OR.\n\nImmediately before starting the anesthesia induction, the anesthesiologist reconfirmed the patient’s medical history and whether she had any allergies or bronchial asthma. The patient did not provide any new medical information. Electrocardiography, pulse oximetry (SpO2), noninvasive blood pressure, and capnometry were applied. After preoxygenation with 100% oxygen for 3 min, general anesthesia was induced with fentanyl 50 μg and propofol 100 mg. After confirming the patient’s spontaneous breathing cessation, assisted ventilation was initiated with a face mask, followed by rocuronium 50 mg. Immediately after that, the patient threw up a massive amount of watery vomit. The vomit in her oral cavity was immediately suctioned, and then her trachea was intubated. A small amount of watery vomit was suctioned through the endotracheal tube. Lung compliance was low with manual ventilation, and wheezing was heard on auscultation with an obstructive pattern on capnography. Bronchospasm due to aspiration was suspected, and treatment was initiated. Under anesthesia (sevoflurane 2% in oxygen 100%), her SpO2 remained above 98%. Hydrocortisone 100 mg and aminophylline 250 mg were administered by drip infusion. Forty-five minutes after the event, her wheezing disappeared, and mostly normal lung compliance returned. The scheduled surgery was postponed, the patient was awakened from anesthesia with the aid of sugammadex to antagonize rocuronium, and her trachea was extubated.\n\nAfter returning to the ward, a more detailed medical history was obtained from the patient. She said that she usually had to drink a large amount of water to get food into her stomach. Therefore, she made it a daily habit to purge watery vomit before bed, as it would reflux when she lay down. Although she had an upper gastrointestinal endoscopy a few years prior, the physician had not pointed out anything unusual. Since then, she believed that this was a constitutional problem as opposed to a disease. The patient had not experienced any weight loss for the past few years.\n\nAlthough no clear image of pneumonia was seen on a chest X-ray at the ward, ampicillin and sulbactam were administered for prevention. The patient was discharged the next day without any medical problems. Based on an overall assessment of the episode, we believed that this patient had esophageal achalasia and advised her to visit a gastroenterologist.\n\nAt the gastroenterology department in another hospital, fluid retention in the dilated esophagus was revealed by upper endoscopy and chest computed tomography (CT) (Fig. 1). The esophagogram showed a dilated esophagus with a diameter of 32 mm and functional narrowing of the esophagogastric junction (Fig. 2). Esophageal manometry showed the disappearance of primary peristaltic waves and the occurrence of simultaneous contraction waves. Based on these results, the patient was diagnosed with esophageal achalasia and underwent laparoscopic Heller myotomy with Dor fundoplication surgery. After the surgery, her subjective symptoms, including choking with food and daily vomiting before bed, disappeared. She was discharged on the sixth day after surgery. Three months later, she underwent posterior interbody fusion of the lumbar spine without any anesthetic complications.Fig. 1 Preoperative thoracic computed tomography showing fluid retention in the dilated esophagus. a Upper thoracic region. b Middle thoracic region\n\nFig. 2 Preoperative esophagogram showed a dilated esophagus and functional narrowing of the esophagogastric junction. A mouthful of contrast medium was retained in the esophagus until the end of the imaging\n\nDiscussion\n\nEsophageal achalasia is defined as an esophageal motility disorder of unknown etiology characterized by failure of lower esophageal sphincter (LES) relaxation and impaired peristalsis of the lower esophageal body [2]. Diagnosis is difficult because achalasia is a rare disease (incidence, 1 in 100,000 people) with nonspecific subjective symptoms [3]. The most frequent symptoms of achalasia include dysphagia of solids and liquids (> 90%), regurgitation of undigested food (76–91%), respiratory complications such as nocturnal cough (30%) and aspiration (8%), chest pains (25–64%), heartburn (18–52%), and weight loss (35–91%) [4]. Oral reflux in patients with achalasia does not originate from the stomach and thus does not contain acidic contents. Furthermore, if the volume of the oral reflux is mild, the patient may be unaware of the reflux.\n\nWe assume two reasons for the aspiration during the first scheduled orthopedic surgery in this case. First, the patient was not aware of her rare disease. She had unusual habits such as washing food into her stomach with large amounts of water and purging watery vomit every night before bed. Nonetheless, she did not consider it unusual because her gastroenterologist told her that nothing was wrong. The diagnostic features of esophageal achalasia on upper gastrointestinal endoscopy include (1) dilatation of the esophageal lumen, (2) abnormal retention of food and fluid in the esophagus, (3) whitening and thickening of the esophageal mucosal surface, (4) functional narrowing of the esophagogastric junction, and (5) abnormal contraction waves of the esophagus [2]. In this case, preoperative endoscopy before Heller and Dor surgery showed fluid retention in the esophagus and functional narrowing of the esophagogastric junction, but the dilation of the esophageal lumen was mild. As a result, the gastroenterologist at the time was unable to detect achalasia, leading to her misconception that it was not a disease.\n\nSecond, we could not obtain information regarding dysphagia and food regurgitation in the preoperative examination. Our routine preoperative examination for orthopedic patients without gastrointestinal complications includes a detailed medical history, allergies, and asthma, but not dysphagia or food regurgitation. In patients with esophageal achalasia, 37% have solid residue, and 14.8% retain water, even after fasting for 24 h before surgery [5]. Fortunately, because this patient had a habit of vomiting every night before bed, and the vomit did not contain any solids, she did not develop severe pneumonia.\n\nAchalasia is a rare disease, and only a few cases have been detected by aspiration during the induction of anesthesia [1, 6, 7]. Since achalasia is a chronic benign disease, patients may recognize it as a constitutional problem, as in this case. A detailed history of dysphagia and regurgitation should be taken from all patients during preoperative examinations to avoid aspiration risk, even if achalasia is not suspected. Pillow stains with drool while sleeping suggests the existence of achalasia. Although chest X-rays appear normal in the early phase of achalasia, the dilated esophagus creates new interfaces with the lung as the disease progresses, which makes achalasia-specific findings, including convex opacity overlapping the right mediastinum, air-fluid levels in the thorax esophagus, and small or absent gastric bubbles [8]. In this case, the esophageal dilatation was so mild that no suspicious contour was seen on the chest X-ray (Fig. 3). However, it should be worthwhile for physicians to get into the habit of looking for achalasia-specific findings on routine X-ray readings to detect undiagnosed achalasia. Furthermore, we would like to emphasize that achalasia should not be ruled out even if there are no findings specific to achalasia, especially in patients with symptoms such as dysphagia or regurgitation. If a chest CT is taken for the preoperative evaluation, physicians should also note the dilated image of the esophagus.Fig. 3 Preoperative chest X-ray did not show any abnormalities\n\nConclusions\n\nAlthough esophageal achalasia is a rare disease, it is associated with a high risk of aspiration pneumonia if general anesthesia is induced without caution. A detailed history of dysphagia and regurgitation of solids and liquids in the preoperative examination is essential and practical for detecting the existence of achalasia and preventing unexpected aspiration due to undiagnosed achalasia. Additionally, getting into the habit of checking for achalasia-specific findings on chest X-rays and chest CT may reduce the occurrence of unexpected aspiration.\n\nAcknowledgements\n\nNot applicable.\n\nAuthors’ contributions\n\nKA wrote and prepared the final draft of the manuscript. TK and YN helped draft and review the manuscript. The authors read and approved the final manuscript.\n\nFunding\n\nNot applicable.\n\nDeclarations\n\nEthics approval and consent to participate\n\nNot applicable.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient for publication of this case report and the accompanying images.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Inadomi C Yamashita K Takada M Terao Y Fukusaki M Regurgitation during anesthesia induction in a patient with preoperatively undiagnosed esophageal achalasia J Jpn Soc Clin Anesth. 2005 25 347 351 10.2199/jjsca.25.347\n2. Boeckxstaens GE Zaninotto G Richter JE Achalasia Lancet 2014 383 83 93 10.1016/S0140-6736(13)60651-0 23871090\n3. Japan Esophageal Society Descriptive rules for achalasia of the esophagus. 2012: 4th edition Esophagus. 2017 14 275 289 10.1007/s10388-017-0589-1 28983228\n4. Hoshino M Omura N Yano F Tsuboi K Yamamoto SR Akimoto S Is esophageal manometry essential for the diagnosis of achalasia? Identifying patients with achalasia by the esophageal clearance method Esophagus. 2021 18 163 168 10.1007/s10388-020-00756-3 32556734\n5. Tanaka E Murata H Minami H Sumikawa K Anesthetic management of peroral endoscopic myotomy for esophageal achalasia: a retrospective case series J Anesth. 2014 28 456 459 10.1007/s00540-013-1735-0 24185834\n6. Layton J Ward PW Miller DW Roan RM Acute respiratory failure secondary to esophageal dilation from undiagnosed achalasia A A Case Rep. 2014 3 65 67 10.1213/XAA.0000000000000064 25611356\n7. Kendall AP Lin E Respitatory failure as presentation of achalasia of the oesophagus Anaesthesia. 1991 46 1039 1040 10.1111/j.1365-2044.1991.tb09918.x 1781529\n8. Cole TJ Turner MA Manifestations of gastrointestinal disease on chest radiographs RadioGraphics. 1993 13 1013 1034 10.1148/radiographics.13.5.8210587 8210587\n\n",
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"abstract": "Petroleum aspiration as a reason for lipid pneumonia is a rare complication. Mostly children are affected and mortality rates are low. In most case series, virtually every subject survived.We describe here the case of a patient who developed ARDS and pneumatoceles with a fatal outcome. Due to the undulant nature of the disease, multipe thoracic CT were performed, enabling us to describe the precise radiologic course of the disease.",
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"title": "ARDS after Incidental Aspiration of Petroleum in an Adult.",
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"abstract": "Tacrolimus, a reversible calcineurin inhibitor, is known for its diabetogenic potential. The incidence of diabetes is less frequent among the patients of nephrotic syndrome in comparison to organ transplant recipients. Diabetic ketoacidosis (DKA) is even rarer. DKA as the first presentation of new onset tacrolimus induced transient type 1 diabetes despite a lower dose range and low trough level of the drug is being reported in a 12-y-old girl with steroid resistant nephrotic syndrome.",
"affiliations": "Department of Pediatrics, IPGME&R, Kolkata, West Bengal, India. sumantra.com@gmail.com",
"authors": "Sarkar|Sumantra|S|;Mondal|Rakesh|R|;Nandi|Madhumita|M|;Das|Anjan Kumar|AK|",
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"title": "Tacrolimus induced diabetic ketoacidosis in nephrotic syndrome.",
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"abstract": "Hyperleukocytosis is a rare but potentially serious complication of haematological malignancies. It is usually treated with rehydration, prevention of tumour lysis syndrome and the administration of cytotoxic therapy. Leukapheresis may be life-saving in emergency cases. In this article we describe how, in a resource-limited setting where leukapheresis was not available, manual exchange transfusion was utilised as a life-saving intervention in three patients with different haematological malignancies complicated by hyperleukocytosis. Further we outline the procedure that was carried out and evaluated possible complications associated with this rarely used practice.",
"affiliations": "Department of Internal Medicine, University of the Free State, Bloemfontein, South Africa. Electronic address: claire.armour.barrett@gmail.com.",
"authors": "Barrett|Claire L|CL|;Louw|Vernon J|VJ|;Webb|Michael J|MJ|",
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"title": "Exchange transfusion as a life-saving intervention in three patients with different haematological malignancies with severe hyperleukocytosis where leukapheresis was not available.",
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"abstract": "Purpose The standard treatment of patients with diffuse large B-cell lymphoma (DLBCL) is rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Lenalidomide, an immunomodulatory agent, has shown activity in DLBCL. This randomized phase III trial compared lenalidomide as maintenance therapy with placebo in elderly patients with DLBCL who achieved a complete response (CR) or partial response (PR) to R-CHOP induction. Methods Patients with previously untreated DLBCL or other aggressive B-cell lymphoma were 60 to 80 years old, had CR or PR after six or eight cycles of R-CHOP, and were randomly assigned to lenalidomide maintenance 25 mg/d or placebo for 21 days of every 28-day cycle for 24 months. The primary end point was progression-free survival (PFS). Results A total of 650 patients were randomly assigned. At the time of the primary analysis (December 2015), with a median follow-up of 39 months from random assignment, median PFS was not reached for lenalidomide maintenance versus 58.9 months for placebo (hazard ratio, 0.708; 95% CI, 0.537 to 0.933; P = .01). The result was consistent among analyzed subgroups (eg, male v female, age-adjusted International Prognostic Index 0 or 1 v 2 or 3, age younger than 70 v ≥ 70 years), response (PR v CR) after R-CHOP, and positron emission tomography status at assignment (negative v positive). With longer median follow-up of 52 months (October 2016), overall survival was similar between arms (hazard ratio, 1.218; 95% CI, 0.861 to 1.721; P = .26). Most common grade 3 or 4 adverse events associated with lenalidomide versus placebo maintenance were neutropenia (56% v 22%) and cutaneous reactions (5% v 1%), respectively. Conclusion Lenalidomide maintenance for 24 months after obtaining a CR or PR to R-CHOP significantly prolonged PFS in elderly patients with DLBCL.",
"affiliations": "Catherine Thieblemont, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis; Diderot University, Sorbonne Paris-Cité; Catherine Thieblemont and Josette Briere, Descartes University; Josette Briere, Hôpital Necker, Paris; Hervé Tilly, University of Rouen, Institut National de la Santé et de la Recherche Médicale U1245, Rouen; Rene-Olivier Casasnovas, Centre Hospitalier Universitaire Dijon; Institut National de la Santé et de la Recherche Médicale UMR1231, Dijon; Christophe Fruchart, Institut d'Hématologie de Basse Normandie, Centre Hospitalier Universitaire, Caen; Franck Morschhauser, Centre Hospitalier Universitaire Régional de Lille, Lille; Corinne Haioun and Philippe Gaulard, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Mondor; Philippe Gaulard, Institut National de la Santé et de la Recherche Médicale U955; Université Paris-Est, Créteil; Julien Lazarovici, Gustave Roussy Cancer Center, Villejuif; Aurore Perrot, University Hospital, Vandoeuvre les Nancy; Catherine Sebban, Centre Leon Berard, University Claude Bernard Lyon 1; Gilles Salles, Hospices Civils de Lyon, Université Claude Bernard U1052, Lyon; Hugo Gonzalez, Centre Hospitalier René Dubos, Pontoise; Reda Bouabdallah, Institut Paoli Calmettes, Marseille; Lucie Oberic, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse; Bernadette Corront, Centre Hospitalier Régional Annecy, Annecy; Bachra Choufi, Centre Hospitalier Dr Duchenne, Boulogne-sur-mer; Gilles Salles and Bertrand Coiffier, Institut National de la Santé et de la Recherche Médicale U1052, Hospices Civils de Lyon, Pierre-Benite, France; Maria Gomes da Silva and Jose Cabeçadas, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal; Anida Grosicka, Medical University of Silesia, Katowice, Poland; Judith Trotman, Concord Repatriation General Hospital, University of Sydney, Concord; John Catalano, Frankston Hospital and Monash University, Frankston, Australia; Dolores Caballero, Hospital Universitario de Salamanca, Salamanca; Armando Lopez-Guillermo, Hospital Clinic Barcelona, Barcelona, Spain; Richard Greil, Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute; Arbeitsgemeinschaft Medikamentöse Tumortherapie, Salzburg, Austria; Koen van Eygen, Algemeen Ziekenhuis Groeninge Hospital, President Kennedylaan 4, Kortrijk; Achiel Van Hoof, Algemeen Ziekenhuis Sint Jan AV, Brugge; Andre Bosly, UCL Mont Godinne, Yvoir, Belgium; and Amos M. Cohen, Rabin Medical Center, Beilinson Hospital, Davidoff Cancer Center, Tel-Aviv University, Ramat-Aviv, Israel.;Catherine Thieblemont, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis; Diderot University, Sorbonne Paris-Cité; Catherine Thieblemont and Josette Briere, Descartes University; Josette Briere, Hôpital Necker, Paris; Hervé Tilly, University of Rouen, Institut National de la Santé et de la Recherche Médicale U1245, Rouen; Rene-Olivier Casasnovas, Centre Hospitalier Universitaire Dijon; Institut National de la Santé et de la Recherche Médicale UMR1231, Dijon; Christophe Fruchart, Institut d'Hématologie de Basse Normandie, Centre Hospitalier Universitaire, Caen; Franck Morschhauser, Centre Hospitalier Universitaire Régional de Lille, Lille; Corinne Haioun and Philippe Gaulard, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Mondor; Philippe Gaulard, Institut National de la Santé et de la Recherche Médicale U955; Université Paris-Est, Créteil; Julien Lazarovici, Gustave Roussy Cancer Center, Villejuif; Aurore Perrot, University Hospital, Vandoeuvre les Nancy; Catherine Sebban, Centre Leon Berard, University Claude Bernard Lyon 1; Gilles Salles, Hospices Civils de Lyon, Université Claude Bernard U1052, Lyon; Hugo Gonzalez, Centre Hospitalier René Dubos, Pontoise; Reda Bouabdallah, Institut Paoli Calmettes, Marseille; Lucie Oberic, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse; Bernadette Corront, Centre Hospitalier Régional Annecy, Annecy; Bachra Choufi, Centre Hospitalier Dr Duchenne, Boulogne-sur-mer; Gilles Salles and Bertrand Coiffier, Institut National de la Santé et de la Recherche Médicale U1052, Hospices Civils de Lyon, Pierre-Benite, France; Maria Gomes da Silva and Jose Cabeçadas, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal; Anida Grosicka, Medical University of Silesia, Katowice, Poland; Judith Trotman, Concord Repatriation General Hospital, University of Sydney, Concord; John Catalano, Frankston Hospital and Monash University, Frankston, Australia; Dolores Caballero, Hospital Universitario de Salamanca, Salamanca; Armando Lopez-Guillermo, Hospital Clinic Barcelona, Barcelona, Spain; Richard Greil, Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute; Arbeitsgemeinschaft Medikamentöse Tumortherapie, Salzburg, Austria; Koen van Eygen, Algemeen Ziekenhuis Groeninge Hospital, President Kennedylaan 4, Kortrijk; Achiel Van Hoof, Algemeen Ziekenhuis Sint Jan AV, Brugge; Andre Bosly, UCL Mont Godinne, Yvoir, Belgium; and Amos M. Cohen, Rabin Medical Center, Beilinson Hospital, Davidoff Cancer Center, Tel-Aviv University, Ramat-Aviv, Israel.;Catherine Thieblemont, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis; Diderot University, Sorbonne Paris-Cité; Catherine Thieblemont and Josette Briere, Descartes University; Josette Briere, Hôpital Necker, Paris; Hervé Tilly, University of Rouen, Institut National de la Santé et de la Recherche Médicale U1245, Rouen; Rene-Olivier Casasnovas, Centre Hospitalier Universitaire Dijon; Institut National de la Santé et de la Recherche Médicale UMR1231, Dijon; Christophe Fruchart, Institut d'Hématologie de Basse Normandie, Centre Hospitalier Universitaire, Caen; Franck Morschhauser, Centre Hospitalier Universitaire Régional de Lille, Lille; Corinne Haioun and Philippe Gaulard, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Mondor; Philippe Gaulard, Institut National de la Santé et de la Recherche Médicale U955; Université Paris-Est, Créteil; Julien Lazarovici, Gustave Roussy Cancer Center, Villejuif; Aurore Perrot, University Hospital, Vandoeuvre les Nancy; Catherine Sebban, Centre Leon Berard, University Claude Bernard Lyon 1; Gilles Salles, Hospices Civils de Lyon, Université Claude Bernard U1052, Lyon; Hugo Gonzalez, Centre Hospitalier René Dubos, Pontoise; Reda Bouabdallah, Institut Paoli Calmettes, Marseille; Lucie Oberic, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse; Bernadette Corront, Centre Hospitalier Régional Annecy, Annecy; Bachra Choufi, Centre Hospitalier Dr Duchenne, Boulogne-sur-mer; Gilles Salles and Bertrand Coiffier, Institut National de la Santé et de la Recherche Médicale U1052, Hospices Civils de Lyon, Pierre-Benite, France; Maria Gomes da Silva and Jose Cabeçadas, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal; Anida Grosicka, Medical University of Silesia, Katowice, Poland; Judith Trotman, Concord Repatriation General Hospital, University of Sydney, Concord; John Catalano, Frankston Hospital and Monash University, Frankston, Australia; Dolores Caballero, Hospital Universitario de Salamanca, Salamanca; Armando Lopez-Guillermo, Hospital Clinic Barcelona, Barcelona, Spain; Richard Greil, Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute; Arbeitsgemeinschaft Medikamentöse Tumortherapie, Salzburg, Austria; Koen van Eygen, Algemeen Ziekenhuis Groeninge Hospital, President Kennedylaan 4, Kortrijk; Achiel Van Hoof, Algemeen Ziekenhuis Sint Jan AV, Brugge; Andre Bosly, UCL Mont Godinne, Yvoir, Belgium; and Amos M. Cohen, Rabin Medical Center, Beilinson Hospital, Davidoff Cancer Center, Tel-Aviv University, Ramat-Aviv, Israel.;Catherine Thieblemont, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis; Diderot University, Sorbonne Paris-Cité; Catherine Thieblemont and Josette Briere, Descartes University; Josette Briere, Hôpital Necker, Paris; Hervé Tilly, University of Rouen, Institut National de la Santé et de la Recherche Médicale U1245, Rouen; Rene-Olivier Casasnovas, Centre Hospitalier Universitaire Dijon; Institut National de la Santé et de la Recherche Médicale UMR1231, Dijon; Christophe Fruchart, Institut d'Hématologie de Basse Normandie, Centre Hospitalier Universitaire, Caen; Franck Morschhauser, Centre Hospitalier Universitaire Régional de Lille, Lille; Corinne Haioun and Philippe Gaulard, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Mondor; Philippe Gaulard, Institut National de la Santé et de la Recherche Médicale U955; Université Paris-Est, Créteil; Julien Lazarovici, Gustave Roussy Cancer Center, Villejuif; Aurore Perrot, University Hospital, Vandoeuvre les Nancy; Catherine Sebban, Centre Leon Berard, University Claude Bernard Lyon 1; Gilles Salles, Hospices Civils de Lyon, Université Claude Bernard U1052, Lyon; Hugo Gonzalez, Centre Hospitalier René Dubos, Pontoise; Reda Bouabdallah, Institut Paoli Calmettes, Marseille; Lucie Oberic, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse; Bernadette Corront, Centre Hospitalier Régional Annecy, Annecy; Bachra Choufi, Centre Hospitalier Dr Duchenne, Boulogne-sur-mer; Gilles Salles and Bertrand Coiffier, Institut National de la Santé et de la Recherche Médicale U1052, Hospices Civils de Lyon, Pierre-Benite, France; Maria Gomes da Silva and Jose Cabeçadas, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal; Anida Grosicka, Medical University of Silesia, Katowice, Poland; Judith Trotman, Concord Repatriation General Hospital, University of Sydney, Concord; John Catalano, Frankston Hospital and Monash University, Frankston, Australia; Dolores Caballero, Hospital Universitario de Salamanca, Salamanca; Armando Lopez-Guillermo, Hospital Clinic Barcelona, Barcelona, Spain; Richard Greil, Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute; Arbeitsgemeinschaft Medikamentöse Tumortherapie, Salzburg, Austria; Koen van Eygen, Algemeen Ziekenhuis Groeninge Hospital, President Kennedylaan 4, Kortrijk; Achiel Van Hoof, Algemeen Ziekenhuis Sint Jan AV, Brugge; Andre Bosly, UCL Mont Godinne, Yvoir, Belgium; and Amos M. Cohen, Rabin Medical Center, Beilinson Hospital, Davidoff Cancer Center, Tel-Aviv University, Ramat-Aviv, Israel.;Catherine Thieblemont, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis; Diderot University, Sorbonne Paris-Cité; Catherine Thieblemont and Josette Briere, Descartes University; Josette Briere, Hôpital Necker, Paris; Hervé Tilly, University of Rouen, Institut National de la Santé et de la Recherche Médicale U1245, Rouen; Rene-Olivier Casasnovas, Centre Hospitalier Universitaire Dijon; Institut National de la Santé et de la Recherche Médicale UMR1231, Dijon; Christophe Fruchart, Institut d'Hématologie de Basse Normandie, Centre Hospitalier Universitaire, Caen; Franck Morschhauser, Centre Hospitalier Universitaire Régional de Lille, Lille; Corinne Haioun and Philippe Gaulard, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Mondor; Philippe Gaulard, Institut National de la Santé et de la Recherche Médicale U955; Université Paris-Est, Créteil; Julien Lazarovici, Gustave Roussy Cancer Center, Villejuif; Aurore Perrot, University Hospital, Vandoeuvre les Nancy; Catherine Sebban, Centre Leon Berard, University Claude Bernard Lyon 1; Gilles Salles, Hospices Civils de Lyon, Université Claude Bernard U1052, Lyon; Hugo Gonzalez, Centre Hospitalier René Dubos, Pontoise; Reda Bouabdallah, Institut Paoli Calmettes, Marseille; Lucie Oberic, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse; Bernadette Corront, Centre Hospitalier Régional Annecy, Annecy; Bachra Choufi, Centre Hospitalier Dr Duchenne, Boulogne-sur-mer; Gilles Salles and Bertrand Coiffier, Institut National de la Santé et de la Recherche Médicale U1052, Hospices Civils de Lyon, Pierre-Benite, France; Maria Gomes da Silva and Jose Cabeçadas, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal; Anida Grosicka, Medical University of Silesia, Katowice, Poland; Judith Trotman, Concord Repatriation General Hospital, University of Sydney, Concord; John Catalano, Frankston Hospital and Monash University, Frankston, Australia; Dolores Caballero, Hospital Universitario de Salamanca, Salamanca; Armando Lopez-Guillermo, Hospital Clinic Barcelona, Barcelona, Spain; Richard Greil, Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute; Arbeitsgemeinschaft Medikamentöse Tumortherapie, Salzburg, Austria; Koen van Eygen, Algemeen Ziekenhuis Groeninge Hospital, President Kennedylaan 4, Kortrijk; Achiel Van Hoof, Algemeen Ziekenhuis Sint Jan AV, Brugge; Andre Bosly, UCL Mont Godinne, Yvoir, Belgium; and Amos M. Cohen, Rabin Medical Center, Beilinson Hospital, Davidoff Cancer Center, Tel-Aviv University, Ramat-Aviv, Israel.;Catherine Thieblemont, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis; Diderot University, Sorbonne Paris-Cité; Catherine Thieblemont and Josette Briere, Descartes University; Josette Briere, Hôpital Necker, Paris; Hervé Tilly, University of Rouen, Institut National de la Santé et de la Recherche Médicale U1245, Rouen; Rene-Olivier Casasnovas, Centre Hospitalier Universitaire Dijon; Institut National de la Santé et de la Recherche Médicale UMR1231, Dijon; Christophe Fruchart, Institut d'Hématologie de Basse Normandie, Centre Hospitalier Universitaire, Caen; Franck Morschhauser, Centre Hospitalier Universitaire Régional de Lille, Lille; Corinne Haioun and Philippe Gaulard, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Mondor; Philippe Gaulard, Institut National de la Santé et de la Recherche Médicale U955; Université Paris-Est, Créteil; Julien Lazarovici, Gustave Roussy Cancer Center, Villejuif; Aurore Perrot, University Hospital, Vandoeuvre les Nancy; Catherine Sebban, Centre Leon Berard, University Claude Bernard Lyon 1; Gilles Salles, Hospices Civils de Lyon, Université Claude Bernard U1052, Lyon; Hugo Gonzalez, Centre Hospitalier René Dubos, Pontoise; Reda Bouabdallah, Institut Paoli Calmettes, Marseille; Lucie Oberic, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse; Bernadette Corront, Centre Hospitalier Régional Annecy, Annecy; Bachra Choufi, Centre Hospitalier Dr Duchenne, Boulogne-sur-mer; Gilles Salles and Bertrand Coiffier, Institut National de la Santé et de la Recherche Médicale U1052, Hospices Civils de Lyon, Pierre-Benite, France; Maria Gomes da Silva and Jose Cabeçadas, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal; Anida Grosicka, Medical University of Silesia, Katowice, Poland; Judith Trotman, Concord Repatriation General Hospital, University of Sydney, Concord; John Catalano, Frankston Hospital and Monash University, Frankston, Australia; Dolores Caballero, Hospital Universitario de Salamanca, Salamanca; Armando Lopez-Guillermo, Hospital Clinic Barcelona, Barcelona, Spain; Richard Greil, Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute; Arbeitsgemeinschaft Medikamentöse Tumortherapie, Salzburg, Austria; Koen van Eygen, Algemeen Ziekenhuis Groeninge Hospital, President Kennedylaan 4, Kortrijk; Achiel Van Hoof, Algemeen Ziekenhuis Sint Jan AV, Brugge; Andre Bosly, UCL Mont Godinne, Yvoir, Belgium; and Amos M. Cohen, Rabin Medical Center, Beilinson Hospital, Davidoff Cancer Center, Tel-Aviv University, Ramat-Aviv, Israel.;Catherine Thieblemont, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis; Diderot University, Sorbonne Paris-Cité; Catherine Thieblemont and Josette Briere, Descartes University; Josette Briere, Hôpital Necker, Paris; Hervé Tilly, University of Rouen, Institut National de la Santé et de la Recherche Médicale U1245, Rouen; Rene-Olivier Casasnovas, Centre Hospitalier Universitaire Dijon; Institut National de la Santé et de la Recherche Médicale UMR1231, Dijon; Christophe Fruchart, Institut d'Hématologie de Basse Normandie, Centre Hospitalier Universitaire, Caen; Franck Morschhauser, Centre Hospitalier Universitaire Régional de Lille, Lille; Corinne Haioun and Philippe Gaulard, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Mondor; Philippe Gaulard, Institut National de la Santé et de la Recherche Médicale U955; Université Paris-Est, Créteil; Julien Lazarovici, Gustave Roussy Cancer Center, Villejuif; Aurore Perrot, University Hospital, Vandoeuvre les Nancy; Catherine Sebban, Centre Leon Berard, University Claude Bernard Lyon 1; Gilles Salles, Hospices Civils de Lyon, Université Claude Bernard U1052, Lyon; Hugo Gonzalez, Centre Hospitalier René Dubos, Pontoise; Reda Bouabdallah, Institut Paoli Calmettes, Marseille; Lucie Oberic, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse; Bernadette Corront, Centre Hospitalier Régional Annecy, Annecy; Bachra Choufi, Centre Hospitalier Dr Duchenne, Boulogne-sur-mer; Gilles Salles and Bertrand Coiffier, Institut National de la Santé et de la Recherche Médicale U1052, Hospices Civils de Lyon, Pierre-Benite, France; Maria Gomes da Silva and Jose Cabeçadas, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal; Anida Grosicka, Medical University of Silesia, Katowice, Poland; Judith Trotman, Concord Repatriation General Hospital, University of Sydney, Concord; John Catalano, Frankston Hospital and Monash University, Frankston, Australia; Dolores Caballero, Hospital Universitario de Salamanca, Salamanca; Armando Lopez-Guillermo, Hospital Clinic Barcelona, Barcelona, Spain; Richard Greil, Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute; Arbeitsgemeinschaft Medikamentöse Tumortherapie, Salzburg, Austria; Koen van Eygen, Algemeen Ziekenhuis Groeninge Hospital, President Kennedylaan 4, Kortrijk; Achiel Van Hoof, Algemeen Ziekenhuis Sint Jan AV, Brugge; Andre Bosly, UCL Mont Godinne, Yvoir, Belgium; and Amos M. Cohen, Rabin Medical Center, Beilinson Hospital, Davidoff Cancer Center, Tel-Aviv University, Ramat-Aviv, Israel.;Catherine Thieblemont, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis; Diderot University, Sorbonne Paris-Cité; Catherine Thieblemont and Josette Briere, Descartes University; Josette Briere, Hôpital Necker, Paris; Hervé Tilly, University of Rouen, Institut National de la Santé et de la Recherche Médicale U1245, Rouen; Rene-Olivier Casasnovas, Centre Hospitalier Universitaire Dijon; Institut National de la Santé et de la Recherche Médicale UMR1231, Dijon; Christophe Fruchart, Institut d'Hématologie de Basse Normandie, Centre Hospitalier Universitaire, Caen; Franck Morschhauser, Centre Hospitalier Universitaire Régional de Lille, Lille; Corinne Haioun and Philippe Gaulard, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Mondor; Philippe Gaulard, Institut National de la Santé et de la Recherche Médicale U955; Université Paris-Est, Créteil; Julien Lazarovici, Gustave Roussy Cancer Center, Villejuif; Aurore Perrot, University Hospital, Vandoeuvre les Nancy; Catherine Sebban, Centre Leon Berard, University Claude Bernard Lyon 1; Gilles Salles, Hospices Civils de Lyon, Université Claude Bernard U1052, Lyon; Hugo Gonzalez, Centre Hospitalier René Dubos, Pontoise; Reda Bouabdallah, Institut Paoli Calmettes, Marseille; Lucie Oberic, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse; Bernadette Corront, Centre Hospitalier Régional Annecy, Annecy; Bachra Choufi, Centre Hospitalier Dr Duchenne, Boulogne-sur-mer; Gilles Salles and Bertrand Coiffier, Institut National de la Santé et de la Recherche Médicale U1052, Hospices Civils de Lyon, Pierre-Benite, France; Maria Gomes da Silva and Jose Cabeçadas, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal; Anida Grosicka, Medical University of Silesia, Katowice, Poland; Judith Trotman, Concord Repatriation General Hospital, University of Sydney, Concord; John Catalano, Frankston Hospital and Monash University, Frankston, Australia; Dolores Caballero, Hospital Universitario de Salamanca, Salamanca; Armando Lopez-Guillermo, Hospital Clinic Barcelona, Barcelona, Spain; Richard Greil, Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute; Arbeitsgemeinschaft Medikamentöse Tumortherapie, Salzburg, Austria; Koen van Eygen, Algemeen Ziekenhuis Groeninge Hospital, President Kennedylaan 4, Kortrijk; Achiel Van Hoof, Algemeen Ziekenhuis Sint Jan AV, Brugge; Andre Bosly, UCL Mont Godinne, Yvoir, Belgium; and Amos M. Cohen, Rabin Medical Center, Beilinson Hospital, Davidoff Cancer Center, Tel-Aviv University, Ramat-Aviv, Israel.;Catherine Thieblemont, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis; Diderot University, Sorbonne Paris-Cité; Catherine Thieblemont and Josette Briere, Descartes University; Josette Briere, Hôpital Necker, Paris; Hervé Tilly, University of Rouen, Institut National de la Santé et de la Recherche Médicale U1245, Rouen; Rene-Olivier Casasnovas, Centre Hospitalier Universitaire Dijon; Institut National de la Santé et de la Recherche Médicale UMR1231, Dijon; Christophe Fruchart, Institut d'Hématologie de Basse Normandie, Centre Hospitalier Universitaire, Caen; Franck Morschhauser, Centre Hospitalier Universitaire Régional de Lille, Lille; Corinne Haioun and Philippe Gaulard, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Mondor; Philippe Gaulard, Institut National de la Santé et de la Recherche Médicale U955; Université Paris-Est, Créteil; Julien Lazarovici, Gustave Roussy Cancer Center, Villejuif; Aurore Perrot, University Hospital, Vandoeuvre les Nancy; Catherine Sebban, Centre Leon Berard, University Claude Bernard Lyon 1; Gilles Salles, Hospices Civils de Lyon, Université Claude Bernard U1052, Lyon; Hugo Gonzalez, Centre Hospitalier René Dubos, Pontoise; Reda Bouabdallah, Institut Paoli Calmettes, Marseille; Lucie Oberic, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse; Bernadette Corront, Centre Hospitalier Régional Annecy, Annecy; Bachra Choufi, Centre Hospitalier Dr Duchenne, Boulogne-sur-mer; Gilles Salles and Bertrand Coiffier, Institut National de la Santé et de la Recherche Médicale U1052, Hospices Civils de Lyon, Pierre-Benite, France; Maria Gomes da Silva and Jose Cabeçadas, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal; Anida Grosicka, Medical University of Silesia, Katowice, Poland; Judith Trotman, Concord Repatriation General Hospital, University of Sydney, Concord; John Catalano, Frankston Hospital and Monash University, Frankston, Australia; Dolores Caballero, Hospital Universitario de Salamanca, Salamanca; Armando Lopez-Guillermo, Hospital Clinic Barcelona, Barcelona, Spain; Richard Greil, Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute; Arbeitsgemeinschaft Medikamentöse Tumortherapie, Salzburg, Austria; Koen van Eygen, Algemeen Ziekenhuis Groeninge Hospital, President Kennedylaan 4, Kortrijk; Achiel Van Hoof, Algemeen Ziekenhuis Sint Jan AV, Brugge; Andre Bosly, UCL Mont Godinne, Yvoir, Belgium; and Amos M. Cohen, Rabin Medical Center, Beilinson Hospital, Davidoff Cancer Center, Tel-Aviv University, Ramat-Aviv, Israel.;Catherine Thieblemont, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis; Diderot University, Sorbonne Paris-Cité; Catherine Thieblemont and Josette Briere, Descartes University; Josette Briere, Hôpital Necker, Paris; Hervé Tilly, University of Rouen, Institut National de la Santé et de la Recherche Médicale U1245, Rouen; Rene-Olivier Casasnovas, Centre Hospitalier Universitaire Dijon; Institut National de la Santé et de la Recherche Médicale UMR1231, Dijon; Christophe Fruchart, Institut d'Hématologie de Basse Normandie, Centre Hospitalier Universitaire, Caen; Franck Morschhauser, Centre Hospitalier Universitaire Régional de Lille, Lille; Corinne Haioun and Philippe Gaulard, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Mondor; Philippe Gaulard, Institut National de la Santé et de la Recherche Médicale U955; Université Paris-Est, Créteil; Julien Lazarovici, Gustave Roussy Cancer Center, Villejuif; Aurore Perrot, University Hospital, Vandoeuvre les Nancy; Catherine Sebban, Centre Leon Berard, University Claude Bernard Lyon 1; Gilles Salles, Hospices Civils de Lyon, Université Claude Bernard U1052, Lyon; Hugo Gonzalez, Centre Hospitalier René Dubos, Pontoise; Reda Bouabdallah, Institut Paoli Calmettes, Marseille; Lucie Oberic, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse; Bernadette Corront, Centre Hospitalier Régional Annecy, Annecy; Bachra Choufi, Centre Hospitalier Dr Duchenne, Boulogne-sur-mer; Gilles Salles and Bertrand Coiffier, Institut National de la Santé et de la Recherche Médicale U1052, Hospices Civils de Lyon, Pierre-Benite, France; Maria Gomes da Silva and Jose Cabeçadas, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal; Anida Grosicka, Medical University of Silesia, Katowice, Poland; Judith Trotman, Concord Repatriation General Hospital, University of Sydney, Concord; John Catalano, Frankston Hospital and Monash University, Frankston, Australia; Dolores Caballero, Hospital Universitario de Salamanca, Salamanca; Armando Lopez-Guillermo, Hospital Clinic Barcelona, Barcelona, Spain; Richard Greil, Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute; Arbeitsgemeinschaft Medikamentöse Tumortherapie, Salzburg, Austria; Koen van Eygen, Algemeen Ziekenhuis Groeninge Hospital, President Kennedylaan 4, Kortrijk; Achiel Van Hoof, Algemeen Ziekenhuis Sint Jan AV, Brugge; Andre Bosly, UCL Mont Godinne, Yvoir, Belgium; and Amos M. Cohen, Rabin Medical Center, Beilinson Hospital, Davidoff Cancer Center, Tel-Aviv University, Ramat-Aviv, Israel.;Catherine Thieblemont, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis; Diderot University, Sorbonne Paris-Cité; Catherine Thieblemont and Josette Briere, Descartes University; Josette Briere, Hôpital Necker, Paris; Hervé Tilly, University of Rouen, Institut National de la Santé et de la Recherche Médicale U1245, Rouen; Rene-Olivier Casasnovas, Centre Hospitalier Universitaire Dijon; Institut National de la Santé et de la Recherche Médicale UMR1231, Dijon; Christophe Fruchart, Institut d'Hématologie de Basse Normandie, Centre Hospitalier Universitaire, Caen; Franck Morschhauser, Centre Hospitalier Universitaire Régional de Lille, Lille; Corinne Haioun and Philippe Gaulard, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Mondor; Philippe Gaulard, Institut National de la Santé et de la Recherche Médicale U955; Université Paris-Est, Créteil; Julien Lazarovici, Gustave Roussy Cancer Center, Villejuif; Aurore Perrot, University Hospital, Vandoeuvre les Nancy; Catherine Sebban, Centre Leon Berard, University Claude Bernard Lyon 1; Gilles Salles, Hospices Civils de Lyon, Université Claude Bernard U1052, Lyon; Hugo Gonzalez, Centre Hospitalier René Dubos, Pontoise; Reda Bouabdallah, Institut Paoli Calmettes, Marseille; Lucie Oberic, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse; Bernadette Corront, Centre Hospitalier Régional Annecy, Annecy; Bachra Choufi, Centre Hospitalier Dr Duchenne, Boulogne-sur-mer; Gilles Salles and Bertrand Coiffier, Institut National de la Santé et de la Recherche Médicale U1052, Hospices Civils de Lyon, Pierre-Benite, France; Maria Gomes da Silva and Jose Cabeçadas, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal; Anida Grosicka, Medical University of Silesia, Katowice, Poland; Judith Trotman, Concord Repatriation General Hospital, University of Sydney, Concord; John Catalano, Frankston Hospital and Monash University, Frankston, Australia; Dolores Caballero, Hospital Universitario de Salamanca, Salamanca; Armando Lopez-Guillermo, Hospital Clinic Barcelona, Barcelona, Spain; Richard Greil, Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute; Arbeitsgemeinschaft Medikamentöse Tumortherapie, Salzburg, Austria; Koen van Eygen, Algemeen Ziekenhuis Groeninge Hospital, President Kennedylaan 4, Kortrijk; Achiel Van Hoof, Algemeen Ziekenhuis Sint Jan AV, Brugge; Andre Bosly, UCL Mont Godinne, Yvoir, Belgium; and Amos M. Cohen, Rabin Medical Center, Beilinson Hospital, Davidoff Cancer Center, Tel-Aviv University, Ramat-Aviv, Israel.;Catherine Thieblemont, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis; Diderot University, Sorbonne Paris-Cité; Catherine Thieblemont and Josette Briere, Descartes University; Josette Briere, Hôpital Necker, Paris; Hervé Tilly, University of Rouen, Institut National de la Santé et de la Recherche Médicale U1245, Rouen; Rene-Olivier Casasnovas, Centre Hospitalier Universitaire Dijon; Institut National de la Santé et de la Recherche Médicale UMR1231, Dijon; Christophe Fruchart, Institut d'Hématologie de Basse Normandie, Centre Hospitalier Universitaire, Caen; Franck Morschhauser, Centre Hospitalier Universitaire Régional de Lille, Lille; Corinne Haioun and Philippe Gaulard, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Mondor; Philippe Gaulard, Institut National de la Santé et de la Recherche Médicale U955; Université Paris-Est, Créteil; Julien Lazarovici, Gustave Roussy Cancer Center, Villejuif; Aurore Perrot, University Hospital, Vandoeuvre les Nancy; Catherine Sebban, Centre Leon Berard, University Claude Bernard Lyon 1; Gilles Salles, Hospices Civils de Lyon, Université Claude Bernard U1052, Lyon; Hugo Gonzalez, Centre Hospitalier René Dubos, Pontoise; Reda Bouabdallah, Institut Paoli Calmettes, Marseille; Lucie Oberic, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse; Bernadette Corront, Centre Hospitalier Régional Annecy, Annecy; Bachra Choufi, Centre Hospitalier Dr Duchenne, Boulogne-sur-mer; Gilles Salles and Bertrand Coiffier, Institut National de la Santé et de la Recherche Médicale U1052, Hospices Civils de Lyon, Pierre-Benite, France; Maria Gomes da Silva and Jose Cabeçadas, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal; Anida Grosicka, Medical University of Silesia, Katowice, Poland; Judith Trotman, Concord Repatriation General Hospital, University of Sydney, Concord; John Catalano, Frankston Hospital and Monash University, Frankston, Australia; Dolores Caballero, Hospital Universitario de Salamanca, Salamanca; Armando Lopez-Guillermo, Hospital Clinic Barcelona, Barcelona, Spain; Richard Greil, Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute; Arbeitsgemeinschaft Medikamentöse Tumortherapie, Salzburg, Austria; Koen van Eygen, Algemeen Ziekenhuis Groeninge Hospital, President Kennedylaan 4, Kortrijk; Achiel Van Hoof, Algemeen Ziekenhuis Sint Jan AV, Brugge; Andre Bosly, UCL Mont Godinne, Yvoir, Belgium; and Amos M. Cohen, Rabin Medical Center, Beilinson Hospital, Davidoff Cancer Center, Tel-Aviv University, Ramat-Aviv, Israel.;Catherine Thieblemont, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis; Diderot University, Sorbonne Paris-Cité; Catherine Thieblemont and Josette Briere, Descartes University; Josette Briere, Hôpital Necker, Paris; Hervé Tilly, University of Rouen, Institut National de la Santé et de la Recherche Médicale U1245, Rouen; Rene-Olivier Casasnovas, Centre Hospitalier Universitaire Dijon; Institut National de la Santé et de la Recherche Médicale UMR1231, Dijon; Christophe Fruchart, Institut d'Hématologie de Basse Normandie, Centre Hospitalier Universitaire, Caen; Franck Morschhauser, Centre Hospitalier Universitaire Régional de Lille, Lille; Corinne Haioun and Philippe Gaulard, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Mondor; Philippe Gaulard, Institut National de la Santé et de la Recherche Médicale U955; Université Paris-Est, Créteil; Julien Lazarovici, Gustave Roussy Cancer Center, Villejuif; Aurore Perrot, University Hospital, Vandoeuvre les Nancy; Catherine Sebban, Centre Leon Berard, University Claude Bernard Lyon 1; Gilles Salles, Hospices Civils de Lyon, Université Claude Bernard U1052, Lyon; Hugo Gonzalez, Centre Hospitalier René Dubos, Pontoise; Reda Bouabdallah, Institut Paoli Calmettes, Marseille; Lucie Oberic, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse; Bernadette Corront, Centre Hospitalier Régional Annecy, Annecy; Bachra Choufi, Centre Hospitalier Dr Duchenne, Boulogne-sur-mer; Gilles Salles and Bertrand Coiffier, Institut National de la Santé et de la Recherche Médicale U1052, Hospices Civils de Lyon, Pierre-Benite, France; Maria Gomes da Silva and Jose Cabeçadas, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal; Anida Grosicka, Medical University of Silesia, Katowice, Poland; Judith Trotman, Concord Repatriation General Hospital, University of Sydney, Concord; John Catalano, Frankston Hospital and Monash University, Frankston, Australia; Dolores Caballero, Hospital Universitario de Salamanca, Salamanca; Armando Lopez-Guillermo, Hospital Clinic Barcelona, Barcelona, Spain; Richard Greil, Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute; Arbeitsgemeinschaft Medikamentöse Tumortherapie, Salzburg, Austria; Koen van Eygen, Algemeen Ziekenhuis Groeninge Hospital, President Kennedylaan 4, Kortrijk; Achiel Van Hoof, Algemeen Ziekenhuis Sint Jan AV, Brugge; Andre Bosly, UCL Mont Godinne, Yvoir, Belgium; and Amos M. Cohen, Rabin Medical Center, Beilinson Hospital, Davidoff Cancer Center, Tel-Aviv University, Ramat-Aviv, Israel.;Catherine Thieblemont, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis; Diderot University, Sorbonne Paris-Cité; Catherine Thieblemont and Josette Briere, Descartes University; Josette Briere, Hôpital Necker, Paris; Hervé Tilly, University of Rouen, Institut National de la Santé et de la Recherche Médicale U1245, Rouen; Rene-Olivier Casasnovas, Centre Hospitalier Universitaire Dijon; Institut National de la Santé et de la Recherche Médicale UMR1231, Dijon; Christophe Fruchart, Institut d'Hématologie de Basse Normandie, Centre Hospitalier Universitaire, Caen; Franck Morschhauser, Centre Hospitalier Universitaire Régional de Lille, Lille; Corinne Haioun and Philippe Gaulard, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Mondor; Philippe Gaulard, Institut National de la Santé et de la Recherche Médicale U955; Université Paris-Est, Créteil; Julien Lazarovici, Gustave Roussy Cancer Center, Villejuif; Aurore Perrot, University Hospital, Vandoeuvre les Nancy; Catherine Sebban, Centre Leon Berard, University Claude Bernard Lyon 1; Gilles Salles, Hospices Civils de Lyon, Université Claude Bernard U1052, Lyon; Hugo Gonzalez, Centre Hospitalier René Dubos, Pontoise; Reda Bouabdallah, Institut Paoli Calmettes, Marseille; Lucie Oberic, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse; Bernadette Corront, Centre Hospitalier Régional Annecy, Annecy; Bachra Choufi, Centre Hospitalier Dr Duchenne, Boulogne-sur-mer; Gilles Salles and Bertrand Coiffier, Institut National de la Santé et de la Recherche Médicale U1052, Hospices Civils de Lyon, Pierre-Benite, France; Maria Gomes da Silva and Jose Cabeçadas, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal; Anida Grosicka, Medical University of Silesia, Katowice, Poland; Judith Trotman, Concord Repatriation General Hospital, University of Sydney, Concord; John Catalano, Frankston Hospital and Monash University, Frankston, Australia; Dolores Caballero, Hospital Universitario de Salamanca, Salamanca; Armando Lopez-Guillermo, Hospital Clinic Barcelona, Barcelona, Spain; Richard Greil, Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute; Arbeitsgemeinschaft Medikamentöse Tumortherapie, Salzburg, Austria; Koen van Eygen, Algemeen Ziekenhuis Groeninge Hospital, President Kennedylaan 4, Kortrijk; Achiel Van Hoof, Algemeen Ziekenhuis Sint Jan AV, Brugge; Andre Bosly, UCL Mont Godinne, Yvoir, Belgium; and Amos M. Cohen, Rabin Medical Center, Beilinson Hospital, Davidoff Cancer Center, Tel-Aviv University, Ramat-Aviv, Israel.;Catherine Thieblemont, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis; Diderot University, Sorbonne Paris-Cité; Catherine Thieblemont and Josette Briere, Descartes University; Josette Briere, Hôpital Necker, Paris; Hervé Tilly, University of Rouen, Institut National de la Santé et de la Recherche Médicale U1245, Rouen; Rene-Olivier Casasnovas, Centre Hospitalier Universitaire Dijon; Institut National de la Santé et de la Recherche Médicale UMR1231, Dijon; Christophe Fruchart, Institut d'Hématologie de Basse Normandie, Centre Hospitalier Universitaire, Caen; Franck Morschhauser, Centre Hospitalier Universitaire Régional de Lille, Lille; Corinne Haioun and Philippe Gaulard, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Mondor; Philippe Gaulard, Institut National de la Santé et de la Recherche Médicale U955; Université Paris-Est, Créteil; Julien Lazarovici, Gustave Roussy Cancer Center, Villejuif; Aurore Perrot, University Hospital, Vandoeuvre les Nancy; Catherine Sebban, Centre Leon Berard, University Claude Bernard Lyon 1; Gilles Salles, Hospices Civils de Lyon, Université Claude Bernard U1052, Lyon; Hugo Gonzalez, Centre Hospitalier René Dubos, Pontoise; Reda Bouabdallah, Institut Paoli Calmettes, Marseille; Lucie Oberic, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse; Bernadette Corront, Centre Hospitalier Régional Annecy, Annecy; Bachra Choufi, Centre Hospitalier Dr Duchenne, Boulogne-sur-mer; Gilles Salles and Bertrand Coiffier, Institut National de la Santé et de la Recherche Médicale U1052, Hospices Civils de Lyon, Pierre-Benite, France; Maria Gomes da Silva and Jose Cabeçadas, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal; Anida Grosicka, Medical University of Silesia, Katowice, Poland; Judith Trotman, Concord Repatriation General Hospital, University of Sydney, Concord; John Catalano, Frankston Hospital and Monash University, Frankston, Australia; Dolores Caballero, Hospital Universitario de Salamanca, Salamanca; Armando Lopez-Guillermo, Hospital Clinic Barcelona, Barcelona, Spain; Richard Greil, Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute; Arbeitsgemeinschaft Medikamentöse Tumortherapie, Salzburg, Austria; Koen van Eygen, Algemeen Ziekenhuis Groeninge Hospital, President Kennedylaan 4, Kortrijk; Achiel Van Hoof, Algemeen Ziekenhuis Sint Jan AV, Brugge; Andre Bosly, UCL Mont Godinne, Yvoir, Belgium; and Amos M. Cohen, Rabin Medical Center, Beilinson Hospital, Davidoff Cancer Center, Tel-Aviv University, Ramat-Aviv, Israel.;Catherine Thieblemont, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis; Diderot University, Sorbonne Paris-Cité; Catherine Thieblemont and Josette Briere, Descartes University; Josette Briere, Hôpital Necker, Paris; Hervé Tilly, University of Rouen, Institut National de la Santé et de la Recherche Médicale U1245, Rouen; Rene-Olivier Casasnovas, Centre Hospitalier Universitaire Dijon; Institut National de la Santé et de la Recherche Médicale UMR1231, Dijon; Christophe Fruchart, Institut d'Hématologie de Basse Normandie, Centre Hospitalier Universitaire, Caen; Franck Morschhauser, Centre Hospitalier Universitaire Régional de Lille, Lille; Corinne Haioun and Philippe Gaulard, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Mondor; Philippe Gaulard, Institut National de la Santé et de la Recherche Médicale U955; Université Paris-Est, Créteil; Julien Lazarovici, Gustave Roussy Cancer Center, Villejuif; Aurore Perrot, University Hospital, Vandoeuvre les Nancy; Catherine Sebban, Centre Leon Berard, University Claude Bernard Lyon 1; Gilles Salles, Hospices Civils de Lyon, Université Claude Bernard U1052, Lyon; Hugo Gonzalez, Centre Hospitalier René Dubos, Pontoise; Reda Bouabdallah, Institut Paoli Calmettes, Marseille; Lucie Oberic, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse; Bernadette Corront, Centre Hospitalier Régional Annecy, Annecy; Bachra Choufi, Centre Hospitalier Dr Duchenne, Boulogne-sur-mer; Gilles Salles and Bertrand Coiffier, Institut National de la Santé et de la Recherche Médicale U1052, Hospices Civils de Lyon, Pierre-Benite, France; Maria Gomes da Silva and Jose Cabeçadas, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal; Anida Grosicka, Medical University of Silesia, Katowice, Poland; Judith Trotman, Concord Repatriation General Hospital, University of Sydney, Concord; John Catalano, Frankston Hospital and Monash University, Frankston, Australia; Dolores Caballero, Hospital Universitario de Salamanca, Salamanca; Armando Lopez-Guillermo, Hospital Clinic Barcelona, Barcelona, Spain; Richard Greil, Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute; Arbeitsgemeinschaft Medikamentöse Tumortherapie, Salzburg, Austria; Koen van Eygen, Algemeen Ziekenhuis Groeninge Hospital, President Kennedylaan 4, Kortrijk; Achiel Van Hoof, Algemeen Ziekenhuis Sint Jan AV, Brugge; Andre Bosly, UCL Mont Godinne, Yvoir, Belgium; and Amos M. Cohen, Rabin Medical Center, Beilinson Hospital, Davidoff Cancer Center, Tel-Aviv University, Ramat-Aviv, Israel.;Catherine Thieblemont, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis; Diderot University, Sorbonne Paris-Cité; Catherine Thieblemont and Josette Briere, Descartes University; Josette Briere, Hôpital Necker, Paris; Hervé Tilly, University of Rouen, Institut National de la Santé et de la Recherche Médicale U1245, Rouen; Rene-Olivier Casasnovas, Centre Hospitalier Universitaire Dijon; Institut National de la Santé et de la Recherche Médicale UMR1231, Dijon; Christophe Fruchart, Institut d'Hématologie de Basse Normandie, Centre Hospitalier Universitaire, Caen; Franck Morschhauser, Centre Hospitalier Universitaire Régional de Lille, Lille; Corinne Haioun and Philippe Gaulard, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Mondor; Philippe Gaulard, Institut National de la Santé et de la Recherche Médicale U955; Université Paris-Est, Créteil; Julien Lazarovici, Gustave Roussy Cancer Center, Villejuif; Aurore Perrot, University Hospital, Vandoeuvre les Nancy; Catherine Sebban, Centre Leon Berard, University Claude Bernard Lyon 1; Gilles Salles, Hospices Civils de Lyon, Université Claude Bernard U1052, Lyon; Hugo Gonzalez, Centre Hospitalier René Dubos, Pontoise; Reda Bouabdallah, Institut Paoli Calmettes, Marseille; Lucie Oberic, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse; Bernadette Corront, Centre Hospitalier Régional Annecy, Annecy; Bachra Choufi, Centre Hospitalier Dr Duchenne, Boulogne-sur-mer; Gilles Salles and Bertrand Coiffier, Institut National de la Santé et de la Recherche Médicale U1052, Hospices Civils de Lyon, Pierre-Benite, France; Maria Gomes da Silva and Jose Cabeçadas, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal; Anida Grosicka, Medical University of Silesia, Katowice, Poland; Judith Trotman, Concord Repatriation General Hospital, University of Sydney, Concord; John Catalano, Frankston Hospital and Monash University, Frankston, Australia; Dolores Caballero, Hospital Universitario de Salamanca, Salamanca; Armando Lopez-Guillermo, Hospital Clinic Barcelona, Barcelona, Spain; Richard Greil, Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute; Arbeitsgemeinschaft Medikamentöse Tumortherapie, Salzburg, Austria; Koen van Eygen, Algemeen Ziekenhuis Groeninge Hospital, President Kennedylaan 4, Kortrijk; Achiel Van Hoof, Algemeen Ziekenhuis Sint Jan AV, Brugge; Andre Bosly, UCL Mont Godinne, Yvoir, Belgium; and Amos M. Cohen, Rabin Medical Center, Beilinson Hospital, Davidoff Cancer Center, Tel-Aviv University, Ramat-Aviv, Israel.;Catherine Thieblemont, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis; Diderot University, Sorbonne Paris-Cité; Catherine Thieblemont and Josette Briere, Descartes University; Josette Briere, Hôpital Necker, Paris; Hervé Tilly, University of Rouen, Institut National de la Santé et de la Recherche Médicale U1245, Rouen; Rene-Olivier Casasnovas, Centre Hospitalier Universitaire Dijon; Institut National de la Santé et de la Recherche Médicale UMR1231, Dijon; Christophe Fruchart, Institut d'Hématologie de Basse Normandie, Centre Hospitalier Universitaire, Caen; Franck Morschhauser, Centre Hospitalier Universitaire Régional de Lille, Lille; Corinne Haioun and Philippe Gaulard, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Mondor; Philippe Gaulard, Institut National de la Santé et de la Recherche Médicale U955; Université Paris-Est, Créteil; Julien Lazarovici, Gustave Roussy Cancer Center, Villejuif; Aurore Perrot, University Hospital, Vandoeuvre les Nancy; Catherine Sebban, Centre Leon Berard, University Claude Bernard Lyon 1; Gilles Salles, Hospices Civils de Lyon, Université Claude Bernard U1052, Lyon; Hugo Gonzalez, Centre Hospitalier René Dubos, Pontoise; Reda Bouabdallah, Institut Paoli Calmettes, Marseille; Lucie Oberic, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse; Bernadette Corront, Centre Hospitalier Régional Annecy, Annecy; Bachra Choufi, Centre Hospitalier Dr Duchenne, Boulogne-sur-mer; Gilles Salles and Bertrand Coiffier, Institut National de la Santé et de la Recherche Médicale U1052, Hospices Civils de Lyon, Pierre-Benite, France; Maria Gomes da Silva and Jose Cabeçadas, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal; Anida Grosicka, Medical University of Silesia, Katowice, Poland; Judith Trotman, Concord Repatriation General Hospital, University of Sydney, Concord; John Catalano, Frankston Hospital and Monash University, Frankston, Australia; Dolores Caballero, Hospital Universitario de Salamanca, Salamanca; Armando Lopez-Guillermo, Hospital Clinic Barcelona, Barcelona, Spain; Richard Greil, Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute; Arbeitsgemeinschaft Medikamentöse Tumortherapie, Salzburg, Austria; Koen van Eygen, Algemeen Ziekenhuis Groeninge Hospital, President Kennedylaan 4, Kortrijk; Achiel Van Hoof, Algemeen Ziekenhuis Sint Jan AV, Brugge; Andre Bosly, UCL Mont Godinne, Yvoir, Belgium; and Amos M. Cohen, Rabin Medical Center, Beilinson Hospital, Davidoff Cancer Center, Tel-Aviv University, Ramat-Aviv, Israel.;Catherine Thieblemont, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis; Diderot University, Sorbonne Paris-Cité; Catherine Thieblemont and Josette Briere, Descartes University; Josette Briere, Hôpital Necker, Paris; Hervé Tilly, University of Rouen, Institut National de la Santé et de la Recherche Médicale U1245, Rouen; Rene-Olivier Casasnovas, Centre Hospitalier Universitaire Dijon; Institut National de la Santé et de la Recherche Médicale UMR1231, Dijon; Christophe Fruchart, Institut d'Hématologie de Basse Normandie, Centre Hospitalier Universitaire, Caen; Franck Morschhauser, Centre Hospitalier Universitaire Régional de Lille, Lille; Corinne Haioun and Philippe Gaulard, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Mondor; Philippe Gaulard, Institut National de la Santé et de la Recherche Médicale U955; Université Paris-Est, Créteil; Julien Lazarovici, Gustave Roussy Cancer Center, Villejuif; Aurore Perrot, University Hospital, Vandoeuvre les Nancy; Catherine Sebban, Centre Leon Berard, University Claude Bernard Lyon 1; Gilles Salles, Hospices Civils de Lyon, Université Claude Bernard U1052, Lyon; Hugo Gonzalez, Centre Hospitalier René Dubos, Pontoise; Reda Bouabdallah, Institut Paoli Calmettes, Marseille; Lucie Oberic, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse; Bernadette Corront, Centre Hospitalier Régional Annecy, Annecy; Bachra Choufi, Centre Hospitalier Dr Duchenne, Boulogne-sur-mer; Gilles Salles and Bertrand Coiffier, Institut National de la Santé et de la Recherche Médicale U1052, Hospices Civils de Lyon, Pierre-Benite, France; Maria Gomes da Silva and Jose Cabeçadas, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal; Anida Grosicka, Medical University of Silesia, Katowice, Poland; Judith Trotman, Concord Repatriation General Hospital, University of Sydney, Concord; John Catalano, Frankston Hospital and Monash University, Frankston, Australia; Dolores Caballero, Hospital Universitario de Salamanca, Salamanca; Armando Lopez-Guillermo, Hospital Clinic Barcelona, Barcelona, Spain; Richard Greil, Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute; Arbeitsgemeinschaft Medikamentöse Tumortherapie, Salzburg, Austria; Koen van Eygen, Algemeen Ziekenhuis Groeninge Hospital, President Kennedylaan 4, Kortrijk; Achiel Van Hoof, Algemeen Ziekenhuis Sint Jan AV, Brugge; Andre Bosly, UCL Mont Godinne, Yvoir, Belgium; and Amos M. Cohen, Rabin Medical Center, Beilinson Hospital, Davidoff Cancer Center, Tel-Aviv University, Ramat-Aviv, Israel.;Catherine Thieblemont, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis; Diderot University, Sorbonne Paris-Cité; Catherine Thieblemont and Josette Briere, Descartes University; Josette Briere, Hôpital Necker, Paris; Hervé Tilly, University of Rouen, Institut National de la Santé et de la Recherche Médicale U1245, Rouen; Rene-Olivier Casasnovas, Centre Hospitalier Universitaire Dijon; Institut National de la Santé et de la Recherche Médicale UMR1231, Dijon; Christophe Fruchart, Institut d'Hématologie de Basse Normandie, Centre Hospitalier Universitaire, Caen; Franck Morschhauser, Centre Hospitalier Universitaire Régional de Lille, Lille; Corinne Haioun and Philippe Gaulard, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Mondor; Philippe Gaulard, Institut National de la Santé et de la Recherche Médicale U955; Université Paris-Est, Créteil; Julien Lazarovici, Gustave Roussy Cancer Center, Villejuif; Aurore Perrot, University Hospital, Vandoeuvre les Nancy; Catherine Sebban, Centre Leon Berard, University Claude Bernard Lyon 1; Gilles Salles, Hospices Civils de Lyon, Université Claude Bernard U1052, Lyon; Hugo Gonzalez, Centre Hospitalier René Dubos, Pontoise; Reda Bouabdallah, Institut Paoli Calmettes, Marseille; Lucie Oberic, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse; Bernadette Corront, Centre Hospitalier Régional Annecy, Annecy; Bachra Choufi, Centre Hospitalier Dr Duchenne, Boulogne-sur-mer; Gilles Salles and Bertrand Coiffier, Institut National de la Santé et de la Recherche Médicale U1052, Hospices Civils de Lyon, Pierre-Benite, France; Maria Gomes da Silva and Jose Cabeçadas, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal; Anida Grosicka, Medical University of Silesia, Katowice, Poland; Judith Trotman, Concord Repatriation General Hospital, University of Sydney, Concord; John Catalano, Frankston Hospital and Monash University, Frankston, Australia; Dolores Caballero, Hospital Universitario de Salamanca, Salamanca; Armando Lopez-Guillermo, Hospital Clinic Barcelona, Barcelona, Spain; Richard Greil, Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute; Arbeitsgemeinschaft Medikamentöse Tumortherapie, Salzburg, Austria; Koen van Eygen, Algemeen Ziekenhuis Groeninge Hospital, President Kennedylaan 4, Kortrijk; Achiel Van Hoof, Algemeen Ziekenhuis Sint Jan AV, Brugge; Andre Bosly, UCL Mont Godinne, Yvoir, Belgium; and Amos M. Cohen, Rabin Medical Center, Beilinson Hospital, Davidoff Cancer Center, Tel-Aviv University, Ramat-Aviv, Israel.;Catherine Thieblemont, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis; Diderot University, Sorbonne Paris-Cité; Catherine Thieblemont and Josette Briere, Descartes University; Josette Briere, Hôpital Necker, Paris; Hervé Tilly, University of Rouen, Institut National de la Santé et de la Recherche Médicale U1245, Rouen; Rene-Olivier Casasnovas, Centre Hospitalier Universitaire Dijon; Institut National de la Santé et de la Recherche Médicale UMR1231, Dijon; Christophe Fruchart, Institut d'Hématologie de Basse Normandie, Centre Hospitalier Universitaire, Caen; Franck Morschhauser, Centre Hospitalier Universitaire Régional de Lille, Lille; Corinne Haioun and Philippe Gaulard, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Mondor; Philippe Gaulard, Institut National de la Santé et de la Recherche Médicale U955; Université Paris-Est, Créteil; Julien Lazarovici, Gustave Roussy Cancer Center, Villejuif; Aurore Perrot, University Hospital, Vandoeuvre les Nancy; Catherine Sebban, Centre Leon Berard, University Claude Bernard Lyon 1; Gilles Salles, Hospices Civils de Lyon, Université Claude Bernard U1052, Lyon; Hugo Gonzalez, Centre Hospitalier René Dubos, Pontoise; Reda Bouabdallah, Institut Paoli Calmettes, Marseille; Lucie Oberic, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse; Bernadette Corront, Centre Hospitalier Régional Annecy, Annecy; Bachra Choufi, Centre Hospitalier Dr Duchenne, Boulogne-sur-mer; Gilles Salles and Bertrand Coiffier, Institut National de la Santé et de la Recherche Médicale U1052, Hospices Civils de Lyon, Pierre-Benite, France; Maria Gomes da Silva and Jose Cabeçadas, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal; Anida Grosicka, Medical University of Silesia, Katowice, Poland; Judith Trotman, Concord Repatriation General Hospital, University of Sydney, Concord; John Catalano, Frankston Hospital and Monash University, Frankston, Australia; Dolores Caballero, Hospital Universitario de Salamanca, Salamanca; Armando Lopez-Guillermo, Hospital Clinic Barcelona, Barcelona, Spain; Richard Greil, Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute; Arbeitsgemeinschaft Medikamentöse Tumortherapie, Salzburg, Austria; Koen van Eygen, Algemeen Ziekenhuis Groeninge Hospital, President Kennedylaan 4, Kortrijk; Achiel Van Hoof, Algemeen Ziekenhuis Sint Jan AV, Brugge; Andre Bosly, UCL Mont Godinne, Yvoir, Belgium; and Amos M. Cohen, Rabin Medical Center, Beilinson Hospital, Davidoff Cancer Center, Tel-Aviv University, Ramat-Aviv, Israel.;Catherine Thieblemont, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis; Diderot University, Sorbonne Paris-Cité; Catherine Thieblemont and Josette Briere, Descartes University; Josette Briere, Hôpital Necker, Paris; Hervé Tilly, University of Rouen, Institut National de la Santé et de la Recherche Médicale U1245, Rouen; Rene-Olivier Casasnovas, Centre Hospitalier Universitaire Dijon; Institut National de la Santé et de la Recherche Médicale UMR1231, Dijon; Christophe Fruchart, Institut d'Hématologie de Basse Normandie, Centre Hospitalier Universitaire, Caen; Franck Morschhauser, Centre Hospitalier Universitaire Régional de Lille, Lille; Corinne Haioun and Philippe Gaulard, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Mondor; Philippe Gaulard, Institut National de la Santé et de la Recherche Médicale U955; Université Paris-Est, Créteil; Julien Lazarovici, Gustave Roussy Cancer Center, Villejuif; Aurore Perrot, University Hospital, Vandoeuvre les Nancy; Catherine Sebban, Centre Leon Berard, University Claude Bernard Lyon 1; Gilles Salles, Hospices Civils de Lyon, Université Claude Bernard U1052, Lyon; Hugo Gonzalez, Centre Hospitalier René Dubos, Pontoise; Reda Bouabdallah, Institut Paoli Calmettes, Marseille; Lucie Oberic, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse; Bernadette Corront, Centre Hospitalier Régional Annecy, Annecy; Bachra Choufi, Centre Hospitalier Dr Duchenne, Boulogne-sur-mer; Gilles Salles and Bertrand Coiffier, Institut National de la Santé et de la Recherche Médicale U1052, Hospices Civils de Lyon, Pierre-Benite, France; Maria Gomes da Silva and Jose Cabeçadas, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal; Anida Grosicka, Medical University of Silesia, Katowice, Poland; Judith Trotman, Concord Repatriation General Hospital, University of Sydney, Concord; John Catalano, Frankston Hospital and Monash University, Frankston, Australia; Dolores Caballero, Hospital Universitario de Salamanca, Salamanca; Armando Lopez-Guillermo, Hospital Clinic Barcelona, Barcelona, Spain; Richard Greil, Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute; Arbeitsgemeinschaft Medikamentöse Tumortherapie, Salzburg, Austria; Koen van Eygen, Algemeen Ziekenhuis Groeninge Hospital, President Kennedylaan 4, Kortrijk; Achiel Van Hoof, Algemeen Ziekenhuis Sint Jan AV, Brugge; Andre Bosly, UCL Mont Godinne, Yvoir, Belgium; and Amos M. Cohen, Rabin Medical Center, Beilinson Hospital, Davidoff Cancer Center, Tel-Aviv University, Ramat-Aviv, Israel.;Catherine Thieblemont, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis; Diderot University, Sorbonne Paris-Cité; Catherine Thieblemont and Josette Briere, Descartes University; Josette Briere, Hôpital Necker, Paris; Hervé Tilly, University of Rouen, Institut National de la Santé et de la Recherche Médicale U1245, Rouen; Rene-Olivier Casasnovas, Centre Hospitalier Universitaire Dijon; Institut National de la Santé et de la Recherche Médicale UMR1231, Dijon; Christophe Fruchart, Institut d'Hématologie de Basse Normandie, Centre Hospitalier Universitaire, Caen; Franck Morschhauser, Centre Hospitalier Universitaire Régional de Lille, Lille; Corinne Haioun and Philippe Gaulard, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Mondor; Philippe Gaulard, Institut National de la Santé et de la Recherche Médicale U955; Université Paris-Est, Créteil; Julien Lazarovici, Gustave Roussy Cancer Center, Villejuif; Aurore Perrot, University Hospital, Vandoeuvre les Nancy; Catherine Sebban, Centre Leon Berard, University Claude Bernard Lyon 1; Gilles Salles, Hospices Civils de Lyon, Université Claude Bernard U1052, Lyon; Hugo Gonzalez, Centre Hospitalier René Dubos, Pontoise; Reda Bouabdallah, Institut Paoli Calmettes, Marseille; Lucie Oberic, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse; Bernadette Corront, Centre Hospitalier Régional Annecy, Annecy; Bachra Choufi, Centre Hospitalier Dr Duchenne, Boulogne-sur-mer; Gilles Salles and Bertrand Coiffier, Institut National de la Santé et de la Recherche Médicale U1052, Hospices Civils de Lyon, Pierre-Benite, France; Maria Gomes da Silva and Jose Cabeçadas, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal; Anida Grosicka, Medical University of Silesia, Katowice, Poland; Judith Trotman, Concord Repatriation General Hospital, University of Sydney, Concord; John Catalano, Frankston Hospital and Monash University, Frankston, Australia; Dolores Caballero, Hospital Universitario de Salamanca, Salamanca; Armando Lopez-Guillermo, Hospital Clinic Barcelona, Barcelona, Spain; Richard Greil, Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute; Arbeitsgemeinschaft Medikamentöse Tumortherapie, Salzburg, Austria; Koen van Eygen, Algemeen Ziekenhuis Groeninge Hospital, President Kennedylaan 4, Kortrijk; Achiel Van Hoof, Algemeen Ziekenhuis Sint Jan AV, Brugge; Andre Bosly, UCL Mont Godinne, Yvoir, Belgium; and Amos M. Cohen, Rabin Medical Center, Beilinson Hospital, Davidoff Cancer Center, Tel-Aviv University, Ramat-Aviv, Israel.;Catherine Thieblemont, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis; Diderot University, Sorbonne Paris-Cité; Catherine Thieblemont and Josette Briere, Descartes University; Josette Briere, Hôpital Necker, Paris; Hervé Tilly, University of Rouen, Institut National de la Santé et de la Recherche Médicale U1245, Rouen; Rene-Olivier Casasnovas, Centre Hospitalier Universitaire Dijon; Institut National de la Santé et de la Recherche Médicale UMR1231, Dijon; Christophe Fruchart, Institut d'Hématologie de Basse Normandie, Centre Hospitalier Universitaire, Caen; Franck Morschhauser, Centre Hospitalier Universitaire Régional de Lille, Lille; Corinne Haioun and Philippe Gaulard, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Mondor; Philippe Gaulard, Institut National de la Santé et de la Recherche Médicale U955; Université Paris-Est, Créteil; Julien Lazarovici, Gustave Roussy Cancer Center, Villejuif; Aurore Perrot, University Hospital, Vandoeuvre les Nancy; Catherine Sebban, Centre Leon Berard, University Claude Bernard Lyon 1; Gilles Salles, Hospices Civils de Lyon, Université Claude Bernard U1052, Lyon; Hugo Gonzalez, Centre Hospitalier René Dubos, Pontoise; Reda Bouabdallah, Institut Paoli Calmettes, Marseille; Lucie Oberic, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse; Bernadette Corront, Centre Hospitalier Régional Annecy, Annecy; Bachra Choufi, Centre Hospitalier Dr Duchenne, Boulogne-sur-mer; Gilles Salles and Bertrand Coiffier, Institut National de la Santé et de la Recherche Médicale U1052, Hospices Civils de Lyon, Pierre-Benite, France; Maria Gomes da Silva and Jose Cabeçadas, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal; Anida Grosicka, Medical University of Silesia, Katowice, Poland; Judith Trotman, Concord Repatriation General Hospital, University of Sydney, Concord; John Catalano, Frankston Hospital and Monash University, Frankston, Australia; Dolores Caballero, Hospital Universitario de Salamanca, Salamanca; Armando Lopez-Guillermo, Hospital Clinic Barcelona, Barcelona, Spain; Richard Greil, Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute; Arbeitsgemeinschaft Medikamentöse Tumortherapie, Salzburg, Austria; Koen van Eygen, Algemeen Ziekenhuis Groeninge Hospital, President Kennedylaan 4, Kortrijk; Achiel Van Hoof, Algemeen Ziekenhuis Sint Jan AV, Brugge; Andre Bosly, UCL Mont Godinne, Yvoir, Belgium; and Amos M. Cohen, Rabin Medical Center, Beilinson Hospital, Davidoff Cancer Center, Tel-Aviv University, Ramat-Aviv, Israel.;Catherine Thieblemont, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis; Diderot University, Sorbonne Paris-Cité; Catherine Thieblemont and Josette Briere, Descartes University; Josette Briere, Hôpital Necker, Paris; Hervé Tilly, University of Rouen, Institut National de la Santé et de la Recherche Médicale U1245, Rouen; Rene-Olivier Casasnovas, Centre Hospitalier Universitaire Dijon; Institut National de la Santé et de la Recherche Médicale UMR1231, Dijon; Christophe Fruchart, Institut d'Hématologie de Basse Normandie, Centre Hospitalier Universitaire, Caen; Franck Morschhauser, Centre Hospitalier Universitaire Régional de Lille, Lille; Corinne Haioun and Philippe Gaulard, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Mondor; Philippe Gaulard, Institut National de la Santé et de la Recherche Médicale U955; Université Paris-Est, Créteil; Julien Lazarovici, Gustave Roussy Cancer Center, Villejuif; Aurore Perrot, University Hospital, Vandoeuvre les Nancy; Catherine Sebban, Centre Leon Berard, University Claude Bernard Lyon 1; Gilles Salles, Hospices Civils de Lyon, Université Claude Bernard U1052, Lyon; Hugo Gonzalez, Centre Hospitalier René Dubos, Pontoise; Reda Bouabdallah, Institut Paoli Calmettes, Marseille; Lucie Oberic, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse; Bernadette Corront, Centre Hospitalier Régional Annecy, Annecy; Bachra Choufi, Centre Hospitalier Dr Duchenne, Boulogne-sur-mer; Gilles Salles and Bertrand Coiffier, Institut National de la Santé et de la Recherche Médicale U1052, Hospices Civils de Lyon, Pierre-Benite, France; Maria Gomes da Silva and Jose Cabeçadas, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal; Anida Grosicka, Medical University of Silesia, Katowice, Poland; Judith Trotman, Concord Repatriation General Hospital, University of Sydney, Concord; John Catalano, Frankston Hospital and Monash University, Frankston, Australia; Dolores Caballero, Hospital Universitario de Salamanca, Salamanca; Armando Lopez-Guillermo, Hospital Clinic Barcelona, Barcelona, Spain; Richard Greil, Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute; Arbeitsgemeinschaft Medikamentöse Tumortherapie, Salzburg, Austria; Koen van Eygen, Algemeen Ziekenhuis Groeninge Hospital, President Kennedylaan 4, Kortrijk; Achiel Van Hoof, Algemeen Ziekenhuis Sint Jan AV, Brugge; Andre Bosly, UCL Mont Godinne, Yvoir, Belgium; and Amos M. Cohen, Rabin Medical Center, Beilinson Hospital, Davidoff Cancer Center, Tel-Aviv University, Ramat-Aviv, Israel.;Catherine Thieblemont, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis; Diderot University, Sorbonne Paris-Cité; Catherine Thieblemont and Josette Briere, Descartes University; Josette Briere, Hôpital Necker, Paris; Hervé Tilly, University of Rouen, Institut National de la Santé et de la Recherche Médicale U1245, Rouen; Rene-Olivier Casasnovas, Centre Hospitalier Universitaire Dijon; Institut National de la Santé et de la Recherche Médicale UMR1231, Dijon; Christophe Fruchart, Institut d'Hématologie de Basse Normandie, Centre Hospitalier Universitaire, Caen; Franck Morschhauser, Centre Hospitalier Universitaire Régional de Lille, Lille; Corinne Haioun and Philippe Gaulard, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Mondor; Philippe Gaulard, Institut National de la Santé et de la Recherche Médicale U955; Université Paris-Est, Créteil; Julien Lazarovici, Gustave Roussy Cancer Center, Villejuif; Aurore Perrot, University Hospital, Vandoeuvre les Nancy; Catherine Sebban, Centre Leon Berard, University Claude Bernard Lyon 1; Gilles Salles, Hospices Civils de Lyon, Université Claude Bernard U1052, Lyon; Hugo Gonzalez, Centre Hospitalier René Dubos, Pontoise; Reda Bouabdallah, Institut Paoli Calmettes, Marseille; Lucie Oberic, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse; Bernadette Corront, Centre Hospitalier Régional Annecy, Annecy; Bachra Choufi, Centre Hospitalier Dr Duchenne, Boulogne-sur-mer; Gilles Salles and Bertrand Coiffier, Institut National de la Santé et de la Recherche Médicale U1052, Hospices Civils de Lyon, Pierre-Benite, France; Maria Gomes da Silva and Jose Cabeçadas, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal; Anida Grosicka, Medical University of Silesia, Katowice, Poland; Judith Trotman, Concord Repatriation General Hospital, University of Sydney, Concord; John Catalano, Frankston Hospital and Monash University, Frankston, Australia; Dolores Caballero, Hospital Universitario de Salamanca, Salamanca; Armando Lopez-Guillermo, Hospital Clinic Barcelona, Barcelona, Spain; Richard Greil, Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute; Arbeitsgemeinschaft Medikamentöse Tumortherapie, Salzburg, Austria; Koen van Eygen, Algemeen Ziekenhuis Groeninge Hospital, President Kennedylaan 4, Kortrijk; Achiel Van Hoof, Algemeen Ziekenhuis Sint Jan AV, Brugge; Andre Bosly, UCL Mont Godinne, Yvoir, Belgium; and Amos M. Cohen, Rabin Medical Center, Beilinson Hospital, Davidoff Cancer Center, Tel-Aviv University, Ramat-Aviv, Israel.;Catherine Thieblemont, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis; Diderot University, Sorbonne Paris-Cité; Catherine Thieblemont and Josette Briere, Descartes University; Josette Briere, Hôpital Necker, Paris; Hervé Tilly, University of Rouen, Institut National de la Santé et de la Recherche Médicale U1245, Rouen; Rene-Olivier Casasnovas, Centre Hospitalier Universitaire Dijon; Institut National de la Santé et de la Recherche Médicale UMR1231, Dijon; Christophe Fruchart, Institut d'Hématologie de Basse Normandie, Centre Hospitalier Universitaire, Caen; Franck Morschhauser, Centre Hospitalier Universitaire Régional de Lille, Lille; Corinne Haioun and Philippe Gaulard, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Mondor; Philippe Gaulard, Institut National de la Santé et de la Recherche Médicale U955; Université Paris-Est, Créteil; Julien Lazarovici, Gustave Roussy Cancer Center, Villejuif; Aurore Perrot, University Hospital, Vandoeuvre les Nancy; Catherine Sebban, Centre Leon Berard, University Claude Bernard Lyon 1; Gilles Salles, Hospices Civils de Lyon, Université Claude Bernard U1052, Lyon; Hugo Gonzalez, Centre Hospitalier René Dubos, Pontoise; Reda Bouabdallah, Institut Paoli Calmettes, Marseille; Lucie Oberic, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse; Bernadette Corront, Centre Hospitalier Régional Annecy, Annecy; Bachra Choufi, Centre Hospitalier Dr Duchenne, Boulogne-sur-mer; Gilles Salles and Bertrand Coiffier, Institut National de la Santé et de la Recherche Médicale U1052, Hospices Civils de Lyon, Pierre-Benite, France; Maria Gomes da Silva and Jose Cabeçadas, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal; Anida Grosicka, Medical University of Silesia, Katowice, Poland; Judith Trotman, Concord Repatriation General Hospital, University of Sydney, Concord; John Catalano, Frankston Hospital and Monash University, Frankston, Australia; Dolores Caballero, Hospital Universitario de Salamanca, Salamanca; Armando Lopez-Guillermo, Hospital Clinic Barcelona, Barcelona, Spain; Richard Greil, Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute; Arbeitsgemeinschaft Medikamentöse Tumortherapie, Salzburg, Austria; Koen van Eygen, Algemeen Ziekenhuis Groeninge Hospital, President Kennedylaan 4, Kortrijk; Achiel Van Hoof, Algemeen Ziekenhuis Sint Jan AV, Brugge; Andre Bosly, UCL Mont Godinne, Yvoir, Belgium; and Amos M. Cohen, Rabin Medical Center, Beilinson Hospital, Davidoff Cancer Center, Tel-Aviv University, Ramat-Aviv, Israel.;Catherine Thieblemont, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis; Diderot University, Sorbonne Paris-Cité; Catherine Thieblemont and Josette Briere, Descartes University; Josette Briere, Hôpital Necker, Paris; Hervé Tilly, University of Rouen, Institut National de la Santé et de la Recherche Médicale U1245, Rouen; Rene-Olivier Casasnovas, Centre Hospitalier Universitaire Dijon; Institut National de la Santé et de la Recherche Médicale UMR1231, Dijon; Christophe Fruchart, Institut d'Hématologie de Basse Normandie, Centre Hospitalier Universitaire, Caen; Franck Morschhauser, Centre Hospitalier Universitaire Régional de Lille, Lille; Corinne Haioun and Philippe Gaulard, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Mondor; Philippe Gaulard, Institut National de la Santé et de la Recherche Médicale U955; Université Paris-Est, Créteil; Julien Lazarovici, Gustave Roussy Cancer Center, Villejuif; Aurore Perrot, University Hospital, Vandoeuvre les Nancy; Catherine Sebban, Centre Leon Berard, University Claude Bernard Lyon 1; Gilles Salles, Hospices Civils de Lyon, Université Claude Bernard U1052, Lyon; Hugo Gonzalez, Centre Hospitalier René Dubos, Pontoise; Reda Bouabdallah, Institut Paoli Calmettes, Marseille; Lucie Oberic, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse; Bernadette Corront, Centre Hospitalier Régional Annecy, Annecy; Bachra Choufi, Centre Hospitalier Dr Duchenne, Boulogne-sur-mer; Gilles Salles and Bertrand Coiffier, Institut National de la Santé et de la Recherche Médicale U1052, Hospices Civils de Lyon, Pierre-Benite, France; Maria Gomes da Silva and Jose Cabeçadas, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal; Anida Grosicka, Medical University of Silesia, Katowice, Poland; Judith Trotman, Concord Repatriation General Hospital, University of Sydney, Concord; John Catalano, Frankston Hospital and Monash University, Frankston, Australia; Dolores Caballero, Hospital Universitario de Salamanca, Salamanca; Armando Lopez-Guillermo, Hospital Clinic Barcelona, Barcelona, Spain; Richard Greil, Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute; Arbeitsgemeinschaft Medikamentöse Tumortherapie, Salzburg, Austria; Koen van Eygen, Algemeen Ziekenhuis Groeninge Hospital, President Kennedylaan 4, Kortrijk; Achiel Van Hoof, Algemeen Ziekenhuis Sint Jan AV, Brugge; Andre Bosly, UCL Mont Godinne, Yvoir, Belgium; and Amos M. Cohen, Rabin Medical Center, Beilinson Hospital, Davidoff Cancer Center, Tel-Aviv University, Ramat-Aviv, Israel.;Catherine Thieblemont, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis; Diderot University, Sorbonne Paris-Cité; Catherine Thieblemont and Josette Briere, Descartes University; Josette Briere, Hôpital Necker, Paris; Hervé Tilly, University of Rouen, Institut National de la Santé et de la Recherche Médicale U1245, Rouen; Rene-Olivier Casasnovas, Centre Hospitalier Universitaire Dijon; Institut National de la Santé et de la Recherche Médicale UMR1231, Dijon; Christophe Fruchart, Institut d'Hématologie de Basse Normandie, Centre Hospitalier Universitaire, Caen; Franck Morschhauser, Centre Hospitalier Universitaire Régional de Lille, Lille; Corinne Haioun and Philippe Gaulard, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Mondor; Philippe Gaulard, Institut National de la Santé et de la Recherche Médicale U955; Université Paris-Est, Créteil; Julien Lazarovici, Gustave Roussy Cancer Center, Villejuif; Aurore Perrot, University Hospital, Vandoeuvre les Nancy; Catherine Sebban, Centre Leon Berard, University Claude Bernard Lyon 1; Gilles Salles, Hospices Civils de Lyon, Université Claude Bernard U1052, Lyon; Hugo Gonzalez, Centre Hospitalier René Dubos, Pontoise; Reda Bouabdallah, Institut Paoli Calmettes, Marseille; Lucie Oberic, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse; Bernadette Corront, Centre Hospitalier Régional Annecy, Annecy; Bachra Choufi, Centre Hospitalier Dr Duchenne, Boulogne-sur-mer; Gilles Salles and Bertrand Coiffier, Institut National de la Santé et de la Recherche Médicale U1052, Hospices Civils de Lyon, Pierre-Benite, France; Maria Gomes da Silva and Jose Cabeçadas, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal; Anida Grosicka, Medical University of Silesia, Katowice, Poland; Judith Trotman, Concord Repatriation General Hospital, University of Sydney, Concord; John Catalano, Frankston Hospital and Monash University, Frankston, Australia; Dolores Caballero, Hospital Universitario de Salamanca, Salamanca; Armando Lopez-Guillermo, Hospital Clinic Barcelona, Barcelona, Spain; Richard Greil, Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute; Arbeitsgemeinschaft Medikamentöse Tumortherapie, Salzburg, Austria; Koen van Eygen, Algemeen Ziekenhuis Groeninge Hospital, President Kennedylaan 4, Kortrijk; Achiel Van Hoof, Algemeen Ziekenhuis Sint Jan AV, Brugge; Andre Bosly, UCL Mont Godinne, Yvoir, Belgium; and Amos M. Cohen, Rabin Medical Center, Beilinson Hospital, Davidoff Cancer Center, Tel-Aviv University, Ramat-Aviv, Israel.;Catherine Thieblemont, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis; Diderot University, Sorbonne Paris-Cité; Catherine Thieblemont and Josette Briere, Descartes University; Josette Briere, Hôpital Necker, Paris; Hervé Tilly, University of Rouen, Institut National de la Santé et de la Recherche Médicale U1245, Rouen; Rene-Olivier Casasnovas, Centre Hospitalier Universitaire Dijon; Institut National de la Santé et de la Recherche Médicale UMR1231, Dijon; Christophe Fruchart, Institut d'Hématologie de Basse Normandie, Centre Hospitalier Universitaire, Caen; Franck Morschhauser, Centre Hospitalier Universitaire Régional de Lille, Lille; Corinne Haioun and Philippe Gaulard, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Mondor; Philippe Gaulard, Institut National de la Santé et de la Recherche Médicale U955; Université Paris-Est, Créteil; Julien Lazarovici, Gustave Roussy Cancer Center, Villejuif; Aurore Perrot, University Hospital, Vandoeuvre les Nancy; Catherine Sebban, Centre Leon Berard, University Claude Bernard Lyon 1; Gilles Salles, Hospices Civils de Lyon, Université Claude Bernard U1052, Lyon; Hugo Gonzalez, Centre Hospitalier René Dubos, Pontoise; Reda Bouabdallah, Institut Paoli Calmettes, Marseille; Lucie Oberic, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse; Bernadette Corront, Centre Hospitalier Régional Annecy, Annecy; Bachra Choufi, Centre Hospitalier Dr Duchenne, Boulogne-sur-mer; Gilles Salles and Bertrand Coiffier, Institut National de la Santé et de la Recherche Médicale U1052, Hospices Civils de Lyon, Pierre-Benite, France; Maria Gomes da Silva and Jose Cabeçadas, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal; Anida Grosicka, Medical University of Silesia, Katowice, Poland; Judith Trotman, Concord Repatriation General Hospital, University of Sydney, Concord; John Catalano, Frankston Hospital and Monash University, Frankston, Australia; Dolores Caballero, Hospital Universitario de Salamanca, Salamanca; Armando Lopez-Guillermo, Hospital Clinic Barcelona, Barcelona, Spain; Richard Greil, Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute; Arbeitsgemeinschaft Medikamentöse Tumortherapie, Salzburg, Austria; Koen van Eygen, Algemeen Ziekenhuis Groeninge Hospital, President Kennedylaan 4, Kortrijk; Achiel Van Hoof, Algemeen Ziekenhuis Sint Jan AV, Brugge; Andre Bosly, UCL Mont Godinne, Yvoir, Belgium; and Amos M. Cohen, Rabin Medical Center, Beilinson Hospital, Davidoff Cancer Center, Tel-Aviv University, Ramat-Aviv, Israel.",
"authors": "Thieblemont|Catherine|C|;Tilly|Hervé|H|;Gomes da Silva|Maria|M|;Casasnovas|Rene-Olivier|RO|;Fruchart|Christophe|C|;Morschhauser|Franck|F|;Haioun|Corinne|C|;Lazarovici|Julien|J|;Grosicka|Anida|A|;Perrot|Aurore|A|;Trotman|Judith|J|;Sebban|Catherine|C|;Caballero|Dolores|D|;Greil|Richard|R|;van Eygen|Koen|K|;Cohen|Amos M|AM|;Gonzalez|Hugo|H|;Bouabdallah|Reda|R|;Oberic|Lucie|L|;Corront|Bernadette|B|;Choufi|Bachra|B|;Lopez-Guillermo|Armando|A|;Catalano|John|J|;Van Hoof|Achiel|A|;Briere|Josette|J|;Cabeçadas|Jose|J|;Salles|Gilles|G|;Gaulard|Philippe|P|;Bosly|Andre|A|;Coiffier|Bertrand|B|",
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"title": "Lenalidomide Maintenance Compared With Placebo in Responding Elderly Patients With Diffuse Large B-Cell Lymphoma Treated With First-Line Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone.",
"title_normalized": "lenalidomide maintenance compared with placebo in responding elderly patients with diffuse large b cell lymphoma treated with first line rituximab plus cyclophosphamide doxorubicin vincristine and prednisone"
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"abstract": "The current report presents a case of a pregnant woman with breast cancer metastasized to liver and lungs. The standard of care for breast cancer in pregnancy is anthracycline/taxane-based chemotherapy regimens. Docetaxel has shown a favorable toxicity profile during the second and third trimesters of pregnancy. A novel nanosomal docetaxel lipid suspension (NDLS) (DoceAqualip), with a proven efficacy and tolerability profile, has been approved in India for the treatment of advanced solid tumors since 2013. We present here a case of a pregnant woman with metastatic breast cancer managed with NDLS based TAC regimen showing a partial response after six cycles. The patient delivered a healthy male child with normal Apgar score and weight at the 32nd week of gestation.",
"affiliations": "Department of Medical Oncology, Velammal Medical College and Research Institute, Madurai, Tamil Nadu 625009, India.;Department of Medical Affairs & Clinical Development, Intas Pharmaceuticals Ltd., Ahmedabad, Gujarat 380054, India.;Department of Medical Affairs & Clinical Development, Intas Pharmaceuticals Ltd., Ahmedabad, Gujarat 380054, India.;Department of Medical Oncology, Velammal Medical College and Research Institute, Madurai, Tamil Nadu 625009, India.",
"authors": "Ramaswamy|Rajkumar|R|;Joshi|Nisarg|N|;Khan|Mujtaba A|MA|;Siddhara|Seerin|S|",
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"fulltext": "\n==== Front\nOnco Targets TherOnco Targets TherOTTottOncoTargets and therapy1178-6930Dove 20657310.2147/OTT.S206573Case ReportNanosomal docetaxel lipid suspension based chemotherapy in a pregnant MBC patient – a case report Ramaswamy et alRamaswamy et alRamaswamy Rajkumar 1Joshi Nisarg 2Khan Mujtaba A 2Siddhara Seerin 11 Department of Medical Oncology, Velammal Medical College and Research Institute, Madurai, Tamil Nadu\n625009, India2 Department of Medical Affairs & Clinical Development, Intas Pharmaceuticals Ltd., Ahmedabad, Gujarat\n380054, IndiaCorrespondence: Rajkumar RamaswamyDepartment of Medical Oncology, Velammal Medical College and Research Institute, Madurai, Tamil Nadu625009, IndiaTel +91 967 772 2024Fax +91 452 251 0010/11Email drraj12319@gmail.com15 7 2019 2019 12 5679 5685 23 2 2019 15 6 2019 © 2019 Ramaswamy et al.2019Ramaswamy et al.This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Abstract\nThe current report presents a case of a pregnant woman with breast cancer metastasized to liver and lungs. The standard of care for breast cancer in pregnancy is anthracycline/taxane-based chemotherapy regimens. Docetaxel has shown a favorable toxicity profile during the second and third trimesters of pregnancy. A novel nanosomal docetaxel lipid suspension (NDLS) (DoceAqualip), with a proven efficacy and tolerability profile, has been approved in India for the treatment of advanced solid tumors since 2013. We present here a case of a pregnant woman with metastatic breast cancer managed with NDLS based TAC regimen showing a partial response after six cycles. The patient delivered a healthy male child with normal Apgar score and weight at the 32nd week of gestation.\n\nKeywords\nNDLSPABCDoceAqualippregnancybreast cancermetastatic\n==== Body\nIntroduction\nPregnancy-associated cancer ranges from ~25 to 190/100,000 pregnancies,1 and has become a leading cause of maternal death.2 Breast, cervical, lymphoma, ovarian, and melanoma cancers are the most common types reported during pregnancy.3 Breast cancer is one of the most common malignancy associated with pregnancy, arising in 1/10,000–1/3000 pregnancies.4 Breast cancer during pregnancy generally occurs in women with advanced age, with only 10% reported under 40 years of age.5,6 Pregnancy-associated breast cancer (PABC) is defined as breast cancer diagnosed during pregnancy or within one year of delivery.6,7 The average age of diagnosis of PABC is 33 years with a median gestational age of 21 weeks.6 The incidence of PABC is ~15–35/100,000 deliveries.8 During pregnancy, breast cancer is generally diagnosed after it has metastasized due to advanced maternal age and difficulty in diagnosis arising from the pregnancy-related changes in the breast.9 The average reported delay for diagnosis of breast cancer during pregnancy is 5–15 months from the onset of symptoms.10\n\nThe optimal treatment of cancer during pregnancy remains elusive because there are limited data from retrospective studies with small samples.11 The management of PABC is dependent on the trimester of pregnancy, type, and stage of the cancer. Surgery is recommended in all trimesters, chemotherapy in the second and third trimesters, and radiotherapy only in the postpartum period.6 The National Comprehensive Cancer Network (NCCN) Clinical Practice Guideline suggests chemotherapy followed by endocrine therapy and palliative radiotherapy for the management of breast cancer during the second and third trimester of pregnancy.12,13 In literature, several agents have been evaluated for the treatment of PABC including anthracyclines and taxanes.\n\nWe report here a case of a pregnant woman with breast cancer metastasized to liver and lungs. The patient was treated with nanosomal docetaxel lipid suspension (NDLS, DoceAqualip) based TAC (NDLS, doxorubicin, cyclophosphamide) regimen for six cycles.\n\nCase report\nA 44-year-old pregnant woman presented with a lump in the left breast and pedal edema. The patient was married from the past 2 years and it was a non-consanguineous marriage. She was a second gravida woman with intracytoplasmic sperm injection conception after 1 year of a previous abortion (conception by in vitro fertilization) a single live uterine pregnancy of 26 weeks (second trimester). She was a known case of hypertension and hypothyroidism, and was receiving nifedipine 10 mg OD and thyroxine 75 µg OD. Medical history showed the patient was anemic with low hemoglobin levels (10.7 gm%). Genotyping for BRCA1, BRCA2, or FANCJ was not performed. Magnetic resonance imaging (MRI) of chest and abdomen (Jun 2018) showed a large soft tissue intensity irregular mass lesion with central necrosis with restricted diffusion measuring 6.1×5.5×5.0 cm in the inner quadrant of the left breast parenchyma with adjusted lobulated prominent ducts suggestive of left breast malignant mass. Multiple enlarged lymphnodes were seen in the left axillary region. Multiple tiny randomly distributed pulmonary nodules with restricted diffusion were observed suggestive of lung metastasis. Multiple mixed hyperintense necrotic, non-necrotic lesions with restricted diffusion of varying size (1.9–8 cm) were seen in both lobes of liver with the largest measuring 8×7 cm. Staging was done as T3N2M1 – Stage IV.\n\nBiopsy from the left breast lump showed a tumor occupying 60% of the biopsy specimen. Tumor cells were arranged in a diffuse pattern; few glands and pseudo papillae with surrounding desmoplastic stroma were noted. Tumor cells showed moderate pleomorphic nuclei, coarse chromatin, and moderate cytoplasm. In addition, few benign ductules were noted. Frequent mitotic figures were reported (12/10 hpf). The impression was made as invasive carcinoma, no special type (NOS) (Figure 1).Figure 1 Biopsy of left breast: (A) Diffuse pattern (100x); (B) Pseudo papilla; (C) Occasional tubular pattern with desmoplastic stroma (400x); (D) Frequent mitosis (400x).\n\n\n\nImmunohistochemical examination showed negative estrogen receptor, weak positive progesterone receptor (10%), and negative HER2 neu status. The final diagnosis was PABC with lung and liver metastases. 2D ECHO with Color Doppler showed normal cardiac functions with an ejection fraction of 63%.\n\nThe patient was planned for palliative chemotherapy with 3-weekly NDLS based TAC (NDLS, doxorubicin, cyclophosphamide) regimen for six cycles. The first chemotherapy cycle was started in Jul 2018 with intravenous (IV) NDLS 100 mg (75 mg/m2), IV doxorubicin 80 mg, and IV cyclophosphamide 800 mg on Day 1 of the cycle along with IV ranitidine 50 mg BD, IV dexamethasone 8 mg BD, and IV ondansetron 8 mg BD. Filgrastim 300 µg was given subcutaneously on Days 2–4 of the cycle.\n\nUltrasound antenatal scan with Doppler done a day before the second chemotherapy cycle demonstrated a single live intrauterine fetus in cephalic presentation with fetal spine to the maternal right side. Active fetal movements and fetal cardiac pulsations were present with fetal heart rate measuring 132/min. Placenta was seen in fundal posterior and left lateral wall with grade II maturity. The average gestational age was 31 weeks and 5 days with normal Doppler parameters. After 3 weeks following the first chemotherapy cycle, a second cycle with NDLS based TAC regimen was administered similar to the first cycle.\n\nAt the 32nd week of gestation, the patient presented with the complaints of diminished fetal movements. There was no bleeding or prevaginal draining. Her amniotic fluid index was 7.2 cm. Medical oncologists’ opinion was sought for emergency low segment cesarean section (LSCS). She was advised 6 units of fresh frozen plasma and 6 units of platelets transfusion. She was administered 4 doses of IV dexamethasone 6 mg at 6 hourly intervals. Emergency LSCS was performed, and intraoperative findings were normal. The patient delivered an alive male child. The child’s birth weight was 1.76 kg which was normal as per the gestational age, and Apgar score was also normal. The child was kept for observation in the neonatal intensive care unit for 2 days as a precautionary measure. Tablet cabergoline 0.25 mg (two tablets) was given to the patient to suppress breast milk secretion. Her Hb level was 7.7 g%, and platelets were 182,000/mm3; 2 units of packed cell volume was administered, and the patient was asked to check and inform in case of any bleeding. The patient was advised to take plenty of oral fluids, salt-restricted diet, postnatal exercises, to avoid lifting heavy weight, and use of temporary contraception.\n\nHer 3rd, 4th, and 5th chemotherapy cycles with NDLS based TAC regimen were given similar to previous cycles in Aug, Sep, and Oct 2018, respectively. The sixth chemotherapy cycle was given in Nov 2018 similar to the previous cycles except inj. filgrastim 300 µg OD for 3 days was replaced with inj. pegfilgrastim 6 mg OD on Day 2 of the cycle.\n\nAfter completion of six chemotherapy cycles, MRI done in Nov 2018 showed a small focus of restricted diffusion measuring 8×7 mm noted in the inner quadrant of the left breast. There were no significantly enlarged mediastinal or axillary lymphnodes. Lung parenchyma showed normal densities with no evidence of alveolar densities, intrinsic thickening, fibrosis, or emphysematous changes – suggestive of no lung metastasis. Trachea and main bronchi were within normal limits. A few heterogeneous lesions with restricted diffusion were noted in the liver measuring 2.5×2 cm in segment VIII, suggestive of residual liver metastasis. A cystic lesion measuring 1.2×1.5 cm was noted in segment VIII of the liver. Overall, in comparison to the baseline MRI (Jun 2018; Figure 2) as per RECIST 1.1 criteria a “partial response” was reported with the NDLS based TAC chemotherapy regimen (Figure 3). Table 1 highlights pre- and post-NDLS based chemotherapy MRI findings. The patient is currently stable and receiving hormonal therapy with tamoxifen 20 mg PO. Consent was obtained from the patient for publication of this case report.\nTable 1 Pre- and post-NDLS based chemotherapy MRI findings\n\nPre-treatment evaluation\tPost-treatment evaluation\t\nMalignant mass (6.1×5.5×5.0 cm) in the inner quadrant of left breast parenchyma\n\nMultiple enlarged lymphnodes in the left axillary region\n\nMultiple mixed hyperintense necrotic, non-necrotic lesions in liver\n\nPulmonary nodules with restricted diffusion in lung suggestive of lung metastasis\n\n\tSmall focus of restricted diffusion in the left breast inner quadrant\n\nHeterogeneous lesions with restricted diffusion in segment VIII of liver – suggestive of residual liver metastasis\n\nLung parenchyma shows normal densities with no evidence of alveolar densities, intrinsic thickening, fibrosis, or emphysematous changes – suggestive of no lung metastasis\n\n\t\nAbbrevition: NDLS, nanosomal docetaxel lipid suspension.\n\n\nFigure 2 Baseline MRI: (A) Malignant mass in the inner quadrant of left breast; (B) Multiple mixed hyperintense necrotic, non-necrotic lesions in liver; (C) Pulmonary nodules with restricted diffusion in lung.Figure 3 Post treatment MRI: (A) Small focus of restricted diffusion in the left breast inner quadrant; (B) Heterogeneous lesions with restricted diffusion in segment VIII of liver suggestive of residual liver metastasis; (C) Lung parenchyma showed normal densities with no evidence of alveolar densities, intrinsic thickening, fibrosis or emphysematous changes – suggestive of no lung metastasis.\n\n\n\n\n\nDiscussion\nPregnancy can delay breast cancer diagnosis, evaluation, and treatment.7 PABC is not so common and requires thorough workup of breast symptoms to diagnose at early stages so that the treatment can be started as soon as the diagnosis is made.7 The risk of axillary lymph node metastasis is increased by ~0.9% to 1.8% in case of delayed diagnosis by one month.14 The incidence of PABC is lower (0.7% in India) in developing countries as the age of the mother at delivery is younger.15 Pregnancy should not be considered as an obstacle for cancer treatment and majority of PABC woman are candidates for chemotherapy.16 A multidisciplinary approach is required in the diagnosis and treatment of PABC in order to treat the cancer and at the same time to protect the fetus.17\n\nWe report here a case of a pregnant woman with advanced stage (Stage IV) breast cancer metastasized to liver and lungs who was successfully managed with NDLS based TAC regimen.\n\nThe gold standard for diagnosis of PABC remains the histopathological diagnosis based on core biopsy.17 This patient underwent MRI and core biopsy to confirm the diagnosis as invasive carcinoma of left breast – NOS. Breast cancer is usually diagnosed with metastasis in pregnant women with advanced age,9 and similar was the case with this 44-year-old patient in whom the cancer had spread to the lungs and liver. Estrogen and progesterone receptors are frequently negative in PABC,18 as evidenced in this patient who was estrogen receptor negative and weak progesterone positive.\n\nPABC is associated with an increased risk of preterm delivery but it does not increase the risk of growth restriction, stillbirths, or congenital malformations.19 Similarly, this patient also delivered a healthy child at 32nd week, whose birth weight was normal as per the gestational age and had normal psychomotor development.\n\nAnemia is common in pregnant women and in India ~50% of the pregnant women in are anemic as per National Family Health Survey-4.20 Few studies have correlated the biallelic mutation in BRCA1/BRCA2 with Fanconi’s anemia.21 Bona fide Fanconi anemia proteins, BRCA2 (FANCD1), PALB2 (FANCN), and BRIP1 (FANCJ) genes along with BRCA1 have a role in DNA interstrand crosslink (ICL) repair, and deficiency in BRCA-dependent ICL repair is associated with breast cancer susceptibility.22 However, genotyping was not performed in our patient.\n\nThe management of breast cancer during pregnancy includes surgery during all three trimesters and chemotherapy in the second and third trimesters without increasing the risk of fetal malformations.17 However, lower birth weight has been reported in infants exposed to chemotherapy in utero. According to the NCCN guidelines, surgery should not be considered for advanced stage (Stage IV) patients, and the treatment should involve chemotherapy. Several chemotherapeutic agents belonging to pregnancy category D including 5-fluorouracil, doxorubicin, epirubicin, cyclophosphamide, docetaxel, paclitaxel, and trastuzumab have been evaluated for the treatment of breast cancer in pregnancy.16 During pregnancy, systemic therapy with taxanes and platinum agents can be safely used after careful risk/benefit assessment for mother and child.23\n\nThe standard of care for PABC is anthracycline/taxane-based chemotherapy regimens.23,24 As per the published data, doxorubicin in combination with cyclophosphamide and 5-fluorouracil after the first trimester of pregnancy was not associated with antepartum complications,25 and the anthracycline‐based chemotherapy can be used with minimal risk to the fetus in the second and third trimesters.26 Similarly, taxanes such as docetaxel and paclitaxel when used after the first trimester of gestation showed no increase in the occurrence of fetal malformations and maternal complications.16,27 A systematic review of 16 studies (50 pregnancies) demonstrated that exposure to docetaxel or paclitaxel was well-tolerated during pregnancy with manageable toxicities and can be considered as an optimal treatment option for patients with PABC.28\n\nPreclinical evidence shows low levels of docetaxel/paclitaxel presence in the fetal tissue.29 Mir et al, in a systematic review mention that an increase (50–100%) in the activity of cytochrome P-450 (CYP) 3A4 during the third trimester of pregnancy may increase the metabolism of docetaxel, a substrate of CYP-450 3A4, that may result in a shorter half-life and a higher clearance.30,31 Thus, the favorable toxicity profile of taxanes during the second and third trimesters of pregnancy makes it a potential choice toward management of cancers in such cases.\n\nDocetaxel has demonstrated efficacy and tolerability for the treatment of breast cancer as a part of the TAC regimen in several studies in neoadjuvant, adjuvant, and metastatic settings.32–36 Furthermore, docetaxel has been successfully evaluated for the treatment of PABC. Santis and colleagues published the first case report on the use of docetaxel in PABC in a 34-year-old woman with 15 weeks of gestation and skeletal metastasis. The patient was successfully treated with docetaxel monotherapy for three cycles and the patient delivered a female infant during the 32nd week of pregnancy with normal birth weight and Apgar score without any abnormalities.37 Potluri et al,27 reported that adjuvant treatment with docetaxel (four cycles) after doxorubicin and cyclophosphamide-based neoadjuvant treatment (four cycles) resulted in a delivery of a normal child at the 34th week of gestation.27 Neoadjuvant therapy with doxorubicin/docetaxel at 14 weeks of gestation did not show any fetal malformations after completion of six cycles and resulted in delivery of a normal child at the 35th week of gestation. Potluri et al, concluded that pregnant patients with cancer can be treated with chemotherapy including taxanes during the second and third trimesters without significant risks to the fetus.27 Several other reports have established the use of docetaxel alone or in combination with other chemotherapeutic agents for the treatment of PABC.38\n\nConventional docetaxel formulation uses polysorbate-80 and ethanol as excipients, which may cause acute hypersensitivity reactions necessitating corticosteroid use as a premedication.39 Published evidence suggests that solvent-free nanoparticle drug formulations may alter the pharmacokinetic and pharmacodynamics properties of docetaxel resulting in improved efficacy and decreased incidence of adverse effects associated with wide and nonspecific body distribution (eg, neurotoxicity, musculo-skeletal toxicity, neutropenia).40 A novel NDLS formulation of docetaxel was developed based on “Aqualip” technology (patented [WO2008127358] in Europe, Japan, and Canada) with lipids Generally Regarded As Safe (GRAS) by the US Food and Drug Administration. NDLS is devoid of polysorbate-80 and ethanol, thus, not expected to cause adverse effects such as acute hypersensitivity reaction and cumulative fluid retention.40–45 NDLS has shown efficacy and safety in the treatment of breast cancer without corticosteroid premedication.46 NDLS is also effective and safe for gastric, ovarian, cervical, penile, hormone refractory prostate, and non-small cell lung cancers.39,47–50 NDLS has been approved by the Drug Controller General of India. In this patient, NDLS was preferred over conventional docetaxel as it does not contain polysorbate-80 as a carrier, which can potentially trigger acute hypersensitivity reactions and cumulative fluid retention.41–43\n\nThis report presents the evidence for efficacy and safety of NDLS in the treatment of breast cancer with liver and lung metastasis in a pregnant woman. NDLS, when used in combination with cyclophosphamide and doxorubicin, was effective in controlling the symptoms and have reduced the disease burden in this patient. The patient delivered a healthy child with normal body weight and Apgar score without any malformations, consistent with published literature of conventional docetaxel.37 Overall, the patient was clinically asymptomatic with NDLS based chemotherapy and showed a partial response as per RECIST 1.1. Furthermore, the patient completed six cycles of TAC and is on treatment with tamoxifen. On follow-up, both the mother and infant were doing well. The patient tolerated NDLS treatment well without any clinically significant adverse events.\n\nConclusion\nThe current report highlights that NDLS with cyclophosphamide and doxorubicin as first-line therapy was effective in a pregnant woman with MBC. The treatment demonstrated a partial response with complete resolution of lung metastasis. The treatment was well-tolerated. Due to its favorable tolerability profile, NDLS can potentially be used in pregnant women.\n\nAcknowledgments\nThe development of this case report was supported by Intas Pharmaceuticals Ltd. We would like to thank Mr. Shreekant Sharma (Lambda Therapeutic Research) for his support in developing the concept/medical writing, and follow-up with the journal/publisher, Dr. Venugopal Madhusudhana (Lambda Therapeutic Research) for additional editorial assistance, and Mr. Vinju Eswaran Hariharan (Intas Pharmaceuticals Ltd) for assisting in data collection.\n\nEthics approval and consent to participate\nThe patient provided written informed consent for the publication of this report and the accompanying images. Institutional approval was not required to publish this manuscript.\n\nAuthor contributions\nRR, NJ, MK, SS contributed to the concept and design, acquisition, analysis, and interpretation of data. RR and SS provided medical care for the patients and collected the data. All authors contributed to data analysis, drafting, or revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.\n\nDisclosure\nDrs. Nisarg Joshi and Mujtaba A Khan are employees of Intas Pharmaceuticals Ltd. The authors report no other conflicts of interest in this work.\n==== Refs\nReferences\n1. Froehlich \nK , Stensheim \nH , Markert \nUR , Turowski \nG . Breast carcinoma in pregnancy with spheroid-like placental metastases – a case report . APMIS . 2018 ;5 :448 –452 . doi:10.1111/apm.2018.126.issue-5 \n2. Sekine \nM , Kobayashi \nY , Tabata \nT , et al. Malignancy during pregnancy in Japan: an exceptional opportunity for early diagnosis . BMC Pregnancy Childbirth . 2018 ;1 :50 . doi:10.1186/s12884-018-1678-4 \n3. Pavlidis \nNA . Coexistence of pregnancy and malignancy . Oncologist . 2002 ;4 :279 –287 .\n4. Balaya \nV , Bonsang-Kitzis \nH , Ngo \nC , et al. 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New Delhi (India): National Institute of Health and Family Welfare ; 2019 \nAvailable from : https://www.nhp.gov.in/disease/gynaecology-and-obstetrics/anaemia-during-pregnancy-maternal-anemia.\n21. Howlett \nNG , Taniguchi \nT , Olson \nS , et al. Biallelic inactivation of BRCA2 in Fanconi anemia . Science . 2002 ;5581 :606 –609 . doi:10.1126/science.1073834 \n22. Sawyer \nSL , Tian \nL , Kahkonen \nM , et al. Biallelic mutations in BRCA1 cause a new Fanconi anemia subtype . Cancer Discov . 2015 ;2 :135 –142 . doi:10.1158/2159-8290.CD-14-1156 \n23. Loibl \nS , Schmidt \nA , Gentilini \nO , et al. Breast cancer diagnosed during pregnancy: adapting recent advances in breast cancer care for pregnant patients . JAMA Oncol . 2015 ;8 :1145 –1153 . doi:10.1001/jamaoncol.2015.2413 \n24. Peccatori \nFA , Lambertini \nM , Scarfone \nG , et al. Biology, staging, and treatment of breast cancer during pregnancy: reassessing the evidences . Cancer Biol Med . 2018 ;1 :6 –13 .\n25. Berry \nDL , Theriault \nRL , Holmes \nFA , et al. Management of breast cancer during pregnancy using a standardized protocol . J Clin Oncol . 1999 ;3 :855 –861 . doi:10.1200/JCO.1999.17.3.855 \n26. Loibl \nS , von Minckwitz \nG , Gwyn \nK , et al. Breast carcinoma during pregnancy . Cancer . 2006 ;2 :237 –246 . doi:10.1002/cncr.21610 \n27. Potluri \nV , Lewis \nD , Burton \nGV . Chemotherapy with taxanes in breast cancer during pregnancy: case report and review of the literature . Clin Breast Cancer . 2006 ;2 :167 –170 . doi:10.3816/CBC.2006.n.029 \n28. Zagouri \nF , Sergentanis \nTN , Chrysikos \nD , et al. Taxanes for breast cancer during pregnancy: a systematic review . Clin Breast Cancer . 2013 ;1 :16 –23 . doi:10.1016/j.clbc.2012.09.014 \n29. Calsteren \nKV , Verbesselt \nR , Devlieger \nR , et al. Transplacental transfer of paclitaxel, docetaxel, carboplatin, and trastuzumab in a baboon model . Int J Gynecol Cancer . 2010 ;9 :1456 –1464 .\n30. Anderson \nGD . Pregnancy-induced changes in pharmacokinetics: a mechanistic-based approach . Clin Pharmacokinet . 2005 ;10 :989 –1008 . doi:10.2165/00003088-200544100-00001 \n31. Mir \nO , Goldwasser \nF , Treluyer \nJ-M , et al. Taxanes for breast cancer during pregnancy: a systematic review . Ann Oncol . 2009 ;2 :425 –426 .\n32. O’Regan \nRM , Von Roenn \nJH , Carlson \nRW , et al. Final results of a phase II trial of preoperative TAC (docetaxel/doxorubicin/cyclophosphamide) in stage III breast cancer . Clin Breast Cancer . 2005 ;2 :163 –168 . doi:10.3816/CBC.2005.n.019 \n33. Martin \nM . Docetaxel, doxorubicin and cyclophosphamide (the TAC regimen): an effective adjuvant treatment for operable breast cancer . Womens Health (Lond) . 2006 ;4 :527 –537 . doi:10.2217/17455057.2.4.527 \n34. Eiermann \nW , Pienkowski \nT , Crown \nJ , et al. Phase III study of doxorubicin/cyclophosphamide with concomitant versus sequential docetaxel as adjuvant treatment in patients with human epidermal growth factor receptor 2-normal, node-positive breast cancer: BCIRG-005 trial . J Clin Oncol . 2011 ;29 :3877 –3884 . doi:10.1200/JCO.2010.28.5437 21911726 \n35. Mackey \nJR , Martin \nM , Pienkowski \nT , et al. Adjuvant docetaxel, doxorubicin, and cyclophosphamide in node-positive breast cancer: 10-year follow-up of the phase 3 randomised BCIRG 001 trial . Lancet Oncol . 2013 ;1 :72 –80 . doi:10.1016/S1470-2045(12)70525-9 \n36. Martin \nM , Lluch \nA , Seguí \nMÁ , et al. Toxicity and health-related quality of life (HRQoL) in node-negative breast cancer (BC) patients (pts) receiving adjuvant treatment with TAC (docetaxel, doxorubicin, cyclophosphamide) or FAC (5-fluorouracil, doxorubicin, cyclophosphamide): impact of adding prophylactic growth factors (GF) to TAC. GEICAM study 9805 . J ClinOncol . 2005 ;16_suppl :604 .\n37. De Santis \nM , Lucchese \nA , De Carolis \nS , Ferrazzani \nS , Caruso \nA . Metastatic breast cancer in pregnancy: first case of chemotherapy with docetaxel . Eur J Cancer Care (Engl) . 2000 ;4 :235 –237 . doi:10.1046/j.1365-2354.2000.00231.x \n38. Nakagomi \nH , Miyauchi \nY , Okuda \nJ , et al. [A patient with recurrent breast cancer whose liver metastasis regressed following combined use of weekly docetaxel and MPA.5ʹ-DFUR] . Gan To Kagaku Ryoho . 2001 ;10 :1431 –1435 .\n39. Naik \nR , Khan \nMA . Doceaqualip in a patient with prostate cancer who had an allergic reaction to conventional docetaxel: a case report . Mol ClinOncol . 2017 ;3 :341 –343 . doi:10.3892/mco.2017.1147 \n40. Engels \nFK , Mathot \nRA , Verweij \nJ . Alternative drug formulations of docetaxel: a review . Anticancer Drugs . 2007 ;2 :95 –103 . doi:10.1097/CAD.0b013e3280113338 \n41. Weiszhar \nZ , Czucz \nJ , Revesz \nC , et al. Complement activation by polyethoxylated pharmaceutical surfactants: Cremophor-EL, Tween-80 and Tween-20 . Eur J Pharm Sci . 2012 ;4 :492 –498 . doi:10.1016/j.ejps.2011.09.016 \n42. Fumoleau \nP , Tubiana-Hulin \nM , Soulie \nP , et al. A dose finding and pharmacokinetic (PK) phase I study of a new formulation of docetaxel (D) in advanced solid tumors. [abstract] . Ann Oncol . 1998 ;Suppl. 2 :101 .\n43. Ten Tije \nAJ , Verweij \nJ , Loos \nWJ , Sparreboom \nA . Pharmacological effects of formulation vehicles: implications for cancer chemotherapy . Clin Pharmacokinet . 2003 ;7 :665 –685 . doi:10.2165/00003088-200342070-00005 \n44. Mei \nL , Zhang \nY , Zheng \nY , et al. A novel docetaxel-loaded poly (epsilon-caprolactone)/pluronic F68 nanoparticle overcoming multidrug resistance for breast cancer treatment . Nanoscale Res Lett . 2009 ;12 :1530 –1539 . doi:10.1007/s11671-009-9431-6 \n45. Zheng \nD , Li \nD , Lu \nX , et al. Enhanced antitumor efficiency of docetaxel-loaded nanoparticles in a human ovarian xenograft model with lower systemic toxicities by intratumoral delivery . Oncol Rep . 2010 ;3 :717 –724 .\n46. Ahmad \nA , Sheikh \nS , Taran \nR , et al. Therapeutic efficacy of a novel nanosomal docetaxel lipid suspension compared with taxotere in locally advanced or metastatic breast cancer patients . Clin Breast Cancer . 2014 ;3 :177 –181 . doi:10.1016/j.clbc.2013.09.011 \n47. Ashraf \nM , Sajjad \nR , Khan \nM , et al. 156P Efficacy and safety of a novel nanosomal docetaxel lipid suspension (NDLS) as an anti cancer agent – a retrospective study . Ann Oncol . 2016 ;suppl_9 :ix46 –ix51 .\n48. Prasanna \nR , Bunger \nD , Khan \nMA . Efficacy and safety of DoceAqualip in a patient with locally advanced cervical cancer: a case report . Mol Clin Oncol . 2018 ;2 :296 –299 .\n49. Vyas \nV , Joshi \nN , Khan \nM . Novel Docetaxel Formulation (NDLS) in low cardiac reserve ovarian cancer . Open Access J Cancer Oncol . 2018 ;2 :000122 .\n50. Gupta \nS , Pawar \nSS , Bunger \nD . Successful downstaging of locally recurrent penile squamous cell carcinoma with neoadjuvant nanosomal docetaxel lipid suspension (NDLS) based regimen followed by curative surgery . BMJ Case Rep . 2017 ;bcr2017220686 . doi:10.1136/bcr-2017-220686\n\n",
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"issue": "12()",
"journal": "OncoTargets and therapy",
"keywords": "DoceAqualip; NDLS; PABC; breast cancer; metastatic; pregnancy",
"medline_ta": "Onco Targets Ther",
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"pages": "5679-5685",
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"pmid": "31406465",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
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"title": "Nanosomal docetaxel lipid suspension based chemotherapy in a pregnant MBC patient - a case report.",
"title_normalized": "nanosomal docetaxel lipid suspension based chemotherapy in a pregnant mbc patient a case report"
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"abstract": "The present study aimed to analyze the imaging, clinical and pathological features of fungal infection involvement in primary biliary cirrhosis (PBC) by retrospectively analyzing and reviewing the features of two patients with fungal infection involvement in PBC. Both patients were female. One patient had a confirmed diagnosis of PBC. The other patient had confirmed Sjogren syndrome and PBC. The two cases of PBC were infected with fungal infection after treatment with hormonal and immunosuppressive agents. RCR of sputum confirmed Pneumocystis spp. infection in the patient with PBC alone. The mucormycosis infection was confirmed in the other patient after pathological examination of a renal biopsy. The state of the illnesses progressed quickly and both patients ultimately succumbed to their conditions. The patient prognosis of fungal infection involvement PBC is poor. Patients treated with long-term hormone and immunosuppressive agents should be monitored.",
"affiliations": "Department of Rheumatology, Chinese PLA General Hospital, Beijing 100853, P.R. China.;Department of Rheumatology, Chinese PLA General Hospital, Beijing 100853, P.R. China.;Department of Nephrology, First Hospital Affiliated to General Hospital of PLA, Beijing 100048, P.R. China.;Department of Rheumatology, Chinese PLA General Hospital, Beijing 100853, P.R. China; Department of Rheumatology, Chinese PLA General Hospital, Beijing 100853, P.R. China.;Department of Rheumatology, Chinese PLA General Hospital, Beijing 100853, P.R. China.",
"authors": "Wang|Yanyan|Y|;Zhao|Zheng|Z|;Lu|Hui|H|;Zhang|Jianglin|J|;Huang|Feng|F|",
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"doi": "10.3892/etm.2016.3977",
"fulltext": "\n==== Front\nExp Ther MedExp Ther MedETMExperimental and Therapeutic Medicine1792-09811792-1015D.A. Spandidos 10.3892/etm.2016.3977ETM-0-0-3977ArticlesFungal infection involvement in primary biliary cirrhosis: A review of 2 cases Wang Yanyan 1*Zhao Zheng 1*Lu Hui 2Zhang Jianglin 13Huang Feng 11 Department of Rheumatology, Chinese PLA General Hospital, Beijing 100853, P.R. China2 Department of Nephrology, First Hospital Affiliated to General Hospital of PLA, Beijing 100048, P.R. China3 Department of Rheumatology, Chinese PLA General Hospital, Beijing 100853, P.R. ChinaCorrespondence to: Dr Jianglin Zhang, Department of Rheumatology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853, P.R. China, E-mail: jianglinzhangcn@163.com* Contributed equally\n\n2 2017 16 12 2016 16 12 2016 13 2 489 494 03 10 2014 07 11 2016 Copyright: © Wang et al.2017This is an open access article distributed 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.The present study aimed to analyze the imaging, clinical and pathological features of fungal infection involvement in primary biliary cirrhosis (PBC) by retrospectively analyzing and reviewing the features of two patients with fungal infection involvement in PBC. Both patients were female. One patient had a confirmed diagnosis of PBC. The other patient had confirmed Sjogren syndrome and PBC. The two cases of PBC were infected with fungal infection after treatment with hormonal and immunosuppressive agents. RCR of sputum confirmed Pneumocystis spp. infection in the patient with PBC alone. The mucormycosis infection was confirmed in the other patient after pathological examination of a renal biopsy. The state of the illnesses progressed quickly and both patients ultimately succumbed to their conditions. The patient prognosis of fungal infection involvement PBC is poor. Patients treated with long-term hormone and immunosuppressive agents should be monitored.\n\nprimary biliary cirrhosispneumocystis carinii pneumoniamucormycosis\n==== Body\nIntroduction\nFungal infection has rarely been reported in patients with primary biliary cirrhosis (PBC); however it may occur following live transplant (LT) in patients with PBC, predisposing factors for the development of fungal infection following LT include diabetes mellitus, cholestasis, hypertransfusion, acute rejection, treatment with high-dose of steroids and immunosuppressive agents, renal failure and bacterial infection (1). The present study aimed to analyze the imaging, clinical and pathological features of fungal infection involvement in PBC by retrospectively analyzing and reviewing the features of two patients with fungal infection involvement in PBC who were admitted to our department.\n\nCase report\n\nCase 1\nThe present study was approved by the Ethics Committee of the Chinese PLA General Hospital and written informed consent was obtained from all patients. A 20-year-old female presented with the following: Liver dysfunction lasting >2 years; xanthochromia lasting three months; and edema of the lower limb lasting one week, and was hospitalized in 2008. Liver dysdunction was confirmed in the patient following a physical examination in 2005; however, the patient refused standard treatment. In 2007, facial and yellow sclera and dark urine gradually developed. Following the administration of compound glycyrrhizin tablets (50 mg, 3/d; Minophagen Pharmaceutical Co., Ltd., Tokyo, Japan) and ademrtionine (500 mg, 3/d; Hospira UK Ltd., Hurley, UK), the patient suffered from a fever for five days; however, after terminating ingestion of the drugs, the fever was relieved. Abdominal distension, loss of appetite, dysfunction of liver, pancytopenia and ascites followed. A local hospital diagnosed the patient with sicca syndrome, cirrhosis and hypersplenism, and she was prescribed intravenous methylprednisolone (40 mg; 8 d; Pfizer Manufacturing Belgium, Puurs, Belgium), followed by implosive therapy of intravenous methylprednisolone (1 g; 1 d). The dosage of intravenous methylprednisolone was maintained at 40 mg/d, and the patient was treated with ursodeoxycholic acid (500 mg, 3/d; Losan Pharma GmbH, Neuenburg am Rhein, Germany) and glutathione (0.6 g; 3/d, Pharmainvest SPA, Boumedian, Algeria). The liver function of the patient was not greatly improved, and she presented with the following: petechia on both upper limbs; congestive rash on the palms; malaise; progressive decline of blood corpuscle; and edema below the lower limbs. Following progressive aggravation of her symptoms, the patient was admitted to our hospital.\n\nPhysical examination demonstrated the following: Moon face; symmetry congestive erythema on the face and hands; petechia and ecchymosis on the upper limbs (predominantly) and the nape of the neck; no jaundice of the skin; the superficial lymph node was not large and the lungs were normal; and hepatosplenomegaly, shifting dullness was negative.\n\nLaboratory tests results were conducted and the results were as follows (normal reference range): Routine blood tests: white blood cell count (WBC), 0.59 (3.5–10)x109/l; red blood cell count (RBC), 3.12 (3.5–5.5)x1012/l; hemoglobin (Hb), 94 (110–176) g/l; and platelet count (PLT), 42×109/l. Routine urine tests: WBC, 2–3/HP; and urine protein (−). Routine stool tests: Helicobacter pylori, weakly positive; erythrocyte sedimentation rate (ESR), 11 mm/h; immunoglobin G (IgG), 1730 (700–1600) mg/dl; IgA 35.7 (70–400) mg/dl, C3, 43.2 (90–180) mg/dl; C4, 7.63 (10–40) mg/dl; and C-reactive protein (CRP), <0.308 (0–0.8) mg/dl. Autoantibody tests: Anti-nuclear antibody (ANA) (1:1,000 particles), positive, anti-SSA antibody, positive; anti-SSB antibody, positive; and anti-mitochondrial antibody (AMA), positive. Blood biochemistry tests: Albumin (Alb), 27.1 (35–50) g/l; total bilirubin (TBIL), 66.8 (0–21) µmol/l; direct bilirubin (DBIL), 48.9 (0–8.6)/mol/l; alanine aminotransferase (ALT), 296.7 (0–40) U/l; aspartate aminotransferase (AST), 109.5 (0–40) U/l; alkaline phosphatase (ALP), 244.9 (0–130) U/l; gamma glutamyl transferase (GGT), 213.1 (0–50) U/l; lactate dehydrogenase, 346.6 (0–200) U/l; glucose (GLU) 9.07 mmol/l; blood urea nitrogen (BUN), 7.35 (1.8–7.5) mmol/l; creatinine (Cr), 76 (30–110) µmol/l; cancer antigen (CA) 125, 421.3 U/ml; CA19-9, 455.7 U/ml; and blood ammonia, 92.1 µmol/l. Purified protein derivative (PPD) test demonstrated and tuberculosis antibody were negative (1). Abdominal ultrasound demonstrated liver cirrhosis, splenomegaly and a small amount of ascites. Magnetic resonance (MR) imaging of the abdomen also indicated liver cirrhosis, splenomegaly, a small amount of ascites (Fig. 1).\n\nFollowing admission to our hospital, the patient suffered from a cough producing white sputum. Lung CT tests showed that the upper lung was shadowed, and the possibility of tuberculosis was not excluded. Moxifloxacin hydrochloride (0.4 g; 1/d; Bayer AG, Leverkusen, Germany), streptomycin (0.75 g; im; 1/d; Merro Pharmaceutical Co., Ltd., Dalian, China) and ethambutol (0.75 g; 1/d; China Resources Double-Crane Pharmaceutical Co., Ltd., Beijing, China) were administered; however, the symptoms did not improve. The patient subsequently presented with wheezing, shortness of breath and difficult breathing. Blood gas analysis suggested hypoxemia and respiratory alkalosis. Lung CT scans indicated high-density imaging of the full lung (Fig. 2). Serum β-glucan test was positive and polymerase chain reaction analysis of the sputum detected inclusion bodies of Pneumocystis spp. The patient was treated with caspofungin acetate (70 mg; i.v.; 1/d; MSD; Merck Millipore, Darmstadt, Germany); two slices of cotrimoxazole (3/d; Southwest Synthetic Pharmaceutical Co., Ltd., Chongqing, China) and bedside hemofiltration. The patient's condition became progressively aggravated and a chest radiograph showed pneumonia of both upper lungs (Fig. 3). Even with anti-infective treatment, the patient eventually succumbed to the severity of her condition. The final diagnosis was PBC and pneumonia caused by Pneumocystis carinii, which led to respiratory and circulatory failure.\n\nCase 2\nA 49-year-old female presented with intermittent fever and abdominal distension for more than a year. The patient was admitted to our hospital in 2006. The patient suffered from an intermittent fever without any known cause or regularity a year prior to admission (body temperature, 38°C). Fever was accompanied by fatigue, anorexia, cough, yellow sputum, night sweats and abdominal distension. ANA was positive, anti-dsDNA was confirmed as weakly positive and liver transaminase levels were mildly elevated. The patient was diagnosed with autoimmune hepatitis and was treated using compound glycyrrhizin tablets (50 mg; 3/d) and alprostadil (20 mg; i.v.; 1/d; Beijing TIDE Pharmaceutical Co., Ltd., Beijing, China), the patient was administered hepatic treatment. The patient's condition did not improve, rather it gradually worsened as her temperature reached up to 40°C, peaking in the afternoon. Anti-smooth muscle antibody and AMA were positive. Taking the autoimmune cirrhosis and pulmonary infection into consideration, hepatic and anti-inflammatory symptomatic treatment consisting of ursodeoxycholic acid and cefuroxime axetil tablets (0.5 g, 2/d; GlaxoSmithKline, Brentford, UK) was administered, and the symptoms of cough and expectoration eased but were accompanied by an intermittent fever. One week prior to hospital admission, hypogastrium pain (persistent dull pain) appeared with no nausea, vomiting, diarrhea or other symptoms. During the course of the disease, symptoms of thirst and joint pain were noted; however no obvious limitations in ingesting dry food were detected. The patient did not suffer from dry eyes, muscle pain, muscle weakness, facial butterfly spots or photophobia. The patient suffered from tuberculosis for 12 years, which was subsequently been cured.\n\nPhysical examination revealed scattered spider angioma on the anterior part of the neck and the left palm and mild pitting edema of the lower limbs. No other abnormalities were found. Laboratory test results were as follows: ANA autoantibodies (1:1,000 homogeneous particles), positive; anti-dsDNA, positive; anti-SSA antibody, negative; anti-SSB antibody, negative; IgA, 853 (70–400) mg/dl; IgG, 2820 (700–1600) mg/dl; IgM, 924 (40–230) mg/dl; IgE, 1400 (0–100) IU/ml; C3, 79.3 mg/dl; C4, 17.6 mg/dl; and RF, 5410 (0–20) IU/ml. Routine blood tests: Hb, 107 g/l; RBC, 3.46×1012/l; WBC, 1.0×109/l; PLT, 86×109/l; ESR, 129 (<20) mm/h; and CRP, <.313 mg/dl. Routine urine tests revealed a normal range and tests for hepatitis B and C and HIV were detected negative.\n\nBlood biochemistry results were as follows: Alb, 32.9 (35–50) g/l; TBIL, 33.9 umol/l; DBIL, 19.4 umol/l; ALT, 35 U/l; AST, 84.1 U/l; ALP, 184.2 U/l; GGT, 140.8 U/l; BUN, 2.42 (1.8–7.5) mmol/l; Cr, 38.8 (30–110) µmol/lU; K, 3.47 (3.5–5.5) mmol/l, Ca, 2.20 (2.25–2.75) mmol/l; acid-fast stain (sputum), negative; tumor marker, negative. PPD test (1) demonstrated and tuberculosis antibody were negative. Sputum smear exhibited Gram-negative cocci and Gram-negative bacteria. Schirmer's test was 0 cm; labial gland biopsy showed interstitial multifocal lymphocytic infiltration of the salivary gland tissue (Fig. 4). Bone marrow aspiration revealed hyperplasia of marrow activity, megakaryocytes were visible. Abdominal ultrasound indicated cirrhosis, splenauxe, portal hypertension, gallbladder wall thickening, echo nodules next to the spleen, an accessory spleen and small amount of ascites. The kidneys were normal.\n\nPlain CT scanning of the lung revealed bilateral patchy high-density shadows, the boundary was unclear. In addition to changes in the lungs that were indicative of inflammation, several lymph glands were seen in the bilateral oxters and mediastinum.\n\nThe patient was diagnosed with Sjogren's syndrome, PBC and hypersplenism. She was treated with hormones (methylprednisolone; 36 mg/d) immunosuppressants (mycophenolate; 1 g; 2/d; Roche Pharma Inc., Basel, Switzerland), ursodeoxycholic acid (0.25 g; 3/d), and polyene phosphatidylcholine capsules (456 mg, 3/d; Sanofi-aventis Hong Kong Ltd., Hong Kong, China) and cefuroxime sodium for injection (1.5 g, 2/d). Following treatment, the patient's body temperature dropped to within normal levels. Compared to the symptoms exhibited upon admission to our hospital, the patient's upper abdominal pain was markedly reduced. However, 14 days after she was admitted to hospital, routine urine tests indicated the following: WBC15, ~18/HP; PRO, negative; 80% of erythrocytes were abnormally formed and 20% were uniform. Following this, gross hematuria appeared, the offside costalpinal angle exhibited tenderness and percussion pain, and pitting edema was confirmed in the patient's lower limbs. Renal ultrasound showed offside hydronephrosis accompanied by upside expansion of the offside ureter. Flocculent echo was detected in the right renal pelvis, which was indicative of a blood clot. Intravenous pyelography showed that the right kidney and ureter were undeveloped (Fig. 5). MR urograph demonstrated 5×6 cm flakiness imaging in the parenchyma of right kidney. The kidney MRI and dynamic contrast-enhanced scan suggested cirrhosis, splenomegaly, a little ascites with abnormality of the right kidney (Fig. 6).\n\nThe patient subsequently suffered from sudden impaired vision of the left eye, hyperemia of bulbar conjunctiva, photophobia and lacrimation. An eye examination indicated hypopyon of the left eye, the liquid was at the height of ~1/5 of the anterior chamber, cellulose before cystals of floating liquid material of aqueous humour (+++) exuded and vitreous opacities appeared. The patient was diagnosed with hypopyon of the left eye and uveitis of the left eye was confirmed. Atropine timolol (1%; 1/d; Santen Pharmaceutical Co., Ltd., Osaka, Japan) was administered into the left eye and a dexamethasone and gentamicin mixture was inserted next to the left eye ball; however, the patient's vision did not markedly improved. To identify the nature of the disease, a renal biopsy was conducted under ultrasound guidance. The results suggested a renal mucormycosis infection (Fig. 7). The patient was provided with active anti-fungal amphotericin B therapy (2 mg, IV, 1/d; Northeast Pharmaceutical Group Co., Ltd., Shenyang, China) and nutritional support [human serum albumin (10 g, 1/d, Shanghai RAAS, Shanghai, China]. Due to the severity of the illness, the patient succumbed to the condition. The final diagnosis was Sjogren's syndrome leading to PBC and mucormycosis.\n\nDiscussion\nPBC is a chronic intrahepatic cholestatic hepatopathy, the cause of which remains unclear. This condition predominantly occurs in middle-aged women and is characterized by progressive bile duct destruction in the liver, inflammation and fibrosis in the portal area and around the periportal, and eventual portal hypertension, liver cirrhosis and liver failure (2). With advances in diagnostic techniques and knowledge of the disease in recent years, the incidence rates of this disease have increased in China (3).\n\nPBC is an autoimmune disease caused by immune system abnormalities. Previous studies have confirmed that PBC and other autoimmune diseases, such as Sjogren's syndrome and rheumatoid arthritis, have a common immunopathologic basis (4,5). There is currently a lack of satisfactory therapies for the disease, as symptomatic treatment remains the main therapy option. Ursodeoxycholic acid has been successful in some patients for the relief of symptoms and has been shown to improve the indicators of liver function, delay disease progression and improve quality of life (6). If the patient has an additional connective tissue diseases, the patient is required to take hormones and immunosuppressive therapy simultaneously. Long-term use of hormones and immunosuppressive agents may increase the patient's risk of developing a variety of concurrent infections, particularly opportunistic infections (7,8).\n\nIn the present study, two cases of fungal infection involvement in PBC, which was diagnosed in line with American Association for the Study of Liver Disease's PBC diagnosis recommendations published in 2000 (9). In case 1, the patient suffered from subsequent respiratory and cardiac failure; in case 2, the patient's condition was complicated by Sjogren's syndrome. Both of the patients were receiving hormonal and immunosuppressive therapy due to PBC prior to the development of concurrent P. carinii and mucormycosis infection. P. carinii infection and mucormycosis infection are opportunistic infections.\n\nP. carinii pneumonia (PCP) is an opportunistic infectious disease. Individuals of any age can be infected with PCP, and people with normal immune function do not typically exhibit symptoms after infection. However, when the host's immune system is weakened, pneumocystis bacteria begin to multiply, and spread in the lungs, resulting in interstitial plasma cell pneumonia. Patients with connective tissue disease are at an increased risk of infection with PCP as they receive large doses of hormonal and immunosuppressive agents for long periods of time (10). In recent years, with the extensive use of biological agents, the incidence of fungal infections has significantly increased (11–14). In Japan, the rate of rheumatoid arthritis (RA) involvement in PCP infection after applying infliximab treatment is 0.4%, at an average of 8.5 weeks after the application of infliximab (15). Rituximab monoclonal antibody treatment of RA and Wegener's granulomatosis (WG) has also been demonstrated to increase involvement in PCP (16).\n\nNumerous clinical studies have reported systemic lupus erythematosus and WG involvement PCP infection (16–18). Reports of WG involvement in PCP infection are most common. In a meta-analysis of 11,905 cases of patients with connective tissue disease, 12% of the 578 cases of WG were complicated by PCP infection, whereas dermatomyositis/polymyositis involvement in PCP infection was only 6%, SLE was 5% and RA was 1% (19). Connective tissue disease patients' infection with fungi and PCP is not only related to immune disorders of connective tissue disease but is also associated with the long-term use of hormonal and immunosuppressive therapy (20). However, it is difficult to elucidate which factor specifically causes the disease. In the present study, the two cases exhibited leukopenia upon admission to our hospital, as leukopenia may increase the chance of opportunistic infection.\n\nConnective tissue disease involvement in PCP infection is related to treatment with cyclophosphamide, methotrexate, hormones, azathioprine, cyclosporine and other biological agents, such as anti-TNF inhibitors and anti-CD20 inhibitors (21,22). Hormone therapy is the uppermost risk factor; >90% of patients who present with fungal infection involvement PCP have received long-term hormone therapy (23). If elderly patients, patients with nutritional deficiency or patients with low-lymphocytes lipoproteinaemia receive >16 mg/d equivalent hormone (>2 months) or >20 mg/d (>1-month) hormone therapy, the risk of PCP infection markedly increases (24). Cyclophosphamide treatment involvement in PCP infection may be related to significant inhibition of the lymphocyte count; therefore, patients regularly treated with cyclophosphamide should consider monitoring their CD4+ lymphocyte count.\n\nTo the best of our knowledge, there are no previous reports of PBC involvement in renal mucormycosis infection. In a clinical setting, there have been a small number of reports about liver involvement in mucormycosis infection after transplantation; the majority involve lung mucormycosis infection and reports of renal mucormycosis infection are rare (25). Mucormycosis describes various serious opportunistic infections caused by the following strains: Mucor spp., Absidia spp., Rhizopus spp. and Rhizomucor spp. which belong to the order of Mucoraceae (26). As the incidence rate is low, diagnosis remains difficult. Patients with the disease are predominantly complicated by diabetic acidosis, malnutrition, severe burns, trauma, leukemia, lymphoma, acquired immune deficiency syndrome or other serious wasting diseases, or have received long-term immunosuppressive agents, cytotoxic drugs or adrenocortical hormone (27). Most of the mucormycosis diseases are dangerous and the mortality rates are high (28).\n\nThe main feature of mucormycosis is sexual propagation producing zygosperm and asexual reproduction forming sporangia. Features include: i) hyphae are relatively thick, unseparated or rarely separated; ii) the mycelium wall is relatively thick, the side shoot is at right angle with the base shoot; and iii) tend to violate the vessel wall and lumen, thus forming a vessel clot that leads to ischemia, hemorrhage infarction and necrotizing inflammation of adjacent tissues (29). The clinical manifestations of mucor infections are cerebral, lung, gastrointestinal, cutaneous and systemically-spreading infections. The symptoms of patients with acute disease progress quickly and patients often succumb to the disease within several days or several weeks (30). Chronic infection can be manifested as simple granuloma or pyogenic inflammation and granulomatous mixed inflammation (31,32). Clinical diagnosis is often based on clinical symptoms, susceptible factors, mycological examination and pathological biopsy, of which, locating hypha in pathological tissue is of most diagnostic significance. There are various reports of pulmonary mucormycosis imaging (33). Its initial performance is unilateral or bilateral bronchial pneumonia integrating into a large consolidation rapidly and often forming porosis. Single or multiple nodules can also be detected. If the pulmonary embolism is relatively large, the wedge-shaped shadow close to the pleura at the bottom can be seen, which has diagnostic significance. High-resolution CT can detect symptoms that cannot be seen on an X-ray, such as lumen blocking, vignette and pulmonary artery pseudoaneurysm caused by mucormycosis within the bronchus. It has not yet been described in the imaging literature of mucor infection. Mucormycosis progresses rapidly, therefore, early diagnosis and effective treatment are of decisive significance for the prognosis of patients with mucormycosis.\n\nRenal involvement of systemically disseminated mucormycosis is rare, and simple renal mucormycosis is scarcer. Case 2 received hormonal and immunosuppressive therapy due to Sjogren's syndrome involvement in PBC. Following therapy, the patient was infected with renal mucormycosis. Despite active amphotericin B anti-infective therapy, the course of disease progressed quickly, and lead to mortality in this patient.\n\nThe present study provided a retrospective analysis of two cases of PBC involvement in opportunistic fungal infections. The patients in these cases were infected with fungi after taking hormones and immunosuppressive agents for a long period of time. This suggests that in patients with rheumatic autoimmune diseases, who receive long-term hormonal and immunosuppressive therapy, the probability of opportunistic pathogen infections increases. These findings are of particular use in clinical situations. When confronted with an infection whose response to antibiotic therapy is not ideal, a sputum smear and tests for fungi should be conducted. When necessary, an early histopathological biopsy should be performed to make time for the treatment of the patient. At the same time, actively seeking pathological diagnosis will improve our understanding of these difficult diseases.\n\nFigure 1. Case 1: Abdominal magnetic resonance scanning demonstrated cirrhosis with high density hypersplenotrophy splenomegaly.\n\nFigure 2. Case 1: Chest computed tomography scanning of the lungs.\n\nFigure 3. Case 1: Chest X ray demonstrated inflammation of both lungs, cirrhosis and hypersplenotrophy splenomegaly.\n\nFigure 4. Case 2: Labial gland biopsy demonstrated focal lymphocytic infiltration.\n\nFigure 5. The right kidney and ureter were not visualized on intravenous urography until 60 min. The left kidney and ureter revealed normal.\n\nFigure 6. Case 2: T2-weighted magnetic resonance imaging of the kidney demonstrated cirrhosis and hypersplenotrophy splenomegaly abnormal changes in the right kidney.\n\nFigure 7. Case 2: Mucoraceous hyphae were detected (magnification, ×400).\n==== Refs\nReferences\n1 Davari HR Malekhossini SA Salahi HA Bahador A Saberifirozi M Geramizadeh B Lahsaee SM Khosravi MB Imanieh MH Bagheri MH Outcome of mucormycosis in liver transplantation: Four cases and a review of literature Exp Clin Transplant 1 147 152 2003 15859921 \n2 Liberal R Grant CR Cirrhosis and autoimmune liver disease: Current understanding World J Hepatol 8 1157 1168 2016 10.4254/wjh.v8.i28.1157 27729952 \n3 Liu H Liu Y Wang L Xu D Lin B Zhong R Gong S Podda M Invernizzi P Prevalence of primary biliary cirrhosis in adults referring hospital for annual health check-up in Southern China BMC Gastroenterol 10 100 2010 10.1186/1471-230X-10-100 20815889 \n4 Smyk DS Bogdanos DP Mytilinaiou MG Burroughs AK Rigopoulou EI Rheumatoid arthritis and primary biliary cirrhosis: Cause, consequence, or coincidence? Arthritis 2012 391567 2012 23150824 \n5 Selmi C Meroni PL Gershwin ME Primary biliary cirrhosis and Sjögren's syndrome: Autoimmune epithelitis J Autoimmun 39 34 42 2012 10.1016/j.jaut.2011.11.005 22178199 \n6 Poupon R Ursodeoxycholic acid and bile-acid mimetics as therapeutic agents for cholestatic liver diseases: An overview of their mechanisms of action Clin Res Hepatol Gastroenterol 36 (Suppl 1) S3 S12 2012 10.1016/S2210-7401(12)70015-3 23141891 \n7 Mino Y Optimization of immunosuppression and the prevention of fungal infection in autoimmune diseases Yakugaku Zasshi 135 1123 1127 2015 (In Japanese) 10.1248/yakushi.15-00193 26423867 \n8 Takizawa Y Inokuma S Tanaka Y Saito K Atsumi T Hirakata M Kameda H Hirohata S Kondo H Kumagai S Clinical characteristics of cytomegalovirus infection in rheumatic diseases: Multicentre survey in a large patient population Rheumatology 47 1373 1378 2008 10.1093/rheumatology/ken231 18577548 \n9 Toda G Revised criteria for diagnosis of autoimmune hepatitis Intern Med 39 999 1000 2000 10.2169/internalmedicine.39.999 11197810 \n10 Chen M Tian X Qin F Zhou J Liu J Wang M Xu KF Pneumocystis pneumonia in patients with autoimmune diseases: A retrospective study focused on clinical characteristics and prognostic factors related to death PLoS One 10 e0139144 2015 10.1371/journal.pone.0139144 26422246 \n11 Wissmann G Morilla R Martín-Garrido I Friaza V Respaldiza N Povedano J Praena-Fernández JM Montes-Cano MA Medrano FJ Goldani LZ Pneumocystis jirovecii colonization in patients treated with infliximab Eur J Clin Invest 41 343 348 2011 10.1111/j.1365-2362.2010.02415.x 21299548 \n12 Takeuchi T Kameda H The Japanese experience with biologic therapies for rheumatoid arthritis Nat Rev Rheumatol 6 644 652 2010 10.1038/nrrheum.2010.154 20877307 \n13 Karino T Osaki K Kanamori K Yahata T Case of pulmonary cryptococcosis which developed in a patient receiving abatacept therapy for rheumatoid arthritis Nihon Kokyuki Gakkai Zasshi 48 980 984 2010 (In Japanese) 21226309 \n14 Yamazaki H Nanki T Miyasaka N Harigai M Methotrexate and trimethoprim-sulfamethoxazole for Pneumocystis pneumonia prophylaxis J Rheumatol 38 777 author reply 778 2011 10.3899/jrheum.100858 21459958 \n15 Kameda H Tokuda H Sakai F Johkoh T Mori S Yoshida Y Takayanagi N Taki H Hasegawa Y Hatta K Clinical and radiological features of acute-onset diffuse interstitial lung diseases in patients with rheumatoid arthritis receiving treatment with biological agents: Importance of Pneumocystis pneumonia in Japan revealed by a multicenter study Intern Med 50 305 313 2011 10.2169/internalmedicine.50.4508 21325762 \n16 Hugle B Solomon M Harvey E James A Wadhwa A Amin R Bell-Peter A Benseler S Pneumocystis jiroveci pneumonia following rituximab treatment in Wegener's granulomatosis Arthritis Care Res 62 1661 1664 2010 10.1002/acr.20279 \n17 Weng CT Liu MF Weng MY Lee NY Wang MC Lin WC Ou CY Lai WW Hsu SC Chao SC Pneumocystis jirovecii pneumonia in systemic lupus erythematosus from southern Taiwan J Clin Rheumatol 19 252 258 2013 10.1097/RHU.0b013e31829d5017 23872548 \n18 Khellaf M Godeau B Pneumocystis pneumonia among patients with systemic diseases Presse Med 38 251 259 2009 (In French) 10.1016/j.lpm.2008.11.004 19062243 \n19 Falagas ME Manta KG Betsi GI Pappas G Infection-related morbidity and mortality in patients with connective tissue diseases: A systematic review Clin Rheumatol 26 663 670 2007 10.1007/s10067-006-0441-9 17186117 \n20 Dilger K Hohenester S Winkler-Budenhofer U Bastiaansen BA Schaap FG Rust C Beuers U Effect of ursodeoxycholic acid on bile acid profiles and intestinal detoxification machinery in primary biliary cirrhosis and health J Hepatol 57 133 140 2012 10.1016/j.jhep.2012.02.014 22414767 \n21 Ogawa J Harigai M Nagasaka K Nakamura T Miyasaka N Prediction of and prophylaxis against Pneumocystis pneumonia in patients with connective tissue diseases undergoing medium- or high-dose corticosteroid therapy Mod Rheumatol 15 91 96 2005 10.3109/PL00021707 17029042 \n22 Jenks KA Stamp LK O'Donnell JL Savage RL Chapman PT Leflunomide-associated infections in rheumatoid arthritis J Rheumatol 34 2201 2203 2007 17937473 \n23 Meuli K Chapman P O'Donnell J Frampton C Stamp L Audit of pneumocystis pneumonia in patients seen by the Christchurch Hospital rheumatology service over a 5-year period Intern Med J 37 687 692 2007 17517083 \n24 Einollahi B Lessan-Pezeshki M Aslani J Nemati E Rostami Z Hosseini MJ Ghadiani MH Ahmadpour P Shahbazian H Pour-Reza-Gholi F Two decades of experience in mucormycosis after kidney transplantation Ann Transplant 16 44 48 2011 10.12659/AOT.881994 21959509 \n25 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 36 692 705 2015 10.1055/s-0035-1562896 26398536 \n26 Ribes JA Vanover-Sams CL Baker DJ Zygomycetes in human disease Clin Microbiol Rev 13 236 301 2000 10.1128/CMR.13.2.236-301.2000 10756000 \n27 Langford S Trubiano JA Saxon S Spelman D Morrissey CO Mucormycete infection or colonisation: Experience of an Australian tertiary referral centre Mycoses 59 291 295 2016 10.1111/myc.12467 26857435 \n28 Guarner J Brandt ME Histopathologic diagnosis of fungal infections in the 21st century Clin Microbiol Rev 24 247 280 2011 10.1128/CMR.00053-10 21482725 \n29 Wu X Xu G Wen W Guo J Clinical study on aggressive rhinocerebral mucormycosis Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 22 1060 1062 2008 (In Chinese) 19253528 \n30 Vaezi A Moazeni M Rahimi MT de Hoog S Badali H Mucormycosis in Iran: A systematic review Mycoses 59 402 415 2016 10.1111/myc.12474 26906121 \n31 Jung J Kim MY Lee HJ Park YS Lee SO Choi SH Kim YS Woo JH Kim SH Comparison of computed tomographic findings in pulmonary mucormycosis and invasive pulmonary aspergillosis Clin Microbiol Infect 21 e11 e18 2015 10.1016/j.cmi.2015.03.019 25682279 \n32 Nampoory MR Khan ZU Johny KV Constandi JN Gupta RK Al-Muzairi I Samhan M Mozavi M Chugh TD Invasive fungal infections in renal transplant recipients J Infect 33 95 101 1996 10.1016/S0163-4453(96)92986-2 8889996 \n33 Chkhotua A Yussim A Tovar A Weinberger M Sobolev V Bar-Nathan N Shaharabani E Shapira Z Mor E Mucormycosis of the renal allograft: Case report and review of the literature Transpl Int 14 438 441 2001 10.1111/j.1432-2277.2001.tb00083.x 11793042\n\n",
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"issn_linking": "1792-0981",
"issue": "13(2)",
"journal": "Experimental and therapeutic medicine",
"keywords": "mucormycosis; pneumocystis carinii pneumonia; primary biliary cirrhosis",
"medline_ta": "Exp Ther Med",
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"nlm_unique_id": "101531947",
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"pages": "489-494",
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"pubdate": "2017-02",
"publication_types": "D016428:Journal Article",
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"title": "Fungal infection involvement in primary biliary cirrhosis: A review of 2 cases.",
"title_normalized": "fungal infection involvement in primary biliary cirrhosis a review of 2 cases"
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"abstract": "OBJECTIVE\nThe aim of this study is to investigate the association between oral lichen planus (OLP) and a variety of systemic conditions, medication, and supplement usage.\n\n\nMETHODS\nA total of 156 patients diagnosed with OLP and 156 controls at Columbia University Irving Medical Center from 2000 to 2013 were selected as part of the matched (1:1) case-control study. Demographics, systemic conditions, prescription medications and supplements were extracted from the patients' medical records. A univariable conditional logistic regression (CLR) analysis was performed to calculate unadjusted odds ratio, to identify significant variables associated with OLP (p < .10). Significant variables were further tested using multivariable CLR analysis with both forward and backward selection to calculate adjusted odds ratio (aOR) and further distinguish variables associated with OLP (p < .05).\n\n\nRESULTS\nThis analysis identified six significant variables: thyroid disorder (aOR:5.1,95%CI:2.3-11.2), any form of cancer (aOR:3.4,95%CI:1.4-8.4), type 2 diabetes (aOR:2.8,95%CI:1.2-6.3), hyperlipidemia (aOR:2.3,95%CI:1.3-4.1), oral sedative usage (aOR:6.3,95%CI:1.8-22.5), and vitamin D supplementation (aOR:2.7,95%Cl:1.3-6.0).\n\n\nCONCLUSIONS\nThyroid disorders, cancer, type 2 diabetes, hyperlipidemia, sedatives, and vitamin D supplementation were found to be associated with OLP. Additional investigation is required to explore these associations, which could shed light on the potential mechanism of OLP and reinforce the idea that oral lesions could be predicative of previously undetected systemic conditions.",
"affiliations": "College of Dental Medicine, Columbia University, New York, NY, USA.;Division of Periodontics, Section of Oral, Diagnostic and Rehabilitation Sciences, College of Dental Medicine, Columbia University, New York, NY, USA.;Division of Oral and Maxillofacial Pathology, Columbia University Irving Medical Center and College of Dental Medicine, New York, NY, USA.",
"authors": "Dave|Anjali|A|https://orcid.org/0000-0001-5592-9050;Shariff|Jaffer|J|https://orcid.org/0000-0003-1357-2967;Philipone|Elizabeth|E|",
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"doi": "10.1111/odi.13572",
"fulltext": null,
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"issn_linking": "1354-523X",
"issue": "27(3)",
"journal": "Oral diseases",
"keywords": "cancer; medications; oral lichen planus; systemic diseases; thyroid disorders",
"medline_ta": "Oral Dis",
"mesh_terms": "D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2; D006801:Humans; D017676:Lichen Planus, Oral; D013959:Thyroid Diseases",
"nlm_unique_id": "9508565",
"other_id": null,
"pages": "515-524",
"pmc": null,
"pmid": "32750751",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article",
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"title": "Association between oral lichen planus and systemic conditions and medications: Case-control study.",
"title_normalized": "association between oral lichen planus and systemic conditions and medications case control study"
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"activesubstancename": "ZOLPIDEM TARTRATE"
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... |
{
"abstract": "Cardiac dysfunction occurring secondary to neurologic disease, termed neurogenic stunned myocardium, is an incompletely understood phenomenon that has been described after several distinct neurologic processes. We present a case of neurogenic stunned myocardium, discovered intraoperatively after anesthetic induction, in a patient who presented to our operating room with a recent intraparenchymal hemorrhage. We discuss the longitudinal cardiac functional course after neurogenic stunned myocardium. Finally, we discuss the pathophysiology of neurogenic stunned myocardium, as well as its implications for anesthesiologists caring for neurosurgical patients.",
"affiliations": "From the *Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington; and †The Ohio State College of Medicine, Columbus, Ohio.",
"authors": "Krishnamoorthy|Vijay|V|;Wilson|Thomas|T|;Sharma|Deepak|D|;Vavilala|Monica S|MS|",
"chemical_list": "D010656:Phenylephrine; D008694:Methamphetamine; D000077287:Levetiracetam; D009529:Nicardipine; D010889:Piracetam",
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000000207",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2325-7237",
"issue": "6(1)",
"journal": "A & A case reports",
"keywords": null,
"medline_ta": "A A Case Rep",
"mesh_terms": "D000328:Adult; D000768:Anesthesia, General; D002543:Cerebral Hemorrhage; D004636:Emergency Service, Hospital; D006321:Heart; D020786:Hemangioma, Cavernous, Central Nervous System; D006801:Humans; D006973:Hypertension; D007022:Hypotension; D000077287:Levetiracetam; D008297:Male; D008694:Methamphetamine; D017682:Myocardial Stunning; D009529:Nicardipine; D059035:Perioperative Period; D010656:Phenylephrine; D010889:Piracetam; D012640:Seizures; D019966:Substance-Related Disorders; D054549:Takotsubo Cardiomyopathy",
"nlm_unique_id": "101637720",
"other_id": null,
"pages": "3-5",
"pmc": null,
"pmid": "26462162",
"pubdate": "2016-01-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "12650423;5782382;5052586;15703419;16286583;17239752;17606855;18645066;23415170;24037954;24614323",
"title": "Prolonged Cardiac Dysfunction After Intraparenchymal Hemorrhage and Neurogenic Stunned Myocardium.",
"title_normalized": "prolonged cardiac dysfunction after intraparenchymal hemorrhage and neurogenic stunned myocardium"
} | [
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"activesubstancename": "LIDOCAINE"
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"abstract": "Curcumin has a potent antiproliferative activity and can also potentiate the antitumor effect of gemcitabine. This study was undertaken to evaluate the activity and feasibility of gemcitabine in combination with curcumin in patients with advanced pancreatic cancer. Seventeen patients were enrolled in the study and received 8,000 mg of curcumin by mouth daily, concurrently with gemcitabine 1,000 mg/m(2) IV weekly × 3 of 4 wk; 5 patients (29%) discontinued curcumin after a few days to 2 wk due to intractable abdominal fullness or pain, and the dose of curcumin was reduced to 4,000 mg/day because of abdominal complaints in 2 other patients. One of 11 evaluable patients (9%) had partial response, 4 (36%) had stable disease, and 6 (55%) had tumor progression. Time to tumor progression was 1-12 mo (median 2½), and overall survival was 1-24 mo (median 5). Low compliance for curcumin at a dose of 8,000 mg/day, when taken together with systemic gemcitabine, may prevent the use of high doses of oral curcumin needed to achieve systemic effect. Further studies should be conducted to evaluate the ability of other formulations of curcumin to enhance the effect of chemotherapy in cancer patients.",
"affiliations": "Department of Oncology, Rambam Health Care Campus, Haifa, Israel. epelbaum@rambam.health.gov.il",
"authors": "Epelbaum|Ron|R|;Schaffer|Moshe|M|;Vizel|Bella|B|;Badmaev|Vladimir|V|;Bar-Sela|Gil|G|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; C542281:bisdesmethoxycurcumin; C542280:desmethoxycurcumin; D003841:Deoxycytidine; C056507:gemcitabine; D003474:Curcumin",
"country": "United States",
"delete": false,
"doi": "10.1080/01635581.2010.513802",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-5581",
"issue": "62(8)",
"journal": "Nutrition and cancer",
"keywords": null,
"medline_ta": "Nutr Cancer",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D000971:Antineoplastic Combined Chemotherapy Protocols; D003474:Curcumin; D003841:Deoxycytidine; D018450:Disease Progression; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D010190:Pancreatic Neoplasms; D012720:Severity of Illness Index; D016019:Survival Analysis",
"nlm_unique_id": "7905040",
"other_id": null,
"pages": "1137-41",
"pmc": null,
"pmid": "21058202",
"pubdate": "2010",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": null,
"title": "Curcumin and gemcitabine in patients with advanced pancreatic cancer.",
"title_normalized": "curcumin and gemcitabine in patients with advanced pancreatic cancer"
} | [
{
"companynumb": "IL-CIPLA LTD.-2017IL21184",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CURCUMIN"
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... |
{
"abstract": "Trichinosis is a parasitic disease that, due to variable clinical syndromes, is often underrecognized. We present the case of a patient with eosinophilia, focal neurological signs and multiple bilateral brain lesions, distributed mainly in the border zones. The diagnostic workup revealed neurotrichinosis, which should be suspected even without a clear history of consumption of poorly cooked meat.",
"affiliations": "University of Medicine and Pharmacy \"Victor Babes\" Timisoara, Department of Neurology, Romania; Clinical Emergency County Hospital Timisoara, Department of Neurology, Romania. Electronic address: roscacecilia@yahoo.com.;University of Medicine and Pharmacy \"Victor Babes\" Timisoara, Department of Neurology, Romania; Clinical Emergency County Hospital Timisoara, Department of Neurology, Romania.",
"authors": "Rosca|Elena Cecilia|EC|;Simu|Mihaela|M|",
"chemical_list": null,
"country": "Canada",
"delete": false,
"doi": "10.1016/j.ijid.2017.12.011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1201-9712",
"issue": "67()",
"journal": "International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases",
"keywords": "Border zone cerebral lesions; MRI; Neurotrichinosis",
"medline_ta": "Int J Infect Dis",
"mesh_terms": "D001921:Brain; D020809:Central Nervous System Helminthiasis; D004802:Eosinophilia; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D014235:Trichinellosis",
"nlm_unique_id": "9610933",
"other_id": null,
"pages": "43-45",
"pmc": null,
"pmid": "29253712",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Border zone brain lesions due to neurotrichinosis.",
"title_normalized": "border zone brain lesions due to neurotrichinosis"
} | [
{
"companynumb": "RO-IPCA LABORATORIES LIMITED-IPC-2018-RO-000123",
"fulfillexpeditecriteria": "1",
"occurcountry": "RO",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CEFTRIAXONE"
},
"drugad... |
{
"abstract": "The cholesterol embolization syndrome (CES) results from the distal embolization of cholesterol crystals from atheromatous plaques in large vessels such as the aorta and results in multiorgan damage.\n\n\n\nWe present the case of a patient with definite CES with skin manifestations (e.g., blue toes) and renal and neurological dysfunction, including parenchymal hematoma with cytotoxic and vasogenic edema after he had undergone left carotid artery stenting for symptomatic critical left carotid artery stenosis.\n\n\n\nOur patient with CES had cutaneous involvement affecting the lower limbs and renal and neurological involvement. High clinical suspicion and early treatment can reduce the mortality and morbidity after endovascular procedures. The neurological symptoms had most likely resulted from delayed cerebral hyperperfusion syndrome resulting in intracerebral hemorrhage.",
"affiliations": "Department of Neurology, All India Institute of Medical Sciences, Delhi, India. Electronic address: akpandit.med@gmail.com.;Neuroendovascular Therapy Center, Aichi Medical University, Aichi, Japan.;Department of Neurosurgery, Aichi Medical University, Aichi, Japan.;Department of Neurology, All India Institute of Medical Sciences, Delhi, India.;Neuroendovascular Therapy Center, Aichi Medical University, Aichi, Japan; Department of Neurosurgery, Aichi Medical University, Aichi, Japan.",
"authors": "Pandit|Awadh Kishor|AK|;Ohshima|Tomotaka|T|;Kawaguchi|Reo|R|;Srivastava|Mv Padma|MP|;Miyachi|Shigeru|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.wneu.2020.07.021",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-8750",
"issue": "142()",
"journal": "World neurosurgery",
"keywords": "CES; Carotid artery stenting; Cholesterol embolization syndrome; Hyperperfusion hemorrhage",
"medline_ta": "World Neurosurg",
"mesh_terms": "D000368:Aged; D002343:Carotid Artery, Internal; D016893:Carotid Stenosis; D002406:Catheterization, Peripheral; D002543:Cerebral Hemorrhage; D017700:Embolism, Cholesterol; D006801:Humans; D008297:Male; D015607:Stents; D013997:Time Factors",
"nlm_unique_id": "101528275",
"other_id": null,
"pages": "274-282",
"pmc": null,
"pmid": "32679361",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Cholesterol Embolization Syndrome After Carotid Artery Stenting Associated with Delayed Cerebral Hyperperfusion Intracerebral Hemorrhage.",
"title_normalized": "cholesterol embolization syndrome after carotid artery stenting associated with delayed cerebral hyperperfusion intracerebral hemorrhage"
} | [
{
"companynumb": "IN-ACCORD-198968",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
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... |
{
"abstract": "BACKGROUND\nPolycystic liver disease is a clinical feature of autosomal dominant polycystic kidney disease, and it can sometimes cause health damage more serious than polycystic kidney. Dialysis therapy can be used for renal failure, but liver transplantation is the only method available for liver failure. Thus, giant and multiple hepatic cysts may affect mortality. However, liver transplantation is not indicated in many cases because of the preserved liver function.\n\n\nMETHODS\nA 54-year-old Japanese woman with polycystic liver disease was transferred back to our hospital for abdominal pain caused by liver cyst infection with abdominal wall herniation. She had been diagnosed with polycystic liver disease associated with sporadic autosomal dominant polycystic kidney disease 25 years earlier. Although she had several surgical interventions to reduce her liver volume, including right hepatic lobectomy and fenestration for liver cysts in another hospital, she needed further repair of the recurrent incisional herniation with patch graft surgery using fascia lata to cover the herniation site. However, new herniation sites reemerged in the fragile abdominal wall area around the patch, and therefore, she reduced the recurrent abdominal wall herniation by herself. Recurrent intestinal obstructions were luckily released by fasting with decompression treatment via nasogastric tube insertion, but multiple skin ulcers around the enlarged hernia sac gradually developed, and ascites was extremely difficult to control with any medication. At final admission, her abdominal wall was even more prominent, causing shortness of breath, and it spontaneously ruptured many times, which was accompanied by discharge of around 5 liters of ascites each time. She died from sepsis caused by drug-resistant Enterococcus.\n\n\nCONCLUSIONS\nWe report a case of autosomal dominant polycystic kidney disease with ruptured abdominal wall resulting from a hepatic cyst enlargement despite multiple laparotomy operations. Throughout the entire disease course, her liver volume increased rapidly, and her quality of life was severely impaired, but she could not undergo liver transplantation after readmission to our hospital. We will discuss the therapeutic strategy for this patient, including the timing and indication for liver transplantation.",
"affiliations": "Department of Pediatrics, Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan.;Department of Gastroenterological Surgery and Oncology, Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan.;Department of Nephrology and Dialysis, Tazuke Kofukai Medical Research Institute, Kitano Hospital, 2-4-20 Ohgimachi, kita-ku, Osaka, 530-8480, Japan.;Department of Nephrology and Dialysis, Tazuke Kofukai Medical Research Institute, Kitano Hospital, 2-4-20 Ohgimachi, kita-ku, Osaka, 530-8480, Japan.;Department of Nephrology and Dialysis, Tazuke Kofukai Medical Research Institute, Kitano Hospital, 2-4-20 Ohgimachi, kita-ku, Osaka, 530-8480, Japan.;Department of Pathology, Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan.;Department of Gastroenterological Surgery and Oncology, Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan.;Department of Nephrology and Dialysis, Tazuke Kofukai Medical Research Institute, Kitano Hospital, 2-4-20 Ohgimachi, kita-ku, Osaka, 530-8480, Japan. t-tsukamoto@kitano-hp.or.jp.",
"authors": "Akuzawa|Daichi|D|;Uchida|Yoichiro|Y|;Ishimura|Takuya|T|;Kakita|Hiroko|H|;Endo|Tomomi|T|;Matsuzaki|Naomi|N|;Terajima|Hiroaki|H|;Tsukamoto|Tatsuo|T|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s13256-021-02964-6",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947\nBioMed Central London\n\n2964\n10.1186/s13256-021-02964-6\nCase Report\nPolycystic liver disease with lethal abdominal wall rupture: a case report\nAkuzawa Daichi 12\nUchida Yoichiro 34\nIshimura Takuya 25\nKakita Hiroko 2\nEndo Tomomi 2\nMatsuzaki Naomi 67\nTerajima Hiroaki 3\nTsukamoto Tatsuo t-tsukamoto@kitano-hp.or.jp\n\n2\n1 grid.415392.8 0000 0004 0378 7849 Department of Pediatrics, Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan\n2 grid.415392.8 0000 0004 0378 7849 Department of Nephrology and Dialysis, Tazuke Kofukai Medical Research Institute, Kitano Hospital, 2-4-20 Ohgimachi, kita-ku, Osaka, 530-8480 Japan\n3 grid.415392.8 0000 0004 0378 7849 Department of Gastroenterological Surgery and Oncology, Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan\n4 grid.258799.8 0000 0004 0372 2033 Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan\n5 grid.258799.8 0000 0004 0372 2033 Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan\n6 grid.415392.8 0000 0004 0378 7849 Department of Pathology, Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan\n7 grid.416952.d 0000 0004 0378 4277 Department of Pathology, Tenri Hospital, Nara, Japan\n3 8 2021\n3 8 2021\n2021\n15 42112 6 2020\n16 6 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nPolycystic liver disease is a clinical feature of autosomal dominant polycystic kidney disease, and it can sometimes cause health damage more serious than polycystic kidney. Dialysis therapy can be used for renal failure, but liver transplantation is the only method available for liver failure. Thus, giant and multiple hepatic cysts may affect mortality. However, liver transplantation is not indicated in many cases because of the preserved liver function.\n\nCase presentation\n\nA 54-year-old Japanese woman with polycystic liver disease was transferred back to our hospital for abdominal pain caused by liver cyst infection with abdominal wall herniation. She had been diagnosed with polycystic liver disease associated with sporadic autosomal dominant polycystic kidney disease 25 years earlier. Although she had several surgical interventions to reduce her liver volume, including right hepatic lobectomy and fenestration for liver cysts in another hospital, she needed further repair of the recurrent incisional herniation with patch graft surgery using fascia lata to cover the herniation site. However, new herniation sites reemerged in the fragile abdominal wall area around the patch, and therefore, she reduced the recurrent abdominal wall herniation by herself. Recurrent intestinal obstructions were luckily released by fasting with decompression treatment via nasogastric tube insertion, but multiple skin ulcers around the enlarged hernia sac gradually developed, and ascites was extremely difficult to control with any medication. At final admission, her abdominal wall was even more prominent, causing shortness of breath, and it spontaneously ruptured many times, which was accompanied by discharge of around 5 liters of ascites each time. She died from sepsis caused by drug-resistant Enterococcus.\n\nConclusions\n\nWe report a case of autosomal dominant polycystic kidney disease with ruptured abdominal wall resulting from a hepatic cyst enlargement despite multiple laparotomy operations. Throughout the entire disease course, her liver volume increased rapidly, and her quality of life was severely impaired, but she could not undergo liver transplantation after readmission to our hospital. We will discuss the therapeutic strategy for this patient, including the timing and indication for liver transplantation.\n\nKeywords\n\nPolycystic liver disease\nAbdominal wall herniation\nCase report\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nPolycystic liver disease (PLD) is characterized by multifocal cysts that grow in the liver parenchyma. Pathologically, the liver cysts are caused by intrahepatic bile duct dilation and isolation from the original ducts to form cysts. The increase in the number and growth of these cysts leads to liver enlargement, which causes compression of other abdominal organs.\n\nPLD is genetically classified into two groups: isolated autosomal dominant polycystic liver disease (ADPLD) and PLD that is associated with autosomal dominant polycystic kidney disease (ADPKD) [1-3]. ADPKD affects 0.2% of the general population, and 75–90% of patients with ADPKD have associated PLD. However, isolated PLD affects less than 0.01% of the general population [2]. Both ADPLD and PLD are associated with ADPKD and have similar characteristics such as female dominance and the manner of inheritance. ADPLD has been linked to mutations in PRKCSH and SEC63, while the causative mutation of PLD that is associated with ADPKD is PKD1 or PKD2. There is no difference in the PKD1 and PKD2 mutation prevalence between ethnicities, but the PRKCH gene mutation has been reported in Holland, Belgium, Finland, and North America, but not in Taiwan [4, 5]. The SEC63 gene mutation has also been reported in those with a European background, but a clear localization is unknown [6]. For isolated ADPLD, the cysts are limited to the liver, with no cyst formation in other organs, whereas for PLD associated with ADPKD, patients have both liver and kidney cysts. The responsible genes of both PLD types have been identified [3, 7-10]. Growth rates of renal and hepatic cysts are not synchronized, indicating that other unknown factors that accelerate cyst growth in the liver and kidney could exist to determine the severity of PLD in ADPKD patients [11-13]. Female hormones can be an intrinsic factor that affects cyst growth because massive liver cysts at a younger age have been found mostly in women, particularly in those who experienced pregnancy [14].\n\nAs the initial treatment, partial hepatic resection is often used to control the growth of the multiple liver cysts, but limited success has been experienced, especially in cases of massive PLD. For the surgical assessment of PLD, the Gigot classification is commonly used [15]. Gigot type I patients are the best candidates for sclerotherapy and fenestration, which leads to a good prognosis [16]. However, for Gigot type III patients who are resistant to any surgery including fenestration, sclerotherapy, and partial hepatic resection, liver transplantation is the only successful treatment option [16, 17]. Treatments for Gigot type II patients remain controversial because most patients respond well to palliative surgery including sclerotherapy, fenestration, or partial hepatic resection, while some patients need a liver transplantation because of an uncontrollable liver volume increase after palliative surgery [16, 18-22]. Medical treatment including immunosuppressants is still in the development stage.\n\nWe report here a case with massive PLD in a female patient with ADPKD. For many years, multiple surgical treatments for the gradually growing liver cysts had been performed as palliative rather than radical therapy. Finally, liver growth caused uncontrollable abdominal wall ruptures before the patient died. We also discuss the timing of liver transplantation as a radical treatment along with a literature review of this disease.\n\nCase presentation\n\nA 54-year-old Japanese woman presented with severe abdominal pain, and she was transferred to the emergency room at our hospital. She had given birth twice and was a housewife who had no significant problems other than high blood pressure and iron deficiency anemia. She was a never-smoker and a never-drinker and took candesartan 8 mg for hypertension. Her father had hypertension, brain infarction, and myocardial infarction. Her medical history included PLD associated with sporadic ADPKD, which was first diagnosed at 34 years of age during her second pregnancy, but she refused to undergo liver transplantation from a living donor at that time. Fenestration of liver cysts was performed at 39 years of age (Fig. 1, ▼①), and right hepatic lobectomy was performed at 44 years of age (Fig. 1, ▼②) at another hospital. Her liver size gradually increased, and she was referred to the surgical department at our hospital because of severe abdominal pain when she was 50 years old.Fig. 1 Liver volume change measured by a computed tomography (CT) image analyzer. Black triangle 1 (▼①) indicates liver fenestration of the cysts. Black triangle 2 (▼②) indicates partial right hepatic lobectomy. Surgery ① and ② were conducted at another hospital. Black triangle 3 (▼③) indicates partial liver resection, repair of the abdominal wall herniation, liver cyst fenestration, partial right hepatic lobectomy, and ovariectomy. Black triangle 4 (▼④) indicates surgery to repair the adhesive abdominal obstruction. Black triangle 5 (▼⑤) indicates surgery to repair the abdominal incisional hernia and liver cyst fenestration. White triangles (▽) indicate abdominal ruptures during the patient’s hospitalization\n\nThe cause of the abdominal pain was a strangulated hernia in the abdominal wall that included her gut and part of the liver. At that time, she underwent surgery, which was a partial hepatic resection with liver cyst fenestration, repair of the abdominal wall herniation, and ovariectomy to remove cysts that were affected by endometriosis (Fig. 1, ▼③ and Fig. 2, A and D). After surgery, she underwent abdominal incisional hernia repair twice within 6 months including partial ileectomy during the first operation (Fig. 1, ▼④) and closure of the herniation site using a native patch graft from fascia lata during the second operation (Fig. 1, ▼⑤). Despite the liver resections, her abdominal wall hernia was gradually reaggravated because of uncontrollable ascites. However, she did not require hospitalization for about 2 years because she could reduce the recurrent hernia by herself.Fig. 2 Alteration of abdominal appearances, corresponding CT images, and autopsy findings of liver parenchyma and liver cysts. Liver volume was calculated using SYNAPSE VINCENT, Fujifilm 3D image analysis system (Tokyo, Japan) using a 0.5-mm thick Axial CT image. Liver area was identified in each CT slice by hand, and integration of each slice volume led to the total volume of the cystic liver. To reduce errors, we calculated the liver volume three times and plotted the average volume. A and D Abdominal appearance and corresponding CT image after partial hepatic resection with liver cyst fenestration, repair of the abdominal wall herniation, and ovariectomy at 50 years of age. B and E Abdominal appearance and corresponding CT image at 52 years of age when the patient had an abdominal herniation. C and F Abdominal appearance and corresponding CT image on last admission at 54 years of age. Note that the prominent abdominal hernia sac can be seen with multiple skin ulcers, resulting in abdominal rupture. G Gross pathology of the liver parenchyma and cyst after death. The patient’s liver was filled with cysts of various sizes, leaving only a few areas of compressed parenchyma. H Microscopic examination of liver parenchyma. Note that many small cysts are scattered in the patient’s grossly normal liver parenchyma, and neutrophil infiltrations are found possibly because of sepsis\n\nAt the age of 52 years, she noticed severe abdominal pain unlike before, and she was transferred to our hospital. An intestinal obstruction was suspected, but her symptoms were luckily relieved by fasting with decompression treatment via nasogastric tube insertion. She asked for second opinions about liver transplantation, but she was not selected as a recipient candidate at three major liver transplant facilities on the basis of her normal liver function, Child–Pugh score (7: B), and Model for End-Stage Liver Disease (MELD) score [10] (Fig. 2, B and E). At that time, the distribution of her liver cysts had progressed to Gigot type 2.\n\nAt 54 years of age, she was readmitted to our hospital for fever, general fatigue, edema in her lower extremities, and abdominal pain. Her vital signs were as follows: body temperature 38 ℃, blood pressure 88/45 mmHg, and heat rate 109 beats/minute. Physical examination results showed conjunctival pallor, no heart murmur, no rale on lung auscultation, prominent abdominal distension with multiple skin ulcers, and edema in both lower legs. There were no abnormalities in neurological findings. Laboratory test results on admission suggested liver cyst infection (Table 1). However, the causal bacteria were not detected in her blood or in ascitic fluid culture. We treated her for a cystic infection or abscess. Tazobactam piperacillin 4.5 g was administered intravenously every 8 hours (q8h), and her fever and laboratory data [C-reactive protein (CRP) level and complete blood chemistry (CBC) test results] returned to normal within 1 month. We changed tazobactam piperacillin to amoxicillin clavulanic acid 1 g every 12 hours (q12h) because a drug allergy was suspected, but her CRP level increased again. We changed the drug treatment to meropenem 0.5 g intravenously q12h, and her CRP level started to decrease. The patient’s infection was under control in 2 weeks. Her abdominal wall was even more prominent with growing liver cysts and increasing ascites. Excessive abdominal hernia sac distention was seen around this period and led to multiple skin ulcers with oozing on the sac (Fig. 2, C and F). The severity of liver dysfunction or failure was expressed as the Child–Pugh and MELD scores, which were only B [8] and 17, respectively, until the day of her death (Fig. 1). We had no choice but to increase the amount of diuretics to control the progressive ascites that were worsening the abdominal distension. Azosemide 60 mg/day, flosemide 60 mg/day, and tolvaptan 15 mg/day were administered orally to control edema and progressive ascites that were worsening the abdominal distension. However, these medications did not relieve the patient’s symptoms. In addition, she received heparin 10,000 U/day for 20 days and apixaban 5 mg/day to prevent deep vein thrombosis for 5 months after treatment because she had difficulty moving, and her admission laboratory test results indicated that she had hypercoagulability.Table 1. Laboratory data on admission\n\nUrinalysis\tBlood chemistry\t\nProtein\t(1+)\t\tAST\t76\tU/L\t\nSugar\t(−)\t\tALT\t64\tU/L\t\nOccult blood\t(−)\t\tALP\t1039\tU/L\t\nRBC\t1–4\t/HPF\tγ-GTP\t231\tU/L\t\nWBC\t1–4\t/HPF\tT-Bil\t1.9\tmg/dL\t\n\t\t\tTP\t6.7\tg/dL\t\nCBC\tAlb\t3.4\tg/dL\t\n RBC\t386 × 104\t/µL\tCK\t81\tmg/dL\t\n Hb\t9.5\tg/dL\tAmy\t68\tmg/dL\t\n Ht\t30.5\t%\tT-Chol\t114\tmg/dL\t\n PLT\t29.9\t/µL\tBUN\t26.2\tmg/dL\t\n WBC\t7900\t/µL\tUA\t6.1\tmg/dL\t\n Neu\t81.3\t%\tCre\t1.55\tmg/dL\t\n Lymph\t8.5\t%\teGFR\t28\tmL/min/1.73 m2\t\n\t\t\tNa\t131\tmEq/L\t\nCoagulation\tK\t3.4\tmEq/L\t\n PT-INR\t1.41\tINR\tCl\t94\tmEq/L\t\n PT (%)\t48\tmg/dL\tCa\t9.1\tmg/dL\t\n Fibrinogen\t479\tmg/dL\tP\t3.4\tmg/dL\t\n D-dimer\t5.9\tμg/mL\tCRP\t16.83\tmg/dL\t\nRBC red blood cell, Hb hemoglobin, Ht hematocrit, PLT platelet, WBC white blood cell, Neu neutrophil, Lymph lymphocyte, RT-INR prothrombin time international normalized ratio, TP prothrombin time, AST aspartate aminotransferase, ALT alanine aminotransferase, ALP alkaline phosphatase, γ-GTP gamma-glutamyl transpeptidase, T-Bil total bilirubin TP total protein, Alb albumin, CK creatin kinase, Amy amylase, T-Chol total cholesterol, BUN blood urea nitrogen, UA uric acid, Cre creatinin, eGFR estimated glomerular filtration rate, Na sodium, K potassium, Cl chloride, Ca calcium, P phosphate, CRP C-reactive protein\n\nWe determined the patient’s liver volume by manually plotting the size of the liver on her CT image and reconstructing it three-dimensionally using SUNAPSE VINCENT (Fujifilm 3D Image Analysis System, Tokyo, Japan). Her liver size increased from 5.7 to 8.2 liters in 3 years, and the normal liver tissue was gradually compressed by the growing cysts (Fig. 1Ba–c). Finally, she had spontaneous abdominal wall rupture, and almost 5 liters of ascites was discharged from her abdominal cavity. After that, the ruptured abdominal wall persisted, but the ascites loss was not constant from 0.1 to 8.6 liters a day. In the last 3 months of hospitalization, a total of 2 liters or more of ascites was discharged ten times, and additional fluid supplementation was required after massive ascites loss. Antibiotics administration was also needed for comorbid peritonitis. Only a topical therapy was performed for the wound, which was a topical spray that included trafermin. The frequency of large amounts of ascites leakage had been gradually shortened, and more than 5 liters of ascites drainage was found twice a month before death. Although the abdominal distention was relieved after the rupture, her nutritional state worsened each day. She developed a high fever again after bathing. We detected Enterococcus faecium, Achromobacter xylosoxidans, Candida tropicalis, and Candida glabrata in ascitic fluid culture, while no bacteria were detected in a blood culture. Opiates were needed for unbearable abdominal wall pain. She was treated with vancomycin 0.5 g intravenously q12h, teicoplanin 400 mg intravenously every 48 hours (q48h), and linezolid 600 mg orally q12hr because the detected E. faecium was susceptible to only those antibiotics. However, it became difficult to continue these medications because of severe thrombocytopenia. Meropenem 0.5 g intravenously q24h and micafungin 50 mg intravenously q24h were also administered, but her infection and bleeding became uncontrollable, and she died from sepsis. Inflammatory markers such as white blood cell count and CRP level fluctuated during the patient’s disease course. However, liver enzymes indicating cholangitis showed subtle changes but no particular exacerbation in renal function. We performed an autopsy after receiving approval from her family to perform a pathological examination and their permission to publish the results. Many neutrophils had accumulated in the liver in addition to the cysts on microscopic examination (Fig. 2 G and H). The kidneys also showed typical changes in polycystic kidney disease, but no notable findings in other organs. The patient’s kidney cysts increased minimally during the disease course.\n\nDiscussion and conclusion\n\nThere is no well-established therapy regimen for rapidly growing PLD [16, 18]. Historically, several surgical treatments have been reported for this disease, including fenestration of the liver cysts, segmental resection of the liver, and liver transplantation [22].\n\nThe Gigot classification is commonly used to determine the surgical indication of PLD [15]. In this classification, PLD is classified into three stages based on the CT image. Type I is defined as patients with a limited number (< 10) of large cysts (> 10 cm in diameter). Type II is defined as patients with diffuse involvement of the liver parenchyma by multiple medium-sized cysts with remaining large areas of noncystic liver parenchyma. Type III is defined as a severe form of PLD with massive, diffuse involvement of liver parenchyma by small- and medium-sized liver cysts and only a few areas of normal liver parenchyma between cysts [15]. This classification is convenient to classify PLD; however, three stages do not have clear border line. Therefore, it is difficult to precisely estimate prognosis and appropriate therapy only by this classification. For this reason, therapeutic strategy, especially for Gigot type II PLD, is still controversial. For type II patients, palliative surgery reduces the liver volume, but in some cases, liver cysts regrow and, ironically, these patients are no longer eligible to undergo liver transplantation because of postoperative complications including abdominal incisional hernia and adhesions. Previously, only 24% of PLD patients after fenestration and 34% of patients after hepatic segmental resection had been reported to experience liver cyst reenlargement [16]. However, if the patient has a history of multiple births, similar to our patient, worsening of the long-term prognosis should be considered. It is estimated that over 80% of patients who underwent liver transplantation were female because the cyst growth rate is relatively rapid among female patients and it has a suspected estrogen-mediated mechanism [19, 22].\n\nTo the best of our knowledge, there are no reports focusing on cyst reenlargement after palliative surgery. According to previous research, the liver volume after fenestration in PLD patients is lower than the preoperative volume for 2–8 years after fenestration regardless of the Gigot classification [15]. In our patient, the liver volume increased again to the same size within 2 years after the palliative surgery via a suspected estrogen-mediated mechanism, indicating that higher-risk patients should be identified and early liver transplantation should be recommended even if they are classified as having a lower grade using the Gigot classification. As shown in our case, because liver function is preserved until the terminal phase in PLD, PLD patients often do not satisfy the general indication for liver transplantation even in the terminal stage. Another problem is that the Child–Pugh and MELD scores are not good metrics for liver transplantation in PLD patients because they were originally designed to evaluate general liver failure (Fig. 1) [23-25].\n\nWe performed an autopsy on this patient. Her liver was filled with cysts of various sizes, leaving only few areas of compressed parenchyma (Fig. 2G). These cysts were filled with bilious viscous liquid, which indicated inflammation. Microscopic findings demonstrated that there were many neutrophils that had accumulated around the cysts, which may indicate a cyst infection, and many small cysts were scattered in her grossly normal liver parenchyma (Fig. 2H), indicating that, although her liver looked normal, it was not normal in this case. No yeast such as fungi nor purulent matter was detected in the liver or kidney. The patient’s kidney cysts increased minimally during the disease course.\n\nFinally, we discuss the ideal timing of liver transplantation for patients who are refractory to any palliative surgeries and review the non-incisional therapeutic options. First, when is the best timing for liver transplantation for PLD patients? It seems to be hard for patients to decide in the early stage of PLD when there are fewer complications and normal liver function. Most patients choose palliative therapy at first, but some of them need liver transplantation during the disease course. We suggest performing organ transplantation before the development of an abdominal hernia because, if a mesh graft is selected instead of an autogenous patch graft, it could increase the incidence of postoperative infection, and thereby make it difficult to use immunosuppressants. Uncontrollable ascites, cyst infection, and mechanical obstruction may develop concurrently with abdominal herniation, and these complications also increase debilitation in the patient and make them ineligible for liver transplantation [26]. Combined liver and kidney transplantation might be an ideal solution for severe symptomatic PLD that is associated with ADPKD [27, 28].\n\nWe also reviewed the non-incisional therapeutics for PLD. Percutaneous transcatheter artery embolization is an option for a patient without surgical indication. In many cases of PLD that is associated with ADPKD, cyst distribution is not uniform [29]. Therefore, selective embolization is considered to be an ideal treatment. Additionally, medical therapeutics are also being developed for ADPKD and PLD. Tolvaptan, a recently approved vasopressin type 2 (V2) receptor antagonist, was approved by the United States Food and Drug Administration (USFDA) to reduce the volume of the kidney in ADPKD. However, this is not effective for suppressing liver cyst growth because the V2 receptor is not expressed in the liver cysts [3]. Sirolimus, an immunosuppressive agent for organ transplantation, might decrease the liver volume through a potential antiproliferative effect [30, 31]. Octreotide, a somatostatin analog, could reduce kidney and liver cyst fluid accumulation among patients with ADPKD or isolated PLD [31-33]. Some current drugs under development are very expensive, but they can provide options for developing drugs that can inhibit the growth of both liver and kidney cysts in PLD patients. In the present situation, early liver transplantation is the only radical treatment, but the development of these noninvasive therapeutics will provide us with new treatment strategies in the future.\n\nWe report a case of rapidly growing PLD associated with ADPKD. In a female patient, especially in multiparous patients, it may be desirable to perform an early liver transplantation instead of palliative surgery because the liver cysts may grow rapidly. The development of new drugs to reduce liver and kidney cysts is expected for these patients with PLD.\n\nAbbreviations\n\nPLD Polycystic liver disease\n\nADPKD Autosomal dominant polycystic kidney disease\n\nV2 Vasopressin type 2\n\nAcknowledgements\n\nWe are grateful to Ms. Takamine for helpful assistance with the liver volume measurement, and to the nursing staff at Kitano Hospital on the 10th floor West ward.\n\nAuthors’ contributions\n\nDA wrote this paper under the guidance of TT and YU. TI, HK, and TE were attending physicians either in the outpatient clinic or on admission. NM performed the autopsy in this case. YU and HT performed multiple surgical operations. All authors read and approved the final manuscript.\n\nFunding\n\nNo funding was obtained for this case report.\n\nAvailability of data and materials\n\nNot applicable\n\nDeclarations\n\nEthics approval and consent to participate\n\nTh ethical committee at Kitano Hospital provided approvals for this case report.\n\nConsent for publication\n\nBefore her death, the patient and her family provided written informed consent for her personal and clinical details along with any identifying images to be published in this case report. Written informed consent was obtained from the patient‘s next of kin for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Peces R Drenth JP Te Morsche RH Gonzalez P Peces C Autosomal dominant polycystic liver disease in a family without polycystic kidney disease associated with a novel missense protein kinase C substrate 80K-H mutation World J Gastroenterol 2005 11 48 7690 7693 10.3748/wjg.v11.i48.7690 16437702\n2. Abu-Wasel B Walsh C Keough V Molinari M Pathophysiology, epidemiology, classification and treatment options for polycystic liver diseases World J Gastroenterol 2013 19 35 5775 5786 10.3748/wjg.v19.i35.5775 24124322\n3. Chebib FT Torres VE Recent advances in the management of autosomal dominant polycystic kidney disease Clin J Am Soc Nephrol 2018 13 11 1765 1776 10.2215/CJN.03960318 30049849\n4. Yang AM Shih SC Chu CH Wang TE Yang WS PRKCSH genetic mutation was not found in Taiwanese patients with polycystic liver disease Dig Dis Sci 2010 55 3 815 819 10.1007/s10620-009-0776-6 19308730\n5. Lanktree MB Haghighi A Guiard E Iliuta IA Song X Harris PC Prevalence estimates of polycystic kidney and liver disease by population sequencing J Am Soc Nephrol 2018 29 10 2593 2600 10.1681/ASN.2018050493 30135240\n6. Davila S Furu L Gharavi AG Tian X Onoe T Qian Q Mutations in SEC63 cause autosomal dominant polycystic liver disease Nat Genet 2004 36 6 575 577 10.1038/ng1357 15133510\n7. Fedeles SV Tian X Gallagher AR Mitobe M Nishio S Lee SH A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation Nat Genet 2011 43 7 639 647 10.1038/ng.860 21685914\n8. Perugorria MJ Masyuk TV Marin JJ Marzioni M Bujanda L LaRusso NF Polycystic liver diseases: advanced insights into the molecular mechanisms Nat Rev Gastroenterol Hepatol 2014 11 12 750 761 10.1038/nrgastro.2014.155 25266109\n9. Besse W Dong K Choi J Punia S Fedeles SV Choi M Isolated polycystic liver disease genes define effectors of polycystin-1 function J Clin Invest 2017 127 5 1772 1785 10.1172/JCI90129 28375157\n10. Cornec-Le Gall E Alam A Perrone RD Autosomal dominant polycystic kidney disease Lancet 2019 393 10174 919 935 10.1016/S0140-6736(18)32782-X 30819518\n11. Gabow PA Johnson AM Kaehny WD Manco-Johnson ML Duley IT Everson GT Risk factors for the development of hepatic cysts in autosomal dominant polycystic kidney disease Hepatology 1990 11 6 1033 1037 10.1002/hep.1840110619 2365280\n12. Torres VE Chapman AB Perrone RD Bae KT Abebe KZ Bost JE Analysis of baseline parameters in the HALT polycystic kidney disease trials Kidney Int 2012 81 6 577 585 10.1038/ki.2011.411 22205355\n13. Besse W, Chang AR, Luo JZ, Triffo WJ, Moore BS, Gulati A, et al. ALG9 mutation carriers develop kidney and liver cysts. J Am Soc Nephrol. 2019.\n14. Chebib FT Jung Y Heyer CM Irazabal MV Hogan MC Harris PC Effect of genotype on the severity and volume progression of polycystic liver disease in autosomal dominant polycystic kidney disease Nephrol Dial Transplant 2016 31 6 952 960 10.1093/ndt/gfw008 26932689\n15. Gigot JF Jadoul P Que F Van Beers BE Etienne J Horsmans Y Adult polycystic liver disease: is fenestration the most adequate operation for long-term management? Ann Surg 1997 225 3 286 294 10.1097/00000658-199703000-00008 9060585\n16. Drenth JP Chrispijn M Nagorney DM Kamath PS Torres VE Medical and surgical treatment options for polycystic liver disease Hepatology 2010 52 6 2223 2230 10.1002/hep.24036 21105111\n17. Everson GT Taylor MR Doctor RB Polycystic disease of the liver Hepatology 2004 40 4 774 782 10.1002/hep.1840400404 15382167\n18. Schnelldorfer T Torres VE Zakaria S Rosen CB Nagorney DM Polycystic liver disease: a critical appraisal of hepatic resection, cyst fenestration, and liver transplantation Ann Surg 2009 250 1 112 118 10.1097/SLA.0b013e3181ad83dc 19561475\n19. Cnossen WR Drenth JP Polycystic liver disease: an overview of pathogenesis, clinical manifestations and management Orphanet J Rare Dis 2014 9 69 10.1186/1750-1172-9-69 24886261\n20. Chebib FT Harmon A Irazabal Mira MV Jung YS Edwards ME Hogan MC Outcomes and durability of hepatic reduction after combined partial hepatectomy and cyst fenestration for massive polycystic liver disease J Am Coll Surg. 2016 223 1 118 26 10.1016/j.jamcollsurg.2015.12.051 27016902\n21. Wijnands TF Gortjes AP Gevers TJ Jenniskens SF Kool LJ Potthoff A Efficacy and safety of aspiration sclerotherapy of simple hepatic cysts: a systematic review AJR Am J Roentgenol 2017 208 1 201 207 10.2214/AJR.16.16130 27824501\n22. van Aerts RMM van de Laarschot LFM Banales JM Drenth JPH Clinical management of polycystic liver disease J Hepatol 2018 68 4 827 837 10.1016/j.jhep.2017.11.024 29175241\n23. Ueda M Egawa H Oike F Taira K Uryuhara K Fujimoto Y Living-donor liver transplantation for polycystic liver disease Transplantation 2004 77 3 480 481 10.1097/01.TP.0000110319.60723.31 14966436\n24. Morgan DE Lockhart ME Canon CL Holcombe MP Bynon JS Polycystic liver disease: multimodality imaging for complications and transplant evaluation Radiographics. 2006 26 6 1655 68 10.1148/rg.266065013 17102042\n25. Acar S Gencdal G Tokac M Eren E Alkara U Tellioglu G Liver transplantation for polycystic liver disease due to huge liver with related complications: a case report Transplant Proc 2017 49 3 603 605 10.1016/j.transproceed.2017.01.033 28340841\n26. Gringeri E D'Amico FE Bassi D Mescoli C Bonsignore P Boetto R Liver transplantation for massive hepatomegaly due to polycystic liver disease: an extreme case Transplant Proc 2012 44 7 2038 2040 10.1016/j.transproceed.2012.06.041 22974902\n27. Kirchner GI Rifai K Cantz T Nashan B Terkamp C Becker T Outcome and quality of life in patients with polycystic liver disease after liver or combined liver-kidney transplantation Liver Transpl 2006 12 8 1268 1277 10.1002/lt.20780 16741930\n28. Akihisa T Ino A Egawa H Kotera Y Ariizumi S Oomori A A case of a maintenance hemodialysis patient with autosomal dominant polycystic kidney disease who underwent living donor liver transplantation alone due to refractory liver cyst infection CEN Case Rep. 2018 7 2 307 312 10.1007/s13730-018-0348-8 29956096\n29. Takei R Ubara Y Hoshino J Higa Y Suwabe T Sogawa Y Percutaneous transcatheter hepatic artery embolization for liver cysts in autosomal dominant polycystic kidney disease Am J Kidney Dis 2007 49 6 744 752 10.1053/j.ajkd.2007.03.018 17533017\n30. Qian Q Du H King BF Kumar S Dean PG Cosio FG Sirolimus reduces polycystic liver volume in ADPKD patients J Am Soc Nephrol 2008 19 3 631 638 10.1681/ASN.2007050626 18199797\n31. Khan S Dennison A Garcea G Medical therapy for polycystic liver disease Ann R Coll Surg Engl 2016 98 1 18 23 10.1308/rcsann.2016.0023 26688394\n32. Hogan MC Masyuk TV Page L Holmes DR 3rd Li X Bergstralh EJ Somatostatin analog therapy for severe polycystic liver disease: results after 2 years Nephrol Dial Transplant 2012 27 9 3532 3539 10.1093/ndt/gfs152 22773240\n33. Pisani A Sabbatini M Imbriaco M Riccio E Rubis N Prinster A Long-term effects of octreotide on liver volume in patients with polycystic kidney and liver disease Clin Gastroenterol Hepatol. 2016 14 7 1022 30 10.1016/j.cgh.2015.12.049 26844873\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "15(1)",
"journal": "Journal of medical case reports",
"keywords": "Abdominal wall herniation; Case report; Polycystic liver disease",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D034861:Abdominal Wall; D003560:Cysts; D005260:Female; D006801:Humans; D008107:Liver Diseases; D008875:Middle Aged; D016891:Polycystic Kidney, Autosomal Dominant; D011788:Quality of Life",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "421",
"pmc": null,
"pmid": "34340688",
"pubdate": "2021-08-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19308730;16741930;24886261;29956096;28340841;19561475;24124322;2365280;9060585;22773240;31395617;18199797;14966436;30819518;26688394;27016902;28375157;16437702;15382167;25266109;30135240;26844873;30049849;29175241;27824501;22205355;26932689;17533017;21685914;17102042;21105111;22974902;15133510",
"title": "Polycystic liver disease with lethal abdominal wall rupture: a case report.",
"title_normalized": "polycystic liver disease with lethal abdominal wall rupture a case report"
} | [
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"companynumb": "JP-PFIZER INC-202200110581",
"fulfillexpeditecriteria": "1",
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"abstract": "BK virus nephropathy (BKVN) is an important clinical problem in kidney transplant (KT) recipients. The sequence of disease is usually viruria, viremia and then nephropathy. Diagnosis of BK virus (BKV) infection includes checking BKV DNA in the urine, in the plasma and histology on renal biopsy. This last method is used to diagnose BKVN. We describe a KT patient with BKVN without detectable BK viremia. A 62-year-old female with hypertensive nephropathy underwent renal transplant from a living relative donor in December 2011. Fourteen months after transplantation, her serum creatinine(SCr) rose up from 1.2 to 1.6 mg/dl with biopsy-proven acute antibody-mediated and cellular rejection. After pulse methylprednisolone, plasmapheresis and intravenous immunoglobulin, her SCr decreased to baseline but she subsequently developed cytomegalovirus infection with pancytopenia and transaminitis. The SCr rose to 1.9 mg/dl despite ganciclovir treatment. Renal ultrasound and antegrade pyelogram showed partial obstruction of the proximal ureter with moderate hydronephrosis. A quantitative polymerase chain reaction (PCR) assay for BKV DNA was negative (less than 10 copies/ml). A renal biopsy was performed and the pathology revealed viral cytopathic changes in the tubular epithelium with interstitial inflammation. The renal biopsy also showed BKV nucleic acid sequences by in-situ hybridization confirming BKVN. Immunosuppression regimen was changed to cyclosporine, low-dose prednisolone and leflunomide. A temporary percutaneous nephrostomy was performed. Her renal function improved within one week. The diagnosis of BKVN should be considered in a KT recipient with a rising SCr with or without BK viremia and should be made by renal biopsy.",
"affiliations": null,
"authors": "Ruangkanchanasetr|Prajej|P|;Pumchandh|Norawee|N|;Satirapoj|Bancha|B|;Termmathurapoj|Sumeth|S|;Pongthanapisith|Viroj|V|",
"chemical_list": "D004279:DNA, Viral; D007166:Immunosuppressive Agents",
"country": "Thailand",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0125-1562",
"issue": "46(4)",
"journal": "The Southeast Asian journal of tropical medicine and public health",
"keywords": null,
"medline_ta": "Southeast Asian J Trop Med Public Health",
"mesh_terms": "D001739:BK Virus; D001706:Biopsy; D004279:DNA, Viral; D005260:Female; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents; D007668:Kidney; D007674:Kidney Diseases; D016030:Kidney Transplantation; D008875:Middle Aged; D027601:Polyomavirus Infections; D014412:Tumor Virus Infections; D014766:Viremia",
"nlm_unique_id": "0266303",
"other_id": null,
"pages": "657-61",
"pmc": null,
"pmid": "26867385",
"pubdate": "2015-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "BIOPSY-PROVEN BK VIRUS NEPHROPATHY WITHOUT DETECTABLE BK VIREMIA IN A ONE-YEAR POST-KIDNEY TRANSPLANT RECIPIENT.",
"title_normalized": "biopsy proven bk virus nephropathy without detectable bk viremia in a one year post kidney transplant recipient"
} | [
{
"companynumb": "TH-ACCORD-043414",
"fulfillexpeditecriteria": "1",
"occurcountry": "TH",
"patient": {
"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "HUMAN IMMUNOGLOBULIN G"
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... |
{
"abstract": "BACKGROUND\nRecurrent respiratory papillomatosis (RRP) is a rare disease, which is characterised by the growth of papillomavirus-induced papillomas within the respiratory tract. Malignant transformation occurs in less than 1% of the cases.\n\n\nMETHODS\nWe report a case of human papillomavirus (HPV) type 11-associated juvenile-onset RRP (JORRP) initially diagnosed at the age of two years. Remarkably high copy numbers of HPV11 DNA and antibody titres targeting the capsid protein L1 were detected in the patient's serum. The patient developed squamous cell carcinomas in both lungs and extraordinarily an HPV11 DNA-positive papillary endocardial lesion in the left atrium of the heart, which caused thromboembolic events leading to the patient's death at 19 years old.\n\n\nCONCLUSIONS\nWe here report a severe case of JORRP hallmarked by HPV11 DNAemia and very high antibody titres directed against the major viral capsid protein L1. Furthermore, the extent of malignant transformation and the discovery of a very rare fatal endocardial lesion highlight the unpredictability of JORRP and the complexity of its clinical management.",
"affiliations": "Division of Experimental Virology, Institute for Medical Virology, University Hospital Tuebingen, Elfriede-Aulhorn-Str, 6, 72076 Tuebingen, Germany. Thomas.Iftner@med.uni-tuebingen.de.",
"authors": "Mauz|Paul-Stefan|PS|;Zago|Manola|M|;Kurth|Ralf|R|;Pawlita|Michael|M|;Holderried|Martin|M|;Thiericke|John|J|;Iftner|Angelika|A|;Stubenrauch|Frank|F|;Sotlar|Karl|K|;Iftner|Thomas|T|",
"chemical_list": "D000914:Antibodies, Viral; D004279:DNA, Viral",
"country": "England",
"delete": false,
"doi": "10.1186/1743-422X-11-114",
"fulltext": "\n==== Front\nVirol JVirol. JVirology Journal1743-422XBioMed Central 1743-422X-11-1142494288410.1186/1743-422X-11-114Case ReportA case of recurrent respiratory papillomatosis with malignant transformation, HPV11 DNAemia, high L1 antibody titre and a fatal papillary endocardial lesion Mauz Paul-Stefan 1Paul-Stefan.Mauz@med.uni-tuebingen.deZago Manola 2Manola.Zago@med.uni-tuebingen.deKurth Ralf 3Ralf.Kurth@med.uni-tuebingen.dePawlita Michael 4m.pawlita@dkfz.deHolderried Martin 1Martin.Holderried@med.uni-tuebingen.deThiericke John 1John.Thiericke@med.uni-tuebingen.deIftner Angelika 2Angelika.Iftner@med.uni-tuebingen.deStubenrauch Frank 2Frank.Stubenrauch@med.uni-tuebingen.deSotlar Karl 5karl.sotlar@med.uni-muenchen.deIftner Thomas 2Thomas.Iftner@med.uni-tuebingen.de1 Department of Otolaryngology, Head and Neck Surgery, University Hospital Tuebingen, Tuebingen, Germany2 Division of Experimental Virology, Institute for Medical Virology, University Hospital Tuebingen, Elfriede-Aulhorn-Str. 6, 72076 Tuebingen, Germany3 Institute of Pathology, University Hospital Tuebingen, Tuebingen, Germany4 Department of Genome Modifications and Carcinogenesis, Research Program Infection and Cancer, German Cancer Research Centre (DKFZ), Heidelberg, Germany5 Institute of Pathology, University of Munich, Munich, Germany2014 18 6 2014 11 114 114 23 1 2014 12 6 2014 Copyright © 2014 Mauz et al.; licensee BioMed Central Ltd.2014Mauz et al.; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nRecurrent respiratory papillomatosis (RRP) is a rare disease, which is characterised by the growth of papillomavirus-induced papillomas within the respiratory tract. Malignant transformation occurs in less than 1% of the cases.\n\nCase presentation\nWe report a case of human papillomavirus (HPV) type 11-associated juvenile-onset RRP (JORRP) initially diagnosed at the age of two years. Remarkably high copy numbers of HPV11 DNA and antibody titres targeting the capsid protein L1 were detected in the patient’s serum. The patient developed squamous cell carcinomas in both lungs and extraordinarily an HPV11 DNA-positive papillary endocardial lesion in the left atrium of the heart, which caused thromboembolic events leading to the patient’s death at 19 years old.\n\nConclusion\nWe here report a severe case of JORRP hallmarked by HPV11 DNAemia and very high antibody titres directed against the major viral capsid protein L1. Furthermore, the extent of malignant transformation and the discovery of a very rare fatal endocardial lesion highlight the unpredictability of JORRP and the complexity of its clinical management.\n\nJORRPHPV11HPV DNAemia\n==== Body\nBackground\nJuvenile onset recurrent respiratory papillomatosis (JORRP) is a relatively rare disease, but still the most common pediatric neoplasm found in the larynx. Papillomas generally appear in the larynx of children before the age of five and recur after surgical excision in a majority of cases. Only 5% of the patients show involvement of trachea and bronchi and 1% of patients will develop manifestations within the lung parenchyma [1,2]. Rarely, spontaneous carcinomatous transformation occurs [3]. Generally, distant metastases do not occur [2]. Clinical and epidemiological studies have determined that HPV is the etiological agent of JORRP [4,5] with HPV6 and 11 accounting for most cases. Most reports of JORRP-associated squamous cell carcinomas of the lung, in which an HPV type was determined, describe male patients with HPV11-associated JORRP [3,6-11].\n\nHere we describe a 19-year-old male patient with an aggressive form of JORRP that required a total of 132 interventions within the 17 years following diagnosis.\n\nCase presentation\nA 14 year old male patient was referred to the Department of Otolaryngology, Head and Neck Surgery at the University Hospital Tuebingen in August 2002. Diagnosed at the age of two he underwent tracheostomy and since had been treated for juvenile onset recurrent respiratory papillomatosis (JORRP) through multiple surgeries. Papillomas were detectable in the larynx, trachea, and main bronchi and the patient had progressive lung manifestations. At the time of referral the patient had already undergone 116 operations. A total of 16 surgical excisions and laser ablations were performed during the following 5 years. In addition to ablative therapies, the patient was treated with the antiviral drug cidofovir for three years (2004–2007): first intralesionally, later systemically and finally via inhalations.\n\nAt the age of 18, he presented with a tracheal stenosis that was treated by balloon dilatation; he was also affected by pneumothorax and subcutaneous emphysema of his upper body, which was treated by a thoracic drainage. One year later the patient developed symptoms of Leriche’s syndrome caused by thromboembolic occlusion of the aortoiliac bifurcation. An embolectomy was performed. Additional thromboembolic events caused minor infarctions in both kidneys and the spleen. An ischemic stroke in the supply area of the left middle cerebral artery caused aphasia, hemiparesis and facial nerve paresis. Four days later, another thromboembolic crisis led to an occlusion of both femoral arteries. Magnetic resonance imaging revealed a suspicious mass in the left cardiac atrium, involving the right pulmonary vein. About one month later a series of thromboembolic events involving the brain, liver, heart, kidneys, aorta, and pelvic arteries occurred. The patient finally died and an autopsy was performed at the Institute of Pathology, University Hospital Tuebingen.\n\nAssociation of the patient’s disease with HPV11\nTo characterise the patient’s viral infection in more detail, DNA was extracted from surgically removed laryngeal papillomas. Exclusively HPV11 DNA was detected in the specimens and qRT-PCR (see Additional file 1) estimated the viral genome copy number as 1.2 × 104 copies/cell. These viral load values are suggestive of a productive infection at the larynx. A full length HPV11 genome was isolated from a laryngeal papilloma and completely sequenced. The genome was 99% identical to the prototype sequence [12] (NCBI number: M14119), with a total of 27 nucleotide deviations. Fifteen of which did not result in amino acid substitutions in the respective proteins. Three mutations, one deletion and three nucleotide insertions occurred in the Long Control Region. The remaining five mutations affected the amino acid sequence of viral proteins (Table 1), however, the analysis of the protein sequences revealed that these mutations do not occur in conserved or functional domains and most probably do not interfere with the proteins’ activities.\n\nTable 1 Detected amino acid changes within the isolated HPV11 genome\n\nNucleotide position\tReference sequence HPV11\tDetected change\tAffected amino acid\tAffected viral protein\t\n662\tG\tT\tAla 45 → Ser 45\tE7\t\n1783-1784\tCG\tGC\tArg 318 → Ala 318\tE1\t\n3645\tA\tG\tLys 308 → Arg 308\tE2\t\n3952\tA\tT\tLeu 28 → Phe 28\tE5A\t\n3991\tG\tC\tVal 41 → Leu 41\tE5A\t\nPatient’s blood samples were investigated for the presence of HPV11 (Table 2). Total DNA was extracted from 200 μl of whole blood, plasma, leukocyte and erythrocyte fractions. HPV11 DNA was only detected in whole blood and the plasma fraction but not in any of the cellular fractions. qRT-PCR determined that 8.85 × 105 viral genome copies/ml were present in the whole blood and 1.55 × 106 viral genome copies/ml were measured within the plasma fraction. These data suggest that most viral genomes were not cell associated, which was supported by the data obtained by measuring the viral load within the filtered plasma fraction (0.2 μm filters), where all possible residual cells were eliminated, and 5.61 × 105 viral genome copies/ml remained. As a way of indirectly demonstrating the presence of viral particles, plasma samples were treated with Benzonase in order to digest all unencapsidated DNA. Benzonase treatment has previously been reported to be both effective and safe for the elimination of free viral DNA from papillomavirus suspensions [13]. Our results indicate that probably no viral particles were present within the patient’s plasma samples (Table 3).\n\nTable 2 Viral genome copy numbers in whole blood and plasma\n\nPatient specimen\tViral genome copies/ml\t\nWhole blood\t8.85 × 105\t\nPlasma fraction\t1.55 × 106\t\nFiltered plasma fraction\t5.61 × 105\t\nTable 3 Viral particles are not present in the patient’s plasma after treatment with Benzonase\n\n \tProteinase K\tBenzonase\tLiPa genotyping results\t\nSiHa control\t+\t \tHPV16\t\nSiHa control\t+\t+\tHPV-negative\t\nSiHa control\t \t+\tHPV-negative\t\nPlasma\t+\t \tHPV11\t\nPlasma\t+\t+\tHPV-negative\t\nPlasma\t \t+\tHPV-negative\t\nThe patient’s immune-response against HPV was determined in blood samples from August 2005 and April 2007. In 2005 a significant response to the major capsid protein L1 of HPV11 was present with about 3,000 median fluorescence units (MFI) at a dilution of 1:100. The antibody response increased further to 30,000 MFI in the 2007 sample indicating a more than 10-fold increase in titre. No antibodies against HPV11 E6 and E7 were detected.\n\nAutopsy findings\nPost mortem examinations revealed that the patient presented with a papillomatous neoplasia of the trachea and main bronchi with what appeared to be microinvasive growth (Figure 1A). Canalicular dissemination within the respiratory tree had occurred. Notably, all pulmonary lobes were affected by multiple confluent well-differentiated squamous cell carcinomas (Figure 1B) with minor foci of keratinisation (Figure 1C) and focal necrosis, developing on the basis of respiratory papillomas with marked cytological atypias (Figure 1D). In the left atrium, a large thrombus was found (Figure 1E, F) behind a sessile papillomatous lesion (Figure 1G), structurally, cytologically, and immunohistochemically identical to the tracheal and pulmonary respiratory papillomas (Figure 1H). Immunohistochemical examination revealed cytokeratin 5 and 6 expression in all neoplastic lesions indicating that the lesion was of epithelial origin (Figure 2). Notably, no lymph node or hematogenous metastases were found.\n\nFigure 1 Post-mortem autopsy results. Laryngeal respiratory papillomas with focal squamous metaplasia (A); multiple nodules (B) of well differentiated squamous cell carcinoma (C); shed tumor cells with marked cytologic atypia, reminiscent of respiratory papilloma (D); left atrial thrombus (E) and thromboembolus riding on the aorto-iliacal bifurcation (F); area of endocardial papillomatosis in the left atrium (G, H) as the basis for recurrent thrombosis.\n\nFigure 2 Immunohistochemical staining for the expression of cytokeratin 5/6, a typical marker of squamous epithelium, on a section of a focal squamous papillary metaplasia of the left atrium.\n\nMolecular biological analyses revealed the presence of HPV DNA in autoptic tissues of lung tumors and left atrial papillomas. In addition, HPV DNA was detected in the left atrial thrombus and the aorto-iliac thromboembolus. HPV-genotyping by nested multiplex PCR [14] revealed strong bands specific for HPV6/11. In order to distinguish between HPV6 and HPV11 DNA, direct sequencing was performed (see Additional file 1) demonstrating the exclusive presence of HPV11 in lung tissue and atrial papillomas which was confirmed by LiPa V2 genotyping as an independent method of HPV detection.\n\nConclusion\nJORRP is a rare disease which is typically diagnosed in early childhood. It is thought to be caused by the HPV types 6 and 11, which may have been vertically transmitted to the child at birth. It usually affects the larynx, but up to 5% of the patients show involvement of trachea and bronchi and 1% of patients develop manifestations within the lung parenchyma [1,2]. Rarely spontaneous carcinomatous transformation occurs [3], but distant metastases do not develop [2]. We here describe a 19-year-old male patient with an aggressive form of JORRP that required numerous interventions after diagnosis. Scattered papillomas were found in the trachea, bronchi, and both lungs. In multiple locations, bilateral malignant transformation into well-differentiated squamous cell carcinomas had occurred. HPV11 was detected in laryngeal biopsies at high viral load, suggestive of an on-going productive infection. Moreover, HPV11 was detected in autopsy material of the pulmonary squamous cell carcinomas, the left atrial papilloma, the left atrial thrombus, and the thromboembolic material. The same HPV type was isolated and cloned from the laryngeal biopsy. Sequencing of the patient’s HPV11 isolate showed that it is 99% identical to the HPV11 reference nucleotide sequence [12]. It revealed 15 mutations previously observed in an HPV11 isolate from a squamous cell carcinoma of the penis [15,16].\n\nHPV infections usually remain localised and viral particles are not shed into the blood stream. Interestingly however, high viral genome copy numbers were detected in the plasma fraction of the patient’s blood, but not in the cellular fraction demonstrating that the viral genomes were not cell associated. The increased number of viral genomes detected within the plasma as compared to the whole blood (Table 2) is explained by the exclusion of the HPV-negative cellular fraction, which ultimately led to a concentration of the remaining plasma fraction. In connection with the high viral load within the serum, our patient presented high antibody titres against the viral structural protein L1. The antibody titre measured in the 2007 sample (Table 2) is one of the highest ever seen in our laboratory, which usually processes samples from patients vaccinated with the quadrivalent vaccine against HPV6, 11, 16 and 18. Interestingly, no antibodies against the oncoproteins E6 and E7 were detected. A similar immune response against the structural proteins of the virus is typically induced by HPV vaccines or by viral particles entering the blood stream, however, we were not able to show the presence of viral particles within the patient’s plasma. As HPV infections usually remain localised and viral particles are not shed into the blood stream, we hypothesise that a potential angioinvasion of the lung squamous cell carcinoma may have provided a way which enabled viral DNA to enter the blood stream. On another note, it is possible that the high HPV DNA levels originate from necrotic cells or thrombi shed from the endocardial lesion and/or respiratory tumors. In a study from Maloney et al., only 20% of the patients show detectable antibody levels [17]. Interestingly, those three reported patients also had the highest levels of HPV11 viral load and the highest average numbers of annual surgical procedures. HPV DNA has previously been detected within blood cells of healthy individuals [18] and in the plasma of HIV-1 patients [19] and women with cervical cancer [20,21]. However, none of these studies examined the immune response.\n\nFrom the history of our patient it appears that the spread of the HPV infection was not contained by high antibody titres directed against L1. Alternatively, spread of infection might have occurred at a very early stage especially considering that multiple surgical interventions might have increased the risk for tracheal and pulmonary involvement. Viral DNA could therefore have persisted for a considerable time before disease progression and we speculate that a high antibody titre might reflect an increase in disease progression and an elevation of productive infection within existing papillomas.Post mortem examination revealed that descending tracheobronchial respiratory papillomas had undergone squamous metaplasia and subsequent malignant transformation into well-differentiated squamous cell carcinomas. Based on the structural and cytological similarity, including cytological atypia of the tracheobronchial, pulmonary and atrial papillomatous lesions, we conclude that all, especially the latter lesion, were HPV-induced. More importantly, these papillomatous lesions were the source for the recurrent thromboembolic events (Figure 1F) that had led to two episodes of Leriche’s syndrome and to multiple ischemic infractions in various organs, including spleen, kidneys, lower extremities, brain, and heart.\n\nOn the basis of the detection of HPV11 DNA in the atrial papilloma, we demonstrated the presence of a very rare endocardial papilloma [22]. To our knowledge this is the first report of an HPV-induced endocardial papilloma as the source of fatal thromboembolic complications during the course of canalicular disseminating HPV11-associated longstanding JORRP disease with malignant transformation into well-differentiated squamous cell carcinoma. In addition, this case is remarkable considering the high levels of viral DNA detected within the patient’s serum and the high immune response directed against the viral structural surface protein L1. A humoral immune response against structural proteins is outmost uncommon in RRP patients and may in our case be explained by the presence of productive papilloma tissue. In summary, we here reported a severe case of JORRP hallmarked by HPV11 DNAemia and very high L1-antibody titres. Furthermore, our unusual and unexpected finding of the extent of malignant transformation and the discovery of a very rare fatal endocardial lesion highlight the unpredictability of JORRP and the complexity of its clinical management.\n\nEthics and consent\nEthical approval for the Cidofovir inhalation therapy was obtained from the Ethics Committee of the University Hospital Tuebingen. Written informed consent for the inhalation therapy and the publication of this case report and accompanying images and data was obtained from the patient and his next of kin. A copy of the written consent is available for review by the Editor of this journal. All methodology reported in this paper served for the sole purpose of diagnostics.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\nPSM was the leading clinician in this case, who was involved in acquisition and interpretation of clinical data and contributed in the writing of the article. MZ drafted the manuscript, contributed to the study design, was involved in acquisition, analysis and interpretation of molecular-biological data. RK, MH, JT were involved in the acquisition of clinical data. MP, AI acquired molecular-biological data. FS substantially contributed to the manuscript. KS was the leading pathologist and involved in acquisition of the autopsy data. TI was the leading molecular biologist, substantially contributed to the writing of the article. All authors have read and approved the final manuscript.\n\nSupplementary Material\nAdditional file 1\nMethods.\n\nClick here for file\n\n Acknowledgement\nWe thank Dr Juliane Haedicke for assistance in drafting the manuscript. Molecular-biological detection methods were funded by the German Research Foundation (DFG; grant SFB773/B4) to TI. In addition, publication was supported by the DFG and the Open Access Publishing Fund of Tuebingen University.\n==== Refs\nKramer SS Wehunt WD Stocker JT Kashima H Pulmonary manifestations of juvenile laryngotracheal papillomatosis AJR Am J Roentgenol 1985 144 4 687 94 10.2214/ajr.144.4.687 3872022 \nMagid MS Chen YT Soslow RA Boulad F Kernan NA Szabolcs P Juvenile-onset recurrent respiratory papillomatosis involving the lung: a case report and review of the literature Pediatr Dev Pathol 1998 1 2 157 63 10.1007/s100249900021 9507042 \nGuillou L Sahli R Chaubert P Monnier P Cuttat JF Costa J Squamous cell carcinoma of the lung in a nonsmoking, nonirradiated patient with juvenile laryngotracheal papillomatosis. evidence of human papillomavirus-11 DNA in both carcinoma and papillomas Am J Surg Pathol 1991 15 9 891 8 10.1097/00000478-199109000-00010 1659237 \nDickens P Srivastava G Loke SL Larkin S Human papillomavirus 6, 11, and 16 in laryngeal papillomas J Pathol 1991 165 3 243 6 10.1002/path.1711650308 1662265 \nLindeberg H Johansen L The presence of human papillomavirus (HPV) in solitary adult laryngeal papillomas demonstrated by in-situ DNA hybridization with sulphonated probes Clin Otolaryngol Allied Sci 1990 15 4 367 71 10.1111/j.1365-2273.1990.tb00485.x 2171818 \nByrne JC Tsao MS Fraser RS Howley PM Human papillomavirus-11 DNA in a patient with chronic laryngotracheobronchial papillomatosis and metastatic squamous-cell carcinoma of the lung N Engl J Med 1987 317 14 873 8 10.1056/NEJM198710013171406 2442608 \nCook JR Hill DA Humphrey PA Pfeifer JD El-Mofty SK Squamous cell carcinoma arising in recurrent respiratory papillomatosis with pulmonary involvement: emerging common pattern of clinical features and human papillomavirus serotype association Mod Pathol 2000 13 8 914 8 10.1038/modpathol.3880164 10955460 \nLee AS Rosen CA Efficacy of cidofovir injection for the treatment of recurrent respiratory papillomatosis J Voice 2004 18 4 551 6 10.1016/j.jvoice.2003.07.007 15567056 \nLindeberg H Syrjanen S Karja J Syrjanen K Human papillomavirus type 11 DNA in squamous cell carcinomas and pre-existing multiple laryngeal papillomas Acta Otolaryngol 1989 107 1–2 141 9 2538994 \nRady PL Schnadig VJ Weiss RL Hughes TK Tyring SK Malignant transformation of recurrent respiratory papillomatosis associated with integrated human papillomavirus type 11 DNA and mutation of p53 Laryngoscope 1998 108 5 735 40 10.1097/00005537-199805000-00021 9591556 \nXu H Lu DW El-Mofty SK Wang HL Metachronous squamous cell carcinomas evolving from independent oropharyngeal and pulmonary squamous papillomas: association with human papillomavirus 11 and lack of aberrant p53, Rb, and p16 protein expression Hum Pathol 2004 35 11 1419 22 10.1016/j.humpath.2004.06.003 15668901 \nDartmann K Schwarz E Gissmann L zur Hausen H The nucleotide sequence and genome organization of human papilloma virus type 11 Virology 1986 151 1 124 30 10.1016/0042-6822(86)90110-8 3008427 \nBuck CB Pastrana DV Lowy DR Schiller JT Efficient intracellular assembly of papillomaviral vectors J Virol 2004 78 2 751 7 10.1128/JVI.78.2.751-757.2004 14694107 \nSotlar K Diemer D Dethleffs A Hack Y Stubner A Vollmer N Menton S Menton M Dietz K Wallwiener D Kandolf R Bultmann B Detection and typing of human papillomavirus by e6 nested multiplex PCR J Clin Microbiol 2004 42 7 3176 84 10.1128/JCM.42.7.3176-3184.2004 15243079 \nMcGlennen RC Ghai J Ostrow RS LaBresh K Schneider JF Faras AJ Cellular transformation by a unique isolate of human papillomavirus type 11 Cancer Res 1992 52 21 5872 8 1327518 \nMcGlennen RC Ghai J Ostrow RS LaBresh K Schneider JF Faras AJ Correction Cancer Res 1997 57 17 3867 \nMaloney EM Unger ER Tucker RA Swan D Karem K Todd NW Reeves WC Longitudinal measures of human papillomavirus 6 and 11 viral loads and antibody response in children with recurrent respiratory papillomatosis Arch Otolaryngol Head Neck Surg 2006 132 7 711 5 10.1001/archotol.132.7.711 16847177 \nChen AC Keleher A Kedda MA Spurdle AB McMillan NA Antonsson A Human papillomavirus DNA detected in peripheral blood samples from healthy Australian male blood donors J Med Virol 2009 81 10 1792 6 10.1002/jmv.21592 19697401 \nSirera G Videla S Romeu J Canadas M Fernandez MT Balo S Cirauqui B Darwich L Rey-Joly C Clotet B Fatal fast-evolution of nasopharyngeal squamous cell carcinoma in an HIV patient with EBV and HPV (-16 AND -33) in blood serum Open AIDS J 2008 2 1 2 10.2174/1874613600802010001 18923693 \nSathish N Abraham P Peedicayil A Sridharan G John S Shaji RV Chandy G HPV DNA in plasma of patients with cervical carcinoma J Clin Virol 2004 31 3 204 9 10.1016/j.jcv.2004.03.013 15465413 \nGnanamony M Peedicayil A Subhashini J Ram TS Rajasekar A Gravitt P Abraham P Detection and quantitation of HPV 16 and 18 in plasma of Indian women with cervical cancer Gynecol Oncol 2010 116 3 447 51 10.1016/j.ygyno.2009.10.081 19922992 \nSalyer WR Page DL Hutchins GM The development of cardiac myxomas and papillary endocardial lesions from mural thrombus Am Heart J 1975 89 1 4 17 10.1016/0002-8703(75)90003-4 1109550\n\n",
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"title": "A case of recurrent respiratory papillomatosis with malignant transformation, HPV11 DNAemia, high L1 antibody titre and a fatal papillary endocardial lesion.",
"title_normalized": "a case of recurrent respiratory papillomatosis with malignant transformation hpv11 dnaemia high l1 antibody titre and a fatal papillary endocardial lesion"
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"abstract": "Treatment and prognosis of neuroendocrine neoplasia depends on tumor size, stage, grade, resectability, and extent of distant metastasis. In most cases a multimodality approach including surgical, locally invasive procedures, peptide-guided radioreceptor therapy (PRRT), and medical therapies represent the mainstay of treatment in advanced disease. In the reported case, a 68-year-old man was diagnosed in 2010 with an initially functional (histamine) neuroendocrine tumor of gastric type III, G2, stage IVB, cT4cN1cM1 (hepatic, peritoneal, nodal, osseous), including a hepatic tumor load of 25%. Intensive multimodality approaches including combined immunotherapy (vaccination and PD-1/CTLA-4 blockade) led to a survival of 8 years until now with a high quality of life and minimal residual disease (only a single, small paragastric recurrence) despite the dedifferentiation of the tumor into a neuroendocrine carcinoma G3 (Ki-67 of 80%) including a nonfunctional stage.",
"affiliations": "Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Berlin, Germany.;Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Berlin, Germany.",
"authors": "Schmidt|Daniel|D|;Wiedenmann|Bertram|B|",
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"keywords": "CTLA-4; Combined immunotherapy; Neuroendocrine carcinoma; Neuroendocrine neoplasia; Neuroendocrine tumor; PD-1",
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"mesh_terms": "D000368:Aged; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D000971:Antineoplastic Combined Chemotherapy Protocols; D006801:Humans; D007167:Immunotherapy; D000074324:Ipilimumab; D008113:Liver Neoplasms; D008297:Male; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D018358:Neuroendocrine Tumors; D013274:Stomach Neoplasms",
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"title": "Extremely Long Survival under Combined Immunotherapy in a Metastatic Functional Neuroendocrine Neoplasia Patient.",
"title_normalized": "extremely long survival under combined immunotherapy in a metastatic functional neuroendocrine neoplasia patient"
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{
"abstract": "Hypersensitivity reactions (HSRs) to platinum salts (PS) and taxanes (TX) are a challenge to cancer management. Allergy evaluation based on skin tests (ST) and graded challenges can provide a diagnosis of an allergy to a suspected drug and indicate possible treatment with alternative same-class drugs.\n\n\n\nThis study aimed to estimate the negative predictive value of ST in the diagnosis of HSRs to TX and PS.\n\n\n\nThis multicenter study prospectively enrolled patients with a suspected HSR to PS and TX. ST were performed for chemotherapy, drugs of the same pharmacological class, and other agents (latex or cotreatments). For patients with negative ST, a graded challenge was performed by the cancer teams trained in allergy management.\n\n\n\nA total of 119 consecutive patients were included during a 6-year period. ST results were positive for 58% of the cohort: for TX in 7 patients and for PS in 62 patients. Other agents were responsible for 4.2% of cases. Skin cross-reactivity was 50% for TX and 30% for PS. A graded challenge was performed in 14 patients for TX and in 50 patients for PS. Negative predictive values (NPVs) for ST were 100% for TX and 92% for PS, with NPVs for individuals PS of 100% for cisplatin, 89% for oxaliplatin, and 87% for carboplatin.\n\n\n\nST to PS or TX offered a high NPV, making allergy evaluation a key element in the management of patients with cancer. Graded challenges can be safely performed by oncology teams trained in anaphylaxis management.",
"affiliations": "Department of Pulmonary Medicine and Allergology, CHU de Nice, FHU OncoAge, Université Côte d'Azur, Nice, France.;Department of Pulmonary Medicine and Allergology, CHU de Nice, FHU OncoAge, Université Côte d'Azur, Nice, France.;Department of Pulmonary Medicine and Allergology, CHU de Nice, FHU OncoAge, Université Côte d'Azur, Nice, France.;Department of Gastroenterology, CHU de Nice, Université Côte d'Azur, Nice, France.;Department of Oncology, Centre Antoine Lacassagne, Nice, France.;Department of Pharmacology, CHU de Nice, Université Côte d'Azur, Nice, France.;Department of Pulmonary Medicine and Allergology, CHU de Nice, FHU OncoAge, Université Côte d'Azur, Nice, France; IRCAN, Inserm U1081/CNRS 7284, FHU OncoAge, Université Côte d'Azur, Nice, France.;Department of Pulmonary Medicine and Allergology, CHU de Nice, FHU OncoAge, Université Côte d'Azur, Nice, France; IRCAN, Inserm U1081/CNRS 7284, FHU OncoAge, Université Côte d'Azur, Nice, France.;Department of Pulmonary Medicine and Allergology, CHU de Nice, FHU OncoAge, Université Côte d'Azur, Nice, France.;Department of Pulmonary Medicine and Allergology, CHU de Nice, FHU OncoAge, Université Côte d'Azur, Nice, France; Institut de Pharmacologie Moléculaire et Cellulaire, CNRS UMR 7275, Université Côte d'Azur, Sophia Antipolis, Nice, France. Electronic address: leroy.s2@chu-nice.fr.",
"authors": "Pradelli|Johana|J|;Verdoire|Paul|P|;Boutros|Jacques|J|;Frin|Anne-Claire|AC|;Follana|Philippe|P|;Duquesne|Julien|J|;Marquette|Charles-Hugo|CH|;Benzaquen|Jonathan|J|;Ben Hayoun|Michèle|M|;Leroy|Sylvie|S|",
"chemical_list": "D004364:Pharmaceutical Preparations; D012492:Salts; D043823:Taxoids; D010984:Platinum",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jaip.2019.12.032",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "8(5)",
"journal": "The journal of allergy and clinical immunology. In practice",
"keywords": "Chemotherapy; Drug allergy; Graded challenge; Platinum salts; Skin tests; Taxanes",
"medline_ta": "J Allergy Clin Immunol Pract",
"mesh_terms": "D004342:Drug Hypersensitivity; D006801:Humans; D004364:Pharmaceutical Preparations; D010984:Platinum; D012492:Salts; D012882:Skin Tests; D043823:Taxoids",
"nlm_unique_id": "101597220",
"other_id": null,
"pages": "1658-1664",
"pmc": null,
"pmid": "31918017",
"pubdate": "2020-05",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Allergy Evaluation of Hypersensitivity to Platinum Salts and Taxanes: A Six-Year Experience.",
"title_normalized": "allergy evaluation of hypersensitivity to platinum salts and taxanes a six year experience"
} | [
{
"companynumb": "FR-TEVA-2020-FR-1512620",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "Renal lymphoma is an uncommon renal tumor in children. Unlike renal lymphomas presenting as bilateral disease and renal failure, we report a boy who presented with unilateral renal involvement. After initial nephrectomy, he achieved remission with multiagent chemotherapy but relapsed systemically within 3 months. He was initiated on salvage chemotherapy with autologous bone marrow transplant. Even though the initial manifestation was localized lymphoma eventually, it turned out to be a systemic disease. He succumbed to disease at 14 months from diagnosis.",
"affiliations": "Department of Medical Oncology, Mazumdar-Shaw Cancer Center, Bangalore, Karnataka, India.;PGY2, Pediatric, TTUHSC, Amarillo, TX, USA.;Department of Medical Oncology, Nizams Institute of Medical Science, Hyderabad, Telangana, India.;Department of Pathology, Nizams Institute of Medical Science, Hyderabad, Telangana, India.",
"authors": "Coca|Pragnya|P|;Linga|Vijay Gandhi|VG|;Gundeti|Sadashivudu|S|;Tandon|Ashwani|A|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.4103/ijmpo.ijmpo_48_16",
"fulltext": "\n==== Front\nIndian J Med Paediatr OncolIndian J Med Paediatr OncolIJMPOIndian Journal of Medical and Paediatric Oncology : Official Journal of Indian Society of Medical & Paediatric Oncology0971-58510975-2129Medknow Publications & Media Pvt Ltd India IJMPO-38-53810.4103/ijmpo.ijmpo_48_16Practitioner SectionRenal Lymphoma: Primary or First Manifestation of Aggressive Pediatric B-cell Lymphoma Coca Pragnya Linga Vijay Gandhi 1Gundeti Sadashivudu 2Tandon Ashwani 3Department of Medical Oncology, Mazumdar-Shaw Cancer Center, Bangalore, Karnataka, India1 PGY2, Pediatric, TTUHSC, Amarillo, TX, USA2 Department of Medical Oncology, Nizams Institute of Medical Science, Hyderabad, Telangana, India3 Department of Pathology, Nizams Institute of Medical Science, Hyderabad, Telangana, IndiaAddress for correspondence: Dr. Sadashivudu Gundeti, Department of Medical Oncology, Nizams Institute of Medical Science, Hyderabad - 500 082, Telangana, India. E-mail: drssgundeti@yahoo.comOct-Dec 2017 38 4 538 541 Copyright: © 2017 Indian Journal of Medical and Paediatric Oncology2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Renal lymphoma is an uncommon renal tumor in children. Unlike renal lymphomas presenting as bilateral disease and renal failure, we report a boy who presented with unilateral renal involvement. After initial nephrectomy, he achieved remission with multiagent chemotherapy but relapsed systemically within 3 months. He was initiated on salvage chemotherapy with autologous bone marrow transplant. Even though the initial manifestation was localized lymphoma eventually, it turned out to be a systemic disease. He succumbed to disease at 14 months from diagnosis.\n\nKeywords\nChemotherapynephrectomyrenal lymphoma\n==== Body\nIntroduction\nPrimary renal lymphoma (PRL) is an uncommon renal tumor and constitutes 0.7% of extranodal lymphomas.[1] PRL is a rare diagnosis in pediatric age group.[23] Secondary involvement of kidneys in lymphoma is very common entity but primary involvement is rare.[4] PRL in pediatric age groups manifest as bilateral renal involvement, renal failure, and anemia.[23] There is no standard treatment approach in case of PRL in children.[25] We report a very interesting case in a 10-year-old boy presenting as unilateral renal involvement, without any symptoms. With a suspicion of Wilms tumor, he underwent nephrectomy. In spite of aggressive treatment, he relapsed systemically and succumbed to disease.\n\nCase Report\nA 10-year-old boy presented to outside facility with complaints of a diffuse lump in the left flank, incidentally noticed by his mother. There is no history of fever, chills, pain, nausea, vomiting, diarrhea, constipation, urinary complaints, chronic infections, or any other palpable masses. Preliminary physical examination showed no fever, dysmorphic features, hypertension, or lymphadenopathy. There was a ballotable left flank mass that was firm to hard in consistency with ill-defined border. An abdominal sonogram revealed a large, solid, reniform mass with heterogeneous echo pattern in the left renal fossa. Hemogram, metabolic, and liver functions were within normal limits, and blood urea was 22 mg/dl and creatinine was 0.7 mg/dl. He was negative for HIV, HbsAg, and HCV. A contrast-enhanced computed tomography study of the chest and abdomen showed an enlarged left kidney, measuring 17.9 cm × 11.5 cm × 10.5 cm, with loss of internal morphological architecture, uniform hypoattenuation, and few areas of heterogeneous enhancement. There were no calcific foci. The renal artery was encased by the mass while the renal vein was patent. There were a few subcentimeter left paraaortic nodes. Lungs and mediastinum were normal. A provisional diagnosis of Wilms tumor was made. The boy was transferred to the care of a surgical oncologist. He underwent a left radical nephrectomy. Postoperative histopathological examination of the specimen was reported as malignant small round cell tumor, without capsular infiltration or vascular emboli, not involving the ureter, possibly Wilms tumor with the diffuse blastemal pattern. The resected lymph nodes were free of metastases. Postoperatively, he received locoregional radiation therapy (RT) to the tumor bed with three-drug regimen as per National Wilms Tumor Study Group IV.\n\nA month later, the boy developed enlargement of the right tonsil and swelling in the right groin. Physical examination showed mild pallor, a right tonsillar mass that was 5 cm × 5 cm and displacing the uvula to other side and right inguinal lymphadenopathy of 3 cm × 3 cm. A fine needle aspiration of the right inguinal lymph node showed metastatic deposits of a malignant round cell tumor. At this point of time, he was referred to our center for further management. The histopathology of the nephrectomy specimen was reviewed. Morphology and immunohistochemistry showed small, round, relatively undifferentiated cells in sheets positive for CD20 and negative for WT-2 and pancytokeratin. A diagnosis of B-non-Hodgkin lymphoma (B-NHL) of the kidney was made. Staging investigations with the whole body 18F fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) showed hypermetabolic large residual disease in the right renal bed and multiple hypermetabolic right tonsil, mediastinal, abdominal and inguinal lymphadenopathy. Bone marrow biopsy was normal. He was diagnosed as B-NHL Stage III A. He was started on chemotherapy with NHL-BFM 95 protocol. He tolerated chemotherapy well and responded well. At the end of six cycles of chemotherapy, he was in complete remission. After 3 months, he again presented with bilateral cervical lymphadenopathy, and biopsy confirmed relapse of B-NHL. Staging workup showed disease on both sides of diaphragm and bone marrow biopsy was negative. He was given salvage treatment with 4 cycles of ifosfamide, etoposide, and carboplatin. He had a very good partial response. In view of limited options and guarded prognosis in a case of early relapsed extranodal NHL in a child, parents consented for autologous bone marrow transplant. After evaluating for the organ reserve, a standard myeloablative regimen of BCNU, etoposide, cytarabine, and melphalan was used. He tolerated the procedure well with mucositis and myelosuppression as main toxicity. At end of 1 month, he was clinical in remission. Two months after autologous BMT, he once again had florid relapse and succumbed to disease, 14 months after diagnosis.\n\nDiscussion\nMost common causes of benign enlargement of kidneys are hydronephrosis, polycystic kidney disease, mesoblastic nephroma, multilocular cystic nephroma, multicystic dysplastic kidneys, renal abscess, mesoblastic nephroma, and medullary cystic disease complex. Common malignant kidney tumor is Wilms tumor, neuroblastoma [Table 1].[6]\n\nTable 1 Common Pediatric Renal Tumors\n\nInvolvement of kidneys in NHL is common and presents as hypodense nodular lesions on imaging or autopsies.[4] Primary involvement of kidney is rare and its existence has been doubted.[7] Based on a report of nine cases in adults, one group suggested the following criteria (1) renal failure as the initial presentation, (2) bilateral enlargement of the kidneys without obstruction and other organ or nodal involvement, (3) diagnosis only made by renal biopsy, (4) absence of other causes of renal failure, and (5) rapid improvement of renal function after radiotherapy or systemic chemotherapy.[8] In this present case, the diagnosis was established in nephrectomy specimen and response to chemotherapy with first-line drugs.\n\nEven though the most common manifestation is bilateral renal involvement, acute renal failure, anemia, hematuria, fatigue, and musculoskeletal pains there are few case reports of unilateral involvement.[23] Both T- and B-cell renal lymphoma has been reported.[29] In this present case, it manifested as single kidney involvement with no systemic symptoms or renal failure. The patient was 10-year-old, on initial radiological findings, there was suspicion of Wilms tumor, and he underwent nephrectomy. In a case of WT, the common radiological findings are intrarenal heterogeneous mass with pseudo capsule with calcification and involvement of renal vein or inferior vena cava with or without lymphadenopathy, but in a case of lymphoma, there is some hypodense nodular lesion with homogenous involvement with our distinct borders and ± nodal involvement [Table 1]. There are case reports of PRL who underwent nephrectomy, based on radiological features.[10]\n\nAggressive lymphomas fall into the differential diagnosis of small blue round cells tumors and may be confused with other round cells tumor like neuroblastoma or blastemal component of WT, where immunohistochemitsry (IHC) is of great help. The differential diagnoses of the renal mass with common IHC markers are presented in Table 1. There is growing evidence that a renal mass in a doubtful situation can be subjected to 18FDG PET especially before contemplating nephrectomy. 18FDG PET may be useful in differentiating lymphomas as they have more avid uptake.[11]\n\nIn most cases, pediatric renal lymphomas are treated as in adults with six cycles of chemotherapy ± rituximab with varied outcome.[25] Patients with renal lymphoma rarely survive more than 1 year.[12]\n\nThe interesting lesson learnt from our patient is that PRL can manifest initially with an asymptomatic renal mass and can relapse later with systemic disease. Better radiological, nuclear imaging and comprehensive pathology could have established an earlier and accurate diagnosis. We have treated with multiagent protocol NHL-BFM-95 and autologous transplant, but still, the patient could not be salvaged. Pediatric renal lymphomas are an aggressive form of lymphoma with guarded prognosis.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n\nAcknowledgment\nAuthors would like to thank Department of Pathology, Nizams Institute of Medical Science.\n==== Refs\nReferences\n1 Freeman C Berg JW Cutler SJ Occurrence and prognosis of extranodal lymphomas Cancer 1972 29 252 60 5007387 \n2 Dhull VS Mukherjee A Karunanithi S Durgapal P Bal C Kumar R Bilateral primary renal lymphoma in a pediatric patient: Staging and response evaluation with 18 F-FDG PET/CT Rev Esp Med Nucl Imagen Mol 2015 34 49 52 25065972 \n3 Dash SC Purohit K Mohanty SK Dinda AK An unusual case of bilateral renal enlargement due to primary renal lymphoma Indian J Nephrol 2011 21 56 8 21655173 \n4 Tefekli A Baykal M Binbay M Barut M Muslumanoglu AY Lymphoma of the kidney: Primary or initial manifestation of rapidly progressive systemic disease? Int Urol Nephrol 2006 38 775 8 17111087 \n5 Lee SM Son IC Kim JJ Lee T Yoon SM Kim SG Primary renal lymphoma in a child Korean J Urol 2001 42 1220 3 \n6 Lowe LH Isuani BH Heller RM Stein SM Johnson JE Navarro OM Pediatric renal masses: Wilms tumor and beyond Radiographics 2000 20 1585 603 11112813 \n7 Kandel LB McCullough DL Harrison LH Woodruff RD Ahl ET Jr Munitz HA Primary renal lymphoma. Does it exist? Cancer 1987 60 386 91 3594375 \n8 Malbrain ML Lambrecht GL Daelemans R Lins RL Hermans P Zachée P Acute renal failure due to bilateral lymphomatous infiltrates. Primary extranodal non-Hodgkin's lymphoma (p-EN-NHL) of the kidneys: Does it really exist? Clin Nephrol 1994 42 163 9 7994934 \n9 Sharma SB Debnath PR Tripathi R Primary renal lymphoma in a child Indian J Pediatr 2006 73 947 17090912 \n10 Hayakawa A Shimotake N Kubokawa I Mitsuda Y Mori T Yanai T Primary pediatric stage III renal diffuse large B-cell lymphoma Am J Case Rep 2013 14 34 7 23569559 \n11 Ye XH Chen LH Wu HB Feng J Zhou WL Yang RM 18F-FDG PET/CT evaluation of lymphoma with renal involvement: Comparison with renal carcinoma South Med J 2010 103 642 9 20531045 \n12 Kose F Sakalli H Mertsoylu H Sezer A Kocer NE Tokmak N Primary renal lymphoma: Report of four cases Oncol Res Treat 2009 32 200 2\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0971-5851",
"issue": "38(4)",
"journal": "Indian journal of medical and paediatric oncology : official journal of Indian Society of Medical & Paediatric Oncology",
"keywords": "Chemotherapy; nephrectomy; renal lymphoma",
"medline_ta": "Indian J Med Paediatr Oncol",
"mesh_terms": null,
"nlm_unique_id": "9604571",
"other_id": null,
"pages": "538-541",
"pmc": null,
"pmid": "29333026",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "20531045;5007387;21655173;11112813;17090912;7994934;3594375;19372716;17111087;23569559;25065972",
"title": "Renal Lymphoma: Primary or First Manifestation of Aggressive Pediatric B-cell Lymphoma.",
"title_normalized": "renal lymphoma primary or first manifestation of aggressive pediatric b cell lymphoma"
} | [
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"companynumb": "IN-PFIZER INC-2018076687",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
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"activesubstancename": "CYTARABINE"
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{
"abstract": "There have been no previous reports on the use of interferon-free combinations in pediatric patients with chronic hepatitis C infection. An infected adolescent with severe sickle cell disease underwent stem cell transplantation and subsequent treatment with sofosbuvir and simeprevir during ongoing immunosuppression. Despite the emergence of peripheral edema as a side effect, treatment was continued with sustained antiviral response.",
"affiliations": "From the *Division of Pediatrics, CLINTEC, Karolinska Institutet; and †Department of Pediatrics, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.",
"authors": "Fischler|Björn|B|;Priftakis|Peter|P|;Sundin|Mikael|M|",
"chemical_list": "D000998:Antiviral Agents; D011480:Protease Inhibitors; D000069616:Simeprevir; D000069474:Sofosbuvir",
"country": "United States",
"delete": false,
"doi": "10.1097/INF.0000000000001122",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0891-3668",
"issue": "35(6)",
"journal": "The Pediatric infectious disease journal",
"keywords": null,
"medline_ta": "Pediatr Infect Dis J",
"mesh_terms": "D000293:Adolescent; D000755:Anemia, Sickle Cell; D000998:Antiviral Agents; D064420:Drug-Related Side Effects and Adverse Reactions; D004487:Edema; D019698:Hepatitis C, Chronic; D006801:Humans; D008297:Male; D011480:Protease Inhibitors; D000069616:Simeprevir; D000069474:Sofosbuvir; D033581:Stem Cell Transplantation; D000072230:Sustained Virologic Response; D066027:Transplant Recipients",
"nlm_unique_id": "8701858",
"other_id": null,
"pages": "708-10",
"pmc": null,
"pmid": "26928522",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Sofosbuvir and Simeprevir Treatment of a Stem Cell Transplanted Teenager With Chronic Hepatitis C Infection.",
"title_normalized": "sofosbuvir and simeprevir treatment of a stem cell transplanted teenager with chronic hepatitis c infection"
} | [
{
"companynumb": "PHHY2016SE088499",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
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"activesubstancename": "TREOSULFAN"
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{
"abstract": "Meningiomas are the most frequent benign head tumors, although spontaneous hemorrhage is a rare form of presentation of such lesions. Of all possible bleeding locations associated with them, the subdural space is one of the most uncommon, with very few cases reported worldwide.\nA middle-aged woman presented with progressively worsening left-sided headache, initiated 2 weeks before, with no other complaints, denying any previous head trauma. Head computed tomography revealed a subacute left hemisphere subdural hematoma and left frontal, suggestive of meningioma on magnetic resonance imaging. Surgical treatment was performed with hematoma evacuation and lesion removal. Neuropathology showed a transitional meningioma with signs of hemorrhage. After surgery, no neurological deficits were registered, and headache abated.\nAs we could not identify any other cause for the subacute subdural hematoma, hemorrhage from the meningioma was the most probable cause, and thus, we decided to remove it along with clot evacuation. Based on neuropathological findings, we propose an alternative mechanism for this spontaneous hemorrhage from the meningioma, involving the place where the periphery of the lesion insertion, the dura mater as the origin of the hemorrhage. Knowledge of this association could help define the best treatment in such cases.",
"affiliations": "Department of Neurosurgery, Coimbra University Hospital Centre, Portugal.;Department of Neurosurgery, Coimbra University Hospital Centre, Portugal.",
"authors": "Matos|Daniela|D|;Pereira|Ricardo|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.25259/SNI_337_2020",
"fulltext": "\n==== Front\nSurg Neurol Int\nSurg Neurol Int\nSurgical Neurology International\n2229-5097 2152-7806 Scientific Scholar USA \n\nSNI-11-264\n10.25259/SNI_337_2020\nCase Report\nMeningioma-related subacute subdural hematoma: A case report\nMatos Daniela 1matosdp@gmail.com Pereira Ricardo 12ricardo.henriquespereira@gmail.com 1 Department of Neurosurgery, Coimbra University Hospital Centre, Portugal.\n2 Faculty of Medicine, University of Coimbra, Coimbra, Portugal.\n* Corresponding author: Daniela Matos, Department of Neurosurgery, Coimbra University Hospital Centre, Praceta Prof. Mota Pinto, Coimbra 3000-075, Portugal. matosdp@gmail.com\n2020 \n29 8 2020 \n11 26406 6 2020 08 8 2020 Copyright: © 2020 Surgical Neurology International2020This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Background: \nMeningiomas are the most frequent benign head tumors, although spontaneous hemorrhage is a rare form of presentation of such lesions. Of all possible bleeding locations associated with them, the subdural space is one of the most uncommon, with very few cases reported worldwide.\n\nCase Description: \nA middle-aged woman presented with progressively worsening left-sided headache, initiated 2 weeks before, with no other complaints, denying any previous head trauma. Head computed tomography revealed a subacute left hemisphere subdural hematoma and left frontal, suggestive of meningioma on magnetic resonance imaging. Surgical treatment was performed with hematoma evacuation and lesion removal. Neuropathology showed a transitional meningioma with signs of hemorrhage. After surgery, no neurological deficits were registered, and headache abated.\n\nConclusion: \nAs we could not identify any other cause for the subacute subdural hematoma, hemorrhage from the meningioma was the most probable cause, and thus, we decided to remove it along with clot evacuation. Based on neuropathological findings, we propose an alternative mechanism for this spontaneous hemorrhage from the meningioma, involving the place where the periphery of the lesion insertion, the dura mater as the origin of the hemorrhage. Knowledge of this association could help define the best treatment in such cases.\n\nMeningioma hemorrhageMeningiomaSpontaneous bleedingSubdural hematomaTumor hemorrhage\n==== Body\nINTRODUCTION\nThe most frequent benign brain tumors, meningiomas, are generally slow-growing lesions that may have a broad clinical presentation depending on its location. Convexity meningiomas comprising 15% of these lesions, most frequently present with headache, followed by seizures, and other site-specific symptoms.[22,29] Spontaneous hemorrhages from these lesions are very rare, and its underlying mechanisms are yet to be understood.[4,8,9]\n\nCASE REPORT\nA postmenopausal woman presented to our emergency room with an intense left-sided parieto- occipital pulsatile headache, with 2 weeks of evolution and progressive worsening in the previous 2 days and minimal response to acetaminophen. She had no other symptoms or history of head trauma. The neurological examination was normal.\n\nThe patient, hypocoagulated with acenocoumarol due to previous deep vein thrombosis, was also medicated with amlodipine for chronic hypertension.\n\nHead computed tomography (CT) showed a subacute left hemisphere and tentorial subdural hemorrhage with 17 mm of maximum width and signs of acute hemorrhage in the frontal region, as well as a left frontal dural-based lesion, well-demarcated, spontaneously hyperdense, and partially calcified, measuring 15 mm × 18 mm in diameter, causing surrounding edema and mass effect, inducing a 10 mm midline shift [Figure 1]. The bone window revealed hyperostosis overlying the lesion. Blood tests were normal, with no signs of infection.\n\nFigure 1: (a and b) Head computed tomography in soft tissue and bone window, showing a spontaneously hyperdense left frontal rounded lesion with ipsilateral subdural hemorrhage and the hyperostotic bone reaction.\n\nThe patient was then admitted to the neurosurgery ward and head magnetic resonance imaging (MRI) confirmed an extra- axial left frontal lesion with adjacent dural enhancement after intravenous contrast [Figure 2]. A magnetic resonance angiogram excluded cerebral aneurysms or other vascular malformations.\n\nFigure 2: (a and b) Axial and coronal T2-weighted head magnetic resonance imaging confirming the presence of the left frontal lesion with adjacent subdural hemorrhage causing important mass effect and right midline shift.\n\nSurgery with clot evacuation and lesion removal was the treatment option.\n\nOperative procedure\nThe patient underwent a small left frontal craniotomy using neuronavigational guidance. The dural opening revealed subacute subdural hemorrhage and a yellowish rounded lesion, very well delimited, that was carefully separated from [Figure 3] the cortical surface, preserving the arachnoid membrane, and removed with the adjacent dural thickening (Simpson I). The subdural hemorrhage was drained, and a soft drain was left in the subdural space. Duraplasty was made with the dural substitute.\n\nFigure 3: (a and b) Intraoperative images of meningioma exposure after major subdural hemorrhage evacuation.\n\nBony hyperostosis was drilled, and the bone flap regularized.\n\nHistology\nHistology showed a transitional meningioma (the World Health Organization Grade I/III) infiltrating the adjacent dura mater. Along with some areas of fibrosis and necrosis, a few areas of internal hemorrhage were identified. The adjacent dura mater showed signs of fibrovascular proliferation [Figures 4 and 5] and hemosiderin deposits, both intra- and extracellularly.\n\nFigure 4: H and E ×25, in the left corner, we see the subdural hematoma membrane detached from the meningioma periphery. At the right corner, the transitional meningioma is shown.\n\nFigure 5: H and E ×100, in the left upper corner: subdural hematoma membrane (superior) and the dura-mater (inferior) infiltrated by erythrocytes.\n\nPostoperative outcome\nThe subdural drain was removed 24 h postsurgery. Steroids were slowly weaned postoperatively over the course of days, and seizure prophylaxis was continued for 1 month. Postoperative head CT showed a very good imaging result, with total subdural hematoma evacuation. After surgery, the patient noticed significant headache relief and needed no analgesics at discharge, maintaining a normal neurologic evaluation.\n\nPostoperative head MRI showed complete lesion removal [Figure 6].\n\nFigure 6: Axial T1-weighted head magnetic resonance imaging 6-month postoperatively showing no signs of the previous lesions.\n\nAt the last follow-up appointment, 2 years after surgery, the patient remained asymptomatic.\n\nDISCUSSION\nThe most common type of bleeding in meningiomas is subarachnoid hemorrhage, followed by intratumoral and intracerebral hemorrhage. Subdural hematoma, however, is extremely rare.[2-4,8,17]\n\nWe performed a thorough literature review and found that, in many cases, there was a lack of compelling data establishing a relationship between subdural collections and the presence of a convexity meningioma. This was particularly true in cases of chronic subdural collections in the elderly population and in cases where head trauma led to the diagnosis of both lesions. [Table 1][5-7,10-14,16,18,19,21,23,24,26,27] summarizes all cases reported, in which subdural hematomas could result from meningioma hemorrhage rather than just being coincidentally diagnosed.\n\nTable 1: Review of all cases reported in which subdural hematomas could result from meningioma hemorrhage rather than just being coincidentally diagnosed.\n\nThe underlying pathophysiologic mechanisms have been subject to several studies, although it remains unclear as to the reason why and which under the circumstances some meningiomas bleed.[15] Accepted to date theories suggest that rupture of tumor vessels, tumor growth causing subdural bridging vein rupture, rapidly expanding tumors, tumor cells invading and disrupting blood vessels and tumor-derived vasoactive substances could lead to tumor bleeding.[1,2,8] Nevertheless this still does not explain why this is such a rare event, since most meningiomas we see in our daily practice do not follow this course.[15,28] It is accepted that several mechanisms might simultaneously be involved in the development of hemorrhage.[4]\n\nThis patient was under amlodipine, which has a known vasodilator effect, reducing the peripheral resistance that added to the hypocoagulating effect of acenocoumarol which could possibly have influenced the development of the hemorrhage.\n\nIn this particular case, hypertension and hypocoagulation are considered risk factors causing the tumor to be more prone to bleeding when some minor tumor change occurs.[25] Other risk factors postulated in the review studies are age >70 or <30; location of meningioma being intraventricular or convexity; histopathology consistent with being malignant, fibrous, or angioblastic; and traumatic brain injury.[4,20]\n\nNotwithstanding hypertension and hypocoagulatory states being common in the Portuguese population and thus present in many patients that harbor meningiomas, we found no other cases reported in our population, meaning those factors are probably not by themselves essential to this clinical presentation.\n\nConsidering neuropathological examination, the proximity of meningioma periphery and contiguous dura mater infiltrated by erythrocytes to the subdural hematoma membrane make this the probable origin of the hemorrhage. The rupture of a vessel in this transition zone could explain this phenomenon. Furthermore, the fact that the meningioma had minor intrinsic hemorrhages that seem to have no contact with the exterior layers of the lesion further supports this theory.\n\nAs we considered the bleeding of the meningioma as the probable cause for the acute subdural hemorrhage, we opted to remove both the hematoma and the lesion simultaneously in the same craniotomy.\n\nCONCLUSION\nSpontaneous subdural hemorrhage is an extremely rare presentation for convexity meningioma, but the possibility of an underlying lesion should always be entertained in cases of spontaneous intracranial hemorrhage, even those occurring in the subdural space.\n\nThorough characterization of possible causality between lesions is necessary, as it will greatly impact on therapeutic decisions.\n\nHow to cite this article: Matos D, Pereira R. Meningioma-related subacute subdural hematoma: A case report. Surg Neurol Int 2020;11:264.\n\nDeclaration of patient consent\nPatient’s consent not required as patients identity is not disclosed or compromised.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Agazzi S Burkhardt K Rilliet B Acute haemorrhagic presentation of an intracranial meningioma J Clin Neurosci 1999 6 242 5 \n2 Aloraidi A Abbas M Fallatah B Alkhaibary A Ahmed M Alassiri A Meningioma presenting with spontaneous subdural hematoma: A report of two cases and literature review World Neurosurg 2019 127 150 4 30947005 \n3 Bloomgarden GM Byrne TN Spencer DD Heafner MD Meningioma associated with aneurysm and subarachnoid hemorrhage: Case report and review of the literature Neurosurgery 1987 20 24 6 3808267 \n4 Bosnjak R Derham C Popović M Ravnik J Spontaneous intracranial meningioma bleeding: Clinicopathological features and outcome J Neurosurg 2005 103 473 84 16235680 \n5 Chaskis C Raftopoulos C Noterman J Flament-Durand J Brotchi J Meningioma associated with subdural haematoma: Report of two cases and review of the literature Clin Neurol Neurosurg 1992 94 269 74 1327621 \n6 Chen JW Hoi-Sang U Grafe MR Unsuspected meningioma presenting as a subdural haematoma J Neurol Neurosurg Psychiatry 1992 55 167 8 \n7 Chonan M Niizuma K Koyama S Kon H Sannohe S Kurotaki H An operated case of a meningioma causing acute subdural hematoma No Shinkei Geka 2013 41 235 9 23459521 \n8 Hambra DV Danilo de P Alessandro R Sara M Juan GR Meningioma associated with acute subdural hematoma: A review of the literature Surg Neurol Int 2014 5 S469 71 25422791 \n9 Helle TL Conley FK Haemorrhage associated with meningioma: A case report and review of the literature J Neurol Neurosurg Psychiatry 1980 43 725 9 7431034 \n10 Jones NR Blumbergs PC Intracranial haemorrhage from meningiomas: A report of five cases Br J Neurosurg 1989 3 691 8 2697215 \n11 Kashimura H Arai H Ogasawara K Beppu T Kurose A Ogawa A Lipomatous meningioma with concomitant acute subdural hematoma Neurol Med Chir 2008 48 466 9 \n12 Kim JH Gwak HS Hong EK Bang CW Lee SH Yoo H A case of benign meningioma presented with subdural hemorrhage Brain Tumor Res Treat 2015 3 30 3 25977904 \n13 Kotwica Z Zawirski M Subdural hematoma caused by cerebral tumors Zentralbl Neurochir 1986 47 259 62 3028011 \n14 Koumtchev Y Petkov S Gozmanov G Meningiom accompanied by a subdural hematoma. A case report Review of 17 cases in the literature Folia Med (Plovdiv) 1993 35 61 3 7927058 \n15 Kouyialis AT Stranjalis G Analyti R Boviatsis EJ Korfias S Sakas DE Peritumoural haematoma and meningioma: A common tumour with an uncommon presentation J Clin Neurosci 2004 11 906 9 15519875 \n16 Lefranc F Nagy N Dewitte O Baleriaux D Brotchi J Intracranial meningiomas revealed by non-traumatic subdural haematomas. A series of four cases Acta Neurochir 2001 143 977 83 11685604 \n17 Masoudi MS Zafarshamspour S Ghasemi-Rad M Soleimani N Rakhsha A Lincoln C Acute subdural hemorrhage of a convexity meningioma in the postpartum period; case report and literature review Bull Emerg Trauma 2019 7 324 9 31392235 \n18 Modesti LM Binet EF Collins GH Meningiomas causing spontaneous intracranial hematomas J Neurosurg 1976 45 437 41 956880 \n19 Niikawa S Kawaguchi M Sugimoto S Hattori T Ohkuma A Meningioma associated with subdural hematoma case report Neurol Med Chir (Tokyo) 1990 30 169 72 1697043 \n20 Pressman E Penn D Patel N Intracranial hemorrhage from meningioma: 2 Novel risk factors World Neurosurg 2020 135 217 21 31698125 \n21 Ravindran K Gaillard F Lasocki A Spontaneous subdural haemorrhage due to meningioma in the post-partum setting J Clin Neurosci 2017 39 77 9 28087186 \n22 Sanai N Sughrue ME Shangari G Chung K Berger MS McDermott MW Risk profile associated with convexity meningioma resection in the modern neurosurgical era J Neurosurg 2010 112 913 9 19645533 \n23 Sato K Sugawara T Fujiwara S Mizoi K Yoshimoto T A case of small meningioma with acute subdural hematoma No Shinkei Geka 1989 17 687 90 2682340 \n24 Shimizu J Tazawa T Park-Matsumoto YC Katano T Akiba Y Kuroiwa T Meningioma associated with acute subdural hematoma: A case report No Shinkei Geka 1998 26 743 7 9744005 \n25 Spektor S Ashkenazi E Israel Z Intracranial haemorrhage from a meningioma in a patient receiving aspirin prophylaxis: A case report Acta Neurochir 1995 134 51 3 7668127 \n26 Tokunaga T Kuboyama M Kojo N Matsuo H Shigemori M Kuramoto S A case of acute subdural hematoma associated with convexity meningioma No Shinkei Geka 1988 16 1389 93 3067106 \n27 Ueno M Nakai E Naka Y Kido T Itakura T Komai N Acute subdural hematoma associated with vacuolated meningioma case report Neurol Med Chir 1993 33 36 9 \n28 Wang HC Wang BD Chen MS Li SW Chen H Xu W An underlying pathological mechanism of meningiomas with intratumoral hemorrhage: Undifferentiated microvessels World Neurosurg 2016 94 319 27 27443229 \n29 Wu A Garcia MA Magill ST Chen W Vasudevan HN Perry A Presenting symptoms and prognostic factors for symptomatic outcomes following resection of meningioma World Neurosurg 2018 111 e149 59 29248774\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "2152-7806",
"issue": "11()",
"journal": "Surgical neurology international",
"keywords": "Meningioma; Meningioma hemorrhage; Spontaneous bleeding; Subdural hematoma; Tumor hemorrhage",
"medline_ta": "Surg Neurol Int",
"mesh_terms": null,
"nlm_unique_id": "101535836",
"other_id": null,
"pages": "264",
"pmc": null,
"pmid": "33024602",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "25422791;16235680;30947005;3028011;3808267;29248774;7680782;3067106;7927058;2682340;27443229;18948682;956880;31392235;11685604;28087186;18639160;1327621;7668127;1697043;9744005;19645533;15519875;7431034;23459521;31698125;2697215;1538230;25977904",
"title": "Meningioma-related subacute subdural hematoma: A case report.",
"title_normalized": "meningioma related subacute subdural hematoma a case report"
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"companynumb": "PT-PFIZER INC-2020462647",
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"activesubstancename": "AMLODIPINE BESYLATE"
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"abstract": "A new coronavirus, named severe acute respiratory syndrome-coronavirus-2 by the WHO, has rapidly spread around the world since its first reported case in late December of 2019 from Wuhan, the People's Republic of China. As of mid-April 2020, this virus has affected more than 180 countries and territories, infecting more than 1,650,000 individuals and causing over 100,000 deaths. With approximately 20 million new cases globally per year, cancer affects a substantial portion of the population. Individuals affected by cancer are more susceptible to infections owing to coexisting chronic diseases (cardiovascular, pulmonary, and diabetes), overall poor health status, and systemic immunosuppressive states caused by both cancer and the anticancer treatment. As a consequence, patients with malignancies, especially those with lung cancer who develop coronavirus disease 2019, experience more difficult outcomes. A recent multicenter study carried out by the Hubei Anti-Cancer Association has also documented that patients with lung cancer had an increased risk of death, intensive care unit requirement, risk of presenting severe or critical symptoms, and use of invasive mechanical ventilation. Here, we present two representative cases of patients with lung cancer and coronavirus disease 2019 without respiratory compromise and with atypical and severe skin manifestations-findings that could be influenced by the long-term use of anti-programmed cell death protein 1 antibody.",
"affiliations": "Thoracic Oncology Unit, Marlene and Stewart Comprehensive Cancer Center, University of Maryland, Baltimore, Maryland.;Foundation for Clinical and Applied Cancer Research (FICMAC), Bogotá, Colombia; Molecular Oncology and Biology Systems Research Group (FOX-G), Universidad el Bosque, Bogotá, Colombia; Clinical and Traslational Oncology Group, Clínica del Country, Bogotá, Colombia. Electronic address: christian.rolfo@umm.edu.;Foundation for Clinical and Applied Cancer Research (FICMAC), Bogotá, Colombia; Molecular Oncology and Biology Systems Research Group (FOX-G), Universidad el Bosque, Bogotá, Colombia.;Dermatology Oncology Department, Clínica Colsanitas, Bogotá, Colombia.;Thoracic Oncology Unit, Instituto Nacional de Cancerología (INCan), México City, México.;Oncology Department, Institute of Oncology - Carlos Ardila Lülle Cancer Institute (ICAL), Fundación Santa Fe de Bogotá, Bogotá, Colombia.;Thoracic Oncology Unit, Fundación Neumológica Colombiana - FNM, Bogotá, Colombia.;Thoracic Oncology Unit, Marlene and Stewart Comprehensive Cancer Center, University of Maryland, Baltimore, Maryland; Medical Oncology Unit, A.O. Papardo, Messina, Italy.;Foundation for Clinical and Applied Cancer Research (FICMAC), Bogotá, Colombia; Molecular Oncology and Biology Systems Research Group (FOX-G), Universidad el Bosque, Bogotá, Colombia; Clinical and Traslational Oncology Group, Clínica del Country, Bogotá, Colombia; Clínical Oncology Department, Clínica Colsanitas, Bogotá, Colombia.;Pathology Department, Mayo Clinic, Rochester, Minnesota.;Thoracic Oncology Unit, Instituto Nacional de Cancerología (INCan), México City, México.",
"authors": "Rolfo|Christian|C|;Cardona|Andrés F|AF|;Ruiz-Patiño|Alejandro|A|;Ariza|Santiago|S|;Zatarain-Barron|Lucia|L|;Pino|Luis E|LE|;Viola|Lucia|L|;Russo|Alessandro|A|;Rojas|Leonardo|L|;Ricaurte|Luisa|L|;Arrieta|Oscar|O|",
"chemical_list": "D060890:B7-H1 Antigen",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jtho.2020.06.019",
"fulltext": null,
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"issn_linking": "1556-0864",
"issue": "15(11)",
"journal": "Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer",
"keywords": "Anti–PD-1 therapy; COVID-19; Erythema multiforme; Lung cancer; Urticarial; Vasculitis",
"medline_ta": "J Thorac Oncol",
"mesh_terms": "D060890:B7-H1 Antigen; D000073640:Betacoronavirus; D000086382:COVID-19; D018352:Coronavirus Infections; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D058873:Pandemics; D011024:Pneumonia, Viral; D000086402:SARS-CoV-2; D012871:Skin Diseases",
"nlm_unique_id": "101274235",
"other_id": null,
"pages": "1767-1772",
"pmc": null,
"pmid": "32653627",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "27043866;32215952;32073213;32282949;28068177;32338827;31986264;27136138;32845568;30574166;32345594;32348545;31995857;22866124;32265531;12077582",
"title": "Atypical Skin Manifestations During Immune Checkpoint Blockage in Coronavirus Disease 2019-Infected Patients With Lung Cancer.",
"title_normalized": "atypical skin manifestations during immune checkpoint blockage in coronavirus disease 2019 infected patients with lung cancer"
} | [
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"companynumb": "CO-EAGLE PHARMACEUTICALS, INC.-CO-2021EAG000007",
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"activesubstancename": "PEMBROLIZUMAB"
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"abstract": "Methotrexate (MTX) is an effective medication in the treatment of rheumatoid arthritis (RA), other rheumatic diseases and various solid tumors. However, its side effects, including gastrointestinal discomfort, oral ulcers, and especially bone marrow suppression, could be fatal and require special attention, particularly in patients with renal failure. We present two hemodialysis patients with RA who presented with a complication of severe pancytopenia after treatment with MTX. After receiving various supportive and blood purification treatments, both patients recovered. We reviewed twenty-four pancytopenia patients on dialysis associated with methotrexate. Among these patients, high morbidity and mortality were observed, indicating that MTX should be used cautiously in the absence of alternatives in such a population. Compared with the patients who recovered, the deceased patients showed a lower level of leukocytes. Which dialysis method might be the best choice is unclear. The mode of renal replacement therapy can be chosen according to the actual situation.",
"affiliations": "Department of Nephrology and Rheumatology, The Affiliated Hospital of Zunyi Medical University, Guizhou, PR China. Electronic address: hf1399@sina.com.;Department of Nephrology and Rheumatology, The Affiliated Hospital of Zunyi Medical University, Guizhou, PR China. Electronic address: 25287316@qq.com.;Key Laboratory of Cell Engineering in Guizhou Province, The Affiliated Hospital of Zunyi Medical University, Guizhou, PR China. Electronic address: 732389217@qq.com.;Key Laboratory of Cell Engineering in Guizhou Province, The Affiliated Hospital of Zunyi Medical University, Guizhou, PR China. Electronic address: 1622552458@qq.com.;Key Laboratory of Cell Engineering in Guizhou Province, The Affiliated Hospital of Zunyi Medical University, Guizhou, PR China. Electronic address: 2323458861@qq.com.;Key Laboratory of Cell Engineering in Guizhou Province, The Affiliated Hospital of Zunyi Medical University; The Team of Scientific and Technological Innovation Talents on The Basic and Clinical Research of Amniotic Membrane and Bone Marrow Stem Cells in Guizhou Province, Zunyi, Guizhou Province, PR China. Electronic address: ylm720@sina.com.",
"authors": "Pu|Tao|T|;Ni|Yu|Y|;Li|Pan-Hong|PH|;Yu|Dan|D|;Yu|Qiong|Q|;Yu|Li-Mei|LM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.amjms.2021.08.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9629",
"issue": null,
"journal": "The American journal of the medical sciences",
"keywords": "Methotrexate; dialysis; pancytopenia; rheumatoid arthritis",
"medline_ta": "Am J Med Sci",
"mesh_terms": null,
"nlm_unique_id": "0370506",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34562416",
"pubdate": "2021-09-22",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Pancytopenia After Low-Dose Methotrexate Therapy in Two Hemodialysis Patients with Rheumatoid Arthritis.",
"title_normalized": "pancytopenia after low dose methotrexate therapy in two hemodialysis patients with rheumatoid arthritis"
} | [
{
"companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-317868",
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"actiondrug": "5",
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"activesubstancename": "METHOTREXATE"
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"abstract": "To present a novel case of sarcoid choroidal granulomas due to nivolumab therapy for metastatic cutaneous melanoma.\nA 55 year-old male with a history of stage III metastatic cutaneous melanoma treated by nivolumab presented with bilateral choroidal lesions. The ophthalmologic examination revealed bilateral creamy, yellow choroidal lesions with no ocular inflammation. The systemic workup revealed pulmonary sarcoidosis confirmed by biopsy.\nNivolumab is an immune checkpoint inhibitor therapy used in the treatment of metastatic melanoma. With the increasing use of immune checkpoint inhibitors in patients with advanced melanoma, clinicians should be aware of this potential associated immune-related adverse event.",
"affiliations": "Massachusetts Eye and Ear, Department of Ophthalmology, Retina Service, Harvard Medical School, Boston, MA, USA.;Massachusetts Eye and Ear, Department of Ophthalmology, Retina Service, Harvard Medical School, Boston, MA, USA.",
"authors": "Ung|Cindy|C|;Gragoudas|Evangelos|E|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajoc.2020.100652",
"fulltext": "\n==== Front\nAm J Ophthalmol Case Rep\nAm J Ophthalmol Case Rep\nAmerican Journal of Ophthalmology Case Reports\n2451-9936 2451-9936 Elsevier \n\nS2451-9936(20)30033-5\n10.1016/j.ajoc.2020.100652\n100652\nCase Report\nCheckpoint inhibitor-induced sarcoid choroidal granulomas\nUng Cindy Gragoudas Evangelos Evangelos_gragoudas@meei.harvard.edu∗ Massachusetts Eye and Ear, Department of Ophthalmology, Retina Service, Harvard Medical School, Boston, MA, USA\n∗ Corresponding author. Charles Edward Whitten Professor of Ophthalmology Harvard Medical School Massachusetts Eye and Ear Infirmary 243 Charles Street, 12th Floor Boston, MA, 02114, USA. Evangelos_gragoudas@meei.harvard.edu\n06 3 2020 \n6 2020 \n06 3 2020 \n18 1006528 12 2019 16 1 2020 5 3 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nTo present a novel case of sarcoid choroidal granulomas due to nivolumab therapy for metastatic cutaneous melanoma.\n\nObservations\nA 55 year-old male with a history of stage III metastatic cutaneous melanoma treated by nivolumab presented with bilateral choroidal lesions. The ophthalmologic examination revealed bilateral creamy, yellow choroidal lesions with no ocular inflammation. The systemic workup revealed pulmonary sarcoidosis confirmed by biopsy.\n\nConclusion\nNivolumab is an immune checkpoint inhibitor therapy used in the treatment of metastatic melanoma. With the increasing use of immune checkpoint inhibitors in patients with advanced melanoma, clinicians should be aware of this potential associated immune-related adverse event.\n\nKeywords\nSarcoidosisMelanomaNivolumabCheckpoint inhibitors\n==== Body\n1 Introduction\nImmune checkpoint inhibitors (ICIs) are relatively new immunologic agents that block inhibitory receptors of the immune system including cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed death 1 (PD-1) and its ligand (PDL-1). The Food and Drug Administration-approved ICIs include the anti-CTLA-4 antibody ipilimumab, the anti-PD1 antibodies pembrolizumab and nivolumab and the anti-PDL1 antibodies atezolizumab, durvalumab and avelumab. These drugs are used for solid tumors including melanoma, non-small-cell lung cancer, squamous cell carcinoma of the head and neck, and hematologic malignancies including Hodgkin Lymphoma. Ocular side effects secondary to ICI use are rare and occur in approximately 1% of patients.1,2\n\nWe report the first case of sarcoid choroidal granulomas due to nivolumab therapy for metastatic cutaneous melanoma.\n\n2 Case report\nA 55-year-old male with history of stage III cutaneous melanoma on nivolumab therapy was referred by his local ophthalmologist to the retina service for new bilateral choroidal lesions. The patient was initially diagnosed with metastatic melanoma in March 2018 when core biopsy of his right axillary lymph node revealed melanoma. He began adjuvant nivolumab therapy in May 2018 for 6 cycles and subsequently developed cough and chills.\n\nOn presentation, his uncorrected visual acuity was 20/20 in each eye. His intraocular pressure (IOP) was 13 mmHg in the right eye and 15 in the left eye. Slit lamp examination revealed no anterior or posterior intraocular inflammation. Fundus examination of the right eye revealed the presence of two creamy yellow choroidal lesions, one inferotemporal and one superotemporal to the macula. In the left eye, there was a similar lesion inferior to the arcade (Fig. 1). The retina was attached in both eyes. B-scan ultrasound showed no posterior elevation of the lesions. The differential at the time included metastatic melanoma versus choroidal granuloma.Fig. 1 Fundus photography revealed two creamy, yellowish choroidal lesions in the macula of the right eye (A) and similar lesion below the inferior arcade in the left eye (B).\n\nFig. 1\n\nThe patient underwent chest CT in August 2018, which revealed new bulky mediastinal lymphadenopathy, hilar adenopathy and new bilateral pulmonary nodules. He underwent a biopsy that was consistent with sarcoidosis, likely caused from immunotherapy. A clinical diagnosis of choroidal granulomas due to sarcoidosis was made. Nivolumab was discontinued by his oncologist and there were no subsequent changes in the lesions.\n\n3 Discussion\nImmune checkpoint inhibitors (ICI) have transformed the treatment of melanoma and other cancers and is now part of standard management. Nivolumab is a humanized monoclonal antibody that targets the programmed cell death-1 (PD-1) receptor in T-cells. The most frequently reported adverse events of nivolumab are dermatologic, gastrointestinal and neurologic toxicity.3 To date, few case reports evaluating the ocular side-effects of checkpoint inhibitors have been published. We report the first case of nivolumab-induced sarcoid choroidal granulomas.\n\nCancer patients receiving ICIs are prone to develop immune-related adverse events (IRAEs) caused by non-specific activation of the host's own immune system resulting in inflammation. Ocular IRAEs are rare and have been reported in less than 1% of patients.4 A recent review of ocular adverse events cases found that the most frequent ICI side effects included uveitis, dry eye, inflammatory orbitopathy, and myasthenia gravis with ocular involvement.5 Nivolumab has been found to have the highest association with ocular myasthenia compared to other ICIs.6\n\nSeveral reports have described an association between the use of ICIs and the development of sarcoidosis-like reactions.7, 8, 9, 10 In a recent comprehensive review of the literature, 55 cases were described to have developed granulomatous, sarcoid-like lesions associated with ICIs.11 Ocular findings occurred in four patients and included dry-eye syndrome, acute iritis, retinochoroiditis, and panuveitis with multifocal choroiditis.12, 13, 14, 15 Bilateral panuveitis with multifocal choroiditis was described as the first sign of systemic sarcoidosis in a patient on pembrolizumab for metastatic melanoma.15 The patient had pre-existing smaller and asymptomatic mediastinal and hilar adenopathy. No cases have described nivoluzimab-induced sarcoid choroidal granulomas.\n\nSarcoid-like reactions have been described in the setting of malignancy and have been reported during or after treatment for malignancies.16, 17, 18, 19 It is possible that the sarcoid choroidal granulomas may be a paraneoplastic manifestation of the patient's melanoma. One study found that 4% of melanoma patients undergoing immunotherapy developed sarcoid-like reactions.20 Ocular sarcoid-like reactions can also occur.21 The mechanism for these reactions remains unknown.\n\nOn initial presentation, there were bilateral creamy, yellow choroidal lesions with no elevation on B-scan ultrasound. The differential diagnosis included choroidal metastasis versus granuloma. Though cutaneous melanoma commonly metastasizes to the lymphatic system, central nervous system, liver, and lung, it accounts for only 2.2% to 4.4% of primary tumors metastasizing to the uvea.22,23 The diagnosis of choroidal granuloma due to sarcoidosis was made clinically given the new hilar adenopathy and pulmonary nodules on CT scan and the confirmatory biopsy for sarcoidosis. In addition, the patient was followed for 1 year after initial presentation with no change in the choroidal lesions.\n\nTo our knowledge, this is the first report of nivolumab-induced sarcoid choroidal granulomas. This case illustrates that ocular sarcoidosis can be induced by nivolumab treatment. With the increasing use of ICIs in cancer patients, clinicians should be aware of this potential associated immune-related adverse event.\n\nPatient consent\nWritten consent to publish this case has not been obtained. This report does not contain any personal identifying information.\n\nAuthorship\nAll authors attest that they meet the current ICMJE criteria for Authorship.\n\nAcknowledgements and disclosures\nNo funding or grant support.\n\nDeclaration of competing interest\nThe following authors have no financial disclosures: CU, EG.\n\nAcknowledgements\nNone.\n==== Refs\nReferences\n1 Antoun J. Titah C. Cochereau I. Ocular and orbital side-effects of checkpoint inhibitors: a review article Curr Opin Oncol 28 4 2016 288 294 27136135 \n2 Abdel-Rahman O. Oweira H. Petrausch U. Immune-related ocular toxicities in solid tumor patients treated with immune checkpoint inhibitors: a systematic review Expert Rev Anticancer Ther 17 4 2017 387 394 28277102 \n3 Lemiale V. Meert A.P. Vincent F. Severe toxicity from checkpoint protein inhibitors: what intensive care physicians need to know? Ann Intensive Care 9 1 2019 25 30707321 \n4 Della Vittoria Scarpati G. Fusciello C. Perri F. Ipilimumab in the treatment of metastatic melanoma: management of adverse events OncoTargets Ther 7 2014 203 209 \n5 Dalvin L.A. Shields C.L. Orloff M. Sato T. Shields J.A. Checkpoint inhibitor immune therapy: systemic indications and ophthalmic side effects Retina 38 6 2018 1063 1078 29689030 \n6 Fang T. Maberley D.A. Etminan M. Ocular adverse events with immune checkpoint inhibitors J Curr Ophthalmol 31 3 2019 319 322 31528768 \n7 Danlos F.X. Pages C. Baroudjian B. Nivolumab-induced sarcoid-like granulomatous reaction in a patient with advanced melanoma Chest 149 5 2016 e133 136 27157227 \n8 Andersen R. Norgaard P. Al-Jailawi M.K. Svane I.M. Late development of splenic sarcoidosis-like lesions in a patient with metastatic melanoma and long-lasting clinical response to ipilimumab OncoImmunology 3 8 2014 e954506 \n9 Birnbaum M.R. Ma M.W. Fleisig S. Nivolumab-related cutaneous sarcoidosis in a patient with lung adenocarcinoma JAAD Case Rep 3 3 2017 208 211 28443311 \n10 Firwana B. Ravilla R. Raval M. Hutchins L. Mahmoud F. Sarcoidosis-like syndrome and lymphadenopathy due to checkpoint inhibitors J Oncol Pharm Pract 23 8 2017 620 624 27590328 \n11 Rambhia P.H. Reichert B. Scott J.F. Immune checkpoint inhibitor-induced sarcoidosis-like granulomas Int J Clin Oncol 24 10 2019 1171 1181 31321613 \n12 Toumeh A. Sakhi R. Shah S. Arudra S.K. De Las Casas L.E. Skeel R.T. Ipilimumab-induced granulomatous disease occurring simultaneously with disease progression in a patient with metastatic melanoma Am J Therapeut 23 4 2016 e1068 1071 \n13 Cotliar J. Querfeld C. Boswell W.J. Raja N. Raz D. Chen R. Pembrolizumab-associated sarcoidosis JAAD Case Rep 2 4 2016 290 293 27504482 \n14 Montaudie H. Pradelli J. Passeron T. Lacour J.P. Leroy S. Pulmonary sarcoid-like granulomatosis induced by nivolumab Br J Dermatol 176 4 2017 1060 1063 27291635 \n15 Lise Q.K. Audrey A.G. Multifocal choroiditis as the first sign of systemic sarcoidosis associated with pembrolizumab Am J Ophthalmol Case Rep 5 2017 92 93 29503956 \n16 Kaikani W. Boyle H. Chatte G. Sarcoid-like granulomatosis and testicular germ cell tumor: the 'Great Imitator Oncology 81 5-6 2011 319 324 22179558 \n17 Kamiyoshihara M. Hirai T. Kawashima O. Ishikawa S. Morishita Y. Sarcoid reactions in primary pulmonary carcinoma: report of seven cases Oncol Rep 5 1 1998 177 180 9458317 \n18 Nakamura M. Mizuta E. Morioka H. Nakamura M. Isiglo K. Multiple early gastric cancer associated with sarcoid-like reaction in the regional lymph nodes J Gastroenterol 36 10 2001 710 717 11686483 \n19 Green J.S. Norris D.A. Wisell J. Novel cutaneous effects of combination chemotherapy with BRAF and MEK inhibitors: a report of two cases Br J Dermatol 169 1 2013 172 176 23413975 \n20 Dimitriou F. Frauchiger A.L. Urosevic-Maiwald M. Sarcoid-like reactions in patients receiving modern melanoma treatment Melanoma Res 28 3 2018 230 236 29485531 \n21 Balasubramaniam S.C. Salomao D.R. Davies J.B. Paraneoplastic sarcoid-like reactions and the eye Retina 35 4 2015 789 797 25526097 \n22 Shields C.L. Shields J.A. Gross N.E. Schwartz G.P. Lally S.E. Survey of 520 eyes with uveal metastases Ophthalmology 104 8 1997 1265 1276 9261313 \n23 Zografos L. Ducrey N. Beati D. Metastatic melanoma in the eye and orbit Ophthalmology 110 11 2003 2245 2256 14597536\n\n",
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"keywords": "Checkpoint inhibitors; Melanoma; Nivolumab; Sarcoidosis",
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"abstract": "Among attempts to delay development of resistance to tyrosine kinase inhibitors (TKIs) in patients with advanced non-small cell lung cancer (NSCLC) with activating mutations of epidermal growth factor receptor (EGFR), intercalated therapy has not been properly evaluated. In a phase II trial, 38 patients with EGFR mutated NSCLC in advanced stage were treated with 4 to 6 3-weekly cycles of intercalated schedule with gemcitabine (1250 mg/m2, days 1 and 4), cisplatin (75 mg/m2, day 2) and erlotinib (150 mg, days 5 - 15), followed by continuous erlotinib as maintenance. In addition to standard radiologic evaluation according to RECIST, PET/CT was done prior to treatment and at 6 months, using PERCIST as a method for assessment of response. The primary endpoint was progression-free survival (PFS). In general, tolerance to treatment was good, even among 8 patients with performance status 2-3 and 13 patients with brain metastases; grade 4 toxicity included 2 cases of neutropenia and 4 thrombo-embolic events. Complete response (CR) or partial response (PR) were seen in 15 (39.5%) and 17 (44.7%) cases, respectively. All cases of CR were confirmed also by PET/CT. Median PFS was 23.4 months and median overall survival (OS) was 38.3 months. After a median follow-up of 35 months, 8 patients are still in CR and on maintenance erlotinib. In conclusion, intercalated treatment for treatment-naive patients with EGFR activating mutations leads to excellent response rate and prolonged PFS and survival. Comparison of the intercalated schedule to monotherapy with TKIs in a randomized trial is warranted.",
"affiliations": "a Institute of Oncology , Ljubljana , Slovenia.;a Institute of Oncology , Ljubljana , Slovenia.;a Institute of Oncology , Ljubljana , Slovenia.;a Institute of Oncology , Ljubljana , Slovenia.;a Institute of Oncology , Ljubljana , Slovenia.;c Institute for Nuclear Medicine, University Clinical Center Ljubljana , Slovenia.;c Institute for Nuclear Medicine, University Clinical Center Ljubljana , Slovenia.;d University Hospital for Pulmonary Diseases Golnik , Slovenia.;a Institute of Oncology , Ljubljana , Slovenia.",
"authors": "Zwitter|Matjaz|M|;Rajer|Mirjana|M|;Stanic|Karmen|K|;Vrankar|Martina|M|;Doma|Andrej|A|;Cuderman|Anka|A|;Grmek|Marko|M|;Kern|Izidor|I|;Kovac|Viljem|V|",
"chemical_list": "D003841:Deoxycytidine; C056507:gemcitabine; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D002945:Cisplatin",
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"doi": "10.1080/15384047.2016.1195049",
"fulltext": "\n==== Front\nCancer Biol TherCancer Biol. TherKCBTkcbt20Cancer Biology & Therapy1538-40471555-8576Taylor & Francis 27261103119504910.1080/15384047.2016.1195049Research PaperIntercalated chemotherapy and erlotinib for non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations M. ZWITTER ET AL.CANCER BIOLOGY & THERAPYZwitter Matjaz abRajer Mirjana aStanic Karmen aVrankar Martina aDoma Andrej aCuderman Anka cGrmek Marko cKern Izidor dKovac Viljem aa Institute of Oncology, Ljubljana, Sloveniab Faculty of Medicine, University of Maribor, Sloveniac Institute for Nuclear Medicine, University Clinical Center Ljubljana, Sloveniad University Hospital for Pulmonary Diseases Golnik, SloveniaCONTACT Matjaz Zwitter matjaz.zwitter@guest.arnes.si, Institute of Oncology, Zaloska, Ljubljana, Slovenia8 2016 3 6 2016 3 6 2016 17 8 833 839 6 4 2016 15 5 2016 22 5 2016 © 2016 The Author(s). Published with license by Taylor & Francis Group, LLC2016The Author(s)This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted.ABSTRACT\nAmong attempts to delay development of resistance to tyrosine kinase inhibitors (TKIs) in patients with advanced non-small cell lung cancer (NSCLC) with activating mutations of epidermal growth factor receptor (EGFR), intercalated therapy has not been properly evaluated. In a phase II trial, 38 patients with EGFR mutated NSCLC in advanced stage were treated with 4 to 6 3-weekly cycles of intercalated schedule with gemcitabine (1250 mg/m2, days 1 and 4), cisplatin (75 mg/m2, day 2) and erlotinib (150 mg, days 5 – 15), followed by continuous erlotinib as maintenance. In addition to standard radiologic evaluation according to RECIST, PET/CT was done prior to treatment and at 6 months, using PERCIST as a method for assessment of response. The primary endpoint was progression-free survival (PFS). In general, tolerance to treatment was good, even among 8 patients with performance status 2–3 and 13 patients with brain metastases; grade 4 toxicity included 2 cases of neutropenia and 4 thrombo-embolic events. Complete response (CR) or partial response (PR) were seen in 15 (39.5%) and 17 (44.7%) cases, respectively. All cases of CR were confirmed also by PET/CT. Median PFS was 23.4 months and median overall survival (OS) was 38.3 months. After a median follow-up of 35 months, 8 patients are still in CR and on maintenance erlotinib. In conclusion, intercalated treatment for treatment-naive patients with EGFR activating mutations leads to excellent response rate and prolonged PFS and survival. Comparison of the intercalated schedule to monotherapy with TKIs in a randomized trial is warranted.\n\nKEYWORDS\nCisplatinerlotinibEGFR activating mutationsgemcitabineintercalated treatmentNSCLCresponse evaluationTKI18F-FDG PET/CT\n==== Body\nAbbreviations\n\n18F-FDG18-fluorodeoksyglucose\n\nCIconfidence interval\n\nCRcomplete response\n\nCTcomputer tomography\n\nEGFRepidermal growth factor receptor\n\nMcrmetabolic complete remission\n\nmPDmetabolic progressive disease\n\nmPRmetabolic partial response\n\nmSDmetabolic stable disease\n\nNSCLCnon-small cell lung cancer\n\nORRobjective response rate\n\nOSoverall survival\n\nPDprogressive disease\n\nPERCISTPET response criteria in solid tumors\n\nPETpositron emission tomography\n\nPFSprogression-free survival\n\nPRpartial response\n\nPSperformance status\n\nRECISTresponse evaluation criteria for solid tumors\n\nSUVstandard uptake value\n\nTKItyrosine kinase inhibitor\n\n\n\nIntroduction\nDiscovery of activating mutations of epidermal growth factor receptor (EGFR) has changed dramatically the treatment of a relatively small subset of patients with non-small cell lung cancer (NSCLC). In these patients, treatment with tyrosine kinase inhibitors (TKIs) such as erlotinib, gefitinib or afatinib offers excellent quality of life with over 70% objective remissions, a figure clearly superior to treatment with chemotherapy. In randomized trials, superiority of TKIs against treatment with cytotoxic drugs has been confirmed.1,2\n\nIn spite of high proportion of remissions, treatment with TKIs almost invariably leads to resistance. Most of current pre-clinical and clinical research focuses on intercalated application of targeted and cytotoxic drugs, and on new targeted drugs designed to overcome acquired TKI resistance.3-5\n\nThe concept of intercalated therapy arose after 4 large trials failed to show any benefit of adding TKIs to cytotoxic drugs in a continuous schedule.6-9 Suspected mutual antagonism between the 2 classes of drugs was confirmed in laboratory experiments: TKIs cause G1 cell cycle arrest, leading to resistance of tumor cells to cycle-specific cytotoxic drugs.10 An interval of 6 d without TKIs is needed to restore sensitivity of tumor cells to cytotoxic agents.11 After treatment with cytotoxic drugs, reversed or delayed development of resistance to TKIs were reported.12,13 With intercalated treatment, patients would therefore benefit from the 2 classes of drugs. In addition, treatment with TKIs would reduce tumor repopulation during gaps between individual applications of cytotoxic drugs.\n\nIn our recent Phase II trial, gemcitabine, cisplatin and erlotinib were applied in an intercalated schedule.14 Here we present mature data on responses, PFS and OS, including analysis for 30 patients who had PET/CT scanning prior to treatment and after 6 months.\n\nPatients and methods\nPatients eligible for the trial had histologically confirmed NSCLC with activating mutations of EGFR; were in advanced stage (IIIB or IV) not suitable for treatment with radical radio-chemotherapy; did not receive previous chemotherapy or treatment with TKIs; were in fair performance status (PS 0 – 3 according to Eastern Cooperative Oncology Group); fulfilled standard criteria for platin-based chemotherapy; and gave written informed consent.\n\nTreatment consisted of induction and maintenance. Patients started with 4 to 6 3-weekly cycles of intercalated therapy with gemcitabine (1250 mg/m2, i.v. infusion, days 1 and 4), cisplatin (75 mg/m2, i.v. infusion with appropriate hydration and antiemetics, day 2) and erlotinib (150 mg daily p.o., days 5 – 15). After induction phase, treatment continued with uninterrupted erlotinib (150 mg daily p.o.) as maintenance. Effect of treatment was monitored with standard radiological examinations and assessed according to Response Evaluation Criteria for Solid Tumors (RECIST).\n\nPET/CT scanning was recommended as an optional additional instrument for evaluation of treatment. 18F-FDG PET/CT was performed prior to any treatment and at 6 months after entering the trial. At baseline and for control examination, the patient was referred to the same institution – either to Institute of Oncology Ljubljana or to Department of Nuclear Medicine, University Medical Center Ljubljana. European Association of Nuclear Medicine procedure guidelines for tumor PET imaging were used for patient preparation and PET/CT acquisition protocols. Control PET/CT examinations included all initial sites of disease, with measurement of corresponding maximal standardized uptake value (SUVmax). Appearance of any new lesion or increase in SUV of a previously known lesion together with ≥ 20% increase in its size was declared as metabolic progression (mPD). For metabolic partial remission (mPR), all previously known lesions should either disappear or show at least 50% reduction in uptake. Patients between progression and partial response were classified as metabolic stable disease (mSD). Finally, normalization of PET/CT and disappearance of all lesions with initially increased SUV were required to declare a metabolic complete remission (mCR).15\n\nThe primary endpoint of the trial was PFS. Taking 20 months as the expected PFS for the intercalated regimen, 35 patients were needed for a 80% power to confirm, at the one-sided 0.10 significance level, a difference to the reported 12 months as median PFS for monotherapy with TKIs.16 Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Differences between subgroups were compared by the log-rank test.\n\nThe trial was approved by the Institutional Review Board Committee (Institute of Oncology Ljubljana) and by the National Committee for Medical Ethics, and was registered with the European Medicines Agency, EudraCT Number 2010-023362-44.\n\nResults\nBetween September 2005 and October 2013, 38 patients (17 male, 21 female) with EGFR mutant NSCLC with non-squamous histology entered the trial. All patients were Caucasians. With the exception of one patient in Stage IIIB, all other patients had distant metastases, including 12 after whole-brain radiotherapy for multiple brain metastases and one with untreated brain disease. Six patients were in PS 2, and 2 in PS 3. Demographics, sites of metastatic disease and types of EGFR mutations are presented in Table 1.\nTable 1. Demographics, prognostic factors, extent of disease and type of EGFR mutations.\n\n \t \t38 patients\t\nAGE\tmedian\t61\t\n \trange\t37 – 74\t\nGENDER\tmale\t17\t\n \tfemale\t21\t\nSMOKING\tnever smoker\t24\t\n \tlight smoker (< 10 pack years)\t5\t\n \tsmoker\t9\t\nPERFORMANCE STATUS\tEGOG PS 0\t10\t\n \t1\t20\t\n \t2\t6\t\n \t3\t2\t\nSTAGE\tIII B\t1\t\n \tIV\t37\t\nSITE(S) OF METASTATIC DISEASE\tbone\t24\t\n \tdistant lung\t18\t\n \tpleura and pericardium\t16\t\n \tliver and/or suprarenals\t11\t\n \tbrain (after whole-brain radiotherapy)\t13 a\t\n \tdistant lymph nodes and/or soft tissues\t10\t\nNUMBER OF METASTATIC SITES\t1\t10\t\n \t2\t14\t\n \t3 or more\t14\t\nTYPE OF EGFR MUTATION\tExon 19 deletion b\t25\t\n \tG719X b\t4\t\n \tL858R\t9\t\n \tS 768i\t1\t\na Includes 1 patient with asymptomatic untreated multiple brain metastases\n\nb One patient had deletions and G719X mutation\n\n\n\n\nThe actual number of cycles of intercalated therapy was from 1 to 6 (median: 4 cycles).\n\nGrade 4 toxicity was limited to the induction phase of the treatment and was seen in 6 patients: 2 with neutropenia and 4 who developed deep vein thrombosis and/or pulmonary embolisms. Due to toxicity, 10 patients received only 1 – 3 cycles of the intercalated regimen and continued with erlotinib as maintenance. During the maintenance phase of the treatment, the only serious and common side effect was skin toxicity, with grades 2 and 3 in 11 and 13 patients, respectively, leading to a lower dose of erlotinib in 21 patients (Table 2).\nTable 2. Treatment toxicity.\n\n \tGrade\tINDUCTION\tMAINTENANCE\t\nAnemia\t2\t11\t2\t\n \t3\t1\t0\t\nNeutropenia\t2\t12\t0\t\n \t3\t4\t0\t\n \t4\t2\t0\t\nThrombocytopenia\t2\t3\t0\t\n \t3\t2\t0\t\nNephotoxicity\t2\t1\t0\t\nSkin toxicity a\t2\t8\t11\t\n \t3\t3\t13\t\nNausea/vomiting\t2\t4\t0\t\nAsthenia\t2\t1\t2\t\nThrombo-embolic events\t2\t1\t0\t\n \t4\t4\t0\t\nDiarrhea\t2\t3\t1\t\na Leading to reduced daily dose of erlotinib to 100 mg (12 patients), 75 mg (4 patients) or 50 mg (5 patients)\n\n\n\n\nThe first evaluation for response according to RECIST was performed during the 3rd cycle of intercalated therapy, with confirmation 6 weeks later. Radiologic assessment confirmed complete response (CR) in 15 (39.5%) and partial response (PR) in 17 (44.7%). Four patients had minimal response or stable disease, and one progressed.\n\nSeven patients did not have PET/CT at baseline and an additional patient failed to undergo control PET/CT scanning due to Grade 4 deep venous thrombosis. Thus, data on 30 patients are available for analysis of metabolic response to treatment. According to PERCIST criteria, mCR was confirmed in 17 patients and mPR in 7, with good correlation between radiological response and metabolic response (Table 3).\nTable 3. Response to treatment according to RECIST and metabolic response.\n\n \t \t18F-FDG PET/CT (PERCIST)\t\n \t \tmCR\tmPR\tmSD\tmPD\tNot performed\t\nRADIOLOGY (RECIST)\tCR\t15\t \t \t \t \t\n \tPR\t2\t7\t \t2a\t6\t\n \tSD\t \t \t \t3\t2\t\n \tPD\t \t \t1\t \t \t\na Partial response according to RECIST during cycle 3 and confirmed in cycle 5; new lesions on PET-CT at 6 months\n\n\n\n\nA total of 149 lesions were examined for maximal SUV prior to treatment and at 6 months. It appears that sensitivity does not depend on the organ of metastasis (Fig. 1). On the basis of PET/CT, 5 patients were classified as mPD. Among these 5 patients, 4 had new lesions but also showed marked reduction of the metabolic activity in most other lesions – evidence on tumor heterogeneiety in sensitivity to anti-cancer treatment (Fig. 2).\nFigure 1. Metabolic response to treatment for individual lesions. For each patient, 2 – 6 lesions are shown. Colors of the dots indicate the metastatic site.\n\n\nFigure 2. (A, B) Complete response to treatment in a woman aged 72, with initial PS 2; EGFR deletions. PET/CT scan with representative sections before treatment (A) and after treatment (B). C, D, E, F: Mixed response to treatment in a woman aged 41, EGFR deletions. At 6 months, comparison of PET/CT scans before treatment (C) and after treatment (D) reveals complete metabolic response on the site of the primary tumor. However, a new lesion (F) is visible in a previously uninvolved site on the neck (E). In accordance with the rules for assessment of metabolic response to treatment, this was classified as progression.\n\n\n\n\nMedian PFS for all patients was 23.4 months (95% CI 17.6 – 29.2 months) (Fig. 3). For patients in PS 0 or 1, median PFS was 25.0 months (95% CI 19.8 – 30.2), to be compared to 15.3 months (95% CI 2.9 – 27.6) for those in PS 2 or 3 (p = 0.28). Patients with initial SUVmax lower than 12 had longer median PFS, when compared to those with higher initial SUVmax (25.6 months, 95% CI 13.1 – 38.1 vs 17.7 months, 95% CI 6.7 – 28.6; p=0.09). No difference in PFS was seen between patients with exon 19 deletions and those with other mutations (data not shown).\nFigure 3. (A) Progression-free survival for patients with initial performance status 0 – 1 and 2 – 3. (B) Progression-free survival for patients with initial SUVmax below or under 12. (C) Overall survival for patients with initial performance status 0 – 1 and 2 – 3. (D) Overall survival for patients with initial SUVmax below or under 12.\n\n\n\n\nThe most frequent sites of progression were bone (10), lung (10), brain (6), liver (3), or distant lymph nodes (3). Two patients with brain metastases and one patient with diffuse progression in the liver did not receive additional systemic treatment. Seventeen patients continued with erlotinib beyond progression. Other choices were gefitinib or afatinib (8 patients) or different combinations of cytotoxic chemotherapy (6 patients); more than one treatment option per patient may apply.\n\nMedian survival was 38.3 months (95% CI 27.1 – 49.4). Patients with initial PS 0–1 had longer OS, when compared to those with PS 2–3 (38.7 months, 95% CI 29.8 – 47.5 vs 23.9 months, 95% CI 13.4 – 34.4; p = 0.42). Similarly, patients with initial SUVmax lower than 12 had longer survival, when compared to those with higher initial SUVmax (48.1 months, 95% CI 35.9 – 60.3 vs, 29.8 months, 95% CI 20.6 – 38.9; p = 0.10). At the close-out date (February 3, 2016), 13 patients are alive, of whom 8 are still in complete remission and continue with maintenance erlotinib.\n\nDiscussion\nA survey of 17 published trials of intercalated therapy for advanced NSCLC reveals significant differences in inclusion criteria and in treatment schedules.17-33 Nine trials recruited patients in progression after first-line treatment.17-25 None of these trials could offer convincing evidence for advantage of intercalated schedule over standard second-line treatment. Of the remaining 8 trials on treatment-naive disease, only 2 reported a meaningful proportion of patients with EGFR mutations. One of these 2 trials (FASTACT 2)32 used treatment with no gap after erlotinib, a schedule which is not in line with the proposed 6 d for wash-out period before application of cytotoxic drugs. In addition, interpretation of experience of the FASTACT 2 trial is difficult since the intercalated arm was compared to chemotherapy alone, a treatment which is currently not the optimal approach for EGFR mutated NSCLC. Thus, only one trial with 31 EGFR mutant treatment-naive patients remains which is fully in line with the theoretical background for intercalated treatment. This trial indeed reported very high objective response rate (ORR) of 76.9% and a promising curve of PFS, with no figure for median value due to relatively short follow-up.33\n\nIn a recent phase II randomized trial of concurrent vs. sequential application of pemetrexed, carboplatin and gefitinib for patients with sensitive EGFR mutations, both arms had excellent response rate of over 80%.34 While this trial did not include an intercalated schedule, its experience confirmed the value of combining TKIs and cytotoxic drugs in the treatment of advanced EGFR mutant lung cancer.\n\nTurning to our trial, small number of patients is obviously its weak point. Since the proportion of patients with EGFR mutant NSCLC among Caucasians is relatively small, we decided to recruit also patients with poor performance status. Also eligible were patients with brain metastases – a frequent occurrence in EGFR mutant disease.35 In spite of such wide eligibility criteria, our experience with intercalated treatment is very good. Objective response in 84.2%, median PFS 23.4 months and median OS 38.3 months are figures which have not been reported in any other trial of advanced NSCLC, at least not in Caucasian patients. CR was confirmed in 39.5% of patients – a striking difference to virtually all reports on monotherapy with TKIs where the proportion of patients with CR remains below 5%.16,36 Two explanations are offered for high efficacy of intercalated therapy. This schedule combines 3 drugs with proven activity, a different mechanism of action, and a different toxicity profile and applies the principle of pharmaco-dynamic separation to avoid their mutual antagonism. In addition, erlotinib fills the gaps between individual applications of cytotoxic drugs and prevents tumor repopulation, a decisive factor for failure of standard chemotherapy schedules for solid tumors.37 Significantly inferior results of other trials support the opinion that intercalated treatment should be reserved for patients who are sensitive to both classes of drugs: it is unlikely that the intercalated schedule would be effective for EGFR wild-type disease, or for patients who developed resistance to either treatment alone. In our opinion, only treatment-naive EGFR-mutant patients are candidates for this treatment.\n\nWhile some patients in PS 2 or 3 had durable responses, their survival was inferior when compared to those in PS 0 or 1. The benefit of adding cytotoxic drugs to TKIs for this subset of patients is questionnable. Until more experience is available, future trials on intercalated treatment should limit inclusion to patients in PS 0 and 1.\n\nThe cytotoxic part of our regimen was designed at the time when gemcitabin in combination with platin was widely accepted as the first-line treatment for advanced NSCLC. An obvious option for future trials is pemetrexed with platin, currently the preferred doublet for adenocarcinoma.\n\nAnother promising approach toward more effective treatment for patients with advanced EGFR mutant tumors is combination of erlotinib with bevacuzimab. In a randomized trial, addition of bevacuzimab to erlotinib significantly improved the results.38 The possibility of a triple combination – intercalated regimen of cytotoxic and targeted drugs with additional bevacuzimab – remains a challenge for future research. \n\nThis report illustrates the role of PET/CT in 4 important aspects: meaningful interpretation of small clinical trials; assessment of response for lesions not evaluable by classical radiology such as bone metastases or pleural invasion; prognostic information; and rational approach to heterogeneiety of cancer.\n\nEvaluation with PET/CT is of special importance for trials with a limited number of patients, a situation which is likely to become a reality for many diagnostic sub-categories treated with targeted drugs. Small clinical trials demand precise tools for assessment of efficacy of treatment. In comparison to classical radiology and RECIST, PET/CT scanning gives numerical result with little observer's bias and offers better distinction between categories of stable disease, partial remission and complete response.39,40 In our trial, 15/30 (50%) patients had complete response both according to RECIST and to PET/CT. Without confirmation of metabolic CR, doubt regarding the validity of this report might remain, the more so since a substantial proportion of our patients had bone or pleural metastases – sites which are not evaluable with classical radiology.\n\nRegarding prognostic information, patients with baseline SUV over 12 had shorter survival, when compared to those with lower initial activity. This is in line with previous reports on correlation among poorly differentiated histological pattern, high initial SUV and shorter survival.41\n\nOur trial offers a new insight into heterogeneiety of lung cancer. In 4 of the 5 patients with mPD, PET/CT revealed some lesions in progression, concurrently with markedly diminished metabolic activity in other lesions. This observation points to heterogeneiety of the tumor and supports the concept of treatment beyond progression.42\n\nIn conclusion, intercalated treatment with gemcitabine, cisplatin and erlotinib offers excellent response rate and prolonged survival for treatment-naive patients with advanced EGFR mutant NSCLC. Responses were confirmed by PET/CT scanning. A randomized trial with comparison against monotherapy with TKIs as the standard treatment is warranted.\n\nDisclosure of potential conflicts of interest\nNo potential conflicts of interest were disclosed.\n\nAcknowledgments\nThe authors thank all patients and their families for their cooperation, nurses from the Outpatient Department and Day Hospital and data managers from the Unit for Clinical Trials for their help in conducting the trial, and Dyanne Søraas for language editing.\n\nFunding\nThis work was supported by grant 2010-I/761 from The Ministry of Science, Education and Sport, Republic of Slovenia.\n\nAuthor's Contribution\nConception, design, conduct and analysis: M Zwitter, M Rajer, K Stanic, M Vrankar, I Kern, V Kovac; Statistical evaluation: M Zwitter, M Rajer, K Stanic; PET/CT evaluation and analysis: A Doma, A Cuderman, M Grmek; Manuscript writing: all authors; Final approval of manuscript: all authors\n==== Refs\nReferences\n1. 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"fulltext_license": "CC BY-NC",
"issn_linking": "1538-4047",
"issue": "17(8)",
"journal": "Cancer biology & therapy",
"keywords": "18F-FDG PET/CT; Cisplatin; EGFR activating mutations; NSCLC; TKI; erlotinib; gemcitabine; intercalated treatment; response evaluation",
"medline_ta": "Cancer Biol Ther",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002289:Carcinoma, Non-Small-Cell Lung; D002945:Cisplatin; D003841:Deoxycytidine; D004334:Drug Administration Schedule; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009154:Mutation",
"nlm_unique_id": "101137842",
"other_id": null,
"pages": "833-9",
"pmc": null,
"pmid": "27261103",
"pubdate": "2016-08-02",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": "25175099;25521095;21825259;14990632;16043829;26845114;23986090;10673991;21892109;26105600;17442998;23993733;23782814;26169499;26834517;25435849;22285168;21850211;25640373;26141208;14990633;25082565;16800963;24755888;23207920;19738125;11905673;24976990;21783417;26331815;23890768;25669832;26493267;25538894;25275069;24991207;25547902;25450874;24575793;26725184",
"title": "Intercalated chemotherapy and erlotinib for non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations.",
"title_normalized": "intercalated chemotherapy and erlotinib for non small cell lung cancer nsclc with activating epidermal growth factor receptor egfr mutations"
} | [
{
"companynumb": "SI-ASTELLAS-2014US006279",
"fulfillexpeditecriteria": "1",
"occurcountry": "SI",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
"dr... |
{
"abstract": "OBJECTIVE\nTo assess in multiple sclerosis (MS) the effect of intense immunosuppression followed by autologous hematopoietic stem cells transplantation (AHSCT) vs mitoxantrone (MTX) on disease activity measured by MRI.\n\n\nMETHODS\nWe conducted a multicenter, phase II, randomized trial including patients with secondary progressive or relapsing-remitting MS, with a documented increase in the last year on the Expanded Disability Status Scale, in spite of conventional therapy, and presence of one or more gadolinium-enhancing (Gd+) areas. Patients were randomized to receive intense immunosuppression (mobilization with cyclophosphamide and filgrastim, conditioning with carmustine, cytosine-arabinoside, etoposide, melphalan, and anti-thymocyte globulin) followed by AHSCT or MTX 20 mg every month for 6 months. The primary endpoint was the cumulative number of new T2 lesions in the 4 years following randomization. Secondary endpoints were the cumulative number of Gd+ lesions, relapse rate, and disability progression. Safety and tolerability were also assessed. Twenty-one patients were randomized and 17 had postbaseline evaluable MRI scans.\n\n\nRESULTS\nAHSCT reduced by 79% the number of new T2 lesions as compared to MTX (rate ratio 0.21, p = 0.00016). It also reduced Gd+ lesions as well as the annualized relapse rate. No difference was found in the progression of disability.\n\n\nCONCLUSIONS\nIntense immunosuppression followed by AHSCT is significantly superior to MTX in reducing MRI activity in severe cases of MS. These results strongly support further phase III studies with primary clinical endpoints. The study was registered as EUDRACT No. 2007-000064-24.",
"affiliations": "From the MRI Center for Neurological Diseases (L.R.), Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health (G.L.M., D.C.), and the Biostatistic Unit, Department of Health Sciences (M.P.S., L.R.), University of Genova; the Bone Marrow Transplantation Unit (F.G.), S. Martino Hospital, Genova, Italy; the Service of Neurology (A.S.) and the Hematology Department (E.C.), Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer, Hospital Clínic, University of Barcelona, Spain; the Department of Neurosciences (E.M.) and the Bone Marrow Transplantation Unit, Department of Hematology and Oncology (A.D.), University of Modena and Reggio Emilia; the MS Center, Department of Neuroscience, Imaging and Clinical Sciences (A.L.), University Gabriele D'Annunzio, Chieti-Pescara; the Bone Marrow Transplant Center, Department of Hematology (P.D.B.), Spirito Santo Hospital, Pescara; the Multiple Sclerosis Unit Ospedale Papa Giovanni XXIII (M.R.R.), Bergamo; the Hematology and Bone Marrow Transplant Unit Azienda Ospedaliera Papa Giovanni XXIII (A.R.), Bergamo; Division Neurology 1 (M.P.A.) and Division Neurology 2, Drug and Child Health (L.M., L.V.), Department of Neurosciences, and Bone Marrow Transplantation Unit (M.D.G., R.S.), Careggi University Hospital, University of Firenze; the Neuroimaging Research Unit (M.F.), Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan; the Department of Medical and Surgical Sciences (U.A.), Magna Graecia University of Catanzaro; the Advanced Cellular Therapy Center IRCCS \"Istituto Tumori Giovanni Paolo II\" Bari (P.I.), Italy; and the Internal Medicine and Vascular Disease Unit (D.F.), Assistance Publique Hospitaux de Paris (AP-HP) INSERM U 796, Paris 7 University, Saint-Louis Hospital, Paris, France. glmancardi@neurologia.unige.it.;From the MRI Center for Neurological Diseases (L.R.), Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health (G.L.M., D.C.), and the Biostatistic Unit, Department of Health Sciences (M.P.S., L.R.), University of Genova; the Bone Marrow Transplantation Unit (F.G.), S. Martino Hospital, Genova, Italy; the Service of Neurology (A.S.) and the Hematology Department (E.C.), Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer, Hospital Clínic, University of Barcelona, Spain; the Department of Neurosciences (E.M.) and the Bone Marrow Transplantation Unit, Department of Hematology and Oncology (A.D.), University of Modena and Reggio Emilia; the MS Center, Department of Neuroscience, Imaging and Clinical Sciences (A.L.), University Gabriele D'Annunzio, Chieti-Pescara; the Bone Marrow Transplant Center, Department of Hematology (P.D.B.), Spirito Santo Hospital, Pescara; the Multiple Sclerosis Unit Ospedale Papa Giovanni XXIII (M.R.R.), Bergamo; the Hematology and Bone Marrow Transplant Unit Azienda Ospedaliera Papa Giovanni XXIII (A.R.), Bergamo; Division Neurology 1 (M.P.A.) and Division Neurology 2, Drug and Child Health (L.M., L.V.), Department of Neurosciences, and Bone Marrow Transplantation Unit (M.D.G., R.S.), Careggi University Hospital, University of Firenze; the Neuroimaging Research Unit (M.F.), Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan; the Department of Medical and Surgical Sciences (U.A.), Magna Graecia University of Catanzaro; the Advanced Cellular Therapy Center IRCCS \"Istituto Tumori Giovanni Paolo II\" Bari (P.I.), Italy; and the Internal Medicine and Vascular Disease Unit (D.F.), Assistance Publique Hospitaux de Paris (AP-HP) INSERM U 796, Paris 7 University, Saint-Louis Hospital, Paris, France.;From the MRI Center for Neurological Diseases (L.R.), Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health (G.L.M., D.C.), and the Biostatistic Unit, Department of Health Sciences (M.P.S., L.R.), University of Genova; the Bone Marrow Transplantation Unit (F.G.), S. Martino Hospital, Genova, Italy; the Service of Neurology (A.S.) and the Hematology Department (E.C.), Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer, Hospital Clínic, University of Barcelona, Spain; the Department of Neurosciences (E.M.) and the Bone Marrow Transplantation Unit, Department of Hematology and Oncology (A.D.), University of Modena and Reggio Emilia; the MS Center, Department of Neuroscience, Imaging and Clinical Sciences (A.L.), University Gabriele D'Annunzio, Chieti-Pescara; the Bone Marrow Transplant Center, Department of Hematology (P.D.B.), Spirito Santo Hospital, Pescara; the Multiple Sclerosis Unit Ospedale Papa Giovanni XXIII (M.R.R.), Bergamo; the Hematology and Bone Marrow Transplant Unit Azienda Ospedaliera Papa Giovanni XXIII (A.R.), Bergamo; Division Neurology 1 (M.P.A.) and Division Neurology 2, Drug and Child Health (L.M., L.V.), Department of Neurosciences, and Bone Marrow Transplantation Unit (M.D.G., R.S.), Careggi University Hospital, University of Firenze; the Neuroimaging Research Unit (M.F.), Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan; the Department of Medical and Surgical Sciences (U.A.), Magna Graecia University of Catanzaro; the Advanced Cellular Therapy Center IRCCS \"Istituto Tumori Giovanni Paolo II\" Bari (P.I.), Italy; and the Internal Medicine and Vascular Disease Unit (D.F.), Assistance Publique Hospitaux de Paris (AP-HP) INSERM U 796, Paris 7 University, Saint-Louis Hospital, Paris, France.;From the MRI Center for Neurological Diseases (L.R.), Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health (G.L.M., D.C.), and the Biostatistic Unit, Department of Health Sciences (M.P.S., L.R.), University of Genova; the Bone Marrow Transplantation Unit (F.G.), S. Martino Hospital, Genova, Italy; the Service of Neurology (A.S.) and the Hematology Department (E.C.), Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer, Hospital Clínic, University of Barcelona, Spain; the Department of Neurosciences (E.M.) and the Bone Marrow Transplantation Unit, Department of Hematology and Oncology (A.D.), University of Modena and Reggio Emilia; the MS Center, Department of Neuroscience, Imaging and Clinical Sciences (A.L.), University Gabriele D'Annunzio, Chieti-Pescara; the Bone Marrow Transplant Center, Department of Hematology (P.D.B.), Spirito Santo Hospital, Pescara; the Multiple Sclerosis Unit Ospedale Papa Giovanni XXIII (M.R.R.), Bergamo; the Hematology and Bone Marrow Transplant Unit Azienda Ospedaliera Papa Giovanni XXIII (A.R.), Bergamo; Division Neurology 1 (M.P.A.) and Division Neurology 2, Drug and Child Health (L.M., L.V.), Department of Neurosciences, and Bone Marrow Transplantation Unit (M.D.G., R.S.), Careggi University Hospital, University of Firenze; the Neuroimaging Research Unit (M.F.), Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan; the Department of Medical and Surgical Sciences (U.A.), Magna Graecia University of Catanzaro; the Advanced Cellular Therapy Center IRCCS \"Istituto Tumori Giovanni Paolo II\" Bari (P.I.), Italy; and the Internal Medicine and Vascular Disease Unit (D.F.), Assistance Publique Hospitaux de Paris (AP-HP) INSERM U 796, Paris 7 University, Saint-Louis Hospital, Paris, France.;From the MRI Center for Neurological Diseases (L.R.), Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health (G.L.M., D.C.), and the Biostatistic Unit, Department of Health Sciences (M.P.S., L.R.), University of Genova; the Bone Marrow Transplantation Unit (F.G.), S. Martino Hospital, Genova, Italy; the Service of Neurology (A.S.) and the Hematology Department (E.C.), Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer, Hospital Clínic, University of Barcelona, Spain; the Department of Neurosciences (E.M.) and the Bone Marrow Transplantation Unit, Department of Hematology and Oncology (A.D.), University of Modena and Reggio Emilia; the MS Center, Department of Neuroscience, Imaging and Clinical Sciences (A.L.), University Gabriele D'Annunzio, Chieti-Pescara; the Bone Marrow Transplant Center, Department of Hematology (P.D.B.), Spirito Santo Hospital, Pescara; the Multiple Sclerosis Unit Ospedale Papa Giovanni XXIII (M.R.R.), Bergamo; the Hematology and Bone Marrow Transplant Unit Azienda Ospedaliera Papa Giovanni XXIII (A.R.), Bergamo; Division Neurology 1 (M.P.A.) and Division Neurology 2, Drug and Child Health (L.M., L.V.), Department of Neurosciences, and Bone Marrow Transplantation Unit (M.D.G., R.S.), Careggi University Hospital, University of Firenze; the Neuroimaging Research Unit (M.F.), Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan; the Department of Medical and Surgical Sciences (U.A.), Magna Graecia University of Catanzaro; the Advanced Cellular Therapy Center IRCCS \"Istituto Tumori Giovanni Paolo II\" Bari (P.I.), Italy; and the Internal Medicine and Vascular Disease Unit (D.F.), Assistance Publique Hospitaux de Paris (AP-HP) INSERM U 796, Paris 7 University, Saint-Louis Hospital, Paris, France.;From the MRI Center for Neurological Diseases (L.R.), Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health (G.L.M., D.C.), and the Biostatistic Unit, Department of Health Sciences (M.P.S., L.R.), University of Genova; the Bone Marrow Transplantation Unit (F.G.), S. Martino Hospital, Genova, Italy; the Service of Neurology (A.S.) and the Hematology Department (E.C.), Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer, Hospital Clínic, University of Barcelona, Spain; the Department of Neurosciences (E.M.) and the Bone Marrow Transplantation Unit, Department of Hematology and Oncology (A.D.), University of Modena and Reggio Emilia; the MS Center, Department of Neuroscience, Imaging and Clinical Sciences (A.L.), University Gabriele D'Annunzio, Chieti-Pescara; the Bone Marrow Transplant Center, Department of Hematology (P.D.B.), Spirito Santo Hospital, Pescara; the Multiple Sclerosis Unit Ospedale Papa Giovanni XXIII (M.R.R.), Bergamo; the Hematology and Bone Marrow Transplant Unit Azienda Ospedaliera Papa Giovanni XXIII (A.R.), Bergamo; Division Neurology 1 (M.P.A.) and Division Neurology 2, Drug and Child Health (L.M., L.V.), Department of Neurosciences, and Bone Marrow Transplantation Unit (M.D.G., R.S.), Careggi University Hospital, University of Firenze; the Neuroimaging Research Unit (M.F.), Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan; the Department of Medical and Surgical Sciences (U.A.), Magna Graecia University of Catanzaro; the Advanced Cellular Therapy Center IRCCS \"Istituto Tumori Giovanni Paolo II\" Bari (P.I.), Italy; and the Internal Medicine and Vascular Disease Unit (D.F.), Assistance Publique Hospitaux de Paris (AP-HP) INSERM U 796, Paris 7 University, Saint-Louis Hospital, Paris, France.;From the MRI Center for Neurological Diseases (L.R.), Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health (G.L.M., D.C.), and the Biostatistic Unit, Department of Health Sciences (M.P.S., L.R.), University of Genova; the Bone Marrow Transplantation Unit (F.G.), S. Martino Hospital, Genova, Italy; the Service of Neurology (A.S.) and the Hematology Department (E.C.), Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer, Hospital Clínic, University of Barcelona, Spain; the Department of Neurosciences (E.M.) and the Bone Marrow Transplantation Unit, Department of Hematology and Oncology (A.D.), University of Modena and Reggio Emilia; the MS Center, Department of Neuroscience, Imaging and Clinical Sciences (A.L.), University Gabriele D'Annunzio, Chieti-Pescara; the Bone Marrow Transplant Center, Department of Hematology (P.D.B.), Spirito Santo Hospital, Pescara; the Multiple Sclerosis Unit Ospedale Papa Giovanni XXIII (M.R.R.), Bergamo; the Hematology and Bone Marrow Transplant Unit Azienda Ospedaliera Papa Giovanni XXIII (A.R.), Bergamo; Division Neurology 1 (M.P.A.) and Division Neurology 2, Drug and Child Health (L.M., L.V.), Department of Neurosciences, and Bone Marrow Transplantation Unit (M.D.G., R.S.), Careggi University Hospital, University of Firenze; the Neuroimaging Research Unit (M.F.), Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan; the Department of Medical and Surgical Sciences (U.A.), Magna Graecia University of Catanzaro; the Advanced Cellular Therapy Center IRCCS \"Istituto Tumori Giovanni Paolo II\" Bari (P.I.), Italy; and the Internal Medicine and Vascular Disease Unit (D.F.), Assistance Publique Hospitaux de Paris (AP-HP) INSERM U 796, Paris 7 University, Saint-Louis Hospital, Paris, France.;From the MRI Center for Neurological Diseases (L.R.), Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health (G.L.M., D.C.), and the Biostatistic Unit, Department of Health Sciences (M.P.S., L.R.), University of Genova; the Bone Marrow Transplantation Unit (F.G.), S. Martino Hospital, Genova, Italy; the Service of Neurology (A.S.) and the Hematology Department (E.C.), Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer, Hospital Clínic, University of Barcelona, Spain; the Department of Neurosciences (E.M.) and the Bone Marrow Transplantation Unit, Department of Hematology and Oncology (A.D.), University of Modena and Reggio Emilia; the MS Center, Department of Neuroscience, Imaging and Clinical Sciences (A.L.), University Gabriele D'Annunzio, Chieti-Pescara; the Bone Marrow Transplant Center, Department of Hematology (P.D.B.), Spirito Santo Hospital, Pescara; the Multiple Sclerosis Unit Ospedale Papa Giovanni XXIII (M.R.R.), Bergamo; the Hematology and Bone Marrow Transplant Unit Azienda Ospedaliera Papa Giovanni XXIII (A.R.), Bergamo; Division Neurology 1 (M.P.A.) and Division Neurology 2, Drug and Child Health (L.M., L.V.), Department of Neurosciences, and Bone Marrow Transplantation Unit (M.D.G., R.S.), Careggi University Hospital, University of Firenze; the Neuroimaging Research Unit (M.F.), Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan; the Department of Medical and Surgical Sciences (U.A.), Magna Graecia University of Catanzaro; the Advanced Cellular Therapy Center IRCCS \"Istituto Tumori Giovanni Paolo II\" Bari (P.I.), Italy; and the Internal Medicine and Vascular Disease Unit (D.F.), Assistance Publique Hospitaux de Paris (AP-HP) INSERM U 796, Paris 7 University, Saint-Louis Hospital, Paris, France.;From the MRI Center for Neurological Diseases (L.R.), Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health (G.L.M., D.C.), and the Biostatistic Unit, Department of Health Sciences (M.P.S., L.R.), University of Genova; the Bone Marrow Transplantation Unit (F.G.), S. Martino Hospital, Genova, Italy; the Service of Neurology (A.S.) and the Hematology Department (E.C.), Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer, Hospital Clínic, University of Barcelona, Spain; the Department of Neurosciences (E.M.) and the Bone Marrow Transplantation Unit, Department of Hematology and Oncology (A.D.), University of Modena and Reggio Emilia; the MS Center, Department of Neuroscience, Imaging and Clinical Sciences (A.L.), University Gabriele D'Annunzio, Chieti-Pescara; the Bone Marrow Transplant Center, Department of Hematology (P.D.B.), Spirito Santo Hospital, Pescara; the Multiple Sclerosis Unit Ospedale Papa Giovanni XXIII (M.R.R.), Bergamo; the Hematology and Bone Marrow Transplant Unit Azienda Ospedaliera Papa Giovanni XXIII (A.R.), Bergamo; Division Neurology 1 (M.P.A.) and Division Neurology 2, Drug and Child Health (L.M., L.V.), Department of Neurosciences, and Bone Marrow Transplantation Unit (M.D.G., R.S.), Careggi University Hospital, University of Firenze; the Neuroimaging Research Unit (M.F.), Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan; the Department of Medical and Surgical Sciences (U.A.), Magna Graecia University of Catanzaro; the Advanced Cellular Therapy Center IRCCS \"Istituto Tumori Giovanni Paolo II\" Bari (P.I.), Italy; and the Internal Medicine and Vascular Disease Unit (D.F.), Assistance Publique Hospitaux de Paris (AP-HP) INSERM U 796, Paris 7 University, Saint-Louis Hospital, Paris, France.;From the MRI Center for Neurological Diseases (L.R.), Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health (G.L.M., D.C.), and the Biostatistic Unit, Department of Health Sciences (M.P.S., L.R.), University of Genova; the Bone Marrow Transplantation Unit (F.G.), S. Martino Hospital, Genova, Italy; the Service of Neurology (A.S.) and the Hematology Department (E.C.), Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer, Hospital Clínic, University of Barcelona, Spain; the Department of Neurosciences (E.M.) and the Bone Marrow Transplantation Unit, Department of Hematology and Oncology (A.D.), University of Modena and Reggio Emilia; the MS Center, Department of Neuroscience, Imaging and Clinical Sciences (A.L.), University Gabriele D'Annunzio, Chieti-Pescara; the Bone Marrow Transplant Center, Department of Hematology (P.D.B.), Spirito Santo Hospital, Pescara; the Multiple Sclerosis Unit Ospedale Papa Giovanni XXIII (M.R.R.), Bergamo; the Hematology and Bone Marrow Transplant Unit Azienda Ospedaliera Papa Giovanni XXIII (A.R.), Bergamo; Division Neurology 1 (M.P.A.) and Division Neurology 2, Drug and Child Health (L.M., L.V.), Department of Neurosciences, and Bone Marrow Transplantation Unit (M.D.G., R.S.), Careggi University Hospital, University of Firenze; the Neuroimaging Research Unit (M.F.), Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan; the Department of Medical and Surgical Sciences (U.A.), Magna Graecia University of Catanzaro; the Advanced Cellular Therapy Center IRCCS \"Istituto Tumori Giovanni Paolo II\" Bari (P.I.), Italy; and the Internal Medicine and Vascular Disease Unit (D.F.), Assistance Publique Hospitaux de Paris (AP-HP) INSERM U 796, Paris 7 University, Saint-Louis Hospital, Paris, France.;From the MRI Center for Neurological Diseases (L.R.), Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health (G.L.M., D.C.), and the Biostatistic Unit, Department of Health Sciences (M.P.S., L.R.), University of Genova; the Bone Marrow Transplantation Unit (F.G.), S. Martino Hospital, Genova, Italy; the Service of Neurology (A.S.) and the Hematology Department (E.C.), Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer, Hospital Clínic, University of Barcelona, Spain; the Department of Neurosciences (E.M.) and the Bone Marrow Transplantation Unit, Department of Hematology and Oncology (A.D.), University of Modena and Reggio Emilia; the MS Center, Department of Neuroscience, Imaging and Clinical Sciences (A.L.), University Gabriele D'Annunzio, Chieti-Pescara; the Bone Marrow Transplant Center, Department of Hematology (P.D.B.), Spirito Santo Hospital, Pescara; the Multiple Sclerosis Unit Ospedale Papa Giovanni XXIII (M.R.R.), Bergamo; the Hematology and Bone Marrow Transplant Unit Azienda Ospedaliera Papa Giovanni XXIII (A.R.), Bergamo; Division Neurology 1 (M.P.A.) and Division Neurology 2, Drug and Child Health (L.M., L.V.), Department of Neurosciences, and Bone Marrow Transplantation Unit (M.D.G., R.S.), Careggi University Hospital, University of Firenze; the Neuroimaging Research Unit (M.F.), Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan; the Department of Medical and Surgical Sciences (U.A.), Magna Graecia University of Catanzaro; the Advanced Cellular Therapy Center IRCCS \"Istituto Tumori Giovanni Paolo II\" Bari (P.I.), Italy; and the Internal Medicine and Vascular Disease Unit (D.F.), Assistance Publique Hospitaux de Paris (AP-HP) INSERM U 796, Paris 7 University, Saint-Louis Hospital, Paris, France.;From the MRI Center for Neurological Diseases (L.R.), Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health (G.L.M., D.C.), and the Biostatistic Unit, Department of Health Sciences (M.P.S., L.R.), University of Genova; the Bone Marrow Transplantation Unit (F.G.), S. Martino Hospital, Genova, Italy; the Service of Neurology (A.S.) and the Hematology Department (E.C.), Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer, Hospital Clínic, University of Barcelona, Spain; the Department of Neurosciences (E.M.) and the Bone Marrow Transplantation Unit, Department of Hematology and Oncology (A.D.), University of Modena and Reggio Emilia; the MS Center, Department of Neuroscience, Imaging and Clinical Sciences (A.L.), University Gabriele D'Annunzio, Chieti-Pescara; the Bone Marrow Transplant Center, Department of Hematology (P.D.B.), Spirito Santo Hospital, Pescara; the Multiple Sclerosis Unit Ospedale Papa Giovanni XXIII (M.R.R.), Bergamo; the Hematology and Bone Marrow Transplant Unit Azienda Ospedaliera Papa Giovanni XXIII (A.R.), Bergamo; Division Neurology 1 (M.P.A.) and Division Neurology 2, Drug and Child Health (L.M., L.V.), Department of Neurosciences, and Bone Marrow Transplantation Unit (M.D.G., R.S.), Careggi University Hospital, University of Firenze; the Neuroimaging Research Unit (M.F.), Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan; the Department of Medical and Surgical Sciences (U.A.), Magna Graecia University of Catanzaro; the Advanced Cellular Therapy Center IRCCS \"Istituto Tumori Giovanni Paolo II\" Bari (P.I.), Italy; and the Internal Medicine and Vascular Disease Unit (D.F.), Assistance Publique Hospitaux de Paris (AP-HP) INSERM U 796, Paris 7 University, Saint-Louis Hospital, Paris, France.;From the MRI Center for Neurological Diseases (L.R.), Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health (G.L.M., D.C.), and the Biostatistic Unit, Department of Health Sciences (M.P.S., L.R.), University of Genova; the Bone Marrow Transplantation Unit (F.G.), S. Martino Hospital, Genova, Italy; the Service of Neurology (A.S.) and the Hematology Department (E.C.), Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer, Hospital Clínic, University of Barcelona, Spain; the Department of Neurosciences (E.M.) and the Bone Marrow Transplantation Unit, Department of Hematology and Oncology (A.D.), University of Modena and Reggio Emilia; the MS Center, Department of Neuroscience, Imaging and Clinical Sciences (A.L.), University Gabriele D'Annunzio, Chieti-Pescara; the Bone Marrow Transplant Center, Department of Hematology (P.D.B.), Spirito Santo Hospital, Pescara; the Multiple Sclerosis Unit Ospedale Papa Giovanni XXIII (M.R.R.), Bergamo; the Hematology and Bone Marrow Transplant Unit Azienda Ospedaliera Papa Giovanni XXIII (A.R.), Bergamo; Division Neurology 1 (M.P.A.) and Division Neurology 2, Drug and Child Health (L.M., L.V.), Department of Neurosciences, and Bone Marrow Transplantation Unit (M.D.G., R.S.), Careggi University Hospital, University of Firenze; the Neuroimaging Research Unit (M.F.), Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan; the Department of Medical and Surgical Sciences (U.A.), Magna Graecia University of Catanzaro; the Advanced Cellular Therapy Center IRCCS \"Istituto Tumori Giovanni Paolo II\" Bari (P.I.), Italy; and the Internal Medicine and Vascular Disease Unit (D.F.), Assistance Publique Hospitaux de Paris (AP-HP) INSERM U 796, Paris 7 University, Saint-Louis Hospital, Paris, France.;From the MRI Center for Neurological Diseases (L.R.), Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health (G.L.M., D.C.), and the Biostatistic Unit, Department of Health Sciences (M.P.S., L.R.), University of Genova; the Bone Marrow Transplantation Unit (F.G.), S. Martino Hospital, Genova, Italy; the Service of Neurology (A.S.) and the Hematology Department (E.C.), Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer, Hospital Clínic, University of Barcelona, Spain; the Department of Neurosciences (E.M.) and the Bone Marrow Transplantation Unit, Department of Hematology and Oncology (A.D.), University of Modena and Reggio Emilia; the MS Center, Department of Neuroscience, Imaging and Clinical Sciences (A.L.), University Gabriele D'Annunzio, Chieti-Pescara; the Bone Marrow Transplant Center, Department of Hematology (P.D.B.), Spirito Santo Hospital, Pescara; the Multiple Sclerosis Unit Ospedale Papa Giovanni XXIII (M.R.R.), Bergamo; the Hematology and Bone Marrow Transplant Unit Azienda Ospedaliera Papa Giovanni XXIII (A.R.), Bergamo; Division Neurology 1 (M.P.A.) and Division Neurology 2, Drug and Child Health (L.M., L.V.), Department of Neurosciences, and Bone Marrow Transplantation Unit (M.D.G., R.S.), Careggi University Hospital, University of Firenze; the Neuroimaging Research Unit (M.F.), Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan; the Department of Medical and Surgical Sciences (U.A.), Magna Graecia University of Catanzaro; the Advanced Cellular Therapy Center IRCCS \"Istituto Tumori Giovanni Paolo II\" Bari (P.I.), Italy; and the Internal Medicine and Vascular Disease Unit (D.F.), Assistance Publique Hospitaux de Paris (AP-HP) INSERM U 796, Paris 7 University, Saint-Louis Hospital, Paris, France.;From the MRI Center for Neurological Diseases (L.R.), Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health (G.L.M., D.C.), and the Biostatistic Unit, Department of Health Sciences (M.P.S., L.R.), University of Genova; the Bone Marrow Transplantation Unit (F.G.), S. Martino Hospital, Genova, Italy; the Service of Neurology (A.S.) and the Hematology Department (E.C.), Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer, Hospital Clínic, University of Barcelona, Spain; the Department of Neurosciences (E.M.) and the Bone Marrow Transplantation Unit, Department of Hematology and Oncology (A.D.), University of Modena and Reggio Emilia; the MS Center, Department of Neuroscience, Imaging and Clinical Sciences (A.L.), University Gabriele D'Annunzio, Chieti-Pescara; the Bone Marrow Transplant Center, Department of Hematology (P.D.B.), Spirito Santo Hospital, Pescara; the Multiple Sclerosis Unit Ospedale Papa Giovanni XXIII (M.R.R.), Bergamo; the Hematology and Bone Marrow Transplant Unit Azienda Ospedaliera Papa Giovanni XXIII (A.R.), Bergamo; Division Neurology 1 (M.P.A.) and Division Neurology 2, Drug and Child Health (L.M., L.V.), Department of Neurosciences, and Bone Marrow Transplantation Unit (M.D.G., R.S.), Careggi University Hospital, University of Firenze; the Neuroimaging Research Unit (M.F.), Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan; the Department of Medical and Surgical Sciences (U.A.), Magna Graecia University of Catanzaro; the Advanced Cellular Therapy Center IRCCS \"Istituto Tumori Giovanni Paolo II\" Bari (P.I.), Italy; and the Internal Medicine and Vascular Disease Unit (D.F.), Assistance Publique Hospitaux de Paris (AP-HP) INSERM U 796, Paris 7 University, Saint-Louis Hospital, Paris, France.;From the MRI Center for Neurological Diseases (L.R.), Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health (G.L.M., D.C.), and the Biostatistic Unit, Department of Health Sciences (M.P.S., L.R.), University of Genova; the Bone Marrow Transplantation Unit (F.G.), S. Martino Hospital, Genova, Italy; the Service of Neurology (A.S.) and the Hematology Department (E.C.), Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer, Hospital Clínic, University of Barcelona, Spain; the Department of Neurosciences (E.M.) and the Bone Marrow Transplantation Unit, Department of Hematology and Oncology (A.D.), University of Modena and Reggio Emilia; the MS Center, Department of Neuroscience, Imaging and Clinical Sciences (A.L.), University Gabriele D'Annunzio, Chieti-Pescara; the Bone Marrow Transplant Center, Department of Hematology (P.D.B.), Spirito Santo Hospital, Pescara; the Multiple Sclerosis Unit Ospedale Papa Giovanni XXIII (M.R.R.), Bergamo; the Hematology and Bone Marrow Transplant Unit Azienda Ospedaliera Papa Giovanni XXIII (A.R.), Bergamo; Division Neurology 1 (M.P.A.) and Division Neurology 2, Drug and Child Health (L.M., L.V.), Department of Neurosciences, and Bone Marrow Transplantation Unit (M.D.G., R.S.), Careggi University Hospital, University of Firenze; the Neuroimaging Research Unit (M.F.), Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan; the Department of Medical and Surgical Sciences (U.A.), Magna Graecia University of Catanzaro; the Advanced Cellular Therapy Center IRCCS \"Istituto Tumori Giovanni Paolo II\" Bari (P.I.), Italy; and the Internal Medicine and Vascular Disease Unit (D.F.), Assistance Publique Hospitaux de Paris (AP-HP) INSERM U 796, Paris 7 University, Saint-Louis Hospital, Paris, France.;From the MRI Center for Neurological Diseases (L.R.), Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health (G.L.M., D.C.), and the Biostatistic Unit, Department of Health Sciences (M.P.S., L.R.), University of Genova; the Bone Marrow Transplantation Unit (F.G.), S. Martino Hospital, Genova, Italy; the Service of Neurology (A.S.) and the Hematology Department (E.C.), Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer, Hospital Clínic, University of Barcelona, Spain; the Department of Neurosciences (E.M.) and the Bone Marrow Transplantation Unit, Department of Hematology and Oncology (A.D.), University of Modena and Reggio Emilia; the MS Center, Department of Neuroscience, Imaging and Clinical Sciences (A.L.), University Gabriele D'Annunzio, Chieti-Pescara; the Bone Marrow Transplant Center, Department of Hematology (P.D.B.), Spirito Santo Hospital, Pescara; the Multiple Sclerosis Unit Ospedale Papa Giovanni XXIII (M.R.R.), Bergamo; the Hematology and Bone Marrow Transplant Unit Azienda Ospedaliera Papa Giovanni XXIII (A.R.), Bergamo; Division Neurology 1 (M.P.A.) and Division Neurology 2, Drug and Child Health (L.M., L.V.), Department of Neurosciences, and Bone Marrow Transplantation Unit (M.D.G., R.S.), Careggi University Hospital, University of Firenze; the Neuroimaging Research Unit (M.F.), Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan; the Department of Medical and Surgical Sciences (U.A.), Magna Graecia University of Catanzaro; the Advanced Cellular Therapy Center IRCCS \"Istituto Tumori Giovanni Paolo II\" Bari (P.I.), Italy; and the Internal Medicine and Vascular Disease Unit (D.F.), Assistance Publique Hospitaux de Paris (AP-HP) INSERM U 796, Paris 7 University, Saint-Louis Hospital, Paris, France.;From the MRI Center for Neurological Diseases (L.R.), Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health (G.L.M., D.C.), and the Biostatistic Unit, Department of Health Sciences (M.P.S., L.R.), University of Genova; the Bone Marrow Transplantation Unit (F.G.), S. Martino Hospital, Genova, Italy; the Service of Neurology (A.S.) and the Hematology Department (E.C.), Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer, Hospital Clínic, University of Barcelona, Spain; the Department of Neurosciences (E.M.) and the Bone Marrow Transplantation Unit, Department of Hematology and Oncology (A.D.), University of Modena and Reggio Emilia; the MS Center, Department of Neuroscience, Imaging and Clinical Sciences (A.L.), University Gabriele D'Annunzio, Chieti-Pescara; the Bone Marrow Transplant Center, Department of Hematology (P.D.B.), Spirito Santo Hospital, Pescara; the Multiple Sclerosis Unit Ospedale Papa Giovanni XXIII (M.R.R.), Bergamo; the Hematology and Bone Marrow Transplant Unit Azienda Ospedaliera Papa Giovanni XXIII (A.R.), Bergamo; Division Neurology 1 (M.P.A.) and Division Neurology 2, Drug and Child Health (L.M., L.V.), Department of Neurosciences, and Bone Marrow Transplantation Unit (M.D.G., R.S.), Careggi University Hospital, University of Firenze; the Neuroimaging Research Unit (M.F.), Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan; the Department of Medical and Surgical Sciences (U.A.), Magna Graecia University of Catanzaro; the Advanced Cellular Therapy Center IRCCS \"Istituto Tumori Giovanni Paolo II\" Bari (P.I.), Italy; and the Internal Medicine and Vascular Disease Unit (D.F.), Assistance Publique Hospitaux de Paris (AP-HP) INSERM U 796, Paris 7 University, Saint-Louis Hospital, Paris, France.;From the MRI Center for Neurological Diseases (L.R.), Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health (G.L.M., D.C.), and the Biostatistic Unit, Department of Health Sciences (M.P.S., L.R.), University of Genova; the Bone Marrow Transplantation Unit (F.G.), S. Martino Hospital, Genova, Italy; the Service of Neurology (A.S.) and the Hematology Department (E.C.), Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer, Hospital Clínic, University of Barcelona, Spain; the Department of Neurosciences (E.M.) and the Bone Marrow Transplantation Unit, Department of Hematology and Oncology (A.D.), University of Modena and Reggio Emilia; the MS Center, Department of Neuroscience, Imaging and Clinical Sciences (A.L.), University Gabriele D'Annunzio, Chieti-Pescara; the Bone Marrow Transplant Center, Department of Hematology (P.D.B.), Spirito Santo Hospital, Pescara; the Multiple Sclerosis Unit Ospedale Papa Giovanni XXIII (M.R.R.), Bergamo; the Hematology and Bone Marrow Transplant Unit Azienda Ospedaliera Papa Giovanni XXIII (A.R.), Bergamo; Division Neurology 1 (M.P.A.) and Division Neurology 2, Drug and Child Health (L.M., L.V.), Department of Neurosciences, and Bone Marrow Transplantation Unit (M.D.G., R.S.), Careggi University Hospital, University of Firenze; the Neuroimaging Research Unit (M.F.), Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan; the Department of Medical and Surgical Sciences (U.A.), Magna Graecia University of Catanzaro; the Advanced Cellular Therapy Center IRCCS \"Istituto Tumori Giovanni Paolo II\" Bari (P.I.), Italy; and the Internal Medicine and Vascular Disease Unit (D.F.), Assistance Publique Hospitaux de Paris (AP-HP) INSERM U 796, Paris 7 University, Saint-Louis Hospital, Paris, France.;From the MRI Center for Neurological Diseases (L.R.), Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health (G.L.M., D.C.), and the Biostatistic Unit, Department of Health Sciences (M.P.S., L.R.), University of Genova; the Bone Marrow Transplantation Unit (F.G.), S. Martino Hospital, Genova, Italy; the Service of Neurology (A.S.) and the Hematology Department (E.C.), Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer, Hospital Clínic, University of Barcelona, Spain; the Department of Neurosciences (E.M.) and the Bone Marrow Transplantation Unit, Department of Hematology and Oncology (A.D.), University of Modena and Reggio Emilia; the MS Center, Department of Neuroscience, Imaging and Clinical Sciences (A.L.), University Gabriele D'Annunzio, Chieti-Pescara; the Bone Marrow Transplant Center, Department of Hematology (P.D.B.), Spirito Santo Hospital, Pescara; the Multiple Sclerosis Unit Ospedale Papa Giovanni XXIII (M.R.R.), Bergamo; the Hematology and Bone Marrow Transplant Unit Azienda Ospedaliera Papa Giovanni XXIII (A.R.), Bergamo; Division Neurology 1 (M.P.A.) and Division Neurology 2, Drug and Child Health (L.M., L.V.), Department of Neurosciences, and Bone Marrow Transplantation Unit (M.D.G., R.S.), Careggi University Hospital, University of Firenze; the Neuroimaging Research Unit (M.F.), Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan; the Department of Medical and Surgical Sciences (U.A.), Magna Graecia University of Catanzaro; the Advanced Cellular Therapy Center IRCCS \"Istituto Tumori Giovanni Paolo II\" Bari (P.I.), Italy; and the Internal Medicine and Vascular Disease Unit (D.F.), Assistance Publique Hospitaux de Paris (AP-HP) INSERM U 796, Paris 7 University, Saint-Louis Hospital, Paris, France.;From the MRI Center for Neurological Diseases (L.R.), Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health (G.L.M., D.C.), and the Biostatistic Unit, Department of Health Sciences (M.P.S., L.R.), University of Genova; the Bone Marrow Transplantation Unit (F.G.), S. Martino Hospital, Genova, Italy; the Service of Neurology (A.S.) and the Hematology Department (E.C.), Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer, Hospital Clínic, University of Barcelona, Spain; the Department of Neurosciences (E.M.) and the Bone Marrow Transplantation Unit, Department of Hematology and Oncology (A.D.), University of Modena and Reggio Emilia; the MS Center, Department of Neuroscience, Imaging and Clinical Sciences (A.L.), University Gabriele D'Annunzio, Chieti-Pescara; the Bone Marrow Transplant Center, Department of Hematology (P.D.B.), Spirito Santo Hospital, Pescara; the Multiple Sclerosis Unit Ospedale Papa Giovanni XXIII (M.R.R.), Bergamo; the Hematology and Bone Marrow Transplant Unit Azienda Ospedaliera Papa Giovanni XXIII (A.R.), Bergamo; Division Neurology 1 (M.P.A.) and Division Neurology 2, Drug and Child Health (L.M., L.V.), Department of Neurosciences, and Bone Marrow Transplantation Unit (M.D.G., R.S.), Careggi University Hospital, University of Firenze; the Neuroimaging Research Unit (M.F.), Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan; the Department of Medical and Surgical Sciences (U.A.), Magna Graecia University of Catanzaro; the Advanced Cellular Therapy Center IRCCS \"Istituto Tumori Giovanni Paolo II\" Bari (P.I.), Italy; and the Internal Medicine and Vascular Disease Unit (D.F.), Assistance Publique Hospitaux de Paris (AP-HP) INSERM U 796, Paris 7 University, Saint-Louis Hospital, Paris, France.;From the MRI Center for Neurological Diseases (L.R.), Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health (G.L.M., D.C.), and the Biostatistic Unit, Department of Health Sciences (M.P.S., L.R.), University of Genova; the Bone Marrow Transplantation Unit (F.G.), S. Martino Hospital, Genova, Italy; the Service of Neurology (A.S.) and the Hematology Department (E.C.), Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer, Hospital Clínic, University of Barcelona, Spain; the Department of Neurosciences (E.M.) and the Bone Marrow Transplantation Unit, Department of Hematology and Oncology (A.D.), University of Modena and Reggio Emilia; the MS Center, Department of Neuroscience, Imaging and Clinical Sciences (A.L.), University Gabriele D'Annunzio, Chieti-Pescara; the Bone Marrow Transplant Center, Department of Hematology (P.D.B.), Spirito Santo Hospital, Pescara; the Multiple Sclerosis Unit Ospedale Papa Giovanni XXIII (M.R.R.), Bergamo; the Hematology and Bone Marrow Transplant Unit Azienda Ospedaliera Papa Giovanni XXIII (A.R.), Bergamo; Division Neurology 1 (M.P.A.) and Division Neurology 2, Drug and Child Health (L.M., L.V.), Department of Neurosciences, and Bone Marrow Transplantation Unit (M.D.G., R.S.), Careggi University Hospital, University of Firenze; the Neuroimaging Research Unit (M.F.), Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan; the Department of Medical and Surgical Sciences (U.A.), Magna Graecia University of Catanzaro; the Advanced Cellular Therapy Center IRCCS \"Istituto Tumori Giovanni Paolo II\" Bari (P.I.), Italy; and the Internal Medicine and Vascular Disease Unit (D.F.), Assistance Publique Hospitaux de Paris (AP-HP) INSERM U 796, Paris 7 University, Saint-Louis Hospital, Paris, France.",
"authors": "Mancardi|Giovanni L|GL|;Sormani|Maria P|MP|;Gualandi|Francesca|F|;Saiz|Albert|A|;Carreras|Eric|E|;Merelli|Elisa|E|;Donelli|Amedea|A|;Lugaresi|Alessandra|A|;Di Bartolomeo|Paolo|P|;Rottoli|Maria R|MR|;Rambaldi|Alessandro|A|;Amato|Maria P|MP|;Massacesi|Luca|L|;Di Gioia|Massimo|M|;Vuolo|Luisa|L|;Currò|Daniela|D|;Roccatagliata|Luca|L|;Filippi|Massimo|M|;Aguglia|Umberto|U|;Iacopino|Pasquale|P|;Farge|Dominique|D|;Saccardi|Riccardo|R|;|||;|||",
"chemical_list": "D000970:Antineoplastic Agents; D005682:Gadolinium; D008942:Mitoxantrone",
"country": "United States",
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"doi": "10.1212/WNL.0000000000001329",
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"issn_linking": "0028-3878",
"issue": "84(10)",
"journal": "Neurology",
"keywords": null,
"medline_ta": "Neurology",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D005260:Female; D005682:Gadolinium; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007089:Image Enhancement; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone; D020528:Multiple Sclerosis, Chronic Progressive; D020529:Multiple Sclerosis, Relapsing-Remitting; D019172:Transplantation Conditioning; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "0401060",
"other_id": null,
"pages": "981-8",
"pmc": null,
"pmid": "25672923",
"pubdate": "2015-03-10",
"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": "Autologous hematopoietic stem cell transplantation in multiple sclerosis: a phase II trial.",
"title_normalized": "autologous hematopoietic stem cell transplantation in multiple sclerosis a phase ii trial"
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"abstract": "Meropenem is a broad-spectrum carbapenem widely used to treat both Gram-positive and negative bacterial infections, including extended-spectrum beta-lactamase-producing microbes. We describe the occurrence of thrombocytopenia and hypersensitivity in a boy receiving intravenous meropenem for intra-abdominal sepsis secondary to perforated appendicitis. The patient developed a pruritic maculopapular rash with occasional petechiae, associated with severe thrombocytopenia, after 7 days of meropenem administration. Investigations for other causes of thrombocytopenia, including possible line sepsis, were unfruitful, and the thrombocytopenia did not resolve until cessation of meropenem. Drug-induced reactions should be considered in children receiving meropenem who present with a rash and thrombocytopenia.",
"affiliations": "Department of Paediatrics, Mater Dei Hospital, Msida, Malta joanna.cachia@gmail.com.;Department of Paediatrics, Mater Dei Hospital, Msida, Malta.;Department of Paediatrics, Mater Dei Hospital, Msida, Malta.",
"authors": "Cachia|Joanna|J|http://orcid.org/0000-0003-3114-3277;Torpiano|Paul|P|;Pace|David|D|",
"chemical_list": "D000900:Anti-Bacterial Agents; D013845:Thienamycins; D000077731:Meropenem",
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"doi": "10.1136/bcr-2021-243443",
"fulltext": "\n==== Front\nBMJ Case Rep\nBMJ Case Rep\nbmjcr\nbmjcasereports\nBMJ Case Reports\n1757-790X\nBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR\n\n34479885\nbcr-2021-243443\n10.1136/bcr-2021-243443\nCase Report\n1506\n1323\n1560\n1372\n1314\n1330\n181\nMeropenem-induced thrombocytopenia: a paediatric case\nhttp://orcid.org/0000-0003-3114-3277\nCachia Joanna\nTorpiano Paul\nPace David\nDepartment of Paediatrics, Mater Dei Hospital, Msida, Malta\nCorrespondence to Dr Joanna Cachia; joanna.cachia@gmail.com\n2021\n3 9 2021\n3 9 2021\n14 9 e24344312 8 2021\n© BMJ Publishing Group Limited 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.\n\nMeropenem is a broad-spectrum carbapenem widely used to treat both Gram-positive and negative bacterial infections, including extended-spectrum beta-lactamase-producing microbes. We describe the occurrence of thrombocytopenia and hypersensitivity in a boy receiving intravenous meropenem for intra-abdominal sepsis secondary to perforated appendicitis. The patient developed a pruritic maculopapular rash with occasional petechiae, associated with severe thrombocytopenia, after 7 days of meropenem administration. Investigations for other causes of thrombocytopenia, including possible line sepsis, were unfruitful, and the thrombocytopenia did not resolve until cessation of meropenem. Drug-induced reactions should be considered in children receiving meropenem who present with a rash and thrombocytopenia.\n\ncontraindications and precautions\npaediatrics (drugs and medicines)\nhaematology (drugs and medicines)\ndrugs: infectious diseases\nspecial-featureunlocked\n==== Body\npmcBackground\n\nMeropenem is a widely prescribed broad-spectrum antimicrobial belonging to the carbapenem family. It has activity against Gram-positive and Gram-negative micro-organisms, as well as anaerobes and extended-spectrum beta-lactamase-producing microbes. Indications for use include septicaemia and complicated infections of the abdomen, skin, respiratory tract and urinary tract, making it a widely prescribed antibiotic in the hospital setting. Common side effects include nausea, vomiting and diarrhoea, while unusual side effects include skin hypersensitivity reactions.1 Here we report a rare occurrence of meropenem-induced thrombocytopenia and hypersensitivity in an 11-year-old boy. To our knowledge, such a reaction to meropenem has not yet been specifically documented in the paediatric setting.2 Although rare, drug-induced thrombocytopenia can quickly lead to life-threatening complications if not adequately addressed in a timely manner.3 We explore the differential diagnoses, investigations and management options used and described in the literature pertaining to this adverse event.\n\nCase presentation\n\nA previously healthy 11-year-old boy was admitted with a 1-day history of severe abdominal pain, initially generalised and subsequently localising to the right iliac fossa (RIF). He was diagnosed with acute appendicitis and underwent emergency laparoscopic appendectomy, at which a perforated gangrenous appendix was resected successfully. Postoperatively, the child was treated with intravenous cefuroxime, gentamicin and metronidazole for possible intra-abdominal sepsis complicating the perforated appendicitis.\n\nDespite exhibiting significant clinical improvement postoperatively, the patient’s C reactive protein was noted to be persistently raised at 281 mg/L (five times the baseline) on day 5 postappendectomy, with recurrence of fever of up to 38℃ recorded on day 8. Abdominal ultrasonography revealed a hypoechoic heterogenous fluid collection in the RIF, measuring around 4 cm by 2 cm on day 8 postappendectomy. The collection was deemed too small to be amenable to radiological or surgical aspiration. Cefuroxime and gentamicin were thus switched to intravenous cefotaxime, and metronidazole was continued. In view of persistent abdominal pain and fever, CT imaging of the abdomen was done on day 13 postappendectomy, confirming a persistent collection in the periappendicular space.\n\nUltrasound-guided drainage of the fluid collection was performed on day 14 postappendectomy. Extended-spectrum beta-lactamase-producing and carbapenem-resistant Klebsiella pneumoniae, as well as Enterococcus faecalis and Enterococcus avium, was cultivated from the drained fluid in the periappendicular space. The Klebsiella isolate was resistant to ertapenem but sensitive to meropenem. A peripherally inserted central catheter (PICC) was placed and treatment as changed to high-dose intravenous meropenem 40 mg/kg three times a day and teicoplanin on day 20 postappendectomy. The patient demonstrated sustained clinical improvement with defervescence thereafter, with serial ultrasonography showing gradual resolution of the intra-abdominal fluid collection.\n\nOn day 7 of intravenous meropenem administration (day 27 postappendectomy), a rapidly spreading pruritic, non-tender maculopapular blanching rash with occasional petechiae was noted to have developed over the child’s trunk and upper limbs associated with recrudescence of fever up to 38℃.\n\nInvestigations\n\nSerial complete blood counts revealed progressively worsening isolated thrombocytopenia with a drop to 101×109/L from 322×109/L coinciding with the appearance of the rash and fever on day 7 of meropenem administration, and falling to 14×109/L on day 8 of intravenous meropenem. This was associated with a mild rise in C reactive protein (30 mg/L), though there was no derangement of the other cell lines, including leucocytes, and haematinics. Activated partial thromboplastin time ratio, international normalised ratio and fibrinogen assay were within normal limits. Repeat abdominal CT showed improvement of the RIF collection consistent with continued response to treatment. While the PICC line was removed in view of possible line sepsis, line tip and blood cultures were negative, as were stool and urine cultures. Repeated viral serology and molecular diagnostic testing were also taken and remained persistently negative.\n\nDifferential diagnosis\n\nCauses of acquired thrombocytopenia in children can be classified according to the underlying pathology. Thrombocytopenia can result from either decreased platelet production, increased peripheral platelet destruction, redistribution or laboratory artefact. Causes of decreased platelet production include viral infection (such as Epstein-Barr virus, cytomegalovirus and parvovirus); bacterial sepsis; nutritional deficiencies; bone marrow suppression secondary to chemotherapy and toxins; aplastic anaemia; and bone marrow infiltration as occurs in myelodysplastic syndrome and lymphoproliferative disease. Increased peripheral platelet destruction may result from disseminated intravascular coagulation (DIC), immune thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura and autoimmune disorders such as systemic lupus erythematosus. Redistributive causes include haemodilution resulting from large volume resuscitation, and sequestration as in splenomegaly and portal hypertension secondary to liver cirrhosis.4 5\n\nThe process of narrowing down the aforementioned differential diagnoses required multiple serial investigations. Spurious thrombocytopenia, which occurs due to clumping of platelets during analysis, was confidently ruled out by low platelet count being repeatedly confirmed on serial blood counts. Viral causes were excluded on the basis of negative viral serology and molecular diagnostic testing for Epstein-Barr virus, cytomegalovirus and parvovirus. The benign clinical picture, stable vital signs, normal coagulation screen, minimally raised C reactive protein and normal white cell count, as well as negative blood, urine and faecal cultures, argued against sepsis and DIC as likely causes for acute thrombocytopenia in this case. The absence of clinically evident infection at the PICC line insertion site, together with negative PICC line tip and blood cultures, also discounted line sepsis as a possible cause.\n\nAplastic anaemia and lymphoproliferative diseases such as acute leukaemia were confidently excluded early in the differential due to normal blood films as well as the absence of derangement of erythropoietic, myeloid and lymphoid cell lines. In addition, lack of hepatosplenomegaly, lymphadenopathy and history of recurrent opportunistic infections further argued against aplastic anaemia or malignant processes. Absence of splenomegaly also ruled out sequestration and portal hypertension as causes. Furthermore, the child’s normal growth parameters, haematinics and good socioeconomic background discounted nutritional deficiency as a possible cause of thrombocytopenia.4 5\n\nDespite the presence of fever, autoimmune disorders, such as systemic lupus erythematosus, were also ruled out on the basis of the absence of other systemic signs or symptoms such as arthralgia, along with the presence of normal cell lines other than thrombocytopenia. Thrombotic thrombocytopenic purpura usually manifests as a pentad of fever, neurological signs, renal failure, anaemia and thrombocytopenia. As such, it was considered highly unlikely to be the cause in this case in view of normal neurological examination and renal function together with normal haemoglobin levels.4 5 Postoperative thrombocytopenia was ruled out as it tends to develop more acutely within 4 days of surgery and usually results from haemodilution.6\n\nThe two main differential diagnoses were thus drug-induced thrombocytopenia and ITP. Both are diagnoses of exclusion, and there is no reliable readily available single confirmatory laboratory test for either of these pathologies.7 In our case, thrombocytopenia was noted to have developed within 1 week of starting intravenous meropenem and teicoplanin, consistent with a possible diagnosis of drug-induced thrombocytopenia. The associated evidence of hypersensitivity in the form of a pruritic maculopapular rash and fever pointed away from ITP and towards a drug-related cause. The resolution postcessation of meropenem, without the concomitant need to administer steroids and intravenous immunoglobulins, further confirmed drug-induced thrombocytopenia secondary to meropenem treatment as the underlying cause.8 While thrombocytopenia with teicoplanin treatment has also been reported, this is exceptionally rare, and the improving platelet count despite ongoing teicoplanin argues against teicoplanin as the cause of thrombocytopenia in this case.9–11\n\nTreatment\n\nThe timing of onset of thrombocytopenia after starting meropenem and evidence of hypersensitivity prompted discontinuation of intravenous meropenem on day 8 of treatment (day 28 postappendectomy). The child was treated with intravenous chlorphenamine for the intense pruritus. The rash resolved over the following 2 days, and following transfusion of a single unit of platelets after the platelet count fell to 2×109/L (day 30 postappendicectomy), the patient subsequently exhibited a gradual rise in the platelet count on serial blood count monitoring. Teicoplanin was continued, and based on the culture and sensitivity results from the intra-abdominal fluid collection, co-trimoxazole was initiated instead of the meropenem.\n\nOutcome and follow-up\n\nFever resolved within 24 hours of cessation of meropenem, and the child remained afebrile and systemically well. He was discharged from hospital on day 35 postappendectomy with a platelet count of 471×109/L. The boy is currently being followed up annually for monitoring of growth and platelet counts. No further intra-abdominal or haematological complications have been reported thus far.\n\nDiscussion\n\nThrombocytopenia in children is defined as a platelet count of less than 150×109/L.5 Drug-induced thrombocytopenia often manifests as an acute severe drop in platelet count, typically occuring within 1 week following initiation of drug administration, with platelet counts frequently falling below 50×109/L, as observed in this case.12 Systemic symptoms such as fever, chills, nausea and vomiting often predate hypersensitivity skin reactions, bruising, ecchymoses or petechiae. These typically resolve around 1–2 days after the offending agent is withdrawn and diagnosis is often reached after excluding other possible relevant causes of thrombocyopenia.13 14\n\nNon-immune and immune mechanisms have been suggested for drug-induced thrombocytopenia. Non-immune mechanisms include impaired maturation or replication of megakaryocytes and reduced release of platelets from the bone marrow.12 15 16 Where an immune mechanism is involved, increased rate of apoptosis or increased peripheral destruction of platelets is implicated, and antibodies specific to individual drug structures have been identified. Such antibodies may naturally occur as immunoglobulins with predilection for epitopes on glycoproteins found on the platelet membranes. In the absence of the specific drug, these are not sufficiently reactive to cause platelet destruction, but when the implicated drug is introduced, it serves as a reversible binder of the antibody to the platelet glycoproteins, most commonly glycoprotein IIb–IIIa and glycoprotein Ib–V–IX.17\n\nDrug-induced platelet antibodies targeting glycoproteins are most commonly detectable by enzyme immunoassay, flow cytometry or monoclonal antibody immobilisation of platelet antigens. Platelet antibody testing may hence be diagnostic of meropenem-associated drug-induced thrombocytopenia.18 However, glycoprotein assays have been found to have low sensitivity and high specificity. This implies that serological testing is useful to rule in but not rule out immune causes of thrombocytopenia, limiting its diagnostic utility. This may be due to the fact that these immune conditions are caused by various mechanisms, some of which are not solely secondary to platelet autoantibody formation. Antibody testing is thus arguably still of limited clinical utility.7 19 Furthermore, testing is not widely accessible and and standardised testing protocols are not uniformly adopted.20 For these reasons, platelet autoantibody testing was not employed in this case. In preference, a combination of clinical and laboratory features was used to elucidate the final clinical diagnosis of meropenem-induced thrombocytopenia.\n\nMeropenem hypersensitivity is rare, with serious hypersensitivity and adverse haematological effects being reported in less than 1% of patients.21 These represent serious and potentially life-threatening complications.18 The association of meropenem with isolated thrombocytopenia seems particularly rare and is confined only to case reports or case series.3 In infants and children, no such case has been reported in the literature thus far.2 In adults, meropenem-induced thrombocytopenia has been reported in two case reports and in a study on meropenem side effects in a teaching hospital in Pakistan.18 21 22 In one case report, a 59-year-old man developed severe thrombocytopenia 8 days after initiation of meropenem treatment. After ruling out other causes of thrombocytopenia and with positive platelet antibody testing, meropenem administration was stopped and restoration of platelet count was noted soon after.18 In the other case report, a 57-year-old man with a medical history of diabetes, hypertension and chronic kidney disease received standard meropenem dosing following an upper gastrointestinal bleed and developed thrombocytopenia 1 day after administration. No further bleeding episodes were observed and meropenem was stopped after 3 days, with restoration of platelet count within 5 days. Platelet antibody testing was not carried out in this case.21 In the study conducted by Khan et al, correlation of meropenem side effects with renal function was studied in a Pakistani teaching hospital. Thrombocytopenia was observed in 37.81% of patients receiving the drug, with a linear increase in side-effect profile observed with worsening renal function.22 In the second case report described, the patient’s meropenem dose was not adjusted for the deranged renal function. This could explain the earlier onset of thrombocytopenia in this case.\n\nSimilarly rare is the association of meropenem with pancytopenia, with only three case reports identified after an extensive search. Pancytopenia was described in a preterm neonate, a 3-year-old child with a head injury and another child (age not specified) who had undergone liver transplantation. In all cases, derangement of all cell lineages was noted to develop in a staggered fashion, with thrombocytopenia predating drops in haemoglobin and absolute neutrophil counts. Derangements were noted over a range of 3 days–2 weeks after initiation of meropenem. Restoration of normal cell counts was obtained after stopping treatment, without immediate life-threatening complications. In none of these cases was platelet antibody testing performed.23–25\n\nIn most cases of drug-induced thrombocytopenia, cessation of treatment is sufficient for subsequent resolution of hypersensitivity and restoration of platelet count. Prognosis is generally deemed quite favourable.12 15 16 Corticosteroids have occasionally been used in cases where ITP could not be confidently excluded in the differential diagnosis. In our case, corticosteroids were not administered in view of the rapidity by which thrombocytopenia improved after cessation of meropenem, as well as due to initial concerns about possible sepsis secondary to multidrug-resistant organisms, which was in turn eventually ruled out. Drug-induced platelet antibodies have been shown to persist for years after exposure, indicating that the causative drug might cause further reactions if reinstated in future.14 Platelet transfusions in drug-induced thrombocytopenia are mostly indicated to control overt haemorrhage or when thrombocytopenia is severe enough to risk spontaneous haemorrhage (platelet counts of less than 10×109/L). Transfusions, however, may be ineffective if the drug or its metabolites have not yet been cleared.26–28 The patient reported here had a platelet transfusion in view of severe thrombocytopenia and an already previously complicated postoperative course.\n\nLearning points\n\nReview of patient medication for sources of adverse drug events should be an essential part of the diagnostic work-up of patients who present with new onset of rashes and cell line derangements.\n\nThe association of meropenem with thrombocytopenia, although rare, should be considered in children with an acute severe drop in platelet count after exclusion of other pathologies.\n\nManagement of drug-induced thrombocytopenia varies according to severity and risk of haemorrhage. Immediate recognition of the reaction and prompt cessation of the drug are necessary in order to prevent development of life-threatening complications.\n\nUse of antimicrobials should always be objectively justified and follow approved guidelines to minimise morbidity and mortality from adverse drug events.\n\nEthics statements\n\nPatient consent for publication\n\nParents/guardian consent obtained.\n\nContributors: JC contributed to investigation, writing of the original draft, as well as editing and visualisation of the manuscript after a review by other coauthors. PT contributed to conceptualisation, methodology, resource acquisition, investigation and data interpretation, as well as review and editing of the original draft. DP contributed to conceptualisation, investigation and data interpretation, review and editing of the original draft, as well as overall supervision of the manuscript preparation.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n\n1 BaldwinCM, Lyseng-WilliamsonKA, KeamSJ. Meropenem: a review of its use in the treatment of serious bacterial infections. Drugs 2008;68 :803–38. 10.2165/00003495-200868060-00006 18416587\n2 Maria PacificiG. Clinical pharmacology of meropenem in infants and children. Clin Med Invest 2019;4 :1–9. 10.15761/CMI.1000178\n3 JohansenME, JensenJ-U, BestleMH, et al . The potential of antimicrobials to induce thrombocytopenia in critically ill patients: data from a randomized controlled trial. PLoS One 2013;8 :e81477. 10.1371/journal.pone.0081477 24312305\n4 KaplanRN, BusselJB. Differential diagnosis and management of thrombocytopenia in childhood. Pediatr Clin North Am 2004;51 :1109–40. 10.1016/j.pcl.2004.03.008 15275991\n5 GauerRL, BraunMM. Thrombocytopenia. Am Fam Physician 2012;85 :612–22.22534274\n6 SkeithL, Baumann KreuzigerL, CrowtherMA, et al . A practical approach to evaluating postoperative thrombocytopenia. Blood Adv 2020;4 :776–83. 10.1182/bloodadvances.2019001414 32097460\n7 VrbenskyJR, MooreJE, ArnoldDM, et al . The sensitivity and specificity of platelet autoantibody testing in immune thrombocytopenia: a systematic review and meta-analysis of a diagnostic test. J Thromb Haemost 2019;17 :787–94. 10.1111/jth.14419 30801909\n8 OnisâiM, VlădăreanuA-M, SpînuA, et al . Idiopathic thrombocytopenic purpura (ITP) - new era for an old disease. Rom J Intern Med 2019;57 :273–83. 10.2478/rjim-2019-0014 31199777\n9 AgnelliG, LongettiM, GuercioliniR, et al . Effects of the new glycopeptide antibiotic teicoplanin on platelet function and blood coagulation. Antimicrob Agents Chemother 1987;31 :1609–12. 10.1128/AAC.31.10.1609 2963587\n10 TerolMJ, SierraJ, GatellJM, et al . Thrombocytopenia due to use of teicoplanin. Clin Infect Dis 1993;17 :927. 10.1093/clinids/17.5.927 8286643\n11 VeldmanRG, van der PijlJW, ClaasFH. Teicoplanin-induced thrombocytopenia. Nephron 1996;73 :721–2. 10.1159/000189175 8856285\n12 DaneseE, MontagnanaM, FavaloroEJ, et al . Drug-induced thrombocytopenia: mechanisms and laboratory diagnostics. Semin Thromb Hemost 2020;46 :264–74. 10.1055/s-0039-1697930 31563127\n13 AsterRH, BougieDW. Drug-induced immune thrombocytopenia. N Engl J Med 2007;357 :580–7. 10.1056/NEJMra066469 17687133\n14 AsterRH, CurtisBR, McFarlandJG, et al . Drug-induced immune thrombocytopenia: pathogenesis, diagnosis, and management. J Thromb Haemost 2009;7 :911–8. 10.1111/j.1538-7836.2009.03360.x 19344362\n15 Savage-ElliottI, WuVJ, SanchezFL. Drug-induced thrombocytopenia secondary to commonly used antibiotics in total joint arthroplasty. Arthroplast Today 2020;6 :137–40. 10.1016/j.artd.2020.03.006 32346584\n16 NarayananPK, LiN. In vitro monocyte/macrophage phagocytosis assay for the prediction of drug-induced thrombocytopenia. Curr Protoc Toxicol 2019;79 :e68. 10.1002/cptx.68 30673165\n17 GeorgeJN, AsterRH. Drug-induced thrombocytopenia: pathogenesis, evaluation, and management. Hematology 2009;2009 :153–8. 10.1182/asheducation-2009.1.153\n18 HuangR, CaiG-Q, ZhangJ-H, et al . Meropenem-induced immune thrombocytopenia and the diagnostic process of laboratory testing. Transfusion 2017;57 :2715–9. 10.1111/trf.14267 28782250\n19 SchmidtDE, LakerveldAJ, Heitink-PolléKMJ, et al . Anti-platelet antibody immunoassays in childhood immune thrombocytopenia: a systematic review. Vox Sang 2020;115 :323–33. 10.1111/vox.12894 32080872\n20 ArnoldDM, KukaswadiaS, NaziI, et al . A systematic evaluation of laboratory testing for drug-induced immune thrombocytopenia. J Thromb Haemost 2013;11 :169–76. 10.1111/jth.12052 23121994\n21 DhandeP, DeshmukhS. Acute thrombocytopenia due to meropenem: a case report. Int J Basic Clin Pharmacol 2019;8 :2766. 10.18203/2319-2003.ijbcp20195294\n22 KhanMU, YousufRI, ShoaibMH. Drug utilization evaluation of meropenem and correlation of side effects with renal status of patients in a teaching based Hospital. Pak J Pharm Sci 2014;27 :1503–8.25176244\n23 HussainK, SalatMS, MohammadN, et al . Meropenem-induced pancytopenia in a preterm neonate: a case report. J Med Case Rep 2021;15 :25. 10.1186/s13256-020-02632-1 33509295\n24 EstellaJ, VillanuevaJ, CalvoM, et al . Bone marrow aplasia and meropenem in a paediatric patient. Br J Haematol 2000;111 :984–5. 10.1046/j.1365-2141.2000.02393.x 11122164\n25 Pérez-GorrichoB, Zapardiel FerreroJ, Grupo de Estudio de Meropenem en Pediatría. [Meropenem as empirical therapy in moderate to severe infections in hospitalized children aged 3 to 12 months and 1 to 14 years]. Rev Esp Quimioter 2004;17 :341–9.15696225\n26 BakchoulT, MariniI. Drug-associated thrombocytopenia. Hematology Am Soc Hematol Educ Program 2018;2018 :576–83. 10.1182/asheducation-2018.1.576 30504360\n27 Ho-Tin-NoéB, JadouiS. Spontaneous bleeding in thrombocytopenia: is it really spontaneous? Transfus Clin Biol 2018;25 :210–6. 10.1016/j.tracli.2018.06.005 30017659\n28 KenneyB, StackG. Drug-induced thrombocytopenia. Arch Pathol Lab Med 2009;133 :309–14. 10.5858/133.2.309 19195976\n\n",
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"journal": "BMJ case reports",
"keywords": "contraindications and precautions; drugs: infectious diseases; haematology (drugs and medicines); paediatrics (drugs and medicines)",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000900:Anti-Bacterial Agents; D001424:Bacterial Infections; D002648:Child; D006801:Humans; D008297:Male; D000077731:Meropenem; D013845:Thienamycins; D013921:Thrombocytopenia",
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"title": "Meropenem-induced thrombocytopenia: a paediatric case.",
"title_normalized": "meropenem induced thrombocytopenia a paediatric case"
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"abstract": "Cross-intolerance to NSAIDs is a class of drug hypersensitivity reaction, of which NSAIDs-induced urticaria and/or angioedema (NIUA) are the most frequent clinical entities. They are considered to involve dysregulation of the arachidonic acid pathway; however, this mechanism has not been confirmed for NIUA. In this work, we assessed copy number variations (CNVs) in eight of the main genes involved in the arachidonic acid pathway and their possible genetic association with NIUA.\n\n\n\nCNVs in ALOX5, LTC4S, PTGS1, PTGS2, PTGER1, PTGER2, PTGER3, and PTGER4 were analyzed using TaqMan copy number assays. Genotyping was carried out by real-time quantitative PCR. Individual genotypes were assigned using the CopyCaller Software. Statistical analysis was carried out using GraphPad prism 5, PLINK, EPIDAT, and R version 3.1.2.\n\n\n\nA total of 151 cases and 139 controls were analyzed during the discovery phase and 148 cases and 140 controls were used for replication. CNVs in open reading frames were found for ALOX5, PTGER1, PTGER3, and PTGER4. Statistically significant differences in the CNV frequency between NIUA and controls were found for ALOX5 (Pc=0.017) and PTGER1 (Pc=1.22E-04). This study represents the first analysis showing an association between CNVs in exonic regions of ALOX5 and PTGER1 and NIUA. This suggests a role of CNVs in this pathology that should be explored further.",
"affiliations": "aAllergy service, Infanta Leonor Hospital bResearch Unit and Biomedical Research Center in Respiratory Diseases, Carlos III Health Institute, Tenerife cAllergy Unit dResearch Laboratory, IBIMA, Regional University Hospital of Malaga, UMA, Malaga Departments of ePharmacology fBiochemistry and Molecular Biology, University of Extremadura, Cáceres, Spain gINSERM U-954, University of Lorraine and University Hospital Center (CHU) of Nancy, Nancy, France.",
"authors": "Plaza-Serón|María Del Carmen|Mdel C|;Ayuso|Pedro|P|;Pérez-Sánchez|Natalia|N|;Doña|Inmaculada|I|;Blanca-Lopez|Natalia|N|;Flores|Carlos|C|;Galindo|Luisa|L|;Molina|Ana|A|;Perkins|James R|JR|;Cornejo-García|Jose A|JA|;Agúndez|Jose A|JA|;García-Martín|Elena|E|;Campo|Paloma|P|;Canto|Gabriela|G|;Blanca|Miguel|M|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; C545635:PTGER1 protein, human; D058306:Receptors, Prostaglandin E, EP1 Subtype; D001094:Arachidonate 5-Lipoxygenase; C583212:ALOX5 protein, human",
"country": "United States",
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"mesh_terms": "D000328:Adult; D000799:Angioedema; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001094:Arachidonate 5-Lipoxygenase; D016022:Case-Control Studies; D056915:DNA Copy Number Variations; D005260:Female; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D058306:Receptors, Prostaglandin E, EP1 Subtype; D014581:Urticaria",
"nlm_unique_id": "101231005",
"other_id": null,
"pages": "280-7",
"pmc": null,
"pmid": "26959713",
"pubdate": "2016-06",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Copy number variation in ALOX5 and PTGER1 is associated with NSAIDs-induced urticaria and/or angioedema.",
"title_normalized": "copy number variation in alox5 and ptger1 is associated with nsaids induced urticaria and or angioedema"
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"abstract": "Transfusion of blood products is a frequent and often necessary lifesaving intervention. While changes to blood bank practices over the past several decades have reduced the infectious complications associated with transfusions, risks still exist. Septic transfusion reactions caused by bacterial contamination of blood products, especially platelets, still occur relatively frequently. Unfortunately, clinical recognition of septic transfusion reactions is difficult due to significant symptom, exam, and laboratory abnormality overlap between different types of transfusion reactions, as well as other conditions. Novel methods have been developed to detect blood product contamination but have yet to be widely implemented in the United States.\nA 67-year-old male with chronic thrombocytopenia was transfused with platelets prior to a planned procedure. Shortly afterwards, he developed fever and hypotension. He was transferred to the intensive care unit where he was treated with aggressive fluid resuscitation and broad-spectrum antibiotics. The patient went on to develop progressively worsening shock and profound disseminated intravascular coagulation. Blood cultures from the patient and the transfused platelets grew an Acinetobacter species. Despite aggressive resuscitative efforts and appropriate antibiotics, the patient died approximately 48 hours following the transfusion reaction.\nWe report a fatal case of septic shock associated with Acinetobacter bacteremia caused by platelet transfusion. Our review of the literature revealed only one other documented platelet transfusion associated fatality caused by Acinetobacter species. Novel pathogen reduction and contamination detection methods have been developed but have yet to be widely adopted in the United States.",
"affiliations": "Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.;Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.;Department of Pulmonary Medicine and Critical Care, University of Utah, Salt Lake City, UT, USA.;Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.",
"authors": "Nevala-Plagemann|C|C|;Powers|P|P|;Mir-Kasimov|M|M|;Rose|R|R|https://orcid.org/0000-0002-5473-0709",
"chemical_list": null,
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"delete": false,
"doi": "10.1155/2019/3136493",
"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi 10.1155/2019/3136493Case ReportA Fatal Case of Septic Shock Secondary to Acinetobacter Bacteremia Acquired from a Platelet Transfusion Nevala-Plagemann C. \n1\nPowers P. \n1\nMir-Kasimov M. \n2\n\n3\nhttps://orcid.org/0000-0002-5473-0709Rose R. richard.rose@hsc.utah.edu\n1\n\n3\n\n1Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA\n2Department of Pulmonary Medicine and Critical Care, University of Utah, Salt Lake City, UT, USA\n3Department of Medicine, Veterans Affairs Medical Center, Salt Lake City, UT, USAAcademic Editor: Lothar Bergmann\n\n2019 27 12 2019 2019 313649319 8 2019 4 12 2019 5 12 2019 Copyright © 2019 C. Nevala-Plagemann et al.2019This 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.Background\n Transfusion of blood products is a frequent and often necessary lifesaving intervention. While changes to blood bank practices over the past several decades have reduced the infectious complications associated with transfusions, risks still exist. Septic transfusion reactions caused by bacterial contamination of blood products, especially platelets, still occur relatively frequently. Unfortunately, clinical recognition of septic transfusion reactions is difficult due to significant symptom, exam, and laboratory abnormality overlap between different types of transfusion reactions, as well as other conditions. Novel methods have been developed to detect blood product contamination but have yet to be widely implemented in the United States. \n\nCase Report\n A 67-year-old male with chronic thrombocytopenia was transfused with platelets prior to a planned procedure. Shortly afterwards, he developed fever and hypotension. He was transferred to the intensive care unit where he was treated with aggressive fluid resuscitation and broad-spectrum antibiotics. The patient went on to develop progressively worsening shock and profound disseminated intravascular coagulation. Blood cultures from the patient and the transfused platelets grew an Acinetobacter species. Despite aggressive resuscitative efforts and appropriate antibiotics, the patient died approximately 48 hours following the transfusion reaction. \n\nConclusion\n We report a fatal case of septic shock associated with Acinetobacter bacteremia caused by platelet transfusion. Our review of the literature revealed only one other documented platelet transfusion associated fatality caused by Acinetobacter species. Novel pathogen reduction and contamination detection methods have been developed but have yet to be widely adopted in the United States.\n==== Body\n1. Introduction\nAccording to the most recent National Blood Collection and Utilization Survey (NBCUS) and the United States Food and Drug Administration (FDA), there were 11.3 million whole blood and red blood cell transfusions, 2.1 million apheresis platelet transfusions, and 3.6 million plasma transfusions in the United States in 2015 [1]. Given the sheer number of transfusions that occur each year, it is not surprising that despite improvements in blood bank practices over the past few decades, transfusion reactions remain a commonly encountered problem in our medical system.\n\nWhile many of these transfusion reactions are relatively benign, a recent retrospective analysis of academic centers in the United States found that approximately 1% of all transfusions result in a serious reaction [2]. The most recently published report by the FDA identified 201 deaths that could be attributed to transfusion reactions from 2014 to 2017 [1].\n\nGiven the seriousness and frequency of transfusion reactions, prompt and accurate diagnosis is extremely important. This is especially true in cases of septic transfusion reactions, for which prompt initiation of antibiotics is necessary. Unfortunately, the signs, symptoms, and laboratory abnormalities found in septic transfusion reactions share significant overlap with other types of transfusion reactions and other conditions often making diagnosis difficult and delaying appropriate treatment [3, 4].\n\nIn this report, we describe a fatal case of septic shock secondary to Acinetobacter bacteremia caused by a platelet transfusion. We will discuss the current literature regarding frequency of septic platelet transfusion reactions and will briefly discuss current and future methods being implemented to help prevent these serious reactions from occurring in the future.\n\n2. Case Presentation\nA 67-year-old male with a history of type II diabetes, chronic obstructive pulmonary disorder, and alcoholic cirrhosis was admitted to our hospital for medical optimization prior to a planned transarterial chemoembolization procedure for recently diagnosed hepatocellular carcinoma. The patient was feeling well at the time of admission with no significant acute complaints. Admission vitals were unremarkable, and his admission labs were notable only for chronic thrombocytopenia with a platelet count of 27,000 per microliter.\n\nIn anticipation of his upcoming procedure, two units of apheresis platelets were ordered with a goal of raising his platelet count above 50,000 per microliter to prevent bleeding. Shortly after initiation of the first platelet transfusion, the patient complained of chills and was noted to have a temperature of 100.8 F. The transfusion was stopped, and the patient was administered acetaminophen and diphenhydramine. Approximately 1 hour later, the patient developed tachycardia, tachypnea, and hypotension and was found to have an increased temperature of 104.9 F.\n\nThe patient was transferred to the intensive care unit of our facility where he was aggressively fluid resuscitated and started on vasopressors due to persistent hypotension. Broad-spectrum antibiotics were initiated with piperacillin/tazobactam and vancomycin. Within a few hours of admission to the ICU the patient developed severe DIC requiring aggressive blood product replacement and intubation for airway protection due to development of a large hematoma at the site of his right internal jugular central line.\n\nBlood culture results were available approximately 18 hours after the transfusion reaction and revealed bacteremia with a Gram-variable organism. Cultures were grown on MacConkey agar and had variable lactose fermentation. Given morphology and lactose fermentation results, the specimens were sent for immediate matrix-assisted laser desorption/ionization—time of flight (MALDI-TOF), which positively identified them as genus Acinetobacter. Cultures were obtained from the unit of platelets, and the patient had been transfused with grew Acinetobacter as well, identified via the same methodology. Antibiotic coverage was changed to tobramycin and meropenem to cover possible resistant strains of Acinetobacter. Unfortunately, over the subsequent 24 hours, the patient's vasopressor requirements continued to rise. Given his ongoing clinical deterioration, further aggressive treatment was felt to be unlikely to improve his condition. A family meeting was held, care was withdrawn, and the patient expired shortly after. Autopsy revealed the likely cause of death to be septic shock with multiorgan failure. Bacterial susceptibility results available following the patient's death revealed full susceptibility to meropenem but only intermediate susceptibility to piperacillin-tazobactam.\n\nThe case was reported to the FDA, and samples were sent for genomic sequencing. Per the FDA, from May 2018 to October 2018, there were four patients from three states who experienced sepsis after platelet transfusions contaminated with Acinetobacter. Sequencing demonstrated that both the patient and platelet bag Acinetobacter isolates were molecularly related. The platelet donor was investigated, and no Acinetobacter isolates were identified in the patient's urine, perianal area, or multiple skin sites. During their investigation, swabs from the platelet agitators at the platelet manufacturing facility, as well as the hospital platelet agitator, identified Acinetobacter [5].\n\n3. Discussion\nAround two million platelet transfusions are performed each year in the United States [6]. While platelet transfusions are often necessary to prevent life-threatening bleeding in thrombocytopenic patients, they do come with a risk. Septic transfusion reactions caused by bacterial contamination of blood products have long been known to be a problem, especially with transfusion of platelets due to their storage at room temperature. In fact, the bacterial contamination rate of apheresis platelet has been shown to be around 1 in 5000 transfusions with a risk of transfusion-associated sepsis around 1 in 100,000 transfusions [6].\n\nDeath related to transfusion of contaminated platelets, however, remains rare. From 2012 to 2015, there were only 10 reported fatalities related to bacterial contamination of platelets in the United States. Furthermore, infection and death related to Acinetobacter species, as was the case in this patient, is exceedingly rare. Prior to the four cases in 2018, only one other case had been reported by the FDA in 2013 [1]. Acinetobacter species are Gram-negative bacteria that possess inherent resistance to desiccation, allowing them to persist on environmental surfaces [7]. This fact, coupled with a natural predilection to virulence factors that allow immune evasion and high frequency of extreme drug resistance, makes Acinetobacter a formidable organism.\n\nThe finding of a potentially multidrug-resistant pathogen as the causative organism in this case and the fact that this patient died despite relatively prompt diagnosis and appropriate antibiotic treatment reveals the need for further implementation of transfusion-associated infection prevention methods. In 2004, the AABB introduced standard 5.1.5.1, requiring the blood collection industry to implement measures to detect and limit bacteria in platelet components [8]. This includes screening of the donor for symptoms that may indicate septicemia, proper skin disinfection prior to venipuncture, diversion of the first aliquot of collected blood, and cultures at time of apheresis. This resulted in a 50–75% reduction in septic transfusion reactions [9]. At our facility, once received, the platelets undergo a visual inspection, and those with evidence of swirling or visual contamination are discarded. In this case, the contaminated platelet concentrate (PC) had documented negative cultures at 24 hours and a negative visual inspection prior to release to the patient. Other methods such as pH, glucose levels, and Gram-stain coloration have been shown to be of low sensitivity [10].\n\nSeveral methods are currently being developed and utilized in facilities to reduce the number of transfusion-transmitted bacterial infections (TTBIs) and can broadly be split into secondary detection and pathogen reduction. Of the secondary detection methods, there are currently two antigen-based tests approved by the FDA. The first, the Platelet Pan Genera Detection (PGD) test, developed by Verax Biomedical, detects either lipoteichoic acid in Gram-positive bacteria, or lipopolysaccharide in Gram-negative bacteria [11]. The second, the BacTx assay, developed by Immunetics, Inc., detects bacterial peptidoglycan [12]. These tests have been demonstrated to both increase bacterial detection, and in so doing potentially increase platelet shelf life to 7 days [13]. Other groups have examined the utility of secondary bacterial cultures. Bloch et al. implemented secondary bacterial cultures in their standard testing for PCs and were able to detect 8 contaminated platelets that would have otherwise been transfused out of a total of 23,044 PCs [14].\n\nThe competing strategy to address contaminated platelets is pathogen reduction. Currently, there are three main technologies, which use a photochemical approach for the reduction of potential pathogens [15]. The THERAFLEX system developed by Macopharma and the German Red Cross Blood Service uses UVC light to form pyrimidine dimers that block the elongation of nucleic acid transcripts. The INTERCEPT (Cerus Corporation) and MIRASOL (TerumboBCT) systems utilize UVA/B light in concert with either psoralen or riboflavin, respectively, to crosslink DNA and reduce bacterial, viral, and parasitic load in treated products. The INTERCEPT method is presently the only method that is approved by FDA for pathogen reduction of platelets in the United States.\n\nWhile the use of secondary detection or pathogen reduction methods has been demonstrated to be effective in reducing TTBIs, they can be costly and work-intensive. Prior to the implementation of these methods, a cost analysis is a prudent exercise, especially in large transfusion centers. In one example, Li et al. compared platelets using PRT (INTERCEPT) and those using secondary testing (PGD) and found that PRT was significantly more costly and did not reliably extend shelf life to 7 days [16]. An exhaustive comparison between methodologies is beyond the scope of this article, but these and other studies highlight the importance of a critical evaluation of institutional platelet transfusion practices. In September 2019, the FDA released an updated bacterial risk control strategy to continue reducing the number of TTBIs [17]. They divided PCs into two main classes: (1) apheresis platelets and/or prestorage pools of WBD platelets and (2) single units and poststorage pools of WBD platelets. Specific recommendations were given for each group and warrant detailed review by individual institutions. Broadly, the FDA has begun to recommend secondary detection including rapid testing and secondary culture, as well as pathogen reduction.\n\n4. Conclusion\nWhile transfusion reaction due to bacterial contamination is rare, it is an important complication to consider when a reaction occurs. Newer methods of detection of bacterial contamination may help reduce transfusion complications.\n\nDisclosure\nNevala-Plagemann C. and Powers P. are co-first authors.\n\nConflicts of Interest\nThe authors declare no conflicts of interest.\n==== Refs\n1 U.S. Food and Drug Administration Fatalities Reported to FDA Following Blood Collection and Transfusion 2017 White Oak, MA, USA U.S. Food and Drug Administration https://www.fda.gov/media/124796/download \n2 Hendrickson J. E. Roubinian N. H. Chowdhury D. Incidence of transfusion reactions: a multicenter study utilizing systematic active surveillance and expert adjudication Transfusion 2016 56 10 2587 2596 10.1111/trf.13730 2-s2.0-84979582283 27460200 \n3 Benjamin R. J. Transfusion-related sepsis: a silent epidemic Blood 2016 127 4 380 381 10.1182/blood-2015-12-685198 2-s2.0-84958191069 26823510 \n4 Reading F. C. Brecher M. E. Transfusion-related bacterial sepsis Current Opinion in Hematology 2001 8 6 380 386 10.1097/00062752-200111000-00011 2-s2.0-0034760973 11604579 \n5 Jones S. A. Jones J. M. Leung V. Sepsis attributed to bacterial contamination of platelets associated with a potential common source—multiple states, 2018 MMWR. Morbidity and Mortality Weekly Report 2019 68 23 519 523 10.15585/mmwr.mm6823a2 2-s2.0-85068197343 31194723 \n6 Ellingson K. D. Sapiano M. R. P. Haass K. A. Continued decline in blood collection and transfusion in the United States-2015 Transfusion 2017 57 2 1588 1598 10.1111/trf.14165 2-s2.0-85020240080 28591469 \n7 Wong D. Nielsen T. B. Bonomo R. A. Pantapalangkoor P. Luna B. Spellberg B. Clinical and pathophysiological overview of acinetobacter infections: a century of challenges Clinical Microbiology Reviews 2017 30 1 409 447 10.1128/CMR.00058-16 2-s2.0-85007173821 27974412 \n8 Silva M. A. Gregory K. R. Carr-Greer M. A. Summary of the AABB interorganizational task force on bacterial contamination of platelets: fall 2004 impact survey Transfusion 2006 46 4 636 641 10.1111/j.1537-2995.2006.00768.x 2-s2.0-33645307401 16584441 \n9 Brecher M. E. Jacobs M. R. Katz L. M. Survey of methods used to detect bacterial contamination of platelet products in the United States in 2011 Transfusion 2013 53 4 911 918 10.1111/trf.12148 2-s2.0-84876160077 23461271 \n10 Védy D. Robert D. Canellini G. Waldvogel S. Tissot J.-D. Bacterial contamination of platelet concentrates: pathogen detection and inactivation methods Hematology Reviews 2009 1 1 p. 5 10.4081/hr.2009.e5 \n11 Vollmer T. Hinse D. Kleesiek K. Dreier J. The pan genera detection immunoassay: a novel point-of-issue method for detection of bacterial contamination in platelet concentrates Journal of Clinical Microbiology 2010 48 10 3475 3481 10.1128/jcm.00542-10 2-s2.0-77957767358 20702673 \n12 Heaton W. A. Good C. E. Galloway-Haskins R. Yomtovian R. A. Jacobs M. R. Evaluation of a rapid colorimetric assay for detection of bacterial contamination in apheresis and pooled random-donor platelet units Transfusion 2014 54 6 1634 1641 10.1111/trf.12603 2-s2.0-84902182647 24635513 \n13 Bloch E. M. Residual risk of bacterial contamination: what are the options? Transfusion 2017 57 10 2289 2292 10.1111/trf.14306 2-s2.0-85029789232 28944544 \n14 Bloch E. M. Marshall C. E. Boyd J. S. Implementation of secondary bacterial culture testing of platelets to mitigate residual risk of septic transfusion reactions Transfusion 2018 58 7 1647 1653 10.1111/trf.14618 2-s2.0-85044761875 29607515 \n15 Seltsam A. Pathogen inactivation of cellular blood products-an additional safety layer in transfusion medicine Frontiers in Medicine 2017 4 p. 219 10.3389/fmed.2017.00219.eCollection_2017 \n16 Li J. W. Brecher M. E. Jacobson J. L. Addressing the risk of bacterial contamination in platelets: a hospital economic perspective Transfusion 2017 57 10 2321 2328 10.1111/trf.14216 2-s2.0-85029815964 28703862 \n17 U.S. Food and Drug Administration, Center for Biologics Evaluation and Research Bacterial Risk Control Strategies for Blood Collection Establishments and Transfusion Services to Enhance the Safety and Availability of Platelets for Transfusion: Guidance for Industry 2019 White Oak, MA, USA U.S. Food and Drug Administration https://www.fda.gov/media/123448/download\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2019()",
"journal": "Case reports in medicine",
"keywords": null,
"medline_ta": "Case Rep Med",
"mesh_terms": null,
"nlm_unique_id": "101512910",
"other_id": null,
"pages": "3136493",
"pmc": null,
"pmid": "32089699",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "11604579;29607515;24635513;16584441;28703862;23461271;27460200;26823510;29255710;31194723;28944544;20702673;28591469;27974412",
"title": "A Fatal Case of Septic Shock Secondary to Acinetobacter Bacteremia Acquired from a Platelet Transfusion.",
"title_normalized": "a fatal case of septic shock secondary to acinetobacter bacteremia acquired from a platelet transfusion"
} | [
{
"companynumb": "US-AXELLIA-002967",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
"... |
{
"abstract": "Parathyroid carcinoma (PTC) has a high rate of recurrence, which typically occurs within 5 years of diagnosis involving locoregional sites. Immunosuppressive therapies pose a theoretical increased risk of malignancy. We report an atypical case of PTC recurrence in a patient receiving infliximab therapy for ulcerative colitis (UC).\nMain diagnostic tests performed included calcium and parathyroid hormone (PTH) levels, computed tomography, and a venous sampling study.\nA patient with PTC, who was \"cured\" by parathyroidectomy, presented with recurrent hypercalcemia 21 years after his initial diagnosis. He had recently been diagnosed with UC and was started on infliximab. His serum PTH level was elevated. After negative routine neck imaging studies and sestamibi scan, he underwent selective venous sampling with PTH measurements, which localized the source lesion to the thoracic wall. Subsequent imaging showed multiple left lung and pleural nodules, which were surgically resected. Hypercalcemia abated after surgery, but quickly returned and was recalcitrant to treatment with cinacalcet and zoledronic acid. Further imaging demonstrated recurrent lung metastases, some along the left diaphragm. He underwent 2 additional surgical resections, after which PTH and calcium levels normalized. Infliximab was replaced with vedolizumab for treatment of UC.\nAtypical presentation of PTC may occur in the context of immunosuppressive therapy. Venous sampling with PTH measurements can aid in localization of atypical metastatic PTC. Additional surveillance for PTC recurrence may be prudent following the initiation of immunosuppressive therapy in patients with a history of PTC.",
"affiliations": null,
"authors": "Gunawan|Felona|F|;Holt|Elizabeth|E|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4158/ACCR-2019-0519",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2376-0605",
"issue": "6(3)",
"journal": "AACE clinical case reports",
"keywords": null,
"medline_ta": "AACE Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101670593",
"other_id": null,
"pages": "e113-e116",
"pmc": null,
"pmid": "32524023",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "27313750;27688201;27039969;24938563;22948700;24742584;9735131;19877027;20510594;16705109;23155441;8334754",
"title": "ATYPICAL RECURRENCE OF PARATHYROID CARCINOMA FOLLOWING INFLIXIMAB THERAPY IN A PATIENT WITH ULCERATIVE COLITIS.",
"title_normalized": "atypical recurrence of parathyroid carcinoma following infliximab therapy in a patient with ulcerative colitis"
} | [
{
"companynumb": "US-JNJFOC-20200620340",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "Three patients (3 female patients; aged 7, 35, and 61 years) who had recalcitrant idiopathic sclerosing orbital inflammation were treated with rituximab. The disease was bilateral in 1 patient (4 orbits in total): diffuse in 2 and localized in 2 orbits. It caused optic neuropathy in 1 orbit of each patient. Conventional immunotherapy and tumor debulking surgery were unsuccessful in controlling the disease. After rituximab infusions (375 mg/m2/week for 4 weeks), all patients improved symptomatically. Radiologically, the local lesions resolved completely and diffuse lesions partially. Two patients with recurrent inflammation during follow up (78, 58, and 51 months) responded well to immediate, short-term steroid treatments. Short-term rituximab therapy can induce effective remissions in patients with refractory idiopathic sclerosing orbital inflammation. Early and local lesions may respond better to treatment than diffuse lesions. Nevertheless, inflammatory exacerbations can occur during late follow up.",
"affiliations": "Departments of Ophthalmology.;Departments of Immunology.;Departments of Pathology, Uludag University, Bursa, Turkey.;Departments of Immunology.",
"authors": "Yazici|Bulent|B|;Cekic|Sukru|S|;Yalcinkaya|Ulviye|U|;Kilic|S Sebnem|SS|",
"chemical_list": "D007155:Immunologic Factors; D000069283:Rituximab",
"country": "United States",
"delete": false,
"doi": "10.1097/IOP.0000000000001843",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0740-9303",
"issue": "37(3)",
"journal": "Ophthalmic plastic and reconstructive surgery",
"keywords": null,
"medline_ta": "Ophthalmic Plast Reconstr Surg",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D002648:Child; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D007249:Inflammation; D008875:Middle Aged; D009915:Orbit; D016727:Orbital Pseudotumor; D000069283:Rituximab; D055815:Young Adult",
"nlm_unique_id": "8508431",
"other_id": null,
"pages": "e91-e97",
"pmc": null,
"pmid": "33060512",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Rituximab Therapy for Recalcitrant Idiopathic Sclerosing Orbital Inflammation.",
"title_normalized": "rituximab therapy for recalcitrant idiopathic sclerosing orbital inflammation"
} | [
{
"companynumb": "TR-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-306740",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"dr... |
{
"abstract": "The objective of this exploratory, multicenter, randomized, double-blind study, was to evaluate the efficacy and safety/tolerability of milnacipran and venlafaxine administered at flexible doses (100, 150 or 200 mg/day, bid administration) for 24 weeks (including 4 weeks up titration period) in the outpatient treatment of adults presenting with a moderate or severe episode of major depressive disorder (MDD) without high suicidal risk (MINI-DSM IV-TR). Of the 195 patients included, 134 (68.7%) completed the study. At baseline the two groups were similar, except there was a higher proportion of patients whose episode was severe-DSM IV in the milnacipran group (63.3% versus 54.0% in the venlafaxine group). The initial MADRS score (mean 31.0) decreased progressively during the study, and this decrease was in the two treatment groups (n = 177: 90 milnacipran; 87 venlafaxine) at week 24 (observed case/OC, mean change -23.1 milnacipran; -22.4 venlafaxine). The rate of MADRS response (reduction >/= 50%) at week 8 and week 24-last observation carried forward/LOCF was similar in the two groups (week 8: 64.4% milnacipran; 65.5% venlafaxine; week 24: 70% milnacipran; 77% venlafaxine), as was the rate of MADRS remission (score </= 10) (week 8: 42.2% milnacipran; 42.5% venlafaxine; week 24: 52.2% milnacipran; 62.1% venlafaxine). In both groups, the most common adverse events were: nausea, dizziness, headache, hyperhidrosis and, in males, genito-urinary problems. The overall safety/tolerability and efficacy profiles of milnacipran and venlafaxine administered at flexible dosages (up to 200 mg/day) were similar in the long term treatment of adults during episodes of MDD in an outpatient setting.",
"affiliations": "Service de Santé Mentale et Thérapeutique, Centre Hospitalier Sainte-Anne, Paris, France. jp.olie@ch-sainte-anne.fr",
"authors": "Olié|Jean-Pierre|JP|;Gourion|David|D|;Montagne|Agnès|A|;Rostin|Michel|M|;Poirier|Marie-France|MF|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1176-6328",
"issue": "6()",
"journal": "Neuropsychiatric disease and treatment",
"keywords": "adult; major depressive episode; milnacipran; serotonin and norepinephrine reuptake inhibitors; venlafaxine",
"medline_ta": "Neuropsychiatr Dis Treat",
"mesh_terms": null,
"nlm_unique_id": "101240304",
"other_id": null,
"pages": "71-9",
"pmc": null,
"pmid": "20396639",
"pubdate": "2010-04-07",
"publication_types": "D016428:Journal Article",
"references": "16968586;19165525;9179630;17163244;8656541;16142213;1821700;8732439;19300602;9466161;9118813;20004291;17917550;5481206;18622367;444788;19132781",
"title": "Milnacipran and venlafaxine at flexible doses (up to 200 mg/day) in the outpatient treatment of adults with moderate-to-severe major depressive disorder: a 24-week randomized, double-blind exploratory study.",
"title_normalized": "milnacipran and venlafaxine at flexible doses up to 200 mg day in the outpatient treatment of adults with moderate to severe major depressive disorder a 24 week randomized double blind exploratory study"
} | [
{
"companynumb": "FR-PFIZER INC-202200004328",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VENLAFAXINE HYDROCHLORIDE"
},
"drugadditiona... |
{
"abstract": "In this case report, two cases of bilateral atypical femoral fractures after prolonged bisphosphonate therapy are described. Two elderly females had more than ten years of antiresorptive treatment with bisphosphonate, and they were diagnosed with bilateral atypical femoral fracture (AFF) after a dual energy X-ray absorptiometry scanning of the entire femoral shaft. They were both subjected to intramedullary nails and anabolic treatment. Currently, bisphosphonate treatment of osteoporosis has been reduced because of side effects such as AFF.",
"affiliations": "brattanette@hotmail.com.",
"authors": "Solis|Anette Maria Bratt|AMB|;Hitz|Mette Friberg|MF|;Jensen|Jens-Erik Beck|JB|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates",
"country": "Denmark",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-5782",
"issue": "181(24)",
"journal": "Ugeskrift for laeger",
"keywords": null,
"medline_ta": "Ugeskr Laeger",
"mesh_terms": "D015502:Absorptiometry, Photon; D000368:Aged; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D005260:Female; D005264:Femoral Fractures; D005269:Femur; D006801:Humans; D010024:Osteoporosis",
"nlm_unique_id": "0141730",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31267952",
"pubdate": "2019-06-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bilateral atypical femoral fractures after prolonged antiresorptive treatment.",
"title_normalized": "bilateral atypical femoral fractures after prolonged antiresorptive treatment"
} | [
{
"companynumb": "DK-AMGEN-DNKSP2019156727",
"fulfillexpeditecriteria": "2",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DENOSUMAB"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nAlkaptonuria (AKU) is a rare disorder with no licensed treatment; nitisinone may reduce symptoms and progression. The All Alkaptonuria Severity Score Index (AKUSSI) measures disease severity in clinical, joint and spine domains, with 57 subcomponent feature scores. Our primary aim was to assess tools for validating scores such as the AKUSSI by detecting relationships between features both before and during nitisinone treatment.\n\n\nMETHODS\nAKUSSI measurements from nitisinone-treated patients visiting the National AKU Centre between 01-Jun-2012 and 31-May-2016 were analysed pre-treatment, at first treatment and annually to Year 3 post-treatment. Principal component analysis (PCA) and redundancy analysis assessed whether any AKUSSI features contributed little information to the overall score.\n\n\nRESULTS\n65 AKU patients were included: 17 with a pre-treatment AKUSSI measurement (10 later received nitisinone) and 48 with a first measurement at their first treatment visit. In PCA, the first four principal components (PC1-PC4) explained ≥50% of AKUSSI variance at all visits (54.1-87.3%). Some features regularly dominated their domain's PC1: ears, aortic sclerosis, and nasal/temporal eye scores (clinical), pain-related scores (joint) and cervical, lumbar and thoracic spine scores (spine). Only the right-hand/wrist score was consistently redundant. Right eye (nasal) and left ear scores were redundant pre-treatment, potentially correlating with other dominant clinical PC1 features.\n\n\nCONCLUSIONS\nPCA and redundancy analysis supported the AKUSSI as a robust AKU disease severity measure, although some AKUSSI features could be removed for simplicity. For small patient populations and rare diseases, PCA and redundancy analysis together can aid validation of disease severity metrics.",
"affiliations": "Costello Medical, Cambridge, UK. bryony.langford@costellomedical.com.;Costello Medical, Cambridge, UK.;Costello Medical, Cambridge, UK.;Costello Medical, Cambridge, UK.;AKU Society, Cambridge, UK.;Department of Musculoskeletal Biology, University of Liverpool, Liverpool, UK.;Royal Liverpool University Hospital, Liverpool, UK.",
"authors": "Langford|Bryony|B|;Besford|Megan|M|;Hall|Aimée|A|;Eddowes|Lucy|L|;Timmis|Oliver|O|;Gallagher|James A|JA|;Ranganath|Lakshminarayan|L|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/8904_2018_98",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2192-8304",
"issue": "41()",
"journal": "JIMD reports",
"keywords": "Alkaptonuria; Assessment; Efficacy; Nitisinone; Ochronosis; Severity",
"medline_ta": "JIMD Rep",
"mesh_terms": null,
"nlm_unique_id": "101568557",
"other_id": null,
"pages": "53-62",
"pmc": null,
"pmid": "29654544",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "20032918;21744089;25860819;12501223;23486607;21720873;25475116;23511227;15931605;21620748",
"title": "Alkaptonuria Severity Score Index Revisited: Analysing the AKUSSI and Its Subcomponent Features.",
"title_normalized": "alkaptonuria severity score index revisited analysing the akussi and its subcomponent features"
} | [
{
"companynumb": "GB-BIOVITRUM-2018GB0326",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BISOPROLOL"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nBisphosphonates are commonly used in the treatment of metabolic bone disease. However, they are associated with gastrointestinal side effects including acid reflux, mucosal erosion, and oesophageal stricture. We present a rare case of alendronate causing perforated gastric volvulus in a patient with giant hiatus hernia.\n\n\nMETHODS\nAn 82-year-old woman presented to our hospital with central chest pain, palpitations and new onset atrial fibrillation on the background of 2 weeks of vomiting. Computed tomography (CT) imaging revealed a perforated, mixed type organoaxial/mesoenteroaxial gastric volvulus within a giant hiatus hernia, with partial gastric outlet obstruction. The patient underwent laparoscopic reduction of hiatus hernia and gastric volvulus, conversion to laparotomy, and distal gastrectomy with Bilroth II reconstruction. An alendronate tablet was found in the right mediastinum. The patient had a prolonged post-operative course and was discharged home after completing extensive physical rehabilitation.\n\n\nCONCLUSIONS\nBisphosphonates are widely used to treat metabolic bone disease, however can have devastating adverse effects on the gastrointestinal tract. There are a number of mechanisms postulated for how these medications cause injury to the gastric and oesophageal mucosa.\n\n\nCONCLUSIONS\nThis case illustrates the importance of considering the gastrointestinal effects associated with bisphosphonates when prescribing them to patients, especially those with functional or anatomical disorders of the gastrointestinal tract. The presence of a large hiatus hernia should be a contraindication to prescribing alendronate.",
"affiliations": "Department of Surgery, Redcliffe Hospital, Anzac Avenue, Redcliffe, QLD, Australia. Electronic address: bianca.kwan@health.qld.gov.au.;Department of Surgery, Redcliffe Hospital, Anzac Avenue, Redcliffe, QLD, Australia.",
"authors": "Kwan|Bianca|B|;Wong|Jason|J|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ijscr.2020.06.068",
"fulltext": "\n==== Front\nInt J Surg Case Rep\nInt J Surg Case Rep\nInternational Journal of Surgery Case Reports\n2210-2612 Elsevier \n\nS2210-2612(20)30471-5\n10.1016/j.ijscr.2020.06.068\nArticle\nPerforation of gastric volvulus within a giant hiatus hernia secondary to alendronate: A rare complication of bisphosphonate use☆\nKwan Bianca bianca.kwan@health.qld.gov.au⁎ Wong Jason Department of Surgery, Redcliffe Hospital, Anzac Avenue, Redcliffe, QLD, Australia\n⁎ Corresponding author at: Department of Surgery, Redcliffe Hospital, Anzac Avenue, Redcliffe, QLD, Australia. bianca.kwan@health.qld.gov.au\n20 6 2020 \n2020 \n20 6 2020 \n73 5 8\n17 5 2020 10 6 2020 13 6 2020 © 2020 The Authors2020This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Highlights\n• A case of perforation due to alendronate in patient with gastric volvulus within giant hiatus hernia.\n\n• Bisphosphonates can have devastating gastrointestinal side effects.\n\n• Gastric or oesophageal perforation due to bisphosphonates is rare but serious.\n\n• Bisphosphonates should be avoided in those with functional or anatomical disorders of the gastrointestinal tract.\n\n\n\nIntroduction\nBisphosphonates are commonly used in the treatment of metabolic bone disease. However, they are associated with gastrointestinal side effects including acid reflux, mucosal erosion, and oesophageal stricture. We present a rare case of alendronate causing perforated gastric volvulus in a patient with giant hiatus hernia.\n\nPresentation of case\nAn 82-year-old woman presented to our hospital with central chest pain, palpitations and new onset atrial fibrillation on the background of 2 weeks of vomiting. Computed tomography (CT) imaging revealed a perforated, mixed type organoaxial/mesoenteroaxial gastric volvulus within a giant hiatus hernia, with partial gastric outlet obstruction. The patient underwent laparoscopic reduction of hiatus hernia and gastric volvulus, conversion to laparotomy, and distal gastrectomy with Bilroth II reconstruction. An alendronate tablet was found in the right mediastinum. The patient had a prolonged post-operative course and was discharged home after completing extensive physical rehabilitation.\n\nDiscussion\nBisphosphonates are widely used to treat metabolic bone disease, however can have devastating adverse effects on the gastrointestinal tract. There are a number of mechanisms postulated for how these medications cause injury to the gastric and oesophageal mucosa.\n\nConclusion\nThis case illustrates the importance of considering the gastrointestinal effects associated with bisphosphonates when prescribing them to patients, especially those with functional or anatomical disorders of the gastrointestinal tract. The presence of a large hiatus hernia should be a contraindication to prescribing alendronate.\n\nKeywords\nAlendronateBisphosphonatesMassive hiatus herniaPerforated gastric volvulusCase report\n==== Body\n1 Introduction\nBisphosphonates are commonly used in the treatment of metabolic bone disease such as osteoporosis and Paget’s disease. Bisphosphonates decrease bone resorption by reducing activity of osteoclasts, the cells responsible for breakdown of bone matrix [2].\n\nThese medications are also associated with a number of adverse events such as osteonecrosis of the jaw and atypical femoral fractures. However, by far the most common negative consequences of bisphosphonates are gastrointestinal side effects, including acid reflux, mucosal erosion, and oesophageal stricture [1]. In those unable to tolerate these gastrointestinal effects associated with oral bisphosphonates, intravenous preparations exist.\n\nWe present a rare case of perforated gastric volvulus in a patient with massive hiatus hernia, where the perforation is likely secondary to alendronate. This is the only reported case in the literature. This case has been reported in line with the SCARE criteria [2].\n\n2 Presentation of case\n2.1 Case history\nAn 82-year-old woman presented to our hospital with central chest pain, palpitations and new onset atrial fibrillation with rapid ventricular rate. This was on the background of 2 weeks of vomiting and 6 kg associated weight loss. The patient had a past history of osteoporosis, angina, hypertension and osteoarthritis.\n\nLaboratory investigations revealed an elevated white cell count of 27.3 × 109/L, with a neutrophilia of 25.76 × 109/L. Haemoglobin was 13.2 g/dL. The patient had an acute kidney injury with creatinine of 155 μmol/L (baseline 60 μmol/L). Venous blood gas showed a normal pH of 7.33, with an elevated lactate of 4.1 mmol/L.\n\nChest X-ray showed evidence of a large hiatus hernia (Fig. 1). Subsequent contrast computed tomography (CT) imaging of the chest and abdomen revealed a mixed organoaxial/mesoenteroaxial gastric volvulus within a large hiatus hernia. The entire stomach was within the thoracic cavity. There was a degree of outlet obstruction but no gastric torsion. An associated large right pleural effusion with compressive atelectasis of the right lower lobe could be seen. There was subsequent compression of the heart against the sternum. A small hyperdensity could be seen in the right mediastinum, thought to be a tablet (Fig. 2a, b, c).Fig. 1 Chest radiograph showing a large retrocardiac shadow with an intrathoracic gas bubble on the right, indicating a large hiatus hernia.\n\nFig. 1Fig. 2 Computed tomography images of the chest, showing gastric volvulus within a giant hiatal hernia. (a); Axial image showing associated right pleural effusion (white asterisk) and compression of the heart (white arrow) and right lower lobe. (b); Coronal image showing the entire stomach within the thoracic cavity. (c); A tablet (white arrow) can be seen in the right mediastinum on this coronal image.\n\nFig. 2\n\n2.2 Operative techniques\nLaparoscopy was performed where contamination of all quadrants of the abdomen was found. There was a large hiatal hernia, with the entire stomach and first part of the duodenum located within the mediastinum. There was gross contamination of the mediastinum with mediastinitis present, along with food matter and a single medication tablet (Fig. 3). Lavage and laparoscopic reduction of the hiatus hernia and gastric volvulus was performed, with reduction and excision of hernia sac. When the source of perforation was unable to be found, the procedure was converted to exploratory laparotomy and a 1.2 cm perforation was found in the gastric antrum. The aforementioned white, oval-shaped medication tablet was found in the right mediastinum, adjacent to the site of perforation.Fig. 3 Intraoperative photograph of white oval tablet, likely Alendronate, found in the right mediastinum.\n\nFig. 3\n\nDistal gastrectomy with Bilroth II reconstruction were performed, with suture closure of the hiatus with 0-Novafil (Covidien, Dublin, Ireland). A surgical drain was placed through the hiatus into the mediastinum. Two further drains were placed in the upper abdomen and pelvis.\n\nPostoperatively, review of the patient’s regular medications with the assistance of the hospital pharmacist revealed 70 mg of Alendronate in combination with calcium and vitamin D, taken once weekly. The bisphosphonate was the only white, oval-shaped tablet out of all the patient’s regular medications. The patient was not taking non-steroidal anti-inflammatory drugs (NSAIDs) or any other gastropathic medications.\n\nThe patient had a prolonged admission due to delirium, postoperative ileus, and reluctance to engage with allied health services. This resulted in severe physical deconditioning and poor nutrition. She was stepped down to a rehabilitation facility on the 41st postoperative day. After extensive physical rehabilitation for a further 27 days, the patient was eventually discharged home independently. She has subsequently been non-compliant with any follow-up appointments offered to her at our hospital.\n\n3 Discussion\nThe authors postulate the alendronate tablet found intraoperatively could have caused, or at least contributed to, perforation of this patient’s gastric volvulus. While this association cannot be proven, we feel it is certainly possible, due to the proximity of the tablet to the perforation site at operation, and the known erosive effects bisphosphonates can have on the gastrointestinal mucosa. Stasis of the alendronate tablet secondary to volvulus with partial gastric outlet obstruction would have led to mucosal ulceration and subsequent perforation.\n\nGastrointestinal adverse effects are well-established with oral nitrogen-containing bisphosphonates such as alendronate and risedronate. They can commonly cause abdominal pain and discomfort, dyspepsia, oesophagitis/gastritis, heartburn, nausea and gastro-oesophageal reflux [3,4]. There is mixed evidence on whether there is any difference in tolerability between risedronate and alendronate [5,6], with some studies suggesting lower rates of adverse events with risedronate and others finding no difference [4,7].\n\nBisphosphonates can cause adverse effects from damage to the both oesophageal or gastric mucosa. Oesophageal injury is more commonly studied and described. At endoscopy, oesophageal irritation, ulceration and stricture can be seen. A classic endoscopic and pathological appearance has even been characterised in studies of patients taking alendronate. Thick, white exudate loosely adherent to circumscribed white erosions is seen endoscopically. Pathological examination of this exudate reveals birefringent, crystalline material resembling the matrix material of alendronate [8,9].\n\nIn addition to oesophageal injury, evidence also suggests gastric and duodenal irritation secondary to the use of oral bisphosphonates. Endoscopic studies have shown alendronate causes gastric erosions and ulcers within as little as four days after initiating treatment [10,11]. There is also likely a synergistic ulcerogenic effect when used with NSAIDs [12]. This is important in the elderly population likely to be using bisphosphonates for osteoporosis, as they are also commonly using NSAIDs for chronic pain from conditions such as arthritis.\n\nTo avoid gastrointestinal irritation, manufacturers recommend that patients take the medication with a full glass of water and remain upright for at least 30 min after administration and until after the first meal of the day. There has been much evidence to show that bisphosphonates cause oesophageal irritation. Some postulate this is due to incorrect administration of the drug and failure of patients to follow the aforementioned dosing instructions. However, studies have shown some a significant proportion of patients still developed gastrointestinal side effects despite compliance with administration instructions [10].\n\nThe exact biochemical mechanism of mucosal injury from bisphosphonates is still being investigated. It is thought that in a mechanism similar to that of NSAIDs, bisphosphonates cause gastric mucosal injury by inducing cellular injury, cellular lipid peroxidation, and superoxide production [13]. Other processes, such as the involvement of specific T cell populations and interference with the mevalonate pathway also appear to be involved [10].\n\nPill oesophagitis, which is the prolonged exposure of the mucosa to the caustic alendronate tablet, has been postulated as a mechanism for oesophageal irritation and perforation [14]. A topical irritant effect of oral bisphosphonates on the gastric mucosa has also been shown, due to reduction in the protective hydrophobic barrier [15,16]. This is supported by the finding that most alendronate gastric ulcers are found in the greater curve of the gastric antrum [3], where tablets would usually settle due to gravity [10]. In addition, the low pH of gastric contents causes alendronate to be converted to its free acid form, which has been shown to damage oesophageal mucosa. This conversion of the drug in those with gastro-oesophageal reflux or hiatus hernia could lead to increased risk of mucosal damage [10].\n\nThe white, oval-shaped tablet found intraoperatively in this case was likely the patient’s regular Alendronate. We believe this medication was unable to be cleared from the patient’s stomach due to her gastric volvulus and massive hiatus hernia. This sustained mucosal contact then caused a perforated gastric ulcer due to the erosive properties of the medication.\n\nThe gastrointestinal adverse effects of bisphosphonates should be carefully considered when prescribing this medication to patients. Presence of oesophageal strictures, Barrett’s oesophagus and ulcers in the upper gastrointestinal tract are already contraindications to their use. Due to their erosive properties, we believe they should also be avoided in those with functional or anatomical disorders of the upper gastrointestinal tract, such as massive hiatus hernia, oesophageal diverticulum, gastroparesis and achalasia.\n\n3.1 Conclusion\nThis is the only reported case in the literature where alendronate is postulated to be the cause of perforation in a gastric volvulus with massive hiatus hernia. Although rare, oesophageal and gastric perforations are devastating complications secondary to oral bisphosphonates. This case highlights how they should be avoided in those with functional or anatomical disorders of the gastrointestinal tract, such as massive hiatus hernia.\n\nDeclaration of Competing Interest\nNo conflict of interest exists.\n\nSources of funding\nNo sources of funding.\n\nEthical approval\nWe have reported a single case, not a clinical study, with no requirement for ethical approval.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nAuthor contribution\nDr Bianca Kwan: Investigation, Writing – original draft, Writing – Review and Editing, Visualisation.\n\nDr Jason Wong: Conceptualization, Writing – Review and Editing, Supervision.\n\nRegistration of research studies\nNot applicable.\n\nGuarantor\nDr Bianca Kwan.\n\nDepartment of Surgery, Redcliffe Hospital, Anzac Avenue, Redcliffe, Queensland, Australia.\n\nPhone: +61 7 3883 7777.\n\nEmail: bianca.kwan@health.qld.gov.au.\n\nProvenance and peer review\nNot commissioned, externally peer-reviewed.\n\n☆ This case was presented in poster format at the ANZGOSA/ANZMOSS Joint Annual Scientific Meeting in Brisbane, Queensland, Australia on 2 October 2019.\n==== Refs\nReferences\n1 Papapetrou P. Bisphosphonate-associated adverse events Int. J. Endocrinol. Metab. 8 2 2009 96 110 10.14310/horm.2002.1226 \n2 Agha R.A. Borrelli M.R. Farwana R. Koshy K. Fowler A.J. Orgill D.P. The SCARE 2018 statement: updating consensus Surgical CAse REport (SCARE) guidelines Int. J. Surg. 60 2018 132 136 10.1016/j.ijsu.2018.10.028 30342279 \n3 Graham Malaty Alendronate gastric ulcers Aliment. Pharmacol. Ther. 13 4 1999 515 519 10.1046/j.1365-2036.1999.00488.x 10215737 \n4 Pazianas M. Abrahamsen B. Safety of bisphosphonates Bone 49 1 2011 103 110 10.1016/j.bone.2011.01.003 21236370 \n5 Lanza F.L. Hunt R.H. Thomson A.B.R. Provenza J.M. Blank M.A. Endoscopic comparison of esophageal and gastroduodenal effects of risedronate and alendronate in postmenopausal women Gastroenterology 119 3 2000 631 638 10.1053/gast.2000.16517 10982755 \n6 Thomson A.B.R. Marshall J.K. Hunt R.H. Provenza J.M. Lanza F.L. Royer M.G. 14 day endoscopy study comparing risedronate and alendronate in postmenopausal women stratified by Helicobacter pylori status J. Rheumatol. 29 9 2002 1965 1974 12233894 \n7 Cadarette S. Katz J. Brookhart M. Stürmer T. Stedman M. Levin R. Comparative gastrointestinal safety of weekly oral bisphosphonates. With other metabolic bone diseases Osteoporos. Int. 20 10 2009 1735 1747 10.1007/s00198-009-0871-8 19266138 \n8 Ribeiro A. Devault K.R. Wolfe J. Stark M.E. Alendronate-associated esophagitis: endoscopic and pathologic features Gastrointest. Endosc. 47 6 1998 525 528 10.1016/S0016-5107(98)70256-1 9647380 \n9 Abraham S.C. Cruz-Correa M. Lee L.A. Yardley J.H. Wu T.T. Alendronate-associated esophageal injury: pathologic and endoscopic features Mod. Pathol. 12 12 1999 1152 1157 Epub 2000/01/05. PubMed PMID: 10619269 10619269 \n10 Graham D. What the gastroenterologist should know about the gastrointestinal safety profiles of bisphosphonates Dig. Dis. Sci. 2002 1665 1678 12184516 \n11 Lanza F.L. Hunt R.H. Thomson A.B. Provenza J.M. Blank M.A. Endoscopic comparison of esophageal and gastroduodenal effects of risedronate and alendronate in postmenopausal women Gastroenterology 119 3 2000 631 638 10.1053/gast.2000.16517 Epub 2000/09/13, PubMed PMID: 10982755 10982755 \n12 Graham D.Y. Malaty H.M. Alendronate and naproxen are synergistic for development of gastric ulcers Arch. Intern. Med. 161 1 2001 107 110 10.1001/archinte.161.1.107 Epub 2001/01/09, PubMed PMID: 11146706 11146706 \n13 Nagano Y. Matsui H. Shimokawa O. Hirayama A. Nakamura Y. Tamura M. Bisphosphonate-induced gastrointestinal mucosal injury is mediated by mitochondrial superoxide production and lipid peroxidation J. Clin. Biochem. Nutr. 51 3 2012 196 203 10.3164/jcbn.12-41 23170047 \n14 Peter C. Handt L. Smith S. Esophageal irritation due to alendronate sodium tablets (Possible mechanisms) Dig. Dis. Sci. 43 9 1998 1998 2002 10.1023/A:1018894827961 9753265 \n15 Peter C.P. Kindt M.V. Majka J.A. Comparative study of potential for bisphosphonates to damage gastric mucosa of rats Dig. Dis. Sci. 43 5 1998 1009 1015 10.1023/a:1018826600877 Epub 1998/05/20. PubMed PMID: 9590415 9590415 \n16 Lichtenberger L.M. Romero J.J. Gibson G.W. Blank M.A. Effect of bisphosphonates on surface hydrophobicity and phosphatidylcholine concentration of rodent gastric mucosa Dig. Dis. Sci. 45 9 2000 1792 1801 10.1023/a:1005574009856 Epub 2000/10/29, PubMed PMID: 11052322 11052322\n\n",
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"title": "Perforation of gastric volvulus within a giant hiatus hernia secondary to alendronate: A rare complication of bisphosphonate use.",
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"abstract": "A 64-year old man developed alopecia universalis after one month of treatment with metformin and sitagliptin, a dipeptidyl peptidase‑4 (DPP-4) inhibitor. Diabetes treatment was changed to another genericum of sitagliptin and dapagliflozin. Following our recommendation, sitagliptin was interrupted and monotherapy with dapagliflozin was continued. After 6 weeks, sitagliptin was reassumed due to unsatisfactory diabetes control. Alopecia did not improve. We suspect a connection between DPP‑4 inhibition and development of alopecia due to its immunological potential. We assume that the treatment interruption might have been too short to induce regrowth of hair. DPP‑4 may result in both inhibition and activation of the immune system.",
"affiliations": "Klinik für Dermatologie, Venerologie und Allergologie, Universität Leipzig, Philipp-Rosenthal-Str. 23, 04103, Leipzig, Deutschland. Johannes.Kohlmann@medizin.uni-leipzig.de.;Klinik für Dermatologie, Venerologie und Allergologie, Universität Leipzig, Philipp-Rosenthal-Str. 23, 04103, Leipzig, Deutschland.;Klinik für Dermatologie, Venerologie und Allergologie, Universität Leipzig, Philipp-Rosenthal-Str. 23, 04103, Leipzig, Deutschland.;Klinik für Dermatologie, Venerologie und Allergologie, Universität Leipzig, Philipp-Rosenthal-Str. 23, 04103, Leipzig, Deutschland.;Klinik für Dermatologie, Venerologie und Allergologie, Universität Leipzig, Philipp-Rosenthal-Str. 23, 04103, Leipzig, Deutschland.",
"authors": "Kohlmann|Johannes|J|;Ferrer|Rubén A|RA|;Markovic|Aleksander|A|;Illes|Monica|M|;Kunz|Manfred|M|",
"chemical_list": "D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D000068900:Sitagliptin Phosphate",
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"fulltext": "\n==== Front\nHautarzt\nHautarzt\nDer Hautarzt; Zeitschrift Fur Dermatologie, Venerologie, Und Verwandte Gebiete\n0017-8470\n1432-1173\nSpringer Medizin Heidelberg\n\n33205256\n4727\n10.1007/s00105-020-04727-8\nKasuistiken\nAlopecia areata universalis nach Sitagliptin-Einnahme\nMögliche immunologische Wirkung von Dipeptidylpeptidase-4-Inhibitoren?\nAlopecia areata universalis under treatment with sitagliptinPossible immunological effect of dipeptidyl peptidase-4 inhibitors?\nKohlmann Johannes Johannes.Kohlmann@medizin.uni-leipzig.de\n\nFerrer Rubén A.\nMarkovic Aleksander\nIlles Monica\nKunz Manfred\ngrid.9647.c 0000 0004 7669 9786 Klinik für Dermatologie, Venerologie und Allergologie, Universität Leipzig, Philipp-Rosenthal-Str. 23, 04103 Leipzig, Deutschland\n17 11 2020\n17 11 2020\n2021\n72 7 607609\n© The Author(s) 2020\nhttps://creativecommons.org/licenses/by/4.0/ Open Access Dieser Artikel wird unter der Creative Commons Namensnennung 4.0 International Lizenz veröffentlicht, welche die Nutzung, Vervielfältigung, Bearbeitung, Verbreitung und Wiedergabe in jeglichem Medium und Format erlaubt, sofern Sie den/die ursprünglichen Autor(en) und die Quelle ordnungsgemäß nennen, einen Link zur Creative Commons Lizenz beifügen und angeben, ob Änderungen vorgenommen wurden.\nDie in diesem Artikel enthaltenen Bilder und sonstiges Drittmaterial unterliegen ebenfalls der genannten Creative Commons Lizenz, sofern sich aus der Abbildungslegende nichts anderes ergibt. Sofern das betreffende Material nicht unter der genannten Creative Commons Lizenz steht und die betreffende Handlung nicht nach gesetzlichen Vorschriften erlaubt ist, ist für die oben aufgeführten Weiterverwendungen des Materials die Einwilligung des jeweiligen Rechteinhabers einzuholen.\nWeitere Details zur Lizenz entnehmen Sie bitte der Lizenzinformation auf http://creativecommons.org/licenses/by/4.0/deed.de.\nEin 64-jähriger Patient entwickelte 1 Monat nach Therapieeinleitung mit Sitagliptin, einem Dipeptidylpeptidase-4(DPP‑4)-Inhibitor, und Metformin eine Alopecia universalis. Die Therapie des Diabetes wurde auf das Sitagliptin eines anderen Herstellers und Dapagliflozin umgestellt. Auf unser Anraten wurde Sitagliptin abgesetzt und eine Monotherapie mit Dapagliflozin fortgeführt. Nach 6 Wochen war eine erneute Therapie mit Sitagliptin bei unzureichend eingestelltem Diabetes notwendig. Die Alopezie persistierte. Aufgrund des immunologischen Interaktionspotenzials vermuten wir eine Assoziation zwischen DPP-4-Inhibition und der Alopezie. Der kurze therapiefreie Zeitraum scheint zu gering, um ein erneutes Haarwachstum zu beobachten. DPP‑4 kann sowohl eine Inhibition als auch Aktivierung des Immunsystems bewirken.\n\nA 64-year old man developed alopecia universalis after one month of treatment with metformin and sitagliptin, a dipeptidyl peptidase‑4 (DPP-4) inhibitor. Diabetes treatment was changed to another genericum of sitagliptin and dapagliflozin. Following our recommendation, sitagliptin was interrupted and monotherapy with dapagliflozin was continued. After 6 weeks, sitagliptin was reassumed due to unsatisfactory diabetes control. Alopecia did not improve. We suspect a connection between DPP‑4 inhibition and development of alopecia due to its immunological potential. We assume that the treatment interruption might have been too short to induce regrowth of hair. DPP‑4 may result in both inhibition and activation of the immune system.\n\nSchlüsselwörter\n\nMetformin\nDapagliflozin\nDiabetes\nHaarverlust\nImmunsystem\nKeywords\n\nMetformin\nDapagliflozin\nDiabetes mellitus\nHair loss\nImmune system disorders\nUniversitätsklinikum Leipzig (8929)Open Access funding enabled and organized by Projekt DEAL.\n\nissue-copyright-statement© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2021\n==== Body\nAnamnese\n\nWir berichten über den Fall eines 64-jährigen Patienten mit Erstdiagnose eines Diabetes mellitus Typ 2. Die Initialtherapie erfolgte mit Metformin 1000 mg und dem Dipeptidylpeptidase-4(DPP-4)-Inhibitor Sitagliptin 50 mg täglich. Nach 1 Monat entwickelte der Patient eine Alopecia universalis, die Maximalvariante einer Alopecia areata, mit vollständigem Verlust der gesamten Körper- und Gesichtsbehaarung. Andere Medikamente wurden nach Angaben des Patienten mit Ausnahme von Candesartan im vorangegangenen halben Jahr nicht eingenommen. Vorangegangene Alopezieepisoden wurden verneint, ebenso eine Atopie in der Eigen- oder Familienanamnese. Nach 1 Monat wurde die Diabetestherapie auf 10 mg Dapagliflozin und erneut 50 mg Sitagliptin (anderer Handelsname) jeweils täglich umgestellt. Zwei Monate später stellte sich der Patient in unserer Klinik vor.\n\nBefund\n\nEs zeigte sich ein vollständiger narbenloser Verlust der Körperbehaarung. Exemplarisch ist das Gesicht in Abb. 1 dargestellt. Schilddrüsenparameter, -autoantikörper sowie ANA(antinukleäre Antikörper)-Titer waren normwertig bzw. negativ.\n\nDiagnose\n\nAlopecia universalis, am ehesten als unerwünschte Arzneimittelwirkung (UAW) auf Sitagliptin.\n\nTherapie und Verlauf\n\nAufgrund vorheriger Fallberichte [3, 11] vermuteten wir einen Zusammenhang zwischen der Neueinnahme von Sitagliptin und der Alopezie. Nach unserer Empfehlung erfolgte seitens des Diabetologen eine Umstellung auf eine Monotherapie mit Dapagliflozin. Nach 6 Wochen wurde die Therapie mit Sitagliptin aufgrund eines unzureichend eingestellten Diabetes erneut eingeleitet.\n\nBeobachtung\n\nIm 6‑wöchigen, therapiefreien Intervall blieb eine Besserung der Alopecia aus. Bis dato ist diese bestehend.\n\nDiskussion\n\nDie Alopecia universalis wird wegen eines Verlustes des immunologischen Privilegs des Haarfollikels mit konsekutiver autoimmunologischer Inflammation als Autoimmunerkrankung angesehen [10]. Während des Anagens, der Haarwachstumsphase, umzingeln T‑Helfer-Zellen, zytotoxische T‑Zellen, natürliche Killer(NK)- und plasmazytoide dendritische Zellen den unteren Teil des Follikels [1, 13]. In der Vergangenheit wurden genomische Regionen identifiziert, die mit der Alopecia areata assoziiert sind. In diesen Regionen werden unter anderem das zytotoxische T‑Lymphozyten-assoziierte Antigen 4 (CTLA-4), Interleukin(IL)-2, IL-21, IL-2-Rezeptor A und Eos (bekannt als IKZF4) kodiert [10]. Assoziationen bestehen auch für Gene des Haarfollikels (PRDX5 und STX17) und das ULBP(„cytomegalovirus UL16-binding protein“)-Gen-Cluster. ULBP wiederum aktiviert den NK-Rezeptor-Liganden NKG2D und induziert dadurch möglicherweise eine autoimmunologische Reaktion.\n\nEine Dysregulation der Immunogenität des Haarfollikels kann grundsätzlich durch bestimmte Zytokine regulatorische Vorgänge des Immunsystems beeinflussen oder einen proinflammatorischen Zustand mit konsekutiver Immunantwort begünstigen.\n\nSitagliptin, ein DPP-4-Inhibitor, und Metformin, ein Biguanid, sind etablierte Therapieoptionen des Diabetes mellitus Typ 2. Die Naranjo-Wahrscheinlichkeitsskala, ein Punktesystem für die Wahrscheinlichkeit einer UAW, erreicht in unserem Fall für Sitagliptin einen Punktwert von 5/13 und in Bezug auf Metformin 2/13. Es besteht daher eine stärkere Assoziation zwischen der Alopezie und Sitagliptin als kausalem Faktor.\n\nUnsere Literaturrecherche ergab 2 Kasuistiken mit möglicher Assoziation zwischen der Einnahme von Sitagliptin bzw. Metformin und dem Auftreten einer Alopezie. Der erste Fall handelt von einer Patientin, die eine akute Alopezie in Form von Ausdünnen des Haupthaares 3 Monate nach Einnahme von Metformin (Dosierung unbekannt) und einem weiteren Monat mit Dosissteigerung auf 1000 mg 2‑mal täglich entwickelt hatte [3]. Sechs Monate nach Absetzen der Medikation war die Alopezie vollständig regredient. Der zweite Fall handelt von einem Patienten, der initial unter 4‑monatiger Therapie mit Metformin keine UAW zeigte. Vier Monate später, nach Beginn einer kombinierten Therapie mit 50 mg Sitagliptin und 850 mg Metformin, zeigten sich eine Alopezie der Augenbrauen, schnell fortschreitendes Grauwerden des Haupthaars, der Brustbehaarung sowie ein verlangsamtes Bartwachstum [11]. Unter Monotherapie mit Metformin (2850 mg täglich) war die Alopezie 3 Monate später reversibel. Beide Fälle wurden von nichtdermatologischen Fachärzten publiziert und betreut, sodass die klinisch dermatologische Befundbeschreibung nicht eindeutig ist.\n\nAufgrund der zahlreichen Fixkombinationen aus Gliptinen und Metformin ist eine eindeutige kausale Zuordnung zu einem Auslöser in unserem Fall nicht sicher möglich. Denkbar wäre auch eine Beeinflussung durch Kombination beider Präparate. Aufgrund des autoimmunologischen Interaktionspotenzials vermuten wir jedoch Sitagliptin als mitverantwortlichen Auslöser der Alopezie. Pathophysiologisch kann die Inhibition von DPP‑4 durch Sitagliptin die regulatorische Funktion von DPP‑4 auf T‑Zellen (hier als T‑Zell-Aktivator), stimulierten NK-Zellen, aktivierten B‑Zellen, dendritischen Zellen, Monozyten und Makrophagen stören [5]. DPP‑4 spielt als Korezeptor für CD8+-Zellen eine wichtige Rolle bei der erworbenen Immunantwort, der Gedächtnis-T-Zell-Generierung und -Emigration sowie während der Immunseneszenz [5]. Eine Verbindung zu immunologischen Erkrankungen wie Psoriasis, rheumatoide Arthritis, Lupus erythematodes, Sjögren-Syndrom oder dem allergischen Asthma wird beschrieben [5].\n\nGliptine zeigen teilweise auch ein protektives und immunsuppressives Potenzial. So vermittelt Sitagliptin einen immunsuppressiven Effekt durch Inhibition der T‑Zell-Rezeptor-Signaltransduktion und Proliferation von CD4+- und CD8+-Zellen [4].\n\nIn einem Tiermodell zeigte Linagliptin eine protektive Wirkung bezüglich einer Alopezie [2]. In diesem Modell resultierte die Alopezie aus einem aktivierten Wnt-Signalweg [8], der die Homöostase von Stammzellen negativ beeinflusst. Linagliptin scheint diesen Signalweg zu antagonisieren. Vermutet wird eine Inhibition über die Wnt/β-Catenin-Kaskade, die immunologisch zu einer Aktivierung von dendritischen Zellen mit IL-10-Sekretion und Th1- und Th17-Hemmung führt [12].\n\nIm Gegensatz hierzu werden DPP-4-Inhibitoren ebenfalls mit dem Auftreten eines bullösen Pemphigoids (BP) in Verbindung gebracht [6, 7]. Es wird eine Inhibition von DPP‑8 und DPP‑9 durch Vildagliptin wegen einer geringen Selektivität innerhalb der DPPs vermutet [7]. Dies bewirkt eine konsekutive Aktivierung des Caspase-1-Signalwegs, die zu einem erhöhten Risiko der Entstehung eines BP beisteuert. Andererseits kann DPP‑4 proinflammatorische Zytokine wie TNF (Tumor-Nekrose-Faktor), IL-1β, IL-22, IL-17, IL-23 durch die Peptidaseaktivität deaktivieren [9]. Eine Inhibition kann in einer erhöhten Verfügbarkeit dieser Zytokine resultieren und folglich zu einer Aktivierung einer chronisch inflammatorischen Antwort und/oder Verschlimmerung eines autoimmunologischen Prozesses führen.\n\nDer exakte Einfluss auf Autoimmunologie und immunologische Prozesse ist nicht hinreichend geklärt, da sowohl Aktivierung als auch Inhibition möglich scheinen.\n\nZusammenfassend vermuten wir in diesem Fall Sitagliptin als auslösenden Faktor für die Alopezie, weil DPP‑4 einen wichtigen Stellenwert hinsichtlich des Immunsystems und der Autoimmunität besitzt. Das therapiefreie Intervall von 6 Wochen vor erneuter Gabe von Sitagliptin erscheint zu kurz, um einen Besserungseffekt zu erzielen. In Fällen, in denen eine immunologische Erkrankung entsteht oder sich verschlimmert, sollte eine Verbindung zu DPP-4-Inhibitoren erwogen werden.\n\nFazit für die Praxis\n\nNeben einer Assoziation zum bullösen Pemphigoid könnten ebenfalls andere autoimmunologische Erkrankungen wie eine Alopezie mit DPP-4(Dipeptidylpeptidase-4)-Inhibitoren in Verbindung stehen.\n\nBei Neuauftreten oder Verschlimmerung von vorbestehenden autoimmunologischen Erkrankungen sollte eine Assoziation zu DPP-4-Inhibitoren berücksichtigt werden.\n\nDer genaue Einfluss (Hemmung oder Aktivierung) von DPP‑4 auf das Immunsystem ist nicht hinreichend geklärt, sodass weitere Untersuchungen sinnvoll erscheinen.\n\nFunding\n\nOpen Access funding enabled and organized by Projekt DEAL.\n\nEinhaltung ethischer Richtlinien\n\nInteressenkonflikt\n\nJ. Kohlmann, R.A. Ferrer, A. Markovic, M. Illes und M. Kunz geben an, dass kein Interessenkonflikt besteht.\n\nFür diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien. Für Bildmaterial oder anderweitige Angaben innerhalb des Manuskripts, über die Patienten zu identifizieren sind, liegt von ihnen und/oder ihren gesetzlichen Vertretern eine schriftliche Einwilligung vor.\n==== Refs\nLiteratur\n\n1. Abou Rahal J Kurban M Kibbi AG Plasmacytoid dendritic cells in alopecia areata: missing link? J Eur Acad Dermatol Venereol 2016 30 119 123 10.1111/jdv.12932 25545019\n2. Hasegawa Y Hayashi K Takemoto Y DPP-4 inhibition with linagliptin ameliorates the progression of premature aging in klotho−/− mice Cardiovasc Diabetol 2017 16 154 10.1186/s12933-017-0639-y 29195509\n3. Jothilakshmi PK Watson AJ Jude E Acute alopecia due to metformin treatment for polycystic ovarian syndrome J Obstet Gynaecol 2006 26 584 585 10.1080/01443610600831266\n4. Kitagawa N Hamaguchi M Majima S Dipeptidyl peptidase-4 inhibitors have adverse effects for the proliferation of human T cells J Clin Biochem Nutr 2018 63 106 112 10.3164/jcbn.17-64 30279621\n5. Klemann C Wagner L Stephan M Cut to the chase: a review of CD26/dipeptidyl peptidase-4’s (DPP4) entanglement in the immune system Clin Exp Immunol 2016 185 1 21 10.1111/cei.12781 26919392\n6. Kridin K Cohen AD Dipeptidyl-peptidase IV inhibitor-associated bullous pemphigoid: a systematic review and meta-analysis. J Am Acad Dermatol 2018 10.1016/j.jaad.2018.09.048\n7. Lee SG Lee HJ Yoon MS Association of Dipeptidyl Peptidase 4 inhibitor use with risk of Bullous Pemphigoid in patients with diabetes JAMA Dermatol 2019 155 172 177 10.1001/jamadermatol.2018.4556 30624566\n8. Liu H Fergusson MM Castilho RM Augmented Wnt signaling in a mammalian model of accelerated aging Science 2007 317 803 806 10.1126/science.1143578 17690294\n9. Ou X O’leary HA Broxmeyer HE Implications of DPP4 modification of proteins that regulate stem/progenitor and more mature cell types Blood 2013 122 161 169 10.1182/blood-2013-02-487470 23637126\n10. Petukhova L Duvic M Hordinsky M Genome-wide association study in alopecia areata implicates both innate and adaptive immunity Nature 2010 466 113 117 10.1038/nature09114 20596022\n11. Succurro E Palleria C Ruffo M Loss of eyebrows and eyelashes during concomitant treatment with Sitagliptin and Metformin Curr Drug Saf 2017 12 10 12 10.2174/1574886311666161014125536 27758711\n12. Swafford D Manicassamy S Wnt signaling in dendritic cells: its role in regulation of immunity and tolerance Discov Med 2015 19 303 310 25977193\n13. Xing L Dai Z Jabbari A Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition Nat Med 2014 20 1043 1049 10.1038/nm.3645 25129481\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0017-8470",
"issue": "72(7)",
"journal": "Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete",
"keywords": "Dapagliflozin; Diabetes mellitus; Hair loss; Immune system disorders; Metformin",
"medline_ta": "Hautarzt",
"mesh_terms": "D000506:Alopecia Areata; D003924:Diabetes Mellitus, Type 2; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006801:Humans; D007004:Hypoglycemic Agents; D008297:Male; D008875:Middle Aged; D000068900:Sitagliptin Phosphate",
"nlm_unique_id": "0372755",
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"pubdate": "2021-07",
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"title": "Alopecia areata universalis under treatment with sitagliptin : Possible immunological effect of dipeptidyl peptidase-4 inhibitors?",
"title_normalized": "alopecia areata universalis under treatment with sitagliptin possible immunological effect of dipeptidyl peptidase 4 inhibitors"
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"abstract": "We report 3 cases of pneumocystis pneumonia (PCP) in patients with advanced cancer who received palliative care. All patients received long-term steroid therapy for symptom management. A diagnosis of PCP was based on clinical symptoms and a positive Pneumocystis jiroveci polymerase chain reaction test from induced sputum specimens. Despite appropriate treatment, only 1 patient recovered from PCP. Long-term steroid, often prescribed in palliative care settings, is the most common risk factor for PCP in non-HIV patients. Pneumocystis pneumonia may cause distressing symptoms such as severe dyspnea, and the mortality rate is high. Therefore, it is important to consider PCP prophylaxis for high-risk patients and to diagnose PCP early and provide appropriate treatment to alleviate PCP-related symptoms and avert unnecessary shortening of a patient's life expectancy.",
"affiliations": "Department of General Internal Medicine, Teine Keijinkai Hospital, Sapporo, Japan Palliative Care Team, Teine Keijinkai Hospital, Sapporo, Japan Department of Palliative Medicine, Kobe University Graduate School of Medicine, Kobe, Japan ikagoro@pop06.odn.ne.jp.;Department of General Internal Medicine, Teine Keijinkai Hospital, Sapporo, Japan.;Department of Palliative and Supportive Care, Seirei Mikatahara General Hospital, Hamamatsu, Japan.;Department of Palliative Medicine, Tsukuba Medical Center Hospital, Tsukuba, Japan.;Palliative Care Team, Teine Keijinkai Hospital, Sapporo, Japan.;Palliative Care Team, Teine Keijinkai Hospital, Sapporo, Japan.;Department of Palliative Medicine, Tsukuba Medical Center Hospital, Tsukuba, Japan.",
"authors": "Yamaguchi|Takashi|T|;Nagai|Yuki|Y|;Morita|Tatsuya|T|;Kiuchi|Daisuke|D|;Matsumoto|Mina|M|;Hisahara|Ko|K|;Hisanaga|Takayuki|T|",
"chemical_list": "D003907:Dexamethasone; D001623:Betamethasone",
"country": "United States",
"delete": false,
"doi": "10.1177/1049909113504238",
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"issn_linking": "1049-9091",
"issue": "31(8)",
"journal": "The American journal of hospice & palliative care",
"keywords": "advanced cancer; palliative care; pneumocystis pneumonia; prophylaxis; steroid",
"medline_ta": "Am J Hosp Palliat Care",
"mesh_terms": "D001623:Betamethasone; D003907:Dexamethasone; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D010166:Palliative Care; D045363:Pneumocystis carinii; D011020:Pneumonia, Pneumocystis; D012307:Risk Factors",
"nlm_unique_id": "9008229",
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"pages": "857-61",
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"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pneumocystis pneumonia in patients treated with long-term steroid therapy for symptom palliation: a neglected infection in palliative care.",
"title_normalized": "pneumocystis pneumonia in patients treated with long term steroid therapy for symptom palliation a neglected infection in palliative care"
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"abstract": "There is mounting evidence that combination of antibiotic therapy with vancomycin and piperacillin/tazobactam (pip/tazo) is associated with acute kidney injury (AKI). To determine whether vancomycin plus pip/tazo is associated with higher rates of AKI compared to vancomycin plus cefepime among pediatric hematology/oncology (heme/onc) patients, we examined 121 heme/onc patients receiving at least two consecutive days of therapy with vancomycin and either pip/tazo or cefepime. Rate of AKI was higher in the pip/tazo than the cefepime group (4/27 [14.8%] vs 2/94 [2.1%], P = 0.022).",
"affiliations": "Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Vanderbilt University, Nashville, Tennessee.;Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Vanderbilt University, Nashville, Tennessee.;Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Vanderbilt University, Nashville, Tennessee.;Division of Pediatric Infectious Diseases, Vanderbilt University Medical Center, Vanderbilt University, Nashville, Tennessee.",
"authors": "Quach|Henry T|HT|0000-0001-9142-6397;Esbenshade|Adam J|AJ|0000-0002-0154-4996;Zhao|Zhiguo|Z|;Banerjee|Ritu|R|",
"chemical_list": "D014640:Vancomycin; D000077723:Cefepime; D000078142:Tazobactam; D010878:Piperacillin",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.27750",
"fulltext": null,
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"issn_linking": "1545-5009",
"issue": "66(7)",
"journal": "Pediatric blood & cancer",
"keywords": "acute kidney injury; cefepime; hematology/oncology; infections; piperacillin/tazobactam; vancomycin",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D058186:Acute Kidney Injury; D000293:Adolescent; D000077723:Cefepime; D002648:Child; D002675:Child, Preschool; D005260:Female; D019337:Hematologic Neoplasms; D006801:Humans; D008297:Male; D010878:Piperacillin; D012189:Retrospective Studies; D000078142:Tazobactam; D014640:Vancomycin",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e27750",
"pmc": null,
"pmid": "30989780",
"pubdate": "2019-07",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Incidence of acute kidney injury among pediatric hematology/oncology patients receiving vancomycin in combination with piperacillin/tazobactam or cefepime.",
"title_normalized": "incidence of acute kidney injury among pediatric hematology oncology patients receiving vancomycin in combination with piperacillin tazobactam or cefepime"
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"companynumb": "US-QILU PHARMACEUTICAL CO.LTD.-QLU-000364-2019",
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"abstract": "Recently, BAPGM enrichment culture has documented Bartonella bacteremia in previously healthy, \"nonimmunocompromised\" patients following arthropod exposures. Neurobartonellosis should be among the differential diagnoses for patients with persistent or recurrent neurological symptoms of undetermined etiology. Microbiological and immunological testing should be concurrently pursued to determine whether defective immune function accompanies Bartonella bacteremia.",
"affiliations": "Open Medicine Institute Mountain View California.;Open Medicine Institute Mountain View California.;Galaxy Diagnostics Research Triangle Park North Carolina.;Galaxy Diagnostics Research Triangle Park North Carolina.;Department of Clinical Sciences and the Intracellular Pathogens Research Laboratory Institute for Comparative Medicine College of Veterinary Medicine North Carolina State University Raleigh North Carolina.",
"authors": "Kaufman|David L|DL|;Kogelnik|Andreas M|AM|;Mozayeni|Robert B|RB|;Cherry|Natalie A|NA|0000-0001-9771-2677;Breitschwerdt|Edward B|EB|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.977",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.977CCR3977Case ReportCase ReportsNeurological and immunological dysfunction in two patients with Bartonella henselae bacteremia D. L. Kaufman et al.Kaufman David L. \n1\nKogelnik Andreas M. \n1\nMozayeni Robert B. \n2\nCherry Natalie A. http://orcid.org/0000-0001-9771-2677\n2\nBreitschwerdt Edward B. ed_breitschwerdt@ncsu.edu \n3\n1 Open Medicine InstituteMountain ViewCalifornia2 Galaxy DiagnosticsResearch Triangle ParkNorth Carolina3 Department of Clinical Sciences and the Intracellular Pathogens Research LaboratoryInstitute for Comparative MedicineCollege of Veterinary MedicineNorth Carolina State UniversityRaleighNorth Carolina* Correspondence\n\nEdward Breitschwerdt, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Dr., Raleigh, NC 27607. Tel: 919‐513‐8277; Fax: 919‐513‐6464; E‐mail: ed_breitschwerdt@ncsu.edu\n26 4 2017 6 2017 5 6 10.1002/ccr3.2017.5.issue-6931 935 07 12 2016 13 2 2017 10 3 2017 © 2017 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Key Clinical Message\nRecently, BAPGM enrichment culture has documented Bartonella bacteremia in previously healthy, “nonimmunocompromised” patients following arthropod exposures. Neurobartonellosis should be among the differential diagnoses for patients with persistent or recurrent neurological symptoms of undetermined etiology. Microbiological and immunological testing should be concurrently pursued to determine whether defective immune function accompanies Bartonella bacteremia.\n\nBartonellaimmune dysfunctionInfectionneurological symptomsvectorborne source-schema-version-number2.0component-idccr3977cover-dateJune 2017details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.1.0 mode:remove_FC converted:05.06.2017\n==== Body\nCase Reports\nPatient 1\nA 49‐year‐old female veterinarian from California was previously healthy working 60 h a week managing a cat shelter with 500 cats. These factors may have predisposed acquisition of B. henselae and failure to immunologically eliminate the infection. In October 2011, she experienced an extensive infestation of mange mites (Sarcoptes scabiei or Notoedres cati) after handling an infested cat. One month later, she experienced an episode of confusion and severe headache. There was no prior history of headaches or migraines. That evening, she again became confused, experienced a 15‐min episode of total aphasia, witnessed by her husband, and had a headache. All symptoms resolved after 3 h. Over the next few months, she continued to have headaches, episodic confusion, and aphasia. Because an aura preceded symptoms, she would stop performing surgery, sit down, or stop driving. Initially, these episodes occurred one to two times a month; however, over the next 4 years, all symptoms increased in frequency and duration, occurring 20–25 days a month and lasting minutes to hours. She subsequently developed seizures and balance and disequilibrium problems causing gait impairment and falls.\n\nShe was examined by multiple physicians. An extensive neurological workup included an MRI performed in August 2013; all results were negative except for electroencephalographic “left temporal lobe slowing.” After treatment with the anticonvulsant levetiracetam, she reported a 3‐week period of mental clarity and felt normal. Subsequently, symptoms recurred and she did not respond to dose adjustment or additional medications. Her illness progressively worsened, and she stopped working 4 years after symptom onset.\n\nBased on her clinical history, high arthropod and feral cat exposure risk, ambiguous neurological test results, and failure to improve with medical therapy, a search for an infectious cause was initiated. Initial serology results (Quest Diagnostics, Inc.) were negative for Borrelia burgdorferi, Anaplasma phagocytophilum, Ehrlichia chaffeensis, Babesia, Bartonella, Toxoplasma, and Cryptococcus. In December 2014, a repeat MRI revealed left frontal convexity falx calcifications. A SPECT scan documented heterogeneous decreased uptake bilaterally in the frontal and anterior temporal lobes with greater decrease involving the left hemisphere. Cerebrospinal fluid analyses were within laboratory reference ranges. Due to progressive illness and lack of a diagnosis, immunological testing was performed. There were decreased total IgG and deficiencies in subclasses 1, 2, and 3. CD3, CD4, and CD8 absolute cell counts were abnormally low, and a natural killer cell (NK) function assay was profoundly low (Table 1).\n\nTable 1 Selected hematologic and immunological test results for Patients 1 and 2 by month and year (MM/YY)\n\n\tRef Range\tPatient 1\tPatient 2\t\n12/14\t12/14\t2/15\t7/15a\n\t10/15\t12/15\t2/15\t4/15\t9/15\t9/15\t10/15\t11/15\t\nWBC\t3.8–10.8\t5.1\t\t6.0\t4.9\t8.9\t6.5\t3.6\t3.6\t4.3\t\t6.0\t\t\nHCT\t38.5–45.0\t38.6\t\t38.4\t38.5\t\t39.6\t34.4\t36.3\t37.1\t\t35.3\t\t\nPLT\t140–400\t332\t\t295\t273\t277\t272\t327\t301\t209\t\t244\t\t\nANC\t1500–7800\t3570\t\t4680\t3675\t7716\t4570\t2304\t2448\t2731\t\t4368\t\t\nALCb\n\t850–3900\t1275\t\t1020\t960\t1024\t1541\t828\t828\t692\t\t1056\t\t\nIGG 1\t382–929\t287\t318\t328\t415\t\t\t470\t558\t\t507\t\t522\t\nIGG 2\t241–700\t183\t174\t176\t338\t\t\t356\t398\t\t347\t\t360\t\nIGG 3\t22–178\t20\t20\t20\t24\t\t\t20\t25\t\t20\t\t23\t\nIGG 4\t4–86\t5.4\t4.1\t6.0\t12.1\t\t\t35.4\t45.1\t\t62.5\t\t63\t\nTotal IgG\t694–1618\t545\t581\t560\t825\t860\t\t881\t1054\t\t1005\t\t960\t\nCD3+ ABS\t840–3060\t1060\t\t811\t\t643\t1299\t673\t664\t\t758\t\t797\t\nCD4+ ABS\t490–1740\t775\t\t562\t\t395\t844\t548\t547\t\t625\t\t679\t\nCD8+ ABS\t180–1170\t265\t\t223\t\t219\t372\t118\t125\t\t130\t\t154\t\nHelp/ Supp Ratio\t0.86–5.00\t2.93\t\t2.52\t\t1.81\t2.27\t4.64\t4.39\t\t4.83\t\t4.41\t\nNK Cells ABS\t70–760\t168\t\t107\t\t251\t297\t98\t95\t\t102\t\t92\t\nCD19+ ABS\t110–660\t162\t\t64\t\t101\t160\t56\t55\t\t51\t\t55\t\nALCc\n\t850–3900\t1380\t\t998\t\t996\t1763\t840\t819\t\t935\t\t952\t\nNK Cells, FUNC\t7–125\t3\t\t\t\t4\t10\t6\t14\t\t14\t\t8\t\na IVIG administered prior to obtaining blood specimen for this testing date.\n\nb Absolute lymphocyte count derived from Coulter Counter.\n\nc Absolute lymphocyte count derived from flow cytometry.\n\nRef (reference) range; WBC, white blood cells (109 cells/L); HCT, hematocrit (volume %); PLT, platelet count (109 cells/L); ANC, absolute neutrophil count (109 cells/L); ALC, absolute lymphocyte count (109 cells/L); IgG, immunoglobulin G (g/L); CD3+ ABS, absolute CD3+ cells (109 cells/L); CD4+ ABS, absolute CD4+ cells (109 cells/L); CD8+ ABS, absolute CD8+ cells (109 cells/L); Help/supp (helper/suppressor) ratio; NK cells ABS, absolute natural killer cells (109 cells/L); CD19+ ABS, absolute CD19+ cells (109 cells/L); NK cells, FUNC, functional natural killer cells (LU30). The LU 30 represents the number of lytic sets contained within a preparation of 10 million lymphocytes. One lytic set is defined as the number of lymphocytes required to lyse 30% of the target cells in the NK assay (Quest Diagnostics).\n\nJohn Wiley & Sons, LtdBecause immunological test results were abnormal, additional infectious disease testing was pursued. Given her daily work with cats, frequent exposure to fleas, and historical mite infestation, Bartonella spp. bacteremia remained a diagnostic consideration. EDTA‐anticoagulated blood specimens were screened for Bartonella using the Bartonella alpha‐proteobacteria growth medium (BAPGM) enrichment culture/PCR diagnostic platform. (Bartonella enrichment PCR™ or ePCR™ (Galaxy Diagnostics, Inc., Research Triangle Park, NC)) Serological analysis of Bartonella henselae and Bartonella quintana was performed using indirect fluorescent antibody (IFA) testing (Galaxy Diagnostics, Inc., Research Triangle Park, NC). Bartonella henselae DNA was amplified and sequenced from a 21‐day BAPGM enrichment blood culture. Serum was not reactive to B. henselae or B. quintana antigens at 1:16 or 1:32 screening dilutions. Genus PCR assays (Galaxy Diagnostics, Inc., Research Triangle Park, NC) for Anaplasma, Babesia, Ehrlichia, and Rickettsia spp. were negative.\n\nBased on these results, she was treated with clarithromycin, rifampin, and intravenous gamma globulin every 3 weeks. By week six of antibiotic/IVIG administration, her headaches slowly improved, and she returned to work. After 9 months of antibiotics, she was B. henselae and B. quintana seroreactive at titers of 1:128 and 1:64, respectively. Three BAPGM enrichment blood cultures collected on alternate days were PCR negative. During the subsequent 9‐month follow‐up, she has experienced no seizures. An MRI, repeated 14 months after the December 2014 MRI study, and 11 months after beginning antibiotics, was unchanged. Her previously abnormal lymphocyte subsets normalized, although NK function remained depressed at 10.\n\nPatient 2\nA 69‐year‐old previously healthy woman hiking in New York State during November 2013 became acutely ill 3 weeks after returning to California. She reported flu‐like symptoms including headaches, nausea, vertigo with disequilibrium, and fatigue but no fever or pain. She developed a bulls‐eye rash on her right infraclavicular fossa, consistent with erythema chronicum migrans. Lyme disease was diagnosed by another physician, who initiated doxycycline treatment for 2 weeks.\n\nShe continued to have symptoms and was examined by the primary author 10 days after starting doxycycline (Open Medicine Institute, Mountain View, CA). Laboratory testing results for Borrelia burgdorferi, Anaplasma phagocytophilum, Ehrlichia chaffeensis, Babesia, and Bartonella antibodies (Quest Diagnostics, Inc.) were negative. Doxycycline was continued for 4 weeks resulting in a transient decrease in symptoms. Headaches, vertigo, disequilibrium, and nausea recurred 2 weeks after completing antibiotics. Treatment with doxycycline and azithromycin initiated on January 2014 resulted in symptomatic improvement; however, antibiotic administration ceased after 2 weeks due to a photosensitivity reaction while visiting Florida. Symptoms returned after 2 weeks, only to resolve again with amoxicillin and azithromycin administration. Within 5 days, she developed severe diarrhea, antibiotics were stopped, and within 3 days, her headache and vertigo returned. A neurology workup in August 2014, including MRI, MRA, and cerebral angiogram, detected no abnormalities.\n\nIn October 2014, she was treated with minocycline and metronidazole for headaches, vertigo, and disequilibrium. After 5 weeks, there was symptomatic improvement that continued through 8 weeks, when antibiotics were stopped. Six weeks later, all symptoms recurred. In April 2015, immunological testing documented an IgG subclass 3 deficiency; low absolute CD3, CD8, and CD19 cell counts; and decreased NK cell function (Table 1). Repeat serological testing (Quest Diagnostics, Inc.) for tickborne diseases remained negative. Bartonella henselae DNA was amplified and sequenced from a 21‐day BAPGM enrichment blood culture (Bartonella enrichment PCR™ or ePCR™ (Galaxy Diagnostics, Inc., Research Triangle Park, NC)). Serum was not B. henselae or B. quintana seroreactive at 1:16 or 1:32 screening dilutions. Genus PCR assays (Galaxy Diagnostics, Inc., Research Triangle Park, NC) for Anaplasama, Babesia, Ehrlichia, and Rickettsia spp. were negative. After being treated with clarithromycin and rifampin for 5 months, headaches and vertigo were almost completely resolved and she remained B. henselae and B. quintana IFA seronegative, although lymphocyte subsets and NK function remained abnormal. She remained B. henselae or B. quintana seronegative, and three BAPGM enrichment blood cultures collected on alternate days were PCR negative.\n\nDiscussion\nTwo important clinical observations evolved out of the microbiological, immunological, and therapeutic findings associated with the medical management of these two patients. First, persistent or recurrent neurological symptoms of undetermined etiology in patients with historical vector exposures should prompt testing for bartonellosis. Historically, B. henselae infections in immunocompetent individuals have been associated with self‐limiting cat scratch disease, whereas recent research supports persistent and potentially relapsing bacteremia 1, 2, 3. As previously reported 2, 3, both of these B. henselae bacteremic patients experienced headaches and disequilibrium. Patient 1 also experienced seizures, episodic confusion, and aphasia, which resolved completely following antibiotic therapy, despite persistence of the MRI abnormalities 1. Secondly, immunological testing should be concurrently pursued to determine whether defective immune function accompanies neurological symptoms. Both patients had immunological abnormalities, including suppression of NK function, despite lacking a prior medical history indicative of immunodeficiency. The extent to which persistent B. henselae bacteremia may have induced immunocompromise or whether a chronic latent infection resulted in bacterial reactivation is unknown. It is important to note that after 9 months of treatment, the CD3, CD4, and CD19 deficiencies in Patient 1 resolved, while Patient 2 remained immunologically impaired after 5 months of therapy. There remains a substantial need for sequential electroencephalographic, MRI, immunological, and bacteriological patient data to guide physician decision making in patients with longstanding B. henselae bacteremia.\n\nUsing a previously validated diagnostic approach 3, 4, B. henselae bacteremia was confirmed in both patients by BAPGM enrichment blood culture, PCR amplification, and DNA sequence confirmation. Importantly, PCR did not amplify B. henselae DNA from patient's blood, serum, 8‐day, or 14‐day BAPGM enrichment blood cultures, supporting the need for prolonged bacterial incubation times to obtain PCR confirmation for some B. henselae bacteremic patients. Consistent with previous studies3, 5 in which a subset of patients with persistent bacteremia were not IFA seroreactive to a panel of Bartonella sp. antigens, neither patient was initially B. henselae or B. quintana IFA seroreactive, whereas antibody reactivity was documented after antibiotic treatment in Patient 1, potentially due to enhanced immunological recognition of antigenic epitopes. Based upon these patients and previously published studies 3, 5, enrichment blood culture and PCR should be used in conjunction with Bartonella sp. serological analysis when attempting to confirm bacteremic infection with a Bartonella sp.\n\nVector transmission of B. henselae was the suspected source of infection for both patients. The veterinarian had ongoing vector (flea, mite, and potentially ticks) and animal exposure, which are occupational risks for animal health workers 3, 5. The cat flea (Ctenocephalides felis) transmits B. henselae among cats that develop a relapsing bacteremia and remain persistently infected reservoir hosts for months to years 6. Although there is no evidence that cat‐associated mites (S. scabiei or N. cati) are vector competent for the transmission of Bartonella species, rat mite (Ornithonyssus bacoti) and pigeon mite (Dermanyssus spp.) transmissions of B. henselae and B. quintana, respectively, have been suspected 7, 8. Due to an acute‐onset illness and presumed tick attachment in a Lyme‐endemic region with the subsequent development of erythema chronicum migrans, Lyme disease was initially suspected in Patient 2. Rapid treatment with doxycycline may have prevented serodiagnostic confirmation of B. burgdorferi transmission, whereas testing for other tickborne pathogens was negative. Although tick transmission of B. henselae has not been proven, organism‐specific DNA has been PCR‐amplified and sequenced from Ixodes sp. ticks 9, vector competence for Bartonella transmission has been demonstrated in a rodent model 10, and French investigators have recently documented Bartonella spp. bacteremia in patients following tick exposures 11.\n\nHistorically, systemic bartonellosis has been reported in immunocompromised patients, such as those with HIV/AIDS and transplant recipients. Recently, infection with Bartonella spp. has been reported in healthy asymptomatic Brazilian blood donor candidates12 and in previously immunocompetent patients with chronic neurological or rheumatologic symptoms 2, 3, 5.\n\nBecause Bartonella spp. can infect erythrocytes, endothelial cells, and various macrophage‐type cells, including brain‐derived dendritic cells in vitro, the spectrum of neurological symptoms attributable to bartonellosis appear to be extremely diverse among patients 1, 2. Physicians should be aware of the rapidly increasing number of Bartonella spp., the large number of proven and suspected arthropod vectors, and the large number of reservoir hosts, all of which are collectively contributing to the enhanced recognition of neurobartonellosis as a medically important emerging infectious disease.\n\nAuthorship\nDK: principal investigator and physician of patients presented in this publication – analyzed clinical data and prepared the manuscript. AMK: provided medical consultation and received funding resources. RBM: provided medical consultation. NAC: involved in laboratory data collection and analysis and prepared the manuscript. EBB, MD: principal investigator – is involved in data analysis and manuscript preparation.\n\nConflict of Interest\nIn conjunction with Dr. Sushama Sontakke and North Carolina State University, Edward B. Breitschwerdt, DVM, holds U.S. Patent No. 7,115,385; Media and Methods for cultivation of microorganisms, which was issued on 3 October 2006. He is a co‐founder, shareholder, and chief scientific officer for Galaxy Diagnostics, a company that provides advanced diagnostic testing for the detection of Bartonella species infections. Robert B. Mozayeni, MD, is chief medical officer, and Natalie Cherry, PhD, is the laboratory supervisor and research analyst for Galaxy Diagnostics. The remaining authors have no competing interests.\n\nAcknowledgments\nWe would like to thank Rowena Moss for her efforts in patient testing and editorial assistance.\n==== Refs\nReferences\n1 \n\nBreitschwerdt , E. B. \n, \nS. \nSontakke \n, and \nS. \nHopkins \n. 2012 \nNeurological manifestations of bartonellosis in immunocompetent patients: a composite of reports from 2005‐2012 . J. Neuroparasitol. \n3 :1 –15 .\n2 \n\nBreitschwerdt , E. B. \n, \nR. G. \nMaggi \n, \nW. L. \nNicholson \n, \nN. A. \nCherry \n, and \nC. W. \nWoods \n. 2008 \n\nBartonella spp. bacteremia in patients with neurological and neuro‐cognitive dysfunction . J. Clin. Microbiol. \n46 :2856 –2861 .18632903 \n3 \n\nLantos , P. M. \n, \nR. G. \nMaggi \n, \nB. \nFerguson \n, \nJ. \nVarkey \n, \nL. P. \nPark \n, \nE. B. \nBreitschwerdt \n, et al. 2015 \nDetection of Bartonella species in the blood of veterinarians and veterinary technicians: a newly recognized occupational hazard . Vector. Borne. Zoonotic. Dis. \n14 :563 –570 .\n4 \n\nDuncan , A. W. \n, \nR. G. \nMaggi \n, and \nE. B. \nBreitschwerdt \n. 2007 \nA combined approach for the enhanced detection and isolation of Bartonella species in dog blood samples: pre‐enrichment culture followed by PCR and subculture onto agar plates . J. Microbiol. Meth. \n69 :273 –281 .\n5 \n\nMaggi , R. G. \n, \nP. E. \nMascarelli \n, \nE. L. \nPultorak \n, \nB. C. \nHegarty \n, \nJ. M. \nBradley \n, \nB. R. \nMozayeni \n, et al. 2011 \n\nBartonella spp. bacteremia in high‐risk immunocompetent patients . Diagn. Microbiol. Infect. Dis. \n71 :430 –437 .21996096 \n6 \n\nKordick , D. L. \n, \nK. H. \nWilson \n, \nD. J. \nSexton \n, \nT. L. \nHadfield \n, \nH. A. \nBerkhoff \n, \nE. B. \nBreitschwerdt \n. 1995 \nProlonged Bartonella bacteremia in cats associated with cat scratch disease patients . J. Clin. Microbiol. \n33 :3245 –3251 .8586710 \n7 \n\nBradley , J. M. \n, \nP. E. \nMascarelli \n, \nC. L. \nTrull \n, \nR. G. \nMaggi \n, and \nE. B. \nBreitschwerdt \n. 2014 \n\nBartonella henselae infections in an owner and two Papillon dogs exposed to tropical rat mites (Ornithonyssus bacoti) . Vector. Borne. Zoonotic. Dis. \n14 :703 –709 .25325313 \n8 \n\nMelter , O. \n, \nM. \nArvand \n, \nJ. \nVotýpka \n, and \nD. \nHulínská \n. 2012 \n\nBartonella quintana transmission from mite to family with high socioeconomic status . Emerg. Infect. Dis. \n18 :163 –165 .22257438 \n9 \n\nDietrich , F. \n, \nT. \nSchmidgen \n, \nR. G. \nMaggi \n, \nD. \nRichter \n, \nF.‐R. \nMatuschka \n, \nR. \nVonthein \n, et al. 2010 \nPrevalence of Bartonella henselae and Borrelia burgdorferi in Ixodes ricinus ticks in Europe . Appl. Environ. Microbiol. \n76 :1395 –1398 .20061459 \n10 \n\nReis , C. \n, \nM. \nCote \n, \nD. \nLe Rhun \n, \nB. \nLecuelle \n, \nM. L. \nLevin \n, \nM. \nVayssier‐Taussat \n, et al. 2011 \nVector competence of the tick Ixodes ricinus for transmission of Bartonella birtlesii\n . PLoS Negl. Trop Dis. \n5 :e1186 .21655306 \n11 \n\nVayssier‐Taussat , M. \n, \nS. \nMoutailler \n, \nF. \nFéménia \n, \nP. \nRaymond \n, \nO. \nCroce \n, \nB. \nLa Scala \n, et al. 2016 \nIdentification of novel zoonotic activity of Bartonella spp., France . Emerg. Infect. Dis. \n22 :457 –462 .26885624 \n12 \n\nPitassi , L. H. \n, \nP. P. \nde Paiva Diniz \n, \nD. G. \nScorpio \n, \nM. R. \nDrummond \n, \nB. G. \nLania \n, \nM. L. \nBarjas‐Castro \n, et al. 2015 \n\nBartonella spp. bacteremia in blood donors from Campinas, Brazil . PLoS Negl. Trop Dis. \n9 :e0003467 .25590435\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-0904",
"issue": "5(6)",
"journal": "Clinical case reports",
"keywords": "Bartonella; Infection; immune dysfunction; neurological symptoms; vectorborne",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "931-935",
"pmc": null,
"pmid": "28588842",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports",
"references": "20061459;25325313;17346836;25072986;18632903;22257438;21996096;8586710;25590435;21655306;26885624",
"title": "Neurological and immunological dysfunction in two patients with Bartonella henselae bacteremia.",
"title_normalized": "neurological and immunological dysfunction in two patients with bartonella henselae bacteremia"
} | [
{
"companynumb": "US-UCBSA-2017025921",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "3",
... |
{
"abstract": "Anticoagulant-related nephropathy (ARN), a significant but frequently undiagnosed problem in patients receiving anticoagulation, is found to be associated with increased renal morbidity and all-cause mortality. While ARN is mainly associated with warfarin use, recent case reports suggest that it may also occur in patients taking direct oral anticoagulants (DOAC). We report a patient who had a history of alcoholic liver cirrhosis and paroxysmal atrial fibrillation, and received dabigatran 110 mg twice daily for 1 year. He presented with gross hematuria and severe acute kidney injury with an international normalized ratio of 4.09. Dabigatran was stopped and he was put on temporary hemodialysis support. His renal function gradually improved when the hematuria subsided. Renal biopsy later confirmed the presence of red blood cell casts inside the renal tubules with features of IgA nephropathy. Finally, his renal function returned back to baseline level. As DOAC has been increasingly used nowadays for the treatment of various thromboembolic diatheses, regular monitoring of renal function is warranted, especially in patients with underlying glomerular diseases and coagulopathy such as chronic liver diseases.",
"affiliations": "Department of Microbiology, Queen Mary Hospital, Hong Kong, SAR, China.;Renal Unit, Department of Medicine, Queen Elizabeth Hospital, 30 Gascoigne Road, Kowloon, Hong Kong, SAR, China. simoncycheung@gmail.com.",
"authors": "Li|Xin|X|;Cheung|Chi Yuen|CY|0000-0001-9940-2568",
"chemical_list": "D000933:Antifibrinolytic Agents; D000991:Antithrombins; D014812:Vitamin K; D000069604:Dabigatran",
"country": "Japan",
"delete": false,
"doi": "10.1007/s13730-019-00378-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2192-4449",
"issue": "8(2)",
"journal": "CEN case reports",
"keywords": "Acute kidney injury; Dabigatran; Glomerulonephritis; Hemodialysis",
"medline_ta": "CEN Case Rep",
"mesh_terms": "D058186:Acute Kidney Injury; D061605:Administration, Intravenous; D000933:Antifibrinolytic Agents; D000991:Antithrombins; D000069604:Dabigatran; D006801:Humans; D007684:Kidney Tubules; D008103:Liver Cirrhosis; D008297:Male; D008875:Middle Aged; D009336:Necrosis; D012720:Severity of Illness Index; D016896:Treatment Outcome; D014812:Vitamin K",
"nlm_unique_id": "101636244",
"other_id": null,
"pages": "125-127",
"pmc": null,
"pmid": "30659506",
"pubdate": "2019-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19577348;4046327;17699387;21389969;30032039;26120444;26670286;12495289;8385283;28219912;28161838;26347498;22096039",
"title": "Dabigatran causing severe acute kidney injury in a patient with liver cirrhosis.",
"title_normalized": "dabigatran causing severe acute kidney injury in a patient with liver cirrhosis"
} | [
{
"companynumb": "CN-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2019-BI-003025",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "Sleep disordered breathing (SDB) which includes obstructive sleep apnoea (OSA) and upper airway resistance syndrome (UARS), has emerged as a risk factor for adverse maternal-foetal outcomes in pregnancy. Physiological changes of pregnancy predispose a woman 'at risk' towards developing SDB. The increasing incidence of OSA in pregnancy closely correlates with the population trends of obesity. Common screening tools validated in non-pregnant subjects including Epworth Sleepiness Scale (ESS) and Berlin Questionnaire (BQ) are poor predictors of SDB in pregnancy. Preeclampsia, gestational hypertension and gestational diabetes mellitus (GDM) are linked with SDB. Preeclampsia and OSA share common pathological associations. It is unclear if one predisposes the other. Foetal morbidity includes intrauterine growth restriction (IUGR), preterm delivery, low birth weight, neonatal intensive care unit (NICU) admission and Apgar score of less than seven at one minute. Continuous positive airway pressure (CPAP) is a well-documented treatment of SDB in pregnancy and has been shown to reverse some of the adverse events. It becomes imperative to diagnose and manage this condition as OSA causes substantial morbidity in the untreated pregnant patient and foetus. Three short clinical cases and a literature review on SDB on pregnancy are presented.",
"affiliations": "a Greenslopes Private Hospital , Brisbane , Australia.;b Department of Obstetric Medicine , Mater Health Services , Brisbane , Australia.;b Department of Obstetric Medicine , Mater Health Services , Brisbane , Australia.",
"authors": "Carnelio|Shanthi|S|;Morton|Adam|A|;McIntyre|H David|HD|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/01443615.2016.1229273",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0144-3615",
"issue": "37(2)",
"journal": "Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology",
"keywords": "Sleep disordered breathing; foetal morbidity; obstructive sleep apnoea; pregnancy",
"medline_ta": "J Obstet Gynaecol",
"mesh_terms": "D000328:Adult; D045422:Continuous Positive Airway Pressure; D016640:Diabetes, Gestational; D005260:Female; D005865:Gestational Age; D006801:Humans; D006973:Hypertension; D009765:Obesity; D017286:Polysomnography; D011225:Pre-Eclampsia; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D059285:Pregnancy, Twin; D012307:Risk Factors; D020181:Sleep Apnea, Obstructive; D011795:Surveys and Questionnaires",
"nlm_unique_id": "8309140",
"other_id": null,
"pages": "170-178",
"pmc": null,
"pmid": "27924661",
"pubdate": "2017-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Sleep disordered breathing in pregnancy: the maternal and fetal implications.",
"title_normalized": "sleep disordered breathing in pregnancy the maternal and fetal implications"
} | [
{
"companynumb": "AU-BAYER-2017-069222",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CALCIUM CARBONATE"
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"drugadditional": null,
... |
{
"abstract": "We report a Japanese boy with Graves' disease (GD) which developed during drug-free remission of juvenile dermatomyositis (JDM). He had been diagnosed with JDM at the age of 6 years by typical skin rashes, muscle weakness, elevated serum transaminase levels, and typical findings of both magnetic resonance imaging and muscle biopsy. Although anti-melanoma differentiation antigen 5 autoantibody was positive, there was no complication of interstitial lung disease. He showed good response to methylprednisolone pulse therapy followed by oral prednisolone in combination with weekly methotrexate (MTX) and achieved drug-free remission after 3.5 years of treatment. Nevertheless, serum levels of soluble interleukin-2 receptor (sIL-2R) gradually elevated to 3185 U/ml despite no signs of relapse or malignancy. Hyperactivity and attention deficit was also noted. One year and 3 months after the cessation of MTX, he presented with abdominal pain, tachycardia, and apparent goitre. Laboratory tests showed elevated free triiodothyronine, undetectable thyroid stimulating hormone (TSH), and positive anti-TSH receptor antibodies. 99mTc scintigraphy showed high levels of thyroid uptake. He was diagnosed with GD and treated with 15 mg/day of thiamazole. Although transient drug eruption was observed, his thyroid functions are currently well-controlled on 5 mg/day of thiamazole. In conclusion, to our knowledge, this is the first report in English literature describing complication of GD with JDM. Unexpected elevation of sIL-2R could be a clue to the diagnosis of GD during the follow-up of JDM.",
"affiliations": "Center for Pediatric Allergy and Rheumatology, KKR Sapporo Medical Center, Sapporo, Japan.;Center for Pediatric Allergy and Rheumatology, KKR Sapporo Medical Center, Sapporo, Japan.;Department of Pediatrics, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaidô, Japan.;Department of Pediatrics, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaidô, Japan.;Center for Pediatric Allergy and Rheumatology, KKR Sapporo Medical Center, Sapporo, Japan.;Center for Pediatric Allergy and Rheumatology, KKR Sapporo Medical Center, Sapporo, Japan.;Department of Pediatrics, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaidô, Japan.;Center for Pediatric Allergy and Rheumatology, KKR Sapporo Medical Center, Sapporo, Japan.;Department of Pediatrics, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaidô, Japan.",
"authors": "Kobayashi|Ichiro|I|0000-0003-4956-4010;Shimomura|Masaki|M|;Ueki|Masahiro|M|;Takezaki|Shunichiro|S|;Okura|Yuka|Y|;Nawate|Mitsuru|M|;Yamada|Masafumi|M|;Takahashi|Yutaka|Y|;Ariga|Tadashi|T|",
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"journal": "Modern rheumatology case reports",
"keywords": "Graves’ disease; Juvenile dermatomyositis; anti-melanoma differentiation antigen 5; soluble interleukin-2 receptor",
"medline_ta": "Mod Rheumatol Case Rep",
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"title": "Development of Graves' disease during drug-free remission of juvenile dermatomyositis.",
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"abstract": "Carbamazepine intoxication manifests as altered mental status ranging from drowsiness to a coma and/or cardiac abnormalities such as sinus tachycardia, prolongation of the QRS interval, ventricular tachycardia, and hypotension. The patient may be agitated, but central nervous system (CNS) depression and presentation with coma is more common and could be lethal. Serious CNS toxicity often requires hemoperfusion and/or hemodialysis (HD). Herein, we present a case of a comatose patient, who was treated with a combination of hemoperfusion and HD in series. Our approach to treat the patient with a combination of hemoperfusion and HD was based on evidence from the literature supporting that the hemoperfusion and HD in series might provide the best clearance of carbamazepine.",
"affiliations": "Department of Internal Medicine, Evangelismos General Hospital, Athens, Greece.;Department of Nephrology, Evangelismos General Hospital, Athens, Greece.;Department of Internal Medicine, Evangelismos General Hospital, Athens, Greece.;Department of Nephrology, Evangelismos General Hospital, Athens, Greece.;Department of Internal Medicine, Evangelismos General Hospital, Athens, Greece.;Department of Nephrology, Evangelismos General Hospital, Athens, Greece.",
"authors": "Vallianou|Natalia|N|;Giannopoulou|Myrto|M|;Trigkidis|Kyriakos|K|;Bei|Elefteria|E|;Margellou|Evangelia|E|;Apostolou|Theofanis|T|",
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"journal": "Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia",
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"medline_ta": "Saudi J Kidney Dis Transpl",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D002220:Carbamazepine; D003128:Coma; D003131:Combined Modality Therapy; D062787:Drug Overdose; D006464:Hemoperfusion; D006801:Humans; D008297:Male; D020127:Recovery of Function; D006435:Renal Dialysis; D013406:Suicide, Attempted; D016896:Treatment Outcome",
"nlm_unique_id": "9436968",
"other_id": null,
"pages": "906-908",
"pmc": null,
"pmid": "28748895",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A case of severe carbamazepine overdose treated successfully with combined hemoperfusion and hemodialysis technique.",
"title_normalized": "a case of severe carbamazepine overdose treated successfully with combined hemoperfusion and hemodialysis technique"
} | [
{
"companynumb": "GR-SUN PHARMACEUTICAL INDUSTRIES LTD-2019RR-215656",
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"abstract": "Hollow visceral myopathy (HVM) is described as impaired intestinal function and motility in the absence of mechanical obstruction. In this case report, we describe a unique case of an 18-year-old female who presented to the hospital with complaints of persistent nausea, vomiting, inability to tolerate oral feeds, and substantial weight loss for 2 months. After appropriate investigations, a diagnosis of gastroparesis was established. The patient was started on metoclopramide, which led to significant symptomatic improvement, and she was eventually discharged home. One month after discharge, she presented to the hospital with symptoms similar to her initial presentation. After further laboratory and radiological investigation, she was diagnosed with severe gastroparesis and chronic intestinal pseudo-obstruction. Over the next month, the patient was given an extensive trial of multiple prokinetic agents such as mirtazapine, ondansetron, pyridostigmine, octreotide, and promethazine, but she failed to show clinical improvement. Due to failure of medical therapy, a nasojejunal feeding tube was placed for enteral nutrition. However, the patient reported worsening of her symptoms despite slow feeding rates; hence, a decision was made to start the patient on total parenteral nutrition and transfer her to a larger tertiary center for higher level of care. At the tertiary hospital, the patient was continued on total parenteral nutrition and underwent extensive evaluation. Ultimately, she was diagnosed with HVM after a laparoscopic full-thickness intestinal biopsy showed histopathological evidence of the disease. She underwent isolated small intestine transplant, which led to significant improvement of her symptoms and was eventually discharged home. The patient continues to be symptom-free and follows up with Gastroenterology and Transplant Surgery regularly. This case report highlights a rare clinical condition, HVM, as a potential diagnosis in patients with clinical features of intestinal obstruction without mechanical obstruction.",
"affiliations": "Central Michigan University, Saginaw, MI, USA.;University of Louisville, Louisville, KY, USA.;Central Michigan University, Saginaw, MI, USA.;Samaritan Medical Center, Watertown, NY, USA.;Guthrie Robert Packer, Sayre, PA, USA.;Central Michigan University, Saginaw, MI, USA.",
"authors": "Dahiya|Dushyant Singh|DS|0000-0002-8544-9039;Batth|Arshdeep|A|0000-0002-7806-8545;Batth|Jaspreet|J|;Wani|Farah|F|;Singh|Jagmeet|J|;Kichloo|Asim|A|0000-0003-4788-8572",
"chemical_list": null,
"country": "United States",
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"doi": "10.1177/23247096211034303",
"fulltext": "\n==== Front\nJ Investig Med High Impact Case Rep\nJ Investig Med High Impact Case Rep\nHIC\nsphic\nJournal of Investigative Medicine High Impact Case Reports\n2324-7096\nSAGE Publications Sage CA: Los Angeles, CA\n\n34378443\n10.1177/23247096211034303\n10.1177_23247096211034303\nCase Report\nHollow Visceral Myopathy, a Rare Gastrointestinal Disorder: A Case Report and Short Review\nhttps://orcid.org/0000-0002-8544-9039\nDahiya Dushyant Singh MD 1\nhttps://orcid.org/0000-0002-7806-8545\nBatth Arshdeep MBBS 2\nBatth Jaspreet MD 1\nWani Farah MD 3\nSingh Jagmeet MD 4\nhttps://orcid.org/0000-0003-4788-8572\nKichloo Asim MD 13\n1 Central Michigan University, Saginaw, MI, USA\n2 University of Louisville, Louisville, KY, USA\n3 Samaritan Medical Center, Watertown, NY, USA\n4 Guthrie Robert Packer, Sayre, PA, USA\nAsim Kichloo, MD, Department of Internal Medicine, Central Michigan University, 1000 Houghton Avenue, Saginaw, MI 48602, USA. Email: kichlooasim@gmail.com\n11 8 2021\nJan-Dec 2021\n9 2324709621103430313 4 2021\n27 6 2021\n1 7 2021\n© 2021 American Federation for Medical Research\n2021\nAmerican Federation for Medical Research\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nHollow visceral myopathy (HVM) is described as impaired intestinal function and motility in the absence of mechanical obstruction. In this case report, we describe a unique case of an 18-year-old female who presented to the hospital with complaints of persistent nausea, vomiting, inability to tolerate oral feeds, and substantial weight loss for 2 months. After appropriate investigations, a diagnosis of gastroparesis was established. The patient was started on metoclopramide, which led to significant symptomatic improvement, and she was eventually discharged home. One month after discharge, she presented to the hospital with symptoms similar to her initial presentation. After further laboratory and radiological investigation, she was diagnosed with severe gastroparesis and chronic intestinal pseudo-obstruction. Over the next month, the patient was given an extensive trial of multiple prokinetic agents such as mirtazapine, ondansetron, pyridostigmine, octreotide, and promethazine, but she failed to show clinical improvement. Due to failure of medical therapy, a nasojejunal feeding tube was placed for enteral nutrition. However, the patient reported worsening of her symptoms despite slow feeding rates; hence, a decision was made to start the patient on total parenteral nutrition and transfer her to a larger tertiary center for higher level of care. At the tertiary hospital, the patient was continued on total parenteral nutrition and underwent extensive evaluation. Ultimately, she was diagnosed with HVM after a laparoscopic full-thickness intestinal biopsy showed histopathological evidence of the disease. She underwent isolated small intestine transplant, which led to significant improvement of her symptoms and was eventually discharged home. The patient continues to be symptom-free and follows up with Gastroenterology and Transplant Surgery regularly. This case report highlights a rare clinical condition, HVM, as a potential diagnosis in patients with clinical features of intestinal obstruction without mechanical obstruction.\n\nhollow visceral myopathy\nfamilial myopathy\nchronic intestinal pseudo-obstruction\nintestinal transplant\ngastroenterology\ncover-dateJanuary-December 2021\ntypesetterts1\n==== Body\nIntroduction\n\nVisceral myopathies (VMs) consist of a heterogeneous group of genetic disorders characterized by dysfunctional smooth muscle cells.1 It can be subdivided into different groups based on the area of smooth muscle involvement and clinical features. Enteric visceral myopathy (EVM), a subtype of VM, has predominantly gastrointestinal (GI) involvement with characteristic symptoms such as abdominal pain, distention, features of malabsorption, and, in some cases, even death.2 EVM shows significant variance in clinical presentation with severe cases often diagnosed in the prenatal or neonatal period while milder forms of the disease may remain undiagnosed until adulthood.3 Hollow VM (HVM), a milder form of EVM, is a rare and often underdiagnosed GI disorder with only a handful of cases described in current literature. It is characterized by the presence of impaired intestinal function or motility in the absence of an obvious mechanical occlusion.4 It may involve the smooth muscles of the whole or specific sections of the GI tract and occasionally the smooth muscles of the urinary tract.5 In the literature, patients with HVM usually have a chronic duration of symptoms coupled with nausea, vomiting, abdominal pain, and distention, such as that seen in our patient.6 Furthermore, to establish a diagnosis, mechanical obstruction should be ruled out via radiological investigations, and these patients often require histological examination of the bowel mucosa, both of which were performed for our patient.7 Our case report is unique as it not only describes a rare clinical condition but also discusses the diagnostic challenges associated with the disease entity due to varied clinical symptoms and its similarity with other more common GI disorders. Additionally, we also describe the management strategies for these patients. This case report is presented in accordance with the CARE reporting checklist.\n\nCase Presentation\n\nAn 18-year-old female with a past medical history of migraine headaches presented to the hospital with chief complaints of persistent nausea, vomiting, inability to tolerate oral feeds, and significant weight loss for the past 2 months. The patient reported that she vomited after every meal, and vomitus mainly consisted of undigested food particles without blood. The patient also had intermitted constipation; however, she had no diarrhea. She also observed substantial weight loss despite good appetite but was unable to quantify the weight loss. The patient did not take any medications for her migraine headaches and her last flare-up was about 1 year ago. She reported multiple outpatient visits for similar complaints in the last 2 months; however, on this visit with her primary care provider, she was referred to the hospital. On clinical evaluation, she had stable vital signs. Physical examination revealed dry mucous membranes and abdominal examination was positive for mild epigastric tenderness along with decreased bowel sounds. The patient was started on intravenous (IV) fluids. Laboratory investigations such as complete blood count and comprehensive metabolic panel were ordered, which revealed a low hemoglobin level of 10.2 g/dL, hematocrit 30.2%, serum sodium 132 mEq/L, and serum potassium 3.3 mEq/L. An abdominal X-ray did not reveal mechanical obstruction. Due to concerns for gastroparesis (GP) as the underlying etiology, a Gastric Emptying Study was ordered, which revealed markedly delayed gastric emptying time as the tracer was distributed in the stomach on initial views with activity not appearing in the duodenum until 45 minutes and emptying half time was not reached with 77% of initial gastric contents remaining at the end of the examination. Hence, a diagnosis of GP was established. The patient was started on metoclopramide, which led to improvement of her presenting symptoms, and she was eventually discharged home with recommendations to taper the doses of metoclopramide as needed.\n\nOne month after discharge, the patient presented to the hospital with similar complaints as her initial presentation despite metoclopramide therapy. Laboratory investigations were similar to initial hospitalization and revealed hemoglobin level of 10.7 g/dL, hematocrit 31.9%, serum sodium 133 mEq/L, and serum potassium 3.2 mEq/L. An abdominal X-ray was ordered, which revealed dilated bowel segments with high burden of stool in the colon without obvious mechanical obstruction. A diagnosis of severe GP and chronic intestinal pseudo-obstruction (CIPO) was established. Over the next month, the patient was given an extensive trial of numerous prokinetic agents such as mirtazapine, ondansetron, pyridostigmine, octreotide, and promethazine, but she failed to show clinical improvement. With failure of medical therapy, a nasojejunal feeding tube was placed for nutrition; however, the patient noted worsening nausea despite the slow feeding rate of 10 mL/h. Hence, after detailed discussions with the patient, a decision was made to start her on total parenteral nutrition (TPN) after which she was transferred to a tertiary center for higher level of care. At the tertiary care center, she was continued on TPN and underwent extensive evaluation. Laboratory investigations were within normal limits except mild elevation of the liver enzymes. Additionally, antinuclear antibody, extractable nuclear antigens panel, paraneoplastic antibody panel, and acetylcholine receptor binding antibodies were found to be negative, thereby ruling out an autoimmune etiology. A right upper quadrant ultrasound revealed the presence of gallbladder sludge and normal liver architecture. An esophagogastroduodenoscopy (EGD) and colonoscopy were found to be negative. A small bowel follow-through ruled out mechanical obstruction. Magnetic resonance enterography and computed tomography angiography of the abdomen were noted to be unremarkable. Furthermore, a deep rectal biopsy was performed, which was negative for amyloidosis. However, antroduodenal manometry, a diagnostic tool for GI motility disorders, showed paucity of contractile activity with very low amplitudes highly suggestive of a myopathic etiology. This was followed up with a laparoscopic full-thickness intestinal biopsy, which revealed decreased actin staining in the circular muscles of the muscularis propria of small intestine consistent with a diagnosis of HVM. During the course of the hospital stay, the patient developed recurrent bacteremia, the source of which was identified to be the central venous catheter used for TPN. She was treated with appropriate antibiotics, which led to resolution of the bacteremia. Eventually, she underwent isolated small intestine transplant and was started on mycophenolate 500 mg daily, everolimus 5 mg daily, and prednisone 10 mg daily. This led to eventual resolution of her presenting symptoms, and she was discharged home. The patient continues to be asymptomatic and follows up with Gastroenterology and Transplant Surgery regularly.\n\nDiscussion\n\nVM may be classified as inherited, primary idiopathic, or secondary to other etiologies (Table 1).8 Intestinal involvement may range from malrotations, microcolon (neonates), and CIPO (all ages) to a more severe form, namely, megacystis-microcolon-intestinal hypoperistalsis syndrome. The pathogenic mechanism of VM includes missense mutations of genes such as ACTG2 and MYH11 leading to the synthesis of abnormal proteins, which are hypothesized to affect the polymerization of actin filaments thereby affecting smooth muscle contraction.9,10\n\nTable 1. Classification of Visceral Myopathy.\n\nInherited visceral myopathy\tPrimary idiopathic visceral myopathy\tVisceral myopathy secondary to other disorders\t\nFamilial visceral myopathy (eg, hollow visceral myopathy)\tNonfamilial visceral myopathy\tScleroderma\t\n\t\tSystemic lupus erythematosus\t\n\t\tAmyloidosis\t\n\t\tEhler-Danlos syndrome\t\n\t\tStroke\t\n\t\tEncephalitis\t\n\nHVM, a milder form of VM, is a pathological condition involving the smooth muscles of the GI tract resulting in impaired intestinal function and motility in the absence of a mechanical obstruction.4 It is a rare cause of CIPO, which results from failure of propulsive peristalsis secondary to myogenic-mediated disturbances of the GI tract.11 The affected smooth muscles undergo progressive degeneration and fibrous replacement resulting in the loss of GI motility.12\n\nIn patients with HVM, there is significant variance in the involvement of the GI tract, which may either be diffuse or limited to specific focal segments of the bowel.12 This leads of a wide spectrum of clinical features. These patients may be completely asymptomatic or may present to the emergency department with symptoms of acute intestinal pseudo-obstruction (Ogilvie syndrome), while others, such as that seen in our case, may have symptoms of CIPO. Additionally, a rare case of intestinal perforation secondary to VM has also been reported.6 As per current literature, the predominant symptoms include nausea, vomiting, chronic constipation, abdominal pain, abdominal distension, and features of malnutrition. A few cases were also reported to present with diarrhea and steatorrhea secondary to small intestinal bacterial overgrowth due to intestinal stasis.13 Furthermore, extraintestinal manifestations reported in literature include ophthalmoplegia, megacystis, dementia, and seizures.14,15 On examination, these patients may have abdominal distention and abdominal tenderness of varying degree, such as that seen in our patient.\n\nEstablishing a diagnosis of HVM is challenging and it is often delayed due to significant overlap in the clinical features with other more common GI disorders. In these patients, mechanical obstruction must be ruled out, and the diagnosis is usually established via histological examination of the layers of the intestinal mucosa.9 An abdominal X-ray is usually the first investigation and may reveal bowel distension and air fluid levels without signs of mechanical obstruction. In our case, the abdominal X-ray showed dilated bowel loops with evidence of high stool burden in the colon without obvious mechanical obstruction. An EGD may be performed to not only rule out obstruction but to also obtain duodenal biopsies to help rule out celiac disease or eosinophilic gastroenteropathy. In our case, EGD and colonoscopy were both negative. Furthermore, a small bowel follow-through was also performed to rule out distal intestinal obstruction. Other advanced imaging techniques such as magnetic resonance enterography allows simultaneous internal and external views of the gut wall to investigate possible causes of gut compression, while computed tomography angiography may be used to diagnose vascular abnormalities. When a neuromuscular motility disorder is suspected, intestinal manometry is an important and often diagnostic test. On manometry, uncoordinated contractions are seen in patients with neuropathic disorders, while those with myopathies have low amplitude coordinated contractions.16 Moreover, along with imaging studies, these patients need extensive laboratory investigations to rule out secondary causes of CIPO such as diabetes mellitus (HbA1C), celiac disease (anti-tissue transglutaminase and antigliadin antibodies), connective tissue, and skeletal muscle disorders (antinuclear antibody, anti-double strand DNA antibody, anti-Scl-70 antibody, creatinine kinase, and aldolase). Additionally, thyroid-stimulating hormone for hypothyroidism, urine catecholamines for pheochromocytoma, and enteric neuronal antibodies (anti-hu antibodies) in patients with suspected paraneoplastic antibodies should also be investigated. The gold standard test to establish a diagnosis of HVM is the full-thickness intestinal biopsy, which can be done via a laparoscopic or endoscopic approach.17 On histopathological analysis, there is decreased muscle actin stating, vacuolar degeneration of smooth muscle, or fibrous replacement of the smooth muscle in the muscularis propria.9 Additionally, it may also rule out other disorders such as amyloidosis and systemic sclerosis.\n\nThe treatment for HVM, like the diagnosis, is often challenging and involves a multidisciplinary approach. The focus of management is symptomatic improvement, improvement of the nutritional status, and avoiding complications related to nutrition. For symptomatic improvement, patients are encouraged to have small, frequent meals with low fat and fiber content. Pro-kinetic agents, which increase intestinal transit times such as metoclopramide, erythromycin, domperidone, somatostatin analogues (octreotide), cholinesterase inhibitors (neostigmine and pyridostigmine), and serotoninergic agents (prucalopride), may also be used.2,18 However, no current evidence exists which supports their use.18 Gastric electrical stimulation may be considered a therapeutic option in patients with intractable nausea and vomiting. Additionally, these patients may require IV fluids and electrolyte replacement along with gastric and colonic decompression with nasogastric or rectal tubes.6 From a nutritional perspective, enteral feeding may be initiated in patients with persistent symptoms and intolerance to oral feeds. In severe cases, TPN may be required; however, TPN is associated with numerous complications such as catheter-related sepsis. Our patient developed recurrent bacteremia secondary to the central venous catheter used for TPN. She was treated with appropriate antibiotics, which led to resolution of her bacteremia. As per literature, in patients with severe complications of TPN such as ≥3 catheter-related sepsis, intestinal transplant (isolated or multivisceral) is the treatment of choice.19 Hence, our patient underwent an isolated small intestine transplant which included proximal segment end-to-side anastomosis of the proximal donor intestine to the recipient jejunum, distal segment end-to-side anastomosis of the donor bowel to the recipient sigmoid colon, and creation of an ileostomy from a cadaveric donor. She was started on a combination of mycophenolate, everolimus, and prednisone after the transplant, which led to marked clinical improvement.\n\nConclusion\n\nHVM is a rare GI disorder and may often be underdiagnosed due to an overlap of symptoms with other more common GI disorders. It should be considered as a differential diagnosis in patients presenting with clinical features of intestinal obstruction without radiological evidence. The first imaging investigation of choice for these patients is an abdominal X-ray. Intestinal manometry, which demonstrates low-amplitude coordinated contractions in myopathies, may also be useful. The gold standard diagnostic test for HVM is a full-thickness intestinal biopsy, either laparoscopic or endoscopic, with histopathological analysis. The management for these patients is focused on symptomatic improvement with dietary modifications and use of prokinetic agents, improvement in nutritional status via enteral nutrition and TPN in severe cases if necessary, and the avoidance of complications. Patients who develop complications on TPN benefit from intestinal transplant.\n\nAuthor Contributions: Conception and design: Dushyant Singh Dahiya\n\nElectronic medical record chart review: Dushyant Singh Dahiya and Jaspreet Batth\n\nReview of literature and data collection: All authors\n\nDrafting the manuscript: All authors\n\nRevision of key components of manuscript: Jagmeet Singh and Asim Kichloo\n\nFinal approval of manuscript: All authors\n\nAgreement to be accountable for all aspects of the work: All authors\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nEthics Approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nInformed Consent: Verbal informed consent was obtained from the patient(s) for their anonymized information to be published.\n\nORCID iDs: Dushyant Singh Dahiya https://orcid.org/0000-0002-8544-9039\n\nArshdeep Batth https://orcid.org/0000-0002-7806-8545\n\nAsim Kichloo https://orcid.org/0000-0003-4788-8572\n==== Refs\nReferences\n\n1 Klar J Raykova D Gustafson E , et al . Phenotypic expansion of visceral myopathy associated with ACTG2 tandem base substitution. Eur J Hum Genet. 2015;23 :1679-1683.25782675\n2 Antonucci A Fronzoni L Cogliandro L , et al . Chronic intestinal pseudo-obstruction. World J Gastroenterol. 2008;14 :2953-2961.18494042\n3 Gosemann JH Puri P. Megacystis microcolon intestinal hypoperistalsis syndrome: systematic review of outcome. Pediatr Surg Int. 2011;27 :1041-1046.21792650\n4 Lehtonen HJ Sipponen T Tojkander S , et al . Segregation of a missense variant in enteric smooth muscle actin γ-2 with autosomal dominant familial visceral myopathy. Gastroenterology. 2012;143 :e1482-e1491.e3.\n5 Ghavamian R Wilcox DT Duffy PG Milla PJ. The urological manifestations of hollow visceral myopathy in children. J Urol. 1997;158 (3 pt 2 ):1286-1290.9258196\n6 Burcharth J Olsen C Rosenberg J. Acute abdomen and perforated bowel with a rare pathology: nonfamilial visceral myopathy. Case Rep Surg. 2011;2011 :645349.22606588\n7 Munoz-Yague MT Marin JC Colina F , et al . Chronic primary intestinal pseudo-obstruction from visceral myopathy [in Spanish]. Rev Esp Enferm Dig. 2006;98 :292-302.16792457\n8 Angkathunyakul N Treepongkaruna S Molagool S Ruangwattanapaisarn N. Abnormal layering of muscularis propria as a cause of chronic intestinal pseudo-obstruction: a case report and literature review. World J Gastroenterol. 2015;21 :7059-7064.26078585\n9 Moreno CA Metze K Lomazi EA , et al . Visceral myopathy: clinical and molecular survey of a cohort of seven new patients and state of the art of overlapping phenotypes. Am J Med Genet A. 2016;170 :2965-2974.27481187\n10 Collins RRJ Barth B Megison S , et al . ACTG2-associated visceral myopathy with chronic intestinal pseudoobstruction, intestinal malrotation, hypertrophic pyloric stenosis, choledochal cyst, and a novel missense mutation. Int J Surg Pathol. 2019;27 :77-83.30019982\n11 Moore SW Schneider JW Kaschula RDC . Non-familial visceral myopathy: clinical and pathologic features of degenerative leiomyopathy. Pediatr Surg Int. 2002;18 :6-12.11793055\n12 Kharbuja P Thakur R Suo J. Visceral myopathy presenting as acute appendicitis and Ogilvie syndrome. Case Rep Surg. 2013;2013 :906457.23738185\n13 Schuffler MD Rohrmann CA Chaffee RG Brand DL Delaney JH Young JH. Chronic intestinal pseudo-obstruction. A report of 27 cases and review of the literature. Medicine (Baltimore). 1981;60 :173-196.6894476\n14 Anuras S Mitros FA Nowak TV , et al . A familial visceral myopathy with external ophthalmoplegia and autosomal recessive transmission. Gastroenterology.1983;84 :346-353.6687359\n15 Rode H Brown R Numanoglu A . Degenerative hollow visceral myopathy mimicking Hirschsprung’s disease. In: Holschneider A Puri P , eds. Hirschsprung’s Disease and Allied Disorders. Springer; 2008 :275-286.\n16 Bassotti G Bologna S Ottaviani L Russo M Dore MP. Intestinal manometry: who needs it? Gastroenterol Hepatol Bed Bench. 2015;8 :246-252.26468344\n17 Reddy SB Hamerski CM Gavankar SS , et al . Sporadic visceral myopathy: full thickness rectal biopsy to clinch the diagnosis. J Gastroenterol Hepatol Res. 2012;1 :161-164.\n18 Zhu CZ Zhao HW Lin HW Wang F Li YX. Latest developments in chronic intestinal pseudo-obstruction. World J Clin Cases. 2020;8 :5852-5865.33344584\n19 Gotthardt DN Gauss A Zech U , et al . Indications for intestinal transplantation: recognizing the scope and limits of total parenteral nutrition. Clin Transplant. 2013;27 :49-55.23909502\n\n",
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"keywords": "chronic intestinal pseudo-obstruction; familial myopathy; gastroenterology; hollow visceral myopathy; intestinal transplant",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": "D000293:Adolescent; D001706:Biopsy; D002908:Chronic Disease; D005260:Female; D006801:Humans; D007418:Intestinal Pseudo-Obstruction; D035583:Rare Diseases",
"nlm_unique_id": "101624758",
"other_id": null,
"pages": "23247096211034303",
"pmc": null,
"pmid": "34378443",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "11793055;22960657;6894476;30019982;25782675;23738185;27481187;18494042;26078585;23909502;26468344;6687359;22606588;21792650;9258196;16792457;33344584",
"title": "Hollow Visceral Myopathy, a Rare Gastrointestinal Disorder: A Case Report and Short Review.",
"title_normalized": "hollow visceral myopathy a rare gastrointestinal disorder a case report and short review"
} | [
{
"companynumb": "US-MYLANLABS-2021M1074596",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MIRTAZAPINE"
},
"drugadditional": null,
... |
{
"abstract": "Ibrutinib is an oral inhibitor of Bruton tyrosine kinase approved for the treatment of chronic lymphocytic leukaemia, mantle cell lymphoma and refractory Waldenstrom's disease. It increases progression-free survival, overall survival, response rate. The most frequent adverse reactions, are increased risk in of bleeding and atrial fibrillation, but several reports of more dangerous rhythm disturbances have been recently reported in literature. A case of a patient with refractory Waldenstrom's disease, who developed ventricular fibrillation while taking ibrutinib, is reported, along with a concise literature review.",
"affiliations": "Hematology Unit, Ospedale S.Giuseppe, Empoli, Italy.;Hematology Unit, Ospedale S.Giuseppe, Empoli, Italy.;Cardiology Unit, Ospedale S.Giuseppe, Empoli, Italy.;Hematology Unit, Ospedale S.Giuseppe, Empoli, Italy.;Oncology Unit, Ospedale S.Giuseppe, Empoli, Italy.",
"authors": "Bernardeschi|Paolo|P|https://orcid.org/0000-0002-3018-4280;Pirrotta|Maria Teresa|MT|;Del Rosso|Attilio|A|;Fontanelli|Giulia|G|;Milandri|Carlo|C|",
"chemical_list": "D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D000225:Adenine",
"country": "England",
"delete": false,
"doi": "10.1111/ejh.13290",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-4441",
"issue": "103(4)",
"journal": "European journal of haematology",
"keywords": null,
"medline_ta": "Eur J Haematol",
"mesh_terms": "D000225:Adenine; D016757:Death, Sudden, Cardiac; D004562:Electrocardiography; D006801:Humans; D008297:Male; D008875:Middle Aged; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D014693:Ventricular Fibrillation; D008258:Waldenstrom Macroglobulinemia",
"nlm_unique_id": "8703985",
"other_id": null,
"pages": "442-443",
"pmc": null,
"pmid": "31287200",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Sudden ventricular fibrillation and death during ibrutinib therapy-A case report.",
"title_normalized": "sudden ventricular fibrillation and death during ibrutinib therapy a case report"
} | [
{
"companynumb": "IT-JNJFOC-20190817775",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "1",
"d... |
{
"abstract": "OBJECTIVE\nThe aim of this systematic review is to identify case reports of citalopram use resulting in QTc prolongation, torsades de pointes, or both, in the medical literature.\n\n\nMETHODS\nA literature search was conducted of PubMed, MEDLINE, EMBASE, Scopus, and PsycINFO databases for case reports published in any language that reported the relationship between citalopram use and the development of QTc prolongation or torsades de pointes or both. In addition, bibliographic databases of published articles were searched for additional cases.\n\n\nRESULTS\nA total of 18 case reports of citalopram use resulting in QTc prolongation were identified. Of these, 10 cases were also associated with the development of torsades de pointes. A total of 14 cases occurred in women and 4 in men. There were 7 cases involving an overdose with citalopram. Of the 18 cases, 12 occurred in individuals who were aged <60 years and 6 were in individuals aged >60 years. In 8 of the 18 cases, the individuals were taking a dose between 20 and 60mg of citalopram in a day. Hypertension was the most common comorbid medical condition, as seen in 5 of the cases.\n\n\nCONCLUSIONS\nQTc prolongation or torsades de pointes are infrequently reported adverse effects associated with citalopram use.",
"affiliations": "Department of Psychiatry, Regional Academic Health Center, University of Texas Health Science Center at San Antonio, Harlingen, TX (RRT, MM, AK, JM). Electronic address: rajesh.tampi@gmail.com.;Department of Internal Medicine, Valley Baptist Hospital, University of Texas Health Science Center at San Antonio, Harlingen, TX (MB).;Mario E. Ramirez, M.D., Library, Regional Academic Health Center, University of Texas Health Science Center at San Antonio, Harlingen, TX (KVC).;Behavioral Health Services, Saint Francis Hospital and Medical Center, Hartford, CT (DJT).;Department of Psychiatry, Regional Academic Health Center, University of Texas Health Science Center at San Antonio, Harlingen, TX (RRT, MM, AK, JM).;Department of Psychiatry, Regional Academic Health Center, University of Texas Health Science Center at San Antonio, Harlingen, TX (RRT, MM, AK, JM).;Department of Psychiatry, Regional Academic Health Center, University of Texas Health Science Center at San Antonio, Harlingen, TX (RRT, MM, AK, JM).",
"authors": "Tampi|Rajesh R|RR|;Balderas|Michael|M|;Carter|Kathleen V|KV|;Tampi|Deena J|DJ|;Moca|Marian|M|;Knudsen|Amy|A|;May|Jacquelyn|J|",
"chemical_list": "D017367:Serotonin Uptake Inhibitors; D015283:Citalopram",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0033-3182",
"issue": "56(1)",
"journal": "Psychosomatics",
"keywords": null,
"medline_ta": "Psychosomatics",
"mesh_terms": "D015283:Citalopram; D004562:Electrocardiography; D006801:Humans; D008133:Long QT Syndrome; D017367:Serotonin Uptake Inhibitors; D016171:Torsades de Pointes",
"nlm_unique_id": "0376506",
"other_id": null,
"pages": "36-43",
"pmc": null,
"pmid": "25619672",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D016454:Review; D000078182:Systematic Review",
"references": null,
"title": "Citalopram, QTc Prolongation, and Torsades de Pointes.",
"title_normalized": "citalopram qtc prolongation and torsades de pointes"
} | [
{
"companynumb": "PHHY2017GB190059",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAMOTRIGINE"
},
"drugadditional": "3",
"drug... |
{
"abstract": "BACKGROUND\nLomentospora prolificans (formerly S prolificans) is a saprophyte fungi that causes opportunistic infections in solid organ transplant (SOT) recipients. Resulting disseminated infections are difficult to treat and have a high mortality. Indications for antifungal prophylaxis after heart transplantation (HT) include CMV disease, reoperation, renal replacement therapy, extracorporeal membrane oxygenation (ECMO), and high environmental exposure to Aspergillus spores. However, the risk of breakthrough infections, such as Lomentosporiosis, remains a cause of concern.\n\n\nMETHODS\nWe report the clinical findings, microbiology, treatment and outcome of a disseminated Lomentosporiosis in a heart transplant recipient with ECMO and antifungal prophylaxis.\n\n\nRESULTS\nA 25-year-old male with complex grown-up congenital heart disease (GUCHD) was admitted for HT. He presented severe post-surgical complications including acute kidney injury and right heart and respiratory failure requiring venoarterial-ECMO, continuous renal replacement therapy (CCRT) and later on (+14) a ventricular assist device (VAD). Ganciclovir, cotrimoxazole, and antifungal prophylaxis with anidulafungin at standard doses had been started on day + 3 post HT. The patient presented seizures (+4), pancytopenia with mild neutropenia (days + 6 to + 11), influenza B (+7), and bacteremic Pseudomonas aeruginosa ventilator associated pneumonia (VAP) (+10). On days + 14 to + 16 Lomentospora prolificans was recovered from blood cultures, broncho aspirate, catheter tip, and skin biopsy. Despite treatment with L-AMB, voriconazole and terbinafine the patients died on day 17 after HT. Necropsy revealed disseminated infection with fungal invasion in central nervous system, heart, lung, cutaneous, and subcutaneous tissue. Broth microdilution tests demonstrated resistance to all antifungals.\n\n\nCONCLUSIONS\nLomentosporiosis is a rare complication that may emerge as a breakthrough invasive fungal infection in heart transplant recipients on ECMO despite antifungal prophylaxis.",
"affiliations": "Clinical Microbiology and Infectious Diseases Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.;Clinical Microbiology and Infectious Diseases Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.;Clinical Microbiology and Infectious Diseases Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.;Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.;Clinical Microbiology and Infectious Diseases Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.;Clinical Microbiology and Infectious Diseases Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.;Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.;Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.;Clinical Microbiology and Infectious Diseases Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.;Clinical Microbiology and Infectious Diseases Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.;Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.;Clinical Microbiology and Infectious Diseases Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.;Clinical Microbiology and Infectious Diseases Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.",
"authors": "Valerio|Maricela|M|https://orcid.org/0000-0001-6394-2861;Vásquez|Víctor|V|;Álvarez-Uria|Ana|A|;Zatarain-Nicolás|Eduardo|E|;Pavone|Paolo|P|;Martínez-Jiménez|María Del Carmen|MDC|;Barrio-Gutiérrez|José María|JM|;Cuerpo|Gregorio|G|;Guinea-Ortega|Jesús|J|;Vena|Antonio|A|;Peligros-Gómez|María Isabel|MI|;Bouza|Emilio|E|;Muñoz|Patricia|P|https://orcid.org/0000-0001-5706-5583",
"chemical_list": "D000935:Antifungal Agents; D065819:Voriconazole",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13574",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "23(4)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "\nLomentospora prolificans\n; disseminated fungal infection; heart transplant; solid organ transplantation",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D000935:Antifungal Agents; D016027:Heart Transplantation; D006801:Humans; D000072742:Invasive Fungal Infections; D008297:Male; D021681:Scedosporium; D065819:Voriconazole",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13574",
"pmc": null,
"pmid": "33527651",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports; D016454:Review",
"references": null,
"title": "Disseminated lomentosporiosis in a heart transplant recipient: Case report and review of the literature.",
"title_normalized": "disseminated lomentosporiosis in a heart transplant recipient case report and review of the literature"
} | [
{
"companynumb": "ES-STRIDES ARCOLAB LIMITED-2021SP003687",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugaddition... |
{
"abstract": "BACKGROUND\nOpioids are good painkillers, but many patients treated with opioids as painkillers developed a secondary addiction. These patients need to stop misusing opioids, but the mild-to-severe clinical symptoms associated with opioid withdrawal risk increasing their existing pain. In such cases, ketamine, which is used by anaesthetists and pain physicians to reduce opioid medication, may be an effective agent for managing opioid withdrawal.\n\n\nMETHODS\nWe describe the case of a woman who developed a severe secondary addiction to opioids in the context of lombo-sciatic pain. She presented a severe opioid addiction, and her physicians refused to prescribe such high doses of opioid treatment (oxycontin® extended-release 120 mg daily, oxycodone 60 mg daily, and acetaminophen/codeine 300 mg/25 mg 6 times per day). To assist her with her opioid withdrawal which risked increasing her existing pain, she received 1 mg/kg ketamine oral solution, and two days after ketamine initiation her opioid treatment was gradually reduced. The patient dramatically reduced the dosage of opioid painkillers and ketamine was withdrawn without any withdrawal symptoms.\n\n\nCONCLUSIONS\nKetamine displays many interesting qualities for dealing with all symptoms relating to opioid withdrawal. Accordingly, it could be used instead of many psychotropic treatments, which interact with each other, to help with opioid withdrawal. However, the literature describes addiction to ketamine. All in all, although potentially addictive, ketamine could be a good candidate for the pharmacological management of opioid withdrawal.",
"affiliations": "Department of Psychiatry and Addictology, Fédération de Médecine Translationnelle de Strasbourg (FMTS), University Hospital of Strasbourg, Strasbourg, France. laurence.lalanne@chru-strasbourg.fr.;Department of Psychiatry and Addictology, Fédération de Médecine Translationnelle de Strasbourg (FMTS), University Hospital of Strasbourg, Strasbourg, France.;Department of Psychiatry and Addictology, Fédération de Médecine Translationnelle de Strasbourg (FMTS), University Hospital of Strasbourg, Strasbourg, France.;Department of Psychiatry and Addictology, Fédération de Médecine Translationnelle de Strasbourg (FMTS), University Hospital of Strasbourg, Strasbourg, France.;Centre d'Evaluation et de Traitement de la Douleur, University Hospital of Strasbourg, Strasbourg, France.",
"authors": "Lalanne|Laurence|L|;Nicot|Chloe|C|;Lang|Jean-Philippe|JP|;Bertschy|Gilles|G|;Salvat|Eric|E|",
"chemical_list": "D000700:Analgesics; D007649:Ketamine",
"country": "England",
"delete": false,
"doi": "10.1186/s12888-016-1112-2",
"fulltext": "\n==== Front\nBMC PsychiatryBMC PsychiatryBMC Psychiatry1471-244XBioMed Central London 27832755111210.1186/s12888-016-1112-2Case ReportExperience of the use of Ketamine to manage opioid withdrawal in an addicted woman: a case report Lalanne Laurence + 0033 388116648laurence.lalanne@chru-strasbourg.fr 12Nicot Chloe chloe.nicot@chru-strasbourg.fr 1Lang Jean-Philippe jean-philippe.lang@chru-strasbourg.fr 1Bertschy Gilles gilles.bertschy@chru-strasbourg.fr 12Salvat Eric eric.salvat@chru-strasbourg.fr 341 Department of Psychiatry and Addictology, Fédération de Médecine Translationnelle de Strasbourg (FMTS), University Hospital of Strasbourg, Strasbourg, France 2 INSERM 1114, Fédération de Médecine Translationnelle de Strasbourg (FTMS), University Hospital of Strasbourg, Strasbourg, France 3 Centre d’Evaluation et de Traitement de la Douleur, University Hospital of Strasbourg, Strasbourg, France 4 Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Strasbourg, France 10 11 2016 10 11 2016 2016 16 39511 2 2016 4 11 2016 © The Author(s). 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nOpioids are good painkillers, but many patients treated with opioids as painkillers developed a secondary addiction. These patients need to stop misusing opioids, but the mild-to-severe clinical symptoms associated with opioid withdrawal risk increasing their existing pain. In such cases, ketamine, which is used by anaesthetists and pain physicians to reduce opioid medication, may be an effective agent for managing opioid withdrawal.\n\nCase presentation\nWe describe the case of a woman who developed a severe secondary addiction to opioids in the context of lombo-sciatic pain. She presented a severe opioid addiction, and her physicians refused to prescribe such high doses of opioid treatment (oxycontin® extended-release 120 mg daily, oxycodone 60 mg daily, and acetaminophen/codeine 300 mg/25 mg 6 times per day). To assist her with her opioid withdrawal which risked increasing her existing pain, she received 1 mg/kg ketamine oral solution, and two days after ketamine initiation her opioid treatment was gradually reduced. The patient dramatically reduced the dosage of opioid painkillers and ketamine was withdrawn without any withdrawal symptoms.\n\nConclusion\nKetamine displays many interesting qualities for dealing with all symptoms relating to opioid withdrawal. Accordingly, it could be used instead of many psychotropic treatments, which interact with each other, to help with opioid withdrawal. However, the literature describes addiction to ketamine. All in all, although potentially addictive, ketamine could be a good candidate for the pharmacological management of opioid withdrawal.\n\nKeywords\nKetamineOpioid addictionOpioid withdrawalPainkillersissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nOpioid addiction affects 15.5 million people in the world, including 11.1 million heroin users (WHO) (United Nations Office on Drugs and Crime, 2007) [1]. Although in the USA, opioid prescriptions rose between 2002 and 2010 but have been decreasing since 2013, owing to physicians’ awareness of a rise in the opioid-related death rate and the increase in opioid medications [2]. Consequently, these patients need to end their misuse of opioids, but the mild to severe clinical symptoms associated with opioid withdrawal risk increasing the pain already present. Such symptoms are dysphoria, restlessness, rhinorrhea, lacrimation, myalgias, arthralgias, nausea, vomiting, abdominal cramps, diarrhea, yawning, increased flatulence and piloerection. Accordingly, in cases of severe somatic or psychiatric withdrawal symptoms, it might be preferable to manage opioid withdrawal when patients are hospitalized (Guidelines for the management of opioid withdrawal, WHO, 2009) [3]. There is a risk of complications such as distress, increased heart rate, high or low blood pressure. Anxiety, depression and, more rarely, psychotic episodes have been described when opioids are stopped suddenly [4–6]. Opiate withdrawal may be done gradually, using opiate substitution drugs such as methadone or buprenorphine, or abruptly. In the latter case, withdrawal symptoms are managed with adjunctive medication such as clonidine and benzodiazepine, and medication to treat the symptoms. Clonidine binds to a central alpha 2 adrenergic receptor that shares potassium channels with opioids and blunts withdrawal symptoms. In addition to clonidine, benzodiazepines and other GABAergic drugs reduce catecholamine release during severe withdrawal, and the benzodiazepines themselves have been shown to reduce withdrawal symptoms in animal models [7, 8]. Symptomatic medications such as loperamide, phosphoglucinol, and octreotide could be added for gastro-intestinal symptoms. Thus, managing opiate withdrawal requires multiple prescriptions, with a high risk of drug-drug interaction and incomplete patient relief, a particularly sensitive issue in the case of patients taking opioid drugs in the context of pain associated with somatic disease.\n\nIn such cases, it might be worth investigating whether ketamine, widely used by anaesthetists to limit opioid tolerance, reduce use of painkillers, and increase the time preceding the first request for painkillers during the postoperative period [9], may be efficient for managing opioid withdrawal. Ketamine has also shown it has a role to play as an anti-hyperalgesic and tolerance-protective drug. It is acknowledged that it is of interest for managing various pain conditions, such as pain connected with opioid tolerance, acute pain or chronic pain [10–12]. Pain physicians use ketamine at sub-anaesthetic doses to treat refractory chronic pain syndromes, especially cancer- and non-cancer-related pain, or pain with a neuropathic component [13–15]. Moreover, recent publications showed that use of alpha2-adrenoreceptor agonists such as clonidine and NMDA antagonists such as ketamine or dextromethorphan could minimize tolerance development during opioid treatment [16]. As well as the tolerance effect, it is well known that chronic opioid medication can potentially increase subjective pain when prescribed for a long period [17]. Chronic treatment with opioids may also be complicated by abnormal pain sensitivity such as opioid-induced hyperalgesia [18, 19]. In cancer pain patients who have lost an analgesic response to high doses of opioids, a synergistic effect between oral ketamine and opioids and a rightward shift of the opioid-response curve were observed [20].\n\nKetamine is classified as an NMDA receptor antagonist but has many other pharmacological actions on mu, delta, kappa opioid receptors and monoamine transporters, inhibiting serotonin, dopamine and norepinephrine reuptake. Low doses of ketamine reduce morphine use, nausea and vomiting after surgery [21, 22], an effect mediated by NMDA antagonism plus μ-opioid and sigma receptor activation. In the central nervous system, ketamine, like other NMDA receptor antagonists, triggers anesthetic, amnesic, dissociative, and hallucinogenic effects. Activation of κ-opioid receptors and possibly sigma and mACh receptors may also contribute to its psychotomimetic properties [21]. Dopamine and serotonin reuptake inhibition is likely to underlie an antidepressant effect which is clinically relevant in depressed patients [23], although an additional but weak action of μ-opioid receptor activation cannot be ruled out [21]. In peripheral systems, ketamine enhances catecholaminergic transmission, producing measurable changes in peripheral organ systems, including the cardiovascular, gastrointestinal, and respiratory systems [24], increasing sympathetic stimulation of the cardiovascular system, and reducing nausea and vomiting and respiratory complications like bronchoconstriction. However, ketamine side effects may induce aberrant percepts, including musical and auditory verbal hallucinations [25], and its repetitive administration may lead to the development of additive behavior [26, 27]. Accordingly, its use in medical care should be strictly supervised.\n\nSome studies looked at the effect of ketamine for managing opioid withdrawal in the case of precipitated opiate withdrawal. One study, involving 58 patients who underwent rapid opiate antagonist induction under general anesthesia, showed that ketamine could help manage opioid withdrawal [28]. Prior to opiate antagonist induction, patients were given either a placebo (normal saline) or subanaesthetic ketamine infusion of 0.5 mg/kg/h. The ketamine group presented better control of withdrawal symptoms, lasting beyond the ketamine infusion itself. Significant differences were noted between the ketamine and control groups in the anaesthetic and early postanaesthetic phases, but no differences in effects were observed in terms of outcome after 4 months. In the same year, a Japanese team reported the case of a 2 year-old girl who received ketamine perfusion to manage symptoms caused by opioid withdrawal precipitated by naloxone [29]. To the best of our knowledge, there is no literature on ketamine use in opioid withdrawal not precipitated by naloxone. Here we report, according to the CARE (CAse REport) guidelines [30], the case of a 36 year-old woman hospitalized for opioid painkiller addiction who was treated with ketamine for the purpose of opioid reduction and withdrawal.\n\nCase presentation\nIn 2015, a 36 year-old woman was admitted to the rheumatology department of Strasbourg University Hospital (CHU) suffering from lumbar pain (or low back pain) with hyperalgesia and addiction to painkillers. A divorced mother of a child, the patient had been employed until 2008. Her medical history included chronic spinal pain over a one-year period, two cases of deep vein thrombophlebitis (2001), pulmonary embolism (2001), a transient ischaemic attack (2004) with negative blood test results, and an appendectomy (2008). Owing to the functional consequences of left wrist surgery following a work accident, she left her job and received disability benefits. In 2014, she received opioid treatment and 3 epidural infiltrations for lumbar and radicular pain. As an outpatient, she was treated with pregabalin combined with transcutaneous electrical nerve stimulation (TENS), but the hospital then lost track of her. Her psychiatric and addictological record contained reports of an episode of depression, a morphine overdose-induced coma, hospitalization for opioid withdrawal, and an addiction to tobacco. When admitted to the rheumatology department in 2015, her treatment consisted of diazepam 10 mg three times per day, hydroxyzine 100 mg twice daily, venlafaxine 150 mg in the morning, oxycontin® extended-release 60 mg twice daily, oxycodone 10 mg every 4 h, and acetaminophen/codeine 300 mg/25 mg 6 times per day. She abused oxycodone and codeine, and her physicians refused to prescribe opioid treatment in such high dosages. Her medical examination revealed lumbosacral pain with intermittent irradiation towards the posterior side of her thigh down to the top of her left knee, painful limitation of flexion, extension, right rotation of the spine, limited flexion in both directions. The patient also reported pain upon palpation of the left pelvic-trochanter region, and cellulalgia in the dorso-lumbar region. She was suffering from dysuria and constipation due to opioid treatment. Biological investigations, CT-scan and X-ray results were normal. A spinal MRI scan found lumbar degenerative disc disease (L4-L5 and L5-S1). Rheumatologists asked for a specialist opinion from a pain specialist, who, in view of the patient’s prior psychiatric history, decided to contact psychiatrists and addictologists for their opinion. The patient presented with a histrionic personality (eg. need to be the center of attention, dramatization within the therapeutic relationship, reactivity of mood, excessive sensitivity to criticism or disapproval, inappropriate seductive appearance, rapidly shifting emotional states that may appear superficial and rash decision-making according to DSM-5 [31]). She also presented with some borderline traits (eg. unstable interpersonal relationships alternating idealization/devaluation, identity disturbance with unstable sense of self, difficulty controlling anger, transient paranoid ideations). Given the patient’s psychiatric symptoms and the fact that she wanted to withdraw opioid treatment by herself and attempted to do so, the physicians proposed she be admitted to the hospital’s psychiatry department to be treated for opioid withdrawal with the administration of ketamine to manage lombo-sciatic pain. She was informed of the side effects of ketamine and of the need to follow the protocol correctly and to report any opioid withdrawal symptoms. Faced with the fact that no physician could prescribe such high dosages of opioid medication, the patient agreed to be transferred to the psychiatric department. There she received ketamine oral solution (5 mg/ml, magistral formulae) 1 mg/kg, and two days after ketamine initiation her opioid treatment was gradually reduced (10 % reduction in the initial dosage each two days). The patient reported no withdrawal symptoms (Clinical Opioid Withdrawal Symptoms score of 0/11 in the first and seconds week after the physician started reducing her opioid medication), pain or cravings while her opioid treatment was being reduced. She complained of no side effects of ketamine other than an unusual weakness. However, because of her borderline and histrionic traits, the reduction in opioid treatment took longer, and we had to extend the period of ketamine treatment. In fact, the patient’s need to be at the center of attention caused many problems with other patients and with nurses, who found her demands difficult to deal with. As she presented with emotional and paranoid reactions, the medical staff proposed a long weekend break, thus interrupting her care and delaying her treatment. Although we had to extend the hospitalization period and ketamine treatment, in the end ketamine withdrawal was achieved without withdrawal symptoms, and the patient was discharged from the hospital. She consulted her addictologist and psychiatrist. She now takes very small dosage of opioids for pain relief (codeine 50 mg three times per day). To control administration of the remaining opioid medication, it is administered at home by a nurse. Functional re-education was also organized.\n\nDiscussion\nIn this case, we reported on withdrawal of opioid medication in a woman presenting opioid addictive disorders but also suffering from chronic lumbar pain that justified the use of painkillers. According to DSM-5 criteria [31], her opioid use disorder was severe, insofar as she could not stop using opioids and, although she tried to lower the dosage of opioid medication, she increased it each time she got out of the hospital. Moreover, she risked her life by overdosing on opioid medication. The decision to stop taking opioid painkillers was not a spontaneous request on the part of the patient but a decision she took when she realized that no physician would prescribe her such a high daily dose. In the literature, it has been shown that replacing opioid medication with a substitution treatment of buprenorphine and buprenorphine-naloxone is effective for chronic pain and offers patients a good degree of satisfaction [32, 33]. However, as buprenorphine is off-label and buprenorphine-naloxone was off-label in France at this time, these treatments should be proposed only after withdrawal has been shown to have failed. Accordingly, the patient had difficulty accepting the idea of withdrawing opioid medications but agreed to reduce the dosage and to combine it with treatment, such as ketamine, for her lumbar pain. Ketamine introduction was easy, and the treatment was well tolerated by the patient, apart from an unusual weakness. Under ketamine, there were no opioid withdrawal symptoms (no nausea, vomiting, abdominal cramps, diarrhea, yawning, piloerection, restlessness) during the 3 weeks of ketamine medication and reduced opioid dosage. This observation is consistent with those described in the literature and confirms that ketamine could help cope with symptoms of opioid withdrawal [34]. As the patient had a history of depressive disorders, and as she was treated with antidepressants (venlafaxine 150 mg daily), she was assessed daily for depressive disorders by a physician. She showed no increase in depressive symptoms. As suggested in our introduction, the action of the ketamine on the dopamine and serotonin neurotransmissions have an antidepressant effect [23], which has been very interesting in the present case for avoiding depressive disorders which might emerge in the event of opioid withdrawal. This antidepressant effect was also interesting for avoiding a relapse in the patient’s opiate addiction, which most of the time is due to depressive behaviors induced by opioid decrease or withdrawal.\n\nIn our present case report, we showed that it is possible to use ketamine to reduce and almost withdraw opioid medications in the case of painful situations. We did not precipitate opioid withdrawal with naloxone before ketamine initiation, but, for the first time, ketamine was initiated just before opioid reduction. In this way, the combination of ketamine and opioid treatments reduced lumbosacral pain, and the use of ketamine counteracted withdrawal signs due to opioid reduction. Furthermore, we showed that ketamine could help patients lower their consumption of opioid medication with good tolerance levels, even if they present addictive disorders. It could be another way of dealing with opioid withdrawal symptoms in patients suffering from opioid addictive behaviors which are often an obstacle for them. Moreover, opioid withdrawal symptoms are currently managed with polytherapy based on benzodiazepine, hydroxyzine, antipsychotics, clonidine and many symptomatic treatments for nausea, vomiting, diarrhea, etc. There is uncertainty surrounding these associations, which are sometimes also insufficient for dealing with dysphoric symptoms, which are a main cause of relapse [5]. That is why ketamine’s long-lasting antidepressant effects could be very helpful during opioid withdrawal [23]. However, our case report is very complex given that the patient was prescribed many psychotropic and antidepressant medications, and it is difficult to conclude whether ketamine alone could counter all physical and psychological withdrawal symptoms in this case. Moreover, the patient’s histrionic personality might affect the successful use of ketamine due to her suggestibility. Since she received special treatment in a psychiatric unit, she was the center of attention during her spell in hospital. This attention probably made her feel she was a very special patient. This situation led to a brief interruption in her hospitalization and prolonged the ketamine treatment and care, such that she did not have to confront her own issues. To assess whether it is worth using ketamine to withdraw opioid medication, it may be necessary to study this effect in a clinical trial.\n\nConclusion\nAll in all, ketamine displays many interesting qualities for dealing with all physical and psychological symptoms relating to opioid withdrawal. Accordingly, we propose that ketamine could be used instead of many psychotropic treatments for helping with opioid withdrawal, and, in this way, might be safer for patients suffering from addictive behaviors. However, the literature also describes addiction to ketamine [26, 27], which is why its use in patients suffering from addictive behaviors must be subject to stronger and stricter criteria. With this risk in mind, we propose testing ketamine medication for dealing with opioid withdrawal in the case of opioid addictive disorders in a “proof of concept” open study.\n\nAcknowledgements\nSpecial acknowledgement goes to the Centre Hospitalier Régional Universitaire in Strasbourg for its contribution.\n\nFunding\nNone.\n\nAvailability of data and materials\nThe datasets generated and analysed during the current study are not publicly available due the confidentiality for the person whose case is presented in the manuscript and the obligation of the anonymization of these data. However, data are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nAll the authors were involved in psychiatric care. The article was written by LL, CN, JPL, ES, and GB has made substantial contributions to the analysis and interpretation of data and has been involved in revising the article critically for important intellectual content. LL, CN, JPL, ES and GB have given final approval of the version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.\n\nAuthors’ information\nGB, LL, JPL, CN have an expertise in Psychiatry and in Addictology. ES is a pain physician and has an expertise in the use of ketamine at sub-anaesthetic doses to treat refractory chronic pain syndromes.\n\nCompeting interests\nWe have no competing interests. We have no conflict of interest to declare with respect to the manuscript, including no financial, consultant, institutional, political, personal, religious, ideological, academic, intellectual, commercial or other relationships that could lead to any bias or a conflict of interest. We have no financial disclosure to make. We have no financial gain or loss from the publication of the manuscript. We received no support from any pharmaceutical company or other industry.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of her case report. A copy of the written consent is available for review by the Editor of this journal.\n\nEthics approval and consent to participate\nNot Applicable.\n==== Refs\nReferences\n1. United Nations Office on Drugs and Crime (2007). World Drug Report\n2. Dart RC Surratt HL Cicero TJ Parrino MW Severtson SG Bucher-Bartelson B Green JL Trends in opioid analgesic abuse and mortality in the United States N Engl J Med 2015 372 3 241 8 10.1056/NEJMsa1406143 25587948 \n3. WHO. Guidelines for the psychosocially assisted pharmacological treatment of opioid dependence. 2009: 39.\n4. Karila L Berlin I Benyamina A Reynaud M Psychotic symptoms following buprenorphine withdrawal Am J Psychiatry 2008 165 3 400 1 10.1176/appi.ajp.2007.07071103 18316438 \n5. Koob GF Volkow ND Neurocircuitry of addiction Neuropsychopharmacology 2010 35 1 217 38 10.1038/npp.2009.110 19710631 \n6. Powell JE Taylor D Anger, depression, and anxiety following heroin withdrawal Int J Addict 1992 27 1 25 35 10.3109/10826089109063460 1537638 \n7. Elman I D’Ambra MN Krause S Breiter H Kane M Morris R Tuffy L Gastfriend DR Ultrarapid opioid detoxification: effects on cardiopulmonary physiology, stress hormones and clinical outcomes Drug Alcohol Depend 2001 61 163 10.1016/S0376-8716(00)00139-3 11137281 \n8. Suzuki T Tsuda M Narita M Funada M Mizoguchi H Misawa M Diazepam pretreatment suppresses morphine withdrawal signs in the mouse Life Sci 1996 58 349 10.1016/0024-3205(95)02294-5 8538371 \n9. Radvansky BM, Shah K, Parikh A, Sifonios AN, Le V, Eloy JD. Role of ketamine in acute postoperative pain management: a narrative review. Biomed Res Int. 2015; 749837. doi: 10.1155/2015/749837.\n10. Griffiths R Opioid-induced hyperalgesia: low-dose ketamine does work for some orthopaedic problems already Br J Anaesth 2010 104 5 660 1 10.1093/bja/aeq075 20400615 \n11. Laulin JP Maurette P Corcuff JB Rivat C Chauvin M Simonnet G The role of ketamine in preventing fentanyl-induced hyperalgesia and subsequent acute morphine tolerance Anesth Analg 2002 94 5 1263 9 10.1097/00000539-200205000-00040 11973202 \n12. Visser E Schug SA The role of ketamine in pain management Biomed Pharmacother 2006 60 7 341 8 10.1016/j.biopha.2006.06.021 16854557 \n13. Bell RF Ketamine for chronic non-cancer pain Pain 2009 141 3 210 4 10.1016/j.pain.2008.12.003 19128879 \n14. Niesters M Martini C Dahan A Ketamine for chronic pain: risks and benefits Br J Clin Pharmacol 2014 77 2 357 67 10.1111/bcp.12094 23432384 \n15. Blonk MI Koder BG van den Bemt PM Huygen FJ Use of oral ketamine in chronic pain management: a review Eur J Pain 2010 14 5 466 72 10.1016/j.ejpain.2009.09.005 19879174 \n16. Raith K Hochhaus G Drugs used in the treatment of opioid tolerance and physical dependence: a review Int J Clin Pharmacol Ther 2004 42 4 191 203 10.5414/CPP42191 15124977 \n17. Jamison RN Mao J Opioid Analgesics Mayo Clin Proc 2015 90 7 957 68 10.1016/j.mayocp.2015.04.010 26141334 \n18. Chu LF Clark DJ Angst MS Opioid tolerance and hyperalgesia in chronic pain patients after one month of oral morphine therapy: a preliminary prospective study J Pain 2006 7 1 43 8 10.1016/j.jpain.2005.08.001 16414554 \n19. Lee M Silverman SM Hansen H Patel VB Manchikanti L A comprehensive review of opioid-induced hyperalgesia Pain Physician 2011 14 2 145 61 21412369 \n20. Mercadante S Ketamine in cancer pain: an update Palliat Med 1996 10 3 225 30 8817593 \n21. Kohrs R Durieux ME Ketamine: Teaching an old drug new tricks Anesth Analg 1998 87 5 1186 93 9806706 \n22. Bell RF Dahl JB Moore RA Kalso EA Perioperative ketamine for acute postoperative pain. Pain, Palliative and Supportive Care Group Cochrane Database Syst Rev 2005 49 10 1405 28 \n23. Iadarola ND Niciu MJ Richards EM Vande Voort JL Ballard ED Lundin NB Nugent AC Machado-Vieira R Zarate CA Jr Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: a perspective review Ther Adv Chronic Dis 2015 6 3 97 114 10.1177/2040622315579059 25954495 \n24. Aroni F Iacovidou N Dontas I Pourzitaki C Xanthos T Pharmacological aspects and potential new clinical applications of ketamine: Reevaluation of an old drug J Clin Pharmacol 2009 49 8 957 64 10.1177/0091270009337941 19546251 \n25. Powers AR 3rd Gancsos MG Finn ES Morgan PT Corlett PR Ketamine-Induced Hallucinations Psychopathology 2015 48 6 376 85 10.1159/000438675 26361209 \n26. Delimbeuf N Petit A Karila L Lejoyeux M Ketamine: psychiatric indications and misuses Rev Med Liege 2014 69 7-8 434 40 25158385 \n27. Liu JX Zerbo E Ross S Intensive ketamine use for multiple years: A case report Am J Addict 2015 24 1 7 9 10.1111/ajad.12153 25823629 \n28. Jovaisa T Laurinenas G Vosylius S Sipylaite J Badaras R Ivaskevicius J Effects of ketamine on precipitated opiate withdrawal Medicina (Kaunas) 2006 42 8 625 34 16963828 \n29. Ito H Sobue K Hirate H Sugiura T So M Azami T Sasano H Katsuya H Use of ketamine to facilitate opioid withdrawal in a child Anesthesiology 2006 104 5 1113 10.1097/00000542-200605000-00043 16645479 \n30. Gagnier J Kienle G Altman DG Moher D Sox H Riley DS and the CARE group The CARE guidelines: consensus-based clinical case report guideline development J Clin Epidemiol 2013 67 1 46 51 10.1016/j.jclinepi.2013.08.003 24035173 \n31. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Publishing; 2013.\n32. Streltzer J Davidson R Goebert D An observational study of buprenorphine treatment of the prescription opioid dependent pain patient Am J Addict 2015 24 4 357 61 10.1111/ajad.12198 25675861 \n33. Barry DT Savant JD Beitel M Cutter CJ Moore BA Schottenfeld RS Fiellin DA Use of conventional, complementary, and alternative treatments for pain among individuals seeking primary care treatment with buprenorphine-naloxone J Addict Med 2012 6 4 274 9 10.1097/ADM.0b013e31826d1df3 23041680 \n34. Morgan CJ Curran HV Independent Scientific Committee on Drugs Ketamine use: a review Addiction 2012 107 1 27 38 10.1111/j.1360-0443.2011.03576.x 21777321\n\n",
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"title": "Experience of the use of Ketamine to manage opioid withdrawal in an addicted woman: a case report.",
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"abstract": "Perinatal transmission remains one of the important causes of the transmission of the human immunodeficiency virus (HIV). Over the years, with better knowledge and awareness of HIV, the perinatal transmission rate has been significantly reduced. We previously reported on the pregnancy outcomes of HIV-positive mothers from 1997 to 2007 in our institution. This paper aims to review standards of care of HIV-positive pregnant women since then.\n\n\n\nA retrospective study reviewed 84 HIV-positive women who delivered in a tertiary centre from January 2008 to December 2015. Patient demographics and antenatal, intrapartum, postnatal and immediate neonatal data were analysed.\n\n\n\nThere were a total of 97 deliveries with 98 neonates. 12 women delivered more than once and there was one set of twins. Mean maternal age at diagnosis of HIV was 27.8 years. Of the study population, 63.1% of women were non-Singaporeans. 56 women were known to have HIV on presentation and 90.7% were on antiretroviral therapy during pregnancy. 88.7% of the women received intrapartum intravenous zidovudine, and 93.1% of women with detectable and 58.7% with undetectable viral load underwent Caesarean sections. All neonates were HIV-negative.\n\n\n\nHaving high standards of care for HIV-positive women has successfully reduced our perinatal transmission rate to zero.",
"affiliations": "Department of Obstetrics and Gynaecology, KK Women’s and Children’s Hospital, Singapore;Paediatrics Infectious Disease, Department of Paediatrics, KK Women’s and Children’s Hospital, Singapore;Department of Obstetrics and Gynaecology, KK Women’s and Children’s Hospital, Singapore;Department of Obstetrics and Gynaecology, KK Women’s and Children’s Hospital, Singapore",
"authors": "Loh|Michelle|M|;Thoon|Koh Cheng|KC|;Mathur|Manisha|M|;Kathirvel|Rajeswari|R|",
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"title": "Management of HIV-positive pregnant women: a Singapore experience.",
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"abstract": "Neural tube defects contribute to severe morbidity and mortality in children and adults; however, they are largely preventable through maternal intake of folic acid before and during early pregnancy. We examined the association between maternal prenatal folic acid supplement intake and risk of myelomeningocele (a severe and common type of neural tube defect) in the offspring. We performed secondary analysis using data from a case-control study conducted at Dhaka Community Hospital, Bangladesh between April and November of 2013. Cases and controls included children with and without myelomeningocele, respectively, and their mothers. Cases were identified from local hospitals and rural health clinics served by Dhaka Community Hospital. Controls were selected from pregnancy registries located in the same region as the cases, and matched (1:1) to cases by age and sex. Myelomeningocele in the offspring was confirmed by a pediatrician with expertise in classifying neural tube defects. Maternal prenatal folic acid supplement intake was the main exposure of interest. We estimated crude and adjusted odds ratios (OR) and 95% confidence intervals (CI) using conditional logistic regression analysis. There were 53 pairs of matched cases and controls in our study. Overall, 51% of case mothers reported using folic acid supplements during pregnancy compared to 72% of control mothers (p = 0.03). Median plasma folate concentrations at the time of study visit were 2.79 ng/mL and 2.86 ng/mL among case and control mothers, respectively (p = 0.85). Maternal prenatal folic acid use significantly decreased the odds of myelomeningocele in the offspring (unadjusted OR = 0.42, 95% CI = 0.18-0.96). The association was slightly attenuated after adjusting for maternal age at the time of pregnancy (adjusted OR = 0.43, 95% CI = 0.18-1.02). Our study confirms the protective association between maternal prenatal folic acid supplement use and myelomeningocele among children born in Bangladesh. Our findings point to an overall low folic acid supplement use and low plasma folate concentrations among women of reproductive age in Bangladesh. Mandatory fortification of staple foods with folic acid can address low folate status among women of child-bearing age, and prevent child morbidity and mortality associated with myelomeningocele in Bangladesh.",
"affiliations": "Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, United States of America.;Dhaka Community Hospital, Dhaka, Bangladesh.;Bangladesh Medical College, Dhaka, Bangladesh.;Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts, United States of America.;Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts, United States of America.;Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, United States of America.;Dhaka Community Hospital, Dhaka, Bangladesh.;Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, United States of America.",
"authors": "Kancherla|Vijaya|V|;Ibne Hasan|Md Omar Sharif|MOS|;Hamid|Rezina|R|;Paul|Ligi|L|;Selhub|Jacob|J|;Oakley|Godfrey|G|;Quamruzzaman|Quazi|Q|;Mazumdar|Maitreyi|M|",
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"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0188726PONE-D-16-46837Research ArticlePhysical SciencesChemistryChemical CompoundsOrganic CompoundsVitaminsB VitaminsFolic AcidPhysical SciencesChemistryOrganic ChemistryOrganic CompoundsVitaminsB VitaminsFolic AcidMedicine and Health SciencesWomen's HealthMaternal HealthPregnancyMedicine and Health SciencesWomen's HealthObstetrics and GynecologyPregnancyMedicine and Health SciencesCongenital DisordersBirth DefectsNeural Tube DefectsBiology and Life SciencesDevelopmental BiologyMorphogenesisBirth DefectsNeural Tube DefectsPeople and PlacesGeographical LocationsAsiaBangladeshBiology and Life SciencesAnatomyBody FluidsBloodBlood PlasmaMedicine and Health SciencesAnatomyBody FluidsBloodBlood PlasmaBiology and Life SciencesPhysiologyBody FluidsBloodBlood PlasmaMedicine and Health SciencesPhysiologyBody FluidsBloodBlood PlasmaResearch and Analysis MethodsResearch DesignCase-Control StudiesPeople and PlacesPopulation GroupingsAge GroupsChildrenInfantsPeople and PlacesPopulation GroupingsFamiliesChildrenInfantsMedicine and Health SciencesCongenital DisordersBirth DefectsBiology and Life SciencesDevelopmental BiologyMorphogenesisBirth DefectsPrenatal folic acid use associated with decreased risk of myelomeningocele: A case-control study offers further support for folic acid fortification in Bangladesh Prenatal folic acid and myelomeningoceleKancherla Vijaya ConceptualizationMethodologySupervisionWriting – original draftWriting – review & editing1*Ibne Hasan Md Omar Sharif MethodologyWriting – original draft2Hamid Rezina MethodologyWriting – original draftWriting – review & editing3Paul Ligi MethodologyWriting – original draftWriting – review & editing4Selhub Jacob ConceptualizationWriting – original draftWriting – review & editing4Oakley Godfrey ConceptualizationWriting – original draftWriting – review & editing1Quamruzzaman Quazi MethodologyWriting – original draftWriting – review & editing2Mazumdar Maitreyi ConceptualizationData curationFunding acquisitionInvestigationMethodologySupervisionWriting – original draftWriting – review & editing561 \nDepartment of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, United States of America2 \nDhaka Community Hospital, Dhaka, Bangladesh3 \nBangladesh Medical College, Dhaka, Bangladesh4 \nJean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts, United States of America5 \nDepartment of Neurology, Boston Children’s Hospital, Boston, Massachusetts, United States of America6 \nDepartment of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of AmericaLee Jung Eun EditorSeoul National University, REPUBLIC OF KOREACompeting Interests: The authors have declared that no competing interests exist.\n\n* E-mail: vkanche@emory.edu30 11 2017 2017 12 11 e018872625 11 2016 13 11 2017 © 2017 Kancherla et al2017Kancherla 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.Neural tube defects contribute to severe morbidity and mortality in children and adults; however, they are largely preventable through maternal intake of folic acid before and during early pregnancy. We examined the association between maternal prenatal folic acid supplement intake and risk of myelomeningocele (a severe and common type of neural tube defect) in the offspring. We performed secondary analysis using data from a case-control study conducted at Dhaka Community Hospital, Bangladesh between April and November of 2013. Cases and controls included children with and without myelomeningocele, respectively, and their mothers. Cases were identified from local hospitals and rural health clinics served by Dhaka Community Hospital. Controls were selected from pregnancy registries located in the same region as the cases, and matched (1:1) to cases by age and sex.\n\nMyelomeningocele in the offspring was confirmed by a pediatrician with expertise in classifying neural tube defects. Maternal prenatal folic acid supplement intake was the main exposure of interest. We estimated crude and adjusted odds ratios (OR) and 95% confidence intervals (CI) using conditional logistic regression analysis. There were 53 pairs of matched cases and controls in our study. Overall, 51% of case mothers reported using folic acid supplements during pregnancy compared to 72% of control mothers (p = 0.03). Median plasma folate concentrations at the time of study visit were 2.79 ng/mL and 2.86 ng/mL among case and control mothers, respectively (p = 0.85). Maternal prenatal folic acid use significantly decreased the odds of myelomeningocele in the offspring (unadjusted OR = 0.42, 95% CI = 0.18–0.96). The association was slightly attenuated after adjusting for maternal age at the time of pregnancy (adjusted OR = 0.43, 95% CI = 0.18–1.02). Our study confirms the protective association between maternal prenatal folic acid supplement use and myelomeningocele among children born in Bangladesh. Our findings point to an overall low folic acid supplement use and low plasma folate concentrations among women of reproductive age in Bangladesh. Mandatory fortification of staple foods with folic acid can address low folate status among women of child-bearing age, and prevent child morbidity and mortality associated with myelomeningocele in Bangladesh.\n\nNational Institutes of Environmental Health Sciences (NIEHS), National Institutes of HealthR01 ES 016317Mazumdar Maitreyi http://dx.doi.org/10.13039/100000066National Institute of Environmental Health SciencesP30 ES 000002http://dx.doi.org/10.13039/100000066National Institute of Environmental Health SciencesP30 HD 18655Funding for this study was provided by the National Institutes of Environmental Health Sciences (NIEHS), National Institutes of Health (R01 ES 016317) (Grantee: MM). Additional support was provided by the Child Neurology Foundation, the Harvard T.H. Chan School of Public Health NIEHS Center (P30 ES 000002) and the Boston Children’s Hospital Intellectual and Developmental Disabilities Research Center (P30 HD 18655). The authors declare that there are no financial or personal relationships or affiliations that could influence or bias the manuscript, and that there are no conflicts of interest. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data AvailabilityDue to ethical and legal restrictions, the data underlying this study are available to qualified, interested researchers from URL: http:mazumdargroup.org. Requests for data should be sent to Michelle Paul (michelle.paul@childrens.harvard.edu). Ms. Paul is a data manager in the Department of Neurology at Boston Children’s Hospital, is not a co-author, and will facilitate data sharing. All qualified, interested researchers will be granted access to these data provided that they receive ethical approval and consent to any relevant terms of use.Data Availability\nDue to ethical and legal restrictions, the data underlying this study are available to qualified, interested researchers from URL: http:mazumdargroup.org. Requests for data should be sent to Michelle Paul (michelle.paul@childrens.harvard.edu). Ms. Paul is a data manager in the Department of Neurology at Boston Children’s Hospital, is not a co-author, and will facilitate data sharing. All qualified, interested researchers will be granted access to these data provided that they receive ethical approval and consent to any relevant terms of use.\n==== Body\nIntroduction\nNeural tube defects are serious birth defects characterized by incomplete development of the brain, spinal column, and spinal cord. They occur at about 3 to 4 weeks of gestation, when most women are unaware of their pregnancies. These birth defects contribute to neonatal, infant, and child mortality [1,2], and result in severe and life-long disabilities among those who survive [3]. Neural tube defects are associated with increased medical care costs, as well as loss of human potential, due to disability and death [4–6].\n\nBangladesh is believed to have a high rate of neural tube defects, although current national population-based prevalence estimates are lacking in the country. The March of Dimes Global Report on Birth Defects, using available data from surveillance and birth defects registries, modelled the average worldwide birth prevalence of neural tube defects to be 2.4 per 1000 live births [7]. In comparison, the report’s extrapolated data for Bangladesh indicated that the birth prevalence of neural tube defects in the country was 4.7 per 1000 live births, almost twice as high as the average global prevalence [7].\n\nMaternal intake of folic acid before and during early pregnancy is a proven intervention for preventing a majority of cases of neural tube defects [8–10]. Despite recommendations from the World Health Organization (WHO) for the use of folic acid supplements among women of childbearing age [11], several studies have revealed low prevalence (~20%) of prenatal folic acid supplement intake in Bangladesh [12,13]. Bangladesh also has a high prevalence of malnutrition and micronutrient deficiencies, including folate deficiency, hindering optimal birth outcomes among babies born to malnourished mothers [14,15]. According to the Food Fortification Initiative (http://www.ffinetwork.org), Bangladesh does not currently have a national program for mandatory folic acid fortification for staple grains (wheat, maize, rice).\n\nAlthough the role of folic acid in the prevention of neural tube defects is well- established in developed regions of the world, studies examining the magnitude of this association are lacking in Bangladesh. Given the country’s high prevalence of folate deficiency [16] and burden of neural tube defects [7], it is especially important to understand this association, and apply insights gained to ensure healthy lives and promote well-being, as proposed in the 2030 health-related Sustainable Development Goals for Bangladesh [17]. We hypothesized that maternal intake of folic acid supplements during pregnancy decrease the risk of myelomeningocele, a common and severe type of neural tube defect, in the offspring.\n\nMaterials and methods\nWe used data from a case-control study conducted in the communities served by Dhaka Community Hospital in Bangladesh between April and November 2013, to assess the association between maternal prenatal folic acid supplement intake and myelomeningocele in the offspring. The original study was designed to examine the associations between environmental arsenic exposure and myelomeningocele risk, and no main effect of arsenic on myelomeningocele was observed [18].\n\nThe design, inclusion criteria, and recruitment strategy for the original study have been described previously [18,19]. Participants for our current analysis included children with myelomeningocele (cases) and their mothers. Cases were identified through regular communication with local hospitals and rural health clinics served by Dhaka Community Hospital, a large, trust-owned health system that operates primary health care centers across Bangladesh. All cases were confirmed by a pediatrician with expertise in classifying neural tube defects, using physical examination or photographs (when a case was deceased) and including an evaluation for level of neural tube defect. Control children and their mothers were randomly enrolled from pregnancy registries in the same geographic regions. Cases and controls were matched 1:1 by the child’s sex and age within 2 months. Participation rate was 98% and 83% among case and control mothers, respectively. The reasons for refusing to participate in the study were similar between case and control mothers, including lack of interest to participate, and unwillingness to provide blood samples due to fear of sickness. The sample size was estimated a priori based on the original study hypothesis [18]. Trained interviewers collected information on history of maternal folic acid use to ascertain folic acid-containing supplement intake during the pregnancy. Interviewers also collected information from mothers about their medical histories, medication use during pregnancy, family history, and reproductive history. Study activities consisted of a single clinical visit during which we administered questionnaires, performed physical examinations, and collected samples. The age of the infant at the study visit, therefore, represents the age of the infant since delivery as well as the time since postpartum state of the mother.\n\nMaternal blood samples were collected via venipuncture at the time of the interview. Blood samples were transported to Dhaka within one day of collection in an insulated container, and stored at −20°C. Plasma from the centrifuged blood samples was collected into microcentrifuge tubes and stored at −20°C. Blood/plasma samples were shipped to Harvard School of Public Health on dry ice. Folate analyses were performed at the Vitamin Metabolism Laboratory at the Jean Mayer United States Department of Agriculture (USDA) Human Nutrition Research Center at Tufts University. Total folate concentrations in the plasma samples were measured by microbial assay with the use of Lactobacillus casei [19]. Each plasma sample (5 μL) was serially diluted and plated in triplicate onto a 96-microtiter well plate with 150 μL of Lactobacillus casei growth medium. Plates were intubated overnight in a 37°C humid incubator and then absorbance was measured, which indicated microbial growth, with the use of a 96-well plate reader (PowerWave HT; BioTek Instruments Inc, Winooski, VT USA) at 595 nm. As arsenic is a major concern in Bangladesh, tests were done to check if any arsenic in plasma affected the microbial assay, including spiking 3 random samples with 5 ng/mL folic acid, and there were no inhibitory components detected in the plasma. The coefficients of variation for the assay using one plasma sample with high folate concentration and one sample with low folate concentration were 6.78% and 4.73%, respectively. For our study analysis, we used the World Health Organization’s guideline on establishing plasma folate deficiency at a cut-off value of 4.0 ng/mL (http://apps.who.int/iris/bitstream/10665/75584/1/WHO_NMH_NHD_EPG_12.1_eng.pdf Accessed on November 1, 2017).\n\nThe Human Research Committees at the Boston Children’s Hospital and Dhaka Community Hospital approved this study. Consent documents were provided to participants in Bengali and reviewed with potential participants by local study staff. All participants provided written informed consent.\n\nStatistical analysis\nWe conducted a descriptive analysis of selected child and maternal characteristics by case and control status. We tested distribution using Shapiro-Wilk Test for Normality. We used independent sample t-test to compare mean ages of case and control infants and mothers at the time of the study visit, and Wilcoxon two-sample test to compare median folate concentrations between case and control mothers. We examined the difference between maternal prenatal folic acid intake among matched case-control pairs using McNemar’s Test. We used conditional logistic regression to estimate unadjusted and adjusted odds ratios (uOR and aOR) and associated 95% confidence intervals (CI) for the association between maternal prenatal folic acid supplement use and risk of myelomeningocele in the offspring. Potential confounding due to maternal age at delivery, family history of birth defects, family history of neural tube defects, valproic acid use during pregnancy, and pre-pregnancy diabetes was considered. Co-factors were selected based on a priori criteria assessed from previous studies [4]. All analyses were conducted using SAS (version 9.4) for windows (SAS Institute, Inc. Cary, NC, USA).\n\nResults\nThere were 53 pairs of matched cases and controls in our study. The mean ages of case and control infants, and case and control mothers, at the time of the study visit, are presented in Table 1. Among the case infants, 60% were males, 27% were born preterm, 32% had a low birth weight (<2500 grams), 50% were delivered at home, and none had a family history of neural tube defects or other birth defects (Table 1). Almost 85% and 90% of case and control mother, respectively, reported to have received an ultrasound examination before their index pregnancy (data not shown). Except for low birth weight, no other characteristic differed significantly between the case and control infants. We compared selected characteristics between case and control mothers, and found that case mothers were four times more likely to be older (>30 years) than control mothers at the time of delivery. There were no significant differences between case and control mothers with respect to prenatal exposures to smoking and valproic acid. None of the case or control mothers reported being exposed to alcohol or pesticides during pregnancy, or having a history of pre-pregnancy diabetes (Table 1).\n\n10.1371/journal.pone.0188726.t001Table 1 Infant and maternal characteristics of cases (myelomeningocele) and controls.\n\tCases\n(n = 53)\tControls\n(n = 53)\t\t\t\n\tMean (SD)\tMean (SD)\tp value\t\t\nChild’s age at study visit (Months)\t5.7 (5.3)\t7.8 (4.8)\t0.03\t\t\nMother’s age at study visit (Years)\t22.2 (4.1)\t24.7 (5.3)\t0.01\t\t\n\tn\t(%)\tn\t(%)\tUnadjusted Odds Ratio\n(95% CI)\tAdjusted Odds Ratio\n(95% CI)\t\nChild\t\t\t\t\t\t\t\nGestational age at delivery\t\t\t\t\t\t\t\n Term\t37\t(70)\t31\t(59)\tReference\t—\t\n Preterm\t14\t(26)\t17\t(32)\t0.64 (0.26–1.59)\t\t\n Post-term\t2\t(4)\t5\t(9)\t0.33 (0.06–1.80)\t\t\nBirth weight, grams\t\t\t\t\t\t\t\n <2500\t17\t(32)\t8\t(15)\t2.50 (0.97–6.44)\t—\t\n 2500\t36\t(68)\t45\t(85)\tReference\t\t\nPlace of birth\t\t\t\t\t\t\t\n Home\t26\t(49)\t21\t(40)\t2.11 (0.82–5.44)\t—\t\n Clinic\t15\t(28)\t9\t(17)\t2.36 (0.88–6.32)\t\t\n Hospital\t12\t(23)\t23\t(43)\tReference\t\t\nDelivery type\t\t\t\t\t\t\t\n Vaginal\t30\t(57)\t32\t(60)\tReference\t—\t\n Cesarean Section\t23\t(43)\t21\t(40)\t0.86 (0.40–1.85)\t\t\nBirth Order\t\t\t\t\t\t\t\n First born\t22\t(42)\t25\t(47)\tReference\t—\t\n Second or higher\t31\t(58)\t28\t(53)\t1.38 (0.55–3.42)\t\t\nFamily history of birth defects\t\t\t\t\t\t\t\n No\t53\t(100)\t53\t(100)\tNA\t—\t\n Yes\t0\t-\t0\t-\t\t\t\nFamily history of NTD\t\t\t\t\t\t\t\n No\t53\t(100)\t53\t(100)\tNA\t—\t\n Yes\t0\t-\t0\t-\t\t\t\nMother\t\t\t\t\t\t\t\nAge at delivery (years)\t\t\t\t\t\t\t\n <20\t10\t(19)\t14\t(26)\t0.95 (0.35–2.57)\t1.00 (0.35, 2.84)\t\n 20–30\t35\t(66)\t37\t(70)\tReference\tReference\t\n >30\t8\t(15)\t2\t(4)\t3.88 (0.74–20.36)\t2.79 (0.67, 21.29)\t\nPrenatal folic acid supplement use\t\t\t\t\t\t\t\n No\t26\t(49)\t15\t(28)\tReference\tReference\t\n Yes\t27\t(51)\t38\t(72)\t0.42 (0.18, 0.96)\t0.43 (0.18, 1.02)\t\nFolic acid deficiency at study visit\t\t\t\t\t\t\t\n No (≥4.0 ng/mL)\t18\t(35)\t16\t(30)\tReference\t—\t\n Yes (<4.0 ng/mL)\t33\t(65)\t37\t(70)\t0.80 (0.35–1.80)\t\t\nPre-pregnancy diabetes\t\t\t\t\t\t\t\n No\t53\t(100)\t53\t(100)\tNA\t—\t\n Yes\t0\t-\t0\t-\tReference\t\t\nSmoking during pregnancy\t\t\t\t\t\t\t\n No\t52\t(98)\t53\t100\tNA\t—\t\n Yes\t1\t(2)\t0\t-\t\t\t\nAlcohol during pregnancy\t\t\t\t\t\t\t\n No\t53\t(100)\t53\t(100)\tNA\t—\t\n Yes\t0\t-\t0\t-\t\t\t\nPesticide exposure during pregnancy\t\t\t\t\t\t\t\n No\t53\t(100)\t53\t(100)\tNA\t—\t\n Yes\t0\t-\t0\t-\t\t\t\nValproic acid use during pregnancy\t\t\t\t\t\t\t\n No\t53\t(100)\t53\t(100)\tNA\t—\t\n Yes\t0\t-\t0\t-\t\t\t\nCI, Confidence Interval; NA, Not Applicable; NTD, Neural Tube Defects\n\nFrequencies and percentage may not equal total due to missing data.\n\nWe noted that 65% and 70% of case and control mothers, respectively, had low plasma folate concentrations at the time of the study visit (defined as a level lower than 4.0 ng/mL) at the time of the study visit (Table 1). The median plasma folate levels were 2.79 ng/mL among case mothers and 2.86 ng/mL among control mothers; however, the difference between the groups was not statistically significant (p = 0.85) (data not shown). Fig 1 shows the distribution of plasma folate concentrations among mothers at the time of study visit, by self-reported prenatal folic acid supplement use during pregnancy. It is clear from this figure that mothers who reported taking prenatal supplements were more likely to have higher plasma folate concentrations at the time of the study visit compared to mothers who did not report taking supplements.\n\n10.1371/journal.pone.0188726.g001Fig 1 Plasma folate concentrations at the time of the study by maternal prenatal folic acid supplement intake during pregnancy.\nSolid black line represents the distribution of plasma folate concentrations at the time of the study visit among mothers who reported prenatal folic acid supplement intake during pregnancy. Dotted line represents the distribution of plasma folate concentrations among mothers who reported that they did not use prenatal folic acid supplements during pregnancy. The threshold for optimal folic acid concentration is represented by the straight line at 4 ng/ml.\n\nAnalysis of matched pairs showed that there were 27 discordant pairs, i.e., pairs in which case mothers did not take folic acid but the control took folic acid (n = 8); and pairs in which the control mother did not take folic acid but the case mother did (n = 19). This difference in prenatal folic acid intake was statistically significant among the matched case-control pairs (McNemar’s p = 0.03).\n\nResults from the conditional logistic regression showed that maternal prenatal folic acid supplement use had a significant protective association with the risk of myelomeningocele (uOR = 0.42, 95% CI = 0.18–0.96) (Table 1). This association slightly attenuated after adjusting for maternal age at delivery (aOR = 0.43, 95% CI = 0.18–1.02); however, the magnitude of protective effect persisted. We were unable to examine potential confounding due to family history of neural tube defects, maternal pre-pregnancy diabetes, and prenatal exposure to valproic acid use, which are known risk factors for myelomeningocele, due to null exposures among case or control mothers.\n\nDiscussion\nOur study is the first case-control study to report the association between maternal prenatal folic acid supplement use and myelomeningocele in Bangladesh. We found a strong protective association, with up to 60% reduction in the risk of myelomeningocele from maternal prenatal folic acid use. There was a significant difference among case and control mothers with regard to the prevalence of folic acid supplement use during pregnancy. Up to three-quarters of both case and control mothers had low plasma folate concentrations at the time of the study visit. The protective findings of prenatal folic acid supplementation in our study, and the low use of folic acid supplementation by women of reproductive age, strongly suggest that folic acid fortification of the food supply would be a more effective preventive strategy for major and common neural tube defects in Bangladesh.\n\nOur results are consistent with findings from other case-control studies conducted in countries that did not have fortification programs at the time the study was conducted. A case-control study in Japan, a country that currently has no required folic acid fortification of staple foods showed maternal periconceptional folic acid-containing supplement intake reduced the risk of spina bifida in offspring by approximately 50% during two different study periods (study years 2001–2006: aOR = 0.48, 95% CI = 0.23–0.96; and study years 2007–2012: aOR = 0.53, 95% CI = 0.34–0.84) [20].\n\nBefore the United States implemented mandatory folic acid fortification of staples including wheat and maize (prior to 1998), a protective association was noted between maternal periconceptional multivitamin intake and the risk of spina bifida among births in Metropolitan Atlanta with an estimated relative risk of 0.37 (95% CI = 0.19–0.70) [21]. Post- folic acid fortification studies in the United States failed to demonstrate a protective effect of extra folic acid in multivitamin supplement pills on the risk of neural tube defects, where mandatory folic acid fortification has been attributed to near complete prevention of spina bifida [22].\n\nThe World Health Organization has recently released guidelines on optimal blood folate concentrations among women of reproductive age to prevent neural tube defects [23]. According to these guidelines, one can achieve maximum prevention of neural tube defects at a population level when the red blood cell concentrations of women of reproductive age are above 400 ng/mL (or 906 nmol/L). Concentrations below this threshold indicate folate insufficiency (i.e. concentrations that increase the risk of having an NTD-affected pregnancy). No established threshold exists for plasma folate concentration. However, folate deficiency has been established at a concentration of less than 4.0 ng/mL (<10 nmol/L) [24]. Our study, as well as other studies conducted recently in Bangladesh, indicate marked folate deficiency among women in Bangladesh [25,26]. We used plasma folate in our studies as this is measure widely used in Bangladesh.\n\nOur findings have limitations as they were based on a retrospective, observational study design. There is a potential for recall bias in responses related to pregnancy exposures and medical history. Plasma samples for folate assessments were drawn after the index pregnancy and not in the first trimester. Information on folic acid supplement use before conception was not collected. Further, the exact time of use and dosage of folic acid supplements taken during pregnancy was not inquired. However, we noticed that the mean plasma folate concentrations were higher at the time of study visit among women who reported folic acid use compared to their counterparts. The strong correlation between maternal report of prenatal folic acid supplement use and plasma folate concentrations validates maternal responses in the study, though it is important to reiterate that the plasma was collected many months after the pregnancy was completed and therefore represents current plasma folate and not folate levels during early pregnancy.\n\nThere were many strengths to our study. We had a high diagnostic accuracy and specificity in all myelomeningocele phenotypes, which were confirmed by an expert pediatrician. Controls were selected randomly from the same region as the cases. Maternal interviews were conducted by trained interviewers, and several important risk factors were assessed that allowed for a thorough analysis of potential confounders.\n\nBangladesh does not require folic acid fortification of staple foods. Instead, the country has invested in the national prenatal care program that promotes supplemental folic acid intake among women of reproductive age, which is largely determined by individual health behaviors and adherence patterns [27]. Our case-control study highlights the protective effect of folic acid supplement use alone on myelomeningocele, and possibly other neural tube defects. Bangladeshi women have also been found to be consuming a diet that does not provide an adequate daily dose of folate [17].\n\nOne would expect that case-control studies in areas with mandatory folic acid fortification would not suggest an additional protective effect from folic acid in supplements [28,29]. This can be attributed to improved blood folate concentrations gained through fortification, therefore yielding no additional protective effect from folic acid supplements. Bangladesh does not yet have a folic acid fortification mandate; thus, as expected, we were able to demonstrate a protective effect from folic acid supplements on the risk of myelomeningocele.\n\nData from several countries demonstrate that the mandatory fortification of staple foods is a more effective public health strategy for neural tube defects prevention than folic acid supplementation alone [30]. Folic acid supplementation program alone is less effective as a mass public health intervention because of several reasons, including unplanned pregnancies, lack of preconception care (aiming at the critical period for development of neural tube defects at 28 days after conception), delay in receiving prenatal care early in pregnancy, lack of knowledge or access to folic acid, and achieving compliance in supplement intake behaviors of women. In the backdrop of aforementioned conditions, the World Health Organization recommends folic acid fortification for countries where there is a high prevalence of malnutrition and unplanned pregnancies, such as Bangladesh [24]. Findings from our study suggest that if Bangladesh were to require folic acid fortification of a widely eaten and centrally processed food, such as rice or wheat, women would benefit from availability of folic acid from fortified foods at the right time, i.e., prior to the conception and during early pregnancy, the period when the neural tube develops in the embryo. At the same time, supplementation programs can be rolled out in areas where mandatory fortification cannot reach populations of Bangladesh. In combination, the two interventions would provide a complimentary and fast-paced solution in addressing neural tube defects reduction in Bangladesh. Preventing the mortality and morbidity associated with neural tube defects through folic acid fortification has the potential to help Bangladesh to move towards achieving the 2030 Sustainable Development Goals.\n\nWe would like to thank the field teams at Dhaka Community Hospital, in particular, Selim Mia, Biplop Biswas, and Md Soheil Rana who conducted field visits.\n==== Refs\nReferences\n1 Elwood JH , Nevin NC . Anencephalus and spina bifida in Belfast (1964–1968) . Ulster Med J . 1973 ; 42 (2 ):213 –222 . 4589090 \n2 Botto LD , Moore CA , Khoury MJ , Erickson JD . Neural-tube defects . N Engl J Med \n1999 ; 341 (20 ):1509 –1519 . doi: 10.1056/NEJM199911113412006 \n10559453 \n3 Sutton M , Daly LE , Kirke PN . Survival and disability in a cohort of neural tube defect births in Dublin, Ireland . Birth Defects Res A Clin Mol Teratol . 2008 ; 82 (10 ):701 –709 . doi: 10.1002/bdra.20498 \n18803309 \n4 Oakeshott P , Hunt GM , Poulton A , Reid F . Expectation of life and unexpected death in open spina bifida: a 40-year complete, non-selective, longitudinal cohort study . Dev Med Child Neurol . 2010 ; 52 (8 ):749 –753 . doi: 10.1111/j.1469-8749.2009.03543.x \n20015251 \n5 Kancherla V , Druschel CM , Oakley GP Jr. Population-based study to determine mortality in spina bifida: New York State Congenital Malformations Registry, 1983 to 2006 . Birth Defects Res A Clin Mol Teratol . 2014 ; 100 (8 ):563 –575 . doi: 10.1002/bdra.23259 \n24975407 \n6 Grosse SD , Berry RJ , Mick Tilford J , Kucik JE , Waitzman NJ . Retrospective Assessment of Cost Savings From Prevention: Folic Acid Fortification and Spina Bifida in the U.S . Am J Prev Med . 2016 ; 50 (5 Suppl 1 ):S74 –80 . doi: 10.1016/j.amepre.2015.10.012 \n26790341 \n7 Christianson A, Howson CP, Modell B. March of Dimes global report on birth defects: the hidden toll of dying and disabled children. White Plains, NY: March of Dimes Birth Defects Foundation; 2006.\n8 MRC Vitamin Study Research Group . Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group . Lancet . 1991 ; 338 (8760 ):131 –137 . 1677062 \n9 Czeizel AE , Dudas I . Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation . N Engl J Med . 1992 ; 327 (26 ):1832 –1835 . doi: 10.1056/NEJM199212243272602 \n1307234 \n10 Berry RJ , Li Z , Erickson JD , Li S , Moore CA , Wang H , et al\nPrevention of neural-tube defects with folic acid in China. China-U.S. Collaborative Project for Neural Tube Defect Prevention . N Engl J Med . 1999 ; 341 (20 ):1485 –1490 . doi: 10.1056/NEJM199911113412001 \n10559448 \n11 World Health Organization . Guideline: Daily Iron and Folic Acid Supplementation in Pregnant Women . Geneva : World Health Organization (WHO) ; 2012 .\n12 Khambalia A , O’Connor DL , Zlotkin S . Periconceptional iron and folate status is inadequate among married, nulliparous women in rural Bangladesh . J Nutr . 2009 ; 139 (6 ):1179 –1184 . doi: 10.3945/jn.108.101022 \n19403710 \n13 Alam N , Roy SK , Ahmed T , Ahmed AM . Nutritional status, dietary intake, and relevant knowledge of adolescent girls in rural Bangladesh . J Health Popul Nutr . 2010 ;28 (1 ):86 –94 . 20214090 \n14 Akhtar S . Malnutrition in South Asia-A Critical Reappraisal . Crit Rev Food Sci Nutr . 2016 ; 56 (14 ):2320 –2330 . doi: 10.1080/10408398.2013.832143 \n25830938 \n15 Lindström E , Hossain MB , Lönnerdal B , Raqib R , El Arifeen S , Ekström EC . Prevalence of anemia and micronutrient deficiencies in early pregnancy in rural Bangladesh, the MINIMat trial . Acta Obstet Gynecol Scand . 2011 ; 90 (1 ):47 –56 . doi: 10.1111/j.1600-0412.2010.01014.x \n21275915 \n16 Leyvraz M , Laillou A , Rahman S , Ahmed T , Rahman AS , Alam N , et al\nAn Assessment of the Potential Impact of Fortification of Staples and Condiments on Micronutrient Intake of Young Children and Women of Reproductive Age in Bangladesh . Nutrients . 2015 ; 7 (12 ):9960 –9971 . doi: 10.3390/nu7125511 \n26633483 \n17 Sustainable Development Goals. http://www.un.org/sustainabledevelopment/sustainable-development-goals/ accessed September 9, 2016.\n18 Mazumdar M , Ibne Hasan MO , Hamid R , Valeri L , Paul L , Selhub J , et al\nArsenic is associated with reduced effect of folic acid in myelomeningocele prevention: a case control study in Bangladesh . Environ Health . 2015 ; 14 :34 \ndoi: 10.1186/s12940-015-0020-0 \n25885259 \n19 Horne DW , Patterson D . Lactobacillus casei microbiological assay of folic acid derivatives in 96-well microtiter plates . Clin Chem . 1988 ; 34 (11 ):2357 –9 . 3141087 \n20 Kondo A , Morota N , Date H , Yoshifuji K , Morishima T , Miyazato M , et al\nAwareness of folic acid use increases its consumption, and reduces the risk of spina bifida . Br J Nutr . 2015 ; 114 (1 ):84 –90 . doi: 10.1017/S0007114515001439 \n25999131 \n21 Mulinare J , Cordero JF , Erickson JD , Berry RJ . Periconceptional use of multivitamins and the occurrence of neural tube defects . JAMA . 1988 ; 260 (21 ):3141 –3145 . 3184392 \n22 Ahrens K , Yazdy MM , Mitchell AA , Werler MM . 2011 \nFolic acid intake and spina bifida in the era of dietary folic acid fortification . Epidemiology . 2011; 22 (5 ):731 –737 . doi: 10.1097/EDE.0b013e3182227887 \n21659881 \n23 Cordero AM , Crider KS , Rogers LM , Cannon MJ , Berry RJ . Optimal serum and red blood cell folate concentrations in women of reproductive age for prevention of neural tube defects: World Health Organization guidelines . MMWR Morb Mortal Wkly Rep . 2015 ; 64 (15 ):421 –423 . See comment in PubMed Commons below 25905896 \n24 de Benoist B . Conclusions of a WHO Technical Consultation on folate and vitamin B12 deficiencies . Food Nutr Bull . 2008 ; 29 (2 Suppl ):S238 –S244 . doi: 10.1177/15648265080292S129 \n18709899 \n25 Gamble MV , Ahsan H , Liu X . Folate and cobalamin deficiencies and hyperhomocysteinemia in Bangladesh . Am J Clin Nutr . 2005 ; 81 (6 ):1372 –1377 . 15941889 \n26 Khambalia A , O’Connor DL , Zlotkin S . Periconceptional iron and folate status is inadequate among married, nulliparous women in rural Bangladesh . J Nutr . 2009 ; 139 (6 ):1179 –1184 . doi: 10.3945/jn.108.101022 \n19403710 \n27 Shaheen R , Streatfield PK , Naved RT , Lindholm L , Persson LA . Equity in adherence to and effect of prenatal food and micronutrient supplementation on child mortality: results from the MINIMat randomized trial, Bangladesh . BMC Public Health . 2014 ; 14 :5 \ndoi: 10.1186/1471-2458-14-5 \n24393610 \n28 Mosley BS , Cleves MA , Siega-Riz AM , Shaw GM , Canfield MA , Waller DK , et al\nNeural tube defects and maternal folate intake among pregnancies conceived after folic acid fortification in the United States . Am J Epidemiol . 2009 ; 169 (1 ):9 –17 . doi: 10.1093/aje/kwn331 \n18953063 \n29 Ahrens K , Yazdy MM , Mitchell AA , Werler MM . Folic acid intake and spina bifida in the era of dietary folic acid fortification . Epidemiology . 2011 ; 22 (5 ):731 –737 . doi: 10.1097/EDE.0b013e3182227887 \n21659881 \n30 Atta CA , Fiest KM , Frolkis AD , Jette N , Pringsheim T , St Germaine-Smith C , et al\nGlobal Birth Prevalence of Spina Bifida by Folic Acid Fortification Status: A Systematic Review and Meta-Analysis . Am J Public Health . 2016 ; 106 (1 ):e24 –e34 . doi: 10.2105/AJPH.2015.302902 \n26562127\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "12(11)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D001459:Bangladesh; D016022:Case-Control Studies; D005260:Female; D005492:Folic Acid; D006801:Humans; D007231:Infant, Newborn; D008591:Meningomyelocele; D011247:Pregnancy; D011295:Prenatal Care; D012307:Risk Factors; D055815:Young Adult",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e0188726",
"pmc": null,
"pmid": "29190654",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": "26562127;25830938;20214090;24393610;4589090;3184392;10559448;18803309;21275915;25905896;26790341;3141087;25999131;24975407;18953063;21659881;1307234;25885259;18709899;20015251;19403710;26633483;15941889;10559453;1677062",
"title": "Prenatal folic acid use associated with decreased risk of myelomeningocele: A case-control study offers further support for folic acid fortification in Bangladesh.",
"title_normalized": "prenatal folic acid use associated with decreased risk of myelomeningocele a case control study offers further support for folic acid fortification in bangladesh"
} | [
{
"companynumb": "US-CIPLA LTD.-2017BD24887",
"fulfillexpeditecriteria": "1",
"occurcountry": "BD",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FOLIC ACID"
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"drugadditional": null,
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{
"abstract": "BACKGROUND\nLocalized neuropathic pain (LNP) is a subgroup of neuropathic pain characterized by consistent and circumscribed area(s) of maximum pain, associated with negative or positive sensory signs and/or spontaneous symptoms characteristic of NP. Lidocaine medicated plasters (LMP) have shown to be effective in pain relief in selective LNP syndromes.\n\n\nMETHODS\nWe collected data of 130 patients in our database with LNP syndromes who used LMP.\n\n\nRESULTS\nForty-one patients out of 130 patients (32%) were treated with antiepileptics, antidepressants and opioids without improvement and/or with intolerable adverse effects and are not assuming systemic therapy anymore. Globally, during the 12 months follow-up, 15% of patients reached a complete pain relief without any systemic therapy, mainly in trigeminal and post-herpetic neuralgia (P=0.009), 38% of patients reduced analgesic drug consumption with the highest reduction in radiculopathy, post-herpetic neuralgia and trigeminal neuralgia. Topical and transient adverse effects, such as itching or local erythema, were seen in 19/130 (14.6%) patients; 7 of these patients (5.4%) needed to discontinue the treatment due to the occurrence of adverse effects. The dropout rate on global population (excluding cured and lost to follow-up) was 45%, and the main cause of dropouts was the inefficacy of treatment in the first 3 months of therapy with LMP.\n\n\nCONCLUSIONS\nLMP treatment is safe and worth consideration also as add-on therapy in order to reduce analgesic drug consumption in selected LNP.",
"affiliations": "Department of Surgery, Dentistry, Maternal and Infant Sciences, Pain Therapy Center, Verona University Hospital, Policlinico GB Rossi, Verona, Italy - alvise.martini@univr.it.;Section of Forensic Medicine, Department of Medicine and Public Health, Verona University Hospital, Policlinico GB Rossi, Verona, Italy.;Department of Surgery, Dentistry, Maternal and Infant Sciences, Pain Therapy Center, Verona University Hospital, Policlinico GB Rossi, Verona, Italy.;Department of Surgery, Dentistry, Maternal and Infant Sciences, Pain Therapy Center, Verona University Hospital, Policlinico GB Rossi, Verona, Italy.;Department of Neurosciences, Biomedicine and Movement Sciences, Neuromotor and Cognitive Rehabilitation Research Center, Verona University Hospital, Policlinico GB Rossi, Verona, Italy.;Department of Surgery, Dentistry, Maternal and Infant Sciences, Pain Therapy Center, Verona University Hospital, Policlinico GB Rossi, Verona, Italy.;School of Science and Engineering, Middlesex University, London, UK.;Department of Neurosciences, Biomedicine, and Movement Sciences, Verona University Hospital, Policlinico GB Rossi, Verona, Italy.;Department of Surgery, Dentistry, Maternal and Infant Sciences, Pain Therapy Center, Verona University Hospital, Policlinico GB Rossi, Verona, Italy.",
"authors": "Martini|Alvise|A|;Del Balzo|Giovanna|G|;Schweiger|Vittorio|V|;Zanzotti|Michele|M|;Picelli|Alessandro|A|;Parolini|Massimo|M|;Chinellato|Eris|E|;Tamburin|Stefano|S|;Polati|Enrico|E|",
"chemical_list": "D000700:Analgesics; D000779:Anesthetics, Local; D008012:Lidocaine",
"country": "Italy",
"delete": false,
"doi": "10.23736/S0026-4806.18.05690-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0026-4806",
"issue": "109(5)",
"journal": "Minerva medica",
"keywords": null,
"medline_ta": "Minerva Med",
"mesh_terms": "D000368:Aged; D000700:Analgesics; D000779:Anesthetics, Local; D004341:Drug Evaluation; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D004890:Erythema; D005260:Female; D006801:Humans; D008012:Lidocaine; D008297:Male; D008875:Middle Aged; D009437:Neuralgia; D051474:Neuralgia, Postherpetic; D010352:Patient Dropouts; D017060:Patient Satisfaction; D011537:Pruritus; D012189:Retrospective Studies; D012869:Skin Absorption; D057968:Transdermal Patch; D014277:Trigeminal Neuralgia",
"nlm_unique_id": "0400732",
"other_id": null,
"pages": "344-351",
"pmc": null,
"pmid": "29856191",
"pubdate": "2018-10",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Efficacy of lidocaine 5% medicated plaster (VERSATIS®) in patients with localized neuropathic pain poorly responsive to pharmacological therapy.",
"title_normalized": "efficacy of lidocaine 5 medicated plaster versatis in patients with localized neuropathic pain poorly responsive to pharmacological therapy"
} | [
{
"companynumb": "IT-ALKEM LABORATORIES LIMITED-IT-ALKEM-2018-04311",
"fulfillexpeditecriteria": "2",
"occurcountry": "IT",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LIDOCAINE"
},
"drugad... |
{
"abstract": "The patient was a 83-year- old male who worked as a farmer. He had complaints of weight loss, abdominal pain and joint pains for almost 5 months. Twenty days ago, the patient was checked at another hospital for complaints of occasional coughing and bloody sputum. He was treated with a diagnosis of pneumonia. His respiratory complaints were reduced, but there was no relief of his ongoing abdominal pain. Gastroduodenoscopy and colonoscopy were performed to examine for possible etiologies of continuous abdominal pain. Biopsies were taken from duodenal bulbus and second duodenal segment. Intense eosinophilic leukocyte infiltration and Strongyloides stercoralis larvae were observed in pathologic examination. The patient was successfully treated with albendazole 2x400 mg/day for 7+7 day.",
"affiliations": "Kahramanmaraş Sütçü İmam University Faculty of Medicine, Department of Infectious Disease and Clinical Microbilogy, Kahramanmaraş, Turkey.;Kahramanmaraş Sütçü İmam University Faculty of Medicine, Department of Rheumatology, Kahramanmaraş, Turkey.",
"authors": "Nazik|Selçuk|S|0000-0003-0587-0104;Yıldız|Fatih|F|0000-0003-3628-8870",
"chemical_list": "D000871:Anthelmintics; D015766:Albendazole",
"country": "Turkey",
"delete": false,
"doi": "10.4274/tpd.galenos.2020.6222",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1300-6320",
"issue": "44(2)",
"journal": "Turkiye parazitolojii dergisi",
"keywords": "Rheumatoid arthritis; Strongyloides stercoralis; hyperinfection",
"medline_ta": "Turkiye Parazitol Derg",
"mesh_terms": "D015746:Abdominal Pain; D000369:Aged, 80 and over; D000382:Agricultural Workers' Diseases; D015766:Albendazole; D000818:Animals; D000871:Anthelmintics; D018771:Arthralgia; D001172:Arthritis, Rheumatoid; D001706:Biopsy; D004386:Duodenum; D004802:Eosinophilia; D000067565:Farmers; D006801:Humans; D007814:Larva; D008297:Male; D011014:Pneumonia; D017171:Strongyloides stercoralis; D013322:Strongyloidiasis",
"nlm_unique_id": "9425544",
"other_id": null,
"pages": "112-114",
"pmc": null,
"pmid": "32482045",
"pubdate": "2020-06-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Rheumatoid Arthritis with Strongyloides stercoralis Hyperinfection.",
"title_normalized": "a case of rheumatoid arthritis with strongyloides stercoralis hyperinfection"
} | [
{
"companynumb": "TR-TEVA-2021-TR-1871890",
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"occurcountry": "TR",
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"activesubstancename": "PREDNISOLONE"
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... |
{
"abstract": "Many challenges remain in diagnosing monoclonal immunoglobulin-associated renal disease, despite widespread application of immunofluorescence (IF) and immunohistochemistry. Here, we report a newly diagnosed case of multiple myeloma with clinical suspicion of renal amyloidosis, which had negative IF staining for kappa and lambda light chains in the glomeruli. Although laser microdissection and mass spectrometry-based proteomic analysis have emerged as important tools for amyloid typing in the literature, such facilities are still not widely available in Asia. We propose that a clinicopathological algorithm for the evaluation of organized monoclonal renal deposits, together with a combined nephrological-haematological approach, will still be adequate to generate an unequivocal diagnosis in the majority of cases.",
"affiliations": "Department of Medicine, National University Health System, Singapore, Singapore.;Department of Pathology, National University Heath System, Singapore, Singapore.;Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore, Singapore.;Department of Medicine, National University Health System, Singapore, Singapore.;Department of Medicine, National University Health System, Singapore, Singapore.",
"authors": "Chang|Zi Yun|ZY|;Thamboo|Thomas Paulraj|TP|;Choong|Clarice Shi Hui|CSH|;Wong|Weng Kin|WK|;Ngoh|Clara Lee Ying|CLY|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000508785",
"fulltext": "\n==== Front\nCase Rep Nephrol Dial\nCase Rep Nephrol Dial\nCND\nCase Reports in Nephrology and Dialysis\n2296-9705 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\n10.1159/000508785\ncnd-0010-0095\nCase Report\nMultiple Myeloma-Associated Light Chain Amyloidosis and a Proposed Approach to Monoclonal Immunoglobulin-Associated Renal Disease\nChang Zi Yun a Thamboo Thomas Paulraj b Choong Clarice Shi Hui c Wong Weng Kin a Ngoh Clara Lee Ying a* aDepartment of Medicine, National University Health System, Singapore, Singapore\nbDepartment of Pathology, National University Heath System, Singapore, Singapore\ncDepartment of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore, Singapore\n*Clara Lee Ying Ngoh, Department of Medicine, National University of Singapore, 1E Kent Ridge Road, Level 10 NUHS Tower Block, Singapore 119228 (Singapore), clara_ly_ngoh@nuhs.edu.sg\nSep-Dec 2020 \n11 9 2020 \n11 9 2020 \n10 3 95 103\n27 2 2020 16 5 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.Many challenges remain in diagnosing monoclonal immunoglobulin-associated renal disease, despite widespread application of immunofluorescence (IF) and immunohistochemistry. Here, we report a newly diagnosed case of multiple myeloma with clinical suspicion of renal amyloidosis, which had negative IF staining for kappa and lambda light chains in the glomeruli. Although laser microdissection and mass spectrometry-based proteomic analysis have emerged as important tools for amyloid typing in the literature, such facilities are still not widely available in Asia. We propose that a clinicopathological algorithm for the evaluation of organized monoclonal renal deposits, together with a combined nephrological-haematological approach, will still be adequate to generate an unequivocal diagnosis in the majority of cases.\n\nKeywords\nImmunoglobulin deposition diseaseMyelomaAmyloidosis\n==== Body\nIntroduction\nLight chain (AL) amyloidosis is the most frequently diagnosed entity amongst monoclonal immunoglobulin (MIg)-associated renal diseases. Making a distinction between varying MIg-associated nephropathies can be challenging due to nonspecific staining on immunofluorescence (IF) and immunohistochemistry (IHC). This is likely related to the varied physicochemical and protein conformational properties of pathogenic MIgs. We present a case of multiple myeloma with AL amyloidosis, where glomerular deposits did not demonstrate sufficient light chain restriction, and a proposed clinicopathological algorithm to aid diagnosis.\n\nCase Description\nA 54-year-old Asian male presented with facial and lower limb oedema. There was no significant medical history (including diabetes mellitus and hypertension) or family history of renal disease. Physical examination revealed a blood pressure of 100/45 mm Hg. He had anasarca with no palpable lymph nodes or hepatosplenomegaly.\n\nLaboratory evaluation demonstrated abnormal serum creatinine of 270 μmol/L with nephrotic syndrome (urine protein to creatinine ratio 19 g/g, serum albumin 21 g/dL), haematocrit level of 22% and serum kappa to lambda free light chain ratio of 0.03. Serum M-protein was undetected. Subsequent serologic workup, including autoimmune serologies, infectious workup and anti-neutrophil cytoplasmic antibody (ANCA) studies were negative. Serum C-reactive protein and serum amyloid A (SAA) were not elevated at <5 mg/dL (range 10–45 mg/dL) and 4 mg/L (range 0–322 mg/L), respectively. Laboratory results are summarised in Table 1. Baseline renal function was unknown.\n\nA native renal biopsy was performed to evaluate the nephrotic syndrome with presumed acute kidney injury. On light microscopy, there were deposits of an amorphous substance in the mesangium and some capillary loops of the glomeruli (Fig. 1a), as well as in the interstitium, arteries and arterioles. Three of 19 glomeruli contained cellular crescents (Fig. 1b). The deposits stained weakly with periodic acid-Schiff stain and were pale on haematoxylin and eosin stain. There was also a focal “cock's comb” appearance in the glomeruli on periodic-acid silver stain. Amyloid was confirmed by the deposits exhibiting diffuse congophilia with apple-green birefringence seen under polarized light. In the glomeruli, however, this birefringence was weak and focal (Fig. 2a). While the deposits within the interstitium and arterioles demonstrated lambda light chain restriction by IF, the deposits in the glomeruli were negative for IgG, IgA, IgM, C1q, C3, fibrin and kappa and lambda light chains. Repeated IF on formalin-fixed and paraffin-embedded tissue after proteinase digestion yielded similar results. On immunohistochemical staining, the deposits in the glomeruli, blood vessels and interstitium were positive for amyloid P but were negative for amyloid A. The deposits were also positive for thioflavin T. There was no vasculitis or atypical tubular casts. Mild interstitial fibrosis and tubular atrophy were present (approximately 15%).\n\nHaematology was consulted urgently to evaluate for a lymphoproliferative disorder. Bone marrow biopsy showed 10–15% lambda-light chain-restricted plasma cells, diagnostic of multiple myeloma. No amyloid protein was found in the bone marrow. Separately, radiographs showed a lytic lesion in the right humerus. Cardiac ultrasonographic examination revealed a thickened myocardium wall suspicious for cardiac amyloid.\n\nRenal electron microscopy results returned from the pathologist 4 days later, confirming the presence of electron dense deposits within the mesangium, some glomerular capillary loops and the tubular basement membrane. These deposits were composed of randomly oriented fibrils with a diameter of approximately 8 nm (Fig. 2b). In many areas, the mesangial deposits appeared partially washed out. No unstructured deposits or tubuloreticular inclusions were identified.\n\nThe final diagnosis was multiple myeloma-associated AL amyloidosis, with glomerular crescents. He was planned for high-dose chemotherapy with cyclophosphamide, bortezomib and dexamethasone followed by autologous stem cell transplant. However, chemotherapy was complicated in its 4th month by respiratory failure from Pneumocystis jirovecii pneumonia requiring ventilatory support. Subsequent months of chemotherapy were interrupted by recurrent admissions for mucositis leading to dehydration and malnutrition. His renal function continued to decline, and he was initiated on dialysis 5 months after his initial diagnosis.\n\nDiscussion\nThis case illustrates the fact that despite widespread availability of IF and IHC, many challenges remain in diagnosing MIg-associated renal diseases. This is compounded by the fact that pathogenic MIgs are known to have varied physicochemical properties, giving rise to a wide spectrum of renal lesions or multiple renal manifestations in a single patient [1, 2]. In this case, the glomerular deposits did not show lambda light chain restriction congruent with the diagnosis of AL amyloidosis, although there was congophilia with focal weak birefringence under polarised light.\n\nSeveral possibilities need to be considered for this interesting phenomenon. The first is if another type of amyloid process was involved. However, the clinical suspicion for hereditary amyloidosis was low, given that the patient had neither family history of renal disease nor extra-renal manifestations of peripheral dysautonomia or liver impairment, common in amyloid transthyretin amyloidosis [3]. Other hereditary amyloid nephropathies, such as hereditary fibrinogen amyloidosis, have a distinct histological appearance of marked glomerular amyloid deposition with obliterated capillary lumens and minimal extraglomerular deposition − features not apparent in this patient [3, 4]. Furthermore, the patient's initial clinical management would be unchanged regardless, as he required cyclical chemotherapy for treatment of multiple myeloma and AL amyloidosis.\n\nThe alternative possibility of a concomitant glomerular pathology, such as fibrillary glomerulonephritis (FGN), has to be considered, given the presence of renal crescents, which is otherwise rare in AL amyloidosis [5]. Most reported cases of crescentic glomerulonephritis and concurrent amyloidosis have been seen with type AA amyloidosis due to serum amyloid A protein, in the clinical setting of rheumatoid arthritis or malignancy. In this patient, extensive autoimmune serologies did not point to a second glomerular disease. DnaJ homolog subfamily B member 9 (DNAJB9) IHC has been developed as a highly specific marker for FGN but is not available in local laboratories [6]. However, Nasr et al. [6] demonstrated in a recent study that paraffin IF unmasked polytypic IgG deposits in 43% of FGN initially believed to have light chain restriction on routine IF. The study authors hence concluded that DNAJB9-positive FGN was not associated with monoclonal gammopathy in the vast majority (>98%) of patients. This casts new questions on whether FGN can even be considered a differential in MIg-associated renal disease [7].\n\nInstead, the phenomenon of weakly staining glomeruli deposits could have been due to circulating plasma proteins which became non-specifically trapped by amyloid precursors in the glomeruli, masking relevant stains [8]. Alternatively, the quantities of circulating MIg may have been too minute.\n\nNonetheless, we acknowledge that the absence of certain techniques for protein typing in our laboratory are limitations for definitive exclusion of a different amyloid process. Current IHC techniques using commercial antibody-based amyloid typing have limited ability to detect the full spectrum of amyloid precursor proteins [8]. Laser microdissection (LMD) combined with mass spectrometry (MS)-based proteomics has recently emerged as a valuable tool for identifying protein signatures associated with different amyloid nephropathies [8, 9, 10]. LMD/MS would be additionally useful in this patient to exclude FGN, given the electron dense deposits seen on electron microscopy [8, 9]. In addition, spectrometry overcomes the problem of inadequate tissue for repeated IF, as it can be performed on a paraffin block without additional reagents. LMD/MS has also been reported in the literature to be useful in cases of membranoproliferative glomerulonephritis associated with MIg where deposits were masked and undetected by IF [11].\n\nHowever, the usage of LMD/MS will remain limited across Asia because it requires the aid of a highly experienced laboratory and is associated with significant setup costs [10, 12]. Our institution did not have a renal LMD/MS facility. Local pathology units are disincentivized because MIg-associated renal disease remains a rare entity, despite systemic monoclonal gammopathies affecting an estimated 4% of the general population. While efforts need to be made to acquire such highly specialised tools in a centralised unit, we recognise that the majority of institutions here in Asia will not have direct access to LMD/MS and, thus, propose a clinicopathological algorithmic approach to renal diseases with MIg deposits (Fig. 3).\n\nWe believe that in the majority of cases, careful evaluation and correlation of light microscopy, IF and ultrastructural findings, properly integrated with the clinical history and laboratory data, generally would provide enough information to generate an unequivocal diagnosis. This is true of our case. Based on this algorithmic approach, a nephrological-haematological approach becomes necessary for prognostication and treatment purposes once a MIg-related renal disease is suspected [2, 13]. There should be a low threshold for both native kidney and bone marrow biopsies, respectively, even if biopsy of one organ has isolated a preliminary diagnosis [2, 14]. Said et al. [3] have proposed that there are specific cases where LMD/MS may still remain necessary (Table 2). These include equivocal Congo red stain where clinical evaluation was unable to rule out a FGN, and all cases with positive IF staining for immunoglobulin heavy chains, where routine IF/IHC often is unable to type the amyloid deposits.\n\nConclusion\nDespite widespread application of IF and IHC, many challenges remain in diagnosing MIg-associated renal disease. This is partially due to the wide and heterogenous spectrum and properties of monoclonal precursor proteins. Occasionally, histological findings do not fit into a classical picture. When advanced ancillary techniques like LMD/MS are not widely available, such as in Asia, careful evaluation of clinicopathological evidence and a combined nephrological-haematological approach, where appropriate, may still help to generate an unequivocal diagnosis.\n\nStatement of Ethics\nThe patient gave written informed consent for this case to be published (including images). The research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki.\n\nConflict of Interest Statement\nThe manuscript has not been published previously in whole or part. The authors have no conflicts of interest to declare.\n\nFunding Sources\nNo funding was obtained for this project.\n\nAuthor Contributions\nZ.Y.C. and C.L.Y.N. contributed to patient care and writing the manuscript. Histopathology images and description were provided by T.P.T. All authors reviewed and approved the final version of the manuscript.\n\nFig. 1 In the glomeruli, there was diffuse mesangial widening due to deposition of an amorphous substance, which stained weakly with periodic acid-Schiff stain (a). One glomerulus contained a cellular crescent (b). PAS stain, original magnification ×40.\n\nFig. 2 The deposits in the blood vessel walls and glomeruli exhibited diffuse congophilia. However, while the stained deposits in the blood vessel walls showed strong apple-green birefringence under polarised light, this phenomenon was only seen weakly and focally in the glomerular deposits (a). On electron microscopy, the glomerular deposits were composed of randomly arranged fibrils with a mean diameter of 8 nm (b). Original magnification ×135,000.\n\nFig. 3 Proposed clinicopathological algorithm for suspected monoclonal immunoglobulin (MIg)-associated renal disease.\n\nTable 1 Results of the initial laboratory investigations\n\n\tResult\tNormal range\t\nBlood\t\t\t\nHaemoglobin\t10.1 g/dL\t11.4–14.7 g/dL\t\nPlatelets\t312×109/L\t164–387×109/L\t\nSodium\t141 mmol/L\t135–145 mmol/L\t\nPotassium\t3.6 mmol/L\t3.5–5.0 mmol/L\t\nUrea\t7.3 mmol/L\t2.0–4.5 mmol/L\t\nCreatinine\t270 µmol/L\t60–107 µmol/L\t\nAlbumin\t27 g/L\t38–48 g/L\t\nAdjusted calcium\t2.36 mmol/L\t2.15–2.55 mmol/L\t\nLactate dehydrogenase\t548 U/L\t250–580 U/L\t\nInfection serology\tNegative for HBV, HCV and HIV\t\t\nC-reactive protein\t<5 mg/dL\t10–45 mg/dL\t\nComplement\tNormal\t−\t\nAnti-nuclear antibody\tNegative\t−\t\nAnti-GBM\tNegative\t−\t\nANCA\tNegative\t−\t\nSerum M-protein\tNegative\t−\t\nFLC assay\tKappa FLC: 38.8 mg/L\tKappa: 3.3–19.4 mg/L\t\n\tLambda FLC: 1,176.0 mg/L\tLambda: 5.7–26.3 mg/L\t\nImmunofixation\tLambda light chain restriction\t\t\nSerum amyloid A protein\t4 mg/L\t0–322 mg/L\t\n\t\nUrine\t\t\t\nLeukocytes\t1/HPF\t−\t\nErythrocytes\t1/HPF\t−\t\nEstimated total urine protein\t19.0 g/L\t<0.2 g/L\t\nCasts\tNot seen\t−\t\nHBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; Anti- GBM, anti-glomerular basement membrane; ANCA, anti-neutrophil cytoplasmic antibody; FLC, free light chain; HPF, high-power field.\n\nTable 2 Proposed indications for use of LMD/MS proteomics for amyloid typing in native kidney biopsies\n\n1\tEquivocal Congo red staining, where fibrillary glomerulonephritis cannot be ruled out after thorough clinical and haematological evaluation\t\n\t\n2\tPositive IF staining for immunoglobulin heavy chains, with or without light chain staining, with or without positive IHC staining for serum amyloid A protein\t\n\t\n3\tEqual IF staining for kappa and lambda light chains, despite repeating IF on pronase-digested paraffin tissue\t\n\t\n4\tUnusual glomerular features such as endocapillary or extracapillary proliferation in the context of renal amyloid\n==== Refs\nReferences\n1 Bridoux F Leung N Hutchison CA Touchard G Sethi S Fermand JP International Kidney and Monoclonal Gammopathy Research Group Diagnosis of monoclonal gammopathy of renal significance Kidney Int 2015 4 87 (4) 698 711 25607108 \n2 Kim JH Kim JW Kim YN Kim HI Kim JY Kwon GY Progression of monoclonal gammopathy with undetermined significance to multiple myeloma diagnosed by kidney biopsy: A case report Case Rep Nephrol Dial 2015 9 5 (3) 180 6 26558251 \n3 Said SM Sethi S Valeri AM Leung N Cornell LD Fidler ME Renal amyloidosis: origin and clinicopathologic correlations of 474 recent cases Clin J Am Soc Nephrol 2013 9 8 (9) 1515 23 23704299 \n4 Gillmore JD Lachmann HJ Rowczenio D Gilbertson JA Zeng CH Liu ZH Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A α-chain amyloidosis J Am Soc Nephrol 2009 2 20 (2) 444 51 19073821 \n5 Yamagata H Satoskar A Kim J Marein S Maroz N Crescenteric glomerulonephritis related to AL amyloidosis Am J Kidney Dis 2018 71 (4) 598 \n6 Nasr SH Vrana JA Dasari S Bridoux F Fidler ME Kaaki S DNAJB9 is a specific immunohistochemical marker for fibrillary glomerulonephritis Kidney Int Rep 2017 8 3 (1) 56 64 29340314 \n7 Said SM Leung N Alexander MP Cornell LD Fidler ME Grande JP DNAJB9-positive monotypic fibrillary glomerulonephritis is not associated with monoclonal gammopathy in the vast majority of patients Kidney Int 2020 \n8 Sethi S Rajkumar SV D'Agati VD The complexity and heterogenity of monoclonal immunoglobulin-associated renal diseases J Am Soc Nephrol 2018 7 29 (7) 1810 23 29703839 \n9 Leung N Bridoux F Batuman V Chaidos A Cockwell P D'Agati VD The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group Nat Rev Nephrol 2019 1 15 (1) 45 59 30510265 \n10 Sethi S Vrana JA Theis JD Leung N Sethi A Nasr SH Laser microdissection and mass spectrometry-based proteomics aids the diagnosis and typing of renal amyloidosis Kidney Int 2012 7 82 (2) 226 34 22495291 \n11 Larsen CP Messias NC Walker PD Fidler ME Cornell LD Hernandez LH Membranoproliferative glomerulonephritis with masked monotypic immunoglobulin deposits Kidney Int 2015 10 88 (4) 867 73 26154922 \n12 Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Classification of amyloidosis by laser microdissection and mass spectrometry-based proteomic analysis in clinical biopsy specimens Blood 2009 12 114 (24) 4957 9 19797517 \n13 Khalighi MA Dean Wallace W Palma-Diaz MF Amyloid nephropathy Clin Kidney J 2014 4 7 (2) 97 106 25852856 \n14 Haubitz M Peest D Myeloma—new approaches to combined nephrological-haematological management Nephrol Dial Transplant 2006 3 21 (3) 582 90 16396976\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": null,
"issue": "10(3)",
"journal": "Case reports in nephrology and dialysis",
"keywords": "Amyloidosis; Immunoglobulin deposition disease; Myeloma",
"medline_ta": "Case Rep Nephrol Dial",
"mesh_terms": null,
"nlm_unique_id": "101636294",
"other_id": null,
"pages": "95-103",
"pmc": null,
"pmid": "33083386",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "19073821;16396976;19797517;22495291;25852856;30510265;25607108;29703839;26154922;32622524;23704299;26558251;29340314",
"title": "Multiple Myeloma-Associated Light Chain Amyloidosis and a Proposed Approach to Monoclonal Immunoglobulin-Associated Renal Disease.",
"title_normalized": "multiple myeloma associated light chain amyloidosis and a proposed approach to monoclonal immunoglobulin associated renal disease"
} | [
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"companynumb": "SG-FRESENIUS KABI-FK202102151",
"fulfillexpeditecriteria": "1",
"occurcountry": "SG",
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"activesubstancename": "DEXAMETHASONE"
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{
"abstract": "BACKGROUND\nThe role of perfusion computed tomography (pCT) in detecting changes in tumor vascularization as part of a response to antiangiogenic therapy in non-small cell lung cancer (NSCLC) remains unclear.\n\n\nMETHODS\nIn this prospective pilot study (IMPACT trial, NCT02316327), we aimed to determine the ability of pCT to detect early changes in blood flow (BF), blood volume (BV), and permeability (PMB), and to explore whether these changes could predict the response at day +42 in patients with advanced, treatment-naive, non-squamous NSCLC treated with cisplatin and gemcitabine plus bevacizumab.\n\n\nRESULTS\nAll of the perfusion parameters showed a consistent decrease during the course of treatment. The BV difference between baseline and early assessment was significant (p = 0.013), whereas all perfusion parameters showed significant differences between baseline and day +42 (p = 0.003, p = 0.049, and p = 0.002, respectively). Among the 16 patients evaluable for efficacy, a significant decline in BV at day +7 from baseline was observed in tumors with no response (p = 0.0418).\n\n\nCONCLUSIONS\nOur results confirm that pCT can capture early changes in tumor vasculature. A substantial early decline of BV from baseline might identify tumors less likely responsive to antiangiogenic-drugs.",
"affiliations": "Department of Medical Oncology, Hospital Clínic, 08036 Barcelona, Spain.;Department of Radiology, Hospital Clínic, 08036 Barcelona, Spain.;Department of Medical Oncology, Hospital Clínic, 08036 Barcelona, Spain.;Department of Medical Oncology, Hospital Clínic, 08036 Barcelona, Spain.;Department of Radiology, Hospital Clínic, 08036 Barcelona, Spain.;Department of Medical Oncology, Hospital Clínic, 08036 Barcelona, Spain.;Department of Radiology, Hospital Clínic, 08036 Barcelona, Spain.;Department of Medical Oncology, Hospital Clínic, 08036 Barcelona, Spain.",
"authors": "Aya|Francisco|F|0000-0002-3452-7607;Benegas|Mariana|M|;Viñolas|Nuria|N|;Reyes|Roxana|R|;Vollmer|Ivan|I|0000-0002-8051-3994;Arcocha|Ainara|A|;Sánchez|Marcelo|M|0000-0002-5754-7723;Reguart|Noemi|N|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/cancers13215566",
"fulltext": "\n==== Front\nCancers (Basel)\nCancers (Basel)\ncancers\nCancers\n2072-6694\nMDPI\n\n10.3390/cancers13215566\ncancers-13-05566\nArticle\nA Pilot Study to Evaluate Early Predictive Value of Thorax Perfusion-CT in Advanced NSCLC\nhttps://orcid.org/0000-0002-3452-7607\nAya Francisco 1234\nBenegas Mariana 56\nViñolas Nuria 16\nReyes Roxana 16\nhttps://orcid.org/0000-0002-8051-3994\nVollmer Ivan 56\nArcocha Ainara 16\nhttps://orcid.org/0000-0002-5754-7723\nSánchez Marcelo 56\nReguart Noemi 126*\nCerdá Alberich Leonor Academic Editor\nAlberich-Bayarri Ángel Academic Editor\nFanti Stefano Academic Editor\nHindie Elif Academic Editor\n1 Department of Medical Oncology, Hospital Clínic, 08036 Barcelona, Spain; faya@clinic.cat (F.A.); nvinolas@clinic.cat (N.V.); rmreyes@clinic.cat (R.R.); aarcocha@clinic.cat (A.A.)\n2 Translational Genomics and Targeted Therapies in Solid Tumors, IDIBAPS, 08036 Barcelona, Spain\n3 Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, 08003 Barcelona, Spain\n4 Pompeu Fabra University, 08002 Barcelona, Spain\n5 Department of Radiology, Hospital Clínic, 08036 Barcelona, Spain; mnbenega@clinic.cat (M.B.); vollmer@clinic.cat (I.V.); msanche@clinic.cat (M.S.)\n6 Thoracic Oncology Unit, Hospital Clínic, 08036 Barcelona, Spain\n* Correspondence: nreguart@clinic.cat; Tel.: +34-93-227-54-02\n06 11 2021\n11 2021\n13 21 556606 8 2021\n03 11 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nSimple Summary\n\nThe use of targeted drugs has brought about the development of new imaging techniques which are able to assess in vivo processes and changes in vascularization parameters can be captured as part of the antitumor response to antiangiogenic therapies. This pilot study (IMPACT trial, NCT02316327) aimed to explore the capacity of Perfusion-Computed Tomography (pCT) to detect early changes in tumor vascularization in non-small cell lung cancer (NSCLC) patients treated with an antiangiogenic-based therapy. Our results confirm the feasibility of pCT to capture early changes in tumor vasculature and suggest the potential of blood volume (BV) to early identify differential tumor responses to antiangiogenic therapy.\n\nAbstract\n\nBackground: The role of perfusion computed tomography (pCT) in detecting changes in tumor vascularization as part of a response to antiangiogenic therapy in non-small cell lung cancer (NSCLC) remains unclear. Methods: In this prospective pilot study (IMPACT trial, NCT02316327), we aimed to determine the ability of pCT to detect early changes in blood flow (BF), blood volume (BV), and permeability (PMB), and to explore whether these changes could predict the response at day +42 in patients with advanced, treatment-naive, non-squamous NSCLC treated with cisplatin and gemcitabine plus bevacizumab. Results: All of the perfusion parameters showed a consistent decrease during the course of treatment. The BV difference between baseline and early assessment was significant (p = 0.013), whereas all perfusion parameters showed significant differences between baseline and day +42 (p = 0.003, p = 0.049, and p = 0.002, respectively). Among the 16 patients evaluable for efficacy, a significant decline in BV at day +7 from baseline was observed in tumors with no response (p = 0.0418). Conclusions: Our results confirm that pCT can capture early changes in tumor vasculature. A substantial early decline of BV from baseline might identify tumors less likely responsive to antiangiogenic-drugs.\n\nimaging\nperfusion CT\nNSCLC\nantiangiogenic\nbiomarkers\ntumor perfusion\nbevacizumab\n==== Body\npmc1. Introduction\n\nIn recent decades, lung cancer treatment has drastically changed, shifting towards personalized therapies with specific molecular therapies, including kinase inhibitors, antiangiogenics, and immunotherapies, which has led to a paradigm shift in the approach for lung cancer patients [1].\n\nThe role of the vascular endothelial growth factor (VEGF) in the stimulation of tumor angiogenesis, the maintenance of existing vessels, and the resistance to therapies, along with its negative prognostic significance in non-small cell lung cancer (NSCLC), have made it an important therapeutic target against this tumor [2]. Bevacizumab is a humanized anti-VEGF antibody that can function as an antiangiogenic link by binding directly to VEGF and deactivate it in the tumor microenvironment [3]. It was the first antiangiogenic drug approved for advanced lung cancer [4,5].\n\nTraditionally, the evaluation of efficacy has been based purely on morphological data, by means of studying changes in the diameter of lesions according to the Response Evaluation Criteria in Solid Tumors (RECIST) [6]. However, evaluation of the response based exclusively on size change misses important biological and physiological information of the tumor that can be relevant in treatment decision-making [7]. To overcome this limitation, several functional imaging techniques, such as perfusion computed tomography (pCT), have been the subject of extensive research to evaluate the response to therapy in advanced NSCLC patients, particularly to antiangiogenic agents. However, the data is conflicting and most of these approaches have not been evaluated in clinical studies.\n\nIn this prospective pilot study, we aimed to assess whether pCT could capture early changes in the tumor vasculature of NSCLC patients treated with a combination of antiangiogenic therapy and chemotherapy. Secondly, we explored if perfusion parameters dynamics (early at day +7 and at day +42) correlate with tumor response to therapy (day +42).\n\n2. Materials and Methods\n\n2.1. Study Design and Patients\n\nThis is a single-arm, non-interventional, pilot study performed at a single institution. The study was done in accordance with the International Conference on Harmonization Good Clinical Practice guidelines, the Declaration of Helsinki, and applicable local regulations with approval from local ethics committees and institutional review boards. Written informed consent was obtained from all participants. This study is registered at ClinicalTrials.gov (NCT02316327) and has been completed.\n\nPatients were recruited from July 2013 to April 2016 at the Hospital Clinic of Barcelona. Eligible patients had cytologically or histologically confirmed, advanced or metastatic non-squamous NSCLC (stage IV according to the seventh edition of the American Joint Committee on Cancer TNM staging system) for which they had not received prior systemic chemotherapy. All patients were required to have at least one unidimensional, measurable thoracic lesion of ≥1 cm as shown by conventional computed tomography (CT). Other eligibility criteria included a World Health Organization (WHO) performance status score of 0 or 1, suitability for first-line platinum-based chemotherapy, and an adequate organ and bone marrow function. Patients with brain metastases were eligible provided they were asymptomatic or treated and stable, and off steroids and anticonvulsants for at least one month before study entry.\n\nThe main exclusion criteria included a history of hemoptysis grade ≥2 (defined as 2.5 mL or more of fresh blood) within three months prior to treatment, mixed adenosquamous carcinoma, radiological evidence of compression or invasion of great blood vessels (i.e., pulmonary artery or superior vena cava), bleeding risk factors (such as coagulopathy, thrombolytic therapy within 10 days prior to treatment), and uncontrolled, concurrent illness or active infections. A complete description of all inclusion and exclusion criteria is included in Supplementary Materials. Adverse events were collected and graded according to the National Cancer Institute common terminology criteria for adverse events (NCI-CTCAE), version 4.0.\n\n2.2. Treatment\n\nTreatment was administered intravenously (IV) and consisted of chemotherapy with cisplatin at 80 mg/m2 administered on day 1 and gemcitabine at 1250 mg/m2 on days 1 and 8, plus Bevacizumab 7.5 mg/kg IV on day 1. Treatment was repeated every 21 days for up to six cycles. Patients with non-progressive disease were allowed to continue with bevacizumab monotherapy as maintenance until disease progression, unacceptable adverse events, withdrawal of consent, or death.\n\n2.3. Imaging Protocol\n\nPerfusion-CT was performed at day −1 (baseline), day +7 and day +42, followed by a CT of the thorax and abdomen to perform the RECIST 1.1 assessment. Then, only a CT of the thorax and abdomen was performed every two cycles until disease progression (Figure S1). A dual-source scanner with 128 detector rows (Flash Definition®, Siemens; Forchheim, Germany) was used.\n\nAn 18-gauge cannula was placed into a superficial vein of the antecubital fossa while the patient lay supine on the table. All patients were instructed to smoothly breathe during image acquisition to avoid excessive lung motion. No further preparation was necessary.\n\nFifty milliliters of iodinated contrast was injected (Iopromide 300, Ultravist® Bayer Healthcare; Berlin, Germany) at 5 mL/s, followed by 50 mL of saline at the same rate. The pCT scan was initiated 5 s after the injection of the contrast commenced, using the following parameters: 80 kVp and 100 mAs; 0.33 s tube rotation time. The total time of the pCT study was always 45 s. The time interval between scans was 1.5 s. The total length of the studies along the z-axis was always 21 cm. After finishing the pCT, an additional dose of 50 mL of iodinated contrast was administered to perform the chest and abdomen CT.\n\nThe data was processed using a dedicated workstation (Multi-Modality Workplace®, Siemens, Forchheim, Germany) running the Syngo Volume Perfusion Computed Tomography (VPCT) Body program, VE36A. First, the automatic motion and noise correction algorithms included in the VPCT Body software were applied. An arterial density-to-time curve was obtained by placing a region of interest in the thoracic aorta. The tumor volume was selected via manual segmentation, drawing the contours of the lesion in the axial, coronal, and sagittal planes. For the perfusion evaluation, we included the best thoracic lesion to be segmented, including parenchymal lung tumors in 11 patients, mediastinal lymph nodes in 4 patients, and pleural metastases in 2 patients. The following perfusion parameters were calculated using a variant of the deconvolution algorithm: BF, in mL/100 mL/min; BV, in mL/100 mL; and PMB, in mL/100 mL/min. For the radiological response evaluation, the overall tumor burden was assessed according to RECIST v1.1 criteria [6]. Target and non-target lesions of non-thoracic lesions were also taken into account and the definitions of complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) from RECIST 1.1 were used to categorize the overall response.\n\nAll perfusion parameters and efficacy assessments were performed by the same reader, a senior chest radiologist with broad experience in lung cancer and specific training in perfusion post-processing (M.S).\n\n2.4. Statistical Analysis\n\nThe co-primary endpoints of the study were to assess early changes evaluated at day +7 after treatment in perfusion parameters (BF, BV, and PMB), and to correlate the perfusion parameters at different timepoints, as well as their changes with radiological tumor response, according to RECIST v1.1 (day +42).\n\nThis is a pilot study with an initial expected sample size of 20 patients. In order to decide the sample size of our study, we considered delving into the perfusion parameters of the responders’ population, and estimated that we had to include 20 patients to achieve the minimum of 3 responders, according to the formula given by Viechtbauer et al. (confidence 0.95, probability 0.15).\n\nIn the end, 19 patients signed the informed-consent form. The baseline and patient characteristics, as well as objective response rates were analyzed in the intent-to-treat (ITT) population, which included all patients who signed the informed consent. The per protocol (PP) population was all patients who received at least one cycle of treatment and were assessed with conventional and perfusion CT at day +7. Progression-free survival (PFS) and overall survival (OS) were analyzed in the PP assessed at day +42. The pCT parameters and characteristics, such as the type of thoracic target lesion, as well as overall survival and progression-free survival, were analyzed in the PP. PFS was defined as the time from treatment initiation until disease progression per RECIST v1.1 as assessed by the investigator or death from any cause. OS was defined as the time from treatment initiation until death from any cause.\n\nWe conducted univariate analyses using Fisher’s exact test for categorical factors and paired or independent Wilcoxon and Friedman tests for comparisons among continuous variables. The Bonferroni method was used for p value adjustments when needed for multiple comparisons. Survival curves were estimated using the Kaplan–Meier method and the log rank test was performed to compare PFS between groups. All statistical analyses were performed with R 4.0.3.\n\n3. Results\n\n3.1. Patient Characteristics\n\nBetween July 2013 and April 2016, 19 patients were enrolled. Of these, two patients did not receive treatment because of a protocol deviation due to vascular compromise (invasion or compression) and one patient withdrew consent after one cycle of treatment (Figure 1).\n\nFifteen patients were male, and the median age was 66 years old (range: 38–75 years old). All patients had a history of tobacco exposure and 10 patients were active smokers at screening. The most frequent histology was adenocarcinoma (17 patients, 89.5%), and 18 patients were diagnosed as stage IV (42.1% M1a and 52.6% M1b). No EGFR mutation nor ALK translocation were found, and 10 tumors (52.6%) harbored a KRAS mutation. Four patients were previously treated with surgery and two patients had received prior radiotherapy. The mean number of chemotherapy cycles was 4.5 (range 1–6) and the mean number of bevacizumab doses as maintenance was 7.5 (range 0–27). Twelve patients received at least one line of subsequent treatment (range 0–7), of which five patients were treated with immunotherapy. The median follow-up was 19.5 months (95% confidence interval [CI]: 10.8–31). Sixteen patients were suitable for response assessment at day +42. Among them, seven patients (36.8%) had a PR, eight (42.1%) had SD, and one patient (5.2%) showed PD as the best overall objective response, according to RECIST v1.1. The baseline characteristics are summarized in Table 1.\n\nNo unexpected adverse events were reported, and the safety profile was consistent with previously published data [4]. No deaths deemed by investigators to be related to the treatment were reported (Table S1).\n\n3.2. Baseline Perfusion Parameters and Early Changes in Absolute Values\n\nBaseline and early (day +7) assessments were performed of 17 patients (Figure 1) while day +42 assessment was performed of 16 patients. For the pCT evaluation and follow-up upon treatment, the selected baseline thoracic target lesions included lung nodules in 11 patients (64.7%), lymph nodes in 4 patients (23.5%), and pleura in 2 cases (11.8%).\n\nIndividual measurements of perfusion parameters over time and over all patients are summarized in Figure 2. Mean values of the three perfusion parameters (BF, BV, and PMB) measured at baseline, early at day +7 and at day +42 showed a consistent decrease during the treatment (Figure 3). The mean values of the different perfusion parameters at the different time-points were significantly different among them (Table 2). Moreover, a paired Wilcoxon test between measurements at baseline and at day +42 showed statistically significant differences in BF (p = 0.003), BV (p = 0.049), and PMB (p = 0.002). Interestingly, a statistically significant difference between paired baseline and early measurement (day +7 after treatment) was also found for BV (p = 0.013) (Figure 3).\n\n3.3. Percentage Change in Perfusion Parameters from Baseline\n\nWe then evaluated the percentage change of each perfusion parameter taking into account values from day +7 and day +42 in comparison to baseline values (Table 3 and Figure 4). No statistically significant differences were found between the early percentage change and the day +42 percentage change in any perfusion parameter.\n\n3.4. Perfusion Parameters Changes and Tumor Response\n\nThe tumor response evaluation according to RECIST v1.1 and the perfusion parameters by pCT were evaluated at day +42 after treatment in 16 patients (Figure 1 and Table 4). Twelve patients (75%) were considered non-responders (including 11 patients with stable disease and 1 with progressive disease) and 4 patients (25%) were considered responders (all of them presented partial responses). Except for response rates, no differences were found in baseline and demographic data between responder and non-responder patients (Table 1).\n\nNo statistically significant differences were found at baseline or at day +42 in terms of BF, BV, and PMB between responders and non-responders (Table 5). Early assessments at day +7 only showed significant differences in BV parameters, being lower in non-responders than responders (4.7 vs. 7.52 mL/100 mL, p = 0.0337) (Figure 5 and Figure 6). Consistent with the absolute values, a significant decline in the percentage of BV at day +7 from baseline was observed in non-responders with respect to responders (−38.01% vs. +1.02%, p = 0.0418) (Table 6 and Figure 5). No correlation was found between tumor burden in terms and BV neither at baseline nor at day +42 (Spearman’s rank correlation coefficient: −0.212 and −0.25, respectively).\n\n3.5. Survival Analyses\n\nThe median PFS was 7.71 months (95% CI 5.48–14.92) and median OS was 17.6 months (95% CI 10.8–NA) with 14 deaths (87.5%) of the 16 patients undergoing follow-up.\n\nWe could not find significant differences in terms of PFS or OS in patients according to early BV changes, neither for other perfusion parameters at different time points.\n\n4. Discussion\n\nOur study was designed as a pilot study with the aim of deciphering the feasibility of pCT in a homogeneous cohort of advanced non-squamous NSCLC patients receiving cisplatin and gemcitabine plus bevacizumab as a first-line treatment. Our results meet both co-primary endpoints: first, indicating the capacity of pCT in capturing early changes at day +7 after treatment initiation; and, secondly, suggesting that a dynamic perfusion parameter, such as BV, might identify tumors less likely to respond to antiangiogenic therapy. To our knowledge, this is the first study carried out in a prospective manner showing the feasibility of pCT in detecting early changes as soon as day +7 after the first treatment administration in addition to at different time points.\n\nThe role of pCT imaging in tumor response assessment in lung cancer remains uncertain despite several publications attempting to elucidate it and, to date, no functional imaging technique has been routinely established for use in clinical practice. The incorporation of bevacizumab, the first antiangiogenic drug approved for the treatment of advanced NSCLC, raised high expectations regarding the usefulness of dynamic perfusion techniques to stratify outcomes in patients treated with antiangiogenic agents. However, the results in the literature are rather conflicting. This is most likely due to the notable variability in treatments (different chemotherapy combinations, targeted therapies, and/or radiotherapy), in the time points used for imaging acquisition, and in the criteria used for response evaluation, which is mostly limited to the same single lesion from which the perfusion parameters were measured [8,9,10,11,12,13,14,15] (Table S2).\n\nOur results indicate the presence of early changes in tumor vasculature after therapy with an antiangiogenic agent that can be detected through BV measured with pCT. We also observed that the relative drop was not increased over time under treatment in any perfusion parameter, suggesting that an early evaluation at day +7 is indeed sufficient to capture significant tumor vasculature changes. Despite the small sample size, this study points BV as the most reliable and sensitive perfusion parameter and propose the limited capacity of BF and PMB in evaluating tumor response to antiangiogenics. This finding is consistent with other previous publications [13,14,15] which have seen a correlation between BV values and dynamics with response to therapy. Fraioli et al. [13] evaluated the role of pCT in NSCLC in a similar setting of patients treated with antiangiogenic therapy (bevacizumab) in combination with chemotherapy (carboplatin and paclitaxel). They also reported a significant decrease in terms of BF and PMB in the overall population and higher BV values in responders at different time points throughout the treatment. In the same line, Tacelli et al. [15], using newly defined concepts of BV and PMB (TTV, total tumor vascular volume, and TEF, total tumor extravascular flow, respectively), also found that both parameters decreased throughout the treatment, with higher values found among responders when chemotherapy was administered with bevacizumab.\n\nOn the contrary, in our pilot study, none of the perfusion parameters (BF, BV, and PMB) at baseline or at day +42 were predictive of response. These results contrast with other reports in which higher responses were seen in tumors with higher baseline BF and BV perfusion values [14]. Another striking observation of our pilot study is the identification of preliminary signals suggesting a potential role of BV as an early predictive biomarker as we observed a significant decrease and, consequently, a significantly lower BV at day +7, among the non-responder patient population. Some other studies have suggested a decrease in BV among responders in comparison to non-responders [8,9]. However, the decrease in BV in responders was not consistent and was only observed among patients treated with chemoradiation [8] and in those tumors of non-adenocarcinoma histology [9].\n\nEven though our pilot study was exploratory in nature, it avoids some of the weaknesses of previous publications, such as the heterogeneity of lung cancer histologies, the flexible time points for imaging acquisitions and the wide variety of treatments in the same study, which might result in misleading conclusions. In our study, the outcomes are consistent with other pivotal trials in literature in the same first-line setting for NSCLC [4]. On the other hand, we believed that the use of cisplatin and gemcitabine as the chemotherapeutic backbone was optimal in order to prevent the confusing anti-angiogenic effect led by taxanes, which have been recognized as a strong modulator of angiogenesis [16,17,18]. This regimen allowed us to assess changes in the perfusion parameters mostly induced by the antiangiogenic bevacizumab. Unlike most previous publications, we applied RECIST v1.1 not only in the target perfusion lesion, but also in the whole patient for the assessment of the overall tumor burden. Evaluation of a single lesion may result in a misinterpretation of the response even if using RECIST criteria, and correlation of perfusion parameters with a complete evaluation of tumor response is a more realistic approach, mimicking a real clinical scenario. Moreover, both perfusion parameters and radiological assessments were conducted by the same observer, which gives a stronger internal validity, preventing inter-observer variability.\n\nAlong with this, we hypothesized that there can be two different biological scenarios that could explain the early drop of BV at day +7 in non-responder patients. First, the inability of BV (measured by pCT) to discriminate between differentiated and undifferentiated blood vessels. An increased density of pathological undifferentiated vessels (defined as intratumor CD34+ cells) has been described in tumors with high BV levels [19,20]. Interestingly, Zhao et al. [21] found a negative correlation between tumor shrinkage upon antiangiogenic therapy and the degree of vascular differentiation (CD31+/CD34– and CD31–/CD34+), suggesting that tumors bearing a higher proportion of undifferentiated vessels (CD31–/CD34+) display a greater susceptibility to bevacizumab. Therefore, it might be possible that those tumors with higher baseline BV values were enriched with undifferentiated vessels, thus having a greater initial drop of BV after antiangiogenic treatment, despite its poor response at day +42. Unfortunately, no data on the correlation between perfusion parameters and vascular differentiation has been reported so far. Secondly, although antiangiogenic therapy is hypothesized to revert tumor vasculature to a more normal state, therefore improving the drug delivery, several studies have reported a decrease in the delivery of chemotherapy due to the reduction in tumor perfusion induced by the antiangiogenic therapy [22,23]. Therefore, it could be feasible that the early drop of BV seen in tumors without response reflects a more undifferentiated vascular content in which chemotherapy delivery would be negatively affected, limiting tumor response. Correlative sequential histopathological analyses, as well as different antiangiogenic schedules within the context of a clinical trial, are warranted to elucidate our hypothesis.\n\nThis pilot study has inherent limitations as it was designed as exploratory to obtain an initial proof-of-concept on the potential of pCT parameters to capture early tumor changes. As, a pilot study we did not provide a meaningful sample estimate that might overcome the imprecision resulting of small study designs. Therefore, conclusions driven on the potential predictive value of pCT parameters must be taken with caution and considered only of descriptive nature. Secondly, we acknowledge that the use of an active comparator arm without bevacizumab could have provided more insights about the definitive causality of the antiangiogenic. We could have also increased the informative value of our results by using other radiomic parameters (that have been shown to be useful in building predictive models) [24,25], or using multiple target lesions. However, this would add further complexity for use in clinical practice.\n\nGrowing evidence suggests that VEGF inhibitors can modulate the tumor microenvironment by promoting the differentiation and function of immune cells, ultimately increasing the antitumor effect of immunotherapy [26]. With the advent of immunotherapy, novel combination approaches with antiangiogenic agents—such as lenvatinib (NCT03976375), ramucirumab (NCT03971474), sitravatinib (NCT03906071), or nintedanib (NCT02856425), among others—are currently under investigation in several phase II-III trials, particularly in lung cancer patients with acquired resistance to immunotherapy. Thus, the development of innovative imaging evaluation methods—especially for tumor response evaluation—still represents a largely unexplored area of study that warrants further investigation.\n\n5. Conclusions\n\nOur pilot study confirms the feasibility of pCT in detecting early perfusion changes in tumor vasculature of NSCLC treated with antiangiogenic therapy and suggests BV as the most reliable and sensitive measurement to identify tumors less likely responsive to antiangiogenic-drugs.\n\nAcknowledgments\n\nThe authors wish to thank all the patients, family members, and staff from all the units that participated in the study. The authors thank Kyla M. Juett for improving the use of English in the manuscript.\n\nSupplementary Materials\n\nThe following are available online at https://www.mdpi.com/article/10.3390/cancers13215566/s1, Supplementary Methods: Inclusion and Exclusion criteria; Table S1: Adverse events of any cause in the treated population; Table S2: Summary of main publications of perfusion CT assessments in lung cancer; Figure S1: IMPACT trial—study design. Parameters used for pCT evaluation: Blood Flow (BF, mL/100 mL/min), Blood Volume (BV, mL/100 mL), and Permeability (PMB, mL/100 mL/min).\n\nClick here for additional data file.\n\nAuthor Contributions\n\nConceptualization, N.R. and M.S.; methodology, N.R. and M.S.; formal analysis, F.A., N.R. and M.S.; investigation, F.A., N.V., R.R., M.B., A.A., M.S. and N.R.; data curation, F.A., M.S. and N.R.; writing—original draft preparation, F.A. and N.R.; writing—review and editing, F.A., N.R., M.S., N.V., I.V., R.R., M.B. and A.A.; supervision, N.R.; project administration, A.A.; funding acquisition, N.R. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research was funded by F. Hoffmann-La Roche Ltd. (Basel, Switzerland).\n\nInstitutional Review Board Statement\n\nThe study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Local Committee of Research Ethics of Hospital Clinic, Barcelona, Spain. Written informed consent was obtained from all patients and data was de-identified for patient confidentiality.\n\nInformed Consent Statement\n\nInformed consent was obtained from all subjects involved in the study.\n\nData Availability Statement\n\nAll of the data generated or analyzed during this study is included in this published article, and the supplementary information files are available from the authors upon reasonable request.\n\nConflicts of Interest\n\nF.A. has received travel grants and other honoraria from BMS, MSD, Novartis, and Roche. N.V. has received fees for consultancy/advisory roles from Roche, Pfizer, and Boerhinger, and has received travel grants and other honoraria from BMS, MSD, Roche, Boeringher, AstraZeneca, and Lilly. R.R. has received lecture fees roles from Roche, BMS, and MSD. N.R. has received fees for consultancy/advisory roles from MSD, BMS, Roche, and Pfizer, and research funding from Pfizer, Novartis, and the Ministry of Health, Instituto de Salud Carlos III, Spain. M.S., I.V., M.B. and A.A. have declared no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.\n\nFigure 1 Study patients’ flow chart.\n\nFigure 2 Line charts showing individual values of blood flow (A), blood volume (B), and permeability (C) at baseline (blue line), day +7 (red line), and day +42 (yellow line) after treatment initiation, case by case.\n\nFigure 3 Boxplots showing values of blood flow (A), blood volume (B), and permeability (C) at baseline, day +7, and day +42 after treatment initiation in the entire population.\n\nFigure 4 Boxplots showing percentage changes of blood flow (A), blood volume (B), and permeability (C) at day +7, and day +42 after treatment initiation compared to basal values in the entire population.\n\nFigure 5 (A–C) Boxplots showing values of blood flow (A), blood volume (B), and permeability (C) at baseline, day +7, and day +42 after treatment initiation in non-responder and responder patients according to RECIST v1.1 at day +42. (D–F) Boxplots showing relative changes in percentages over time, at day +7, and at day +42 after treatment initiation in terms of blood flow (D), blood volume (E) and permeability (F) in non-responder and responder patients according to RECIST v1.1 at day +42.\n\nFigure 6 Axial thoracic CT of a 52-year-old man with stage IVa NSCLC showing a lung tumor in the right upper lobe, at baseline (A), day +7 (E), and day +42 (I). Perfusion CT of the lesion with parameters: Blood Flow, BF, (mL/100 mL/min) at baseline (B), day +7 (F), and day +42 (J); Blood Volume, BV, (mL/100 mL) at baseline (C), day +7 (G), and day +42 (K); Permeability, PMB, (mL/100 mL/min) at baseline (D), day +7 (H), and day +42 (L). Color-coded maps and quantification showed an early decrease in BV at day +7 with stable disease according to RECIST at day +42.\n\ncancers-13-05566-t001_Table 1 Table 1 Demographic and baseline characteristics of patients.\n\nVariation\tn (%)\tNon-Responders, n (%)\tResponders, n (%)\tp Value\t\nSex\tMale\t15 (78.9)\t11 (91.7)\t3 (75)\t0.45\t\nAge\tmedian (range)\t66 (38–75)\t66.8 (41–74)\t57.6 (38–75)\t0.521\t\nSmoking Status\tActive smoker\t10 (52.6)\t5 (41.7)\t3 (75)\t0.569\t\nFormer smoker\t9 (47.4)\t7 (58.3)\t1 (25)\t\nHistology\tAdenocarcinoma\t17 (89.5)\t12 (100)\t4 (0)\t1\t\nNon-adenocarcinoma\t2 (10.5)\t0\t0\t\nStage\tIIIB\t1 (5.3)\t1 (25)\t0\t0.426\t\nIV-M1a\t8 (42.1)\t1 (25)\t5 (41.7)\t\nIV-M1b\t10 (52.6)\t2 (50)\t7 (58.3)\t\nKRAS Status\tMutant\t10 (52.6)\t2 (50)\t6 (50)\t0.548\t\nWild type\t5 (26.3)\t2 (50)\t2 (16.7)\t\nUnknown\t4 (21.1)\t0\t4 (33.3)\t\nPrior Treatment\tSurgery\t4 (21.1)\t2 (16.7)\t0 (0)\t0.728\t\nRadiotherapy\t2 (10.5)\t1 (8.33)\t1 (25)\t\nChemotherapy\t0 (0)\t0\t0\t\nECOG PS\t0\t5 (26.3)\t2 (16.7)\t3 (75)\t0.063\t\n1\t14 (73.7)\t10 (83.3)\t1 (25)\t\nTreatment, Mean (Range)\tCT + BVZ\t4.5 (1–6)\t4 (2–6)\t5 (3–6)\t0.494\t\nBVZ maintenance\t7.5 (0–27)\t4.5 (0–27)\t9.5 (2–20)\t0.36\t\nOverall Objective Response at Day +42\tPR\t4 (21)\t0\t4 (100)\t<0.001\t\nSD\t11 (58)\t11 (91.7)\t0\t\nPD\t1 (5.2)\t1 (8.33)\t0\t\nNE\t3 (15.8)\t-\t-\t\nBest Overall Objective Response\tPR\tPR\t7 (36.8)\t3 (25)\t0.038\t\nSD\tSD\t8 (42.1)\t8 (66.7)\t\nPD\tPD\t1 (5.2)\t1 (8.33)\t\nNE\tNE\t3 (15.8)\t-\t\nSubsequent Lines of Treatment\t0\t5 (26.3)\t5 (41.7)\t0\t0.299\t\n1\t6 (31.6)\t4 (33.3)\t1 (25)\t\n>1\t6 (31.6)\t3 (25)\t3 (75)\t\nAbbreviations: n, number; ECOG PS, European Cooperative Oncology Group Performance Status; CT, chemotherapy; BVZ, bevacizumab; PR, partial response; SD, stable disease; PD, progressive disease; and NE, not evaluable.\n\ncancers-13-05566-t002_Table 2 Table 2 Perfusion parameters shown are mean values, with the standard deviation in parentheses.\n\nParameter\tBaseline (n = 17)\tEarly Day +7 (n = 17)\tDay +42 (n = 16)\tp Value 1\t\nBlood Flow (mL/100 mL/min)\t57.23 (26.63)\t44.27 (28.12)\t36.52 (27.88)\t0.003\t\nBlood Volume (mL/100 mL)\t8.11 (4.8)\t5.36 (4.19)\t5.25 (5.36)\t0.015\t\nPermeability (mL/100 mL/min)\t15.48 (6.73)\t10.51 (8.26)\t8.68 (7.59)\t0.005\t\n1p value results from Friedman tests.\n\ncancers-13-05566-t003_Table 3 Table 3 Changes in perfusion parameters from baseline values. Mean values are shown, with the standard deviation in parentheses.\n\nParameter\tEarly Day +7 (n = 17)\tDay +42 (n = 16)\tp Value 1\t\nBlood Flow (change from baseline, %)\t−19.6 (43.1)\t−34.9 (31.9)\t0.058\t\nBlood Volume (change from baseline, %)\t−30.3 (34.0)\t−33.4 (39.9)\t0.706\t\nPermeability (change from baseline, %)\t−34.3 (42.6)\t−47 (39.3)\t0.215\t\n1p value results from Wilcoxon tests.\n\ncancers-13-05566-t004_Table 4 Table 4 RECIST assessments in non-responder and responder patients. Mean values are shown, with the standard deviation in parentheses.\n\nParameter\tTime\tNon-Responders (n = 12)\tResponders (n = 4)\tp Value 1\t\nOverall tumor burden of target lesions (mm)\tBaseline\t106 (79.1)\t53.8 (22.1)\t0.317\t\nDay 42\t94.8 (74.6)\t34.5 (14.4)\t0.078\t\nPercentage change (%)\t−10.6 (12)\t−36 (2.85)\t0.001\t\nTarget lesion for perfusion evaluation (mm)\tBaseline\t39.2 (24.5)\t34.8 (14.1)\t0.856\t\nDay 42\t34.5 (21.9)\t21.5 (10.8)\t0.362\t\nPercentage change (%)\t−12.3 (17.8)\t−39.8 (7.56)\t0.013\t\n1p value results from Wilcoxon tests.\n\ncancers-13-05566-t005_Table 5 Table 5 Perfusion parameters in non-responder and responder patients. Mean values are shown, with the standard deviation in parentheses.\n\nParameter\tTime\tNon-Responders (n = 12)\tResponders (n = 4)\tp Value 1\t\nBlood Flow (mL/100 mL/min)\tBaseline\t51.71 (24.02)\t58.90 (18.79)\t0.379\t\nDay 7\t42.89 (32.24)\t49.26 (19.03)\t0.521\t\nDay 42\t34.69 (31.97)\t42.02 (9.19)\t0.446\t\nBlood Volume (mL/100 mL)\tBaseline\t7.96 (5.58)\t7.38 (0.88)\t0.953\t\nDay 7\t4.70 (4.71)\t7.52 (2.06)\t0.034\t\nDay 42\t5.17 (6.11)\t5.46 (2.60)\t0.599\t\nPermeability (mL/100 mL/min)\tBaseline\t14.35 (7.06)\t15.82 (1.96)\t0.599\t\nDay 7\t9.45 (8.66)\t11.97 (8.13)\t0.446\t\nDay 42\t7.56 (8.00)\t12.02 (5.79)\t0.262\t\n1p value results from Wilcoxon tests.\n\ncancers-13-05566-t006_Table 6 Table 6 Changes in perfusion parameters in non-responder and responder patients from baseline value. Mean values are shown, with the standard deviation in parentheses.\n\nParameter\tTime\tNon-Responders (n = 12)\tResponders (n = 4)\tp Value 1\t\nBlood Flow (change from baseline, %)\tDay 7\t−18.78 (45.96)\t−10.56 (36.69)\t0.521\t\nDay 42\t−38.01 (35.77)\t−25.68 (15.69)\t0.648\t\nBlood Volume (change from baseline, %)\tDay 7\t−38.01 (32.08)\t1.02 (21.51)\t0.042\t\nDay 42\t−36.41 (40.99)\t−24.32 (40.43)\t0.684\t\nPermeability (change from baseline, %)\tDay 7\t−37.49 (41.77)\t−23.89 (55.78)\t0.77\t\nDay 42\t−54.95 (37.73)\t−23.31 (38.58)\t0.212\t\n1p value results from Wilcoxon tests.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Heigener D.F. Kerr K.M. Laing G.M. Mok T.S.K. Moiseyenko F.V. Reck M. Redefining Treatment Paradigms in First-line Advanced Non–Small-Cell Lung Cancer Clin. Cancer Res. 2019 25 4881 4887 10.1158/1078-0432.CCR-18-1894 30910855\n2. Sandler A.B. Johnson D.H. Herbst R.S. Anti-Vascular Endothelial Growth Factor Monoclonals in Non-Small Cell Lung Cancer Clin. Cancer Res. 2004 10 4258s 4262s 10.1158/1078-0432.CCR-040023 15217970\n3. Presta L.G. Chen H. O’Connor S.J. Chisholm V. Meng Y.G. Krummen L. Winkler M. Ferrara N. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders Cancer Res. 1997 57 4593 4599 9377574\n4. Reck M. von Pawel J. Zatloukal P. Ramlau R. Gorbounova V. Hirsh V. Leighl N. Mezger J. Archer V. Moore N. Phase III Trial of Cisplatin Plus Gemcitabine With Either Placebo or Bevacizumab As First-Line Therapy for Nonsquamous Non–Small-Cell Lung Cancer: AVAiL J. Clin. Oncol. 2009 27 1227 1234 10.1200/JCO.2007.14.5466 19188680\n5. Sandler A. Gray R. Perry M.C. Brahmer J. Schiller J.H. Dowlati A. Lilenbaum R. Johnson D.H. Paclitaxel–Carboplatin Alone or with Bevacizumab for Non–Small-Cell Lung Cancer New Engl. J. Med. 2006 355 2542 2550 10.1056/NEJMoa061884 17167137\n6. Eisenhauer E.A. Therasse P. Bogaerts J. Schwartz L. Sargent D. Ford R. Dancey J. Arbuck S. Gwyther S. Mooney M. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1) Eur. J. Cancer 2009 45 228 247 10.1016/j.ejca.2008.10.026 19097774\n7. Fernández-Pérez G. Sánchez-Escribano R. García-Vicente A.M. Luna-Alcalá A. Ceballos-Viro J. Bolton R.D. Vilanova-Busquets J.C. Sánchez-Rovira P. Fierro-Alanis M.P. García-Figueiras R. SEOM–SERAM–SEMNIM guidelines on the use of functional and molecular imaging techniques in advanced non-small-cell lung cancer Clin. Transl. Oncol. 2018 20 837 852 10.1007/s12094-017-1795-y 29256154\n8. Wang J. Wu N. Cham M.D. Song Y. Tumor Response in Patients With Advanced Non–Small Cell Lung Cancer: Perfusion CT Evaluation of Chemotherapy and Radiation Therapy Am. J. Roentgenol. 2009 193 1090 1096 10.2214/AJR.08.1367 19770333\n9. López C.T. Aguado J.D.L.F. Pernas R.O. Sánchez-Gracián C.D. Armentia E.S. Liste A.V. González R.P. Bayarri M.S. Evaluation of response to conventional chemotherapy and radiotherapy by perfusion computed tomography in non-small cell lung cancer (NSCLC) Eur. Radiol. Exp. 2019 3 1 10 10.1186/s41747-019-0101-x 30671863\n10. Sudarski S. Shi J. Schmid-Bindert G. Manegold C. Pilz L.R. Zhou C. Schoenberg S.O. Henzler T. Dynamic Volume Perfusion Computed Tomography Parameters versus RECIST for the Prediction of Outcome in Lung Cancer Patients Treated with Conventional Chemotherapy J. Thorac. Oncol. 2015 10 164 171 10.1097/JTO.0000000000000376 25247342\n11. Lind J.S.W. Meijerink M.R. Dingemans A.-M.C. van Kuijk C. Öllers M.C. de Ruysscher D. Postmus P. Smit E.F. Dynamic contrast-enhanced CT in patients treated with sorafenib and erlotinib for non-small cell lung cancer: A new method of monitoring treatment? Eur. Radiol. 2010 20 2890 2898 10.1007/s00330-010-1869-5 20625738\n12. Yabuuchi H. Kawanami S. Iwama E. Okamoto I. Kamitani T. 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Cortot A. Lafitte J.-J. Wallyn F. Remy J. Perfusion CT allows prediction of therapy response in non-small cell lung cancer treated with conventional and anti-angiogenic chemotherapy Eur. Radiol. 2013 23 2127 2136 10.1007/s00330-013-2821-2 23553586\n16. Michailidou M. Brown H.K. Lefley D.V. Evans A. Cross S.S. Coleman R.E. Brown N.J. Holen I. Microvascular Endothelial Cell Responses in vitro and in vivo: Modulation by Zoledronic Acid and Paclitaxel? J. Vasc. Res. 2010 47 481 493 10.1159/000313876 20431297\n17. Kim H.S. Oh J.M. Jin D.H. Yang K.-H. Moon E.-Y. Paclitaxel Induces Vascular Endothelial Growth Factor Expression through Reactive Oxygen Species Production Pharmacology 2008 81 317 324 10.1159/000119756 18322419\n18. Pasquier E. Honore S. Pourroy B. Jordan M.A. Lehmann M. Briand C. Braguer D. Antiangiogenic Concentrations of Paclitaxel Induce an Increase in Microtubule Dynamics in Endothelial Cells but Not in Cancer Cells Cancer Res. 2005 65 2433 2440 10.1158/0008-5472.CAN-04-2624 15781659\n19. Tacelli N. Remy-Jardin M. Copin M.-C. Scherpereel A. Mensier E. Jaillard S. Lafitte J.-J. Klotz E. Duhamel A. Remy J. Assessment of Non–Small Cell Lung Cancer Perfusion: Pathologic-CT Correlation in 15 Patients Radiology 2010 257 863 871 10.1148/radiol.10100181 20843993\n20. Spira D. Neumeister H. Spira S.M. Hetzel J. Spengler W. von Weyhern C.H. Horger M. Assessment of Tumor Vascularity in Lung Cancer Using Volume Perfusion CT (VPCT) With Histopathologic Comparison: A further step toward an individualized tumor characterization J. Comput. Assist. Tomogr. 2013 37 15 21 10.1097/RCT.0b013e318277c84f 23321828\n21. Zhao Y.-Y. Xue C. Jiang W. Zhao H.-Y. Huang Y. Feenstra K. Resau J.H. Qian C.-N. Zhang L. Predictive Value of Intratumoral Microvascular Density in Patients with Advanced Non-small Cell Lung Cancer Receiving Chemotherapy Plus Bevacizumab J. Thorac. Oncol. 2012 7 71 75 10.1097/JTO.0b013e31823085f4 22011670\n22. Van der Veldt A.A. Lubberink M. Bahce I. Walraven M. de Boer M.P. Greuter H.N. Hendrikse N.H. Eriksson J. Windhorst A. Postmus P. Rapid Decrease in Delivery of Chemotherapy to Tumors after Anti-VEGF Therapy: Implications for Scheduling of Anti-Angiogenic Drugs Cancer Cell 2012 21 82 91 10.1016/j.ccr.2011.11.023 22264790\n23. Gerstner E.R. Emblem K. Chang K. Vakulenko-Lagun B. Yen Y.-F. Beers A.L. Dietrich J. Plotkin S.R. Catana C. Hooker J.M. Bevacizumab Reduces Permeability and Concurrent Temozolomide Delivery in a Subset of Patients with Recurrent Glioblastoma Clin. Cancer Res. 2020 26 206 212 10.1158/1078-0432.CCR-19-1739 31558474\n24. Bogowicz M. Riesterer O. Bundschuh R.A. Veit-Haibach P. Hüllner M. Studer G. Stieb S. Glatz S. Pruschy M. Guckenberger M. Stability of radiomic features in CT perfusion maps Phys. Med. Biol. 2016 61 8736 8749 10.1088/1361-6560/61/24/8736 27893446\n25. Choe J. Lee S.M. Do K.-H. Lee J.B. Lee J.-G. Seo J.B. Prognostic value of radiomic analysis of iodine overlay maps from dual-energy computed tomography in patients with resectable lung cancer Eur. Radiol. 2019 29 915 923 10.1007/s00330-018-5639-0 30054795\n26. Ohm J.E. Gabrilovich D.I. Sempowski G.D. Kisseleva E. Parman K.S. Nadaf S. Carbone D.P. VEGF inhibits T-cell development and may contribute to tumor-induced immune suppression Blood 2003 101 4878 4886 10.1182/blood-2002-07-1956 12586633\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2072-6694",
"issue": "13(21)",
"journal": "Cancers",
"keywords": "NSCLC; antiangiogenic; bevacizumab; biomarkers; imaging; perfusion CT; tumor perfusion",
"medline_ta": "Cancers (Basel)",
"mesh_terms": null,
"nlm_unique_id": "101526829",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34771728",
"pubdate": "2021-11-06",
"publication_types": "D016428:Journal Article",
"references": "19097774;23908346;17167137;30054795;20431297;29256154;31558474;15217970;23553586;19188680;31197486;29059037;25247342;18322419;9377574;22011670;27893446;30910855;23321828;12586633;20843993;15781659;21357523;22264790;20625738;19770333",
"title": "A Pilot Study to Evaluate Early Predictive Value of Thorax Perfusion-CT in Advanced NSCLC.",
"title_normalized": "a pilot study to evaluate early predictive value of thorax perfusion ct in advanced nsclc"
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"abstract": "Left atrial appendage closure device embolization is a rare yet serious complication. The location of the embolized device is a major determinant of the retrieval approach, percutaneous or surgical. This paper presents the case of Watchman device embolization in the left ventricle, which was retrieved percutaneously by using a transarterial approach. (Level of Difficulty: Intermediate.).",
"affiliations": "Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio.;Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio.;Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio.;Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio.;Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio.",
"authors": "Spilias|Nikolaos|N|;Kochar|Arshneel|A|;Patel|Jayendrakumar|J|;Saliba|Walid|W|;Kapadia|Samir|S|",
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"doi": "10.1016/j.jaccas.2019.11.029",
"fulltext": "\n==== Front\nJACC Case Rep\nJACC Case Rep\nJACC Case Reports\n2666-0849\nElsevier\n\nS2666-0849(19)30484-X\n10.1016/j.jaccas.2019.11.029\nCase Report\nClinical Case\nPercutaneous Retrieval of a Watchman Device from the Left Ventricle Using a Transarterial Approach\nSpilias Nikolaos MD spilian@ccf.org\n∗\nKochar Arshneel MD\nPatel Jayendrakumar MD\nSaliba Walid MD\nKapadia Samir MD\nDepartment of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio\n∗ Address for correspondence: Dr. Nikolaos Spilias, Cleveland Clinic, 9500 Euclid Avenue, Desk J3-3, Cleveland, Ohio 44195. spilian@ccf.org\n18 12 2019\n18 12 2019\n18 12 2019\n1 5 876883\n26 9 2019\n6 11 2019\n6 11 2019\n© 2019 The Authors\n2019\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/).\nLeft atrial appendage closure device embolization is a rare yet serious complication. The location of the embolized device is a major determinant of the retrieval approach, percutaneous or surgical. This paper presents the case of Watchman device embolization in the left ventricle, which was retrieved percutaneously by using a transarterial approach. (Level of Difficulty: Intermediate.)\n\nGraphical abstract\n\nLeft atrial appendage closure device embolization is a rare yet serious complication. The location of the embolized device is a major determinant…\n\nKey Words\n\ncomplication\nimaging\nleft ventricle\nmitral valve\noccluder\nsupraventricular arrhythmia\nAbbreviations and Acronyms\n\nEP, electrophysiology\nLA, left atrium\nLAA, left atrial appendage\nLV, left ventricle\nLVOT, left ventricular outflow tract\nMR, mitral regurgitation\nMV, mitral valve\nTEE, transesophageal echocardiography\n==== Body\nCase\n\nPresentation\n\nA 79-year-old man presented to the electrophysiology (EP) clinic to discuss options for long-term stroke prevention. His CHA2DS2-VASc (Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Prior stroke, transient ischemic attack [TIA], or thromboembolism, Vascular disease, Age 65–74 years, Sex category [female]) score was 8 and HASBLED (Hypertension, Abnormal renal and liver function, Stroke, Bleeding, Labile INRs, Elderly >65 years, Alcohol or drugs) score was 4.Learning Objectives\n\n• To understand the risk factors and complications associated with WATCHMAN device embolization.\n\n• To review the retrieval options for an embolized device.\n\nMedical history\n\nThe patient had a history of permanent atrial fibrillation, transient ischemic attack, coronary artery disease, systolic heart failure (left ventricular ejection fraction of 35% to 40%), hypertension, diabetes, and spontaneous right occipital hemorrhage on warfarin therapy. Given the recent intracerebral hemorrhage, left atrial appendage (LAA) occlusion with a Watchman device (Boston Scientific Corp., Marlborough, Massachusetts) was pursued.\n\nInvestigations\n\nImaging of the LAA for appropriate sizing was performed. Computed tomography with intravenous contrast showed an LAA ostium measuring 2.3 × 2.5 cm and a maximal depth of 3.2 cm (Figure 1). Intraprocedural transesophageal echocardiography (TEE) showed a multilobed LAA without evidence of thrombus and with an ostium measuring 2.0 × 1.9 cm. The LAA dimensions (width × depth) were measured at 2.1 × 2.8 cm (0°), 2.1 × 2.5 cm (45°), 2.1 × 2.8 cm (90°), and 2.1 × 2.7 cm (135°). On 3-dimensional (3D) TEE, the maximal LAA orifice area was measured at 2.48 cm2 (Figure 2).Figure 1 Computed Tomography With Intravenous Contrast\n\nMeasurement of left atrial appendage dimensions.\n\nFigure 2 Intraprocedural Transesophageal Echocardiography\n\nMeasurements of left atrial appendage dimensions.\n\nBased on those measurements, a 27-mm Watchman device was placed successfully under TEE and fluoroscopic guidance. TEE showed a well-seated device without evidence of residual flow or paradevice leak by color Doppler. Device compression was excellent at 13% to 18%, and tug test did not show migration, hence meeting proper position, anchor, size and seal criteria (Figure 3).Figure 3 Transesophageal Echocardiography Post-Device Implantation\n\nSix hours after the procedure, the patient developed atrial fibrillation with rapid ventricular response and acute hypoxic respiratory failure. Physical examination was remarkable for respiratory distress with bilateral crackles over the lung fields. A bedside echocardiogram showed that the Watchman had migrated into the LV (Figure 4).Figure 4 Bedside Echocardiogram Showing the Watchman in the Left Ventricle\n\nManagement\n\nGiven the patient’s age and comorbidities, the decision was made to attempt percutaneous retrieval of the device in the cardiac catheterization laboratory. The procedure was performed with the patient under general anesthesia, by TEE and fluoroscopic guidance. Baseline TEE demonstrated the Watchman device was within the mitral valve (MV) apparatus, with the tines abutting the septum (Figures 5 and 6). Vascular access was obtained in the right common femoral artery (18-F 85-cm Cook sheath, Cook Medical, Bloomington, Indiana) and vein (20-F sheath, Cook Medical).Figure 5 Transesophageal Echocardiography Showing the Embolized Watchman in the Left Ventricle\n\nFigure 6 3-Dimensional Transesophageal Echocardiography Showing the Embolized Watchman in the Left Ventricle\n\nRetrieval by using the transseptal approach was initially attempted by crossing the previously performed septal puncture with a Mullins sheath (Medtronic, Fridely, Minnesota). With the use of a Lunderquist and a Toray guidewire (Toray America, New York, New York) to minimize risk of perforation, an 8-F medium curl Agilis (Foster City, California) steerable guide was advanced into the left atrium (LA). Then a 30-mm One-Snare (Medtronic) was advanced through the MV into the LV. At the same time, a 4-F angled Glidecath (Medtronic) was advanced into the LV cavity from the arterial side. An attempt to free or mobilize the device from the mitral apparatus was performed using a Whisper J coronary wire (Medtronic) to minimize risk of damage to the chordae tendineae.\n\nThen, the Watchman was grasped with the snare and partially pulled up into the MV. This resulted in severe mitral regurgitation, worsening hypoxemia, and hypotension (Figure 7). The device was then released, and it fell back into the LV and was ejected into the left ventricular outflow tract (LVOT) (Figure 8).Figure 7 Transesophageal Echocardiography Showing the Attempt to Retrieve the Device Transseptally Resulting in Severe Mitral Regurgitation\n\nFigure 8 Transesophageal Echocardiography Showing the Watchman Device in the Left Ventricular Outflow Tract\n\nAt that point, the 18-F arterial sheath was tracked into the ascending aorta, and a 25-mm One-Snare device was advanced into the LV cavity. The Watchman device was grasped and pulled out through the aortic valve and into the 18-F sheath (Figure 9). Post-retrieval TEE demonstrated no evidence of damage to the aortic or mitral valve.Figure 9 Fluoroscopy Images Showing the Watchman\n\nFluoroscopy images showing the Watchman in the LV (top left), the attempt for transseptal retrieval (top right), the use of the snare to retrieve the device through the aorta (bottom right), and grabbing of the side of the device with the snare (bottom left). The Watchman device is shown by the red arrows.\n\nFollow-up\n\nThe patient was admitted to the cardiac intensive care unit, extubated the next morning, and discharged 2 days later with a prescription for apixaban. One month later, on his follow-up clinic appointment, he was asymptomatic, without any bleeding issues.\n\nDiscussion\n\nComplications of Watchman implantation are overall low, with device embolization rates of 0.6% and 0.7% in the PROTECT-AF (Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial) and PREVAIL (Prospective randomized evaluation of the Watchman Left Atrial Appendage Closure device in patients with atrial fibrillation versus long-term warfarin therapy) trials (1, 2, 3). The CAP (College of American Pathologists) registry data similarly reported a 0.2% rate of embolization within 7 days of implantation (4). Causes for device migration include incorrect sizing, suboptimal placement, and vigorous tug testing. In the present case, it was most likely related to improper position, as TEE (Figure 3) revealed a shoulder protruding from the appendage. Sizing was appropriate given confirmation of 13% compression after deployment.\n\nDevice size can be selected based on computed tomography or TEE. Measurements of the LAA on TEE should be obtained at 0°, 45°, 90°, and 135°. The landing zone diameter is measured from the top of the MV annulus or left circumflex artery to a point 2 cm below the tip of the left upper pulmonary vein. The depth is measured from the LAA orifice to the apex. Devices should be upsized by 8% to 20% from the largest LAA landing zone diameter (5). Confirmation of correct placement includes proper position, anchor, size, and seal criteria. In regard to position, the shoulder should protrude <40% to 50% of the device depth. Anchoring is verified by a tug test. Appropriate sizing is confirmed by compression of the device diameter by 15% to 30% from its original size. Seal is confirmed by measuring the vena contracta of any para device leak (<5 mm) (5).\n\nDevice embolization typically occurs early after the procedure with one-third of cases occurring during the procedure (6). The device can migrate into the LA, LV, or aorta. Embolization into the ventricle poses a risk for papillary muscle rupture, damage to the MV apparatus, LVOT obstruction, or damage to the AV. Percutaneous retrieval of LAA closure devices from the LA has been reported; however, migration to the ventricle typically requires open heart surgery.\n\nIn a systematic review of published studies, Arminian et al. (6) reported 9 cases of Watchman embolization into the LV, 8 of which required sternotomy and 1 transapical extraction. In a review performed by the present authors, there was only 1 case of successful percutaneous retrieval of an Amulet device (St. Jude Medical, Memphis, Tennessee) from the LV through a transarterial approach (7). In this case, both the transseptal and transarterial approaches were used.\n\nThe technical challenges of percutaneous retrieval from the ventricle are related to the location of the device in association with the MV apparatus. The anchors of the device are usually tangled in the chordae tendineae with the cap pointing towards the LV apex. One option is to grab the side of the device with the snare and try to slowly mobilize it out of the MV apparatus and through the MV into the LA. If this is not feasible, bidirectional jiggling of the device can be attempted using a dual approach, transseptal and transarterial. This is a very delicate procedure that needs to be performed under continuous TEE and fluoroscopic guidance. If there is significant resistance to pulling the device out of the MV apparatus, the procedure should be aborted, and surgical options need to be sought.\n\nConclusions\n\nLAA occlusion device embolization is a rare yet serious complication that requires emergent management. The most common cause of device embolization is inappropriate sizing. Although the retrieval from the LA or the aorta can be achieved percutaneously, retrieval from the LV usually requires surgery in order to avoid damage to the MV apparatus.\n\nPercutaneous retrieval of a Watchman device from the LV is technically challenging but can be safely performed in select cases by experienced operators, decreasing the morbidity and prolonged hospitalization associated with surgery.\n\nThe authors have reported that they have no relationships relevant to the contents of this paper to disclose. Takashi Matsukage, MD, served as Guest Associate Editor for this paper.\n\nInformed consent was obtained for this case.\n==== Refs\nReferences\n\n1 Holmes D.R. Reddy V.Y. Turi Z.G. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomized non-inferiority trial Lancet 374 2009 534 542 19683639\n2 Holmes D.R. Jr. Kar S. Price M.J. Prospective randomized evaluation of the Watchman left atrial appendage closure device in patients with atrial fibrillation versus long-term warfarin therapy: the PREVAIL trial J Am Coll Cardiol 64 2014 1 12 24998121\n3 Reddy V.Y. Doshi S.K. Kar S. 5 year outcomes after left atrial appendage closure: from the PREVAIL and PROTECT AF trials J Am Coll Cardiol 70 2017 2964 2975 29103847\n4 Reddy V.Y. Holmes D. Doshi S.K. Neuzil P. Kar S. Safety of percutaneous left atrial appendage closure: results from the Watchman left atrial appendage system for embolic protection in patients with AF (PROTECT AF) clinical trial and the continued access registry Circulation 123 2011 417 424 21242484\n5 Vainrib A.F. Harb S.C. Jaber W. Left atrial appendage occlusion/exclusion: procedural image guidance with transesophageal echocardiography J Am Soc Echocardiogr 31 2018 454 474 29158017\n6 Aminian A. Lalmand J. Tzikas A. Budts W. Benit E. Kefer J. Embolization of left atrial appendage closure devices: a systematic review of cases reported with the Watchman and the Amplatzer cardiac plug Catheter Cardiovasc Interv 86 2015 128 135 25676316\n7 Kaczmarek K. Czarniak B. Jakubowski P. Ptaszynski P. Device embolization into the LV following left atrial endage closure with an Amplatzer Amulet J Interv Card Electrophysiol 52 2018 171 172 29725891\n\n",
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"keywords": "EP, electrophysiology; LA, left atrium; LAA, left atrial appendage; LV, left ventricle; LVOT, left ventricular outflow tract; MR, mitral regurgitation; MV, mitral valve; TEE, transesophageal echocardiography; complication; imaging; left ventricle; mitral valve; occluder; supraventricular arrhythmia",
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"title": "Percutaneous Retrieval of a Watchman Device from the Left Ventricle Using a Transarterial Approach.",
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"affiliations": "Department of Obstetrics & Gynecology, University of Texas Southwestern Medical Center at Dallas 75235.",
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"abstract": "The practice of carboplatin dosing is not concordant among different centres and oncologists. Some clinical guidelines recommend capping of the carboplatin dose at, for example, creatinine-clearance (Crea-Cl) of 125 mL/min because of concerns of excessive toxicity. Clinical data to support such recommendations are lacking, especially in patients with seminoma.\nThis is a retrospective analysis of acute haematotoxicity of patients with stage I seminoma treated with adjuvant carboplatin area under the curve (AUC) 7 in routine practice in two Swiss centres in 2005-2015, and a comparison of incidence and grade (according to Common Terminology Criteria for Adverse Events v4.0) of haematological adverse events (hAEs) in patients with Crea-Cl <125 mL/min vs >125 mL/min without dose capping.\n74 patients with 229 documented measurements were included (median 3/patient). A total of 151 hAEs occurred. Platelet nadir occurred earlier than median white cell/neutrophil count (median day 15 vs day 22; P<0.0001). The majority of hAEs were mild, with more than 80% being of grade 1. Only two (2.7%) clinically relevant hAEs necessitating subsequent interventions occurred (one patient received platelet transfusion, one patient with febrile neutropaenia). Haematological toxicities were not statistically different in patients dosed with Crea-Cl >125 mL/min versus those with Crea-Cl <125 mL/min. No hAEs other than grade 1 occurred before day 10 and after day 24.\nToxicity after single-dose carboplatin AUC 7 is generally mild. No excess of toxicity occurs in patients with high Crea-Cl above 125 mL/min, and therefore dose capping is not routinely necessary. In addition, this study provides a rationale for efficient use of healthcare services without compromising patients' safety.",
"affiliations": "Clinic for Medical Oncology and Haematology, Cantonal Hospital St Gallen, St Gallen, Switzerland.;Department of Oncology/Haematology, Cantonal Hospital Grisons, Chur, Switzerland.;Clinic for Medical Oncology and Haematology, Cantonal Hospital St Gallen, St Gallen, Switzerland.;Clinic for Medical Oncology and Haematology, Cantonal Hospital St Gallen, St Gallen, Switzerland.;Department of Oncology/Haematology, Cantonal Hospital Grisons, Chur, Switzerland.",
"authors": "Fehr|Martin|M|;Maranta|Angela Fischer|AF|;Reichegger|Hermann|H|;Gillessen|Silke|S|;Cathomas|Richard|R|",
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"fulltext": "\n==== Front\nESMO OpenESMO OpenesmoopenesmoopenESMO Open2059-7029BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR 29531843esmoopen-2018-00032010.1136/esmoopen-2018-000320Original Research1506Carboplatin dose based on actual renal function: no excess of acute haematotoxicity in adjuvant treatment in seminoma stage I Fehr Martin 1Maranta Angela Fischer 2Reichegger Hermann 1Gillessen Silke 1Cathomas Richard 21 Clinic for Medical Oncology and Haematology, Cantonal Hospital St Gallen, St Gallen, Switzerland2 Department of Oncology/Haematology, Cantonal Hospital Grisons, Chur, SwitzerlandCorrespondence to Dr Martin Fehr, Clinic for Medical Oncology & Haematology, Cantonal Hospital St. Gallen, 9007 St. Gallen, Switzerland; Martin.Fehr@kssg.ch2018 8 3 2018 3 3 e00032001 1 2018 13 2 2018 14 2 2018 © European Society for Medical Oncology (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.2018This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/Introduction\nThe practice of carboplatin dosing is not concordant among different centres and oncologists. Some clinical guidelines recommend capping of the carboplatin dose at, for example, creatinine-clearance (Crea-Cl) of 125 mL/min because of concerns of excessive toxicity. Clinical data to support such recommendations are lacking, especially in patients with seminoma.\n\nMethods\nThis is a retrospective analysis of acute haematotoxicity of patients with stage I seminoma treated with adjuvant carboplatin area under the curve (AUC) 7 in routine practice in two Swiss centres in 2005–2015, and a comparison of incidence and grade (according to Common Terminology Criteria for Adverse Events v4.0) of haematological adverse events (hAEs) in patients with Crea-Cl <125 mL/min vs >125 mL/min without dose capping.\n\nResults\n74 patients with 229 documented measurements were included (median 3/patient). A total of 151 hAEs occurred. Platelet nadir occurred earlier than median white cell/neutrophil count (median day 15 vs day 22; P<0.0001). The majority of hAEs were mild, with more than 80% being of grade 1. Only two (2.7%) clinically relevant hAEs necessitating subsequent interventions occurred (one patient received platelet transfusion, one patient with febrile neutropaenia). Haematological toxicities were not statistically different in patients dosed with Crea-Cl >125 mL/min versus those with Crea-Cl <125 mL/min. No hAEs other than grade 1 occurred before day 10 and after day 24.\n\nConclusions\nToxicity after single-dose carboplatin AUC 7 is generally mild. No excess of toxicity occurs in patients with high Crea-Cl above 125 mL/min, and therefore dose capping is not routinely necessary. In addition, this study provides a rationale for efficient use of healthcare services without compromising patients’ safety.\n\ncarboplatindose cappingcreatinine clearanceseminoma stage Itoxicityspecial-featureunlocked\n==== Body\nKey questions\nWhat is already known about this subject?\nSome experts and clinical guidelines (Food and Drug Administration, American Society of Clinical Oncology, Gynecologic Oncology Group) recommend capping of the carboplatin dose at a creatinine-clearance (Crea-Cl) of 125 mL/min because of concerns of excessive toxicity. Patients with stage I seminoma receiving adjuvant carboplatin often have high Crea-Cl, but there is a paucity of data on acute haematological toxicities in relation to the different clinical practices and recommendations.\n\nWhat does this study add?\nToxicity after single-dose carboplatin area under the curve 7 is generally mild with a low rate (2.7%) of haematological adverse events (hAEs) necessitating clinical interventions.\n\nNo excess of toxicity occurs in patients with carboplatin dosing based on Crea-Cl greater than 125 mL/min.\n\nNo new hAEs other than grade 1 occurred before day 10 and after day 24.\n\nHow might this impact on clinical practice?\nThis study provides a rationale for efficient use of healthcare services without compromising patients’ safety: either omitting routine blood count controls in view of the very low rate of clinically relevant adverse events or timing of regular blood count control at the time of lowest platelet and neutrophil counts (eg, around days 15–22) and omitting any further blood count analyses.\n\nIntroduction\nThe practice of carboplatin dosing is not concordant among different centres and oncologists—for example, some may use measured actual glomerular filtration rate (GFR) by a radioisotope method, while others prefer to use formula-based estimations of creatinine-clearance (Crea-Cl) from a single serum-creatinine value for the dose calculation according to the ‘Calvert-formula’1 2; in addition, the issue of dose capping versus non-capping in patients with very high GFR is not resolved. Some experts and clinical guidelines recommend capping of the carboplatin dose at a Crea-Cl of 125 mL/min because of concerns of excessive toxicity in view of changes in assays used to measure serum-creatinine and alerts by the Food and Drug Administration (FDA) and Gynecologic Oncology Group (GOG).3 4\n\nStage I seminoma is the most commonly diagnosed testis cancer and accounts for ∼40%–45% of all testis cancers.5 The risk of recurrence after tumour orchiectomy is 10%–20%; active surveillance and adjuvant treatment are possible management options.6 Contemporary guidelines favour active surveillance for seminoma stage I and single-dose carboplatin is listed as adjuvant treatment option.6 7 Many of the patients receiving single-dose carboplatin area under the curve (AUC) 7 have a very good renal function, and hence high absolute doses of carboplatin are frequently administered: about 50% of patients treated on study protocols and reported in cohorts had a GFR of 125 mL/min and higher.8 9\n\nHowever, there is a paucity of data on acute haematological toxicities in relation to the different clinical practices and recommendations of carboplatin dosing in patients with very high GFR in general and in particular in the adjuvant treatment of patients with seminoma stage I. As a consequence, great variations in monitoring for haematological toxicities, frequency and timing of follow-up visits and insecurity of expectable haematological acute adverse events (hAEs) exist.\n\nIn order to fill this gap of knowledge, we conducted a retrospective analysis of haematological toxicities in patients with seminoma stage I and GFR >125 mL/min having received carboplatin without capping compared with those with GFR <125 mL/min and/or having received capped doses. In addition, we analysed the pattern of acute hAEs to offer guidance for monitoring.\n\nMethods\nThis is a retrospective analysis of a cohort of patients with stage I seminoma treated with adjuvant carboplatin AUC 7 in routine practice in two Swiss centres between 2005 and 2015.\n\nThe main inclusion criteria were a normal blood count at treatment and a minimum of two documented blood count measurements during the first 8 weeks after treatment. The main exclusion criterion was a documented denial by patients to use their data for research purposes.\n\nThe following factors were analysed: incidence of hAE, grade of hAE according to common clinical toxicity criteria for adverse events (V.4.0) and time of nadir of hAEs. All factors were separately analysed for patients with Crea-Cl <125 mL/min vs >125 mL/min without dose capping, respectively. Moreover hAEs in patients with and without capping were compared.\n\nStatistical analysis was performed with GraphPad InStat V.3.1a for Macintosh computer software using Tukey-Kramer multiple comparisons test, Fisher’s exact test and Χ2 test.\n\nResults\nA total of 92 patient charts were screened, but 18 were excluded for not fulfilling the criteria of two or more documented follow-up blood counts. Seventy-four patients with 229 documented follow-up measurements (median of 3 measurements per patient, range 2–6) were included. Ten patients had carboplatin dosing based on radioisotope measurement of GFR after a change of institutional practice in 2014. The remaining majority of 64 patients had formula-based estimation (Cockroft-Gault) of Crea-Cl.\n\nSixty-five patients were dosed without capping according to the Crea-Cl received by formula calculation from a single serum-creatinine value (n=55) or measured GFR by radioisotope method (n=10), respectively. In nine patients with Crea-Cl >125 mL/min based on the Cockroft-Gault formula, the carboplatin dose was capped at 1000 or 1050 mg, respectively.\n\nThe median age was 41 years (range 22–71), the median Crea-Cl (Cockroft-Gault) was 126 mL/min (range 70–206) and the median carboplatin dose was 1013 mg (700–1477). The characteristics of patients in different subgroups are shown in table 1.\n\nTable 1 Baseline characteristics: subgroups according to Crea-Cl (median; range)\n\n\tCrea-Cl <125 mL/min \nn=36\tCrea-Cl >125 mL/min \nNo dose capping, n=29\t\t\nAge (years)\t47 (22–71)\t33 (23–53)\tP=0.0001\t\nSCr (μmol/L)\t79 (51–117)\t77 (52–92)\tNS\t\nCrea-Cl (mL/min)\t109 (70–120)*\t143 (125–184)*\t\t\nCarboplatin dose (g)\t950 (700–1020)*\t1200 (1050–1480)*\t\t\n*Significant differences due to definition of subgroup.\n\nCrea-Cl, creatinine-clearance; SCr, serum-creatinine.\n\nWith a median follow-up time of the whole cohort of 60 months (22–136 months), one patient (1.3%) experienced a relapse 24 months after adjuvant treatment and was salvaged with combination chemotherapy.\n\nOverall, a total of 151 hAEs occurred in 70 patients. Four (5.4%) patients had no hAEs. The hAEs were of grade 1 only in 49 (66%) patients, maximum of grade 2 in 15 (22%) patients, maximum of grade 3 in 5 (6.8%) patients and of grade 4 in 1 (1.4%) patient, respectively. Overall, clinical relevant hAE necessitating subsequent clinical interventions occurred in two (2.7%) patients. Decreased platelet count of any grade (69%) was significantly more frequent than decreased neutrophil (43%) and white cell count (36%) (P=0.0027 and P=0.0001, respectively). More detailed information is found in table 2.\n\nTable 2 Haematological adverse events after carboplatin AUC 7: patients with Crea-Cl <125 mL/min vs >125 mL/min and no dose capping\n\n\tCrea-Cl <125 mL/min \nn=36\tCrea-Cl >125 mL/min \nNo dose capping, n=29\t\nAnaemia overall\t71% (25)\t52% (15)\t\n Anaemia grade 1\t71% (25)\t52%(15)\t\nThrombocytopaenia overall\t56% (20)\t76% (22)\t\n Thrombocytopaenia grade 1\t44% (16)\t55% (16)\t\n Thrombocytopaenia grade 2\t11% (4)\t18% (5)\t\n Thrombocytopaenia grade 4\t–\t3% (1)\t\nLeucopaenia overall\t36% (13)\t48% (14)\t\n Leucopaenia grade 1\t33% (12)\t41% (12)\t\n Leucopaenia grade 2\t3% (1)\t7% (2)\t\nNeutropaenia overall\t39% (14)\t35% (10)\t\n Neutropaenia grade 1\t22% (8)\t24% (7)\t\n Neutropaenia grade 2\t6% (2)\t7% (2)\t\n Neutropaenia grade 3\t11% (4)\t3% (1)\t\nAdverse events with clinical interventions\t3% (1 hospitalisation with febrile neutropaenia grade 3)\t3% (1 platelet transfusion in thrombocytopaenia grade 4)\t\nThe sum of percentages of different grades may differ from percentage of overall due to rounding.\n\nCrea-Cl, creatinine-clearance.\n\nDecreased platelet count occurred also significantly earlier than decreased neutrophil and white cell count: the median platelet nadir was on day 15 and the median white cell/neutrophil count nadir was on day 22 (P<0.0001). Before day 10 and after day 24, no new toxicities higher than grade 1 were documented.\n\nIn 36 patients with Crea-Cl <125 mL/min, a total of 74 hAEs (81% grade 1) were documented, corresponding to a mean of 2.1 (95% CI 1.8 to 2.6) hAEs per patient. In 29 patients with Crea-Cl >125 mL/min and no dose capping, a total of 64 hAEs (80% grade 1) were found, corresponding to a mean of 2.2 (95% CI 1.8 to 2.5) hAEs per patient (P=0.84 when compared with group with Crea-Cl <125 mL/min). In each group one clinically relevant hAE with subsequent interventions occurred: one case of febrile neutropaenia grade 3 in a patient with Crea-Cl <125 mL/min, and one patient with Crea-Cl >125 mL/min and thrombocytopaenia grade 4 and absence of haemorrhage received one prophylactic platelet transfusion in accordance with institutional guidelines (thrombocyte nadir was 14×109/L followed by a rapid increase to 89×109/L 1 week later). Overall, this corresponds to a rate of severe, clinically relevant hAEs of 2.8% in patients with Crea-Cl <125 mL/min vs 3.4% in patients with Crea-Cl >125 mL/min, respectively (P=0.89). No statistically significant differences between groups of Crea-Cl <125 mL/min vs Crea-Cl >125 mL/min (no capping) were found (for further details see table 2).\n\nThere were no statistically significant differences nor trends between different cohorts.\n\nA capped carboplatin dose at 1000 mg or 1050 mg had been administered in nine patients with Crea-Cl >125 mL/min, which is in line with some recommendations to limit the carboplatin dose to a Crea-Cl maximum of 125 mL/min but consequently results in an AUC <7. This decision was at the individual discretion of the treating physician. In retrospect, the main reasons to apply dose capping were consideration of the alerts by the FDA and GOG on the one hand, and concerns of excessive toxicity in older patients with numerically very high doses (if uncapped) on the other hand. These nine cases were analysed separately: the mean age was 37 years (range 22–56), and the mean carboplatin dose administered was 12.9% lower than the full dose calculated for AUC 7 (median difference 148 mg; range 45–344 mg). A total of 15 hAEs occurred, with a mean of 1.7 hAEs per patient, 87% (13/15) of them were of grade 1 and no clinical interventions were necessary. No statistically significant differences between Crea-Cl >125 mL/min (no capping) versus capping at Crea-Cl 125 mL/min were found. Due to the relatively small number of patients with Crea-Cl >125 mL/min and dose capping (n=9), these results should be interpreted with caution.\n\nIn the subgroup of patients with radionuclide GFR measurement (n=10), the mean age was 41 years (range 23–54), and the mean carboplatin dose administered was 1.9% higher (median difference +74.5 mg, range −228 to +178 mg) than if it would have been if based on Crea-Cl from formula estimation (Cockroft-Gault).\n\nA total of 22 hAEs occurred, with a mean of 2.2 hAEs per patient, 77% (17/22) of them were of grade 1. No clinical interventions were necessary. No statistically significant differences between patients with radionuclide measurement of GFR and formula-based estimation of Crea-Cl were found. Due to the relatively small number of patients with carboplatin dose based on GFR measurement (n=10), these results should be interpreted with caution.\n\nIn terms of non-haematological adverse events, no signals were observed for relevant acute renal dysfunction as serum-creatinine values in the weeks 1–4 after treatment remained within normal limits with a median of 83 μmol/L (range 48–115) and not significantly different from before treatment with a median at baseline of 79 μmol/L (range 51–117) (P=0.12). No chemotherapy-induced nausea and emesis of grade 3 or greater occurred in this cohort.\n\nDiscussion\nAccording to our knowledge, this is the first study to assess toxicities associated with capping versus non-capping of carboplatin doses in patients with seminoma stage I and a very high GFR. It is also the first comparison of hAEs in patients with Crea-Cl above versus below 125 mL/min.\n\nIn this patient population the majority of haematological toxicities were very mild and of relatively short duration, with more than 80% of documented hAEs being of grade 1 and more than 70% of patients with no hAEs or grade 1 hAEs only. Of note, grade 1 haematological toxicities are usually asymptomatic and hardly ever affect patients—for example, anaemia with haemoglobin level below normal but >100 g/L. Among 74 patients, only in two patients (2.7%) clinically relevant hAEs necessitating subsequent clinical interventions occurred.\n\nThe American Society of Clinical Oncology clinical guidelines as well as some other experts and organisations recommend that capping of the carboplatin dose calculated with the Calvert formula should occur at a Crea-Cl of 125 mL/min due to concerns of excess of toxicity.3 4 However, our data do not support any of these recommendations in patients with seminoma stage I receiving adjuvant carboplatin: there was no excess of haematological toxicity in patients with Crea-Cl >125 mL/min without dose capping, and there were neither statistically significant nor relevant differences in patients with Crea-Cl >125 mL/min (and no dose capping) compared with below 125 mL/min. In the small subgroup of patients with Crea-Cl >125 mL/min and capped carboplatin dose, the rate of hAEs per patient was numerically lower when compared with those without capping. But the pattern of hAEs with more than 80% being grade 1 was similar in both groups, and the differences are not statistically significant. However, due to the small number of patients in this subgroup (n=9), these results should be interpreted with caution.\n\nOur results should be interpreted with caution in regard to the weaknesses and strengths of this study. The heterogeneity of our data reflects the variations in clinical practice by different oncologists and centres over time. On the other hand this facilitates the generalisability of our results and conclusions for daily clinical practice. It is a retrospective study with a small number of patients. Nevertheless, our conclusions can be substantiated due to the very similar proportion and equal distribution of low-grade toxicities as well as the very few severe hAEs between the different groups with Crea-Cl>125 mL/min or <125 mL/min and capping versus no capping, respectively.\n\nWith all the limitations that apply to retrospective studies, it is unlikely that the data are prone to a selection bias of patients with a more favourable post-treatment course. The patients excluded due to missing documentation of blood counts were followed up at their general practitioners, who were instructed to immediately report any toxicities of higher grade. In addition, any clinically relevant complications of higher degree would have been retrospectively captured and documented at the first surveillance visit scheduled at 3 months after treatment.10 This was not the case in any of the patients excluded due to incomplete documentation of follow-up blood counts during the first 8 weeks after treatment. Taken together these measures are more likely to result in overestimation of severe, relevant hAEs rather than underestimation.\n\nThis study focused on acute toxicities, and it was neither designed nor powered to elucidate on chronic and long-term toxicities of single-dose carboplatin AUC 7. However, in the follow-up of the large Medical Research Council (MRC) TE19/European Organisation for Research and Treatment of Cancer (EORTC) 30982 trial, no safety signals concerning long-term toxicities were reported.8 Therefore it seems unlikely that chronic toxicities after single-dose carboplatin are significantly different between patients with capped or uncapped carboplatin doses.\n\nOur data are also in line with a single-centre retrospective study that identified no significant toxicity in an even smaller number of patients receiving carboplatin with GFR >110 mL/min, who did not have their doses capped. The authors concluded that carboplatin doses should be based on actual GFR and that dose titration at subsequent carboplatin treatments should occur in case of myelotoxicity.11\n\nAlthough radionuclide measurement of GFR is the reference standard for the calculation of the carboplatin dose in patients with seminoma stage I, the majority of our patients had estimations of Crea-Cl from serum-creatinine values by the Cockcroft-Gault formula before radioisotope measurement was introduced at our institutions in 2014.12–16 According to the published literature, it is reasonable to conclude that the rates of adverse events could be further improved by basing the carboplatin dose on radioisotope-measured GFR, as this eliminates the inaccuracy associated with formula-based Crea-Cl estimations.12 17–19 In addition, a post-hoc analysis of the large prospective MRC TE19/EORTC 30982 trial revealed that lowering carboplatin doses by 10% was associated with a trend for an increased rate of recurrences (in those patients in whom the carboplatin dose calculation was based on a Crea-Cl estimate from a 24-hour urine collection).8 However, this has not been reproduced in a cohort from routine clinical practice so far and has been challenged recently.1\n\nUsing healthcare services efficiently without compromising patients safety will become increasingly important in the future in view of rising healthcare costs, economic constraints and other limitations for healthcare services. In this study we did not find any onset of new hAEs other than grade 1 before day 10 and after day 24. Therefore this study provides a rationale to concentrate any blood count analyses at the time when the thrombocyte nadir and white cell/neutrophil nadir are most likely to occur (median day 15 and day 22, respectively)—if the treating physician regards a routine analysis necessary. In view of the very low rate of clinically relevant toxicities in this series, one could consider to completely abstain from any routine blood count analyses after single-dose adjuvant carboplatin in informed patients with unrestricted access to emergency services. In any case, outside the days 10–24 period, routine blood count analyses can be omitted without compromising patients’ safety.\n\nConclusions\nToxicity after single-dose carboplatin AUC 7 in the adjuvant treatment of seminoma stage 1 is generally mild. According to our data, no excess of toxicity occurs in patients with higher Crea-Cl above 125 mL/min and therefore dose capping is neither necessary nor indicated and may negatively impact outcome in patients with seminoma stage 1.\n\nIn addition, this study provides a rationale for an efficient use of healthcare services with regard to limiting and timing of blood count analysis during the immediate follow-up period without compromising patients’ safety.\n\nContributors: All authors of this research paper have directly participated in the planning, execution or analysis of this study. The revised manuscript has been seen and approved by all authors.\n\nFunding: This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nPatient consent: Not required.\n\nEthics approval: Ethics Committee of Eastern Switzerland, St Gallen. The study was approved by the respective local ethical committees.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nData sharing statement: There are no additional unpublished data available to third parties.\n==== Refs\nReferences\n1. Tandstad T , Ståhl O , Dahl O , et al \nTreatment of stage I seminoma, with one course of adjuvant carboplatin or surveillance, risk-adapted recommendations implementing patient autonomy: a report from the Swedish and Norwegian Testicular Cancer Group (SWENOTECA) . Ann Oncol \n2016 ;27 :1299 –304 . 10.1093/annonc/mdw164 27052649 \n2. Hematology/Oncology Pharmacy association . (2010) Newsletter, Fall . 2010 \nhttp://www.hoparx.org/uploads/files/newsletterfall_2010.pdf/; (accessed 06 Feb 2014 ).\n3. Griggs JJ , Mangu PB , Anderson H , et al \nAppropriate chemotherapy dosing for obese adult patients with cancer: American Society of Clinical Oncology clinical practice guideline . J Clin Oncol \n2012 ;30 :1553 –61 . 10.1200/JCO.2011.39.9436 22473167 \n4. Collins IM , Roberts-Thomson R , Faulkner D , et al \nCarboplatin dosing in ovarian cancer: problems and pitfalls . Int J Gynecol Cancer \n2011 ;21 :1213 –8 . 10.1097/IGC.0b013e31822127ad 21705909 \n5. Townsend JS , Richardson LC , German RR \nIncidence of testicular cancer in the United States, 1999-2004 . Am J Mens Health \n2010 ;4 :353 –60 . 10.1177/1557988309356101 20031937 \n6. Beyer J , Albers P , Altena R , et al \nMaintaining success, reducing treatment burden, focusing on survivorship: highlights from the third European consensus conference on diagnosis and treatment of germ-cell cancer . Ann Oncol \n2013 ;24 :878 –88 . 10.1093/annonc/mds579 23152360 \n7. Nichols CR , Roth B , Albers P , et al \nActive surveillance is the preferred approach to clinical stage I testicular cancer . J Clin Oncol \n2013 ;31 :3490 –3 . 10.1200/JCO.2012.47.6010 24002502 \n8. Oliver RT , Mead GM , Rustin GJ , et al \nRandomized trial of carboplatin versus radiotherapy for stage I seminoma: mature results on relapse and contralateral testis cancer rates in MRC TE19/EORTC 30982 study (ISRCTN27163214) . J Clin Oncol \n2011 ;29 :957 –62 . 10.1200/JCO.2009.26.4655 21282539 \n9. Chau C , Cathomas R , Wheater M , et al \nTreatment outcome and patterns of relapse following adjuvant carboplatin for stage I testicular seminomatous germ-cell tumour: results from a 17-year UK experience . Annals of Oncology \n2015 ;26 :1865 –70 . 10.1093/annonc/mdv254 26037797 \n10. Cathomas R , Helbling D , Stenner F , et al \nInterdisciplinary evidence-based recommendations for the follow-up of testicular cancer patients: a joint effort . Swiss Med Wkly \n2010 ;140 :356 –69 . doi:smw-1299320544409 \n11. Roy AC , Jones DN , Slavotinek JP , et al \nVery high GFR in cancer patients undergoing chemotherapy: prevalence, carboplatin dosing patterns and chemotherapy toxicity . Asia Pac J Clin Oncol \n2011 ;7 :281 –6 . 10.1111/j.1743-7563.2011.01409.x 21884440 \n12. Cathomas R , Klingbiel D , Geldart TR , et al \nRelevant risk of carboplatin underdosing in cancer patients with normal renal function using estimated GFR: lessons from a stage I seminoma cohort . Ann Oncol \n2014 ;25 :1591 –7 . 10.1093/annonc/mdu129 24669017 \n13. Quinton A , Lewis P , Ali P , et al \nA comparison of measured and estimated glomerular filtration rate for carboplatin dose calculation in stage I testicular seminoma . Med Oncol \n2013 ;30 :661 \n10.1007/s12032-013-0661-1 23864250 \n14. Shepherd ST , Gillen G , Morrison P , et al \nPerformance of formulae based estimates of glomerular filtration rate for carboplatin dosing in stage 1 seminoma . Eur J Cancer \n2014 ;50 :944 –52 . 10.1016/j.ejca.2013.12.021 24445148 \n15. Bertelli G , Quinton AE , Lewis PD , et al \nReply to the letter to the editor ’Measured and estimated glomerular filtration rate for carboplatin dose calculation' by Cathomas et al . Ann Oncol \n2015 ;26 :249 –50 . 10.1093/annonc/mdu475 25319063 \n16. Fehr M , Geldart T , Klingbiel D , et al \nMeasurement or estimation of glomerular filtration rate in seminoma patients: quite another cup of tea . Eur J Cancer \n2014 ;50 :2176 –7 . 10.1016/j.ejca.2014.04.028 24915777 \n17. Ainsworth NL , Marshall A , Hatcher H , et al \nEvaluation of glomerular filtration rate estimation by cockcroft-gault, jelliffe, wright and Modification of Diet in Renal Disease (MDRD) formulae in oncology patients . Ann Oncol \n2012 ;23 :1845 –53 . 10.1093/annonc/mdr539 22104575 \n18. Lauritsen J , Gundgaard MG , Mortensen MS , et al \nReliability of estimated glomerular filtration rate in patients treated with platinum containing therapy . Int J Cancer \n2014 ;135 :1733 –9 . 10.1002/ijc.28816 24585507 \n19. Poole SG , Dooley MJ , Rischin D \nA comparison of bedside renal function estimates and measured glomerular filtration rate (Tc99mDTPA clearance) in cancer patients . Ann Oncol \n2002 ;13 :949 –55 . 10.1093/annonc/mdf236 12123341\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2059-7029",
"issue": "3(3)",
"journal": "ESMO open",
"keywords": "carboplatin; creatinine clearance; dose capping; seminoma stage I; toxicity",
"medline_ta": "ESMO Open",
"mesh_terms": null,
"nlm_unique_id": "101690685",
"other_id": null,
"pages": "e000320",
"pmc": null,
"pmid": "29531843",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "24002502;23864250;21282539;24915777;21884440;25319063;24445148;23152360;22473167;22104575;26037797;21705909;24669017;12123341;24585507;27052649;20031937;20544409",
"title": "Carboplatin dose based on actual renal function: no excess of acute haematotoxicity in adjuvant treatment in seminoma stage I.",
"title_normalized": "carboplatin dose based on actual renal function no excess of acute haematotoxicity in adjuvant treatment in seminoma stage i"
} | [
{
"companynumb": "CH-TEVA-2020-CH-1167604",
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"activesubstance": {
"activesubstancename": "CARBOPLATIN"
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{
"abstract": "Clonazepam undergoes nitroreduction to 7-amino-clonazepam via CYP3A4/5, followed by acetylation to 7-acetamido-clonazepam via NAT2 enzyme. While no pharmacological activity is attributed to the metabolites of clonazepam, 7-amino-clonazepam has some affinity for the benzodiazepine receptor as a partial agonist for the gamma aminobutyric acid-A receptor and can compete with clonazepam. Interindividual variability in the incidence of adverse events in patients may, in part, be attributable to differences in clonazepam metabolism. Here, we report on a case of a 70-year-old Caucasian female with insomnia and difficulty weaning off long-term use of clonazepam suggesting that a slow acetylator phenotype contributing to patient's presentation. This hypothesis was confirmed by NAT2 gene sequencing. NAT2 genotyping may play a role in guiding clonazepam therapy.",
"affiliations": "Department of Pharmacotherapeutics & Clinical Research, University of South Florida College of Pharmacy, Tampa, FL 33612, USA.;Department of Pharmaceutical Sciences, University of South Florida College of Pharmacy, Tampa, FL 33612, USA.;Department of Pediatrics, USF Health South Tampa Center for Advanced Healthcare, Tampa, FL 33606, USA.",
"authors": "Ho|Teresa T|TT|;Gupta|Sheeba Varghese|SV|;Sanchez-Valle|Amarilis|A|",
"chemical_list": "D002998:Clonazepam; D051544:Cytochrome P-450 CYP3A; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human",
"country": "England",
"delete": false,
"doi": "10.2217/pgs-2018-0145",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1462-2416",
"issue": "20(2)",
"journal": "Pharmacogenomics",
"keywords": " genotype; pharmacogenomics; clonazepam; personalized clonazepam therapy",
"medline_ta": "Pharmacogenomics",
"mesh_terms": "D000107:Acetylation; D000368:Aged; D001191:Arylamine N-Acetyltransferase; D002998:Clonazepam; D051544:Cytochrome P-450 CYP3A; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005838:Genotype; D006801:Humans; D011110:Polymorphism, Genetic; D057285:Precision Medicine; D013375:Substance Withdrawal Syndrome",
"nlm_unique_id": "100897350",
"other_id": null,
"pages": "69-73",
"pmc": null,
"pmid": "30520338",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Prolonged clonazepam-induced withdrawal symptoms in an NAT2 ultraslow acetylator.",
"title_normalized": "prolonged clonazepam induced withdrawal symptoms in an nat2 ultraslow acetylator"
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{
"companynumb": "US-APOTEX-2019AP007519",
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"occurcountry": "US",
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"activesubstancename": "CLONAZEPAM"
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... |
{
"abstract": "The anesthetic management of dilated cardiomyopathy (DCM) is challenging and is associated with a high mortality rate. We present a case of a 44-year-old pregnant female known for DCM with low ejection fraction who underwent an elective cesarean section and tubal ligation. The patient was transferred to the intensive care unit in a stable condition with a favorable outcome. Awareness about the appropriate anesthetic management for this type of patients is of paramount importance because similar cases are likely to be encountered with the advances in modern medicine.",
"affiliations": "Department of Anesthesiology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.;Department of Anesthesiology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.",
"authors": "Bin Suhaym|Nawaf A|NA|;Aamri|Etedal|E|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/sja.SJA_456_19",
"fulltext": "\n==== Front\nSaudi J AnaesthSaudi J AnaesthSJASaudi Journal of Anaesthesia1658-354X0975-3125Wolters Kluwer - Medknow India SJA-14-12010.4103/sja.SJA_456_19Case ReportAnesthetic management of dilated cardiomyopathy for cesarean section: A case report Bin Suhaym Nawaf A. Aamri Etedal Department of Anesthesiology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi ArabiaAddress for correspondence: Dr. Nawaf A. Bin Suhaym, Department of Anesthesiology, King Faisal Specialist Hospital and Research Center, MBC 22, P.O. Box 3354, Riyadh 11211, Kingdom of Saudi Arabia. E-mail: nawaf.suh@gmail.comJan-Mar 2020 06 1 2020 14 1 120 122 21 7 2019 03 9 2019 Copyright: © 2020 Saudi Journal of Anesthesia2020This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.The anesthetic management of dilated cardiomyopathy (DCM) is challenging and is associated with a high mortality rate. We present a case of a 44-year-old pregnant female known for DCM with low ejection fraction who underwent an elective cesarean section and tubal ligation. The patient was transferred to the intensive care unit in a stable condition with a favorable outcome. Awareness about the appropriate anesthetic management for this type of patients is of paramount importance because similar cases are likely to be encountered with the advances in modern medicine.\n\nCesarean sectiondilated cardiomyopathymanagement\n==== Body\nIntroduction\nDilated cardiomyopathy (DCM) is one of the most common types of nonischemic heart muscle disease among the adult population, and it is associated with a high perioperative mortality. Systolic function impairment and left ventricular or biventricular enlargements are the hallmark of DCM which have a significant impact on myocardial contractility.[12] Despite the high prevalence of DCM among adults, limited evidence has been published regarding the ideal anesthetic management in noncardiac surgery.[2] In this report, we describe successful management of a case of DCM that underwent cesarean section and tubal ligation under neuraxial blockade (epidural anesthesia) with a favorable outcome.\n\nCase Report\nA 44-year-old female, gravida 8 para 5 plus 2 at 37 weeks' gestation admitted electively for cesarean section and tubal ligation. She is a known case of DCM with an ejection fraction of 30% for a few years. Her symptoms were well-controlled on treatment with oral frusemide, Carvedilol, Hydralazine, and Iso dinitrate. The patient is New York Heart Association (NYHA) class 3, following up with a cardiologist who increased frusemide from 40 to 60 per day, 2 months before the procedure, and she has a regular follow-up appointment. In addition, she is on a diet plan for a well-controlled gestational diabetes mellitus.\n\nIn the preoperative evaluation, the patient was doing well, with no active complaint and good fetal movement with no history of vaginal leakage. She has a history of shortness of breath on mild to moderate physical exercise, unable to climb a flight of stairs without becoming breathless. On examination, she was 165 cm tall and weighed 90.3 kg with body mass index of 33.2, her heart rate (HR) was 90/min and blood pressure (BP) was 127/71 mmHg, and her SpO2 was 99% while breathing room air. There were no features suggestive of congestive heart failure. Routine laboratory investigations were within normal limits with a hemoglobin level of 8.6 g/dL. 12-lead electrocardiography (ECG) showed sinus rhythm with occasional premature ventricular complexes, otherwise normal ECG. Chest X-ray was unremarkable.\n\nEchocardiogram (Echo) showed severely dilated left ventricle with moderately to severely reduced systolic function due to global hypokinesis and indeterminate filling pressures, and no thrombi were present. Other findings included normal right ventricle size, systolic function, and filling pressures with moderately dilated left atria. Moreover, the mitral valve had a restricted bileaflet closure resulting in moderate regurgitation. No other significant valvular malfunction was noted. There was no indeterminate pulmonary artery pressure. There was no pericardial effusion.\n\nThe last formal ultrasound (US) on 36 weeks showed an estimated fetal weight of 2.8 kg, cephalic with normal amniotic fluid, and normal Doppler. The epidural anesthesia technique was explained to the patient, and the consent was signed.\n\nThe plan was to admit her for cesarean section after cardiology clearance. So, the cardiologist suggested to keep her on frusemide 60 mg BID and input/output charting and daily weight after the procedure (due to high risk of developing postoperative heart failure decompensation). After admitting the patient, the anesthesia plan is to proceed with epidural anesthesia with a backup plan of general anesthesia.\n\nRoutine noninvasive monitoring was established, including noninvasive blood pressure, hr, pulse oximetry (SpO2), and ECG. Her SpO2 was 99% on face mask 5 L/min, and ECG results showed normal sinus rhythm. An awake arterial line was inserted first followed by epidural in the sitting position, followed by central venous catheter insertion under US guidance and confirmed with X-ray. Two large intravenous accesses were inserted, and the chest pads were attached preoperatively. The crash cart was brought in the operative room, and inotropes and vasopressors were on pumps ready to go.\n\nThe patient was very anxious; midazolam 1 mg was administered before epidural, another 1 mg around 20 min later and a third dose 30 min later; the nephrologist was informed after placing in the sitting position and then 4 mL of 2% lidocaine was used for local infiltration anesthesia at L3–4 space. The epidural space was located with an 18-G Tuohy needle at the first attempt. After confirming the space by loss of resistance, bupivacaine 0.25% 20 mL + 40 μg fentanyl was given into the epidural space. The depth of the epidural space was 9.5 cm, while the depth of the catheter was 5.5 cm. The epidural was uneventful, and we changed the patient position into a supine position.\n\nIntravenous fluids were maintained at 60–80 mL/h. Dexmedetomidine was administered at a bolus of 0.5 μg/kg over 10 min followed by a second bolus intravenously; norepinephrine infusion was initiated with a total dose of 0.30 mg throughout the procedure; her BP decreased to 125/63 mmHg and HR to 87/min. There were no complaints from the patient, and a baby girl was delivered. The surgeon was asked to massage the uterus for a long time to avoid the administration of uterotonic medications, with estimated blood loss of around 700 mL. The surgery lasted for 90 min. The Apgar score for the newborn infant was 9 points. The cesarean section went smoothly with no complications. The patient was admitted to the intensive care unit (ICU) for observation as she is in a high risk for having decompensated heart failure post operation. She was stable in the ICU, and they transferred her back to the ward with a stable condition after 24 h. No perioperative or anesthetic complications occurred. The patient was discharged home 2 weeks later.\n\nDiscussion\nAnesthetic management goals in a patient with DCM consist of maintaining contractility, avoid an increase in the afterload, minimize the use of drugs that induce myocardial depression, and to maintain normovolemia.[3] The importance of invasive blood pressure monitoring is to detect any change in the blood pressure immediately to provide treatment according to the changes as it measures the BP beat to beat where central venous pressure monitoring helped in optimizing fluid therapy.[3]\n\nThe reason for using epidural anesthesia is to provides less variation in hemodynamic status when accompanied by intravenous fluids and inotropes.[45]\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n\nAcknowledgments\nThe authors are grateful to the Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.\n==== Refs\n1 Dec GW Fuster V Idiopathic dilated cardiomyopathy N Engl J Med 1994 331 1564 75 7969328 \n2 Chen CQ Wang X Zhang J Zhu SM Anesthetic management of patients with dilated cardiomyopathy for noncardiac surgery Eur Rev Med Pharmacol Sci 2017 21 627 34 28239802 \n3 Kumar M Batra M Raj R Anaesthetic management of a case of dilated cardiomyopathy for emergency appendectomy Anesth Essays Res 2014 8 105 25886117 \n4 Brown G O'Leary M Douglas I Herkes R Perioperative management of a case of severe peripartum cardiomyopathy Anaesth Intens Care 1992 20 80 3 \n5 Dutt A Agarwal A Chatterji R Ahmed F Anesthetic management for caesarean section in a case of peripartum cardiomyopathy Anesth Essays Res 2013 7 273 25885847\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": null,
"issue": "14(1)",
"journal": "Saudi journal of anaesthesia",
"keywords": "Cesarean section; dilated cardiomyopathy; management",
"medline_ta": "Saudi J Anaesth",
"mesh_terms": null,
"nlm_unique_id": "101500601",
"other_id": null,
"pages": "120-122",
"pmc": null,
"pmid": "31998034",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "1535183;25885847;28239802;7969328;25886117",
"title": "Anesthetic management of dilated cardiomyopathy for cesarean section: A case report.",
"title_normalized": "anesthetic management of dilated cardiomyopathy for cesarean section a case report"
} | [
{
"companynumb": "NVSC2020SA047847",
"fulfillexpeditecriteria": "1",
"occurcountry": "SA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HYDRALAZINE HYDROCHLORIDE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe brain is a frequent site of metastases in small-cell lung cancer. Symptoms of cerebral involvement are headache, disorientation, nausea/vomiting and seizures.\n\n\nMETHODS\nA man with small-cell lung cancer developed a human herpesvirus 6 (HHV-6) meningoencephalitis with neurological symptoms that simulated brain involvement from the lung cancer. HHV-6 is a T cell lymphotropic virus which may be pathogenic in the immunocompromised host. HHV-6 remains latent after the first infection, and when the immune system is compromised it can reactivate. The treatment of HHV-6 infection is highly specific and the drugs recommended are the two antivirals, ganciclovir or foscarnet.\n\n\nCONCLUSIONS\nIn cancer patients neurologic symptoms are usually due to brain metastases. This case shows that in a cancer patient any aspecific neurologic symptom should be carefully evaluated in order to exclude a non-oncologic cause. This statement is particularly true if the therapies for the oncological and neurological diseases are effective.",
"affiliations": "Dipartimento Oncologia-Ematologia, Ospedale Guglielmo da Saliceto, Piacenza, Italy.",
"authors": "Mordenti|Patrizia|P|;Zaffignani|Elena|E|;Immovilli|Paolo|P|;Nobili|Elisabetta|E|;Cavanna|Luigi|L|",
"chemical_list": "D000998:Antiviral Agents; D017245:Foscarnet; D015774:Ganciclovir",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000360616",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-3157",
"issue": "59(5)",
"journal": "Chemotherapy",
"keywords": null,
"medline_ta": "Chemotherapy",
"mesh_terms": "D000998:Antiviral Agents; D001932:Brain Neoplasms; D018792:Encephalitis, Viral; D017245:Foscarnet; D015774:Ganciclovir; D015654:Herpesvirus 6, Human; D006801:Humans; D016867:Immunocompromised Host; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D019349:Roseolovirus Infections; D055752:Small Cell Lung Carcinoma",
"nlm_unique_id": "0144731",
"other_id": null,
"pages": "385-6",
"pmc": null,
"pmid": "24852190",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Human herpesvirus 6 encephalitis simulating brain metastases in a patient with advanced small-cell lung cancer.",
"title_normalized": "human herpesvirus 6 encephalitis simulating brain metastases in a patient with advanced small cell lung cancer"
} | [
{
"companynumb": "IT-CIPLA LTD.-2015IT04726",
"fulfillexpeditecriteria": "1",
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"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "BRAF mutations are present in a variety of cancers and cause constitutive activation of the Ras-Raf-MEK-ERK signaling pathway. In cutaneous malignant melanoma, combined treatment with BRAF and MEK inhibitors is associated with high response rates and has been shown to improve progression free as well as overall survival compared to BRAF inhibition alone. In multiple myeloma, BRAF mutations are detectable only in a minority of patients. Only few data are available regarding the clinical activity of BRAF inhibitors in BRAF-positive multiple myeloma patients, including some anecdotal reports on remarkable responses in individuals being resistant to all other available anti-myeloma treatment approaches. We here present the first report on the combination of vemurafenib and cobimetinib in a young patient with highly resistant and rapidly progressing multiple myeloma harboring the BRAF V600E mutation who achieved a rapid and sustained response to this combination therapy.",
"affiliations": "Medical Oncology and Hematology, Kantonsspital Graubuenden, Chur, Switzerland.;Oncology Centre Hirslanden & Zurich, Zurich, Switzerland.;Medical Oncology and Hematology, Kantonsspital Graubuenden, Chur, Switzerland.",
"authors": "Mey|Ulrich J M|UJM|;Renner|Christoph|C|;von Moos|Roger|R|",
"chemical_list": "D001384:Azetidines; D007211:Indoles; D010880:Piperidines; D013449:Sulfonamides; D000077484:Vemurafenib; D048493:Proto-Oncogene Proteins B-raf; C574276:cobimetinib",
"country": "England",
"delete": false,
"doi": "10.1002/hon.2353",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0278-0232",
"issue": "35(4)",
"journal": "Hematological oncology",
"keywords": "BRAF V600E; cobimetinib; multiple myeloma; vemurafenib",
"medline_ta": "Hematol Oncol",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001384:Azetidines; D005260:Female; D006801:Humans; D007211:Indoles; D009101:Multiple Myeloma; D009154:Mutation; D010880:Piperidines; D048493:Proto-Oncogene Proteins B-raf; D013449:Sulfonamides; D000077484:Vemurafenib",
"nlm_unique_id": "8307268",
"other_id": null,
"pages": "890-893",
"pmc": null,
"pmid": "27641727",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Vemurafenib in combination with cobimetinib in relapsed and refractory extramedullary multiple myeloma harboring the BRAF V600E mutation.",
"title_normalized": "vemurafenib in combination with cobimetinib in relapsed and refractory extramedullary multiple myeloma harboring the braf v600e mutation"
} | [
{
"companynumb": "CH-AMGEN-CHESP2018002430",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LENALIDOMIDE"
},
"drugadditional": null,
... |
{
"abstract": "We report an interesting case of warfarin resistance and subtherapeutic international normalized ratio (INR) in the setting of chronic smokeless tobacco use. A 33-year-old white male with a mechanical mitral valve failed to achieve therapeutic INR despite being on warfarin doses of up to 30 mg by mouth daily. The patient admits to chewing tobacco daily for the past 16 years. While evaluating potential causes of subtherapeutic INR, nonadherence, drug interactions, genetic polymorphisms, and dietary factors were considered. Subtherapeutic INR may be due to increased exposure to vitamin K from chewing tobacco. Tobacco is rich in vitamin K, and its chronic use may have caused the failure to attain a therapeutic INR. To our knowledge, there is only one other case of warfarin resistance resulting from smokeless tobacco described in published literature.",
"affiliations": "Department of Pharmacy, Steward St. Elizabeth's Medical Center, Brighton, MA, USA.;Department of Medicine, Steward St. Elizabeth's Medical Center, Brighton, MA, USA.;School of Pharmacy, MCPHS University, Worcester Campus, Worcester, MA, USA.;Faculty of Nursing and Health Sciences, Notre Dame University, Louaize, Zouk Mosbeh, Lebanon.;Department of Medicine, Steward St. Elizabeth's Medical Center, Brighton, MA, USA.;Department of Medicine, Steward St. Elizabeth's Medical Center, Brighton, MA, USA.",
"authors": "Nicolas|Diala|D|0000-0001-5697-761X;Elmouhayyar|Christopher|C|;Nicolas|Samar|S|;Talj|Juliana|J|;Hattar|Laith|L|;Alhudairy|Maad|M|",
"chemical_list": "D000925:Anticoagulants; D014812:Vitamin K; D014859:Warfarin",
"country": "England",
"delete": false,
"doi": "10.1111/jth.15057",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1538-7836",
"issue": "18(11)",
"journal": "Journal of thrombosis and haemostasis : JTH",
"keywords": "INR; interaction; tobacco; vitamin K; warfarin",
"medline_ta": "J Thromb Haemost",
"mesh_terms": "D000328:Adult; D000925:Anticoagulants; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D014030:Tobacco, Smokeless; D014812:Vitamin K; D014859:Warfarin",
"nlm_unique_id": "101170508",
"other_id": null,
"pages": "2954-2957",
"pmc": null,
"pmid": "32794311",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Subtherapeutic INR due to warfarin interaction with smokeless tobacco.",
"title_normalized": "subtherapeutic inr due to warfarin interaction with smokeless tobacco"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-070478",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "WARFARIN SODIUM"
},
"dr... |
{
"abstract": "Cabazitaxel and abiraterone have both received approval for treating metastatic castrate-resistant prostate cancer (mCRPC) patients after first-line docetaxel therapy. In the cabazitaxel and abiraterone sequential treatment (CAST) study, the clinical outcome of docetaxel-treated mCRPC patients treated sequentially with both cabazitaxel and abiraterone was studied. Data were collected retrospectively from mCRPC patients at 12 hospitals across the Netherlands who initiated cabazitaxel and/or abiraterone before December 2012. Primary outcome measure was overall survival (OS); secondary measures were progression-free survival (PFS), biochemical PFS, and best clinical and PSA response. Hospital admission data during treatment were collected, as well as toxicities resulting in treatment discontinuation or patient death. Sixty-three and 69 patients received Cab→Abi (cabazitaxel prior to abiraterone) and Abi→Cab before July 10th, 2013, respectively. Median OS was 19.1 months and 17.0 months in Cab→Abi and Abi→Cab treated patients, respectively (p = 0.369). Median PFS and biochemical PFS were significantly longer in Cab→Abi treated patients: 8.1 versus 6.5 (p = 0.050) and 9.5 versus 7.7 months (p = 0.024), respectively. Although partial responses to cabazitaxel occurred in both groups, Abi→Cab treated patients had a significantly decreased antitumor response from cabazitaxel than Cab→Abi treated patients (median PFS 5.0 versus 2.6 months, p < 0.001). Minor differences in toxicities were observed based on therapy sequence; generally, toxicity from cabazitaxel could be severe, while abiraterone toxicity was milder. This retrospective analysis indicates that primary progression on cabazitaxel or abiraterone did not preclude a response to the other agent in mCRPC patients. However, tumor response of both agents, particularly cabazitaxel, was lower when administered as higher-line therapy in the selected study population.",
"affiliations": "Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands.",
"authors": "Wissing|Michel D|MD|;Coenen|Jules L L M|JL|;van den Berg|Pieter|P|;Westgeest|Hans M|HM|;van den Eertwegh|Alfons J M|AJ|;van Oort|Inge M|IM|;Bos|Monique M|MM|;Bergman|André M|AM|;Hamberg|Paul|P|;Ten Tije|Albert J|AJ|;Los|Maartje|M|;Lolkema|Martijn P J K|MP|;de Wit|Ronald|R|;Gelderblom|Hans|H|",
"chemical_list": "D000736:Androstenes; D043823:Taxoids; D000077143:Docetaxel; C552428:cabazitaxel; D000069501:Abiraterone Acetate",
"country": "United States",
"delete": false,
"doi": "10.1002/ijc.29231",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0020-7136",
"issue": "136(6)",
"journal": "International journal of cancer",
"keywords": "abiraterone; cabazitaxel; docetaxel; prostate cancer; sequential treatment",
"medline_ta": "Int J Cancer",
"mesh_terms": "D000069501:Abiraterone Acetate; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000736:Androstenes; D000971:Antineoplastic Combined Chemotherapy Protocols; D018572:Disease-Free Survival; D000077143:Docetaxel; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D064129:Prostatic Neoplasms, Castration-Resistant; D012189:Retrospective Studies; D043823:Taxoids",
"nlm_unique_id": "0042124",
"other_id": null,
"pages": "E760-72",
"pmc": null,
"pmid": "25242736",
"pubdate": "2015-03-15",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "CAST: A retrospective analysis of cabazitaxel and abiraterone acetate sequential treatment in patients with metastatic castrate-resistant prostate cancer previously treated with docetaxel.",
"title_normalized": "cast a retrospective analysis of cabazitaxel and abiraterone acetate sequential treatment in patients with metastatic castrate resistant prostate cancer previously treated with docetaxel"
} | [
{
"companynumb": "NL-JNJFOC-20150108575",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
... |
{
"abstract": "Pancuronium is a typical non-depolarizing, curare-mimetic, very potent muscle relaxant. Besides application in anesthesiology and intensive care, it is used in execution as a part of lethal injection. In medico-legal practice, there are cases of using this substance in order to commit suicide or to deprive other people of their lives. Accidental pancuronium intoxications are very rare. The authors present such case ended in sudden death of hospitalized woman after mistakenly injection of the drug. 57-year-old female alcoholic was admitted to the Acute Poisoning Centre after ethylene glycol ingestion. During the fifth day of treatment the nurse by mistake, instead of furosemide, intravenously administered her pancuronium. Sudden respiratory and circulatory arrest occurred, so she was intubated and resuscitation with artificial ventilation were undertaken, however within 1 hour and 45 minutes the patient died. Due to the vague background of a sudden deterioration in the patient's condition, the case was brought for prosecution. The autopsy and histopathological studies did not reveal the cause of death, but undertaken chemico-toxicological examinations identified the presence of pancuronium in blood, liver and kidney (190 ng/ml, 70 ng/g and 125 ng/g, respectively). Chemico-toxicological analysis proved that the cause of death of the 57-year-old hospitalized woman was pancuronium intoxication due to evident medical error during drug administration. In our case the concentration of pancuronium in blood was in therapeutic range (200-600 ng/ml). However, even a therapeutic pancuronium dose administered to patient the breath of whom is not supported and monitored can be a threat to his life.",
"affiliations": null,
"authors": "Skowronek|Rafał|R|;Korczyńska|Małgorzata|M|;Kulikowska|Joanna|J|;Nowicka|Joanna|J|;Kabiesz-Neniczka|Stanisława|S|",
"chemical_list": "D010197:Pancuronium",
"country": "Poland",
"delete": false,
"doi": "10.5114/amsik.2017.75056",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0324-8267",
"issue": "67(4)",
"journal": "Archiwum medycyny sadowej i kryminologii",
"keywords": " lethal poisoning; non-depolarizing muscle relaxants; medical error",
"medline_ta": "Arch Med Sadowej Kryminol",
"mesh_terms": "D003422:Critical Care; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D019300:Medical Errors; D008875:Middle Aged; D010197:Pancuronium; D012131:Respiratory Insufficiency",
"nlm_unique_id": "1260766",
"other_id": null,
"pages": "254-263",
"pmc": null,
"pmid": "29663745",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Patient's death as a result of mistakenly injection of pancuronium.",
"title_normalized": "patient s death as a result of mistakenly injection of pancuronium"
} | [
{
"companynumb": "PL-VALIDUS PHARMACEUTICALS LLC-PL-2019VAL000557",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
},
"drugadd... |
{
"abstract": "Exertional heat stroke incidence is on the rise and has become the third leading cause of death in high school athletes. It is entirely preventable, yet this is a case of a 15-year-old, 97-kg male football player who presented unresponsive and hyperthermic after an August football practice. His blood pressure was 80/30, and his pulse was 180. He had a rectal temperature of 107.3°F, and upon entering the emergency department, he was rapidly cooled in 40 minutes. As he progressed, he developed metabolic acidosis, elevated liver enzymes, a prolapsed mitral valve with elevated troponin levels, and worsening hypotension even with extracorporeal membrane oxygenation support. After 3 days in the hospital, this young man was pronounced dead as a result of complications from exertional heat stroke. We address not only the complications of his hospital course relative to his positive blood cultures but also the complications that can result from attention-deficit/hyperactivity disorder medication our patient was taking. As the population of young adults becomes more obese and more highly medicated for attention-deficit/hyperactivity disorder, we sought out these growing trends in correlation with the increase in incidence of heat-related illness. We also address the predisposing factors that make young high school athletes more likely to experience heat illness and propose further steps to educate this susceptible population.",
"affiliations": "From the Division of Pediatric Emergency Medicine, Department of Pediatrics, School of Medicine, University of Louisville, Louisville, KY.",
"authors": "Allen|Samantha B|SB|;Cross|Keith P|KP|",
"chemical_list": "C090411:Adderall; D000662:Amphetamines; D014151:Anti-Anxiety Agents; D001569:Benzodiazepines; D008874:Midazolam",
"country": "United States",
"delete": false,
"doi": "10.1097/PEC.0000000000000296",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0749-5161",
"issue": "30(12)",
"journal": "Pediatric emergency care",
"keywords": null,
"medline_ta": "Pediatr Emerg Care",
"mesh_terms": "D000293:Adolescent; D000662:Amphetamines; D014151:Anti-Anxiety Agents; D001569:Benzodiazepines; D001803:Blood Transfusion; D017809:Fatal Outcome; D005538:Football; D018883:Heat Stroke; D006801:Humans; D008297:Male; D008874:Midazolam",
"nlm_unique_id": "8507560",
"other_id": null,
"pages": "904-10",
"pmc": null,
"pmid": "25469604",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Out of the frying pan, into the fire: a case of heat shock and its fatal complications.",
"title_normalized": "out of the frying pan into the fire a case of heat shock and its fatal complications"
} | [
{
"companynumb": "US-TEVA-532557USA",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AMPHETAMINE SULFATE\\DEXTROAMPHETAMINE"
},
"drugaddi... |
{
"abstract": "Collaboration of the Dutch centers for kidney transplantation in children started in 1997 with a shared immunosuppressive protocol, aimed at improving graft survival by diminishing the incidence of acute rejections. This study compares the results of transplantations in these patients to those in a historical reference group. Ninety-six consecutive patients receiving a first kidney transplant were treated with an immunosuppressive regimen consisting of mycophenolate mofetil, cyclosporine and corticosteroids. The results were compared with those of historic controls (first transplants between 1985 and 1995, n = 207), treated with different combinations of corticosteroids, cyclosporine A and/or azathioprine. Cytomegalovirus (CMV) prophylaxis was prescribed to high-risk patients in the study group, and only a small proportion of the reference group. The graft survival at 1 yr improved significantly: 92% in the study group, vs. 73% in the reference group (p < 0.001). In the study group 63% of patients remained rejection-free during the first year; in the reference group 28% (p < 0.001). After statistical adjustment of differences in baseline data, as cold ischemia time, the proportion of LRD, preemptive transplantation, and young donors, the difference between study and reference group in graft survival (RR 0.33, p = 0.003) and incidence of acute rejection (RR 0.37, p < 0.001), as the only factor, remained statistically significant, indicating the effect of the immunosuppressive therapy. In the first year one case of malignancy occurred in each group. CMV disease occurred less frequently in the study group (11%) than in the reference group (26%, p = 0.02). As a new complication in 4 patients bronchiectasis was diagnosed. A new consensus protocol, including the introduction of mycophenolate mofetil, considerably improved the outcome of pediatric kidney transplantation in the Netherlands, measured as reduction of the incidence of acute rejection and improved graft survival.",
"affiliations": "Department of Pediatric Nephrology of Erasmus MC Sophia, Rotterdam, the Netherlands. k.cransberg@erasmusmc.nl",
"authors": "Cransberg|Karlien|K|;Marlies Cornelissen|E A|EA|;Davin|Jean-Claude|JC|;Van Hoeck|Koen J M|KJ|;Lilien|Marc R|MR|;Stijnen|Theo|T|;Nauta|Jeroen|J|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid; D001379:Azathioprine",
"country": "Denmark",
"delete": false,
"doi": "10.1111/j.1399-3046.2005.00271.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "9(1)",
"journal": "Pediatric transplantation",
"keywords": null,
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D000293:Adolescent; D000305:Adrenal Cortex Hormones; D001379:Azathioprine; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D016572:Cyclosporine; D003586:Cytomegalovirus Infections; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D015994:Incidence; D016030:Kidney Transplantation; D009173:Mycophenolic Acid; D009426:Netherlands; D017063:Outcome Assessment, Health Care; D013997:Time Factors",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "104-11",
"pmc": null,
"pmid": "15667622",
"pubdate": "2005-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Improved outcome of pediatric kidney transplantations in the Netherlands -- effect of the introduction of mycophenolate mofetil?",
"title_normalized": "improved outcome of pediatric kidney transplantations in the netherlands effect of the introduction of mycophenolate mofetil"
} | [
{
"companynumb": "NL-ROCHE-1944401",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "In the last few years, gamma hydroxybutyric acid (GHB) has been used increasingly as a party drug; this has led to a marked increase in the number of requests for professional help with the treatment of GHB addiction. Pharmaceutical GHB (sodium oxybate, the sodium-salt of GHB), registered for cataplexia in narcolepsy patients, is used off-label to treat the withdrawal symptoms associated with GHB addiction. Pharmaceutical GHB has a high sodium load. In this report we present the cases of two patients who developed symptomatic hypernatremia following treatment with pharmaceutical GHB and who thereafter needed intensive care for the severe withdrawal symptoms that they experienced.",
"affiliations": null,
"authors": "Rood|I M|IM|;Seijger|C G W|CG|;van Waarde|J A|JA|;de Maat|M M R|MM|;Verhave|J C|JC|;Blans|M J|MJ|",
"chemical_list": "D012978:Sodium Oxybate",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0303-7339",
"issue": "59(1)",
"journal": "Tijdschrift voor psychiatrie",
"keywords": null,
"medline_ta": "Tijdschr Psychiatr",
"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D006955:Hypernatremia; D008297:Male; D012978:Sodium Oxybate; D013375:Substance Withdrawal Syndrome",
"nlm_unique_id": "0423731",
"other_id": null,
"pages": "47-51",
"pmc": null,
"pmid": "28098924",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hypernatremia caused by treatment with GHB obtained via a doctor's prescription.",
"title_normalized": "hypernatremia caused by treatment with ghb obtained via a doctor s prescription"
} | [
{
"companynumb": "NL-JAZZ-2017-NL-002710",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "SODIUM OXYBATE"
},
"drugadditional": "1",
... |
{
"abstract": "Kaposi sarcoma (KS) can develop following organ transplantation through reactivation of recipient human herpesvirus 8 (HHV-8) infection or through donor-derived HHV-8 transmission. We describe 6 cases of donor-derived HHV-8 infection and KS investigated from July 2018 to January 2020. Organs from 6 donors, retrospectively identified as HHV-8-positive, with a history of drug use disorder, were transplanted into 22 recipients. Four of 6 donors had risk factors for HHV-8 infection reported in donor history questionnaires. Fourteen of 22 organ recipients (64%) had evidence of posttransplant HHV-8 infection. Lung recipients were particularly susceptible to KS. Four of the 6 recipients who developed KS died from KS or associated complications. The US opioid crisis has resulted in an increasing number and proportion of organ donors with substance use disorder, and particularly injection drug use history, which may increase the risk of HHV-8 transmission to recipients. Better awareness of the risk of posttransplant KS for recipients of organs from donors with HHV-8 infection risk could be useful for recipient management. Testing donors and recipients for HHV-8 is currently challenging with no validated commercial serology kits available. Limited HHV-8 antibody testing is available through some US reference laboratories and the Centers for Disease Control and Prevention.",
"affiliations": "Centers for Disease Control and Prevention, Atlanta, Georgia, USA.;Centers for Disease Control and Prevention, Atlanta, Georgia, USA.;Centers for Disease Control and Prevention, Atlanta, Georgia, USA.;Liver Transplant Department, University of California Los Angeles, Los Angeles, California, USA.;Centers for Disease Control and Prevention, Atlanta, Georgia, USA.;Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.;Division of Pulmonary Critical Care and Sleep Medicine, University of Washington, Seattle, Washington, USA.;Department of Pulmonary Medicine, Cleveland Clinic Foundation, Cleveland, Ohio, USA.;Department of Pathology, Cleveland Clinic Foundation, Cleveland, Ohio, USA.;Centers for Disease Control and Prevention, Atlanta, Georgia, USA.;Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.",
"authors": "Dollard|Sheila C|SC|0000-0003-3969-9659;Annambhotla|Pallavi|P|;Wong|Phili|P|;Meneses|Katherine|K|;Amin|Minal M|MM|;La Hoz|Ricardo M|RM|0000-0002-1560-3192;Lease|Erika D|ED|;Budev|Maria|M|;Arrossi|Andrea Valeria|AV|;Basavaraju|Sridhar V|SV|;Thomas|Christie P|CP|0000-0002-5989-9685",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/ajt.16181",
"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\n32633035\n10.1111/ajt.16181\nAJT16181\nOriginal Article\nORIGINAL ARTICLES\nClinical Science\nDonor‐derived human herpesvirus 8 and development of Kaposi sarcoma among 6 recipients of organs from donors with high‐risk sexual and substance use behavior\nDOLLARD et al.Dollard Sheila C. https://orcid.org/0000-0003-3969-9659\n1\nsdollard@cdc.gov Annambhotla Pallavi \n1\n Wong Phili \n1\n Meneses Katherine \n2\n Amin Minal M. \n1\n La Hoz Ricardo M. https://orcid.org/0000-0002-1560-3192\n3\n Lease Erika D. \n4\n Budev Maria \n5\n Arrossi Andrea Valeria \n6\n Basavaraju Sridhar V. \n1\n Thomas Christie P. https://orcid.org/0000-0002-5989-9685\n7\n\n8\n \n1 \nCenters for Disease Control and Prevention\nAtlanta\nGeorgia\nUSA\n\n\n2 \nLiver Transplant Department\nUniversity of California Los Angeles\nLos Angeles\nCalifornia\nUSA\n\n\n3 \nDepartment of Internal Medicine\nUniversity of Texas Southwestern Medical Center\nDallas\nTexas\nUSA\n\n\n4 \nDivision of Pulmonary Critical Care and Sleep Medicine\nUniversity of Washington\nSeattle\nWashington\nUSA\n\n\n5 \nDepartment of Pulmonary Medicine\nCleveland Clinic Foundation\nCleveland\nOhio\nUSA\n\n\n6 \nDepartment of Pathology\nCleveland Clinic Foundation\nCleveland\nOhio\nUSA\n\n\n7 \nDepartment of Internal Medicine\nUniversity of Iowa Carver College of Medicine\nIowa City\nIowa\nUSA\n\n\n8 \nVeterans Affairs Medical Center\nIowa City\nIowa\nUSA\n\n* Correspondence\n\nSheila C. Dollard\n\nEmail: sdollard@cdc.gov\n\n04 8 2020 \n2 2021 \n21 2 10.1111/ajt.v21.2681 688\n02 4 2020 24 6 2020 25 6 2020 © 2020 The Authors. American Journal of Transplantation published by Wiley Periodicals, LLC. 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.Kaposi sarcoma (KS) can develop following organ transplantation through reactivation of recipient human herpesvirus 8 (HHV‐8) infection or through donor‐derived HHV‐8 transmission. We describe 6 cases of donor‐derived HHV‐8 infection and KS investigated from July 2018 to January 2020. Organs from 6 donors, retrospectively identified as HHV‐8‐positive, with a history of drug use disorder, were transplanted into 22 recipients. Four of 6 donors had risk factors for HHV‐8 infection reported in donor history questionnaires. Fourteen of 22 organ recipients (64%) had evidence of posttransplant HHV‐8 infection. Lung recipients were particularly susceptible to KS. Four of the 6 recipients who developed KS died from KS or associated complications. The US opioid crisis has resulted in an increasing number and proportion of organ donors with substance use disorder, and particularly injection drug use history, which may increase the risk of HHV‐8 transmission to recipients. Better awareness of the risk of posttransplant KS for recipients of organs from donors with HHV‐8 infection risk could be useful for recipient management. Testing donors and recipients for HHV‐8 is currently challenging with no validated commercial serology kits available. Limited HHV‐8 antibody testing is available through some US reference laboratories and the Centers for Disease Control and Prevention.\n\nThe authors report a series of human herpesvirus 8 infections transmitted from deceased donors with drug use and/or sexual risk factors that led to Kaposi sarcoma in organ transplant recipients.\n\nclinical research/practicedonors and donation: donor‐derived infectionsinfection and infectious agentsinfectious diseaseCenters for Disease Control and Prevention 10.13039/100000030 source-schema-version-number2.0cover-dateFebruary 2021details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.7 mode:remove_FC converted:18.02.2021\n\n\nDollard \nSC \n, \nAnnambhotla \nP \n, \nWong \nP \n, et al. Donor-derived human herpesvirus 8 and development of Kaposi sarcoma among six recipients of organs from donors with high-risk sexual and substance use behavior\n. Am J Transplant .2021 ;21 :681 –688\n. 10.1111/ajt.16181 \n32633035\n==== Body\nAbbreviations\nCDCCenters for Disease Control and Prevention\n\nCNIcalcineurin inhibitor\n\nDTACDisease Transmission Advisory Committee\n\nHBVhepatitis B virus\n\nHCVhepatitis C virus\n\nHHV‐8human herpesvirus 8\n\nHIVhuman immunodeficiency virus\n\nIDUinjection drug use\n\nIRDincreased risk donor\n\nKSKaposi sarcoma\n\nMMFmycophenolate mofetil\n\nMSMmen who have sex with men\n\nOPTNOrgan Procurement and Transplantation Network\n\nPHSPublic Health Service\n\n1 INTRODUCTION\nKaposi sarcoma (KS) is a cutaneous malignancy caused by human herpesvirus 8 (HHV‐8), also known as Kaposi sarcoma–associated herpesvirus. There are four epidemiological forms of KS that are all associated with some form of immunosuppression: AIDS‐related KS, classic KS in Mediterranean Europe, endemic KS in sub‐Saharan Africa, and iatrogenic KS in transplant recipients.\n1\n In the United States, HHV‐8 infection and KS are primarily associated with human immunodeficiency virus (HIV) infection and Acquired Immunodeficiency Syndrome (AIDS). In the US HIV population, HHV‐8 has transmission routes similar to that of HIV, mainly men who have sex with men (MSM) behavior and injection drug use (IDU).\n1\n, \n2\n, \n3\n, \n4\n HHV‐8 seroprevalence is 2%‐5% among US blood donors,\n5\n 7%‐9% among blood transfusion recipients,\n6\n 15%‐25% among HIV‐negative MSM, and 40%‐50% among HIV‐positive MSM.\n2\n HHV‐8 seroprevalence has not been assessed in the context of US organ transplantation; however, solid organ transplant (SOT) recipients are at 60‐ to 200‐fold elevated risk for KS compared to the general population because of their medical immunosuppression.\n1\n, \n7\n Transplant‐associated KS more often results from reactivation of HHV‐8 in previously infected patients.\n8\n Donor‐derived KS is less common but associated with higher rates of severe illness and mortality.\n9\n, \n10\n, \n11\n\n\n\nHistorically, MSM behavior and IDU have been associated with risk of donor HIV, hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. With the goal of minimizing possible transmission of these infections during transplantation, the 2013 Public Health Service (PHS) guidelines recommended ascertainment of 11 donor risk factors for HIV, HBV, and HCV, including substance use disorder, MSM behavior and incarceration in the 12 months prior to death. Donors with one or more risk factors are designated as increased risk donors (IRDs) per these recommendations. Due largely to the current US opioid crisis, a growing number and proportion of organ donors are IRDs, increasing from 8.9% in 2010 to 26.3% in 2017.\n12\n Because HHV‐8 infection shares risk factors with HIV, HBV, and HCV infection, increasing numbers of IRD may elevate the risk of donor‐derived HHV‐8 and development of KS. The present report describes 6 unrelated cases of donor‐derived KS from various transplant centers in the United States that were investigated by the Centers for Disease Control and Prevention (CDC) within an 18‐month period, July 2018 to January 2020.\n\n2 METHODS\n2.1 Clinical and epidemiologic investigation\nTransplant centers with KS cases are required to report suspected donor derived infections to the Organ Procurement and Transplantation Network (OPTN)/Disease Transmission Advisory Committee (DTAC), which monitors the transmission of disease through organ transplantation. DTAC examines potential transmission cases reported to the OPTN in an effort to confirm transmissions where possible. A subset of DTAC cases are investigated by the CDC, typically those with high public health significance, severe outcomes, multiple recipients, donors with known risk factors, or infections for which there are no commercial tests. All organ donor and recipient medical records were reviewed. All donors were deceased. Donor medical and social history data were provided by individuals knowledgeable of the donor lifestyle as part of organ procurement evaluation. In the current study these individuals self‐identified as family, friend, partner, or roommate. Donor history responses were reviewed for HHV‐8 risk factors; high‐risk sexual behavior including MSM, substance use disorder, and history of incarceration within the previous 12 months. All recipients of organs from a common donor were grouped for these analyses. The index case was defined as the first recipient from each group who developed KS resulting in reporting to OPTN/DTAC, and a portion of cases underwent subsequent CDC investigation.\n\n2.2 Diagnosis of KS and HHV‐8 testing\nAll recipient tumor samples showed variable degrees of spindle cell proliferations that were positive for at least one vascular immunohistochemical marker (CD31, CD34, ERG) and positive for HHV‐8, confirming a diagnosis of KS. To investigate whether KS in recipients may have resulted from donor‐derived HHV‐8 infection, archived blood samples from the 6 donors and from their 22 recipients pretransplant (when available) and at least 3 months posttransplant were retrieved and sent to the CDC for HHV‐8 serology and PCR testing. All samples were tested for IgG antibodies to HHV‐8 using 2 enzyme immunoassays (EIAs) based on the K8.1 and orf65 viral genes and a whole cell lytic immunofluorescence assay (IFA). These 3 serology tests were developed or modified in‐house by CDC and have a combined sensitivity of 96.3% based on testing patients with KS and specificity of 97.5% based on testing US blood donors.\n5\n, \n6\n Samples were also tested for HHV‐8 DNA using TaqMan‐based real‐time PCR targeting the viral open reading frame 25 region as described previously.\n13\n\n\n\n3 RESULTS\n3.1 HHV‐8 infection status of 6 donors and 22 recipients\nAll 6 organ donors were HHV‐8 antibody and/or DNA positive (Table 1); 5 of 6 were antibody positive and one donor (#5) who was an active IDU, was antibody negative and DNA positive, indicating very recent primary infection. The donors were all male, 18‐ to 54‐years‐old; 5 of 6 were younger than 40‐years‐old. All six donors had a history of substance use disorder. Four donors had known risk factors for HHV‐8 infection; MSM (Donors 2 and 6) or IDU (Donors 4 and 5). Donors 1 and 3 had probable risk factors for HHV‐8 infection as regular users of methamphetamine (also heroin and cocaine for Donor 3), which is associated with high‐risk sexual behaviors (trading sex for drugs and money)\n14\n, \n15\n and IDU.\n16\n Organs from 6 donors were transplanted into 22 recipients (Table 2). Four of the 6 index cases had pretransplant serum available, which demonstrated absence of HHV‐8 infection prior to transplantation. The other 2 index cases had no pretransplant serum and no reported risk factors for HHV‐8 infection. Overall, 14 of 22 (64%) organ recipients had evidence of posttransplant HHV‐8 infection. Four of 6 index (67%) cases were lung recipients. Four of 6 index cases (67%) died directly from KS or from complications involving KS as described below.\n\nTABLE 1 Cause of death, sexual behavior, substance use history, and incarceration among selected HHV‐8 infected organ donors—United States, July 2018 to January 2020\n\nDonor #\tCause of death\tSexual risk for HHV‐8 infection\tSubstance use history\tIncarceration last 12 mo\tHHV‐8 antibody\tHHV‐8 DNA copies/mL\t\n1\tStroke\tSexual preference listed as unknown\tInhalation (meth, marijuana)\tNo\tPositive\tNot detected\t\n2\tSeizure\tMSM\tInhalation (marijuana)\tNo\tPositive\t1.18E+04\t\n3\tStroke\tNone reported\tInhalation (meth, cocaine, heroin)\tNo\tPositive\tNot detected\t\n4\tHeroin overdose\tNone reported\tInhalation + Injection (cocaine, heroin)\tYes\tPositive\tNot detected\t\n5\tEndocarditis\tPartner with history of IDU\tInjection (heroin)\tYes\tNegative\t1.13E+04\t\n6\tSuicide by hanging\tMSM, Sex for drugs\tInhalation (meth, cocaine, heroin)\tNo\tPositive\tNot detected\t\nNote\nAll donors were male ages 18‐54 years. Only Donor 2 had history of prior residence in an HHV‐8 endemic region.\n\nAbbreviations: HHV‐8, human herpesvirus 8; Meth, methamphetamine; MSM, men who have sex with men.\n\nJohn Wiley & Sons, LtdTABLE 2 HHV‐8 infection and Kaposi sarcoma outcomes among recipients of organs from HHV‐8–positive donors\n\nDonor #\tRecipient #\tOrgan\tPretransplant HHV‐8 Ab\tPosttransplant HHV‐8 Ab/PCR VL\tKS/time from transplant to KS\t\n1\t1 (Index)\tBilateral lung\tNegative\tPositive/negative\tYes/7 mo\t\n2\tLiver\tNot available\tPositive/1.13E+04\tNo\t\n2\t1 (Index)\tBilateral lung\tNegative\tPositive/negative\tYes/4 mo\t\n2\tRt kidney\tNegative\tNegative/negative\tNo\t\n3\tLt kidney + pancreas\tNegative\tPositive/1.21E+04\tNo\t\n4\tHeart\tNegative\tNegative/negative\tNo\t\n5\tLiver\tNot available\tPositive/negative\tNo\t\n3\t1 (Index)\tLiver\tNot available\tPositive/8.07E+03\tYes/11 mo\t\n2\tHeart + Lt kidney\tNot available\tNegative/negative\tNo\t\n3\tRt kidney\tNot available\tNegative/negative\tNo\t\n4\t1 (Index)\tBilateral lung\tNot available\tPositive/9.61E+03\tYes/8 mo\t\n2\tRt kidney\tNegative\tPositive/negative\tNo\t\n3\tHeart\tNegative\tNegative/negative\tNo\t\n4\tLiver\tNot available\tNegative/negative\tNo\t\n5\tLt kidney + pancreas\tNegative\tPositive/negative\tNo\t\n5\t1 (Index)\tLt kidney\tNegative\tPositive/1.07E+04\tYes/5 mo\t\n2\tRt kidney\tNegative\tPositive/negative\tNo\t\n3\tLiver\tNot available\tPositive/negative\tNo\t\n6\t1 (Index)\tBilateral lung\tNegative\tPositive/7.57E+03\tYes/12 mo\t\n2\tRt kidney\tNot available\tNegative/negative\tNo\t\n3\tLt kidney\tNegative\tNegative/negative\tNo\t\n4\tLiver\tNegative\tPositive/6.06E+03\tNo\t\nRecipients were ages 33‐72 years.\n\nAbbreviations: HHV‐8, human herpesvirus 8; KS, Kaposi sarcoma; VL, viral load, copies HHV‐8/mL blood.\n\nJohn Wiley & Sons, Ltd3.2 Clinical summaries for six KS cases\n3.2.1 Donor 1, index recipient\nA female patient with chronic obstructive pulmonary disease underwent lung transplantation. She received basiliximab as induction and tacrolimus, mycophenolate mofetil (MMF), and prednisone as maintenance immunosuppression. Six months after transplantation, she presented with abdominal pain and diffuse adenopathy. Positron emission tomography (PET) showed [18]F‐fluorine deoxyglucose (FDG)–avid right axillary, inguinal, and hilar lymph nodes and right‐sided lung nodules (Figure 1, panels A and C). A core needle biopsy of the right inguinal lymph node revealed KS. MMF was discontinued, tacrolimus was reduced, and sirolimus was added. She underwent weekly treatment with paclitaxel and had radiographic resolution of the adenopathy and pulmonary nodules on repeat PET after 5 months and she was doing well 19 months after diagnosis (Figure 1, panel B and D).\n\nFIGURE 1 PET scan in Case 1 demonstrating FDG‐avid right lung nodule (panel A) and right inguinal lymph node (panel C). Follow‐up PET scan demonstrating resolution of chest nodule (panel B) and inguinal lymph node (panel D) FDG avidity\n\n3.2.2 Donor 2, index recipient\nA male patient with a history of cystic fibrosis underwent bilateral lung transplantation. He received basiliximab as induction and tacrolimus, azathioprine, and prednisone as maintenance immunosuppression. Azathioprine was held at 3 months for leukopenia and transitioned to MMF once resolved. Five months after transplantation, he presented with cough and shortness of breath. Chest computed tomography (CT) revealed bilateral pulmonary nodules, consolidation, and pleural effusions (Figure 2, panel A). He underwent a left lower lobe wedge biopsy, which revealed KS (Figure 2, panels B,C,E,F). MMF was discontinued and tacrolimus changed to sirolimus. He had progression of pulmonary lesions and monthly doxorubicin was initiated. He completed 6 cycles and has continued sirolimus and prednisone. At 18 months after transplantation, chest CT showed resolution of the lesions (Figure 2, panel D).\n\nFIGURE 2 CT scan in Case 2 showing lung nodules and consolidation at diagnosis (panel A) and subsequent resolution (panel D). Lung biopsy showing proliferating spindle cells with extravasated red blood cells (panels A, B, A: hematoxylin & eosin 10×; B: hematoxylin & eosin 20×). Immunohistochemical stain for CD31 20× (panel E) and human herpesvirus 8 (HHV‐8) 20× (panel F)\n\n3.2.3 Donor 3, index recipient\nA male patient with a history of cryptogenic cirrhosis and hepatocellular cancer underwent liver transplantation. He received no induction immunosuppression and was maintained initially on tacrolimus, MMF, and prednisone. MMF was discontinued after an episode of Clostridioides difficile colitis. He was readmitted 11 months after transplantation with generalized weakness, vomiting, and diarrhea. Abdominal CT revealed inguinal lymphadenopathy. Right inguinal node biopsy was performed and KS was diagnosed. PET showed diffuse lymphadenopathy in the bilateral axillary, mediastinal, supradiaphragmatic, retroperitoneal, and inguinal lymph node chains, with moderate FDG uptake in the thorax and upper abdomen. A liver biopsy performed for worsening ascites and elevated bilirubin showed moderate acute cellular rejection (ACR), which was treated with methylprednisolone. He received one dose of rituximab, but he declined additional chemoradiation and died.\n\n3.2.4 Donor 4, index recipient\nA male patient with a history of respiratory bronchiolitis interstitial lung disease underwent bilateral lung transplantation. He did not receive induction immunosuppression and initial maintenance immunosuppression consisted of tacrolimus, MMF, and prednisone. Early in the postoperative period he was given stress dose steroids for de novo class I donor specific antibodies. Eight months after transplantation, he received a prednisone taper for ACR. The following month, he developed autoantibodies to collagen type V and k‐α1 tubulin. He was treated for presumptive antibody‐mediated rejection with plasma exchange, intravenous Ig, rituximab, anti‐thymocyte globulin, and a prednisone taper. He continued to experience shortness of breath, and a bronchoscopy showed chronically inflamed mucosa. Endobronchial biopsy from the right lung identified KS (Figure 3). MMF was discontinued and tacrolimus dose was lowered, and he continued low‐dose prednisone. He began initial treatment with monthly liposomal doxorubicin. After the fourth dose, he developed febrile neutropenia with worsening shortness of breath. A follow‐up computed tomography (CT) scan showed bilateral confluent lung nodules with his Epstein‐Barr virus PCR elevated at 242486, consistent with Post‐Transplant Lymphoproliferative Disorder. Continuous renal replacement therapy, vasopressors, and ventilatory support were initiated. He continued to decline and died 1 month later.\n\nFIGURE 3 Histopathology in Case 4. Proliferation of monomorphic spindle cells with associated dilated vessels (arrows in panel A). The cells form ill‐defined fascicles (asterisks in B) and are separated by spaces containing erythrocytes (arrows in B). A: Hematoxylin & eosin 10×. B: Hematoxylin & eosin 20×. Immunohistochemical stain for ETS‐related gene (ERG) 20 × (panel C) and human herpesvirus 8 (HHV‐8) 20× (panel D)\n\n3.2.5 Donor 5, index recipient\nA male patient with a prior unilateral nephrectomy and end‐stage renal disease underwent kidney transplantation. At transplantation, he was given anti‐thymocyte globulin and was maintained initially on tacrolimus, MMF, and prednisone. Because the donor had HCV infection, the recipient was treated with glicaprevir and pibrentasvir for 12 weeks. Five months after transplantation, a transplant renal biopsy was performed for worsening renal function and suggested ACR. He received 3 doses of methylprednisolone and 1 dose of anti‐thymocyte globulin. He developed CMV infection (CMV PCR: 14000 IU/mL) and was treated with ganciclovir. A repeat renal biopsy showed diffuse infiltrative KS. A PET‐CT scan showed enlarged FDG‐avid retroperitoneal, inguinal, and mesenteric nodes. He underwent a transplant nephrectomy, but the resection margins were positive for KS. MMF and tacrolimus were discontinued. Because of persistent inguinal lymphadenopathy, a lymph node biopsy was performed a month later, which confirmed metastatic KS and the recipient died while awaiting chemotherapy.\n\n3.2.6 Donor 6, index recipient\nA female patient with idiopathic pulmonary fibrosis underwent bilateral lung transplantation. She received basiliximab as induction and tacrolimus, MMF, and prednisone as maintenance immunosuppression. One year later, she presented with abdominal pain, nausea, and jaundice. CT scan showed diffuse lymphadenopathy, pulmonary nodules, and biliary dilatation. A right‐sided chest tube was placed for worsening hypoxia and a left supraclavicular lymph node biopsy was performed. The lymph node biopsy confirmed KS. She developed worsening multiorgan system failure and died 3 weeks later.\n\n3.2.7 Status of other recipients\nAs of March 2020, none of the other 16 organ recipients from these 6 donors were showing signs or symptoms of KS, with times from transplantation of 13‐27 months. The time from transplantation to diagnosis of KS for the 6 index cases was 4‐12 months, with a mean of 7.8 months (Table 2), consistent with posttransplant KS risk being highest within 1 year of surgery.\n11\n For the 16 recipients exposed to HHV‐8 but without KS, limited clinical information was provided to the CDC, but several center contacts indicated that follow‐up care would not be altered except for extra vigilance for any signs or symptoms of KS.\n\n4 DISCUSSION\nThis report describes the transmission of HHV‐8 from 6 deceased organ donors to 14 of 22 (64%) recipients, 6 of whom subsequently developed KS. The recipients with KS were shown (n = 4) or presumed (n = 2) to be previously HHV‐8 seronegative. Two of the donors had HHV‐8 DNA in their blood, which is only rarely detected in individuals who do not have KS disease\n5\n, \n17\n and indicates recent primary infection or reinfection. Most of the donors had a history of high‐risk sexual behavior and/or IDU. Relatively low rates of posttransplant KS (163 cases/264 624 transplants) were reported for 1987‐2014 in a comprehensive analysis of KS among US transplant recipients.\n11\n KS incidence was highest within 1 year of transplantation, significantly lower 1‐3 years after transplantation, and decreased sharply thereafter.\n11\n The risk of HHV‐8 transmission in the current transplant setting is unknown, with no prevalence data among organ donors. The identification of HHV‐8 in several donors, all with substance use disorder and some with high‐risk sexual behavior, suggests that organ donation in the setting of the US opioid crisis may pose a growing risk of HHV‐8 transmission and KS.\n\nThere are several notable features of the 6 KS cases described here. The mortality rate was very high; 4 of 6 recipients died due to KS or associated complications. Known risk factors for KS‐related mortality include recipient HHV‐8 seronegativity and older age.\n11\n, \n18\n Additional risk factors may have included profound immunosuppression after transplantation, specifically receiving agents such as anti‐thymocyte globulin (2 of 4 cases), which cause prolonged T cell immune depletion, and late presentation or delayed recognition of KS (2 of 4 cases). Next, although lung transplants comprise only 8% of all SOTs\n19\n and 14 of 22 recipients had evidence of posttransplant HHV‐8 infection (5 liver, 4 lung, 3 kidney, and 2 kidney and pancreas), 4 of the 6 recipients who developed KS received lung transplants. The reason for the apparent higher KS risk with lung transplantation in this group remains unclear and further study may show whether it was related to drug use. HHV‐8 is shed in the saliva of infected persons\n20\n and aspiration of saliva during inhalational drug use could elevate viral levels in the lung relative to other organs. Another potential mechanism may be local inflammation in lungs from chronic inhalation drug use.\n21\n, \n22\n The inflammatory process recruits leukocytes to injured tissue and HHV‐8 is leukocyte associated. Despite the possibility of increasing donor‐derived HHV‐8 infection, awareness and management can greatly improve outcome such that the benefits of organ acceptance are thought to outweigh the risk of declining an organ.\n\nTreatment options for posttransplant KS include reduction of immunosuppression to the lowest possible level that maintains function of the allograft. Regression of KS with less risk to the graft has been obtained by reducing or discontinuing calcineurin inhibitors and adding mammalian target of rapamycin inhibitor (mTORi), such as sirolimus, which is now considered the first‐line treatment of KS for transplant recipients.\n23\n Early diagnosis and better awareness of posttransplant KS, particularly among recipients of organs from donors with HHV‐8 risk factors, with overall immunosuppression reduction and conversion to mTOR and use of chemotherapy appears to be associated with improved survival. It is important to note that T cell–depleting antibody therapy may result in prolonged T cell lymphopenia and that reducing or switching immunosuppressive drugs does not always result in an immediate improvement in immune function.\n24\n Although there is no consensus on chemotherapy, some patients will likely benefit from chemotherapy, especially if the disease appears to be progressing or if KS is detected late with advanced disease. The 2 survivors in our group did not receive anti‐thymocyte globulin, the disease was detected earlier (~6 months), and both patients were given reduced immunosuppression, had an mTORi added, and received chemotherapy.\n\nThese findings on donor behaviors and HHV‐8 transmission are subject to limitations. Donors 1 and 3 did not have HHV‐8 risk factors (MSM, IDU) listed on the donor questionnaire. However, donor history questionnaires can have incomplete information.\n25\n Donor 1 was noted to be sexually active with unknown gender preference, which may imply MSM behavior, and was a frequent user of methamphetamine, which is associated with high‐risk sexual behavior\n14\n, \n15\n and IDU.\n16\n Donor 3 was reported to inhale methamphetamine, cocaine, and heroin, which are associated with high‐risk sexual behavior\n14\n, \n15\n and IDU.\n16\n Therefore, it is the hypothesis of the authors that inhalation drug use disorder is not a newly identified risk factor for HHV‐8 infection but rather is associated with behaviors that are HHV‐8 risk factors. Second, pretransplant serum was not available for HHV‐8 testing for 4 of 14 (28%) recipients who had posttransplant infection (Table 2). However, given evidence of donor infection, infection of other recipients from the same donors, low HHV‐8 population seroprevalence, and lack of HHV‐8 risk factors reported for recipients, donor‐derived infection is more likely than prior infection in the recipient. Finally, our study lacked detailed data on clinical management of the 16 recipients who did not develop KS.\n\nFuture studies may include HHV‐8 seroprevalence studies on organ donors that would better elucidate infection rates, especially in view of the growing number and proportion of donors with substance use disorders. Determination of HHV‐8 infection requires antibody testing for adequate sensitivity because HHV‐8 viremia is rare in seropositive individuals without KS in the United States\n5\n and was detectable in only 7% of HHV‐8 seropositive organ donors in Italy.\n26\n The HHV‐8 serologic tests used for this study are made in‐house by the CDC,\n13\n, \n27\n are labor‐intensive, and not practical for routine screening. At present, there are no validated, commercial HHV‐8 serologic tests available in the United States. All suspected donor‐derived HHV‐8 infection and KS should be referred to the OPTN/DTAC for investigation. The CDC can perform HHV‐8 testing for posttransplant KS as part of HHV‐8 transplant‐transmission investigations (sdollard@cdc.gov). In addition, limited US reference laboratories offer HHV‐8 serology testing.\n28\n\n\n\nIn summary, clinicians caring for recipients of organs from at‐risk donors should have awareness of HHV‐8 infection and related complications. Proposed revision to the CDC PHS guideline reduces the ascertainment time for donor risk factors from 12 months to 1 month prior to organ donation. For the current study, most donors were MSM or had a history of IDU use, which is often daily, thus donor risk factors presented here would likely still be identified by Organ Procurement Organizations. Donor‐derived KS in this series appears to involve the allograft, and it is important to note that allograft dysfunction (acute lung injury, acute kidney injury) may be secondary to allograft KS. Monitoring recipients of these organs for KS development may allow early recognition. In turn, careful reduction of immunosuppression, introduction of an mTORi and consideration of chemotherapy may result in improved survival among these recipients.\n\nDISCLOSURE\nThe authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.\n\nACKNOWLEDGMENTS\nThe authors would like to express their gratitude to the patients and staff of the transplant centers who contributed to this investigation. Costs for the HHV‐8 diagnostic testing and preparation of the manuscript were paid for by the Centers for Disease Control and Prevention (CDC).\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\nCesarman \nE \n, \nDamania \nB \n, \nKrown \nS \n, \nMartin \nJ \n, \nBower \nM \n, \nWhitby \nD \n. Kaposi sarcoma\n. Nat Rev Dis Primers . 2019 ;5 (1 ):9 .30705286 \n2 \n\nMartin \nJN \n, \nGanem \nDE \n, \nOsmond \nDH \n, \nPage‐Shafer \nKA \n, \nMacrae \nD \n, \nKedes \nDH \n. Sexual transmission and the natural history of human herpesvirus 8 infection\n. N Engl J Med . 1998 ;338 (14 ):948 ‐954\n.9521982 \n3 \n\nCannon \nMJ \n, \nDollard \nSC \n, \nSmith \nDK \n, et al. Blood‐borne and sexual transmission of human herpesvirus 8 in women with or at risk for human immunodeficiency virus infection\n. N Engl J Med . 2001 ;344 (9 ):637 ‐643\n.11228278 \n4 \n\nRohner \nE \n, \nWyss \nN \n, \nHeg \nZ \n, et al. HIV and human herpesvirus 8 co‐infection across the globe: systematic review and meta‐analysis\n. Int J Cancer . 2016 ;138 (1 ):45 ‐54\n.26175054 \n5 \n\nPellett \nPE \n, \nWright \nDJ \n, \nEngels \nEA \n, et al. Multicenter comparison of serologic assays and estimation of human herpesvirus 8 seroprevalence among US blood donors\n. Transfusion . 2003 ;43 (9 ):1260 ‐1268\n.12919429 \n6 \n\nCannon \nMJ \n, \nOperskalski \nEA \n, \nMosley \nJW \n, \nRadford \nK \n, \nDollard \nSC \n. Lack of evidence for human herpesvirus‐8 transmission via blood transfusion in a historical US cohort\n. J Infect Dis . 2009 ;199 (11 ):1592 ‐1598\n.19385734 \n7 \n\nEngels \nEA \n, \nPfeiffer \nRM \n, \nFraumeni \nJF \n, et al. Spectrum of cancer risk among US solid organ transplant recipients\n. JAMA . 2011 ;306 (17 ):1891 ‐1901\n.22045767 \n8 \n\nLebbé \nC \n, \nLegendre \nC \n, \nFrancès \nC \n. Kaposi sarcoma in transplantation\n. Transplant Rev . 2008 ;22 (4 ):252 ‐261\n.\n9 \n\nMarcelin \nA‐G \n, \nRoque‐Afonso \nA‐M \n, \nHurtova \nM \n, et al. Fatal disseminated Kaposi's sarcoma following human herpesvirus 8 primary infections in liver‐transplant recipients\n. Liver Transpl . 2004 ;10 (2 ):295 ‐300\n.14762870 \n10 \n\nRazonable \nRR \n. Human herpesviruses 6, 7 and 8 in solid organ transplant recipients\n. Am J Transplant . 2013 ;13 (s3 ):67 ‐78\n.\n11 \n\nCahoon \nE \n, \nLinet \nM \n, \nClarke \nC \n, \nPawlish \nK \n, \nEngels \nE \n, \nPfeiffer \nR \n. Risk of Kaposi sarcoma after solid organ transplantation in the United States\n. Int J Cancer . 2018 ;143 (11 ):2741 ‐2748\n.29987894 \n12 \n\nAbara \nWE \n, \nCollier \nMG \n, \nMoorman \nA \n, et al. Characteristics of deceased solid organ donors and screening results for hepatitis B, C, and human immunodeficiency viruses — United States, 2010–2017\n. Am J Transplant . 2019 ;19 (3 ):939 ‐947\n.\n13 \n\nDollard \nSC \n, \nRoback \nJD \n, \nGunthel \nC \n, et al. Measurements of human herpesvirus 8 viral load in blood before and after leukoreduction filtration\n. Transfusion . 2013 ;53 (10 ):2164 ‐2167\n.23362994 \n14 \n\nTross \nS \n, \nHanner \nJ \n, \nHu \nM‐C \n, et al. Substance use and high risk sexual behaviors among women in psychosocial outpatient and methadone maintenance treatment programs\n. Am J Drug Alcohol Abuse . 2009 ;35 (5 ):368 ‐374\n.20180666 \n15 \n\nKidd \nJD \n, \nTross \nS \n, \nPavlicova \nM \n, et al. Sociodemographic and substance use disorder determinants of HIV sexual risk behavior in men and women in outpatient drug treatment in the NIDA National Drug Abuse Treatment Clinical Trials Network\n. Subst Use Misuse . 2017 ;52 (7 ):858 ‐865\n.28426361 \n16 \n\nWu \nL‐T \n, \nHoward \nMO \n. Is inhalant use a risk factor for heroin and injection drug use among adolescents in the United States?\n\nAddict Behav . 2007 ;32 (2 ):265 ‐281\n.16713124 \n17 \n\nCannon \nMJ \n, \nDollard \nSC \n, \nBlack \nJB \n, et al. Risk factors for Kaposi's sarcoma in men seropositive for both human herpesvirus 8 and human immunodeficiency virus\n. AIDS . 2003 ;17 (2 ):215 ‐222\n.12545082 \n18 \n\nPietrosi \nG \n, \nVizzini \nG \n, \nPipitone \nL \n, et al. Primary and reactivated HHV8 infection and disease after liver transplantation: a prospective study\n. Am J Transplant . 2011 ;11 (12 ):2715 ‐2723\n.21966899 \n19 \n\nDurand \nCM \n, \nBowring \nMG \n, \nThomas \nAG \n, et al. The drug overdose epidemic and deceased‐donor transplantation in the United States\n. Ann Intern Med . 2018 ;168 (10 ):702 ‐711\n.29710288 \n20 \n\nMartin \nJN \n. Moving toward clarity on 2 fronts in the epidemiology of Kaposi sarcoma‐associated herpesvirus infection\n. J Infect Dis . 2007 ;196 (2 ):173 ‐175\n.17570101 \n21 \n\nMégarbane \nB \n, \nChevillard \nL \n. The large spectrum of pulmonary complications following illicit drug use: features and mechanisms\n. Chem Biol Interact . 2013 ;206 (3 ):444 ‐451\n.24144776 \n22 \n\nNazari \nA \n, \nZahmatkesh \nM \n, \nMortaz \nE \n, \nHosseinzadeh \nS \n. Effect of methamphetamine exposure on the plasma levels of endothelial‐derived microparticles\n. Drug Alcohol Depend . 2018 ;186 :219 ‐225\n.29609134 \n23 \n\nLe \nJ \n, \nGantt \nS \n. Human herpesvirus 6, 7 and 8 in solid organ transplantation\n. Am J Transplant . 2013 ;13 (Suppl 4 ):128 ‐137\n.23465006 \n24 \n\nHardinger \nKL \n, \nSchnitzler \nMA \n, \nMiller \nB \n, et al. Five‐year follow up of thymoglobulin versus ATGAM induction in adult renal transplantation\n. Transplantation . 2004 ;78 (1 ):136 ‐141\n.15257052 \n25 \n\nVora \nNM \n, \nBasavaraju \nSV \n, \nFeldman \nKA \n, et al. Raccoon rabies virus variant transmission through solid organ transplantation\n. JAMA . 2013 ;310 (4 ):398 ‐407\n.23917290 \n26 \n\nChiereghin \nA \n, \nBarozzi \nP \n, \nPetrisli \nE \n, et al. Multicenter prospective study for laboratory diagnosis of HHV8 infection in solid organ donors and transplant recipients and evaluation of the clinical impact after transplantation\n. Transplantation . 2017 ;101 (8 ):1935 ‐1944\n.28333859 \n27 \n\nLaney \nAS \n, \nCannon \nMJ \n, \nJaffe \nHW \n, et al. Human herpesvirus 8 presence and viral load are associated with the progression of AIDS‐associated Kaposi's sarcoma\n. AIDS . 2007 ;21 (12 ):1541 ‐1545\n.17630548 \n28 \n\nDollard \nSC \n, \nDouglas \nD \n, \nBasavaraju \nSV \n, \nSchmid \nDS \n, \nKuehnert \nM \n, \nAqel \nB \n. Donor‐derived Kaposi's sarcoma in a liver–kidney transplant recipient\n. Am J Transplant . 2018 ;18 (2 ):510 ‐513\n.28941319 \n29 \n\nSeem \nDL \n, \nLee \nI \n, \nUmscheid \nCA \n, \nKuehnert \nMJ \n. PHS guideline for reducing Human Immunodeficiency virus, hepatitis B virus, and hepatitis C virus transmission through organ transplantation\n. Public Health Reports . 2013 ;128 :247 –344\n.23814319\n\n",
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"keywords": "clinical research/practice; donors and donation: donor-derived infections; infection and infectious agents; infectious disease",
"medline_ta": "Am J Transplant",
"mesh_terms": "D019288:Herpesvirus 8, Human; D006801:Humans; D016030:Kidney Transplantation; D012189:Retrospective Studies; D012514:Sarcoma, Kaposi; D014019:Tissue Donors",
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"publication_types": "D016428:Journal Article; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": "23347215;12919429;17630548;30705286;29987894;11228278;17570101;12545082;24144776;23362994;23917290;29710288;26175054;23814319;18656341;15257052;30677008;23465006;28333859;32633035;29609134;9521982;28941319;22045767;14762870;20180666;19385734;21966899;28426361;16713124",
"title": "Donor-derived human herpesvirus 8 and development of Kaposi sarcoma among 6 recipients of organs from donors with high-risk sexual and substance use behavior.",
"title_normalized": "donor derived human herpesvirus 8 and development of kaposi sarcoma among 6 recipients of organs from donors with high risk sexual and substance use behavior"
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"abstract": "We herein report a fatal case of Legionella pneumophila pneumonia in a tocilizumab-treated rheumatoid arthritis patient who was in a state of shock on admission but remained afebrile even during severe pneumonia. Legionella antigen was detected in the urine and neutrophil CD64 expression was highly elevated. Despite undergoing intensive treatment, the patient developed sepsis and died 12 days after admission. An autopsy indicated that while the Legionella infection had almost been controlled, a subarachnoid hemorrhage was the ultimate cause of death.",
"affiliations": "Department of Rheumatology, National Hospital Organization Sagamihara National Hospital, Japan.",
"authors": "Arinuma|Yoshiyuki|Y|;Nogi|Shinichi|S|;Ishikawa|Yuichi|Y|;Nakayama|Hisanori|H|;Hashimoto|Atsushi|A|;Komiya|Akiko|A|;Minoguchi|Kenji|K|;Horita|Ayako|A|;Saito|Ikuo|I|;Matsui|Toshihiro|T|;Tohma|Shigeto|S|",
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"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D017809:Fatal Outcome; D006760:Hospitalization; D006801:Humans; D016867:Immunocompromised Host; D016952:Legionella pneumophila; D007877:Legionnaires' Disease; D008297:Male; D008875:Middle Aged; D018805:Sepsis; D013345:Subarachnoid Hemorrhage",
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"title": "Fatal complication of Legionella pneumophila pneumonia in a tocilizumab-treated rheumatoid arthritis patient.",
"title_normalized": "fatal complication of legionella pneumophila pneumonia in a tocilizumab treated rheumatoid arthritis patient"
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"abstract": "Spontaneous rupture of the renal pelvis and ureter is associated with obstruction of the urinary collecting system, but is rarely caused by tumors. We describe our experience with a patient who had uterine cervical cancer with mild hydroureter in whom spontaneous ureteral rupture occurred during concurrent chemoradiotherapy. The patient was a 66-year-old woman with stage IIIB uterine cervical cancer and mild hydroureter who received concurrent chemoradiotherapy. The patient felt uncontrolled right-side abdominal pain caused by ureteral rupture after she was given hydration and an intravenous bolus injection of furosemide during the first week of chemoradiotherapy. Contrast-enhanced computed tomography was more useful than ultrasonography for diagnosis of the ureteral rupture. The ureteral rupture in our patient was attributed to a rapid rise in the pressure of the urinary collecting system caused by hydration and the bolus injection of furosemide. Placement of a double-J stent before starting concurrent chemoradiotherapy may help to prevent ureteral rupture in patients who have uterine cervical cancer with mild hydroureter.",
"affiliations": "Division of Gynecology, National Cancer Center Hospital, Tokyo, Japan.;Division of Gynecology, National Cancer Center Hospital, Tokyo, Japan.;Division of Gynecology, National Cancer Center Hospital, Tokyo, Japan.",
"authors": "Ikeda|Shun-Ichi|S|;Ishikawa|Mitsuya|M|;Kato|Tomoyasu|T|",
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"fulltext": "\n==== Front\nGynecol Oncol RepGynecol Oncol RepGynecologic Oncology Reports2352-5789Elsevier S2352-5789(15)00032-610.1016/j.gore.2015.04.006Case SeriesSpontaneous ureteral rupture during concurrent chemoradiotherapy in a woman with uterine cervical cancer Ikeda Shun-ichi shuikeda@ncc.go.jp⁎Ishikawa Mitsuya Kato Tomoyasu Division of Gynecology, National Cancer Center Hospital, Tokyo, Japan⁎ Corresponding author at: Division of Gynecology, National Cancer Center Hospital, Tokyo, Japan, 5-1-1 Tsukiji, Chuo-ku 104-0045, Tokyo, Japan. Fax: + 81 3 3542 3815. shuikeda@ncc.go.jp06 5 2015 8 2015 06 5 2015 13 18 19 16 3 2015 24 4 2015 © 2015 The Authors2015This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Spontaneous rupture of the renal pelvis and ureter is associated with obstruction of the urinary collecting system, but is rarely caused by tumors. We describe our experience with a patient who had uterine cervical cancer with mild hydroureter in whom spontaneous ureteral rupture occurred during concurrent chemoradiotherapy. The patient was a 66-year-old woman with stage IIIB uterine cervical cancer and mild hydroureter who received concurrent chemoradiotherapy. The patient felt uncontrolled right-side abdominal pain caused by ureteral rupture after she was given hydration and an intravenous bolus injection of furosemide during the first week of chemoradiotherapy. Contrast-enhanced computed tomography was more useful than ultrasonography for diagnosis of the ureteral rupture. The ureteral rupture in our patient was attributed to a rapid rise in the pressure of the urinary collecting system caused by hydration and the bolus injection of furosemide. Placement of a double-J stent before starting concurrent chemoradiotherapy may help to prevent ureteral rupture in patients who have uterine cervical cancer with mild hydroureter.\n\nHighlights\n• Ureteral rupture can occur during concurrent chemoradiotherapy in cervical cancer.\n\n• Contrast-enhanced CT is more useful than USG for the diagnosis of this condition.\n\n\n\nKeywords\nUterine cervical cancerConcurrent chemoradiotherapyUreteral ruptureContrast-enhanced computed tomography\n==== Body\n1 Introduction\nMost cases of spontaneous rupture of the renal pelvis and ureter are associated with ureteral obstruction by calculi. Although uterine cervical cancer is an exceedingly rare cause of renal pelvic or ureteral rupture, several cases have been reported (Singh et al., 2009, McClinton et al., 1989, Spurlock et al., 1987). The mechanism by which uterine cervical cancer causes spontaneous rupture of the renal pelvis and ureter has been suggested to involve obstruction of the ureter by tumor or swollen lymph nodes. We report a case of spontaneous ureteral rupture that occurred during concurrent chemoradiotherapy in a woman who had uterine cervical cancer associated with mild hydroureter without obstruction of the urinary collecting system.\n\n2 Case report\nA 66 year-old woman with a diagnosis of uterine cervical cancer was referred to the gynecologic department of our hospital. Pelvic examination showed a 5-cm cervical tumor with bilateral parametrial involvement, which had infiltrated to bilateral pelvic walls. Histopathological examination revealed squamous cell carcinoma of the cervix, and Federation of Gynecology and Obstetrics (FIGO) stage IIIB disease was diagnosed. The patient has never had any surgery on the genitourinary system. Contrast-enhanced computed tomography performed 10 days before starting concurrent chemoradiotherapy showed a normal renal pelvis and right mild hydroureter (Fig. 1). The serum creatinine and hemoglobin levels were 0.68 mg/dl and 12.9 g/dl, respectively. Uniform bilateral enhancement of the renal cortex was seen on contrast-enhanced CT, indicating normal functions of both kidneys. Moreover, contrast-enhanced CT and ultrasonography showed no stone in the ureter or renal pelvis. During the first week of concurrent chemoradiotherapy, 40 mg/m2 of cisplatin and 3 L of infusion solution were administered as an intravenous drip infusion, followed by 2 L of infusion solution on the next day. The patient's body weight increased by 2 kg as compared with before treatment, and 10 mg of furosemide was given as an intravenous bolus injection. After several hours, she felt uncontrolled right-side abdominal pain. Ultrasonography was performed immediately and revealed right hydronephrosis, but no abnormal fluid collection. The serum creatinine and hemoglobin levels were 0.80 mg/dl and 13.3 g/dl, respectively. There was no gross hematuria but positive test of RBC in urine. Subsequently, contrast-enhanced CT was conducted. Extravasation of contrast medium from the right upper ureter was confirmed (Fig. 2). A double-J stent was placed under cystoscopic guidance. There was no tumor, diverticulum, or stone in the bladder. No resistance was felt when the stent was inserted. We diagnosed stenosis of the right ureter, but no obstruction. After placement of the double-J stent, concurrent chemoradiotherapy was resumed.\n\n3 Discussion\nOur experience indicated two important clinical points. First, rupture of the renal pelvis and ureter can occur during concurrent chemoradiotherapy in the presence of uterine cervical cancer with ureteral stenosis. Second, contrast-enhanced CT was more useful than ultrasonography for the diagnosis of this condition.\n\nFirst, our experience showed that rupture of the renal pelvis or ureter can occur during concurrent chemoradiotherapy in patients who have uterine cervical cancer with hydroureter. Our patient had rupture of the upper ureter. Most previously reported cases of ureteral rupture involved the upper ureter. This is most likely attributed to the fact that the lower ureter has three layers of myometrium, whereas the upper ureter has only two layers. Although tumors rarely cause rupture of the renal pelvis or ureter, several previous studies have reported that obstruction of the ureter by tumor or swollen lymph nodes is a potential cause (Singh et al., 2009, McClinton et al., 1989, Spurlock et al., 1987). We confirmed that the ureter was not obstructed when the double-J stent was inserted after ureteral rupture. In the presence of normal kidney function with partial obstruction of the ureter, hydration causes increased urine production. However, hydration does not lead to increased urine production in patients who have decreased renal function with complete obstruction of the ureter. The renal rupture in our patient was apparently caused by the rapid elevation of intrapelvic pressure due to hydration and treatment with furosemide. To our knowledge, this is the first reported case of ureteral rupture occurring during concurrent chemoradiotherapy in a patient who had uterine cervical cancer without obstruction of the urinary collecting system.\n\nOur second important finding was that contrast-enhanced CT was more useful than ultrasonography for diagnosis immediately after ureteral rupture had occurred. Several case reports have documented that renal rupture complicated by retroperitoneal abscess can lead to sepsis (Hadar and Servadio, 1979, Lin et al., 2004, Coelho et al., 2007). Intravenous pyelography can confirm dilation of the ureter and renal pelvis, as well as perirenal extravasation of contrast medium. However, time is required to make a diagnosis. Ultrasonography represents the first line of investigation for renal colic. Although it is easy to diagnose renal rupture when we see a hyperechoic lesion and urine around the kidney, most ruptures of the renal collecting system are not associated with a hyperechoic lesion or urinoma immediately after rupture has occurred (Hwang et al., 2000, Koktener et al., 2007). Our patient showed only dilatation of the renal pelvis on ultrasonography. We diagnosed ureteral rupture on detecting the extravasation of contrast medium from the ureteral pelvis on contrast-enhanced CT. Therefore, if we encounter a patient with dilation of the renal pelvis with acute abdomen during concurrent chemoradiation, spontaneous ureteral rupture should be kept in mind.\n\nRupture of the renal pelvis caused by hydration has been reported previously. One report documented rupture of the renal pelvis in a patient with a ureteral stone who was being observed while receiving hydration and analgesics (Tas et al., 2013). Another study reported on a woman at 19 weeks' gestation in whom rupture of the renal pelvis occurred after she received a rapid intravenous infusion before cervical cerclage during spinal anesthesia (Huang et al., 2002). Both cases of renal pelvic rupture were caused by a hydration-induced increase in urine flow under the condition of ureteral stenosis.\n\nIn conclusion, rupture of the renal pelvis and ureter can occur during concurrent chemoradiotherapy in the presence of uterine cervical cancer with ureteral stenosis. We consider contrast-enhanced CT to be more useful than ultrasonography for the diagnosis of rupture of the renal pelvis or ureter. The early diagnosis of renal pelvic and ureteral rupture can prevent the development of severe complications, such as abscess. In women who have uterine cervical cancer with ureteral stenosis and normal renal function, the placement of a double-J stent before concurrent chemoradiotherapy may help to prevent rupture of the renal pelvis and ureter.\n\nConflict of interest statement\nThe authors declare that there are no conflicts of interest.\n\nFig. 1 Mild dilatation of the right ureter (arrow).\n\nFig. 2 Pararenal extravasation of contrast medium (arrow).\n==== Refs\nReferences\nSingh I. Joshi M. Mehrotra G. Spontaneous renal forniceal rupture due to advanced cervical carcinoma with obstructive uropathy Arch. Gynecol. Obstet. 279 2009 915 918 18958484 \nMcClinton S. Richmond P. Steyn J.H. Spontaneous extravasation and urinoma formation secondary to cervical carcinoma Br. J. Urol. 64 1989 100 101 2670039 \nSpurlock J.W. Burke T.W. Dunn N.P. Heller P.B. Collins H.S. Park R.C. Calyceal rupture with perirenal urinoma in a patient with cervical carcinoma Obstet. Gynecol. 70 1987 511 513 3627616 \nHadar H. Servadio C. Spontaneous extravasation of urine in chronic ureteric obstruction Urology 14 1979 30 32 452215 \nLin D.Y. Fang Y.C. Huang D.Y. Lin S.P. Spontaneous rupture of the ureter secondary to urolithiasis and extravasation of calyceal fornix due to acute urinary bladder distension: four cases report Chin. J. Radiol. 29 2004 269 275 \nCoelho R.F. Schneider-Monteiro E.D. Mesquita J.L. Mazzucchi E. Marmo Lucon A. Srougi M. Renal and perinephric abscesses: analysis of 65 consecutive cases World J. Surg. 31 2007 431 436 17219288 \nHwang S.S. Park Y.H. Lee C.B. Jung Y.J. Spontaneous rupture of hydronephrotic kidney during pregnancy: value of serial sonography J. Clin. Ultrasound 28 2000 358 360 10934336 \nKoktener A. Unal D. Dilmen G. Koc A. Spontaneous rupture of the renal pelvis caused by calculus: a case report J. Emerg. Med. 33 2007 127 129 17692761 \nTas T. Cakıroglu B. Aksoy S.H. Spontaneous renal pelvis rupture: unexpected complication of urolithiasis expected to passage with observation therapy Case Rep. Urol. 2013 Epub, available from<http://www.hindawi.com/journals/criu/2013/932529/ > \nHuang E. Sayegh R. Craigo S. Chelmow D. Rupture of the renal pelvis associated with intravenous fluid bolus J. Matern. Fetal Neonatal Med. 11 2002 345 346 12389678\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2352-5789",
"issue": "13()",
"journal": "Gynecologic oncology reports",
"keywords": "Concurrent chemoradiotherapy; Contrast-enhanced computed tomography; Ureteral rupture; Uterine cervical cancer",
"medline_ta": "Gynecol Oncol Rep",
"mesh_terms": null,
"nlm_unique_id": "101652231",
"other_id": null,
"pages": "18-9",
"pmc": null,
"pmid": "26425712",
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"title": "Spontaneous ureteral rupture during concurrent chemoradiotherapy in a woman with uterine cervical cancer.",
"title_normalized": "spontaneous ureteral rupture during concurrent chemoradiotherapy in a woman with uterine cervical cancer"
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"abstract": "We assessed the risk of chronic kidney disease (CKD) in chronic hepatitis C virus (HCV)-infected patients and the incidence reduction of CKD after receipt of HCV treatment. We also evaluated the risk of membranoproliferative glomerulonephritis (MPGN) and cryoglobulinemia in chronic HCV patients. A retrospective cohort analysis of the Truven Health MarketScan Database (2008-2015) in the United States was conducted. In a cohort of 56,448 HCV-infected patients and 169,344 propensity score (1:3)-matched non-HCV patients, we examined the association of HCV infection with the incidence of CKD. Of 55,818 HCV patients, 6.6 % (n = 3666), 6.3% (n = 3534), and 8.3% (n = 4628) patients received either interferon-based dual, triple, or all-oral direct acting antiviral agent therapy, respectively, whereas 79% of patients did not receive any HCV treatment. Cox proportional hazards models were used to compare the risk of developing CKD in HCV patients compared with non-HCV patients and treated patients compared with untreated HCV patients. In a multivariate time-varying Cox regression model, HCV-infected patients had a 27% increased risk of CKD compared with non-HCV patients (hazard ratio [HR], 1.27; 95% confidence interval [CI], 1.18-1.37). Among HCV patients, individuals who received the minimally effective HCV treatment for dual, triple, or all-oral therapy had a 30% decreased risk of developing CKD (HR, 0.70; 95% CI, 0.55-0.88). In addition, HCV-infected patients experienced a twofold and a nearly 17-fold higher risk of MPGN (HR, 2.23; 95% CI, 1.84-2.71) and cryoglobulinemia (HR, 16.91; 95% CI, 12.00-23.81) respectively, compared with non-HCV patients. Conclusion: HCV-infected individuals in the United States are at greater risk of developing CKD, MPGN, and cryoglobulinemia. Minimally effective treatment of HCV infection can prevent the development of CKD, although the association was not significant for all-oral therapy. (Hepatology 2018;67:492-504).",
"affiliations": "Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville, FL.;Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville, FL.;Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville, FL.;Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville, FL.;Department of Medicine, University of Florida, Gainesville, FL.;Department of Medicine, University of Florida, Gainesville, FL.",
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"doi": "10.1002/hep.29505",
"fulltext": "\n==== Front\nHepatologyHepatology10.1002/(ISSN)1527-3350HEPHepatology (Baltimore, Md.)0270-91391527-3350John Wiley and Sons Inc. Hoboken 10.1002/hep.29505HEP29505Original ArticleOriginal ArticlesViral HepatitisChronic hepatitis C virus (HCV) increases the risk of chronic kidney disease (CKD) while effective HCV treatment decreases the incidence of CKD Park et al.Park et al.Park Haesuk hpark@cop.ufl.edu \n1\nChen Chao \n1\nWang Wei \n1\nHenry Linda \n1\nCook Robert L. \n2\nNelson David R. \n2\n\n1 \nPharmaceutical Outcomes and Policy, College of Pharmacy\nUniversity of Florida\nGainesville\nFL\n\n2 \nDepartment of Medicine\nUniversity of Florida\nGainesville\nFL\n* ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:\nHaesuk Park, Ph.D.\nDepartment of Pharmaceutical Outcomes and Policy\nUniversity of Florida College of Pharmacy\nHPNP Building Room 3325\n1225 Center Drive\nGainesville, FL 32610\nE‐mail: hpark@cop.ufl.edu\nTel.: (352) 273‐6261\n23 12 2017 2 2018 67 2 10.1002/hep.v67.2492 504 30 4 2017 23 8 2017 29 8 2017 © 2017 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.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.We assessed the risk of chronic kidney disease (CKD) in chronic hepatitis C virus (HCV)‐infected patients and the incidence reduction of CKD after receipt of HCV treatment. We also evaluated the risk of membranoproliferative glomerulonephritis (MPGN) and cryoglobulinemia in chronic HCV patients. A retrospective cohort analysis of the Truven Health MarketScan Database (2008‐2015) in the United States was conducted. In a cohort of 56,448 HCV‐infected patients and 169,344 propensity score (1:3)–matched non‐HCV patients, we examined the association of HCV infection with the incidence of CKD. Of 55,818 HCV patients, 6.6 % (n = 3666), 6.3% (n = 3534), and 8.3% (n = 4628) patients received either interferon‐based dual, triple, or all‐oral direct acting antiviral agent therapy, respectively, whereas 79% of patients did not receive any HCV treatment. Cox proportional hazards models were used to compare the risk of developing CKD in HCV patients compared with non‐HCV patients and treated patients compared with untreated HCV patients. In a multivariate time‐varying Cox regression model, HCV‐infected patients had a 27% increased risk of CKD compared with non‐HCV patients (hazard ratio [HR], 1.27; 95% confidence interval [CI], 1.18‐1.37). Among HCV patients, individuals who received the minimally effective HCV treatment for dual, triple, or all‐oral therapy had a 30% decreased risk of developing CKD (HR, 0.70; 95% CI, 0.55‐0.88). In addition, HCV‐infected patients experienced a twofold and a nearly 17‐fold higher risk of MPGN (HR, 2.23; 95% CI, 1.84‐2.71) and cryoglobulinemia (HR, 16.91; 95% CI, 12.00‐23.81) respectively, compared with non‐HCV patients. Conclusion: HCV‐infected individuals in the United States are at greater risk of developing CKD, MPGN, and cryoglobulinemia. Minimally effective treatment of HCV infection can prevent the development of CKD, although the association was not significant for all‐oral therapy. (Hepatology 2018;67:492‐504).\n\n source-schema-version-number2.0component-idhep29505cover-dateFebruary 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.3.2.2 mode:remove_FC converted:16.02.2018Potential conflict of interest: David Nelson has received research grant support from AbbVie, Bristol‐Myers Squibb, Gilead, Jassen, and Merck.\n==== Body\nAbbreviations\nACEIangiotensin‐converting‐enzyme inhibitor\n\nARBangiotensin II receptor blocker\n\nCKDchronic kidney disease\n\nCIconfidence interval\n\nDAAdirect acting antiviral agent\n\nHCVhepatitis C virus\n\nHIVhuman immunodeficiency virus\n\nHRhazard ratio\n\nICD‐9‐CMInternational Classification of Diseases, Ninth Revision, Clinical Modification\n\nMPGNmembranoproliferative glomerulonephritis\n\nPSpropensity score\n\nThe burden of fatal liver disease is increasing in the estimated 3.2 million adults in the United States who are chronically infected with hepatitis C virus (HCV).1 Furthermore, chronic HCV infection is associated with extrahepatic manifestations, reported in up to 74% of patients, which may be present long before advanced liver disease presents itself and responsible for non–liver‐related deaths.2, 3, 4, 5\n\n\nChronic kidney disease (CKD) is one of the more common extrahepatic manifestations present in patients with chronic HCV; however, reports on the risk of CKD in the chronically infected HCV population are inconsistent within the United States.6, 7, 8, 9, 10 Two recent studies conducted in US Veteran populations assessed the association of chronic HCV infection with the development/progression of CKD and reported divergent results.6, 9, 10 Molnar et al.6 found that chronic HCV was associated with higher incidence of decreased kidney function, whereas Rogal et al.10 concluded that chronic HCV was associated with decreased incidence of CKD. Two meta‐analyses determined that patients with HCV had a 23%‐43% greater risk of presenting with CKD,11, 12 whereas another meta‐analysis found that HCV was not associated with reduced glomerular filtration rate.8\n\n\nThe most common HCV‐related nephropathy is membranoproliferative glomerulonephritis (MPGN), usually in the context of cryoglobulinemia.8, 13, 14, 15 Mixed cryoglobulinemia represents 60%‐75% of all cryoglobulinemias,16 leading to clinical manifestations ranging from the mixed cryoglobulinemia syndrome to more serious lesions with neurologic and kidney involvement.17 Recently, two studies reported the prevalence of MPGN (0.3%) and cryoglobulinemia (0.4%‐0.9%) in chronically HCV‐infected patients in the United States.18, 19 However, there is limited evidence regarding the incidence of these renal manifestations in HCV patients.20, 21\n\n\nUntil late 2013, interferon and ribavirin were the main components of HCV treatment. Despite the positive effects on slowing the renal disease progression, supported by recent Taiwanese studies,22, 23, 24 interferon and ribavirin treatment carries substantial side effects, leading to very poor adherence and relatively low cure rates.25, 26, 27, 28, 29, 30 In 2014, the US Food and Drug Administration approved the first all‐oral direct acting antiviral agents (DAAs), which have revolutionized the HCV treatment landscape as a result of excellent adherence and very high cure rates (>95%) in as little as 8 weeks even for patients who are very difficult to treat.28, 29, 30 However, it is unclear whether the new DAAs carry an improvement in renal function and or reduce the incidence of CKD among chronically infected HCV patients residing in the United States.\n\nTherefore, the aims of this study were to 1) determine the incidence of CKD among chronically HCV‐infected beneficiaries enrolled in a large health care plan in the United States, 2) determine the impact of treatment on the CKD incident rate in chronically HCV‐ infected patients within United States, and 3) determine the incidence of MPGN and cryoglobulinemia in chronically HCV‐infected patients.\n\nPatients and Methods\nDATA SOURCE\nWe conducted a retrospective cohort study using the Truven Health Analytic MarketScan Commercial and Medicare Supplemental databases (January 2008 through August 2015, prior to the implementation of International Classification of Diseases, Tenth Revision codes). This 8‐year nationwide administrative claims database contains person‐level information of diagnoses, procedures, and prescriptions for over 100 million individuals in the commercial dataset and 10 million individuals in the Medicare Supplement database. This database captures health care utilization and enrollment records across all settings, including physician outpatient office visits, hospital stays, and pharmacy claims. The study population consisted of employees, dependents, and retirees with employer‐sponsored or Medicare Supplemental insurance plans. Institutional review board approval was obtained from the University of Florida.\n\nSTUDY POPULATION\nIdentification of HCV and Non‐HCV Patients (HCV vs. Non‐HCV Cohorts)\nPatients with newly diagnosed chronic HCV were identified using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD‐9‐CM) codes 070.44, 070.54, 070.70, 070.71, and V02.62. A patient was determined to be infected with chronic HCV if they had one inpatient chronic HCV diagnosis or two outpatient diagnoses of HCV on separate days within 1 year. The first diagnosis was used as the index date. To establish a non‐HCV control group, we selected 20 non‐HCV patients matched for age, sex, and calendar year for each chronic HCV patient. For non–HCV patients, we randomly selected one of their medical service dates as the index date. Patients were included if they were 18 years old and continuously enrolled in the health plan 1 year before and 6 months after the index date. Patients who had a diagnosis of CKD before the index date were excluded. Furthermore, for each chronic HCV patient, three non‐HCV patients were matched using the propensity score (PS) that was calculated to adjust for the baseline differences in risk factors for CKD between HCV and non‐HCV groups. The PS was estimated using logistic regression‐based baseline demographic variables including age and gender, and medical conditions reported in the literature associated with chronic HCV and CKD, including diabetes, hypertension, dyslipidemia, chronic obstructive pulmonary disease, coronary artery disease, peripheral vascular disease, cerebrovascular disease, and heart failure identified by ICD‐9‐CM codes, as well as disease‐modifying medications including angiotensin‐converting‐enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs).\n\nIdentification of HCV Treatment Groups According to Antiviral Treatment (Treated vs. Nontreated HCV Patients)\nThe chronic HCV patients were further categorized based on the receipt, type, and duration of HCV treatment using pharmacy claims for HCV treatment. For this analysis, we excluded patients who had undergone HCV therapy before the index date. HCV treatments included three classes: 1) dual therapy, a combination therapy of interferon and ribavirin (interferon alpha, interferon beta, peg‐ interferon alpha‐2a or peg‐ interferon alpha‐2b with or without ribavirin); 2) triple therapy, a combination of boceprevir, telaprevir, sofosbuvir, or simeprevir plus peg‐interferon and ribavirin; and 3) all‐oral therapy, which included ledipasvir/sofosbuvir, sofosbuvir with ribavirin and ombitasvir/paritaprevir/ritonavir, and dasabuvir with or without ribavirin.31\n\n\nBased on the receipt and duration of treatment received, we classified patients into three different exposure statuses: 1) no treatment, defined as patients who were not exposed to any HCV treatments; 2) minimum effectively treated, defined as patients who received one of three HCV therapeutic treatment regimens prescribed as at least 16 weeks of dual therapy,24 8‐12 weeks of triple therapy,28, 29 or 8 weeks of all‐oral therapy30; and 3) insufficiently treated, defined as patients who received some treatment but did not meet the criteria for minimum effectively treated yet.\n\nSTUDY OUTCOMES\nThe primary outcome was a diagnosis of CKD stages 3‐5. The ICD‐9‐CM codes of 585.3, 585.4, and 585.5 were used to identify CKD cases.32 CKD was considered to be diagnosed if there was one inpatient or two separate outpatient claims for CKD within 1 year. The earliest date of CKD diagnosis was defined as the date of outcome. Follow‐up started from the index date and continued until study outcome, end of enrollment, or August 31, 2015, whichever came first. The secondary outcomes were the investigations of the renal conditions of nephrotic syndrome or MPGN (ICD‐9‐CM codes 581.0, 581.1, 581.2, 581.81, 581.89, 581.9, or V13.03) and cryoglobulinemia (ICD‐9‐CM code 273.2) within the chronically infected HCV adult population.18, 19\n\n\nSTATISTICAL ANALYSIS\nBaseline characteristics were compared between HCV and non‐HCV cohorts using a t test for continuous variables and chi‐square tests for categorical variables. After PS matching, the standardized difference was used to check the balance between two groups, and 0.2 was defined as the threshold to determine statistically significant differences.33, 34 The number of CKD events and person‐years were determined for each group and subsequently used to calculate the incidence rates of CKD (number of events/1000 person‐years). We then stratified CKD by age, sex, diabetes, and cirrhosis status, as previous studies have suggested that there was an effect modification on the rate of CKD among these subpopulations.35, 36 A Cox proportional hazards regression model was used to compare the risk of developing CKD, MPGN, and cryoglobulinemia between HCV and non‐HCV cohorts. A Cox proportional hazards regression model with time‐dependent covariates was also employed in a sensitivity analysis (Model 1) (Supporting Table S1). The covariates were adjusted for alcohol/drug abuse disorders, human immunodeficiency virus (HIV), hepatitis A virus, hepatitis B virus, cirrhosis, decompensated cirrhosis, and hepatocellular carcinoma in addition to covariates adjusted in PS matching. We did not match for presence of liver disease, an effect mediator of HCV rather than a confounder, and variables that were strongly associated with HCV but weakly associated with CKD (e.g., alcohol/drug abuse) and adjusted for regression models, because previous studies found that incorporating these variables can lead to less successful matching and increased variance.37, 38, 39 However, we performed sensitivity analyses with matching/adjustment for all factors including liver disease and other covariates.\n\nTo assess the association between HCV treatment and the risk of developing CKD among patients infected with HCV, a time‐dependent exposure analysis was performed. The number of CKD events and person‐years were summarized for each treatment status. Subgroup analyses were performed by type of HCV treatments including dual, triple, and all‐oral therapy. Cox regression models with time‐dependent covariates were used to adjust for all covariates mentioned in the previous analysis, as well as contraindications to pegylated interferon and ribavirin, which included schizophrenia, depression, seizures, pregnancy, transplantation, anemia, and retinopathy (Model 2) (Supporting Table S1). All the analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC).\n\nResults\nPATIENT CHARACTERISTICS\nWe identified 56,489 HCV patients and 847,113 non‐HCV patients between January 2008 and August 2015 (Fig. 1). Table 1 summarizes the baseline demographic characteristics, comorbid conditions, and medication use between two cohorts before and after PS matching. After PS matching, we identified 56,448 HCV patients and 169,344 non‐HCV patients. In the PS‐matched groups, the patients' demographic characteristics, including age (mean age: 55), sex (60% male), and several comorbid conditions (e.g., hypertension, dyslipidemia, diabetes mellitus) were comparable between two groups. However, heart failure (standardized difference = 0.04) and peripheral vascular disease (standardized difference = 0.04) were slightly more prevalent in the HCV patients compared with the non‐HCV patients, but the differences were still within the threshold of acceptable imbalance.40 The presence of liver disease, not included in PS matching but adjusted in regression models, was more prevalent in HCV patients compared with non‐HCV patients.\n\nTable 1 Baseline Characteristics Before and After Propensity Score (PS) Matching\n\n\tBefore PS Matching\tAfter PS Matchinga\n\t\nPatient Characteristics\tHCV cohort (n = 56,489)\tNon‐HCV cohortb (n = 847,113)\tStandardized difference, %c\n\tHCV cohort (n = 56,448)\tNon‐HCV cohort (n = 169,344)\tStandardized difference, %c\n\t\nPS‐adjusted variables\t\t\t\t\t\t\t\nMedian age, years (IQR)\t55 (48, 59)\t54 (48, 59)\t0.03\t55 (48, 59)\t54 (48, 59)\t0.01\t\nSex, n (%)\t\t\t0.03\t\t\t‐0.01\t\nMen\t34,106 (60.37)\t499,756 (59.00)\t\t34,082 (60.38)\t103,149 (60.91)\t\t\nWomen\t22,383 (39.63)\t347,357 (41.00)\t\t22,366 (39.62)\t66,195 (39.09)\t\t\nComorbidities, n (%)\t\t\t\t\t\t\t\nHypertension\t21,141 (37.42)\t332,581 (39.26)\t−0.04\t21,122 (37.42)\t62,468 (36.89)\t0.01\t\nDyslipidemia\t140,46 (24.87)\t331,064 (39.08)\t−0.31\t140,34 (24.86)\t42,143 (24.89)\t‐0.00\t\nDiabetes mellitus\t9237 (16.35)\t147,461 (17.41)\t−0.03\t9231 (16.35)\t27,508 (16.24)\t0.00\t\nCOPD\t6891 (12.20)\t105,505 (12.45)\t−0.01\t6881 (12.19)\t19,957 (11.78)\t0.01\t\nHeart Failure\t1845 (3.27)\t30,010 (3.54)\t−0.02\t1842 (3.26)\t4412 (2.61)\t0.04\t\nPeripheral vascular disease\t2431 (4.30)\t35,049 (4.14)\t0.01\t2430 (4.30)\t6048 (3.57)\t0.04\t\nCerebrovascular disease\t2245 (3.97)\t40,506 (4.78)\t−0.04\t2243 (3.97)\t5681 (3.35)\t0.03\t\nCoronary artery disease\t4097 (7.25)\t83,462 (9.85)\t−0.09\t4092 (7.25)\t10,948 (6.46)\t0.03\t\nBaseline medication use, n (%)\t\t\t\t\t\t\t\nACEIs\t3003 (5.32)\t58,520 (6.91)\t−0.07\t3001 (5.32)\t8875 (5.24)\t0.00\t\nARBs\t9969 (17.65)\t155,696 (18.38)\t−0.02\t9955 (17.64)\t29,175 (17.23)\t0.01\t\nPS‐unadjusted variablesb\n\t\nComorbidities, n (%)\t\t\t\t\t\t\t\nHIV\t1187 (2.10)\t2749 (0.32)\t0.16\t1187 (2.10)\t552 (0.33)\t0.16\t\nHepatitis A\t210 (0.37)\t187 (0.02)\t0.08\t210 (0.37)\t31 (0.02)\t0.08\t\nHepatitis B\t1193 (2.11)\t1416 (0.17)\t0.18\t1190 (2.11)\t297 (0.18)\t0.18\t\nCirrhosis\t2509 (4.44)\t2440 (0.29)\t0.28\t2505 (4.44)\t509 (0.30)\t0.27\t\nDecompensated cirrhosis\t1888 (3.34)\t6515 (0.77)\t0.18\t1886 (3.34)\t1280 (0.76)\t0.18\t\nHepatocellular carcinoma\t368 (0.65)\t516 (0.06)\t0.10\t367 (0.65)\t119 (0.07)\t0.10\t\nAlcohol abuse\t3138 (5.56)\t13,288 (1.57)\t0.22\t3135 (5.55)\t2578 (1.52)\t0.22\t\nDrug abuse\t8260 (14.62)\t45,287 (5.35)\t0.31\t8257 (14.63)\t8436 (4.98)\t0.33\t\nAbbreviations: ACEIs, angiotensin‐converting‐enzyme inhibitors; ARBs, angiotensin II receptor blockers; COPD, chronic obstructive pulmonary disease; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IQR, interquartile range; PS, propensity score,.\n\na Up to 20 controls without HCV infection were matched for age, sex, and index date with each HCV patient.\n\nb PS matching did not include liver‐related comorbidities, alcohol abuse, drug abuse, or medication use; instead, these covariates were adjusted as time‐dependent covariates in the Cox regression model.\n\nc Difference in means or proportions divided by standard error; imbalance defined as absolute value >0.20 (small effect size)\n\nFigure 1 Flow chart of the cohort creation. Abbreviations: CCAE, Commercial Claims and Encounters; CKD, chronic kidney disease; HCV, hepatitis C virus; MDCR, Medicare Supplemental and Coordination of Benefits.\n\nRISK OF CKD BETWEEN HCV AND NON‐HCV GROUPS\nWe identified 1455 new CKD cases in the HCV group (n = 56,448) and 2518 new CKD cases in the non‐HCV group (n = 169,344). The crude incidence rate of CKD was 10.36 per 1000 person‐years in HCV and 5.72 per 1000 person‐years in non‐HCV groups. The Cox proportional hazards regression model indicated that HCV patients had a 57% (hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.47‐1.68) increased risk of developing CKD after adjusting for demographics, baseline covariates, and use of ACEIs and ARBs.\n\nSensitivity analysis using the Cox regression model with time‐dependent covariates, which took the change of comorbidities and medication use during follow‐up into consideration, revealed that HCV‐infected patients had a 27% increased risk of CKD (HR, 1.27; 95% CI, 1.18‐1.37). In a subgroup analysis, when stratified by different age groups, we found that the association between HCV and CKD was more significant among young adults (age 18‐49 years; HR, 1.47; 95% CI, 1.13‐1.90) compared with the elderly population (age ≥60 years; HR, 1.19; 95% CI, 1.06‐1.33).\n\nThis association appeared to be significant among both men and women and patients with and without diabetes, but it was not significant among patients diagnosed with cirrhosis (Table 2). In a sensitivity analysis, when adjusted after PS matching including all covariates associated with HCV and CKD (52,185 HCV patients and 156,567 non‐HCV patients), we found quantitatively similar results (HR, 1.28; 95% CI, 1.19‐1.38) (Supporting Tables S2 and S3).\n\nTable 2 Incidence Rate and Hazard Ratio (HR) for CKD in the HCV and Non‐HCV Cohorts\n\nStudy Population\tHCV Status\tNo. of Patients\tPerson‐Years\tNo. of CKD Events\tMean Time to CKD Event (Months)\tCrude Incidence of CKDa\n\tAdjusted HR of CKD (95% CI)\t\nBaseline Covariates\tBaseline and Time‐Varying Covariates\t\nAll patients\tHCV\t56,448\t140,468\t1455\t20.53\t10.36\t1.57 (1.47‐1.68)\t1.27 (1.18‐1.37)\t\n\tNon‐HCV\t169,344\t440,495\t2518\t22.37\t5.72\tReference\tReference\t\nAge, years\t\t\t\t\t\t\t\t\t\n18‐49\tHCV\t15,869\t37,643\t139\t19.53\t3.69\t1.87 (1.49‐2.35)\t1.47 (1.13‐1.90)\t\n\tNon‐HCV\t48,044\t122,666\t216\t22.78\t1.76\tReference\tReference\t\n50‐59\tHCV\t27,344\t72,630\t685\t21.95\t9.43\t1.75 (1.58‐1.93)\t1.32 (1.18‐1.47)\t\n\tNon‐HCV\t82,304\t227,193\t1086\t22.81\t4.78\tReference\tReference\t\n≥60\tHCV\t13,235\t30,194\t631\t19.22\t20.90\t1.38 (1.25‐1.53)\t1.19 (1.06‐1.33)\t\n\tNon‐HCV\t38,996\t90,636\t1216\t21.91\t13.42\tReference\tReference\t\nSex\t\t\t\t\t\t\t\t\t\nMen\tHCV\t34,082\t84,721\t956\t20.11\t11.28\t1.59 (1.46‐1.73)\t1.26 (1.14‐1.38)\t\n\tNon‐HCV\t103,149\t268,076\t1673\t22.67\t6.24\tReference\tReference\t\nWomen\tHCV\t22,366\t55,747\t499\t21.34\t8.95\t1.54 (1.37‐1.74)\t1.26 (1.10‐1.43)\t\n\tNon‐HCV\t66,195\t172,418\t845\t21.77\t4.90\tReference\tReference\t\nCirrhosis\tHCV\t2505\t5561\t183\t20.04\t32.90\t0.89 (0.63‐1.26)\t0.91 (0.64‐1.29)\t\n\tNon‐HCV\t509\t1068\t39\t15.55\t36.52\tReference\tReference\t\nNo cirrhosis\tHCV\t53,945\t134,907\t1272\t22.48\t9.43\t1.59 (1.48‐1.70)\t1.29 (1.20‐1.39)\t\n\tNon‐HCV\t168,835\t439,427\t2479\t20.60\t5.64\tReference\tReference\t\nDiabetes\tHCV\t9231\t21,655\t646\t19.36\t29.8\t1.54 (1.40‐1.71)\t1.23 (1.10‐1.38)\t\n\tNon‐HCV\t27,508\t69,534\t1218\t21.49\t17.51\tReference\tReference\t\nNon‐diabetes\tHCV\t47,217\t118,813\t809\t21.47\t6.81\t1.67 (1.53‐1.83)\t1.32 (1.19‐1.46)\t\n\tNon‐HCV\t141,836\t370,961\t1300\t23.20\t3.50\tReference\tReference\t\nAbbreviations: CI, confidence interval; CKD, chronic kidney disease; HCV, hepatitis C virus; HR, hazard ratio.\n\na Per 1000 person‐years.\n\nRISK OF CKD AMONG HCV PATIENTS WHO RECEIVED MINIMALLY EFFECTIVE TREATMENT, INSUFFICIENT TREATMENT, AND NO TREATMENT\nOf 55,818 HCV‐infected patients, 43,990 patients (79%) did not receive any HCV treatment. The remaining 11,828 HCV patients received HCV treatment, including 3666 who received dual therapy, 3534 who received triple therapy, and 4628 who received all‐oral DAA therapy (Table 3). Patients who received the all‐oral DAA regimens were older and had significantly more advanced liver disease (i.e., cirrhosis, decompensated cirrhosis) and comorbidities (e.g., hypertension, diabetes, coronary artery disease, HIV) than the patients in either the dual or triple therapy groups, respectively. However, although the patients in the no treatment group had similar advanced liver disease compared with patients in the all‐oral therapy group, they were more likely to have alcohol/drug abuse and contraindications to pegylated interferon and ribavirin such as schizophrenia, depression, and pregnancy than patients in any of the treatment groups.\n\nTable 3 Demographics and Clinical Characteristics of HCV‐Infected Patients by Receipt and Type of HCV Treatment\n\nPatient Characteristics\tDual Therapy (n = 3666)\tTriple Therapy (n = 3534)\tAll‐Oral Therapy (n = 4628)\tNo Treatment (n = 43,990)\t\nP\n\t\nMedian age, years (IQR)\t52 (47 ,57)\t54 (49, 58)\t56 (51 ,60)\t55 (48 ,59)\t<0.001\t\nSex, n (%)\t\t\t\t\t\t\nMen\t2224 (60.67)\t2267 (64.15)\t2934 (63.40)\t26,242 (59.65)\t<0.001\t\nWomen\t1442 (39.33)\t1267 (35.85)\t1694 (36.60)\t17,748 (40.35)\t\t\nComorbidities, n (%)\t\t\t\t\t\t\nHypertension\t1187 (32.38)\t1246 (35.26)\t1842 (39.80)\t16679 (37.92)\t<0.001\t\nDyslipidemia\t832 (22.70)\t765 (21.65)\t1112 (24.03)\t11186 (25.43)\t<0.001\t\nDiabetes\t457 (12.47)\t514 (14.54)\t794 (17.16)\t7371 (16.76)\t<0.001\t\nCOPD\t363 (9.90)\t283 (8.01)\t446 (9.64)\t5750 (13.07)\t<0.001\t\nHeart failure\t49 (1.34)\t51 (1.44)\t95 (2.05)\t1640 (3.73)\t<0.001\t\nPeripheral vascular disease\t99 (2.70)\t79 (2.24)\t190 (4.11)\t2045 (4.65)\t<0.001\t\nCerebrovascular disease\t91 (2.48)\t75 (2.12)\t147 (3.18)\t1914 (4.35)\t<0.001\t\nCoronary artery disease\t185 (5.05)\t134 (3.79)\t288 (6.22)\t3453 (7.85)\t<0.001\t\nHIV\t76 (2.07)\t45 (1.27)\t106 (2.29)\t960 (2.11)\t0.006\t\nHepatitis A\t22 (0.60)\t19 (0.54)\t18 (0.39)\t148 (0.34)\t0.025\t\nHepatitis B\t46 (1.25)\t32 (0.91)\t37 (0.80)\t1063 (2.42)\t<0.001\t\nCirrhosis\t106 (2.89)\t97 (2.74)\t198 (4.28)\t2058 (4.68)\t<0.001\t\nDecompensated cirrhosis\t62 (1.69)\t52 (1.47)\t146 (3.15)\t1614 (3.67)\t<0.001\t\nHepatocellular carcinoma\t5 (0.14)\t3 (0.08)\t19 (0.41)\t337 (0.77)\t<0.001\t\nAlcohol abuse\t173 (4.72)\t110 (3.11)\t173 (3.74)\t2665 (6.06)\t<0.001\t\nDrug abuse\t468 (12.77)\t409 (11.57)\t522 (11.28)\t6797 (15.45)\t<0.001\t\nContraindications, n (%)\t\t\t\t\t\t\nSchizophrenia\t88 (2.40)\t68 (1.92)\t97 (2.10)\t1404 (3.19)\t<0.001\t\nDepression\t455 (12.41)\t399 (11.29)\t515 (11.13)\t6363 (14.46)\t<0.001\t\nSeizure\t30 (0.82)\t22 (0.62)\t39 (0.84)\t432 (0.98)\t0.126\t\nPregnancy\t27 (0.74)\t20 (0.57)\t20 (0.43)\t599 (1.36)\t<0.001\t\nTransplant\t22 (0.60)\t9 (0.25)\t49 (1.06)\t514 (1.17)\t<0.001\t\nRetinopathy\t1 (0.03)\t0 (0.00)\t3 (0.06)\t26 (0.06)\t0.437\t\nAnemia\t228 (6.22)\t181 (5.12)\t399 (8.62)\t4610 (10.48)\t<0.001\t\nMedication use, n (%)\t\t\t\t\t\t\nACEIs\t161 (4.39)\t173 (4.90)\t271 (5.86)\t2365 (5.38)\t0.015\t\nARBs\t569 (15.52)\t593 (16.78)\t881 (19.04)\t7804 (17.74)\t0.002\t\nAbbreviations: ACEI, angiotensin‐converting‐enzyme inhibitors; ARB, angiotensin II receptor blockers; COPD, chronic obstructive pulmonary disease; HIV, human immunodeficiency virus; IQR,interquartile range.\n\nTable 4 shows the risk of developing CKD among the HCV patients who received minimally effective treatment, insufficient treatment, or no treatment. The majority of CKD events (90%) occurred in patients who received no HCV treatment, carrying a CKD incidence rate of 10.79 per 1000 person‐years. The CKD incidence rate decreased among patients who received treatment (10.07 per 1000 person‐years) but decreased greatly when patients were on a minimally effective dose of treatment (6.73 per 1000 person‐years). After adjusting for baseline and time‐dependent covariates, overall, we found HCV‐infected patients who received the minimum effective duration of therapy had a 30% decreased risk of developing CKD compared with those who received no treatment (HR, 0.70; 95% CI, 0.56‐0.88). However, in a subgroup analysis, these associations were only significant for dual (HR, 0.60; 95% CI, 0.43‐0.85) and triple (HR, 0.59; 95% CI, 0.37‐0.94) therapy but not for all‐oral therapy (HR, 1.03; 95% CI, 0.68‐1.55) (Table 4).\n\nTable 4 HCV Treatment Association with Incidence of CKD Using Time‐Varying Cox‐Proportional Hazards Model\n\nTreatment Statusa\n\tPerson‐Years\tNo. of CKD Events\tCrude Incidence of CKDb\n\tAdjusted HR of CKD (95% CI)\t\nAll HCV patients (N = 55,818)\t\t\t\t\t\nMinimum Effective TX\t11,737\t79\t6.73\t0.70 (0.55‐0.88)\t\nInsufficient TX\t6854\t69\t10.07\t0.85 (0.66‐1.09)\t\nNo TX\t119,698\t1291\t10.79\tReference\t\nDual therapy (n = 3666)\t\t\t\t\t\nMinimum Effective TX\t6115\t34\t5.56\t0.60 (0.43‐0.85)\t\nInsufficient TX\t3245\t34\t10.48\t0.92 (0.65‐1.31)\t\nNo TX\t108,813\t1190\t11.10\tReference\t\nTriple therapy (n = 3534)\t\t\t\t\t\nMinimum Effective TX\t3469\t19\t5.48\t0.59 (0.37‐0.94)\t\nInsufficient TX\t3023\t25\t8.27\t0.72 (0.48‐1.07)\t\nNo TX\t110,623\t1197\t10.82\tReference\t\nAll‐oral therapy (n = 4628)\t\t\t\t\t\nMinimum Effective TX\t2154\t26\t12.07\t1.03 (0.68‐1.55)\t\nInsufficient TX\t585\t10\t17.09\t0.85 (0.39‐1.82)\t\nNo TX\t114,224\t1254\t10.98\tReference\t\nAbbreviations: CI, confidence interval; CKD, chronic kidney disease; HCV, hepatitis C virus; HR, hazard ratio; TX, treatment.\n\na HCV treatment status was coded as a time‐dependent covariate in the Cox regression model. Therefore, each patient may have a different treatment status during the study follow‐up.\n\nb Per 1000 person‐years.\n\nRISK FACTORS RELATED TO INCIDENCE OF CKD IN HCV‐INFECTED PATIENTS\nFigure 2 shows risk factors for CKD in HCV‐infected patients. Factors associated with an increased risk of developing CKD included age ≥60 years (HR, 2.12; 95% CI, 1.74‐2.58), diabetes mellitus (HR, 1.79; 95% CI, 1.60‐2.00), congestive heart failure (HR, 2.14; 95% CI, 1.88‐2.45), peripheral vascular disease (HR, 1.20; 95% CI, 1.05‐1.37), cerebrovascular disease (HR, 1.20; 95% CI, 1.04‐1.37), hypertension (HR, 2.43; 95% CI, 2.05‐2.88), HIV (HR, 1.93; 95% CI, 1.44‐2.57), alcohol abuse (HR, 1.27; 95% CI, 1.10‐1.46), decompensated cirrhosis (HR, 1.91; 95% CI, 1.64‐2.24), history of transplantation (HR, 3.19; 95% CI, 2.70‐3.76), and anemia (HR, 2.20; 95% CI, 1.95‐2.47), in addition to receipt of ACEIs (HR, 7.30; 95% CI, 6.12‐8.71) and ARBs (HR, 5.57; 95% CI, 4.86‐6.39).\n\nFigure 2 Adjusted hazard ratios for chronic kidney disease in HCV patients using time‐varying Cox‐proportional hazards model. Abbreviations: ACEI, angiotensin‐converting‐enzyme inhibitors; ARB, angiotensin II receptor blockers; CI, confidence interval; COPD, chronic obstructive pulmonary disease; HIV, human immunodeficiency virus; HR, hazard ratio; TX, treatment.\n\nRISK OF MPGN AND CRYOGLOBULINEMIA BETWEEN HCV AND NON‐HCV GROUPS\nFor this analysis, we further excluded patients with MPGN and cryoglobulinemia before the index date. Table 5 shows the association between HCV and the development of nephrotic syndrome/MPGN and cryoglobulinemia. The crude incidence rate of MPGN was 0.833 per 1000 person‐years in HCV and 0.221 per 1000 person‐years in non‐HCV groups. The crude incidence rate of cryoglobulinemia was 0.876 per 1000 person‐years in HCV and 0.050 per 1000 person‐years in non‐HCV groups. The Cox proportional hazards regression model indicated that HCV patients had 3.7 and 17 times higher risks of developing nephrotic syndrome/MPGN (HR, 3.74; 95% CI, 2.84‐4.93) and cryoglobulinemia (HR, 17.25; 95% CI, 10.91‐27.26), respectively. Sensitivity analyses using the Cox regression model with time‐dependent covariates, which took the change of comorbidities and medication use during follow‐up into consideration, revealed that HCV‐infected patients had 2 times and 17 times increased risk of MPGN (HR, 2.23; 95% CI, 1.84‐2.71) and cryoglobulinemia (HR, 16.91; 95% CI, 12.00‐23.81). We also found that HCV and MPGN association was stronger among women (HR, 3.78; 95% CI, 2.66‐5.36) compared with men (HR, 1.74; 95% CI, 1.37‐2.19). In contrast, there were no significant differences in the development of cryglobulinemia between HCV‐infected men and women. However, we did not find any effects of the HCV treatments on the risk of developing MPGN and cryoglobulin among the HCV patients who received treatments compared with no treatment (Supporting Tables S4 and S5).\n\nTable 5 Incidence Rate and Hazard Ratio for MPGN and Cryoglobulinemia in the HCV and Non‐HCV Cohorts, Adjusting for Baseline Characteristics\n\nSecondary Outcomes\tHCV Status\tNo. of Patients\tPerson‐Years\tNo. of Events\tCrude Incidencea\n\tMean Time to Event (Months)\tAdjusted HR (95% CI)\t\nBaseline Covariates\tBaseline and Time‐Varying Covariates\t\n\nMPGN\n\tHCV\t55,618\t140,408\t120\t0.833\t17.39\t3.74 (2.84‐4.93)\t2.23 (1.84‐2.71)\t\n\tNon‐HCV\t166,854\t438,153\t97\t0.221\t19.03\tReference\tReference\t\n\nMen\n\tHCV\t33,395\t84,325\t83\t0.984\t18.40\t3.50 (2.54‐4.84)\t1.74 (1.37‐2.19)\t\n\tNon‐HCV\t101,422\t266,423\t73\t0.274\t18.81\tReference\tReference\t\n\nWomen\n\tHCV\t22,223\t56,082\t37\t0.660\t15.11\t4.40 (2.59‐7.47)\t3.78 (2.66‐5.36)\t\n\tNon‐HCV\t65,432\t171,730\t24\t0.140\t19.72\tReference\tReference\t\n\nCryoglobulinemia\n\tHCV\t55,646\t140,435\t123\t0.876\t14.17\t17.25 (10.91‐27.26)\t16.91 (12.00‐23.81)\t\n\tNon‐HCV\t166,938\t438,946\t22\t0.050\t24.69\tReference\tReference\t\n\nMen\n\tHCV\t33,423\t84,363\t75\t0.889\t14.96\t21.00 (11.10‐39.73)\t20.03 (12.28‐32.67)\t\n\tNon‐HCV\t100,824\t265,142\t11\t0.041\t27.25\tReference\tReference\t\n\nWomen\n\tHCV\t22,223\t56,072\t48\t0.856\t12.95\t13.11 (6.76‐25.40)\t14.07 (8.68‐22.81)\t\n\tNon‐HCV\t66,114\t173,804\t11\t0.063\t22.12\tReference\tReference\t\nAbbreviations: CI, confidence interval; HCV, hepatitis C virus; HR, hazard ratio; MPGN, membranoproliferative glomerulonephritis.\n\na Per 1000 person‐years.\n\nDiscussion\nThis retrospective cohort, PS‐matched study provides United States general population–based evidence to support that HCV infection is linked to an increased risk of CKD. In fact, the crude incidence rate among our cohort of chronically infected HCV patients was 10.36 per 1000 person‐years compared with 5.72 per 1000 person‐years in non‐HCV groups. This significant finding was further confirmed in our Cox proportional hazards regression model, which indicated that persons diagnosed with chronic HCV had a 57% increased risk of developing CKD and in our time‐varying Cox regression model chronic HCV‐infected patients had a 27% increased risk of CKD. The decrease in the risk from 57% to 27% was explained as we controlled for the risk factors known to be associated with the development of CKD after an HCV diagnosis. Nonetheless, our study demonstrates that HCV is significantly associated with increasing the risk for CKD among patients with HCV in the United States, which corroborates other findings that have associated HCV with the incidence and progression of CKD.6, 9, 11, 12, 22, 23, 24\n\n\nHowever, a recent study conducted by Rogal et al.10 using the Electronically Retrieved Cohort of HCV Infected Veterans Study Group (ERCHIVES) determined that other factors (older age, female sex, diabetes, hypertension, development of cirrhosis, and substance abuse) rather than HCV were associated with the incidence and progression of CKD. They suggested that the reason that HCV was protective for CKD was probably a result of the amount of time patients were exposed to HCV as their patient population was not newly diagnosed with HCV unlike our population who were newly diagnosed chronic HCV patients. We also suggest that the differences in our findings may be due to the variables controlled for in our time‐varying multivariate analysis. With the use of time‐varying Cox regression modeling, we accounted for the dynamic and complex relationship between variables and time allowing us to identify the top five variables associated with CKD in the chronically infected HCV patient. Specifically these variables were: ACEIs, ARBs, congestive heart failure, hypertension, and transplantation variables similar to the variables Rogal et al. found to be predictors of CKD in their population. Because we accounted for changes that can occur over time, our findings lend more strength of the association of these variables in the development of CKD within patients with chronic HCV infection.\n\nA very promising study finding was that exposure to the minimally effective duration of treatment resulted in chronically HCV‐infected patients experiencing a 30% decreased risk of developing CKD. However, in the subgroup analysis, the association was only observed with the less‐tolerated HCV treatment therapies (dual and triple therapies) and not with the new all‐oral regimens. We believe this discrepancy results from shorter follow‐up for patients with the new DAAs for treatment (person‐years at risk) during the period of study. Although the sofosbuvir plus ribavirin regimen was first used in 2013, US Food and Drug Administration approval for the use of the first all‐oral DAA regimen (ledipasvir/sofosbuvir) did not occur until October 2014, so the patients in our study had less than 1 year to be exposed to the newer all‐oral DAA regimens (the study period ended in August 2015). Nonetheless, we noted a trend toward decreasing the risk of CKD in HCV‐infected patients treated with DAAs—a trend we suspect will become significant as more studies investigate the incidence and progression of CKD in patients with HCV who are treated with the new DAAs.\n\nOn the other hand, a disturbing study finding was that the majority of HCV patients (79%) within our study were not treated. Although the no treatment group had similar advanced liver disease (cirrhosis, decompensated cirrhosis) compared with the all‐oral therapy group, the no treatment group was sicker as noted by the increased number of patients with alcohol/drug abuse issues as well as the number of contraindications to pegylated interferon– and ribavirin‐based treatment regimens, which may partially explain why they were not treated. This finding is especially noteworthy because efficacious and safe all‐oral pangenotypic therapies are now available and approved for most people to include patients in whom interferon was contraindicated, difficult‐to‐treat patients, HIV coinfection, and cirrhosis. Nonetheless, the majority of patients not receiving treatment suggests that patients with HCV are still encountering barriers to treatment even within a group with access to health insurance. Therefore, identifying and then overcoming the barriers to identification and treatment remains a significant issue in eradicating HCV as well as eliminating the clinical and economic burden of HCV‐associated extrahepatic manifestations including CKD.3, 41\n\n\nAnother significant and unique finding of this study was the identification of the incidence and risk for developing MPGN and cryoglobunemia among chronically infected HCV patients. To the best of our knowledge, no study has quantified the risk of developing these diseases in the chronically HCV‐infected general population in the United States. The crude incidence rate of MPGN and cryoglobulinemia were 6 times and over 8 times higher compared with non‐HCV patients, respectively. In fact, results from our Cox regression models indicated that chronically infected HCV patients had 2‐3 times higher risk for MPGN and 14‐17 times higher risk of developing cryoglobulinemia after adjusting for covariates. Our results were similar to those in studies of extrahepatic manifestations of HCV in United States veterans.20, 21 A hospital‐based case‐control study performed among hospitalized male United States veterans (1992‐1999) revealed a greater proportion of MPGN (0.36% vs. 0.05%) and cryoglobulinemia (0.57% vs. 0.05%) among patients with HCV infection.20 In another cohort study of veterans (1997‐2004), investigators reported a 4‐fold higher risk of cryoglobulinemia in HCV‐infected US veterans, though the association was notably weaker than our study, perhaps due to differences in the study population and methods.21\n\n\nInterestingly, in our study, female HCV patients were at a significantly higher risk of developing MPGN compared with male HCV patients (HR, 3.78 vs. 1.74; P > 0.05). Several other studies have revealed a stronger association between female sex and cryoglobulinemia,42, 43, 44 but our study did not reveal any significant sex differences in development of cryglobulinemia. Despite the fact that HCV‐related MPGN and cryoglobulinemia are relatively uncommon in the HCV population, these complications are considered a significant problem as a result of the large number of people infected with HCV in the United States and the potential for serious and life‐threatening complications to include end‐stage renal disease. Unfortunately, we did not find evidence to support a protective effect of HCV treatment in the development of these conditions.\n\nThere are several strengths to our study design and the use of a large claims database. First, this study has methodological strength because it employed PS matching, time‐varying Cox proportional hazard models on matched groups, and adjustment for immortal time bias, analyses that are different from other previously published studies and which may help to indicate a stronger relationship of HCV and CKD than that reported elsewhere.22, 23, 24 Second, this study includes the number of strongly associated CKD covariates that were controlled for in the time‐ varying Cox proportional hazard models, including ACEIs, ARBs, congestive heart failure, hypertension, and transplantation; nevertheless, HCV infection was still a positive predictor for developing CKD.6, 10 Third, this study is notable for its large sample size and for it being representative of general populations in the United States. Finally, we conducted numerous sensitivity analyses to assess the robustness of our results and found that none of these analyses produced substantially different results from the main analysis.\n\nSeveral limitations must also be noted. First, the study lacks laboratory results (e.g., sustained virologic response, glomerular filtration rate) to corroborate ICD coding. We adjusted for as many confounders as available and known to be associated with CKD; however, because we were dependent on administrative data, there may have been some unmeasured confounders that were not reported and thus unavailable. Selection bias was present between treated and untreated groups. Detection bias may be introduced by differential screening frequencies for kidney diseases between HCV and non‐HCV individuals. Finally, we had a relatively short follow‐up, which did not allow us to fully explore the use of DAAs in this population.\n\nIn conclusion, individuals infected with chronic HCV in the United States are at a higher risk of developing moderate to severe CKD, MPGN, and cryoglobulinemia. Antiviral treatment for HCV is associated with a decreased incidence of CKD, although the association is yet to be confirmed for the new all‐oral DAA therapy. These findings highlight that treating HCV early helps to change the extrahepatic burden of CKD associated with HCV. Therefore, research must continue to identify barriers to the identification of HCV‐infected patients and improve access to treatment for all HCV patients. 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"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0270-9139",
"issue": "67(2)",
"journal": "Hepatology (Baltimore, Md.)",
"keywords": null,
"medline_ta": "Hepatology",
"mesh_terms": "D000998:Antiviral Agents; D003449:Cryoglobulinemia; D005260:Female; D015432:Glomerulonephritis, Membranoproliferative; D019698:Hepatitis C, Chronic; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D051436:Renal Insufficiency, Chronic; D012189:Retrospective Studies; D012306:Risk",
"nlm_unique_id": "8302946",
"other_id": null,
"pages": "492-504",
"pmc": null,
"pmid": "28873225",
"pubdate": "2018-02",
"publication_types": "D016428:Journal Article",
"references": "26924097;20870037;9802183;17488966;23102733;12360468;16708349;11297888;10760044;25894392;12297847;25398770;26862398;23588727;12407599;21185632;26195311;25624999;19129320;24737271;23293553;19861128;22403269;27216163;17592100;22015442;27741116;25904153;24278667;16905701;16624967;7678440;21394812;24720702;24122848;19606079;26526451;22423262;25529816;24257691;12447870;26266379;23281974",
"title": "Chronic hepatitis C virus (HCV) increases the risk of chronic kidney disease (CKD) while effective HCV treatment decreases the incidence of CKD.",
"title_normalized": "chronic hepatitis c virus hcv increases the risk of chronic kidney disease ckd while effective hcv treatment decreases the incidence of ckd"
} | [
{
"companynumb": "US-009507513-1802USA000194",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugadditional": null,
... |
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