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"abstract": "BACKGROUND\nThe purpose of the study was to categorize the vitality and inflammation of resected bone of patients with medication-related osteonecrosis of the jaw (MRONJ) and to correlate the grade of inflammation with the surgical success.\n\n\nMETHODS\nThis prospective study includes 44 patients with stage III MRONJ. Necrotic bone was resected in a block fashioned way. After demineralization and staining, histological analyses were performed by measuring the areas of necrotic, vital, and regenerative bone. Areas of chronic and acute inflammation were categorized as non, mild, moderate, and severe and were correlated with surgical success and parameters of inflammation in blood plasma (C-reactive protein and leukocytes).\n\n\nRESULTS\nAn average area of 59.0% was necrotic in the examined specimen. Vital bone was measured with an average area of 40.9%. The stage of chronic inflammation correlated with the amount of vital bone (P < .001) and the success of surgery (P = .002). If acute inflammation was dominant, chronic inflammation areas were found less while necrotic areas were observed more (P < .001). Also, the risk of relapses, wound healing disorders, and the level of C-reactive protein were elevated if acute inflammation was severe or moderate (P = .031). Areas of bone regeneration were seen only in 11.3% of vital bone areas and occurred independently of infection stages.\n\n\nCONCLUSIONS\nIf possible, surgery should be delayed in patients with signs of severe acute inflammation. Patients may profit from prolonged pre-operative antibiotic therapy to reduce the level of acute inflammation.",
"affiliations": "Department of Pathology of the University of Regensburg, Regensburg, Germany.;Department of Cranio-Maxillofacial Surgery, University Hospital Regensburg, Regensburg, Germany.;Department of Cranio-Maxillofacial Surgery, University Hospital Regensburg, Regensburg, Germany.;Department of Cranio-Maxillofacial Surgery, University Hospital Regensburg, Regensburg, Germany.;Department of Pathology of the University of Regensburg, Regensburg, Germany.;Department of Cranio-Maxillofacial Surgery, University Hospital Regensburg, Regensburg, Germany.",
"authors": "Mamilos|Andreas|A|;Spörl|Steffen|S|;Spanier|Gerrit|G|;Ettl|Tobias|T|;Brochhausen|Christoph|C|;Klingelhöffer|Christoph|C|https://orcid.org/0000-0002-6241-9216",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates",
"country": "Denmark",
"delete": false,
"doi": "10.1111/jop.13112",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0904-2512",
"issue": "50(1)",
"journal": "Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology",
"keywords": "histopathology; inflammation; medication-related osteonecrosis of the jaw; regeneration; surgery",
"medline_ta": "J Oral Pathol Med",
"mesh_terms": "D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D006801:Humans; D007249:Inflammation; D011446:Prospective Studies",
"nlm_unique_id": "8911934",
"other_id": null,
"pages": "76-84",
"pmc": null,
"pmid": "32946653",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The first quantitative histomorphological analyses of bone vitality and inflammation in surgical specimens of patients with medication-related osteonecrosis of the jaw.",
"title_normalized": "the first quantitative histomorphological analyses of bone vitality and inflammation in surgical specimens of patients with medication related osteonecrosis of the jaw"
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"abstract": "The most serious DNA damage, DNA double strand breaks (DNA-dsb), leads to mutagenesis, carcinogenesis or apoptosis if left unrepaired. Non-homologous end joining (NHEJ) is the principle repair pathway employed by mammalian cells to repair DNA-dsb. Several proteins are involved in this pathway, defects in which can lead to human disease. This review updates on the most recent information available for the specific diseases associated with the pathway.\n\n\n\nA new member of the NHEJ pathway, PAXX, has been identified, although no human disease has been associated with it. The clinical phenotypes of Artemis, DNA ligase 4, Cernunnos-XLF and DNA-PKcs deficiency have been extended. The role of haematopoietic stem cell transplantation, following reduced intensity conditioning chemotherapy, for many of these diseases is being advanced. In the era of newborn screening, urgent genetic diagnosis is necessary to correctly target appropriate treatment for patients with DNA-dsb repair disorders.",
"affiliations": "Paediatric Immunology and Haematopoietic Stem Cell Transplantation, Great North Children's Hospital, Clinical Resource Building, Floor 4, Block 2, Newcastle upon Tyne, UK.;Paediatric Immunology and Haematopoietic Stem Cell Transplantation, Great North Children's Hospital, Clinical Resource Building, Floor 4, Block 2, Newcastle upon Tyne, UK. a.r.gennery@ncl.ac.uk.",
"authors": "Slatter|Mary A|MA|;Gennery|Andrew R|AR|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s11882-020-00955-z",
"fulltext": "\n==== Front\nCurr Allergy Asthma Rep\nCurr Allergy Asthma Rep\nCurrent Allergy and Asthma Reports\n1529-7322 1534-6315 Springer US New York \n\n32648006\n955\n10.1007/s11882-020-00955-z\nImmune Deficiency and Dysregulation (C Kuo, Section Editor)\nUpdate on DNA-Double Strand Break Repair Defects in Combined Primary Immunodeficiency\nSlatter Mary A. 12 Gennery Andrew R. a.r.gennery@ncl.ac.uk 12 1 grid.459561.a0000 0004 4904 7256Paediatric Immunology and Haematopoietic Stem Cell Transplantation, Great North Children’s Hospital, Clinical Resource Building, Floor 4, Block 2, Newcastle upon Tyne, UK \n2 grid.1006.70000 0001 0462 7212Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK \n9 7 2020 \n9 7 2020 \n2020 \n20 10 57© The Author(s) 2020Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Purpose of Review\nThe most serious DNA damage, DNA double strand breaks (DNA-dsb), leads to mutagenesis, carcinogenesis or apoptosis if left unrepaired. Non-homologous end joining (NHEJ) is the principle repair pathway employed by mammalian cells to repair DNA-dsb. Several proteins are involved in this pathway, defects in which can lead to human disease. This review updates on the most recent information available for the specific diseases associated with the pathway.\n\nRecent Findings\nA new member of the NHEJ pathway, PAXX, has been identified, although no human disease has been associated with it. The clinical phenotypes of Artemis, DNA ligase 4, Cernunnos-XLF and DNA-PKcs deficiency have been extended. The role of haematopoietic stem cell transplantation, following reduced intensity conditioning chemotherapy, for many of these diseases is being advanced.\n\nSummary\nIn the era of newborn screening, urgent genetic diagnosis is necessary to correctly target appropriate treatment for patients with DNA-dsb repair disorders.\n\nKeywords\nAtaxia-telangiectasiaNijmegen breakage syndromeDNA-PKDNA ligase 4Cernunnos-XLFRadiosensitivityNewcastle Universityissue-copyright-statement© Springer Science+Business Media, LLC, part of Springer Nature 2020\n==== Body\nIntroduction\nThere are a number of recognized immunodeficiency syndromes due to defects in genes important for DNA-dsb repair and variable, diversity and joining (VDJ) recombination during T- and B lymphocyte formation. This review aims to provide an update on the known disorders including the molecular pathways that are involved, the clinical features and the importance of diagnosis. The immunodeficiency associated with these disorders may be amenable to treatment by haematopoietic stem cell transplantation (HSCT) although features out with the haematopoietic system will remain unchanged. Due to sensitivity to DNA damaging chemotherapeutic agents, specific approaches to transplant are required.\n\nCase Report\nA female infant presented at the age of 12 weeks with skin rash and failure to thrive. She had no dysmorphic features and had a normal head circumference. She was lymphocytopenic and a diagnosis of severe combined immunodeficiency (SCID) was made. Her lymphocyte subsets were as follows:\n\nCD3+ 474, CD19+ 8, CD4+ 187, CD8+ 137, NK 269 (all cells/μl) with absent naïve T-lymphocytes. She had absent IgM and IgA.\n\nGenetic studies to define the underlying disorder were arranged, but in the interim at 8 months of age, in the absence of a matched family donor or well matched unrelated donor, she underwent a paternal haploidentical CD3 + TCR αβ/CD19+ depleted HSCT with standard conditioning according to the IEWP of EBMT guidelines of treosulfan 36 g/m2, fludarabine 160 mg/m2, thiotepa 10 mg/kg with ATG and rituximab. She developed moderate mucositis, capillary leak and chemotherapy-related skin rash and engrafted rapidly with 1st day of neutrophils above 0.5 × 10 [9]/l on day +9 and 100% donor chimerism. She developed stage III skin graft versus host disease, treated with high dose steroids and cyclosporine, and on day +39 post HSCT was found to have adenoviraemia treated with cidofovir. Simultaneously she had features of thrombotic microangiopathy (with hypertension, thrombocytopenia, low haptoglobins, renal dysfunction and elevated urine protein/creatinine ratio). This was accompanied by gastrointestinal bleeding, followed by respiratory distress with pleural and pericardial effusions. She received treatment with defibrotide and eculizumab but sadly deteriorated and died 3 months after HSCT.\n\nDuring this period an unexpected diagnosis of DNA Ligase 4 deficiency was made on the basis of Sanger sequencing after an anomaly in the gene was suggested by experimental whole exome sequencing. She had compound heterozygous mutations leading to p.Arg278Pro, p.Glu582Aspfs. Subsequent radiosensitivity studies showed that her cells were exquisitely sensitive to relatively small doses of radiation suggesting her condition was at the severe end of the spectrum of disease seen with DNA Ligase 4 deficiency.\n\nAlthough HSCT-related mortality for this condition remains very high regardless of the conditioning regimen used, had the diagnosis been made prior to HSCT, the conditioning chemotherapy would have been modified. This case highlights the absolute necessity for rapid genetic results to be available to inform clinicians on appropriate treatment, together with the need for newborn screening for SCID.\n\nMolecular Pathways\nIn order to generate the vast number of antigen specific receptors required to counter any invading pathogen, T- and B-lymphocytes stochastically rearrange gene segments from Variable, Diversity and Joining gene clusters, in a process known as VDJ recombination. This diversity combined with imprecise gene segment junctional alignment, and random insertion or deletion of nucleotides at the gene segment junctions, enables the creation of over 1012 unique T- and B lymphocyte receptors, with most diversity focused on the antigen capture region of the lymphocyte receptor.\n\nInitiation of this process is achieved by breaking the double-stranded DNA, to create DNA double strand breaks (DNA-dsb), in order to access and isolate different gene segments, prior to the assembly of the antigen receptor gene product. The lymphoid specific genes recombination activating gene (RAG)1 and 2 are responsible for initiating these DNA-dsb. Defects in RAG1/2 lead to a number of combined immune deficiencies including T-B- NK+ SCID, combined immunodeficiencies (CID) and more mild forms of immunodeficiencies including IgA deficiency [1]. Repair of these DNA-dsb is performed by the ubiquitous DNA repair machinery found in all nucleated cells. Cells are constantly exposed to exogenous and endogenous DNA damaging agents. Unrepaired, damage to DNA can lead to replication errors, loss or rearrangement of genomic material, mutations or cancer and eventual cell death. In order to solve this, a number of DNA repair pathways have evolved. A particularly serious form of DNA damage is DNA-dsb, which can be a result of irradiation as well as physiological damage during lymphocyte receptor development (Fig. 1i). Two pathways are important to resolve the damage and maintain genome stability following DNA-dsb. In mammalian cells, information from a homologous template on sister chromatids is used to accurately repair breaks, in a process known as homologous recombination, and is generally restricted to the late S phase and G2 phase of the cell cycle. In vertebrate cells, the major DNA-repair pathway that facilitates the joining of regions of DNA that lack extensive homology is the non-homologous end-joining (NHEJ) pathway which is predominantly active during the G1 phase, but can operate at any phase of the cell cycle [2]. T- and B- lymphocytes utilize the ubiquitous NHEJ pathway to repair RAG-initiated DNA-dsb during the rearrangement of antigen receptor gene segments.Fig. 1 DNA double strand break repair by non-homologous end joining. DNA double strand break induced by exogenous causes such as ionizing radiation (ia) or endogenous causes such as intermediate steps in normal metabolic processes including DNA replication and meiotic recombination or physiological adaptive immune system development (ib). The MRN protein complex (MRE11, RAD50 and NBN) binds broken DNA ends and phosphorylates ataxia-telangiectasia mutated kinase (ATM), which initiates cell-cycle arrest and attraction of numerous repair proteins (ii). Ku70/Ku80 heterodimer binds the broken DNA coding ends and recruits DNA-PKcs and Artemis, which is essential to open the DNA hairpin intermediates. The covalently sealed DNA hairpin intermediate is randomly nicked by the DNA-PKcs/Artemis complex, to generate a single-stranded DNA break with 3′ or 5′ overhangs (iii). XRCC4, DNA ligase 4, Cernunnos-XLF and PAXX co-associate and are recruited to the modified DNA ends. DNA ligase 4 directly repairs the damage - the XRCC4/Cernunnos-XLF/PAXX support the enzyme (iv)\n\n\n\nA number of proteins are involved in the NHEJ repair pathway, and are conserved through evolution, indicating the critical role they play in maintaining genomic stability. Defects in a number of these proteins have been described which cause human disease. Many of these diseases include combined immunodeficiency as part of the phenotype. However given the ubiquitous nature of the repair pathway in mammalian cells, many other non-immunological clinical features may be apparent in diseases caused by defects in these genes, and may be implicated in carcinogenesis.\n\nMRN Complex\nThe meiotic recombination 11 homologue 1 (MRE11), RAD50 and Nijmegen breakage syndrome protein 1 (NBS1) proteins play a pivotal role in sensing DNA-dsb and coordinating the response to initiate cell cycle checkpoint arrest and commence DNA repair or initiate apoptosis. This compound (the MRN complex), which exhibits dual single strand DNA endonuclease and double strand DNA exonuclease activity, comes together as a heterodimer complex to execute three indispensable functions in DNA-dsb repair:binding and processing of damaged DNA\n\nsecuring DNA to bridge over short and long distance damage regions\n\nactivation of DNA damage response and checkpoint signalling pathways [3] (Figure 1ii).\n\n\n\nHuman disease has been described due to mutations in MRE11 (Ataxia-Telangiectasia-like disorder, OMIM #604391) [4–6], RAD50 (Nijmegen Breakage Syndrome-like disorder) [7•,8] and NBN, and although the somatic phenotype shows some common features, significant immunodeficiencies are confined to patients with NBN mutations giving rise to Nijmegen Breakage syndrome (NBS) (OMIM #251260).\n\nAtaxia Telangiectasia Mutated\nThe activated MRN complex initiates the cell cycle checkpoint response by promoting the localized activation of ataxia-telangiectasia mutated (ATM) protein, which is a central component of the signal transduction pathway through a variety of cellular signalling pathways in response to DNA damage, including cell cycle control, apoptosis, senescence, transcription, chromatin structure alteration and DNA repair. Activated ATM phosphorylates the MRN complex, resulting in cascade of phosphorylation of hundreds of ATM substrates [9] (Figure 1ii). Whilst the majority (~80%) of irradiation-induced DNA-dsbs are repaired by the NHEJ pathway independently of ATM, a minority are repaired by a pathway requiring ATM and Artemis [10]. Defects in ATM give rise to ataxia-telangiectasia (AT) (OMIM #208900).\n\nNon-Homologous End Joining\nThe NHEJ repair pathway for DNA-dsbs has three aims:synapsis of two broken DNA ends\n\nend processing to make them possible to ligate\n\nligation of these ends together.\n\n\n\nA series of eight proteins have been identified as the critical NHEJ components, which are involved in the ligation of DNA-dsb [11]. The DNA-binding subunits Ku70 and Ku80 together form a ring shaped heterodimer that acts as an anchor protein binding the DNA ends and protecting them from exonucleolytic activity. A single Ku heterodimer binds to each DNA end, and interacts with DNA protein kinase catalytic subunit (DNA-PKcs) to form a holoenzyme, DNA-PK. DNA-PK acts as a bridge between two Ku heterodimer-bound DNA ends, acting to stabilize the local DNA structure to enable end-processing and DNA ligation. The Ku enzymes have not yet been implicated in human disease. Mutations in PRKDC, which encodes the DNA protein kinase catalytic subunit lead to CID (OMIM #615966).\n\nArtemis, encoded by DCLRE1C, is phosphorylated by activated DNA-PKcs, which initiates the endonuclease activities of Artemis allowing resolution of complex DNA ends including the heterologous loop and stem-loop DNA structures that contain single-stranded DNA adjacent to double-stranded DNA (Figure 1iii). Defects in DCLRE1C lead to a number of immunodeficiencies including SCID and CID (OMIM #602450). DNA ligase 4, XRCC4 and Cernunnos-XRCC4-like factor (XLF) act as link proteins, bridging the DNA ends – DNA ligase 4 is required for the ligation reaction that rejoins the DNA-dsbs. DNA ligase 4 (OMIM #606593) and cernunnos-XLF (OMIM #611291) have been implicated in human immunodeficiency. Patients with XRCC4 deficiency are described (OMIM #616541), but although short stature and microcephaly are features, immunodeficiency has not been described. Most of the NHEJ process functions separately from ATM signalling, although a fraction contingent upon Artemis requires ATM activity, demonstrating some relationship between the signalling and repair machinery.\n\nThe most recent factor involved in NHEJ to be described is Paralog of XRCC4 and XLF (PAXX), which has a similar structure to XRCC4, and interacts and binds with Ku, stabilizing the NHEJ protein assembly [12••, 13••, 14••] (Figure 1iv). To date, no human disease has been described involving PAXX, and it is not clear whether defects have any impact on adaptive immunity.\n\nCombined Immunodeficiencies Associated with Defects in DNA Double Strand Break Repair\nAs indicated above, defects in a number of proteins critical for DNA-dsb sensing and repair confer human disease (Table 1). Many of these are associated with immunodeficiency, and all display sensitivity to ionizing radiation.Table 1 Disorders of non homologous end joining DNA double strand break repair\n\nDisorder\tPathway\tClinical features\t\nGene mutations\t\nInheritance\t\nArtemis\tNHEJ\t1.T-B-NK+ SCID - Early infancy viral infection, PJP, Diarrhoea and FTT\t\nNull mutations in DCLRE1C\t2. Omenn syndrome\t\nAR\t3. Atypical late onset SCID - Recurrent infection, AI, EBV-lymphoma\t\nLigase 4 deficiency\tNHEJ\tSCID or atypical SCID, Omenn syndrome, CID, asymptomatic lymphocytopenia, malignancy, marrow hypoplasia, malignancy\t\nHypomorphic mutations in LIG4\t\nAR\t\nMay have microcephaly and growth failure.\t\nCernunnos-XLF\tNHEJ\tMicrocephaly, learning difficulty, growth failure, SCID or CID\t\nHypomorphic mutations in NHEJ1\t\nAR\t\nDNA-PKcs\tNHEJ\tSCID\t\nDefects in PRKDC\tAI, granulomata, microcephaly\t\nAR\t\nXRCC4 Deficiency\tNHEJ\tMicrocephaly, growth retardation and developmental delay\t\nMutations in XRCC4\t\nAR\tNo significant immunodeficiency\t\nAtaxia Telangiectasia\tMRN complex\tProgressive cerebellar ataxia, oculocutaneous telangiectasia, infertility, growth retardation, lymphoid tumours, recurrent infection, chronic lung disease\t\nAtaxia-telangiectasia mutated (ATM) protein defects\t\nAR\t\nNijmegen Breakage Syndrome\tMRN complex\tDysmorphic facies, IUGR, growth retardation\t\nNBS1 mutations\t\nAR\tSkeletal and renal abnormalities, mental retardation\t\nRecurrent sino-pulmonary infection, B-lymphoma, AI\t\nAtaxia telangiectasia-like disorder\tMRN complex\tSimilar to AT, but no telangiectasia. Ataxia later and milder\t\nMutations in MRE11\t\nAR\t\nRAD 50\tMRN complex\tIUGR, microcephaly, and poor postnatal growth\t\nMutations in RAD50\tNo significant immunodeficiency\t\nAR\t\nAbbreviations: NHEJ, non homologous end joining; AR, Autosomal recessive; SCID, Severe Combined Immunodeficiency; PJP, Pneumocystis jirovecii pneumonia; FTT, failure to thrive; AI, Autoimmunity; Lig 4, Ligase 4; CID, Combined Immunedeficiency; XLF, XRCC4-like factor; XRCC4, X-ray cross-complementation group 4; DNA-PKcs, DNA-dependent protein kinase subunit; PRKDC, Protein kinase catalytic subunit; MRN, Complex of 3 proteins – Mre11, Rad50, NBS1; NBS1, Nijmegen Breakage Syndrome protein 1; IUGR, Intrauterine growth retardation; MRE 11, Meiotic recombination 11\n\n\n\nArtemis Deficiency\nArtemis is critical for VDJ recombination, demonstrated by null mutations in DCLRE1C leading to a T-B-NK+ SCID phenotype with absent immunoglobulins [15], which was initially described in Athabascan-speaking native Americans [16]. Patients present as with any other form of SCID, classically in early infancy with viral or pneumocystis pneumonitis, persistent viral diarrhoea and growth failure [17]. There is a systemic increased cellular sensitivity to ionizing radiation. Although SCID is the most common presentation, other clinical phenotypes are described including atypical SCID with hyper IgM [18•], Omenn syndrome [19], progressive CID presenting from later infancy and typified by recurrent infection of the gastrointestinal or sino-respiratory tracts, T- and B-lymphocytopaenia, hypogammaglobulinaemia and autoimmune cytopaenias, some with EBV-associated B lymphomas [20, 21], and antibody deficiency with a common variable immunodeficiency phenoytype [22]. Autoimmunity is commonly described in the non-SCID presentations [23]. The severity of the clinical phenotype correlates with the levels of recombination and DNA repair activity conferred by the protein, determined by the type and genetic locus of the mutation [24]. Microcephaly is not a feature of DCLRE1C mutations.\n\nThe outcome of HSCT in patients with SCID is significantly better in those transplanted without pre-existing infection [25, 26]. This observation has directed the institution of newborn screening programs for SCID in many states in the USA [27], by identification of DNA remnants present in lymphocytes, and left over following successful VDJ recombination, revealing successful T lymphocyte receptor re-arrangement (T lymphocyte receptor excision circles – TRECs). T lymphocyte neo-genesis, successful thymopoiesis and durable T lymphocyte engraftment, as well as probability of B lymphocyte function requires haematopoietic stem cell engraftment, most likely achieved by use of preparative chemotherapy [28, 29]. The use of alkylating-containing conditioning regimens confers longterm immune-reconstitution in patients with DCLRE1C mutations [30], but leads to significant long-term sequalae [31], and possibly an increased risk of early conditioning-related mortality [32•]. These factors have driven the quest for safer alternatives to achieve functioning immunity. Two promising developments which have entered clinical trials are lentiviral-vector gene-addition therapy [33••, 34••] and the use of chemotherapy free antibody-based conditioning [35]. Longterm results are awaited, but preliminary results are encouraging.\n\nAtaxia Telangiectasia\nAT is a rare systemic disorder, inherited in an autosomal recessive fashion, and caused by mutations in ATM [36]. Systemic clinical features include progressive cerebellar ataxia, oculocutaneous telangiectasia (Fig. 2), gonadal sterility, and growth retardation. Patients experience a high frequency of lymphoid tumours. Immunodeficiency may lead to frequent sinopulmonary infections that in conjunction with recurrent aspiration, lead to chronic lung disease [37]. Interstitial lung disease, including lymphoid interstitial pneumonitis is also reported. Patients with AT have a variable incidence of infections;- some experience no more than unaffected siblings, whereas others manifest progressive respiratory infection because of humoral and cellular immunodeficiency. Immune responses, especially to bacterial polysaccharide antigens, are generally reduced [38]. Mutations in ATM do not lead to a significant block in lymphocyte development. Constancy of VDJ recombination rather than completion of VDJ recombination may be affected in the absence of ATM, which may be important to monitor recombination intermediate products. IgA, IgE and IgG subtypes are reduced or absent in AT patients and, in some, IgM may be raised, which may represent a more severe immunological defect with worse prognosis [39–41]. Heterozygote carriers do not display the classical manifestations of disease, but may have a higher incidence of solid tumours, particularly breast cancer in female carriers [42]. Ataxia is normally the earliest clinical manifestation of AT [43]. Most infants appear to be normal during the first year of age - walking develops normally, although some demonstrate ataxia in infancy with a delay in walking. Abnormal eye movements generally develop from the second year of life onwards [44, 45] and oculocutaneous telangiectasias appear on the bulbar conjunctivae and exposed areas of the skin after the neurological deficit has manifest. Café-au-lait patches are also common.Fig. 2 Early bulbar telangiectasia on a 2.5 year old patient with ataxia-telangiectasia\n\n\n\nPatients with AT have a significantly increased risk of developing malignancy - from 10 years of age, the risk of developing a tumour is around 1% annually. Around 25% will develop malignancy, of which lymphoma and leukaemia predominate [46•]. Malignancy may be difficult to treat – the tumours are often aggressive, and because of the systemic nature of the disease, significant morbidity and mortality to chemotherapy and radiotherapy may be experienced. Currently there are no curative therapies for patients with AT, median age of death is 25 years [47], and older patients have significant multi-system co-morbidities [48••].\n\nThere is a tentative suggestion that chronic inflammatory processes, driven in part by persistent genotoxic stress, participate in the pathogenesis in AT [49, 50]. Furthermore, in addition to the intrinsic genomic instability, impaired immune surveillance may contribute to tumorogenesis and development. Murine Atm-deficient T-lymphocytes demonstrate impaired proliferative capacity because of replication stress [51]. These observations raise the possibility that modification of the immune system may alleviate some of the disease sequelae. Haematopoietic stem cell transplantation has been considered for AT patients. Use of fully myelo-ablative conditioning is associated with significant morbidity and mortality [52••]. The adoption of a reduced intensity conditioning regimen gives better survival and enables donor engraftment and immune reconstitution [53–55•]. The long-term outcome with respect to systemic damage to tissues has yet to be determined, and there may be an increase in secondary malignancies, as there is for Fanconi anaemia patients who have been transplanted [56]. Furthermore, the efficacy of HSCT in terms of ameliorating damage secondary to inflammation, and malignancy due to enhanced tumour surveillance are unproven to date. Adoption of HSCT for patients with HSCT would best be undertaken in the context of clinical trials, with careful long-term follow up.\n\nNewborn screening for SCID detects TRECs, the by-product of successful T lymphocyte development. Significant T-lymphocytopenia will therefore be detected by TREC screening, and non-SCID conditions may be picked up incidentally, including patients with AT [57•, 58•]. This presents an ethical dilemma as:Potentially the infant may undergo HSCT, which is not appropriate\n\nIf standard conditioning protocols are used, there is a significant risk of morbidity and mortality\n\nFamilies may not wish to be informed that their newborn infant has a progressive, fatal neurodegenerative disease\n\nA positive diagnosis of AT in the infant is likely to implicate the mother as a carrier, who will need to be counselled about increased risks of developing a tumour, and in particular, breast cancer.\n\n\n\nThe first two points can be resolved by ensuring that a genetic diagnosis is available prior to embarking upon a stem cell procedure. The final points require sensitive counselling before further testing is performed. Many parents would prefer to have information regarding an early diagnosis of AT, although a significant minority would prefer not to know [59••,60].\n\nNijmegen Breakage Syndrome\nNijmegen breakage syndrome (NBS) is typified by a characteristic dysmorphic facial appearance, which becomes exaggerated with advancing age. Intrauterine growth retardation is usually present and patients exhibit profound microcephaly at birth. They display a receding forehead, receding mandible and prominent midface [61]. Other features include short stature, congenital skeletal (clinodactyly, syndactyly) and renal abnormalities, and mild non-progressive mental retardation. Premature ovarian insufficiency is reported in females. Although reported worldwide, there is a particularly high prevalence among Central and Eastern European Slavic populations due to a founder mutation effect (a homozygous deletion of five nucleotides (657_661del5)) [62]. Occasional patients may have normal head size, although display other features typical of NBS [63]. Sino-pulmonary infection is common and patients are susceptible to malignancies, particularly B lymphocyte-lineage lymphomas (Fig. 3), and autoimmune manifestations, including pulmonary granulomata and interstitial lymphocytic lung disease [64, 65]. Cellular and humoral immune deficiency are widely reported, but with a spectrum of clinical expression ranging from clinically-silent laboratory abnormalities (reduced CD4+, CD8+ T-lymphocytes, thymic emigrants, low percentage of naïve T-lymphocytes, increased memory T-lymphocytes, reduced TCRαβ/ TCRγδ ratio in peripheral blood) to clinically relevant immunodeficiency, particularly hypogammaglobulinaemia, which presents with recurrent, chronic respiratory tract infections. This may cause development of bronchiectasis, and many patients require immunoglobulin substitution therapy. Opportunistic infections are rare and there is generally no correlation between the degree of cellular deficiency and infection severity of infections [66]. Some patients with Nijmegen breakage syndrome may be identified on newborn screening for SCID with very low levels of TRECs [67•].Fig. 3 Rapidly progressive left sided thoracic non-Hodgkin lymphoma in an 8 year old patient with Nijmegen Breakage syndrome\n\n\n\nMalignancy remains the most significant risk for patients with NBS, with most tumours arising from the lympho-reticular system. By 20 years of age, over 40% of patients have acquired a malignancy, and the median age at which malignancy develops is 10 years [68]. Because the repair defect is systemic, patients often fail to tolerate treatment, and have a higher frequency of chemotherapy-related toxicity, and severe or fatal infectious complications during chemotherapy than observed in otherwise healthy children receiving chemotherapy. The adverse response to treatment results in a high rate of treatment failure and increased risk of developing secondary malignancies.\n\nGiven these issues, the arguments for considering HSCT to treat patients with NBS are perhaps more compelling than for patients with AT – the neurological problems associated with NBS are not progressive, and many early deaths may be prevented by altering immune surveillance. Regimens using reduced intensity conditioning or Fanconi-anaemia type protocols have resulted in successful outcomes [52••, 62, 64, 69]. The role of pre-emptive HSCT has yet to be formalized, but could be contemplated before malignancy develops, particularly in patients with clinical immunodeficiency, recurrent or chronic infection despite immunoglobulin therapy, latent viral infection (especially EBV) or severe autoimmunity. However, careful long-term follow up is required to determine whether the incidence of secondary malignancy might be lower than that recorded in non-transplanted individuals. One report documents a loss of donor myeloid chimerism in patients receiving reduced intensity conditioning, but improved chimerism when treosulfan was added to the regimen [70]. Follow up was short, however, at only 3 years and longer follow up is required to determine whether the risk of secondary malignancy is increased with the higher intensity regimen.\n\nLigase 4 Deficiency and Cernunnos/XLF Deficiency\nA few patients have been described with hypomorphic mutations in LIG4. Most have microcephaly, although individuals with a normal head circumference are described [71]. The spectrum of presentation in individuals with LIG4 deficiency is wide with cases of SCID or atypical SCID [72, 73], Omenn syndrome [74], CID [75, 76], asymptomatic CD4+ T-lymphocytopenia [77], predisposition to malignancy [71], marrow hypoplasia and even asymptomatic individuals [78••], some of whom display microcephaly and growth failure [79]. As well as immunodeficiency, patients are at significant risk of developing malignancies, predominantly lymphomas or leukaemias, often, but not always associated with EBV [71, 75, 80]. Whilst microcephaly and growth failure are characteristic, they are not universally present, and the clinico-immunological phenotype is indistinguishable from that of patients with NBS. T-lymphocytopenia is often present, and peripheral B-lymphocytes may be almost absent. A high IgM and low IgA and IgG may be seen, due to the role of LIG4 in class switch recombination. Treatment is expectant, with antimicrobial prophylaxis and immunoglobulin replacement as required. Treatment of malignancy is difficult, as tumours are often aggressive and the systemic distribution of the defect means that patients are poorly tolerant of chemotherapy and radiotherapy [71]. The role of HSCT is unclear. A number of patients have successfully been treated, particularly when reduced intensity conditioning regimens are employed [52••], but the optimal patient selection and timing have yet to be determined. Whilst HSCT will correct the immunodeficiency and associated marrow hypoplasia, it is unclear whether successful treatment will prevent development of malignancy or whether late-onset conditioning-related secondary malignancies will develop.\n\nCernunnos-XLF interacts closely with DNA ligase 4. To date, only a few patients with hypomorphic mutations in NHEJ1 have been described. The phenotypic features are similar to those of patients with NBS and LIG4 deficiency, namely profound microcephaly with variable degrees of learning difficulty, growth failure, SCID or CID [81–83]. Lymphoma has also been described in one patient [84•]. The immunological phenotype is similar to that in patients with LIG4, namely T-lymphocytopenia with profound peripheral B-lymphocytopenia, high IgM and low IgA and IgG. A few patients have successfully been transplanted using reduced intensity conditioning regimens [52••].\n\nDNA-PKcs\nDNA-PKcs acts early in the repair of DNA-dsb, and interacts with artemis. Only six patients with defects in PRKDC have been described to date, too few to confidently ascribe a typical phenotype. The first patient had a SCID phenotype, not associated with microcephaly [85]. Microcephaly has been described in one patient with SCID [86]:- other presentations have described autoimmunity with granulomata [87•, 88•]. Stem cell transplantation has been successfully attempted, but there are too few data to make any clear recommendations. It could be predicted that patients will react more like those with artemis deficiency than deficiencies of other core NHEJ proteins.\n\nDiagnosis\nThe key feature of the diseases described above is an exquisite sensitivity to ionizing radiation. However, the diagnosis of radiosensitivity is difficult, and available in only a few laboratories – furthermore, results usually take at least 4–6 weeks, as fibroblasts have to be harvested, cultured, and the experiments set up. A high index of clinical suspicion is required when contemplating the diagnosis. Some clinical and routine laboratory diagnostic signs may suggest the diagnosis. Key clinical features include telangiectasia, especially on the bulbar conjunctiva and when associated with ataxic signs, and microcephaly, particularly when associated with marrow hypoplasia, immunodeficiency, autoimmunity or lymphoid malignancy. However, even in phenotypes where microcephaly is classic, some patients may not display this sign\n\nAlphafeto protein is raised in patients with AT.\n\nAn immunological profile that should raise a suspicion is one with a T- and B-lymphocytopaenia with preserved NK cell count, associated with a raised IgM and low or absent IgA and IgG.\n\nDuring normal lymphocyte development, lymphocyte receptor gene rearrangements advance through a unique somatic recombination development. The TCRα locus uses a multi-step recombination process, using proximal TRAV elements progressively to distal TRAV elements. The persistent reduced recombinase activity over successive waves of TCRα rearrangement in patients with VDJ recombination defects is displayed as a bias in TCRα use of more proximal TRAV/TRAJ associations. These particular patterns can be detected using flow cytometric methods, which may indicate a deficit in VDJ recombination, including NHEJ defects [89•]. Cytogenetic analysis can be helpful to elucidate the diagnosis: an increased number of chromosome 7:14 translocations are seen in ataxia telangiectasia, NBS, artemis deficiency, and may be seen in the other defects described, although absence does not exclude the diagnosis.\n\nSensitivity to ionizing radiation can be established with a clonogenic survival assay. Fibroblasts irradiated with increasing ionizing radiation doses are assessed after 3 weeks to assess percentage survival of cells [21]. Alternatively, cells can be subject to increasing doses of radiation and subsequently stained for H2AXγ foci which cluster at the site of DSBs, but disappear over time as the DNA-dsb are repaired. Foci persistence, visualized microscopically [10] or by flow cytometry [90, 91] indicates impaired repair mechanisms. Ultimately, a confident diagnosis requires genetic analysis to identify the mutations in the appropriate gene.\n\nOther Diseases Caused by Molecular Defects in the NHEJ Pathway\nThe diseases described above are associated with T lymphocyte immune impairment, which has a significant clinical impact. Other diseases are described due to mutations in NHEJ genes where immunodeficiency is a minor issue or immunity is not impaired.\n\nAtaxia-Telangiectasia like Disorder\nAtaxia telangiectasia-like disorder is caused by mutations in MRE11, part of the MRN complex which associates with NBS1, and is extremely rare, with few patients reported worldwide [92, 93•]. Clinical features mimic those of patients with AT although telangiectasia are absent and progressive cerebellar ataxia occurs later and progresses more slowly. Immunoglobulin levels are normal, but deficiency in pneumococcal polysaccharide antigen antibodies has been reported, particularly to pneumococcal polysaccharide antigen [94]. Some patients are reported to exhibit microcephaly.\n\nRAD50 Deficiency\nOnly two patients have been described with NBS-like features, in whom compound heterozygous or homozygous mutations in RAD50, the third component of the MRN complex, were found [7•,8]. The clinical features more resemble NBS than ATLD, with intrauterine growth retardation, microcephaly, and poor postnatal growth. There was no history of excessive infections and immunoglobulin levels were normal.\n\nXRCC4 Deficiency\nNumerous individuals have been described with mutations in XRCC4 [95–99]. Whilst the clinical phenotype is quite severe, with microcephaly, growth retardation and developmental delay, and there is severe radiosensitivity with a DNS-dsb defect, VDJ recombination appears preserved, with no significant immunodeficiency.\n\nKu70, Ku80, PAXX\nWhilst these proteins are represented in NHEJ and presumably VDJ recombination, to date, no human disease has been described attributable to defects in these genes.\n\nDiscussion\nA number of immunodeficiency syndromes are recognized due to defects in genes important for DNA-dsb repair, and necessary for VDJ recombination during T- and B lymphocyte formation. Treatment of these patients requires a specific approach, as the DNA repair defect is ubiquitous to all cells, not just lymphocytes. Therefore, use DNA-damaging agents during HSCT or treatment of malignancies may lead to specific severe morbidities and mortality. The introduction of newborn screening for SCID will detect a number of these diseases, meaning that an accurate and speedy genetic diagnosis is imperative in order to define the most appropriate treatment regimen. Furthermore, the high incidence of lymphoid malignancies in these diseases should alert clinicians treating oncology patients to the possibility of an underlying systemic DNA repair disorder indicative of primary immunodeficiency [100], prior to embarking on treatment, to minimize treatment-related toxicities.\n\n“Online Mendelian Inheritance in Man (OMIM): https://www.omim.org“.\n\nThis article is part of the Topical Collection on Immune Deficiency and Dysregulation\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nCompliance with Ethical Standards\nConflict of Interest\nThe authors declare no conflicts of interest relevant to this manuscript.\n\nHuman and Animal Rights and Informed Consent\nThis article does not contain any studies with human or animal subjects performed by any of the authors.\n==== Refs\nReferences\n\n",
"fulltext_license": "CC BY",
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"issue": "20(10)",
"journal": "Current allergy and asthma reports",
"keywords": "Ataxia-telangiectasia; Cernunnos-XLF; DNA ligase 4; DNA-PK; Nijmegen breakage syndrome; Radiosensitivity",
"medline_ta": "Curr Allergy Asthma Rep",
"mesh_terms": "D053903:DNA Breaks, Double-Stranded; D005260:Female; D006801:Humans; D007223:Infant; D000081207:Primary Immunodeficiency Diseases",
"nlm_unique_id": "101096440",
"other_id": null,
"pages": "57",
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"pmid": "32648006",
"pubdate": "2020-07-09",
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"references": "31690822;25488969;12604777;30121298;16369571;29582093;30719430;16439204;18845326;30800289;31033087;25839420;19075392;30154114;15731174;28622525;31720302;25677497;11505391;22373003;31781088;25917813;1916741;27884168;31767017;31709473;16790721;24123394;25109802;25574025;24230999;25872942;27063650;14747472;30209074;15503472;23911390;31849966;25075835;24144642;31776720;11134242;30772474;11336668;25138334;25742519;29906526;31921190;12569164;16540517;30105620;10657830;23722905;16673875;19409520;17628218;19684627;26119972;30454873;23228243;24144640;17345618;10395545;11779494;25728776;23264026;21273302;16357942;29866155;30619276;32116070;28392333;26255102;7315300;15520243;21479529;25842288;30420857;10612394;25670504;25941166;30061307;16439205;30400801;26271390;31829407;16358361;28318010;15574327;15269180;24794685;28791007;20298636;15574463;32602054;26476407;18937313",
"title": "Update on DNA-Double Strand Break Repair Defects in Combined Primary Immunodeficiency.",
"title_normalized": "update on dna double strand break repair defects in combined primary immunodeficiency"
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"abstract": "Proton pump inhibitors (PPIs) are one of the most frequently prescribed medications across the globe. Esomeprazole is the S-isomer of omeprazole, and it is currently the most widely prescribed PPI. The safety profile of esomeprazole is extremely favorable with only minor side effects, like headache and diarrhea, that are encountered in day to day practice. We report a case of a young female with symptoms of gastroesophageal reflux disease who developed galactorrhea after starting esomeprazole therapy. Resolution of galactorrhea after stopping the drug and self-rechallenge by the patient herself with reappearance of galactorrhea confirmed the culprit to be esomeprazole only. We postulate that esomeprazole may have a mild inhibitory effect on CYP3A4, which leads to decreased metabolism of estrogen, thereby increasing serum estrogen levels. Estrogen causes stimulation and production of prolactin release, which results in development of galactorrhea. This is the first case of esomeprazole induced galactorrhea, to the best of our knowledge.",
"affiliations": "Department of Gastroenterology, Lokmanya Tilak Municipal Medical College and General Hospital, 1st Floor, College Building, Sion, Mumbai, India. niravpipalia@yahoo.com.;Department of Gastroenterology, Lokmanya Tilak Municipal Medical College and General Hospital, 1st Floor, College Building, Sion, Mumbai, India.;Department of Gastroenterology, Lokmanya Tilak Municipal Medical College and General Hospital, 1st Floor, College Building, Sion, Mumbai, India.;Department of Gastroenterology, Lokmanya Tilak Municipal Medical College and General Hospital, 1st Floor, College Building, Sion, Mumbai, India.;Department of Gastroenterology, Lokmanya Tilak Municipal Medical College and General Hospital, 1st Floor, College Building, Sion, Mumbai, India.;Department of Gastroenterology, Lokmanya Tilak Municipal Medical College and General Hospital, 1st Floor, College Building, Sion, Mumbai, India.",
"authors": "Pipaliya|Nirav|N|;Solanke|Dattatray|D|;Rathi|Chetan|C|;Patel|Ruchir|R|;Ingle|Meghraj|M|;Sawant|Prabha|P|",
"chemical_list": "D054328:Proton Pump Inhibitors; D064098:Esomeprazole",
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"keywords": "Esomeprazole; Galactorrhea; Proton pump inhibitors",
"medline_ta": "Clin J Gastroenterol",
"mesh_terms": "D000328:Adult; D000568:Amenorrhea; D064098:Esomeprazole; D005260:Female; D005687:Galactorrhea; D005764:Gastroesophageal Reflux; D006801:Humans; D054328:Proton Pump Inhibitors",
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"title": "Esomeprazole induced galactorrhea: a novel side effect.",
"title_normalized": "esomeprazole induced galactorrhea a novel side effect"
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"abstract": "A 19-year-old male with diarrhea, abdominal pain, fever, and elevated C-reactive protein (CRP) levels was admitted to our hospital. Endoscopic examination and small intestinal contrast radiography revealed multiple longitudinal ulcers in the large intestine and ileum. A specimen biopsied from one of these ulcers revealed non-caseating epithelioid cell granuloma. He also had a draining anal fistula. Plain chest computed tomography (CT) and abdominal contrast-enhanced CT did not reveal any vascular abnormality. A diagnosis of Crohn's disease was made, and infliximab was administered. Following infliximab administration, the diarrhea and abdominal pain disappeared, longitudinal ulcers in the large intestine healed (as evidenced by endoscopic examination), and his anal lesion improved. However, fever and elevated CRP levels persisted. With the concomitant use of prednisolone, the fever and elevation of CRP levels eventually improved, and the patient was discharged. Both, however, recurred as the patient was weaned off prednisolone treatment; consequently, he was re-hospitalized. Contrast-enhanced CT upon re-admission revealed stenoses of the right renal artery, left common carotid artery, and left subclavian artery. In addition to Crohn's disease, the patient was diagnosed with co-existing Takayasu's arteritis.",
"affiliations": "IBD Center, Sapporo Kosei General Hospital.",
"authors": "Miyakawa|Maki|M|;Tanaka|Hiroki|H|;Yamashita|Masaki|M|;Sakemi|Ryosuke|R|;Nasuno|Masanao|M|;Ishii|Manabu|M|;Yanagisawa|Hideyuki|H|;Ichihara|Shin|S|;Gotoda|Hiroko|H|;Motoya|Satoshi|S|",
"chemical_list": "D000069285:Infliximab",
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"journal": "Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology",
"keywords": null,
"medline_ta": "Nihon Shokakibyo Gakkai Zasshi",
"mesh_terms": "D015746:Abdominal Pain; D003424:Crohn Disease; D003967:Diarrhea; D005334:Fever; D006801:Humans; D000069285:Infliximab; D008297:Male; D013625:Takayasu Arteritis; D014057:Tomography, X-Ray Computed; D055815:Young Adult",
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"title": "A case of Takayasu's arteritis detected in a patient with Crohn's disease following infliximab treatment.",
"title_normalized": "a case of takayasu s arteritis detected in a patient with crohn s disease following infliximab treatment"
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"abstract": "Smoking is associated with the induction of the CYP 1A2 enzyme, and hence with diminished levels of drugs metabolized by this enzyme. This article presents a hypothetical patient, diagnosed with schizophrenia, who smokes about 10 cigarettes a day. The progress of the patient is examined across several follow up meetings, each of which presents a fresh clinical problem related to smoking and its interaction with the medication. Clinical guidance for each problem is presented along with a brief discussion on the subject. The article concludes with a discussion of other pharmacokinetic considerations related to smoking and its treatment in patients with schizophrenia.",
"affiliations": "Department of Psychopharmacology, National Institute of Mental Health and Neurosciences, Bangalore, India. candrade@psychiatrist.com",
"authors": "Andrade|Chittaranjan|C|",
"chemical_list": "D019388:Cytochrome P-450 CYP1A2; D003024:Clozapine",
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"title": "Schizophrenia and smoking.",
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"abstract": "Over the past decade, percutaneous coronary interventions (PCIs) performed via radial artery (RA) access have become popular among interventional cardiologists. Since the radial approach may limit the options in complex cases, most interventional cardiologists prefer femoral access to RA access for complex procedures, such as chronic total occlusions (CTOs) and bifurcation lesions. Presently described is a case of CTO of the right coronary artery that was successfully treated with PCI via the left RA. This study demonstrates that if there is an indication for revascularization and the CTO lesions are short and without poor prognostic factors, an intervention for CTO should still be considered, even if there is no femoral access.",
"affiliations": "Department of Cardiology, Sivas Numune State Hospital, Sivas, Turkey.",
"authors": "Tatlisu|Mustafa Adem|MA|",
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"doi": "10.14744/nci.2017.20092",
"fulltext": "\n==== Front\nNorth Clin IstanbNorth Clin IstanbNorthern Clinics of Istanbul2536-4553Kare Publishing Turkey 30374486NCI-5-16010.14744/nci.2017.20092Case ReportSuccessful percutaneous coronary intervention for chronic total occlusion via the radial artery Tatlisu Mustafa Adem Department of Cardiology, Sivas Numune State Hospital, Sivas, TurkeyCorrespondence: Dr. Mustafa Adem TATLISU. Department of Cardiology, Sivas Numune State Hospital, Sivas, Turkey. Phone: +90 536 443 99 06 e-mail: ademtatlisu@gmail.com2018 27 3 2018 5 2 160 162 04 4 2017 05 8 2017 Copyright: © 2018 by Istanbul Northern Anatolian Association of Public Hospitals2018This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International LicenseOver the past decade, percutaneous coronary interventions (PCIs) performed via radial artery (RA) access have become popular among interventional cardiologists. Since the radial approach may limit the options in complex cases, most interventional cardiologists prefer femoral access to RA access for complex procedures, such as chronic total occlusions (CTOs) and bifurcation lesions. Presently described is a case of CTO of the right coronary artery that was successfully treated with PCI via the left RA. This study demonstrates that if there is an indication for revascularization and the CTO lesions are short and without poor prognostic factors, an intervention for CTO should still be considered, even if there is no femoral access.\n\nChronic total occlusionpercutaneous coronary interventiontransradial approach\n==== Body\nOver the past decades, percutaneous coronary interventions (PCIs) performed via the radial access (RA) have become popular among interventional cardiologists. In a meta-analysis of PCI studies performed via both RA and femoral access (FA) incorporating many of these studies, better outcomes were obtained with RA than with FA with respect to access site complications, bleeding, and death [1]. Because the radial approach may limit our options in complex cases, most interventional cardiologists prefer the transfemoral approach over the transradial approach for complex procedures such as those for chronic total occlusions (CTOs) and bifurcation lesions.\n\nHere we present a case of CTO of the right coronary artery (RCA) that was successfully treated with PCI via the left radial artery.\n\nCASE REPORT\nA 52-year-old man presented with shortness of breath and stable class III angina for 7 months despite treatment with acetylsalicylic acid (100 mg/day), clopidogrel (75 mg/day), metoprolol extended-release succinate (200 mg/day), extended-release isosorbide mononitrate (60 mg/day), modified-release trimetazidine (70 mg/day), telmisartan (80 mg/day), and rosuvastatin (40 mg/day). Six year ago, he underwent elective coronary stent placement for symptomatic 80% stenosis in mid-RCA. His second coronary angiogram was performed at 6 months previously because of an unstable angina. Angiogram revealed that the coronary stent in mid-RCA was completely occluded (Fig. 1A) with Rentrop grade II collaterals from the left anterior descending artery (Fig. 1B). PCI failed, and the patient was prescribed optimal anti-ischemic therapy that included isosorbide mononitrate and trimetazidine. The patient had a 10-year history of hypertension and a 2-year history of Leriche’s syndrome that was treated with aorta–iliac artery bypass. He had been smoking two packs of cigarettes daily for 32 years.\n\nFigure 1 (A) Coronary angiogram of the completely occluded right coronary artery. (B) Coronary angiogram showing Rentrop grade II collateral flow to the right coronary artery from the left ascending coronary artery\n\nElectrocardiogram of the patient did not reveal any recent ST-segment elevation myocardial infarction. The patient previously underwent myocardial perfusion single photon emission computed tomography, which revealed significant viability in the inferior, inferoseptal, and inferolateral walls. Left ventricular function was moderately diminished, with significant wall motion abnormality in the inferior, inferoseptal, and inferolateral walls and a calculated ejection fraction of 40%. Therefore, it was decided that the patient would benefit after undergoing PCI for CTO of RCA.\n\nBecause he previously underwent aorta–iliac artery bypass and impalpable right radial pulse, the only option for the procedure was antegrade wire escalation technique via the left radial artery using a 6-Fr right Judkins guiding catheter. The success rate with antegrade wiring and intimal tracking technique is high for short CTOs without proximal cap ambiguity. The Fielder XT®-tapered tip 0.009″ (Asahi Intecc Co. Ltd., Nagoya-shi, Aichi, Japan) failed to penetrate the hard and calcified proximal cap. However, the proximal CTO cap was eventually penetrated using the Asahi Confianza PROTM 12-tapered tip 0.009″ wire (Asahi Intecc Co. Ltd., Nagoya-shi, Aichi, Japan). After predilation using a 1.2-×15-mm balloon, the buddy wire technique with Fielder XT® was used to advance a wider and longer balloon through the lesion. Despite several predilations with 1.5-×20-mm, 2.5-×20-mm, and 3.0-×20-mm balloons, a satisfactory angiographic result was not observed (Fig. 2A). To achieve better results, the 3.0-×15-mm cutting balloon, which resulted in TIMI II flow (Fig. 2B). After an intracoronary injection of nitroglycerin (100 µg), two 3.0-×38-mm everolimus-eluting coronary stents (Promus ElementTM, Boston Scientific, Marlborough, MA, USA) were used in a telescopic manner to cover the previous stent. After dilation at 20 atm of pressure via a 3-×20-mm NC balloon, the result was satisfactory (Fig. 3). During follow-up, the symptoms and exercise capacity of the patients rapidly improved. During follow-up, isosorbide mononitrate and trimetazidine therapies were discontinued. He was advised to quit smoking; however, he continues to smoke. He is currently symptom free for 2.5 years (from July 2014 to March 2017).\n\nFigure 2 (A) Coronary angiogram of the right coronary artery flow before cutting balloon dilatation. (B) Coronary angiogram of the right coronary artery flow after cutting balloon dilatation.\n\nFigure 3 Coronary angiogram of the right coronary artery after two overriding coronary stents.\n\nDISCUSSION\nIdentification of anatomical features of procedural complexity may predict procedural success such as the presence of significant coronary calcium and vessel tortuosity [2]. Several factors are associated with poor procedural success, including the morphology of the proximal cap, presence of bridging collaterals, and length of occlusion [3]. Antegrade wire escalation with intimal tracking should be the preferred initial strategy for short CTOs without poor prognostic factors [4]. Retrograde or antegrade dissection re-entry approach should be reserved for more complex anatomies.\n\nPatients with CTO who remain symptomatic despite optimal medical therapy can be considered for revascularization [5]. In a meta-analysis of long-term clinical outcomes of patients who underwent PCI for CTO, successful PCIs for CTOs were associated with a lower risk for death, stroke, and coronary artery bypass grafting and less recurrent angina pectoris [6]. Most recent data showed that PCI may reduce the risk for cardiac mortality in patients without diabetes but not in patients with diabetes [7]. In light of current evidence, the initial decision regarding the mode of revascularization should be based on the symptoms and complexity of lesions.\n\nIn this case report, left RA was used to treating CTO owing to the lack of FA, which resulted in successful PCI. If there is an indication for revascularization and CTO lesions are short without poor prognostic factors, an intervention for CTO should be considered even if there is no FA.\n\nInformed Consent: Written informed consent was obtained from the patient who participated in this study.\n\nConflict of Interest: No conflict of interest was declared by the authors.\n\nFinancial Disclosure: The authors declared that this study has received no financial support.\n==== Refs\nREFERENCES\n1 Bertrand OF Bélisle P Joyal D Costerousse O Rao SV Jolly SS Comparison of transradial and femoral approaches for percutaneous coronary interventions: a systematic review and hierarchical Bayesian meta-analysis Am Heart J 2012 163 632 48 22520530 \n2 Morino Y Abe M Morimoto T Kimura T Hayashi Y Muramatsu T Predicting successful guidewire crossing through chronic total occlusion of native coronary lesions within 30 minutes: the J-CTO (Multicenter CTO Registry in Japan) score as a difficulty grading and time assessment tool JACC Cardiovasc Interv 2011 4 213 21 21349461 \n3 Muramatsu T Tsuchikane E Oikawa Y Otsuji S Fujita T Ochiai M Incidence and impact on midterm outcome of controlled subintimal tracking in patients with successful recanalisation of chronic total occlusions. J-PROCTOR registry EuroIntervention 2014 10 681 8 25330501 \n4 Wilson W Spratt JC Advances in procedural techniques--antegrade Curr Cardiol Rev 2014 10 127 44 24694104 \n5 Shah PB Management of coronary chronic total occlusion Circulation 2011 123 1780 4 21518991 \n6 Christakopoulos GE Christopoulos G Carlino M Jeroudi OM Roesle M Rangan BV Meta-analysis of clinical outcomes of patients who underwent percutaneous coronary interventions for chronic total occlusions Am J Cardiol 2015 115 1367 75 25784515 \n7 Choi KH Yang JH Song YB Hahn JY Choi JH Gwon HC Long-term clinical outcomes of patients with coronary chronic totalocclusion treated with percutaneous coronary intervention versusmedical therapy according to presence of diabetes mellitus EuroIntervention 2017 13 970 7 28169213\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "2536-4553",
"issue": "5(2)",
"journal": "Northern clinics of Istanbul",
"keywords": "Chronic total occlusion; percutaneous coronary intervention; transradial approach",
"medline_ta": "North Clin Istanb",
"mesh_terms": null,
"nlm_unique_id": "101684520",
"other_id": null,
"pages": "160-162",
"pmc": null,
"pmid": "30374486",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "22520530;28169213;21349461;25330501;21518991;25784515;24694104",
"title": "Successful percutaneous coronary intervention for chronic total occlusion via the radial artery.",
"title_normalized": "successful percutaneous coronary intervention for chronic total occlusion via the radial artery"
} | [
{
"companynumb": "TR-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2018-BI-031541",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ROSUVASTATIN"
},
... |
{
"abstract": "OBJECTIVE\nThe purpose of this study was to evaluate the effectiveness of CT assist for intraarterial chemotherapy in relation to the therapeutic outcomes of intraarterial chemoradiation for advanced head and neck cancer with extension across the anatomical midline (EAM).\n\n\nMETHODS\nThis retrospective study evaluated 64 consecutive patients. In total, 26 and 38 patients had cancer with or without EAM, respectively. These patients underwent an intraarterial cisplatin infusion (200 mg/m(2), days 1 and 35) and intravenous 5-FU infusion (800 mg/m(2), days 1-5 and 36-39) concomitantly with radiotherapy. Angiography-assisted CT was performed to confirm complete coverage during the intraarterial chemotherapy. The accuracy of diagnosing tumor vessels by digital subtraction angiography (DSA) was evaluated using receiver-operating characteristic analysis by two radiologists. The overall survival and locoregional control rates were calculated by the Kaplan-Meier method.\n\n\nRESULTS\nDSA was not useful for diagnosing tumor vessels. The 2-year overall survival rates for the patients with cancer with or without EAM were 83 and 90 %, while the 2-year locoregional control rates were 95 and 82 %, respectively. Locoregional control or the overall survival rates showed no significant differences.\n\n\nCONCLUSIONS\nIntraarterial chemotherapy using angiography-assisted CT during chemoradiation therapy can achieve comparable therapeutic outcomes for cancer with and without EAM.",
"affiliations": "Department of Radiology, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan.",
"authors": "Yunaiyama|Daisuke|D|;Saito|Kazuhiro|K|;Funatsu|Tomokazu|T|;Nakayama|Hidetsugu|H|;Shimizu|Akira|A|;Ito|Hiroyuki|H|;Suzuki|Mamoru|M|;Akata|Soichi|S|;Tokuuye|Koichi|K|",
"chemical_list": "D000970:Antineoplastic Agents; D002945:Cisplatin; D005472:Fluorouracil",
"country": "Japan",
"delete": false,
"doi": "10.1007/s11604-014-0370-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1867-1071",
"issue": "32(12)",
"journal": "Japanese journal of radiology",
"keywords": null,
"medline_ta": "Jpn J Radiol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015901:Angiography, Digital Subtraction; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D059248:Chemoradiotherapy; D002945:Cisplatin; D005260:Female; D005472:Fluorouracil; D006258:Head and Neck Neoplasms; D006801:Humans; D007261:Infusions, Intra-Arterial; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D015996:Survival Rate; D013813:Therapy, Computer-Assisted; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "101490689",
"other_id": null,
"pages": "708-15",
"pmc": null,
"pmid": "25380786",
"pubdate": "2014-12",
"publication_types": "D016428:Journal Article",
"references": "18972429;9226312;10768432;8703389;18642295;11002324;15162349;21167654;16958419;20378262;20187094;21927999;15468946;25249315;21843171;19111999;17885248",
"title": "Effectiveness of CT assists for intraarterial chemotherapy: therapeutic outcome of chemoradiation for advanced head and neck cancer extending across the anatomical midline.",
"title_normalized": "effectiveness of ct assists for intraarterial chemotherapy therapeutic outcome of chemoradiation for advanced head and neck cancer extending across the anatomical midline"
} | [
{
"companynumb": "JP-TEVA-541197ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
"drug... |
{
"abstract": "Ibuprofen was the first over-the-counter nonsteroidal anti-inflammatory drug available in the United States. Despite being a common agent of ingestion, significant toxicity in overdose is rare. We report a case of a massive ibuprofen ingestion who developed polyuria, acidosis, and coma but survived, despite having a serum ibuprofen concentration greater than previous fatal cases. A 19-year-old man ingested 90 g (1,200 mg/kg) ibuprofen. He was initially awake and alert, but his level of consciousness deteriorated over several hours. Seven hours following the ingestion, he was intubated and mechanically ventilated secondary to loss of airway reflexes. He developed a lactic acidosis and polyuria, which lasted for nearly 24 h. His serum creatinine peaked at 1.12 mg/dL. An ibuprofen level drawn 7 h postingestion was 739.2 mg/L (therapeutic 5-49 mg/L). We describe a case of a massive ibuprofen overdose characterized by metabolic acidosis, coma, and a state of high urine output who survived with aggressive supportive care. This case is unique in several ways. First, ibuprofen levels this high have only rarely been described. Second, polyuria is very poorly described following ibuprofen ingestions.",
"affiliations": "Department of Medical Toxicology, Banner Good Samaritan Medical Center, Phoenix, AZ, USA. Michael.Levine@bannerhealth.com",
"authors": "Levine|Michael|M|;Khurana|Amandeep|A|;Ruha|Anne-Michelle|AM|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D007052:Ibuprofen",
"country": "United States",
"delete": false,
"doi": "10.1007/s13181-010-0076-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-9039",
"issue": "6(3)",
"journal": "Journal of medical toxicology : official journal of the American College of Medical Toxicology",
"keywords": null,
"medline_ta": "J Med Toxicol",
"mesh_terms": "D000138:Acidosis; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003128:Coma; D006801:Humans; D007052:Ibuprofen; D008297:Male; D011141:Polyuria",
"nlm_unique_id": "101284598",
"other_id": null,
"pages": "315-7",
"pmc": null,
"pmid": "20419362",
"pubdate": "2010-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Polyuria, acidosis, and coma following massive ibuprofen ingestion.",
"title_normalized": "polyuria acidosis and coma following massive ibuprofen ingestion"
} | [
{
"companynumb": "US-PFIZER INC-2010118093",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": null,
... |
{
"abstract": "Mycobacterium tuberculosis infection in renal transplant recipients is associated with significant morbidity and mortality. Genitourinary tuberculosis is a less frequent presentation and a high level of suspicion is needed to avoid treatment delay. Management is challenging due to the interaction of calcineurin inhibitors with antituberculous medications and the known side effects of these drugs, with higher prevalence in this population. The authors present a case of a renal transplant recipient with urinary and constitutional symptoms whom is diagnosed with tuberculosis after a prostatic biopsy in an already disseminated stage and develops hepatotoxicity to antituberculous therapy.",
"affiliations": "Centro Hospitalar Lisboa Norte, Lisboa.;Universidade Federal de São Paulo.;Universidade Federal de São Paulo.;Universidade Federal de São Paulo.;Universidade Federal de São Paulo.",
"authors": "Rodrigues|Natacha Jardim|NJ|;Viana|Laila|L|;Mansur|Juliana B|JB|;Tedesco-Silva|Hélio|H|;Pestana|José Osmar Medina|JOM|",
"chemical_list": null,
"country": "Brazil",
"delete": false,
"doi": "10.5935/0101-2800.20170040",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0101-2800",
"issue": "39(2)",
"journal": "Jornal brasileiro de nefrologia : 'orgao oficial de Sociedades Brasileira e Latino-Americana de Nefrologia",
"keywords": null,
"medline_ta": "J Bras Nefrol",
"mesh_terms": "D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D014401:Tuberculosis, Urogenital",
"nlm_unique_id": "9426946",
"other_id": null,
"pages": "224-228",
"pmc": null,
"pmid": "29069249",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Genitourinary tuberculosis - a rare presentation of a still frequent infection in renal transplant recipients.",
"title_normalized": "genitourinary tuberculosis a rare presentation of a still frequent infection in renal transplant recipients"
} | [
{
"companynumb": "PT-SA-2018SA247764",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ISONIAZID"
},
"drugadditional": "1",
"drug... |
{
"abstract": "OBJECTIVE\nTo assess the efficacy and tolerability of bortezomib with dexamethasone for patients with renal light chain (AL) amyloidosis.\n\n\nMETHODS\nTwelve newly diagnosed patients with renal AL amyloidosis were treated with a combination of bortezomib (1.3mg/m(2)/d iv, d1, 4, 8, 11) and dexamethasone (20mg/d iv drip, d1-4).\n\n\nRESULTS\nMedian follow-up time was 22.5 months (range, 2.1-53.6). Ten patients were evaluable. Five out of 10 (50%) patients achieved complete hematologic responses (CHR), and totally 8/10 (80%) achieved hematologic responses (HR). Median time to hematologic response was 1 month. All patients who received HR had no hematologic progression during follow-up period. Five patients (50%) had kidney responses and the other 5 patients (50%) were stable. Median time to kidney response was 3 months. No patients presented renal progression during follow-up. One patient achieved PR after 4 cycles of VD and then received autologous peripheral blood stem cell transplantation. Two out of 10 evaluable patients without hematologic response had died with median overall survival of 8.2 months. Eight of them who had HR were alive with median follow-up time of 28.5 months. Infection (6/12) and fatigue (5/12) were the most frequent side effects. Three patients developed herpes zoster and had to discontinue therapy.\n\n\nCONCLUSIONS\nVD produces rapid, deep and durable hematological responses and renal responses in the majority of patients with newly diagnosed renal AL. It is well tolerated. This treatment may be a good option as first-line treatment for renal AL amyloidosis patients.",
"affiliations": "Department of Hematology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China. Electronic address: hbh_st@126.com.;Department of Hematology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China. Electronic address: 13719209240@163.com.;Department of Hematology, Zhongshan City People Hospital, Zhongshan 528403, China. Electronic address: doctorxu@163.com.;Department of Hematology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China. Electronic address: zcxzd@tom.com.;Department of Hematology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China. Electronic address: zhouzhh2013@163.com.;Department of Hematology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China. Electronic address: 13631484622@163.com.",
"authors": "Huang|B|B|;Li|J|J|;Xu|X|X|;Zheng|D|D|;Zhou|Z|Z|;Liu|J|J|",
"chemical_list": "D007147:Immunoglobulin Light Chains; D000069286:Bortezomib; D003907:Dexamethasone",
"country": "France",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0369-8114",
"issue": "63(1)",
"journal": "Pathologie-biologie",
"keywords": "Amylose rénale à chaînes légères; Bortezomib; Bortézomib; Dexamethasone; Dexaméthasone; Renal light chain amyloidosis",
"medline_ta": "Pathol Biol (Paris)",
"mesh_terms": "D000368:Aged; D000686:Amyloidosis; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069286:Bortezomib; D003907:Dexamethasone; D018450:Disease Progression; D005260:Female; D006801:Humans; D007147:Immunoglobulin Light Chains; D000075363:Immunoglobulin Light-chain Amyloidosis; D007674:Kidney Diseases; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "0265365",
"other_id": null,
"pages": "17-20",
"pmc": null,
"pmid": "25455933",
"pubdate": "2015-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Successful treatment of renal light chain (AL) amyloidosis with bortezomib and dexamethasone (VD).",
"title_normalized": "successful treatment of renal light chain al amyloidosis with bortezomib and dexamethasone vd"
} | [
{
"companynumb": "CN-TAKEDA-2016MPI008160",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OMEPRAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "Non-myeloablative haematopoietic progenitor cell transplantation (HPCT) from matched related donors (MRD) has been increasingly utilized in sickle cell disease (SCD). A total of 122 patients received 300 cGy of total body irradiation (TBI), alemtuzumab, unmanipulated filgrastim-mobilized peripheral blood HPC and sirolimus. The median follow-up was four years; median age at HPCT was 29 years. Median neutrophil and platelet engraftment occurred on day 22 and 19 respectively; 41 patients required no platelet transfusions. Overall and sickle-free survival at one and five years were 93% and 85% respectively. Age, sex, pre-HPCT sickle complications, ferritin and infused HPC numbers were similar between graft failure and engrafted patients. Mean donor myeloid chimaerism at one and five years post HPCT were 84% and 88%, and CD3 was 48% and 53% respectively. Two patients developed grade 1 and 2 skin graft-versus-host disease (GVHD) with no chronic GVHD. Median days of recipients taking immunosuppression were 489; 83% of engrafted patients have discontinued immunosuppression. Haemoglobin, haemolytic parameters and hepatic iron levels improved post HPCT. Pulmonary function testing, hepatic histology and neurovascular imaging remained stable, suggesting cessation of further sickle-related injury. Fourteen patients had children. In this largest group of adult SCD patients, this regimen was highly efficacious, well-tolerated despite compromised organ functions pre HPCT, and without clinically significant GVHD.",
"affiliations": "Division of Hematology & Hematopoietic Stem Cell Transplantation, Department of Oncology, King Abdulaziz Medical City, Riyadh, Saudi Arabia.;Division of Hematology & Hematopoietic Stem Cell Transplantation, Department of Oncology, King Abdulaziz Medical City, Riyadh, Saudi Arabia.;Office of Biostatistics Research, National Heart, Lung, and Blood Institute, Bethesda, MD, USA.;Division of Hematology & Hematopoietic Stem Cell Transplantation, Department of Oncology, King Abdulaziz Medical City, Riyadh, Saudi Arabia.;Division of Hematology/Oncology, University of Illinois Hospital and Health Science Systems, Chicago, IL, USA.;Division of Hematology/Oncology, University of Illinois Hospital and Health Science Systems, Chicago, IL, USA.;Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, Bethesda, MD, USA.;Division of Hematology/Oncology, University of Illinois Hospital and Health Science Systems, Chicago, IL, USA.;Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, Bethesda, MD, USA.",
"authors": "Alzahrani|Mohsen|M|;Damlaj|Moussab|M|;Jeffries|Neal|N|;Alahmari|Bader|B|;Singh|Avani|A|;Rondelli|Damiano|D|;Tisdale|John F|JF|;Saraf|Santosh L|SL|0000-0002-8584-4194;Hsieh|Matthew M|MM|0000-0002-3706-6615",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D006680:HLA Antigens; D007166:Immunosuppressive Agents; D000074323:Alemtuzumab; D020123:Sirolimus",
"country": "England",
"delete": false,
"doi": "10.1111/bjh.17311",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1048",
"issue": "192(4)",
"journal": "British journal of haematology",
"keywords": "alemtuzumab; allogeneic transplantation; matched related donor; sickle cell disease; sirolimus",
"medline_ta": "Br J Haematol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000074323:Alemtuzumab; D000755:Anemia, Sickle Cell; D000074322:Antineoplastic Agents, Immunological; D002648:Child; D005260:Female; D006084:Graft Rejection; D006085:Graft Survival; D006086:Graft vs Host Disease; D006680:HLA Antigens; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D020123:Sirolimus; D014019:Tissue Donors; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "761-768",
"pmc": null,
"pmid": "33534948",
"pubdate": "2021-02",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural",
"references": "14985486;28587497;26348889;21628400;30206116;19822218;32062672;28249145;30021096;32396620;28104703;20007560;31199090;26235444;31495699;26348869;20513116;27965196;17379852;28887325;6382010;31816036;11593326;30500440;8663884;29981283;27959701;16556694;25058217;8982148;31784240;30667500;8311167;26261241;22955919;28882446;31578191;16371922;31097628;30772511",
"title": "Non-myeloablative human leukocyte antigen-matched related donor transplantation in sickle cell disease: outcomes from three independent centres.",
"title_normalized": "non myeloablative human leukocyte antigen matched related donor transplantation in sickle cell disease outcomes from three independent centres"
} | [
{
"companynumb": "US-AMGEN-USASP2021022228",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SIROLIMUS"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nOnly moderate to severe Crohn's Disease (CD) patients without a satisfactory conventional therapy effect are eligible to get reimbursement from the National Health Insurance of Taiwan for using adalimumab. These are more stringent criteria than in many Western countries and Japan and Korea. We aim to explore the efficacy of using adalimumab in CD patients under such stringent criteria.\n\n\nMETHODS\nA retrospective analysis was conducted in nine medical centers in Taiwan and we collected the results of CD patients receiving adalimumab from Sep 2009 to Mar 2014. The clinical characteristics, response measured by CDAI (Crohn's Disease Activity Index), adverse events and survival status were recorded and analyzed. CR-70, CR-100, and CR-150 were defined as attaining a CDAI decrease of 70, 100 or 150 points compared with baseline.\n\n\nRESULTS\nA total of 103 CD patient records were used in this study. Sixty percent of these patients received combination therapy of adalimumab together with immunomodulators. CR-70 was 68.7%, 74.5% and 88.4% after week 4, 8 and 12 of treatment, respectively. The steroid-free rate, complications and survival were 47.6%, 9.7% and 99% of patients, respectively. In considering the mucosal healing, only 25% patients achieve mucosal healing after treatment for 6 to 12 months. Surgery was still needed in 16.5% of patients. Combination treatment of adalimumab with immunomodulators further decreased the level of CDAI at week 8 when compared with the monotherapy.\n\n\nCONCLUSIONS\nEven under the stringent criteria for using adalimumab, the response rate was comparable to those without stringent criteria.",
"affiliations": "Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei; Mackay Junior College of Medicine, Nursing and Management, Taipei; Mackay Medical College, New Taipei, Taiwan.;Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.;Division of Colon and Rectal Surgery, Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan.;Department of Internal Medicine, Medical College and Hospital, National Cheng-Kung University, Tainan, Taiwan.;Division of Gastroenterology, Chung Shan Medical University, Taichung, Taiwan.;Department of Gastroenterology, Kaohsiung Medical University, Kaohsiung, Taiwan.;Department of Gastroenterology, Changhua Christian Hospital, Changhua, Taiwan.;Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei; Department of Surgery, School of Medicine, National Yang-Ming University, Taipei, Taiwan.;Division of Gastroenterology, Department of Medicine, Show Chwan Memorial Hospital, Changhuan, Taiwan.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei; Mackay Junior College of Medicine, Nursing and Management, Taipei; Mackay Medical College, New Taipei, Taiwan.;Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei; Department of Surgery, School of Medicine, National Yang-Ming University, Taipei, Taiwan.;Department of Gastroenterology, Kaohsiung Medical University, Kaohsiung, Taiwan.;Department of Pediatrics, National Taiwan University, Taipei, Taiwan.;Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.;Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.",
"authors": "Chang|Chen-Wang|CW|;Wei|Shu-Chen|SC|;Chou|Jen-Wei|JW|;Hsu|Tzu-Chi|TC|;Chuang|Chiao-Hsiung|CH|;Lin|Ching-Pin|CP|;Hsu|Wen-Hung|WH|;Yen|Hsu-Heng|HH|;Lin|Jen-Kou|JK|;Fang|Yi-Jen|YJ|;Wang|Horng-Yuan|HY|;Lin|Hung-Hsin|HH|;Wu|Deng Cheng|DC|;Ni|Yen Hsuan|YH|;Wang|Cheng-Yi|CY|;Wong|Jau-Min|JM|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.5217/ir.2014.12.4.287",
"fulltext": "\n==== Front\nIntestinal ResIntestinal ResIRIntestinal Research1598-91002288-1956Korean Association for the Study of Intestinal Diseases 10.5217/ir.2014.12.4.287Original ArticleSafety and Efficacy of Adalimumab for Patients With Moderate to Severe Crohn's Disease: The Taiwan Society of Inflammatory Bowel Disease (TSIBD) Study Chang Chen-Wang 1Wei Shu-Chen 2Chou Jen-Wei 3Hsu Tzu-Chi 4Chuang Chiao-Hsiung 5Lin Ching-Pin 6Hsu Wen-Hung 7Yen Hsu-Heng 8Lin Jen-Kou 9Fang Yi-Jen 10Wang Horng-Yuan 1Lin Hung-Hsin 9Wu Deng Cheng 7Ni Yen Hsuan 11Wang Cheng-Yi 2Wong Jau-Min 21 Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei; Mackay Junior College of Medicine, Nursing and Management, Taipei; Mackay Medical College, New Taipei, Taiwan.2 Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.3 Division of Gastroenterology and Hepatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.4 Division of Colon and Rectal Surgery, Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan.5 Department of Internal Medicine, Medical College and Hospital, National Cheng-Kung University, Tainan, Taiwan.6 Division of Gastroenterology, Chung Shan Medical University, Taichung, Taiwan.7 Department of Gastroenterology, Kaohsiung Medical University, Kaohsiung, Taiwan.8 Department of Gastroenterology, Changhua Christian Hospital, Changhua, Taiwan.9 Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei; Department of Surgery, School of Medicine, National Yang-Ming University, Taipei, Taiwan.10 Division of Gastroenterology, Department of Medicine, Show Chwan Memorial Hospital, Changhuan, Taiwan.11 Department of Pediatrics, National Taiwan University, Taipei, Taiwan.Correspondence to Jau-Min Wong, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, No.7 Chung-Shan South Road, Taipei 101, Taiwan. Tel: +886-2-23123456 ext. 65768, Fax: +886-2-23947927, jmwong@ntu.edu.tw10 2014 27 10 2014 12 4 287 292 26 9 2014 10 10 2014 11 10 2014 © Copyright 2014. Korean Association for the Study of Intestinal Diseases. All rights reserved.2014This 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.Background/Aims\nOnly moderate to severe Crohn's Disease (CD) patients without a satisfactory conventional therapy effect are eligible to get reimbursement from the National Health Insurance of Taiwan for using adalimumab. These are more stringent criteria than in many Western countries and Japan and Korea. We aim to explore the efficacy of using adalimumab in CD patients under such stringent criteria.\n\nMethods\nA retrospective analysis was conducted in nine medical centers in Taiwan and we collected the results of CD patients receiving adalimumab from Sep 2009 to Mar 2014. The clinical characteristics, response measured by CDAI (Crohn's Disease Activity Index), adverse events and survival status were recorded and analyzed. CR-70, CR-100, and CR-150 were defined as attaining a CDAI decrease of 70, 100 or 150 points compared with baseline.\n\nResults\nA total of 103 CD patient records were used in this study. Sixty percent of these patients received combination therapy of adalimumab together with immunomodulators. CR-70 was 68.7%, 74.5% and 88.4% after week 4, 8 and 12 of treatment, respectively. The steroid-free rate, complications and survival were 47.6%, 9.7% and 99% of patients, respectively. In considering the mucosal healing, only 25% patients achieve mucosal healing after treatment for 6 to 12 months. Surgery was still needed in 16.5% of patients. Combination treatment of adalimumab with immunomodulators further decreased the level of CDAI at week 8 when compared with the monotherapy.\n\nConclusions\nEven under the stringent criteria for using adalimumab, the response rate was comparable to those without stringent criteria.\n\nCrohn diseaseAdalimumabEfficacySafety\n==== Body\nINTRODUCTION\nThe incidence and prevalence of IBD, which includes CD and UC, are lower in Asian countries than in Western countries. However, this has been recently changing.1 CD causes intestinal transmural inflammation, presenting with ulceration and can involve the entire gastrointestinal tract. Prolonged ulceration with inflammation and fibrosis without healing can lead to stricture or other complications.2,3 Therefore, mucosal healing is one of the important goals in treating CD. Treating the inflamed mucosa is associated with a decreased hospitalization risk and surgical resection. Current medications such as 5-aminosalicylic acid and other immunomodulators can relieve the symptoms, but usually do not achieve deep mucosal remission. On the other hand, tumor necrosis factor-alpha antibodies (Anti-TNF-α) have been found to be effective in treating both the symptoms and mucosal inflammations of CD.4\n\nAdalimumab (ADA), one of the available anti-TNF-α antibodies, is an effective therapy for inducing and maintaining remission of moderate to severe CD.5 In one retrospective analysis of 149 patients treated with ADA at a mean duration of 20 months, the results showed 45% anti-TNF-naïve patients and 32% anti-TNF-exposed patients achieved clinical remission. Fistulas healed in 19% and an improvement was seen in the additional 19% of the patients. Adverse events were also seen in 38% of patients, infection being the most common (20%). Mortality in CD patient due to ADA is rare (<1%).6\n\nIn Taiwan, dating back to 2008 and till 2014, ADA is the only one available biologics that could be used for CD patients. The criteria of ADA usage is more stringent than most of the other countries, such as Japan and Korea. So far, there was no published data about using ADA in moderate to severe CD patients in Asia. This study aims to evaluate the efficacy and adverse effects of using ADA for CD patients in Taiwan.\n\nMETHODS\n1. Patients\nCollaborating with the Taiwan Society of Inflammatory Bowel Disease (TSIBD), we conducted a retrospective analysis of 9 medical centers in Taiwan from Sep 2009 to Mar 2014. Moderate to severe CD patients who were treated with ADA were included and analyzed. Diagnosis of CD was based on clinical, radiological, and histological features. The clinical response and remission was measured by the standardized CDAI and clinical characteristics were collected and analyzed.\n\n2. Inclusion Criteria\nAccording to the guidelines from the National Health Insurance of Taiwan, reimbursement for ADA therapy depends on the following criteria: First of all, the diagnosis of CD has to be validated and the patient must be registered as having a catastrophic illness. Secondly, patients have received conventional therapies including 5-aminosalicylic acid, immunomodulators or steroids without having satisfactory results. Thirdly, the following medical criteria must be fulfilled: (1) Moderate to severe degree of CD (CDAI >250) despite conventional treatments; (2) Persistent abdominal fistula or anal fistula with symptoms despite medical or surgical treatments with CDAI >100.\n\n3. Definitions of the Efficacy and Safety\nThe response of ADA was recorded using the following definitions: (1) Steroid-free: taper and then discontinue of steroid use after introducing the ADA. (2) Mucosal healing: Crohn's disease endoscopic index of severity (CDEIS) <6, or no ulceration in the endoscopic finding. (3) CR-70: a decrease in CDAI of at least 70 points. CR-100: a decrease in CDAI of at least 100 points. CR-150: a decrease in CDAI of at least 150 points. Clinical remission was defined as CDAI <150 or healing of fistula. (4) Primary non-response 70 (PNR-70) was defined as not attaining a CDAI decrease of 70 points compared with baseline, primary non-response 100 (PNR-100) was defined as not attaining a CDAI decrease of 100 points compared with baseline, and primary non-response 150 (PNR-150) was defined as not attaining a CDAI decrease of 150 points compared with baseline at week 12 respectively. (5) Adverse events: an undesired harmful effect during ADA treatment.\n\nExtracted and analyzed data included demographics, remission and response rates with ADA, and the safety and efficacy of ADA.\n\n4. Statistical Analysis\nContinuous data was expressed as mean±SD and categorical data as percentages. Student's t-test was used for continuous variables and chi-square test for categorical variables. A value of P <0.05 was considered statistically significant. Regressions with a generalized linear model were also performed to assess the relationship between the level of CDAI-decrease and other parameters. The β-value and 95% CI were used to examine the potential relationships of the CDAI-decreased level and other parameters. All statistical analyses were conducted using SAS software, version 9.2 (SAS institute Inc., Cary, North Carolina, USA).\n\nRESULTS\nA total of 103 patients were enrolled from 9 medical centers. As shown in Table 1, about two thirds of the patients were male (66.9%). Their ages ranged from 16 to 86 years-old, with a mean±SD of 37.9±15.7 years-old. The duration of treatment ranged from 1 to 253 weeks, with the mean±SD of 74.6±59.1 weeks. Sixty percent of the patients received a combo therapy with ADA combined with azathioprine or methotrexate. The survival rate was 99% after the ADA treatment. For the Montreal classification, most patients were between 17 and 40 years-old (A2) (71.8%) with bowel stricturing (B2) (38.8%) located in the ileocolonic area (L3) (44.7%) (Table 1).\n\nAs shown in Fig. 1, the clinical response and remission after ADA treatment, was a CDAI (mean±SD) of 342.2±113.5, 201.3±77.2, 175.3±80.9 and 170.4±89.0 at weeks 0, 4, 8 and 12, respectively. The rates of CR-70 were 68.7%, 74.5% and 88.4% at weeks 4, 8 and 12, respectively. The rates of CR-100 were 61.2%, 68.6% and 79.7% at weeks 4, 8 and 12, respectively. In addition, the rates of CR-150 were 35.8%, 35.3% and 56.5% at weeks 4, 8 and 12, respectively (Fig. 2). After 12 weeks of treatment, 56.5% patients achieved clinical remission with the definition of CDAI <150 (Table 2).\n\n47.6% of the patients receiving ADA became steroid-free as far as treatment. Sixty eight patients underwent endoscopic evaluation for mucosal healing from 6 to 12 months after ADA treatment. Of these patients, 25% (17/68) patients had CDEIS <6 or no mucosal ulceration and 27.9% (19/68) patients had improved endoscopic findings but still had ulcers (partial healing). When we used the CR-70 at 12 weeks after treatment as a cut-off point for primary response, the PNR-70 was only 11.6%. However, if we used the CR-100 at 12 weeks after treatment, the PNR-100 increased to 20.3%. When we used the CR-150 at 12 weeks after treatment, the PNR-150 was as high as 43.5%. There were still 16.5% patients who underwent ADA treatment that needed surgical intervention, mostly due to the stenosis or perforation complications (Table 3).\n\nAbout 60% of the patients received the ADA and an immunomodulator as combo therapy. By using generalized linear regression models, we found that there was a significant difference in the CDAI-decreased level at week 8 when comparing the combo and monotherapy (using ADA alone) with the CDAI decreasing for the combo group by 158.5±114.2 and 101.0±75.6 for the monotherapy group (P =0.02) (Table 4).\n\nAdverse events were observed in 9.7% of the patients receiving ADA treatment. Six patients (6/103, 5.8%) had infections and one patient died of sepsis. Other associated adverse events such as intracranial hemorrhage (1/103), myofascial pain (1/103), palpitation (1/103) and a new onset right parotid pleomorphic adenoma (1/103) were also noted. No malignancies were found, so far, in these patients (Table 5). There was also no statistical difference between monotherapy and combo therapy (P =0.18, chi-square test) in adverse events.\n\nDISCUSSION\nThe safety and efficacy of ADA for CD have been extensively tested in Western countries, but much less so in Asian countries.3,6,7,8,9,10,11 In Japan, ADA was approved for CD treatment since 2010. Anti-TNF-α agents, such as infliximab (IFX) or ADA, are suggested for refractory cases, remission maintenance, prevention of postoperative relapse and anal lesions. Refractory cases are defined as steroid-resistant, steroid-dependent and cases that surgical treatment is a consideration.12 In Taiwan, as of September 2014, ADA is the only available anti-TNF-α antibody for CD patients. According to the guidelines from the National Health Insurance of Taiwan, the criteria for using ADA in CD are more stringent and limited to the moderate to severe CD with CDAI more than 250 and not responded to conventional therapy. Historically, IBD has been rare in the Far East, however, the incidence and prevalence of IBD are increasing now.13 This phenomenon was also found to be true in Taiwan.14 In Asia, Japan and Korea, so far, have the highest incidence and prevalence for IBD and they approved the use of anti-TNF antibodies similar to its use in western countries. The governments of these countries also support the treatment when IBD patients register and are in need of the antibody treatment. However, most other Asian countries do not provide such governmental support for IBD patients or only providing limited support. Therefore, balancing the cost and benefit of such a treatment is an important issue. Therefore, we set out to examine whether there is an added benefit of antibody treatment using the very stringent criteria used in Taiwan, compared with those countries using the anti-TNF antibody treatment without such stringent criteria.\n\nCDAI is a validated score for CD monitoring with a range from 0 to approximately 600. CDAI below 150 points is considered a reasonable non-active disease status. A CDAI score of 150-219 is defined as a mildly active disease and scores of 220-450 as moderately active disease. Finally, a severe degree is defined as a cut-off value of more than 450 points.15 In our study, the criteria of \"moderate to severe degree\" is even more stringent, which the CDAI was more than 250 points in order to get the reimbursement of ADA usage. In the Clinical Assessment of ADA Safety and Efficacy Studied as Induction Therapy in Crohn's Disease I (CLASS I) and the Crohn's Trial of the Fully Human Antibody ADA for Remission Maintenance (CHARM) studies, the CR-70 was 54-59% and 64.1% at week 4, respectively.16,17 Our result showed similar findings with 68.7% of the patients attaining CR-70 at week 4, and a better CR-70 at week 12 (88.4%) compared with the Extend the Safety and Efficacy of ADA Through Endoscopic Healing (EXTEND) trial (65-66%).4 As for the clinical remission rate, previous studies also had different results. In the EXTEND trial, the rates of remission were 52% and 28% at week 12 and week 52, respectively. In the CHARM study, the remission rates were 40% in the every other week ADA treatment group, and 47% in the group of weekly ADA treatment, respectively, at week 26.17 Our results showed that 56.5% patients had clinical remission at week 12. For comparing the combo or monotherapy, we found that ADA with concomitant azathioprine was significantly more effective for decreasing the CDAI level after treatment, which was consistent to the previous report.18 In considering the side effects, there's no statistically difference between the combo and monotherapy group (12.9%, 4.9%, respectively; P =0.18).\n\nBecoming steroid-free is another aim in treating CD patients. According to our results, 47.6% patients achieved steroid-free disease management. A previous study showed similar findings with a 44.4% steroid-free rate during anti-TNF-α (IFX) treatment.19 Mucosal healing is the current goal of treating CD patients to reduce the need for hospitalizations and surgery.7 In our study, the mucosal healing rate was 25% after 6-12 months treatment, which is similar to the EXTEND trial of 27% at week 12.4 In a previous report, when using anti-TNF treatment (ADA 74, IFX 109) in CD patients with the median treatment duration as 23 months, 43% patient case had achieved deep mucosal healing.20 Our results showed that most of our patients did not achieve deep mucosal healing after 6-12 months treatment, it implies that longer treatment is needed to help improve the mucosal healing rate, especially when treating the moderate to severe CD patients.\n\nAdverse events of ADA are another important issue for treating CD patients. From the EXTEND trial, adverse events and serious adverse events were noted in 42.2% and 6.3% of the patients.7 Serious infections developed during IFX treatment for CD was noted in 4.9% of the patients.19 Our study also showed that the adverse events rate is 9.7%, which were mostly infections (5.8%). In CHARM trial, there were 3 cases (0.2%) with active tuberculosis (TB) during treatment.21 Two cases of TB (1.9%) were also noted during treatment in our study. One was de novo TB and the other as latent TB, both received anti-TB treatment consequently.\n\nThere were limitations of our study. First, this is a retrospective study with missing data. Therefore, how was the proportion of patients with perianal lesions, how many patients were under steroid before they used the ADA were not able to be known from this study. Second, since there was no universal protocol of endoscopic evaluation for mucosal healing, we could only have the endoscopic results as a range of 6 to 12 months for evaluating the mucosa healing rate.\n\nIn summary, our results have demonstrated that even using more stringent criteria for choosing CD patients to treat with anti-TNF-α, the efficacy is comparable to those not under such stringent criteria. We also observed similar rates of adverse effects. However, more than one year of anti-TNF treatment might be needed to increase the deep mucosal healing rate for CD patients.\n\nFinancial support: None.\n\nConflict of interest: None.\n\nFig. 1 Levels of CDAI at week 0, week 4, week 8 and week 12 of CD patients receiving adalimumab treatment.\n\nFig. 2 The percentages of CR-70, CR-100 and CR-150 at week 4, week 8 and week 12. CR-70, decrease in CDAI of at least 70 points; CR-100, decrease in CDAI of at least 100 points; CR-150, decrease in CDAI of at least 150 points.\n\nTable 1 Demographics of the Study Patients\n\nValues are presented as mean±SD or n (%).\n\n*Combination with azathioprine or methotrexate.\n\nTable 2 The Decrease of CDAI Compared With Baseline at Week 4, 8 and 12\n\nValuses are presented as mean±SD or % (n).\n\n*There were 6 patients who received adalimumab due to persistent abdominal fistula and the baseline CDAI <150.\n\nCR-70, decrease in CDAI of at least 70 points; CR-100, decrease in CDAI of at least 100 points; CR-150, decrease in CDAI of at least 150 points.\n\nTable 3 Efficacy of Adalimumab (n=103)\n\n*The definition of clinical remission is CDAI <150 points.\n\n†PNR-70 (primary non-response): did not attain a CDAI decrease of 70 points compared with baseline.\n\nCDEIS, Crohn's disease endoscopic index of severity.\n\nTable 4 The Relationship Between CDAI-Decrease Levels (Week 4, 8 and 12) and Parameters*\n\n*Data was analyzed with generalized linear regression models.\n\n†Combination of azathioprine/methotrexate and adalimumab.\n\nTable 5 Adverse Events During Adalimumab Treatment (n=103)\n\n*Two bacterial infections, 2 tuberculosis and 2 herpes zoster infections. In addition, one patient died due to sepsis.\n==== Refs\n1 Sung JJ Kamm MA Marteau P Asian perspectives in the management of inflammatory bowel disease: findings from a recent survey J Gastroenterol Hepatol 2010 25 183 193 19929931 \n2 Rieder F Fiocchi C Intestinal fibrosis in inflammatory bowel disease - current knowledge and future perspectives J Crohns Colitis 2008 2 279 290 21172225 \n3 Tursi A Elisei W Picchio M Effectiveness and safety of infliximab and adalimumab for ambulatory Crohn's disease patients in primary gastroenterology centres Eur J Intern Med 2014 25 485 490 24631020 \n4 Rutgeerts P Van Assche G Sandborn WJ Adalimumab induces and maintains mucosal healing in patients with Crohn's disease: data from the EXTEND trial Gastroenterology 2012 142 1102 1111 22326435 \n5 Peters CP Eshuis EJ Toxopeus FM Adalimumab for Crohn's disease: long-term sustained benefit in a population-based cohort of 438 patients J Crohns Colitis 2014 8 866 875 24491515 \n6 Teriaky A Gregor J Yan B Ponich T Chande N Mosli M The safety and efficacy of adalimumab in patients with Crohn's disease: the experience of a single Canadian tertiary care centre Scand J Gastroenterol 2014 49 280 286 24329040 \n7 Asgharpour A Cheng J Bickston SJ Adalimumab treatment in Crohn's disease: an overview of long-term efficacy and safety in light of the EXTEND trial Clin Exp Gastroenterol 2013 6 153 160 24039442 \n8 Zorzi F Zuzzi S Onali S Efficacy and safety of infliximab and adalimumab in Crohn's disease: a single centre study Aliment Pharmacol Ther 2012 35 1397 1407 22519466 \n9 Lichtenstein GR Panaccione R Mallarkey G Efficacy and safety of adalimumab in Crohn's disease Therap Adv Gastroenterol 2008 1 43 50 \n10 Seiderer J Brand S Dambacher J Adalimumab in patients with Crohn's disease--safety and efficacy in an open-label single centre study Aliment Pharmacol Ther 2007 25 787 796 17373917 \n11 Hinojosa J Gomollon F Garcia S Efficacy and safety of short-term adalimumab treatment in patients with active Crohn's disease who lost response or showed intolerance to infliximab: a prospective, open-label, multicentre trial Aliment Pharmacol Ther 2007 25 409 418 17269996 \n12 Ueno F Matsui T Matsumoto T Matsuoka K Watanabe M Hibi T Evidence-based clinical practice guidelines for Crohn's disease, integrated with formal consensus of experts in Japan J Gastroenterol 2013 48 31 72 23090001 \n13 Thia KT Loftus EV Jr Sandborn WJ Yang SK An update on the epidemiology of inflammatory bowel disease in Asia Am J Gastroenterol 2008 103 3167 3182 19086963 \n14 Wei SC Lin MH Tung CC A nationwide population-based study of the inflammatory bowel diseases between 1998 and 2008 in Taiwan BMC Gastroenterol 2013 13 166 24314308 \n15 Sostegni R Daperno M Scaglione N Lavagna A Rocca R Pera A Review article: Crohn's disease: monitoring disease activity Aliment Pharmacol Ther 2003 17 Suppl 2 11 17 12786607 \n16 Hanauer SB Sandborn WJ Rutgeerts P Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial Gastroenterology 2006 130 323 333 16472588 \n17 Colombel JF Sandborn WJ Rutgeerts P Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial Gastroenterology 2007 132 52 65 17241859 \n18 Ishida K Inoue T Fujiwara K Clinical effects of adalimumab treatment with concomitant azathioprine in Japanese Crohn's disease patients World J Gastroenterol 2013 19 2676 2682 23674875 \n19 Colombel JF Sandborn WJ Reinisch W Infliximab, azathioprine, or combination therapy for Crohn's disease N Engl J Med 2010 362 1383 1395 20393175 \n20 Molander P Sipponen T Kemppainen H Achievement of deep remission during scheduled maintenance therapy with TNFα-blocking agents in IBD J Crohns Colitis 2013 7 730 735 23182163 \n21 Panaccione R Colombel JF Sandborn WJ Adalimumab maintains remission of Crohn's disease after up to 4 years of treatment: data from CHARM and ADHERE Aliment Pharmacol Ther 2013 38 1236 1247 24134498\n\n",
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"keywords": "Adalimumab; Crohn disease; Efficacy; Safety",
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"title": "Safety and Efficacy of Adalimumab for Patients With Moderate to Severe Crohn's Disease: The Taiwan Society of Inflammatory Bowel Disease (TSIBD) Study.",
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"abstract": "Inflammatory bowel diseases (IBDs) are a public health issue with over 3.5 million patients in Europe, but the advent of several biologic agents has completely changed their management. Pharmacovigilance is needed to early detect expected/unexpected adverse events (AEs) to assess the safety of drugs in a real-world setting. Aim of this prospective pharmacovigilance study was to evaluate the occurrence of AEs in patients treated with biologic drugs in gastroenterology units in Southern Italy.\n\n\n\nAll consecutive patients treated with one biologic drug during a 2-years period (2017-2018) in six gastroenterology tertiary units and satisfying inclusion criteria were enrolled. Demographic and clinical characteristics of patients, type of treatment used, therapy discontinuation, failures, switch/swap to another biologic, and possible onset of AEs were collected. Adverse events have been compared to the number of AEs reported in the same centres in the two years before the protocol.\n\n\n\nOverall, 623 patients (253 females) with Crohn's disease (352; 56.5%) or ulcerative colitis (271; 43.5%) have been included. Infliximab (IFX) was the most commonly used (308, 49.4%), followed by adalimumab (ADA; 215, 34.5%), vedolizumab (VED; 73, 11.7%), golimumab (GOL; 26, 4.2%) and ustekinumab (UST; 0.2%). Ninety-two patients have experienced AEs (14.8%) and 10 serious adverse events (SAEs) (1.6%) were recorded. Adverse events and SAEs have been reported with GOL (7/26; p = .88), IFX (51/308; p = .54), ADA (28/125; p = .40) and VED (6/73; p = .11), no AEs occurred with UST (0/1).\n\n\n\nOverall, considering the low rate of AEs reported and discontinuation from therapy, our data seems to confirm the positive beneficial/risk ratio of biologic treatment for IBDs and provide useful data on biologic drugs in gastroenterology.",
"affiliations": "Science of Health Department, School of Medicine, University of Catanzaro, Catanzaro, Italy.;Science of Health Department, School of Medicine, University of Catanzaro, Catanzaro, Italy.;Science of Health Department, School of Medicine, University of Catanzaro, Catanzaro, Italy.;Science of Health Department, School of Medicine, University of Catanzaro, Catanzaro, Italy.;Department of Clinical and Experimental Medicine, University of Catanzaro, Catanzaro, Italy.;Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.;Science of Health Department, School of Medicine, University of Catanzaro, Catanzaro, Italy.;Science of Health Department, School of Medicine, University of Catanzaro, Catanzaro, Italy.;Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.;Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.;Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.;Science of Health Department, School of Medicine, University of Catanzaro, Catanzaro, Italy.;Science of Health Department, School of Medicine, University of Catanzaro, Catanzaro, Italy.;UOC Pharmacy, \"Mater Domini\" Hospital, Catanzaro, Italy.;Science of Health Department, School of Medicine, University of Catanzaro, Catanzaro, Italy.;Science of Health Department, School of Medicine, University of Catanzaro, Catanzaro, Italy.;Science of Health Department, School of Medicine, University of Catanzaro, Catanzaro, Italy.;Science of Health Department, School of Medicine, University of Catanzaro, Catanzaro, Italy.;Science of Health Department, School of Medicine, University of Catanzaro, Catanzaro, Italy.;Division of Gastroenterology, \"Ciaccio-Pugliese\" Hospital, Catanzaro, Italy.;Department of Clinical and Experimental Medicine, University of Catanzaro, Catanzaro, Italy.;Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.;Science of Health Department, School of Medicine, University of Catanzaro, Catanzaro, Italy.;Science of Health Department, School of Medicine, University of Catanzaro, Catanzaro, Italy.",
"authors": "Roberti|Roberta|R|;Iannone|Luigi Francesco|LF|;Palleria|Caterina|C|;De Sarro|Caterina|C|;Spagnuolo|Rocco|R|0000-0002-0871-4644;Barbieri|Maria Antonietta|MA|;Vero|Ada|A|;Manti|Antonia|A|;Pisana|Valentina|V|;Fries|Walter|W|;Trifirò|Gianluca|G|;Naturale|Maria Diana|MD|;Larussa|Tiziana|T|;De Francesco|Adele Emanuela|AE|;Bosco|Vincenzo|V|;Donato di Paola|Eugenio|E|;Citraro|Rita|R|;Luzza|Francesco|F|;Bennardo|Luigi|L|;Rodinò|Stefano|S|;Doldo|Patrizia|P|;Spina|Edoardo|E|;Russo|Emilio|E|0000-0002-1279-8123;De Sarro|Giovambattista|G|",
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"doi": "10.1080/03007995.2020.1786681",
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"issue": "36(9)",
"journal": "Current medical research and opinion",
"keywords": "Adverse events; biologics; inflammatory bowel diseases; pharmacovigilance",
"medline_ta": "Curr Med Res Opin",
"mesh_terms": "D000328:Adult; D001685:Biological Factors; D005260:Female; D006801:Humans; D015212:Inflammatory Bowel Diseases; D008297:Male; D008875:Middle Aged; D060735:Pharmacovigilance; D011446:Prospective Studies",
"nlm_unique_id": "0351014",
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"pages": "1457-1463",
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"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Safety profiles of biologic agents for inflammatory bowel diseases: a prospective pharmacovigilance study in Southern Italy.",
"title_normalized": "safety profiles of biologic agents for inflammatory bowel diseases a prospective pharmacovigilance study in southern italy"
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"abstract": "BACKGROUND\nTAFRO syndrome, which was first reported in 2010 in Japan, is a relatively rare disease characterized by thrombocytopenia, anasarca, fever, renal impairment, reticulin fibrosis, and organomegaly. Although this disease is considered similar to multicentric Castleman disease, some of the clinical features, such as thrombocytopenia, are different from typical cases of multicentric Castleman disease. In addition, the etiology of TAFRO syndrome remains unknown and controversial. There have only been a few cases of TAFRO syndrome complicated with adrenal gland lesions, and all of them have had hemorrhagic involvement.\n\n\nMETHODS\nThis report describes the case of a 46-year-old Asian man who presented with fever, epigastric pain, and back pain for 1 month. A computed tomographic scan revealed ascites, mild lymphadenopathy, and left adrenal necrosis without hemorrhage. A blood test showed thrombocytopenia, anemia, and elevated C-reactive protein, alkaline phosphatase, and creatinine levels. Based on the edema, severe thrombocytopenia, fever, reticulin myelofibrosis shown by bone marrow biopsy, mild lymphadenopathy, and progressive renal insufficiency, we diagnosed this patient as having TAFRO syndrome. He was successfully treated by immediate administration of glucocorticoids and tocilizumab.\n\n\nCONCLUSIONS\nThere have been no previous reports of a case of TAFRO syndrome complicated with adrenal necrosis. Because the biopsy of the left adrenal gland revealed necrosis without any evidence of hemorrhage, we concluded that the unilateral adrenal necrosis in this case was caused by either ischemia from infarction or organomegaly itself under severe hypercytokinemia. This unusual clinical course is useful for further analysis of the etiology of TAFRO syndrome.",
"affiliations": "Department of Internal Medicine, Musashino Red Cross Hospital, 1-26-1, Kyonancho, Musashino-shi, Tokyo, 1808610, Japan. yuwara2323@gmail.com.;Department of Rheumatology and Collagen Disease, Musashino Red Cross Hospital, Tokyo, Japan.;Department of Rheumatology and Collagen Disease, Musashino Red Cross Hospital, Tokyo, Japan.;Department of General Internal Medicine, Musashino Red Cross Hospital, Tokyo, Japan.",
"authors": "Fujiwara|Yu|Y|http://orcid.org/0000-0003-1406-2352;Ito|Kanae|K|;Takamura|Akito|A|;Nagata|Kaoru|K|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D005938:Glucocorticoids; D007155:Immunologic Factors; D012155:Reticulin; C502936:tocilizumab",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-018-1814-9",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 181410.1186/s13256-018-1814-9Case ReportThe first case of thrombocytopenia, anasarca, fever, renal impairment or reticulin fibrosis, and organomegaly (TAFRO) syndrome with unilateral adrenal necrosis: a case report http://orcid.org/0000-0003-1406-2352Fujiwara Yu yuwara2323@gmail.com 1Ito Kanae kanae20062003@yahoo.co.jp 2Takamura Akito takamura.rheu@musashino.jrc.or.jp 2Nagata Kaoru nagata@musashino.jrc.or.jp 31 0000 0000 9887 307Xgrid.416332.1Department of Internal Medicine, Musashino Red Cross Hospital, 1-26-1, Kyonancho, Musashino-shi, Tokyo, 1808610 Japan 2 0000 0000 9887 307Xgrid.416332.1Department of Rheumatology and Collagen Disease, Musashino Red Cross Hospital, Tokyo, Japan 3 0000 0000 9887 307Xgrid.416332.1Department of General Internal Medicine, Musashino Red Cross Hospital, Tokyo, Japan 8 10 2018 8 10 2018 2018 12 29530 4 2018 23 8 2018 © The Author(s). 2018Open 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\nTAFRO syndrome, which was first reported in 2010 in Japan, is a relatively rare disease characterized by thrombocytopenia, anasarca, fever, renal impairment, reticulin fibrosis, and organomegaly. Although this disease is considered similar to multicentric Castleman disease, some of the clinical features, such as thrombocytopenia, are different from typical cases of multicentric Castleman disease. In addition, the etiology of TAFRO syndrome remains unknown and controversial. There have only been a few cases of TAFRO syndrome complicated with adrenal gland lesions, and all of them have had hemorrhagic involvement.\n\nCase presentation\nThis report describes the case of a 46-year-old Asian man who presented with fever, epigastric pain, and back pain for 1 month. A computed tomographic scan revealed ascites, mild lymphadenopathy, and left adrenal necrosis without hemorrhage. A blood test showed thrombocytopenia, anemia, and elevated C-reactive protein, alkaline phosphatase, and creatinine levels. Based on the edema, severe thrombocytopenia, fever, reticulin myelofibrosis shown by bone marrow biopsy, mild lymphadenopathy, and progressive renal insufficiency, we diagnosed this patient as having TAFRO syndrome. He was successfully treated by immediate administration of glucocorticoids and tocilizumab.\n\nConclusions\nThere have been no previous reports of a case of TAFRO syndrome complicated with adrenal necrosis. Because the biopsy of the left adrenal gland revealed necrosis without any evidence of hemorrhage, we concluded that the unilateral adrenal necrosis in this case was caused by either ischemia from infarction or organomegaly itself under severe hypercytokinemia. This unusual clinical course is useful for further analysis of the etiology of TAFRO syndrome.\n\nKeywords\nTAFRO syndromeCastleman diseaseAdrenal necrosisTocilizumabissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nTAFRO syndrome (thrombocytopenia, anasarca, fever, renal impairment or reticulin fibrosis, and organomegaly) was first reported by Takai et al. in 2010 [1], and several cases have since been reported, mainly in Japan, but also in other countries. At first, TAFRO syndrome was thought to be a subtype of human herpesvirus 8 (HHV-8)-negative idiopathic multicentric Castleman disease (iMCD), but Iwaki et al. recently reported that the pathophysiology of TAFRO syndrome seemed to differ from that of iMCD [2]. Along with increasing case reports, the diagnosis criteria and treatment guidelines, as well as the concept of this disease, have been established gradually [2, 3]. In terms of organ damage, the kidneys are commonly involved, and temporal hemodialysis is required in some cases [2]. Notably, there have only been a few cases of TAFRO syndrome complicated with adrenal lesions, and all of them have had hemorrhagic involvement [4, 5]. No cases accompanied by adrenal gland necrosis without hemorrhage have yet been reported.\n\nThis is the first case of TAFRO syndrome complicated with unilateral adrenal necrosis proven pathologically. Our findings reveal the possibility of ischemic involvement with this unusual unilateral adrenal necrosis. Because the etiology of TAFRO syndrome is still unclear and controversial, further analysis is necessary to understand the clinicopathology of this disease, and this case will be beneficial for investigations into the pathophysiology of TAFRO syndrome.\n\nCase presentation\nA 46-year-old Asian man without any significant past medical history presented to an out-patient clinic complaining of fever, epigastric pain, and back pain. He was diagnosed as having gastric ulcer by upper gastrointestinal endoscopy and prescribed a proton pomp inhibitor; however, his fever of approximately 38 °C and his back pain remained. Two weeks later, his back pain had worsened, and the laboratory data of the out-patient clinic showed an elevated C-reactive protein level (17.2 mg/dL); thus, he came to our hospital for further evaluation. His medication included only orally administered azelnidipine for hypertension. There was no significant family medical history. He denied smoking tobacco, alcohol consumption, and exposure to toxins. He worked at a ceremonial hall without any ill contacts. He had a fever of 37.9 °C, heart rate of 90 beats per minute (bpm), respiratory rate of 20 breaths/minute, blood pressure of 126/78 mmHg, and oxygen saturation of 97% on room air. A physical examination including a neurological examination showed a well man without any specific abnormal findings. Blood tests at the first encounter revealed a white blood cell count of 10,300/μL with 70% neutrophils, 14% lymphocytes, and 16% monocytes, and the platelet count was 275,000/μL. His lactate dehydrogenase level was 299 IU/L (normal range, 119–229 IU/L), his alkaline phosphatase level was 983 U/L (normal range, 103–335 U/L), and his gamma-glutamyl transpeptidase level was 256 IU/L (normal range, 0–73 IU/L). His C-reactive protein level was 23.47 mg/dL (normal range, 0–0.29 mg/dL). Other results are shown in Table 1. A contrasted computed tomography (CT) scan showed edema around his gallbladder without gallstones or bile duct dilation, along with left adrenal enlargement without contrast, suggesting necrosis and slight pleural effusion (Fig. 1). His right adrenal gland was contrasted normally. Contrasted magnetic resonance imaging (MRI) of his adrenal glands was also performed, and the results showed necrosis of his left adrenal gland with a slight possibility of infarction and no specific evidence of hemorrhage. He was hospitalized for further investigation into the cause of the unilateral adrenal necrosis.Table 1 Laboratory data at first hospitalization and rehospitalization\n\nHospitalization\t1st\t2nd\t\t\nComplete blood cell\t\n WBC\t10300\t11200\t/μL\t\n Neutro\t70.0\t71.0\t%\t\n Lympho\t14.0\t16.0\t%\t\n Mono\t16.0\t13.0\t%\t\n RBC\t531\t517\t104/μL\t\n Hgb\t14.7\t14.0\tg/dL\t\n PLT\t275000\t5000\t/μL\t\nImmunochemistry\t\n CRP\t23.5\t31.9\tmg/dL\t\n Anti-SS-A Ab\t\t113\tU/mL\t\n Anti-dsDNA Ab\t\tNegative\t\t\n ANA Speckled\t1:80\t\t\t\n Cytoplasm\t1:40\t\t\t\n PR3-ANCA\t\t< 1.0\t\t\n MPO-ANCA\t\t< 1.0\t\t\n PAIgG\t\t1310\tng/107cell\t\n IgG\t1514\t1497\tmg/dL\t\n IgA\t226.1\t194.6\tmg/dL\t\n IgM\t115.9\t79.6\tmg/dL\t\n IgG4\t\t73.6\tmg/dL\t\n C3\t170.9\t133.2\tmg/dL\t\n C4\t35.7\t25.7\tmg/dL\t\n CH50\t47.0\t47.2\tmg/dL\t\n ADAMTS-13\t\t61\t%\t\n AMA M2\t19\t\t\t\nBiochemistry\t\n TP\t6.8\t6.0\tg/dL\t\n Alb\t2.7\t2.1\tg/dL\t\n LDH\t299\t347\tIU/L\t\n T-Bil\t0.3\t0.6\tmg/dL\t\n AST\t26\t36\tU/L\t\n ALT\t25\t37\tU/L\t\n ALP\t983\t1410\tU/L\t\n γGTP\t256\t247\tU/L\t\n BUN\t10.5\t16.3\tmg/dL\t\n Cr\t0.85\t1.03\tmg/dL\t\n Na\t140\t140\tmEq/L\t\n K\t4.5\t4.1\tmEq/L\t\n Cl\t106\t107\tmEq/L\t\n eGFR\t77.2\t62.6\tmL/min/L\t\nCoagulation test\t\n PT-INR\t1.19\t1.26\t\t\n APTT\t43.0\t47.6\tsecond\t\n Fibrinogen\t> 600\t> 600\tmg/dL\t\n FDP\t\t28.3\tμg/mL\t\n D-Dimer\t5.1\t8.3\tμg/mL\t\n AT-III\t63\t69\t%\t\n Anti-β2GPI Ab\t< 1.2\t< 1.2\t\t\n LAC (dRVVT)\t1.16\t1.33\t\t\n Coombs test\t\tNegative\t\t\nAb antibody, ADAMTS-13 a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13, Alb albumin, ALP alkaline phosphatase, ALT alanine aminotransferase, AMA antimitochondrial antibody, ANA antinuclear antibody, APTT activated partial thromboplastin time, AST aspartate aminotransferase, AT-IIIantithrombin III, BUN blood urea nitrogen, CH50 50% complement hemolytic unit, Cr creatinine, CRP C-reactive protein, dRVVT diluted Russell’s viper venom time, ds-DNA double-stranded DNA, eGFR estimated glomerular filtration rate, FDP fibrinogen degradation products, Hgb hemoglobin, LAC lupus anticoagulant, LDH lactate dehydrogenase, Lympho lymphocytes, Mono monocytes, MPO-ANCA myeloperoxidase-ANCA, Neutro neutrocyte, PAIgG platelet-associated immunoglobulin G, PLT platelet, PR-3 ANCA proteinase-3 anti-neutrophil cytoplasmic antibody, PT-INR prothrombin time-international ratio, RBC red blood cell, SS-A Sjögren syndrome-A, T-Bil total bilirubin, TP total protein, WBC white blood cell, β2GPI beta-2-glycoprotein I, γGTP γ-glutamyl transpeptidase\n\nFig. 1 The images of the first contrasted computed tomography scan. a Edema around the gallbladder. b Ascites. c Left adrenal gland without the contrast effect (arrow). Organomegaly including hepatosplenomegaly and lymphadenopathy is not seen here\n\n\n\nLupus anticoagulant and don't break the value complex antibody were measured, and both were negative, which suggested a low possibility of antiphospholipid syndrome. He did not meet the criteria for diagnosis of systemic lupus erythematosus. We considered the possibility of adrenal insufficiency or pheochromocytoma and measured several types of adrenal hormones, such as serum cortisol, adrenocorticotropic hormone, plasma renin activity, plasma aldosterone activity, and urinary metanephrine and normetanephrine, but none of them explained our patient’s condition. The culture results from blood drawn at the first encounter were all negative. We performed CT-guided needle biopsy of his left adrenal gland, which revealed necrosis and the formation of fibrotic granulomatous tissue (Fig. 2). There was no epithelioid granuloma, malignant lymphoma cells, or hemosiderin deposition, suggesting a low possibility of the involvement of a hemorrhagic etiology. The bacterial culture of this biopsy tissue was also negative. After the biopsy was finished, he was discharged. However, 1 week later, severe thrombocytopenia (5000/μL) appeared, and he was rehospitalized. His creatinine level had increased to 1.03 mg/dL from the initial value of 0.85 mg/dL. Bone marrow aspiration first resulted in a dry tap, but subsequent results showed increased megakaryocytes and hypercellular marrow with fibrosis classified as MF-1 according to the European consensus on bone marrow fibrosis staging (Fig. 3). A contrasted CT scan showed new left axillary lymphadenopathy with a size of 15 mm, right pleural effusion, and increased ascites (Fig. 4). Because our patient’s condition was worsening, we needed to start immediate treatment for any possible underlying causes, including bacterial infection and autoimmune disease, before obtaining the exact diagnosis. The laboratory data from the second hospitalization are shown in Table 1. The clinical course of this case is shown in Fig. 5. The initial treatment included ampicillin/sulbactam and a methylprednisolone pulse followed by orally administered prednisolone and intravenous immunoglobulin therapy (400 mg/kg for 5 days), considering the underlying causes mentioned above, such as severe bacterial infection or autoimmune diseases including antiphospholipid syndrome and immune thrombocytopenia; however, all of these treatments seemed to be ineffective. We also used recombinant thrombomodulin (380 U/kg) for 7 days to cope with the possibility of a thrombotic event or disseminated intravascular coagulation. Because the blood and adrenal gland biopsy culture results were both negative, we stopped the antibiotic treatment. On hospital day 9, we performed a left axillary lymph node needle biopsy, which showed no evidence of malignant lymphoma. With the edema, severe thrombocytopenia, fever above 37.5 °C, reticulin myelofibrosis (MF), mild lymphadenopathy, and progressive renal insufficiency and with other diseases excluded, we diagnosed this patient as having TAFRO syndrome according to the diagnostic criteria [3]. The administration of intravenously administered tocilizumab (8 mg/kg) was begun on the same day with tapering prednisolone dose; his C-reactive protein and alkaline phosphatase levels gradually improved, along with his renal function and fever (Fig. 5). For the anasarca, furosemide and potassium canrenoate were used and were highly effective.Fig. 2 a, b Histological findings of the left adrenal gland by computed tomography-guided needle biopsy. Necrosis of the left adrenal gland is seen. There is no hemosiderin accumulation, suggesting a low possibility of a hemorrhagic etiology. (Hematoxylin and eosin staining; scale bar, 100 μm)\n\nFig. 3 Histological findings for bone marrow. a, b Hypercellular marrow with fibrosis and an increase in megakaryocytes are seen. (Hematoxylin and eosin staining.) (c) Increased and crossing of reticulin fibers form the MF-1 fibrosis. (Silver staining; scale bar, 100 μm)\n\nFig. 4 Images of the second contrasted computed tomography scan. a Left axillary lymphadenopathy (15 mm) (arrow). b Pleural effusion\n\nFig. 5 Clinical course. ALP alkaline phosphatase, Cr creatinine, CRP C-reactive protein, Hgb hemoglobin, IVIg intravenous immunoglobulin, IL-6 interleukin-6, mPSL methylprednisolone, PC platelet concentrate, PLT platelet, PSL prednisolone, TCZ tocilizumab VEGF vascular endothelial growth factor\n\n\n\nBecause the thrombocytopenia remained, we added eltrombopag, a thrombopoietin receptor agonist, on hospital day 14, followed by tocilizumab administered on hospital day 16. Then, his platelet count began to increase. Under the strong immunosuppressive treatment, he contracted methicillin-resistant Staphylococcus epidermidis bacteremia on hospital day 20 and cytomegalovirus viremia on hospital day 31, which were successfully treated with vancomycin and ganciclovir, respectively. Tocilizumab was administered a third time on hospital day 47, and our patient was discharged on hospital day 48. After discharge, he remained afebrile and with an alkaline phosphate level within normal limits, and tocilizumab administration was no longer necessary. Eltrombopag administration was stopped because his platelet count increased and remained stable within normal limits. Nine months after the first treatment, this patient continues to do well. He is only being treated with low-dose prednisolone at approximately 5 mg per day and is still tapering carefully because of the presence of unilateral adrenal necrosis, considering the possibility of adrenal insufficiency.\n\nDiscussion\nSince 2010, when the first case of TAFRO syndrome was reported [1], the concept and clinicopathology of TAFRO syndrome has gradually been established [3]. However, there are only a few cases of TAFRO syndrome involving adrenal gland lesions, and there are no reports to date about TAFRO syndrome with adrenal necrosis shown pathologically. As a result, this is the first case of a middle-aged man diagnosed as having TAFRO syndrome with unilateral adrenal necrosis. The pathological investigations and the clinical course in this case are useful for understanding the etiology of TAFRO syndrome.\n\nFirst, we need to discuss why this unusual unilateral adrenal necrosis occurred in this relatively rare disease. In general, the cause of adrenal necrosis ranges widely and includes hemorrhage, infarction, hemorrhagic infarction, bacterial infection, malignancy, and autoimmune inflammation, among other causes. In this patient, no contrast was observed in the left adrenal gland. The blood and adrenal tissue culture results showed no bacterial growth, and the adrenal gland biopsy showed no malignant cells or hemosiderin accumulation. These facts reduce the possibility of hemorrhagic involvement. In addition, malignant cells were not detected by the adrenal gland, bone marrow, or lymph node biopsy. Thus, we assumed that infarction or an autoimmune process was the leading cause of adrenal necrosis in this case. The possibility of infarction seemed to be higher than that of autoimmune destruction in this case. Although the imaging studies and pathological tests could not detect a thrombus itself, the fact that the adrenal lesion was unilateral increases the possibility of infarction. Moreover, adrenal lesions in autoimmune adrenalitis, or Addison’s disease, are typically bilateral, and to the best of our knowledge, no cases of unilateral adrenal lesions caused by an autoimmune process have been reported. In general, most cases of adrenal infarction are accompanied by hemorrhage and bilateral lesions versus unilateral lesions [6]. In some cases, the infarction has been suggested as a sign of antiphospholipid syndrome, essential thrombocytosis, or polycythemia vera [7–9]. There have also been several cases of unilateral adrenal infarction occurring along with pregnancy [6, 10]. Considering these findings, coagulopathy seems to be related to unilateral adrenal infarction.\n\nNotably, prednisolone and tocilizumab therapy were highly effective in this case, which suggests that the pathophysiology of TAFRO syndrome may be relevant to autoimmune or autoinflammation processes, or hypercytokinemia. The pathophysiology of TAFRO syndrome is not yet fully understood. TAFRO syndrome is thought to be classified as iMCD [2], but the etiology of iMCD itself also remains unknown. Recently, the Castleman Disease Collaborative Network proposed a hypothesis of the etiological factors of iMCD, including autoimmunity, autoinflammation by germline mutation, neoplasm, and infection by non-HHV-8 virus [2, 11]. The involvement of autoimmunity is considered to be mediated by innate antibodies, which cause the release of several cytokines, such as interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF), thereby playing an important role in clinical flares of iMCD [12]. However, there is little evidence of an association between the IL-6 level and the efficacy of anti-IL-6 antibody treatment in iMCD and TAFRO cases, suggesting the existence of other primary drivers [2, 12]. In this case, the level of IL-6 gradually decreased after the treatment, but the VEGF level did not show this trend (Fig. 5). Approximately 30% of iMCD cases, including cases with TAFRO features, exhibit autoantibody involvement, such as anti-nuclear antibodies, anti-Sjögren syndrome-A (SS-A) antibodies, or a history of autoimmune hemolytic anemia [13, 14]. In addition, in several other cases, as in this case, increased peripheral thrombocyte consumption refractory to platelet transfusion has been reported [2]. These features indicate the clinicopathological involvement of autoimmunity.\n\nThe problem is that whether autoimmunity and hypercytokinemia are the primary causes of TAFRO syndrome or secondary reactions due to triggers, such as autoinflammation, malignancy, or some viral infection, remains to be determined; thus, further research is necessary.\n\nTherefore, we concluded that systemic inflammation caused a hypercoagulable state in this case, leading to unilateral adrenal gland infarction or severe inflammation, causing left adrenal gland enlargement and, in turn, leading to ischemia itself. In terms of the association between adrenal lesions and TAFRO syndrome, there have been a few cases of TAFRO syndrome with adrenal hemorrhage [4, 5]. Bilateral hemorrhage occurred in one case and a unilateral lesion in another. In each case, the proposed etiology for the hemorrhage was retroperitoneal inflammation, thrombocytopenia, and organomegaly of the adrenal gland itself. These were cases of adrenal hemorrhage without necrosis; there have been no previous reports of a case of TAFRO syndrome with adrenal necrosis. This is the first case of TAFRO syndrome accompanied by unilateral adrenal necrosis without evidence of hemorrhage shown by biopsy. In this case, hypercytokinemia led to ischemia of the adrenal gland, suggesting the possibility of hypercoagulability in TAFRO cases or the involvement of ischemia in organomegaly, which is one of the features of TAFRO syndrome. As the whole etiology is still unknown, further investigation of the pathophysiology of TAFRO syndrome and its influence on adrenal glands is warranted.\n\nConclusions\nThis is the first case of TAFRO syndrome complicated with unilateral adrenal necrosis without evidence of hemorrhage. Based on the results of pathological investigation, we conclude that the unilateral adrenal necrosis in this case was caused by ischemia of the adrenal gland itself. Hypercytokinemia, which is one of the features of TAFRO syndrome, may be related to this ischemia, and immunosuppressive therapy is key for treating TAFRO syndrome.\n\nAbbreviations\nbpmBeats per minute\n\nCTComputed tomography\n\nHHV-8Human herpesvirus 8\n\nIL-6Interleukin-6\n\niMCDIdiopathic multicentric Castleman disease\n\nMFMyelofibrosis\n\nSS-ASjögren syndrome-A\n\nVEGFVascular endothelial growth factor\n\nAvailability of data and materials\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nYF mainly cared for this patient on hospitalization and wrote the manuscript. AT and KI provided professional opinions regarding patient care and helped to draft the manuscript. KN currently cares for this patient at the out-patient clinic and provided opinions regarding patient care. All authors have read and approved the final manuscript.\n\nEthics approval and consent to participate\nThe ethics approval and consent for submitting case reports is usually waived by the ethical review committee at Musashino Red Cross Hospital. We follow the Declaration of Helsinki and take care of the protection of personal information cautiously.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images and tables. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Takai K Nikkuni K Shibuya H Hashidate H Thrombocytopenia with mild bone marrow fibrosis accompanied by fever, pleural effusion, ascites and hepatosplenomegaly Rinsho Ketsueki 2010 51 5 320 325 20534952 \n2. Iwaki N Fajgenbaum DC Nabel CS Gion Y Kondo E Kawano M Clinicopathologic analysis of TAFRO syndrome demonstrates a distinct subtype of HHV-8-negative multicentric Castleman disease Am J Hematol 2016 91 2 220 226 10.1002/ajh.24242 26805758 \n3. Masaki Y Kawabata H Takai K Kojima M Tsukamoto N Ishigaki Y Proposed diagnostic criteria, disease severity classification and treatment strategy for TAFRO syndrome, 2015 version Int J Hematol 2016 103 6 686 692 10.1007/s12185-016-1979-1 27084250 \n4. Nara M Komatsuda A Itoh F Kaga H Saitoh M Togashi M Two cases of thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly (TAFRO) syndrome with high serum procalcitonin levels, including the first case complicated with adrenal hemorrhaging Intern Med 2017 56 10 1247 1252 10.2169/internalmedicine.56.7991 28502946 \n5. Ito F Kameoka Y Nara M Ubukawa K Fujishima M Yoshioka T TAFRO syndrome with bilateral adrenal hemorrhage J Jpn Soc Int Med 2017 106 288 294 10.2169/naika.106.288 \n6. Green P.-A. D. Ngai I. M. Lee T. T. Garry D. J. Unilateral adrenal infarction in pregnancy Case Reports 2013 2013 aug23 1 bcr2013009997 bcr2013009997 \n7. Satta MA Corsello SM Della Casa S Adrenal insufficiency as the first clinical manifestation of the primary antiphospholipid antibody syndrome Clin Endocrinol 2000 52 123 126 10.1046/j.1365-2265.2000.00903.x \n8. Verbeeck N Ries F Dicato M Hermes G Niedercorn J-B Unilateral partial adrenal necrosis in a case of polycythemia vera with severe thrombocytosis: unique CT and MR imaging Eur J Radiol Extra 2007 61 19 22 10.1016/j.ejrex.2006.10.002 \n9. Burnet G Lambert M Annet L Lefebvre C Unilateral adrenal hemorrhagic infarction in essential thrombocythemia Acta Clin Belg 2015 70 6 461 462 10.1179/2295333715Y.0000000038 26133054 \n10. Aljenaee KY Ali SA Cheah SK Alroomi MJ Unilateral adrenal infarction in pregnancy secondary to elevated factor VIII Saudi Med J 2017 38 6 654 656 10.15537/smj.2017.6.18520 28578446 \n11. Fajgenbaum DC Shilling D Castleman disease pathogenesis Hematol Oncol Clin North Am 2018 32 1 11 21 10.1016/j.hoc.2017.09.002 29157613 \n12. Fajgenbaum DC Uldrick TS Bagg A Frank D Wu D Srkalovic G International , evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease Blood 2017 129 12 1646 1658 10.1182/blood-2016-10-746933 28087540 \n13. Liu AY Nabel CS Finkelman BS Ruth JR Kurzrock R van Rhee F Idiopathic multicentric Castleman’s disease: a systematic literature review Lancet Haematol 2016 3 4 e163 e175 10.1016/S2352-3026(16)00006-5 27063975 \n14. Louis C Vijgen S Samii K Chalandon Y Terriou L Launay D TAFRO syndrome in Caucasians: a case report and review of the literature Front Med 2017 4 149 10.3389/fmed.2017.00149\n\n",
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"issn_linking": "1752-1947",
"issue": "12(1)",
"journal": "Journal of medical case reports",
"keywords": "Adrenal necrosis; Castleman disease; TAFRO syndrome; Tocilizumab",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000307:Adrenal Gland Diseases; D000311:Adrenal Glands; D061067:Antibodies, Monoclonal, Humanized; D001853:Bone Marrow; D003937:Diagnosis, Differential; D004487:Edema; D005334:Fever; D005938:Glucocorticoids; D006801:Humans; D007155:Immunologic Factors; D008297:Male; D008875:Middle Aged; D009336:Necrosis; D055728:Primary Myelofibrosis; D051437:Renal Insufficiency; D012155:Reticulin; D013577:Syndrome; D013921:Thrombocytopenia; D016896:Treatment Outcome",
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"pages": "295",
"pmc": null,
"pmid": "30293532",
"pubdate": "2018-10-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "26133054;27084250;28578446;28502946;29018798;30182658;20534952;27063975;10651763;28087540;26805758;29157613",
"title": "The first case of thrombocytopenia, anasarca, fever, renal impairment or reticulin fibrosis, and organomegaly (TAFRO) syndrome with unilateral adrenal necrosis: a case report.",
"title_normalized": "the first case of thrombocytopenia anasarca fever renal impairment or reticulin fibrosis and organomegaly tafro syndrome with unilateral adrenal necrosis a case report"
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"abstract": "The aim of this study was to determine the following in patients who have undergone magnetic resonance imaging with gadolinium-based contrast agents (GBCAs) and meet the proposed diagnostic criteria for gadolinium deposition disease (GDD): (1) the effectiveness of chelation therapy (CT) with intravenous Ca-diethylenetriaminepentaacetic acid in removing retained gadolinium (Gd) and factors affecting the amount removed; (2) the frequency of CT-induced Flare, that is, GDD diagnostic symptom worsening, and factors affecting Flare intensity; (3) whether, as reported in a separate cohort, GDD patients' serum cytokine levels differ significantly from those in healthy normal controls and change significantly in response to CT; and (4) whether urine Gd, Flare reaction, and serum cytokine findings in GDD patients are mimicked in non-ill patients described as having gadolinium storage condition (GSC).\n\n\n\nTwenty-one GDD subjects and 3 GSC subjects underwent CT. Patients provided pre-CT and post-CT 24-hour urine samples for Gd content determination along with pre-CT and 24-hour post-CT serum samples for cytokine analysis. Patients rated potential Flare 24 hours after CT. Pre-CT and post-CT 24-hour urine Gd analyses and Luminex serum cytokine assays were performed blind to patients' GDD and GSC status and all other data except age and sex. Serum cytokine levels in a healthy normal control group of age- and sex-matched subjects drawn from Stanford influenza vaccination studies were measured once, contemporaneously with those of GDD and GSC patients, using the same Luminex assay.\n\n\n\nUrine Gd amounts increased post-CT by 4 times or more after 87% of the 30 CT sessions. The most important factors appeared to be the time since the last GBCA dose and the cumulative dose received. Urine Gd amounts for GDD and GSC patients fell in the same ranges. All GDD patients, and no GSC patient, reported a Flare 24 hours post-CT. Linear regression found that Flare intensity was significantly predicted by a model including pre- and post-CT Gd amounts and the number of GBCA-enhanced magnetic resonance imaging. Post-CT, multiple cytokines showed strong positive relationships with GDD patients' Flare intensity in multivariable models. The pre-CT serum levels of 12 cytokines were significantly different in GDD patients compared with healthy flu vaccine controls. The small number of GSC patients precluded analogous statistical testing. Post-CT, GDD patients' serum levels of 20 cytokines were significantly decreased, and 2 cytokines significantly increased. These cytokines did not exhibit the same change pattern in the 3 GSC patients. The small number of GSC patients precluded statistical comparisons of GSC to GDD patients' results.\n\n\n\nIn this preliminary study, 24-hour urine Gd content increased markedly and similarly in GDD and GSC patients after Ca-diethylenetriaminepentaacetic acid CT. Post-CT Flare reaction developed only in GDD patients. The current study is the second finding significantly different serum cytokine levels in GDD patients compared with healthy normal controls. These differences and the difference between GDD and GSC patients' Flare and cytokine responses to CT suggest some inflammatory, immunologic, or other physiological differences in patients with GDD. Further research into the treatment and physiological underpinnings of GDD is warranted.",
"affiliations": "From the Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Stanford, CA.;CytoAnalytics, Denver, CO.;From the Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Stanford, CA.;Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA.;Department of Radiology, Hospital Garcia de Orta, Almada, Portugal.;Richard Semelka Consulting, PLLC, Chapel Hill, NC.",
"authors": "Maecker|Holden T|HT|;Siebert|Janet C|JC|;Rosenberg-Hasson|Yael|Y|;Koran|Lorrin M|LM|;Ramalho|Miguel|M|;Semelka|Richard C|RC|",
"chemical_list": "D003287:Contrast Media; D016207:Cytokines; D009942:Organometallic Compounds; D005682:Gadolinium; D019786:Gadolinium DTPA",
"country": "United States",
"delete": false,
"doi": "10.1097/RLI.0000000000000752",
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"issn_linking": "0020-9996",
"issue": "56(6)",
"journal": "Investigative radiology",
"keywords": null,
"medline_ta": "Invest Radiol",
"mesh_terms": "D015913:Chelation Therapy; D003287:Contrast Media; D016207:Cytokines; D005682:Gadolinium; D019786:Gadolinium DTPA; D006801:Humans; D008279:Magnetic Resonance Imaging; D009942:Organometallic Compounds; D057566:Self Report",
"nlm_unique_id": "0045377",
"other_id": null,
"pages": "374-384",
"pmc": null,
"pmid": "33449576",
"pubdate": "2021-06-01",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Acute Chelation Therapy-Associated Changes in Urine Gadolinium, Self-reported Flare Severity, and Serum Cytokines in Gadolinium Deposition Disease.",
"title_normalized": "acute chelation therapy associated changes in urine gadolinium self reported flare severity and serum cytokines in gadolinium deposition disease"
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"abstract": "We present the case of a 71-year-old woman diagnosed with chronic lymphocytic leukemia who received multiple chemotherapeutic lines and evolved to acute lymphoblastic leukemia. The patient was Rai stage 0 at the time of the diagnosis and was monitored for almost 9 years. After that, the disease progressed and the patient began chemotherapy (fludarabine/cyclophosphamide combination), obtained complete remission and relapsed one year later after finishing treatment. She received multiple therapeutic regimens, accompanied by multiple infectious complications. After 8 years of evolution since she started chemotherapy, bone marrow aspirate and immunophenotyping revealed acute lymphoblastic leukemia. The occurrence of acute leukemia in CLL is rare and may arise from the same clone; however, most cases appear after patients have received chemotherapy, suggesting that they are therapy-related.",
"affiliations": null,
"authors": "Andrus|Elena|E|;Nicolescu|Anca|A|;Bumbea|H|H|;Vlădăreanu|Ana-Maria|AM|",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating",
"country": "Germany",
"delete": false,
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"issue": "53(2)",
"journal": "Romanian journal of internal medicine = Revue roumaine de medecine interne",
"keywords": null,
"medline_ta": "Rom J Intern Med",
"mesh_terms": "D000368:Aged; D018906:Antineoplastic Agents, Alkylating; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D016609:Neoplasms, Second Primary; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma",
"nlm_unique_id": "9304507",
"other_id": null,
"pages": "184-8",
"pmc": null,
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"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute Lymphoblastic Leukemia after previously treated, relapsed Chronic Lymphocytic Leukemia: A Case Report.",
"title_normalized": "acute lymphoblastic leukemia after previously treated relapsed chronic lymphocytic leukemia a case report"
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"abstract": "We report the case of a 36-year-old woman with a subarachnoid haemorrhage (SAH) caused by a rupture of a right-sided middle cerebral artery aneurysm and subsequent malignant infarction of the right hemisphere leading to a persistent vegetative state and severe spastic tetraparesis with recurrent myocloni. Nine months after disease onset, the patient was transferred to our department for diagnostic and therapeutic re-evaluation. The poor clinical condition could not be explained by the brain lesion caused by the SAH or infarction. Moreover, glucose metabolism was normal in brain regions not affected by SAH and infarction as shown by positron emission tomography with 18F-fluorodeoxyglucose. We terminated baclofen and reduced antiepileptics known to impair vigilance and cognitive functions. However, only after starting amantadine treatment we observed a stunning awakening of the patient fully orientated within days. Our findings warrant trials to investigate amantadine in the treatment of unresponsive wakefulness syndromes due to acute central nervous system diseases.",
"affiliations": "Department of Experimental Neurology, NeuroCure Clinical Research Center, and Department of Neurology, Charite´-University Medicine Berlin, Berlin, Germany.;Department of Experimental Neurology, NeuroCure Clinical Research Center, and Department of Neurology, Charite´-University Medicine Berlin, Berlin, Germany.;Department of Nuclear Medicine, Charite´-University Medicine Berlin, Berlin, Germany.;Department of Neuroradiology, Charite´-University Medicine Berlin, Berlin, Germany.;Department of Experimental Neurology, NeuroCure Clinical Research Center, and Department of Neurology, Charite´-University Medicine Berlin, Berlin, Germany.",
"authors": "Lehnerer|Sophie Mirabell|SM|;Scheibe|Franziska|F|;Buchert|Ralph|R|;Kliesch|Stefan|S|;Meisel|Andreas|A|",
"chemical_list": "D015259:Dopamine Agents; D000547:Amantadine",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-220305",
"fulltext": "\n==== Front\nBMJ Case RepBMJ Case RepcasereportsbmjcasereportsBMJ Case Reports1757-790XBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR bcr-2017-22030510.1136/bcr-2017-220305ArticleNovel Treatment (New Drug/Intervention; Established Drug/Procedure in New Situation)15061522Female31-50 yearsWhiteEurope (West)Case ReportAwakening with amantadine from a persistent vegetative state after subarachnoid haemorrhage Lehnerer Sophie Mirabell 1Scheibe Franziska 1Buchert Ralph 2Kliesch Stefan 3Meisel Andreas 11 Department of Experimental Neurology, NeuroCure Clinical Research Center, and Department of Neurology, Charite´–University Medicine Berlin, Berlin, Germany2 Department of Nuclear Medicine, Charite´–University Medicine Berlin, Berlin, Germany3 Department of Neuroradiology, Charite´–University Medicine Berlin, Berlin, GermanyCorrespondence to Dr Sophie Mirabell Lehnerer, sophie.lehnerer@charite.de2017 24 7 2017 24 7 2017 2017 bcr201722030511 6 2017 © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.2017This 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/We report the case of a 36-year-old woman with a subarachnoid haemorrhage (SAH) caused by a rupture of a right-sided middle cerebral artery aneurysm and subsequent malignant infarction of the right hemisphere leading to a persistent vegetative state and severe spastic tetraparesis with recurrent myocloni. Nine months after disease onset, the patient was transferred to our department for diagnostic and therapeutic re-evaluation. The poor clinical condition could not be explained by the brain lesion caused by the SAH or infarction. Moreover, glucose metabolism was normal in brain regions not affected by SAH and infarction as shown by positron emission tomography with 18F-fluorodeoxyglucose. We terminated baclofen and reduced antiepileptics known to impair vigilance and cognitive functions. However, only after starting amantadine treatment we observed a stunning awakening of the patient fully orientated within days. Our findings warrant trials to investigate amantadine in the treatment of unresponsive wakefulness syndromes due to acute central nervous system diseases.\n\nComa And Raised Intracranial PressureNeuro ITUspecial-featureunlocked\n==== Body\nBackground\nDifferent causes of brain damage (eg, global ischemia, hypoxia, infarction, bleeding, trauma, or infection) can result in unresponsive wakefulness syndromes. Evaluation of cognitive functions in these patients is difficult and requires a precise clinical examination supported by additional investigations like electrophysiological studies, brain MRI and positron emission tomography (PET). Contradictive findings of clinical syndrome and diagnostic test results should direct physicians to therapeutic consequences like reduction, discontinuation or substitution of drugs affecting brain function, such as sedatives or antiepileptics. Moreover, the addition of neurostimulant drugs should be considered.\n\nCase presentation\nA 36-year-old woman suffered from a subarachnoid haemorrhage (SAH) after rupture of a right-sided middle cerebral artery aneurysm. Due to a secondary vasospastic malignant infarction of the right middle cerebral artery territory, a haemicraniectomy was performed. A subsequent posthaemorrhagic cerebrospinal fluid circulatory dysfunction required implantation of a ventriculoperitoneal shunt. After initial coma, the patient was affected by a left-sided hemiparesis, but was able to communicate on a basic level and could execute simple actions like drinking from a feeding cup (for overview of clinical course see figure 1). During rehabilitation the condition of the patient deteriorated over several weeks. Finally, she became unresponsive to external stimuli and showed vegetative dysfunction such as vomiting, extreme sweating, tachypnoea and tachycardia. After correcting a suspected overdrainage of the ventriculoperitoneal shunt and cranioplastic skull reconstruction 5 months after the initial bleeding, the patient did not return to her best neurological status after brain haemorrhage. In particular she presented an unresponsive wakefulness syndrome. In the further course she was weaned from respirator breathing spontaneously through a tracheal cannula. Several complications like infected decubiti, upper limb phlegmon, pneumothorax, anaemia, anovesical fistula and multiple infections including pneumonia, urinary tract infection and catheter-associated sepsis resulted in a prolonged stay on the intensive care unit (ICU). Enhanced by stressful stimuli, she additionally presented a rhythmic myoclonus of the right upper and lower limbs and mandible muscles including the tongue. A tremor was considered as a differential diagnosis, but did not respond to pramipexole. Three antiepileptic drugs (levetiracetam 4 g/day, valproic acid 300 mg/day, clonazepam 1.5 mg/day) were used without effect on the myoclonus. Noteworthy, the patient showed no seizures and no epileptic activity had been demonstrated in several electroencephalographies (EEGs). The prognosis of the patient was considered to be poor with no options for further treatments beyond home care nursing or an end-of-life decision by the maximum care hospital. Initiated by her family, the patient was transferred to our university hospital for a second opinion including re-evaluation of prognosis and treatment options 9 months after disease onset.\n\nFigure 1 Schematic overview of the clinical course from the initial event (subarachnoid haemorrhage) to the improvement of vigilance, cognitive function and motor symptoms 13 months later. The graph shows the CRS-R. The blue boxes provide additional information about the clinical condition. Events worsening the status of our patient are marked with red arrows, interventions with a positive effect are highlighted by green checks. Some of the CRS-R scores have not been mentioned explicitly in the reports of former hospitals but were extrapolated from detailed medical reports. AED, antiepileptic drug; CRS-R, revised coma recovery scale; GCS, Glasgow Coma Scale. \n\nInvestigations\nConsidering the subacute progression into the persistent vegetative state as well as the severe tetraparesis, which was at least in part not explained by the initial brain damage, we discussed possible causes for the late-onset deterioration like another ischaemic or haemorrhagic infarction, over or underdrainage of the ventriculoperitoneal shunt, septic encephalopathy due to multiple bacterial infections, side effects of medication or central nervous system (CNS) infection due to shunt implantation. First we performed a cranial CT that showed no signs of over or underdrainage of the ventriculoperitoneal shunt. MRI of the brain exhibited a superficial siderosis and laminar necrosis in the territory of the former right middle cerebral artery infarction with temporal, frontal and opercular atrophies, and consequently widened ventricle of the right hemisphere (figure 2). Although the patient presented clinically with a severe proportional spastic tetraparesis, brain and spinal MRI exhibited structural abnormalities neither in the left hemisphere nor in the brainstem and myelon. Consistent with the MRI findings, PET with the glucose analogue 18F-fluorodeoxyglucose (FDG) revealed normal glucose metabolism in the brain except in the infarction area (figure 3). Cerebral glucose metabolism as measured by FDG-PET serves as a surrogate marker for synaptic signalling in the brain sensitive to focal structural damage and dysfunction and to interruption of complex brain networks. Considering these findings we expected rather a focal neurological deficit but not a global brain dysfunction.\n\nFigure 2 Axial T1SE (left), susceptibility-weighted (middle) and coronal fluid attenuated inversion recovery (right) MR images obtained during re-evaluation at our institution reveal defect-associated volume loss and signs of laminar necrosis in the area of the chronic middle cerebral artery infarction. SWI shows residual superficial siderosis due to the subarachnoid haemorrhage. Artefact due to valve of the ventriculoperitoneal shunt system pronounced in SWI. SWI, susceptibility-weighted imaging.\n\nFigure 3 PET of the brain with the glucose analogue FDG 9 months after disease onset. Transversal slices (left) show a large frontotemporal defect in the right hemisphere consistent with the area of the cerebral infarction (figure 2). Glucose metabolism in the left hemisphere appears normal by visual inspection. This was confirmed by voxelwise statistical testing of the patient’s FDG-PET against a database of healthy subjects (right). Brain areas with significantly reduced metabolism are indicated in blue in the render display of the statistical parametric map. FDG, 18F-fluorodeoxyglucose; PET, positron emission tomography. \n\nNeuroinflammation as underlying cause of the condition is not excluded but rather unlikely due to normal findings in the examination of the cerebrospinal fluid including cell counts, lactate, glucose and protein levels as well as negative antibodies for autoimmune disorders of the nervous system. Investigated under analgosedation, about 50% of movement restriction was attributed to spasticity and the other 50% to primarily distal located fixed contractions.\n\nTreatment\nSince oral baclofen (30 mg/day) given over several months had no significant effect on spasticity, we tapered it off. In addition, we tested responsiveness to baclofen by increasing dosages administered intrathecally. Even repeated dosages of 300 µg baclofen had insignificant effects on the spasticity. Since we suspected among other causes an antiepileptic drug-induced encephalopathy, we reduced and finally stopped levetiracetam, valproic acid and clonazepam. Although cessation of the antiepileptic drugs did not increase the myoclonus, it did not improve cognitive functions. Due to a single self-limiting generalised epileptic seizure associated with a prior intrathecal baclofen injection, we treated the patient with lamotrigine. In repeated EEGs no epileptiform activity was noted.\n\nWe supposed the myoclonus in our patient was caused by a dopamine deficiency. Amantadine is known to increase indirectly dopamine via antagonistic effects at the N-methyl-D-aspartate (NMDA) receptor by increasing the release and blocking the reuptake of dopamine. Since amantadine might also enhance arousal from coma due to dopamine effects,1 we initiated a therapy with amantadine starting with 100 mg/day intravenously, increasing the dose 100 mg per day, and switched to an enteral drug administration after reaching the maximum dose of 300 mg/day given once in the morning.\n\nOutcome and follow-up\nUnder this treatment the patient improved within 16 days from initially 5 points of the revised coma recovery scale to the maximum score of 23 points. With a speaking valve she was able to talk, although a speech apraxia was seen (see online supplementary video 1). Our patient had a retrograde amnesia but she was subsequently fully orientated and was able to communicate adequately in two to six-word sentences. Being able to realise instructions she could move all extremities with a muscle power up to 4/5 in the big muscles. Upon these active movements the spasticity was remarkably reduced. The myoclonus of the right extremities and the tongue stopped apart from rare situations when the patient was agitated. For further improvement of motor and cognitive functions we transferred the patient to a specialised neurorehabilitation centre. Visiting the patient 3 months later, we saw a fully oriented patient in much improved general condition. Apart from a retrograde amnesia regarding her stay on the ICUs, she presented only very mild cognitive deficits (see online supplementary video 2). By that time she was decanulated, eating autonomously precut food (see online supplementary video 3) and was able to stand with help. Walking was still difficult due to fixed contractions (see online supplementary video 4).\n\n10.1136/bcr-2017-220305.supp1Supplementary material1\n\n\n 10.1136/bcr-2017-220305.supp2Supplementary material3\n\n\n 10.1136/bcr-2017-220305.supp3supplementary material4\n\n\n 10.1136/bcr-2017-220305.supp4supplementary material2\n\n\n Discussion\nHere we describe a patient with an unexplained unresponsive wakefulness syndrome accompanied by a tetraparesis due to a SAH complicated by a malignant infarction in the right middle cerebral artery territory and severe systemic bacterial infections in the chronic course. The patient improved significantly under amantadine treatment to remaining moderate motor deficits and minor cognitive dysfunction.\n\nAmantadine was introduced in the 1960s for the treatment of the influenza A virus. Although it lost its importance in the antiviral treatment, amantadine is still frequently used in the treatment of Parkinson’s disease.2 Amantadine’s mechanism of action is still not completely understood, but it is thought to act as a non-competitive NMDA receptor antagonist increasing dopamine synthesis and dopamine release in the striatum. Sufficient synaptic dopamine levels are necessary for a number of physiological functions including movement control, emotion, motivation and cognitive processing.3 Amantadine has successfully been evaluated for neurostimulation in patients with traumatic brain injury (TBI) in a multicentre trial.4 Mechanistically, severe brain trauma leads to diffuse axonal injury which results among other in a reduced dopamine turnover.5 There are no trials investigating amantadine for the treatment of cognitive dysfunctions following other causes of cerebral damage such as stroke, intracranial bleeding or hypoxia.\n\nMost clinical studies report the use of amantadine within the first weeks after the initial event. In our patient, we observed dramatic improvement on amantadine treatment 9 months after the initial brain damage. The improvement encompassed quantitative and qualitative aspects of consciousness and the severe tetraparesis and myoclonus.\n\nWe suppose that the myoclonus of the right limbs and mandible muscles including the tongue resulted from dopamine deficiency that was effectively treated by amantadine. Some patients with TBI present parkinsonian symptoms associated with mild brain dysfunction.6 There might have been similar midbrain dysfunction in our patient caused by overdrainage of the ventriculoperitoneal shunt, which is however unlikely since we have not observed a definite overdrainage. A further possible rare cause of myoclonus in our patient is a sepsis-associated encephalopathy.\n\nOur report of awakening on amantadine treatment in a patient suffering from a chronic course of a severe CNS lesion emphasises the importance of a careful neuroprognostic (re)evaluation considering the medical history, current clinical findings as well as state-of-the art neuroimaging. Cerebral FDG-PET could be used to complement bedside examinations and predict long-term recovery of patients with unresponsive wakefulness syndrome.7 In our patient, the PET showed hypometabolism only in the area of the malignant infarction of the right medial cerebral artery, which could not explain the persistent vegetative state and the spastic tetraparesis. Even in the chronic course after severe brain damage discrepancies between the clinical condition and paraclinical findings should initiate a re-evaluation of the medication, in particular one should consider termination of drugs known to affect neuronal function, such as antiepileptic or neuroleptic agents. Moreover, treatment should consider the use of neurostimulants such as amantadine. Several further approaches to stimulate arousal in patients with unresponsive wakefulness syndromes or coma have been described including pharmacological therapy with ketamine, bromocriptine, zolpidem or methylphenidate as well as non-pharmacological interventions such as transcranial magnetic stimulation or deep brain stimulation.8 The personalised approach of careful re-evaluation and trying different therapy options is often time and personal intensive requiring a highly specialised team of professionals trained in neurological intensive care and in neuroprognostics.\n\nLearning points\nDiscrepancies between the clinical condition and paraclinical findings of patients with disorders of consciousness should initiate a re-evaluation, even in the chronic course after severe brain damage.\n\nCerebral 18F-fluorodeoxyglucose-positron emission tomography could be used to complement bedside examinations and to predict long-term recovery of patients with unresponsive wakefulness syndrome.\n\nFor drugs known to affect neuronal function, such as antiepileptics or neuroleptics, a dose reduction or even termination should be considered under careful monitoring.\n\nNeurostimulants such as amantadine should be considered in cases of minimal conscious state or even unresponsive wakefulness syndrome.\n\nContributors: SML: design and conceptualisation of the case report, involved in clinical care, acquisition of data, analysis and interpretation of data, drafting of manuscript. FS: involved in clinical care, acquisition and interpretation of data, revision of manuscript for intellectual content. RB: acquisition, description and interpretation of PET data, revision of manuscript for intellectual content. SK: acquisition, description and interpretation of MRI data, revision of manuscript for intellectual content. A. Meisel: involved in conceptualisation of the case report, interpretation of data, revision of manuscript for intellectual content.\n\nCompeting interests: None declared.\n\nPatient consent: Obtained.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n1 Sawyer E , Mauro LS , Ohlinger MJ \nAmantadine enhancement of arousal and cognition after traumatic brain injury . Ann Pharmacother \n2008 ;42 :247 –52 . 10.1345/aph.1K284 18212258 \n2 Connolly BS , Lang AE \nPharmacological treatment of Parkinson disease: a review . JAMA \n2014 ;311 :1670 –83 . 10.1001/jama.2014.3654 24756517 \n3 Bales JW , Wagner AK , Kline AE , et al \nPersistent cognitive dysfunction after traumatic brain injury: a dopamine hypothesis . Neurosci Biobehav Rev \n2009 ;33 :981 –1003 . 10.1016/j.neubiorev.2009.03.011 19580914 \n4 Giacino JT , Whyte J , Bagiella E , et al \nPlacebo-controlled trial of amantadine for severe traumatic brain injury . N Engl J Med \n2012 ;366 :819 –26 . 10.1056/NEJMoa1102609 22375973 \n5 Meythaler JM , Brunner RC , Johnson A , et al \nAmantadine to Improve Neurorecovery in traumatic brain Injury–Associated Diffuse Axonal Injury . J Head Trauma Rehabil \n2002 ;17 :300 –13 . 10.1097/00001199-200208000-00004 12105999 \n6 Formisano R , Zasler ND \nPosttraumatic parkinsonism . J Head Trauma Rehabil \n2014 ;29 :387 –90 . 10.1097/HTR.0000000000000027 24695262 \n7 Stender J , Gosseries O , Bruno MA , et al \nDiagnostic precision of PET imaging and Functional MRI in disorders of consciousness: a Clinical validation study . Lancet \n2014 ;384 :514 –22 . 10.1016/S0140-6736(14)60042-8 24746174 \n8 Cossu G \nTherapeutic options to enhance Coma arousal after traumatic brain injury: state of the art of current treatments to improve Coma recovery . Br J Neurosurg \n2014 ;28 :187 –98 . 10.3109/02688697.2013.841845 24090192\n\n",
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"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "Coma And Raised Intracranial Pressure; Neuro ITU",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000547:Amantadine; D001921:Brain; D015259:Dopamine Agents; D005260:Female; D006801:Humans; D002532:Intracranial Aneurysm; D018458:Persistent Vegetative State; D049268:Positron-Emission Tomography; D013345:Subarachnoid Hemorrhage",
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"pmid": "28739616",
"pubdate": "2017-07-24",
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"title": "Awakening with amantadine from a persistent vegetative state after subarachnoid haemorrhage.",
"title_normalized": "awakening with amantadine from a persistent vegetative state after subarachnoid haemorrhage"
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{
"abstract": "OBJECTIVE\nDe novo cancers of head and neck area in solid organ transplantation recipients show standardized incidence ratio (SIR) of 3.8. Immunosuppression following transplantation is suggested to play as a crucial factor in pathogenesis of secondary malignancy. Prognosis of head and neck cancer arising in solid organ transplantation recipients is proven to have poor prognosis. The incidence, risk, prognosis, and survival of de novo malignancy of head and neck area in solid organ transplantation recipients in single-tertiary medical center followed up for 20 years.\n\n\nMETHODS\nA retrospective medical record review of the patients who received solid organ transplantation in Asan Medical Center from 1997 to 2016 was conducted. Patients confirmed as de novo malignancy in the head and neck area after organ transplantation were included, and presented as in the case-series format. Patients with previous history of head and neck malignancy, irradiation history of head and neck area, cutaneous malignant lesion, hematopoietic malignant lesion, malignancy of thyroid and parathyroid gland and metastatic lesions newly developed in head and neck area were excluded. The incidence of head and neck malignancy in South Korea were reviewed from the National Cancer Information Center of South Korea. For the statistical analysis, standardized incidence ratio (SIR) was obtained with 95% confidence interval.\n\n\nRESULTS\nSolid organ transplantation recipients show 20 times higher incidence of de novo cancer of head and neck area compared to general population. Of 13 de novo head and neck malignancy arising after solid organ transplantation, 2 (15.4%) patients were unable to withstand definitive management due to poor general condition. 2 (15.4%) patients had loco-regional recurrence, 1 (7.7%) patient with distant metastasis, and 3 (23.1%) patients died of cancer progression.\n\n\nCONCLUSIONS\nImmunosuppression following solid organ transplantation gives a twenty-fold increased risk for the development of de novo head and neck cancer. A more precise and frequent checkup on head and area should be planned, suggesting a multi-disciplinary approach in combination with organ transplantation team.",
"affiliations": "Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.;Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.;Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.;Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.;Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.;Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address: yselee@amc.seoul.kr.",
"authors": "Park|Marn Joon|MJ|;Roh|Jong-Lyel|JL|;Choi|Seung-Ho|SH|;Nam|Soon Yuhl|SY|;Kim|Sang Yoon|SY|;Lee|Yoon Se|YS|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.anl.2017.11.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-8146",
"issue": "45(4)",
"journal": "Auris, nasus, larynx",
"keywords": "De novo cancer; Head and neck malignancy; Immunosuppression; Organ recipients; Organ transplantation; Prognosis; Solid organ transplantation; Squamous cell carcinoma",
"medline_ta": "Auris Nasus Larynx",
"mesh_terms": "D000328:Adult; D000368:Aged; D005260:Female; D006084:Graft Rejection; D006258:Head and Neck Neoplasms; D006801:Humans; D007166:Immunosuppressive Agents; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D016377:Organ Transplantation; D011379:Prognosis; D056910:Republic of Korea; D012189:Retrospective Studies; D062606:Tertiary Care Centers",
"nlm_unique_id": "7708170",
"other_id": null,
"pages": "838-845",
"pmc": null,
"pmid": "29150348",
"pubdate": "2018-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "De novo head and neck cancer arising in solid organ transplantation recipients: The Asan Medical Center experience.",
"title_normalized": "de novo head and neck cancer arising in solid organ transplantation recipients the asan medical center experience"
} | [
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"abstract": "Systemic lupus erythematosus (SLE) and bullous pemphigoid (BP) are chronic autoimmune diseases in which B cells play an important pathogenic role in the different stages of the disease. B cell-targeted therapies have been suggested as a new rational approach for treating SLE. Rituximab (RTX), an anti-CD20 chimeric monoclonal antibody, failed to achieve primary endpoints in two clinical trials (EXPLORER and LUNAR) despite multiple observational and retrospective studies showing its beneficial effect on SLE. Moreover, RTX is recommended in cases of BP that is unresponsive to conventional treatments. Belimumab (BLM), a human immunoglobulin G1 λ monoclonal antibody that inhibits soluble B-lymphocyte stimulator (BlyS)/B-cell activating factor (BAFF), is the only biological treatment approved for standard therapy of refractory autoantibody-positive active SLE. Animal models and a few case reports have supported the efficacy of the combined use of RTX followed by BLM as maintenance therapy in severe lupus nephritis (LN), suggesting that their combined use may be more effective than their single use, without compromising safety. In this study, we describe the clinical case of a SLE patient with predominant renal involvement in overlap with BP, refractory to conventional therapy including RTX alone, achieving significant steroid sparing and clinical remission under sequential treatment of RTX-BLM. Moreover, we describe the first case of BP successfully treated with BLM. This case report may encourage further clinical research studies in B lymphocyte targeted combination therapy in patients affected by SLE with major organ involvement or with refractory disease, suggesting that RTX and BLM sequential therapy may be a valid option for the treatment of SLE manifestations, including conventional therapy and RTX-resistant LN.",
"affiliations": "Division of Rheumatology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.;Division of Rheumatology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.;Division of Rheumatology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.;Nephrology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.;Nephrology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.;Division of Rheumatology, Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy.;Division of Rheumatology, Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy.;Division of Rheumatology, Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy.;Division of Rheumatology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.;Division of Rheumatology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.;Nephrology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.;Division of Rheumatology, Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy.;Division of Rheumatology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.",
"authors": "Petricca|Luca|L|;Gigante|Maria Rita|MR|;Paglionico|Annamaria|A|;Costanzi|Stefano|S|;Vischini|Gisella|G|;Di Mario|Clara|C|;Varriano|Valentina|V|;Tanti|Giacomo|G|;Tolusso|Barbara|B|;Alivernini|Stefano|S|;Grandaliano|Giuseppe|G|;Ferraccioli|Gianfranco|G|;Gremese|Elisa|E|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fmed.2020.553075",
"fulltext": "\n==== Front\nFront Med (Lausanne)\nFront Med (Lausanne)\nFront. Med.\nFrontiers in Medicine\n2296-858X Frontiers Media S.A. \n\n10.3389/fmed.2020.553075\nMedicine\nCase Report\nRituximab Followed by Belimumab Controls Severe Lupus Nephritis and Bullous Pemphigoid in Systemic Lupus Erythematosus Refractory to Several Combination Therapies\nPetricca Luca 1 Gigante Maria Rita 1 Paglionico Annamaria 1 Costanzi Stefano 2 Vischini Gisella 2 Di Mario Clara 3 Varriano Valentina 3 Tanti Giacomo 3 Tolusso Barbara 1 Alivernini Stefano 13 Grandaliano Giuseppe 24 Ferraccioli Gianfranco 3 Gremese Elisa 13* 1Division of Rheumatology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy\n2Nephrology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy\n3Division of Rheumatology, Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy\n4Nephrology Unit, Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy\nEdited by: Maria Leandro, University College London Hospitals NHS Foundation Trust, United Kingdom\n\nReviewed by: Mittermayer Barreto Santiago, Bahiana School of Medicine and Public Health, Brazil; Mitsuhiro Takeno, Nippon Medical School, Japan\n\n*Correspondence: Elisa Gremese elisa.gremese@unicatt.itThis article was submitted to Rheumatology, a section of the journal Frontiers in Medicine\n\n\n28 10 2020 \n2020 \n7 55307517 4 2020 25 9 2020 Copyright © 2020 Petricca, Gigante, Paglionico, Costanzi, Vischini, Di Mario, Varriano, Tanti, Tolusso, Alivernini, Grandaliano, Ferraccioli and Gremese.2020Petricca, Gigante, Paglionico, Costanzi, Vischini, Di Mario, Varriano, Tanti, Tolusso, Alivernini, Grandaliano, Ferraccioli and GremeseThis 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.Systemic lupus erythematosus (SLE) and bullous pemphigoid (BP) are chronic autoimmune diseases in which B cells play an important pathogenic role in the different stages of the disease. B cell-targeted therapies have been suggested as a new rational approach for treating SLE. Rituximab (RTX), an anti-CD20 chimeric monoclonal antibody, failed to achieve primary endpoints in two clinical trials (EXPLORER and LUNAR) despite multiple observational and retrospective studies showing its beneficial effect on SLE. Moreover, RTX is recommended in cases of BP that is unresponsive to conventional treatments. Belimumab (BLM), a human immunoglobulin G1 λ monoclonal antibody that inhibits soluble B-lymphocyte stimulator (BlyS)/B-cell activating factor (BAFF), is the only biological treatment approved for standard therapy of refractory autoantibody-positive active SLE. Animal models and a few case reports have supported the efficacy of the combined use of RTX followed by BLM as maintenance therapy in severe lupus nephritis (LN), suggesting that their combined use may be more effective than their single use, without compromising safety. In this study, we describe the clinical case of a SLE patient with predominant renal involvement in overlap with BP, refractory to conventional therapy including RTX alone, achieving significant steroid sparing and clinical remission under sequential treatment of RTX-BLM. Moreover, we describe the first case of BP successfully treated with BLM. This case report may encourage further clinical research studies in B lymphocyte targeted combination therapy in patients affected by SLE with major organ involvement or with refractory disease, suggesting that RTX and BLM sequential therapy may be a valid option for the treatment of SLE manifestations, including conventional therapy and RTX-resistant LN.\n\nlupus nephritisbullous pemphigoidbelimumabrituximabsequential therapy\n==== Body\nIntroduction\nSystemic lupus erythematosus (SLE) and bullous pemphigoid (BP) are chronic autoimmune diseases in which B lymphocytes play a primary pathogenic role as they are implicated in the induction and progression of these diseases (1, 2). Only a few cases of patients affected by SLE in overlap with BP have been described in the literature (3–5). B cells exert their pathogenic action not only by producing autoantibodies but also by presenting autoantigens to T lymphocytes and secreting of a wide variety of proinflammatory cytokines, thus perpetuating the activation of the immune system (6). Rituximab (RTX), a chimeric monoclonal antibody that targets CD20 antigen on B cells, is successfully used to treat various autoimmune diseases by depleting B lymphocytes. Although some observational and retrospective studies have shown beneficial effects of RTX in SLE patients (7, 8), it failed to achieve the primary endpoints in the EXPLORER and LUNAR trials (9, 10), probably due to a wrong trial design. Moreover, RTX has been shown to be effective in BP patients who were unresponsive or with unacceptable side effects to conventional immunosuppressive drugs (11–15). However, the position of RTX within the therapeutic flowchart of SLE and BP diseases is still unknown. Belimumab (BLM) is a human immunoglobulin G1 λ monoclonal antibody that inhibits soluble B-lymphocyte stimulator (BlyS)/B-cell activating factor (BAFF) (16), and in 2011, BLM was approved for the treatment of standard therapy-refractory autoantibody-positive active SLE (17, 18). Moreover, BLM has been proven to be effective to treat moderate SLE with skin, articular, and hematologic abnormalities (19), although it is not licensed to treat severe lupus nephritis (LN) (20–22). To date, sequential therapeutic schemes of RTX followed by BLM have not been well-studied. Animal models (23) and few case reports support the efficacy of the combined use of RTX followed by BLM as maintenance therapy in severe LN (24–27), suggesting that their combined use may be more effective than their single use, without compromising safety. In this study, we reported the clinical case of a SLE patient with predominant renal involvement in overlap with BP, refractory to conventional therapy including RTX alone, achieving significant steroid sparing and clinical remission under sequential treatment of RTX-BLM. Moreover, we describe here the first case of BP successfully treated with BLM.\n\nCase Presentation\nWe describe the clinical case of a 51-year-old Italian man who was diagnosed as having Undifferentiated Connective Tissue Disease in 2010 because of the presence of Raynaud's phenomenon, arthralgias, positivity for antinuclear antibody (ANA, 1:160 fine speckled), antiphospholipid antibodies (aPL) [(anticardiolipin antibodies (ACLA) IgM, 42 U/ml (normal range <20 U/ml), and anti-β2 Glycoprotein 1 (antiB2GP1) IgM, 38 U/ml (normal range <20 U/ml)], and a mild hypocomplementemia, C3 81 mg/dl (normal range 90–180 mg/dl) and C4 8 mg/dl (normal range 8–32 mg/dl). The patient did not report a family history of rheumatic disorders or a personal history of comorbidities and/or previous major surgery. A treatment with hydroxychloroquine (HQC) 400 mg daily and acetylsalicylic acid 100 mg daily was started. In 2011, the patient developed diffuse bullous skin lesions and a skin biopsy of a trunk lesion showed a typical histological picture for BP. Therefore, topical and oral steroid (0.25 mg/kg daily) therapy was started. Subsequently, the patient developed periorbital and lower limb edema, with proteinuria (6.2 g/daily), and a renal biopsy was performed showing histological findings of diffuse membranous glomerulonephritis associated with moderate mesangial hypercellularity (Class V according to ISN/RPS classification, 2003) (28). Therefore, a diagnosis of SLE was made [due to the presence of nephritis, arthritis, ANA/aPL positivity (ACLA IgM 46 U/ml and antiB2GP1 IgM 38 U/ml), and complement level reduction (C3 78 mg/dl and C4 8 mg/dl)] with a Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) of 10; intravenous therapy with steroid (methyl-prednisolone pulses 250 mg for three consecutive days) was started followed by oral prednisone 1 mg/kg daily, subsequently tapered, and combined with mycophenolate mofetil (MMF) 2,000 mg daily and angiotensin-converting enzyme inhibitors, obtaining renal and cutaneous remission. In 2013, after steroid discontinuation, the patient experienced a proteinuric flare (2.5 g/daily) and a BP exacerbation. A second renal biopsy was performed confirming the previous histological nephritis class, and the repetition of skin biopsy documented a histological picture of leukocytoclastic vasculitis in overlap with BP. Oral prednisone was restarted at a dose of 0.5 mg/kg daily, with a slow tapering, and MMF dose was increased at 3,000 mg daily, reaching a resolution of the skin manifestations. In 2014, because of a further proteinuric flare (3 g/daily) and BP skin lesions worsening, B cells depletive treatment with RTX (two infusions of 1 g 14 days apart) was administered in association with MMF (3,000 mg daily) with a partial and temporary clinical remission. Therefore, therapy with Tacrolimus (5 mg/daily) in association with MMF was started, but quickly stopped because of a facial cutaneous rash, and followed by a combination treatment of MMF and Cyclosporine (200 mg/daily), discontinued for the same adverse event. In December 2015 and July 2016, two further retreatments with RTX were performed, with partial clinical response. In December 2016, because of the persistence of hypocomplementemia (C3 81 mg/dl, C4 9 mg/dl), proteinuria (3 g/daily) (SLEDAI 6), and BP lesions, the patient repeated skin and kidney biopsy, showing persistence of skin and kidney active inflammation (Figure 1). Therefore, RTX was discontinued and intravenous BLM (SLE therapeutic scheme, 10 mg/kg monthly) in association with MMF 2,000 mg daily and low-dose prednisone (10 mg daily) was started, leading to a progressive improvement of both renal and skin manifestations. At 24 weeks of follow up, the patient showed a complete cutaneous remission and a significant reduction until normalization of proteinuria, maintaining a complete clinical remission (SLEDAI 0) up to 52 weeks of follow up, allowing a significant reduction of prednisone dosage to 2.5 mg/daily. At the last clinical assessment, proteinuria was absent with normal complement levels (C3 91 mg/dl, C4 18 mg/dl) (Figure 2). Nowadays, the patient is continuing therapy with BLM and MMF and with low dose (2.5 mg/daily) of prednisone without further SLE and BP flares.\n\nFigure 1 (A) Active bullous pemphigoid skin lesions. (B) Histological images in hematoxylin and eosin staining of skin lesion biopsy showing subepidermal blister with a mixed inflammatory infiltrate rich in eosinophils mostly localized in a superficial dermis (10× and 20× magnification, respectively). (C) Periodic acid–Schiff staining images of kidney biopsy showing mesangial hypercellularity; the vessels show a slight moderate reduction of the lumen for sclerosis and myointimal hyperplasia, and vasculitic aspects are not observed (20× and 40× magnification, respectively). (D) Improvement of skin manifestations after therapy.\n\nFigure 2 Changes of SLEDAI, proteinuria, and blood parameters across disease course of patient with systemic lupus erythematosus and bullous pemphigoid. Graphs depict the dynamics of each parameter while receiving different therapeutic schemes. SLEDAI, Systemic Lupus Erythematosus Disease Activity Index; C3, fraction 3 of the complement; C4, fraction 4 of the complement; ESR, erythrocyte sedimentation rate; ACLA, anti-cardiolipin antibodies; antiβ2-GPI, anti-β2 Glycoprotein 1 antibodies.\n\nDiscussion\nThe patient described in this clinical case had long-standing relapsing LN and BP, with skin and kidney biopsies showing persistent tissue inflammation. He had been treated with many different schemes, all of them with unsuccessful outcomes. Renal and skin flares were repeatedly treated with RTX, a drug frequently effective in this clinical setting (29). However, in the patient we describe, RTX only helped to achieve partial remission with early relapses. Thus, BLM was used as an additional option. To date, BLM has been used in patients with LN, mainly to maintain remission (25, 30); however, some clinical cases have been described reporting the use of BLM in the treatment of multiple therapy refractory patients with LN (31). Awaiting the results of ongoing clinical trials, we believe that BLM could be added to the list of potential treatments for patients with refractory LN. It is established that B cell hyperactivity is a landmark in SLE (32), and autoantibody positivity significantly characterizes patients with LN. The randomized trials BLISS-52 and BLISS-76 have documented the efficacy of BLM in autoantibody-positive SLE without previous RTX exposure and without major organ involvement (17, 18), and there is a randomized clinical trial demonstrating that BLM plus Standard Therapy (ST) significantly improves LN renal responses compared with ST alone (BLISS-LN trials; Clinicaltrials.gov identifier: NCT01639339; GSK study 114054) (33). RTX acts by causing a marked B cell depletion (BCD) compared to the more modest effects on BCD induced by BLM. Therefore, the rationale for their consecutive use comes from the observation that significantly higher serum BLyS levels were found during B cell repopulation after RTX treatment, thus leading to disease flares (25, 31, 32). In this context, BCD may lead to ever-increasing levels of BAFF, with an increase in anti-dsDNA antibody levels and disease flare even at low B cell rate (23, 31). Moreover, elevated BLyS plasma levels after RTX would be associated with a paradoxical proliferation of pathogenic B lymphocytes, possibly explaining the therapeutic failure of RTX in clinical trials (34). On the other hand, the increase in BLyS levels could be due to the reduction of its specific receptors that are expressed on B lymphocytes (BAFF-R) (35). Therefore, further studies are needed to address this specific issue.\n\nCurrently, two ongoing open-label clinical trials are evaluating the efficacy of sequential therapy of RTX and BLM: the CALIBRATE (Rituximab and Belimumab for Lupus Nephritis, https://clinicaltrials.gov/ct2/show/NCT02260934, 2015) and the SYNBIoSe study (Synergetic B-Cell Immunomodulation in SLE, https://clinicaltrials.gov/ct2/show/NCT02284984, 2015), respectively. Therefore, the rationale for the combination therapy of BLM with RTX could be to operate through complementary and synergistic mechanisms, as demonstrated in preclinical studies in a lupus-prone mouse model (34, 36). BLM induces the mobilization of memory B lymphocytes from tissues despite an overall reduction in peripheral B cells (37). This phenomenon may lead tissue-resident B cells to be more susceptible to depletion by RTX. Moreover, inhibition of high serum BLyS levels could have favorable quantitative and qualitative effects on the reconstitution of B cells after BCD (32). Recently, a randomized, double-blind, placebo-controlled, 104-weeks superiority study (BLISS-BELIEVE) was started, whose objective is to evaluate the efficacy, safety, and tolerability of a combination therapy with subcutaneous BLM and a single cycle of RTX (1,000 mg at weeks 4 and 6 from the beginning of BLM) compared with BLM alone in adult SLE patients (38). In a phase 2, open-label, single-arm proof-of-concept study conducted by Kraaij et al. (39), SLE patients with severe and refractory disease were treated with a combination of RTX (1000 mg at weeks 0 and 2) and BLM (10 mg/kg BLM at weeks 4, 6, 8, and then every 4 weeks) where an increase of BlyS levels upon RTX-mediated BCD was observed, repealed by subsequent BLM treatment, leading to ANA reduction and to regression of excessive NET formation (neutrophil extracellular traps, web-like structures composed of chromatin backbones and granular molecules, released by activated neutrophils through a process called “NETosis”), with a reduction of proteinuria, SLEDAI, and steroid doses.\n\nIn conclusion, our clinical case suggests that the RTX and BLM combination therapeutic scheme appears to be safe and successful in achieving a clinically significant response, thus representing a valid option for the treatment of severe SLE manifestations, including LN resistant to conventional therapy and RTX. Moreover, to our knowledge, this is the first case of BP described in the literature successfully treated with BLM.\n\nData Availability Statement\nThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.\n\nEthics Statement\nWritten informed consent was obtained from the patient for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\nAll authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.\n\nConflict of Interest\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==== Refs\nReferences\n1. 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Effect of belimumab treatment on renal outcomes: result from the phase 3 belimumab clinical trials in patients with SLE\n. Lupus. (2013 ) 22 :63 –72\n. 10.1177/0961203312465781 23263865 \n17. Navarra SV Guzmán RM Gallacher AE Hall S Levy RA Jimenez RE . Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomized, placebo-controlled, phase 3 trial\n. Lancet. (2011 ) 377 :721 –31\n. 10.1016/S0140-6736(10)61354-2 21296403 \n18. Furie R Petri M Zamani O Cervera R Wallace DJ Tegzová D . A phase III, randomized, placebo controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus\n. Arthritis Rheum. (2011 ) 63 :3918 –30\n. 10.1002/art.30613 22127708 \n19. Hahn BH . Belimumab for systemic lupus erythematosus\n. N Engl J Med. (2013 ) 368 :1528 –35\n. 10.1056/NEJMct1207259 23594005 \n20. Ramos-Casals M Ruiz-Irastorza G Jimé-Nez-Alonso J Khamashta MA . Recommendations on the use of belimumab in systemic lupus erythematosus. GEAS-SEMI clinical practice guide\n. Rev Clin Esp. (2013 ) 213 :42 –58\n. 10.1016/j.rce.2012.10.004 23266125 \n21. Bertsias GK Tektonidou M Amoura Z Aringer M Bajema I Berden JH . Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis\n. Ann Rheum Dis. (2012 ) 71 :1771 –82\n. 10.1136/annrheumdis-2012-201940 22851469 \n22. Fanouriakis A Kostopoulou M Alunno A Aringer M Bajema I Boletis JN . 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus\n. Ann Rheum Dis . (2019 ) 78 :736 –45\n. 10.1136/annrheumdis-2019-215089 30926722 \n23. Lin W Seshasayee D Lee WP Caplazi P McVay S Suto E \nDual B cell immunotherapy is superior to individual anti-CD20 depletion or BAFF blockade in murine models of spontaneous or accelerated lupus\n. Arthritis Rheumatol. (2015 ) 67 :215 –24\n. 10.1002/art.38907 25303150 \n24. Gonzalez-Echavarri C Ugarte A Ruiz-Irastorza G . Rituximab-refractory lupus nephritis successfully treated with belimumab\n. Clin Exp Rheumatol. (2016 ) 34 :355 −6\n. 26886714 \n25. Kraaij T Huizinga TWJ Rabelink TJ Teng YKO . Belimumab after rituximab as maintenance therapy in lupus nephritis\n. Rheumatology. (2014 ) 53 :2122 –4\n. 10.1093/rheumatology/keu369 25205827 \n26. Simonetta F Allali D Roux-Lombard P Chizzolini C . Successful treatment of refractory lupus nephritis by the sequential use of rituximab and belimumab\n. Joint Bone Spine. (2017 ) 84 :235 –6\n. 10.1016/j.jbspin.2016.01.008 27238199 \n27. Gualtierotti R Borghi MO Gerosa M Schioppo T Larghi P Geginat J . Successful sequential therapy with rituximab and belimumab in patients with active systemic lupus erythematosus: a case series\n. Clin Exp Rheum. (2018 ) 36 :643 –7\n. 29533753 \n28. Weening JJ D'Agati VD Schwartz MM Seshan SV Alpers CE Appel GB . The classification of glomerulonephritis in systemic lupus erythematosus revisited\n. J Am Soc Nephrol. (2004 ) 15 :241 –50\n. 10.1097/01.ASN.0000108969.21691.5D 14747370 \n29. Díaz-Lagares C Croca S Sangles S Vital EM Catapano F . Efficacy of rituximab in 164 patients with biopsy proven lupus nephritis: pooled data from European cohorts\n. Autoimmun Rev. (2012 ) 11 :357 –64\n. 10.1016/j.autrev.2011.10.009 22032879 \n30. Flieber E Korsten P Koziolek M Niewold TB Patschan D Müller GA \nSuccessful treatment of a mycophenolate mofetil-refractory proliferative lupus nephritis with belimumab in a 19-year-old woman\n. Lupus. (2013 ) 22 :1523 –5\n. 10.1177/0961203313504145 24014569 \n31. Carter LM Isemberg DA Ehrenstein MR . Elevated serum BAFF levels are associated with rising anti-double-stranded DNA antibody levels and disease flare following B cell depletion therapy in systemic lupus erythematosus\n. Arthritis Rheum. (2013 ) 65 :2672 –9\n. 10.1002/art.38074 23839909 \n32. Dorner T Jacobi AM Lee J Lipsky PE . Abnormalities of B cell subsets in patients with systemic lupus erythematosus\n. J Immunol Methods. (2011 ) 363 :187 –97\n. 10.1016/j.jim.2010.06.009 20598709 \n33. Furie R Rovin BH Houssiau F Malvar A Teng YKO Contrera G . Two-year, randomized, controlled trial of belimumab in lupus nephritis\n. N Engl J Med. (2020 ) 388 :1117 –28\n. 10.1056/NEJMoa2001180 32937045 \n34. Ehreinstein MR Wing C . The BAFFling effects of rituximab in lupus: danger ahead?\n\nNat Rev Rheumatol. (2016 ) 12 :367 –72\n. 10.1038/nrrheum.2016.18 26888554 \n35. Ferraccioli G Gremese E . B cell activating factor (BAFF) and BAFF receptors: fakes and facts\n. Clin Exp Immunol. (2017 ) 190 :291 –2\n. 10.1111/cei.13039 28834574 \n36. Paz Z Tsokos GC . New therapeutics in systemic lupus erythematosus\n. Curr Opin Rheumatol. (2013 ) 25 :297 –303\n. 10.1097/BOR.0b013e32835fd682 23492737 \n37. Stohl W Hiepe F Latinis KM Thomas M Scheinberg MA Clarke A . Belimumab reduces autoantibodies, normalizes low complement levels, and reduces select B cell populations in patients with systemic lupus erythematosus\n. Arthritis Rheum. (2012 ) 64 :2328 –37\n. 10.1002/art.34400 22275291 \n38. Teng YKO Bruce IN Diamond B Furie RA van Vollenhoven RF Gordon D . Phase III, multicentre, randomised, double-blind, placebo-controlled, 104-week study of subcutaneous belimumab administered in combination with rituximab in adults with systemic lupus erythematosus (SLE): BLISS-BELIEVE study protocol\n. BMJ Open. (2019 ) 9 :e025687 . 10.1136/bmjopen-2018-025687 30898822 \n39. Kraaij T Kamerling SWA de Rooij ENM van Daele PLA Bredewold OW Bakker JA . The NET-effect of combining rituximab with belimumab in severe systemic lupus erythematosus\n. J Autoimmun. (2018 ) 91 :45 –54\n. 10.1016/j.jaut.2018.03.003 29636274\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2296-858X",
"issue": "7()",
"journal": "Frontiers in medicine",
"keywords": "belimumab; bullous pemphigoid; lupus nephritis; rituximab; sequential therapy",
"medline_ta": "Front Med (Lausanne)",
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"nlm_unique_id": "101648047",
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"pages": "553075",
"pmc": null,
"pmid": "33195302",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "23263865;20598709;24461673;28852833;22127708;23492737;22231479;23266125;22275291;26886714;27238199;26053285;32937045;24014569;27312166;11821508;23594005;25205827;30926722;25303150;6367666;28834574;28342637;30837635;6752222;14747370;21296403;28352068;22851469;26888554;25529394;29636274;22032879;30898822;27651920;29533753;20039413;23839909;27872476",
"title": "Rituximab Followed by Belimumab Controls Severe Lupus Nephritis and Bullous Pemphigoid in Systemic Lupus Erythematosus Refractory to Several Combination Therapies.",
"title_normalized": "rituximab followed by belimumab controls severe lupus nephritis and bullous pemphigoid in systemic lupus erythematosus refractory to several combination therapies"
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"abstract": "With the exponential growth of COVID-19 cases, the neurological complications reported during or after the infection became more common. There is limited knowledge regarding the pathophysiological mechanisms that are responsible for these complications. Recent data provides compelling evidence for the neurotropic nature of SARS-CoV-2, based on neurological manifestations reported during the current pandemic, as well as on previous experience with other coronaviruses. We present the case of a patient who developed headaches, motor deficit and dysphasia after respiratory COVID-19. Imaging tests showed heterogeneous central nervous system lesions (multiple subarachnoid hemorrhages and two ischemic strokes). Given the plethora of atypical neurological complications of COVID-19 described in the current literature, establishing a positive diagnosis and deciding on a treatment plan proved to be particularly challenging. We set to discuss some of the possible pathologies, hypothesized to be associated with COVID-19, that could lead to concomitant neurological lesions, similar to those noticed in our patient.",
"affiliations": "Neurology Department, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.;Neurology Department, Cluj-Napoca County Emergency Hospital, Cluj-Napoca, Romania.;Neurology Department, Cluj-Napoca County Emergency Hospital, Cluj-Napoca, Romania.",
"authors": "Vacaras|Vitalie|V|;Frunze|Sorina|S|;Cordos|Adrian Mihai|AM|",
"chemical_list": "D000914:Antibodies, Viral",
"country": "Romania",
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"doi": "10.25122/jml-2021-0045",
"fulltext": "\n==== Front\nJ Med Life\nJ Med Life\nJMedLife\nJournal of Medicine and Life\n1844-122X\n1844-3117\nCarol Davila University Press Romania\n\n10.25122/jml-2021-0045\nJMedLife-14-216\nOriginal Article\nNeurological complications in COVID-19 – a diagnostic challenge\nVacaras Vitalie 12\nFrunze Sorina 2*\nCordos Adrian Mihai 2\n1. Neurology Department, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania\n2. Neurology Department, Cluj-Napoca County Emergency Hospital, Cluj-Napoca, Romania\n* Corresponding Author: Sorina Frunze, Resident Doctor, Neurology Department, Cluj-Napoca County Emergency Hospital, 43 Victor Babes street, Cluj-Napoca, Romania. Phone: +40743491496 E-mail: sorina_frunze@yahoo.com\nMar-Apr 2021\n14 2 216224\n23 2 2021\n2 4 2021\n©2021 JOURNAL of MEDICINE and LIFE\n2021\nhttps://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use and redistribution provided that the original author and source are credited.\nWith the exponential growth of COVID-19 cases, the neurological complications reported during or after the infection became more common. There is limited knowledge regarding the pathophysiological mechanisms that are responsible for these complications. Recent data provides compelling evidence for the neurotropic nature of SARS-CoV-2, based on neurological manifestations reported during the current pandemic, as well as on previous experience with other coronaviruses. We present the case of a patient who developed headaches, motor deficit and dysphasia after respiratory COVID-19. Imaging tests showed heterogeneous central nervous system lesions (multiple subarachnoid hemorrhages and two ischemic strokes). Given the plethora of atypical neurological complications of COVID-19 described in the current literature, establishing a positive diagnosis and deciding on a treatment plan proved to be particularly challenging. We set to discuss some of the possible pathologies, hypothesized to be associated with COVID-19, that could lead to concomitant neurological lesions, similar to those noticed in our patient.\n\nneurology\nCOVID-19\nstroke\nsubarachnoid hemorrhage\ncardiovascular medicine\nACE2 – angiotensin converting enzyme II\nBBB – blood-brain barrier\nBMI – body mass index\nBP – blood pressure\nCNS – central nervous system\nCOVID-19 – coronavirus disease\nCRP – C-reactive protein\nCSF – cerebrospinal fluid\nCT – Computer tomography\nCTA – Computer tomography angiography\nCVT – cerebral venous thrombosis\nECG – electrocardiogram\nHolter ECG – Holter electrocardiogram\nHR – heart rate\nI.V. – intravenous\nMRA – Magnetic resonance angiography\nLMWH – low molecular weight heparin\nMRC scale – Medical Research Council's scale\nMRI – Magnetic resonance imaging\nPACNS – primary angiitis of the central nervous system\nPCA – posterior cerebral artery\nPCoA – posterior communicating artery\nPCR – polymerase chain reaction\nRCVS – reversible cerebral vasoconstriction syndrome\nRT-PCR – real-time polymerase chain reaction\nRR – reference range\nSAH – subarachnoid hemorrhage\nSARS-CoV-2 – severe acute respiratory syndrome coronavirus 2\nUL – upper limit\n==== Body\nIntroduction\n\nIn December 2019, several health facilities in China reported clusters of patients presenting with pneumonia of unknown etiology, which soon led to the discovery of a novel coronavirus named 2019-nCoV [1, 2]. The virus was later given the official name, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), and the disease it was responsible for was named Coronavirus Disease 2019 (COVID-19) [3]. On March 11, 2020, after the virus spread to 114 countries and the total number of cases reached 118.000, COVID-19 was declared a pandemic [4].\n\nA retrospective, single-center case series of 138 hospitalized patients with confirmed COVID-19 pneumonia, set in Wuhan, China, reported in 2020 that the most common symptoms at illness onset were fever, fatigue, dry cough, myalgia, and dyspnea. Less common symptoms were also reported and included neurological manifestations, such as headache and dizziness [5]. With the exponential growth of reported COVID-19 cases, the neurological complications reported became more common. In a review by Sheraton et al., the authors discussed the various neurological manifestations reported in retrospective studies, systematic reviews, and case reports published in previous months. The possible signs, symptoms, and complications that were observed regarding the central nervous system (CNS) were: headache, dizziness, alteration of mental status and delirium, dysexecutive syndrome, ataxia, acute cerebrovascular attacks, seizures, acute encephalitis, infectious and para-infectious encephalopathy, meningitis. Both ischemic and hemorrhagic stroke types were seen, with ischemic strokes being more common [6]. We reviewed the literature for proposed pathophysiological mechanisms by which SARS-CoV-2 can lead to the neurological complications presented above. They can be grouped as follows:\n\n• Direct infection injury – resulting from infection of neurons and glial cells through blood circulation and neuronal pathways [6–9];\n\n• Indirect effects of the infection on the nervous system – through hypoxia, systemic inflammatory response, hypercoagulability, and endothelial lesions (through direct lesions of the endothelial cells caused by the virus) [6–8, 10].\n\nThere are six other members, besides SARS-CoV-2, of the pathogenic coronaviruses family that cause human disease. The data from various studies regarding these coronaviruses suggest an evident neurotropism [10]. The new coronavirus may not be any different in this regard. It has been proposed that SARS-CoV-2 could use the expression of angiotensin-converting enzyme-2 (ACE2) in nervous tissue to gain entry inside neurons and glial cells [8, 10]. Non-ACE2 pathways for the infection of neural cells cannot be excluded (such as direct endocytotic infection) [10].\n\nThe neuronal pathway refers to the entry of a neurotropic virus in the CNS through the infection of sensory or motor nerve endings [6]. An example of a neuronal pathway is through the olfactory nerves and the olfactory bulb via a direct trans-synaptic route. This mechanism has been shown to be true for other coronaviruses as well [6, 10] and can lead to neuronal damage without substantial inflammation [9, 11]. In mice, ablation of the olfactory bulb prevented the spread of mouse hepatitis virus (MHV), a coronavirus that is genetically related to human coronaviruses, to the brain tissue [9]. Netland et al. used mice transgenic for human ACE2 to show that SARS-CoV enters the brain primarily via the olfactory bulb [11]. It is hypothesized that the data could be extrapolated for SARS-CoV-2 [8, 9, 11].\n\nThe blood circulation pathway refers to the entry of a virus in the CNS through the blood-brain barrier (BBB). It is potentiated by an increase in the BBB's permeability through endothelial lesions and systemic inflammation [6]. Endothelial cells also express ACE2, which allegedly interacts with the virus. Damage to the endothelial lining can favor viral access to the brain [8, 10]. Endothelial lesions resulting from the virus binding to the ACE2 and the cytokines and chemokines released during the systemic inflammatory response could also potentially lead to a rupture of the capillaries accompanied by bleeding within the cerebral tissue. They could also lead to neuroinflammation that severely disturbs brain homeostasis and causes neuronal cell death [8, 10]. Hypoxia due to respiratory distress is also an essential factor that could potentially lead to cerebral vasodilatation, cell swelling, and edema or stroke [7, 12]. The significantly increased inflammatory response due to the cytokine storm caused by the SARS-CoV-2 could be one of the causes of abnormal blood coagulation and lead to ischemic strokes and other cardiovascular events [7, 13].\n\nThe pathophysiology of CNS involvement in COVID-19 is mostly hypothetical. It is based on previous experience with other coronaviruses and could potentially be used as an explanation for the neurological manifestations in COVID-19. We present the case of a patient who developed multiple cerebral lesions, both ischemic and hemorrhagic, after being diagnosed with COVID 19 without a clear pathophysiological mechanism, which required taking into account various differential diagnoses.\n\nCase Presentation\n\nA 50-year old Caucasian male residing in an urban area with right laterality was admitted to our Neurology Department with the complaint of weakness of the right limbs and impairment of the speaking ability. The symptoms had an acute onset, 5 days prior to presentation to our department. Family history revealed that the patient’s father had type II diabetes mellitus and suffered a cerebral ischemic stroke at 52. The patient had been a smoker (3 packs per day for 30 years) but was abstinent for the last 8 years. He also had class III obesity (body mass index of 42 kg/m22).\n\nPatient history\n\nNine days prior to developing neurological symptoms, the patient presented to the Emergency Department nearest to home with dry cough, myalgia, pronounced fatigue, shivers, and fever (up to 39°C). A real-time polymerase chain reaction (RT-PCR) test was performed from a nasal swab sample in order to test for COVID-19, and the test came back positive. The patient was admitted to the Infectious Diseases Unit. A computed tomography (CT) scan of the chest was performed. It revealed bilateral, relatively symmetrical areas with ground-glass attenuation. Notable laboratory findings showed a biological inflammatory syndrome consisting of elevated C-reactive protein (CRP) levels – 8.3 mg/l, upper limit (UL) <5 mg/l), elevated fibrinogen (470 mg/dl, UL<400mg/dl), total leukocytes within the normal range but with lymphopenia – 5.5%, reference range (RR) = 20–40%) and neutrophilia (90.3%, RR=50–70%). During this time, D-dimer levels and platelet count were within the normal range. According to the World Health Organization (WHO) criteria for the severity of COVID-19 infection [14], the patient had a moderate form of infection. The treatment regimen consisted of Lopinavir/Ritonavir, Hydroxychloroquine 800mg/day, Enoxaparin 6000 IU/day, and Paracetamol (up to 2g per day). O2 saturation levels remained >96%. During the following week, the symptoms subsided, as well as the biological inflammatory syndrome. After 6 days, another RT-PCR test was performed. It came back negative, and the patient was discharged on the seventh day.\n\nTwo days after discharge, the patient woke up with weakness in the right limbs and troubled speaking, associated with generalized headache, nausea, and vomiting. He was transported to the regional Emergency Department. The on-call neurologist examined the patient. On neurological examination, hemiparesis (with a score of 4/5 on the Medical Research Council’s scale (MRC scale), central face palsy, diminished deep tendon reflexes, and extensor plantar reflex regarding the right side were objectified, along with motor dysphasia.\n\nA CT scan of the head without contrast medium was performed (about 6 hours after the patient noted the symptoms), but it did not show any abnormalities in the brain parenchyma. The bloodwork revealed mild leukocytosis (12.000/mm3, RR= 4.000–10.000/mm3) with neutrophilia (8.700/mm3, RR = 2.000–8000/mm3), elevated D-dimers (897.56 ng/ml, RR< 500 ng/ml). An acute cerebrovascular event was suspected, and the patient was started on dual antiplatelet therapy (Aspirin 75 mg per day + Clopidogrel 75 mg per day) and statin (Atorvastatin 40 mg per day). The blood pressure and heart rate were within the normal range. The electrocardiogram (ECG) was also normal. Thrombolysis was not indicated given the uncertainty regarding the moment of onset of the symptoms. A head CT without contrast medium was repeated (about 13 hours after the first one), along with a CT scan of the chest (Figures 1, 2).\n\nFigure 1. CT-scan, axial cross-sections of the brain. A, C, D - Arrows pointing to punctate subarachnoid hemorrhages. B - Arrow points to a small ischemic lesion with a narrow rim of hemorrhage.\n\nFigure 2. Chest CT. Axial cross-section (A) and coronal cross-section (B) showing diffuse areas with ground-glass attenuation.\n\nThe CT scan showed multiple hyperdense lesions, two of them located in the left frontal lobe (Figure 1A, Figure 1D), the right parietal lobe (Figure 1C), and the left parietal lobe (Figure 1D) that the radiologist interpreted as minimal subarachnoid hemorrhage. A small hypodense lesion with a narrow hyperdense rim was seen in the left temporoparietal region that was suggestive of an acute ischemic stroke with minimal hemorrhagic transformation (Figure 1B). The second chest CT was similar to the previous one, with bilateral relatively symmetrical areas with ground-glass attenuation (Figure 2).\n\nGiven the hemorrhagic nature of the lesions seen on the head CT (Figure 1), antiplatelet therapy was temporarily ceased. The patient received prophylactic Low-molecular-weight heparin (LMWH) – Enoxaparin 6000 IU/day and Paracetamol (up to 2g per day). An RT-PCR test was performed on the second day of admission with an equivocal result and another on the fourth day with a negative result. Nausea and vomiting did not persist after the first day. The intermittent frontal headache persisted during the time of admission, as well as the motor deficit and dysphasia, with a slight improvement. The patient was afterward transferred to our department, 5-days after the onset of the neurological symptoms.\n\nOn admission to our neurology hospital, the general and neurological examination and also hematological and biochemical parameters did not reveal any additional information compared to the prior examinations. Intermittent frontal headaches were persistent. The blood pressure (BP), heart rate, and O2 saturation levels were within the normal range. The patient was not dyspneic and had only mild coughing.\n\nA head CT with angiography was performed 6 days after the onset of neurological symptoms. A slight improvement over the previous examination was seen regarding the subarachnoid and intraparenchymal hemorrhages (Figure 3A and 3B). A filling defect was observed in the C1 segment of the left internal carotid artery on angiography (Figure 3C) that was interpreted as partial thrombosis of the artery. Partial occlusion of the P1 segment of the right posterior cerebral artery, as well as narrowing of the P1 and P2 segments of the left posterior cerebral artery, were observed (Figure 4A). Tubular stenosis in the V4 segment of the left vertebral artery was also noted (Figure 4B).\n\nFigure 3. CT scan of the brain. Axial cross-section images showing the subarachnoid hemorrhage in the left frontal lobe (A) and the ischemic lesion in the left temporoparietal region (B). CT angiography, coronal cross-section, revealing a small filling defect in the cervical segment of the left internal carotid artery (C).\n\nFigure 4. CT Angiography. Posterior circulation revealing both P1 segments of the posterior cerebral arteries are abnormally narrow (A). Arrow pointing to a tubular stenosis of the V4 segment of the left vertebral artery (B). PCA – Posterior cerebral artery; PCoA – Posterior communicating artery.\n\nA pulmonologist was consulted, and Dexamethasone 8 mg/day i.v. for 5 days with subsequent dose tapering was recommended, alongside prophylactic LMWH. Multiple ECG examinations were performed during the patient’s stay in the hospital, but none showed abnormalities.\n\nA head magnetic resonance imaging (MRI) with contrast medium was performed 8 days after the onset of neurological symptoms to evaluate better the heterogeneous lesions in the brain parenchyma as well as the arterial and venous circulation. The cortico-subcortical temporoparietal lesion in the left hemisphere was compatible with a subacute ischemic stroke associated with minimal hemorrhagic transformation in the superficial territory of the left middle cerebral artery (Figure 5A-E). A similar, smaller lesion without any sign of hemorrhagic conversion was also observed in the left parietal lobe, posteriorly to the first one (Figure 5F-H). Minimal subarachnoid hemorrhage was described adjacent to the left frontal lobe (Figure 5I-K). The magnetic resonance angiography (MRA) revealed the same arterial lesions that were previously described on the computed tomography angiography (CTA): a small filling defect regarding the C1 segment of the left internal carotid artery as well as the stenoses of the left vertebral artery and the P1 segments of both posterior cerebral arteries. The MR-venogram did not show any abnormalities.\n\nFigure 5. MRI scan of the brain, axial cross-section images. A–C) T2WI, FLAIR and DWI sequences showing the ischemic lesion in the left temporoparietal region. D, E) T1WI and SWI sequences revealing the hemorrhagic conversion of the lesion. F–H) T2WI, FLIAR and DWI sequences revealing a second ischemic lesion in the posterior area of the left parietal lobe. I–K) FLAIR and SWI sequences showing a convexal subarachnoid hemorrhage in the left frontal lobe. T2WI – T2 weighted image; FLAIR – Fluid attenuated inversion recovery; DWI – diffusion-weighted imaging.\n\nGiven the heterogeneous nature of lesions present in our case and the plethora of atypical neurological complications in COVID-19 described in current literature (see the Discussion section), a lumbar puncture was performed to evaluate the possibility of encephalitis and cerebral vasculitis. Macroscopically, the cerebrospinal fluid (CSF) was clear. The biochemical and cytological examination was normal. Due to technical limitations, RT-PCR was not performed, so the presence of the SARS-Cov-2 genome in the CSF was not evaluated. The IgG index and the IgG ratio were normal as well. The serum biomarkers for autoimmune vasculitis were not present. CSF and serum analysis for various infectious pathogens that could cause encephalitis was performed, and we did not find any causative agents in our patient (Tables 1, 2). Thus, a diagnosis of encephalitis or cerebral vasculitis was considered to be unlikely.\n\nTable 1. Multiplex PCR for Microbial Detection in Spinal Fluid (BIOFIRE FLMARRAY Panel).\n\nCausative agent\tResult\t\nEscherichia coli K1\tUndetectable\t\nHaemophilus influenzae\tUndetectable\t\nListeria monocytogenes\tUndetectable\t\nNeisseria meningitidis\tUndetectable\t\nStreptococcus agalactiae\tUndetectable\t\nStreptococcus pneumoniae\tUndetectable\t\nCytomegalovirus\tUndetectable\t\nEnterovirus\tUndetectable\t\nHerpes simplex virus 1\tUndetectable\t\nHerpes simplex virus 2\tUndetectable\t\nHerpes simplex virus 6\tUndetectable\t\nParechovirus\tUndetectable\t\nVaricella Zoster virus\tUndetectable\t\nCryptococus neoformans/gattii\tUndetectable\t\n\nTable 2. Serum antibodies (IgG and IgM) for various causative agents.\n\nCausative agent\tIgM antibodies\tIgG antibodies\t\nHerpes simplex virus 1\tNegative\tPositive\t\nHerpes simplex virus 2\tNegative\tNegative\t\nEpstein – Barr virus\tNegative\tPositive\t\nCytomegalovirus\tNegative\tPositive\t\nVaricella Zoster virus\tNegative\tPositive\t\nToxoplasma gondii\tNegative\tPositive\t\nBorrelia burgdorferi\tNegative\tNegative\t\n\nThe clinical evolution was favorable during his 7-day stay in our hospital. The headaches disappeared after a few days. The motor deficit and dysphasia showed improvement as well. No abnormal laboratory results were present at the moment of discharge. The patient was referred to a cardiologist, a kinesiotherapist, and a logopedist after discharge, and the treatment plan consisted of Enoxaparin 6000 UI/day for a month and Aspirin 75 mg/day. A neurological re-examination (clinical and imaging) was scheduled one month later.\n\nDiscussion\n\nThe case we presented raised multiple questions and possibilities regarding the differential diagnosis and the pathophysiological mechanism which could have been responsible for the lesions. There are a few pathologies that can lead to concomitant multifocal subarachnoid bleeds and ischemic strokes and could potentially be associated with a viral infection, such as COVID-19.\n\nIschemic strokes in the setting of COVID-19 have been described in recent literature and seem to be relatively frequent. In a study published by Li et al., 10 out of 219 patients hospitalized for a COVID-19 infection developed an ischemic stroke [13]. The median time span from the first symptoms of SARS-CoV-2 infection to cerebrovascular disease was 10 days (ranging from 1 to 29). There are other studies that have also reported acute cerebrovascular events amongst these patients, and the severity of COVID-19 varied from mild to severe illness [15, 16]. It has been proposed that any acute infection could elicit an inflammatory activation in the plaque that could potentially lead to ischemic atherothrombotic events. Given the fact that COVID-19 also interacts with endothelial cells through the ACE receptors, this mechanism seems plausible. As previously mentioned, our patient also had a filling defect on the left internal carotid artery that could be interpreted in this setting [17, 18]. The possibility of a cardioembolic event was also discussed. There is emerging evidence that COVID-19 can associate with myocarditis [19], which could lead to cardioembolic events through various mechanisms (e.g., atrial fibrillation). Multiple ECG examinations were performed during admission, and although they were normal, paroxysmal arrhythmias cannot be excluded. The patient was referred to a cardiologist immediately after discharge for a Holter-ECG and an echocardiogram. A short note should be made regarding the D-dimer levels dynamic seen in our patient. D-dimers can increase during a COVID-19 infection, and abnormal levels could potentially indicate a poor prognosis [20]. The levels seen in our patient were normal until he developed neurological symptoms. Thus, it is more probable that the increase was due to the thrombus presence in a cerebral artery.\n\nUnfortunately, the aspect discussed above did not explain the subarachnoid bleeds associated, and other possible pathologies were thus taken into account.\n\nGiven the presence of headache alongside neurological deficits, the imaging features, and the cerebral territories affected, we raised the suspicion of multiple cerebral venous thromboses (CVT). It has been proposed that SARS-CoV-2 could predispose to endothelial lesions and hypercoagulability, which could in turn potentially lead to CVT [18, 21, 22]. Numerous cases of CVT in patients infected with SARS-CoV-2 were reported in the literature [23–28]. Shakibajahromi et al. suggested that the presence of any unexplained and atypical hemorrhagic lesion in the initial brain CT of COVID-19 patients should raise the suspicion of CVT [27]. Oppenheim et al. also concluded that CVT should be considered when SAH is present, and the basal cistern is not involved [29], even if the subarachnoid hemorrhage is infrequent in the setting of a CVT [30]. An ischemic lesion, sometimes with a hemorrhagic component that crosses usual arterial boundaries or in close proximity to a venous sinus, is suggestive of CVT [30]. Our MRI and MR-venography excluded this possibility; however, any clinician should take into account the possibility of CVT when a COVID-19 patient presents with similar symptoms.\n\nTwo other similar pathologies we took into account, in terms of clinical features and imaging particularities, were primary angiitis of the central nervous system and the reversible cerebral vasoconstriction syndrome [31, 32]. Both pathologies could potentially be associated with infectious events and can cause ischemic strokes and small subarachnoid hemorrhage (SAH). We have also found in the literature a couple of case reports of patients who developed primary angiitis of the central nervous system (PACNS) [33] or reversible cerebral vasoconstriction syndrome (RCVS) [34] during or after COVID-19. Dakay et al. even proposed a mechanism through which SARS-CoV-2 could lead to RCVS and SAH. By interacting with endothelial cells and ACE2 receptors, it could cause dynamic vessel wall changes, vasoconstriction followed by vasodilation, leading to reperfusion injury and hemorrhage [34]. There are a few differentiating factors regarding RCVS and PACNS. RCVS usually present with severe thunderclap headaches, while PACNS patients have progressive, dull headaches [31, 32]. Our patient had moderate, intermittent headaches that subsided after a few days. However, in rare cases, headaches in RCVS can be mild or even absent [32]. We could hypothesize that cases with mild or moderate headaches could be more frequent, given the fact that RCVS is often misdiagnosed and a major criterion for establishing the diagnosis is the presence of severe, acute headaches [31, 32]. On the other hand, CSF examination is usually normal in RCVS and abnormal in >95% of PACNS patients [31, 32]. As we stated above, the CSF analysis was normal in the case of our patient. The CT and MR angiographies (performed 6–8 days after the onset of neurological symptoms) revealed some abnormalities concerning a segment of the left vertebral artery and both posterior cerebral arteries (P1 segments). In RCVS, the abnormalities on neurovascular imaging are present in the acute stage and are reversible within days to weeks, while those in PACNS are frequently irreversible [31, 32]. Nevertheless, in our patient, the stenoses present on the P1 segment of the posterior cerebral arteries could be a congenital variant. These aspects remain to be evaluated at the 1-month follow-up. Therefore, we could not rule out either of these diagnoses, and they both remain possible, albeit somewhat improbable.\n\nLast but not least, there have been cases of SARS-CoV-2-associated encephalitis and encephalopathy, with various atypical clinical manifestations and imaging features, in recent publications [35–40]. Moriguchi et al. presented a case of meningitis/encephalitis with a positive RT-PCR test for SARS-CoV-2 from the CSF, thus showing the neuro-invasive potential of the virus [38]. Zuhorn et al. presented a case of parainfectious encephalitis that they believed was of autoimmune nature, given that their patient had a negative RT-PCR test from the CSF [40]. Paniz et al. hypothesized that failure to detect the virus in the CSF in their case and others could have several explanations. The first potential explanation is that the virus is mainly cell-bound, spreading from cell to cell. Another possibility is that the virus may be at concentrations below the level of detection of the testing method and a third possibility is the presence of low concentrations of endonucleases/exonucleases and proteins acting as inhibitors in the CSF [18]. Patel et al. published a case presentation of a Varicella-zoster virus encephalitis associated with the COVID-19 infection, underlying the fact that COVID-19 could lead to an immunosuppressed state (due to the infection itself or immunosuppressant drugs) that allows other pathogens to reactivate (41). As we stated before, we could not evaluate the presence of SARS-CoV-2 in the CSF of our patient due to technical limitations. However, given the unspecific and equivocal neurological findings in patients with COVID-19, we prompt our readers to be diligent when evaluating such patients.\n\nConclusion\n\nThe spectrum of neurological complications in COVID-19 is not yet sufficiently understood and remains to be discovered and explained through more extensive studies. Still, the limited knowledge at this time should not cloud the clinical judgment but determine clinicians to fully investigate their patients, be diligent in evaluating current literature, and report their findings, even if a conclusive, positive diagnosis could not be established. Our case proved to be challenging in terms of differential diagnosis, and we hope that future research will shed light on the pathophysiological mechanisms through which SARS-CoV-2 interacts with and affects the nervous system.\n\nAcknowledgments\n\nThe authors would like to thank Ioana Robu from the Iuliu Hatieganu University of Medicine and Farmacy of Cluj, Romania, for her help in editing this manuscript.\n\nConflict of interest\n\nThe authors declare that there is no conflict of interest.\n==== Refs\nReferences\n\n1. Zhu N Zhang D Wang W Li X Yang B Song J Zhao X Huang B Shi W Lu R Niu P Zhan F Ma X Wang D Xu W Wu G Gao GF Tan W. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020 382 8 727 733 31978945\n2. World Health Organization. Pneumonia of unknown cause – China. WHO. 2020 1 5 Accesed November 12, 2020. https://www.who.int/csr/don/05-january-2020-pneumonia-of-unkown-cause-china/en/\n3. World Health Organization. Naming the coronavirus disease (COVID-19) and the virus that causes it. 2020. Accesed November 12, 2020. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance/naming-the-coronavirus-disease-(covid-2019)-and-the-virus-that-causes-it\n4. World Health Organization. WHO Director-General's opening remarks at the media briefing on COVID-19 – 11 March 2020. 2020 3 11 Accesed November 12, 2020. https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020\n5. Wang D Hu B Hu C Zhu F Liu X Zhang J Wang B Xiang H Cheng Z Xiong Y Zhao Y Li Y Wang X Peng Z. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China. JAMA. 2020 323 11 1061 32031570\n6. Sheraton M Deo N Kashyap R Surani S A review of neurological complications of covid-19. Cureus. 12 5 e8192 32455089\n7. Wu Y Xu X Chen Z Duan J Hashimoto K Yang L Liu C Yang C Nervous system involvement after infection with COVID-19 and other coronaviruses. Brain, Behavior, and Immunity. 2020 87 18 22\n8. Baig AM Khaleeq A Ali U Syeda H Evidence of the covid-19 virus targeting the cns: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms. ACS Chem Neurosci. 2020 11 7 995 998 32167747\n9. Bohmwald K Gálvez NMS Ríos M Kalergis AM Neurologic alterations due to respiratory virus infections. Front Cell Neurosci. 2018 12 386 30416428\n10. Steardo L Steardo L Zorec R Verkhratsky A Neuroinfection may contribute to pathophysiology and clinical manifestations of COVID-19. Acta Physiol. 2020 229 3\n11. Netland J Meyerholz DK Moore S Cassell M Perlman S Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ace2. J Virol. 2008 82 15 7264 7275 18495771\n12. Groppa S Zota E Zota E Chiosa V Gasnaș A Ciobanu N Vatamanu A Ciolac D Munteanu C Leahu P Catereniuc D Condratiuc E Efremova D Crivorucica I Aftene D Glavan D Bălănuță T Balitei D Ropot D. Neurological aspects in the context of the SARS-Cov-2 pandemic. Revista de Ştiinţe ale Sănătăţii din Moldova. 2020 1 23 2345 1467\n13. Li Y Li M Wang M Zhou Y Chang J Xian Y Wang D Mao L Jin H Hu B Acute cerebrovascular disease following COVID-19: a single center, retrospective, observational study. Stroke Vasc Neurol. 2020 5 3 279 284 32616524\n14. World Health Organization. Clinical management of COVID-19. WHO Headquarters: WHO 2020 https://www.who.int/publications/i/item/clinical-management-of-covid-19. Accesed November 12, 2020\n15. Mao L Jin H Wang M Hu Y Chen S He Q Chang J Hong C Zhou Y Wang D Miao X Li Y. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in wuhan, china. JAMA Neurol. 2020 77 6 683 32275288\n16. Tunç A Ünlübaş Y Alemdar M Akyüz E. Coexistence of COVID-19 and acute ischemic stroke report of four cases. Journal of Clinical Neuroscience. 2020 77 227 229 32409210\n17. Hansson GK Libby P Tabas I Inflammation and plaque vulnerability. J Intern Med. 2015 278 5 483 493 26260307\n18. Paniz-Mondolfi A Bryce C Grimes Z Gordon RE Reidy J Lednicky J Sordillo EM Fowkes M Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). J Med Virol. 2020 92 7 699 702 32314810\n19. Siripanthong B Nazarian S Muser D Deo R Santangeli P Khanji MY Cooper LT, Jr Chahal CAA Recognizing COVID-19–related myocarditis: The possible pathophysiology and proposed guideline for diagnosis and management. Heart Rhythm. 2020 17 9 1463 1471 32387246\n20. Yu B Li X Chen J Ouyang M Zhang H Zhao X Tang L Luo Q Xu M Yang L Huang G Liu X Tang J. Evaluation of variation in D-dimer levels among COVID-19 and bacterial pneumonia: a retrospective analysis. J Thromb Thrombolysis. 2020 50 3 548 557 32524516\n21. CRICS TRIGGERSEP Group (Clinical Research in Intensive Care and Sepsis Trial Group for Global Evaluation and Research in Sepsis) Helms J Tacquard C Severac F Leonard-Lorant I Ohana M Delabranche X Merdji H Clere-Jehl R Schenck M Gandet FF Fafi-Kremer S Castelain V Schneider F Grunebaum L Anglés Cano E Sattler L Mertes PM Meziani F. High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. 2020 46 6 1089 1098 32367170\n22. Singhania N Bansal S Nimmatoori DP Ejaz AA McCullough PA Singhania G Current overview on hypercoagulability in covid-19. Am J Cardiovasc Drugs. 2020 20 5 393 403 32748336\n23. Hemasian H Ansari B First case of Covid-19 presented with cerebral venous thrombosis: A rare and dreaded case. Revue Neurologique. 2020 176 6 521 523 32414532\n24. Chougar L Mathon B Weiss N Degos V Shor N Atypical deep cerebral vein thrombosis with hemorrhagic venous infarction in a patient positive for covid-19. AJNR Am J Neuroradiol. 2020 41 8 1377 1379 32554423\n25. Poillon G Obadia M Perrin M Savatovsky J Lecler A Cerebral venous thrombosis associated with COVID-19 infection: Causality or coincidence? Journal of Neuroradiology. 2020 5 Published online\n26. Klein DE Libman R Kirsch C Arora R Cerebral venous thrombosis: Atypical presentation of COVID-19 in the young. Journal of Stroke and Cerebrovascular Diseases. 2020 29 8 104989 32689590\n27. Shakibajahromi B Borhani-Haghighi A Haseli S Mowla A Cerebral venous sinus thrombosis might be under-diagnosed in the COVID-19 era. eNeurologicalSci. 2020 20 100256 32704578\n28. Mowla A Shakibajahromi B Shahjouei S Shahjouei S Borhani-Haghighi A Rahimian N Baharvahdat H Naderi S Khorvash F Altafi D Ebrahimzadeh SA Farahmand G Far AV Sharma VK Neshin SAS Tsivgoulis G Zand R. Cerebral venous sinus thrombosis associated with SARS-CoV-2; a multinational case series. Journal of the Neurological Sciences. 2020 419 117183 33075595\n29. Oppenheim C Domigo V Gauvrit JY Lamy C Mackowiak-Cordoliani MA Pruvo JP Méder JF. Subarachnoid hemorrhage as the initial presentation of dural sinus thrombosis. AJNR Am J Neuroradiol 2005 26 614 15760875\n30. Saposnik G Barinagarrementeria F Brown RD Bushnell CD Cucchiara B Cushman M deVeber G Ferro JM Tsai FY Diagnosis and management of cerebral venous thrombosis: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011 42 4 1158 1192 21293023\n31. Calabrese LH Dodick DW Schwedt TJ Singhal AB Narrative review: reversible cerebral vasoconstriction syndromes. Ann Intern Med. 2007 146 1 34 44 17200220\n32. Ducros A. Reversible cerebral vasoconstriction syndrome. The Lancet Neurology. 2012 11 10 906 917 22995694\n33. Vaschetto R Cena T Sainaghi PP Meneghetti G Bazzano S Vecchio D Pirisi M Brustia D Barini M Cammarota G Castello L Corte FD. Cerebral nervous system vasculitis in a Covid-19 patient with pneumonia. J Clin Neurosci. 2020 79 71 73 33070922\n34. Dakay K Kaur G Gulko E Santarelli J Bowers C Mayer SA Gandhi CD Al-Mufti F. Reversible cerebral vasoconstriction syndrome and dissection in the setting of COVID-19 infection. J Stroke Cerebrovasc Dis. 2020 29 9 105011 32807426\n35. Chalil A Baker CS Johnston RB Just C Bebicki DB Mayich MS Bosma KJ Steven DA Acute hemorrhagic encephalitis related to covid-19. Neurol Clin Pract. Published online July 8, 2020:10.1212/CPJ.0000000000000900\n36. Poyiadji N Shahin G Noujaim D Stone M Patel S Griffith B Covid-19–associated acute hemorrhagic necrotizing encephalopathy: imaging features. Radiology. 2020 296 2 E119 E120 32228363\n37. Filatov A Sharma P Hindi F Espinosa PS Neurological complications of coronavirus disease (COVID-19): encephalopathy. Cureus. 12 3\n38. Moriguchi T Harii N Goto J Harada D Sugawara H Takamino J Ueno M Sakata H Kondo K Myose N Nakao A Takeda M Haro H Inoue O Suzuki-Inoue K Kubokawa K Ogihara S Sasaki T Kinouchi H Kojin H Ito M Onishi H Shimizu T Sasaki Y Enomoto N Ishihara H Furuya S Yamamoto T Shimada S. A first case of meningitis/encephalitis associated with SARS-Coronavirus-2. International Journal of Infectious Diseases. 2020 94 55 58 32251791\n39. Krett JD Jewett GAE Elton-Lacasse C Fonseca K Hahn C Au S Koch MW Hemorrhagic encephalopathy associated with COVID-19. Journal of Neuroimmunology. 2020 346 577326 32683185\n40. Zuhorn F Omaimen H Ruprecht B Stellbrinck C Rauch M Rogalewski A Klingebiel R Schäbitz WR. Parainfectious encephalitis in covid-19: “the claustrum sign.” J Neurol. 2020 9 3 1 4 Published online\n41. Patel P Undavia A Choudry R Zhang Y Prabhu AM COVID-19 associated with concomitant Varicella Zoster Viral Encephalitis. Neurol Clin Pract. 2020 7 8 Published online 10.1212/CPJ.0000000000000902\n\n",
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"keywords": "ACE2 – angiotensin converting enzyme II; BBB – blood-brain barrier; BMI – body mass index; BP – blood pressure; CNS – central nervous system; COVID-19; COVID-19 – coronavirus disease; CRP – C-reactive protein; CSF – cerebrospinal fluid; CT – Computer tomography; CTA – Computer tomography angiography; CVT – cerebral venous thrombosis; ECG – electrocardiogram; HR – heart rate; Holter ECG – Holter electrocardiogram; I.V. – intravenous; LMWH – low molecular weight heparin; MRA – Magnetic resonance angiography; MRC scale – Medical Research Council's scale; MRI – Magnetic resonance imaging; PACNS – primary angiitis of the central nervous system; PCA – posterior cerebral artery; PCR – polymerase chain reaction; PCoA – posterior communicating artery; RCVS – reversible cerebral vasoconstriction syndrome; RR – reference range; RT-PCR – real-time polymerase chain reaction; SAH – subarachnoid hemorrhage; SARS-CoV-2 – severe acute respiratory syndrome coronavirus 2; UL – upper limit; cardiovascular medicine; neurology; stroke; subarachnoid hemorrhage",
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"mesh_terms": "D000914:Antibodies, Viral; D000086382:COVID-19; D000072226:Computed Tomography Angiography; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009422:Nervous System Diseases; D058873:Pandemics; D000086402:SARS-CoV-2; D013909:Thorax; D014057:Tomography, X-Ray Computed",
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"title": "Neurological complications in COVID-19 - a diagnostic challenge.",
"title_normalized": "neurological complications in covid 19 a diagnostic challenge"
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"abstract": "This case report is about a 70-year-old man, who developed bilateral vestibulopathy due to intravenous gentamicin for endocarditis, and during admission he developed dizziness and oscillopsia. He was diagnosed with bilateral vestibulop-athy, when saccades were found on a video head impulse test (vHIT). The diagnosis was postponed by the lack of severe vertigo and nystagmus, which is seen in acute unilateral vestibulopathy. When gentamicin-induced vestibulapathy is suspected, a vHIT examination is recommended.",
"affiliations": "Hertz.jonas@gmail.com.",
"authors": "Hertz|Jonas|J|;Djurhuus|Bjarki Ditlev|BD|",
"chemical_list": "D005839:Gentamicins",
"country": "Denmark",
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"issn_linking": "0041-5782",
"issue": "181(5)",
"journal": "Ugeskrift for laeger",
"keywords": null,
"medline_ta": "Ugeskr Laeger",
"mesh_terms": "D000368:Aged; D000071699:Bilateral Vestibulopathy; D005839:Gentamicins; D064087:Head Impulse Test; D006801:Humans; D008297:Male; D012027:Reflex, Vestibulo-Ocular; D014717:Vertigo",
"nlm_unique_id": "0141730",
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"pmid": "30722816",
"pubdate": "2019-01-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Bilateral vestibulopathy after intravenous gentamicin therapy.",
"title_normalized": "bilateral vestibulopathy after intravenous gentamicin therapy"
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"abstract": "BACKGROUND\nMammalian target rapamycin inhibitors (m-TORi) are increasingly used in patients undergoing liver transplantation (LT). Yet, there is rising concern that they also could impair wound healing and favor the development of several surgical complications. This report was designed to evaluate both feasibility and safety of major surgery in liver transplant recipients receiving m-TORi-based immunosuppression without therapeutic discontinuation.\n\n\nMETHODS\nFrom 2007 to 2012, six liver transplant recipients underwent nine major abdominal or thoracic surgical procedures without m-TORi discontinuation or specific dosage adjustment. Their characteristics and postoperative outcomes were retrospectively analyzed.\n\n\nRESULTS\nIndications for m-TORi were de novo or recurrent malignant disease in five patients and calcineurin inhibitors related neurologic toxicity in one patient. Abdominal procedures, thoracic procedures, and combined thoracic and abdominal procedures were performed in six, two, and one cases respectively. Emergency surgery was performed in one case and elective procedures were performed in eight cases, including five for malignant disease and three for late surgical complications following LT. No patient died postoperatively. One major complication was observed, but no patient required reoperation. No evisceration, incisional surgical site infection, or lymphocele occurred.\n\n\nCONCLUSIONS\nMajor surgery in liver transplant recipients receiving m-TOR inhibitors appears both feasible and safe without therapeutic discontinuation or specific dosage adjustment.",
"affiliations": "Department of Hepatobiliary and Liver Transplantation Surgery, Hopital Saint Antoine, Assistance publique-Hopitaux de Paris, 184 rue du Faubourg Saint-Antoine, 75012, Paris Cedex, France, lilian.schwarz@gmail.com.",
"authors": "Schwarz|Lilian|L|;Cauchy|François|F|;Conti|Filomena|F|;Sepulveda|Ailton|A|;Perdigao|Fabiano|F|;Bernard|Denis|D|;Calmus|Yvon|Y|;Soubrane|Olivier|O|;Scatton|Olivier|O|",
"chemical_list": "D007166:Immunosuppressive Agents; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus",
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"mesh_terms": "D000714:Anastomosis, Surgical; D000068338:Everolimus; D005260:Female; D006498:Hepatectomy; D006500:Hepatic Duct, Common; D059685:Herniorrhaphy; D006801:Humans; D007166:Immunosuppressive Agents; D007583:Jejunum; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D016577:Pancreaticoduodenectomy; D011013:Pneumonectomy; D012086:Reoperation; D012189:Retrospective Studies; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D013908:Thoracotomy; D066027:Transplant Recipients",
"nlm_unique_id": "7704052",
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"pages": "3193-8",
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"title": "Preliminary report of major surgery in liver transplant recipients receiving m-TOR inhibitors without therapeutic discontinuation.",
"title_normalized": "preliminary report of major surgery in liver transplant recipients receiving m tor inhibitors without therapeutic discontinuation"
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"abstract": "Lung cancer is one of the most common neoplasms to appear leptomeningeal metastasis (LM). Contrast-enhanced magnetic resonance imaging (MRI) is better diagnostic choice for LM and usually shows focal nodular or diffuse linear enhancement on the leptomeninges along the sulci and tentorium in the brain. We experienced atypical 2 cases of lung cancer in patients who showed unusual brain MRI finding of symmetrical curvilinear or band-like, nonenhancing cytotoxic edema along the surface of the brain stem. This finding is unique and different from the general findings of leptomeningeal metastasis. This unique imaging finding of symmetric curvilinear nonenhancing cytotoxic edema along the brainstem is extremely rare and represents a new presentation of leptomeningeal carcinomatosis.",
"affiliations": "From Department of Radiology, Soonchunhyang University Bucheon Hospital, Gyunggi-do, South Korea (EKK, ALL, K-HC, HSH); Department of Radiology, Seoul National University Hospital, Seoul, South Korea (TJY).",
"authors": "Khil|Eun Kyung|EK|;Lee|A Leum|AL|;Chang|Kee-Hyun|KH|;Yun|Tae Jin|TJ|;Hong|Hyun Sook|HS|",
"chemical_list": null,
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 2620061110.1097/MD.0000000000001053010536800Research ArticleClinical Case ReportSymmetrical Curvilinear Cytotoxic Edema Along the Surface of the Brain Stem: A Probable New Magnetic Resonance Imaging Finding of Leptomeningeal Carcinomatosis Khil Eun Kyung MDLee A Leum MDChang Kee-Hyun MDYun Tae Jin MDHong Hyun Sook MDSergio Gonzalez Bombardiere. From Department of Radiology, Soonchunhyang University Bucheon Hospital, Gyunggi-do, South Korea (EKK, ALL, K-HC, HSH); Department of Radiology, Seoul National University Hospital, Seoul, South Korea (TJY)Correspondence: A Leum Lee, Department of Radiology, Soonchunhyang University Bucheon Hospital, Gyunggi-do, South Korea (e-mail: aleerad@schmc.ac.kr).7 2015 24 7 2015 94 29 e10536 5 2015 24 5 2015 30 5 2015 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.2015This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0, where it is permissible to download, share and reproduce the work in any medium, provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nLung cancer is one of the most common neoplasms to appear leptomeningeal metastasis (LM). Contrast-enhanced magnetic resonance imaging (MRI) is better diagnostic choice for LM and usually shows focal nodular or diffuse linear enhancement on the leptomeninges along the sulci and tentorium in the brain. We experienced atypical 2 cases of lung cancer in patients who showed unusual brain MRI finding of symmetrical curvilinear or band-like, nonenhancing cytotoxic edema along the surface of the brain stem. This finding is unique and different from the general findings of leptomeningeal metastasis.\n\nThis unique imaging finding of symmetric curvilinear nonenhancing cytotoxic edema along the brainstem is extremely rare and represents a new presentation of leptomeningeal carcinomatosis.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\nThe incidence of leptomeningeal metastases (LM) of solid tumors has increased owing to prolonged patient survival because of increasingly effective systemic chemotherapy, but its prognosis remains poor. Lung cancer is the most common primary tumor leading to brain metastases1 and is one of the most common neoplasms that metastasize to the leptomeninges.2 LM occurs in approximately 5% of nonsmall cell lung cancers, including adenocarcinoma.3\n\nEven though the gold standard for the diagnosis of LM is cerebrospinal fluid (CSF) cytology, contrast-enhanced (CE) brain magnetic resonance imaging (MRI) is the first diagnostic choice for LM evaluation in clinical practice. On CE MRI, LM usually appears as a focal or diffuse, nodular or linear enhancement of the leptomeninges along the brain sulci and cisterns.3 However, CE MRI yields approximately 30% of false-negative findings.4 We report unfamiliar brain MRI findings, a symmetrical curvilinear or band-like cytotoxic edema without enhancement along the surface of the brain stem and middle cerebellar peduncles, in 2 patients with leptomeningeal metastases from lung cancer, which is considered a probable new finding suggestive of leptomeningeal carcinomatosis.\n\nCASE REPORTS\nCase 1\nA 75-year-old man was diagnosed with lung adenocarcinoma with bone metastases in December 2011. At that time, brain MRI did not show evidence of metastasis. He was treated with chemotherapy using Iressa (gefitinib) for 8 weeks, and showed partial response of the tumor after 1 year, in November 2012. However, 1 month later, he was admitted to the hospital with headache and dizziness. Brain MRI revealed previously unreported curvilinear or band-like parenchymal lesions of high signal intensity on T2-weighted images and diffusion-weighted images (DWI), with restricted diffusion along the anterior and posterior surface of the midbrain, pons, and on both sides of the anterolateral surface of the middle cerebellar peduncles (Figure 1). There was no contrast enhancement in the brain parenchyma and the leptomeninges, and no hydrocephalus was observed. Therefore, we initially suspected chemotherapy-induced toxic encephalopathy and paraneoplastic syndrome rather than LM. On cytological examination of CSF, there were malignant metastatic adenocarcinoma cells. Serum antineuronal antibodies (anti-Hu, anti-Ri, and anti-Yo) were negative. One month later, he showed respiratory failure and expired.\n\nFIGURE 1 Case 1. A 75-year-old man with lung adenocarcinoma. (A) A T2-FLAIR (fluid-attenuated inversion recovery) image shows bilateral symmetrical curvilinear high signal intensity along the surface of the pons. (B) A contrast-enhanced T1-weighted image reveals no enhancement in the lesion. (C) DWI. (D) An ADC map shows symmetrical curvilinear cytotoxic edema along the pons.\n\nCase 2\nA 47-year-old woman was diagnosed with lung adenocarcinoma with brain metastases approximately 3 months before admission to our hospital. Initial brain MRI showed multiple small enhancing metastatic nodules on both sides of the cerebral and cerebellar hemispheres, and multiple short linear enhancements in the cerebellar sulci, suggesting leptomeningeal metastases without hydrocephalus. Chemotherapy with a combination of docetaxel and carboplatin was initiated. She was also treated with palliative whole brain radiotherapy up to a total dose of 30 Gy in 10 fractions over 2 weeks for brain metastases. After 3 cycles of chemotherapy for approximately 3 months, she presented persistent general weakness. A second brain MRI showed new findings of bilateral symmetrical curvilinear high signal intensity on T2-weighted images and DWI (b = 1000 s/mm2) with a low apparent diffusion coefficient (ADC) along the surface of the pons and on both sides of the middle cerebellar peduncles. However, the lesions showed no definite parenchymal or leptomeningeal enhancement (Figure 2). Additionally, hydrocephalus developed, with slight increases in the size and the number of multiple small parenchymal metastases as well as more prominent leptomeningeal enhancement along the cerebellar folia. Serum and CSF antibody examination for the evaluation of paraneoplastic syndrome was not performed. The patient presented with recurring seizures and persistent drowsiness despite antiepileptic medication. Eventually, she was transferred to hospice care.\n\nFIGURE 2 Case 2. A 47-year-old woman with lung adenocarcinoma. (A) A T2-FLAIR image reveals bilateral symmetrical curvilinear high signal intensity on the surface of the anterior pons. (B) A contrast-enhanced T1-weighted image shows no enhancement. There are diffuse linear enhancing lesions along the cerebellar folia, consistent with leptomeningeal metastasis. (C) DWI. (D) An ADC map demonstrates symmetrical band-like cytotoxic edema along the surface of the pons.\n\nDISCUSSION\nWe report an unusual MRI finding with symmetrical curvilinear or band-like cytotoxic edema along the surface of the brain stem. The most reasonable etiology is leptomeningeal carcinomatosis. To our knowledge, only one case with similar MRI findings has been recently reported.5 The pathogenesis of the cytotoxic edema along the brain stem surface is unknown. We think there are 3 possible explanations for our finding: microinfarctions secondary to tumor cell infiltration in the perforating vessels, paraneoplastic encephalopathy involving the brain stem, and toxic encephalopathy caused by chemotherapy. First, we hypothesized that the findings would be explained by microinfarctions. In LM, the tumor cells are usually concentrated in the subarachnoid cisterns along the surface of the brain stem. The brain stem has many short circumferential perforating arteries originating from the basilar artery and both the superior cerebellar arteries on the anterior, lateral, and posterior aspects of its surface.6 The malignant cells in the CSF cistern around the brain stem could directly infiltrate the microvessels or extend into the subpial space, causing perivascular inflammatory reaction and thrombosis.7,8 Crombe et al5 reported of a patient diagnosed with lung adenocarcinoma who showed diffuse high signal intensity on T2-weighted images and DWI, only along the anterior surface of the brain stem and on both sides of the middle cerebellar peduncles. However, our patient showed high signal intensity along the entire surface of the brain stem. Therefore, it would be presented by curvilinear or band-like cytotoxic edema along the surface of the brain stem without leptomeningeal enhancement. Paraneoplastic disorders (PNDs) are a second possible etiologic factor potentially responsible for the cytotoxic edema in the brain stem. Most PNDs are known to be autoimmune-mediated, the best evidence of which comes from the demonstration of antineuronal antibodies in the CSF and serum of patients. PNDs present with various patterns such as limbic encephalitis, cerebellar degeneration, and brain stem encephalitis. Brain stem encephalitis is uncommon compared with other PNDs.9 Brain stem encephalitis is usually not observed on initial MRI images, showing mostly normal findings, but later presents with progressive ascending involvement of the brainstem.10 MRI reveals high T2 signal intensity in the midbrain tectum, periaqueductal gray matter, pons, medulla, and superior and middle cerebellar peduncles, with or without nodular enhancement.9 However, circumferentially peripheral involvement of the brain stem with cytotoxic edema has never been reported. Paraneoplastic brainstem encephalitis is usually associated with serum anti-Hu (ANNA-1), anti-Ri (ANNA-2), or anti-Ma antibodies. Case 1 was negative for antineuronal antibodies. Therefore, we suppose that PND is a less likely etiologic factor.\n\nThe last hypothesis is toxic encephalitis caused by chemotherapy. The most common chemotherapeutic agents causing central nervous system (CNS) toxicity include methotrexate, vincristine, ifosfamide, cyclosporine, cytarabine, and 5-fuorouracil. It is well known that intrathecal or high-dose methotrexate may cause transient or persistent diffuse white matter degeneration.11 In addition, calcineurin inhibitors such as cyclosporine or tacrolimus can lead to posterior reversible encephalopathy syndrome (PRES), mainly involving the subcortical regions of the occipital, posterior temporal, and parietal lobes.11 Both patients in our report were treated with different chemotherapy regimens: one with gefitinib, the other with docetaxel plus carboplatin. There are a few reports about the adverse effects of gefitinib or of the docetaxel–carboplatin combination in the CNS. The most common adverse effects associated with gefitinib use are rash, acne, and diarrhea, while those associated with docetaxel–carboplatin use are hematologic effects related to myelosuppression and alopecia. Docetaxel–carboplatin occasionally can cause peripheral neuropathy but its CNS toxicity is rare.12 Moreover, gefitinib is less neurotoxic than docetaxel–carboplatin.13 We could not find any reports in the English literature describing brain stem encephalitis resulting from gefitinib and docetaxel–carboplatin on brain MRI, although PRES due to carboplatin and/or docetaxel has been rarely reported.14 Toxic encephalopathy is less likely to cause cytotoxic edema in the brain stem.\n\nIn conclusion, MRI finding of curvilinear or band-like cytotoxic edema without LM enhancement may be an extremely rare new MRI finding of leptomeningeal carcinomatosis. The findings likely reflect microinfarctions caused by perivascular tumor infiltration on the surface or the subpial regions of the brain stem.\n\nAbbreviations: ADC = apparent diffusion coefficient, CE = contrast-enhanced, CNS = central nervous system, CSF = cerebrospinal fluid, DWI = diffusion-weighted images, FLAIR = fluid-attenuated inversion recovery, LM = leptomeningeal metastasis, MRI = magnetic resonance imaging, PNDs = paraneoplastic disorders, PRES = posterior reversible encephalopathy syndrome.\n\nThis work was supported in part by the Soonchunhyang University Research Fund.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nREFERENCES\n1. Martinez N Boire A Deangelis LM \nMolecular interactions in the development of brain metastases . Int J Mol Sci \n2013 ; 14 :17157 –17167 .23965978 \n2. Fukui MB Meltzer CC Kanal E \nMR imaging of the meninges. Part II. Neoplastic disease . Radiology \n1996 ; 201 :605 –612 .8939203 \n3. Chamberlain MC Kormanik P \nCarcinoma meningitis secondary to non-small cell lung cancer: combined modality therapy . Arch Neurol \n1998 ; 55 :506 –512 .9561978 \n4. Oschmann P Bauer T Kaps M \nLeptomeningeal metastasis: a CT and MRI study . Eur Radiol \n1994 ; 4 :337 –340 .\n5. Crombe A Alberti N Durieux M \nExceptional symmetric anterior brainstem involvement in leptomeningeal carcinomatosis . J Neuroradiol \n2014 ; 41 :279 –281 .24931698 \n6. Schmahmann JD Ko R MacMore J \nThe human basis pontis: motor syndromes and topographic organization . Brain \n2004 ; 127 :1269 –1291 .15128614 \n7. Olson ME Chernik NL Posner JB \nInfiltration of the leptomeninges by systemic cancer. A clinical and pathologic study . Arch Neurol \n1974 ; 30 :122 –137 .4405841 \n8. Klein P Haley EC Wooten GF \nFocal cerebral infarctions associated with perivascular tumor infiltrates in carcinomatous leptomeningeal metastases . Arch Neurol \n1989 ; 46 :1149 –1152 .2552969 \n9. Saket RR Geschwind MD Josephson SA \nAutoimmune-mediated encephalopathy: classification, evaluation, and MR imaging patterns of disease . Neurographics \n2011 ; 16 :2 –16 .\n10. Vigliani MC Novero D Cerrato P \nDouble step paraneoplastic brainstem encephalitis: a clinicopathological study . J Neurol Neurosurg Psychiatry \n2009 ; 80 :693 –695 .19448098 \n11. Tamrazi B1 Almast J \nYour brain on drugs: imaging of drug-related changes in the central nervous system . Radiographics \n2012 ; 32 :701 –719 .22582355 \n12. Sioka C Kyritsis AP \nCentral and peripheral nervous system toxicity of common chemotherapeutic agents . Cancer Chemother Pharmacol \n2009 ; 63 :761 –767 .19034447 \n13. Mitsudomi T Morita S Yatabe Y \nGefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial . Lancet Oncol \n2010 ; 11 :121 –128 .20022809 \n14. Imai H Okuno N Ishihara S \nReversible posterior leukoencephalopathy syndrome after carboplatin and paclitaxel regimen for lung cancer . Intern Med \n2012 ; 51 :911 –915 .22504249\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0025-7974",
"issue": "94(29)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000368:Aged; D001933:Brain Stem; D004487:Edema; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008279:Magnetic Resonance Imaging; D008297:Male; D055756:Meningeal Carcinomatosis; D008875:Middle Aged",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e1053",
"pmc": null,
"pmid": "26200611",
"pubdate": "2015-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Symmetrical Curvilinear Cytotoxic Edema Along the Surface of the Brain Stem: A Probable New Magnetic Resonance Imaging Finding of Leptomeningeal Carcinomatosis.",
"title_normalized": "symmetrical curvilinear cytotoxic edema along the surface of the brain stem a probable new magnetic resonance imaging finding of leptomeningeal carcinomatosis"
} | [
{
"companynumb": "KR-ACTAVIS-2015-22455",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nChemotherapy-induced interstitial lung disease (ILD) in colorectal cancer (CRC) patients is rarely reported, but its clinical features remain to be clarified.\n\n\nMETHODS\nUsing a computerized database, we retrospectively identified patients who developed ILD from 734 patients with CRC treated with infusional 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX) or infusional 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) from April 2005 to December 2008 at the National Cancer Center Hospital East.\n\n\nRESULTS\nOf 734 patients, 11 patients developed ILD (1.5%) and 4 of those patients died (0.54%). Of the 11 patients, 10 showed pulmonary shadows other than lung metastases before chemotherapy. ILD developed during FOLFOX in six patients, at 137 days after completion of FOLFOX in one patient, during oxaliplatin interruption of FOLFOX in one patient and during FOLFIRI in the remaining three patients. FOLFOX had been administered at some point for all ILD patients, with a median of 10 cycles (range 2-17 cycles) and a median dose of administered oxaliplatin of 850 mg/m(2) (range 170-1445 mg/m(2)).\n\n\nCONCLUSIONS\nILD following FOLFOX or FOLFIRI is an uncommon but life-threatening complication. Care must be taken regarding the onset of ILD, not only during but also after chemotherapy for CRC.",
"affiliations": "Division of Gastrointestinal Oncology and Digestive Endoscopy, National Cancer Center Hospital East, Kashiwa; Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya, Japan.;Division of Gastrointestinal Oncology and Digestive Endoscopy, National Cancer Center Hospital East, Kashiwa. Electronic address: nofuse@east.ncc.go.jp.;Division of Gastrointestinal Oncology and Digestive Endoscopy, National Cancer Center Hospital East, Kashiwa.;Division of Gastrointestinal Oncology and Digestive Endoscopy, National Cancer Center Hospital East, Kashiwa.;Division of Gastrointestinal Oncology and Digestive Endoscopy, National Cancer Center Hospital East, Kashiwa.;Division of Gastrointestinal Oncology and Digestive Endoscopy, National Cancer Center Hospital East, Kashiwa.;Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya, Japan.;Division of Gastrointestinal Oncology and Digestive Endoscopy, National Cancer Center Hospital East, Kashiwa.",
"authors": "Shimura|T|T|;Fuse|N|N|;Yoshino|T|T|;Minashi|K|K|;Tahara|M|M|;Doi|T|T|;Joh|T|T|;Ohtsu|A|A|",
"chemical_list": "D009944:Organoplatinum Compounds; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin",
"country": "England",
"delete": false,
"doi": "10.1093/annonc/mdq061",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0923-7534",
"issue": "21(10)",
"journal": "Annals of oncology : official journal of the European Society for Medical Oncology",
"keywords": null,
"medline_ta": "Ann Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D015179:Colorectal Neoplasms; D005260:Female; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D017563:Lung Diseases, Interstitial; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds; D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome",
"nlm_unique_id": "9007735",
"other_id": null,
"pages": "2005-2010",
"pmc": null,
"pmid": "20305036",
"pubdate": "2010-10",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Clinical features of interstitial lung disease induced by standard chemotherapy (FOLFOX or FOLFIRI) for colorectal cancer.",
"title_normalized": "clinical features of interstitial lung disease induced by standard chemotherapy folfox or folfiri for colorectal cancer"
} | [
{
"companynumb": "JP-PFIZER INC-2017386245",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
... |
{
"abstract": "We report the first case of disseminated Mycobacterium colombiense infection in a solid organ transplant recipient. Co-infection with Cryptococcus neoformans led to fatal multisystem organ failure. We review the pathogen and host factors contributing to these opportunistic infections.",
"affiliations": "Division of Medical Microbiology, Department of Pathology, Ottawa Hospital General Campus, University of Ottawa, Ottawa, ON, Canada.;Division of Infectious Diseases, Department of Medicine, Faculty of Medicine, Ottawa Hospital General Campus, University of Ottawa, Ottawa, ON, Canada.",
"authors": "Gosal|Jasmine|J|;Lee|B Craig|BC|http://orcid.org/0000-0003-4368-5006",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12890",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "20(4)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "\nMycobacterium colombiense\n; interferon-γ; solid organ transplant; urease",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000900:Anti-Bacterial Agents; D060085:Coinfection; D003453:Cryptococcosis; D003455:Cryptococcus neoformans; D017809:Fatal Outcome; D005260:Female; D006084:Graft Rejection; D006801:Humans; D016867:Immunocompromised Host; D007165:Immunosuppression Therapy; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008875:Middle Aged; D009102:Multiple Organ Failure; D015269:Mycobacterium avium Complex; D015270:Mycobacterium avium-intracellulare Infection; D009894:Opportunistic Infections",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e12890",
"pmc": null,
"pmid": "29569810",
"pubdate": "2018-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case report of fatal disseminated Mycobacterium colombiense infection in a renal transplant recipient.",
"title_normalized": "a case report of fatal disseminated mycobacterium colombiense infection in a renal transplant recipient"
} | [
{
"companynumb": "CA-PFIZER INC-2019109292",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ETHAMBUTOL HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "Chronic granulomatous disease (CGD) is a primary immunodeficiency due to a malfunction of NADPH oxidase. It is characterized by recurrent and severe infections caused by catalase-positive microorganisms and autoinflammatory manifestations. Recently, there has been described an NCF4 gene variant that causes a deficiency of p40<sup>phox</sup>, a subunit of NADPH oxidase. Patients with this deficiency appear to have a less severe clinical form as compared to classic CGD.\nA 15-year-old girl with vulvar lichen planus since she was 2 years old and suspected Crohn's disease (CD) was first seen at our hospital. At the age of 12 years, she had been submitted to sacrococcygeal cyst exeresis, without cicatrization of the surgical wound and extension of the lesion to the perianal area. The diagnosis of CD was questioned, and the patient underwent an endoscopic and radiologic assessment, which was normal. A skin biopsy from the perianal area revealed a granuloma; thus, CD with isolated perianal disease was assumed. After several different treatments including antibiotics, infliximab, and adalimumab, the perianal lesion persisted, with no associated gastrointestinal symptoms. Therefore, the hypothesis of an immunodeficiency was considered. An immunologic and genetic study revealed reduced oxidative burst in the phorbol myristate acetate test, with diminished reactive oxygen species production and a homozygous mutation in the NCF4 gene. The adolescent started prophylactic trimethoprim-sulfamethoxazole and became asymptomatic.\nThe present case highlights that alternative diagnoses to CD must be considered in the presence of isolated perianal disease with granulomatous inflammation, especially when the disease is refractory to conventional CD therapy.",
"affiliations": "Pediatric Gastroenterology Unit, Centro Hospitalar Universitário do São João, Porto, Portugal.;Pediatric Gastroenterology Unit, Centro Hospitalar Universitário do São João, Porto, Portugal.;Pediatric Gastroenterology Unit, Centro Hospitalar Universitário do São João, Porto, Portugal.;Pediatric Primary Immunodeficiencies Unit, Centro Hospitalar Universitário do São João, Porto, Portugal.;Centre d'Etudes des Déficits Immunitaires, Hôpital Necker Enfants-Malades, Paris, France.;Pediatric Gastroenterology Unit, Centro Hospitalar Universitário do São João, Porto, Portugal.",
"authors": "Reis-Melo|Ana|A|;Espinheira|Maria do Céu|MDC|;Pinto-Pais|Isabel|I|;Bonito Vitor|Artur|A|;Bustamante|Jacinta|J|;Trindade|Eunice|E|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000502358",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2387-1954",
"issue": "27(2)",
"journal": "GE Portuguese journal of gastroenterology",
"keywords": "Chronic granulomatous diseases; Crohn's disease; NCF4 gene; p40phox deficiency",
"medline_ta": "GE Port J Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "101685861",
"other_id": null,
"pages": "119-123",
"pmc": null,
"pmid": "32266309",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports",
"references": "29947781;26603166;26983962;29746675;19023863;23821607;30506560;21752492;19692703;22398059;25537876;25865355;27472695;24909831;29969437;29168144",
"title": "Perianal Disease and Granulomas: Think Out of the Box….",
"title_normalized": "perianal disease and granulomas think out of the box"
} | [
{
"companynumb": "PT-SAMSUNG BIOEPIS-SB-2020-26852",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": "3"... |
{
"abstract": "Proliferative glomerulonephritis with monoclonal immunoglobulin G (IgG) deposits (PGNMID) is a rare disease that recently became recognized. Its pathological findings are characterized by the deposition of a single heavy chain subclass and a single light chain isotype. PGNMID has been proven to recur in renal allografts. Herein, the authors describe the case of a 46-year-old man who presented with nephrotic syndrome and progressive kidney injury following kidney transplantation. One month after transplantation, his clinical condition stabilized; however, the protocol biopsy showed depositions of IgG and complement on the glomeruli by immunofluorescence staining. Electron microscopy (EM) revealed granular electron-dense deposits (EDD) in the mesangium. Thereafter, renal biopsy was repeated because his proteinuria level increased. Proliferative glomerulonephritis, mainly in the mesangium, with IgG and complement deposits and mesangial and subendothelial EDD were observed; however, the pathological diagnosis was difficult. Renal dysfunction then became apparent, and renal biopsy was performed again 4 years and 10 months after kidney transplantation. Glomerular deposits on a single IgG subclass and a single light chain isotype (IgG3 kappa) with membranoproliferative features were observed. Abundant subendothelial EDD were detected on EM. Finally, the patient was diagnosed with PGNMID. Since it seemed that PGNMID had already developed at 1 month after transplantation, we considered recurrent PGNMID case in the allograft. The treatment for PGNMID has not been established yet, and even in this case, the graft function was eventually lost. For improving renal prognosis, early diagnosis and further investigation on the treatment are necessary.",
"affiliations": "Department of Nephrology and Rheumatology, Aichi Medical University, 1-1 Karimata, Yazako, Nagakute, 480-1195, Japan. t-katsuno@aichi-med-u.ac.jp.;Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Urology, Japanese Red Cross Nagoya Daiichi Hospital, Nagoya, Japan.;Department of Nephrology and Rheumatology, Aichi Medical University, 1-1 Karimata, Yazako, Nagakute, 480-1195, Japan.;Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan.",
"authors": "Katsuno|Takayuki|T|;Kato|Masashi|M|;Fujita|Takashi|T|;Tsuboi|Naotake|N|;Hattori|Ryohei|R|;Ito|Yasuhiko|Y|;Maruyama|Shoichi|S|",
"chemical_list": "D007074:Immunoglobulin G",
"country": "Japan",
"delete": false,
"doi": "10.1007/s13730-019-00384-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2192-4449",
"issue": "8(3)",
"journal": "CEN case reports",
"keywords": "Kidney transplantation; Proliferative glomerulonephritis with monoclonal IgG deposits; Recurrent glomerulonephritis; Renal pathology",
"medline_ta": "CEN Case Rep",
"mesh_terms": "D005921:Glomerulonephritis; D006801:Humans; D007074:Immunoglobulin G; D007678:Kidney Glomerulus; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D012008:Recurrence",
"nlm_unique_id": "101636244",
"other_id": null,
"pages": "151-158",
"pmc": null,
"pmid": "30805792",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports",
"references": "21705124;27432742;28616219;20876681;26664209;19470674;19875378;25607108;28946960;14675039",
"title": "Chronological change of renal pathological findings in the proliferative glomerulonephritis with monoclonal IgG deposits considered to have recurred early after kidney transplantation.",
"title_normalized": "chronological change of renal pathological findings in the proliferative glomerulonephritis with monoclonal igg deposits considered to have recurred early after kidney transplantation"
} | [
{
"companynumb": "JP-ASTELLAS-2019JP017635",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "Dermatomyositis is a chronic systemic autoimmune disease characterized by inflammatory infiltrates in the skin and muscle. The wide variability in clinical and serologic presentation poses a diagnostic challenge for the internist. Appreciation of the clinical variants of dermatomyositis allows for expedient diagnosis and avoidance of diagnostic error. We illustrate these challenges with the case of a 51-year-old Vietnamese-American man who initially presented with fever of unknown origin in the absence of overt skin and muscle manifestations. The diagnosis of dermatomyositis was not evident on several clinical encounters due to the absence of these hallmark symptoms. We review the variable clinical manifestations of a subtype of dermatomyositis associated with an autoantibody against melanoma differentiation-associated protein 5 (anti-MDA5) and suggest consideration of dermatomyositis as a diagnosis in patients presenting with systemic illness and markedly elevated ferritin, even in the absence of elevated muscle enzymes and classic autoantibodies.",
"affiliations": "Stanford University School of Medicine, Stanford, CA, USA. lwhlee@stanford.edu.;Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA.;Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA.;Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA.;Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.",
"authors": "Lee|Lori W|LW|;Narang|Neera S|NS|;Postolova|Anna|A|;Seminara|Nicole|N|;Kantor|Molly A|MA|",
"chemical_list": "C452815:IFIH1 protein, human; D000072640:Interferon-Induced Helicase, IFIH1",
"country": "United States",
"delete": false,
"doi": "10.1007/s11606-016-3769-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0884-8734",
"issue": "31(12)",
"journal": "Journal of general internal medicine",
"keywords": "case report; clinical evaluation; clinical reasoning; clinical vignette; dermatomyositis; diagnosis; errors in clinical reasoning; evaluation; fever of unknown origin; rheumatology",
"medline_ta": "J Gen Intern Med",
"mesh_terms": "D003882:Dermatomyositis; D003937:Diagnosis, Differential; D005335:Fever of Unknown Origin; D006801:Humans; D000072640:Interferon-Induced Helicase, IFIH1; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "8605834",
"other_id": null,
"pages": "1530-1536",
"pmc": null,
"pmid": "27350281",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "20498012;18373151;21987216;26000158;16937360;18238791;18930994;22258483;20075704;15657159;22623119;21654717;16126945;21632230;12217249;11092195;17075819;6405755;20015976;23106304;22843487;19439503;17368112;21883412;22589330;15880816;17763420;17008257;21482889;24467910;22884621;1659647;16059425;22378718;20497129;23436757;25331610;21953614;7406938;19558555;21828139;26453338;24037894;8554033;2409985;21531040;23908005;19565506;20827200;19444719",
"title": "Anti-MDA5-Positive Dermatomyositis Presenting as Fever of Unknown Origin.",
"title_normalized": "anti mda5 positive dermatomyositis presenting as fever of unknown origin"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2018SP008250",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"dru... |
{
"abstract": "Belatacept use has been constrained by higher rates of acute rejection. We hypothesized that belatacept with low-dose rATG and initial mycophenolate maintenance with conversion to everolimus at 1 month post-transplant ± corticosteroids would improve efficacy and maintain safety. Retrospective single-center analysis of the first 44 low immunologic risk kidney transplant recipients treated with this regimen. The cohort was 59% male, mean age at transplant of 57 years. Diabetes was the most common cause of ESRD (39%). The mean 1-year eGFR was 61.4 (SD 18.4) mL/min/1.73 m2 . There were five acute cellular rejections (11.4%) that occurred in patients who had changed from everolimus to mycophenolate mofetil due to side effects. Thirty-two percent developed BK viremia and 12% developed CMV viremia. There were no cases of PTLD. A novel belatacept regimen with rATG induction and maintenance everolimus demonstrated a low acute rejection rate and maintained an excellent 1-year eGFR.",
"affiliations": "Division of Nephrology, Massachusetts General Hospital, Boston, MA, USA.;Division of Nephrology, University of California San Francisco, San Francisco, CA, USA.;Division of Transplant Surgery, University of California San Francisco, San Francisco, CA, USA.;Division of Transplant Surgery, University of California San Francisco, San Francisco, CA, USA.;Division of Nephrology, University of California San Francisco, San Francisco, CA, USA.",
"authors": "Wojciechowski|David|D|http://orcid.org/0000-0001-5342-0277;Chandran|Sindhu|S|;Yang|Joshua Y C|JYC|http://orcid.org/0000-0003-2410-7817;Sarwal|Minnie M|MM|;Vincenti|Flavio|F|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents; D000069594:Abatacept; D000068338:Everolimus; C512542:thymoglobulin; D009173:Mycophenolic Acid",
"country": "Denmark",
"delete": false,
"doi": "10.1111/ctr.13042",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-0063",
"issue": "31(9)",
"journal": "Clinical transplantation",
"keywords": "Fusion proteins: belatacept, immunosuppressant; Immunosuppressant; mechanistic target of rapamycin: everolimus, immunosuppressive regimens",
"medline_ta": "Clin Transplant",
"mesh_terms": "D000069594:Abatacept; D000305:Adrenal Cortex Hormones; D000328:Adult; D000368:Aged; D000961:Antilymphocyte Serum; D004359:Drug Therapy, Combination; D000068338:Everolimus; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents; D060828:Induction Chemotherapy; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D060046:Maintenance Chemotherapy; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "8710240",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28662293",
"pubdate": "2017-09",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": null,
"title": "Retrospective evaluation of the efficacy and safety of belatacept with thymoglobulin induction and maintenance everolimus: A single-center clinical experience.",
"title_normalized": "retrospective evaluation of the efficacy and safety of belatacept with thymoglobulin induction and maintenance everolimus a single center clinical experience"
} | [
{
"companynumb": "PHHY2017US108815",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BELATACEPT"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Familial hypercholesterolemia (FH) and chronic kidney disease, especially end-stage renal disease (ESRD), are common and put patients at a high risk of developing atherosclerotic cardiovascular disease (ASCVD). ESRD concomitant with FH may further increase the risk of ASCVD. Achieving target levels of low-density lipoprotein cholesterol (LDL-C) is difficult owing to the limitations of statin administration due to its side effects in ESRD. Therefore, some FH patients with ESRD require lipoprotein apheresis for the prevention of secondary ASCVD events. Although proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors may offer a safe and effective option for lowering lipid levels in such patients, no guidelines are available for their use. Here, we report the case of two male siblings with FH in secondary prevention undergoing hemodialysis combined with PCSK9 inhibitor treatment. The siblings, who showed a heterozygous c.1846-1G>A mutation in the LDLR gene, underwent hemodialysis. In combination with the lipoprotein apheresis, siblings were administered evolocumab, a PCSK9 inhibitor. Both the siblings had coronary artery disease, diabetes, and ESRD, and received hemodialysis. Their LDL-C levels did not reach the target values despite administering statin, ezetimibe, and biweekly lipoprotein apheresis. On the introduction of evolocumab treatment, their LDL-C levels were significantly reduced without any adverse effects, resulting in successful withdrawal from lipoprotein apheresis therapy. Although the effects of switching from lipoprotein apheresis to PCSK9 inhibitors for cardiovascular protection remain unclear in FH patients with and without ESRD, our case report will be helpful in guiding future therapeutic decisions.",
"affiliations": "Zenjinkai Yokohama Daiichi Hospital, 2-5-15 Takashima Nishi-ku, Yokohama, Kanagawa, 220-0011, Japan. takeo.ishii@grp.zenjinkai.or.jp.;Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe-shimmachi, Suita, Osaka, 564-8565, Japan.;Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan.;Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe-shimmachi, Suita, Osaka, 564-8565, Japan.;Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe-shimmachi, Suita, Osaka, 564-8565, Japan.;Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan.;Zenjinkai Yokohama Daiichi Hospital, 2-5-15 Takashima Nishi-ku, Yokohama, Kanagawa, 220-0011, Japan.",
"authors": "Ishii|Takeo|T|;Ogura|Masatsune|M|;Nakamori|Haruka|H|;Hori|Mika|M|;Harada-Shiba|Mariko|M|;Tamura|Kouichi|K|;Oyama|Kunio|K|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s13730-021-00605-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2192-4449",
"issue": "10(4)",
"journal": "CEN case reports",
"keywords": "Evolocumab; Hemodialysis; Heterozygous familial hypercholesterolemia; Proprotein convertase subtilisin kexin 9",
"medline_ta": "CEN Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101636244",
"other_id": null,
"pages": "592-597",
"pmc": null,
"pmid": "34100221",
"pubdate": "2021-11",
"publication_types": "D016428:Journal Article",
"references": "30646217;17671394;26908947;27755983;17108318;31196453;31491741;28927706;30085243",
"title": "Switching from lipoprotein apheresis to evolocumab in FH siblings on hemodialysis: case reports and discussion.",
"title_normalized": "switching from lipoprotein apheresis to evolocumab in fh siblings on hemodialysis case reports and discussion"
} | [
{
"companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2021-04004",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "EZETIMIBE"
},
"drugad... |
{
"abstract": "Case 1: A 65-year-old man with novel coronavirus infection (COVID-19) complicated with acute respiratory failure. On admission, the patient was started on favipiravir and corticosteroid. However, due to a lack of significant improvement, he was introduced to mechanical ventilation and extracorporeal membrane oxygenation (ECMO). Although iliopsoas hematoma occurred as a complication, the patient recovered. Case 2: A 49-year-old man with COVID-19 had been started on favipiravir and corticosteroid. Due to progressive respiratory failure, the patient underwent mechanical ventilation and ECMO. The patient recovered without complications. We successfully treated these severe cases with a multimodal combination of pharmacological and non-pharmacological supportive therapy.",
"affiliations": "Department of Respiratory Medicine, Tokyo Shinagawa Hospital, Japan.;Department of Surgery, Tokyo Shinagawa Hospital, Japan.;Department of Respiratory Medicine, Tokyo Shinagawa Hospital, Japan.;Department of Respiratory Medicine, Tokyo Shinagawa Hospital, Japan.;Department of Emergency Medicine, Tokyo Shinagawa Hospital, Japan.;Department of Respiratory Medicine, Tokyo Shinagawa Hospital, Japan.;Department of Respiratory Medicine, Tokyo Shinagawa Hospital, Japan.;Department of Respiratory Medicine, Tokyo Shinagawa Hospital, Japan.;Department of Respiratory Medicine, Tokyo Shinagawa Hospital, Japan.;Department of Respiratory Medicine, Tokyo Shinagawa Hospital, Japan.;Department of Emergency Medicine, Tokyo Shinagawa Hospital, Japan.;Department of Cardiology, Tokyo Shinagawa Hospital, Japan.;Department of Respiratory Medicine, Tokyo Shinagawa Hospital, Japan.",
"authors": "Shinoda|Masahiro|M|;Kamachi|Kenichi|K|;Ota|Shinichiro|S|;Yoshimatsu|Lynn|L|;Boku|Ryuichi|R|;Yoshida|Yuto|Y|;Hirouchi|Takatomo|T|;Shinada|Kanako|K|;Sato|Takashi|T|;Morikawa|Miwa|M|;Iwata|Koki|K|;Matsumoto|Takashi|T|;Shinkai|Masaharu|M|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000577:Amides; D000998:Antiviral Agents; D011719:Pyrazines; C462182:favipiravir; D008775:Methylprednisolone",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.5475-20",
"fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918 1349-7235 The Japanese Society of Internal Medicine \n\n33390469\n10.2169/internalmedicine.5475-20\nCase Report\nTwo Cases of Severe COVID-19 Pneumonia Effectively Treated with Extracorporeal Membrane Oxygenation in Addition to Favipiravir and Corticosteroid\nShinoda Masahiro 1 Kamachi Kenichi 2 Ota Shinichiro 1 Yoshimatsu Lynn 1 Boku Ryuichi 3 Yoshida Yuto 1 Hirouchi Takatomo 1 Shinada Kanako 1 Sato Takashi 1 Morikawa Miwa 1 Iwata Koki 3 Matsumoto Takashi 4 Shinkai Masaharu 1 \n1 Department of Respiratory Medicine, Tokyo Shinagawa Hospital, Japan\n\n2 Department of Surgery, Tokyo Shinagawa Hospital, Japan\n\n3 Department of Emergency Medicine, Tokyo Shinagawa Hospital, Japan\n\n4 Department of Cardiology, Tokyo Shinagawa Hospital, Japan\nCorrespondence to Dr. Masaharu Shinkai, shinkai050169@gmail.com\n\n\n1 1 2021 \n1 1 2021 \n60 1 123 130\n2 6 2020 13 9 2020 Copyright © 2021 by The Japanese Society of Internal MedicineThe Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Case 1: A 65-year-old man with novel coronavirus infection (COVID-19) complicated with acute respiratory failure. On admission, the patient was started on favipiravir and corticosteroid. However, due to a lack of significant improvement, he was introduced to mechanical ventilation and extracorporeal membrane oxygenation (ECMO). Although iliopsoas hematoma occurred as a complication, the patient recovered. Case 2: A 49-year-old man with COVID-19 had been started on favipiravir and corticosteroid. Due to progressive respiratory failure, the patient underwent mechanical ventilation and ECMO. The patient recovered without complications. We successfully treated these severe cases with a multimodal combination of pharmacological and non-pharmacological supportive therapy. \n\nCOVID-19favipiravircorticosteroidextracorporeal membrane oxygenationmechanical ventilation\n==== Body\nIntroduction\nCoronavirus disease 2019 (COVID-19) was first identified in December 2019 in Wuhan, China, and has since rapidly spread globally. At present, there are few established treatments for COVID-19 with confirmed efficacy, resulting in numerous deaths.\n\nGlobally, as of August 1, 2020, 17,396,943 confirmed cases and 675,060 deaths related to COVID-19 have been reported to WHO, and the mortality rate is 3.9% (1). The overall hospital mortality rate from COVID-19 is approximately 15% to 20%, increasing to 40% among patients requiring ICU admission. By age, the hospital mortality rate is 35% for patients 70 to 79 years old and 60% for patients 80 to 89 years old (2). The mortality in COVID-19 patients who develope severe respiratory compromise and require mechanical ventilation is high.\n\nFavipiravir obtained manufacturing and marketing approval in March 2014 for “new or re-emerging influenza virus infections (provided that other anti-influenza virus drugs were ineffective)”. With regard to the mechanism of action of this drug, favipiravir taken up into cells is metabolized and converted by intracellular enzymes to become favipiravir ribofuranosyl triphosphate, which selectively inhibits viral RNA-dependent RNA polymerase. Therefore, this agent may also be effective against RNA viruses other than influenza virus, and indeed, nonclinical studies have reported its efficacy against several RNA viruses, including Ebola virus (3), Arenaviridae and Bunyaviridae (4). In an open-label, controlled trial in China, the time to viral clearance of mild to moderate COVID-19 treated with favipiravir and interferon alfa was significantly shorter than that of lobinavir ritonavir and interferon alfa (5).\n\nThere have been several reports of the efficacy of administering corticosteroids for COVID-19 patients, although opinions on this approach were initially negative (6,7). Corticosteroids are a viable therapeutic strategy for modulating the inflammatory response in patients with COVID-19.\n\nThe high mortality rate in severe cases is important, given the potential access to extracorporeal membrane oxygenation of venous blood, which may serve as a life-saving emergency treatment. Although the efficacy of ECMO in COVID-19 is controversial, ECMO is a proposed as a treatment option in the interim guidance document published by the WHO and interim guidance for clinical management of COVID-19 patients provided by the United States Centers for Disease Control (8).\n\nWe herein report two cases of COVID-19 in which the early introduction of ECMO was extremely effective for managing patients whose pneumonia was aggravated even under the use of favipiravir and corticosteroid.\n\nCase Reports\nCase 1\nA 65-year-old Japanese man with no significant medical history developed malaise at the end of March, 2020, and eventually developed pyrexia, cough and dyspnea. He visited a local clinic 9 days later. Because the patient presented with decreased percutaneous oxygen saturation (SpO2) and ground-glass opacities in both lungs, he was suspected of having COVID-19 pneumonia. On the same day, he was taken to our hospital by an ambulance, where he was immediately admitted. He had neither a history of close contact with COVID-19-positive patients nor any recent travel history. He was a former smoker (37.5 packs per year).\n\nAt the time of admission, the patient had no disorientation, with a body temperature of 37.5℃, blood pressure of 140/78 mmHg, pulse rate of 72 beats per minute (regular), respiratory rate of 24 breaths per minute and SpO2 of 82% on room air. At the time of admission, a marked increase was observed in lactate dehydrogenase and C-reactive protein (CRP), being 628 U/L and 24.99 mg/dL, respectively. Although no increase was found in white blood cell count, an increased neutrophil fraction and decreased lymphocyte fraction were detected. Surfactant protein D increased to 221 ng/mL (Table 1).\n\nTable 1. Case 1: Laboratory Findings at the Time of Hospital Admission.\n\nTP\t\t6.1\tg/dL\t\tWBC\t\t8,300\t/μL\t\nalb\t\t2.6\tg/dL\t\tneutro\t\t87.4\t%\t\nT-bil\t\t0.5\tmg/dL\t\tlymph\t\t6.9\t%\t\nAST\t\t66\tU/L\t\tmono\t\t5.4\t%\t\nALT\t\t33\tU/L\t\teosino\t\t0.1\t%\t\nLDH\t\t628\tU/L\t\tHb\t\t16.3\tg/dL\t\nγ-GTP\t\t27\tU/L\t\tHct\t\t47.5\t%\t\nCK\t\t69\tU/L\t\tPlt\t\t27.9\t×104/μL\t\nBUN\t\t13.8\tmg/dL\t\t\t\t\t\t\nCr\t\t0.76\tmg/dL\t\tPT-INR\t\t1.16\t\t\nUA\t\t4.2\tmg/dL\t\tAPTT\t\t35.8\tsec\t\nNa\t\t136\tmEq/L\t\tD-dimer\t\t8.8\tpg/mL\t\nK\t\t4.8\tmEq/L\t\tfibrinogen\t\t774\tmg/dL\t\nCl\t\t102\tmEq/L\t\t\t\t\t\t\nglu\t\t99\tmg/dL\t\t\t\t\t\t\nCRP\t\t24.99\tmg/dL\t\t\t\t\t\t\nIgG\t\t846\tmg/dL\t\t\t\t\t\t\nIgA\t\t157\tmg/dL\t\t\t\t\t\t\nIgM\t\t36\tmg/dL\t\t\t\t\t\t\nIgE\t\t92\tmg/dL\t\tinfluenza\t\tA\tnegative\t\nSPA\t\t92.8\tng/mL\t\t\t\tB\tnegative\t\nSPD\t\t221\tng/mL\t\t\t\t\t\t\nKL-6\t\t370\tU/mL\t\t\t\t\t\t\nβ-D-glucan\t\t12.0\tpg/mL\t\t\t\t\t\t\nNT-proBNP\t\t125\tpg/mL\t\t\t\t\t\t\nPCT\t\t0.20\tng/mL\t\t\t\t\t\t\nTP: thyroid peroxidase, Alb: albumin, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, γ-GTP: γ-glutamyl transpeptidase, CK: creatine kinase, BUN; blood urea nitrogen, Cr: creatinine, CRP: C-reactive protein, IgG: immunoglobulinG, IgA: immunoglobulin A, IgM: immunoglobulin M, IgE: immunoglobulin E, SPA: surfactant protein A, SPD: surfactant protein D, KL-6: Krebs von den Lungen, NT-proBNP: N-terminal pro-brain natriuretic peptide, PCT: procalcitonin, WBC: white blood cells, Hb: hemoglobin, Hct: hematocrit, PT-INR: prothrombin time-international normalized ratio, APTT: activated partial thromboplastin time\n\nAt the time of hospital admission, chest radiography showed diffuse ground-glass opacities in both lungs (Fig. 1a), and plain chest computed tomography (CT) showed diffuse ground-glass opacities in nearly all layers of both lungs (Fig. 1b).\n\nFigure 1. Case 1: Imaging findings at the time of hospital admission. (a) Chest radiography shows diffuse ground-glass opacities in both lungs. (b) Chest CT shows diffuse ground-glass opacities in nearly all layers of both lungs.\n\nThe patient was found to have progressive acute respiratory failure and started to receive high-flow nasal cannula oxygen therapy [delivery of 50 L of flow; fraction of inspired oxygen (FiO2) of 50%]. Methylprednisolone pulse therapy (administered at 1 g/day for 3 days) was started to treat the progressive acute respiratory failure as empirical treatment for severe pneumonia and acute interstitial pneumonia. Intravenous infusion of meropenem (1 g every 8 hours) and azithromycin (500 mg every 24 hours) was started under suspicion of severe bacterial pneumonia, and continuous intravenous infusion of sivelestat (400 mg/day) was also started to treat acute respiratory distress syndrome (ARDS).\n\nA COVID-19 real-time polymerase chain reaction (RT-PCR) test was performed, and the patient was found to be positive for COVID-19 on Day 3 of hospitalization. With the patient's consent, treatment with favipiravir was started on a compassionate-use basis. On Day 5, further progression of respiratory failure required the patient to be intubated and moved to mechanical ventilation. On the same day, veno-venous (V-V) ECMO was employed for this patient with severe progressive COVID-19 pneumonia with no irreversible underlying disease because mechanical ventilation was considered insufficient to sustain the cardiorespiratory system due to the patient's poor oxygenation even at an FiO2 of 1.0. ECMO cannulae were placed in the superior and inferior vena cavae, draining blood from the right femoral vein and returning it to the right internal jugular vein after extracorporeal oxygenation with a flow of 3.0 L/min. From days 3 to 5, platelets decreased from 24.5×104 to 17.8×104/μL, fibrinogen decreased from 426 to 54 mg/dL, and D-dimer increased from 68.1 to 98.2 μg/mL. No bleeding tendency, circulatory failure due to microthrombus, or multiple organ failure was observed. Since the criteria established by the Japanese Association for Acute Medicine for disseminated intravascular coagulation (DIC) were met, we administered recombinant thrombomodulin. His oxygenation promptly improved after the start of ECMO therapy. For pulmonary protection, the mode of the mechanical ventilator was set as follows: pressure-controlled ventilation (PCV), FiO2 of 0.35, positive end-expiratory pressure (PEEP) of 9 cmH2O, inspiratory pressure of 7 cmH2O and respiratory frequency of 10 per minute. After introduction of mechanical ventilation and ECMO, the patient's blood pressure decreased. Based on the echocardiographic and electrocardiographic findings, the patient was diagnosed with concurrent takotsubo cardiomyopathy, for which treatment with noradrenaline was started.\n\nThe patient's condition gradually improved in terms of inflammatory reaction and infiltrative opacities in both lungs. His blood oxygen level stabilized even when the level of oxygen received through ECMO was reduced. Therefore, he was weaned from ECMO on Day 12. He was extubated on Day 14. As an adverse event, the patient developed left iliopsoas bleed that required a number of blood transfusions, which resulted in transfusion-associated circulatory overload. The patient was re-intubated and placed on mechanical ventilation on Day 15. His condition improved after fluid management, and he was extubated again on Day 23. The radio-opaque areas in the lung fields became smaller. The flow of supplemental oxygen was decreased to 1 L/min/cannula on Day 33. The patient was discharged on Day 41 (Fig. 2).\n\nFigure 2. Case 1: Clinical course after hospital admission.\n\nCase 2\nA 49-year-old Japanese man with bronchial asthma presented with pyrexia, malaise and dyspnea at the middle of April, 2020, and visited a local clinic. Due to his poor response to any symptomatic treatments given, the patient was taken by ambulance to our hospital 3 days later. He had had close contact with his wife, who had contracted COVID-19 pneumonia. He was suspected of also having COVID-19 pneumonia based on chest CT findings and was admitted to the hospital on the same day. He had no smoking history.\n\nAt the time of admission, the patient had no disorientation, with a body temperature of 39.9℃, blood pressure of 142/88 mmHg, pulse rate of 126 beats per minute, regular, respiratory rate of 22 breaths per minute and percutaneous oxygen saturation (SpO2) of 97% on room air, and a slight increase in CRP (0.70) was observed. Although no increase was found in white blood cell count, an increased neutrophil fraction and decreased lymphocyte fraction were noted (Table 2).\n\nTable 2. Case 2: Laboratory Findings at the Time of Hospital Admission.\n\nTP\t\t7.1\tg/dL\t\tWBC\t\t5,500\t/μL\t\nalb\t\t4.1\tg/dL\t\tneutro\t\t80.6\t%\t\nT-bil\t\t0.52\tmg/dL\t\tlymph\t\t11.2\t%\t\nAST\t\t22\tU/L\t\tmono\t\t8.2\t%\t\nALT\t\t32\tU/L\t\teosino\t\t0\t%\t\nLDH\t\t190\tU/L\t\tHb\t\t16.0\tg/dL\t\nγ-GTP\t\t17\tU/L\t\tHct\t\t46.2\t%\t\nCK\t\t65\tU/L\t\tPlt\t\t20.2\t×104/μL\t\nBUN\t\t8.8\tmg/dL\t\t\t\t\t\t\nCr\t\t0.99\tmg/dL\t\tPT-INR\t\t1.07\t\t\nUA\t\t6.4\tmg/dL\t\tAPTT\t\t35.0\tsec\t\nNa\t\t139\tmEq/L\t\tD-dimer\t\t0.4\tpg/mL\t\nK\t\t3.4\tmEq/L\t\tfibrinogen\t\t334\tmg/dL\t\nCl\t\t107\tmEq/L\t\t\t\t\t\t\nglu\t\t112\tmg/dL\t\t\t\t\t\t\nCRP\t\t0.70\tmg/dL\t\t\t\t\t\t\nIgG\t\t1,186\tmg/dL\t\tinfluenza\t\tA\tnegative\t\nIgA\t\t297\tmg/dL\t\t\t\tB\tnegative\t\nIgM\t\t37\tmg/dL\t\t\t\t\t\t\nIgE\t\t223\tmg/dL\t\tPneumococcal urinary antigen test\tnegative\t\nSPA\t\t16.1\tng/mL\t\t\t\t\t\t\nSPD\t\t25.6\tng/mL\t\tLegionella urinary antigen test\tnegative\t\nKL-6\t\t165\tU/mL\t\t\t\t\t\t\nβ-D-glucan\t\t5.1\tpg/mL\t\t\t\t\t\t\nNT-proBNP\t\t16\tpg/mL\t\t\t\t\t\t\nPCT\t\t0.04\tng/mL\t\t\t\t\t\t\nTP: thyroid peroxidase, Alb: albumin, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, γ-GTP: γ-glutamyl transpeptidase, CK: creatine kinase, BUN; blood urea nitrogen, Cr: creatinine, CRP: C-reactive protein, IgG: immunoglobulinG, IgA: immunoglobulin A, IgM: immunoglobulin M, IgE: immunoglobulin E, SPA: surfactant protein A, SPD: surfactant protein D, KL-6: Krebs von den Lungen, NT-proBNP: N-terminal pro-brain natriuretic peptide, PCT: procalcitonin, WBC: white blood cells, Hb: hemoglobin, Hct: hematocrit, PT-INR: prothrombin time-international normalized ratio, APTT: activated partial thromboplastin time\n\nChest radiography at admission showed nodular opacity in the right upper lobe (Fig. 3a), and plain chest CT showed numerous circular ground-glass opacities and consolidation in the right upper lobe and left lower lobe, which were most obvious around the bronchovascular bundle on the peripheral side (Fig. 3b).\n\nFigure 3. Case 2: Imaging findings at the time of hospital admission. (a) Chest radiography shows nodular opacity in the right upper lobe. (b) Chest CT shows numerous circular ground-glass opacities and consolidation in the right upper lobe and left lower lobe, which were most obvious around the bronchovascular bundle on the peripheral side.\n\nTreatment was started with intravenous infusion of methylprednisolone (80 mg/day) and azithromycin (500 mg every 24 hours) to alleviate inflammation, ceftriaxone (2 g every 24 hours) in consideration of bacterial pneumonia and peramivir (600 mg/day on Day 1 and 300 mg/day from Day 2 onward) as an antiviral agent (Fig. 4). The patient showed positive results of a COVID-19 RT-PCR test on Day 3 of hospitalization when treatment with favipiravir was started. Pyrexia in the patient persisted, and respiratory failure progressed even after the initiation of favipiravir. The dose of methylprednisolone was increased to 250 mg/day from Day 6 onward. On Day 7, continuous intravenous infusion of sivelestat (400 mg/day) was started. Since the platelet count had decreased to 13.9×104/μL and COVID-19 often causes abnormal coagulation, intravenous infusion of recombinant thrombomodulin (32,000 U/day) was also started. The D-dimer level slightly increased to 1.8 μg/mL on Day 10 but improved thereafter.\n\nFigure 4. Case 2: Clinical course after hospital admission.\n\nThe further progression of respiratory failure necessitated noninvasive intermittent positive-pressure ventilation on Day 8 and intubation and mechanical ventilation on Day 9. On Day 10, V-V ECMO was employed for this patient with severe progressive COVID-19 pneumonia with no irreversible underlying disease and poor oxygenation, even at an FiO2 of 1.0. ECMO cannulae were placed in the superior and inferior vena cavae, draining blood from the right femoral vein and returning it to the right internal jugular vein after extracorporeal oxygenation with a flow of 3.5 L/min. His oxygenation promptly improved after the start of ECMO therapy. For pulmonary protection, the mode of the mechanical ventilator was set as follows: PCV, FiO2 of 0.21, PEEP of 8 cmH2O, inspiratory pressure of 8 cmH2O and respiratory frequency of 12 per minute.\n\nThe patient's condition gradually improved in terms of inflammatory reaction and infiltrative opacities in both lungs. His blood oxygen level stabilized even when the level of oxygen received ECMO was reduced. Therefore, he was weaned from ECMO on Day 15. He was extubated on Day 19. No ECMO-associated adverse events were observed. The patient no longer required supplemental oxygen supply on Day 23. The patient was discharged on Day 32 (Fig. 4).\n\nDiscussion\nAlthough the majority of cases of COVID-19 result in mild, reversible symptoms, some patients develop dyspnea and hypoxemia within about a week of the onset of the disease. Wang et al. reported that 26.1% of patients hospitalized with COVID-19 pneumonia required treatment in the intensive-care unit (ICU); 61.1% of these patients in the ICU had ARDS, and the mortality rate was approximately 4.3% (9). A total of 60 patients with COVID-19 pneumonia had been admitted to our hospital as of the middle of May, 2020. Eight of these 60 patients required intubation and mechanical ventilation, including the 2 presently reported patients who also required the use of ECMO.\n\nARDS is characterized by excessive local inflammation in the lung, which can progress to an “out-of-control” state. Excessive production of mediators, such as cytokines (e.g., interleukin-6, tumor necrosis factor alpha, interleukin-8) and arachidonate metabolites (i.e., cytokine storm), interstitial lung edema caused by enhanced pulmonary vascular permeability, and diffuse alveolar damage induce a rapid decrease in oxygenation and the accumulation of carbon dioxide (10). Antiviral treatment and pharmacological and non-pharmacological supportive therapies are considered to serve as important therapeutic strategies for COVID-19 pneumonia patients with ARDS.\n\nIt was previously reported that the fulminant activation of coagulation and consumption of clotting factors occur in severe cases of COVID-19. Inflammation of lung tissues and endothelial cells causes microthrombi formation, leading to thrombotic complications, such as deep venous thrombosis, pulmonary embolism and thrombotic arterial complications (11). T tD-dimer and fibrinogen degradation product (FDP) levels were increased in both of the present cases. Furthermore, in Case 1, the patient developed DIC and pulmonary thromboembolism despite the use of anticoagulants.\n\nDIC in patients with COVID-19 has previously been described, and its characteristics include a lack of bleeding risk, mildly low platelet counts and elevated plasma fibrinogen levels, none of which are seen in typical DIC. Therefore, instead of DIC, these data might more closely resemble complement-mediated thrombotic microangiopathy (TMA) syndromes. Importantly, another essential aspect of DIC seen in COVID-19 is the detection of both COVID-19 and complement components in regions of TMA. Mediators of TMA syndromes overlap with those released by cytokine storm, suggesting close connections between ineffective immune responses to COVID-19, severe pneumonia and life-threatening microangiopathy (12). Although the diagnostic criteria for DIC were met in case 1, TMA syndrome might have occurred in both cases (particularly in case 2) because of the lack of typical symptoms of DIC.\n\nFor the two cases presented in this report, favipiravir administration was started as an antiviral treatment immediately after the diagnosis of COVID-19. At a meeting of the Japanese Association for Infectious Diseases, we presented an immediate report on cases of COVID-19 pneumonia with progressive respiratory failure, for which favipiravir may have worked promptly and effectively (13). However, rapid progression of respiratory failure was observed in the patients in this report despite the initiation of treatment with favipiravir. This can be interpreted as suggesting that the clinical benefit of treatment with an antiviral agent alone is limited in patients with concurrent ARDS. At present, multiple clinical trials of favipiravir are underway in patients with mild to severe COVID-19 pneumonia. Future data from these trials may provide new insights into the drug's clinical benefits.\n\nAs a pharmacological supportive therapy, we administered methylprednisolone (an anti-inflammatory agent for inhibiting cytokine storm), sivelestat (a neutrophil elastase inhibitor) and macrolide antibiotics with an immunoregulatory function (14) effective for suppressing hyperimmunization and excessive inflammation. The World Health Organization (WHO) has advised against the use of corticosteroids to treat COVID-19. The interim WHO guidance on the management of patients with severe acute respiratory infection caused by COVID-19 presents negative views on the use of steroids in the treatment of this patient population (“routine use of steroids should be avoided unless the patient has symptoms including bronchial asthma, aggravated chronic obstructive pulmonary disease, and septic shock”) based on data from studies of steroid therapy in patients with severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) or influenza (15). However, a study by the RECOVERY Collaborative Group showed that the use of dexamethasone in hospitalized COVID-19 patients resulted in a lower 28-day mortality than in those who were solely receiving either invasive mechanical ventilation or oxygen (6). In addition, Wu et al. performed a retrospective cohort study in patients with COVID-19 pneumonia and reported that the mortality in a cohort using methylprednisolone was lower than that in a cohort not using methylprednisolone, although the number of severe cases included in the former cohort was larger than that in the latter cohort (7). In our hospital, we have actively used steroids in patients with hypoxemia and achieved good outcomes. Based on these experiences, we are considering participating in a clinical study conducted to evaluate the efficacy of steroids in patients with COVID-19 pneumonia to verify the clinical effects of steroids in this patient population. Regarding macrolides, some researchers have reported that macrolide therapy was effective for reducing mortality in patients with ARDS (16). Although the mechanism underlying this reduction in mortality has not been fully elucidated, macrolides are likely to have effects on cytokine production and the neutrophil function (16).\n\nAs non-pharmacological supportive therapy, intubation, mechanical ventilation and ECMO were employed. ECMO is a life-supporting method used in patients with severe respiratory or cardiac failure (used particularly as a resuscitative measure taken for patients in cardiopulmonary arrest), called “respiratory ECMO” and “cardiac ECMO”, respectively. Respiratory ECMO is indicated for patients with reversible acute respiratory failure. Its use is considered for patients for whom conventional mechanical ventilation is insufficient for sustaining life or in whom continuous use of the mechanical ventilation system can result in irreversible damage to the lung. Respiratory ECMO is regarded as a treatment of ARDS (17). In the treatment of novel influenza A (H1N1) 2009, the results of ECMO database-based cohort studies (18,19) and the study on conventional ventilatory support vs. ECMO for severe adult respiratory failure (CESAR study) (20) demonstrated the efficacy of ECMO therapy based on the finding that the mortality in patients using ECMO was significantly lower than that in patients not using ECMO. In a retrospective study in MERS patients with refractory respiratory failure in 2018, the use of ECMO was required as an emergency treatment. The mortality in MERS patients with refractory hypoxemia in the ECMO cohort was significantly lower than that in the non-ECMO cohort (65% vs. 100%; p = 0.02) (21). Although little evidence for the efficacy of ECMO has been obtained with respect to COVID-19 pneumonia, results from two retrospective studies have been reported. In a retrospective study by Yang et al., of 52 patients admitted to the ICU with severe COVID-19 pneumonia, 32 died within 28 days of admission. ECMO was introduced to 6 patients, of whom 5 died, while the other was still on ECMO at the time of the endpoint assessment (22). In a retrospective study by Zhang et al., 48 of 221 patients with COVID-19 pneumonia had concurrent ARDS, and 10 of these 48 patients required mechanical ventilation and ECMO therapy. Of these 10 patients, 2 were successfully treated and discharged from the hospital, and 3 died. The other five patients were still on ECMO at the time of the endpoint assessment (23). According to the interim WHO guidance, ECMO, despite little evidence for its efficacy, is regarded as an emergency treatment of COVID-19 patients who have concurrent refractory hypoxemia even after being treated with lung-protective ventilation strategy (15). The condition of the two patients in the present case report was improved by intubation, mechanical ventilation and the prompt introduction of ECMO. COVID-19 pneumonia with ARDS is associated with high mortality. Pulmonary protection initiated before obtaining clinical benefits of antiviral treatment and pharmacological supportive therapy is considered to contribute to a reduction in mortality. Concerning complications, iliopsoas hematoma was identified in Case 1. In general, hemorrhagic complications, such as cannulation site bleeding, occur in approximately 50% of patients undergoing ECMO (17). ECMO-associated bleeding, which is attributed to the effect of heparinization as well as circuit-related consumption of coagulation factors, can be severe. It may be difficult to arrest bleeding if no measures other than monitoring the patient are taken. In Case 1, although the patient required blood transfusion, bleeding was arrested during the observation of the patient's condition. Infection is another critical complication said to occur in approximately 20% of patients on ECMO (17). However, the two patients in this report were able to safely receive ECMO therapy with no ECMO-related infectious complications.\n\nOur two patients were already suffering from severe respiratory failure at the time of the diagnosis of COVID-19. They were successfully treated by a combination of antiviral treatment with favipiravir, corticosteroid, mechanical ventilation and ECMO. The positive outcomes of these cases underscore the importance of promptly treating severe COVID-19 pneumonia after the diagnosis with non-pharmacological supportive therapy, such as mechanical ventilation and ECMO, in combination with pharmacological supportive therapy, notably favipiravir for antiviral treatment and corticosteroid for anti-inflammatory treatment.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nWHO Coronavirus Disease (COVID-19) Dashboard\n [Internet]. [cited 2020 Aug 1]. Available from: https://covid19.who.int\n2. \nWiersinga WJ , Rhodes A , Cheng AC , et al \nPathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review\n. JAMA . Forthcoming .\n3. \nOestereich L , Lüdtke A , Wurr S , Rieger T , Muñoz-Fontela C , Günther S \nSuccessful treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal model\n. Antiviral Res \n105 : 17 -21\n, 2014 .24583123 \n4. \nGowen BB , Wong MH , Jung KH , et al \nIn vitro and in vivo activities of T-705 against arenavirus and bunyavirus infections\n. Antimicrob Agents Chemother \n51 : 3168 -3176\n, 2007 .17606691 \n5. \nCai Q , Yang M , Liu D , et al \nExperimental treatment with favipiravir for COVID-19: an open-label control study\n. Engineering . Forthcoming .\n6. \nHorby P , Lim WS , Emberson JR , et al; RECOVERY Collaborative Group . Dexamethasone in hospitalized patients with covid-19 - preliminary report\n. N Engl J Med . Forthcoming .\n7. \nWu C , Chen X , Cai Y , et al \nRisk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China\n. JAMA Intern Med . Forthcoming .\n8. \nKowalewski M , Fina D , Słomka A , et al \nCOVID-19 and ECMO: the interplay between coagulation and inflammation-a narrative review\n. Crit Care \n24 : 205 , 2020 .32384917 \n9. \nWang D , Hu B , Hu C , et al \nClinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China\n. JAMA \n323 : 1061 -1069\n, 2020 .32031570 \n10. \nThe Japanese Society of Intensive Care Medicine, Japanese Society of Respiratory Care Medicine, and the Japanese Respiratory Society\n. Clinical practice guideline for the management of acute respiratory distress syndrome (ARDS) \n2016 (in Japanese).\n11. \nWiersinga WJ , Rhodes A , Cheng AC , et al \nPathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review\n. JAMA . Forthcoming .\n12. \nMerrill JT , Erkan D , Winakur J , James JA \nEmerging evidence of a COVID-19 thrombotic syndrome has treatment implications\n. Nat Rev Rheumatol \n30 : 1 -9\n, 2020 .\n13. \nThe Japanese Association for Infectious Diseases\n [Internet]. [cited 2020 Aug 13]. Available from:\nhttp://www.kansensho.or.jp/modules/en/index.php?content_id=3.\n14. \nWong EH , Porter JD , Edwards MR , Johnston SL \nThe role of macrolides in asthma: current evidence and future directions\n. Lancet Respir Med \n2 : 657 -670\n, 2014 .24948430 \n15. \nClinical management of severe acute respiratory infection when novel coronavirus infection is suspected\n [Internet]. [cited 2020 Jun 2]. Available from:\nwww.who.int/publications-detail/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected\n16. \nSimonis FD , Iudibus G , Cremer OL , et al \nMacrolide therapy is associated with reduced mortality in acute respiratory distress syndrome (ARDS) patients\n. Ann Transl Med \n6 : 24 , 2018 .29430441 \n17. \nBrodie D , Bacchetta M \nExtracorporeal membrane oxygen- ation for ARDS in adults\n. N Engl J Med \n365 : 1905 -1914\n, 2011 .22087681 \n18. \nThe Australia and New Zealand Extracorporeal Membrane Oxygenation (ANZ ECMO) Influenza Investigators . Extracorporeal membrane oxygenation for 2009 influenza A(H1N1) acute respiratory distress syndrome\n. JAMA \n302 : 1888 -1895\n, 2009 .19822628 \n19. \nNoah MA , Peek GJ , Finney SJ , et al \nReferral to an extracorporeal membrane oxygenation center and mortality among patients with severe 2009 influenza A(H1N1)\n. JAMA \n306 : 1659 -1668\n, 2011 .21976615 \n20. \nPeek GJ , Mugford M , Tiruvoipati R , et al \nEfficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial\n. Lancet \n374 : 1351 -1363\n, 2009 .19762075 \n21. \nAlshahrani MS , Sindi A , Alshamsi F , et al \nExtracorporeal membrane oxygenation for severe Middle East respiratory syndrome coronavirus\n. Ann Intensive Care \n8 : 3 , 2018 .29330690 \n22. \nYang X , Yu Y , Shu J , et al \nClinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study\n. Lancet Respir Med \n8 : 475 -481\n, 2020 .32105632 \n23. \nZhang G , Hu C , Luo L , et al \nClinical features and short-term outcomes of 221 patients with COVID-19 in Wuhan, China\n. J Clin Virol \n127 : 104364 , 2020 .32311650\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "60(1)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "COVID-19; corticosteroid; extracorporeal membrane oxygenation; favipiravir; mechanical ventilation",
"medline_ta": "Intern Med",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000368:Aged; D000577:Amides; D000998:Antiviral Agents; D000086382:COVID-19; D015199:Extracorporeal Membrane Oxygenation; D006801:Humans; D008297:Male; D008775:Methylprednisolone; D008875:Middle Aged; D011719:Pyrazines; D012121:Respiration, Artificial; D012131:Respiratory Insufficiency; D000086402:SARS-CoV-2",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "123-130",
"pmc": null,
"pmid": "33390469",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19822628;32648899;32384917;32311650;17606691;24948430;32167524;19762075;21976615;32031570;29430441;29330690;24583123;32733003;22087681;32678530;32105632",
"title": "Two Cases of Severe COVID-19 Pneumonia Effectively Treated with Extracorporeal Membrane Oxygenation in Addition to Favipiravir and Corticosteroid.",
"title_normalized": "two cases of severe covid 19 pneumonia effectively treated with extracorporeal membrane oxygenation in addition to favipiravir and corticosteroid"
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"abstract": "The aim of the study was to evaluate the efficacy and long-term safety of tocilizumab treatment in children with systemic-onset juvenile idiopathic arthritis in a single centre.\nThe study was based on a retrospective analysis of a cohort of 10 patients with systemic-onset juvenile idiopathic arthritis who were treated with tocilizumab in the period September 2011-July 2017. Their medical records were analysed taking into consideration the effectiveness of tocilizumab treatment and frequency of side effects.\nBefore the initiation of treatment, 9/10 patients from the study group complained of fever and had significantly increased values of inflammatory markers, with the median CRP concentration 41.1 mg/l (norm < 5 mg/l) and ESR 37 mm/h (norm < 12 mg/l). The period of the initial 12 weeks of treatment was a quantum leap in the course of the disease: all children were afebrile, and inflammatory markers values decreased by 99.4% in the case of CRP and 91.9% in ESR. All patients fulfilled ACR Pedi 50 criteria, and 3 of them achieved ACR Pedi 70. In the next stages of treatment the response to tocilizumab was sustained, reaching 10 children achieving ACR Pedi 70 and 5 ACR Pedi 90 after one year of therapy. Tocilizumab appeared to be relatively safe in the study group. Although elevation of transaminases and neutropenia were observed in 5/10 patients, they were usually mild and transitional in their course.\nTocilizumab is both effective and has a relatively good safety profile in children with severe systemic-onset juvenile idiopathic arthritis. It should be considered in the recommendations as a first-line treatment of this disease.",
"affiliations": "Department of Paediatric Cardiology and Rheumatology, Medical University of Łódź, Poland.;Department of Paediatric Cardiology and Rheumatology, Medical University of Łódź, Poland.;Department of Paediatric Cardiology and Rheumatology, Medical University of Łódź, Poland.",
"authors": "Roszkiewicz|Justyna|J|;Orczyk|Krzysztof|K|;Smolewska|Elżbieta|E|",
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"doi": "10.5114/reum.2018.79497",
"fulltext": "\n==== Front\nReumatologiaReumatologiaRUReumatologia0034-62332084-9834Narodowy Instytut Geriatrii, Reumatologii i Rehabilitacji w Warszawie 7949710.5114/reum.2018.79497Original PaperTocilizumab in the treatment of systemic-onset juvenile idiopathic arthritis – single-centre experience Roszkiewicz Justyna Orczyk Krzysztof Smolewska Elżbieta Department of Paediatric Cardiology and Rheumatology, Medical University of Łódź, PolandAddress for correspondence: Elżbieta Smolewska, Department of Paediatric Cardiology and Rheumatology, Medical University of Łódź, Maria Konopnicka Memorial Teaching Hospital No. 4, 36/50 Sporna St., 91-738 Łódź, Poland. e-mail: e.smolewska@wp.pl31 10 2018 2018 56 5 279 284 08 8 2018 08 9 2018 Copyright: © 2018 Narodowy Instytut Geriatrii, Reumatologii i Rehabilitacji w Warszawie2018This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License, allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.Objectives\nThe aim of the study was to evaluate the efficacy and long-term safety of tocilizumab treatment in children with systemic-onset juvenile idiopathic arthritis in a single centre.\n\nMaterial and methods\nThe study was based on a retrospective analysis of a cohort of 10 patients with systemic-onset juvenile idiopathic arthritis who were treated with tocilizumab in the period September 2011–July 2017. Their medical records were analysed taking into consideration the effectiveness of tocilizumab treatment and frequency of side effects.\n\nResults\nBefore the initiation of treatment, 9/10 patients from the study group complained of fever and had significantly increased values of inflammatory markers, with the median CRP concentration 41.1 mg/l (norm < 5 mg/l) and ESR 37 mm/h (norm < 12 mg/l). The period of the initial 12 weeks of treatment was a quantum leap in the course of the disease: all children were afebrile, and inflammatory markers values decreased by 99.4% in the case of CRP and 91.9% in ESR. All patients fulfilled ACR Pedi 50 criteria, and 3 of them achieved ACR Pedi 70. In the next stages of treatment the response to tocilizumab was sustained, reaching 10 children achieving ACR Pedi 70 and 5 ACR Pedi 90 after one year of therapy. Tocilizumab appeared to be relatively safe in the study group. Although elevation of transaminases and neutropenia were observed in 5/10 patients, they were usually mild and transitional in their course.\n\nConclusions\nTocilizumab is both effective and has a relatively good safety profile in children with severe systemic-onset juvenile idiopathic arthritis. It should be considered in the recommendations as a first-line treatment of this disease.\n\ntocilizumabsystemic-onset juvenile idiopathic arthritistreatment responsebiologic treatment effectiveness\n==== Body\nIntroduction\nSystemic-onset juvenile idiopathic arthritis (sJIA) is the most severe and distinctive subtype of juvenile idiopathic arthritis (JIA). In contrast to other JIA subtypes, the clinical course of sJIA is characterised by prominent features of systemic inflammation: spiking fever, macular rash, hepatosplenomegaly, lymphadenopathy and serositis in combination with arthritis. Laboratory test results show remarkably high values of acute phase proteins such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and ferritin, and a shift in blood morphology: leukocytosis with predominant neutrophilia and thrombocytosis [1].\n\nThe presence of systemic manifestations is suggested to be caused by continuous activation of innate immunity pathways leading to dysregulated production of proinflammatory cytokines, such as IL-1β and IL-6 [2]. Treatment of sJIA is challenging. The systemic features during the flare of the disease are very severe, and there is a possibility of developing macrophage activation syndrome (MAS), a potentially life-threatening complication of sJIA. Before the introduction of biologic treatment, patients usually required long-term administration of systemic steroids in high doses, which could lead to numerous side effects of the therapy such as growth delay, osteoporosis and hypertension. Efficacy of many disease-modifying antirheumatic drugs (DMARDs) such as methotrexate (MTX) and tumour necrosis factor α inhibitors (anti-TNFs) is lower in sJIA than in other JIA subtypes [3–5].\n\nTocilizumab (TCZ) is a humanized monoclonal antibody that acts as a receptor-inhibitor of IL-6. IL-6 is a cytokine possessing multiple biologic functions that are important in inflammation: it induces hepatocytes to produce acute-phase proteins, promotes osteoclast activation, increases angiogenesis and induces fever generation. IL-6 contributes to B-cell and T-cell differentiation and inhibition of regulatory T-cell production. Levels of IL-6 are significantly higher in sera of JIA patients than in healthy controls [6]. Registration of biologic agents targeting IL-6 was a milestone in the treatment of sJIA and nowadays inactive disease and remission are within reach of most patients. According to the Polish guidelines [7], TCZ is indicated in children with sJIA over the age of two who fulfil one of the clinical criteria:\n\nsJIA with predominant systemic features, not responding adequately to at least a two-week course of systemic steroids in the dose 1–2 mg/kg/day of oral prednisone or 10–30 mg/kg/day of intravenous methylprednisolone,\n\nsJIA with involvement of at least five peripheral joints or two joints and coexisting fever, in whom the disease is active despite at least three-month treatment with systemic steroids and MTX or another immunosuppressive drug.\n\nThe aim of our study was to evaluate the efficacy and safety of tocilizumab treatment in all children with systemic-onset juvenile idiopathic arthritis in our department. To our knowledge, this is the first study on that topic in the Polish population.\n\nMaterial and methods\nMedical histories of sJIA patients treated with TCZ in our department between September 2011 and April 2017 were retrospectively analysed. The diagnosis of sJIA was based on the International League of Associations for Rheumatology (ILAR) classification criteria of JIA [8]. The dose of TCZ was 12 mg/kg/dose every 2 weeks in children weighing under 30 kg and 8 mg/kg/dose every 2 weeks in children weighing over 30 kg. Patient demographic data, including age, gender, clinical manifestations of the disease, duration of symptoms and medications used in the history, were collected at the initiation of TCZ treatment. Laboratory test results included in the study were obtained before initiation of TCZ treatment, after one dose of TCZ and after 3, 6 and 12 months of drug administration. The treatment response was evaluated at 3, 6 and 12 months of treatment using American College of Rheumatology Paediatric criteria (ACR Pedi).\n\nMedical records of patients were also analysed for treatment side effects, including leukopenia, hepatotoxicity and opportunistic infections during the first two years of the therapy. Baseline characteristics, treatment response, and ACR Pedi 30, 50, 70 were calculated using simple descriptive statistics. Spearman rank correlation analysis between age at diagnosis, baseline inflammatory markers values, time from disease onset to TCZ treatment initiation and time to achieve ACR 30, 50, 70 criteria was performed. The data were analysed using Statistica 13 software (StatSoft Polska, Kraków, Poland).\n\nResults\nGroup baseline characteristics\nThe study group was composed of 10 patients: 6 girls and 4 boys diagnosed with sJIA aged from 2 to 15 years (mean age 7.11 ±2.06 years). Nine of the patients were febrile at the baseline of treatment, and in 6 of them we found a limited range of motion within peripheral joints with coexistence of oedema in 3 patients. The median time of TCZ treatment initiation was 167 days. The first patient was administered TCZ 4.5 years after sJIA diagnosis, the last one after 23 days. This shift probably reflects progress in access to biologic treatment in Poland. At the baseline of TCZ treatment all patients from the study group received systemic steroids and DMARDs: MTX in 9 patients, cyclosporine in 1. Three of them were previously treated with a biologic DMARD – etanercept – in their medical history.\n\nBefore administration of the first TCZ dose, we observed increased values of inflammatory markers in 9 out of 10 patients. Their median values were as follows: CRP 41.1 mg/l (range 4.96–182.0), ESR 37 mm/h (range 3–70). The disease activity was measured using the VAS analogue scale assessed both by parent of the patient and their physician. Their median values were 75 mm (range 40–100) and 40 mm (range 30–60), respectively. Median value of the Childhood Health Assessment Questionnaire (CHAQ) was 1.275 (range 0.5–1.4) (Table I).\n\nTable I Patient baseline characteristics\n\nCharacteristic\tPatients (N = 10)\t\nFemale gender\t6\t\nAge (in years)\t7.11 ±2.06\t\nDuration of disease (in days)\t330\t\nPrior use of DMARDs\t10\t\nMethotrexate\t9\t\nCyclosporin A\t1\t\nPrior use of a biologic agent\t3\t\nPrior use of anti-TNF agent\t3\t\nPrior use of IL-1 inhibitor\t0\t\nOral glucocorticoid use\t10\t\nPlus–minus values are means ±\n\nSD DMARD – disease-modifying antirheumatic drug; TNF – tumour necrosis factor\n\nTreatment effectiveness after 12 weeks\nAt 12-week assessment none of the patients complained of fever. The number of children who achieved ACR Pedi 30, 50 and 70 at this time point was 10, 10 and 3, respectively (Fig. 1). At this time point all of the children reached the state of clinically inactive disease according to Wallace criteria [9]. In all patients we observed a significant decrease of inflammatory marker values. The median CRP value was 0.225 mg/l (range 0.1–1.56). Absolute change of CRP concentrations from baseline was –40.775 mg/l, and median percentage change was –99.4%. The median ESR value at the same time point was 3 mm/h (range 2–12), which means the absolute median change from baseline was –34 mm/h, and the median percentage change was –91.9%.\n\nFig. 1 Time courses of American College of Rheumatology Pediatric (ACR Pedi) 30, 50, and 70 responses.\n\nIn 5/10 patients we observed a decrease in inflammatory marker values to normal limits after infusion of one TCZ dose (Table II). After 12 weeks of TCZ therapy all of the children were still receiving oral corticosteroids, but in 9 of them we were able to reduce their doses by at least 30%.\n\nTable II Change from Baseline in ACR Core Set of Variables\n\nVariable\tBaseline\tWeek 12\tWeek 24\tWeek 48\t\nJIA ACR 70 response and no fever (n)\t–\t3 (30%)\t8 (80%)\t10 (100%)\t\nACR core set variables\t\nNo. of patients with active arthritis\t3\t0\t0\t0\t\nNo. of patients with limited range of motion\t6\t0\t0\t0\t\nScore for physician’s global assessment of disease activity\t40*\t10*\t5*\t0*\t\nScore for patient’s global assessment of overall wellbeing\t75*\t35*\t20*\t15*\t\nCHAQ score\t1.275*\t0.675*\t0.55*\t0.375*\t\nESR (mm/h)\t37*\t3*\t2*\t2.5*\t\n* values are medians\n\nTreatment effectiveness after 24 weeks\nAfter 6 months of therapy the number of children who achieved ACR Pedi 30, 50, 70 had improved and reached 10, 10 and 8, respectively. Three patients achieved ACR Pedi 90 (Fig. 1). None of the children complained of joint stiffness, and peripheral joint oedema was not noted. The values of inflammatory markers remained within normal limits. The median CRP value was 0.2 mg/l (range 0.14–1.36), which means no significant change in this parameter between 3 and 6 months of treatment (absolute median change – 0.025 mg/l, percentage change –11.2%). The same observation applied to ESR. Median ESR value was 2 mm/h (range 2–10), which corresponds to the absolute median change of –1.0, which is not clinically significant. Due to satisfactory treatment results in half of patients, systemic corticosteroids were discontinued, and in the remaining half their doses were gradually tapered down.\n\nTreatment effectiveness after 48 weeks\nAt 12 months of treatment we were able to analyse 8 of the patients from the study group, as 2 of them had not completed one year of the treatment period yet. Only 2/8 patients were still receiving oral corticosteroids at low doses at this time point. In 1 patient MTX was discontinued and TCZ was used in monotherapy without aggravation of symptoms. At 48 weeks of TCZ treatment all of the patients had achieved ACR Pedi 30, 50 and 70, and half of them had reached ACR Pedi 90 (Fig. 1). The values of inflammatory markers were within normal limits. There was no change in CRP median concentration between 24 and 48 weeks of treatment (0.2 mg/l, range 0.1–0.38), and ESR was also at the same level (median 2.5 mm/h, range 2–6).\n\nWe found no significant correlations between duration of the disease before the initiation of TCZ treatment, age of the patient, baseline values of inflammatory markers and the clinical outcome of TCZ treatment, measured as time to achieve ACR Pedi criteria (Spearman’s rank correlation R-values for ACR Pedi 70 response:\n\nRESR = 0.07, RCRP = –0.12, Rage = –0.04, Rtime = 0.23).\n\nAdverse effects of the therapy\nMild upper respiratory tract infections, which led to omitting one dose of TCZ, were reported with the frequency 0.4 infection/patient-year. No tuberculosis or Pneumocystis jiroveci opportunistic infection was noted. Herpes simplex type 1 infection was rare (0.11/patient-year) during the period of TCZ treatment.\n\nIn half of patients neutropenia was observed, which corresponds to 0.77 incident/patient-year. In all cases it was transitional, grade 1 neutropenia, described as an absolute neutrophil count < 2.0 × 109/l and > 1.1 × 109/l. The median TCZ dose received before the first episode of neutropenia was 10 (range 5–15). Increase in aspartate aminotransferase and alanine aminotransferase activities was the most common side effect of TCZ treatment (3.33 episodes/patient-year). All the patients who developed hepatotoxicity were simultaneously treated with MTX. However, in only 1 patient liver function test values were three times above the normal limits (grade 2 of hepatic toxicity) and treatment with TCZ was suspended until their normalisation. There were no infusion-related treatment adverse effects in our study group. None of the patients developed MAS.\n\nDiscussion\nIntroduction of TCZ is considered as a breakthrough in the management of sJIA. TCZ shows both high effectiveness and a satisfactory drug safety profile, which makes it an invaluable treatment option even in monotherapy [6], especially in patients resistant to other DMARDs and with high doses of corticosteroid dependency.\n\nThis study confirmed both TCZ features, despite the presence of limitations related to retrospective analysis of the data and small study group size. In our patients the most spectacular differences in disease course were observed in the initial 12-week phase of treatment. At this time point none of the children had fever and the values of inflammatory markers decreased significantly, reaching –99.4% and –91.9% in concentrations of CRP and ESR, respectively.\n\nMoreover, all of the patients reached the state of clinically inactive disease according to Wallace criteria [9] and achieved an ACR Pedi 50 response, with 3 of them reaching ACR Pedi 70. Those results show a similar therapy outcome regarding ACR Pedi 30 and ACR Pedi 50 in comparison to the TCZ therapy response rates achieved in phase III of the randomised, double-blind, placebo-controlled study by Yokota et al. [10], where ACR Pedi 30, 50 and 70 were achieved by 80, 80 and 75%, respectively. The difference in achieving ACR 70 criteria at this time point is likely to be affected by the disproportionally high CHAQ values in our study group and the baseline characteristics of our patients, such as relatively low presence of symptoms of arthritis in the course of sJIA (3/10 patients). On the other hand, our outcomes of ACR Pedi 70 and 90 at this time point are comparable with data from the BIKeR study [5], in which after 3 months of treatment ACR Pedi 70 and 90 were reached by 44% and 16% of patients, respectively.\n\nIn 2005, Woo et al. [11] described achievement of ACR Pedi 30 response criteria in 73% of sJIA patients after a single TCZ dose. Due to missing data, calculating the ACR 30 criteria response after one dose of TCZ was unachievable. However, we observed absence of fever in all of the patients and normalisation of inflammatory marker values in half of them after one TCZ infusion. As described in previous studies on TCZ efficacy and safety, the response to TCZ is sustained in the following one-year treatment period [12].\n\nIn our study group, after 48 weeks of therapy, all patients achieved ACR Pedi 70 and half of them ACR Pedi 90 criteria. Despite the limited study group size, those outcomes are comparable with results obtained by Yokota et al. [10], where ACR Pedi 30, 50, 70 response rates were 98%, 94% and 90% and similar to the TENDER study [13], where 87.4% of patients achieved ACR Pedi 70 after 52 weeks of treatment. In contrast, the results of all the studies mentioned above are divergent from BIKeR registry data [5], in which after 24 months of therapy ACR Pedi 70 and 90 were reached by 40 and 35% of children. In our patients effectiveness of TCZ treatment was not influenced by duration of the disease and disease features at study entry, similarly as observed in the TENDER study. Tapering down the doses of systemic corticosteroids may also be perceived as an indicator of TCZ therapy response. In the TENDER study 61% of patients discontinued steroids after two years of TCZ treatment [14]. In our population this percentage reached 75% after the initial 48 weeks of treatment and TCZ proved to be effective even in monotherapy.\n\nTocilizumab is described as the biologic agent with the highest risk of therapy side effects [5, 15, 16], with serious adverse effects occurring more frequently in sJIA than in the polyarticular subtype of the disease [6]. In our study group the most common side effects were elevations of liver enzyme activities and neutropenia. Despite the high incidence, both of them were transitional and mild in course. Neutropenia in all cases resolved spontaneously, as observed previously in TENDER and the study by Yokota et al. [10, 14], when it appeared in 15% and 17.9% of children, respectively. It is important to note that in the studies mentioned above patients had grade 3 neutropenia (classified as a neutrophil count ≥ 0.5 to < 1.0 × 109/l), whereas in our population we observed only grade 1, defined as a neutrophil count < 2.0 × 109/l and > 1.1 x 109/l. Elevated transaminases in our study group were observed in half of the cases, although only 1 patient had grade 2 of this side effect (classified as transaminase activity > 3–5 times more than the upper limit of normal value) and required temporary suspension of treatment. In other patients values of liver enzyme activities after hepatoprotective treatment decreased to values within normal limits. In previous studies on TCZ, infections were described as the most frequent adverse effect of the therapy. In our population infections occurred with an incidence 0.4 infection/patient-year. In the TENDER study this rate reached 3.0/patient-year and 0.115/patient-year in reference to severe diseases. Such a considerable difference between our study group and TENDER is probably the consequence of retrospective analysis of the data and missing information about infections that children faced between the TCZ infusions that resolved spontaneously and did not result in omitting a TCZ dose.\n\nConclusions\nTreatment of rheumatic diseases has significantly changed during the last decade. The emerge of biologic drugs has contributed to that fact and made remission or clinically inactive disease within reach of most JIA patients. Tocilizumab is efficacious in severe cases of sJIA, refractory to other therapy. Despite the acceptable safety profile of the drug, the possible treatment benefits in every patient must be weighted against the risk of adverse effects of therapy that is higher in TCZ than in other biologic drugs. Our study should be followed by a multicenter prospective analysis in order to evaluate the real safety of TCZ treatment and its potential as a first-line therapy in sJIA.\n\nThe study was supported by grant No. 503/8-000-04/503-81-002-17 from the Medical University of Łódź, Poland.\n\nThe authors declare no conflict of interest.\n==== Refs\nReferences\n1 De Benedetti F Brunner HI Ruperto N Randomised trial of tocilizumab in systemic juvenile idiopathic arthritis N Engl J Med 2012 367 2385 2395 23252525 \n2 Cimaz R Systemic-onset juvenile idiopathic arthritis Autoimmun Rev 2016 15 931 934 27392503 \n3 Prince FH Twilt M ten Cate R Long-term follow-up on effectiveness and safety of etanercept in juvenile idiopathic arthritis: the Dutch national register Ann Rheum Dis 2009 68 635 641 18413443 \n4 Horneff G De Bock F Foeldvari I Safety and efficacy of combination of etanercept and methotrexate compared to treatment with etanercept only in patients with juvenile idiopathic arthritis (JIA): preliminary data from the German JIA Registry Ann Rheum Dis 2009 68 519 525 18413440 \n5 Horneff G Schulz AC Klotsche J Experience with etanercept, tocilizumab and interleukin-1 inhibitors on systemic onset juvenile idiopathic arthritis patients from the BIKER registry Arthritis Res Ther 2017 19 256 29166924 \n6 Turnier JL Brunner HI Tocilizumab for treating juvenile idiopathic arthritis Expert Opin Biol Ther 2016 16 559 566 26848760 \n7 Program leczenia reumatoidalnego zapalenia stawów i młodzieńczego idiopatycznego zapalenia stawów o przebiegu agresywnym [online] 2017 [Access: 5.08.2018]. Available at: htps://www.gov.pl/documents/292343/436711/b.33.-nowyod11.2017.docx/7ce53e37-6ef9-d6a2-0143-7385f7011713 \n8 Petty RE Southwood TR Manners P International league of associations for rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001 J Rheumatol 2004 31 390 392 14760812 \n9 Wallace CA Giannini EH Huang H American College of Rheumatology provisional criteria for defining clinical inactive disease in select categories of juvenile idiopathic arthritis Arthritis Care Res (Hoboken) 2011 63 929 936 21717596 \n10 Yokota S Imagawa T Mori M Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial Lancet 2008 371 998 1006 18358927 \n11 Woo P WN Prieur AM Southwood T Open label phase II trial of single, ascending doses of MRA in Caucasian children with severe systemic juvenile idiopathic arthritis: proof of principle of the efficacy of IL-6 receptor blockade in this type of arthritis and demonstration of prolonged clinical improvement Arthritis Res Ther 2005 7 R1281 1288 16277681 \n12 Yokota S Itoh Y Morio T Tocilizumab in systemic juvenile idiopathic arthritis in a real-world clinical setting: results from 1 year of postmarketing surveillance follow-up of 417 patients in Japan Ann Rheum Dis 2016 75 1654 1660 26644233 \n13 De Benedetti F Brunner HI Allen R The efficacy of tocilizumab in patients with systemic juvenile idiopathic arthritis: 52-week data from a phase 3 clinical trial British Society of Rheumatology Annual Meeting May 2012 \n14 De Benedetti F Brunner H Ruperto N FRI0328 Efficacy and safety of tocilizumab (TCZ) in patients with systemic juvenile idiopathic arthritis (SJIA): 2-year data from tender, a phase 3 clinical trial Ann Rheum Dis 2013 71 425 \n15 Horneff G Biologic-associated infections in pediatric rheumatology Curr Rheumatol Rep 2015 17 66 26385753 \n16 Tarp S Amarilyo G Foeldvari I Efficacy and safety of biological agents for systemic juvenile idiopathic arthritis: a systemic review and meta-analysis of randomized trials Rheumatology (Oxford) 2016 55 669 679 26628580\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0034-6233",
"issue": "56(5)",
"journal": "Reumatologia",
"keywords": "biologic treatment effectiveness; systemic-onset juvenile idiopathic arthritis; tocilizumab; treatment response",
"medline_ta": "Reumatologia",
"mesh_terms": null,
"nlm_unique_id": "20130190R",
"other_id": null,
"pages": "279-284",
"pmc": null,
"pmid": "30505008",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "16277681;18413440;18358927;26385753;23252525;26848760;29166924;14760812;26628580;27392503;21717596;18413443;26644233",
"title": "Tocilizumab in the treatment of systemic-onset juvenile idiopathic arthritis - single-centre experience.",
"title_normalized": "tocilizumab in the treatment of systemic onset juvenile idiopathic arthritis single centre experience"
} | [
{
"companynumb": "PL-ROCHE-2228263",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TOCILIZUMAB"
},
"drugadditional": "1",
"drug... |
{
"abstract": "OBJECTIVE\nWe sought to determine predictors of adverse neonatal outcomes in women with intrahepatic cholestasis of pregnancy (ICP).\n\n\nMETHODS\nThis study was a multicenter retrospective cohort study of all women diagnosed with ICP across 5 hospital facilities from January 2009 through December 2014. Obstetric and neonatal complications were evaluated according to total bile acid (TBA) level. Multivariable logistic regression models were developed to evaluate predictors of composite neonatal outcome (neonatal intensive care unit admission, hypoglycemia, hyperbilirubinemia, respiratory distress syndrome, transient tachypnea of the newborn, mechanical ventilation use, oxygen by nasal cannula, pneumonia, and stillbirth). Predictors including TBA level, hepatic transaminase level, gestational age at diagnosis, underlying liver disease, and use of ursodeoxycholic acid were evaluated.\n\n\nRESULTS\nOf 233 women with ICP, 152 women had TBA levels 10-39.9 μmol/L, 55 had TBA 40-99.9 μmol/L, and 26 had TBA ≥100 μmol/L. There was no difference in maternal age, ethnicity, or prepregnancy body mass index according to TBA level. Increasing TBA level was associated with higher hepatic transaminase and total bilirubin level (P < .05). TBA levels ≥100 μmol/L were associated with increased risk of stillbirth (P < .01). Increasing TBA level was also associated with earlier gestational age at diagnosis (P < .01) and ursodeoxycholic acid use (P = .02). After adjusting for confounders, no predictors were associated with composite neonatal morbidity. TBA 40-99.9 μmol/L and TBA ≥100 μmol/L were associated with increased risk of meconium-stained amniotic fluid (adjusted odds ratio, 3.55; 95% confidence interval, 1.45-8.68 and adjusted odds ratio, 4.55; 95% confidence interval, 1.47-14.08, respectively).\n\n\nCONCLUSIONS\nIn women with ICP, TBA level ≥100 μmol/L was associated with increased risk of stillbirth. TBA ≥40 μmol/L was associated with increased risk of meconium-stained amniotic fluid.",
"affiliations": "Department of Obstetrics and Gynecology, MedStar Washington Hospital Center, Washington, DC. Electronic address: tetsuya.x.kawakita@gunet.georgetown.edu.;Department of Obstetrics and Gynecology, MedStar Washington Hospital Center, Washington, DC.;Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio, TX.;Department of Biostatistics and Epidemiology, MedStar Health Research Institute, Hyattsville, MD.;Department of Biostatistics and Epidemiology, MedStar Health Research Institute, Hyattsville, MD.;Department of Obstetrics and Gynecology, Virginia Hospital Center, Arlington, VA.;Department of Obstetrics and Gynecology, MedStar Franklin Square Medical Center, Baltimore, MD.;Department of Obstetrics and Gynecology, MedStar Washington Hospital Center, Washington, DC.",
"authors": "Kawakita|Tetsuya|T|;Parikh|Laura I|LI|;Ramsey|Patrick S|PS|;Huang|Chun-Chih|CC|;Zeymo|Alexander|A|;Fernandez|Miguel|M|;Smith|Samuel|S|;Iqbal|Sara N|SN|",
"chemical_list": "D001647:Bile Acids and Salts; D002756:Cholagogues and Choleretics; D014580:Ursodeoxycholic Acid; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9378",
"issue": "213(4)",
"journal": "American journal of obstetrics and gynecology",
"keywords": "bile acid; intrahepatic cholestasis of pregnancy; neonatal outcome; ursodeoxycholic acid",
"medline_ta": "Am J Obstet Gynecol",
"mesh_terms": "D000328:Adult; D000410:Alanine Transaminase; D001219:Aspartate Aminotransferases; D001647:Bile Acids and Salts; D002756:Cholagogues and Choleretics; D002780:Cholestasis, Intrahepatic; D015331:Cohort Studies; D005260:Female; D005865:Gestational Age; D006801:Humans; D006932:Hyperbilirubinemia; D007003:Hypoglycemia; D007231:Infant, Newborn; D007363:Intensive Care Units, Neonatal; D016015:Logistic Models; D015999:Multivariate Analysis; D010102:Oxygen Inhalation Therapy; D011014:Pneumonia; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D012121:Respiration, Artificial; D012127:Respiratory Distress Syndrome, Newborn; D012189:Retrospective Studies; D012307:Risk Factors; D050497:Stillbirth; D059245:Transient Tachypnea of the Newborn; D014580:Ursodeoxycholic Acid; D055815:Young Adult",
"nlm_unique_id": "0370476",
"other_id": null,
"pages": "570.e1-8",
"pmc": null,
"pmid": "26071912",
"pubdate": "2015-10",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural",
"references": "8141222;24901263;12850612;25468047;450556;25687562;22695903;25371372;16651322;11950183;23857305;15198757;23794285;25046809;18509787;2911423;22403605;22892336;15368452",
"title": "Predictors of adverse neonatal outcomes in intrahepatic cholestasis of pregnancy.",
"title_normalized": "predictors of adverse neonatal outcomes in intrahepatic cholestasis of pregnancy"
} | [
{
"companynumb": "US-ALLERGAN-1921570US",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "URSODIOL"
},
"drugadditional": "3",
"dr... |
{
"abstract": "The goal of this study was to evaluate the efficacy and safety of uninterrupted direct oral anticoagulant (DOAC) use and uninterrupted warfarin administration in elderly patients undergoing catheter ablation for atrial fibrillation (AF).\n\n\n\nThere is limited knowledge regarding the uninterrupted use of oral anticoagulant agents in elderly patients undergoing catheter ablation for AF.\n\n\n\nThis retrospective study included 2,164 patients (n = 325 ≥75 years of age and n = 1,839 <75 years of age) who underwent catheter ablation for AF. All the patients received uninterrupted oral anticoagulant agents during the procedure. We investigated the occurrences of periprocedural events and compared these between the DOAC and warfarin groups of the elderly and younger groups.\n\n\n\nMajor bleeding events (3.1% vs. 1.3%; p = 0.023) and minor bleeding events (9.2% vs. 5.0%; p = 0.002), except for thromboembolic events (0% vs. 0.8%; p = 0.248), were significantly higher in the elderly group than in the younger group. No significant differences in thromboembolic and bleeding events were found between the DOAC and warfarin groups of both the elderly and younger groups. Adverse complications did not differ between the groups after adjustment using propensity score matching analysis. Multivariate analysis revealed that lower body weight (odds ratio: 0.96; p = 0.010) and antiplatelet drug use (odds ratio: 2.21; p = 0.039) were independent predictors of adverse events in the elderly group.\n\n\n\nThe periprocedural bleeding risk during the use of uninterrupted oral anticoagulants was higher in the elderly group than in the younger group. This area needs more attention for these patients in whom caution is required.",
"affiliations": "Department of Advanced Cardiovascular Therapeutics, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address: pinponstar@yahoo.co.jp.;Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Advanced Cardiovascular Therapeutics, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.",
"authors": "Yanagisawa|Satoshi|S|;Inden|Yasuya|Y|;Fujii|Aya|A|;Ando|Monami|M|;Funabiki|Junya|J|;Murase|Yosuke|Y|;Takenaka|Masaki|M|;Otake|Noriaki|N|;Ikai|Yoshihiro|Y|;Sakamoto|Yusuke|Y|;Shibata|Rei|R|;Murohara|Toyoaki|T|",
"chemical_list": "D000925:Anticoagulants; D014859:Warfarin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jacep.2018.02.013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2405-500X",
"issue": "4(5)",
"journal": "JACC. Clinical electrophysiology",
"keywords": "atrial fibrillation; catheter ablation; direct oral anticoagulant; elderly patients; warfarin",
"medline_ta": "JACC Clin Electrophysiol",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D001281:Atrial Fibrillation; D017115:Catheter Ablation; D005260:Female; D006470:Hemorrhage; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013923:Thromboembolism; D014859:Warfarin",
"nlm_unique_id": "101656995",
"other_id": null,
"pages": "592-600",
"pmc": null,
"pmid": "29798785",
"pubdate": "2018-05",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Uninterrupted Direct Oral Anticoagulant and Warfarin Administration in Elderly Patients Undergoing Catheter Ablation for Atrial Fibrillation: A Comparison With Younger Patients.",
"title_normalized": "uninterrupted direct oral anticoagulant and warfarin administration in elderly patients undergoing catheter ablation for atrial fibrillation a comparison with younger patients"
} | [
{
"companynumb": "JP-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2018-NB-002927",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "Triazole antifungal drugs may rarely cause serious allergic reactions including angioedema. No standardized tests are available to predict cross-reactivity within the azole class and little guiding information exists on whether to change therapy within the class or to another class after a serious allergic reaction. Herein we report the first successful use, to our knowledge, of graded isavuconazole introduction for treatment of aspergillosis in a liver transplant recipient with severe voriconazole allergy.",
"affiliations": "Transplant and Oncology Infectious Diseases Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA.;Division of Hospital Medicine, Johns Hopkins Bayview Medical Center, Baltimore, MD, USA.;Transplant and Oncology Infectious Diseases Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA.",
"authors": "Morales|Megan K|MK|http://orcid.org/0000-0001-5840-6124;Harris|Ché|C|;Shoham|Shmuel|S|",
"chemical_list": "D000935:Antifungal Agents; D009570:Nitriles; D011725:Pyridines; D014230:Triazoles; C068538:liposomal amphotericin B; C508735:isavuconazole; D000666:Amphotericin B; D065819:Voriconazole",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12772",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "19(6)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "angioedema; azole allergy; azole cross-reactivity; isavuconazole challenge; voriconazole allergy",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000666:Amphotericin B; D000799:Angioedema; D000935:Antifungal Agents; D001230:Aspergillus; D003888:Desensitization, Immunologic; D004334:Drug Administration Schedule; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D008103:Liver Cirrhosis; D016031:Liver Transplantation; D008168:Lung; D008875:Middle Aged; D009570:Nitriles; D055732:Pulmonary Aspergillosis; D011725:Pyridines; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D014230:Triazoles; D065819:Voriconazole",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28851131",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Graded isavuconazole introduction in a patient with voriconazole allergy.",
"title_normalized": "graded isavuconazole introduction in a patient with voriconazole allergy"
} | [
{
"companynumb": "US-MYLANLABS-2018M1009917",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VORICONAZOLE"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nSulfasalazine (SSZ) is an anti-rheumatic drug that has been used to treat chronic arthritis. In many reports, the use of SSZ in children with systemic onset juvenile rheumatoid arthritis (JRA) revealed frequent side effects which required discontinuation of the drug. We examined whether there were frequent side effects of SSZ in patients with adult-onset Still's Disease (AOSD).\n\n\nMETHODS\nFrom July 1990 to April 1998, we followed 41 AOSD patients. Ten were given SSZ for the treatment of arthritis and the side effects were studied. We also studied 109 consecutive patients with RA who had been given SSZ, as a control group. In addition, we retrospectively studied the side effects and efficacy of SSZ in both groups through their medical records.\n\n\nRESULTS\nSix patients (60%, p < 0.01) with AOSD experienced side effects ranging from mild ones like abdominal pain, nausea and vomiting, urticaria, and facial flushing to severe ones such as high fever, hypotension, and severe myelosuppression as well as fulminant hepatitis, which led to the death of one patient. However, 16 patients (14.7%) with RA stopped using SSZ due to mild side effects such as rash, urticaria, gastrointestinal troubles, mild leukopenia, and fever. Three AOSD patients (30%, p = 0.053) and 15 RA patients (13.8%) stopped using SSZ due to its inefficacy.\n\n\nCONCLUSIONS\nWe conclude that SSZ appears to have frequent severe side effects in AOSD, as in systemic onset JRA. These potential adverse effects of SSZ should be considered when it is used to treat chronic arthritides with systemic symptoms. Further study of SSZ in the treatment of AOSD in a multi-center, placebo-controlled environment is needed.",
"affiliations": "Department of Internal Medicine, Eulji Medical College Hospital, Taejon, Korea.",
"authors": "Jung|J H|JH|;Jun|J B|JB|;Yoo|D H|DH|;Kim|T H|TH|;Jung|S S|SS|;Lee|I H|IH|;Bae|S C|SC|;Kim|S Y|SY|",
"chemical_list": "D018501:Antirheumatic Agents; D012460:Sulfasalazine",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0392-856X",
"issue": "18(2)",
"journal": "Clinical and experimental rheumatology",
"keywords": null,
"medline_ta": "Clin Exp Rheumatol",
"mesh_terms": "D015746:Abdominal Pain; D000293:Adolescent; D000328:Adult; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009325:Nausea; D011446:Prospective Studies; D012189:Retrospective Studies; D016706:Still's Disease, Adult-Onset; D012460:Sulfasalazine; D016896:Treatment Outcome; D014581:Urticaria; D014839:Vomiting",
"nlm_unique_id": "8308521",
"other_id": null,
"pages": "245-8",
"pmc": null,
"pmid": "10812499",
"pubdate": "2000",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "High toxicity of sulfasalazine in adult-onset Still's disease.",
"title_normalized": "high toxicity of sulfasalazine in adult onset still s disease"
} | [
{
"companynumb": "KR-PFIZER INC-2017025339",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SULFASALAZINE"
},
"drugadditional": null,
... |
{
"abstract": "Information regarding treatment of post-transplant lymphoproliferative disease (PTLD) beyond reduction in immunosuppression (RI) is limited. We retrospectively evaluated patients receiving rituximab and/or chemotherapy for PTLD for response, time to treatment failure (TTF) and overall survival (OS). Thirty-five patients met inclusion criteria. Twenty-two underwent rituximab treatment, with overall response rate (ORR) 68%. Median TTF was not reached at 19 months and estimated OS was 31 months. In univariable analysis, Epstein-Barr virus (EBV) positivity predicted response and TTF. LDH elevation predicted shorter OS. No patient died of rituximab toxicity and all patients who progressed underwent further treatment with chemotherapy. Twenty-three patients received chemotherapy. ORR was 74%, median TTF was 10.5 months and estimated OS was 42 months. Prognostic factors for response included stage, LDH and allograft involvement by tumor. These factors and lack of complete response (CR) predicted poor survival. Twenty-six percent of the patients receiving chemotherapy died of toxicity. Rituximab and chemotherapy are effective in patients with PTLD who fail or do not tolerate RI. While rituximab is well tolerated, toxicity of chemotherapy is marked. PTLD patients requiring therapy beyond RI should be considered for rituximab, especially with EBV-positive disease. Chemotherapy should be reserved for patients who fail rituximab, have EBV-negative tumors or need a rapid response.",
"affiliations": "Department of Medicine, University of Pennsylvania Medical Center, Philadelphia, USA.",
"authors": "Elstrom|R L|RL|;Andreadis|C|C|;Aqui|N A|NA|;Ahya|V N|VN|;Bloom|R D|RD|;Brozena|S C|SC|;Olthoff|K M|KM|;Schuster|S J|SJ|;Nasta|S D|SD|;Stadtmauer|E A|EA|;Tsai|D E|DE|",
"chemical_list": "D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1111/j.1600-6143.2005.01211.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1600-6135",
"issue": "6(3)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": null,
"medline_ta": "Am J Transplant",
"mesh_terms": "D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008232:Lymphoproliferative Disorders; D008297:Male; D008875:Middle Aged; D016377:Organ Transplantation; D011241:Prednisone; D012189:Retrospective Studies; D000069283:Rituximab; D015996:Survival Rate; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "569-76",
"pmc": null,
"pmid": "16468968",
"pubdate": "2006-03",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Treatment of PTLD with rituximab or chemotherapy.",
"title_normalized": "treatment of ptld with rituximab or chemotherapy"
} | [
{
"companynumb": "US-BAXTER-2015BAX060093",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "We report a case of long-standing inexplicable perianal ulcers. After exclusion of an inflammatory, infectious or neoplastic origin, a thorough personal history revealed that for many years the patient had been using analgesic suppositories containing indomethacin, caffeine, and prochlorperazine dimaleate, four to five times a week, for migraine. On stopping the suppositories, there was complete healing within 12 weeks. We hypothesize that vasoconstriction and vascular damage were the pathogenetic mechanisms behind the perianal ulcers.",
"affiliations": "Unit of Dermatology, Department of Experimental, Diagnostic and Specialty Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.;Unit of Dermatology, Department of Experimental, Diagnostic and Specialty Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.;Unit of Dermatology, AUSL della Romagna, Ravenna, Italy.;Pathologic Anatomy Unit, AUSL della Romagna, Ravenna, Italy.;Unit of Dermatology, Department of Experimental, Diagnostic and Specialty Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.;Unit of Dermatology, Department of Experimental, Diagnostic and Specialty Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.;Unit of Dermatology, Department of Experimental, Diagnostic and Specialty Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.",
"authors": "Savoia|Francesco|F|;Sechi|Andrea|A|http://orcid.org/0000-0003-3026-2434;Tabanelli|Michela|M|;Zago|Silvia|S|;Leuzzi|Miriam|M|;Baraldi|Carlotta|C|;Patrizi|Annalisa|A|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D000697:Central Nervous System Stimulants; D018492:Dopamine Antagonists; D004338:Drug Combinations; D013488:Suppositories; D002110:Caffeine; D007213:Indomethacin; D011346:Prochlorperazine",
"country": "Australia",
"delete": false,
"doi": "10.1111/ajd.12888",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0004-8380",
"issue": "60(1)",
"journal": "The Australasian journal of dermatology",
"keywords": "caffeine; indomethacin; perianal ulcers; prochlorperazine dimaleate; suppositories",
"medline_ta": "Australas J Dermatol",
"mesh_terms": "D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001004:Anus Diseases; D002110:Caffeine; D000697:Central Nervous System Stimulants; D002908:Chronic Disease; D018492:Dopamine Antagonists; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007213:Indomethacin; D011346:Prochlorperazine; D012883:Skin Ulcer; D013488:Suppositories",
"nlm_unique_id": "0135232",
"other_id": null,
"pages": "50-52",
"pmc": null,
"pmid": "30039854",
"pubdate": "2019-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Multiple perianal ulcers due to suppositories.",
"title_normalized": "multiple perianal ulcers due to suppositories"
} | [
{
"companynumb": "IT-HERITAGE PHARMACEUTICALS-2019HTG00069",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CAFFEINE\\INDOMETHACIN\\PROCHLORPERAZINE"
... |
{
"abstract": "Relationship-based medical care is essential in the management of chronic pain. Opioids are often ineffective and can cause significant harm. However, there is significant time pressure, and there are insufficient resources and guidelines for GPs to be able to offer alternatives, putting the NHS at risk of a growing opioid epidemic.",
"affiliations": "The Medical School The University of Sheffield Sheffield UK.;The Valleys Medical Partnership Sheffield UK.;School of Health And Related Research (ScHARR) University of Sheffield Sheffield UK.;The Medical School The University of Sheffield Sheffield UK.",
"authors": "Quah|Michael C H|MCH|https://orcid.org/0000-0002-9180-3276;Marney|Bethany C|BC|;Cooper|Richard J|RJ|;Dickson|Jon M|JM|https://orcid.org/0000-0002-1361-2714",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.4370",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904\nJohn Wiley and Sons Inc. Hoboken\n\n10.1002/ccr3.4370\nCCR34370\nCase Report\nCase Report\nChronic pain and opioid analgesic use: A case report\nQUAH et al.\nQuah Michael C. H. https://orcid.org/0000-0002-9180-3276\n1\nMarney Bethany C. 2\nCooper Richard J. 3\nDickson Jon M. https://orcid.org/0000-0002-1361-2714\n1 j.m.dickson@sheffield.ac.uk\n\n1 The Medical School The University of Sheffield Sheffield UK\n2 The Valleys Medical Partnership Sheffield UK\n3 School of Health And Related Research (ScHARR) University of Sheffield Sheffield UK\n* Correspondence\nJon M. Dickson, The Medical School, The University of Sheffield, Sheffield, South Yorkshire, UK.\nEmail: j.m.dickson@sheffield.ac.uk\n\n06 7 2021\n7 2021\n9 7 10.1002/ccr3.v9.7 e0437023 12 2020\n18 8 2020\n07 5 2021\n© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.\n\nAbstract\n\nRelationship‐based medical care is essential in the management of chronic pain. Opioids are often ineffective and can cause significant harm. However, there is significant time pressure, and there are insufficient resources and guidelines for GPs to be able to offer alternatives, putting the NHS at risk of a growing opioid epidemic.\n\nRelationship‐based medical care is essential in the good management of chronic pain. Opioids are often ineffective and can cause significant harm. However, there is significant time pressure, and there are insufficient resources and guidelines for GPs to be able to offer alternatives, putting the NHS at risk of a growing opioid epidemic.\n\nanesthesia\nchronic pain\nhealth maintenance\npain management\nsource-schema-version-number2.0\ncover-dateJuly 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.4 mode:remove_FC converted:06.07.2021\nQuah MCH , Marney BC , Cooper RJ , Dickson JM . Chronic pain and opioid analgesic use: A case report. Clin Case Rep. 2021;9 :e04370. 10.1002/ccr3.4370\n==== Body\n1 INTRODUCTION\n\nOpioids are often ineffective for managing chronic non‐malignant pain. If prescribed, they should be as part of an opioid trial with clear aims of therapy, tapering/stopping the opiate if they are ineffective, or if they are causing adverse effects. Clinical guidance is available but there are many gaps in the evidence.\n\nOpioid analgesics are commonly prescribed to relieve pain. They range in strength from weak opioids, for example, codeine, which is found in the most commonly prescribed opioid preparation co‐codamol (a combination of paracetamol and codeine) to strong opioids such as morphine, fentanyl, and oxycodone. Their important role in the management of acute and terminal cancer pain is well established but their benefits have been increasingly challenged in other conditions. In particular, concerns have emerged about their use in chronic non‐cancer pain, such as lower back pain, which is estimated to affect 35%‐51% of adults in the UK. 1\n\nOpioid analgesic prescribing in recent decades in England and many other developed countries has increased and has been described as an ‘opioid epidemic’. 2 Concerns about the use of opioid analgesics in chronic pain related to the lack of evidence of effectiveness 3 and the risk of tolerance, dependence, addiction, and side effects, leading to reduced quality of life and increased use of healthcare resources. 1 , 3 Here we report the case of a young man who developed chronic pain after a relatively minor injury, we highlight the problematic aspects of his opioid use and we discuss the best available evidence to guide doctors in treating similar cases.\n\n2 REPORT\n\n2.1 Clinical details\n\nIn August 1996, a 25‐year‐old male injured his left knee and dislocated his left elbow falling approximately 3 m from a fence in the course of his duty as a police officer. He was seen in A&E, his shoulder dislocation was reduced under Entonox, and he was discharged, but despite physiotherapy he continued to complain of pain in his left knee.\n\nIn September 1996, he was acutely tender over the anteromedial joint line and was suspected to have a peripheral tear in his medial meniscus for which he underwent an arthroscopy which showed some patellar degeneration and a peripheral lesion on the medial meniscus. He continued with physiotherapy post‐surgery but he was still experiencing pain, and a follow‐up orthopedic appointment noted a patellofemoral click and also a snapping sensation on lateral movements of the patella and he was admitted for another arthroscopy and lateral released in May 1998. However, the pain continued and he was given two cortisone injections in October and December.\n\nHis pain persisted in the posterior knee and was characterized as a constant dull ache that worsened with activity. An MRI in July 1999 showed a peripheral tear of the medial meniscus and he underwent another arthroscopy and partial medial meniscectomy. He was on Voltarol 50 mg TDS post‐operation. He had another arthroscopy in April 2002 to address the persisting pain and instability in his knee and the main pathology reported was flap tear of the medial meniscus, and they also found crush tearing of the posterior horn of the lateral meniscus. He was discharged with Kapake BD.\n\nHe had a left ACL reconstruction in Oct 2002 due to recurrent episodes of his knee giving way. The surgery was successful in restoring stability, however, the pain was not resolved. He was given celecoxib 200 mg BD and paracetamol 1 g QDS post‐operation.\n\nIn September 2003, he had another arthroscopy, chondroplasty in the patellofemoral compartment, and release of adhesion and scar tissue. He was given Voltarol 75 mg BD and Cocodomol. There was still pain and discomfort in his knee and was advised to continue physiotherapy and regular NSAID therapy. His orthopedic surgeon discussed with him that they will not be taking further surgical intervention and would be aiming for symptomatic control. A follow‐up MRI in April 2004 showed minor chondral damage but no more surgical intervention would be taken at that point. He was taking Celecoxib 100 mg BD and Codeine 15 mg QDS.\n\nIn the 8 years following his accident, the patient saw numerous orthopedic surgeons, and his pain was attributed to several different pathologies. He underwent six separate surgical procedures, none of which led to any improvement in his pain.\n\n2.2 Analgesics\n\nHe began taking regular analgesia in 2001 starting with diclofenac and codeine. In 2003, his pain was impeding his ability to work and celecoxib was added. This was still an insufficient analgesic and he was prescribed co‐dydramol and diclofenac. However, his pain was still intolerable and he was started on tramadol and paracetamol. The tramadol was effective in helping him manage his pain but caused nausea. He tried meptazinol and nefopam but both were ineffective and he reverted to tramadol. In 2005, gabapentin was added to his drug regime as tramadol and paracetamol alone were no longer sufficient.\n\nIn 2005, he was referred to an NHS 6‐week pain management program (PMP) at the Northern General Hospital which adopts a holistic, multi‐disciplinary way of helping chronic pain patients understand and manage their pain. The aim was to help him find ways to make his pain more bearable and look at non‐drug treatment options. He saw a pain specialist as part of the PMP who cautioned against further dose increases of all analgesics and advised him to reduce his opiates. This intervention helped him realize that opiates had largely been unhelpful for him. He concluded that there would be no complete resolution of his pain with medication alone and he adopted a routine of daily exercise including swimming and treadmill walking, weekly massages, and regular Reiki. To avoid further adverse effects from his medications he stopped tramadol and gabapentin abruptly without medical advice and he experienced significant unpleasant withdrawal effects such as hot sweats, intense pain, and nausea.\n\nIn 2010, work‐related and social stress led to a decrease in his pain tolerance, and amitriptyline was added to his regime. His GP also supported and monitored the gradual decrease of his gabapentin use.\n\nHe currently uses tramadol 50 mg QDS, paracetamol QDS, amitriptyline 25 mg nocte, and topical Diclofenac. He has been stable on the same doses of these medications for many years. He does not identify as being dependent on any of his analgesics although he recognizes that he has developed some tolerance to tramadol and this is his primary motivation for avoiding further dose increases.\n\n2.3 Social history\n\nAt the time of the injury, the patient was a police officer working with the South Yorkshire Police. He was single and had no children. The pain he experienced affected his ability to perform his job which led to tension with his employers and then depression/anxiety which exacerbated his pain. His employer provided cognitive behavioral therapy which helped him to cope with his anxiety but despite this, he was deemed permanently incapacitated in 2008 and was given a part‐time administrative role which led to a pay cut and a loss in self‐esteem and job satisfaction. He eventually retired on ill‐health grounds in 2014.\n\nDespite having a good relationship with his GPs, he blames them for iatrogenic harm from medication side effects and for not explaining the nature and natural history of chronic pain. He remains in pain which adversely affects his life but with his exercise regimen and support from his GPs, he feels in control.\n\n3 DISCUSSION\n\n3.1 Avoid opioids if possible\n\nThere is little good quality evidence to support the effectiveness of opioids for chronic pain, most of the published trials lasted no more than 4 months, they excluded high‐risk individuals and they did not assess addiction risk. 4 There is no consensus on how opioids compare with alternative pharmacologic options such as tricyclic antidepressants, muscle relaxants and NSAIDs in treating musculoskeletal pain, but there is an increasing body of literature surrounding the development of tolerance and pain sensitization caused by endogenous and exogenous opioids, resulting in a decrease of its analgesic effects. 4 , 5 When the patient's pain intensified in 2010, amitriptyline was prescribed which was effective in combination with other analgesics. As a result, a higher dosage of opioids was not required. Patients often still take opioids the despite waning of analgesic effects due to dependence or addiction. 6 Psychologic dependence on opioids and the adverse effects of long‐term use were discussed with the patient during his PMP. He recognized that he was developing tolerance to opioids and became motivated to start a gradual deprescribing.\n\n3.2 Alternatives to opioids\n\nThe Centres for Disease Control and Prevention (CDC) recommend the use of non‐pharmacologic (CBT and exercise therapy) and non‐opioid options as first‐line treatments for chronic pain. 7 Increasing physical activity is a low‐cost intervention with minimal risks which can improve pain levels, improve physical function and reduce work disability. Biopsychosocial interventions such as pain management programs (PMPs) are aimed at addressing the complexities faced by patients with chronic pain. PMPs are delivered in group settings by an interdisciplinary team working closely with patients. 8 Patients that have undergone a PMP have demonstrated improvements in pain intensity, pain‐related beliefs such as catastrophizing, mood, and pain‐related disabilities. 8 Undergoing a 6‐week PMP led to significant changes in the patient's outlook on his pain management. It also introduced non‐medical alternatives which were pivotal in helping him self‐manage his chronic pain. The non‐pharmacologic intervention was introduced after undergoing PMP which could have contributed to his struggle to maintain physical function at the start of his pain. Live Well with Pain is a free online resource that aims to help patients self‐manage. The online site includes a section called the Opioid Thermometer which is targeted to think about the doses of medication they are taking and serve as a reminder of the harms associated with opioids. 9 There is also a Pain Toolkit that guides patients on how to self‐manage their pain. 9\n\n3.3 Practical steps in opioid prescribing\n\nThe CDC 7 and Opioid Aware 10 provide guidelines and practical steps in opioid prescribing, describing how to undertake an opioid trial, and how to taper and stop opiates. Both resources highlight the need to establish goals for pain management and emphasize that complete pain relief should not be the goal, but rather reducing pain enough to engage in self‐management. After the patient's last surgery in 2003, it was decided that there was no surgical solution to his problem with his left knee, leading to frustration due to the impact of his ongoing pain. When opioids were first prescribed, there was no discussion documented about goal‐setting which led to unrealistic expectations about pain relief. Both CDC and Opiod Aware recommend keeping a record of adverse effects, dosing, discussions about risks and benefits, and circumstances under which prescribing should cease. Opioid therapy should be discontinued if the benefits are outweighed by the adverse effects. Opioid Aware recommends the involvement of relevant medical specialties such as mental health and substance abuse if the patient presents with complex needs. Good communication and shared decision‐making are essential parts of good care. 3\n\n3.4 An opioid trial\n\nOpioid therapy should only be considered if other multimodal therapies have not yielded adequate improvements in pain and function. Patients should only start an opioid trial if they do not have contraindications for opioid therapy and after a discussion about the potential harms and benefits of opioid therapy. 3 An opioid trial helps to establish if the patient has a reduction in pain with the use of opioids. Managing side effects and achieving optimal doses can be further explored if opioid therapy is pursued after a trial. 10\n\nOpioid Aware provides some practical steps on how to conduct an opiate trial. A trial should first begin with a discussion with the patient on assessable outcomes such as achieving functional improvements for example, attending work, exercise, and sleep. A trial can last for 1‐2 weeks and patients should start on a low dose of immediate‐release morphine (liquid or tablets). The patient could be advised to explore a range of doses between 5 and 10 mg of morphine. To assess success, a diary should be kept during the trial, with a twice‐daily record of outcomes discussed such as pain intensity, activity level, and sleep. 10\n\n3.5 Tapering and stopping strong opiates\n\nTapering means reducing doses whilst minimizing withdrawal symptoms, often with the aim of complete discontinuation. 3 Abrupt discontinuation can result in opioid withdrawal symptoms which was experienced by the patient when he tried to stop taking his pain medication leading to hot sweats, nausea, and increased pain. 5 Consider dependence in the following scenarios: long‐term use for non‐malignant pain, history of psychiatric illnesses or emotional trauma, history of substance misuse, problems with prescriptions (lost prescriptions, early requests, taking higher doses than prescribed), family members are concerned about opioid use, refusal or failure to attend medication reviews, ‘doctor shopping’ for prescriptions, functional deterioration (eg, being unable to work) and declining specialist referral to assess the underlying problem. 3 Before tapering, discuss the rationale and potential benefits with the patient, agree on outcomes and an appropriate time frame and discuss signs and symptoms of withdrawal. Close monitoring and regular medication reviews with his GP was an essential part of the tapering process. The good relationship with his GP allowed for open communication about the necessity to be on certain opioids and the possibility of reducing doses. The dose should be tapered by 10% weekly or two‐weekly. 3\n\n4 CONCLUSION\n\nThere is a compelling logic to treating pain with analgesics including using opioids. However, for chronic pain, this logic does not fit with the evidence which shows that opioids are often ineffective and can cause significant harm. Most prescribing for long‐term conditions is done by primary care, most consultations about chronic pain are with GPs, and they are often difficult consultations, 6 there is significant time pressure and there is a lack of guidance to support for GPs. 5 Developing a shared understanding with the patient requires sufficient time to discuss complex ideas, it requires trust, regular follow‐up, and continuity of care all of which are under threat from a shortage of doctors, growing demand and the prioritization of access over continuity. In many areas, specialist services are not easily accessible or are not available at all. In the absence of sufficient resources to meaningfully assess and manage a large number of patients with chronic pain, pharmacologic management including opiates is likely to remain the default response, deprescribing is unlikely to be prioritized and the NHS is at risk of a growing opioid epidemic.\n\nCONFLICT OF INTEREST\n\nRichard J. Cooper has received funding for research consultancy from Indivior. No other external funding or competing interests are declared by the authors.\n\nAUTHOR CONTRIBUTIONS\n\nMichael C. H. Quah: Interviewed the patient and prepared the manuscript. Bethany C. Marney: The patient's General Practitioner and interviewed the patient. Richard J. Cooper: Prepared the manuscript and provided expert opinion. Jon M. Dickson: Supervised, prepared the manuscript, and gave final approval for the manuscript.\n\nETHICAL STATEMENT\n\nEthics committee permission was not required.\n\nCONSENT STATEMENT\n\nPublished with the written consent of the patient. The patient gave consent and approved the final manuscript. All the mentioned authors consent for publication.\n\nACKNOWLEDGMENTS\n\nPublished with written consent of the patient.\n\nDATA AVAILABILITY STATEMENT\n\nData sharing is not applicable to this article as no new data were created or analyzed in this study.\n==== Refs\nREFERENCES\n\n1 Fayaz A , Croft P , Langford RM , Donaldson LJ , Jones GT . Prevalence of chronic pain in the UK: a systematic review and meta‐analysis of population studies. BMJ Open. 2016;6 (6 ):e010364. 10.1136/bmjopen-2015-010364\n2 Addressing Problematic Opioid Use in OECD Countries. OECD. 2019. 10.1787/a18286f0-en\n3 Red Whale . The MSK and Chronic Pain Update Handbook. MSK/M/2; Reading, UK: Red Whale. 2019. gp‐update.co.uk\n4 Chou R , Huffman LH . Medications for acute and chronic low back pain: A review of the evidence for an American Pain Society/American College of Physicians clinical practice guideline. Ann Intern Med. 2007;147 (7 ):505‐514. 10.7326/0003-4819-147-7-200710020-00008 17909211\n5 Sandhu H , Underwood M , Furlan AD , Noyes J , Eldabe S . What interventions are effective to taper opioids in patients with chronic pain? BMJ. 2018;362 :k2990. 10.1136/bmj.k2990 30262590\n6 McCrorie C , Closs SJ , House A , et al. Understanding long‐term opioid prescribing for non‐cancer pain in primary care: a qualitative study. BMC Fam Pract. 2015;16 (1 ):121. 10.1186/s12875-015-0335-5 26362559\n7 Dowell D , Haegerich TM , Chou R . CDC guideline for prescribing opioids for chronic pain‐United States, 2016. JAMA. 2016;315 (15 ):1624. 10.1001/jama.2016.1464 26977696\n8 Gemson L , Hatton K , White S , Hatch D , Sanderson J , Roy M . An evaluation of the effectiveness of a cognitive behavioural therapy‐based multidisciplinary pain management programme for adults living with chronic pain. J Obs Pain Med. 2014;1 (4 ):826‐835.\n9 Resources for patients ‐ Live Well With Pain. https://livewellwithpain.co.uk/resources/resources‐for‐patients/. Accessed July 10, 2020\n10 Opioids Aware: A resource for patients and healthcare professionals to support prescribing of opioid medicines for pain | Faculty of Pain Medicine. https://fpm.ac.uk/opioids‐aware. Accessed December 27, 2019\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2050-0904",
"issue": "9(7)",
"journal": "Clinical case reports",
"keywords": "anesthesia; chronic pain; health maintenance; pain management",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "e04370",
"pmc": null,
"pmid": "34257976",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports",
"references": "27324708;26977696;26362559;17909211;30262590",
"title": "Chronic pain and opioid analgesic use: A case report.",
"title_normalized": "chronic pain and opioid analgesic use a case report"
} | [
{
"companynumb": "GB-MLMSERVICE-20210727-3019176-1",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TRAMADOL HYDROCHLORIDE"
},
"drugadditi... |
{
"abstract": "Advancements in medicine have enabled the use of monoclonal antibodies in the field of oncology. However, the new adverse effects of immunotherapeutic agents are still being reported. We present the first case of pembrolizumab-induced fatal colitis with concurrent Giardia infection in a patient with metastatic ovarian cancer. A 47-year-old woman with metastatic ovarian cancer who was being treated with pembrolizumab admitted to our clinic complaining of persisting bloody diarrhoea. Her stool antigen test was positive for Giardia. The patient received metronidazole. A colonoscopy with mucosal biopsy was performed upon no clinical or laboratory improvement. Colonoscopy detected deep exudative ulcers in sigmoid colon and rectum. The cytopathological evaluation revealed immune-mediated ischemic colitis. The treatment was rearranged with methylprednisolone. Upon an increase in bloody diarrhoea frequency and C-reactive protein levels, infliximab was started. However, the patient became refractory to infliximab therapy after the second dose and was deceased due to septic shock.",
"affiliations": "Department of Internal Medicine, Division of Gastroenterology, School of Medicine, Acibadem Mehmet Ali Aydinlar University (Acıbadem Mehmet Ali Aydınlar Üniversitesi Atakent Hastanesi), Halkalı Merkez Mahallesi, Turgut Özal Bulvarı, No: 16, 34303, Küçükçekmece, Istanbul, Turkey. gurhan.sisman@acibadem.edu.tr.;School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey.;School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey.;Department of Pathology, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey.",
"authors": "Sisman|Gurhan|G|http://orcid.org/0000-0001-8828-122X;Barbur|Erol|E|http://orcid.org/0000-0002-6258-2443;Saka|Didem|D|http://orcid.org/0000-0002-0706-7844;Erdamar Cetin|Sibel|S|http://orcid.org/0000-0001-7470-8835",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; C582435:pembrolizumab",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00262-020-02815-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0340-7004",
"issue": "70(8)",
"journal": "Cancer immunology, immunotherapy : CII",
"keywords": "Cell-mediated immunity; Colitis; Colonoscopy; Drug side effects; Immunotherapy; Medical oncology",
"medline_ta": "Cancer Immunol Immunother",
"mesh_terms": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D001706:Biopsy; D003092:Colitis; D005260:Female; D005873:Giardiasis; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms",
"nlm_unique_id": "8605732",
"other_id": null,
"pages": "2385-2388",
"pmc": null,
"pmid": "33481043",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "29747688;27072927;26079306;24670341;28533998;26783344;19104936;28204866;27539137;31092901",
"title": "Pembrolizumab-induced immune-mediated fatal colitis with concurrent giardia infection.",
"title_normalized": "pembrolizumab induced immune mediated fatal colitis with concurrent giardia infection"
} | [
{
"companynumb": "TR-009507513-2102TUR004994",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "A prospective study was undertaken to assess the type and frequency of adverse side-effects following the use of intravenous phenytoin in children. Twenty-two children received a total of 100 doses over a 10-month period. Six patients (27%) experienced one or more side-effects, including extravasation of the drug, hypotension and cardiac arrhythmia. No patient developed skin necrosis, including the 'purple glove syndrome'. Recovery from all adverse side-effects was spontaneous and complete. It is possible that some or all of these side-effects may have been caused by an excessive rate of infusion of phenytoin or the saline 'flush' following administration of the drug. The overall frequency of side-effects was perhaps less than expected.",
"affiliations": "The Roald Dahl EEG Unit, Department of Neurology, Royal Liverpool Children's Hospital (Alder Hey), Liverpool, UK. richard.appleton@rlch-tr.nwest.nhs.uk",
"authors": "Appleton|Richard E|RE|;Gill|Andrea|A|",
"chemical_list": "D000927:Anticonvulsants; D010672:Phenytoin",
"country": "England",
"delete": false,
"doi": "10.1016/s1059-1311(02)00338-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1059-1311",
"issue": "12(6)",
"journal": "Seizure",
"keywords": null,
"medline_ta": "Seizure",
"mesh_terms": "D000293:Adolescent; D000927:Anticonvulsants; D001146:Arrhythmia, Sinus; D002648:Child; D002675:Child, Preschool; D004827:Epilepsy; D005119:Extravasation of Diagnostic and Therapeutic Materials; D005260:Female; D006801:Humans; D007022:Hypotension; D007223:Infant; D007275:Injections, Intravenous; D008297:Male; D010672:Phenytoin; D011446:Prospective Studies",
"nlm_unique_id": "9306979",
"other_id": null,
"pages": "369-72",
"pmc": null,
"pmid": "12915082",
"pubdate": "2003-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Adverse events associated with intravenous phenytoin in children: a prospective study.",
"title_normalized": "adverse events associated with intravenous phenytoin in children a prospective study"
} | [
{
"companynumb": "GB-PFIZER INC-2016288791",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PHENYTOIN SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "A 62-year-old man was diagnosed with liver metastasis of sigmoid colon cancer, which resulted in bowel obstruction. SOX plus bevacizumab therapy was administered to perform hepatectomy, after the artificial anus construction; however, substantial liver dysfunction occurred. Therefore, we only performed primary tumor resection and waited for improvement in liver function. After 2 months, liver function improved and liver metastasis increased. However, another metastasis was not recognized, so hepatectomy was carried out, and R0 resection was performed. The oxaliplatin-induced liver function disorder was reversible; however, preoperative chemotherapy for resectable colorectal liver metastases increases the risk of missing the resection window. It is necessary to carefully examine the tumor type and preoperative liver function.",
"affiliations": "Dept. of Surgery, Aichi Kouseiren Toyota Kousei Hospital.",
"authors": "Tominaga|Kenta|K|;Kurumiya|Yasuhiro|Y|;Sekoguchi|Ei|E|;Kobayashi|Satoshi|S|;Kawai|Kiyotaka|K|;Kiriyama|Muneyasu|M|",
"chemical_list": "D004338:Drug Combinations; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; C079198:S 1 (combination); D005641:Tegafur; D000068258:Bevacizumab; D010094:Oxonic Acid",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "45(6)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D004338:Drug Combinations; D006498:Hepatectomy; D006504:Hepatic Veno-Occlusive Disease; D006801:Humans; D008099:Liver; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010094:Oxonic Acid; D012811:Sigmoid Neoplasms; D005641:Tegafur",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "989-992",
"pmc": null,
"pmid": "30026429",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe Liver Injury Due to Sinusoidal Obstruction Syndrome Induced by Oxaliplatin in a Patient with Resectable Colorectal Liver Metastases.",
"title_normalized": "severe liver injury due to sinusoidal obstruction syndrome induced by oxaliplatin in a patient with resectable colorectal liver metastases"
} | [
{
"companynumb": "JP-SA-2018SA257438",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": "1",
"dr... |
{
"abstract": "We describe a 51-year-old man with sudden onset involuntary movements of the tongue 2 weeks after initiation of citalopram. The movements were continuous and isolated to the tongue. Speech was minimally dysarthric. Further examination revealed no abnormalities. Citalopram was continued and spontaneous improvement was noticed in the following weeks. There was complete recovery 5 weeks after symptoms had started. We argue that the involuntary tongue movements were a side effect of citalopram. Furthermore, our patient used concomitant citalopram and methylphenidate, a combination which potentially elicits side effects. We include a video of the tongue movements in this patient.",
"affiliations": "Faculty of Medicine, University of Amsterdam, Amsterdam, The Netherlands.;Department of Neurology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands.;Department of Neurology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands.",
"authors": "Gaanderse|Marissa|M|;Kliffen|Jasper|J|;Linssen|Wim|W|",
"chemical_list": "D017367:Serotonin Uptake Inhibitors; D015283:Citalopram",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2016-216126",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2016()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D001008:Anxiety Disorders; D015283:Citalopram; D004409:Dyskinesia, Drug-Induced; D006801:Humans; D008297:Male; D008875:Middle Aged; D012075:Remission, Spontaneous; D017367:Serotonin Uptake Inhibitors; D013315:Stress, Psychological; D014060:Tongue Diseases; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28011457",
"pubdate": "2016-12-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D059040:Video-Audio Media",
"references": "15177061;15567557;20970768;25309711;7249508;7831449;8909330;9694033",
"title": "Citalopram-induced dyskinesia of the tongue: a video presentation.",
"title_normalized": "citalopram induced dyskinesia of the tongue a video presentation"
} | [
{
"companynumb": "PHHY2017NL026392",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CITALOPRAM HYDROBROMIDE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nHepatic artery thrombosis (HAT) increases the risk of complications and mortality after liver transplantation. The incidence for HAT is increased in patients with risk factors (vascular reconstructions, coagulation disorders and acute rejection episodes amongst others). Early retransplantation improves the prognosis for patients, but owing to lack of donors, surgical and interventional radiologic attempts to restore the patency of hepatic artery are made. The prognosis for the liver and the patient can also be improved by the development of collateral circulation.\n\n\nMETHODS\nWe describe a case of a 30-year-old woman with hepatic failure owing to Wilson disease. Liver transplantation with the use of vascular conduit made of donor's iliac arteries was complicated by an early HAT. Heterozygous factor V Leiden mutation was confirmed in the patient. Despite surgical and radiologic attempts to restore patency and despite treatment with fractioned heparin and aspirin, the hepatic artery remained occluded. Retransplantation was not considered, even though the patient was planning a pregnancy. After 1 year of observation of stable liver function, conversion from mycophenolate mofetil to azathioprine treatment, the patient was given consent for a high-risk pregnancy.\n\n\nCONCLUSIONS\nThe course of pregnancy was uneventful, with normal liver function parameters, without pathological bleedings. The patient was treated with doses of enoxaparin adjusted for the patient's weight. In the 34th week, owing to increasing concentration of bile acids, the pregnancy ended with a cesarean section. The newborn had 10-point APGAR score.",
"affiliations": "Department of Transplantation Medicine and Nephrology, Transplantation Institute, Medical University of Warsaw, Warszawa, Poland. Electronic address: olgatronina@wp.pl.;Department of Transplantation Medicine and Nephrology, Transplantation Institute, Medical University of Warsaw, Warszawa, Poland.;First Department of Obstetrics and Gynecology, Medical University of Warsaw, Warszawa, Poland.;Department of General Surgery and Transplantology, Transplantation Institute, Medical University of Warsaw, Warszawa, Poland.;Department of Transplantation Medicine and Nephrology, Transplantation Institute, Medical University of Warsaw, Warszawa, Poland.",
"authors": "Tronina|O|O|;Mikołajczyk|N|N|;Pietrzak|B|B|;Pacholczyk|M|M|;Durlik|M|M|",
"chemical_list": "D000925:Anticoagulants; D017984:Enoxaparin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "46(8)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D020016:Activated Protein C Resistance; D000328:Adult; D000925:Anticoagulants; D003097:Collateral Circulation; D017984:Enoxaparin; D005260:Female; D006499:Hepatic Artery; D006527:Hepatolenticular Degeneration; D006801:Humans; D007668:Kidney; D017093:Liver Failure; D016031:Liver Transplantation; D011247:Pregnancy; D011256:Pregnancy Outcome; D018566:Pregnancy, High-Risk; D012307:Risk Factors; D013927:Thrombosis",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "2929-31",
"pmc": null,
"pmid": "25380954",
"pubdate": "2014-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pregnancy in a patient with hepatic artery thrombosis after liver transplantation: a case report.",
"title_normalized": "pregnancy in a patient with hepatic artery thrombosis after liver transplantation a case report"
} | [
{
"companynumb": "PL-BAYER-2014-173306",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "Patients bearing polymorphisms termed CYP2C19 loss of function (LoF) alleles and ABCB1-C3435T may do not properly respond to standard dosage of clopidogrel and have an increased risk of thrombosis. Moreover, co-administration of proton pump inhibitors (PPIs) and clopidogrel may attenuate the antiplatelet effect. The role of pharmacogenetics and PPIs/clopidogrel drug-drug interaction has been extensively investigated in patients with acute coronary syndrome after stent implantation (ACS/PCI), while data in patients undergoing vascular surgery are scarce. Here we have performed a systematic review to evaluate the available literature in such a clinical setting and have discussed the controversies about the use of CYP2C19 pharmacogenetics and platelet function testing to personalize clopidogrel treatment. In addition, we have made a comparison of the literature data with our findings concerning patients eligible for vascular surgery and treated with clopidogrel, in whom we used a combined management based on the CYP2C19 and ABCB1 pharmacogenetic testing with monitoring of therapeutic adherence and PPIs-clopidogrel interaction. Both our data and those produced during both observational studies and randomized clinical trials confirm the validity of pharmacogenetics to personalize clopidogrel treatment and stress the importance to make a drug monitoring considering all the known variables, potentially responsible for treatment failure. However, the American Heart Association and the European Cardiovascular Society recommend against the routine use of clopidogrel pharmacogenetic testing. An update of the international guidelines on antiplatelet therapy, incorporating the evidence related to CYP2C19 pharmacogenetics and PPIs-clopidogrel drug-drug interactions is warranted both in ACS/PCI patients and subjects undergoing vascular surgery.",
"affiliations": "Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\", University of Salerno- S, Allende street, 84081, Baronissi, Salerno, Italy. vconti@unisa.it.;Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\", University of Salerno- S, Allende street, 84081, Baronissi, Salerno, Italy.;Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\", University of Salerno- S, Allende street, 84081, Baronissi, Salerno, Italy.;Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\", University of Salerno- S, Allende street, 84081, Baronissi, Salerno, Italy.;Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\", University of Salerno- S, Allende street, 84081, Baronissi, Salerno, Italy.;Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\", University of Salerno- S, Allende street, 84081, Baronissi, Salerno, Italy.;Vascular surgery Unit, University Hospital \"San Giovanni di Dio e Ruggi D'Aragona\", Salerno- via S. Leonardo 1, Salerno, Italy.;Vascular surgery Unit, University Hospital \"San Giovanni di Dio e Ruggi D'Aragona\", Salerno- via S. Leonardo 1, Salerno, Italy.;Department of Medicine and Health Sciences, University of Molise, Via Francesco De Sanctis, 1, 86100, Campobasso, Italy.;Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\", University of Salerno- S, Allende street, 84081, Baronissi, Salerno, Italy.",
"authors": "Valeria|Conti|C|http://orcid.org/0000-0001-6964-2739;Carmine|Sellitto|S|;Valentina|Manzo|M|;Teresa|Iannaccone|I|;Maria|Costantino|C|;Martina|Torsiello|T|;Giancarlo|Accarino|A|;Giovanna|Nicolella|N|;Graziamaria|Corbi|C|http://orcid.org/0000-0002-3441-889X;Amelia|Filippelli|F|http://orcid.org/0000-0002-8235-9118",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1038/s41397-020-00189-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1470-269X",
"issue": "21(2)",
"journal": "The pharmacogenomics journal",
"keywords": null,
"medline_ta": "Pharmacogenomics J",
"mesh_terms": null,
"nlm_unique_id": "101083949",
"other_id": null,
"pages": "116-127",
"pmc": null,
"pmid": "33033370",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "30511260;30422888;22316323;19717846;19414633;28092694;19258584;21741610;23698643;22027650;21511218;29936693;20832888;25555855;18056526;24096929;19398674;23990957;16772608;19706858;28198005;26526111;31395432;27411384;27236738;24877854;27464309;19904241;22291500;22704866;29512292;26826508;22656044;22249353;28855078;24076493;28689434;26320110;18498956;23257377;19435740;21252171;19496924;30196751;23850318;25850030;29540324;31479209;27112628;27447737",
"title": "The need of a multicomponent guiding approach to personalize clopidogrel treatment.",
"title_normalized": "the need of a multicomponent guiding approach to personalize clopidogrel treatment"
} | [
{
"companynumb": "IT-ALKEM LABORATORIES LIMITED-IT-ALKEM-2020-07600",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SERENOA REPENS WHOLE"
},
... |
{
"abstract": "OBJECTIVE\nIncreasing incidence of endometrial cancer and late motherhood enhance conservative management in clinical practice. Although different approaches to fertility-sparing treatment are possible, it is still unknown which patients will benefit more from systemic or local treatment. Aim of this paper is to analyze the effectiveness of different methods of conservative management and obstetric outcomes in patients with early endometrial cancer and atypical endometrial hyperplasia.\n\n\nMETHODS\n30 patients (10 with atypical endometrial hyperplasia, 20 with endometrial cancer) treated conservatively were included to retrospective analysis. 24 patients receiving progestins were divided into 2 groups according to the dose (low and high dose); 6 patients were treated with levonorgestrel releasing intrauterine device. Effectiveness of therapy (complete, partial or absent) and obstetric outcomes (number of pregnancies and live births) were assessed. Electronic databases (MEDLINE, Web of Science, Embase) were searched for articles according to criteria: 1) fertility-sparing treatment of endometrial cancer/atypical endometrial hyperplasia in patients of reproductive age, 2) assessment of pregnancy/obstetric results. The risk of bias was assessed with the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Case Series.\n\n\nRESULTS\nComplete and partial remission were achieved in 21 and 3 patients, respectively. 6 patients did not respond to treatment. Relapse was diagnosed in 6 patients. Probability of complete remission according to low-, high-dose regimen and levonorgestrel-releasing intrauterine device were 55.6% (46.5%-64.7%), 73.3% (65.2%-81.4%) and 83.3% (76.5%-90.1%) respectively. 4 patients get pregnant and 3 of them born children. 25 studies (21 retrospective, 4 prospective) with 812 participants were included in the systematic review. The most studied was progestin based treatment. Complete and partial response to fertility-sparing management was diagnosed in 634 and 38 patients, respectively. Relapse was diagnosed in 170 patients. Median times of follow-up range from 17 (1-45) to 98 (35-176) months. The total number of pregnancies and live births were 352 and 246, respectively.\n\n\nCONCLUSIONS\nFertility-sparing treatment is a safe method of management in young women with endometrial cancer/atypical endometrial hyperplasia. While the main goal of conservative management is preserving the possibility of having children, only a small number of women will become pregnant and give birth.",
"affiliations": "Department of Gynecologic Oncology, The Maria Sklodowska-Curie National Research Institute of Oncology, 5 Roentgen Street, 02-781 Warsaw, Poland. Electronic address: szymon.piatek@aol.com.;Department of Biostatistics, The Maria Sklodowska-Curie National Research Institute of Oncology, 5 Roentgen Street, 02-781 Warsaw, Poland.;Department of Gynecologic Oncology, The Maria Sklodowska-Curie National Research Institute of Oncology, 5 Roentgen Street, 02-781 Warsaw, Poland.;Department of Gynecologic Oncology, The Maria Sklodowska-Curie National Research Institute of Oncology, 5 Roentgen Street, 02-781 Warsaw, Poland.;Department of Obstetrics and Perinatology, Medical University of Warsaw, 63A Zwirki I Wigury Street, 02-091 Warsaw, Poland; Institute of Mother and Child, Kasprzaka 17A, 02-211 Warsaw, Poland.",
"authors": "Piatek|Szymon|S|;Michalski|Wojciech|W|;Sobiczewski|Piotr|P|;Bidzinski|Mariusz|M|;Szewczyk|Grzegorz|G|",
"chemical_list": "D011372:Progestins",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.ejogrb.2021.06.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-2115",
"issue": "263()",
"journal": "European journal of obstetrics, gynecology, and reproductive biology",
"keywords": "Atypical endometrial hyperplasia; Conservative management; Endometrial cancer",
"medline_ta": "Eur J Obstet Gynecol Reprod Biol",
"mesh_terms": "D002648:Child; D002675:Child, Preschool; D004714:Endometrial Hyperplasia; D016889:Endometrial Neoplasms; D005260:Female; D059247:Fertility Preservation; D006801:Humans; D009364:Neoplasm Recurrence, Local; D011247:Pregnancy; D011372:Progestins; D011446:Prospective Studies; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "0375672",
"other_id": null,
"pages": "139-147",
"pmc": null,
"pmid": "34214800",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article; D000078182:Systematic Review",
"references": null,
"title": "The results of different fertility-sparing treatment modalities and obstetric outcomes in patients with early endometrial cancer and atypical endometrial hyperplasia: Case series of 30 patients and systematic review.",
"title_normalized": "the results of different fertility sparing treatment modalities and obstetric outcomes in patients with early endometrial cancer and atypical endometrial hyperplasia case series of 30 patients and systematic review"
} | [
{
"companynumb": "PL-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-337975",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
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"actiondrug": "5",
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"activesubstancename": "MEDROXYPROGESTERONE"
},
... |
{
"abstract": "A 56-year-old Asian woman was admitted to hospital for the consideration of hemodialysis (HD). A right femoral dialysis catheter was inserted for HD. Three months after removal of catheter, she was admitted because of right inguinal swelling. A thrill and bruit were felt and heard at the inguinal area. Color Doppler detected a fistula between right superficial femoral artery and right common femoral vein and subsequently confirmed by contrast enhanced computed tomography scan and 3-dimensional reconstruction with computed tomography. At surgery, a 4-mm-diameter fistula was found between the right superficial femoral artery and right common femoral vein. A primary closure of both defects in the artery and vein was then carried out. A follow-up digital vascular study 3 months after surgical repair was normal. In conclusion, nephrologist should have a heightened awareness to the potential of this complication and should at least document a normal exam following the removal of femoral catheters.",
"affiliations": "Department of NephrologyDepartment of Blood PurificationDepartment of SurgeryDepartment of Nephrology, The First Affilliated Hospital to Changchun University of Chinese Medicine, Changchun City, Jilin Province, China.;Department of NephrologyDepartment of Blood PurificationDepartment of SurgeryDepartment of Nephrology, The First Affilliated Hospital to Changchun University of Chinese Medicine, Changchun City, Jilin Province, China.;Department of NephrologyDepartment of Blood PurificationDepartment of SurgeryDepartment of Nephrology, The First Affilliated Hospital to Changchun University of Chinese Medicine, Changchun City, Jilin Province, China.;Department of NephrologyDepartment of Blood PurificationDepartment of SurgeryDepartment of Nephrology, The First Affilliated Hospital to Changchun University of Chinese Medicine, Changchun City, Jilin Province, China.",
"authors": "Tong|YanQing|Y|;Zhao|DongKai|D|;Wu|QiuCheng|Q|;Liu|YanRu|Y|",
"chemical_list": null,
"country": "Canada",
"delete": false,
"doi": "10.1111/j.1542-4758.2010.00522.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1492-7535",
"issue": "15(1)",
"journal": "Hemodialysis international. International Symposium on Home Hemodialysis",
"keywords": "Femoral arteriovenous fistula; catheterization; digital vascular study; hemodialysis",
"medline_ta": "Hemodial Int",
"mesh_terms": "D001164:Arteriovenous Fistula; D002404:Catheterization; D005260:Female; D005268:Femoral Vein; D006801:Humans; D007676:Kidney Failure, Chronic; D008875:Middle Aged; D006435:Renal Dialysis",
"nlm_unique_id": "101093910",
"other_id": null,
"pages": "112-4",
"pmc": null,
"pmid": "21223487",
"pubdate": "2011-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Femoral arteriovenous fistula 3 months after removal of catheter for hemodialysis.",
"title_normalized": "femoral arteriovenous fistula 3 months after removal of catheter for hemodialysis"
} | [
{
"companynumb": "CN-FRESENIUS KABI-FK201607797",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": "3",... |
{
"abstract": "The study reports a case of suicide by ingestion of sodium nitroprusside which resulted in acute cyanide poisoning. Analyses carried out on body fluid yielded the quantitation of total (5.00 mg/L) and free (3.30 mg/L) cyanide in blood and of methemoglobin (blood = 10.5%). At the scene, some solid reddish-brown material was found in a glass, which on toxicological analysis was found to contain sodium nitroprusside; about 9 g of the same substance was identified in stomach contents. The detection and quantification of cyanide and methemoglobin in biological samples from the case indicated that the lethal effect was due to both metabolic products (cyanide and methemoglobin).",
"affiliations": "Institute of Legal Medicine, University of Macerata, Italy.",
"authors": "Froldi|R|R|;Cingolani|M|M|;Cacaci|C|C|",
"chemical_list": "D000959:Antihypertensive Agents; D003486:Cyanides; D009599:Nitroprusside; D008706:Methemoglobin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-1198",
"issue": "46(6)",
"journal": "Journal of forensic sciences",
"keywords": null,
"medline_ta": "J Forensic Sci",
"mesh_terms": "D000328:Adult; D000959:Antihypertensive Agents; D003486:Cyanides; D005260:Female; D005554:Forensic Medicine; D006801:Humans; D008706:Methemoglobin; D009599:Nitroprusside; D013405:Suicide",
"nlm_unique_id": "0375370",
"other_id": null,
"pages": "1504-6",
"pmc": null,
"pmid": "11714168",
"pubdate": "2001-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of suicide by ingestion of sodium nitroprusside.",
"title_normalized": "a case of suicide by ingestion of sodium nitroprusside"
} | [
{
"companynumb": "IT-BAUSCH-BL-2020-030085",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SODIUM NITROPRUSSIDE"
},
"drugadditional": nul... |
{
"abstract": "We herein report a case regarding a 90-year-old woman with a history of recurrent episodes of urinary tract infections presenting with fever. Urinalysis revealed bacteria and white blood cells. Computed tomography showed dilated and fecally loaded rectum and colon with signs of obstructive uropathy. The patient was treated for urinary tract infection and constipation. Her bowel habits were controlled with lubiprostone, and she was discharged in good medical condition. This case highlights the importance of considering fecal impaction as a cause of urinary tract obstruction or infection.",
"affiliations": "Department of Internal Medicine, Kanagawa Prefectural Ashigarakami Hospital, Japan.",
"authors": "Iwata|Yuri|Y|;Kunishi|Yosuke|Y|;Yoshie|Koichiro|K|",
"chemical_list": "D011092:Polyethylene Glycols; D000068238:Lubiprostone; D000527:Alprostadil",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.54.3551",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0918-2918",
"issue": "54(9)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D000527:Alprostadil; D003248:Constipation; D005244:Fecal Impaction; D005260:Female; D006801:Humans; D000068238:Lubiprostone; D011092:Polyethylene Glycols; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D014552:Urinary Tract Infections",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1043-7",
"pmc": null,
"pmid": "25948344",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Obstructive uropathy caused by chronic constipation.",
"title_normalized": "obstructive uropathy caused by chronic constipation"
} | [
{
"companynumb": "JP-BAYER-2015-262214",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VALSARTAN"
},
"drugadditional": null,
"... |
{
"abstract": "Non-small cell lung cancer (NSCLC) patients with pre-existing respiratory diseases have been excluded in clinical trials of immune checkpoint inhibitor (ICI) therapy, and it is unknown whether the same degree of response can be expected as that in patients without pre-existing respiratory diseases and if they are associated with increased risk for various immune-related adverse events (irAEs) and ICI pneumonitis. This study aimed to evaluate predictive factors of clinical response, prognostic factors, risk factors of irAEs, and ICI pneumonitis in NSCLC patients with or without pre-existing respiratory diseases.\n\n\n\nWe conducted a retrospective study of 180 NSCLC patients who received ICI monotherapy of nivolumab, pembrolizumab, or atezolizumab from 1 January 2016 to 31 March 2019.\n\n\n\nA total of 119 patients had pre-existing respiratory diseases, including 20 with pre-existing idiopathic interstitial pneumonias (IIPs). A total of 85 patients experienced irAEs, of which ICI pneumonitis was the most frequent adverse event, occurring in 27 patients. Of the three patients who died from irAEs, all from ICI pneumonitis, two had pulmonary emphysema and one had pre-existing IIP. In multivariate analyses, irAEs were associated with objective response rate (ORR) and favorable OS, and IIPs were associated with increased risk for ICI pneumonitis. However, IIPs were not associated with low ORR or poor OS.\n\n\n\nPre-existing IIPs were a risk factor for ICI pneumonitis. However, this study showed that ICI therapy can be offered to patients with pre-existing respiratory diseases with the expectation of the same degree of response as that in patients without pre-existing respiratory diseases.\n\n\n\nSignificant findings of the study: Pre-existing IIPs were a risk factor for ICI pneumonitis, but objective response rate and prognosis of patients with IIPs were similar to those of other patients.\n\n\n\nIn patients with pre-existing IIPs, ICI pneumonitis should be noted. However, ICI therapy can be offered to patients with pre-existing respiratory diseases with the expectation of the same degree of response as that in patients without pre-existing respiratory diseases.",
"affiliations": "Department of Respiratory Medicine, Saitama Cardiovascular and Respiratory Center, Saitama, Japan.;Department of Respiratory Medicine, Saitama Cardiovascular and Respiratory Center, Saitama, Japan.;Department of Respiratory Medicine, Saitama Cardiovascular and Respiratory Center, Saitama, Japan.;Department of Respiratory Medicine, Saitama Cardiovascular and Respiratory Center, Saitama, Japan.;Department of Respiratory Medicine, Saitama Cardiovascular and Respiratory Center, Saitama, Japan.;Department of Respiratory Medicine, Saitama Cardiovascular and Respiratory Center, Saitama, Japan.;Department of Respiratory Medicine, Saitama Cardiovascular and Respiratory Center, Saitama, Japan.;Department of Respiratory Medicine, Saitama Cardiovascular and Respiratory Center, Saitama, Japan.;Department of Respiratory Medicine, Saitama Cardiovascular and Respiratory Center, Saitama, Japan.;Department of Respiratory Medicine, Saitama Cardiovascular and Respiratory Center, Saitama, Japan.;Department of Respiratory Medicine, Saitama Cardiovascular and Respiratory Center, Saitama, Japan.;Department of Respiratory Medicine, Saitama Cardiovascular and Respiratory Center, Saitama, Japan.",
"authors": "Isono|Taisuke|T|0000-0002-2803-8049;Kagiyama|Naho|N|;Takano|Kenji|K|;Hosoda|Chiaki|C|;Nishida|Takashi|T|;Kawate|Eriko|E|;Kobayashi|Yoichi|Y|;Ishiguro|Takashi|T|;Takaku|Youtaro|Y|;Kurashima|Kazuyoshi|K|;Yanagisawa|Tsutomu|T|;Takayanagi|Noboru|N|",
"chemical_list": "D000082082:Immune Checkpoint Inhibitors",
"country": "Singapore",
"delete": false,
"doi": "10.1111/1759-7714.13736",
"fulltext": "\n==== Front\nThorac Cancer\nThorac Cancer\n10.1111/(ISSN)1759-7714\nTCA\nThoracic Cancer\n1759-7706 1759-7714 John Wiley & Sons Australia, Ltd Melbourne \n\n33201587\n10.1111/1759-7714.13736\nTCA13736\nOriginal Article\nOriginal Articles\nOutcome and risk factor of immune‐related adverse events and pneumonitis in patients with advanced or postoperative recurrent non‐small cell lung cancer treated with immune checkpoint inhibitors\nRespiratory diseases and ICIs in NSCLCT. Isono et al.Isono Taisuke https://orcid.org/0000-0002-2803-8049\n1\nmed.taisuke@gmail.com Kagiyama Naho \n1\n Takano Kenji \n1\n Hosoda Chiaki \n1\n Nishida Takashi \n1\n Kawate Eriko \n1\n Kobayashi Yoichi \n1\n Ishiguro Takashi \n1\n Takaku Youtaro \n1\n Kurashima Kazuyoshi \n1\n Yanagisawa Tsutomu \n1\n Takayanagi Noboru \n1\n \n1 \nDepartment of Respiratory Medicine\nSaitama Cardiovascular and Respiratory Center\nSaitama\nJapan\n\n* Correspondence\n\nTaisuke Isono, Department of Respiratory Medicine, Saitama Cardiovascular and Respiratory Center, 1696 Itai, Kumagaya, Saitama 360‐0197, Japan.\n\nTel: +81 48 536 9900\n\nFax: +81 48 536 9920\n\nEmail: med.taisuke@gmail.com\n\n17 11 2020 \n1 2021 \n12 2 10.1111/tca.v12.2153 164\n12 8 2020 21 10 2020 22 10 2020 © 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Background\nNon‐small cell lung cancer (NSCLC) patients with pre‐existing respiratory diseases have been excluded in clinical trials of immune checkpoint inhibitor (ICI) therapy, and it is unknown whether the same degree of response can be expected as that in patients without pre‐existing respiratory diseases and if they are associated with increased risk for various immune‐related adverse events (irAEs) and ICI pneumonitis. This study aimed to evaluate predictive factors of clinical response, prognostic factors, risk factors of irAEs, and ICI pneumonitis in NSCLC patients with or without pre‐existing respiratory diseases.\n\nMethods\nWe conducted a retrospective study of 180 NSCLC patients who received ICI monotherapy of nivolumab, pembrolizumab, or atezolizumab from 1 January 2016 to 31 March 2019.\n\nResults\nA total of 119 patients had pre‐existing respiratory diseases, including 20 with pre‐existing idiopathic interstitial pneumonias (IIPs). A total of 85 patients experienced irAEs, of which ICI pneumonitis was the most frequent adverse event, occurring in 27 patients. Of the three patients who died from irAEs, all from ICI pneumonitis, two had pulmonary emphysema and one had pre‐existing IIP. In multivariate analyses, irAEs were associated with objective response rate (ORR) and favorable OS, and IIPs were associated with increased risk for ICI pneumonitis. However, IIPs were not associated with low ORR or poor OS.\n\nConclusions\nPre‐existing IIPs were a risk factor for ICI pneumonitis. However, this study showed that ICI therapy can be offered to patients with pre‐existing respiratory diseases with the expectation of the same degree of response as that in patients without pre‐existing respiratory diseases.\n\nKey points\nSignificant findings of the study: Pre‐existing IIPs were a risk factor for ICI pneumonitis, but objective response rate and prognosis of patients with IIPs were similar to those of other patients.\n\nWhat this study adds: In patients with pre‐existing IIPs, ICI pneumonitis should be noted. However, ICI therapy can be offered to patients with pre‐existing respiratory diseases with the expectation of the same degree of response as that in patients without pre‐existing respiratory diseases\n\n\n\n\n\nPre‐existing IIPs were a risk factor for ICI pneumonitis. Objective response rate and prognosis of patients with IIPs were similar to those of other patients.\n\nImmune checkpoint inhibitorimmune‐related adverse eventlung cancerpneumonitis source-schema-version-number2.0cover-dateJanuary 2021details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.6 mode:remove_FC converted:18.01.2021\n==== Body\nIntroduction\nImmune checkpoint inhibitors (ICIs), including programmed cell death‐1 (PD‐1) inhibitor and programmed cell death ligand‐1 (PD‐L1) inhibitor, have become a standard treatment for patients with unresectable advanced or recurrent non‐small cell lung cancer (NSCLC). Nivolumab and pembrolizumab are PD‐1 inhibitors, and atezolizumab is a PD‐L1 inhibitor. In phase III trials, nivolumab, pembrolizumab, and atezolizumab as second‐line treatment provided longer overall survival (OS) than docetaxel in NSCLC patients.\n1\n, \n2\n, \n3\n, \n4\n Additionally, pembrolizumab as a first‐line treatment provided longer OS than platinum‐based chemotherapy in NSCLC patients with a PD‐L1 tumor proportion score (TPS) ≥50% and those with PD‐L1 TPS ≥1%.\n5\n, \n6\n Recently, phase III trials showed that combination therapy of ICIs and platinum‐based chemotherapy as first‐line treatment in NSCLC patients has a higher objective response rate (ORR) and offers longer progression‐free survival (PFS) and OS than chemotherapy alone, regardless of the PD‐L1 TPS.\n7\n, \n8\n, \n9\n However, the clinical benefits remain limited to a subset of patients, and the predictive factors for response and prognosis in patients treated with ICIs are still unclear.\n\nAdditionally, ICIs can induce various immune‐related adverse events (irAEs). In phase III trials, irAEs developed in 20%–30% of patients.\n3\n, \n5\n In the clinical setting, irAEs developed more frequently than those in the phase III trials, with 30%–60% of patients affected.\n10\n, \n11\n, \n12\n Nevertheless, knowledge of the frequency, risk factors, and management of irAEs in the clinical setting is insufficient. In particular, ICI‐related pneumonitis (ICI pneumonitis) accounts for 35% of anti‐PD‐1 inhibitor‐ and anti‐PD‐L1 inhibitor‐related deaths.\n13\n Therefore, it is the most serious and life‐threatening irAE, as stated in the American Thoracic Society research statement published in 2019.\n14\n In this statement, because patients with pre‐existing respiratory diseases were excluded in clinical trials, it is unknown whether such patients are associated with an increased risk for ICI pneumonitis.\n\nTherefore, we retrospectively reviewed the clinical data of NSCLC patients treated with ICI monotherapy and aimed to identify predictive factors for response, prognosis, irAEs, and ICI pneumonitis in the clinical setting of these patients with or without pre‐existing respiratory diseases and those with idiopathic interstitial pneumonias (IIPs).\n\nMethods\nSubjects\nFrom 1 January 2016 to 31 March 2019, 180 patients with unresectable advanced or recurrent NSCLC were treated with ICI monotherapy including nivolumab, pembrolizumab, and atezolizumab at our institution. The diagnosis of lung cancer was based on pathology or cytology findings. The clinical stage was established according to the eighth edition of the TNM classification. Information concerning tumorous characteristics including epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) rearrangement, c‐ros oncogene 1 (ROS‐1) rearrangement, BRAF V600E mutation, and PD‐L1 TPS was collected. The PD‐L1 TPS was assessed by means of the PD‐L1 immunohistochemistry 22C3 pharmDx assay. ICIs were administered until disease progression, intolerable toxicity, or patient refusal occurred. Pre‐existing respiratory diseases were diagnosed according to clinical features and high‐resolution computed tomography of the chest.\n\nStudy design\nWe retrospectively investigated patients' background, ORR, OS, and development and management of irAEs, including ICI pneumonitis. We also investigated the predictive factors for ORR, OS, irAEs, and ICI pneumonitis. Clinical data were collected from medical records. Baseline clinical parameters were obtained within one month of the initial diagnosis. Pre‐existing respiratory diseases were divided into IIPs with or without pulmonary emphysema (PE), radiation‐induced pulmonary fibrosis with or without PE, PE without interstitial lung diseases (ILDs), and others. Radiographic patterns of IIPs were classified according to the international multidisciplinary classification of the IIPs and clinical practice guideline for the diagnosis of idiopathic pulmonary fibrosis.\n15\n, \n16\n Pulmonary emphysema was defined as focal areas or regions of low attenuation, usually without visible walls on chest CT.\n17\n ORR was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.\n18\n OS was measured from first administration of the ICIs to death. The data cutoff date was 31 August 2019. The irAEs were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Radiographic patterns of ICI pneumonitis were classified into nonspecific interstitial pneumonia (NSIP) pattern, cryptogenic organizing pneumonia (COP) pattern, acute interstitial pneumonia/acute respiratory distress syndrome (AIP/ARDS) pattern, and hypersensitivity pneumonitis (HP) pattern.\n19\n The NSIP pattern is ground‐glass opacities (GGOs) and reticular opacities predominantly in peripheral and lower lung distribution, traction bronchiectasis and lower lobe volume loss. The COP pattern is multifocal bilateral parenchymal consolidations, GGOs and reticular opacities with peripheral and lower lung distribution. The HP pattern is diffuse GGOs, centrilobular nodularities, and air trapping. The AIP/ARDS pattern is diffuse or multifocal GGOs or consolidations predominantly in dependent lung regions, lung volume loss and traction bronchiectasis.\n\nThis study was conducted in accordance with the Declaration of Helsinki and was approved by the institutional review board of Saitama Cardiovascular and Respiratory Center.\n\nStatistical analysis\nCategorical data are summarized by frequency and percent, and continuous data are reported as the median and range. The Kaplan‐Meier method was used to estimate OS. Univariate and multivariate analyses were performed using a logistic regression model to determine predictors for ORR and a Cox proportional‐hazards model to determine predictors for OS, irAEs, and ICI pneumonitis. All statistical analyses were performed with EZR version 1.36 (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria, version 3.4.3).\n20\n\n\n\nResults\nPatient characteristics\nIn total, 180 patients with advanced NSCLC underwent ICI monotherapy (Table 1). The median patient age was 68.5 (range, 40–83) years, 77.8% of the patients were male, 84.4% were smokers, 90.6% had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1, 33.9% had no pre‐existing respiratory diseases, 11.1% had IIPs, 11.7% had radiation‐induced pulmonary fibrosis, 41.1% had PE, 55.6% had adenocarcinoma, 78.9% were at stage IV, and 22.8% had brain metastasis. A total of 13 patients used immunosuppressants, and three patients had autoimmune diseases. A total of 21 patients had an EGFR mutation, none had ALK fusion, three patients had ROS1 fusion, and two patients had a BRAF mutation. The percentages of patients with PD‐L1 TPS <1%, 1%–49%, and ≥50% were 13.9%, 18.3%, and 32.8%, respectively. Among the patients, 11.1% had received molecular targeted therapy, 28.9% had received radiation therapy, and 18.3% were treated with ICIs as first‐line therapy. Of the 99 patients with PE, 74 did not have ILDs including IIPs or radiation‐induced pulmonary fibrosis. The median follow‐up period from initiation of ICIs was 299.5 (range: 9–1314) days, and the median number of treatment cycle of ICIs was four (range: 1–70). Patients treated with pembrolizumab had a higher frequency of PD‐L1 TPS ≥50% compared to those treated with nivolumab or atezolizumab. Most patients treated with atezolizumab had PD‐L1 TPS <1%. In addition, about half of the patients treated with pembrolizumab had received it as first‐line therapy.\n\nTable 1 Characteristics of patients treated with immune checkpoint inhibitors (ICIs)\n\nICI\tAll (n = 180)\tNivolumab (n = 99)\tPembrolizumab (n = 70)\tAtezolizumab (n = 11)\t\nAge at ICI initiation\t68.5 (40–83)\t68.0 (40–83)\t70.0 (44–83)\t65.0 (49–80)\t\nSex, male\t140 (77.8)\t79 (79.8)\t55 (78.6)\t6 (54.5)\t\nSmoker\t152 (84.4)\t84 (84.8)\t59 (84.3)\t9 (81.8)\t\nECOG PS 0 or 1\t163 (90.6)\t89 (89.9)\t64 (91.4)\t10 (90.9)\t\nPre‐existing respiratory disease\t\nPE\t99 (55.0)\t57 (57.6)\t38 (54.3)\t4 (36.4)\t\nRIPF\t21 (11.7)\t15 (15.2)\t4 (5.7)\t2 (18.2)\t\nIIPs\t20 (11.1)\t12 (12.1)\t8 (11.4)\t0 (0.0)\t\nUIP pattern\t3 (1.7)\t1 (1.0)\t2 (2.9)\t0 (0.0)\t\nProbable UIP pattern\t6 (3.3)\t4 (4.0)\t2 (2.9)\t0 (0.0)\t\nIndeterminate for UIP pattern\t9 (5.0)\t5 (5.1)\t4 (5.7)\t0 (0.0)\t\nNSIP pattern\t2 (1.1)\t2 (2.0)\t0 (0.0)\t0 (0.0)\t\nAsthma\t8 (4.4)\t3 (3.0)\t5 (7.1)\t0 (0.0)\t\nOld tuberculosis\t3 (1.7)\t1 (1.0)\t2 (2.9)\t0 (0.0)\t\nMAC infection\t1 (0.6)\t1 (1.0)\t0 (0.0)\t0 (0.0)\t\nBronchiectasis\t1 (0.6)\t1 (1.0)\t0 (0.0)\t0 (0.0)\t\nSilicosis\t1 (0.6)\t0 (0.0)\t1 (1.4)\t0 (0.0)\t\nAutoimmune disease\t\nChronic thyroiditis\t2 (1.1)\t0 (0.0)\t1 (1.4)\t1 (9.1)\t\nPBC\t1 (0.6)\t1 (1.0)\t0 (0.0)\t0 (0.0)\t\nUse of corticosteroid or immunosuppressant\t13 (7.2)\t9 (9.1)\t4 (5.7)\t0 (0.0)\t\nHistological type\t\nAdenocarcinoma\t100 (55.6)\t54 (54.5)\t37 (52.9)\t9 (81.8)\t\nSquamous cell carcinoma\t47 (26.1)\t28 (28.3)\t19 (27.1)\t0 (0.0)\t\nPleomorphic carcinoma\t4 (2.2)\t1 (1.0)\t3 (4.3)\t0 (0.0)\t\nAdenosquamous carcinoma\t2 (1.1)\t2 (2.0)\t0 (0.0)\t0 (0.0)\t\nLCNEC\t1 (0.6)\t0 (0.0)\t1 (1.4)\t0 (0.0)\t\nNOS\t26 (14.4)\t14 (14.1)\t10 (14.3)\t2 (18.2)\t\n\nEGFR mutation\t\nExon 19 deletion\t11 (6.1)\t6 (6.1)\t4 (5.7)\t1 (9.1)\t\nL858R\t7 (3.9)\t4 (4.0)\t3 (4.3)\t0 (0.0)\t\nMinor mutation\t3 (1.7)\t3 (3.0)\t0 (0.0)\t0 (0.0)\t\n−\t130 (72.2)\t64 (64.6)\t56 (80.0)\t10 (90.9)\t\nNA\t29 (16.1)\t22 (22.2)\t7 (10.0)\t0 (0.0)\t\nALK rearrangement\t\n+\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t\n−\t139 (77.2)\t70 (70.7)\t59 (84.3)\t10 (90.9)\t\nNA\t41 (22.8)\t29 (29.3)\t11 (15.7)\t1 (9.1)\t\nROS‐1 rearrangement\t\n+\t3 (1.7)\t0 (0.0)\t3 (4.3)\t0 (0.0)\t\n−\t79 (43.9)\t32 (32.3)\t38 (54.3)\t9 (81.8)\t\nNA\t98 (54.4)\t67 (67.7)\t29 (41.4)\t2 (18.2)\t\nBRAF V600E mutation\t\n+\t2 (1.1)\t1 (1.0)\t1 (1.4)\t0 (0.0)\t\n−\t31 (17.2)\t15 (15.2)\t11 (15.7)\t5 (45.5)\t\nNA\t147 (81.7)\t83 (83.8)\t58 (82.9)\t6 (54.5)\t\nPD‐L1 TPS\t\n<1%\t25 (13.9)\t15 (15.2)\t2 (2.9)\t8 (72.7)\t\n1–49%\t43 (23.9)\t17 (17.2)\t13 (32.9)\t3 (27.3)\t\n≥50%\t49 (27.2)\t4 (4.0)\t45 (64.3)\t0 (0.0)\t\nNA\t63 (35.0)\t63 (63.6)\t0 (0.0)\t0 (0.0)\t\nStage\t\nIII\t38 (21.1)\t21 (21.2)\t15 (21.4)\t2 (18.2)\t\nIV\t142 (78.9)\t78 (78.8)\t55 (78.6)\t9 (81.8)\t\nBrain metastasis\t41 (22.8)\t21 (21.2)\t15 (21.4)\t5 (45.5)\t\nPrior treatment for brain metastasis\t33 (18.3)\t17 (17.2)\t12 (17.1)\t4 (36.4)\t\nPrior molecular targeted therapy\t20 (11.1)\t12 (12.1)\t7 (10.0)\t1 (9.1)\t\nEGFR‐TKI\t18 (10.0)\t11 (11.1)\t6 (8.6)\t1 (9.1)\t\nPrior radiotherapy\t52 (28.9)\t33 (33.3)\t13 (32.9)\t6 (54.4)\t\nPrior thoracic radiotherapy\t33 (18.3)\t22 (22.2)\t7 (10.0)\t4 (36.4)\t\nLine of ICI therapy\t\nFirst‐line\t33 (18.3)\t0 (0.0)\t33 (47.1)\t0 (0.0)\t\nSecond‐line\t66 (36.7)\t37 (37.4)\t26 (37.1)\t3 (27.3)\t\n≥Third‐line\t81 (45.0)\t62 (62.6)\t11 (15.7)\t8 (72.7)\t\nNumber of ICI therapies\t4 (1–70)\t3 (1–70)\t5.5 (1–33)\t4 (1–11)\t\nFollow‐up period (days)\t299.5 (9–1314)\t242 (9–1314)\t362 (11–856)\t233 (62–456)\t\nData are presented as n, median (range) or n (%).\n\nALK, anaplastic lymphoma kinase; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; ICIs, immune checkpoint inhibitors; IIPs, idiopathic interstitial pneumonias; LCNEC, large‐cell neuroendocrine carcinoma; MAC, Mycobacterium avium complex; NA, not available; NOS, not otherwise specified; NSIP, nonspecific interstitial pneumonia; PBC, primary biliary cirrhosis; PD‐L1, programmed cell death ligand‐1; PE, pulmonary emphysema; RIPF, radiation‐induced pulmonary fibrosis; ROS‐1, c‐ros oncogene 1; TKI, tyrosine kinase inhibitor; TPS, tumor proportion score; UIP, usual interstitial pneumonia.\n\n\nIrAEs profile\nOf the 180 patients treated with ICIs, 121 (67.2%) developed adverse events, and the most common of these other than irAEs were drug‐related fever and bacterial pneumonia (Table 2). IrAEs were observed in 85 (47.2%) patients, including 27 (15.0%) with ICI pneumonitis, 24 (13.3%) with rash, 23 (12.8%) with thyroid dysfunction, 20 (11.1%) with diarrhea or colitis, 13 (7.2%) with hepatitis, five (2.8%) with nephritis, four (2.2%) with arthritis, and three (1.7%) with isolated adrenocorticotropic hormone deficiency. A total of 21 (11.7%) patients experienced irAEs of grade 3 or higher in which ICI pneumonitis was the most frequent adverse event. Systemic corticosteroids were administered to 36 (42.4%) patients. Among the 34 patients requiring discontinuation of ICIs, seven (20.6%) underwent retreatment with ICIs and two experienced recurrence of irAEs. Most patients who develop side effects develop them within one year, especially within 90 days (Fig 1). In patients treated with nivolumab, pembrolizumab, and atezolizumab, 45 (45.5%), 38 (54.3%), and two (18.2%) had irAEs, and 14 (14.1%), 12 (17.1%), and 1 (9.1%) had ICI pneumonitis, respectively.\n\nTable 2 Adverse events including immune‐related adverse events (irAEs)\n\nEvents\tAny grade\tGrade ≥3\tCorticosteroid treatment\tRetreatment with ICIs\tirAEs after retreatment\t\nAny AEs including irAEs\t121 (67.2)\t24 (13.3)\t\t\t\t\nDrug‐related fever\t26 (14.4)\t1 (0.6)\t\t\t\t\nPneumonia\t12 (6.7)\t10 (5.6)\t\t\t\t\nAsthma\t4 (2.2)\t0 (0.0)\t\t\t\t\nAllergic rhinitis\t3 (1.7)\t0 (0.0)\t\t\t\t\nInfusion reaction\t1 (0.6)\t0 (0.0)\t\t\t\t\nLTBI\t1 (0.6)\t0 (0.0)\t\t\t\t\nPyothorax\t1 (0.6)\t1 (0.6)\t\t\t\t\nCholedocholithic cholangitis\t1 (0.6)\t1 (0.6)\t\t\t\t\nAny irAEs\t85 (47.2)\t21 (11.7)\t36 (42.4)\t7 (20.6)\t2 (28.6)\t\nICI pneumonitis\t27 (15.0)\t10 (5.6)\t20 (74.1)\t1 (5.6)\t0 (0.0)\t\nRash\t24 (13.3)\t2 (1.1)\t4 (16.7)\t1 (50.0)\t1 (100.0)\t\nThyroid dysfunction\t23 (12.8)\t0 (0.0)\t0 (0.0)\t1 (20.0)\t0 (0.0)\t\nColitis or diarrhea\t20 (11.1)\t2 (1.1)\t6 (30.0)\t3 (60.0)\t1 (33.3)\t\nHepatitis\t13 (7.2)\t3 (1.7)\t2 (15.4)\t0 (0.0)\tNA\t\nNephritis\t5 (2.8)\t0 (0.0)\t1 (20.0)\tNA\tNA\t\nArthritis\t4 (2.2)\t0 (0.0)\t1 (25.0)\t1 (100.0)\t0 (0.0)\t\nIsolated ACTH deficiency\t3 (1.7)\t3 (1.7)\t0 (0.0)\tNA\tNA\t\nMyocarditis\t1 (0.6)\t1 (0.6)\t1 (100.0)\t0 (0.0)\tNA\t\nUveitis\t1 (0.6)\t0 (0.0)\t0 (0.0)\tNA\tNA\t\nEosinophilic fasciitis\t1 (0.6)\t1 (0.6)\t1 (100.0)\t0 (0.0)\tNA\t\nData are presented as n, median (range) or n (%).\n\nACTH, adrenocorticotropic hormone; AEs, adverse events; ICIs, immune checkpoint inhibitors; irAEs, immune‐related adverse events; LTBI, latent tuberculosis infection; NA, not available.\n\nFigure 1 Kaplan‐Meier curves showing irAE free survival and irAE free survival rate at 30 days, 60 days, 90 days, 120 days, 150 days, 180 days and 365 days. CI, confidence interval; IIPs, idiopathic interstitial pneumonias; ILD, interstitial lung disease; irAE, immune‐related adverse event; NR, not reached; NSIP, nonspecific interstitial pneumonia; PE, pulmonary emphysema; UIP, usual interstitial pneumonia.\n\nPredictive factors of antitumor response to ICIs\n\nOf the 180 patients treated with ICIs, complete response was achieved in four patients (2.2%) and partial response in 44 (24.4%). Stable disease was present in 51 (28.3%) patients, and progressive disease occurred in 81 (45.0%). The overall ORR was 26.7%. The ORR of patients treated with nivolumab, pembrolizumab, and atezolizumab were 19.2%, 40.0%, and 9.1%, respectively. The ORR of patients with no pre‐existing respiratory disease, IIPs, radiation‐induced pulmonary fibrosis, and PE were 19.7%, 35.0%, 19.0%, and 31.1%, respectively. Univariate analysis indicated that type of ICIs, PD‐L1, line of ICI therapy, eosinophil count, lymphocyte count, lactate dehydrogenase (LDH) level, neutrophil‐to‐lymphocyte ratio (NLR), eosinophil count after treatment with ICIs, and irAEs were factors associated with antitumor response to ICIs (Table S1). In a multivariate logistic regression model, only LDH level and irAEs were significantly associated with antitumor response to ICIs (Table 3).\n\nTable 3 Multivariate analyses of objective response rate and prognostic factors of all‐cause mortality in patients treated with immune checkpoint inhibitors (ICIs)\n\nAnalyses of objective response rate\t\nn\n\tORR (%)\tOR (95% CI)\t\nP‐value\t\nPD‐L1 TPS\t<1%\t25\t12.0\tReference\t\t\n1–49%\t43\t16.3\t1.270 (0.229–7. 300)\t0.785\t\n≥50%\t49\t51.0\t5.140 (0.836–31.600)\t0.077\t\nNA\t63\t20.6\t2.200 (0.403–12.000)\t0.363\t\nICIs\tNivolumab\t99\t19.2\tReference\t\t\nAtezolizumab\t11\t9.1\t0.917 (0.074–11.300)\t0.946\t\nPembrolizumab\t70\t40.0\t1.850 (0.495–6.950)\t0.360\t\nLine of ICI therapy\tFirst‐line\t33\t48.5\t0.876 (0.205–3.74)\t0.858\t\nSecond‐line\t66\t19.7\tReference\t\t\n≥Third‐line\t81\t23.5\t1.960 (0.725–5.320)\t0.184\t\nEosinophils (/μL)\t<500\t158\t22.8\tReference\t\t\n≥500\t22\t54.5\t2.190 (0.618–7.750)\t0.225\t\nLymphocytes (/μL)\t<1500\t103\t20.4\tReference\t\t\n≥1500\t77\t35.1\t1.310 (0.545–3.150)\t0.547\t\nLDH (U/L)\t≥230\t68\t16.2\tReference\t\t\n<230\t112\t33.0\t3.270 (1.340–8.020)\t0.009\t\nNLR\t≥5\t51\t15.7\tReference\t\t\n<5\t129\t31.0\t2.940 (0.969–8.910)\t0.057\t\nEosinophils after starting ICIs (/μL)\t<500\t123\t18.7\tReference\t\t\n≥500\t57\t43.9\t1.990 (0800–4.960)\t0.139\t\nirAEs\tNone\t95\t15.8\tReference\t\t\nPresent\t85\t38.8\t2.460 (1.070–5.650)\t0.034\t\nAnalyses of prognostic factors\t\nn\n\tOS(days)\tHR (95% CI)\t\nP‐value\t\nECOG PS\t0–1\t163\t468\tReference\t\t\n2–3\t17\t123\t3.499 (1.756–6.969)\t< 0.001\t\nPD‐L1 TPS\t≥50%\t49\tNR\tReference\t\t\n1–49%\t43\t444\t1.778 (0.713–4.435)\t0.217\t\n<1%\t25\t272\t1.980 (0.685–5.720)\t0.207\t\nNA\t63\t315\t1.183 (0.430–3.253)\t0.745\t\nStage\tIII\t38\tNR\tReference\t\t\nIV\t142\t367\t1.867 (1.025–3.400)\t0.041\t\nICIs\tPembrolizumab\t70\tNR\tReference\t\t\nNivolumab\t99\t296\t2.493 (1.123–5.536)\t0.025\t\nAtezolizumab\t11\t307\t2.803 (0.938–8.371)\t0.065\t\nLine of ICI therapy\tFirst‐line\t33\tNR\tReference\t\t\nSecond‐line\t66\t289\t1.134 (0.414–3.105)\t0.807\t\n≥Third‐line\t81\t385\t0.692 (0.243–1.968)\t0.490\t\nWBC (/μL)\t<9000\t146\t467\tReference\t\t\n≥9000\t34\t359\t1.876 (0.985–3.570)\t0.056\t\nMonocytes (/μL)\t<600\t116\t592\tReference\t\t\n≥600\t64\t296\t1.170 (0.680–2.014)\t0.570\t\nLymphocytes (/μL)\t≥1500\t77\t592\tReference\t\t\n<1500\t103\t296\t1.313 (0.748–2.303)\t0.343\t\nLDH (U/L)\t<230\t112\t604\tReference\t\t\n≥230\t68\t315\t1.370 (0.888–2.112)\t0.154\t\nNLR\t<5\t129\t493\tReference\t\t\n≥5\t51\t281\t0.848 (0.446–1.614)\t0.615\t\nLMR\t≥3\t83\t744\tReference\t\t\n<3\t97\t281\t1.782 (0.985–3.222)\t0.056\t\nPLR\t<300\t139\t472\tReference\t\t\n≥300\t41\t226\t1.711 (0.966–3.030)\t0.066\t\nEosinophils after starting ICIs (/μL)\t≥500\t57\t744\tReference\t\t\n<500\t123\t322\t1.191 (0.711–1.997)\t0.507\t\nirAEs\tPresent\t85\t670\tReference\t\t\nNone\t95\t303\t1.637 (1.041–2.573)\t0.033\t\nCI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; ICIs, immune checkpoint inhibitors; irAEs, immune‐related adverse events; LDH, lactate dehydrogenase; LMR, lymphocyte‐to‐monocyte ratio; NA, not available; NLR, neutrophil‐to‐lymphocyte ratio; OR, odds ratio; ORR, objective response rate; PD‐L1, programmed cell death ligand‐1; PLR, platelet‐to‐lymphocyte ratio; TPS, tumor proportion score; WBC, white blood cell.\n\nPrognostic factors of all‐cause mortality in patients treated with ICIs\n\nThe median OS was 444 days (95% confidence interval [CI]: 315–561) in all patients treated with ICIs (Fig 2). Univariate analysis indicated that ECOG PS, stage, type of ICI, PD‐L1, line of ICI therapy, white blood cell (WBC) count, monocyte count, lymphocyte count, LDH level, NLR, lymphocyte‐to‐monocyte ratio, platelet‐to‐lymphocyte ratio (PLR), eosinophil count after treatment with ICIs, and irAEs were prognostic factors (Table S2). In a multivariate Cox proportional hazard model, ECOG PS, type of ICI, stage IV, and irAEs were independent prognostic factors of all‐cause mortality (Table 3). Kaplan‐Meier curves for OS stratified by pre‐existing respiratory diseases, including IIPs, revealed no significant differences in patient prognosis between the various diseases (Fig 2a). Patients with IIPs of NSIP pattern tended to have a longer OS and patients with IIPs of UIP pattern tended to have a shorter OS (Fig 2b). However, the number of patients in each group was very small and there was no significant difference in prognosis. Other respiratory diseases included bronchial asthma in three and stable pulmonary tuberculosis in one. There were only four cases, two with PD‐L1 ≥50% and one with unknown PD‐L1, which may be due to the longest survival in this study. On the other hand, stratified by type of ICI revealed that patients treated with pembrolizumab had significantly longer median OS than those treated with nivolumab or atezolizumab (Fig 2c).\n\nFigure 2 Kaplan‐Meier curves showing (a) surOS stratified by pre‐existing respiratory diseases; (b) OS stratified by radiographic pattern of IIPs; and (c) OS stratified by type of ICI in non‐small cell lung cancer patients treated with immune checkpoint inhibitors. The log‐rank test of the difference between survival curves of patients with and without pre‐existing respiratory disease was not significant. On the other hand, the log‐rank test revealed a significant survival benefit in patients treated with pembrolizumab compared to those treated with nivolumab or atezolizumab. CI, confidence interval; IIPs, idiopathic interstitial pneumonias; ILD, interstitial lung disease; NR, not reached; NSIP, nonspecific interstitial pneumonia; PE, pulmonary emphysema; UIP, usual interstitial pneumonia.\n\nRisk factors for irAEs\n\nUnivariate analysis indicated that age, WBC count, and lymphocyte count were risk factors for irAEs (Table S3). In a multivariate Cox proportional hazard model, only age and lymphocyte count were risk factors for irAEs (Table 4).\n\nTable 4 Univariate and multivariate analyses of immune‐related adverse events (irAEs) and pneumonitis\n\nAnalyses of irAEs\t\t\nn\n\tirAEs (%)\tHR (95% CI)\t\nP‐value\t\nAge\t≥75\t42\t31.0\tReference\t\t\n<75\t138\t52.2\t2.109 (1.167–3.813)\t0.013\t\nWBC (/μL)\t<9000\t146\t43.8\tReference\t\t\n≥9000\t34\t61.8\t1.649 (0.991–2.743)\t0.054\t\nLymphocytes (/μL)\t<1500\t103\t37.9\tReference\t\t\n≥1500\t77\t59.7\t1.553 (1.001–2.409)\t0.049\t\nAnalyses of pneumonitis\t\nn\n\tPneumonitis (%)\tHR (95% CI)\t\nP‐value\t\nPre‐existing respiratory disease\tNone\t61\t6.6\tReference\t\t\nIIPs\t20\t35.0\t4.350 (1.225–15.440)\t0.023\t\nRIPF\t21\t19.0\t3.096 (0.735–13.040)\t0.124\t\nPE without ILD\t74\t16.2\t2.088 (0.645–6.760)\t0.219\t\nOthers\t4\t0.0\t<0.001 (0.000–Inf)\t0.998\t\nPD‐L1 TPS\t<1%\t49\t24.0\t3.897 (0.911–16.670)\t0.067\t\n1–49%\t43\t3.0\tReference\t\t\n≥50%\t25\t23.7\t2.488 (0.660–9.380)\t0.178\t\nNA\t63\t9.5\t1.480 (0.352–6.222)\t0.593\t\nWBC (/μL)\t<9000\t146\t12.3\tReference\t\t\n≥9000\t34\t26.5\t1.263 (0.492–3.243)\t0.627\t\nEosinophils (/μL)\t<500\t158\t12.7\tReference\t\t\n≥500\t22\t31.8\t1.853 (0.705–4.873)\t0.211\t\nMonocytes (/μL)\t<600\t116\t8.6\tReference\t\t\n≥600\t64\t26.6\t2.080 (0.875–4.941)\t0.097\t\nAlbumin (g/dL)\t≥4\t50\t6.0\tReference\t\t\n<4\t126\t19.0\t2.090 (0.588–7.420)\t0.254\t\nNA\t4\t0.0\t<0.001 (0.000–Inf)\t0.998\t\nCRP (mg/dL)\t<1\t96\t7.3\tReference\t\t\n≥1\t84\t23.8\t1.711 (0.645–4.537)\t0.281\t\nCI, confidence interval; CRP, C‐reactive protein; HR, hazard ratio; ICIs, immune checkpoint inhibitors; IIPs, idiopathic interstitial pneumonias; ILD, interstitial lung disease; irAEs, immune‐related adverse events; NA. not available; PD‐L1, programmed cell death ligand‐1; PE, pulmonary emphysema; RIPF, radiation‐induced pulmonary fibrosis; TPS, tumor proportion score; WBC, white blood cell.\n\nRisk factors for ICI pneumonitis\nUnivariate analysis indicated that age, IIPs, PD‐L1, WBC count, eosinophil count, monocyte count, and albumin and C‐reactive protein (CRP) levels were risk factors for ICI pneumonitis (Table S4). In a multivariate Cox proportional hazard model, however, IIPs were the only risk factor for ICI pneumonitis (Table 4).\n\nCharacteristics of ICI pneumonitis\nOf the 27 patients with ICI pneumonitis, the most common radiographic pattern was the COP pattern (16 patients; Fig 3a) followed by NSIP pattern (four patients; Fig 3b), HP pattern (three patients; Fig 3c), and AIP/ARDS pattern (three patients; Fig 3d). Time to onset of ICI pneumonitis with AIP/ARDS pattern ranged from five to 17 days and tended to be shorter than that of ICI pneumonitis with other radiographic patterns (Fig 4). Among the three patients who developed ICI pneumonitis with AIP/ARDS pattern, all three had respiratory diseases other than lung cancer (two with pulmonary emphysema and one with IIP), all three were at grade 3 severity at the onset of ICI pneumonitis, and all three died. All of the patients with ICI pneumonitis of grade 2 or higher were treated with corticosteroids, whereas all of the patients with ICI pneumonitis of grade 1 were observed without treatment.\n\nFigure 3 Radiographic pattern of immune checkpoint inhibitor (ICI)‐related pneumonitis (ICI pneumonitis. (a) COP pattern; (b) NSIP pattern; (c) HP pattern; and (d) AIP/ARDS pattern. COP, cryptogenic organizing pneumonia; NSIP, nonspecific interstitial pneumonia; HP, hypersensitivity pneumonitis; AIP/ARDS, acute interstitial pneumonia/acute respiratory distress syndrome.\n\nFigure 4 Radiographic pattern, grade, treatment, and outcome of immune checkpoint inhibitor (ICI)‐related pneumonitis (ICI pneumonitis). Data are presented as number of patients or range of time in days to onset of ICI pneumonitis. AIP/ARDS, acute interstitial pneumonia/acute respiratory distress syndrome; COP, cryptogenic organizing pneumonia; HP, hypersensitivity pneumonitis; mPSL, methylprednisolone; NSIP, nonspecific interstitial pneumonia; PSL, prednisolone.\n\nDiscussion\nIn this study, we revealed predictive factors for clinical outcome and irAEs in patients with advanced NSCLC treated with ICI monotherapy in a clinical setting. Predictive factors for clinical response were LDH level, and irAEs. Predictive factors for prognosis were ECOG PS, stage, type of ICI, and irAEs. Pembrolizumab had the highest frequency of irAEs and the best tumor response and prognosis. About half of the patients experienced irAEs, the risk factors for which were age and lymphocyte count. The most frequent irAE was ICI pneumonitis, and all three deaths were due to ICI pneumonitis with an AIP/ARDS radiographic pattern. Although IIPs were a significant risk factor for ICI pneumonitis, there were no significant differences in the ORR and OS between patients with IIPs and those without respiratory diseases.\n\nPreviously, it was reported that several factors predict the response and prognosis in patients treated with ICIs. In phase III trials, PD‐L1 expression was associated with OS in NSCLC patients treated with ICIs.\n2\n, \n3\n Tamiya et al. showed that ECOG PS ≥2, liver metastasis, and lung metastasis were predictive of poor PFS in NSCLC patients treated with nivolumab.\n21\n Additionally, several studies reported that irAEs were associated with clinical response and prognosis. Sato et al.\n10\n and Toi et al.\n22\n respectively investigated 38 and 70 NSCLC patients treated with nivolumab and reported that patients with irAEs had significantly higher ORR than those without irAEs (63.6 vs. 7.4% and 57 vs. 12%, respectively). Haratani et al.\n23\n investigated 134 NSCLC patients treated with nivolumab and reported that the patients with irAEs had significantly longer median OS than those without irAEs (not reached vs. 11.1 months). Similarly, Ricciuti et al.\n24\n studied 195 NSCLC patients treated with nivolumab and reported that the patients with irAEs experienced significantly longer median OS than those without irAEs (17.8 vs. 4.0 months), and patients who developed ≥2 irAEs had significantly longer median OS than those with one or no irAEs (26.8 vs. 11.9 vs. 4.0 months). The present study also revealed that irAEs were associated with both ORR and OS in NSCLC patients treated with ICIs. In contrast, Ksienski et al.\n25\n studied 271 patients treated with nivolumab or pembrolizumab and showed that treatment interruption due to irAEs was associated with a lower median OS than was continuous treatment (8.27 vs. 14.54 months). Therefore, appropriate assessment and management of irAEs is necessary.\n\nSeveral studies have shown risk factors of irAEs. Diehl et al.\n11\n reported that baseline lymphocyte and eosinophil counts were associated with irAEs in solid tumor patients treated with ICIs. A pooled analysis including NSCLC patients from four trials of ICIs showed that patients aged ≥75 years had a lower incidence of grade 3 or 4 adverse events than patients aged <65 years (23 vs. 47%).\n26\n However, because a pooled analysis including NSCLC patients from three trials for pembrolizumab showed that there were no differences in the incidence of irAEs between patients aged <75 and ≥75 years (24.8 vs. 25.0%),\n27\n it remains controversial whether age is related to the incidence of irAEs.\n\nIn the present study, most of the patients who developed ICI pneumonitis or liver injury after ICI therapy discontinued ICIs permanently. According to the American Society of Clinical Oncology clinical practice guideline, if patients develop irAEs, ICI therapy is continued with close monitoring for grade 1 irAEs, is held for grade 2 or 3 irAEs until they improve to grade 1 or less, and is permanently discontinued for grade 4 irAEs except endocrinopathies.\n28\n Patients with grade 3 or 4 ICI pneumonitis and liver injury were required to permanently discontinue ICI therapy. Mouri et al.\n29\n reported the clinical differences between patients who discontinued ICIs and those who retreated after occurrences of irAEs. They found that patients who discontinued ICIs tended to more frequently have ICI pneumonitis, thyroid dysfunction, and liver injury than those retreated from therapy.\n\nAlthough several clinical trials revealed that 2.5% to 5% of patients developed ICI pneumonitis,\n14\n its incidence was higher in the clinical setting than in the clinical trials, and 5.4% to 16.9% of patients experienced ICI pneumonitis.\n10\n, \n11\n, \n30\n Tone et al.\n31\n reported that patients with ICI pneumonitis of grade 3 or higher were associated with shorter median OS than those with ICI pneumonitis of grade 2 or lower or no ICI pneumonitis. A retrospective study reported that radiographic patterns were associated with grades of ICI pneumonitis, with the AIP/ARDS pattern associated with the highest grade, followed by the COP pattern, and the NSIP and HP patterns associated with lower grades.\n32\n Several studies have reported risk factors of ICI pneumonitis. Cui et al.\n33\n revealed that prior radiotherapy and combination therapy, defined as treatment with anti‐PD‐1 antibody and chemotherapy, targeted therapy, or anticytotoxic T‐lymphocyte‐associated antigen‐4 antibody, were significantly associated with ICI pneumonitis in a multivariable logistic regression model. Oshima et al.\n34\n analyzed the Food and Drug Administration Adverse Event Reporting System database and investigated the association between pneumonitis and the combination of nivolumab and EGFR‐tyrosine kinase inhibitor (TKI). They reported that 18 of the 70 patients who were treated with the combination developed pneumonitis (25.7%), with the order of treatment in 15 patients identified as EGFR‐TKI after nivolumab administration. A systematic review and meta‐analysis showed that the incidence of ICI pneumonitis in NSCLC was higher than that in melanoma.\n35\n Additionally, a retrospective study showed the incidence in NSCLC of the adenocarcinoma histological pattern to be lower than that in NSCLC of the squamous histological pattern.\n36\n Several studies showed the efficacy and safety of ICIs in patients with pre‐existing ILD or interstitial lung abnormalities, which are defined as areas of increased lung density on lung computed tomography in individuals with no known ILD.\n30\n Kanai et al.\n37\n investigated 216 NSCLC patients who had received nivolumab and reported that the incidence of ICI pneumonitis was significantly higher in patients with pre‐existing ILD than in patients without ILD (31 vs. 12%). There were no significant differences in the ORR (27 vs.13%) and median PFS (2.7 vs. 2.9 months). Nakanishi et al.\n30\n studied 83 NSCLC patients who had received nivolumab or pembrolizumab and found that the patients with ICI pneumonitis had a significantly higher frequency of interstitial lung abnormalities than those without ICI pneumonitis (42.9 vs. 10.1%).There were no significant differences in the response to the ICIs. Fujimoto et al.\n38\n studied the efficacy and safety of nivolumab for NSCLC patients with mild IIPs. They reported that two of the 18 patients (11.1%) with IIPs developed ICI pneumonitis. The ORR was 39%, median PFS was 7.4 months, and median OS was 15.6 months. Similar to the previous studies, the incidence of ICI pneumonitis in the present study was significantly higher in patients with pre‐existing IIPs than in those without pre‐existing respiratory diseases (35.0 vs. 6.6%), and the ORR in the patients with IIPs was 35.0%. In addition, patients with IIPs tended to have a longer OS, although the difference was not significant. In this study, patients treated with atezolizumab had the poorest ORR and OS, and none of the patients with IIP received atezolizumab. Furthermore, although IIPs was a risk factor for the development of ICI pneumonitis in this study, two‐thirds of ICI‐pneumonitis patients were Grade 1–2, with a fatality rate of only 10%, and patients with irAEs had better OS than those without irAEs. These findings may have contributed to the present study.\n\nThis study has several limitations. First, because it was retrospective, some patient characteristics were not available. Second, it was performed at a single hospital, and only Japanese patients were treated. Third, the sample size was small. Finally, diagnoses of ICI pneumonitis were largely based on clinical course and CT findings. Only a small percentage of patients underwent bronchoalveolar lavage to exclude pneumonia. However, pneumonitis was not resolved by antimicrobial drugs.\n\nIn summary, the incidence of irAEs might be a useful predictor of clinical response and prognosis in NSCLC patients treated with ICIs, and we believe that appropriate management of irAEs can lead to clinical benefit. Because all three patient deaths were due to ICI pneumonitis, we consider ICI pneumonitis to be the most important irAE, and radiological pattern classification was useful for predicting the prognosis of ICI pneumonitis. Pre‐existing IIPs were a risk factor for ICI pneumonitis; however, this study showed that ICI therapy can be offered to patients with pre‐existing respiratory diseases with the expectation of the same degree of response as that in patients without pre‐existing respiratory diseases.\n\nDisclosure\nThe authors declare there are no conflicts of interest.\n\nSupporting information\n\nTable S1 Univariate and multivariate analyses of objective response rate.\n\n\nTable S2 Univariate and multivariate analyses of prognostic factors of all‐cause mortality in patients treated with ICIs.\n\n\nTable S3 Univariate and multivariate analyses of irAEs.\n\n\nTable S4 Univariate and multivariate analyses of ICI pneumonitis.\n\nClick here for additional data file.\n==== Refs\nReferences\n1 \n\nBrahmer \nJ \n, \nReckamp \nKL \n, \nBaas \nP \n\net al\nNivolumab versus docetaxel in advanced squamous‐cell non‐small‐cell lung cancer\n. 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"fulltext_license": "CC BY",
"issn_linking": "1759-7706",
"issue": "12(2)",
"journal": "Thoracic cancer",
"keywords": "Immune checkpoint inhibitor; immune-related adverse event; lung cancer; pneumonitis",
"medline_ta": "Thorac Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D011014:Pneumonia; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors",
"nlm_unique_id": "101531441",
"other_id": null,
"pages": "153-164",
"pmc": null,
"pmid": "33201587",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Outcome and risk factor of immune-related adverse events and pneumonitis in patients with advanced or postoperative recurrent non-small cell lung cancer treated with immune checkpoint inhibitors.",
"title_normalized": "outcome and risk factor of immune related adverse events and pneumonitis in patients with advanced or postoperative recurrent non small cell lung cancer treated with immune checkpoint inhibitors"
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"abstract": "BACKGROUND\nFor the past decades the mean age of primiparae in Western societies is constantly increasing. At the same time, there is a growing demand for assisted reproductive technologies such as in vitro fertilization and intracytoplasmic sperm injection. Subsequently, a higher prevalence of pregnancy-associated diseases such as gestational hypertension and preeclampsia is observed. To improve pregnancy rates after in vitro fertilization/intracytoplasmic sperm injection and to reduce the risk of pregnancy-associated diseases with a cardiovascular pathophysiology, two anticoagulants are the focus of current research: low molecular weight heparin and acetylsalicylic acid (aspirin).\n\n\nMETHODS\nA 41-year-old white woman, gravida 3, para 0, received low molecular weight heparin to reduce the risk of abortion after five unsuccessful intracytoplasmic sperm injections and two miscarriages. She autonomously discontinued the medication with low molecular weight heparin at 12 weeks and 2 days of gestation and took aspirin instead until 24 weeks and 2 days of gestation as preeclampsia prophylaxis. However, the pregnancy ended with an urgent cesarean section at 27 weeks and 4 days of gestation due to a fast progressing hemolysis, elevated liver enzyme levels, and low blood platelet count syndrome, a potentially life-threatening variant of preeclampsia.\n\n\nCONCLUSIONS\nBased on the current demographic trend toward late-in-life pregnancy it is mandatory to establish clear guidelines concerning preventive treatment options of preeclampsia for patients with risk factors. The establishment of a special first-trimester screening for these women should be discussed. Moreover, it is necessary to raise the awareness among physicians of these contemporary issues to guarantee the best possible medical care.",
"affiliations": "Rottal-Inn-Kliniken Krankenhaus Eggenfelden, Simonsöder Allee 20, 84307, Eggenfelden, Germany. katrinmik@t-online.de.;Walter Brendel Centre for Experimental Medicine, Ludwig-Maximilians-Universität München, Marchioninistraße 15, 81377, Munich, Germany.;Kliniken Nordoberpfalz AG, Krankenhaus Tirschenreuth, St.-Peter-Str. 31, 95643, Tirschenreuth, Germany.;Kliniken Nordoberpfalz AG, Klinikum Weiden, Söllnerstraße 16, 92637, Weiden, Germany.",
"authors": "Mikolaiczik|Katrin|K|;Praetner|Marc|M|;Rüth|Michael|M|;Mark|Karlheinz|K|",
"chemical_list": "D000925:Anticoagulants; D006495:Heparin, Low-Molecular-Weight; D001241:Aspirin",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-018-1943-1",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 194310.1186/s13256-018-1943-1Case ReportDelayed hemolysis, elevated liver enzymes, low platelet count syndrome in succession of switches of preventive anticoagulant treatment in a 41-year-old patient with a history of recurrent assisted implantation failures: a case report Mikolaiczik Katrin katrinmik@t-online.de 1Praetner Marc marc.pr@web.de 2Rüth Michael michael.rueth@kliniken-nordoberpfalz.ag 3Mark Karlheinz karlheinz.mark@kliniken-nordoberpfalz.ag 41 Rottal-Inn-Kliniken Krankenhaus Eggenfelden, Simonsöder Allee 20, 84307 Eggenfelden, Germany 2 0000 0004 1936 973Xgrid.5252.0Walter Brendel Centre for Experimental Medicine, Ludwig-Maximilians-Universität München, Marchioninistraße 15, 81377 Munich, Germany 3 Kliniken Nordoberpfalz AG, Krankenhaus Tirschenreuth, St.-Peter-Str. 31, 95643 Tirschenreuth, Germany 4 0000 0004 0390 7652grid.459568.3Kliniken Nordoberpfalz AG, Klinikum Weiden, Söllnerstraße 16, 92637 Weiden, Germany 19 1 2019 19 1 2019 2019 13 1618 3 2018 5 12 2018 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nFor the past decades the mean age of primiparae in Western societies is constantly increasing. At the same time, there is a growing demand for assisted reproductive technologies such as in vitro fertilization and intracytoplasmic sperm injection. Subsequently, a higher prevalence of pregnancy-associated diseases such as gestational hypertension and preeclampsia is observed. To improve pregnancy rates after in vitro fertilization/intracytoplasmic sperm injection and to reduce the risk of pregnancy-associated diseases with a cardiovascular pathophysiology, two anticoagulants are the focus of current research: low molecular weight heparin and acetylsalicylic acid (aspirin).\n\nCase presentation\nA 41-year-old white woman, gravida 3, para 0, received low molecular weight heparin to reduce the risk of abortion after five unsuccessful intracytoplasmic sperm injections and two miscarriages. She autonomously discontinued the medication with low molecular weight heparin at 12 weeks and 2 days of gestation and took aspirin instead until 24 weeks and 2 days of gestation as preeclampsia prophylaxis. However, the pregnancy ended with an urgent cesarean section at 27 weeks and 4 days of gestation due to a fast progressing hemolysis, elevated liver enzyme levels, and low blood platelet count syndrome, a potentially life-threatening variant of preeclampsia.\n\nConclusion\nBased on the current demographic trend toward late-in-life pregnancy it is mandatory to establish clear guidelines concerning preventive treatment options of preeclampsia for patients with risk factors. The establishment of a special first-trimester screening for these women should be discussed. Moreover, it is necessary to raise the awareness among physicians of these contemporary issues to guarantee the best possible medical care.\n\nElectronic supplementary material\nThe online version of this article (10.1186/s13256-018-1943-1) contains supplementary material, which is available to authorized users.\n\nKeywords\nHELLP syndromePreeclampsiaLow molecular weight heparinAspirinICSIIVFissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nIn Western societies the mean age of women giving birth to their first child is constantly increasing [1, 2]. This epidemiological trend is accompanied by higher rates of infertility, preterm delivery, and a rising incidence of pregnancy-associated diseases such as maternal diabetes, chronic hypertension, and preeclampsia [3–5]. At the same time there is a growing demand for assisted reproductive technologies such as in vitro fertilizations (IVFs) and intracytoplasmic sperm injections (ICSIs) [4, 6]. Therefore, current clinical research focuses not only on improving pregnancy rates after IVF/ICSI but also on reducing the risks of developing pregnancy-associated complications. As increased thrombin generation, inflammation, and vascular lesions are regarded as the pathophysiological hallmarks of preeclampsia and recurrent abortions, two anticoagulants are currently in use as preventive treatments: low molecular weight heparin (LMWH) and acetylsalicylic acid (aspirin) [7].\n\nWhereas most data do not support a beneficial effect of aspirin on pregnancy rates after IVF/ICSI, the application of LMWH seems to improve birth rates, particularly after recurrent implantation failures [8–12]. Regarding preeclampsia, the prophylactic use of aspirin is discussed ambivalently in the literature. However, the latest clinical data suggest that patients with higher risk factors, such as history of preeclampsia, seem to benefit from aspirin, especially when the therapy is initiated in early pregnancy [13–16]. LMWH alone as well as in combination with aspirin seems to be able to reduce the prevalence of preeclampsia [17–21]. Despite these positive findings, a recent meta-analysis from 2016 was not able to detect a beneficial effect of LMWH on recurrent placental-mediated complications such as preeclampsia in women at risk [22]. In summary, the existing data do not allow us to draw final clinical conclusions due to the mixed results reported in the current literature.\n\nIn this report the case of a 41-year-old patient will be discussed; she was treated with LMWH for the first fortnight after ICSI. She continued the treatment with LMWH until 12 weeks and 2 days of gestation and then decided to take aspirin instead until 24 weeks and 2 days of gestation. Based on her own literature research she decided to adjust her medication autonomously to reduce the risks of another abortion or preeclampsia. The pregnancy ended with an urgent cesarean section (C-section) at 27 weeks and 4 days of gestation due to fast progressing hemolysis, elevated liver enzyme levels, and low blood platelet count (HELLP) syndrome, a potentially life-threatening variant of preeclampsia characterized by the core symptoms: hemolysis, elevated liver enzymes, and low platelets [23].\n\nCase presentation\nA 41-year-old white woman, gravida 3, para 0, was admitted to our clinic at 27 weeks and 3 days of gestation. She reported suffering from dizziness, impaired vision, facial edema as well as increasing edema in her lower legs since the previous day. She also mentioned raised blood pressure (approximately 175/105 mmHg) although regularly taking her medication of alpha-methyl-dopa 250 mg 1-2-1. We initiated this therapy 3 weeks earlier due to the development of gestational hypertension. Furthermore, she took magnesium 40 mg 1-1-1 and progesterone 100 mg 2-0-2 since the onset of pregnancy as supportive medication. She had no other additional medication. She had no history of pre-existing diseases. Pregnancy-associated complications never occurred in her family.\n\nObstetric history: At the age of 38, after 3 years of trying to get pregnant, she decided on assisted reproductive technologies. She had three inseminations, followed by five ICSIs without success. The sixth ICSI finally led to pregnancy, although ending with an early abortion at 6 weeks of gestation. After the seventh ICSI two embryos were transferred. In addition, LMWH was prescribed for the first 14 days after transfer. In the following ultrasound examinations only one viable embryo could be detected. However, this pregnancy ended at 7 weeks of gestation. After the second miscarriage our patient and her husband ran through genetic counselling and testing, revealing no pathologies. Furthermore, antiphospholipid syndrome (APS), lupus erythematosus, and thrombophilia were excluded. In search of other possible reasons explaining the dissatisfying clinical course, our patient once more had an ultrasound of the genital organs now revealing a tumor at the posterior wall of her uterus, most probably representing a fibroma. The following hysteroscopy showed an arcuate uterus without the need to interfere surgically.\n\nThen, our patient, now 41-years old, went for another ICSI with the transfer of two embryos. Initially, follow-up ultrasounds showed two amniotic cavities with viable embryos. At 8 weeks of gestation one embryo died and could no longer be detected in the subsequent ultrasound examinations (“vanishing twin”). Again, LMWH (nadroparin 0.4 ml/day subcutaneous injection) was prescribed for the first 14 days after transfer. Based on literature research and out of fear of another miscarriage our patient decided to continue the treatment with nadroparin. Although discussing this topic with her gynecologist, she could not receive the prescription as the gynecologist expressed a lack of experience in preventive anticoagulant treatment after ICSI. Our patient therefore turned to her general practitioner who issued the prescription for nadroparin. With 12 weeks and 2 days of gestation she autonomously discontinued the treatment with nadroparin and changed to aspirin 100 mg/day instead as preeclampsia prophylaxis. At 21 weeks and 2 days of gestation a prenatal care ultrasound revealed bilateral uterine artery notching. Three weeks later she developed hypertensive blood pressure values leading to hospitalization in our clinic. We initiated an antihypertensive therapy with alpha-methyl-dopa 250 mg as described above. The medication with aspirin was discontinued. To estimate further clinical course, preeclampsia-associated angiogenesis biomarkers were analyzed: The soluble fms-like tyrosine kinase-1 (sFlt-1), an antiangiogenic factor, and the placental growth factor (PlGF), an angiogenic factor. Although the cause of preeclampsia is not yet fully understood, angiogenic imbalance in favor of antiangiogenic factors like sFlt-1 is involved in the pathophysiology of preeclampsia resulting in abnormal remodeling of maternal spiral arteries which finally leads to placental malperfusion [24, 25]. The sFlt-1/PIGF ratio already increases before the onset of the clinical symptoms and is therefore used as a predictor for preeclampsia with high sensitive and specific values [24–27]. Her sFlt-1/PIGF ratio of 276 (physiological sFlt/PIGF ratio < 33) indicated a high risk of developing preeclampsia in the next 4 weeks. We therefore initiated a glucocorticoid prophylaxis with betamethasone for respiratory distress syndrome in case of preterm delivery. After adjusting her blood pressure to 150/80–100 mmHg our patient was discharged after 7 days.\n\nFinally, at 27 weeks and 3 days of gestation, she again was admitted to our clinic, now with the symptoms described above leading to the diagnosis of preeclampsia. Cardiotocography (CTG) results and obstetric ultrasound were normal apart from an elevated pulsatility index of 1.2 of the umbilical artery Doppler. Bilateral uterine artery notching could still be detected. Our patient’s blood work did not show any abnormalities apart from recently elevated lactate dehydrogenase (LDH) values (see Additional file 1: Table S1). Blood samples were now taken in a close-meshed timescale: within 16 hours transaminases and hemolysis parameters were rapidly increasing and thrombocyte counts were decreasing, thus fulfilling the criteria of a fast progressing HELLP syndrome (see Additional file 1: Table S1).\n\nAn urgent C-section was performed based on maternal indication due to the deteriorating clinical condition of our patient: constantly raised blood pressure > 185/105 mmHg despite additional treatment with nifedipine; growing pain in her upper abdomen; oliguria with increasing leg, arm, and facial edema; beginning somnolence and apathy. At 27 weeks and 4 days of gestation a girl was delivered, weighing 873 g, with Apgar scores of 8/10/10, umbilical cord pH = 7.35. The girl was immediately attended by the department of pediatrics. The uterus in situ appeared to show signs of diffuse myohyperplasia. In addition, several smaller pedunculated uterine fibroids were apparent. Histopathology of the placenta revealed premature ripened chorionic villi and an older circumscribed infarction.\n\nAfter the C-section our patient was transferred to the intensive care unit (ICU). Postoperative sonography revealed small pleural effusions in both lungs. Diuretic therapy with furosemide rapidly increased urinary excretion. Additional antihypertensive medication with urapidil via syringe pump infusion could be reduced gradually and terminated after 2 days. Perception disorders such as illusory conjunctions in the perception of objects rapidly disappeared. After 2 days she could be transferred to our general ward. She recovered quickly, her blood work normalized. Her blood pressure was adjusted to 140–159/90–99 mmHg with alpha-methyl-dopa 250 mg 1-0-1. Eight days after the C-section she was able to leave our hospital. We recommended follow-up blood samples and regular blood pressure measurements for the next 6 weeks. Antihypertensive medication should be adjusted if applicable. Furthermore, we suggested 24-hour blood pressure measurements on an annual basis due to the higher prevalence of cardiovascular diseases after preeclampsia [28, 29].\n\nApart from a pneumothorax in combination with respiratory distress syndrome within the first days the child did not suffer from any severe complications during her hospital stay. With a weight of 2680 g the healthy girl was finally discharged after 77 days.\n\nDiscussion and conclusion\nLMWH is discussed to have a positive influence on birth rates after recurrent implantation failures [10]. After five unsuccessful ICSIs and one miscarriage our patient received LMWH for the first time. However, two following LMWH-supported pregnancies ended in miscarriage. It can be debated whether she would have had benefited from an application of LMWH after the third unsuccessful ICSI. As among other possible reasons for her recurrent implantation failures and infertility, there are the observed uterine abnormalities: the clinically apparent myohyperplasia which is often caused by endometriosis, as well as the uterine fibroids and the arcuate uterus [30–32]. These anatomical anomalies alone have a negative effect on pregnancy rates and are not directly affected by LMWH.\n\nRegarding preeclampsia, our patient had the following risk factors: advanced age (> 40), nulliparity, and ICSI [4, 5, 33, 34]. The early twin pregnancy could have had an adverse effect as well, as multiple pregnancy is known to correlate positively with the incidence of preeclampsia [5]. However, current data suggest that the vanishing twin phenomenon is associated with small for gestational age babies, preterm delivery, and low birth weight but not preeclampsia [35]. The circumscribed infarction of the placenta could be a remnant of the vanishing twin. On the other hand, casual pathologies of the development of preeclampsia are occlusive hypertensive lesions in the spiral arteries and inadequate placentation which lead to placental ischemia and finally to infarction of the placenta [35–39].\n\nBilateral arterial notching and elevated sFlt-1/PlGF ratio are pregnancy-associated risk factors for the development of preeclampsia [40–44]. With 21 weeks and 2 days of gestation, bilateral arterial notching was detected by umbilical artery Doppler assessment and 3 weeks later, after the development of gestational hypertension, we detected the elevated sFlt-1/PlGF ratio. In synopsis of the pregnancy-associated and anamnestic risk factors, the sFlt-1/PlGF ratio could have been calculated when the bilateral notching was detected at 21 weeks and 2 days of gestation. However, at that time our patient had already taken aspirin autonomously which is the recommended preventive medication of preeclampsia. When we diagnosed the gestational hypertension at 24 weeks of gestation we discontinued this treatment. This decision could be discussed as on the one hand she had not had preeclampsia yet and still faced the increasing probability of developing one. On the other hand she had already shown clear signs of pathophysiological changes, such as the bilateral arterial notching and finally gestational hypertension. This finally led to the conclusion that aspirin as preventive treatment was of no further use. Unfortunately, there are no current data regarding the recommendation of continuing or quitting the medication of aspirin after developing gestational hypertension. A meta-analysis from 2010, however, indicated that low-dose aspirin started at 16 weeks or earlier is not only associated with a reduction in severe preeclampsia and gestational hypertension but also with a reduction in preterm birth [15]. Our patient therefore might have benefited from a continuous application of aspirin. In conclusion, a continuous application of LMWH and aspirin after transfer might have been the best preventive treatment for our patient.\n\nDue to the current demographic trend more patients will face an elevated probability of pregnancy-associated diseases such as preeclampsia. Therefore, there is a need to establish first-trimester screening and a definitive guideline for preventive treatment of preeclampsia in women with risk factors, especially if the case is more complex like the one presented. Moreover, our patient did not receive sufficient medical advice from her pretreating gynecologists concerning the possibilities of improving the birth rate after recurrent implantation failures and preventing the development of preeclampsia. As a result she felt impelled to start a preventive medication on her own based on literature research. Thus, there is not only the need for a guideline but also the need of raising awareness among gynecologists of these contemporary issues.\n\nAdditional file\n\nAdditional file 1: \nTable S1. Blood sample values since admission. ALT alanine transaminase, AST aspartate transaminase, LDH Lactate dehydrogenase. (DOCX 20 kb)\n\n \n\n\nAbbreviations\nAPSAntiphospholipid syndrome\n\nAspirinAcetylsalicylic acid\n\nC-sectionCesarean section\n\nCTGCardiotocography\n\nHELLPHemolysis, elevated liver enzyme levels, and low blood platelet count\n\nICSIIntracytoplasmic sperm injection\n\nICUIntensive care unit\n\nIVFIn vitro fertilization\n\nLDHLactate dehydrogenase\n\nLMWHLow molecular weight heparin\n\nPlGFPlacental growth factor\n\nsFlt-1Soluble fms-like tyrosine kinase-1\n\nAcknowledgements\nWe sincerely thank the patient of this case report for her support.\n\nFunding\nNo funding was used to write this case report.\n\nAvailability of data and materials\nData sharing is not applicable to this article as no datasets were generated or analyzed during the current study.\n\nAuthors’ contributions\nKM contributed to the literature review, initiated the work, and wrote the manuscript. MR was the primary clinician involved in the assessment and management of this patient and contributed to portions of the manuscript. KHM was the clinical supervisor of this case and together with MP facilitated this case report and contributed to the literature review and participated in the preparation of the manuscript. All authors approved the final form of the manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\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. Mathews TJ, Hamilton BE. Mean Age of Mothers is on the Rise: United States, 2000-2014. NCHS Data Brief. 2016;232:1–8.\n2. Eurostat - Tables, Graphs and Maps Interface (TGM) table. Mean age of women at childbirth and at birth of first child. http://ec.europa.eu/eurostat/tgm/table.do?tab=table&init=1&language=en&pcode=tps00017&plugin=1. Accessed 1 Feb 2017.\n3. Dunson DB Baird DD Colombo B Increased Infertility With Age in Men and Women Obstet Gynecol 2004 103 51 56 10.1097/01.AOG.0000100153.24061.45 14704244 \n4. Lamminpaa R, Vehvilainen-Julkunen K, Gissler M, Heinonen S. Preeclampsia complicated by advanced maternal age: a registry-based study on primiparous women in Finland 1997-2008. BMC Pregnancy Childbirth. 2012;12(47) 10.1186/1471-2393-12-47.\n5. Duckitt K Harrington D Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies BMJ 2005 330 565 10.1136/bmj.38380.674340.E0 15743856 \n6. 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Katsi V Kanellopoulou T Makris T Nihoyannopoulos P Nomikou E Tousoulis D Aspirin vs Heparin for the Prevention of Preeclampsia Curr Hypertens Rep 2016 18 57 10.1007/s11906-016-0664-3 27251704 \n21. Groom KM, McCowan LM, Mackay LK, Lee AC, Said JM, Kane SC, et al. Enoxaparin for the prevention of preeclampsia and intrauterine growth restriction in women with a history: a randomized trial. Am J Obstet Gynecol. 2017; 10.1016/j.ajog.2017.01.014.\n22. Rodger MA Gris J-C de Vries JIP Martinelli I Rey É Schleussner E Low-molecular-weight heparin and recurrent placenta-mediated pregnancy complications: A meta-analysis of individual patient data from randomised controlled trials Lancet 2016 388 2629 2641 10.1016/S0140-6736(16)31139-4 27720497 \n23. Rath W Faridi A Dudenhausen JW HELLP syndrome J Perinat Med 2000 28 249 260 10.1515/JPM.2000.033 11031696 \n24. 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Trogstad L Magnus P Stoltenberg C Pre-eclampsia: Risk factors and causal models Best Pract Res Clin Obstet Gynaecol 2011 25 329 342 10.1016/j.bpobgyn.2011.01.007 21349772 \n34. Thomopoulos C Tsioufis C Michalopoulou H Makris T Papademetriou V Stefanadis C Assisted reproductive technology and pregnancy-related hypertensive complications: a systematic review J Hum Hypertens 2013 27 148 157 10.1038/jhh.2012.13 22495105 \n35. Roberts JM Escudero C The placenta in preeclampsia Pregnancy Hypertens 2012 2 72 83 10.1016/j.preghy.2012.01.001 22745921 \n36. Brosens I Renaer M On the pathogenesis of placental infarcts in pre-eclampsia BJOG: Int J O&G 1972 79 794 799 10.1111/j.1471-0528.1972.tb12922.x \n37. van der Merwe JL Hall DR Wright C Schubert P Grove D Are early and late preeclampsia distinct subclasses of the disease--what does the placenta reveal? Hypertens Pregnancy. 2010 29 457 467 10.3109/10641950903572282 20701467 \n38. Vinnars M-T Nasiell J Ghazi S Westgren M Papadogiannakis N The severity of clinical manifestations in preeclampsia correlates with the amount of placental infarction Acta Obstet Gynecol Scand 2011 90 19 25 10.1111/j.1600-0412.2010.01012.x 21275911 \n39. Vinnars M-T Wijnaendts LCD Westgren M Bolte AC Papadogiannakis N Nasiell J Severe preeclampsia with and without HELLP differ with regard to placental pathology Hypertension 2008 51 1295 1299 10.1161/HYPERTENSIONAHA.107.104844 18362224 \n40. Espinoza J Kusanovic JP Bahado-Singh R Gervasi MT Romero R Lee W Should bilateral uterine artery notching be used in the risk assessment for preeclampsia, small-for-gestational-age, and gestational hypertension? J Ultrasound Med 2010 29 1103 1115 10.7863/jum.2010.29.7.1103 20587434 \n41. Gomez-Arriaga PI Herraiz I Lopez-Jimenez EA Escribano D Denk B Galindo A Uterine artery Doppler and sFlt-1/PlGF ratio: prognostic value in early-onset pre-eclampsia Ultrasound Obstet Gynecol 2014 43 525 532 10.1002/uog.13224 24185845 \n42. Forest J-C Theriault S Masse J Bujold E Giguere Y Soluble Fms-like tyrosine kinase-1 to placental growth factor ratio in mid-pregnancy as a predictor of preterm preeclampsia in asymptomatic pregnant women Clin Chem Lab Med 2014 52 1169 1178 10.1515/cclm-2013-0955 24535301 \n43. Herraiz I López-Jiménez EA Puente JM Camaño I Arbués J Galindo A OP14.07: Uterine artery Doppler and sFlt1/PlGF ratio as useful tools to predict severe complications after the diagnosis of preeclampsia is confirmed Ultrasound Obstet Gynecol 2009 34 105 106 10.1002/uog.6782 \n44. Mikat B Gellhaus A Wagner N Birdir C Kimmig R Koninger A Early detection of maternal risk for preeclampsia ISRN Obstet Gynecol 2012 2012 172808 10.5402/2012/172808. 22852092\n\n",
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"issn_linking": "1752-1947",
"issue": "13(1)",
"journal": "Journal of medical case reports",
"keywords": "Aspirin; HELLP syndrome; ICSI; IVF; Low molecular weight heparin; Preeclampsia",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000328:Adult; D000925:Anticoagulants; D001241:Aspirin; D002585:Cesarean Section; D005260:Female; D017359:HELLP Syndrome; D006495:Heparin, Low-Molecular-Weight; D006801:Humans; D007230:Infant, Low Birth Weight; D007231:Infant, Newborn; D011247:Pregnancy; D047928:Premature Birth; D020554:Sperm Injections, Intracytoplasmic; D016896:Treatment Outcome",
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"pmid": "30658715",
"pubdate": "2019-01-19",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Delayed hemolysis, elevated liver enzymes, low platelet count syndrome in succession of switches of preventive anticoagulant treatment in a 41-year-old patient with a history of recurrent assisted implantation failures: a case report.",
"title_normalized": "delayed hemolysis elevated liver enzymes low platelet count syndrome in succession of switches of preventive anticoagulant treatment in a 41 year old patient with a history of recurrent assisted implantation failures a case report"
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"abstract": "Anti-Tumor Necrosis Factor (TNF)-induced lupus (ATIL) is a distinct clinical entity, increasingly recognized in patients with inflammatory bowel disease treated with anti-TNF therapy. Our aims were to evaluate the incidence and clinical and serological markers of ATIL in this population.\nThis observational cohort study reviewed 454 patient treatment courses with anti-TNF therapy (300 infliximab and 154 adalimumab). A diagnosis of ATIL was based on the most widely accepted diagnostic criteria: (i) a temporal relationship between symptoms and anti-TNF therapy and resolution of symptoms following cessation of the offending medication; (ii) at least one serologic American College of Rheumatology (ACR) criterion of Systemic Lupus Erythematosus (SLE); and (iii) at least one nonserological criterion such as arthritis, serositis, or rash. Clinical, demographic, and serological predictors were evaluated.\nThe incidence rate of ATIL was 5.7% for infliximab and 0.6% for adalimumab, which are much higher than previously reported postmarketing estimates. The median duration to diagnosis following commencement of anti-TNF therapy was 15 months (3-62 months). ATIL occurs more commonly patients that commence therapy at an older age (46.47 years ± 13.79 years vs. 38.85 years ± 14.75 years, P = 0.033).\nATIL is a significant complication of anti-TNF therapy, affecting 1 in every 20 patients who commence infliximab. A panel of serological markers is useful to confirm the diagnosis and exclude other conditions that may mimic ATIL. Clinicians using anti-TNF medications should counsel patients about this potential risk and monitor for clinical manifestations of lupus during routine follow up.",
"affiliations": "Department of Gastroenterology and Hepatology Royal Perth Hospital Perth Western Australia Australia.;Department of Gastroenterology and Hepatology Royal Perth Hospital Perth Western Australia Australia.;Department of Gastroenterology and Hepatology Royal Perth Hospital Perth Western Australia Australia.",
"authors": "Picardo|Sherman|S|https://orcid.org/0000-0001-5013-956X;So|Kenji|K|;Venugopal|Kannan|K|",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.1002/jgh3.12291",
"fulltext": "\n==== Front\nJGH Open\nJGH Open\n10.1002/(ISSN)2397-9070\nJGH3\nJGH Open: An Open Access Journal of Gastroenterology and Hepatology\n2397-9070 Wiley Publishing Asia Pty Ltd Melbourne \n\n10.1002/jgh3.12291\nJGH312291\nOriginal Article\nOriginal Articles\nAnti‐TNF‐induced lupus in patients with inflammatory bowel disease\nAnti‐TNF induced lupusS Picardo et al.Picardo Sherman https://orcid.org/0000-0001-5013-956X\n1\nsherman.picardo@health.wa.gov.au So Kenji \n1\n Venugopal Kannan \n1\n \n1 \nDepartment of Gastroenterology and Hepatology\nRoyal Perth Hospital\nPerth\nWestern Australia\nAustralia\n\n* Correspondence\n\nDr Sherman Picardo, Consultant Gastroenterologist. Department of Gastroenterology and Hepatology, Royal Perth Hospital, Wellington Street Campus, 197 Wellington Street, Perth, WA 6000, Australia. Email: sherman.picardo@health.wa.gov.au\n\n19 12 2019 \n6 2020 \n4 3 10.1002/jgh3.v4.3507 510\n10 10 2019 19 11 2019 01 12 2019 © 2019 The Authors. JGH Open: An open access journal of gastroenterology and hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Background and Aims\nAnti‐Tumor Necrosis Factor (TNF)‐induced lupus (ATIL) is a distinct clinical entity, increasingly recognized in patients with inflammatory bowel disease treated with anti‐TNF therapy. Our aims were to evaluate the incidence and clinical and serological markers of ATIL in this population.\n\nMethods\nThis observational cohort study reviewed 454 patient treatment courses with anti‐TNF therapy (300 infliximab and 154 adalimumab). A diagnosis of ATIL was based on the most widely accepted diagnostic criteria: (i) a temporal relationship between symptoms and anti‐TNF therapy and resolution of symptoms following cessation of the offending medication; (ii) at least one serologic American College of Rheumatology (ACR) criterion of Systemic Lupus Erythematosus (SLE); and (iii) at least one nonserological criterion such as arthritis, serositis, or rash. Clinical, demographic, and serological predictors were evaluated.\n\nResults\nThe incidence rate of ATIL was 5.7% for infliximab and 0.6% for adalimumab, which are much higher than previously reported postmarketing estimates. The median duration to diagnosis following commencement of anti‐TNF therapy was 15 months (3–62 months). ATIL occurs more commonly patients that commence therapy at an older age (46.47 years ± 13.79 years vs. 38.85 years ± 14.75 years, P = 0.033).\n\nConclusions\nATIL is a significant complication of anti‐TNF therapy, affecting 1 in every 20 patients who commence infliximab. A panel of serological markers is useful to confirm the diagnosis and exclude other conditions that may mimic ATIL. Clinicians using anti‐TNF medications should counsel patients about this potential risk and monitor for clinical manifestations of lupus during routine follow up.\n\n\nThis is a retrospective study that looks at anti‐TNF‐induced lupus, a distinct clinical entity increasingly identified in patients with inflammatory bowel disease on anti‐TNF therapy. ATIL occurs more commonly than previously reported and is more common in those who commence therapy at an older age. The combination of clinical symptoms, the temporal relationship to anti‐TNF therapy, and a panel of serological markers can assist clinicians in confirming a diagnosis.\n\nadalimumabanti‐tumor necrosis factoranti‐TNF‐induced lupusinflammatory bowel diseaseinfliximablupus source-schema-version-number2.0cover-dateJune 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.8.3 mode:remove_FC converted:05.06.2020\nDeclaration of conflict of interest: There are no conflicts of interest to disclose from any of the authors with regard to this manuscript.\n\n\nAuthor Contribution: S.P. designed the study and performed statistical analyses. S.P., K.S., and K.V. all participated in the writing and review of the final manuscript.\n\n\nConference Presentations: Oral Presentation—Australian Gastroenterology Week (AGW), Brisbane, September 2018. Published in Abstract form in JGH. Poster of Excellence and Poster Champion Presentation—United European Gastroenterology Week, Vienna, October 2018.\n==== Body\nIntroduction\nThe introduction of anti‐tumor necrosis factor alpha (anti‐TNF) medications, including infliximab and adalimumab, has revolutionized the management of patients with inflammatory bowel disease (IBD). These agents have demonstrated efficacy, are well tolerated, and have a relatively good safety profile.1 Pivotal clinical trials and postmarketing surveillance studies have identified some drug‐related adverse events, including infusion reactions, infections, and malignancy, as well as a number of immune‐mediated phenomena.2, 3, 4\n\n\nAnti‐TNF medications have been demonstrated to induce autoimmunity in the form of antinuclear antibodies (ANAs) and anti‐double‐stranded deoxyribonucleic acid (anti‐dsDNA) antibodies. 5, 6 Pooled analysis of the initial open‐labeled clinical trials for infliximab in rheumatoid arthritis demonstrated an increase in ANA positivity from 29% pretreatment to 53% posttreatment.6 In this analysis, 14% of patients also developed anti‐dsDNA antibodies. Some patients may also develop clinical symptoms that mimic idiopathic lupus, and this has been recognized as a distinct clinical entity called anti‐TNF‐induced lupus (ATIL).7 The most widely accepted diagnostic criteria for ATIL are (i) a temporal relationship between symptoms and anti‐TNF therapy and resolution of symptoms following cessation of the offending medication; (ii) at least one serologic American College of Rheumatology (ACR) criterion of SLE, being either a positive ANA or anti‐dsDNA; and (iii) at least one nonserological criterion such as arthritis, serositis, or rash.\n\nThe estimated reported incidence of ATIL based on postmarketing studies is 0.19–0.22% for infliximab and 0.10% for adalimumab.8 The actual incidence, however, is difficult to determine due to lack of prospective studies, lack of recognition of the condition, and the overlap in clinical symptoms with the extraintestinal manifestations of IBD. Given the widespread use of anti‐TNF agents in the management of IBD, our aims were to evaluate the incidence and clinical and serological markers of ATIL in this population.\n\nMaterials and methods\n\nStudy design and participants\n\nThis study was a retrospective observational cohort study based on a prospectively collected registry of all IBD patients who were commenced on anti‐TNF therapy at Royal Perth Hospital, Western Australia between January 1st 2008 and December 31st 2017. The study population included all patients with a confirmed diagnosis of IBD, who were commenced on a course of anti‐TNF therapy, (infliximab or adalimumab), and had completed induction and at least one maintenance dose of therapy. Patient follow up occurred till a census date of 31st March 2018.\n\nPatients were retrospectively defined as having ATIL based on the aforementioned diagnostic criteria: (i) a temporal relationship between symptoms and anti‐TNF therapy and resolution of symptoms following cessation of the offending medication (within 3 months of discontinuation); (ii) at least one serologic ACR criterion of SLE, being either a positive ANA or anti‐dsDNA; and (iii) at least one nonserological criterion such as arthritis, serositis, or rash.7 The incidence of ATIL and time to diagnosis were calculated for both infliximab and adalimumab. Demographic and clinical parameters, including age, gender, type of IBD, and use of concurrent immunomodulatory therapy, were obtained from electronic records.\n\nAge, gender, and IBD type were evaluated as predictors in the development of ATIL. The results of several serological markers, if performed, including ANA, anti‐ds‐DNA, antihistone antibodies, anti‐Smith antibodies (anti‐Sm), anticyclic citrullinated peptide (anti‐CCP), and rheumatoid factor (RF), were also collected.\n\n\nStatistical analysis\n\nStatistical analyses were performed using Stata (StataCorp 2015. Release 14) For the clinical and demographic predictors, continuous variables were analyzed using a two‐sided t‐test and categorical variables using a Fishers exact test or Pearson's χ\n2 test. The threshold for statistical significance was defined as a P value < 0.05.\n\nResults\nA total of 454 patient treatment courses with anti‐TNF therapy were included, comprising 300 with infliximab and 154 with adalimumab. Seventeen (5.7%) patients who received infliximab developed ATIL, and one patient (0.6%) on adalimumab developed ATIL. The clinical, demographic, and serological characteristics of each case of ATIL are summarized in Table 1. Twelve patients received glucocorticoids at the time of symptom manifestation. Patients who developed ATIL were more likely to be older at the time of commencement of anti‐TNF medication (46.47 years ± 13.79 years vs 38.85 years ± 14.75 years, P = 0.033) (Table 2). There was a trend that female gender was a risk factor for ATIL (72.2% vs 47.0%, P = 0.052). The median duration of therapy till development of ATIL was 15 months (range of 3–62 months).\n\nTable 1 Sociodemographic, clinical, and serological characteristics of individual patients diagnosed with anti‐TNF‐induced lupus\n\nAge\tGender\tIBD\tAnti‐TNF\tDuration of therapy (months)\tImmunomodulator\tClinical Symptoms\tANA (baseline) (<7 IU/mL)\tANA (at diagnosis) (<7 IU/mL)\tdsDNA (<7 IU/mL)\tAnti‐histone\tAnti‐Smith\tAnti‐CCP\tRF (<14k U/L)\t\n48\tM\tCD\tInfliximab\t21\tNil\tPolyarthritis\t0\t30\t38\tPos\tNeg\tNA\tNA\t\n69\tF\tCD\tInfliximab\t6\tNil\tPolyarthritis\t5\t25\t35\tNeg\tNeg\t1\t<10\t\n34\tF\tCD\tInfliximab\t9\tMMF\tRash\tNA\t30\tNA\tNeg\tNeg\tNA\tNA\t\n57\tF\tCD\tInfliximab\t10\tNil\tPolyarthritis,\t6\t15\t10\tNeg\tNeg\tNA\t<10\t\n53\tF\tUC\tInfliximab\t3\tNil\tPolyarthritis, Rash\t2\t10\t0\tPos\tNeg\t1\t11\t\n51\tF\tCD\tInfliximab\t30\tAZA\tPolyarthritis\tNA\t30\tNA\tNeg\tNeg\tNA\tNA\t\n37\tF\tCD\tInfliximab\t9\tAZA\tPolyarthritis\t2\t30\tNA\tNA\tNA\tNA\tNA\t\n53\tF\tCD\tInfliximab\t10\tMTX\tPolyarthritis\t0\t30\t22\tNeg\tNeg\tNA\tNA\t\n39\tM\tCD\tInfliximab\t44\tNil\tRash\t0\t30\t35\tNeg\tNeg\t1\t<10\t\n62\tF\tCD\tInfliximab\t30\t6MP\tPolyarthritis,\t7\t30\t6\tNeg\tNeg\tNA\tNA\t\n36\tM\tUC\tInfliximab\t18\tNil\tRash\tNA\t25\t6\tNeg\tNeg\tNA\tNA\t\n49\tM\tCD\tInfliximab\t7\tNil\tPolyarthritis\t2\t30\t5\tNA\tNA\tNA\tNA\t\n45\tF\tUC\tInfliximab\t33\tNil\tRash\t7\t30\t7\tNeg\tNeg\tNA\tNA\t\n21\tM\tCD\tInfliximab\t12\tNil\tPolyarthritis\t7\t30\t11\tNeg\tNeg\tNA\t<10\t\n42\tF\tCD\tInfliximab\t21\tNil\tPolyarthritis\t5\t30\t39\tNeg\tNeg\t5\t<10\t\n77\tF\tCD\tInfliximab\t3\tNil\tPolyarthritis\tNA\t7\t53\tNA\tNA\tNA\t<10\t\n51\tF\tCD\tInfliximab\t28\tNil\tPolyarthritis\t2\t30\t6\tNeg\tNeg\t2\t<10\t\n41\tF\tCD\tAdalimumab\t62\tNil\tPolyarthritis Polyarthritis\t0\t30\t52\tNeg\tNeg\tNA\tNA\t\nAge–age at diagnosis of ATIL, Immunomodulator—concurrent at time of diagnosis.\n\nAZA, Azathioprine; MMF, mycophenolate mofetil; MTX, methotrexate; 6MP, 6 mercaptopurine.\n\nTable 2 Differences in characteristics of between ATIL and non‐ATIL\n\n\tNon‐ATIL (n = 436)\tATIL (n = 18)\t\nP value\t\nMale/female\t231/205\t5/13\t0.052\t\nAge\t\nMean ± SD (years)\t38.85 ± 14.75\t46.47 ± 13.70\t0.033\t\nIBD type\t\nCD\t312 (71.6%)\t15 (83.3%)\t0.209\t\nUC\t119 (27.3%)\t3 (16.7%)\t0.241\t\nIBD‐U\t5 (1.1%)\t0 (0%)\t0.816\t\nAll patients with a diagnosis of ATIL demonstrated an elevated ANA with results ranging from 7 to 30 IU/mL. In those patients who had a baseline ANA performed prior to commencing anti‐TNF therapy, the ANA level increased compared with their baseline level. Additional serological markers that were positive in patients diagnosed with ATIL included anti‐ds‐DNA in 10 of 15 (67%) and antihistone antibodies in 2 of 15 (13%.) Serological testing to exclude other inflammatory conditions, including idiopathic SLE and seropositive arthropathies, were performed in a subset of the patients (Table 3).\n\nTable 3 Serological profile of patients diagnosed with ATIL\n\nAutoantibody\tNumber (%)\t\nANA\t18/18 (100%)\t\ndsDNA\t10/15 (66.7%)\t\nAnti‐Histone\t2/13 (15.4%)\t\nAnti‐Smith\t0/15 (0%)\t\nAnti RF\t0/8 (0%)\t\nAnti‐CCP\t0/5 (0%)\t\nFive patients were on concurrent immunomodulator therapy at time of ATIL diagnosis. Ten patients on infliximab who developed ATIL were subsequently switched to adalimumab, and none of these developed ATIL on adalimumab, with a median follow‐up period of 29.3 months.\n\nDiscussion\nATIL is a distinct clinical entity increasingly recognized and described in the rheumatologic literature. Data remain limited in the IBD population due to lack of recognition of the condition, as well as difficulty making a diagnosis due to significant overlap in symptoms with extraintestinal manifestations of IBD and other autoimmune diseases. Our study demonstrates an incidence rate of 5.7% for infliximab and 0.6% for adalimumab, which are much higher than postmarketing studies.8 This corresponds to a retrospective study in an IBD population, which identified 20 of 289 patients (6.9%) on anti‐TNF therapy who developed a lupus‐like reaction.9\n\n\nThis is a significant finding, given the widespread and increasing utilization of anti‐TNF therapy in IBD patients, as our results suggest that 1 in 20 patients who commence infliximab will develop ATIL. Infliximab is considered more immunogenic compared with adalimumab based on its chimeric structure and is also thought to reach higher tissue concentrations.10 Clinicians should counsel patients about the potential risk prior to commencing therapy and should monitor for clinical manifestations of lupus, which include rash, photosensitivity, and arthritis, as well as rare systemic manifestations, including pericarditis and neurological and hematological disorders, during routine follow up. 11 The extraintestinal manifestations of IBD include some of these symptoms, which make the diagnosis of ATIL more challenging. Peripheral arthritis can occur in both ulcerative colitis and Crohn's disease. It typically manifests as a nonerosive seronegative arthritis and occurs in between 5 and 10% of patients with ulcerative colitis and 10–20% of patients with Crohn's disease.12 Various cutaneous manifestations have also been associated with IBD and can occur in up to 15% of patients.12 There are various other autoimmune conditions, including the seropositive arthropathies and idiopathic SLE, which may occur in patients with IBD and also share clinical manifestations with ATIL. It is very difficult to differentiate ATIL and these various conditions based on clinical symptoms alone, and further information, including the temporal relationship with anti‐TNF therapy and serological markers is required.\n\nAnti‐TNF therapies have been demonstrated to induce autoantibodies; however, no specific tests have been validated for ATIL. The most widely recognized diagnostic criteria require a positive ANA or ds‐DNA.6 All the patients with confirmed ATIL in our cohort had a positive ANA at the time of diagnosis, with an increase in the titer from baseline level. Anti‐ds‐DNA levels were elevated in 66.7% of patients tested. Anti‐Sm antibodies are part of the serological diagnostic criteria for SLE. The presence of these antibodies is almost exclusive to idiopathic SLE, and it is rarely found in drug‐induced SLE. 13 Antihistone antibodies have been found to occur in 95% of cases of drug‐induced SLE; however, this antibody is not pathognomonic as they are also found in 75% of patients with idiopathic SLE.14 The presence of antihistone antibodies in studies of patients with ATIL, however, report much lower rates, ranging from 17% to 57%.13 Only 15.4% of patients diagnosed with ATIL demonstrated positive antihistone antibodies in our cohort. A full panel of autoantibodies, including ANA, anti‐ds‐DNA, anti‐CCP, RF, antihistone antibodies, and anti‐Sm antibodies, should be performed in all patients with a clinical suspicion for ATIL.\n\nWe were unable to establish whether concurrent immunomodulatory therapy was a factor in the development or prevention of ATIL as patients in the cohort who did not develop ATIL were on both varying doses and durations of immunomodulator therapy. It has been postulated that concurrent immunomodulatory therapy may decrease the immunogenicity of a biologic therapy.15 Use of an immunomodulator, in the form of a thiopurine or methotrexate, when used together with a biologic agent has been associated with decreased formation of antidrug antibodies16 Further studies are required to assess whether concurrent immunomodulatory therapy reduces the development of ATIL. Based on small numbers, our study does suggest that it is safe to switch to adalimumab if a patient develops ATIL on infliximab.\n\nOur study had several limitations. It's retrospective nature makes it prone to data entry error. As patients were retrospectively diagnosed with ATIL, the true incidence is likely underestimated as serology, which is a component of the diagnostic criteria, would only be performed if a diagnosis was suspected at the time, at the discretion of the treating physician.\n\nATIL is a complication of anti‐TNF therapy that is more common than previously reported. Diagnosis in an IBD population is often difficult due to lack of recognition of the condition and shared clinical symptoms with both the extraintestinal manifestations of IBDs and other autoimmune conditions. The combination of clinical symptoms, the temporal relationship to anti‐TNF therapy, and a panel of serological markers can assist clinicians in confirming a diagnosis.\n\nAcknowledgment\nS.P. has received speaker fees from Pfizer and Takeda.\n==== Refs\nReferences\n1 \n\nHoentijen \nF \n, \nVan Bodegraven \nA \n. Safety of anti‐tumor necrosis factor therapy in inflammatory bowel disease\n. World J. Gastroenterol. \n2009 ; 15 : 2067 –73\n.19418577 \n2 \n\nHanauer \nSB \n, \nFeagan \nBG \n, \nLichtenstein \nGR \n\net al\nMaintenance Infliximab for Crohn's disease: the ACCENT I randomised trial\n. Lancet . 2002 ; 359 : 1541 –9\n.12047962 \n3 \n\nColombel \nJF \n, \nSandborn \nWJ \n, \nRutgeerts \nP \n\net al\nAdalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial\n. Gastroenterology . 2007 ; 132 : 52 –65\n.17241859 \n4 \n\nWiens \nA \n, \nVenson \nR \n, \nCorrer \nCJ \n\net al\nMeta‐analysis of the efficacy and safety of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis\n. Pharmacotherapy . 2010 ; 30 : 339 –53\n.20334454 \n5 \n\nRamos‐Casals \nM \n, \nBrito‐Zerón \nP \n, \nMuñoz \nS \n\net al\nAutoimmune disease induced by TNF‐ targeted therapies: analysis of 233 cases\n. Medicine (Baltimore) . 2007 ; 86 : 242 –51\n.17632266 \n6 \n\nCharles \nPJ \n, \nSmeenk \nRJ \n, \nDe Jong \nJ \n\net al\nAssessment of antibodies to double‐stranded DNA induced in rheumatoid arthritis patients following treatment with infliximab, a monoclonal antibody to tumor necrosis factor alpha: findings in open‐label and randomized placebo‐controlled trials\n. Arthritis Rheum. \n2000 ; 43 : 2383 –90\n.11083258 \n7 \n\nWilliams \nEL \n, \nGadola \nS \n, \nEdwards \nCJ \n. Anti‐TNF induced lupus\n. Rheumatology . 2009 ; 48 : 716 –20\n.19416947 \n8 \n\nAlmoallim \nH \n, \nAl‐Ghamdi \nY \n, \nAlmaghrabi \nH \n\net al\nAnti tumor necrosis factor—a induced systemic lupus erythematosus\n. Open Rheumatol. J. \n2012 ; 6 : 315 –19\n.23198006 \n9 \n\nYanai \nH \n, \nShuster \nD \n, \nClalbrese \nE \n\net al\nThe incidence and predictors of lupus like reaction in patients with IBD treated with anti‐TNF therapies\n. Inflamm. Bowel Dis. \n2013 ; 19 : 2778 –86\n.24185311 \n10 \n\nKocharla \nL \n, \nMongey \nAB \n. Is the development of drug‐related lupus a contraindication for switching from one TNF alpha inhibitor to another?\n\nLupus . 2009 ; 18 : 169 –71\n.19151120 \n11 \n\nHocehberg \nMC \n, Diagnostic and Therapeutic Criteria Committee of the American College of Rheumatology \n. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus\n. Arthritis Rheum. \n1997 ; 40 : 1725 .\n12 \n\nVavricka \nSR \n, \nSchoepfer \nA \n, \nScharl \nM \n\net al\nExtraintestinal manifestations of inflammatory bowel disease\n. Inflamm. Bowel Dis. \n2015 ; 21 : 1982 –92\n.26154136 \n13 \n\nKatz \nU \n, \nZandman‐Goddard \nG \n. Drug‐induced lupus: an update\n. Autoimmun. Rev. \n2010 ; 10 : 46 –50\n.20656071 \n14 \n\nDe Bandt \nM \n, \nSibilia \nJ \n, \nLe Loet \nX \n\net al\nSystemic lupus erythematosus induced by anti‐tumour necrosis factor alpha therapy: a French national survey\n. Arthritis Res. Ther. \n2005 ; 7 : 545 –51\n.\n15 \n\nKothari \nMM \n, \nNguyen \nDL \n, \nParekh \nNK \n. Strategies for overcoming anti‐tumor necrosis factor drug antibodies in inflammatory bowel disease: case series and review of literature\n. World J. Gastrointest. Pharmacol. Ther. \n2017 ; 8 : 155 –61\n.28828193 \n16 \n\nVermeire \nS \n, \nNoman \nM \n, \nVan Assche \nG \n\net al\nEffectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn's disease\n. Gut . 2007 ; 56 : 1226 –31\n.17229796\n\n",
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"journal": "JGH open : an open access journal of gastroenterology and hepatology",
"keywords": "adalimumab; anti‐TNF‐induced lupus; anti‐tumor necrosis factor; inflammatory bowel disease; infliximab; lupus",
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"title": "Anti-TNF-induced lupus in patients with inflammatory bowel disease.",
"title_normalized": "anti tnf induced lupus in patients with inflammatory bowel disease"
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"abstract": "Onychomycosis (OM) is a common fungal infection of the toenails and/or fingernails that is highly prevalent in the general population and also responsible for significant morbidity. OM is caused by dermatophytes, nondermatophytic molds, or yeast. Today systemic antifungal agents are considered as the gold standard for all types of OM. Here we report a case of aplastic anemia associated with oral terbinafine use and a review of the literature on hematological toxicities associated with terbinafine.",
"affiliations": "Okmeydanı Training and Research Hospital, Clinic of Hematology, İstanbul, Turkey. E-ma-il: bulentkantarcioglu@gmail.com.",
"authors": "Kantarcıoğlu|Bülent|B|;Türköz|Hüseyin Kemal|HK|;Yılmaz|Güven|G|;Pepedil Tanrıkulu|Funda|F|;Kaygusuz Atagündüz|Işık|I|;Adıgüzel|Cafer|C|;Fıratlı Tuğlular|Tülin|T|",
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"fulltext": "\n==== Front\nTurk J HaematolTurk J HaematolTJHTurkish Journal of Hematology1300-77771308-5263Galenos Publishing 2554166010.4274/tjh.2013.01191337Case ReportAplastic Anemia Associated with Oral Terbinafine: A Case Report and Review of the Literature Oral Terbinafin İlişkili Aplastik Anemi: Bir Olgu Sunumu ve Literatür Derlemesi Kantarcıoğlu Bülent 1*Türköz Hüseyin Kemal 2Yılmaz Güven 3Tanrıkulu Funda Pepedil 3Kaygusuz Atagündüz Işık 3Adıgüzel Cafer 3Fıratlı Tuğlular Tülin 31 \nOkmeydanı Training and Research Hospital, Clinic of Hematology, İstanbul, Turkey\n2 \nMarmara University Faculty of Medicine, Department of Pathology, İstanbul, Turkey\n3 \nMarmara University Faculty of Medicine, Department of Hematology, İstanbul, Turkey\n* Address for Correspondence: Okmeydanı Training and Research Hospital, Clinic of Hematology, İstanbul, Turkey Phone: +90 532 547 62 08 E-mail: bulentkantarcioglu@gmail.com12 2014 5 12 2014 31 4 411 416 7 4 2013 14 5 2013 © Turkish Journal of Hematology, Published by Galenos Publishing.\n\n2015This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Onychomycosis (OM) is a common fungal infection of the toenails and/or fingernails that is highly prevalent in the general population and also responsible for significant morbidity. OM is caused by dermatophytes, nondermatophytic molds, or yeast. Today systemic antifungal agents are considered as the gold standard for all types of OM. Here we report a case of aplastic anemia associated with oral terbinafine use and a review of the literature on hematological toxicities associated with terbinafine.\n\nOnikomikoz (OM) el ve ayak tırnaklarının sık görülen fungal enfeksiyonudur. Genel toplumda prevalansı yüksek bir hastalık olması nedeniyle önemli morbiditeye yol açmaktadır. OM dermatofitler, nondermatofitik küf mantarları veya mayalar ile ortaya çıkan hastalıklardır. Günümüzde onikomikozun tedavisinde sistemik antifungal ajanlar tüm OM tiplerinde altın standart tedavi olarak kabul edilmektedir. Biz burada, oral terbinafin kullanımı sırasında gelişen bir aplastik anemi olgumuzu ve literatürde terbinafine ile ilişkilendirilmiş olan hematolojik toksisitelerin derlemesini sunuyoruz. \n\nOnychomycosisTerbinafineAplastic anemiaHematological toxicityPancytopeniaAdverse events\n==== Body\nINTRODUCTION\nOnychomycosis is a very frequent fungal nail infection. The prevalence can be as high as 28%-40%, especially in elderly populations. Terbinafine is an antifungal agent with both fungicidal and fungistatic properties, which is highly effective and is the most frequently used agent in onychomycosis. Oral terbinafine is generally well tolerated with minimal reports of serious drug reactions. These rare adverse events are mostly reported as case presentations, and it is important to be familiar with them in order to be able to evaluate the risk and inform patients accordingly [1,2,3]. Here we report a case of aplastic anemia (AA) associated with oral terbinafine use and a review of the literature on hematological toxicities associated with terbinafine. Written informed consent was obtained from the patient and her husband for publication of this manuscript and accompanying images.\n\nCASE PRESENTATION\nA 41-year-old female presented with malaise, severe fatigue, nausea, and vaginal bleeding in April 2011. In her past history she was healthy, except that she reported taking terbinafine pills for 8 weeks for the treatment of longstanding recurrent toenail onychomycosis. She did not report any immune reactions or allergies to any drugs or substances. Her previous gynecological examination was normal, with a normal β-human chorionic gonadotropin level. Her complete blood count (CBC) revealed pancytopenia with white blood cell count of 3.2x109/L, absolute neutrophil count of 0.8x109/L, hemoglobin of 7.4 g/dL, and platelet count of 34x109/L. Her physical examination was unremarkable with no evidence of lymphadenopathy or organomegaly, except for a few petechiae and ecchymoses on bilateral legs. Peripheral blood smear was consistent with pancytopenia. Reticulocyte count was 0.7. Liver enzymes were elevated [AST: 61 U/L (N: 10-37 U/L), ALT: 117 U/L (N: 10-40 U/L), ALP: 434 U/L (N: 0-270 U/L), GGT: 471 U/L (N: 7-49 U/L)]. Renal function tests and lactate dehydrogenase were normal. Bone marrow aspiration and biopsy revealed severe reduction of all cell lineages without evidence of neoplastic infiltration, dysplasia, or fibrosis. The counted cellularity was 5% in bone marrow. Bone marrow karyotype analysis was normal. A gastroenterology consultation performed for the liver enzyme abnormalities did not provide an etiologic factor, pointing toward drug-induced hepatitis. Further work-ups, including levels of vitamin B12 and folate; neck, chest, and abdominopelvic computerized tomography; serology and polymerase chain reaction (PCR) tests for viral hepatitis, human immunodeficiency, Epstein-Barr virus, parvovirus B19, and cytomegalovirus; FLAER test for paroxysmal nocturnal hemoglobinuria; antinuclear antibody test; HLA-DRB1*15; and quantiferon test for tuberculosis, were all negative. The patient was diagnosed with AA, which was not severe at that time. Terbinafine treatment was stopped. Due to the use of a drug with probable hematologic toxicity, follow-up with supportive care was planned for the patient. During 3-4 weeks of follow-up time, blood values worsened with the need for erythrocyte and thrombocyte transfusions, in accordance with very severe AA (SAA). She did not have a matched related donor for transplantation. After confirming the diagnosis with a second bone marrow biopsy, she received rabbit antithymocyte globulin (ATG) plus cyclosporine-A (CYC). The clinical outcome after ATG + CYC was poor due to transient worsening of hematopoiesis and infectious complications. She spent 3 months in the hospital with perianal abscess, invasive aspergillosis, zoster virus reactivation, and several catheter infections. She required physical and psychological rehabilitation. Fortunately, the blood values began to recover at the end of the fourth month and full hematologic recovery was achieved at the end of the sixth month. The patient is still in complete remission after 18 months of ATG + CYC treatment (Figures 1 and 2).\n\nDISCUSSION AND REVIEW OF THE LITERATURE\nOnychomycosis refers to all fungal infections of the nails. It is difficult to cure, has high recurrence rates, and can significantly affect a patient’s quality of life. Topical therapies are generally ineffective, and today treatment with systemic antifungal agents is accepted as the gold standard method for onychomycosis. In clinical trials, continuous terbinafine has repeatedly demonstrated higher efficacy when compared to other antifungal treatments. The recommended dosage for the treatment of onychomycosis is 250 mg/day orally for 12 weeks for toenails and 6 weeks for fingernails [1,2,3].\n\nOral terbinafine is generally well tolerated with minimal reports of serious drug reactions. Two large-scale postmarketing surveillance studies showed that the incidence of serious side effects was <1% [4,5]. In contrast, 2 studies of registry data from Austria and Denmark drew attention to blood dyscrasias associated with terbinafine [6,7]. Notable adverse events have been reported, including hepatitis requiring liver transplantation [8], drug-induced lupus reactions, severe skin reactions such as Stevens-Johnson syndrome, and, much less often, neutropenia/agranulocytosis and thrombocytopenia [9,10,11,12,13,14,15,16,17]. To our knowledge, ours is the first reported case of AA associated with terbinafine use.\n\nAA is usually diagnosed within the setting of pancytopenia and hypocellular bone marrow when other diseases are excluded. SAA is almost always fatal if untreated. Once SAA is established, therapy should not be delayed in the hope of spontaneous recovery [18,19].\n\nMany drugs have been associated with AA. The vast majority of patients exposed to these drugs do not develop AA and the reason for idiosyncratic reactions is unknown. AA can develop as a direct response to exposure, but it can also develop indirectly through immune-mediated mechanisms. P-glycoprotein (P-gp), the MDR-1 gene product, and the multidrug resistance-associated protein are energy-dependent transmembrane efflux pumps for a variety of lipophilic drugs. Underexpression of P-gp in normal cells might allow cytoplasmic accumulation of drugs and enhance their toxic effects. Two studies found that P-gp activity was decreased in patients with AA; levels were lowest in a subgroup with drug-induced AA [20,21]. In our case, the prolonged use of the highly lipophilic agent terbinafine might have caused direct toxicity, leading to AA.\n\nAdditionally, in a recently published study, the release of IL-8 and TNFα was significantly increased by treatment with terbinafine, which can explain how terbinafine may also cause immune-mediated injury [22]. Lupus-like reactions reported with terbinafine use may be an additional evidence of immune-mediated injury as an underlying mechanism. However, in most cases, the trigger of the mechanism of AA remains unclear. Historically, drug-induced AA has not been easily distinguished from idiopathic forms of the disease since causality is difficult to establish [23].\n\nA review of hematologic toxicities associated with the use of terbinafine showed that the duration of terbinafine exposure leading to hematological toxicity is almost 1 month; the degree of cytopenia can be severe and patients mostly presented with infectious complications requiring hospitalization. While the clinical outcome was reversible in most cases, our patient required additional treatment with a high burden of risk and complications (Table 1).\n\nIn conclusion, keeping in mind the slow and persistent course of onychomycosis requiring long-term treatment, the high rate of success achieved with terbinafine, and the wide range of the population receiving terbinafine treatment, we advise detailed information of patients in regard to adverse events and we recommend monitorization of CBC at baseline and every month during terbinafine treatment. To our knowledge, this is the first case report of irreversible SAA following treatment with terbinafine that required immunosuppressive treatment with ATG + CYC. This case highlights the need for routine blood count monitoring during treatment with terbinafine. In these patients, clinicians should consider the rare incidence of SAA when there is agranulocytosis or pancytopenia.\n\nConflict of Interest Statement\n\nThe authors of this paper have no conflicts of interest, including specific financial interests, relationships, and/or affiliations relevant to the subject matter or materials included.\n\nTable 1 Reported cases of terbinafine-associated hematological toxicity in the literature.\nFigure 1 Bone marrow trephine biopsy: low cellularity in the bone marrow consistent with aplastic anemia (H&E, 20x).\nFigure 2 Bone marrow trephine biopsy: a few hematopoietic cells intermixed with lymphocytes and plasmocytes in interstitial areas (H&E, 100x).\n==== Refs\nReferences\n1 Shemer A Update: medical treatment of onychomycosis Dermatol Ther 2012 25 582 593 23210757 \n2 Grover C Khurana A An update on treatment of onychomycosis Mycoses 2012 55 541 551 22540995 \n3 Van Duyn GL Elewski BE Recent updates in oral terbinafine: its use in onychomycosis and tinea capitis in the US Mycoses 2011 54 679 685 \n4 Hall M Monka C Krupp P O’Sullivan D Safety of oral terbinafine: results of a postmarketing surveillance study in 25,884 patients Arch Dermatol 1997 133 1213 1219 9382559 \n5 O’Sullivan DP Needham CA Bangs A Atkin K Kendall FD Postmarketing surveillance of oral terbinafine in the UK: report of a large cohort study Br J Clin Pharmacol 1996 42 559 565 8951186 \n6 ADRAC Terbinafine and blood dyscrasias Aust Adverse Drug React Bull 2004 23 19 19 \n7 Bangsgaard N Saunte DM Folkenberg M Zachariae C Serious adverse events reporting on systemic terbinafine: a Danish register-based study Acta Derm Venereol 2011 91 358 359 21290086 \n8 Perveze Z Johnson MW Rubin RA Sellers M Zayas C Jones JL Cross R Thomas K Butler B Shrestha R Terbinafine-induced hepatic failure requiring liver transplantation Liver Transpl 2007 13 162 164 17192859 \n9 Pillans PI Boyd IW Toenails and agranulocytosis Intern Med J 2007 37 572 575 17640191 \n10 Gupta AK Soori GS Del Rosso JQ Bartos PB Shear NH Severe neutropenia associated with oral terbinafine therapy J Am Acad Dermatol 1998 38 765 767 9591825 \n11 Ornstein DL Ely P Reversible agranulocytosis associated with oral terbinafine for onychomycosis J Am Acad Dermatol 1998 39 1023 1024 9843023 \n12 Shapiro M Li LJ Miller J Terbinafine-induced neutropenia Br J Dermatol 1999 140 1196 1197 10354111 \n13 Conjeevaram G Vongthavaravat V Sumner R Koff RS Terbinafine-induced hepatitis and pancytopenia Dig Dis Sci 2001 46 1714 1716 11508672 \n14 Aguilar C Mueller KK Reversible agranulocytosis associated with oral terbinafine in a pediatric patient J Am Acad Dermatol 2001 45 632 634 11568763 \n15 Kovacs MJ Alshammari S Guenther L Bourcier M Neutropenia and pancytopenia associated with oral terbinafine J Am Acad Dermatol 1994 31 806 806 7929931 \n16 Tsai HH Lee WR Hu CH Isolated thrombocytopenia associated with oral terbinafine Br J Dermatol 2002 147 627 628 12207625 \n17 Grunwald MH Thrombocytopenia associated with oral terbinafine Int J Dermatol 1998 37 634 634 9732018 \n18 Scheinberg P Aplastic anemia: therapeutic updates in immunosuppression and transplantation Hematology 2012 2012 292 300 23233595 \n19 Guinan EC Diagnosis and management of aplastic anemia Hematology 2011 2011 76 81 22160015 \n20 Calado RT Garcia AB Falcão RP Decreased activity of the multidrug resistance P-glycoprotein in acquired aplastic anaemia: possible pathophysiologic implications Br J Haematol 1998 102 1157 1161 9753037 \n21 Calado RT Garcia AB Gallo DA Falcão RP Reduced function of the multidrug resistance P-glycoprotein in CD34+ cells of patients with aplastic anaemia Br J Haematol 2002 118 320 326 12100168 \n22 Mizuno K Fukami T Toyoda Y Nakajima M Yokoi T Terbinafine stimulates the pro-inflammatory responses in human monocytic THP-1 cells through an ERK signaling pathway Life Sci 2010 87 537 544 20816994 \n23 Mintzer DM Billet SN Chmielewski L Drug-induced hematologic syndromes Adv Hematol 2009 2009 495863 495863 19960059\n\n",
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"issue": "31(4)",
"journal": "Turkish journal of haematology : official journal of Turkish Society of Haematology",
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"medline_ta": "Turk J Haematol",
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"title": "Aplastic anemia associated with oral terbinafine: a case report and review of the literature.",
"title_normalized": "aplastic anemia associated with oral terbinafine a case report and review of the literature"
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"abstract": "Benign intracranial hypertension (BIH) is reported in three children from Australia and one from New Zealand, who were being treated with recombinant human growth hormone (rhGH). Three males and one female, aged between 10.5 and 14.2 y, developed intracranial hypertension within 2 weeks to 3 months of starting treatment. A national database, OZGROW, has been prospectively collecting data on all 3332 children treated with rhGH in Australia and New Zealand from January 1986 to 1996. The incidence of BIH in children treated with growth hormone (GH) is small, 1.2 per 1000 cases overall, but appears to be greater with biochemical GHD (<10 IU ml(-1)), i.e. 6.5/1000 (3 in 465 cases), relative risk 18.4, 95% confidence interval 1.9-176.1, than in all other children on the database. The incidence in patients with Turner's syndrome was 2.3/1000 (1 in 428 cases). No cases in patients with partial GHD (10-20 IU ml(-1)) or chronic renal failure were identified. Possible causative mechanisms are discussed. The authors' practice is now to start GH replacement at less than the usual recommended dose of 14 IU m(-2) week(-1) in those children considered to be at high risk of developing BIH. Ophthalmological evaluation is recommended for children before and during the first few months following commencement of rhGH therapy and is mandatory in the event of peripheral or facial oedema, persistent headaches, vomiting or visual symptoms. The absence of papilloedema does not exclude the diagnosis.",
"affiliations": "Department of Paediatric Endocrinology, John Hunter Children's Hospital, Newcastle, NSW, Australia.",
"authors": "Crock|P A|PA|;McKenzie|J D|JD|;Nicoll|A M|AM|;Howard|N J|NJ|;Cutfield|W|W|;Shield|L K|LK|;Byrne|G|G|",
"chemical_list": "D019382:Human Growth Hormone",
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"medline_ta": "Acta Paediatr",
"mesh_terms": "D000293:Adolescent; D016907:Adverse Drug Reaction Reporting Systems; D001315:Australia; D002648:Child; D005260:Female; D019382:Human Growth Hormone; D006801:Humans; D019586:Intracranial Hypertension; D008297:Male; D009520:New Zealand",
"nlm_unique_id": "9205968",
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"title": "Benign intracranial hypertension and recombinant growth hormone therapy in Australia and New Zealand.",
"title_normalized": "benign intracranial hypertension and recombinant growth hormone therapy in australia and new zealand"
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"abstract": "We report the case of 10-year-old girl who developed retinal neovascularization and vitreous hemorrhage 10 years after successful treatment of type 1 retinopathy of prematurity infant with intravitreal bevacizumab without laser ablation therapy.",
"affiliations": "Texas A&M College of Medicine, College Station, Texas.;Ruiz Department of Ophthalmology and Visual Science, McGovern Medical School at The University of Texas Health Science Center, Houston, Texas, and Robert Cizik Eye Clinic, Houston, Texas.;Retina and Vitreous of Texas, Houston, Texas.;Austin Retina Associates, University of Texas Dell School of Medicine, Austin, Texas, and University of Texas San Antonio, San Antonio, Texas.;Retina and Vitreous of Texas, Houston, Texas. Electronic address: emanmdphd@gmail.com.",
"authors": "Taylor|Kirby|K|;Ghergherehchi|Layla|L|;Rao|Prethy|P|;Harper|C Armitage|CA|;Chang|Emmanuel|E|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab",
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"mesh_terms": "D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab; D002648:Child; D005260:Female; D005865:Gestational Age; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D058449:Intravitreal Injections; D017075:Laser Coagulation; D012178:Retinopathy of Prematurity; D042461:Vascular Endothelial Growth Factor A",
"nlm_unique_id": "9710011",
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"pubdate": "2021-06",
"publication_types": "D002363:Case Reports",
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"title": "Very late-onset reactivation of retinopathy of prematurity post anti-VEGF bevacizumab treatment for type 1 ROP: a case report.",
"title_normalized": "very late onset reactivation of retinopathy of prematurity post anti vegf bevacizumab treatment for type 1 rop a case report"
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"abstract": "Objectives: Non-vitamin K oral anticoagulants (NOACs) are a relatively new group of anticoagulants. Characteristics of adverse drug reactions (ADRs) as experienced by patients in everyday use have not yet been fully clarified. The aim was to gain insight into the safety profile of NOACs from a patient's perspective. Methods: This was a prospective, observational web-based cohort event monitoring study among first-time users of NOACs. Patients were recruited between July 2012 and April 2017. They were invited to complete four web-based questionnaires 2 weeks, 5 weeks, 3 months and 6 months after starting treatment. Information was collected about patient characteristics, drug use, and characteristics of ADRs. Results: 1748 NOAC users were included. 661 (38%) experienced at least one ADR. The reported ADRs were comparable with the information described in the Summary of Product Characteristics and generally occurred within 1 week after the start. In 59% of ADRs the patients recovered. These ADRs had no impact on the use and dosage of the NOAC in 68%. In total, 9% of the patients discontinued the NOAC because of ADRs. Conclusion: Overall NOACs were well tolerated by the participants. Most reported ADRs occurred within 1 week after the start. Patients recovered from most ADRs without changes to the use of the NOAC.",
"affiliations": "a Netherlands Pharmacovigilance Centre Lareb , 's-Hertogenbosch , The Netherlands.;a Netherlands Pharmacovigilance Centre Lareb , 's-Hertogenbosch , The Netherlands.;a Netherlands Pharmacovigilance Centre Lareb , 's-Hertogenbosch , The Netherlands.;a Netherlands Pharmacovigilance Centre Lareb , 's-Hertogenbosch , The Netherlands.;a Netherlands Pharmacovigilance Centre Lareb , 's-Hertogenbosch , The Netherlands.",
"authors": "Rolfes|Leàn|L|;Ekhart|Corine|C|;Hendriks|Judith|J|;van der Horst|Petra|P|;van Puijenbroek|Eugène|E|",
"chemical_list": "D000925:Anticoagulants; D000991:Antithrombins",
"country": "England",
"delete": false,
"doi": "10.1080/14740338.2019.1645120",
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"issue": "18(9)",
"journal": "Expert opinion on drug safety",
"keywords": "Adverse drug reaction; NOAC; adverse events; cohort event monitoring; non-vitamin K oral anticoagulants; patient reported outcomes; pharmacovigilance",
"medline_ta": "Expert Opin Drug Saf",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D000925:Anticoagulants; D000991:Antithrombins; D015331:Cohort Studies; D005260:Female; D006801:Humans; D020407:Internet; D008297:Male; D008875:Middle Aged; D060735:Pharmacovigilance; D011446:Prospective Studies; D011795:Surveys and Questionnaires; D013997:Time Factors",
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"pmid": "31311346",
"pubdate": "2019-09",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Safety profile of non-vitamin K oral anticoagulants (NOACs) from a patient perspective: a web-based cohort event monitoring study.",
"title_normalized": "safety profile of non vitamin k oral anticoagulants noacs from a patient perspective a web based cohort event monitoring study"
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"activesubstancename": "DABIGATRAN"
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"abstract": "OBJECTIVE\nTo describe a case of recanalization of a basilar artery occlusion with intravenous (IV) tenecteplase.\n\n\nMETHODS\nA 74-year-old man with a history of cardiomyopathy presented to an outside hospital with acute vertigo, dysarthria, gaze deviation, and ataxia. Computerized tomography arteriography demonstrated occlusion of the proximal basilar artery. IV tissue plasminogen activator was ordered; however, the patient received a cardiac dose of IV tenecteplase. The patient was transferred to our facility, whereby symptoms resolved, and repeat computerized tomography arteriography displayed recanalization of the basilar artery.\n\n\nCONCLUSIONS\nTenecteplase has enhanced biochemical and pharmacokinetic properties that may be ideal for treatment of basilar artery occlusion and should be further investigated in a randomized clinical trial.",
"affiliations": "Department of Neurology, Georgia Regents University, Augusta, GA. Electronic address: jswitzer@gru.edu.",
"authors": "Switzer|Jeffrey A|JA|;Forseen|Scott E|SE|;Bruno|Askiel|A|;Hess|David C|DC|",
"chemical_list": "D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator; D000077785:Tenecteplase",
"country": "United States",
"delete": false,
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"issn_linking": "1052-3057",
"issue": "22(8)",
"journal": "Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association",
"keywords": "Basilar artery occlusion; acute stroke; tenecteplase; thrombolytic therapy",
"medline_ta": "J Stroke Cerebrovasc Dis",
"mesh_terms": "D000368:Aged; D002533:Cerebral Angiography; D005343:Fibrinolytic Agents; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008508:Medication Errors; D000077785:Tenecteplase; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D014715:Vertebrobasilar Insufficiency",
"nlm_unique_id": "9111633",
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"pmid": "23834852",
"pubdate": "2013-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Serendipitous recanalization of basilar artery occlusion.",
"title_normalized": "serendipitous recanalization of basilar artery occlusion"
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"abstract": "A 92-year-old man hospitalised for cerebral infarction developed haematemesis. The patient was taking low-dose aspirin and apixaban for his cerebral infarction and non-valvular atrial fibrillation. His enteral nutrition was administrated through nasogastric tube. Upper endoscopy revealed active bleeding from a protruded lesion in the upper oesophagus. The lesion was removed by washing with a water jet, followed by successful endoscopic haemostasis. Histopathological examination revealed degenerated squamous epithelium without specific findings; the diagnosis was exfoliative oesophagitis. In our case, mechanical mucosal injury caused by nasogastric tube placement may result in exfoliative oesophagitis. In addition, the use of low-dose aspirin with apixaban may have contributed to the bleeding. We then performed a wire-guided nasogastric tube placement under fluoroscopy. No further bleeding was observed, but the patient died of sepsis 1 month later. This case highlights the importance of a risk assessment and management of oesophageal complications associated with nasogastric tube placement.",
"affiliations": "Department of Gastroenterology and Hepatology, Sapporo Teishinkai Hospital, Sapporo, Hokkaido, Japan.;Department of Gastroenterology and Hepatology, Sapporo Teishinkai Hospital, Sapporo, Hokkaido, Japan.;Department of Pathology, Sapporo Teishinkai Hospital, Sapporo, Hokkaido, Japan.;Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan hiropynakase@gmail.com.",
"authors": "Sudo|Gota|G|;Goto|Akira|A|;Fujisawa|Takashi|T|;Nakase|Hiroshi|H|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-237485",
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"issue": "13(11)",
"journal": "BMJ case reports",
"keywords": "GI bleeding; endoscopy; oesophagus",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000369:Aged, 80 and over; D004750:Enteral Nutrition; D004941:Esophagitis; D004945:Esophagoscopy; D004947:Esophagus; D006471:Gastrointestinal Hemorrhage; D016558:Hemostasis, Endoscopic; D006801:Humans; D007441:Intubation, Gastrointestinal; D008297:Male",
"nlm_unique_id": "101526291",
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"pmid": "33229484",
"pubdate": "2020-11-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Haemorrhagic exfoliative oesophagitis associated with nasogastric tube placement.",
"title_normalized": "haemorrhagic exfoliative oesophagitis associated with nasogastric tube placement"
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"drugadmin... |
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"abstract": "Gram-negative fusiform rods were detected in a blood culture obtained from a 63-year-old man who had been hospitalized for a long duration for severe heart failure. Although the organism could not be identified using a conventional method, it was finally identified as a bacterium of the Capnocytophaga ochracea group based on the results of biochemical testing, 16S rRNA sequencing and a matrix-assisted laser desorption ionization time-of-flight mass spectrometry analysis. Although neutropenic patients with poor oral hygiene are exclusively vulnerable to Capnocytophaga bacteremia, this case was unique because such predisposing conditions were not noted. A multi-centered investigation is warranted for a better understanding of this clinically rare, but potentially pathogenic organism.",
"affiliations": "Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Japan.",
"authors": "Ito|Shimpei|S|;Hagiya|Hideharu|H|;Kimura|Keigo|K|;Nishi|Isao|I|;Yoshida|Hisao|H|;Kioka|Hidetaka|H|;Ohtani|Tomohito|T|;Yamaguchi|Osamu|O|;Tanabe|Kazuaki|K|;Tomono|Kazunori|K|;Sakata|Yasushi|Y|",
"chemical_list": "D012336:RNA, Ribosomal, 16S",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.55.6593",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0918-2918",
"issue": "55(18)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D016470:Bacteremia; D002206:Capnocytophaga; D002312:Cardiomyopathy, Hypertrophic; D016905:Gram-Negative Bacterial Infections; D006801:Humans; D008297:Male; D008875:Middle Aged; D012336:RNA, Ribosomal, 16S; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "2731-5",
"pmc": null,
"pmid": "27629977",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Capnocytophaga ochracea-related Bacterium Bacteremia in a Hypertrophic Cardiomyopathy Patient without Neutropenia.",
"title_normalized": "capnocytophaga ochracea related bacterium bacteremia in a hypertrophic cardiomyopathy patient without neutropenia"
} | [
{
"companynumb": "JP-PFIZER INC-2016466092",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AMPICILLIN SODIUM\\SULBACTAM SODIUM"
},
"druga... |
{
"abstract": "Medical adverse effects and surgical complications have been reported during treatment of patients with inflammatory bowel diseases (IBDs). There is however a shortage of studies describing these in the same cohort of patients.\n\n\n\nTo describe medical adverse effects and surgical complications in a prospectively followed population-based cohort of patients followed for at least 10 years.\n\n\n\nAll newly diagnosed patients with ulcerative colitis (UC) and Crohn's disease (CD) in the county of Uppsala between 2005 and 2009 were prospectively followed. At the end of 2019, the medical notes were scrutinised and all medical adverse effects and postoperative surgical complications were registered.\n\n\n\nA total of 330 patients with UC and 153 patients with CD in all age groups were included in the cohort. Four hundred and forty-two of these (91.5%) could be followed for 10 years or until death. One hundred and twenty-two patients (26.9%) experienced one or more adverse effects during the pharmacological treatment, and 25 of these could be classified as serious. Fifty-seven malignancies were diagnosed during the observation time. Surgery was performed in 16/330 UC and 33/153 CD patients. Frequency of early postoperative complications was 31% for UC patients and 36% for CD patients. Most complications were minor but two patients were re-operated, two needed intensive care and one patient died postoperatively.\n\n\n\nAdverse effects related to medical therapy were experienced by approximately every fourth patient, and by every third patient that was operated.",
"affiliations": "Section of Gastroenterology and Hepatology, Akademiska Hospital, Magtarmmottagningen, Uppsala, Sweden.;Department of Medical Sciences, Uppsala University, Uppsala University Hospital, Uppsala, Sweden.;Department of Surgical Sciences, Uppsala University, University Hospital, Uppsala, Sweden.",
"authors": "Rönnblom|Anders|A|0000-0003-1253-2074;Ljunggren|Östen|Ö|0000-0002-3150-6122;Karlbom|Urban|U|0000-0003-0645-1905",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/00365521.2021.1961309",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0036-5521",
"issue": "56(11)",
"journal": "Scandinavian journal of gastroenterology",
"keywords": "Inflammatory bowel diseases; adverse effects; treatment complications",
"medline_ta": "Scand J Gastroenterol",
"mesh_terms": "D015331:Cohort Studies; D003093:Colitis, Ulcerative; D003424:Crohn Disease; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D015212:Inflammatory Bowel Diseases",
"nlm_unique_id": "0060105",
"other_id": null,
"pages": "1296-1303",
"pmc": null,
"pmid": "34369245",
"pubdate": "2021-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Complications and adverse effects related to surgical and medical treatment in patients with inflammatory bowel disease in a prospectively recruited population-based cohort.",
"title_normalized": "complications and adverse effects related to surgical and medical treatment in patients with inflammatory bowel disease in a prospectively recruited population based cohort"
} | [
{
"companynumb": "SE-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-327000",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SULFASALAZINE"
},
"d... |
{
"abstract": "Cardiac AL amyloidosis (CA) is generally known as a severe disease with very poor prognosis. Here we retrospectively examined seven patients with CA in our cohort who achieved long-term survival. All six patients who underwent high-dose melphalan and autologous stem cell transplantation (ASCT) survived for >3 years, whereas four patients survived for >5 years. Patients who underwent ASCT had prompt hematological responses, and five patients showed organ responses. ASCT helps to achieve a quick and deep hematological response required for long-term survival in patients with CA. New agents have been implemented for the treatment of CA. However, the risks and benefits of each treatment modality should be considered according to patient condition, thus making the best use of ASCT in combination with new agents for the treatment of CA.",
"affiliations": "Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School.;Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School.;Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School.;Department of Internal Medicine, Anan Kyoei Hospital.;Department of Internal Medicine, Anan Kyoei Hospital.;Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School.;Department of Internal Medicine, Tokushima Prefecture Naruto Hospital.;Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School.;Department of Hematology, Tokushima Prefectural Central Hospital.;Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School.;Division of Transfusion Medicine and Cell Therapy, Tokushima University Hospital.;Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School.;Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School.;Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School.;Division of Transfusion Medicine and Cell Therapy, Tokushima University Hospital.;Department of Internal Medicine, Tokushima Municipal Hospital.;Department of Hematology, Tokushima Prefectural Central Hospital.;Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School.",
"authors": "Kagawa|Kumiko|K|;Maeda|Yusaku|Y|;Oura|Masahiro|M|;Sogabe|Kimiko|K|;Fujino|Hikaru|H|;Takahashi|Mamiko|M|;Maruhashi|Tomoko|T|;Iwasa|Masami|M|;Udaka|Kengo|K|;Harada|Takeshi|T|;Ise|Takayuki|T|;Fujii|Shiro|S|;Nakamura|Shingen|S|;Miki|Hirokazu|H|;Yagi|Shusuke|S|;Takeuchi|Kyoko|K|;Ozaki|Shuji|S|;Abe|Masahiro|M|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.58.2197",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "58(11)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": "Autologous hematopoietic stem cell transplantation; Cardiac AL amyloidosis; Long-term survival",
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000328:Adult; D000368:Aged; D000686:Amyloidosis; D005260:Female; D006331:Heart Diseases; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D017741:Survivors; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "2197-2204",
"pmc": null,
"pmid": "29212969",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Analysis of long-term survivors with cardiac AL amyloidosis.",
"title_normalized": "analysis of long term survivors with cardiac al amyloidosis"
} | [
{
"companynumb": "JP-AMGEN-JPNSP2017190982",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEGFILGRASTIM"
},
"drugadditional": "3",
... |
{
"abstract": "Cachexia, a wasting syndrome associated with advanced cancer and metastasis, is rarely documented in breast cancer patients. However, the incidence of cachexia in breast cancer is now thought to be largely underestimated. In our case report of a breast cancer patient with bone metastasis monitored during the course of her treatment, we document the development of cachexia by image analysis in relation to her metastatic burden. Elucidation of the link between metastatic burden and cachexia could unveil a highly specific screening process for metastasis, by assessing true muscle mass loss. Our patient was a 49-year-old premenopausal woman, with metastatic invasive ductal breast carcinoma in the vertebral and iliac bones on presentation, which progressed with new metastases to her hips, thigh bones, and vertebrae. In the two-year period, that is between her diagnosis and death, she lost >10% of her baseline weight. During these two years, we retrospectively identified a decrease in paraspinal muscle (PM) at the third lumbar vertebra followed by a sharp decline in weight. The increased tumor burden over time in metastatic sites was accompanied by a decrease in abdominal muscle and visceral and subcutaneous fat and was followed by the patient's demise. The increasing tumor burden in the patient was correlated with the mass of other tissues to determine the tissue that could best serve as a surrogate marker to cachexia and tumor burden. We noted a strong negative correlation between PM area and metastatic tumor area at the third lumbar vertebral level, with PM loss correlating to increasing tumor burden. The monitoring of PM wasting may serve as a marker, and therefore a prognostic factor, for both cachexia and extent of metastatic disease, especially in breast cancer, where metastasis to bone is frequent. Based on our data and review of the literature in this case study, longitudinal monitoring of cachexia in the selected muscle groups can give clinicians early indications of the extent of cachexia in metastatic breast cancer patients.",
"affiliations": "Department of Medicine, College of Physicians and Surgeons, Columbia University.;Department of Radiology, Columbia University Medical Center, New York, NY, USA.;Institute for Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA.;Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY, USA.;Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA.;Department of Radiology, Columbia University Medical Center, New York, NY, USA.;Division of Hematology and Medical Oncology, Columbia University Medical Center, New York, NY, USA.;Institute for Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA.",
"authors": "Consul|Nikita|N|;Guo|Xiaotao|X|;Coker|Courtney|C|;Lopez-Pintado|Sara|S|;Hibshoosh|Hanina|H|;Zhao|Binsheng|B|;Kalinsky|Kevin|K|;Acharyya|Swarnali|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4137/CMO.S40479",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1179-5549",
"issue": "10()",
"journal": "Clinical Medicine Insights. Oncology",
"keywords": "bone metastasis; breast cancer; cachexia; radiological quantification; vertebral metastasis; weight loss",
"medline_ta": "Clin Med Insights Oncol",
"mesh_terms": null,
"nlm_unique_id": "101525771",
"other_id": null,
"pages": "83-94",
"pmc": null,
"pmid": "27660506",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "16954927;19587829;21436443;22484561;26791720;24560334;19342610;19918173;18375115;25043053;22770218;21216616;20164322;19520168;26540384;19523519;22455306;18718696;24677373;25291291;25422490;25992285",
"title": "Monitoring Metastasis and Cachexia in a Patient with Breast Cancer: A Case Study.",
"title_normalized": "monitoring metastasis and cachexia in a patient with breast cancer a case study"
} | [
{
"companynumb": "PHHY2016US136688",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LETROZOLE"
},
"drugadditional": null,
"druga... |
{
"abstract": "Acamprosate reduces the craving for alcohol by decreasing glutamate activity and increasing gamma-aminobutyric acid (GABA) action in patients with alcohol dependence. Acamprosate has tolerable side effects that include diarrhea, headache, dizziness and pruritus. In this study, we report acamprosate-induced extrapyramidal symptoms in an elderly patient with no history of neurologic disease. Severe extrapyramidal symptoms developed two days after the administration of acamprosate and improved over one week after the acamprosate was stopped. Extrapyramidal symptoms are commonly associated with dopamine receptor antagonists. However, there have been several reports of extrapyramidal symptoms occurring with drugs targeting other systems, including GABA, glutamate and serotonin. Acamprosate may decrease dopamine levels in the ventral tegmental area mediated by glutamatergic action and thus cause extrapyramidal symptoms. We suggest that acamprosate carries the risk of causing extrapyramidal symptoms.",
"affiliations": "Department of Psychiatry, Catholic University of Daegu School of Medicine, Daegu, Korea.;Department of Psychiatry, Kyungpook National University School of Medicine, Daegu, Korea.",
"authors": "Woo|Jungmin|J|;Rim|Hyo-Deog|HD|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.9758/cpn.2014.12.2.166",
"fulltext": "\n==== Front\nClin Psychopharmacol NeurosciClin Psychopharmacol NeurosciCPNClinical Psychopharmacology and Neuroscience1738-10882093-4327Korean College of Neuropsychopharmacology 10.9758/cpn.2014.12.2.166Case ReportAcamprosate-induced Extrapyramidal Symptoms in an Elderly Patient with Alcohol Dependence Woo Jungmin 1Rim Hyo-Deog 21 Department of Psychiatry, Catholic University of Daegu School of Medicine, Daegu, Korea.2 Department of Psychiatry, Kyungpook National University School of Medicine, Daegu, Korea.Address for correspondence: Hyo-Deog Rim, MD, PhD. Department of Psychiatry, Kyungpook National University School of Medicine, 130 Dongdeok-ro, Jung-gu, Daegu 700-721, Korea. Tel: +82-53-420-5755, Fax: +82-53-426-5361, hdrim@knu.ac.kr8 2014 12 8 2014 12 2 166 168 12 6 2014 18 7 2014 22 7 2014 Copyright© 2014, Korean College of Neuropsychopharmacology2014This 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.Acamprosate reduces the craving for alcohol by decreasing glutamate activity and increasing gamma-aminobutyric acid (GABA) action in patients with alcohol dependence. Acamprosate has tolerable side effects that include diarrhea, headache, dizziness and pruritus. In this study, we report acamprosate-induced extrapyramidal symptoms in an elderly patient with no history of neurologic disease. Severe extrapyramidal symptoms developed two days after the administration of acamprosate and improved over one week after the acamprosate was stopped. Extrapyramidal symptoms are commonly associated with dopamine receptor antagonists. However, there have been several reports of extrapyramidal symptoms occurring with drugs targeting other systems, including GABA, glutamate and serotonin. Acamprosate may decrease dopamine levels in the ventral tegmental area mediated by glutamatergic action and thus cause extrapyramidal symptoms. We suggest that acamprosate carries the risk of causing extrapyramidal symptoms.\n\nAcamprosateExtrapyramidal symptomsGlutamateGamma-aminobutyric acid\n==== Body\nINTRODUCTION\nAcamprosate (calcium acetylhomotaurinate) is a derivative of the amino acid taurine, and its structure is similar to that of gamma-aminobutyric acid (GABA). Acamprosate interacts with the glutamate and GABA systems. In patients with chronic alcohol exposure, glutamate hyperactivity and GABA deficiency explain some of the mechanisms of craving; acamprosate reduces these cravings by decreasing the glutamate activity and increasing the action of GABA.1)\n\nAcamprosate has been proven safe and effective for the treatment of alcoholism and is approved by US Food and Drug Administration. Some of the common side effects of acamprosate are diarrhea, headache, dizziness and pruritus.2) Although most cases of drug-induced extrapyramidal symptoms (EPSs) are associated with antipsychotics targeting the dopamine system, EPSs can also develop due to drugs targeting other systems, including selective serotonin reuptake inhibitors.3) The following is a case of acamprosate-induced EPSs in an elderly patient with no history of neurologic disease.\n\nCASE\nA 72-year-old unemployed, married man entered treatment to stop alcohol intake. He had consumed alcohol regularly for ten years. His history revealed no prior hospitalizations and no experience of severe withdrawal symptoms. The patient demonstrated a mild tremor of both hands, a pulse of 79 beats per minute, a respiratory rate of 20 per minute, and blood pressure of 110/70. All blood tests were within normal limits.\n\nHe was diagnosed with alcohol dependency. He was detoxified with lorazepam 4 mg/day for 4 days and was prescribed 999 mg/day of acamprosate and 100 mg/day of thiamine. After 2 days, he exhibited a slowed gait with diminished pendular arm movements, excessive saliva pooling in his mouth, muscle rigidity of arms without cogwheel rigidity and bradykinesia with slowed speech. However, there were no focal signs in a neurological examination. Over the next 2 days, acute onset Parkinsonism developed and prohibited him from daily activity. Acamprosate was discontinued, and the symptoms disappeared over the next week (Fig. 1).\n\nDISCUSSION\nThis is the second case report of a patient with alcohol dependence who developed EPSs following the administration of acamprosate. This patient experienced severe EPSs two days after administration of acamprosate, which continued for nine days. We did not initially recognize these unexpected EPSs as side effects; we explored the possibility of acute-onset neurological disease and researched drugs that may have been responsible for the EPSs. However, there were no signs of neurological disease, and we found no drugs that had EPSs as common side effect. Acamprosate was discontinued, and the EPSs disappeared over the following week.\n\nPreviously, acamprosate-induced EPSs were reported in a 36-year-old patient with alcohol dependence.4) The patient took 1,998 mg/day of acamprosate for one week before the EPSs developed. The dose was reduced to 1,332 mg/day and continued at this level for one week. Nevertheless, the symptoms remained. The EPSs did not end until the medication was discontinued.\n\nIt is important to compare the currently reported case with the previous case from a clinical perspective, despite a lack of information. We prescribed reduced dose of acamprosate (999 mg/day) because the patient was elderly (72 years) with a low body weight (51 kg). The EPSs developed over two days, while in the previous case, the dose was 1,998 mg and the EPS developed after one week. However, symptoms disappeared in both cases after acamprosate was discontinued. Thus, acamprosate-induced EPSs developed at half the recommended dose and more quickly in the elderly patient. The sensitivity to this side effect may be due advanced the patient's age and altered pharmacokinetics. Acamprosate is eliminated via the kidney and must be prescribed at a reduced dose or not at all in patients with renal impairment, depending on the severity of the impairment. Although we could not find any proof, our elderly patient may have had decreased renal function and therefore sensitivity to this side effect. In both cases, it took approximately one week for the EPSs to disappear after the drug was discontinued. In the previous case, dose reduction only attenuated the symptoms. Discontinuing the medication may be the better strategy when EPSs occur, and the disappearance of symptoms may take a considerable length of time, especially in elderly patients. The mean maximum plasma concentration (Cmax) of acamprosate was 180 ng/ml after oral administration of a single dose of 666 mg in healthy subjects.5) Acamprosate reaches steady-state plasma concentrations after 5 to 7 days of treatment and has an elimination half-life of approximately 30 hours.6) In the case of an individual with a possible decrement in renal functioning, such as an elderly patient, the side effects can last longer because Cmax can be higher, time to Cmax can be longer and plasma elimination half-life can be significantly longer than in a healthy subject.\n\nThe pathophysiology of drug-induced EPSs involves decreased dopamine activity in the basal ganglia. Therefore, dopamine receptor antagonists are commonly associated with EPSs. Their affinity to D2 receptors in the basal ganglia is particularly associated with such symptoms. Acamprosate affects the GABA and glutamate system. Acamprosate-induced EPSs are very rare, and the mechanism underlying their appearance is unknown. However, a clue may lie in the glutamate system. The site of acamprosate action, the ventral tegmental area, is highly complex and heterogeneous: it contains dopaminergic, GABAergic and glutamatergic neurons. It has been suggested that the local glutamatergic neurons regulate the neuronal network of the ventral tegmental area.7) Most dopamine neurons in this area show glutamate reactivity, and dopamine release is affected by this action.8) The excitatory synaptic responses of dopamine neurons are mediated by glutamate, which leads to dopamine release and the inhibition of excitatory responses via presynaptic D2 receptors. Thus, acamprosate may diminish glutamate activity in this area, which decreases dopamine and leads to EPSs. Alcohol withdrawal can induce decrements in dopamine release in the ventral tegmental area,9) and there may be additive effects with acamprosate administration that affect the development of extra pyramidal symptoms.\n\nThis is the second case report of the development of EPSs with acamprosate administration. It may be controversial to make conclusions based on two cases, especially when the elderly patient described in this report might have had a transient condition evoking EPSs. Nonetheless, this report suggests that acamprosate carries the risk of causing EPSs, and clinicians should be aware of this possibility. Future studies should be conducted using a placebo-controlled prospective design with precise evaluations during initial two weeks of acamprosate treatment.\n\nFig. 1 Administered medications and the course of extrapyramidal symptoms. EPSs, extrapyramidal symptoms.\n==== Refs\n1 Hunt WA Neuroscience research: how has it contributed to our understanding of alcohol abuse and alcoholism? A review Alcohol Clin Exp Res 1993 17 1055 1065 7506499 \n2 Bouza C Angeles M Muñoz A Amate JM Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review Addiction 2004 99 811 828 15200577 \n3 Madhusoodanan S Alexeenko L Sanders R Brenner R Extrapyramidal symptoms associated with antidepressants--a review of the literature and an analysis of spontaneous reports Ann Clin Psychiatry 2010 22 148 156 20680187 \n4 Sidana AK Mangla D Unusual side effects with acamprosate Indian J Psychiatry 2007 49 143 20711401 \n5 Scott LJ Figgitt DP Keam SJ Waugh J Acamprosate: a review of its use in the maintenance of abstinence in patients with alcohol dependence CNS Drugs 2005 19 445 464 15907154 \n6 Saivin S Hulot T Chabac S Potgieter A Durbin P Houin G Clinical pharmacokinetics of acamprosate Clin Pharmacokinet 1998 35 331 345 9839087 \n7 Morales M Root DH Glutamate neurons within the midbrain dopamine regions Neuroscience 2014 doi: 10.1016/j.neuroscience.2014.05.032 . [Epub ahead of print] \n8 Rayport S Glutamate is a cotransmitter in ventral midbrain dopamine neurons Parkinsonism Relat Disord 2001 7 261 264 11331197 \n9 Diana M Pistis M Carboni S Gessa GL Rossetti ZL Profound decrement of mesolimbic dopaminergic neuronal activity during ethanol withdrawal syndrome in rats: electrophysiological and biochemical evidence Proc Natl Acad Sci U S A 1993 90 7966 7969 8367449\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1738-1088",
"issue": "12(2)",
"journal": "Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology",
"keywords": "Acamprosate; Extrapyramidal symptoms; Gamma-aminobutyric acid; Glutamate",
"medline_ta": "Clin Psychopharmacol Neurosci",
"mesh_terms": null,
"nlm_unique_id": "101207332",
"other_id": null,
"pages": "166-8",
"pmc": null,
"pmid": "25191510",
"pubdate": "2014-08",
"publication_types": "D016428:Journal Article",
"references": "15907154;7506499;8367449;20680187;11331197;24875175;15200577;20711401;9839087",
"title": "Acamprosate-induced Extrapyramidal Symptoms in an Elderly Patient with Alcohol Dependence.",
"title_normalized": "acamprosate induced extrapyramidal symptoms in an elderly patient with alcohol dependence"
} | [
{
"companynumb": "KR-MYLANLABS-2014M1006528",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ACAMPROSATE"
},
"drugadditional": null,
... |
{
"abstract": "Prolonged immunosuppressive therapy is a risk factor for invasive pulmonary aspergillosis. We report a case of a 79-yearold man who underwent immunosuppressive therapy with methylprednisolone and cyclosporine for an acute exacerbation of interstitial lung disease. Ten days after initiation of immunosuppressive therapy, the patient reported night sweats and purulent sputum, and chest computed tomography scan revealed consolidation. He was diagnosed with invasive pulmonary aspergillosis, and required vasopressor support with oxygen therapy. After the administration of voriconazole and the modulation of immunosuppressive therapy, his condition improved. Short-term immunosuppressive therapy can also induce invasive pulmonary aspergillosis.",
"affiliations": "Departments of Respiratory Medicine.;Thoracic Surgery, Nagoya Tokushukai General Hospital, Japan.",
"authors": "Ugajin|Motoi|M|;Kani|Hisanori|H|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.4081/idr.2018.7785",
"fulltext": "\n==== Front\nInfect Dis RepIDRInfectious Disease Reports2036-74302036-7449PAGEPress Publications, Pavia, Italy 10.4081/idr.2018.7785Case ReportA case of invasive pulmonary aspergillosis during treatment for acute exacerbation of interstitial lung disease Ugajin Motoi 1Kani Hisanori 21 Departments of Respiratory Medicine2 Thoracic Surgery, Nagoya Tokushukai General Hospital, JapanDepartment of Respiratory Medicine, Nagoya Tokushukai General Hospital, 2-52 Kozoji-cho-kita, Kasugai 487-0016, Japan. +81.568.518711 - +81.568.517115. ugarin2001@yahoo.co.jpContributions: MU diagnosed and treated the patient, and wrote the manuscript; HK diagnosed the patient, and revised the manuscript.\n\nConflict of interest: the authors declare no potential conflict of interest.\n\n05 12 2018 06 11 2018 10 3 778502 7 2018 09 10 2018 ©Copyright M. Ugajin and H. Kani, 20182018Licensee PAGEPress, ItalyThis article is distributed under the terms of the Creative Commons Attribution Noncommercial License (by-nc 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.Prolonged immunosuppressive therapy is a risk factor for invasive pulmonary aspergillosis. We report a case of a 79-yearold man who underwent immunosuppressive therapy with methylprednisolone and cyclosporine for an acute exacerbation of interstitial lung disease. Ten days after initiation of immunosuppressive therapy, the patient reported night sweats and purulent sputum, and chest computed tomography scan revealed consolidation. He was diagnosed with invasive pulmonary aspergillosis, and required vasopressor support with oxygen therapy. After the administration of voriconazole and the modulation of immunosuppressive therapy, his condition improved. Short-term immunosuppressive therapy can also induce invasive pulmonary aspergillosis.\n\nKey words\nInvasive pulmonary aspergillosisInterstitial lung diseaseImmunosuppressive therapyFunding: none.\n==== Body\nIntroduction\nInvasive pulmonary aspergillosis (IPA) is an opportunistic infection. The mortality rate of IPA is reported to exceed 50% due to the difficulty of its diagnosis and the rapid progression of its clinical course.1 Prolonged immunosuppressive therapy is recognized as a significant risk factor of IPA.2 However, the occurrence of IPA in patients after short-term immunosuppressive therapy for lung diseases is rare. Herein, we present a case of IPA that was diagnosed 10 days after the initiation of immunosuppressive therapy for an acute exacerbation of interstitial lung disease.\n\nCase Report\nA 79-year-old man arrived at our emergency room by ambulance complaining of dyspnea and non-productive cough. He was seen at our hospital every 2 months for interstitial lung disease and his lung function test performed 8 months previously showed that his forced vital capacity was 2.26 L (67.0% of the predicted value). His other medical history was angina pectoris treated with percutaneous coronary intervention 2 years previously. In the emergency room, his respiratory rate was 30 breaths/min and his oxygen saturation was 92% using a face mask with oxygen flow of 6 L/min. Fine crackles were heard in both lungs on chest auscultation and chest computed tomography (CT) revealed groundglass opacities and reticular infiltrates in both lung fields (Figure 1A). He was diagnosed with an acute exacerbation of interstitial lung disease and was administered intravenous methylprednisolone 500 mg once daily with levofloxacin. His general condition improved and his chest CT on day 4 of admission showed improvement of ground-glass opacities and reticular infiltrates in both lung fields (Figure 1B). The dose of intravenous methylprednisolone was reduced to 40 mg once daily and the patient was started on oral cyclosporine 50 mg twice daily. On day 11 of admission, he reported night sweats and purulent sputum. At that time, his serum C-reactive protein level was 13.17 mg/dL (normal value < 0.3 mg/dL) and chest CT showed a wedgeshaped consolidation in the right lower lobe (Figure 1C). The patient was initiated on intravenous micafungin 150 mg once daily with piperacillin/tazobactam. However, his condition deteriorated and he was transferred to the intensive care unit on day 18 of admission for vasopressor support with oxygen therapy. His chest CT on day 18 of admission showed an obvious enlargement of the consolidation in the right lower lobe (Figure 1D). His serum β-D glucan level was elevated (1,662 pg/mL, normal value < 20 pg/mL) and serum aspergillus galactomannan antigen was positive (3.9, cut-off value of 0.5). He was clinically diagnosed with IPA and treated with intravenous voriconazole 300 mg twice daily, followed by 200 mg twice daily starting the following day. His cyclosporine was stopped and the intravenous methylprednisolone was reduced to 20 mg once daily. After initiation of voriconazole, his condition gradually improved. His serum β-D glucan level and serum aspergillus galactomannan antigen index also decreased (Table 1). A bronchoscopy was performed on day 37 of admission and bronchial lavage was obtained from the right lower bronchus. The bronchial lavage revealed filamentous fungi (Figure 2) and Aspergillus fumigatus was cultivated. On day 40 of admission, the intravenous voriconazole was switched to oral administration 200 mg twice daily. On day 51 of admission, he was discharged with marked shrinkage of the consolidation in his right lower lobe.\n\nDiscussion\nThe present case showed that even short-term immunosuppressive therapy can cause IPA. This life-threatening form of aspergillus infection has occasionally been seen in immunocompromised patients with a hematologic disorder or post-organ transplantation. 2 Similarly, immunosuppressive therapy for lung disease is a known risk factor of IPA. However, most previous reports indicate that IPA occurred in patients after a prolonged term of immunosuppressive therapy at least 3 weeks.3,4 In the present case, IPA occurred only 10 days after initiation of immunosuppressive therapy. Hence, we propose that a short term of immunosuppressive therapy can induce IPA.\n\nVoriconazole has been established as the primary antifungal agent for treatment of IPA.5 In fact, the present case showed remarkable clinical improvement after administration of voriconazole. However, voriconazole interacts with a considerable number of drugs.6 Serum cyclosporine concentration has been reported to be elevated after initiation of voriconazole and a high trough concentration of cyclosporine is associated with nephrotoxicity.7,8 Although re-exacerbation of interstitial lung disease was a concern, we decided to stop cyclosporine treatment and reduce the dose of methylprednisolone at initiation of voriconazole in order to avoid cyclosporine-induced nephrotoxicity and to restore host immune status. Kousha et al. assert the importance of decreasing the dosage of systemic corticosteroids and immunosuppressive agents in the treatment of patients with IPA.6 Owing to both the appropriate choice of antifungal agent and the modulation of immunosuppressive therapy, the present case had successful resolution of IPA.\n\nIt remains unclear why only some immunocompromised patients develop IPA while others do not. Host recognition of invading pathogen is an important first process against invasive infection. Recently, some genetic defects of the recognition process have been revealed and considered to be a factor of susceptibility to aspergillus infection.9 As an example, genetic Pentraxin 3 (PTX3) deficiency is known to be a risk factor of invasive aspergillosis.10 PTX3 is an inflammatory protein activating the toll-like receptor pathway by binding aspergillus conidia.11 Among recipients of hematopoietic stemcell transplantation, the incidence of invasive aspergillosis was significantly higher in case of genetic PTX3 deficient donors.12 A study in patients with chronic obstructive pulmonary disease showed that PTX3 rs1840680 single nucleotide polymorphism was associated with susceptibility to aspergillus infection and the polymorphism was detected in 31 out of 173 patients.13 Although we could not investigate genetic defects relating susceptibility to aspergillus infection in the present case, screening of genetic defects may be a potential useful tool to stratify the risk of IPA occurrence in initiating immunosuppressive therapy.\n\nNeutrophils play a key role of the first line defense against aspergillus infection.14 To eliminate aspergillus germinating spores, neutrophils produce extracellular traps, release antimicrobial proteases by degranulation, and activate the toll-like receptor pathway using preliminarily stored PTX3.15-17 In the present case, patient neutrophil function was considered to be quite attenuated because of his high serum galactomannan index. Galactomannan, a component of the cell wall of Aspergillus spp., is released into blood stream during hyphal growth and is captured by neutrophils. It has been known that non-neutropenic patients with invasive aspergillosis have significant lower serum galactomannan indexes as compared to neutropenic Neutrophils play a key role of the first line defense against aspergillus infection.14 To eliminate aspergillus germinating spores, neutrophils produce extracellular traps, release antimicrobial proteases by degranulation, and activate the toll-like receptor pathway using preliminarily stored PTX3.15-17 In the present case, patient neutrophil function was considered to be quite attenuated because of his high serum galactomannan index. Galactomannan, a component of the cell wall of Aspergillus spp., is released into blood stream during hyphal growth and is captured by neutrophils. It has been known that non-neutropenic patients with invasive aspergillosis have significant lower serum galactomannan indexes as compared to neutropenic patients.18 Zhou et al. reported that only 14 out of 37 IPA patients without neutropenia had positive serum galactomannan indexes at a cut-off value of 0.5 and the mean value of galactomannan index in the 37 IPA patients was 0.74.19 Despite a sufficient neutrophil count (16,376 /uL), the present case had a high serum galactomannan index of 3.9 on day 11 of admission. The attenuation of neutrophil function was suggested in the present case and may be an important factor of IPA occurrence.\n\nConclusions\nIn conclusion, we presented a case of IPA associated with short-term immunosuppressive therapy for an acute exacerbation of interstitial lung disease. Adequate diagnosis, appropriate choice of antifungal agent, and careful assessment of host immune status are essential for the management of IPA.\n\nFigure 1. A) Ground-glass opacities and reticular infiltrates were observed in both lung fields on the day of admission. B) Ground-glass opacities and reticular infiltrates almost disappeared by day 4 of admission. C) A wedge-shaped consolidation was observed in the right lower lobe on day 11 of admission. D) Consolidation in the right lower lobe was enlarged on day 18 of admission.\n\nFigure 2. Black stained hyphae were observed in the right lower bronchial lavage (Grocott stain, 200× magnification).\n\nTable 1. Transition of serum β-D glucan level and aspergillus galactomannan antigen index. Normal values: β-D glucan < 20 pg/mL, galactomannan antigen index < 0.5.\n\n\tDay 2\tDay 11\tDay 18\tDay 25\tDay 32\tDay 39\t\nSerum β-D glucan level (pg/mL)\t12.4\t1662.0\t2665.0\t209.7\t67.0\t34.4\t\nGalactomannnan antigen index\t–\t3.9\t–\t0.9\t–\t0.5\n==== Refs\nReferences\n1. Taccone FS Van den Abeele AM Bulpa P \nEpidemiology of invasive aspergillosis in critically ill patients: clinical presentation, underlying conditions, and outcomes . Crit Care \n2015 ;19 :7 .25928694 \n2. Blot SI Taccone FS Van den Abeele AM \nA clinical algorithm to diagnose invasive pulmonary aspergillosis in critically ill patients . Am J Respir Crit Care Med \n2012 ;186 :56 -64 .22517788 \n3. Palmer LB Greenberg HE Schiff MJ \nCorticosteroid treatment as a risk factor for invasive aspergillosis in patients with lung disease . Thorax \n1991 ;46 :15 -20 .1871691 \n4. Jonaitytė B Kibarskytė R Danila E \nFatal pulmonary complication during induction therapy in a patient with ANCA-associated vasculitis . Acta Med Litu \n2016 ;23 :142 -6 .28356801 \n5. See comment in PubMed Commons below \nLimper AH Knox KS Sarosi GA \nAn official American Thoracic Society statement: Treatment of fungal infections in adult pulmonary and critical care patients . Am J Respir Crit Care Med \n2011 ;183 :96 -128 .21193785 \n6. Kousha M Tadi R Soubani AO \nPulmonary aspergillosis: a clinical review . Eur Respir Rev \n2011 ;20 :156 -74 .21881144 \n7. Mori T Aisa Y Kato J \nDrug interaction between voriconazole and calcineurin inhibitors in allogeneic hematopoietic stem cell transplant recipients . Bone Marrow Transplant \n2009 ;44 :371 -4 .19270729 \n8. Jacobson PA Schladt D Israni A \nGenetic and clinical determinants of early, acute calcineurin inhibitor-related nephrotoxicity: results from a kidney transplant consortium . Transplantation \n2012 ;93 :624 -31 .22334041 \n9. Campos CF van de Veerdonk FL Gonçalves SM \nHost Genetic Signatures of Susceptibility to Fungal Disease . Curr Top Microbiol Immunol \n2018 Jul 25. [Epub ahead of print] \n10. Maskarinec SA Johnson MD Perfect JR \nGenetic Susceptibility to Fungal Infections: What is in the Genes? \nCurr Clin Microbiol Rep \n2016 ;3 :81 -91 .27547700 \n11. Bozza S Campo S Arseni B \nPTX3 binds MD-2 and promotes TRIFdependent immune protection in aspergillosis . J Immunol . 2014 ;193 \n2340 -8 .25049357 \n12. Cunha C Aversa F Lacerda JF \nGenetic PTX3 deficiency and aspergillosis in stem-cell transplantation . N Engl J Med \n2014 ; 370 :421 -32 .24476432 \n13. He Q Li H Rui Y \nPentraxin 3 Gene Polymorphisms and Pulmonary Aspergillosis in Chronic Obstructive Pulmonary Disease Patients . Clin Infect Dis \n2018 ;66 :261 -7 .29020397 \n14. Espinosa V Rivera A. \nFirst Line of Defense: Innate Cell-Mediated Control of Pulmonary Aspergillosis . Front Microbiol \n2016 ;7 :272 .26973640 \n15. Bruns S Kniemeyer O Hasenberg M \nProduction of extracellular traps against Aspergillus fumigatus in vitro and in infected lung tissue is dependent on invading neutrophils and influenced by hydrophobin RodA . PLoS Pathog \n2010 ;6 :e1000873 .20442864 \n16. Feldmesser M \nRole of neutrophils in invasive aspergillosis . Infect Immun \n2006 ; 74 : 6514 -6 .17030575 \n17. Jaillon S Peri G Delneste Y \nThe humoral pattern recognition receptor PTX3 is stored in neutrophil granules and localizes in extracellular traps . J Exp Med \n2007 ;204 :793 -804 .17389238 \n18. Cordonnier C Botterel F Ben Amor R \nCorrelation between galactomannan antigen levels in serum and neutrophil counts in haematological patients with invasive aspergillosis . Clin Microbiol Infect \n2009 ;15 :81 -6 .\n19. Zhou W Li H Zhang Y \nDiagnostic Value of Galactomannan Antigen Test in Serum and Bronchoalveolar Lavage Fluid Samples from Patients with Nonneutropenic Invasive Pulmonary Aspergillosis . J Clin Microbiol \n2017 ;55 :2153 -61 .28446576\n\n",
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"keywords": "Immunosuppressive therapy; Interstitial lung disease; Invasive pulmonary aspergillosis",
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"title": "A case of invasive pulmonary aspergillosis during treatment for acute exacerbation of interstitial lung disease.",
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"abstract": "BACKGROUND\nSodium valproate (VPA) and lamotrigine (LTG) are widely used antiepileptic drugs, disabling postural, and action tremors after using LTG with VPA were reported in 1993. However, in this study, we describe a patient in whom disabling resting-type tremor induced by 2-year use of VPA and LTG.\nA 50-year old man was referred to department of neurology because of involuntary upper limbs resting-type tremor with high amplitude that had begun 6 months previously and progressively worsened, and he could not work on the day of visit. Furthermore, he had been treated with VPA, LTG, and benzhexol for 2 years as he suffered from twitch of eyelids and facial region, and amantadine, monolithic compound preparation (flupentixol and melitracen) were added in the last 2 months because of tremor and anxiety. However, the treatment had no benefit on improving involuntary movements of the patient.\nDrug-induced disabling tremor was diagnosed.\n\n\nRESULTS\nLTG, amantadine, and VPA were withdrawn, the remaining 2 drugs, benzhexol and compound preparation (flupentixol and melitracen), were continued to use, and the patient improved in 2.5 months after discontinuation of 3 drugs. There was no recurrence at 6 months follow-up.\n\n\nCONCLUSIONS\nConsidering the wide and long-term utilization of VPA and LTG, healthcare providers should be aware of them as a possible cause of tremor. When necessary, an attempt of discontinuing the suspected drugs should be made to confirm the diagnosis, instead of symptomatic treatment, especially when the adverse event was severe and fatal.",
"affiliations": "Department of Pharmacy Department of Neurology, First Hospital of Lanzhou University, Lanzhou, China.",
"authors": "He|Zhong-Fang|ZF|;Chen|Jun|J|;Zhou|Chao-Ning|CN|;Rao|Zhi|Z|;Wang|Xiao-Hua|XH|",
"chemical_list": "D000927:Anticonvulsants; D000978:Antiparkinson Agents; D014227:Triazines; D014635:Valproic Acid; D014282:Trihexyphenidyl; D000547:Amantadine; D000077213:Lamotrigine",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health MD-D-17-0415310.1097/MD.0000000000008711087114200Research ArticleClinical Case ReportDisabling tremor induced by long-term use of sodium valproate and lamotrigine Case reportHe Zhong-Fang PhDa∗Chen Jun MDbZhou Chao-Ning MDbRao Zhi PhDaWang Xiao-Hua PhDaManchia. Mirko a Department of Pharmacyb Department of Neurology, First Hospital of Lanzhou University, Lanzhou, China.∗ Correspondence: Zhong-Fang He, Department of Pharmacy, First Hospital of Lanzhou University, Dong-Gang West Road No. 1, Chengguan District, Lanzhou 730000, China (e-mail: lzhezf@163.com).11 2017 27 11 2017 96 47 e87114 7 2017 26 10 2017 27 10 2017 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\nRationale:\nSodium valproate (VPA) and lamotrigine (LTG) are widely used antiepileptic drugs, disabling postural, and action tremors after using LTG with VPA were reported in 1993. However, in this study, we describe a patient in whom disabling resting-type tremor induced by 2-year use of VPA and LTG.\n\nPatient concerns:\nA 50-year old man was referred to department of neurology because of involuntary upper limbs resting-type tremor with high amplitude that had begun 6 months previously and progressively worsened, and he could not work on the day of visit. Furthermore, he had been treated with VPA, LTG, and benzhexol for 2 years as he suffered from twitch of eyelids and facial region, and amantadine, monolithic compound preparation (flupentixol and melitracen) were added in the last 2 months because of tremor and anxiety. However, the treatment had no benefit on improving involuntary movements of the patient.\n\nDiagnoses:\nDrug-induced disabling tremor was diagnosed.\n\nInterventions and outcomes:\nLTG, amantadine, and VPA were withdrawn, the remaining 2 drugs, benzhexol and compound preparation (flupentixol and melitracen), were continued to use, and the patient improved in 2.5 months after discontinuation of 3 drugs. There was no recurrence at 6 months follow-up.\n\nLessons:\nConsidering the wide and long-term utilization of VPA and LTG, healthcare providers should be aware of them as a possible cause of tremor. When necessary, an attempt of discontinuing the suspected drugs should be made to confirm the diagnosis, instead of symptomatic treatment, especially when the adverse event was severe and fatal.\n\nKeywords\ndisabling tremorlamotriginelong-term usesodium valproateOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nEpilepsy is a common neurological disorder characterized by episodic convulsions associated with transient confusion. More than 50 million people worldwide are affected by epilepsy.[1] It is not only a medical problem, but also an important public health and social problem. Epilepsy is listed as one of the significant neurological and mental diseases requiring prevention and treatment. Although many patients will remain seizure free on the first or second drug, combinations are usually prescribed in those unresponsive to monotherapy.[2] Sodium valproate (VPA) is the most widely used antiepileptic drug worldwide, and lamotrigine (LTG) is a novel antiepileptic agent. A study shows that VPA-LTG comedication exhibits a favorable pharmacodynamic interaction in patients with refractory partial epilepsy.[3]\n\nGenerally, VPA is well tolerated, and the most commonly occurring adverse reactions are gastrointestinal disturbances, others are neurologic abnormality, such as ataxia, tremor, sedation, drowsiness, and confusion.[4] Various systemic and neurologic side effects of LTG, such as spasticity, ataxia, nystagmus, and tremor, have also been reported.[4] Reutens et al[5] reported disabling postural and action tremors after LTG with VPA in 1993. However, the study on disabling resting-type tremor secondary to simultaneous administration of the 2 medicines has not been reported. To our knowledge, this is the first report about disabling resting-type tremor caused by VPA and LTG.\n\n2 Case report\nA 50-year-old man, weighing 75 kg, was referred to department of neurology because of involuntary upper limbs resting-type tremor with high amplitude that had begun 6 months previously and progressively worsened, and he could not work on the day of visit. Furthermore, he had been treated with VPA, LTG, and benzhexol for 2 years as he suffered from twitch of eyelids and facial region, and amantadine, monolithic compound preparation (flupentixol and melitracen) were added in the last 2 months because of tremor and anxiety. However, the treatment had no benefit on improving involuntary movements of the patient. In lower-grade hospital, the patient had been diagnosed as epilepsy due to twitch of eyelids and facial region, VPA and LTG had been initially given 2 years ago. There was no family history of any neurological disease and clinical features in favor of Wilson disease, he denied hypertension, diabetes mellitus, injury history, and history of drug allergy other than chronic hepatitis B of 30 years. After admission, he was conscious, temperature 36.4°C, pulse was 94 times/min, regular, and blood pressure was 129/91 mm Hg. Neurological examination showed involuntary upper limbs tremor, high muscle tension of extremities, and twitch of eyelids and facial region, the rest of the neurological examination was normal. On further evaluation, routine blood test and other tests such as liver function, kidney function, urine analysis, and random blood glucose were normal. Magnetic resonance imaging of brain, electroencephalography, and neuropsychological examination did not reveal any abnormality.\n\nDisabling tremor induced by drugs was initially diagnosed based on the chronic worsening process, an exposure history of many drugs acting on the central nervous system, and the exclusion of known causes of secondary tremor by above clinical and laboratory evaluation. In treatment, LTG (100 mg qd) and amantadine (100 mg bid) were discontinued immediately; dosage of VPA was gradually reduced (sodium valproate sustained-release tablet: 1000 mg bid for 4 days, subsequently, 500 mg bid for 5 days) and was ceased after 9 days. In other words, within 9 days all of LTG, amantadine, and VPA were withdrawn. The degree of upper limbs tremor was not increased, but somewhat reduced. With that, remaining therapy was benzhexol for 2 mg tid, flupentixol, and melitracen (flupentixol 0.5 mg and melitracen 10 mg) for 1 piece, bid (8 am and noon). At follow-up examination 2.5 months after stopping above 3 drugs, his upper limbs tremor had apparently improved, and twitch of eyelids and facial region also improved except mouth. In addition, his mental state improved compared to 2.5 months ago, and he could work as a security guard according to his wife. There was no recurrence of the upper limbs tremor at 6 months follow-up.\n\n3 Discussion\nIn this case, we have reported an unusual patient with upper limbs resting-type tremor induced by VPA and LTG, which improved after discontinuation of the culprit drugs. This confirms the initial diagnosis of drug-induced tremor. This case is unusual in 2 regards: firstly, his tremor is disabling and not mild; secondly, this case is the first documented case of resting-type tremor which is different from postural and action tremor caused by LTG with VPA reported in 1993.[5]\n\nIndeed, the patient had been treated initially with VPA and LTG due to epilepsy, approximately 1.5 years later, the patient developed resting-type tremor with high amplitude of the arms and gradually worsened. Therefore, amantadine was added because of upper limbs tremor for 4 months, and compound preparation (flupentixol and melitracen) was also added at that time due to psychosomatic disease with anxiety, but upper limbs tremor did not improve within 2 months.\n\nFirstly, to establish the causal relationship between medication (VPA and LTG) and tremor, we applied WHO Uppsala Monitoring Centre criteria,[6] the result showed that this adverse reaction had “probable” relationship with medication administration. Meanwhile, we assessed severity of this adverse reaction according to the Common Terminology Criteria for Adverse Events[7] in grades 1 to 5 (mild to lethal), the grade of the patient was 4 (disabling).\n\nSecondly, we searched the literature of adverse reactions about tremor and extrapyramidal reaction on VPA, LTG, and amantadine. The results showed: Lautin et al[8] firstly reported a case of tremor with VPA in 1979; Reutens et al[5] reported that 3 patients presented disabling postural and action tremor after LTG with VPA, and their symptoms disappeared after reducing dosage of LTG or VPA. In addition, mild tremor was also observed in patients of VPA monotherapy and VPA-LTG combination.[3,9,10] Pathophysiologic mechanisms of extrapyramidal adverse reaction of VPA remains unknown, although a transient imbalance between functionally reciprocal subgroups of GABA pathways leading to remediable dopamine inhibition might be hypothesized.[11] Another study showed that the number of dopaminergic cells in the substantia nigra was reduced after treatment with VPA in mice.[12] Meanwhile, pharmacokinetic interaction of VPA inhibiting LTG metabolism,[13] pharmacodynamic interaction between VPA and LTG, and individual susceptibility such as chronic hepatitis B may have played a part in extrapyramidal adverse reaction of VPA and LTG.[5] However, amantadine is indicated in the treatment of drug-induced extrapyramidal reactions, and amantadine-induced tremor was not found by literature review.\n\nTo our knowledge, we have not found case report of upper limbs disabling tremor induced by VPA, LTG, and amantadine administrated together. In summary, we believe it is not possible to say with certainty if upper limbs tremor of the patient developed as a sole consequence of any one from VPA, LTG, and amantadine or as a consequence of possible synergistic effect of his medications. However, we speculate that simultaneous use of VPA and LTG is a possible culprit cause due to their long-term use of 2 years and antagonism of dopamine. Amantadine is not considered as a main culprit drug in a large part due to its effects on dopamine neurons and short-term use, especially 4 months after developing upper limbs tremor.\n\n4 Conclusion\nThis case demonstrates that the long-term use of VPA and LTG can lead to disabling tremor. Considering the wide and long-term utilization of VPA and LTG, healthcare providers should be aware of them as a possible cause of tremor. When necessary, an attempt of discontinuing the suspected drugs should be made to confirm the diagnosis, instead of symptomatic treatment, especially when the adverse event was severe and fatal.\n\nAbbreviations: LTG = lamotrigine, VPA = sodium valproate.\n\nZ-FH and JC contributed equally to this work.\n\nThis study was supported by Natural Science Foundation of Gansu Province (No. 17JR5RA271).\n\nAll interventions given were part of normal health care and therefore ethics approval was not required in this study. However, informed consent was obtained from the patient.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Zhao M Alleva R Ma H \nOptogenetic tools for modulating and probing the epileptic network . Epilepsy Res \n2015 ;116 :15 –26 .26354163 \n[2] Brodie MJ \nMedical therapy of epilepsy: when to initiate treatment and when to combine? \nJ Neurol \n2005 ;252 :125 –30 .15729515 \n[3] Pisani F Oteri G Russo MF \nThe efficacy of valproate-lamotrigine comedication in refractory complex partial seizures: evidence for a pharmacodynamic interaction . Epilepsy \n1999 ;40 :1141 –6 .\n[4] Sweetman SC \nMartindale: The Complete Drug Reference . 37th ed. London, UK : The Pharmaceutical Press ; 2011 .\n[5] Reutens DC Duncan JS Patsalos PN \nDisabling tremor after lamotrigine with sodium valproate . Lancet \n1993 ;342 :185 –6 .\n[6] The Uppsala Monitoring Centre. The use of the WHO-UMC system for standardised case causality assessment. http://www.who.int/medicines/areas/quality_safety/safety_efficacy/WHOcausality_assessment.pdf. Accessed November 10, 2017 .\n[7] CTCAE. Common Terminology Criteria for Adverse Events v3.0 (CTCAE). 2003. http://ctep.cancer.gov/protocol Development/electronic_ applications/docs/ctcaev3.pdf. Accessed November 10, 2017 .\n[8] Lautin A Stanley M Angrist B \nExtrapyramidal syndrome with sodium valproate . Br Med J \n1979 ;2 :1035 –6 .\n[9] Zeng K Wang X Xi Z \nAdverse effects of carbamazepine, phenytoin, valproate and lamotrigine monotherapy in epileptic adult Chinese patients . Clin Neurol Neurosur \n2010 ;112 :291 –5 .\n[10] Perucca E \nPharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience . CNS Drugs \n2002 ;16 :695 –714 .12269862 \n[11] Sasso E Delsoldato S Negrotti A \nReversible sodium valproate-induced extrapyramidal disorders . Epilepsia \n1994 ;35 :391 –3 .8156962 \n[12] Vamos E Csati A Vecsei L \nEffects of valproate on the dopaminergic system in mice . Neurol Res \n2009 ;31 :217 –9 .18768113 \n[13] Brodie MJ \nLamotrigine—an update . Can J Neurol Sci \n1996 ;23 :S6 –9 .8951213\n\n",
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"abstract": "Loperamide is a μ-opioid receptor agonist with antidiarrhoeal effects. It is considered to have a low abuse potential because of substantial first-pass metabolism and P-glycoprotein-mediated efflux at the level of the blood-brain barrier. Previous case reports have described that high dosage of loperamide can induce an opioid-like effect on the central nervous system. The most common presentation of loperamide intoxication is syncope which is caused by serious cardiac dysrhythmia and can lead to death. Therefore, it was decided to analyze whether drug prescriptions in the prescription drug database from The Directorate of Health would indicate loperamide misuse in Iceland from 2006-2017. In total 94 individuals used more than one DDD (10 mg) and 17 individuals used more than two DDD (20 mg), if taken daily over one year. These results indicate that loperamide is being used excessively but the reason for each prescription and the total amount sold over the counter is unknown. Increased surveillance and decreased availability of prescription opioids might possibly boost the usage of drugs with similar function such as loperamide. Loperamide overdose can result in serious adverse effects and thus, it is important to inform healthcare employees about such severe consequences.",
"affiliations": "Department of Medicine, National University Hospital of Iceland.;Department of Pharmacology and Toxicology, University of Iceland, The Directorate of Health.;Department of Psychiatry, National University Hospital of Iceland.;Department of Psychiatry, National University Hospital of Iceland.",
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"title": "Loperamide abuse - constipation or heart attack?",
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"abstract": "A 65-year-old man with acute myeloid leukemia 6 was treated by bone marrow allograft, developed a systemic classic chronic graft versus host disease with hepatic, rheumatologic, ophthalmic, and muco-cutaneous involvement. He received systemic corticosteroid, ruxolitinib and extracorporeal photopheresis which resulted in complete remission. During follow-up the patient presented with viral cutaneous warts on his neck and submandibular area. After various subsequent topical treatments, he developed localized cutaneous GVHD without any general GVHD reactivation symptoms. To the best of our knowledge, there has been no description in the literature of a graft versus host disease developing after local immunomodulatory or cytotoxic treatments. Topical therapies are commonly used by dermatologists for superficial skin cancers and some viral skin lesions, in high risk populations such as organ transplant patients with regular follow-up.Practitioners should be made aware of a possible localized cutaneous GVHD reactivation induced by Koebner phenomenon after local therapy.",
"affiliations": "Department of Dermatology, CHU Amiens-Picardie, Amiens. raphaella.cs@hotmail.fr.",
"authors": "Cohen-Sors|Raphaella|R|;Arnault|Jean-Philippe|JP|;Attencourt|Christophe|C|;Charbonnier|Amandine|A|;Adas|Alanoud|A|;Chaby|Guillaume|G|;Lok|Catherine|C|",
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"mesh_terms": "D000305:Adrenal Cortex Hormones; D000368:Aged; D064591:Allografts; D016026:Bone Marrow Transplantation; D002908:Chronic Disease; D003872:Dermatitis; D006086:Graft vs Host Disease; D006801:Humans; D007049:Iatrogenic Disease; D056747:Immunomodulation; D015470:Leukemia, Myeloid, Acute; D008297:Male; D009570:Nitriles; D011565:Psoriasis; D011720:Pyrazoles; D011743:Pyrimidines; D012871:Skin Diseases; D014860:Warts",
"nlm_unique_id": "9610776",
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"pmid": "33342180",
"pubdate": "2020-11-15",
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"references": null,
"title": "Iatrogenic cutaneous graft versus host disease.",
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"abstract": "Endometrial stromal sarcomas (ESS) account for 10-15% of uterine malignancies and are classified into four categories: endometrial stromal nodule (ESN), low-grade endometrial stromal sarcoma (LG-ESS), high-grade endometrial stromal sarcoma (HG-ESS) and undifferentiated uterine sarcoma (USS). Depending on stage, ESS is treated with surgery, hormone therapy, chemotherapy or targeted therapy. A rare complication of ESS with metastatic pulmonary disease is recurrent, bilateral pneumothoraces. The current literature has reported on patients with ESS who either presented with pneumothoraces at their initial diagnosis, and thus were untreated, or after treatment with surgical resection and hormone therapy. There have been no case reports of patients with ESS who presented with pneumothoraces while receiving chemotherapy. Furthermore, there have been no reported cases of patients with HG-ESS presenting with this rare complication. We would like to expand the literature by reporting on two patients with HG-ESS who presented with pneumothoraces while concurrently receiving chemotherapy.",
"affiliations": "The University of Texas Southwestern Medical Center, Dallas, TX, USA.;Eastern Virginia Medical School, Norfolk, VA, USA.;Cedars-Sinai Medical Center, Los Angeles, CA, USA.;Keck Hospital of USC, Los Angeles, CA, USA.;Norris Comprehensive Cancer Center, Los Angeles, CA, USA.",
"authors": "Duvalyan|Angela|A|;Tran|Kirk|K|;Lee|Christopher|C|;Chopra|Shefali|S|;Hu|James|J|https://orcid.org/0000-0003-0620-4664",
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"fulltext": "\n==== Front\nRare Tumors\nRare Tumors\nRTU\nsprtu\nRare Tumors\n2036-3605\n2036-3613\nSAGE Publications Sage UK: London, England\n\n10.1177/2036361320972865\n10.1177_2036361320972865\nCase Report\nPneumothorax presentation in endometrial sarcoma patients receiving chemotherapy: A case series\nDuvalyan Angela 1\nTran Kirk 2\nLee Christopher 3\nChopra Shefali 4\nhttps://orcid.org/0000-0003-0620-4664\nHu James 5\n1 The University of Texas Southwestern Medical Center, Dallas, TX, USA\n2 Eastern Virginia Medical School, Norfolk, VA, USA\n3 Cedars-Sinai Medical Center, Los Angeles, CA, USA\n4 Keck Hospital of USC, Los Angeles, CA, USA\n5 Norris Comprehensive Cancer Center, Los Angeles, CA, USA\nJames Hu, Norris Comprehensive Cancer Center, 1441 Eastlake Ave, Los Angeles, CA 90033, USA. Email: jameshu@med.usc.edu\n29 11 2020\n2020\n12 203636132097286519 2 2020\n21 10 2020\n© The Author(s) 2020\n2020\nSAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons Licenses\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nEndometrial stromal sarcomas (ESS) account for 10-15% of uterine malignancies and are classified into four categories: endometrial stromal nodule (ESN), low-grade endometrial stromal sarcoma (LG-ESS), high-grade endometrial stromal sarcoma (HG-ESS) and undifferentiated uterine sarcoma (USS). Depending on stage, ESS is treated with surgery, hormone therapy, chemotherapy or targeted therapy. A rare complication of ESS with metastatic pulmonary disease is recurrent, bilateral pneumothoraces. The current literature has reported on patients with ESS who either presented with pneumothoraces at their initial diagnosis, and thus were untreated, or after treatment with surgical resection and hormone therapy. There have been no case reports of patients with ESS who presented with pneumothoraces while receiving chemotherapy. Furthermore, there have been no reported cases of patients with HG-ESS presenting with this rare complication. We would like to expand the literature by reporting on two patients with HG-ESS who presented with pneumothoraces while concurrently receiving chemotherapy.\n\nEndometrial stromal sarcoma\npneumothorax\nchemotherapy\nhigh-grade endometrial stromal sarcoma\ncavitary lesion\npulmonary metastasis\ncover-dateJanuary-December 2020\ntypesetterts1\n==== Body\nIntroduction\n\nUterine sarcomas account for 3% to 7% of uterine cancers and can be divided into mesenchymal tumors or mixed epithelial and mesenchymal tumors. 1 Endometrial stromal sarcomas account for 10% to 15% of uterine malignancies. 2 The current World Health Organization recognizes four categories of endometrial stromal tumor: endometrial stromal nodule (ESN), low-grade endometrial stromal sarcoma (LG-ESS), high-grade endometrial stromal sarcoma (HG-ESS) and undifferentiated uterine sarcoma (UUS). 3 Microscopically, LG-ESS typically involves the endometrium and infiltrates the myometrium as irregular projections often with lymphovascular invasion. The tumor cells are small, oval to fusiform, imparting a monotonous appearance sometimes, with low cytologic atypia and low mitotic activity (usually <5/10hpf). In the past, mitotic counts have been used to stratify endometrial stromal tumors. However, this is no longer convention as ESSs with high mitotic counts, but otherwise typical low-grade morphologic features, do not appear to have a significantly different prognosis from ESSs with low mitotic counts. HG-ESS are composed of atypical cells bearing histologic resemblance to endometrial stromal cells, but lacking the degree of pleomorphism necessary for a diagnosis of UUS. Most of the HG-ESS have a round cell portion that tends to have larger nuclei compared with LG-ESS, often with more angulated and irregular nuclear contours, supported by a delicate capillary network. The mitotic activity is consistently higher (>10 mitoses/10 HPFs) than the traditional LG-ESS, and tumor cell necrosis and vascular space invasion is more commonly seen. 3\n\nThe mainstay of treatment for most patients diagnosed with ESS is total hysterectomy and bilateral salphingo-oophorectomy. 4 Given that low-grade endometrial stromal sarcomas are often hormone sensitive tumors with overexpression of ER and PR reported in approximately 70% and 95% of cases, respectively, adjuvant targeted hormone therapy has shown to increase median overall survival when compared to an observational cohort not receiving hormone therapy. 5 Currently, hormone therapy is considered for any recurrent or advanced stage disease (stage 3 or 4) in patients with ER/PR positive tumors. 5 Agents used include megestrol or medroxyprogesterone, gonadotropin-releasing hormone analogs and aromatase inhibitors. For patients who continue to progress or develop recurrence, chemotherapy can then be considered.4,5 Systemic chemotherapy agents include doxorubicin and ifosfamide although gemcitabine, docetaxel, liposomal doxorubicin and paclitaxel have also been used. 4\n\nThe prognosis of Stage 1 LG-ESS is favorable with a 5 and 10 year prognosis of 98% and 89%. 6 Although ESS tends to follow an indolent nature, about one-third of patients have recurrent disease that requires long-term follow up. 1 Most commonly these patients develop recurrences in the pelvis and abdomen and less often in the lungs and vagina.6,7 In some cases, patients with metastatic disease in the lungs have been reported to present with recurrent pneumothoraces. The literature has reported on patients with ESS who either presented with pneumothoraces at their initial diagnosis, and thus were untreated, or after treatment with surgical resection and hormone therapy. There have been no case reports of patients with ESS who presented with pneumothoraces while receiving chemotherapy. We would like to expand the literature by reporting on two patients with endometrial sarcoma who presented with pneumothoraces while concurrently receiving chemotherapy.\n\nCase #1\n\nThe patient is a 59-year-old female with no significant history of chronic lung disease or tobacco use who was diagnosed with ER+/PR+ metastatic, high-grade endometrial stromal sarcoma (HG-ESS) in April 42013. A surveillance CT chest on 1/2018 showed an incidental large left-sided pneumothorax while receiving chemotherapy. Her previous treatment for ESS included a hysterectomy at diagnosis (4/2013) followed by adjuvant systemic therapy with Gemcitabine and Taxotere. She developed relapse of her disease in the right upper lung in January 2016 with subsequent wedge resection. She was then started on anastrozole on 2/2016 but was switched to megestrol and later tamoxifen on 7/2016 due to significant bone pain. Unfortunately, she progressed and was started on cabozantinib, a phase 2 clinical trial, which was dose reduced due to nausea and vomiting (9/2017). She was then started on doxorubicin and olaratumab on 11/2017, however her third cycle of chemotherapy was complicated by a large left-sided pneumothorax on 1/2018, requiring ICU admission. CT Chest at the time of admission showed a new large left pneumothorax with multiple bilateral solid and cavitary pulmonary nodules (Figure 1(a)) which required chest tube placement. She then resumed cycle 4 of doxorubicin and olaratumab combination therapy and was switched to maintenance olaratumab for cycle 7 on 4/2018. Restaging CT scans continued to show response to therapy until cycle 18, when scans showed progression of her disease. At this time, the patient reported feeling dyspnea on exertion which progressed to dyspnea at rest and a CT Chest (1/2019) showed upper and lower lobe consolidative, ground glass opacities as well as multiple right-sided pulmonary nodules with cavitation and a large left-sided pneumothorax. She required chest tube placement and supplemental oxygen. She ultimately required a left diagnostic thoracoscopy with talc pleurodesis and was discharged to a skilled nursing facility for physical rehabilitation.\n\nFigure 1. (a) 59 year-old woman with metastatic endometrial stromal sarcoma treated with chemotherapy. CT chest with contrast (upper row) demonstrates scattered peripheral cystic nodules compatible with treated metastatic disease. CT chest without contrast 2 months later (bottom row) demonstrates interval development of a spontaneous large left pneumothorax. Note the subpleural location of several of the left lung nodules, which may result in a pneumothorax secondary to pleural rupture, (b) 56 year-old woman with metastatic endometrial stromal sarcoma. CT chest with contrast (upper row) demonstrates multiple bilateral pulmonary parenchymal nodules compatible with metastatic disease. CT chest with contrast following 2 months of chemotherapy (bottom row) demonstrates interval development of spontaneous large right and moderate left pneumothoraces. Many of the parenchymal nodules have undergone cystic transformation following chemotherapy.\n\nCase #2\n\nThe patient is a 56-year-old Hispanic non-smoking female with no past medical history of chronic lung disease who was diagnosed with ER-/PR- metastatic, high-grade endometrial stromal sarcoma (HG-ESS) in 2019 A CT-guided biopsy of a lung nodule showed tumor morphology consistent with metastatic disease. She underwent a total abdominal hysterectomy with bilateral salpingo-oophorectomy on 2/2019 to control her bleeding. She then received doxorubicin, ifosfamide, and mesna (AIM) (AIM) chemotherapy on 4/2019, but after cycle 2, AIM was discontinued due to encephalopathy. She resumed cycle 3 with doxorubicin alone on 6/2019, but was hospitalized for ten days after CT revealed bilateral pneumothoraces. . A CT angiography during admission redemonstrated innumerable solid pulmonary nodules, now with central cavitation (Figure 1(b)). After placement of bilateral chest tubes resulting in re-expansion, the patient was discharged, but readmitted for recurrence of bilateral pneumothoraxes that necessitated talc pleurodesis bilaterally. She remained pneumothorax free for the duration of her doxorubicin therapy, but eventually her disease progressed. She continues on second line chemotherapy with stable disease at this time.\n\nDiscussion:Pulmonary metastases are a rare complication of ESS with a reported incidence ranging from 7% to 28%. 7 In patients with pulmonary metastases, patients have been found to develop unilateral and bilateral pneumothoraces. A literature review identified 10 other reported cases of women who were found to have pneumothoraces due to either previously diagnosed or unknown metastatic ESS (Table 1).7,8 –16 In 8 of the 10 patients, a diagnosis of low-grade ESS was made while the other two had an unknown grade. The majority of the patients presented with bilateral pneumothoraces (7/10 cases) and some patients experienced multiple episodes of pneumothoraces over a series of months. In four of the case reports, the pneumothorax was the first presenting sign of the malignancy while in five of the cases, the patient had been previously treated with surgery. There was one patient who had received six cycles of doxorubicin, 3 years prior to the pneumothorax, followed by hormonal therapy and 4 months of pazopanib at the time of the pneumothorax. 15 There was no report of any patient who experienced a pneumothorax while receiving chemotherapy. Furthermore, while LG-ESS with pneumothoraces have previously been described in the literature, our case series is the first to describe high-grade endometrial sarcoma presenting with pulmonary metastases leading to pneumothoraces after the start of chemotherapy.\n\nTable 1. A literature review of documented pneumothorax cases caused by metastatic endometrial stromal sarcoma.\n\nAge\tHigh/low risk\tDz course before PTX\tType of PTX\tPTX txt\tDz course after PTX\tReferences\t\n55\tLGESS\tSurgery\tR. PTX (4 times)\tClosed thoracic drainage + VATS for dx\tHormone therapy initiated.\tXu et al. 8\t\nNo new pulmonary metastatic lesions since.\t\n39\tLGESS\tNone\tB. PTX (once)\tMedian sternotomy, bilateral pleurodeses followed by lung transplantation (misdiagnosis of LAM)\tDied from lung transplantation complication.\tMahadeva et al. 9\t\nESS found on autopsy.\t\n33\tLGESS\tNone\tB. PTX (once)\tThoracotomies\tSurgery then chemotherapy.\tAbrams et al. 10\t\nDied of disease progression.\t\n58\tLGESS\tSurgery\tR. PTX (4 times)\tChest tube placement\tHormone therapy and transarterial chemotherapy injection,.\tItoh et al. 11\t\nMetastatic pelvic mass disappeared\t\n65\tLGESS\tNone\tR. PTX (twice)\tCT- guided chest drain 2nd PTX treated w/ pleurectomy\tSurgery and hormone therapy.\tChong et al. 12\t\nL. PTX (once)\t\nB. PTX (once)\t\n32\tLGESS\tNone\tB. PTX (once)\tUnknown\tAlive, tumor status unknown.\tAubry et al. 7\t\n53\tunknown\tSurgery\tB. PTX (once)\tSurgical\tUnknown.\tShomura et al. 13\t\n41\tunknown\tSurgery\tB. PTX (once)\tBilateral tube thoracostomy\tHormone therapy initiated.\tShah et al. 14\t\n40\tLGESS w/ high grade component\tChemotherapy, hormonal therapy, targeted therapy\tB. PTX (once)\tRight-sided pleurodesis\tHormone therapy, chemotherapy and targeted therapy initiated. Died of disease progression.\tVerschoor et al. 15\t\nLeft-side drain placed\t\n57\tLGESS\tSurgery\tR. PTX (once)\tVATS for treatment and diagnosis with partial resection of lung and partial ablation of parietal pleura\tHormone therapy initiated.\tMurakami et al. 16\t\nB. PTX (once)\tPatient remains asymptomatic.\t\n\nRegarding the mechanism by which ESS lung metastases lead to pneumothoraces during chemotherapy, the pathophysiology is likely multifactorial and can be attributed to the ESS histopathology, the location of the lung metastases, and the chemotherapy mechanism of action.\n\nIn our case report, the tumor cells consisted predominantly of atypical round cells with irregular nuclear outlines and a delicate capillary network. The mitotic count was high (18/10 hpf) and with areas of necrosis present (Figure 2(a) and (b)). Immunostain for CD10 was positive in both cases (Figure 2(c)) and ER immunostain was positive in one case (Figure 2(d)). As a result of the variable cell necrosis seen on histopathology and rate of tumor growth, ESS is reported to have variable imaging findings from well-defined or infiltrative masses to unilocular or multilocular cystic appearances. This can result in simultaneous cystic and solitary nodular lesions as was seen in Figure 1.\n\nFigure 2. (a) Atypical round cells with more angulated and irregular nuclear outlines, HE × 200×, (b) cells with pleomorphism and prominent mitotic figures, HE × 400×, (c) tumor cells showing CD10 positivity, CD10 × 200×, and (d) tumor cells showing ER positivity, ER × 200×.\n\nAs seen in Figure 1(b), as these parenchymal nodules evolve, they can undergo cystic transformation and depending on their location within the lung, can result in pneumothoraces. This cystic progression is often seen as a result of extensive tumor necrosis that can either be caused by aggressive tumor growth or exacerbated by chemotherapeutics and has been reported in previous series of chemotherapy associated pneumothoraces in solid tumor patients that included sarcoma patients, but none with ESS. 17 Similarly, other studies and case reports of systemic therapy induced pneumothoraces include eribulin in some types of sarcomas as well as pazopanib, an anti-VEGF targeted tyrosine kinase inhibitor, which was reported and associated with a case of high grade ESS.15,18 A subsequent study looking at the use of pazopanib in sarcoma patients concluded that it’s use did not confer a higher risk of pneumothorax than those not taking pazopanib. 19 Interestingly, the only risk factor associated with a higher risk of pneumothorax on multivariate analysis was the development of cavitary lesions within lung nodules.\n\nIn this case report, the pneumothoraces presented while the patients were being treated with doxorubicin. By inducing necrosis, doxorubicin can lead to cystic or cavitary changes. If these changes occur at susceptible regions such as the subpleural spaces or adjacent bronchi, a pneumothorax could ensue leading to emergent symptoms such as in our two cases. There are currently multiple other theories that attempt to explain the mechanisms by which these pneumothoraces occur. Another theory suggests that the tumor nodules at the lung periphery obstruct the bronchioles and lead to a “ball valve-type effect” that can lead to distension and rupture of the lung. 20 We will likely need more studies to better elucidate this mechanism and it is likely that each pneumothorax is caused by various factors without a single unifying etiology.\n\nConclusion\n\nIn conclusion, HG-ESS can be associated with pneumothoraces in patients receiving chemotherapy. This is the first report in such patients and given that systemic agents have the potential to induce tumor necrosis in ESS patients, clinicians should be made aware of this rare complication and should consider pneumothorax in their differential diagnosis in patients who develop shortness of breath during chemotherapy.\n\nContributorship: Angela Duvalyan and Kirk Tran researched the current literature and drafted the manuscript. Dr. Shefali Chopra and Dr. Christopher Lee provided their expertise for the pathology and radiology findings, respectively. Dr. James Hu was involved in conceiving, editing and organizing the manuscript. All authors reviewed and edited the manuscript and approved the final version of the manuscript.\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nEthical approval (include full name of committee approving the research and if available mention reference number of that approval): No ethical approval was required for this case report.\n\nInformed Consent: Informed consent was obtained from the patient(s) for their anonymized information to be published in this article.\n\nORCID iD: James Hu https://orcid.org/0000-0003-0620-4664\n==== Refs\nReferences\n\n1. Rizzo A Pantaleo MA Saponara M , et al . Current status of the adjuvant therapy in uterine sarcoma: a literature review. World J Clin Cases 2019; 7 (14 ): 1753–1763.31417921\n2. D’Angelo E Prat J. Uterine sarcomas: a review. Gynecol Oncol 2010; 116 (1 ): 131–139.19853898\n3. Ferreira J Felix A Lennerz JK , et al . Recent advances in the histological and molecular classification of endometrial stromal neoplasms. Virchows Arch 2018; 473 (6 ): 665–678.30324234\n4. Amant F Coosemans A Debiec-Rychter M , et al . Clinical management of uterine sarcomas. Lancet Oncol 2009; 10 : 1188–1198.19959075\n5. Rauh-Hain JA del Carmen MG. Endometrial stromal sarcoma: a systematic review. Obstet Gynecol 2013; 122 (3 ): 676–683.23921879\n6. Chang KL Crabtree GS Lim-Tan SK , et al . Primary uterine endometrial STromal neoplasms: a clinicopathologic study of 117 cases. Am J Surg Pathol 1990; 14 (5 ): 415–438.2327549\n7. Aubry M-C Myers JL Colby TV , et al . Endometrial stormal sarcoma metastatic to the lung: a detailed analysis of 16 patients. Am J Surg Pathol 2002; 26 (4 ): 440–449.11914621\n8. Xu Y Liang ZX Guo JT , et al . Cystic and solitary nodular pulmonary metastases in a patient with low-grade endometrial stromal sarcoma: a case report and literature review. Oncol Lett 2019; 18 (2 ): 1133–1144.31423173\n9. Mahadeva R Stewart S Wallwork J. Metastatic endometrial stromal sarcoma masquerading as pulmonary lymphangioleiomyomatosis. J Clin Pathol 1999; 52 : 147–148.10396245\n10. Abrams J Talcott J Corson JM. Pulmonary metastases in patients with low-grade endometrial stromal saroma. Am J Surg Pathol 1989; 13 (2 ): 133–140.2916727\n11. Itoh T Mochizuki M Kumazaki S , et al . Cystic pulmonary metastases of endometrial stromal sarcoma of the uterus, mimicking lymphangiomyomatosis: a case report with immunohistochemistry of HMB45. Pathology International. 1997; 47 : 725–729.9361109\n12. Chong SG Mitchell P Fabre A , et al . Recurrent pneumothoraces in a 65-year-old female: an unusual case of cystic lung disease. Eur Respir Rev 2014; 23 (132 ): 271–272.24881085\n13. Shomura S Suzuki H Yada M , et al . Pneumothorax caused by multiple pulmonary metastases of a uterine endometiral stromal sarcoma: report of a case. Kyobu Geka 2017; 70 (10 ): 871–873.28894063\n14. Shah DJ Phadke VK Oprea-Ilies G , et al . Spontaneous pneumothoraces due to metastatic endometrial stromal sarcoma in a woman infected with HIV. Am J Respir Crit Care Med 2016; 193 (1 ): 96–97.26397026\n15. Verschoor AJ Warmerdam F Bosse T , et al . A remarkable response to pazopanib, despite recurrent liver toxicity, in a patient with a high grade endometrial stromal sarcoma, a case report. BMC Cancer 2018; 18 (1 ): 92.29357824\n16. Murakami A Hayashi T Terao Y , et al . Cystic, nodular and cavitary metastases to the lungs in a patient with endometrial stromal sarcoma of the uterus. Intern Med 2014; 53 (9 ): 1001–1005.24785893\n17. Interiano RB McCarville MB Wu J , et al . Pneumothorax as a complication of combination antiangiogenic therapy in children and young adults with refractory/recurrent solid tumors. J Pediatr Surg 2015; 50 (9 ): 1484–1489.25783402\n18. Takada K Murase K Nakamura H , et al . Pneumothorax as an adverse event in patients with lung metastasis of soft tissue sarcoma under eribulin treatment. Intern Med 2019; 58 (20 ): 3009–3012.31243217\n19. Sabath B Muhammad HA Balagani A , et al . Secondary spontaneous pneumothorax in patients with sarcoma treated with Pazopanib, a case control study. BMC Cancer 2018; 18 (1 ): 937.30285733\n20. Lee M-J Kim E-K Kim MJ , et al . Spontaneous Pneumothorax in Metastatic Thyroid Papillary Carcinoma. J Clin Oncol 2007; 25 (18 ): 2616–2617.17577042\n\n",
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"journal": "Rare tumors",
"keywords": "Endometrial stromal sarcoma; cavitary lesion; chemotherapy; high-grade endometrial stromal sarcoma; pneumothorax; pulmonary metastasis",
"medline_ta": "Rare Tumors",
"mesh_terms": null,
"nlm_unique_id": "101526926",
"other_id": null,
"pages": "2036361320972865",
"pmc": null,
"pmid": "34394884",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "9361109;24785893;11914621;24881085;2327549;31243217;19959075;31417921;29357824;31423173;10396245;23921879;17577042;30285733;2916727;30324234;19853898;25783402;28894063;26397026",
"title": "Pneumothorax presentation in endometrial sarcoma patients receiving chemotherapy: A case series.",
"title_normalized": "pneumothorax presentation in endometrial sarcoma patients receiving chemotherapy a case series"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/20/0130690",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MESNA"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nRamucirumab is a human IgG1 monoclonal antibody that targets the extracellular domain of VEGFR-2. We aimed to assess efficacy and safety of treatment with docetaxel plus ramucirumab or placebo as second-line treatment for patients with stage IV non-small-cell-lung cancer (NSCLC) after platinum-based therapy.\n\n\nMETHODS\nIn this multicentre, double-blind, randomised phase 3 trial (REVEL), we enrolled patients with squamous or non-squamous NSCLC who had progressed during or after a first-line platinum-based chemotherapy regimen. Patients were randomly allocated (1:1) with a centralised, interactive voice-response system (stratified by sex, region, performance status, and previous maintenance therapy [yes vs no]) to receive docetaxel 75 mg/m(2) and either ramucirumab (10 mg/kg) or placebo on day 1 of a 21 day cycle until disease progression, unacceptable toxicity, withdrawal, or death. The primary endpoint was overall survival in all patients allocated to treatment. We assessed adverse events according to treatment received. This study is registered with ClinicalTrials.gov, number NCT01168973.\n\n\nRESULTS\nBetween Dec 3, 2010, and Jan 24, 2013, we screened 1825 patients, of whom 1253 patients were randomly allocated to treatment. Median overall survival was 10·5 months (IQR 5·1-21·2) for 628 patients allocated ramucirumab plus docetaxel and 9·1 months (4·2-18·0) for 625 patients who received placebo plus docetaxel (hazard ratio 0·86, 95% CI 0·75-0·98; p=0·023). Median progression-free survival was 4·5 months (IQR 2·3-8·3) for the ramucirumab group compared with 3·0 months (1·4-6·9) for the control group (0·76, 0·68-0·86; p<0·0001). We noted treatment-emergent adverse events in 613 (98%) of 627 patients in the ramucirumab safety population and 594 (95%) of 618 patients in the control safety population. The most common grade 3 or worse adverse events were neutropenia (306 patients [49%] in the ramucirumab group vs 246 [40%] in the control group), febrile neutropenia (100 [16%] vs 62 [10%]), fatigue (88 [14%] vs 65 [10%]), leucopenia (86 [14%] vs 77 [12%]), and hypertension (35 [6%] vs 13 [2%]). The numbers of deaths from adverse events (31 [5%] vs 35 [6%]) and grade 3 or worse pulmonary haemorrhage (eight [1%] vs eight [1%]) did not differ between groups. Toxicities were manageable with appropriate dose reductions and supportive care.\n\n\nCONCLUSIONS\nRamucirumab plus docetaxel improves survival as second-line treatment of patients with stage IV NSCLC.\n\n\nBACKGROUND\nEli Lilly.",
"affiliations": "David Geffen School of Medicine at UCLA/Translational Research in Oncology-US Network, Los Angeles, CA, USA. Electronic address: egaron@mednet.ucla.edu.;Institute of Oncology Ion Chiricuta and University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca, Romania.;Instituto Nacional de Cancerologia (INCAN), Mexico City, Mexico.;Tata Memorial Centre, Mumbai, India.;Oncology Unit GPP, Sotiria General Hospital, Athens School of Medicine, Athens, Greece.;Ege University School of Medicine, Izmir, Turkey.;Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.;Department of Chemotherapy, N N Blokhin Cancer Research Center, Moscow, Russia.;Centro de Investigaciones Clínicas, Clínica Viedma, Argentina.;Wojewódzkie Centrum Onkologii, Gdansk, Poland.;Chemotherapy Department, John Paul II Hospital, Krakow, Poland.;Pavlov State Medical University, St Petersburg, Russia.;Charing Cross Hospital, London, UK.;Internistische Onkologie der Thoraxtumoren, Thoraxklinik im Universitätsklinikum Heidelberg, Translational Lung Research Center Heidelberg (TLRC-H), German Center for Lung Research (DZL), Heidelberg, Germany.;Medical Oncology, San Gerardo Hospital, Monza, Italy.;Cancer Center of Kansas, Wichita, KS, USA.;St Jansdal Hospital, Herderwijk, Netherlands.;Yonsei Cancer Center, Yonsei University Health System, Seoul, South Korea.;Department of Medical Oncology, Institute of Oncology, Bucharest, Romania.;City Clinical Oncology Dispensary, St Petersburg, Russia.;LungenClinic Grosshansdorf, German Center for Lung Research (DZL), Grosshansdorf, Germany.;Istituto Toscano Tumori, Livorno, Italy.;ImClone Systems, Eli Lilly, Bridgewater, NJ, USA.;Eli Lilly, Indianapolis, IN, USA.;ImClone Systems, Eli Lilly, Bridgewater, NJ, USA.;Léon-Bérard Cancer Centre, Lyon, France.",
"authors": "Garon|Edward B|EB|;Ciuleanu|Tudor-Eliade|TE|;Arrieta|Oscar|O|;Prabhash|Kumar|K|;Syrigos|Konstantinos N|KN|;Goksel|Tuncay|T|;Park|Keunchil|K|;Gorbunova|Vera|V|;Kowalyszyn|Ruben Dario|RD|;Pikiel|Joanna|J|;Czyzewicz|Grzegorz|G|;Orlov|Sergey V|SV|;Lewanski|Conrad R|CR|;Thomas|Michael|M|;Bidoli|Paolo|P|;Dakhil|Shaker|S|;Gans|Steven|S|;Kim|Joo-Hang|JH|;Grigorescu|Alexandru|A|;Karaseva|Nina|N|;Reck|Martin|M|;Cappuzzo|Federico|F|;Alexandris|Ekaterine|E|;Sashegyi|Andreas|A|;Yurasov|Sergey|S|;Pérol|Maurice|M|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D010919:Placebos; D043823:Taxoids; D000077143:Docetaxel; D010984:Platinum; C543333:ramucirumab",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0140-6736",
"issue": "384(9944)",
"journal": "Lancet (London, England)",
"keywords": null,
"medline_ta": "Lancet",
"mesh_terms": "D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D002289:Carcinoma, Non-Small-Cell Lung; D018450:Disease Progression; D000077143:Docetaxel; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010919:Placebos; D010984:Platinum; D011788:Quality of Life; D015996:Survival Rate; D043823:Taxoids",
"nlm_unique_id": "2985213R",
"other_id": null,
"pages": "665-73",
"pmc": null,
"pmid": "24933332",
"pubdate": "2014-08-23",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial.",
"title_normalized": "ramucirumab plus docetaxel versus placebo plus docetaxel for second line treatment of stage iv non small cell lung cancer after disease progression on platinum based therapy revel a multicentre double blind randomised phase 3 trial"
} | [
{
"companynumb": "US-SA-2015SA012453",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "UNSPECIFIED INGREDIENT"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nGlycemic control in pregnancy complicated by diabetes is important. Spontaneous symptomatic hypoglycemia, in the absence of glucose-lowering treatment, is rare and requires evaluation to prevent harm.\n\n\nMETHODS\nAs a result of hypoglycemia, a pregnant woman with type 2 diabetes mellitus had progressive reduction of her insulin requirements until treatment was discontinued at 27 weeks. Despite this, she reported persistent episodes of hypoglycemia. Investigation of possible causes resulted in the discovery that she was covertly treating herself with insulin.\n\n\nCONCLUSIONS\nFactitious hypoglycemia should be considered as part of the differential diagnosis of unexplained hypoglycemia. Blood sampling during an episode of hypoglycemia is pivotal in this assessment.",
"affiliations": "Obstetrics and Gynecology Department and the Endocrinology and Nutrition Department, Complejo Hospitalario Universitario Insular Materno-Infantil, the Endocrinology and Nutrition Department, Hospital Dr Negrín, and the Departamento de Ciencias Médicas y Quirúrgicas, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain.",
"authors": "Vega Guedes|Begoña|B|;Santana Acosta|Concepción|C|;Cabrera|Francisco|F|;Wägner|Ana M|AM|",
"chemical_list": "D007004:Hypoglycemic Agents; D007328:Insulin",
"country": "United States",
"delete": false,
"doi": "10.1097/AOG.0000000000000138",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0029-7844",
"issue": "124(2 Pt 2 Suppl 1)",
"journal": "Obstetrics and gynecology",
"keywords": null,
"medline_ta": "Obstet Gynecol",
"mesh_terms": "D000328:Adult; D003924:Diabetes Mellitus, Type 2; D005162:Factitious Disorders; D005260:Female; D006801:Humans; D007003:Hypoglycemia; D007004:Hypoglycemic Agents; D007328:Insulin; D011247:Pregnancy; D011254:Pregnancy in Diabetics",
"nlm_unique_id": "0401101",
"other_id": null,
"pages": "456-458",
"pmc": null,
"pmid": "25004305",
"pubdate": "2014-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Factitious hypoglycemia in pregnancy in a patient with type 2 diabetes.",
"title_normalized": "factitious hypoglycemia in pregnancy in a patient with type 2 diabetes"
} | [
{
"companynumb": "PHHY2014ES106307",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GLYBURIDE"
},
"drugadditional": null,
"druga... |
{
"abstract": "Treatment of Central Pain Syndrome (CPS) is known to be extremely challenging. Current therapies are unsatisfactory as patients report only mild to moderate pain relief. We report a case of using ketamine as a patient-controlled analgesia (PCA) for the treatment of CPS. A 58-year-old male with CPS presented with severe generalized body pain refractory to multiple pharmacological interventions. He was started on a basal infusion rate at 0.3 mg/kg/h with a ketamine PCA bolus of 10 mg with a 10-minute lockout period. Over the next 7 days, the basal infusion rate was titrated up to 2.1 mg/kg/h relative to the number of times the patient pressed the PCA. At the end of the trial, the patient reported 0/10 pain with lightheadedness on the first day being the only side effect reported. He was discharged home with his regular pain regimen, with significant decrease in pain over the next few months. Rather than trying to establish a \"one size fits all\" protocol for ketamine infusions, this case illustrates a shift in pain management focus by allowing patients to self-titrate and demonstrates the potential for using ketamine PCA as a treatment option for CPS.",
"affiliations": null,
"authors": "Wang|Alex J|AJ|https://orcid.org/0000-0003-3653-9756;Eid|Tarek|T|;Skavinski|Kira|K|;Sharma|Ajay N|AN|https://orcid.org/0000-0002-0078-4322;Liao|Solomon|S|",
"chemical_list": "D007649:Ketamine",
"country": "England",
"delete": false,
"doi": "10.1080/15360288.2020.1814480",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1536-0288",
"issue": "35(1)",
"journal": "Journal of pain & palliative care pharmacotherapy",
"keywords": "Ketamine; NMDA antagonist; PCA; pain; refractory",
"medline_ta": "J Pain Palliat Care Pharmacother",
"mesh_terms": "D016058:Analgesia, Patient-Controlled; D006801:Humans; D007262:Infusions, Intravenous; D007649:Ketamine; D008297:Male; D008875:Middle Aged; D010146:Pain; D059408:Pain Management; D010147:Pain Measurement; D010149:Pain, Postoperative",
"nlm_unique_id": "101125608",
"other_id": null,
"pages": "38-42",
"pmc": null,
"pmid": "32960657",
"pubdate": "2021-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intravenous Ketamine Administered as Patient Controlled Analgesia and Continuous Infusion for Central Pain Syndrome.",
"title_normalized": "intravenous ketamine administered as patient controlled analgesia and continuous infusion for central pain syndrome"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-20-04775",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "KETAMINE"
},
"drug... |
{
"abstract": "OBJECTIVE\nThe purpose of this study is to report a case of Kyrieleis plaques (segmental retinal periarteritis) associated with cytomegalovirus (CMV) retinitis.\n\n\nMETHODS\nA 47-year-old female with recently diagnosed human immunodeficiency virus and a CD4 count of 55 cells/µl presented with decreased vision and floaters in her left eye. Ophthalmic examination revealed an advancing border of white granular CMV retinitis extending into the macula. Intraocular aqueous specimen contained 420,000 copies/ml of CMV DNA by polymerase chain reaction. The patient was treated with intravitreal foscarnet and oral valganciclovir.\n\n\nRESULTS\nKyrieleis plaques involving the retinal arteries were noted on presentation and increased during the first 6 weeks of treatment as the retinitis faded. The plaques on fluorescein angiography did not leak fluorescein dye and slowly faded over 5 months.\n\n\nCONCLUSIONS\nKyrieleis plaques can be seen in the setting of CMV retinitis. These plaques can be differentiated from vascular sheathing and frosted branch angiitis by its occurrence only in the retinal arteries and the absence of leakage of fluorescein dye.",
"affiliations": "Department of Ophthalmology, The New York Eye & Ear Infirmary, 310 East 14th Street, New York, NY, 10003, USA.",
"authors": "Patel|Amar|A|;Pomykala|Matthew|M|;Mukkamala|Krishna|K|;Gentile|Ronald C|RC|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s12348-011-0033-y",
"fulltext": "\n==== Front\nJ Ophthalmic Inflamm Infect\nJournal of Ophthalmic Inflammation and Infection\n1869-5760\nSpringer-Verlag Berlin/Heidelberg\n\n33\n10.1007/s12348-011-0033-y\nBrief Report\nKyrieleis plaques in cytomegalovirus retinitis\nPatel Amar 1\nPomykala Matthew 1\nMukkamala Krishna 1\nGentile Ronald C. +1-212-9794120 +1-212-9794512 rgentile@nyee.edu\n\n12\n1 Department of Ophthalmology, The New York Eye & Ear Infirmary, 310 East 14th Street, New York, NY 10003 USA\n2 Department of Ophthalmology, New York Medical College, Valhalla, NY USA\n12 8 2011\n12 8 2011\n12 2011\n1 4 189191\n24 4 2011\n17 7 2011\n© The Author(s) 2011\nPurpose\n\nThe purpose of this study is to report a case of Kyrieleis plaques (segmental retinal periarteritis) associated with cytomegalovirus (CMV) retinitis.\n\nMethods\n\nA 47-year-old female with recently diagnosed human immunodeficiency virus and a CD4 count of 55 cells/µl presented with decreased vision and floaters in her left eye. Ophthalmic examination revealed an advancing border of white granular CMV retinitis extending into the macula. Intraocular aqueous specimen contained 420,000 copies/ml of CMV DNA by polymerase chain reaction. The patient was treated with intravitreal foscarnet and oral valganciclovir.\n\nResults\n\nKyrieleis plaques involving the retinal arteries were noted on presentation and increased during the first 6 weeks of treatment as the retinitis faded. The plaques on fluorescein angiography did not leak fluorescein dye and slowly faded over 5 months.\n\nConclusions\n\nKyrieleis plaques can be seen in the setting of CMV retinitis. These plaques can be differentiated from vascular sheathing and frosted branch angiitis by its occurrence only in the retinal arteries and the absence of leakage of fluorescein dye.\n\nKeywords\n\nKyrieleis plaque\nCytomegalovirus\nRetinitis\nSegmental periarteritis\nissue-copyright-statement© Springer-Verlag 2011\n==== Body\nIntroduction\n\nKyrieleis plaques, also referred to as segmental retinal periarteritis, were first described in an eye with tuberculosis uveitis by Kyrieleis in 1933 [1]. In 1959, Griffin and Bodian used the term segmental retinal periarteritis to describe them [2]. These plaques appear as whitish, segmented deposits found within the walls of the retinal arteries. Kyrieleis plaques have been primarily described in association with infections of the retina, Toxoplasma gondii chorioretinitis being the most common. They have also been reported with Rickettsia conorii, Mycobacterium tuberculosis, Treponema pallidum, and varicella-zoster virus (VZV) infections [1, 3–7].\n\nThe etiology of Kyrieleis plaques has not been well established. Orzalesi and Ricciardi suggested these lesions are an immune response to an infectious agent and result from the deposition of immune cells and inflammatory debris in the arterial walls [8]. Others have debated this hypothesis since these plaques can persist despite resolution of the infection and treatment with steroids [4]. Wise suggested these plaques represented arteriosclerosis, while others have postulated they resulted from migration of exudates from active choroiditis to periarterial sheaths where anatomical variation leads to compartmentalization of the exudates [2, 9]. No histopathological evaluation of these plaques has been performed.\n\nThe purpose of our report is to describe the presence of Kyrieleis plaques, distinct from vascular sheathing and frosted branch angiitis, associated with cytomegalovirus (CMV) retinitis. To our knowledge, this association appears to be rarely acknowledged and not previously reported.\n\nCase\n\nA 47-year-old Hispanic female with untreated human immunodeficiency virus (HIV) presented with decreased vision and floaters in her left eye for 1-week duration. She was diagnosed with both HIV and type II diabetes mellitus 4 months prior. On ophthalmic examination, best-corrected visual acuity was 20/25 in the right eye and 20/60 in the left eye. The anterior chambers were deep and quiet, and the intraocular pressures were 18 mm Hg in both eyes. A few inflammatory cells were present in the vitreous of the left eye. Funduscopic examination revealed moderate non-proliferative diabetic retinopathy in both eyes and an advancing border of white granular retinitis surrounding the inferior and temporal macula of the left eye. Kyrieleis plaques were present on the retinal arteries without any significant sheathing or involvement of the retinal veins (Fig. 1a). Fluorescein angiography had normal retinal arterial filling with multiple hyperfluorescent microaneurysms and retinal pigment epithelial window defects peripheral to the leading edge of retinitis. Kyrieleis plaques seen on funduscopic examination did not leak or have significant late staining of fluorescein dye (Fig. 1b).Fig. 1 a) Fundus photo of the left eye with Kyrieleis plaques (arrows) involving the retinal arteries associated with an advancing border of granular Cytomegalovirus retinitis located at the border of the temporal and inferior macula. b) Fluoroescein angiography revealed normal arterial filling and absence of dye leakage from the Kyrieleis plaques (arrows). The inset represents a magnified view of the superior retinal artery at 5.5 minutes\n\nLaboratory evaluation revealed an elevated serum CMV IgG antibody with a negative systemic work up for T. gondii, VZV, herpes simplex virus (HSV), T. pallidum, and tuberculosis. CD4 T cell count was 55 cells/μL, and HIV viral load was 193,065 copies/ml. Polymerase chain reaction of the aqueous was positive for CMV DNA (420,000 copies/ml) and negative for HSV and T. gondii DNA.\n\nThe CMV retinitis was treated with intravitreal injections of foscarnet sodium and oral valganciclovir. The patient was also started on HAART, antiglycemic therapy, azithromycin for Mycobacterium avium complex prophylaxis, and atovaquone for Pneumocystis jiroveci pneumonia prophylaxis. Over the first 6 weeks as the retinitis resolved, the Kyrieleis plaques increased in number and become confluent along parts of the retinal arteries (Fig. 2). The Kyrieleis plaques subsequently faded over the next few months with a few persisting adjacent to the optic nerve at 5 months (Fig. 3). On follow-up, the CD4 T cell count increased to 305 cells/μL, and the HIV viral load became undetectable. Despite resolution of the retinitis, vision in the left eye decreased to 20/100, complicated by immune recovery uveitis and macular edema.Fig. 2 Fundus photo after 6 weeks of anti-viral treatment with a marked increase in Kyrieleis plaques as the CMV retinitis resolved\n\nFig. 3 Fundus photo 5 months after initiation of treatment with fading of Kyrieleis plaques\n\nDiscussion\n\nCMV retinitis typically presents with focal areas of retinal necrosis with primary lesions usually located adjacent to blood vessels, secondary to hematogenous spread of the virus [10]. On funduscopic examination, the appearance of CMV retinitis can range from a dry-appearing irregular and granular border with satellite lesions to an edematous and confluent area of thick, yellow-white necrosis associated with retinal hemorrhages and vascular sheathing [10].\n\nVascular involvement in CMV retinitis can result in vascular sheathing. Exudates around retinal vessels, more commonly veins, can result in focal areas of fluffy white cuffing or sheathing, with or without skip areas [11]. When the perivascular sheathing is severe, the retinal arteries and veins appear frosted, and the term “frosted branch angiitis” is used to describe this entity [12]. Kyrieleis plaques can be differentiated from vascular sheathing and frosted branch angiitis by its clinical and fluorescein angiographic features. Kyrieleis plaques affect only the retinal arteries in contrast to frosted branch angiitis that involves both the retinal arteries and veins. In addition, Kyrieleis plaques are confined to the vessel wall and do not leak fluorescein dye in contrast to frosted branch angiitis that extends outside the vessel wall and extensively leaks fluorescein dye [12, 13].\n\nKyrieleis plaques have been primarily reported in association with toxoplasmosis chorioretinitis. Although the cause of Kyrieleis plaques is unclear, the increase in these plaques following treatment and immune recovery in our case supports the theory of an immune response to an infectious agent and deposition of inflammatory debris as the etiology of these plaques. Kyrieleis plaques, although not specifically noted in many reports of infectious chorioretinitis, may be under reported. While many authors have concluded that Kyrieleis plaques are rare, Griffin and Bodian in 1959 felt that they may be more common than the literature suggests [2]. We have found at least one case of CMV retinitis in the literature that appears to also have had Kyrieleis plaques, similar to our patient [14]. Our case adds CMV retinitis to the list of causes of Kyrieleis plaques.\n\nAcknowledgment\n\nThis study was supported in part by the Department of Ophthalmology Research Fund and the Norma Lazar Eye Research Grant of The New York Eye & Ear Infirmary.\n\nOpen Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution and reproduction in any medium, provided the original author(s) and source are credited.\n==== Refs\nReferences\n\n1. Kyrieleis W Uber atypische gerfaesstuberkulose der netzhaut Arch Augenheilkd 1933 107 182 190\n2. Griffin AO Bodian M Segmental retinal periarteritis; a report of three cases Am J Ophthalmol 1959 47 544 548 13637172\n3. Frances-Munoz E Gallego-Pinazo R Lopez-Lizcano R Kyrieleis vasculitis in acute retinal necrosis Clin Ophthalmol 2010 4 837 838 20689738\n4. Schwartz PL Segmental retinal periarteritis as a complication of toxoplasmosis Ann Ophthalmol 1977 9 157 162 843015\n5. Khairallah M Ladjimi A Chakroun M Posterior segment manifestations of Rickettsia conorii infection Ophthalmol 2004 111 529 534 10.1016/j.ophtha.2003.04.012\n6. Krishnamurthy R Cunningham ET Jr Atypical presentation of syphilitic uveitis associated with Kyrieleis plaques Br J Ophthalmol 2008 92 1152 1153 10.1136/bjo.2007.124693 18653612\n7. Brown RM Mendis U Retinal arteritis complicating herpes zoster ophthalmicus Br J Ophthalmol 1973 57 344 346 10.1136/bjo.57.5.344 4541366\n8. Orzalesi N Ricciardi L Segmental retinal periarteritis Am J Ophthalmol 1971 72 55 59 5571211\n9. Wise GN Uveitis with secondary retinal arteriosclerosis Am J Ophthalmol 1961 51 797 807 13785992\n10. Vaudaux JD Holland GN Ryan SJ Schachat AP Wilkinson CP Cytomegalovirus infections of the retina Retina 2006 4 Philadelphia Elsevier 1605 1623\n11. El-Asrar AM Herbort CP Tabbara KF A clinical approach to the diagnosis of retinal vasculitis Int Ophthalmol 2010 30 149 173 10.1007/s10792-009-9301-3 19190857\n12. Walker S Iguchi A Jones NP Frosted branch angiitis: a review Eye 2004 18 527 533 10.1038/sj.eye.6700712 15131687\n13. Walton RC Ashmore ED Retinal vasculitis Curr Opin Ophthalmol 2003 14 413 419 10.1097/00055735-200312000-00015 14615648\n14. Babu K Murthy KR Sudarshan S Bilateral arteritis with cytomegalovirus retinitis in a patient infected with human immunodeficiency virus Retin Cases Brief Rep 2010 4 31 33 10.1097/ICB.0b013e318199d9dc\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1869-5760",
"issue": "1(4)",
"journal": "Journal of ophthalmic inflammation and infection",
"keywords": null,
"medline_ta": "J Ophthalmic Inflamm Infect",
"mesh_terms": null,
"nlm_unique_id": "101553216",
"other_id": null,
"pages": "189-91",
"pmc": null,
"pmid": "21833831",
"pubdate": "2011-12",
"publication_types": "D016428:Journal Article",
"references": "13637172;15131687;19190857;13785992;25390115;843015;5571211;18653612;15019331;14615648;20689738;4541366",
"title": "Kyrieleis plaques in cytomegalovirus retinitis.",
"title_normalized": "kyrieleis plaques in cytomegalovirus retinitis"
} | [
{
"companynumb": "US-CLINIGEN GROUP PLC/ CLINIGEN HEALTHCARE LTD-E2B_00005529",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VALGANCICLOVIR HYDROCHLORIDE"
... |
{
"abstract": "Adenosine can produce arrhythmias, which are generally short living. It may induce PACs and PVCs, sinus bradycardia, and atrial fibrillation. There have been reports of transient polymorphic VT (torsades de pointes) in patients with LQTS and others in people with normal QT interval. We report a case of a long episode of polymorphic VT induced by adenosine. A 27 year old woman received 6 mg adenosine for PSVT, which terminated and torsades de pointes developed, persisting for 17 seconds and terminated spontaneously. This is the longest described duration of the torsades after adenosine administration in patients with normal QT interval.",
"affiliations": "Department of Cardiology, Kaplan Medical Center, Rehovot, Israel; The Hebrew University, Jerusalem, Israel. Electronic address: nickt@netvision.net.il.;Department of Cardiology, Kaplan Medical Center, Rehovot, Israel; The Hebrew University, Jerusalem, Israel.;Department of Cardiology, Kaplan Medical Center, Rehovot, Israel; The Hebrew University, Jerusalem, Israel.;Department of Cardiology, Kaplan Medical Center, Rehovot, Israel; The Hebrew University, Jerusalem, Israel.;Department of Cardiology, Kaplan Medical Center, Rehovot, Israel; The Hebrew University, Jerusalem, Israel.",
"authors": "Teodorovich|Nicholay|N|;Margolin|Elena|E|;Kogan|Yonatan|Y|;Paz|Ofir|O|;Swissa|Moshe|M|",
"chemical_list": "D014665:Vasodilator Agents; D000241:Adenosine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "0022-0736",
"issue": "49(2)",
"journal": "Journal of electrocardiology",
"keywords": "Adenosine; Arrhythmias; PSVT; QT interval; Sinus bradycardia",
"medline_ta": "J Electrocardiol",
"mesh_terms": "D000241:Adenosine; D000328:Adult; D003937:Diagnosis, Differential; D004562:Electrocardiography; D005260:Female; D006801:Humans; D016171:Torsades de Pointes; D014665:Vasodilator Agents",
"nlm_unique_id": "0153605",
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"pages": "171-3",
"pmc": null,
"pmid": "26850499",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Torsades de pointes after adenosine administration.",
"title_normalized": "torsades de pointes after adenosine administration"
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"abstract": "Undifferentiated large-cell lung cancer is a rare type of non-small cell lung cancer (NSCLC) with a poor prognosis. It is insensitive to chemotherapy and easily develops drug resistance. Analysis of the Surveillance, Epidemiology, and End Results (SEER) database showed that patients with stage IV undifferentiated large-cell lung cancer had a median overall survival (OS) of only 4 months and that those who received chemotherapy had a median OS of only 5 months longer than those who did not. For the first time, we report a case of advanced large-cell undifferentiated lung cancer with rare tonsil metastasis. The patient developed resistance after 3 months of platinum-based systemic chemotherapy and local treatment. Antiangiogenic therapy has been continuously progressing and has shown certain efficacy in treating many malignant tumors, such as lung cancer. However, there are no relevant studies or case reports on antiangiogenic therapy in the treatment of undifferentiated large-cell lung cancer. Anlotinib, an orally delivered small-molecule antiangiogenic tyrosine kinase inhibitor (TKI), was administered to this patient after chemotherapy resistance occurred, and the outcome was assessed as continued stable disease (SD). As of the last follow-up evaluation, the progression-free survival (PFS) of the patient was 21.5 months, and the OS was 27.5 months. Retrospective immunohistochemical analysis showed that the patient was positive for one of the targets of anlotinib (PDGFR). In general, the findings in this case suggest that anlotinib may be an option with good efficacy for patients with large-cell undifferentiated lung cancer after chemotherapy resistance that may have good efficacy and also suggest that PDGFR may be the target underlying this effect.",
"affiliations": "Cancer Medical Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.;Cancer Medical Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.;Cancer Medical Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.;Cancer Medical Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.;Cancer Medical Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.",
"authors": "Xu|Tianwei|T|;Wei|Chenchen|C|;Zou|Xiaoteng|X|;Lu|Binbin|B|;Wang|Zhaoxia|Z|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fonc.2021.680818",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X\nFrontiers Media S.A.\n\n10.3389/fonc.2021.680818\nOncology\nCase Report\nCase Report: Long-Term Survival With Anlotinib in a Patient With Advanced Undifferentiated Large-Cell Lung Cancer and Rare Tonsillar Metastasis\nXu Tianwei †\n\nWei Chenchen †\nZou Xiaoteng †\nLu Binbin †\nWang Zhaoxia *\n\nCancer Medical Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China\nEdited by: Zhi Li, The First Affiliated Hospital of China Medical University, China\n\nReviewed by: Lin Wu, Central South University, China; Wei Jing, ShengJing Hospital of China Medical University, China\n\n*Correspondence: Zhaoxia Wang, wangzhaoxia@njmu.edu.cn\n†These authors have contributed equally to this work\n\nThis article was submitted to Pharmacology of Anti-Cancer Drugs, a section of the journal Frontiers in Oncology\n\n24 6 2021\n2021\n11 68081815 3 2021\n31 5 2021\nCopyright © 2021 Xu, Wei, Zou, Lu and Wang\n2021\nXu, Wei, Zou, Lu and Wang\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.\nUndifferentiated large-cell lung cancer is a rare type of non-small cell lung cancer (NSCLC) with a poor prognosis. It is insensitive to chemotherapy and easily develops drug resistance. Analysis of the Surveillance, Epidemiology, and End Results (SEER) database showed that patients with stage IV undifferentiated large-cell lung cancer had a median overall survival (OS) of only 4 months and that those who received chemotherapy had a median OS of only 5 months longer than those who did not. For the first time, we report a case of advanced large-cell undifferentiated lung cancer with rare tonsil metastasis. The patient developed resistance after 3 months of platinum-based systemic chemotherapy and local treatment. Antiangiogenic therapy has been continuously progressing and has shown certain efficacy in treating many malignant tumors, such as lung cancer. However, there are no relevant studies or case reports on antiangiogenic therapy in the treatment of undifferentiated large-cell lung cancer. Anlotinib, an orally delivered small-molecule antiangiogenic tyrosine kinase inhibitor (TKI), was administered to this patient after chemotherapy resistance occurred, and the outcome was assessed as continued stable disease (SD). As of the last follow-up evaluation, the progression-free survival (PFS) of the patient was 21.5 months, and the OS was 27.5 months. Retrospective immunohistochemical analysis showed that the patient was positive for one of the targets of anlotinib (PDGFR). In general, the findings in this case suggest that anlotinib may be an option with good efficacy for patients with large-cell undifferentiated lung cancer after chemotherapy resistance that may have good efficacy and also suggest that PDGFR may be the target underlying this effect.\n\nundifferentiated large-cell lung cancer\nantiangiogenic therapy\nanlotinib\ntonsillar metastasis\nplatelet-derived growth factor receptors (PDGFR)\n==== Body\nIntroduction\n\nMetastasis of tumors to the tonsil is extremely rare, with nearly 100 cases reported to date. The most common primary tumors are digestive tract tumors, renal cancer, and melanoma (1). Most metastatic tonsil tumors from lung cancer result from small cell lung cancer (2). No case of tonsil metastasis from undifferentiated large-cell lung cancer has been reported.\n\nAntiangiogenic therapy has been recommended for the treatment of non-small cell lung cancer (NSCLC) (3), but there have been no clinical trials or case reports of antiangiogenic therapy for undifferentiated large-cell lung cancer. Anlotinib is an oral multitarget small-molecule tyrosine kinase inhibitor (TKI) (4). Its main targets include VEGFR and PDGFR. The Alter0303 study (5) showed that anlotinib as a third-line treatment can benefit advanced NSCLC patients with chemotherapy failure. However, patients with undifferentiated large-cell lung cancer were not included in this study; therefore, the efficacy of anlotinib in this group of patients is unknown. We present the first case of a patient with undifferentiated large-cell lung cancer with rare tonsillar metastases who achieved a long survival time with anlotinib treatment after chemotherapy failure. The following case is presented in accordance with the CARE reporting checklist.\n\nCase Presentation\n\nA 70-year-old man with a 20-year history of smoking presented to the otolaryngology department in January 2019 with a foreign body sensation in his throat. The patient occasionally had dry cough, without sputum, hemoptysis, chest tightness, dyspnea, and other symptoms. A physical examination showed that the trachea was centered, and there was no obvious abnormality in the respiratory sounds of either lung. No superficial lymph node enlargement was observed. The patient reported no family history of cancer. Laryngoscopy revealed a tonsil mass ( Figure 1A ). Chest computed tomography (CT) (January 16, 2019) showed a mass of 78 * 51 mm in the upper left mediastinum ( Figure 1C ). Cranial magnetic resonance imaging (MRI), abdominal CT, and whole body bone scan examinations showed no other metastatic lesions ( Supplementary Figure 1 ). We performed puncture of the lung lesions and tonsillectomy for the tonsil lesions. Hematoxylin and eosin (HE) staining and Ki-67 immunohistochemistry of the tonsil lesion demonstrated malignancy. The TTF1 immunohistochemical results suggested that the lesion might originate from the lung ( Figure 1B ). HE staining and Ki-67 immunohistochemistry of lung tissue indicated large-cell carcinoma. The results of assessment of neuroendocrine-related immunohistochemical indexes, including CGA and SYN, were negative, indicating that the tumor may not have neuroendocrine function ( Figure 1D ). The patient was finally diagnosed with undifferentiated large-cell lung cancer of the left lung [T4NxM1b, American Joint Committee on Cancer (AJCC) 8th edition]. Next generation sequencing (NGS, Geneseeq Technology Inc) found mutations in TP53, PIK3CA, and CD74 and no driver gene mutations that could be used for targeted therapy ( Table 1 ).\n\nFigure 1 Initial diagnosis of advanced undifferentiated large-cell lung cancer with rare tonsillar metastasis. (A) Tonsillar metastasis. (B) Pathology and immunohistochemistry of tonsillar metastasis [KI-67 (40%+); TTF1 (±)]. (C) Primary lung lesion shown by chest CT. (D) Pathology and immunohistochemistry of the primary lung lesion [KI-67 (50%+); CGA (−; SYN (−)].\n\nTable 1 Mutations and their abundance detected by NGS (Geneseeq Technology Inc).\n\nGenes\tMutations\tPeripheral Blood\tCancer tissue\t\nCD74\tc.679C>G (p.L227V)\t–\t1.8%\t\nPIK3CA\tc.1637A>C (p.Q546P)\t0.8%\t8.4%\t\nTP53\tc.434T>A (p.L145Q)\t1.7%\t30.7%\t\n\nAs shown in Figure 2 , from February 15, 2019, the patient received albumin-bound paclitaxel (200 mg on d 1 and 8) + carboplatin (450 mg on d 1) chemotherapy for four cycles. Chest CT (May 15, 2019) showed a 93 * 62 mm mass near the left upper mediastinum, and the efficacy was evaluated as progressive disease (PD). This result indicated that the patient had acquired resistance to chemotherapy, with a progression-free survival (PFS) time of 3 months for this chemotherapy regimen. A bronchial arterial infusion (cisplatin 40 mg + epirubicin 40 mg) was performed on May 22, 2019. Chest CT (June 6, 2019) showed a mass of 102 * 63 mm near the left upper mediastinum, which was evaluated as stable disease (SD). The patient refused further chemotherapy regimens. Immunotherapy was refused for financial reasons. Complying with the patient’s wishes, we administered oral antiangiogenic therapy with anlotinib (12 mg/d). Each cycle was defined as 2 weeks on treatment followed by 1 week off treatment. The patient was followed up at an outpatient clinic. The patient developed tolerable mild fatigue, diarrhea, and a small rash after initial use of anlotinib. These adverse reactions were rated as Level 1 (CTCAE 5.0). These adverse events resolved spontaneously without treatment after two cycles of anlotinib treatment. Chest CT (August 8, 2019) showed a 106 * 63 mm mass near the left upper mediastinum, and the efficacy was evaluated as SD. The patient continued oral treatment with anlotinib monotherapy. Chest CT (April 23, 2020) showed a 101 * 64 mm mass near the left upper mediastinum, and the efficacy was evaluated as SD. The patient continued to receive oral anlotinib monotherapy, and chest CT (October 15, 2020) showed a 93 * 52 mm mass near the left upper mediastinum. Chest CT scan (December 17, 2020.) showed a 93 * 52 mm mass near the left upper mediastinum. The last follow-up chest CT scan (April 1, 2021) showed an 83 * 52 mm mass near the left upper mediastinum, and the efficacy was evaluated as SD. At the last follow-up, the patient’s PFS and overall survival (OS) were 21.5 and 27.5 months, respectively, after anlotinib treatment. A re-examination of head and neck CT showed no new lesions in the tonsils ( Supplementary Figure 1 ). There was also no evidence of new metastasis or progression beyond the primary lesion during follow-up. Timeline of the relevant information is shown in Table 2 .\n\nFigure 2 Graphic summary of the case.\n\nTable 2 Timeline of the relevant information.\n\nTime\tMajor medical examination\tDiagnosis or efficacy evaluation\tTreatment\t\n2019.01.16–2019.01.29\tLaryngoscopy; chest CT; cranial MRI; abdominal CT; whole body bone scan; NGS\tUndifferentiated large-cell lung cancer of the left lung (T4NxM1b, AJCC 8th edition)\tPuncture of the lung lesions and tonsillectomy;\t\n2019.02.15\t-\t\tAlbumin-bound paclitaxel (200 mg on d 1 and 8) + carboplatin (450 mg on d 1);\t\n2019.03.09\t-\t\tAlbumin-bound paclitaxel (200 mg on d 1 and 8) + carboplatin (450 mg on d 1);\t\n2019.04.02\t-\t\tAlbumin-bound paclitaxel (200 mg on d 1 and 8) + carboplatin (450 mg on d 1);\t\n2019.04.22\t-\t\tAlbumin-bound paclitaxel (200 mg on d 1 and 8) + carboplatin (450 mg on d 1);\t\n2019.05.15\tChest CT;\tPD\t\t\n2019.05.22\t-\t\tBronchial arterial infusion (cisplatin 40 mg + epirubicin 40 mg);\t\n2019.06.21\tChest CT;\tSD\tAnlotinib;\t\n2019.08.08\tChest CT;\tSD\t\n2020.04.23\tChest CT;\tSD\t\n2020.10.15\tChest CT;\tSD\t\n2020.12.17\tChest CT;\tSD\t\n2021.04.01\tChest CT;\tSD\t\n\nAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this manuscript and any accompanying images.\n\nDiscussion\n\nThe main pathological types of primary tonsil tumors are squamous cell carcinoma or lymphoma, and metastatic tumors of the tonsil are very rare (6). Metastatic tonsil tumors have been reported to account for only 0.8% of all tonsil tumors (7). Nearly 100 cases of metastatic malignant tumors of the tonsil have been reported, and the most common sources are digestive tract tumors, kidney cancer, and melanoma. In lung cancer, the primary pathological type of tonsil metastasis is small cell lung cancer, and this case is the first report of tonsil metastasis from undifferentiated large-cell lung cancer.\n\nUndifferentiated large-cell lung cancer is a type of NSCLC, but its incidence is significantly lower than that of common lung adenocarcinoma, lung squamous cell carcinoma, and other subtypes (8). The prognosis of patients with advanced undifferentiated large-cell lung cancer is poor (9). We obtained survival data from the Surveillance, Epidemiology, and End Results (SEER) database for 1,129 patients diagnosed with stage IV (AJCC 7th edition) large-cell undifferentiated lung cancer after 2010 ( Figure 3A ). The results showed that the median OS was only 4 months. The median survival of those who received chemotherapy was only 5 months longer than that of those who did not or whose treatment status was unknown (7 vs 2 months, P < 0.0001). This report describes a case of stage IV undifferentiated large-cell lung cancer with rare tonsillar metastases for which genetic testing did not provide a therapeutic target. Platinum-based chemotherapy was selected as the first-line treatment. The PFS with chemotherapy was 3 months, which was similar to the database results.\n\nFigure 3 (A) Kaplan–Meier (KM) analysis of survival of patients with stage IV (AJCC 7th edition) undifferentiated large-cell lung cancer from the SEER database after 2010. (B) Retrospective examination of the expression of angiogenesis-related genes and anlotinib targets by immunohistochemistry [VEGF (++); VEGFR (−); PDGFR (+++)].\n\nThe theory of cutting off the blood supply of tumors to combat them was first proposed in 1971. The first proangiogenesis factor, VEGF, was isolated in 1989. The main recognized tumor angiogenesis signaling pathways are the VEGF/VEGFR and PDGF/PDGFR pathways (10). At present, antiangiogenic therapy with bevacizumab is recommended for the treatment of lung cancer (3). However, there have been no clinical trials or case reports of antiangiogenic therapy for undifferentiated large-cell lung cancer. Anlotinib is an oral small-molecule multitarget antiangiogenic TKI, and its main targets include VEGFR, PDGFR, and other major angiogenesis-related factors. The Alter0303 study showed that the use of oral anlotinib monotherapy as third-line treatment for advanced NSCLC achieved a PFS of 4 months and an OS of 3.3 months (5). However, patients with large-cell undifferentiated carcinoma were not included in this study; therefore, the efficacy of anlotinib in patients with this type of lung cancer is unclear.\n\nIn this case, the tumor size rapidly increased after chemotherapy resistance occurred. We administered the oral antiangiogenic agent anlotinib. Early imaging during anlotinib treatment showed that the tumor remained stable and began to shrink slowly with prolonged treatment. At the last follow-up, the PFS and OS with anlotinib treatment were 21.5 and 27.5 months, respectively. There were no significant adverse reactions with this regimen. We retrospectively examined the expression of angiogenesis-related genes and anlotinib targets in this case by immunohistochemistry ( Figure 3B ). VEGF expression was positive, indicating that tumor angiogenesis activity was very high. Interestingly, VEGFR expression was negative. The expression of PDGFR, another important target of anlotinib, was positive, indicating that the PDGFR signaling pathway may be important for the function of anlotinib in the treatment of this patient. PDGFR is a tyrosine kinase receptor with two structurally related forms. Binding of PDGF and PDGFR activates downstream pathways that mediate angiogenesis (11). Studies have shown that PDGFR can be significantly overexpressed in lung tumors. Animal experiments have also shown that PDGFR inhibitors can significantly inhibit angiogenesis in tumors, while normal tissue angiogenesis is not affected (12). Therefore, the angiogenesis of PDGFR-positive vascular endothelial cells alone may not be significantly affected by PDGFR inhibitors. PDGFR immunohistochemistry in this case also indicated PDGFR positivity of the tumor. These results suggest that patients with PDGFR-positive tumors may receive additional benefit from PDGFR inhibitors such as anlotinib. This case suggests that for large-cell undifferentiated lung cancer patients who exhibit chemotherapy resistance, antiangiogenic therapy with anlotinib can be attempted and may have a good effect. PDGFR may be the target underlying this effect.\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\nEthical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study.\n\nAuthor Contributions\n\nTX, CW, XZ, and BL collected the clinical information, diagnostic information, therapeutic information, and images of the patients. TX wrote the manuscript. ZW identified the case and submitted the manuscript. TX and XZ revised the manuscript. CW and ZW proofread the manuscript. TX, CW, XZ, and BL contributed equally to this work. All authors contributed to the article and approved the submitted version.\n\nFunding\n\nThis work was supported by grants from the Key Research and Development Plan (Social Development) of Science and Technology Department of Jiangsu Province (No. BE2019760); The Key young medical talents of Jiangsu Province (No. QNRC2016662); The “123” advantageous disciplines, core technologies and “789” excellent talent training plan of the Second Affiliated Hospital of Nanjing Medical University (No. 789ZYRC202090148).\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\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2021.680818/full#supplementary-material\n\nSupplementary Figure 1 (A) Cranial magnetic resonance imaging (MRI), abdominal CT, and whole body bone scan examinations showed no other metastatic lesions at initial diagnosis. (B) Metastatic lesion of tonsil before and after treatment.\n\nClick here for additional data file.\n==== Refs\nReferences\n\n1 Chen XH Bao YY Zhou SH Wang QY Zhao K . Palatine Tonsillar Metastasis of Small-Cell Neuroendocrine Carcinoma From the Lung Detected by FDG-PET/CT After Tonsillectomy: A Case Report. Iran J Radiol (2013) 10 (3 ):148–51. 10.5812/iranjradiol.9281\n2 Unsal M Kutlar G Sullu Y Yurtlu S . Tonsillar Metastasis of Small Cell Lung Carcinoma. Clin Respir J (2016) 10 (6 ):681–3. 10.1111/crj.12275\n3 Ettinger DS Wood DE Aggarwal C Aisner DL Akerley W Bauman JR . Nccn Guidelines Insights: Non-Small Cell Lung Cancer, Version 1.2020. J Natl Compr Canc Netw (2019) 17 (12 ):1464–72. 10.6004/jnccn.2019.0059\n4 Sun Y Niu W Du F Du C Li S Wang J . Safety, Pharmacokinetics, and Antitumor Properties of Anlotinib, An Oral Multi-Target Tyrosine Kinase Inhibitor, in Patients With Advanced Refractory Solid Tumors. J Hematol Oncol (2016) 9 (1 ):105. 10.1186/s13045-016-0332-8 27716285\n5 Han B Li K Wang Q Zhang L Shi J Wang Z . Effect of Anlotinib as a Third-Line or Further Treatment on Overall Survival of Patients With Advanced Non-Small Cell Lung Cancer: The ALTER 0303 Phase 3 Randomized Clinical Trial. JAMA Oncol (2018) 4 (11 ):1569–75. 10.1001/jamaoncol.2018.3039\n6 Tsubochi H Isogami K Sato N Imai T . Successfully Treated Lingual Tonsillar Metastasis From Bronchial Adenocarcinoma. Jpn J Thorac Cardiovasc Surg (2005) 53 (8 ):455–7. 10.1007/s11748-005-0085-8\n7 Hyams VJ . Differential Diagnosis of Neoplasia of the Palatine Tonsil. Clin Otolaryngol Allied Sci (1978) 3 (2 ):117–26. 10.1111/j.1365-2273.1978.tb00674.x\n8 Skrickova J Kadlec B Venclicek O Merta Z . Lung Cancer. Cas Lek Cesk (2018) 157 (5 ):226–36.\n9 Shi Y Chen W Li C Qi S Zhou X Zhang Y . Clinicopathological Characteristics and Prediction of Cancer-Specific Survival in Large Cell Lung Cancer: A Population-Based Study. J Thorac Dis (2020) 12 (5 ):2261–9. 10.21037/jtd.2020.04.24\n10 Ferrara N Adamis AP . Ten Years of Anti-Vascular Endothelial Growth Factor Therapy. Nat Rev Drug Discov (2016) 15 (6 ):385–403. 10.1038/nrd.2015.17 26775688\n11 Bauman JE Eaton KD Martins RG . Antagonism of Platelet-Derived Growth Factor Receptor in Non Small Cell Lung Cancer: Rationale and Investigations. Clin Cancer Res (2007) 13 (15 Pt 2 ):s4632–6. 10.1158/1078-0432.CCR-07-0212\n12 Papadopoulos N Lennartsson J . The PDGF/PDGFR Pathway as a Drug Target. Mol Aspects Med (2018) 62 :75–88. 10.1016/j.mam.2017.11.007 29137923\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2234-943X",
"issue": "11()",
"journal": "Frontiers in oncology",
"keywords": "anlotinib; antiangiogenic therapy; platelet-derived growth factor receptors (PDGFR); tonsillar metastasis; undifferentiated large-cell lung cancer",
"medline_ta": "Front Oncol",
"mesh_terms": null,
"nlm_unique_id": "101568867",
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"pages": "680818",
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"pubdate": "2021",
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"title": "Case Report: Long-Term Survival With Anlotinib in a Patient With Advanced Undifferentiated Large-Cell Lung Cancer and Rare Tonsillar Metastasis.",
"title_normalized": "case report long term survival with anlotinib in a patient with advanced undifferentiated large cell lung cancer and rare tonsillar metastasis"
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"abstract": "A durable response after the discontinuation of immune checkpoint-inhibitor therapy has previously been reported in several cancers. We herein describe a patient with gastric cancer who maintained a durable response after the discontinuation of nivolumab. A 65-year-old man was treated with nivolumab as a sixth-line therapy for recurrent gastric cancer. After four cycles of nivolumab therapy, he showed a partial response. But the treatment was discontinued when two immune-related adverse events occurred after six cycles. Disease regression was sustained for approximately 2 years, without the re-administration of nivolumab. The characteristics leading to such responses are unclear, and further studies are warranted in this regard.",
"affiliations": "Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Japan.;Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Japan.;Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Japan.;Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Japan.;Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Japan.;Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Japan.;Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Japan.;Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Japan.;Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Japan.;Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Japan.;Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Japan.;Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Japan.;Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Japan.;Department of Diagnostic Pathology, Faculty of Medicine, University of Tsukuba, Japan.;Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Japan.;Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Japan.",
"authors": "Yatsuda|Yukino|Y|;Hirose|Suguru|S|;Ito|Yoshimi|Y|;Onoda|Tsubasa|T|;Sugiyama|Yutaro|Y|;Nagafuchi|Miho|M|;Suzuki|Hirosumi|H|;Niisato|Yusuke|Y|;Tange|Yoshitaka|Y|;Ikeda|Takafumi|T|;Yamada|Takeshi|T|;Yamamoto|Yoshiyuki|Y|;Ohyama Osawa|Mariko|M|;Sakamoto|Noriaki|N|;Moriwaki|Toshikazu|T|;Mizokami|Yuji|Y|",
"chemical_list": "D000077594:Nivolumab",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.5893-20",
"fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918\n1349-7235\nThe Japanese Society of Internal Medicine\n\n33162479\n10.2169/internalmedicine.5893-20\nCase Report\nA Durable Response after the Discontinuation of Nivolumab in an Advanced Gastric Cancer Patient\nYatsuda Yukino 1\nHirose Suguru 1\nIto Yoshimi 1\nOnoda Tsubasa 1\nSugiyama Yutaro 1\nNagafuchi Miho 1\nSuzuki Hirosumi 1\nNiisato Yusuke 1\nTange Yoshitaka 1\nIkeda Takafumi 1\nYamada Takeshi 1\nYamamoto Yoshiyuki 1\nOhyama Osawa Mariko 2\nSakamoto Noriaki 3\nMoriwaki Toshikazu 1\nMizokami Yuji 1\n1 Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Japan\n2 Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Japan\n3 Department of Diagnostic Pathology, Faculty of Medicine, University of Tsukuba, Japan\nCorrespondence to Dr. Toshikazu Moriwaki, tmoriwak@md.tsukuba.ac.jp\n\n9 11 2020\n1 4 2021\n60 7 10111017\n17 7 2020\n25 9 2020\nCopyright © 2021 by The Japanese Society of Internal Medicine\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ The Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).\nA durable response after the discontinuation of immune checkpoint-inhibitor therapy has previously been reported in several cancers. We herein describe a patient with gastric cancer who maintained a durable response after the discontinuation of nivolumab. A 65-year-old man was treated with nivolumab as a sixth-line therapy for recurrent gastric cancer. After four cycles of nivolumab therapy, he showed a partial response. But the treatment was discontinued when two immune-related adverse events occurred after six cycles. Disease regression was sustained for approximately 2 years, without the re-administration of nivolumab. The characteristics leading to such responses are unclear, and further studies are warranted in this regard.\n\ngastric cancer\nnivolumab\ndurable response\nimmune checkpoint inhibitor\nimmune-related adverse event\nPD-1\n==== Body\nIntroduction\n\nNivolumab, a monoclonal antibody targeting programmed cell death-1 (PD-1), has been shown to provide remarkable efficacy in the treatment of patients with various kinds of malignant tumors and it is approved for the treatment of several cancers, including melanoma (1), non-small cell lung cancer (NSCLC) (2), renal cell carcinoma (RCC) (3), squamous cell carcinoma of the head and neck (4), and Hodgkin's lymphoma (5). The ATTRACTION-2 study was conducted to investigate the efficacy and safety of nivolumab for heavily pretreated advanced gastric cancer (AGC) patients (6). This randomized, double-blind, placebo-controlled phase 3 trial showed the superiority of nivolumab over a placebo, with an objective response rate of 11.2% [95% confidence interval (CI): 7.7-15.6], a median progression-free survival (PFS) of 1.61 months (95% CI: 1.54-2.30), and a median overall survival (OS) of 5.26 months (95% CI: 4.60- 6.37). Based on the results of this study, nivolumab was approved for AGC as either a third- or later-line treatment, and it has been recently recognized as a standard chemotherapeutic regimen in Japan.\n\nUnlike in the case of conventional cytotoxic anticancer drugs or molecular targeted drugs, the blockade of the PD-1 pathway confers an adaptive memory immune response that resets the equilibrium between the tumor and host immune responses, thus indicating its potential to sustain an antitumor response even after treatment cessation (7). Recent studies have reported cases wherein a durable response was observed even after the discontinuation of therapy with immune checkpoint inhibitors (ICIs), including nivolumab, in melanoma, NSCLC, and RCC (8-10), but no such studies have so far been reported in patients with AGC.\n\nThus, in this study, we report a rare case of an AGC patient who maintained a durable response for approximately 2 years after the discontinuation of nivolumab due to immune-related adverse events (irAEs).\n\nCase Report\n\nThe patient was a 65-year-old man who had been diagnosed with gastric cancer and had undergone total gastrectomy with D2 dissection 7.5 years previously, namely in August 2010. The pathological diagnosis was of a moderately differentiated HER2-negative, pT1N1, pStage IB adenocarcinoma. Six months postoperatively, a solitary liver metastasis was discovered. He then received S-1 treatment as palliative chemotherapy 7 years perviously in March 2011, following which he received nab-paclitaxel alone from May 2013, irinotecan alone from February 2016, capecitabine plus oxaliplatin from June 2016, and ramucirumab alone from February 2017. The disappearance of liver metastasis was observed after the administration of nab-paclitaxel alone. However, treatment with S-1, irinotecan, and ramucirumab was considered to be a failure owing to multiple abdominal lymph node metastases, portal tumor thrombus, and solitary lung metastasis, respectively (Fig. 1A).\n\nFigure 1. (A) Abdominal computed tomography images before the commencement of nivolumab treatment. Solitary lung metastasis (arrow), portal tumor thrombus (solid circle), and multiple lymph node metastases (dotted circle) were observed. (B) After four cycles of nivolumab (approximately 2 months after start of nivolumab), the metastatic lesions shrank to 61.2% of the original size (before nivolumab treatment). (C) Twenty-three months after the discontinuation of nivolumab, the metastatic lesions further shrank to 39.1% of the original size (before nivolumab treatment).\n\nSince he exhibited an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, he began to receive nivolumab as sixth-line therapy from March 2018. The laboratory data showed no abnormal findings (Table). The carcinoembryonic antigen and carbohydrate antigen 19-9 levels were within the normal range, which were similar to his preoperative levels. The patient's clinical course during nivolumab treatment is shown in Fig. 2. No adverse events were observed during the first five cycles of nivolumab therapy. However, after the sixth cycle, 15 weeks after the initial treatment, he was hospitalized for severe fatigue (grade 3 by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0). During hospitalization, he exhibited ECOG PS 3. Physical examination revealed that his body temperature was 36.8℃, blood pressure was 81/48 mmHg, pulse rate was 88/min, and oxygen saturation was 99% on room air. No other abnormal findings were identified. A serum examination revealed a decreased level of thyroid-stimulating hormone (TSH) and increased levels of free triiodothyronine and free thyroxine (T4) compared with the levels before nivolumab initiation (Table). The patient tested negative for thyroid autoantibodies. In addition, there was a decrease in the levels of adrenocorticotropic hormone (ACTH) and cortisol. A stimulation test revealed a minor impact of corticotropin-releasing hormone loading on the ACTH and cortisol levels, while growth hormone, luteinizing hormone, follicle-stimulating hormone, prolactin, and TSH showed sufficient responses according to the corresponding stimulation tests. The ultrasound findings of the thyroid and magnetic resonance imaging findings of the pituitary gland showed no abnormalities. Consequently, he was diagnosed to have grade 3 isolated ACTH deficiency with secondary adrenal insufficiency and nivolumab-related grade 3 destructive thyroiditis. Nivolumab therapy was discontinued and prednisolone was supplemented at a starting dose of 15 mg/day for adrenal insufficiency. The patient's fatigue was alleviated within a few days, following which the prednisolone dose was tapered. His serum cortisol level returned to normal, whereas ACTH deficiency persisted. Prednisolone was maintained at a dosage of 5 mg/day since day 37, and no relapse was noted thereafter. The free T4 level decreased on day 23, confirming the hypothyroidism phase of destructive thyroiditis. Levothyroxine (25 μg/day) was administrated until the free T4 level recovered on day 95, and no relapse occurred thereafter.\n\nTable. Laboratory Data.\n\n\t\tReference range\tBefore nivolumab\tAfter 6 cycles of nivolumab\t\nWhite blood cells\t/µL\t4,000-9,000\t3,500\t3,400\t\nNeutrophils\t%\t45-55\t47.8\t47.7\t\nLymophocyte\t%\t25-45\t36.9\t36.5\t\nHemoglobin\tg/dL\t14-18\t14.4\t13.8\t\nPlatelets\t/µL\t15-35×104\t11.3×104\t19.9×104\t\nLactate dehydrogenase\tU/I\t106-211\t155\t249\t\nTotal bilirubin\tmg/dL\t0.3-1.2\t1.2\t1.1\t\nSodium\tmEq/L\t135-147\t141\t138\t\nPotassium\tmEq/L\t3.6-5.0\t4.0\t4.7\t\nChloride\tmEq/L\t98-108\t105\t101\t\nCalcium\tmg/dL\t8.6-10.1\t8.7\t9.4\t\nUrea nitrogen\tmg/dL\t8-20\t10.7\t16.7\t\nCreatinine\tmg/dL\t0.61-1.04\t0.95\t1.00\t\nC-reactive protein\tmg/dL\t0-0.2\t<0.03\t0.46\t\nCasual blood glucose\tmg/dL\t70-199\t–\t192\t\nHemoglobin A1c\t%\t4.6-6.2\t5.5\t5.4\t\nCA19-9\tU/mL\t<37.0\t8.6\t–\t\nCEA\tng/mL\t<5.0\t2.3\t–\t\nTSH\tµU/mL\t0.5-5.0\t4.16\t0.021\t\nFT4\tng/dL\t0.9-1.7\t0.99\t2.48\t\nFT3\tpg/mL\t2.3-4.3\t2.6\t7.9\t\nACTH\tpg/mL\t7.2-63.3\t78.6\t3.5\t\nCortisol\tµg/dL\t7.07-19.6\t14.6\t0.2\t\nGH\tng/mL\t0.0-2.0\t–\t1.2\t\nLH\tmIU/mL\t0.79-5.72\t–\t6.1\t\nFSH\tmIU/mL\t2.00-8.30\t–\t12.8\t\nProlactin\tng/mL\t4.29-13.69\t–\t9.7\t\nACTH: adrenocorticotropic hormone, CA19-9: carbohydrate antigen 19-9, CEA: carcinoembryonic antigen, FSH: follicle stimulating hormone, FT3: free triiodothyronine, FT4: free thyroxine, GH: growth hormone, LH: luteinizing hormone, TSH: thyroid stimulating hormone\n\nFigure 2. The patient’s clinical course during nivolumab treatment. ACTH: adrenocorticotropic hormone, CORT: cortisol, FT4: free thyroxine, LT4: levothyroxine, PSL: prednisolone, TSH: thyroid stimulating hormone\n\nAfter four cycles of nivolumab (approximately 2 months after the start of nivolumab therapy), all metastatic lesions shrank to around 61.2% of the size before nivolumab treatment (Fig. 1B). We determined to observe his course without the re-administration of nivolumab even after the improvement of irAEs. The metastatic lesions further decreased in size after the discontinuation of nivolumab, and the effect was sustained for 23 months after nivolumab initiation (final size, 39.1% of that before nivolumab treatment) (Fig. 1C); the tumor markers were within the normal ranges.\n\nDiscussion\n\nRecently, a durable response after the discontinuation of ICIs in patients with residual disease has been reported for other kinds of cancers (8-10). It has previously been reported that PD-1/PD-L1 blockade rescued “exhausted” T cells, leading to the activation of T-cell effectors and transition to memory cells (7). The level of PD-1 occupancy on circulating T cells was shown to persist much longer than the serum half-life of the PD-1 antibodies (11,12). This might mean that there is no need to perform continuous treatment with ICIs. In fact, our patient showed that the metastatic lesions further decreased after the discontinuation of nivolumab.\n\nSeveral predictive markers of an effective response to ICIs have been previously proposed for many cancers including AGC, such as better ECOG PS, no liver or lung metastases, a higher peripheral lymphocyte count, a lower neutrophil-to-lymphocyte ratio, a higher tumor PD-L1 expression, and a high degree of microsatellite instability (6,13-17). However, there have been a limited number of case reviews about the predictive markers for a durable clinical benefit after the discontinuation of ICIs, namely only in melanoma and RCC cases (8,10,18). In the KEYNOTE-001 study on pembrolizumab in patients with melanoma, 61 of 67 patients (91.0%), who were followed up after pembrolizumab discontinuation after a complete response (CR), achieved a disease-free survival of 24 months (18). It was suggested that the patients with CR were more likely to achieve a durable response. A univariate analysis revealed that high CR rates were associated with a target tumor size between 1 and 5 cm and PD-L1-positive tumors (≥1% staining in tumor cells and mononuclear inflammatory cells) (18). A retrospective cohort study on melanoma patients showed that the risk of disease progression following treatment discontinuation was significantly associated with the overall response and it was lower in patients with CR (19). However, none of these conditions were seen in our patient (no CR, unknown tumor PD-L1 status, and target tumor size: 7.7 cm; data not shown). In addition, our patient did not exhibit any microsatellite instability (data not shown). Since the Epstein-Barr virus (EBV)-positive status might be a marker of an effective response to ICIs in AGC (20,21), we performed EBV-encoded small RNA in situ hybridization on the primary tumor, which showed positivity in the nuclei of the tumor cells (Fig. 3). This result was consistent with that reported in previous reports (20,21). However, there are no reports on the predictive markers for a durable clinical benefit after the discontinuation of ICIs in AGC, and further study in many similar cases will be needed to clarify this, regardless of the distinctive features seen in our patient.\n\nFigure 3. Hematoxylin and Eosin staining (A magnification 40×, C magnification 200×) and Epstein-Barr virus-encoded small RNA in situ hybridization (B magnification 40×, D magnification 200×) in the resected primary tumor.\n\nRecent studies have shown that the development of irAE was associated with a clinical benefit in several cancers, including AGC (22-28). In NSCLC patients, in whom irAEs developed within 2 weeks from the start of nivolumab treatment (25), in whom more than two irAEs were reported (26), or in whom either endocrine irAEs or skin irAEs (28), a more pronounced benefit was observed. In melanoma cases, the occurrence of vitiligo as an irAE was associated with a clinical benefit (23,29,30), while endocrine irAE was not (23). In our patient, although the time to irAE occurrence was 15 weeks, which was longer than 2 weeks, two irAEs were detected, both of which were endocrine irAEs. The association between the types of irAEs and the clinical outcomes in different cancer types is still unclear.\n\nICIs induce multiple-organ irAEs via immune system overactivation (31). Two irAEs were observed in our patient. The incidence of endocrine irAEs varies depending on the agent, and nivolumab induces thyroid disorders in approximately 10% of such patients and hypophysitis in less than 1% of such patients (32,33). A patient often shows the development of multiple irAEs, but the common patterns of irAEs have been rarely reported. Although the pathogenic mechanism of ICI-triggered hypophysitis is unknown, the characteristic symptoms and imaging findings resemble those of autoimmune hypophysitis (34), which was also seen in our patient. The current guidelines suggest corticosteroid therapy and the replacement of deficient hormones to manage endocrine irAEs (35), and long-term hormonal replacement is indicated for ACTH deficiency secondary to hypophysitis (36), which was also effective in our patient.\n\nRecent studies have reported that recurrence of the same or different irAEs was observed in 18-52% of patients who received ICI re-administration (37-39), and these were milder than the initial events (38-40). A large-scale observational study using data from the World Health Organization database reported that colitis, hepatitis, and pneumonitis are associated with a higher recurrence rate, whereas adrenal events are associated with a lower recurrence rate compared with other irAEs (40). The efficacy of ICI re-administration is not yet established. A large retrospective analysis of NSCLC patients who were discontinued nivolumab therapy for any reason showed that OS in patients who received ICI re-administration was significantly better than that in patients who received chemotherapy only after nivolumab, in a sub-group analysis among the patients who initially received nivolumab therapy for more than 3 months (41). On the other hand, a retrospective cohort study on ICI re-administration in patients with solid tumors after the occurrence of an initial grade 2 or higher irAE showed that PFS in the re-administered patients was not better than that in the non-re-administered patients (38). If recurrence is observed in our case, then we will consider the re-administration of ICI while carefully monitoring irAEs.\n\nIn conclusion, we treated a patient with AGC who maintained a durable response for approximately 2 years after discontinuation of nivolumab. To the best of our knowledge, this is the first report to describe a durable clinical benefit after the discontinuation of nivolumab in gastric cancer. Further studies are necessary to elucidate the mechanism and the predictive markers of a durable clinical benefit after ICI discontinuation. The risks and benefits of ICI re-administration should be considered on the basis of the type of initial irAE.\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Robert C , Long GV , Brady B , et al . Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372 : 320-330, 2015.25399552\n2. Borghaei H , Paz-Ares L , Horn L , et al . Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 373 : 1627-1639, 2015.26412456\n3. Motzer RJ , Escudier B , McDermott DF , et al . Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 373 : 1803-1813, 2015.26406148\n4. 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Lung Cancer 140 : 99-106, 2020.31911324\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "60(7)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "PD-1; durable response; gastric cancer; immune checkpoint inhibitor; immune-related adverse event; nivolumab",
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D006801:Humans; D008297:Male; D009364:Neoplasm Recurrence, Local; D000077594:Nivolumab; D013274:Stomach Neoplasms",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1011-1017",
"pmc": null,
"pmid": "33162479",
"pubdate": "2021-04-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "29437040;26406148;29470536;28939128;27750046;25399552;32297899;30013197;31428149;26027431;30282824;29584546;27718784;27306911;29442540;29290265;31638948;30539281;30885550;30506406;26412456;31169866;26446948;26371282;29045547;31911324;30349646;29803573;30528047;27510892;32156744;32297436;31512006;29991499;28975219;28993052;32606951;20207527;29283791;30923820;20516446",
"title": "A Durable Response after the Discontinuation of Nivolumab in an Advanced Gastric Cancer Patient.",
"title_normalized": "a durable response after the discontinuation of nivolumab in an advanced gastric cancer patient"
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"companynumb": "JP-TEVA-2021-JP-1927289",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
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"actiondrug": "1",
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"activesubstancename": "IRINOTECAN"
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{
"abstract": "Dasatinib, an oral tyrosine kinase inhibitor, is approved for therapy of chronic myeloid leukaemia (CML). Common adverse effects of this therapy include myelosuppression, fluid retention and diarrhoea. However, Clostridioides difficile infections (CDIs) in the context of dasatinib therapy, without a history of antecedent antibiotic use, has not been reported previously. We present here a case of a 36-year-old man diagnosed with accelerated phase of CML, who was started on treatment with dasatinib. Two months into therapy, he experienced profuse diarrhoea and abdominal pain. Colonoscopy revealed multiple confluent colonic mucosal ulcerations. Immunoassay study of stool revealed positive C. difficile toxin. The patient was started on oral metronidazole, with discontinuation of all other drugs, including dasatinib. He made a complete uneventful recovery following 2 weeks of antibiotic therapy. Chemotherapeutic agents, such as dasatinib, should be considered as possible etiological agents in the pathogenesis of CDI, even in absence of antibiotic use.",
"affiliations": "Neurology, Institute of Postgraduate Medical Education and Research Bangur Institute of Neurology, Kolkata, India.;Gastroenterology, Topiwala National Medical College, Mumbai, India.;Internal Medicine, RG Kar Medical College and Hospital, Kolkata, India.;Internal Medicine, RG Kar Medical College and Hospital, Kolkata, India chandraatanu123@gmail.com.",
"authors": "Datta|Amlan Kusum|AK|;Debnath|Partha|P|http://orcid.org/0000-0001-6367-545X;Chakraborty|Uddalak|U|;Chandra|Atanu|A|http://orcid.org/0000-0002-3809-8926",
"chemical_list": "D000970:Antineoplastic Agents; D000069439:Dasatinib",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-239394",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(1)",
"journal": "BMJ case reports",
"keywords": "Chronic Myeloid Leukemia; Dasatinib; Infection (gastroenterology); Unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D016360:Clostridioides difficile; D003015:Clostridium Infections; D000069439:Dasatinib; D003967:Diarrhea; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33462050",
"pubdate": "2021-01-18",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Clostridioides difficile-induced diarrhoea following dasatinib therapy.",
"title_normalized": "clostridioides difficile induced diarrhoea following dasatinib therapy"
} | [
{
"companynumb": "IN-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-014841",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DASATINIB"
},
"drugaddi... |
{
"abstract": "OBJECTIVE\nOncology patients present with various skin manifestations related to primary disease and treatments. Although these skin toxicities are well described in adults, studies of pediatric oncology patients are limited. The objective of this study was to evaluate the cutaneous findings in pediatric oncology patients receiving chemotherapy.\n\n\nMETHODS\nIn this prospective cohort study conducted from December 2018 to March 2020, all pediatric oncology patients were examined and patients who had a dermatologic finding at any point during their treatments were recorded. Dermatologic examinations were performed by the same dermatologists, and biopsy and microbiologic tests were performed according to clinical need. Patients were grouped according to their oncologic diagnoses and types of chemotherapies.\n\n\nRESULTS\nA total of 80 patients with a mean age of 9.1 ± 5.0 years were included in the study. Seventy-five (93.7%) of them developed a dermatologic manifestation during the study period. Most of the patients had hematologic malignancies (n = 48, 60%). Antimetabolites were the most frequently used class of chemotherapeutic agents. Anagen effluvium was the most common dermatologic finding (61.3%, n = 49), followed by inflammatory dermatoses (51.2%, n = 41, most commonly diaper dermatitis in 33 patients), xerosis (35%, n = 28), and nail changes (20%, n = 16, most commonly nail pigmentation in seven patients). Mucositis was seen in 13 (16.2%) patients. Five patients (6.2%) had drug-induced cutaneous hyperpigmentation, and five (6.2%) had toxic erythema of chemotherapy. The highest percentage of xerosis (45.4%) was detected in patients using antitumor antibiotics, whereas inflammatory dermatoses were observed more in patients using antimetabolites (48.6% of patients using antimetabolites), and pigmentation changes were more frequently detected in patients using alkylating agents.\n\n\nCONCLUSIONS\nIdentification, diagnosis, and treatment of these reactions are important to dermatologists and oncologists so that appropriate management may be provided to pediatric oncology patients.",
"affiliations": "Dermatology Department, Şişli Hamidiye Etfal Training and Research Hospital, University of Health Sciences, İstanbul, Turkey.;Department of Pediatrics, Şişli Hamidiye Etfal Training and Research Hospital, University of Health Sciences, İstanbul, Turkey.;Dermatology Department, Şişli Hamidiye Etfal Training and Research Hospital, University of Health Sciences, İstanbul, Turkey.;Department of Pediatric Hematology and Oncology, Şişli Hamidiye Etfal Training and Research Hospital, University of Health Sciences, İstanbul, Turkey.;Department of Pediatric Hematology and Oncology, Şişli Hamidiye Etfal Training and Research Hospital, University of Health Sciences, İstanbul, Turkey.;Department of Pediatric Hematology and Oncology, Şişli Hamidiye Etfal Training and Research Hospital, University of Health Sciences, İstanbul, Turkey.;Dermatology Department, Şişli Hamidiye Etfal Training and Research Hospital, University of Health Sciences, İstanbul, Turkey.",
"authors": "Özkur|Ezgi|E|https://orcid.org/0000-0002-9136-7021;Sert|Cansu|C|;Kıvanç Altunay|İlknur|İ|;Yıldırırmak|Zeynep Yıldız|ZY|;Genç|Dildar Bahar|DB|;Vural|Sema|S|;Erdem|Yasemin|Y|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "United States",
"delete": false,
"doi": "10.1111/pde.14375",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": "38(1)",
"journal": "Pediatric dermatology",
"keywords": "adverse effect; cutaneous manifestation; dermatology; pediatric oncology; side effect",
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents; D002648:Child; D002675:Child, Preschool; D004890:Erythema; D006801:Humans; D052016:Mucositis; D009369:Neoplasms; D011446:Prospective Studies",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "58-65",
"pmc": null,
"pmid": "33179835",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Cutaneous manifestations in pediatric oncology patients.",
"title_normalized": "cutaneous manifestations in pediatric oncology patients"
} | [
{
"companynumb": "TR-TEVA-2021-TR-1952347",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
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"drugadditional": "1",
... |
{
"abstract": "To describe the clinical and laboratory profile, natural course, treatment outcome, and risk factors of posttransplant esophageal and nonesophageal eosinophilic gastrointestinal disorders (EGIDs).\n\n\n\nAll children (aged <18 years) who underwent liver transplantation, between 2011 and 2019, in a single transplant center with a follow-up period of 1 year or more posttransplant and with a history of posttransplant endoscopic evaluation were included in this study.\n\n\n\nDuring the study period, 89 children met the inclusion criteria. Patients were followed for a median of 8.0 years. A total of 39 (44%) patients were diagnosed with EGID after transplantation. Of these, 29 (33%) had eosinophilic esophagitis (EoE), and 10 (11%) had eosinophilic gastritis, gastroenteritis or enterocolitis. In comparison with the non-EGID group, patients with EGID were younger at transplant (P ≤ 0.0001), transplanted more frequently due to biliary atresia (P ≤ 0.0001), and had higher rates of pretransplant allergy (P = 0.019). In the posttransplant period, they had higher rates of mammalian Target of Rapamycin inhibitor use (P = 0.006), Epstein-Barr virus viremia (P = 0.03), post-transplant lymphoproliferative disease (P = 0.005), and allergen sensitization (P ≤ 0.0001). In regression analysis, young age at transplant, age at diagnosis, pretransplant atopic dermatitis, and post-transplant lymphoproliferative disease were associated with an increased risk of EGID or EoE. Laboratory abnormalities such as anemia (P = 0.007), thrombocytosis (P = 0.012), and hypoalbuminemia (P = 0.031) were more commonly observed in the eosinophilic gastritis, gastroenteritis or enterocolitis group than in the EoE group. Following treatment, most patients had symptomatic resolution at 3 months and histologic resolution at 6 months postdiagnosis. Among the patients who had 5 years of follow-up, none recurred.\n\n\n\nEGID is a common posttransplant diagnosis, which seems to affect patients who are transplanted earlier and who have pretransplant atopy. Posttransplant EGID is responsive to treatment, but as histologic remission occurs after symptomatic resolution, the decision to perform control endoscopy should be delayed.",
"affiliations": "Department of Pediatric Gastroenterology, Hepatology and Nutrition, Koc University School of Medicine, Istanbul, Turkey.;Department of Pathology, Kent Hospital, Izmir, Turkey.;Department of Pediatric Allergy, Behcet Uz Children's Training Hospital, Izmir, Turkey.;Department of Pediatric Gastroenterology, Hepatology and Nutrition, Koc University School of Medicine, Istanbul, Turkey.",
"authors": "Ozdogan|Elif|E|;Doganay|Latife|L|;Can|Demet|D|;Arikan|Cigdem|C|",
"chemical_list": "D018926:Anti-Allergic Agents; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D019819:Budesonide; D058570:TOR Serine-Threonine Kinases; D016559:Tacrolimus; D007665:Ketotifen",
"country": "United States",
"delete": false,
"doi": "10.14309/ajg.0000000000000934",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9270",
"issue": "116(1)",
"journal": "The American journal of gastroenterology",
"keywords": null,
"medline_ta": "Am J Gastroenterol",
"mesh_terms": "D000367:Age Factors; D018926:Anti-Allergic Agents; D001656:Biliary Atresia; D019819:Budesonide; D002648:Child; D002675:Child, Preschool; D002780:Cholestasis, Intrahepatic; D003876:Dermatitis, Atopic; D018450:Disease Progression; D000084862:Drug Tapering; D004751:Enteritis; D004760:Enterocolitis; D004802:Eosinophilia; D057765:Eosinophilic Esophagitis; D020031:Epstein-Barr Virus Infections; D005260:Female; D005500:Follow-Up Studies; D005756:Gastritis; D005938:Glucocorticoids; D006084:Graft Rejection; D006801:Humans; D006967:Hypersensitivity; D007166:Immunosuppressive Agents; D007223:Infant; D007665:Ketotifen; D017114:Liver Failure, Acute; D016031:Liver Transplantation; D008232:Lymphoproliferative Disorders; D008297:Male; D011183:Postoperative Complications; D015995:Prevalence; D012189:Retrospective Studies; D012307:Risk Factors; D058570:TOR Serine-Threonine Kinases; D016559:Tacrolimus; D016896:Treatment Outcome; D014766:Viremia",
"nlm_unique_id": "0421030",
"other_id": null,
"pages": "188-197",
"pmc": null,
"pmid": "33065587",
"pubdate": "2021-01-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Disease Course and Treatment Response of Eosinophilic Gastrointestinal Diseases in Children With Liver Transplantation: Long-Term Follow-Up.",
"title_normalized": "disease course and treatment response of eosinophilic gastrointestinal diseases in children with liver transplantation long term follow up"
} | [
{
"companynumb": "TR-ASTELLAS-2021US008027",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ACYCLOVIR"
},
"drugadditional": null,
... |
{
"abstract": "Congenital hyperinsulinism (CHI) characterised by inappropriate secretion of insulin despite low blood glucose can result in irreversible brain damage if not promptly treated. The most common genetic cause of hyperinsulinism is the pathogenic variants in ABCC8 and KCNJ11, causing dysregulated insulin secretion. Rapid testing is crucial for all patients because finding a mutation significantly impacts this condition's clinical management. We report a rare case of focal CHI after a homozygous KCNJ11 mutation who underwent a selective lesionectomy and required octreotide for euglycaemia.",
"affiliations": "Department of Neonatology, Bharati Hospital and Research Centre, Pune, Maharashtra, India coolreem18@yahoo.com.;Department of Neonatology, Bharati Hospital and Research Centre, Pune, Maharashtra, India.;Neonatology, Bharati Vidyapeeth University, Pune, Maharashtra, India.;Department of Neonatology, Bharati Hospital and Research Centre, Pune, Maharashtra, India.",
"authors": "Garegrat|Reema|R|;Patnaik|Suprabha|S|;Suryawanshi|Pradeep|P|;Datar|Chaitanya|C|",
"chemical_list": "D024661:Potassium Channels, Inwardly Rectifying; D064233:Sulfonylurea Receptors; D015282:Octreotide",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-240218",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(3)",
"journal": "BMJ case reports",
"keywords": "diabetes; endocrinology; genetics; neonatal health",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D044903:Congenital Hyperinsulinism; D006801:Humans; D006946:Hyperinsulinism; D009154:Mutation; D015282:Octreotide; D024661:Potassium Channels, Inwardly Rectifying; D064233:Sulfonylurea Receptors",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33762279",
"pubdate": "2021-03-24",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Focal congenital hyperinsulinism resulting from biallelic loss of function of KCNJ11 gene.",
"title_normalized": "focal congenital hyperinsulinism resulting from biallelic loss of function of kcnj11 gene"
} | [
{
"companynumb": "IN-MYLANLABS-2021M1040756",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DEXTROSE"
},
"drugadditional": null,
... |
{
"abstract": "Antipsychotics are the cornerstone in the management of psychotic disorders and schizophrenia. They are effective agents but also have a wide range of side effects. In the recent literature constipation as possible side effect has received little attention. A review of the literature concerning constipation associated with antipsychotics was performed. Overall constipation is a rarely studied or reported side effect of antipsychotic medication. Nevertheless constipation is a common side effect. Antipsychotic agents differ in their liability to induce constipation. Constipation can be severe and can lead to serious consequences such as paralytic ileus, bowel occlusion and death. Active screening, monitoring and treatment are recommended. Further research on incidence, prevalence, underlying mechanisms and preventive measures is required.",
"affiliations": "University Psychiatric Centre, Campus Kortenberg, Catholic University Louvain, Leuvensesteenweg 517, 3070 Kortenberg, Belgium. marc.de.hert@uc-kortenberg.be",
"authors": "De Hert|M|M|;Hudyana|H|H|;Dockx|L|L|;Bernagie|C|C|;Sweers|K|K|;Tack|J|J|;Leucht|S|S|;Peuskens|J|J|",
"chemical_list": "D014150:Antipsychotic Agents; D003024:Clozapine",
"country": "England",
"delete": false,
"doi": "10.1016/j.eurpsy.2010.03.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0924-9338",
"issue": "26(1)",
"journal": "European psychiatry : the journal of the Association of European Psychiatrists",
"keywords": null,
"medline_ta": "Eur Psychiatry",
"mesh_terms": "D014150:Antipsychotic Agents; D003024:Clozapine; D003248:Constipation; D006801:Humans; D016032:Randomized Controlled Trials as Topic",
"nlm_unique_id": "9111820",
"other_id": null,
"pages": "34-44",
"pmc": null,
"pmid": "20542667",
"pubdate": "2011-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Second-generation antipsychotics and constipation: a review of the literature.",
"title_normalized": "second generation antipsychotics and constipation a review of the literature"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-04154",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "QUETIAPINE FUMARATE"
},
... |
{
"abstract": "A 24-year-old male presented with abdominal pain, fever, and palpable splenomegaly. His differential count revealed myelocytes, metamyelocytes, and nucleated red cells. A bone marrow biopsy confirmed a diagnosis of hepatosplenic gamma delta T-cell leukemia/lymphoma. We describe here our center's diagnostic and treatment approach for this rare leukemia.",
"affiliations": "Department of Hematology and Oncology Henry Ford Hospital Detroit Michigan.;Department of Pathology and Laboratory Medicine Henry Ford Hospital Detroit Michigan.;Department of Hematology and Oncology Henry Ford Hospital Detroit Michigan.",
"authors": "Saste|Abhijit|A|;Arias-Stella|Javier|J|;Kuriakose|Philip|P|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.453",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.453CCR3453Case ReportCase ReportsProgression of a hepatosplenic gamma delta T‐cell leukemia/lymphoma on hyperCVAD/MTX and ara‐C: literature review and our institutional treatment approach A. Saste et al.Saste Abhijit \n1\nArias‐Stella Javier \n2\nKuriakose Philip \n1\n1 Department of Hematology and OncologyHenry Ford HospitalDetroitMichigan2 Department of Pathology and Laboratory MedicineHenry Ford HospitalDetroitMichigan* Correspondence\n\nAbhijit Saste, Department of Hematology‐Oncology, Henry Ford Health System, 2799 West Grand Blvd, Detroit, MI 48202. Tel:+ 1 (313)916 2194; Fax:+1 (313)916 7911; E‐mail: absdoc1@gmail.com\n23 11 2015 1 2016 4 1 10.1111/ccr3.2016.4.issue-167 71 09 9 2015 28 10 2015 © 2015 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‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Key Clinical Message\nA 24‐year‐old male presented with abdominal pain, fever, and palpable splenomegaly. His differential count revealed myelocytes, metamyelocytes, and nucleated red cells. A bone marrow biopsy confirmed a diagnosis of hepatosplenic gamma delta T‐cell leukemia/lymphoma. We describe here our center's diagnostic and treatment approach for this rare leukemia.\n\nChemotherapyhematologyleukemialymphomamedical oncology source-schema-version-number2.0component-idccr3453cover-dateJanuary 2016details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:4.7.2 mode:remove_FC converted:06.01.2016\n\nClinical Case Reports \n2016 ; 4 (1 ): 67 –71\n==== Body\nCase Presentation\nA 24‐year‐old male presented with 2 weeks of abdominal pain, fever, weakness, and palpable splenomegaly. His complete blood count showed a white cell count of 20,000/cmm, hemoglobin of 6.8 g/dL, and platelet count of 42,000/cmm. His differential count revealed monocytosis, myelocytes, metamyelocytes, and nucleated red cells. His LDH was elevated at 1951 IU/L. Further testing showed prolonged PT and PTT, low haptoglobin, and a very high d‐dimer suggesting disseminated intravascular coagulation (DIC). Testing for mononucleosis, hepatitis, and HIV were all negative. Cerebrospinal fluid (CSF) for cytopathology and flow cytometry were normal. A bone marrow biopsy was performed (Figs 1, 2, 3, 4, 5, 6). A T‐cell predominant infiltrate was noted with a sinusoidal pattern of infiltration. The T cells were predominantly atypical T cells, with a composite immunophenotype of CD3 and CD45 being brightly positive, TIA1+, TCR γδ+, CD4−, CD8+ (minority, dim), CD56+ (minority, dim), granzyme B− on flow cytometry. Testing for Epstein Barr Virus (EBV) and terminal deoxynucleotidyl transferase (TdT) were negative. This confirmed a diagnosis of hepatosplenic gamma delta T‐cell leukemia/lymphoma. Computed tomography (CT) abdomen (Fig. 7) demonstrated splenomegaly. Induction chemotherapy was initiated with hyperfractionated CVAD (cyclophosphamide, vincristine, adriamycin, and dexamethasone)/(1A) alternating with high‐dose methotrexate (MTX) and cytarabine (ara‐C)/(1B). Intrathecal cytarabine (IT ara‐c) prophylaxis was also started. A restaging bone marrow biopsy after cycles 1A/1B showed residual disease. Hence chemotherapy was changed to a second‐line regimen comprising ifosfamide, carboplatin, and etoposide (ICE). He developed neurotoxicity from ifosfamide and sepsis from pneumonia. His cytopenias continued to get worse from disease progression requiring increasingly frequent transfusion support. A restaging CT scan of the abdomen after cycle 1 of ICE showed worsening splenomegaly. Given poor cytoreduction of his leukemia with chemotherapy, progressive multisystem organ dysfunction and worsening performance status he was considered transplant ineligible. He was eventually enrolled in hospice about 6 months from the time of diagnosis.\n\nFigure 1 Leishman stain of bone marrow aspirate smear shows an intermediate sized cell with scant cytoplasm and blastoid nuclear morphology with nuclear irregularities. These comprised approximately 20% of aspirate smear cells.\n\nFigure 2 Hematoxylin and eosin stain of the clot section shows a hypercellular marrow with some preservation of trilineage hematopoiesis as well as a subtle, diffuse mononuclear infiltrate.\n\nFigure 3 \nCD3 staining of bone marrow. Immunohistochemical stain showing markedly increased T‐cell infiltrate with sinusoidal and interstitial pattern.\n\nFigure 4 \nTIA‐1 stain of bone marrow. Immunohistochemical stain showing cells positive for TIA‐1.\n\nFigure 5 \nCD20 stain of bone marrow. Immunohistochemical stain showing only scant B cells.\n\nFigure 6 Flow cytometry of bone marrow aspirate showing cytoplasmic CD3 and TCR γδ positivity.\n\nFigure 7 \nCT scan of the abdomen showing massive splenomegaly.\n\nDiscussion\nEtiopathogenesis of hepatosplenic gamma delta T‐cell leukemia/lymphomas\nT cells in the thymus comprise two subtypes based on their surface expression of either αβ or γδ T‐cell receptors (TCR) 1. The TCR of αβ T cells, which form the majority, is encoded by alpha and beta genes, whereas the TCR of γδ T cell is encoded by the gamma and delta genes 2. γδ T cells constitute only about 5% of lymphocyte population 3. αβ and γδ type T cells originate from a common multipotent double negative precursor in the thymus that homes itself there after originating from the bone marrow precursor lymphoid cells 4. αβ T cells express CD4 or CD8 coreceptors 4. αβ T‐cell activations are restricted via MHC‐directed antigen presentation. γδ T cells on the other hand do not express CD4/CD8 coreceptors, and do not require conventional antigen presentation through MHC expression for their activation 4.\n\nHepatosplenic gamma delta T‐cell leukemia/lymphoma is a type of T‐cell non‐Hodgkin's lymphoma that arises from clonal expansion of γδ T cells which have suffered a derangement of their genetic machinery from unknown reasons. It has been hypothesized that chronic MHC unrestricted antigenic stimulation of γδ T cells seen in chronic infection/inflammation may be a causal factor 5. This is based on the fact that these occur with a slightly higher incidence in immunosuppressed solid organ transplant recipients and HIV patients where gamma delta T cells are overstimulated by varying antigenic challenges from repetitive infections 5, 6. Associations with the use of infliximab, malaria, cytomegalovirus (CMV), and EBV have been reported 6, 7, 8, 9.\n\nEpidemiology\nIt is a rare peripheral T‐cell lymphoma 10. Median age at diagnosis is 34 years 11. A slight male gender preponderance exists 11, 12.\n\nClinical features\nAll patients tend to have splenomegaly and bone marrow involvement 11, 12. In a case series of 21 patients, the incidence of liver involvement was 67%, that of at least one B symptom was 80%, and that of lymphadenopathy was 13% 11.\n\nThis condition has a very aggressive clinical course. In a study by Falchook et al., median duration of complete remission (CR) was 8 months with CHOP like regimens. Median overall survival (OS) was 11 months. Patients who achieved a CR had a median OS of 13 months compared with 7.5 months in patients who did not achieve a CR 10.\n\nPathologic diagnostic correlates\nThis disease shows a distinct sinusoidal pattern of infiltration in the splenic red pulp with sparing of the white pulp. The liver also shows classic sinusoidal infiltration with sparing of hepatic portal triads. Bone marrow morphology is often nonspecific, but is notable for neoplastic cells in the sinusoids in early stages and an interstitial pattern of infiltration in the later stages 10. Atypical appearing lymphocytes and hemophagocytosis may be noted. Immunophenotyping and TCR rearrangement are necessary for diagnosis 12. Immunohistochemistry (IHC) is classically CD3+, TCRδ1+, TIA‐1+, CD4−, and CD8−. TCR rearrangement shows a clonal rearrangement of the γδ gene of the T cell – a hallmark of this disease 10, 12. Few cases have also shown rearrangement of the αβ gene 10. Isochromosome 7q has shown a higher prevalence in this condition 10.\n\nOur institutional treatment approach\nAfter a diagnosis, which is usually made on a bone marrow biopsy and aspiration, we conduct a staging work up that comprises CT scan of the chest, abdomen, and pelvis looking specifically for lymphadenopathy and hepatosplenomegaly. We perform a MRI brain only if symptoms suggest neurologic involvement. A lumbar puncture (LP) is carried out in all patients for performing a cerebrospinal fluid (CSF) flow cytometry and cytopathology for involvement of the nervous system. One prophylactic dose of intrathecal ara‐c is administered at the conclusion of this first LP.\n\nAll of our cases undergo a multidisciplinary review at a leukemia tumor board meeting prior to initiating treatment. Our standard first‐line therapy is HyperCVAD alternated with MTX and high‐dose cytarabine (ara‐c) along with intrathecal prophylaxis, to achieve cytoreduction followed by consolidation with allogeneic bone marrow transplant (allo‐SCT), if eligible. We assess response with a restaging marrow after completing the first cycle of HyperCVAD to help arrive at a decision about continuing the same chemotherapy regimen versus switching to an alternative regimen.\n\nIf HyperCVAD is not possible given a poor performance status of the patient, we use a clinical trial as our standard second‐line approach, if one is available.\n\nIn the absence of a clinical trial, we approach our patients based on their clinical status.\n\n\nIf clinical status is relatively well maintained, then a combination regimen such as ICE/DHAP/ESHAP is employed.\n\nIf clinical status is not favorable, then a single agent approach, such as with romidepsin or pentostatin is considered, unless a poor performance status dictates eligibility for supportive care alone.\n\n\n\n\nAlthough alemtuzumab may be employed as a single agent, it may not be tolerated by patients with a poor performance status.\n\nDuring their chemotherapy treatments, we offer our patients supportive treatment with prophylactic antibiotics, antivirals, and antifungals, judicious transfusion support, and prophylaxis against tumor lysis syndrome.\n\nWe routinely involve specialized chemopharmacists and chemonurses to be a part of our support team for the preparation, dosing, and monitoring of chemotherapy. We also involve an appropriate palliative pain service and hospice support service when the clinical need arises.\n\nConflict of Interest\nNone declared.\n==== Refs\nReferences\n1 \n\nBruno , L. \n, \nA. \nScheffold \n, \nA. \nRadbruch \n, and \nM. J. \nOwen \n. 1999 \nThreshold of pre‐T‐cell‐receptor surface expression is associated with ab T‐cell lineage commitment . Curr. Biol. \n3 :559 –568 .10359697 \n2 \n\nYan‐Ling , W. \n, \nY.‐P. \nDing \n, \nY. \nTanaka \n, \nL.‐W. \nShen \n, \nC.‐H. \nWei \n, \nN. \nMinato \n, et al. 2014 \nγδ T Cells and Their Potential for Immunotherapy . Int. J. Biol. Sci. \n10 :119 –135 .24520210 \n3 \n\nRoden , A. C. \n, \nW. G. \nMorice \n, and \nC. A. \nHanson \n. Immunophenotypic attributes of benign peripheral blood γδ T cells and conditions associated with their increase . Arch. Pathol. Lab. Med. \n2008 \n132 :1774 –1780 .18976014 \n4 \n\nKreslavsky , T. \n, \nM. \nGleimer \n, \nA. \nI Garbe \n, and \nH. \nvon Boehmer \n. αβ versus γδ fate choice: counting the T‐cell lineages at the branch point . Immunol. Rev. \n2010 \n238 :169 –181 .20969592 \n5 \n\nPoccia , F. \n, \nM. \nWallace \n, \nV. \nColizzi \n, and \nM. \nMalkovsky \n. 1998 \nPossible protective and pathogenic roles of gamma delta T lymphocytes in HIV‐infections (Review) . Int. J. Mol. Med. \n1 :409 –413 .9852243 \n6 \n\nCouzi , L. \n, \nX. \nLafarge \n, \nV. \nPitard \n, \nM. \nNeau‐Cransac \n, \nC. \nDromer \n, \nM. A. \nBilles \n, et al. 2011 \nGamma‐delta T cell expansion is closely associated with cytomegalovirus infection in all solid organ transplant recipients . Transpl. Int. \n24 :e40 –e42 .21463369 \n7 \n\nTsunematsu , S. \n, \nM. \nNatsuizaka \n, \nH. \nFujita \n, \nN. \nOtsuka \n, \nK. \nTerashita \n, \nF. \nSato \n, et al. 2014 \nHepatosplenic gamma‐delta T‐cell lymphoma associated with Epstein‐Barr virus . Intern. Med. \n53 :2079 –2082 .25224191 \n8 \n\nHassan , R. \n, \nS. A. \nFranco \n, \nC. G. \nStefanoff \n, \nS. O. \nRomano \n, \nH. R. \nDiamond \n, \nL. G. \nFranco \n, et al. 2006 \nHepatosplenic gammadelta T‐cell lymphoma following seven malaria infections . Pathol. Int. \n56 :668 –673 .17040289 \n9 \n\nKelsen , J. \n, \nA. \nDige \n, \nH. \nSchwindt \n, \nF. \nD'Amore \n, \nF. S. \nPedersen \n, \nJ. \nAgnholt \n, et al. 2011 \nInfliximab induces clonal expansion of γδ‐T cells in Crohn's disease: a predictor of lymphoma risk? \nPLoS One \n6 :e17890 .21483853 \n10 \n\nFalchook , G. S. \n, \nF. \nVega \n, \nN. H. \nDang \n, \nF. \nSamaniego \n, \nM. A. \nRodriguez \n, \nR. E. \nChamplin \n, et al. 2009 \nHepatosplenic gamma‐delta T‐cell lymphoma: clinicopathological features and treatment . Ann. Oncol. \n20 :1080 –1085 .19237479 \n11 \n\nBelhadj , K. \n, \nF. \nReyes \n, \nJ. P. \nFarcet \n, \nH. \nTilly \n, \nC. \nBastard \n, \nR. \nAngonin \n, et al. 2003 \nHepatosplenic gammadelta T‐cell lymphoma is a rare clinicopathologic entity with poor outcome: report on a series of 21 patients . Blood \n102 :4261 –4269 .12907441 \n12 \n\nWang , F. X. \n, \nX. J. \nZhang \n, and \nZ. R. \nDong \n. 2005 \nA case of hepatosplenic gammadelta T cell lymphoma . Zhongguo Shi Yan Xue Ye Xue Za Zhi \n13 :505 –508 .15972153\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2050-0904",
"issue": "4(1)",
"journal": "Clinical case reports",
"keywords": "Chemotherapy; hematology; leukemia; lymphoma; medical oncology",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "67-71",
"pmc": null,
"pmid": "26783439",
"pubdate": "2016-01",
"publication_types": "D002363:Case Reports",
"references": "9852243;24520210;15972153;10359697;17040289;19237479;20969592;18976014;12907441;26783439;25224191;21463369;21483853",
"title": "Progression of a hepatosplenic gamma delta T-cell leukemia/lymphoma on hyperCVAD/MTX and ara-C: literature review and our institutional treatment approach.",
"title_normalized": "progression of a hepatosplenic gamma delta t cell leukemia lymphoma on hypercvad mtx and ara c literature review and our institutional treatment approach"
} | [
{
"companynumb": "US-MYLANLABS-2017M1020546",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IFOSFAMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "In a prospective randomized controlled trial, between May 2001 and January 2003, 132 live-donor kidney transplant recipients were randomized to receive sirolimus primary immunosuppression, either in combination with low dose tacrolimus (Tac group) or in combination with mycophenolate mofetil (MMF group). We have previously reported on 2- and 5-year follow-up results, with favorable patient and graft outcomes obtained in both groups. In view of recent published reports of increased risk of inferior outcomes among sirolimus-treated patients, we herein present results of an observational extension of the previously randomized patients 15 years post-transplantation. Mortality rates were 10.8% and 3% in Tac and MMF groups respectively after mean follow-up period of 11.2-11.8 years. Comparable graft survival rates were obtained in both groups ranging from 60% to 62.7%. The (MMF) group continued to have the advantage of remaining on primary plan of immunosuppression (56.7% of patients) as well as to maintain better graft function in terms of serum creatinine level. Herein, we presented longest term published data for sirolimus-based immunosuppression among live-donor kidney transplants with favorable outcome in terms of survival and graft function.",
"affiliations": "Nephrology Division, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt.;Nephrology Division, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt.;Nephrology Division, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt.;Pathology Division, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt.;Nephrology Division, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt.",
"authors": "Hamdy|Ahmed F|AF|0000-0002-7289-4942;Elhadedy|Muhammed A|MA|;Donia|Ahmed F|AF|;Taha|Noheir M|NM|;Bakr|Mohamed A|MA|",
"chemical_list": "D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D020123:Sirolimus",
"country": "Denmark",
"delete": false,
"doi": "10.1111/ctr.13463",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-0063",
"issue": "33(2)",
"journal": "Clinical transplantation",
"keywords": null,
"medline_ta": "Clin Transplant",
"mesh_terms": "D000293:Adolescent; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007166:Immunosuppressive Agents; D007676:Kidney Failure, Chronic; D007677:Kidney Function Tests; D016030:Kidney Transplantation; D008297:Male; D009173:Mycophenolic Acid; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D020123:Sirolimus; D015996:Survival Rate; D014019:Tissue Donors",
"nlm_unique_id": "8710240",
"other_id": null,
"pages": "e13463",
"pmc": null,
"pmid": "30548935",
"pubdate": "2019-02",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Outcome of sirolimus-based immunosuppression, fifteen years post-live-donor kidney transplantation: Single-center experience.",
"title_normalized": "outcome of sirolimus based immunosuppression fifteen years post live donor kidney transplantation single center experience"
} | [
{
"companynumb": "EG-PFIZER INC-2019156524",
"fulfillexpeditecriteria": "1",
"occurcountry": "EG",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SIROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nPsychotropic agents may frequently be associated with ocular adverse effects, which include angle-closure glaucoma. We report a case of pseudoexfoliation glaucoma in which intraocular pressure (IOP) increased within hours after carbamazepine and gabapentin intake, with no observable evidence of any angle closure.\n\n\nMETHODS\nA 67-year-old woman with pseudoexfoliation glaucoma presented with high IOP in her right eye after carbamazepine and gabapentin intake. To investigate which psychotropic medicine was the cause of this fluctuation, the patient was called for 2 subsequent visits and the order of the medicines she took was changed in each examination. Baseline IOP was recorded in each examination, and the IOP was monitored hourly after the intake of medicines. Baseline and hourly Pentacam measurements were also made to demonstrate changes in anterior segment parameters.\n\n\nCONCLUSIONS\nGabapentin and carbamazepine resulted in deepening of the anterior chamber, widening of the iridocorneal angle, and mild pupillary dilation in 2 visits. Carbamazepine was associated with a significant increase in IOP independent of gabapentin use. The absence of angle closure and plateau iris configuration suggested other mechanisms that might be related to high IOP after carbamazepine intake.\n\n\nCONCLUSIONS\nThis is the first reported case of a large increase in IOP within hours after carbamazepine and gabapentin intake in a pseudoexfoliative eye.",
"affiliations": "Ophthalmology Department, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey.",
"authors": "Atalay|Eray|E|;Tamçelik|Nevbahar|N|;Capar|Olgu|O|",
"chemical_list": "D000588:Amines; D003509:Cyclohexanecarboxylic Acids; D011619:Psychotropic Drugs; D002220:Carbamazepine; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin",
"country": "United States",
"delete": false,
"doi": "10.1097/IJG.0b013e318287aca7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1057-0829",
"issue": "23(8)",
"journal": "Journal of glaucoma",
"keywords": null,
"medline_ta": "J Glaucoma",
"mesh_terms": "D000368:Aged; D000588:Amines; D002220:Carbamazepine; D003509:Cyclohexanecarboxylic Acids; D017889:Exfoliation Syndrome; D005260:Female; D000077206:Gabapentin; D005902:Glaucoma, Open-Angle; D006801:Humans; D007429:Intraocular Pressure; D011619:Psychotropic Drugs; D005680:gamma-Aminobutyric Acid",
"nlm_unique_id": "9300903",
"other_id": null,
"pages": "574-6",
"pmc": null,
"pmid": "23429633",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "High intraocular pressure after carbamazepine and gabapentin intake in a pseudoexfoliative patient.",
"title_normalized": "high intraocular pressure after carbamazepine and gabapentin intake in a pseudoexfoliative patient"
} | [
{
"companynumb": "TR-ACTAVIS-2015-04133",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GABAPENTIN"
},
"drugadditional": null,
... |
{
"abstract": "We report a case of fatal hypermagnesemia in a 53-year-old woman admitted for acute exacerbation of chronic obstructive pulmonary disease and with a history of chronic constipation treated regularly with magnesium-containing laxatives. On admission, her magnesium level was 2.0mg/dL, which rose to a peak of 10.8mg/dL despite hydration and diuresis in the presence of a normal kidney function. Continuous renal replacement therapy was promptly initiated, which reduced her serum magnesium levels, but her condition continued to deteriorate precipitously progressing to shock leading to oligoanuric renal failure, and she died 2 days later. A review of the literature shows that though rare and often unsuspected, severe hypermagnesemia frequently results in death even in individuals with normal renal function despite renal replacement therapy. In patients with constipation, retention of magnesium-based laxative in the gut apparently serves as a reservoir for continuous magnesium absorption and contributes to mortality.",
"affiliations": "Tulane University School of Medicine, New Orleans, Louisiana.; Southeast Louisiana Veterans Healthcare System, New Orleans, Louisiana.;Tulane University School of Medicine, New Orleans, Louisiana.; Southeast Louisiana Veterans Healthcare System, New Orleans, Louisiana.;Tulane University School of Medicine, New Orleans, Louisiana.; Southeast Louisiana Veterans Healthcare System, New Orleans, Louisiana.;Tulane University School of Medicine, New Orleans, Louisiana.; Southeast Louisiana Veterans Healthcare System, New Orleans, Louisiana.. Electronic address: vbatuma@tulane.edu.",
"authors": "Bokhari|Syed Rizwan|SR|;Siriki|Ravi|R|;Teran|Federico J|FJ|;Batuman|Vecihi|V|",
"chemical_list": "D054368:Laxatives; D009942:Organometallic Compounds; D019343:Citric Acid; D008277:Magnesium Oxide; D008274:Magnesium; C110422:magnesium citrate",
"country": "United States",
"delete": false,
"doi": "10.1016/j.amjms.2017.08.013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9629",
"issue": "355(4)",
"journal": "The American journal of the medical sciences",
"keywords": "Epsom salt; Hypermagnesemia; Magnesium sulfate; fatal; laxative",
"medline_ta": "Am J Med Sci",
"mesh_terms": "D058186:Acute Kidney Injury; D019343:Citric Acid; D003248:Constipation; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D054368:Laxatives; D008274:Magnesium; D008277:Magnesium Oxide; D008875:Middle Aged; D009942:Organometallic Compounds; D006435:Renal Dialysis",
"nlm_unique_id": "0370506",
"other_id": null,
"pages": "390-395",
"pmc": null,
"pmid": "29661354",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Fatal Hypermagnesemia Due to Laxative Use.",
"title_normalized": "fatal hypermagnesemia due to laxative use"
} | [
{
"companynumb": "US-MYLANLABS-2018M1034449",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MAGNESIUM"
},
"drugadditional": null,
... |
{
"abstract": "A 69-year-old woman was diagnosed as having non-small cell lung cancer (adenocarcinoma, T1aN3M1b). She had no history of surgery or abdominal trauma. She was treated with ramucirumab (10 mg/kg) plus docetaxel (60 mg/m2) intravenously (RAM + DTX) every 3 weeks. Although an enhanced CT examination showed a partial tumor response after eight courses of RAM + DTX, she gradually began to experience abdominal fullness with severe peripheral pitching edema. Her body weight increased by 18 kg in 2 months and RAM + DTX chemotherapy was discontinued. An enhanced CT examination showed a large amount of ascites and pleural effusion, with no obstructions of the central vein or lymphatic ducts. The ascites were white and milky in appearance and contained 527 mg/dL of triglyceride. In addition, her pleural effusion was also white and milky in appearance. No further increases in ascites and pleural effusion were observed thereafter. Four months after her last RAM + DTX chemotherapy, she continued to exhibit a partial response and no increases in ascites or pleural effusion were present. The chylous effusion might have been caused by the RAM + DTX chemotherapy.",
"affiliations": "1Department of Medical Oncology, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chiba, 260-8670 Japan.;1Department of Medical Oncology, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chiba, 260-8670 Japan.;1Department of Medical Oncology, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chiba, 260-8670 Japan.;2Division of Pharmacy, Chiba University Hospital, Chiba, 260-8670 Japan.;1Department of Medical Oncology, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chiba, 260-8670 Japan.;1Department of Medical Oncology, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chiba, 260-8670 Japan.",
"authors": "Arai|Makoto|M|;Maruta|Susumu|S|;Fan|Meng Meng|MM|;Imai|Chiaki|C|;Tawada|Akinobu|A|;Takiguchi|Yuichi|Y|",
"chemical_list": null,
"country": "Singapore",
"delete": false,
"doi": "10.1007/s13691-019-00366-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2192-3183",
"issue": "8(3)",
"journal": "International cancer conference journal",
"keywords": "Chylothorax; Chylous ascites; Docetaxel; Ramucirumab",
"medline_ta": "Int Cancer Conf J",
"mesh_terms": null,
"nlm_unique_id": "101734231",
"other_id": null,
"pages": "114-117",
"pmc": null,
"pmid": "31218186",
"pubdate": "2019-07",
"publication_types": "D002363:Case Reports",
"references": "17584927;20048182;24023956;25854536;28892178;28950290;29515416",
"title": "Simultaneous chylous ascites and chylothorax during ramucirumab plus docetaxel chemotherapy in a patient with non-small lung cell cancer.",
"title_normalized": "simultaneous chylous ascites and chylothorax during ramucirumab plus docetaxel chemotherapy in a patient with non small lung cell cancer"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2019RR-211428",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"dru... |
{
"abstract": "Cardiac resynchronization therapy (CRT) has become the gold standard for patients with systolic left ventricular function, left ventricular ejection fraction less than or equal to 35%, wide complex QRS, and symptomatic heart failure. Annual implantation volume has steadily increased because of expanding indications for CRT. Improved survival resulted in many of these patients having their CRT devices for many years and eventually requiring an increased number of device-related procedures, including coronary sinus lead revisions and replacements following a coronary sinus lead extraction.",
"affiliations": "Cardiac Arrhythmia Service, Massachusetts General Hospital, 75 Fruit Street, Boston, MA 02114, USA. Electronic address: tmela@mgh.harvard.edu.",
"authors": "Mela|Theofanie|T|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ccep.2018.11.014",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1877-9182",
"issue": "11(1)",
"journal": "Cardiac electrophysiology clinics",
"keywords": "Cardiac resynchronization therapy; Coronary sinus lead; Extraction; Left ventricular lead",
"medline_ta": "Card Electrophysiol Clin",
"mesh_terms": "D058406:Cardiac Resynchronization Therapy; D058409:Cardiac Resynchronization Therapy Devices; D054326:Coronary Sinus; D020878:Device Removal; D006333:Heart Failure; D006801:Humans; D012086:Reoperation",
"nlm_unique_id": "101549998",
"other_id": null,
"pages": "131-140",
"pmc": null,
"pmid": "30717845",
"pubdate": "2019-03",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Explanting Chronic Coronary Sinus Leads.",
"title_normalized": "explanting chronic coronary sinus leads"
} | [
{
"companynumb": "US-BAYER-2019-036312",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nAlendronate sodium is used to reduce the risk of bone fracture in aged osteoporosis patients. However, its side effects should be recognized, especially for those aged patients with one or more basic cardiovascular diseases.\nA 90-year-old and a 75-year-old male patient were admitted to our department. These 2 patients were examined by dual energy X-ray absorptiometry (DXA).\n\n\nMETHODS\nBoth patients were diagnosed with osteoporosis, they also had history of atrial fibrillation (AF) and had long term use of warfarin.\n\n\nMETHODS\nAlendronate sodium was prescribed to the two patients at 70 mg once a week.\n\n\nRESULTS\nThe 2 patients had experienced dramatic increase of international normalized ratio (INR) to 4.69∼4.86 within 24 hours and gradual decrease in the next 5 days. Both patients experienced spontaneous ecchymoses and petechiae in the skin at the first 72 hours.\n\n\nCONCLUSIONS\nAlendronate sodium can transiently increase the INR over 50%, induce spontaneous ecchymoses and petechiae in the skin of aged male osteoporosis patients with AF who took warfarin. Clinicians should pay enough attention when using alendronate sodium on these kinds of patients and be aware of the consequent potential bleeding risk.",
"affiliations": "Department of Geriatrics, Diagnosis and Treatment Center of Osteoporosis, ZheJiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College.;Department of Neurosurgery & Gamma Knife Center, Zhejiang Provincial People's Hospital & People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China.;Department of Geriatrics, Diagnosis and Treatment Center of Osteoporosis, ZheJiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College.;Department of Geriatrics, Diagnosis and Treatment Center of Osteoporosis, ZheJiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College.",
"authors": "Qian|Sufeng|S|;Zhou|Jia|J|;Bian|Pingda|P|;Shi|Lingfei|L|",
"chemical_list": "D000925:Anticoagulants; D050071:Bone Density Conservation Agents; D014859:Warfarin; D019386:Alendronate",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000018698",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 31914073MD-D-19-0345010.1097/MD.0000000000018698186984600Research ArticleClinical Case ReportTransient increase in international normalized ratio (INR) and bleeding risk following Alendronate sodium in elderly patients on warfarin Two case reportsQian Sufeng MDaZhou Jia MD, PhDbBian Pingda MDaShi Lingfei MDa∗NA. a Department of Geriatrics, Diagnosis and Treatment Center of Osteoporosis, ZheJiang Provincial People's Hospital, People's Hospital of Hangzhou Medical Collegeb Department of Neurosurgery & Gamma Knife Center, Zhejiang Provincial People's Hospital & People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China.∗ Correspondence: Lingfei Shi, Department of Geriatrics, Diagnosis and Treatment Center of Osteoporosis, Zhejiang Provincial People's Hospital & People's Hospital of Hangzhou Medical College, Hang Zhou 310014, Zhe Jiang, China (e-mail: 15858155005@163.com).1 2020 10 1 2020 99 2 e186981 5 2019 13 11 2019 10 12 2019 Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.2020This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nIntroduction:\nAlendronate sodium is used to reduce the risk of bone fracture in aged osteoporosis patients. However, its side effects should be recognized, especially for those aged patients with one or more basic cardiovascular diseases.\n\nPatient concerns:\nA 90-year-old and a 75-year-old male patient were admitted to our department. These 2 patients were examined by dual energy X-ray absorptiometry (DXA).\n\nDiagnosis:\nBoth patients were diagnosed with osteoporosis, they also had history of atrial fibrillation (AF) and had long term use of warfarin.\n\nInterventions:\nAlendronate sodium was prescribed to the two patients at 70 mg once a week.\n\nOutcomes:\nThe 2 patients had experienced dramatic increase of international normalized ratio (INR) to 4.69∼4.86 within 24 hours and gradual decrease in the next 5 days. Both patients experienced spontaneous ecchymoses and petechiae in the skin at the first 72 hours.\n\nConclusion:\nAlendronate sodium can transiently increase the INR over 50%, induce spontaneous ecchymoses and petechiae in the skin of aged male osteoporosis patients with AF who took warfarin. Clinicians should pay enough attention when using alendronate sodium on these kinds of patients and be aware of the consequent potential bleeding risk.\n\nKeywords\naged malealendronate sodiumatrial fibrillationosteoporosiswarfarinOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nAlendronate sodium is one of the most commonly used bisphosphonates for aged osteoporosis patients in China. This medication has high affinity with hydroxyapatite in bone union, specifically combined to the bone surface where active bone transformation taken place. Meanwhile, it could inhibit osteoclast function, reduce bone resorption, reduce the risk of bone fracture in centrum, hip and other parts of skeleton.[1,2] Recently, we found that not only international normalized ratio (INR) of coagulation had been upregulated, but spontaneous ecchymoses and petechiae in the skin had also been caused after the administration of alendronate sodium in 2 elderly male atrial fibrillation (AF) patients who received warfarin anticoagulation therapy. To our knowledge, this side effect of alendronate sodium has not been reported before.\n\n2 Case report\n2.1 Case 1\nA 90-year-old male diagnosed with osteoporosis after examined by dual energy X-ray absorptiometry (DXA) was admitted into our department. His serum carboxy-terminal cross-linking telopeptide of type 1 collagen (CTX), procollagen type 1 amino-terminal propeptide (P1NP) and osteocalcin (OC) was 0.73 μg/L (reference value 0.4 μg/L-0.78 μg/L), 104.80 μg/L (reference value 9.06 μg/L-76.24 μg/L), and 34.30 μg/L (reference value 6.00 μg/L-24.66 μg/L), respectively. He had a history of hypertension for over 20 years, chronic AF for 1 year. Six months earlier he suffered from sudden sensation of weakness in the right limb and slurred speech when woke up in the morning, and the brain MRI indicated ‘scattered lacunar infarction foci in right frontal lobe, infarction foci in left dorsal thalamic, malacic foci in right occipital lobe’. From then on, he took warfarin sodium tablet (produced by Orion Corporation in Finland) 2 mg/day. The patient's INR was 3.04 when he was admitted into our department. Oral alendronate sodium tablets (produced by Merck Sharp & Dohme Italia SPA Australia) once a week at 70 mg were prescribed to the patient. Surprisingly, 24 hours after the first dose, the patient's serum INR increased from 3.04 to 4.86, the oral taken of alendronate sodium tablets was stopped immediately. Then the patient's serum INR fell to 4.41 at 48 hours, meanwhile, he experienced spontaneous ecchymoses and petechiae in the skin. Fortunately, the ecchymoses and petechiae stopped progressing on the third day, and INR gradually decreased to 3.67 on the fifth day. The patient denied taken other medication except for warfarin sodium and alendronate sodium tablets, he also denied significant diet change.\n\n2.2 Case 2\nThe patient that admitted into our department was a 75-year-old male, diagnosed with osteoporosis by DXA examination, his serum CTX, P1NP and OC were 0.78 μg/L, 200.70 μg/L, and 24.47 μg/L, respectively. He had a history of 15-year hypertension and 10-year chronic AF. Ten months earlier, he suffered from abrupt dizziness accompanied with nausea and vomiting, right limb dysfunction when he went to the toilet at night. CT scans showed ‘the left basal ganglia infarction foci’. After that, warfarin sodium tablet was orally taken 3 mg/day. The patient's INR was 2.70 when he was admitted into our department. Alendronate sodium tablets were prescribed to the patient at 70 mg once a week. It turned out that the patient serum INR increased from 2.70 to 4.69 at the first 24 hours, the oral taken of alendronate sodium tablets was stopped immediately. Then the patient's serum INR fell to 4.34 at 48 hours; he also had spontaneous ecchymoses and petechiae in the skin during the fluctuation of INR. However, the ecchymoses and petechiae gradually vanished at the following days and INR decreased to 3.32 at the fifth day. The patients denied taken other medication except for warfarin sodium and alendronate sodium tablets, he also denied significant diet change.\n\n3 Discussion\nIn the elderly people, the prevalence of AF is as high as 6% and increases with age. The most serious complication of AF is thromboembolism of brain vessels, which can induce acute cerebral ischemic apoplexy and jeopardize patient's life.[3] Therefore, long-term anticoagulation therapy using warfarin to maintain INR at 2-3 was a common method for these patients.\n\nAfter stroke, elderly male patient's bone loss would significantly accelerated and bone density decreases rapidly due to prolonged bed time, reduced standing and walking, shortened sunshine bath time, and the influence of some drugs (such as hormones).[4] The increased serum level of bone turnover markers (BTMs) has been observed in these patients, such as CTX, P1NP, and OC. Both CTX and P1NP are related to the metabolism of type 1 collagen, P1NP is a metabolite of type 1 procollagen (synthesized and secreted by osteoblasts) that is lysed by polypeptidase, while CTX is the product of type 1 collagen lysed by the activity of osteoclasts. OC is a bone-specific 5–8KD protein produced by osteoblasts, and is the most common protein (about 3%) in bones except type I collagen (90%).[5] Clinical studies have shown that CTX, P1NP and OC are moderate positively correlated, and all of them are negatively correlated with bone density.[6] Therefore, the serum level of BTMs should be paid attention to and monitored after the ischemic stroke of aged patients, and anti-bone resorption drugs like alendronate sodium should be used for patients with rapid increasing or high level of BTMs.\n\nAccording to these 2 cases, it could be inferred that alendronate sodium would enhance the anticoagulant effect of warfarin, and increase the INR on the next day over 50%. Warfarin is a substance containing the basic structure of 4-hydroxycoumarin, which binds to plasma protein over 99% after absorption, but its anticoagulant effect is affected by a variety of environmental factors (such as drugs and food).[7] The mechanism of alendronate sodium enhancing the anticoagulation effect of warfarin may be:\n\n(1) alendronate sodium can compete with warfarin to bind to plasma protein, thus increasing the concentration of free warfarin in blood[8];\n\n(2) warfarin is metabolized in the liver by cytochrome P450–2C9 enzyme (CYP2C9) and vitamin K epoxide reductase (VKORC1), while alendronate sodium and its metabolites may inhibit the activity of CYP2C9 and VKORC1, thereby reducing the metabolism of warfarin[9];\n\n(3) alendronate sodium is a powerful inhibitor of osteoclast activity, which can cause transient decrease of serum calcium after taking, affect the blood coagulation process, extend the prothrombin time, and lead to transient increase of INR.[10]\n\nAlthough the increased INR can fall to a lower level in a few days as well as the spontaneous ecchymoses and petechiae in the skin tend to self-cured after the administration of alendronate sodium, enough attention to the potential bleeding risk should be paid when using this medication. In order to reduce these potential risks for elderly male AF patients that received warfarin anticoagulation therapy who also need to take alendronate sodium, the following advices may be helpful:\n\n(1) before taking alendronate sodium, patient's INR should be rechecked. If the INR is over 3 or fluctuates greatly, the administration of alendronate tablets should be suspended;\n\n(2) on the day of taking alendronate sodium, for those patients with ideal and stable INR, the dose of warfarin should be appropriately reduced, the changes in INR as well as the appearance of ecchymoses and petechiae in the skin should be monitored;\n\n(3) choose new type anticoagulation medication such as Rivaroxaban be the alternative of warfarin.[11]\n\n4 Conclusion\nAlendronate sodium can transiently increase the INR over 50%, induce spontaneous ecchymoses and petechiae in the skin in aged male osteoporosis patients with AF who had long term oral administration of warfarin. The accurate mechanism of this side effect of alendronate sodium in specific patients and whether other bisphosphonates (such as zoledronic acid, etc) would also interference the anticoagulant effect of warfarin need further studies.\n\nAuthor contributions\nConceptualization: Lingfei Shi.\n\nFunding acquisition: Jia Zhou, Pingda Bian.\n\nResources: Lingfei Shi.\n\nSupervision: Lingfei Shi.\n\nWriting – original draft: Sufeng Qian, Jia Zhou.\n\nWriting – review & editing: Sufeng Qian, Jia Zhou, Lingfei Shi.\n\nAbbreviations: AF = atrial fibrillation, BTMs = bone turnover markers, CTX = carboxy-terminal cross-linking telopeptide of type 1 collagen, CYP2C9 = cytochrome P450–2C9 enzyme, DXA = dual energy X-ray absorptiometry, INR = international normalized ratio, OC = osteocalcin, P1NP = procollagen type 1 amino-terminal propeptide, VKORC1 = vitamin K epoxide reductase.\n\nHow to cite this article: Qian S, Zhou J, Bian P, Shi L. Transient increase in international normalized ratio (INR) and bleeding risk following Alendronate sodium in elderly patients on warfarin: two case reports. Medicine. 2020;99:2(e18698).\n\nSQ and JZ contribute equally to this article.\n\nAlthough the patients had been anonymized, the study has received the approval of ethics review board of Zhejiang Provincial People's Hospital, written consent was obtained from the patients to publish the case report.\n\nThis work was supported by grants from: 1. Department of health of Zhejiang Province (2016ZDA002); 2. Department of health of Zhejiang Province (2014KYB-034).\n\nThe authors have no conflicts of interests to disclose.\n==== Refs\nReferences\n[1] The Chinese medical association of osteoporosis and bone mineral salt disease branch . Guidelines for the diagnosis and treatment of primary osteoporosis in 2017 . Chin J Osteoporos Bone Miner Res \n2017 ;10 :413 –36 .\n[2] Vinicola V Giampà E Di Bonito M \nResults of a national multicentric study on compliance to treatment with various disphosphonate formulations in patients with postmenopausal osteoporosis . Minerva Endocrinol \n2015 ;40 :187 –93 .26205647 \n[3] Li J Guo Y Wang C \nClinical features and risk factors of stroke/thromboembolism and bleeding in the elderly patients with atrial fibrillation . Chin J Cardiol \n2013 ;41 :927 –30 .\n[4] Marzolini S McIlroy W Tang A \nPredictors of low bone mineral Density of the stroke-affected hip among ambulatory individuals with chronic stroke . Osteoporos Int \n2014 ;25 :2631 –8 .25001986 \n[5] Jiajue R Jiang Y Wang O \nSuppressed bone turnover was associated with increased osteoporotic fracture risks in non-obese postmenopausal Chinese women with type 2 diabetes mellitus . Osteoporos Int \n2014 ;25 :1999 –2005 .24760246 \n[6] Bian P Ying Q Li X \nOn the relationship between bone mineral density and bone turnover markers in subjects aged 80 and above . Chin J Endocrinol Metab \n2014 ;30 :206 –9 .\n[7] Chinese Medical Association Society of Gerontology . Chinese experts’ consensus on warfarin anticoagulant therapy . Chin J Intern Med \n2013 ;52 :76 –82 .\n[8] Roux C Hofbauer LC Ho PR \nDenosumab compared with risedronate in postmenopausal women suboptimally adherent to alendronate-therapy: efficacy and safety results from a randomized open-label study . Bone \n2014 ;58 :48 –54 .24141036 \n[9] Benavides F Grossman N Poggi H \nEffect of VKORC1 and CYP2C9 variants on dosage of oral anticoagulants in Chilean individuals . Rev Med Chil \n2015 ;143 :1369 –276 .26757860 \n[10] Binkley N Krueger D Engelke J \nVitamin K deficiency from long-term warfarin anticoagulation does not alter skeletal status in male rhesus monkeys . J Bone Miner Res \n2007 ;22 :695 –700 .17295605 \n[11] Yasaka M Minematsu K Toyoda K \nRivaroxaban administration after acute ischemic stroke: the RELAXED study . Plos One \n2019 ;14 :e0212354 .30759158\n\n",
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"abstract": "BACKGROUND\nHepatitis C (HCV) infection is a major cause of liver disease, cirrhosis, and hepatocellular carcinoma. Interferon-based treatments have the potential to decrease the burden of disease, but are complicated by side effects, including neuropsychiatric symptoms.\n\n\nOBJECTIVE\nThe authors described a case of interferon-induced psychosis as a framework to review the literature and discuss the decision to pursue antiviral treatment in psychiatrically ill patients with hepatitis C.\n\n\nMETHODS\nThe authors followed a patient with chronic HCV who received interferon and ribavirin and who developed hallucinations ultimately requiring psychiatric hospitalization.\n\n\nRESULTS\nDespite treatment with various neuroleptics, the psychosis resolved only when the interferon/ribavirin were discontinued.\n\n\nCONCLUSIONS\nPsychiatric illness should not rule out the possibility of interferon-based therapy, but it calls for close integration of psychiatric and medical care and individualized decision-making based on the biological and psychosocial circumstances of each case.",
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"abstract": "BACKGROUND\nAdult-onset Still's disease (AOSD) is a systemic inflammatory disorder characterized by rash, leukocytosis, fevers, and arthralgias. Pulmonary involvement has been reported rarely in AOSD, but acute respiratory distress syndrome (ARDS) is extremely rare and potentially fatal and must be recognized as potential manifestation of underlying AOSD.\n\n\nMETHODS\nWe present a case of AOSD manifested by ARDS and review the previously reported cases in Medline/Pub med.\n\n\nRESULTS\nIncluding this case, 19 cases of AOSD complicated with ARDS have been reported in the literature.\n\n\nCONCLUSIONS\nIt is important to recognize ARDS as a manifestation of AOSD so that proper diagnostic and therapeutic management can be initiated promptly.",
"affiliations": "University of Chicago Medical Center.;Rush University Medical Center and John H. Stroger, Jr. Hospital of Cook County, USA.;Rush University Medical Center and John H. Stroger, Jr. Hospital of Cook County, USA.",
"authors": "Dua|Anisha B|AB|;Manadan|Augustine M|AM|;Case|John P|JP|",
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"fulltext": "\n==== Front\nOpen Rheumatol JOpen Rheumatol JTORJThe Open Rheumatology Journal1874-3129Bentham Open 24459537TORJ-7-12510.2174/1874312901307010125ArticleAdult Onset Still’s Disease Presenting with Acute Respiratory Distress Syndrome: Case Report and Review of the Literature Dua Anisha B. *1Manadan Augustine M. 2Case John P. 21 University of Chicago Medical Center2 Rush University Medical Center and John H. Stroger, Jr. Hospital of Cook County, USA* Address correspondence to this author at the University of Chicago Medical Center, Department of Rheumatology, 5800 S. Maryland Ave, MC0930, Room #N005, Chicago, IL 60637, USA; Tel: 773-702-8702; E-mail: adua@medicine.bsd.uchicago.edu30 12 2013 2013 7 125 128 6 11 2013 12 12 2013 12 12 2013 © Dua et al.; Licensee Bentham Open.2013DuaThis is an open access article licensed 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 work is properly cited.Introduction:\n Adult-onset Still’s disease (AOSD) is a systemic inflammatory disorder characterized by rash, leukocytosis, fevers, and arthralgias. Pulmonary involvement has been reported rarely in AOSD, but acute respiratory distress syndrome (ARDS) is extremely rare and potentially fatal and must be recognized as potential manifestation of underlying AOSD.\n\nMethods: \nWe present a case of AOSD manifested by ARDS and review the previously reported cases in Medline/Pub med.\n\nResults: \nIncluding this case, 19 cases of AOSD complicated with ARDS have been reported in the literature.\n\nConclusions: \nIt is important to recognize ARDS as a manifestation of AOSD so that proper diagnostic and therapeutic management can be initiated promptly. \n\nKeywords: \nStill’s DiseaseARDS.\n==== Body\nINTRODUCTION\nAdult onset Still’s disease (AOSD) is a systemic inflammatory disorder that is related to systemic-onset juvenile idiopathic arthritis. Like the pediatric disease, it is characterized by spiking fevers, arthralgias, salmon colored rash, leukocytosis, sore throat, cytopenias and hyperferritinemia. Severe systemic manifestations associated with AOSD include disseminated intravascular coagulation (DIC), macrophage activation syndrome (MAS), and hepatic failure. Pulmonary involvement, usually pleuritis, is a recognized manifestation of AOSD. Parenchymal lung disease and acute respiratory distress syndrome (ARDS) are rarer pulmonary manifestations of AOSD. We report a case of a 26 year old female with AOSD presenting with ARDS complicated by MAS.\n\nMETHODS\nFirst, a patient with AOSD and ARDS is described and the clinical, laboratory, and radiologic findings are reported. Second, Medline/Pub med was also searched for associations between ARDS, SIRS, and AOSD using combinations of the keywords “acute respiratory distress syndrome”, “ARDS”, “systemic inflammatory response syndrome”, “SIRS”, “adult onset Stills disease”, and “Stills disease”. A search was also done using OVID SP with these same keywords, and relevant citations from reported cases were reviewed.\n\nRESULTS\nCase Report\nA 26-year-old African-American female with a history of type 2 diabetes mellitus presented to her primary care physician with sore throat and cough. She was noted to have a “viral exanthem”, and was started on amoxicillin-clavulanate. Her symptoms did not improve and she went to the emergency department (ED) for shortness of breath, cough and myalgias. Her vital signs were as follows: temperature 36.7 C, pulse rate 112, respiratory rate 18, and blood pressure 100/56 mm Hg. Physical examination was notable for coarse breath sounds bilaterally over lung fields with scattered crackles at the bases and tachycardia. Radiograph of the chest showed bilateral interstitial infiltrates suggestive of ARDS. Arterial blood gas (ABG) showed pH 7.28, pCO2 38 mmHg and pO2 58 mmHg. Her respiratory status worsened and she underwent endotracheal intubation requiring ventilator support, and was started on broad-spectrum antibiotics for presumed pneumonia.\n\nTwo days after admission to the intensive care unit (ICU), the patient developed daily spiking fevers up to 40.0 C. She became more difficult to oxygenate with increasing ventilator requirements. She became hypotensive to 70/49 mmHg and required vasopressors. Antibiotic therapy was broadened and changed multiple times, including treatment with vancomycin, ceftriaxone, azithromycin, piperacillin/ tazobactam, imipenem, metronidazole and fluconazole, without any clinical improvement.\n\nLaboratory analysis included an initial white blood cell (WBC) count of 20 x 103/mm3 (which increased to 49 x 103/mm3 within one week) with 91.8% neutrophils. Hemoglobin (Hb) was initially 10 g/dL (and dropped to 8.3 g/dL within one week), and platelet count 407,000/mL. Aspartate aminotransferase (AST) was 88 IU/L, alanine aminotransferase (ALT) 44 IU/L, and lactate dehydrogenase (LDH) 530 units/L. Autoimmune panel was negative for anti-nuclear antibodies (ANA) and rheumatoid factor (RF). C-reactive protein (CRP) was elevated at 7.19 nmol/L and erythrocyte sedimentation rate (ESR) was 39 mm/h. The ferritin level was 4,022 ng/mL.\n\nThe patient underwent further extensive evaluation during the first ten days of her admission. All cultures during fever spikes were negative, including seven sets of blood cultures. Computerized axial tomography (CT) scans of her neck and sinus were unremarkable. CT of the chest revealed bilateral pleural effusions and diffuse, patchy airspace opacities and interstitial infiltrates. She underwent bronchoscopy which was negative for bacterial, viral (including cytomegalovirus) or fungal infection. Hepatitis panel, urine legionella, serum histoplasma antigen, cryptococcal antigen, Clostridium dificile toxin, and acid fast bacilli were all negative. Transthoracic echocardiogram was normal with an ejection fraction of 55-65%. Bone marrow biopsy and flow cytometry were normal.\n\nShe was diagnosed with AOSD based on fulfillment of the Yamaguchi criteria with major criteria of fevers lasting greater than one week, leukocytosis with neutrophilia, and minor criteria of abnormal liver enzymes, sore throat, and negative RF and ANA [1]. In addition, she had hyperferritinemia and no evidence of infection or malignancy after extensive investigation. She was started on methylprednisolone 60 mg intravenously (IV) every 6 hours on day 13 of her hospital admission, and the next day, her maximum temperature improved to 38.2 C, down from 39.4 C. On day 16 she was given pulse methylprednisolone 1000mg daily for 3 days, followed by prednisone 60mg daily. She remained afebrile until her discharge on hospital day 19. She was weaned off vasopressors, antibiotics were discontinued, mental status was at baseline, and WBC count improved prior to discharge. She had developed an ICU polyneuropathy during her hospital course and required tracheostomy and transfer to a ventilator facility for weaning from ventilator support. At the ventilator facility she was continued on prednisone 60 mg daily except for one missed dose of prednisone the week prior to re-admission.\n\nTwo weeks after her discharge, she was re-admitted to the ICU with spiking fevers to 39.4 C, and again, broad-spectrum antibiotic therapy with vancomycin, tobramycin, and metronidazole was initiated. Two days after admission, she had a seizure followed by hypotension to 87/43 mmHg and required vasopressor support. Seizures were treated with lorazepam and phenytoin. Imipenem, metoclopramide, and metronizadole were discontinued, and meropenem and oral vancomycin were initiated. Laboratory testing revealed a WBC count of 15.1 x 103/mm3, Hb 6.9 g/dL, platelets 61,000/mL, AST 627 IU/L, ALT 507 IU/L, LDH 2,080 units/L, ferritin 110,065 ng/mL, fibrinogen 170 g/L, normal coagulation studies and ESR 16 mm/h.\n\nShe continued to have seizure activity, electromyogram showed moderate to severe axonal sensorimotor polyneuropathy, and electroencephalogram revealed epileptiform activity over the right parietal region and prominent sharp waves over bilateral temporal regions. Magnetic resonance imaging of the brain revealed multifocal stenosis of bilateral posterior cerebral arteries and a segment of the left anterior cerebral arteries. CT chest showed bilateral large pleural effusions with consolidation and airspace opacities consistent with ARDS. The patient was started on methylprednisolone 1000 mg IV daily for three days followed by prednisone 60 mg daily and cyclosporine 3mg/kg/day for presumed macrophage activation syndrome (MAS). Because of her continued deteriorating course, a repeat bone marrow biopsy was done over two weeks after cyclosporine therapy was begun and showed positive staining for cytomegalovirius (CMV) without evidence for hemophagocytosis. CD 163 staining to look for activated histiocytes was not performed. In addition, the cerebrospinal fluid (CSF) was positive for CMV by PCR and the patient was started on gancyclovir. The patient’s presentation was felt to meet criteria for CMV infection and secondary hemophagocytic syndrome despite bone marrow absence of true hemophagocytosis. The patient died despite treatment and supportive care measures six weeks after her initial presentation with ARDS and AOSD.\n\nLITERATURE REVIEW\nA Medline search yielded a total of 12 previously reported cases of ARDS associated with AOSD. Two of these case reports were in Japanese and French, and abstracts were unavailable. Of the other 10, references led to three more articles, one with three reported cases of AOSD with ARDS, one with two reported cases, and the other, a single case report, for a total of 18 reported cases. By description, all 16 accessible cases reviewed met the Yamaguchi criteria for AOSD. The patients ranged from 17-71 years of age. Fever and leukocytosis was present in all cases. Reported ferritin values ranged from 103-42,600 ng/mL. All patients were treated with corticosteroids and a few had additional treatments with methotrexate, azathioprine, cyclosporine, cyclophosphamide, and intravenous immunoglobulin (Table 1).\n\nDISCUSSION\nAOSD is characterized by high spiking fevers, rash, sore throat, and hyperferritinemia. Multiple sets of diagnostic criteria for AOSD have been proposed, but the Yamaguchi criteria have the highest sensitivity of 93.5% [1]. Our patient fulfilled the Yamaguchi criteria with spiking fevers, leukocytosis with neutrophila, sore throat, lymphadenopathy, abnormal liver enzymes, and negative infectious, rheumatic, and malignancy evaluations.\n\nAfter her admission, she rapidly developed ARDS. Viral cultures of bronchoscopic alveolar lavage fluid, tested during her first admission were negative for CMV. This culture has a reported sensitivity of 100% and specificity of 70% [2]. Her initial presentation with ARDS is thus unlikely to be attributable to CMV pneumonia, and all other infectious workup was negative. However, on her second admission, after treatment with high dose corticosteroids for 3 weeks, she was found to have positive CMV staining on bone marrow biopsy and in the CSF by PCR. We concluded that disseminated CMV infection complicated the immunosuppres-sive therapy and resulted in death 6 weeks after her initial presentation. The poor outcome in our patient and many others in the literature can hopefully be improved by early recognition and diagnosis of AOSD in those ARDS patients not responding to antibiotic therapy. It is also critical to re-evaluate for infectious causes if the clinical course declines after initiation of immunosuppressive therapy.\n\nPulmonary involvement in AOSD has been reported in multiple series, but ARDS has only been described in case reports [3-11]. Pleuritis is the most common pulmonary manifestation of AOSD, ranging from 12%-53% in various studies [12]. A review of pulmonary involvement in AOSD found that lung involvement was present ranging from 6%-53% of patients, most commonly pleuritis, followed by pleural effusions [13].\n\nSevere pulmonary involvement, including pleuritis and interstitial pneumonia in AOSD, is associated with a poor prognosis. A retrospective analysis of 61 patients by Zeng et al. [12] found that 11.5% had interstitial pneumonia on CT. Six of the 61 patients in this series died, and 4 died from pneumonia/respiratory failure. Pulmonary involvement was found to be a poor prognostic sign in this study.\n\nThere are 18 case reports in the literature of AOSD manifesting with ARDS, and the 16 reports obtained have similar clinical and serologic findings to our patient [3-11] (Table 1). These cases were initially treated as infectious pneumonia with broad spectrum antibiotics, with subsequent respiratory decompensation and intubation. Antibiotics were discontinued in all cases, and followed by initiation of high dose methylprednisolone therapy. In most case reports, patients responded well clinically and serologically to high dose corticosteroid therapy within hours to days. In the reports by Hirohata [3], Manganelli [10], and Chvojka [11], the patients had AOSD complicated by ARDS, failed corticosteroid therapy and were subsequently treated with other immunosuppressive agents, but eventually died. Imaging findings of ARDS in these case reports were described as dense, diffuse, bilateral infiltrates, without any clear differentiating features between ARDS associated with infectious causes or other autoimmune diseases.\n\nEarly recognition of ARDS in patients with AOSD is clinically difficult, but important because it can lead clinicians to initiate therapy with corticosteroids. After treatment with methylprednisolone, patients had decrease in ferritin levels as well as improvement in respiratory and clinical status. In all the reviewed literature, as well as in our case, patients were initially managed with antibiotic therapy for ARDS. The subsequent diagnosis of AOSD complicated by ARDS led to a change in management.\n\nAlthough our patient’s bone marrow biopsy was negative for hemophagocytosis, her clinical features were consistent with MAS including fevers, thrombocytopenia, hyperferritinemia, transaminitis, anemia, and CNS manifestations. Prevalence of MAS in AOSD ranges from 11-15%, and complications of pleuritis and ARDS were present in more than one third of patients who had MAS complicating AOSD [14].\n\nThe case presented here illustrates the severe presentation of AOSD with ARDS and its response to high dose corticosteroid therapy. Our patient presented with symptoms consistent with AOSD, but early classification and diagnosis was critical to guiding therapy. The diagnosis of AOSD should be considered in the face of ARDS when a patient is not responding to infectious therapy and other clinically compatible manifestat-ions of AOSD are present, including spiking fevers and high ferritin levels. Early recognition of AOSD can lead to prompt initiation of appropriate therapy.\n\nACKNOWLEDGEMENTS\nDeclared none.\n\nCONFLICT OF INTEREST\nThe authors declare that there are no conflicts of interest.\n\nTable 1. Case Reports of Acute Respiratory Distress Syndrome associated with Adult-Onset Still's Disease\n\nName\tAge\tSex\tFever\tWBC (x109/L)\t% neut\tHb (g/dL)\tPlts (x109/L)\tCRP (mg/L)\tESR\tFerritin (ng/mL)\tTherapy\tMed Hx\tOther Symptoms\tOutcome\tTime to \n\nImprovement After\n\nInitiation of Therapy \tTime Until\n Initiation \n\nof Steroid \t\nBiron\n\n(2006)\t39\tF\t+\t22\t90\t8.4\t571\t290\t*\t8590\tCS\tnone\tsore throat, \n\narthralgia, \n\nskin rash\timproved\t2 days \t* \t\nBiron\n\n(2006)\t68\tF\t+\t28\t88\t12.1\t220\t362\t116\t42600\tCS\tpolio, DM\tdyspnea \n\narthralgia, rash\timproved\t3 days \t* \t\nBiron\n\n(2006)\t43\tM\t+\t15.6\t91\t*\t*\t471\t*\t25195\tCS+IVIG\tnone\trepiratory \n\ndistress, \n\nsore throat\timproved\t2 days \t* \t\nChvojka\n\n(2009)\t24\tM\t+\t*\t*\t*\t*\t*\t*\t*\tCS\tnone\tsore throat, \n\nrash, \n\npleural effusion\tdied\t* \t* \t\nGibbs\n\n(1993)\t21\tF\t+\t*\t*\t*\t*\t*\t*\t*\tCS\tnone\tarthralgia, \n\nliver damage, \n\nDIC\timproved\t* \t* \t\nGuignard\n\n(2007)\t23\tM\t+\t21\t*\t*\t*\t118\t83\t>10,000\tCS+MTX\tnone\tsore throat, \n\nrash, arthritis\timproved\t6 days \t* \t\nHagiyama\n\n(2003)\t24\tF\t+\t12.9\t95\t11.9\t271\t26.9\t98\t103\tCS+CYP\tnone\tliver \n\ndamage, DIC\timproved\t6 days \t8 days \t\nHagiyama\n\n(2003)\t20\tM\t+\t12.2\t88\t13.6\t170\t16.4\t*\t14455\tCS\tnone\trash, \n\n adenopathy\timproved\t7 days \t5 days \t\nHirohata\n\n(1986)\t65\tF\t+\t14\t*\t*\t*\t*\t*\t7880\tCS+CYP\tnone\tarthralgia, \n\ndyspnea\tdied\tdied day 37 \t5 days \t\nIglesias\n\n(1999)\t29\tF\t+\t16.6\t*\t10.1\t142\t*\t>100\t2600\tCS\tnone\thypotension, \n\nsore throat \n\narthralgia\timproved\t24 hours \t6 days \t\nManganelli\n\n(2003)\t17\tF\t+\t*\t*\t*\t*\t*\t26\t*\tCS +6MP+CSA+IVIG\tnone\tfever, myalgias, \n\nskin rash,\n\n dyspnea\tdied\timproved \n\nday 20, \n\ndied day 31 \t* \t\nMito\n\n(2002)\t24\tF\t+\t*\t*\t*\t*\t*\t*\t*\tCS+CSA\tnone\tsore throat, \n\nrash, arthritis, \n\nadenopathy\timproved\t* \t* \t\nPederson\n\n(1991)\t40\tM\t+\t33\t*\t*\t*\t*\t114\t*\tCS+AZA\tnone\tarthralgia, \n\njaundice, rash\timproved\t* \t9 days \t\nShinohara\n\n(1999)\t54\tF\t+\t17.7\t84\t12.3\t370\t11.9\t92\t3801\tCS\tnone\trash, \n\npolyarthralgia, \n\nmyalgia, DIC\timproved\t* \t* \t\nSuleiman\n\n(2002)\t36\tF\t+\t30.9\t*\t10.1\t260\t*\t55\t7880\tCS +MTX\tnone\tpleural effusion, \n\ndyspnea\timproved\tless than \n\n1 week \t* \t\nYokoyama\n\n(1995)\t71\tM\t+\t*\t*\t*\t69\t*\t*\t37000\tCS+NM\tnone\tsore throat, \n\nrash, myalgia\timproved\t24 hours \t5 days \t\nOur Case\n\n(2010)\t26\tF\t+\t20\t92\t10\t407\t7.1\t39\t4022\tCS\tdm\tsore throat, \n\nmyalgias\tdied\t2 days \t13 days \t\n* Data/values not reported or unavailable.\n\n\nAbbreviations: F= female, M=male, WBC = white blood cell count, neut= neutrophil, Plts= Platelets, CRP= C reactive protein, gly= glycosolated, Med = medical, Hx= history, CP =\nChest pain, SOB= shortness of breath.\n\nDIC = disseminated intravascular coagulation, DM = diabetes mellitus, CS = corticosteroids, CSA = cyclosporine, CYP = cyclophosphamide, IVIG = intravenous immunoglobulin,\nMTX = methotrexate, AZA = azathioprine.\n\n6-MP = 6 mercaptopurine, NM=nafamostat mesilate.\n\nKey for Table 1: Abbreviations: F= female, M=male, WBC = white blood cell count, neut= neutrophil, Plts= Platelets, CRP= C reactive protein, gly= glycosolated, Med = medical,\nHx= history, CP = Chest pain, SOB= shortness of breath, DIC = disseminated intravascular coagulation, DM = diabetes mellitus, CS = corticosteroids, CSA = cyclosporine, CYP =\ncyclophosphamide, IVIG = intravenous immunoglobulin, MTX = methotrexate, AZA = azathioprine, 6-MP = 6 mercaptopurine, NM = nafamostat mesilate.\n==== Refs\nREFERENCES\n1 Masson C Le Loet X Liote F Comparative Study of 6 types of Criteria in Adult Still’s Disease. J Rheumatol 1996 23 95 7 \n2 Paradis IL Grgurich WF Dummer JS Rapid detection of cytomegalovirus pneumonia from lung lavage cells. Am Rev Respir Dis 1988 138 3 697 702 2849341 \n3 Hirohata S Adult stills disease complicated with adult respiratory distress. Arch Int Med 1986 146 2409 3778078 \n4 Iglesias J Sathiraju S Marik PE Severe systemic inflammatory response syndrome with shock and ARDS resulting from stills disease. Chest 1999 115 1738 40 10378576 \n5 Suleiman M Wolfovitz E Boulman N Adult onset stills disease as a cause of ards and acute respiratory failure. Scand J Rheumatol 2002 31 3 181 3 12195635 \n6 Biron C Chambellan A Agard C Acute Respiratory Failure Revealing Adult onset Stills disease. Clin Rheumatol 2006 25 766 68 16283419 \n7 Shinohara T Hidaka T Matsuki Y Calcinosis cutis and intestinal pseudo-obstruction in a patient with adult onset Still’s disease associated with recurrent relapses of disordered coagulopathy. Internal Med 1999 38 6 516 20 10411361 \n8 Hagiyama H Koike R Nagasaka K Two cases of acute respiratory distress syndrome resulting from adult-onset Still’s disease. Med Rheumatol 2003 13 76 80 \n9 Guignard S Dien G Dougados M Severe systemic inflammatory response syndrome in a patient with adult onset Still’s disease treated with anti-IL1 drug anakinra: a case report. Clin Exp Rheumatology 2007 25 758 59 \n10 Manganelli P Zuccoli P Fietta P Adult-onset Still's disease with respiratory distress syndrome. polyserositis and disseminated intravascular coagulation: a case with a fatal outcome. Clin Exp Rhematol 2013 21 139 \n11 Chvojka J Krouzecky A Radej J 24-year old male with fever. multi-organ dysfunction and fast progressing ARDS. Vnitr Lek 2009 55 10 991 4 \n12 Zeng T Zou Yu-Qiong Wu Mei-Fang Clinical Features and Prognosis of Adult-Onset Still’s Disease: 61 Cases from China. JCR 2009 36 1026 31 \n13 Cheema GS Quismorio FP Jr Pulmonary Involvement in Adult-Onset Still’s Disease. Curr Opin Pulm Med 1999 5 305 10461535 \n14 Artlet JB D Le Thi H Marinho A Reactive Haemophagocytic Syndrome in Adult-onset Still’s disease a report of six patients and a review of the literature. Ann Rheum Dis. 2006 65 1596 601 16540551\n\n",
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"keywords": "ARDS.; Still’s Disease",
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"title": "Adult Onset Still's Disease Presenting with Acute Respiratory Distress Syndrome: Case Report and Review of the Literature.",
"title_normalized": "adult onset still s disease presenting with acute respiratory distress syndrome case report and review of the literature"
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"abstract": "Background. Sudden sensorineural hearing loss (SSHL) caused by opiate abuse or overuse has been well documented in the medical literature. Most documented case reports have involved either heroin or hydrocodone/acetaminophen. Recently, case reposts of methadone induced SSHL have been published. Case Report. We present the case of a 31-year-old man who developed SSHL after a methadone overdose induced stupor. He was subsequently restarted on methadone at his regular dose. On follow-up audiometry exams, he displayed persistent moderately severe sensorineural hearing loss bilaterally. Discussion. This case is notable because unlike all but one previously reported case, the patient-who was restated on methadone-did not make a complete recovery. Conclusion. Methadone overuse in rare cases causes SSHL.",
"affiliations": "Department of Medicine, Staten Island University Hospital, 475 Seaview Avenue, Staten Island, NY 10305, USA.",
"authors": "Saifan|Chadi|C|;Glass|Daniel|D|;Barakat|Iskandar|I|;El-Sayegh|Suzanne|S|",
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"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIM.MEDICINECase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 10.1155/2013/242730Case ReportMethadone Induced Sensorineural Hearing Loss Saifan Chadi *http://orcid.org/0000-0003-1681-2778Glass Daniel Barakat Iskandar El-Sayegh Suzanne Department of Medicine, Staten Island University Hospital, 475 Seaview Avenue, Staten Island, NY 10305, USA*Chadi Saifan: chadisaifan@hotmail.comAcademic Editor: Ting Fan Leung\n\n2013 29 7 2013 2013 24273013 3 2013 18 6 2013 Copyright © 2013 Chadi Saifan et al.2013This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nBackground. Sudden sensorineural hearing loss (SSHL) caused by opiate abuse or overuse has been well documented in the medical literature. Most documented case reports have involved either heroin or hydrocodone/acetaminophen. Recently, case reposts of methadone induced SSHL have been published. Case Report. We present the case of a 31-year-old man who developed SSHL after a methadone overdose induced stupor. He was subsequently restarted on methadone at his regular dose. On follow-up audiometry exams, he displayed persistent moderately severe sensorineural hearing loss bilaterally. Discussion. This case is notable because unlike all but one previously reported case, the patient—who was restated on methadone—did not make a complete recovery. Conclusion. Methadone overuse in rare cases causes SSHL.\n==== Body\n1. Case Report\nMr. A. L is a 31-year-old man who was brought in by ambulance to the emergency department (SIUH South) after being found by his mother confused and stuporous at home. EMS reported that he was found apneic which resolved with naloxone. Mr. A. L has a known medical history of polysubstance abuse. He is also known to have depression and anxiety with recent admission to the psychiatric ward secondary to suicide attempt (wrist cut). He was tapered off benzodiazepines and started on fluoxetine. He had also recently been placed on a methadone program and follows with the methadone clinic for that matter. The patient arrived to the emergency department lethargic but awake and oriented x3 having received naloxone by EMS and was cooperative with the medical staff. His vitals on admission where remarkable for a heart rate of 110, a blood pressure of 88/50 mmHg, and a temperature of 101 F. He claimed that he took the entire weekend supply of methadone (80 mg methadone that was supposed to be divided to 40 mg on Saturday and 40 mg on Sunday) on the same day in an attempt to “feel high” and was not trying to “kill himself.” His only complaint was acute bilateral hearing loss. Work up in the emergency department revealed severe respiratory acidosis (pH = 7.2, CO2 = 57) with right side atelectasis on chest X-ray, acute renal failure (Cr = 3.1 baseline 1.15), possible NSTEMI, and acute hearing loss. He was given ASA 325 mg and was placed on IV fluids and bicarbonate, broad spectrum IV antibiotics, and heparin drip, given a dose of charcoal, placed on a 1 : 1 sitter, and admitted to the intensive care unit for further management and treatment.\n\nOn further questioning he stated that he had normal hearing up until the time that he had become stuporous. Immediately upon wakening and before receiving any medicines besides naloxone, he noticed that he had complete hearing loss bilaterally. He denied tinnitus or vertigo. Otoscopic exam was normal bilaterally.\n\nThe following day the patient was feeling better (mentally and physically), and his physical exam was unremarkable except for bilateral hearing loss which was still complete. Patient had leukocytosis of 14,000 and had a positive urine analysis, and he also spiked a temperature of 102 F that night while still on IV antibiotics. His d-dimer levels were elevated, and in the setting of hypoventilation, a lower extremity duplex was done and came back as negative. He was evaluated by critical care medicine, cardiology, toxicology, renal, and psychiatry. Patient was cleared by cardiology as his cardiac enzymes were trending down, and it was thought to be secondary to his acute kidney injury (to be sent home on ASA 81 mg PO daily along with atorvastatin and metoprolol and was asked to follow up as an outpatient with a stress echo). His renal function continued to improve with IV fluids (renal/bladder sonogram showed mild renal hydronephrosis. Urology was consulted and determined that there is no need for any intervention secondary to nonobstructing stone in patient with known history of nephrolithiasis versus methadone toxicity). Urine toxicology screen came back positive for methadone, benzodiazepines, and barbiturates, the latter two which he was supposed to have been detoxed off of recently. A CT scan of the chest was negative for pulmonary embolism. The decision by the critical care team was to continue the unit monitoring as he continued to spike fevers and have chills. Patient was restarted on methadone 40 mg daily.\n\nOn the third day of admission he stated that, subjectively, his hearing had returned to thirty percent of normal and he was able to understand shouted words. Subsequently, the patient was sent to the medical floor with the active problems as follows: UTI, aspiration pneumonia, and IV site cellulitis. Meantime his hearing was improving slightly daily, although he remained far from baseline. Patient remained in the hospital for four days after that. On the medical floor his course was unremarkable, his vitals were stable, and patient was afebrile and more ambulatory. His subjective report of his hearing was improving day by day yet was still profoundly impaired, and he was given an appointment to see an ENT as an outpatient. He was discharged after a full week of hospitalization on oral levaquin to follow up with cardiology and ENT and methadone clinic.\n\nThree weeks after discharge, patient followed with ENT and reported that his hearing was slightly improved yet still profoundly impaired. He denied vertigo although complained of tinnitus which was new. He underwent an audiology evaluation one week later (Figure 1) which revealed normal hearing at 250 Hz sloping to a moderately severe sensorineural hearing loss bilaterally with poor speech discrimination. Tympanometry revealed normal middle ear function bilaterally, and acoustic reflexes were present bilaterally except for an absent reflex in the left ear at 2,000 Hz. The exam was repeated one month later (Figure 2) with similar results, and he was prescribed binaural hearing aids. After this time, he was lost to follow up.\n\n2. Discussion\nThis case presents a 31-year-old man who chronically uses methadone who developed multisystem failure and sudden sensorineural hearing loss (SSHL) following an acute methadone overdose. SSHL has no single definition but is generally considered hearing loss occurring over less than 72 hours of at least 3 contiguous frequencies with many cases occurring over minutes. It is a rare condition affecting about two patients per 100,000 person-years [5]. Bilateral involvement as in our case is a rare phenomenon. Some patients also describe associated tinnitus, vertigo, or aural fullness [5]. SSHL can be caused by a number of etiologies such as infections agents, otologic disease, trauma, vascular insult, neoplastic disease, and miscellaneous causes but with the majority of cases-being idiopathic [5]. Many of these “idiopathic” causes are caused by autoimmune processes [6, 7] or rarely, drugs, including antibiotics—classically aminoglycosides, diuretics, chemotherapies, and anti-inflammatory agents [3].\n\nNumerous case reports have described SSHL following opiate abuse or overuse. Most cases have involved either heroin [8–14] or hydrocodone/acetaminophen [15–18] with varying degrees of recovery. Recently, four case reports have described acute SSHL in five patients upon awaking from coma or stupor induced by acute methadone overdose [1–4] (Table 1). Although it is difficult to prove causality of methadone for the SSHL, the time course is a compelling indication that methadone may be the cause. At least five of the six reported patients (including our case) received naloxone which improved the patient's level of consciousness which lends support that the altered level of consciousness was due to an opiod medication in exclusion to other medications that the patient may have ingested. As none of the patients who received naloxone were cogent and able to report potential hearing loss until receiving therapy, we are unable to determine whether naloxone may have contributed to the deafness.\n\nThe etiology of SSHL caused by methadone remains unclear. The theory that unknown substances contaminated into the drug are what cause the SSHL, which had been proposed for heroin-induced SSHL, seems dubious for methadone produced by professional laboratories. One author has proposed that SSHL caused by opiates may be partially due to a genetic predisposition but offers no evidence or elucidation [16]. As opiate-induced SSHL is extremely rare, to our knowledge no study has systematically attempted to understand the mechanism.\n\nAlthough most cases of opiate-induced SSHL are thought to involve a retrocochlear process, one reported case of chronic hydrocodone/acetaminophen abuses led to sensorineural hearing loss that only improved after the insertion of cochlear implants [16]. The improvement with cochlear implants seems to suggest that the chronic hearing loss associated with chronic opiate abuse must be a cochlear rather than retrocochlear process. However, it is not clear whether we can extrapolate such a case to our case in which an acute on chronic methadone overdose induced acute hearing loss.\n\nThis paper adds to the growing body of the literature describing cases of SSHL secondary to methadone overdose. Our patient is only the second in the literature to not make a full and speedy recovery following methadone-induced SSHL. Why two of the six reported patients failed to make a full recovery is unclear. However, it should be noted that in our case the patient continued to receive methadone at his usually prescribed dose. In the other reported cases of persistent hearing loss, it is not known whether the patient continued methadone or not. Methadone was withheld in all of the reported cases of improvement in which data is available.\n\nIn summary, methadone overdose may in rare cases cause SSHL.\n\nFigure 1 Audiometry graph one month after discharge.\n\nFigure 2 Audiometry graph two months after discharge.\n\nTable 1 Review of published cases of methadone induced hearing loss. \n\nYear \n\n\tAuthors \tAge \tSex\tPresentation \tNaloxone given? \tSubstances\n Ingested \tAssociated\n conditions \tMethadone withheld? \tFollowup \t\n\n2009\tVan Gaalen et al. [1]\t37 \tM \tNausea, confusion. Deafness upon awakening \tYes \tMethadone \tTinnitus, bradypnea \tYes \tComplete resolution by day 10 \t\n2010 \t\nChristenson et al. [2]\t30 \tM \tUnresponsive and apneic. Deafness upon awakening in ED following naloxone \tYes \tMethadone (large amount), cannabis, alprazolam and oxycodone (small amount) \tRespiratory failure, ARDS, bradycardia, and Hypotension \tUnknown \tResolution of hearing loss after 24 hours \t\n2010 \t\nChristenson et al. [2]\t25 \tF \tUnresponsive. Deafness upon awakening \tYes \tMethadone, citalopram, cannabis (all large amount), and oxymorphone (moderate amount) \tTachycardia, hypoxia \tYes \tMild improvement of hearing by 4 hours with complete resolution by 24 hours \t\n2011 \tShaw et al. [3]\t20 \tM \tStupor following overdose. Deafness upon wakening \tYes \tMethadone, alcohol, cannabis \tRespiratory failure, leukocytosis, hypernatremia, AKI, and rhabdomyolysis \tYes \tComplete resolution by day 4 \t\n2012 \tVorasubin et al. [4]\t23 \tM \tRespiratory arrest. Deafness upon awakening \tUnknown \tNaltrexone, methadone \tRespiratory failure \tUnknown \tSevere sensorineural hearing loss above 500 Hz persistent after at least 9 months \t\n2013 \tSaifan et al. (this paper)\t31 \tM \tApnea. Deafness upon awakening \tYes \tMethadone, benzodiazepines, and barbiturates \tLeukocytosis, fever, AKI, UTI, cellulitis, and aspiration pneumonia \tNo \tSevere sensorineural hearing loss above 250 Hz persistent after at least 2 months\n==== Refs\n1 van Gaalen FA Compier EA Fogteloo AJ Sudden hearing loss after a methadone overdose European Archives of Oto-Rhino-Laryngology 2009 266 5 773 774 2-s2.0-63049100738 19263068 \n2 Christenson BJ Marjala ARP Foss M Two cases of sudden sensorineural hearing loss after methadone overdose Annals of Pharmacotherapy 2010 44 1 207 210 2-s2.0-74549203229 20028962 \n3 Shaw KA Babu KM Hack JB Methadone, another cause of opioid-associated hearing loss: a case report Journal of Emergency Medicine 2011 41 6 635 639 2-s2.0-83655169796 21145191 \n4 Vorasubin N Calzada A Ishiyama A Methadone induced irreversible bilateral severe sensorineural hearing loss Poster Presentation at the Triological Society’s 115th Annual Meeting April 2012 San Diego, Calif, USA \n5 Chau JK Lin JRJ Atashband S Irvine RA Westerberg BD Systematic review of the evidence for the etiology of adult sudden sensorineural hearing loss Laryngoscope 2010 120 5 1011 1021 2-s2.0-77951723807 20422698 \n6 Toubi E Halas K Ben-David J Sabo E Kessel A Luntz M Immune-mediated disorders associated with idiopathic sudden sensorineural hearing loss Annals of Otology, Rhinology and Laryngology 2004 113 6 445 449 2-s2.0-2942672205 \n7 Baek M-J Park H-M Johnson JM Increased frequencies of cochin-specific T cells in patients with autoimmune sensorineural hearing loss Journal of Immunology 2006 177 6 4203 4210 2-s2.0-33645125425 \n8 Mulch G Handrock M Sudden binaural deafness after acute heroin intoxication Laryngologie Rhinologie Otologie 1979 58 5 435 437 2-s2.0-0018763339 \n9 Polpathapee S Tuchinda P Chiwapong S Sensorineural hearing loss in a heroin addict Journal of the Medical Association of Thailand 1984 67 1 57 60 2-s2.0-0021299717 6716028 \n10 Kortequee S Agada FO Coatesworth AP Sudden sensorineural hearing loss following intracarotid injection of heroin International Journal of Clinical Practice 2005 59 147 128 129 2-s2.0-33845435832 15854185 \n11 Schrock A Jakob M Wirz S Bootz F Sudden sensorineural hearing loss after heroin injection European Archives of Oto-Rhino-Laryngology 2008 265 5 603 606 2-s2.0-43349102743 17968577 \n12 Fowler CG King JL Sudden bilateral sensorineural hearing loss following speedballing Journal of the American Academy of Audiology 2008 19 6 461 464 2-s2.0-63149170603 19253779 \n13 Nair EL Cienkowski KM Michaelides E The impact of sudden hearing loss secondary to heroin overdose on fitting outcomes American Journal of Audiology 2010 19 2 86 90 2-s2.0-78650488907 20966353 \n14 Antonopoulos S Balatsouras DG Kanakaki S Dona A Spiliopoulou C Giannoulis G Bilateral sudden sensorineural hearing loss caused by alcohol abuse and heroin sniffing Auris Nasus Larynx 2012 39 3 305 309 2-s2.0-84859712228 21903349 \n15 Friedman RA House JW Luxford WM Gherini S Mills D Profound hearing loss associated with hydrocodone/acetaminophen abuse American Journal of Otology 2000 21 2 188 191 2-s2.0-0034010931 10733182 \n16 Oh AK Ishiyama A Baloh RW Deafness associated with abuse of hydrocodone/acetaminophen Neurology 2000 54 12 p. 2345 2-s2.0-0034720813 10881270 \n17 Ho T Vrabec JT Burton AW Hydrocodone use and sensorineural hearing loss Pain Physician 2007 10 3 467 472 2-s2.0-34250830285 17525781 \n18 Blakley BW Schilling H Deafness associated with acetaminophen and codeine abuse Journal of Otolaryngology 2008 37 4 507 509 2-s2.0-64549112649\n\n",
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"title": "Methadone induced sensorineural hearing loss.",
"title_normalized": "methadone induced sensorineural hearing loss"
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"abstract": "Insights into the mechanism of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) could provide important information for further patient management, including the choice of second-line treatment. The EGFR T790M mutation is the most common mechanism of resistance to first- and second-generation EGFR TKIs. Owing to its biologic relevance in the response of non-small-cell lung cancer (NSCLC) to the selective pressure of treatment, the present study investigated whether the occurrence of T790M at progression differed among patients receiving gefitinib, erlotinib, or afatinib.\n\n\n\nThe present retrospective study included patients with NSCLC with an EGFR activating mutation, who had received gefitinib, erlotinib, or afatinib as first-line treatment. Plasma samples for the analysis of cell-free DNA were taken at disease progression and analyzed using a digital droplet polymerase chain reaction EGFR mutation assay.\n\n\n\nA total of 83 patients were enrolled; 42 had received gefitinib or erlotinib and 41afatinib. The patient characteristics were comparable across the 2 groups. The median time to progression (TTP) was 14.4 months for the gefitinib and erlotinib group and 10.2 months for the afatinib group (P = .09). Of the 83 patients, 47 (56.6%) were positive for the T790M in plasma. A greater incidence of T790M was observed in patients with progression during gefitinib or erlotinib therapy compared with patients treated with afatinib (33 [79%] vs. 14 [34%], respectively; odds ratio, 7.1; 95% confidence interval, 2.7-18.5; P = .0001).\n\n\n\nAlthough gefitinib, erlotinib, and afatinib showed a comparable TTP in patients receiving first-line therapy, the incidence of T790M differed among them, as demonstrated by the present study, which could have implications for the choice of second-line treatment.",
"affiliations": "Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.;Unit of Pneumology, Azienda Ospedaliero-Universitaria Pisana and Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy.;Unit of Medical Oncology, Department of Oncology, University Hospital of Firenze, Firenze, Italy.;Unit of Pneumology, Azienda Ospedaliero-Universitaria Pisana and Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy.;Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.;Unit of Medical Oncology, Department of Oncology, Hospital of Prato, Prato, Italy.;Unit of Pneumology, Azienda Ospedaliero-Universitaria Pisana and Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy.;Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.;Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.;Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.;Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.;Thoraco-pulmonary Medical Oncology Unit, Medical Oncology and Hematology Department, National Tumor Institute, IRCCS, Milan, Italy.;Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. Electronic address: romano.danesi@unipi.it.",
"authors": "Del Re|Marzia|M|;Petrini|Iacopo|I|;Mazzoni|Francesca|F|;Valleggi|Simona|S|;Gianfilippo|Giulia|G|;Pozzessere|Daniele|D|;Chella|Antonio|A|;Crucitta|Stefania|S|;Rofi|Eleonora|E|;Restante|Giuliana|G|;Miccoli|Mario|M|;Garassino|Marina Chiara|MC|;Danesi|Romano|R|",
"chemical_list": "D000073888:Cell-Free Nucleic Acids; D000077716:Afatinib; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib",
"country": "United States",
"delete": false,
"doi": "10.1016/j.cllc.2019.10.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1525-7304",
"issue": "21(3)",
"journal": "Clinical lung cancer",
"keywords": "Drug resistance; EGFR; Mutation; Non-squamous non-small cell lung cancer; Tyrosine kinase inhibitors",
"medline_ta": "Clin Lung Cancer",
"mesh_terms": "D000077716:Afatinib; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002289:Carcinoma, Non-Small-Cell Lung; D000073888:Cell-Free Nucleic Acids; D018450:Disease Progression; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D005260:Female; D005500:Follow-Up Studies; D000077156:Gefitinib; D006801:Humans; D015994:Incidence; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate",
"nlm_unique_id": "100893225",
"other_id": null,
"pages": "232-237",
"pmc": null,
"pmid": "31735523",
"pubdate": "2020-05",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Incidence of T790M in Patients With NSCLC Progressed to Gefitinib, Erlotinib, and Afatinib: A Study on Circulating Cell-free DNA.",
"title_normalized": "incidence of t790m in patients with nsclc progressed to gefitinib erlotinib and afatinib a study on circulating cell free dna"
} | [
{
"companynumb": "IT-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2019-BI-115576",
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"abstract": "BACKGROUND\nEndometriosis usually affects women in their reproductive years. Most commonly, the pelvic organs are involved. Involvement of the chest wall after hysterectomy is rare. The incidence of malignant transformation is less than 1% for ovarian endometriosis, but is unknown for extraovarian endometriosis.\n\n\nMETHODS\nA 47-year-old woman who had undergone hysterectomy and bilateral salpingo-oophorectomy for endometriosis presented four years after surgery with a well-differentiated endometrioid adenocarcinoma arising in the background of endometriosis in the right chest wall. The tumour was resected, and the patient received six courses of adjuvant chemotherapy.\n\n\nCONCLUSIONS\nWomen with endometriosis-associated cancer require individualized management options, depending upon the histopathology and stage of the cancer.",
"affiliations": "Department of Obstetrics and Gynaecology, Division of Gynaecologic Oncology, University of Calgary, Calgary AB.;Department of Obstetrics and Gynaecology, University of Calgary, Calgary AB.;Department of Obstetrics and Gynaecology, University of Calgary, Calgary AB.;Department of Obstetrics and Gynaecology, University of Calgary, Calgary AB.;Department of Obstetrics and Gynaecology, University of Calgary, Calgary AB; Department of Family Medicine, University of Calgary, Calgary AB; Department of Community Health Sciences, University of Calgary, Calgary AB.;Department of Pathology and Laboratory Medicine, University of Calgary, Calgary AB; Tom Baker Cancer Centre, Calgary AB.",
"authors": "Agrawal|Anita|A|;Nation|Jill|J|;Ghatage|Prafull|P|;Chu|Pamela|P|;Ross|Sue|S|;Magliocco|Anthony|A|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/S1701-2163(16)34217-7",
"fulltext": null,
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"issn_linking": "1701-2163",
"issue": "31(6)",
"journal": "Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC",
"keywords": null,
"medline_ta": "J Obstet Gynaecol Can",
"mesh_terms": "D018269:Carcinoma, Endometrioid; D002471:Cell Transformation, Neoplastic; D004715:Endometriosis; D005260:Female; D006801:Humans; D008875:Middle Aged; D013899:Thoracic Neoplasms; D035441:Thoracic Wall",
"nlm_unique_id": "101126664",
"other_id": null,
"pages": "538-541",
"pmc": null,
"pmid": "19646320",
"pubdate": "2009-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Malignant chest wall endometriosis: a case report and literature review.",
"title_normalized": "malignant chest wall endometriosis a case report and literature review"
} | [
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"abstract": "Dexmedetomidine is an α2-adrenergic used as an adjunct therapy for sedation in the intensive care unit. While it is known to cause polyuria exclusively in perioperative conditions, not many cases are known in the intensive care unit, thus making the diagnosis challenging. We present the case of a 61-year-old male who had developed polyuria secondary to central diabetes insipidus after receiving dexmedetomidine intravenous infusion in the medical ICU. Increased awareness of this uncommon side effect of dexmedetomidine will help clinicians recognize and address it early.",
"affiliations": "Internal Medicine, Wayne State University/Detroit Medical Center, 4201 St Antoine, Detroit, MI 48201, USA.;Internal Medicine, Wayne State University/Detroit Medical Center, 4201 St Antoine, Detroit, MI 48201, USA.;Internal Medicine, Wayne State University/Detroit Medical Center, 4201 St Antoine, Detroit, MI 48201, USA.;Internal Medicine, Michigan State University/Sparrow Hospital, 1215 E Michigan Ave, Lansing, MI 48912, USA.;Pulmonary Criticasl Care & Sleep Division, Wayne State University/Detroit Medical Center, 4201 St Antoine, Detroit, MI 48201, USA.;Division of Nephrology, Wayne State University/Detroit Medical Center, 4201 St Antoine, Detroit, MI 48201, USA.",
"authors": "Uddin|Mohammed M|MM|https://orcid.org/0000-0002-5206-0596;Sebastian|Joseph|J|;Usama|Muhammad|M|;Raziq|Fazal I|FI|;Saydain|Ghulam|G|;Rossi|Noreen F|NF|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2021/8850116",
"fulltext": "\n==== Front\nCase Rep Crit Care\nCase Rep Crit Care\nCRICC\nCase Reports in Critical Care\n2090-6420 2090-6439 Hindawi \n\n10.1155/2021/8850116\nCase Report\nDexmedetomidine Induced Polyuria in the Intensive Care Unit\nhttps://orcid.org/0000-0002-5206-0596Uddin Mohammed M. mohammed.uddin2@wayne.edu\n1\n Sebastian Joseph \n1\n Usama Muhammad \n1\n Raziq Fazal I. \n2\n Saydain Ghulam \n3\n Rossi Noreen F. \n4\n \n1Internal Medicine, Wayne State University/Detroit Medical Center, 4201 St Antoine, Detroit, MI 48201, USA\n\n2Internal Medicine, Michigan State University/Sparrow Hospital, 1215 E Michigan Ave, Lansing, MI 48912, USA\n\n3Pulmonary Criticasl Care & Sleep Division, Wayne State University/Detroit Medical Center, 4201 St Antoine, Detroit, MI 48201, USA\n\n4Division of Nephrology, Wayne State University/Detroit Medical Center, 4201 St Antoine, Detroit, MI 48201, USA\nAcademic Editor: Mabrouk Bahloul\n\n\n2021 \n20 2 2021 \n2021 88501169 6 2020 27 9 2020 10 2 2021 Copyright © 2021 Mohammed M. Uddin et al.2021This 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.Dexmedetomidine is an α2-adrenergic used as an adjunct therapy for sedation in the intensive care unit. While it is known to cause polyuria exclusively in perioperative conditions, not many cases are known in the intensive care unit, thus making the diagnosis challenging. We present the case of a 61-year-old male who had developed polyuria secondary to central diabetes insipidus after receiving dexmedetomidine intravenous infusion in the medical ICU. Increased awareness of this uncommon side effect of dexmedetomidine will help clinicians recognize and address it early.\n==== Body\n1. Introduction\nThe use of dexmedetomidine is a common practice in the medical intensive care units (ICU) to minimize delirium and to serve as an adjunctive sedative therapy in intubated patients. Morelli et al. demonstrated that dexmedetomidine is associated with decreased norepinephrine requirements in septic shock patients as compared with propofol [1]. While hypotension and bradycardia [2] are known side effects, the occurrence of central diabetes insipidus (DI) due to dexmedetomidine is a rare phenomenon and not well documented in literature [3, 4]. Rapid onset of dehydration due to fluid loss and electrolyte imbalance may further worsen hypotension and cause complications in already critically ill patients. There is a need for widespread awareness of this rare but potentially serious side effect of dexmedetomidine among critical care physicians, so that this is included in the differential diagnosis early on in cases of polyuria among critically ill patients. We report a case of polyuria in a complex critically ill patient where dexmedetomidine was not initially suspected as a causative agent.\n\n2. Case Report\nA 61-year-old male with a past medical history of advanced stage COPD, heart failure with reduced ejection fraction, was admitted to the medical ICU with acute on chronic hypercapnic respiratory failure secondary to exacerbation of his chronic obstructive pulmonary disease requiring ventilatory support. He was treated with steroids and azithromycin. His kidney function stayed stable with average urine output of around 2 liters per 24 hours for the first 7 days of hospitalization. On the eighth day of hospitalization, he developed abrupt onset polyuria with an increase in urine output from 70-80 cc/hr. to 200-225 cc/hr., totaling approximately 5.4 L over the next 24 hr. Urine osmolality was 193 mOsm/kg H2O, while his random urine sodium also increased from 23 to 179 mmol per liter urine.\n\nThe cause was not immediately apparent. His medications included aspirin, albuterol, isosorbide mononitrate, amiodarone, lisinopril, and metoprolol. CT scan of the head was negative for any intracranial processes ruling out a pituitary lesion as the cause of central DI. The patient was not on any medication known to cause nephrogenic DI and serum electrolytes were within normal limits. The patient was euvolemic and had normal serum glucose, BUN, and other organic acid levels ruling out osmotic diuresis as the cause of polyuria. Renal ultrasound was negative for any obstruction. Pertinent labs included BUN 16 mg/dL, creatinine 0.65 mg/dL, glucose 130 mg/dL, sodium 134 mmol/L, potassium 3.6 mmol/L, and calcium 8.8 mg/dL. Urine electrolytes were sodium 179 mmol/L, potassium 14 mmol/L, chloride 25 mmol/L, creatinine 37 mg/dL, and lithium level <0.1 mmol/L.\n\nA thorough chart review identified that the patient had received dexmedetomidine due to worsening delirium at a rate of 0.2 mcg/kg/hr for a brief period, immediately before the abrupt onset of polyuria. No other instigating cause was identified; we suspected central DI secondary to dexmedetomidine. A DDAVP stimulation test was planned as a therapeutic challenge for central DI, but 48 hours after the cessation of dexmedetomidine, the urine output spontaneously decreased to 50-100 cc/hr and urine osmolality increased to 306 mOsm/kgH2O so the test was not done. His serum osmolality also normalized after that. The patient was not rechallenged with dexmedetomidine. At no time did the patient develop hypernatremia due to strict replacement of carefully calculated water losses.\n\nIn the light of extensive negative workup and temporal relationship of polyuria with dexmedetomidine infusion and resolution of the polyuria with drug abstinence, we concluded that the polyuria was secondary to transient central Diabetes Insipidus secondary to dexmedetomidine infusion. The Naranjo Score for dexmedetomidine induced polyuria for this patient was 8, thereby putting the medication in the probable likelihood of causing the adverse reaction of polyuria [5].\n\n3. Discussion\nPolyuria is defined as a urinary output of greater than 3 L/day, the causes of which can be divided into solute (osmotic) and water diuresis. Solute diuresis most commonly occurs secondary to glycosuria, whereas water diuresis occurs either due to a defect in antidiuretic hormone (ADH) production or due to decreased renal responsiveness to ADH.\n\nIn this case, a thorough review was negative for osmotic diuresis secondary to hyperglycemia, azotemia, or intravenous volume expansion. There was no evidence of neuroendocrine disorders such as head trauma as evidenced by the CT scan, acute renal pathologies such as obstruction, or recovery from acute kidney injury or the use of diuretics that could trigger polyuria. The low urine osmolality could not be attributed to hypokalemia, hypercalcemia, or lithium use that is associated with nephrogenic diabetes insipidus.\n\nTo our knowledge, only one other case in a medical intensive care unit has been published in abstract form [3]. Polyuria associated with dexmedetomidine, a highly selective α2-adrenoceptor agonist that works on the locus coeruleus, has been reported in case report form, almost exclusively in perioperative conditions [6–8]. Lesions of the locus coeruleus have been associated with decreased secretion of ADH [8, 9] thereby resulting in transient central diabetes insipidus. Early work by Sawchenko and Swanson [10] and others [11] demonstrated noradrenergic pathways from the locus coeruleus to the paraventricular and supraoptic nuclei (Figure 1). These pathways have been shown to modulate ADH release from the posterior pituitary into the peripheral circulation particularly under conditions of physiologic stress [12].\n\nPreviously reported cases occurred primarily in the operative setting under anesthesia. They also showed a rapid resolution of polyuria once dexmedetomidine was withheld [6, 7]. Our case is unique in that it occurred within the medical ICU setting and that the effect persisted for 48 hr after stopping dexmedetomidine. The half-life of dexmedetomidine is only 3.7 hr; however, its metabolite has a half-life of 9.7 hr [2]. At least two possibilities present themselves. Either the concurrent administration of drugs metabolized via several CYP450 enzymes prolonged the half-life or the H-3 metabolite or another breakdown product may have an impact on ADH secretion manifesting as polyuria. Our case is distinct in that it highlights that even without a loading dose and a relatively low dose infusion (0.2 mcg/kg/hr) of dexmedetomidine with short duration had induced polyuria that persisted well beyond the time limit in the previously reported cases, suggesting that the side effects are likely to be dose independent.\n\n4. Conclusion\nIncreased awareness of this uncommon but significant side effect of dexmedetomidine will promote providers to include it in the differential diagnoses when assessing for polyuria in the intensive care unit while, at the same time, promoting careful monitoring of concurrent medications, underlying liver disease, and urine output, particularly in susceptible patients.\n\nData Availability\nNone.\n\nConflicts of Interest\nThere are no conflicts of interest.\n\nFigure 1 Neural pathways involved in dexmedetomidine-induced central diabetes insipidus.\n==== Refs\n1 Morelli A. Sanfilippo F. Arnemann P. The effect of propofol and dexmedetomidine sedation on norepinephrine requirements in septic shock patients: a crossover trial Critical Care Medicine 2019 47 2 e89 e95 10.1097/CCM.0000000000003520 2-s2.0-85060173647 30394918 \n2 Weerink M. A. S. Struys M. M. R. F. Hannivoort L. N. Barends C. R. M. Absalom A. R. Colin P. Clinical pharmacokinetics and pharmacodynamics of dexmedetomidine Clinical Pharmacokinetics 2017 56 8 893 913 10.1007/s40262-017-0507-7 2-s2.0-85009837071 28105598 \n3 Charran O. Lee Y. I. A case of dexmedetomidine (precedex)-induced diabetes insipidus in the medical intensive care unit D49. Critical care case reports: neurocritical care, sedation, and delirium May 2019 Dallas, TX, USA A6634 A6634 10.1164/ajrccm-conference.2019.199.1_meetingabstracts.a6634 \n4 Chow P. Akella K. Spiegel L. Hussain K. 1300: a case report of dexmedetomidine-induced polyuria and review of literature Critical Care Medicine 2019 47 1 p. 626 10.1097/01.ccm.0000552044.51504.d4 \n5 Naranjo C. A. Busto U. Sellers E. M. A method for estimating the probability of adverse drug reactions Clinical Pharmacology & Therapeutics 1981 30 2 239 245 10.1038/clpt.1981.154 2-s2.0-0019799332 7249508 \n6 Granger S. Ninan D. Intraoperative dexmedetomidine-induced polyuric syndrome Cureus 2017 9 5 10.7759/cureus.1218 \n7 Ji F. Liu H. Intraoperative hypernatremia and polyuric syndrome induced by dexmedetomidine Journal of Anesthesia 2013 27 4 599 603 10.1007/s00540-013-1562-3 2-s2.0-84882655434 23377505 \n8 Chen Z. Chen T. Ye H. Chen J. Lu B. Intraoperative dexmedetomidine-induced polyuria from a loading dose: a case report Journal of International Medical Research 2020 48 4 10.1177/0300060520910643 32237944 \n9 Rodovalho G. V. Franci C. R. Morris M. Anselmo-Franci J. A. Locus coeruleus lesions decrease oxytocin and vasopressin release induced by hemorrhage Neurochemical Research 2006 31 2 259 266 10.1007/s11064-005-9015-5 2-s2.0-33646507689 16528616 \n10 Sawchenko P. E. Swanson L. W. The organization of noradrenergic pathways from the brainstem to the paraventricular and supraoptic nuclei in the rat Brain Research Reviews 1982 4 3 275 325 10.1016/0165-0173(82)90010-8 2-s2.0-0020468095 \n11 Lightman S. L. Todd K. Everitt B. J. Ascending noradrenergic projections from the brainstem: evidence for a major role in the regulation of blood pressure and vasopressin secretion Experimental Brain Research 1984 55 1 145 151 10.1007/BF00240508 2-s2.0-0021236513 6745345 \n12 Hernández-Pérez O. R. Hernández V. S. Nava-Kopp A. T. A synaptically connected hypothalamic magnocellular vasopressin-locus coeruleus neuronal circuit and its plasticity in response to emotional and physiological stress Frontiers in Neuroscience 2019 13 p. 196 10.3389/fnins.2019.00196\n\n",
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"nlm_unique_id": "101598416",
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"pmid": "33688441",
"pubdate": "2021",
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"references": "16528616;32237944;7249508;6756545;6745345;28589067;30394918;28105598;23377505;30949017",
"title": "Dexmedetomidine Induced Polyuria in the Intensive Care Unit.",
"title_normalized": "dexmedetomidine induced polyuria in the intensive care unit"
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"abstract": "Transitions of care pose a risk to medication safety. To reduce patient harm, medication reconciliation is advised. However, implementation of medication reconciliation is difficult due to time constraints. We present two female patients aged 82 and 84 years. In both women, unintentional discrepancies arose, went undetected and led to patient harm. Accurate information transfer is essential for continuity of patient care. Medication reconciliation comprises four steps, i.e. verification (identify discrepancies), clarification (check the collected list), reconciliation (document the reason for medication changes) and transfer (communicate the updated list). This article discusses the steps of medication reconciliation and those medication errors that arise during a patient's transfer from the home setting to hospitalization or a clinic visit. We show that medication reconciliation is not merely an administrative task. As the patient is the only constant factor in health care, patient participation is essential.",
"affiliations": "Amsterdam UMC, afd. Klinische Farmacie, Amsterdam.;Catharina Ziekenhuis, afd. Geriatrie, Eindhoven.;Amsterdam UMC, afd. Ouderengeneeskunde, Amsterdam.;Radboudumc, afd. Interne Geneeskunde, Nijmegen.;Eindhoven.;OLVG, afd. Klinische Farmacie, Amsterdam.",
"authors": "Teeuwisse|Patty J I|PJI|;van der Linden|Carolien M J|CMJ|;Buurman|Bianca M|BM|;Kramers|C|C|;Spiers|Han Paul|HP|;Karapinar-Çarkit|Fatma|F|",
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"medline_ta": "Ned Tijdschr Geneeskd",
"mesh_terms": "D000369:Aged, 80 and over; D005260:Female; D006760:Hospitalization; D006801:Humans; D008508:Medication Errors; D059065:Medication Reconciliation; D010358:Patient Participation; D010360:Patient Transfer",
"nlm_unique_id": "0400770",
"other_id": null,
"pages": null,
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"pmid": "31580036",
"pubdate": "2019-10-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Medication reconciliation: a hell of a job.",
"title_normalized": "medication reconciliation a hell of a job"
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"companynumb": "NL-AMGEN-NLDSP2019171842",
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"abstract": "Childhood idiopathic pulmonary arterial hypertension is a progressive and fatal disease. When pulmonary artery pressures become suprasystemic and refractory to medical management, atrial septostomy can be recommended for bridging patients to lung transplantation. Recently, a surgical Potts shunt has been recommended as an alternative rescue therapy, and initial outcome data are promising. The placement of a Potts shunt converts the child to Eisenmenger physiology, which is anticipated to provide an improved quality and duration of life. We present the first description of anesthetic management of a child undergoing surgical Potts shunt for pulmonary arterial hypertension and summarize the multiple, unique intraoperative considerations.",
"affiliations": "From the Departments of *Anesthesiology and Pain Medicine, †Pediatric Cardiology, and ‡Pediatric Cardiovascular Surgery, Seattle Children's Hospital, University of Washington, Seattle, Washington.",
"authors": "Eggers|Ashley|A|;Latham|Gregory J|GJ|;Geiduschek|Jeremy|J|;Yung|Delphine|D|;Chen|Jonathan M|JM|;Joffe|Denise C|DC|",
"chemical_list": "D007530:Isoflurane; D005283:Fentanyl",
"country": "United States",
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"doi": "10.1213/XAA.0000000000000268",
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"issue": "6(3)",
"journal": "A & A case reports",
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"mesh_terms": "D000714:Anastomosis, Surgical; D000758:Anesthesia; D002648:Child; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D005283:Fentanyl; D006801:Humans; D007430:Intraoperative Care; D007530:Isoflurane; D016896:Treatment Outcome",
"nlm_unique_id": "101637720",
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"pages": "56-60",
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"pmid": "26579614",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Anesthesia for Potts Shunt in a Child with Severe Refractory Idiopathic Pulmonary Arterial Hypertension.",
"title_normalized": "anesthesia for potts shunt in a child with severe refractory idiopathic pulmonary arterial hypertension"
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"abstract": "Lobular breast cancer metastasis to bowel is rare, however, when it occurs, the prognosis is poor. Possible benefits of investigation with screening endoscopy for gastrointestinal metastases are discussed in order to optimize prognosis for patients.",
"affiliations": "Department of General Surgery Prince of Wales Hospital Sydney NSW Australia.;South East Regional Hospital Bega NSW Australia.;South East Regional Hospital Bega NSW Australia.",
"authors": "Yanagisawa|Waka|W|https://orcid.org/0000-0002-6082-8710;Krishnan|Sandra|S|;Fernandez|Adrian|A|",
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"doi": "10.1002/ccr3.4081",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904\nJohn Wiley and Sons Inc. Hoboken\n\n10.1002/ccr3.4081\nCCR34081\nCase Report\nCase Reports\nA rare case of lobular breast cancer metastasizing to large bowel\nYANAGISAWA et al.\nYanagisawa Waka https://orcid.org/0000-0002-6082-8710\n1 2 Waka.Yanagisawa@health.nsw.gov.au\n\nKrishnan Sandra 2\nFernandez Adrian 2\n1 Department of General Surgery Prince of Wales Hospital Sydney NSW Australia\n2 South East Regional Hospital Bega NSW Australia\n* Correspondence\nWaka Yanagisawa, Department of General Surgery, Prince of Wales Hospital, Sydney, NSW, Australia.\nEmail: Waka.Yanagisawa@health.nsw.gov.au\n\n04 5 2021\n5 2021\n9 5 10.1002/ccr3.v9.5 e0408124 2 2021\n21 1 2021\n13 3 2021\n© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nLobular breast cancer metastasis to bowel is rare, however, when it occurs, the prognosis is poor. Possible benefits of investigation with screening endoscopy for gastrointestinal metastases are discussed in order to optimize prognosis for patients.\n\nLobular breast cancer metastasis to bowel is rare, however, when it occurs, the prognosis is poor. Possible benefits of investigation with screening endoscopy for gastrointestinal metastases are discussed in order to optimize prognosis for patients.\n\nbreast cancer\ninvasive lobular breast cancer\nmetastatic bowel obstruction\nsource-schema-version-number2.0\ncover-dateMay 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.2 mode:remove_FC converted:24.05.2021\nYanagisawa W , Krishnan S , Fernandez A . A rare case of lobular breast cancer metastasizing to large bowel. Clin Case Rep. 2021;9 :e04081. 10.1002/ccr3.4081\n==== Body\n1 INTRODUCTION\n\nLobular breast cancer is rarely known to metastasize to the gastrointestinal tract. 1 A 78‐year‐old with Invasive Lobular carcinoma in remission had partial intestinal obstruction that was discovered from metastasis to the colon. Investigation of gastrointestinal symptoms in patients managed for invasive lobular carcinoma should include possibility of gastrointestinal metastasis.\n\nBreast cancer is the most common malignancy in women, most frequent in the fourth and fifth decades of life and comprises 27% of all cancers. 2 Since the introduction of the national breast screening program such as in the United States, and earlier detection, only 7% of breast malignancies have metastasized at the time of presentation. 2 According to Miller et al (2013), breast cancer most commonly metastasize to lungs, bones, liver, and brain, 2 and in some occasions, invasive lobular carcinoma (ILC) has been demonstrated to metastasize to the gastrointestinal tract. 2 We describe a case of a patient in remission from lobular breast cancer who presented with metastatic lobular breast carcinoma requiring an extended right hemicolectomy. As there is still a lot to be learnt in regard to metastatic spread of the disease, this case report raises the discussion regarding possible benefits of investigating patients for potential gastrointestinal metastases.\n\n2 CASE REPORT\n\nA 78‐year‐old female presented with a 1‐month history of colicky abdominal pain, abdominal distension, vomiting, and unintentional weight loss. Her past medical history included ischemic heart disease on clopidogrel and previous history of deep vein thrombosis. She recently returned a positive stool occult blood test, awaiting colonoscopy. Her past surgical history included a hysterectomy, cholecystectomy, appendectomy and notably, a right lobular Stage IIB, Grade 2 lobular breast cancer. She had a wide local excision and sentinel lymph node excision with 1/3 biopsied lymph nodes positive. Despite her positive lymph node, she was deemed lower risk lobular type, and her treatment included adjuvant radiotherapy for 6 weeks and hormonal therapy letrozole, which was discontinued after 7 months due to arthralgia severely impacting her quality of life. Tamoxifen was deemed unsuitable due to associated risk of thromboembolism and her previous history of deep vein thrombosis. She continued regular outpatient surveillance and was in remission, confirmed by a normal breast ultrasound and mammogram a year prior to presentation.\n\nAn Abdominal Computed Tomography (CT) in the Emergency Department at the time of presentation demonstrated concentric wall thickening and narrowing of the distal transverse colon with dilatation of the proximal transverse colon and ascending colon, concerning for a neoplastic lesion (Figures 1 and 2). Her CEA level was elevated at 5.8. Subsequent investigation with a colonoscopy revealed a circumferential lesion in the proximal descending colon, not typical in appearance for an adenocarcinoma. It was difficult to negotiate past the tumor and biopsies were taken. The histopathology demonstrated features of sessile serrated adenoma with some reactive changes, however, no evidence of dysplasia or malignancy. A semi‐urgent laparotomy with curative intent was performed in view of her progressive abdominal pain and distension and found the offending, thickened segment to involve the distal transverse colon and splenic flexure. An extended right hemicolectomy was performed, and her surgery was routine. The histopathology comprised of a circumferential, firm, ill‐defined partially ulcerated lesion in the transverse colon measuring 25 × 20 mm and measuring 370 mm to the proximal margin, 110 mm to the distal margin. The lesion appeared to invade through the muscularis propria into the pericolic fat by 5 mm and measures 1 mm to the closest serosal surface. Multiple lymph nodes were identified in the mesentery ranging from 2‐20 mm in maximal diameter. This was demonstrated to be a metastatic, grade 2 lobular carcinoma deposit. Lymphovascular invasion was present and three separate extranodal deposits of metastatic lobular carcinoma were seen in the mesenteric tissue. The immunohistochemistry demonstrated ER and PR positive status, HER2 FISH negative and a Ki‐67 of 18% in keeping with the previous lobular breast carcinoma histopathology.\n\nFIGURE 1 CT abdomen/pelvis coronal and sagittal view, respectively—long segment of concentric wall thickening and narrowing of the distal transverse colon with dilatation of proximal transverse colon and ascending colon\n\nFIGURE 2 CT abdomen/pelvis coronal and sagittal view, respectively—long segment of concentric wall thickening and narrowing of the distal transverse colon with dilatation of proximal transverse colon and ascending colon\n\nShe recovered well postoperatively, requiring a short period of rehabilitation. She was recommenced on letrozole to reduce the risk of further recurrence and associated issues including ascites and pleural effusion. She was not a candidate for chemotherapy given her frailty. A CT pan scan and bone scan did not demonstrate any other evidence of metastatic disease. Prior to further follow‐up and a planned PET scan in a tertiary center. Unfortunately, prior to further follow‐up, she passed away, 2 months postoperatively with increasing anorexia and fatigue.\n\n3 DISCUSSION\n\nThis is an interesting case of metastases to the gastrointestinal tract being the first manifestation of breast cancer metastases years following diagnosis of the primary tumor. The clinical presentation may be a specific such as abdominal pain as was a symptom in this case; however, others may present with bleeding or diarrhea as discussed in other case reports of gastrointestinal metastases of breast cancer in available literature. 3 CT scan in this setting therefore is a useful diagnostic tool, which has been demonstrated to be a useful noninvasive assessment for assessing mural penetration. 3 However, for definitive diagnosis, endoscopy and biopsy are required to guide management. Surgery is also often required for treatment of subacute bowel obstruction or bleeding 3 such as a right hemicolectomy in this case. ILC accounts for 10% of all breast cancers and is the second most common breast carcinoma. 1 , 4 The incidence is increasing in postmenopausal women, possibly secondary to the use of hormone replacement therapy in this age group. 4 Breast cancer frequently metastasizes to skeletal and pulmonary systems, however, metastasis to the gastrointestinal tract seems to be more frequent in lobular histology. 5 In a study of 2605 cases of breast cancer with metastases; 359 lobular and 2246 with ductal carcinoma, 4.5% in ILC metastasized to the gastrointestinal tract compared with 0.2% in the ductal carcinoma group. 6 Gastrointestinal tract involvement with metastatic ILC is thought to most commonly involve stomach and small bowel, then followed by colon and rectum. 4 According to available literature, 60% metastasizes to the stomach, 12% to the esophagus, 11% to the colon, 8% to the small intestine, and 7% to the rectum. 3 The reason for this mechanism of spread is unclear, however, some possible reasons may include the histopathology of ILC. ILC is characterized by small cells that infiltrate the breast stroma in a single‐file “Indian‐file” pattern, which does not destroy anatomical structure nor result in a reactive connective tissue response (Figure 3), and can therefore fail to distinctly form a mass in the breast which can be difficult to identify early. 4 Patients are characterized by poor prognostic profile and few survive longer than 2 years following metastasis. 1 , 7 This may account for the higher distant metastatic rate in ILCs. 8 Other reasons for metastasis of lobular breast cancer may be explained by E‐cadherin which is crucial in the maintenance of epithelial cell polarization. E‐cadherin is a calcium‐dependent epithelial cell adhesion molecule when mutated or lost can be associated with metastases as it acts as an invasion suppressor. 9 Deficiency of this molecule is responsible for cancer metastasis due to loss of cell to cell adhesion, with increased cell motility causing spread in blood and lymphatics. 10 In lobular breast cancer, E‐cadherin loss has been observed in most cases but not observed in invasive ductal cancers. In some studies, E‐cadherin has been used to be reliably used as a marker to differentiate between IDC and ILC. 11 This may account for its aggressive behavior compared with IDC. 9 Poor prognostic factors include age over 70 years, and degree of nodal involvement, which are associated with significant increased risk of relapse and death. 12 She had two of these factors including age and involvement of nodes which may have increased risk of poorer outcome. The uncertainty of the nature of ILC makes this an intriguing field, requiring further research and thoughtful consideration in order to most appropriately manage patients. Patients diagnosed with breast ILC and particularly those above 70 years of age should be carefully monitored for any evidence of potential gastrointestinal metastases, and if masses are identified to obtain tissue diagnosis for appropriate treatment.\n\nFIGURE 3 Hematoxylin and eosin stain: Hematoxylin and eosin stained section from the large bowel tumor ×100 magnification. The carcinoma cells are infiltrating upwards toward the bowel mucosa (top). The carcinoma cells are relatively small and are disposed as infiltrating cords and single cells. There is no tubule formation in this tumor. This is typical of classical lobular carcinoma of the breast\n\n4 CONCLUSION\n\nPatients with gastrointestinal symptoms with known invasive lobular breast cancer should be adequately investigated for potential metastases and if any masses are identified, the importance of obtaining tissue diagnosis to rule out metastases or a second primary. Particular attention to the subtype of ILC and prognostic factors including age and nodal involvement should alert clinicians to the likely possibility for gastrointestinal metastases. Knowledge of this unusual pattern of disease will help plan appropriate treatment, in order to optimize prognosis.\n\nCONFLICT OF INTEREST\n\nNone declared.\n\nAUTHOR CONTRIBUTION\n\nWY, SK, and AF: were all involved in reviewing the literature, prepared and edited the manuscript and all authors approved the final version of the manuscript.\n\nETHICAL APPROVAL\n\nThis study does not require any ethical committee approval.\n\nACKNOWLEDGEMENTS\n\nThe authors thank Dr Jonathan A Smiles, Pathologist for his contribution to the paper. The authors thank the patient and family for providing consent for this publication.\n\nDATA AVAILABILITY STATEMENT\n\nData sharing is not applicable to this article as no new data were created or analyzed in this study.\n==== Refs\nREFERENCES\n\n1 Molina‐Barea R , Rios‐Peregrina R , Slim M , Calandre EP , Hernandez‐Garcia MD , Jienez‐Rios JA . Lobular breast cancer metastasis to the colon, appendix and the gallbladder Breast Care. 2014:428‐430.\n2 Miller T . Unexpected diagnosis of both adenocarcinoma of the colon and metastatic lobular carcinoma of the breast in the gastrointestinal tract. Sydney, Australia: Hindawi; 2013.\n3 Ambroggi M , Stroppa EM , Mordenti P , et al. Metastatic breast cancer to the gastrointestinal tract: report of five cases and review of the literature. Int J Breast Cancer. 2012;2012 :1‐8.\n4 He H , Gonzalez A , Robinson E , Yang WT . Distant metastatic disease manifestations in infiltrating lobular carcinoma of the breast. Am J Roentgenol. 2014;202 :1140‐1148.24758672\n5 Santini D , Altomare A , Vincenzi B , et al. An increase of Ca 19.9 as the first clinical sign of ilocecal valve metastasis from breast cancer. In Vivo. 2006;20 :165‐168.16433047\n6 Borst M , Ingold JA . Metastatic patterns of invasive lobular versus invasive ductal carcinoma of the breast. Surgery. 1993;114 :637‐641.8211676\n7 Shah K , Chuang K , Srinivasan I . A rare case of lobular breast cancer with metastasis to the colon. Am J Gastroenterol. 2019;114 :833‐834.\n8 Ferlicot S , Vincent‐Salomon A , Medioni J , et al. Wide metastatic spreading in infiltrating lobular carcinoma of the breast. Eur J Cancer. 2004;40 :336‐341.14746850\n9 Younis LK , Sakka HE , Haque I . The prognostic value of E‐cadherin expression in breast cancer. Int J Health Sci. 2007;1 :43‐51.\n10 Corso G , Pravetooni G , Galimberti V , Veronsei P . Clinical implication of E‐cadherin deficiency in lobular breast cancer. Breast Cancer Res Treat. 2019;173 :751‐752.30448898\n11 Kanthilatha P , Baliga P , Shrestha B . E‐Cadherin expression: a diagnostic utility for differentiating breast carcinomas with ductal and lobular morphologies. J Clin Diagn Res. 2013;7 (5 ):840‐844.23814724\n12 Lorfida M , Maiorano E , Orvieto E , et al. Invasive lobular breast cancer: subtypes and outcome. Breast Cancer Res Treat. 2012;133 :713‐723.22399188\n\n",
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"keywords": "breast cancer; invasive lobular breast cancer; metastatic bowel obstruction",
"medline_ta": "Clin Case Rep",
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"title": "A rare case of lobular breast cancer metastasizing to large bowel.",
"title_normalized": "a rare case of lobular breast cancer metastasizing to large bowel"
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"abstract": "We report a fatality due to massive gastrointestinal haemorrhage in a patient receiving prophylactic dabigatran etexilate following a total hip replacement. A 79-year-old woman was commenced on dabigatran for venous thromboembolic prophylaxis following a total hip replacement. She presented again four days after surgery with haematemesis and hypotension but her coagulopathy could not be corrected, leading to her death. This case highlights the lack of reversal agent for dabigatran etexilate that resulted in this fatal complication.",
"affiliations": "Guy's and St Thomas' NHS Foundation Trust, UK. alicarter@doctors.org.uk.",
"authors": "Carter|A|A|;Sarda|P|P|;George|M|M|;Corbett|S|S|",
"chemical_list": "D000991:Antithrombins; D001562:Benzimidazoles; D011725:Pyridines; D000069604:Dabigatran",
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"fulltext": "\n==== Front\nAnn R Coll Surg EnglAnn R Coll Surg EnglannAnnals of The Royal College of Surgeons of England0035-88431478-7083Royal College of Surgeons 10.1308/003588414X13824511649779649779Online Case ReporthipHip surgerytroTrauma and orthopaedic surgeryHip arthroplasty fatality related to dabigatran induced gastrointestinal haemorrhage HIP ARTHROPLASTY FATALITY RELATED TO DABIGATRAN INDUCED GASTROINTESTINAL HAEMORRHAGECarter A alicarter@doctors.org.ukSarda P George M Corbett S Guy’s and St Thomas’ NHS Foundation Trust,UKCore Surgical Trainee, Department of Orthopaedics, Guy’s Hospital, Great Maze Pond, London SE1 9RT,UK E: alicarter@doctors.org.uk1 2014 1 2014 1 2014 96 1 e01 e03 19 4 2013 Copyright © 2013 Royal College of Surgeons2013This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.We report a fatality due to massive gastrointestinal haemorrhage in a patient receiving prophylactic dabigatran etexilate following a total hip replacement. A 79-year-old woman was commenced on dabigatran for venous thromboembolic prophylaxis following a total hip replacement. She presented again four days after surgery with haematemesis and hypotension but her coagulopathy could not be corrected, leading to her death. This case highlights the lack of reversal agent for dabigatran etexilate that resulted in this fatal complication.\n\nAnticoagulationDabigatranHip arthroplasty\n==== Body\nDabigatran etexilate (Pradaxa®; Boehringer Ingelheim, Ingelheim am Rhein, Germany), a direct inhibitor of the enzyme thrombin, is marketed worldwide for primary prevention of venous thromboembolism (VTE) in patients undergoing total hip or knee replacement surgery. It has been shown to have comparable efficacy with low molecular weight heparin (LMWH) in phase III trials.1 It also showed patient and staff advantages of a higher level of acceptability and greater ease of administration. Dabigatran differs from LMWH in that there is currently no effective reversal agent. This has been highlighted by several recent case reports of fatality emerging from patients who were on dabigatran for other conditions such as atrial fibrillation.2–5\n\nFollowing lower limb joint replacement, dabigatran is one of the drugs recommended by the National Institute for Health and Care Excellence (NICE) for VTE prophylaxis.6 Our institution followed this recommendation until recently. This case report aims to highlight significant gastrointestinal bleeding as a potential side effect of this drug, which, in the absence of a reversal agent, resulted in the death of a patient following an elective total hip replacement (THR).\n\nCase history\nA 79-year-old woman underwent a routine right THR without any intraoperative complications. Her past medical history included a previous duodenal ulcer that had been asymptomatic for a few years prior to the surgery, gastrooesophageal reflux disease, hypertension, a coronary bypass, aortic stenosis, hypothyroidism and chronic obstructive pulmonary disease. She had undergone a THR on the other side previously, where dabigatran had been used for VTE prophylaxis without any side effects. Medications included clopidogrel (stopped ten days prior to surgery and not restarted after surgery while on dabigatran) in addition to suitable medication for other co-morbidities listed above. Her renal function tests revealed an estimated glomerular filtration rate (eGFR) of 65ml/min preoperatively.\n\nThe patient was started on dabigatran after surgery as per the hospital’s and NICE guidelines for VTE prophylaxis after THR. As she was over 75 years old, she received a reduced dosing regime consisting of a starting dose of 75mg 4 hours after surgery to be followed by 28 days of 150mg once a day.\n\nThe patient was discharged on day 3 following her surgery but readmitted on day 5 with abdominal pain and hypotensive shock following haematemesis. She was transferred to the intensive care unit. She received packed red blood cells, platelets, fresh frozen plasma, tranexamic acid and vitamin K, and had haemofiltration in an attempt to correct the coagulopathy. Repeated upper gastrointestinal endoscopies showed a generalised gastritis with superficial ulcerations. Adrenaline injections and clips were applied to bleeding areas. Although she had a history of duodenal ulcers, no active lesions were seen on endoscopy. Despite vigorous resuscitation, the treatment was unsuccessful and she died on day 9 after surgery. The postmortem report confirmed multiorgan failure secondary to shock from a massive gastrointestinal haemorrhage.\n\nDiscussion\nDabigatran is a relatively new drug in the VTE market and has been recommended by NICE since 2008.6 Until the end of 2011, over 50,000 treatment courses (for all causes) were prescribed and 369 spontaneous adverse drug reactions in the UK have been reported to the Medicines and Healthcare products Regulatory Agency (MHRA).7 Out of these, 91 reports pertained to haemorrhagic reaction in patients treated for thromboprophylaxis with the gastrointestinal tract being the most common site (42 patients). Thirteen reports received in association with dabigatran had a fatal outcome, of which nine cases specified that the indication for use was thromboprophylaxis.\n\nAn review across Europe of haemorrhagic events in association with dabigatran resulted in updated monitoring information in patients with impaired renal function, highlighted in the MHRA drug safety bulletin in December 2011.8 The summary of product characteristics guidance highlights that there is limited clinical experience with regard to the elderly (those over 75 years old) and that these patients should be treated with caution.9 It also states that there is very limited clinical experience in patients with a body weight of under 50kg or over 110kg. It specifies that patients with moderate renal failure (eGFR 30–50ml/min) should receive the reduced dose of 150mg per day and that dabigatran is contraindicated in those with severe renal impairment (eGFR under 30ml/min).\n\nIn our case, there was no error in the prescription, which adhered both to NICE guidelines and manufacturer recommendations. Even though the patient’s renal function was satisfactory for the full recommended dose, she was commenced on the lower dose of 150mg once a day as she was over the age of 75.\n\nThe obvious advantage of being an oral medication (therefore not requiring skills for administration) and the lack of need for laboratory monitoring and dose alteration have been welcomed both by patients and healthcare workers.10 When compared with LMWH, the dabigatran dose regimes of either 150mg or 220mg did not show an increase in bleeding in the RE-NOVATE trial.1 Nevertheless, major bleeding remains a potential side effect as with all other VTE prophylaxis agents. Incidence of major bleeding after prophylactic LMWH has been reported as being up to 5.2%.11 There have been sporadic case reports of retroperitoneal haematoma resulting in death following administration of LMWH.12,13\n\nA case series published in 2012 reported 12 episodes of major bleeding within 2 months in patients newly started on dabigatran and raised potential doubts about the safety of this drug.14 The authors identified four major factors (prescriber error, impaired renal function, patient age and complications arising from lack of reversal agent) as the main contributors to bleeding. The site of bleeding can be varied including urethral, oral, rectal, mucosal and subdural sites.\n\nThe summary of product characteristics for dabigatran lists active clinically significant bleeding and a lesion or condition at significant risk of major bleeding such as current or recent gastrointestinal ulceration as contraindications.9 However, it does not specify a specific time duration and was not a part of the initial NICE guidelines. This issue was raised in the coroner’s report and also accepted by the MHRA as needing further clarification. Although this patient had a previous episode of haematemesis due to a duodenal ulcer two years prior to her hip replacement, she had been asymptomatic since then and no active duodenal ulcers were seen during her upper gastrointestinal endoscopies.\n\nReplacement and correction of the coagulopathy with packed red blood cells, fresh frozen plasma, platelets, vitamin K and tranexamic acid as well as mechanical attempts to limit bleeding were unsuccessful. Although haemofiltration was carried out throughout the patient’s admission as recommended for acute emergency reversal of this agent, it was not possible to reverse by this means in her case. The lack of a confirmed reversal agent proved fatal on this occasion.\n\nThere are reports emerging of some reversal success from prothrombin complex concentrate in animal models.15 Nevertheless, published in 2011, a randomised study in healthy human subjects showed no influence on the anticoagulant action of dabigatran.16 FEIBA® (Factor VIII Inhibitor Bypassing Activity; Baxter, Westlake Village, CA, US) was shown to improve the abnormal thrombin generation in one study from 2013.17 However, along with all of the potential antidotes discussed, long-term evidence and further research are still lacking.\n\nConclusions\nIt is hoped that the side effects, as well as the lack of reversal agent, are more widely and seriously appreciated for dabigatran. Further studies are needed to identify possible reversal agents and careful selection of patients deemed suitable to receive this drug for VTE prophylaxis is recommended.\n==== Refs\nReferences\n1. Friedman RJ , Dahl OE , Rosencher N \net al.\nDabigatran versus enoxaparin for prevention of venous thromboembolism after hip or knee arthroplasty: a pooled analysis of three trials . Thromb Res \n2010 ; : 175 –182 .20434759 \n2. Schattner A , Kozak N , Friedman J . Fatality in a patient treated with dabigatran . Am J Emerg Med \n2013 ;: 443.e1 –443.e2 .\n3. Kernan L , Ito S , Shirazi F , Boesen K . Fatal gastrointestinal hemorrhage after a single dose of dabigatran . Clin Toxicol \n2012 ; : 571 –573 .\n4. Cano EL , Miyares MA . Clinical challenges in a patient with dabigatran-induced fatal hemorrhage . Am J Geriatr Pharmacother \n2012 ; : 160 –163 .22386824 \n5. Chen BC , Viny AD , Garlich FM \net al.\nHemorrhagic complications associated with dabigatran use . Clin Toxicol \n2012 ; : 854 –857 .\n6. National Institute for Health and Clinical Excellence . Dabigatran Etexilate for the Prevention of Venous Thromboembolism After Hip or Knee Replacement Surgery in Adults . London : NICE ; 2008 .\n7. Data derived from IMS Health MIDAS 03/08–12/11 by Medicines and Healthcare products Regulatory Agency.\n8. \nDabigatran (Pradaxa): Risk of Serious Haemorrhage – Need for Renal Function Testing . Medicines and Healthcare products Regulatory Agency . http://www.mhra.gov.uk/safetyinformation/drugsafetyupdate/CON137771 (cited 10 \n2013 ).\n9. \nSPC: Pradaxa 110 mg hard capsules . Electronic Medicines Compendium . http://www.medicines.org.uk/emc/medicine/20760 (cited 10 \n2013 ).\n10. Kendoff D , Perka C , Fritsche HM \net al.\nOral thromboprophylaxis following total hip or knee replacement: review and multicentre experience with dabigatran etexilate . Open Orthop J \n2011 ; : 395 –399 .22276081 \n11. Fitzgerald RH , Spiro TE , Trowbridge AA \net al.\nPrevention of venous thromboembolic disease following primary total knee arthroplasty. A randomized, multicenter, open-label, parallel-group comparison of enoxaparin and warfarin . J Bone Joint Surg Am \n2001 ; : 900 –906 .11407799 \n12. Haq MM , Taimur SD , Khan SR , Rahman MA . Retroperitoneal hematoma following enoxaparin treatment in an elderly woman – a case report . Cardiovasc J \n2010 ; : 94 –97 .\n13. Chan-Tack KM . Fatal spontaneous retroperitoneal hematoma secondary to enoxaparin . South Med J \n2003 ; : 58 –60 .12602717 \n14. Harper P , Young L , Merriman E . Bleeding risk with dabigatran in the frail elderly . N Engl J Med \n2012 ; : 864 –866 .\n15. Pragst I , Zeitler SH , Doerr B \net al.\nReversal of dabigatran anticoagulation by prothrombin complex concentrate (Beriplex P/N) in a rabbit model . J Thromb Haemost \n2012 ; : 1,841 –1,848 .22077430 \n16. Eerenberg ES , Kamphuisen PW , Sijpkens MK \net al.\nReversal of rivaroxaban and dabigatran by prothrombin complex concentrate . Circulation \n2011 ; : 1,573 –1,579 .\n17. Khoo TL , Weatherburn C , Kershaw G \net al.\nThe use of FEIBA® in the correction of coagulation abnormalities induced by dabigatran . Int J Lab Hematol \n2013 ;: 222 –224 .\n\n",
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"title": "Hip arthroplasty fatality related to dabigatran induced gastrointestinal haemorrhage.",
"title_normalized": "hip arthroplasty fatality related to dabigatran induced gastrointestinal haemorrhage"
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... |
{
"abstract": "Febrile neutropenia is a complication of myleotoxic chemotherapy that can markedly decrease quality of life and increase healthcare costs. A granulocyte-colony stimulating factor (G-CSF) is used to increase neutrophil production to reduce the risk of developing febrile neutropenia. However, G-CSF administered on the same day as chemotherapy can worsen and prolong neutropenia. To study and compare the effects of pegfilgrastim on the incidence of febrile neutropenia and grade 4 neutropenia in patients receiving pegfilgrastim on the same day (day 1) versus the next day (day 2 or beyond) of chemotherapy, a retrospective, single-center, nonrandomized, cohort study was carried out of adult non-Hodgkin's lymphoma patients who received pegfilgrastim 6 mg subcutaneously on day 1 or beyond of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) with or without rituximab every 3 weeks. Six hundred and fifty-five chemotherapy cycles (320 cycles for the same day and 335 cycles for the next day) were evaluable in 141 patients. Among all cycles, the incidence of febrile neutropenia was 9.4 versus 5.1% in the same-day versus the next-day group (P=0.03). The incidence of febrile neutropenia was the highest after the first cycle in the same-day group, which was 19.4, versus 11.1% for the next-day group (P=0.27). There were three deaths among patients who developed febrile neutropenia, including two in the next-day group versus one in the same-day group. In conclusion, our findings support the need for a randomized phase III study to fully evaluate whether a G-CSF is safer when administered on the next day versus the same day of chemotherapy.",
"affiliations": "aDepartment of Pharmacy, Cleveland Clinic, Cleveland, Ohio bDivision of Pharmaceutical Sciences, Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, New York, USA.",
"authors": "Cheng|Connie|C|;Gallagher|Erika M|EM|;Yeh|Jun-Yen|JY|;Earl|Marc A|MA|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; C455861:pegfilgrastim; D011092:Polyethylene Glycols; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011239:Prednisolone; D000069585:Filgrastim",
"country": "England",
"delete": false,
"doi": "10.1097/CAD.0000000000000115",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-4973",
"issue": "25(8)",
"journal": "Anti-cancer drugs",
"keywords": null,
"medline_ta": "Anticancer Drugs",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D064146:Chemotherapy-Induced Febrile Neutropenia; D003520:Cyclophosphamide; D004317:Doxorubicin; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D015994:Incidence; D016403:Lymphoma, Large B-Cell, Diffuse; D008875:Middle Aged; D011092:Polyethylene Glycols; D011239:Prednisolone; D011994:Recombinant Proteins; D012189:Retrospective Studies; D000069283:Rituximab; D014750:Vincristine; D055815:Young Adult",
"nlm_unique_id": "9100823",
"other_id": null,
"pages": "964-9",
"pmc": null,
"pmid": "24743519",
"pubdate": "2014-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Rates of febrile neutropenia with pegfilgrastim on same day versus next day of CHOP with or without rituximab.",
"title_normalized": "rates of febrile neutropenia with pegfilgrastim on same day versus next day of chop with or without rituximab"
} | [
{
"companynumb": "US-ROXANE LABORATORIES, INC.-2014-BI-53416GD",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugaddit... |
{
"abstract": "BACKGROUND\nThe origin of contactin-associated protein-like 2 (Caspr2) antibodies in patients with Morvan syndrome is currently unknown. This case report investigated a possible association between the production of Caspr2 antibodies and aberrant proliferation of B lymphocytes.\n\n\nMETHODS\nWe admitted a critically ill 65-year-old female patient with a suspected infection of the central nervous system (CNS). In addition to acquired neuromyotonia and CNS involvement, Caspr2 antibodies detected in her serum led to the presumptive diagnosis of Morvan syndrome. However, steroid and immunoglobulin treatment did not result in a satisfactory therapeutic outcome. On the basis of findings from immunohistochemistry, flow cytometric analysis, and immunoglobulin/T-cell receptor gene rearrangement detection of cerebrospinal fluid cells, we also made a concurrent diagnosis of diffuse large B-cell lymphoma in the CNS of this patient. The patient then received 4 cycles of rituximab and methylprednisolone therapy with an interval of 2 weeks, which temporarily led to a near-complete remission of her symptoms. Upon follow-up, her symptoms relapsed at 3 months after the last treatment with rituximab and methylprednisolone.\n\n\nCONCLUSIONS\nThis is a first reported case of a patient who was concurrently diagnosed with Morvan syndrome and diffuse large B-cell lymphoma in the CNS. Additional studies are needed to determine whether aberrantly proliferating B lymphocytes are responsible for the production of Caspr2 antibodies.",
"affiliations": "Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, Henan.;Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, Henan.;Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, Henan.;Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore.;Winston Churchill High School, Potomac, MD.;Department of Neurology, Xijing Hospital, The Fourth Military Medical University, Xi'an, P.R. China.",
"authors": "Jiang|Chao|C|;Zhang|Jing|J|;Jia|Chuanyu|C|;Hong|Michael|M|;Wang|Jiarui|J|;Yang|Yining|Y|",
"chemical_list": "C403049:CNTNAP2 protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins",
"country": "United States",
"delete": false,
"doi": "10.1097/NRL.0000000000000266",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1074-7931",
"issue": "25(3)",
"journal": "The neurologist",
"keywords": null,
"medline_ta": "Neurologist",
"mesh_terms": "D000368:Aged; D005260:Female; D006801:Humans; D020386:Isaacs Syndrome; D016403:Lymphoma, Large B-Cell, Diffuse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D013595:Syringomyelia",
"nlm_unique_id": "9503763",
"other_id": null,
"pages": "73-77",
"pmc": null,
"pmid": "32358465",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Morvan Syndrome and Diffuse Large B-Cell Lymphoma in the Central Nervous System.",
"title_normalized": "morvan syndrome and diffuse large b cell lymphoma in the central nervous system"
} | [
{
"companynumb": "NVSC2020CN156727",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
"druga... |
{
"abstract": "There are many differences between the hair from children and that of adult subjects, the hair being thinner, more porous with a different growth rate from the usual 1 cm/month observed in adults. In order to determine whether hair analysis could discriminate between chronic use and acute administration of a drug in children like in adults, we analyzed hair from 18 children aged between 1 day and 15 years in whom the administration of different drugs was known (single therapeutic administration or acute intoxication). A strand of hair was sampled within 1 to 45 days after treatment or intoxication. Analysis was conducted using LC/MS/MS. In the 10 youngest children, aged between 1 day and 29 months, the compounds administered in hospital or responsible for intoxication (lidocaine, ropivacaine, diazepam, midazolam, levetiracetam, morphine, ketamine, methadone, buprenorphine, THC, MDMA) were found in all segments of the hair independently of the time of sampling (1-45 days after ingestion). The concentrations detected were similar along the hair shaft, showing a radial diffusion and incorporation of the analytes in the hair of young children from the sebum. Concentrations could be very high when sampled shortly after administration (72 ng/mg for methadone, 75 ng/mg for MDMA after 3 days) and lower when sampling later (1.2 ng/mg for MDMA after 45 days). In these cases, hair analysis allowed to highlight the compounds responsible for intoxication even when they had disappeared from the blood or urine but should not be used to discriminate long-term exposure to a drug. In the eight remaining children aged from 34 months to 15 years, the drugs used in hospital (lidocaine, diazepam, morphine) or responsible for intoxication (THC, codeine, buprenorphine) were not found in any analyzed segments sampled 1 to 5 days after administration of the drugs, in agreement with the non-incorporation of the drugs from the sebum into the hair. For those children aged over 34 months, hair analysis allows to determine the chronic administration of a drug, like in adults.",
"affiliations": "Laboratory of Pharmacology-Toxicology, AP-HP, INSERM U-1173, Raymond Poincaré University Hospital, Versailles Saint Quentin-en-Yvelines University, 104 Boulevard Raymond Poincaré, 92380, Garches, France. jean-claude.alvarez@aphp.fr.;Laboratory of Pharmacology-Toxicology, AP-HP, INSERM U-1173, Raymond Poincaré University Hospital, Versailles Saint Quentin-en-Yvelines University, 104 Boulevard Raymond Poincaré, 92380, Garches, France.;Laboratory of Pharmacology-Toxicology, AP-HP, INSERM U-1173, Raymond Poincaré University Hospital, Versailles Saint Quentin-en-Yvelines University, 104 Boulevard Raymond Poincaré, 92380, Garches, France.;Pediatric Emergency Department, Necker-Enfants Malades, Université Paris-Descartes, 149, rue de Sèvres, 7574, Paris Cedex 15, France.;Pediatric Department, Necker-Enfants Malades, Université Paris-Descartes, 149, rue de Sèvres, 75743, Paris Cedex 15, France.;Laboratory of Pharmacology-Toxicology, AP-HP, INSERM U-1173, Raymond Poincaré University Hospital, Versailles Saint Quentin-en-Yvelines University, 104 Boulevard Raymond Poincaré, 92380, Garches, France.;Laboratory of Pharmacology-Toxicology, AP-HP, INSERM U-1173, Raymond Poincaré University Hospital, Versailles Saint Quentin-en-Yvelines University, 104 Boulevard Raymond Poincaré, 92380, Garches, France.",
"authors": "Alvarez|Jean Claude|JC|http://orcid.org/0000-0001-5344-9475;Lasne|Laetitia|L|;Etting|Isabelle|I|;Chéron|Gérard|G|;Abadie|Véronique|V|;Fabresse|Nicolas|N|;Larabi|Islam Amine|IA|",
"chemical_list": "D013287:Illicit Drugs; D004364:Pharmaceutical Preparations",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00414-017-1720-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0937-9827",
"issue": "132(1)",
"journal": "International journal of legal medicine",
"keywords": "Children; Chronic use; Hair; Intoxication",
"medline_ta": "Int J Legal Med",
"mesh_terms": "D000059:Accidents; D000293:Adolescent; D002648:Child; D002650:Child Abuse, Sexual; D002675:Child, Preschool; D002853:Chromatography, Liquid; D005260:Female; D053593:Forensic Toxicology; D006197:Hair; D006760:Hospitalization; D006801:Humans; D013287:Illicit Drugs; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D004364:Pharmaceutical Preparations; D011041:Poisoning; D015813:Substance Abuse Detection; D019966:Substance-Related Disorders; D053719:Tandem Mass Spectrometry",
"nlm_unique_id": "9101456",
"other_id": null,
"pages": "165-172",
"pmc": null,
"pmid": "29043488",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article",
"references": "24263638;20060244;25332846;17916427;25676714;16404812;27399225;24588273;24148016;18004288;24339389;14756718;15516307;21193274;8138238;16872573;19839962;10049570;27914279;26610304",
"title": "Hair analysis does not allow to discriminate between acute and chronic administrations of a drug in young children.",
"title_normalized": "hair analysis does not allow to discriminate between acute and chronic administrations of a drug in young children"
} | [
{
"companynumb": "FR-SUN PHARMACEUTICAL INDUSTRIES LTD-2018R1-184965",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BUPRENORPHINE"
},
"d... |
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