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"abstract": "A patient presented with what appeared to be severe urosepsis. After admission and antibiotic administration, a newly developed rash and subsequent facial swelling appeared to be a reaction to penicillin class antibiotics. However, despite changing class of therapy with continued antimicrobial coverage, end organ damage continued, the rash worsened and facial oedema developed. Drug reaction with eosinophilia and systemic symptoms was ultimately diagnosed and was consistent with clinical and histopathological findings, as well as meeting all criteria for scoring systems. The patient was started on intravenous methylprednisolone 125 mg per 8 hours with rapid improvement of rash, swelling and end organ damage. Initial challenge to decrease dose failed, but the patient was ultimately able to be discharged on an extended taper.",
"affiliations": "Transitional Rotating Internship, Sampson Regional Medical Center, Clinton, NC, USA.;College of Medicine, Campbell University College of Osteopathic Medicine, Clinton, North Carolina, USA.;Dermatology, Sampson Regional Medical Center, Clinton, North Carolina, USA.;Family Medicine, Sampson Regional Medical Center, Clinton, NC, USA.",
"authors": "Maxfield|Luke|L|;Schlick|Toni|T|;Macri|Angela|A|;Thatcher|James|J|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D014640:Vancomycin; D008775:Methylprednisolone",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-221898",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "dermatology; unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D003937:Diagnosis, Differential; D063926:Drug Hypersensitivity Syndrome; D004802:Eosinophilia; D005076:Exanthema; D006801:Humans; D008297:Male; D008775:Methylprednisolone; D008875:Middle Aged; D011550:Pseudomonas aeruginosa; D018805:Sepsis; D014640:Vancomycin",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29054953",
"pubdate": "2017-10-19",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22693316;9069593;22525393;14632808;23882307;23855313;25041771;23602182;25592341;21592453;22679188;22761227;26271788",
"title": "Vancomycin-associated drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome: masquerading under the guise of sepsis.",
"title_normalized": "vancomycin associated drug reaction with eosinophilia and systemic symptoms dress syndrome masquerading under the guise of sepsis"
} | [
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"companynumb": "US-STRIDES ARCOLAB LIMITED-2017SP014616",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"activesubstancename": "VANCOMYCIN"
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"abstract": "Patients with non-small cell lung cancer may develop pneumonitis after thoracic radiotherapy (RT) and immune checkpoint inhibitors (ICIs). We hypothesized that distinct morphologic features are associated with different pneumonitis etiologies.\n\n\n\nWe systematically compared computed tomography (CT) features of RT- versus ICI-pneumonitis. Clinical and imaging features were tested for association with pneumonitis severity. Lastly, we constructed an exploratory radiomics-based machine learning (ML) model to discern pneumonitis etiology.\n\n\n\nBetween 2009 and 2019, 82 patients developed pneumonitis: 29 after thoracic RT, 23 after ICI, and 30 after RT + ICI. Fifty patients had grade 2 pneumonitis, 22 grade 3, and 7 grade 4. ICI-pneumonitis was more likely bilateral (65% vs. 28%; p = .01) and involved more lobes (66% vs. 45% involving at least three lobes) and was less likely to have sharp border (17% vs. 59%; p = .004) compared with RT-pneumonitis. Pneumonitis morphology after RT + ICI was heterogeneous, with 47% bilateral, 37% involving at least three lobes, and 40% sharp borders. Among all patients, risk factors for severe pneumonitis included poor performance status, smoking history, worse lung function, and bilateral and multifocal involvement on CT. An ML model based on seven radiomic features alone could distinguish ICI- from RT-pneumonitis with an area under the receiver-operating curve of 0.76 and identified the predominant etiology after RT + ICI concordant with multidisciplinary consensus.\n\n\n\nRT- and ICI-pneumonitis exhibit distinct spatial features on CT. Bilateral and multifocal lung involvement is associated with severe pneumonitis. Integrating these morphologic features in the clinical management of patients who develop pneumonitis after RT and ICIs may improve treatment decision-making.\n\n\n\nPatients with non-small cell lung cancer often receive thoracic radiation and immune checkpoint inhibitors (ICIs), both of which can cause pneumonitis. This study identified similarities and differences in pneumonitis morphology on computed tomography (CT) scans among pneumonitis due to radiotherapy (RT) alone, ICI alone, and the combination of both. Patients who have bilateral CT changes involving at least three lobes are more likely to have ICI-pneumonitis, whereas those with unilateral CT changes with sharp borders are more likely to have radiation pneumonitis. After RT and/or ICI, severe pneumonitis is associated with bilateral and multifocal CT changes. These results can help guide clinicians in triaging patients who develop pneumonitis after radiation and during ICI treatment.",
"affiliations": "Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Oncology, Johns Hopkins University, Baltimore, Maryland, USA.;Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland, USA.;Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Division of Biostatistics, Department of Oncology, Johns Hopkins University, Baltimore, Maryland, USA.;Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Oncology, Johns Hopkins University, Baltimore, Maryland, USA.;Department of Oncology, Johns Hopkins University, Baltimore, Maryland, USA.;Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.",
"authors": "Chen|Xuguang|X|0000-0001-8761-810X;Sheikh|Khadija|K|0000-0002-1168-1783;Nakajima|Erica|E|;Lin|Cheng Ting|CT|;Lee|Junghoon|J|;Hu|Chen|C|;Hales|Russell K|RK|;Forde|Patrick M|PM|;Naidoo|Jarushka|J|;Voong|Khinh Ranh|KR|",
"chemical_list": "D000082082:Immune Checkpoint Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1002/onco.13900",
"fulltext": "\n==== Front\nOncologist\nOncologist\n10.1002/(ISSN)1549-490X\nONCO\ntheoncologist\nThe Oncologist\n1083-7159\n1549-490X\nJohn Wiley & Sons, Inc. Hoboken, USA\n\n34251728\n10.1002/onco.13900\nONCO13900\n32\n22\n43\n14\nLung Cancer\nLung Cancer\nRadiation Versus Immune Checkpoint Inhibitor Associated Pneumonitis: Distinct Radiologic Morphologies\nClassification of Pneumonitis by CT Features\nChen, Sheikh, Nakajima et al.\nChen Xuguang https://orcid.org/0000-0001-8761-810X\n1\nSheikh Khadija https://orcid.org/0000-0002-1168-1783\n1\nNakajima Erica 4\nLin Cheng Ting 2\nLee Junghoon 1\nHu Chen 3\nHales Russell K. 1\nForde Patrick M. 4\nNaidoo Jarushka 4\nVoong Khinh Ranh 1 kvoong1@jhmi.edu\n\n1 Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine Baltimore Maryland\n2 Department of Radiology and Radiological Science, Johns Hopkins University Baltimore Maryland USA\n3 Division of Biostatistics, Department of Oncology, Johns Hopkins University Baltimore Maryland USA\n4 Department of Oncology, Johns Hopkins University Baltimore Maryland USA\n* Correspondence: Khinh Ranh Voong, M.D., Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Cancer Center, Thoracic Center of Excellence, Johns Hopkins Bayview, 300 Mason Lord Drive, Baltimore, Maryland 21224, USA. Telephone: 410‐550‐6597; e‐mail: kvoong1@jhmi.edu\n\n04 8 2021\n10 2021\n26 10 10.1002/onco.v26.10 e1822e1832\n25 3 2021\n07 7 2021\n© 2021 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.\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\nBackground\n\nPatients with non‐small cell lung cancer may develop pneumonitis after thoracic radiotherapy (RT) and immune checkpoint inhibitors (ICIs). We hypothesized that distinct morphologic features are associated with different pneumonitis etiologies.\n\nMaterials and Methods\n\nWe systematically compared computed tomography (CT) features of RT‐ versus ICI‐pneumonitis. Clinical and imaging features were tested for association with pneumonitis severity. Lastly, we constructed an exploratory radiomics‐based machine learning (ML) model to discern pneumonitis etiology.\n\nResults\n\nBetween 2009 and 2019, 82 patients developed pneumonitis: 29 after thoracic RT, 23 after ICI, and 30 after RT + ICI. Fifty patients had grade 2 pneumonitis, 22 grade 3, and 7 grade 4. ICI‐pneumonitis was more likely bilateral (65% vs. 28%; p = .01) and involved more lobes (66% vs. 45% involving at least three lobes) and was less likely to have sharp border (17% vs. 59%; p = .004) compared with RT‐pneumonitis. Pneumonitis morphology after RT + ICI was heterogeneous, with 47% bilateral, 37% involving at least three lobes, and 40% sharp borders. Among all patients, risk factors for severe pneumonitis included poor performance status, smoking history, worse lung function, and bilateral and multifocal involvement on CT. An ML model based on seven radiomic features alone could distinguish ICI‐ from RT‐pneumonitis with an area under the receiver‐operating curve of 0.76 and identified the predominant etiology after RT + ICI concordant with multidisciplinary consensus.\n\nConclusion\n\nRT‐ and ICI‐pneumonitis exhibit distinct spatial features on CT. Bilateral and multifocal lung involvement is associated with severe pneumonitis. Integrating these morphologic features in the clinical management of patients who develop pneumonitis after RT and ICIs may improve treatment decision‐making.\n\nImplications for Practice\n\nPatients with non‐small cell lung cancer often receive thoracic radiation and immune checkpoint inhibitors (ICIs), both of which can cause pneumonitis. This study identified similarities and differences in pneumonitis morphology on computed tomography (CT) scans among pneumonitis due to radiotherapy (RT) alone, ICI alone, and the combination of both. Patients who have bilateral CT changes involving at least three lobes are more likely to have ICI‐pneumonitis, whereas those with unilateral CT changes with sharp borders are more likely to have radiation pneumonitis. After RT and/or ICI, severe pneumonitis is associated with bilateral and multifocal CT changes. These results can help guide clinicians in triaging patients who develop pneumonitis after radiation and during ICI treatment.\n\nPatients with non‐small cell lung cancer often receive thoracic radiotherapy and immune checkpoint inhibitors (ICIs), both of which can cause pneumonitis. The results of this study can help guide clinicians in triaging patients who develop pneumonitis after receipt of radiation and/or immune checkpoint inhibitor treatment.\n\nImmune checkpoint inhibitor\nImmune‐related adverse event\nImmune‐related pneumonitis\nRadiation pneumonitis\nNon‐small cell lung carcinoma\nsource-schema-version-number2.0\ncover-dateOctober 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.8 mode:remove_FC converted:04.10.2021\nDisclosures of potential conflicts of interest may be found at the end of this article.\n==== Body\npmcIntroduction\n\nPneumonitis can cause significant morbidity or even mortality in patients with non‐small cell lung cancer (NSCLC) after thoracic radiotherapy (RT) or immune checkpoint inhibitors (ICIs) [1, 2]. Computed tomography (CT) scans of the chest are critical in the diagnosis and management of patients with pneumonitis. Both RT‐ and ICI‐pneumonitis can often manifest as ground‐glass opacities (GGOs) and consolidations on CT, and both frequently assume a pattern of cryptogenic organizing pneumonia (COP) or acute interstitial pneumonia/acute respiratory distress syndrome (AIP/ARDS) [3, 4, 5]. However, it is unclear whether RT‐ and ICI‐pneumonitis exhibit distinct radiographic patterns that would allow distinction of these two etiologies in patients with NSCLC. Moreover, CT morphology of pneumonitis after combined thoracic RT and ICI has not been systematically characterized.\n\nThe number of patients with NSCLC who may benefit from both thoracic RT and ICI is increasing [1, 6, 7]. As the indications for RT and ICI expand, more patients are at risk of developing pneumonitis after RT + ICI. Both RT and ICI may act synergistically to promote inflammation of the lung parenchyma, and several studies have suggested that prior thoracic RT is a potential risk factor for pneumonitis after ICI in a dose‐dependent manner [8, 9]. However, studies of ICI‐pneumonitis to date have mostly included heterogeneous patient populations with variable prior RT exposure [3, 4, 10, 11]. Furthermore, there are no universally accepted criteria to define the components of pneumonitis caused mainly by RT and that caused mainly by ICI [12]. Therefore, the respective roles of RT and ICI in pneumonitis pathogenesis among patients receiving RT + ICI remain unclear. This distinction is clinically relevant as treatment algorithms for RT‐ versus ICI‐pneumonitis differ in that ICI‐pneumonitis requires higher dose of steroids and occasionally immunosuppressive agents and may necessitate prolonged or indefinite discontinuation of ICI, which may have a negative impact on tumor control [2, 13, 14, 15]. We hypothesize that pneumonitis after RT + ICI may exhibit unique radiographic features compared with pneumonitis caused by either treatment alone. In this study, we compare CT characteristics of pneumonitis in patients with NSCLC after RT alone, ICI alone, or RT + ICI, using the framework proposed by Nishino et al. [3].\n\nCompared with qualitative radiographic exam, CT radiomics may be able to discern subtle texture features not readily identified by human readers [16, 17]. In patients with NSCLC who receive RT or ICI, radiomic analysis of CT images combined with machine learning (ML) has shown promise in predicting future pneumonitis risk [18, 19, 20, 21]. However, no study to date has evaluated the difference in radiomic signatures between RT‐ and ICI‐pneumonitis. As a proof of concept, we aim to test the utility of CT radiomics (in place of morphologic evaluation) in discerning pneumonitis etiology by developing an unbiased, radiomics‐based ML model and applying this model in patients who developed pneumonitis after receipt of RT and ICI.\n\nMaterials and Methods\n\nPatients\n\nThis study was approved by the institutional review board (IRB00218259). Patients with NSCLC treated at a single tertiary academic institution between 2009 and 2019 were retrospectively reviewed. Patients were included if they received curative‐intent thoracic radiotherapy (≥45 Gy in 1.8–2.5 Gy per fraction) or ICI for any duration of time and developed pneumonitis. Patients who received ICI following thoracic RT after any interval were also included and classified as RT + ICI. Patients received regular follow‐up with clinical and CT exams every 2 to 4 months for the first 2 years after treatment and every 3 to 6 months thereafter.\n\nBaseline patient characteristics and treatment parameters were extracted from electronic medical records. Collected clinical variables included the age of initial diagnosis, gender, performance status, relevant comorbidities (smoking history, prior autoimmune disease, and chronic obstructive pulmonary disease [COPD]), baseline pulmonary function assessment (forced expiratory volume in 1 second [FEV1], forced vital capacity [FVC], and diffusion capacity of carbon monoxide), histology and stage of NSCLC at the time of initial diagnosis (American Joint Committee on Cancer, 7th edition), RT prescription dose, volume of lung receiving 20 Gy or higher (V20), mean lung dose (MLD), the type of ICIs, and additional treatments received (including RT to nonthoracic sites, chemotherapy, and prior surgery).\n\nPneumonitis Classification\n\nPneumonitis was diagnosed clinically by the treating physicians and defined as clinical and radiologic evidence of lung inflammation after RT or ICIs, not attributed to other confirmed causes such as active infection or progressive NSCLC [8]. Pneumonitis diagnosis in patients who received ICIs with or without prior RT was confirmed by a multidisciplinary group of physicians, including a medical oncologist, a radiation oncologist, a pulmonologist, and a radiologist in select cases. Time to pneumonitis was calculated from the date of RT completion in patients treated with RT alone, or from the date of ICI initiation in patients treated with ICIs alone or RT followed by ICIs. Grading of pneumonitis followed the Common Terminology Criteria for Adverse Events version 5.0.\n\nCT Morphologic Evaluation\n\nDiagnostic CTs before treatment initiation (pretreatment) and at the time of pneumonitis diagnosis (post‐treatment) were obtained. Scanning parameters were listed in supplemental online Table 1. For patients who had multiple post‐treatment CTs, the time point that showed maximal imaging changes was selected. Qualitative radiologic features as described by Nishino et al. were scored by a board‐certified thoracic radiologist (C.T.L.) blinded to the patient's past treatment course and pneumonitis etiology [3]. These included number of involved lobes, extent of radiographic changes (<5%, 5%–25%, 25%–50%, and > 50%), distribution of pneumonitis changes (focal vs. multifocal), specific CT findings (GGO, consolidation, or centrilobular nodularity), and radiographic patterns (COP, hypersensitivity pneumonitis, fibrosis, or AIP/ARDS). Sharp border, or the presence of a sharply demarcated linear edge between areas of pneumonitis and normal lung, is common among RT‐pneumonitis [22, 23]. Therefore, the presence or absence of sharp border was also scored as an additional morphologic feature.\n\nStatistical Analysis\n\nBaseline patient and treatment characteristics were presented as number (percent) for categorical variables or median (range) for continuous variables. Comparisons between different treatment groups or pneumonitis severities were made by Fisher's exact test (categorical variables) or Wilcoxon rank sum test (continuous variables). CT morphologic features of RT‐ versus ICI‐pneumonitis were compared using Fisher's exact tests. Statistical significance was defined as p < .05.\n\nRadiomics and Machine Learning\n\nWe explored the feasibility of classifying pneumonitis etiology using radiomic features by training and validating a preliminary ML model. The bilateral whole lungs were automatically segmented using Velocity AI software (version 3.1, Varian, Palo Alto, CA) and shrunk by 3 mm isotropically to avoid partial volume effect at air‐soft tissue interface. Ninety‐three radiomic features (supplemental online Table 2) were extracted for each of the ipsilateral (relative to the primary tumor), contralateral and combined lungs from the pretreatment and post‐treatment (at the time of pneumonitis) CT scans using PyRadiomics software (version 3.0 https://pyradiomics.readthedocs.io/) [24]. Feature selection was performed in a two‐step process: first, t tests were used to compare RT‐ and ICI‐pneumonitis, and the radiomic features with p < .05 were entered into the next step. Second, an iterative least absolute shrinkage and selection operator process with one feature left out in each iteration was used to select the final features (retained in more than one third of all iterations) [25]. Random forest algorithm was used for model training in patients who received RT (n = 29) or ICI (n = 23) alone. Hyperparameters were optimized via grid search, including the number of features used for splitting at each node (search grid: 1 to 10 with a step size of 1) and the number of trees (search grid: 200, 500, 1,000, 2,000, 5,000, 10,000).\n\nThe final model was tested in the group of patients receiving RT + ICI. The model yielded the likelihood of ICI being the predominant etiology (on a continuous scale of 0, least likely, to 1, most likely) in each case. As no gold standard exists to definitively distinguish pneumonitis etiology in this patient population, we compared the results from the model with the consensus attribution by a multidisciplinary group of physicians consisting of both radiation oncologists and medical oncologists with access to all the clinical and imaging records. All predictive modeling was performed using R software.\n\nResults\n\nPatient Characteristics\n\nBaseline patient characteristics are summarized in Table 1. Eighty‐two patients were included in this study, with a median follow‐up of 15.4 months (range, 0.7–129.6). The median patient age was 68 years (range, 45–84), and 50% were male. Thirteen patients (16%) were current smokers and 57 (70%) were former smokers, with a median of 35 pack‐year smoking history (range, 1–110). Thirty‐eight patients (46%) had prior diagnosis of COPD. Two patients had a history of interstitial lung disease (ILD): one had stable subpleural fibrosis on CT consistent with ILD prior to initiating ICI, and the other had an episode of bronchiolitis obliterans organizing pneumonia 7 years prior to diagnosis and received RT and ICI after lung cancer diagnosis. Neither patient was taking corticosteroids at the time of initiating lung cancer treatment.\n\nTable 1 Baseline patient characteristics\n\nCharacteristics\tRT alone\tICI alone\tRT + ICI\tp value\t\nNumber of patients\t29\t23\t30\t\t\nAge, yra\t67 (45–84)\t65 (50–81)\t69 (49–82)\t.57\t\nMale, n (%)\t12 (41)\t11 (48)\t18 (60)\t.35\t\nECOG performance status (%)\t\t\t\t.38\t\n0\t6 (21)\t3 (13)\t5 (17)\t\t\n1\t23 (79)\t17 (74)\t22 (73)\t\t\n2\t0\t3 (13)\t3 (10)\t\t\nSmoking history, n (%)\t\t\t\t.26\t\nCurrent smoker\t2 (7)\t3 (13)\t8 (27)\t\t\nFormer smoker\t23 (79)\t15 (65)\t19 (63)\t\t\nNever smoker\t4 (14)\t5 (22)\t3 (10)\t\t\nPack‐year smokeda\t40 (0–90)\t25 (0–90)\t38 (0–110)\t.02\t\nCOPD (%)\t16 (55)\t8 (35)\t14 (47)\t.34\t\nAutoimmune disease (%)\t\t\t\t.91\t\nILD\t0\t1 (4)\t1 (3)\t\t\nCrohn's disease\t1 (3)\t0\t0\t\t\nRheumatoid arthritis\t1 (3)\t0\t0\t\t\nMyasthenia gravis\t0\t0\t1 (3)\t\t\nPretreatment lung functiona\t\t\t\t\t\nFEV1, L\t1.46 (1.10–1.99)\t1.93 (1.40–2.69)\t1.87 (1.50–2.25)\t.29\t\n% FEV1 predicted\t74 (39–84)\t76 (64–90)\t74 (56–84)\t.47\t\nFVC, L\t2.41 (1.72–3.06)\t2.68 (2.29–3.69)\t2.88 (2.24–3.75)\t.56\t\n% FVC predicted\t80 (56–102)\t87 (78–100)\t94 (66–99)\t.64\t\nDLCO (%)\t54 (51–66)\t85 (60–96)\t80 (62–97)\t.05\t\nHistology (%)\t\t\t\t.04\t\nAdenocarcinoma\t16 (55)\t19 (83)\t13 (43)\t\t\nSquamous cell carcinoma\t8 (28)\t3 (13)\t13 (43)\t\t\nOtherb\t5 (17)\t1 (4)\t4 (13)\t\t\nT stage (%)\t\t\t\t.78\t\n1\t5 (17)\t4 (17)\t5 (17)\t\t\n2\t10 (34)\t9 (39)\t8 (27)\t\t\n3\t6 (21)\t3 (13)\t10 (33)\t\t\n4\t8 (28)\t7 (30)\t7 (23)\t\t\nN stage, n (%)\t\t\t\t.52\t\n0\t4 (14)\t3 (13)\t7 (23)\t\t\n1\t2 (7)\t2 (9)\t6 (20)\t\t\n2\t19 (66)\t13 (56)\t14 (47)\t\t\n3\t4 (14)\t5 (22)\t3 (10)\t\t\nMetastatic disease (%)\t2 (7)\t19 (83)\t6 (20)\t<.001\t\nOverall stage at diagnosis (%)\t\t\t\t<.001\t\nI\t0\t2 (9)\t1 (3)\t\t\nII\t2 (7)\t1 (4)\t4 (13)\t\t\nIII\t25 (86)\t1 (4)\t19 (63)\t\t\nIV\t2 (7)\t19 (83)\t6 (20)\t\t\na Continuous variables are presented as median (range).\n\nb Other histologies included adenosquamous (n = 1), carcinoid (n = 1), large cell (n = 2), and poorly differentiated non‐small cell lung cancer (n = 6).\n\nAbbreviations: COPD, chronic obstructive pulmonary disease; DLCO, diffusing capacity for carbon monoxide; ECOG, Eastern Cooperative Oncology Group; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; ICI, immune checkpoint inhibitor; ILD, interstitial lung disease; RT, radiotherapy.\n\nBaseline characteristics, including age, gender, performance status, smoking history, pre‐existing COPD diagnosis, pretreatment lung function, and tumor T and N stages were similar among patients who received RT alone, ICI alone and RT + ICI. Patients in the ICI alone group compared with the RT alone or RT + ICI alone group had lower median pack‐year smoking history (25 vs. 40 for RT alone and 38 for RT + ICI; p = .02), higher proportion of adenocarcinoma histology (83% vs. 55% for RT alone and 43% for RT + ICI; p = .04), and higher proportion of metastatic disease at the time of initial diagnosis (83% vs. 7% for RT alone and 20% for RT + ICI; p < .001). The majority of patients in the RT alone (86%) and RT + ICI (63%) groups had stage III disease, whereas the majority of patients in the ICI alone group were stage IV (83%).\n\nTreatment Characteristics\n\nRT and ICI treatment characteristics are summarized in Table 2. All thoracic RT treatments were delivered using intensity‐modulated radiotherapy to a median dose of 62 Gy (range, 45–72). The median lung V20 was 25% (range, 14%–41%), and the median MLD was 15.0 Gy (range, 8.6–21.7 Gy). RT doses to the normal lungs were lower in the RT + ICI group compared with the RT alone group (Table 1; median lung V20, 24% vs. 28%; p = .03; MLD: 13.5 vs. 16.1 Gy; p = .02). This may be related to improvement in treatment planning, as the majority of patients who received RT alone (59%) completed RT in or before the year 2014, whereas the majority in the RT + ICI group completed RT after 2014 (70%).\n\nTable 2 Treatment characteristics and clinical features of pneumonitis\n\nCharacteristics\tRT alone\tICI alone\tRT + ICI\tp value\t\nNumber of patients\t29\t23\t30\t\t\nThoracic RTa\t\t\t\t\t\nPrescription dose (Gy)\t61.2 (45–72)\tNA\t63 (52.5–66.6)\t.57\t\nLung V20 (% total lung)\t28 (17–41)\tNA\t24 (14–37)\t.03\t\nMean lung dose (Gy)\t16.1 (9.6–21.7)\tNA\t13.5 (8.6–18.9)\t.02\t\nICI type (%)\tNA\t\t\t.01\t\nNivolumab\tNA\t16 (70)\t13 (43)\t\t\nPembrolizumab\tNA\t3 (13)\t3 (10)\t\t\nIpilimumab‐Nivolumab\tNA\t4 (17)\t3 (10)\t\t\nDurvalumab\tNA\t0\t11 (37)\t\t\nInterval between RT and ICI, mo\tNA\tNA\t4.5 (0.4–48.1)\tNA\t\nOther treatments, n (%)\t\t\t\t\t\nChemotherapy\t15 (65)\t28 (97)\t29 (97)\t.001\t\nThoracic surgery\t4 (17)\t8 (28)\t6 (20)\t.67\t\nTime to pneumonitis onset, moa\t3.1 (0.4–12.0)\t2.7 (0.1–17.5)\t1.2 (0.1–34.3)\t.12\t\nPneumonitis grade (%)\t\t\t\t.59\t\n1\t0\t2 (9)\t1 (3)\t\t\n2\t19 (66)\t12 (52)\t19 (63)\t\t\n3\t9 (31)\t6 (26)\t7 (23)\t\t\n4\t1 (3)\t3 (13)\t3 (10)\t\t\na Continuous variables are presented as median (range).\n\nAbbreviations: ICI, immune checkpoint inhibitor; RT, radiotherapy; V20, volume of the lung receiving 20 Gy or higher.\n\nPatients who received ICI were treated with a variety of agents, including nivolumab (55%), durvalumab (21%), pembrolizumab (11%), or a combination of ipilimumab and nivolumab (13%). All patients in the RT + ICI group initiated ICI after completion of RT. The median time from RT completion to ICI initiation was 4.5 months (range, 0.4–48.1). Among patients who received ICI alone, 83% were treated with an anti–programmed death 1 (PD‐1; nivolumab or pembrolizumab) and 17% received combined anti–cytotoxic T‐lymphocyte antigen 4 (CTLA‐4)/PD‐1 antibodies. In contrast, 53% of patients in the RT + ICI group received an anti–PD‐1 antibody, 37% received anti–programmed death ligand 1 antibody (durvalumab), and 10% received combined anti–CTLA‐4/PD‐1 (Table 2).\n\nClinical Features of Pneumonitis\n\nThe median time to pneumonitis onset was 2.6 months (range, 0.1–34.3) in the entire cohort. There was a trend toward more rapid onset of pneumonitis in patients receiving RT + ICI (median time of onset 1.2 months, range 0.1–34.3), compared with patients who received RT (median onset 3.1 months, range 0.4–12.0) or ICI alone (median onset 2.7 months, range 0.1–17.5; p = .12). The majority of pneumonitis were grade 2 (61%) or grade 3 (27%). There was no significant difference in pneumonitis grades among the three groups (Table 2).\n\nMorphologic Features of RT‐ Versus ICI‐Pneumonitis\n\nFigure 1 demonstrates representative CT images of RT‐ and ICI‐pneumonitis. RT‐pneumonitis often centered on the lung ipsilateral to the primary tumor and had sharp border (arrowheads) after RT alone (Fig. 1A). In contrast, ICI‐pneumonitis was often bilateral, involving multiple lobes, and without sharp border in patients treated with ICIs alone (Fig. 1B). Among patients who received both RT and ICIs, some (Fig. 1C) were confined to the ipsilateral lung with sharp borders similar to RT‐pneumonitis, while others (Fig. 1D) resembled the bilateral distribution of typical ICI‐pneumonitis.\n\nFigure 1 Representative computed tomography (CT) images of RT‐pneumonitis (A), ICI‐pneumonitis (B), and pneumonitis after RT + ICI (C, D). (A): A 66‐year‐old patient with stage IIIA adenocarcinoma of the left upper lobe (LUL) developed RT‐pneumonitis 1.4 months after completing thoracic RT. CT changes included focal consolidation with a sharp border (arrowheads) in the lung ipsilateral to the primary tumor. (B): A 68‐year‐old patient with a stage IV adenocarcinoma of the right lower lobe developed ICI‐pneumonitis 3.7 months after initiating nivolumab. CT changes included bilateral, multifocal ground‐glass opacities (GGOs) without sharp border. (C): A 68‐year‐old patient with stage IIIA adenocarcinoma of the right upper lobe developed RT‐pneumonitis 2.6 months after completing RT and initiating durvalumab. CT changes included focal GGOs and consolidation with a sharp border (arrowheads) in the ipsilateral lung, resembling RT‐pneumonitis. (D): A 62‐year‐old patient with stage IIIA squamous cell carcinoma of the LUL developed ICI‐pneumonitis 0.8 months after completing RT and initiating durvalumab. CT changes included bilateral, multifocal GGOs without sharp border, resembling ICI‐pneumonitis. Abbreviations: ICI, immune checkpoint inhibitor; RT, radiotherapy.\n\nTable 3 summarizes the seven morphologic features of RT‐ and ICI‐pneumonitis. In patients who developed ICI‐pneumonitis after ICIs alone compared with patients who developed RT‐pneumonitis after RT alone, ICI‐pneumonitis was more likely bilateral (65 vs. 28%; p = .01), involved more lobes of the lung (66% vs. 45% involving three or more lobes; p = .02), and was less likely to have sharp border (17% vs. 59%; p = .004). There was a trend of ICI‐pneumonitis involving greater volume of the lung (52% ICI vs. 45% RT involving ≥25% lung volume; p = .25). Specific CT elements (most commonly GGOs and/or consolidations) and radiographic patterns (most commonly AIP/ARDS or COP) were not significantly different between RT‐ and ICI‐pneumonitis.\n\nTable 3 Morphologic features of RT‐ versus ICI‐pneumonitis\n\nFeatures\tRT alone\tICI alone\tp valuea (RT vs. ICI)\tRT + ICI\tp valuea (RT + ICI vs. RT alone)\tp valuea (RT + ICI vs. ICI alone)\t\nn\t29\t23\t\t30\t\t\t\nBilateral\t8 (28)\t15 (65)\t.01\t14 (47)\t.57\t.06\t\nNumber of lobes\t\t\t.02\t\t.87\t.01\t\n1\t5 (17)\t5 (22)\t\t4 (13)\t\t\t\n2\t11 (38)\t3 (13)\t\t15 (50)\t\t\t\n3\t8 (28)\t3 (13)\t\t6 (20)\t\t\t\n4\t3 (10)\t2 (9)\t\t2 (7)\t\t\t\n5\t2 (7)\t10 (44)\t\t3 (10)\t\t\t\nVolume of lung involved\t\t\t.25\t\t.70\t.07\t\n<5%\t2 (7)\t3 (13)\t\t1 (3)\t\t\t\n5%–25%\t14 (48)\t8 (35)\t\t19 (63)\t\t\t\n25%–50%\t10 (35)\t6 (26)\t\t8 (27)\t\t\t\n>50%\t3 (10)\t6 (26)\t\t2 (7)\t\t\t\nMultifocal\t21 (72)\t17 (74)\t.99\t22 (73)\t1.00\t.99\t\nRadiographic elements\t\t\t.44\t\t.31\t.34\t\nGGO\t11 (38)\t9 (39)\t\t7 (23)\t\t\t\nConsolidation\t12 (41)\t10 (44)\t\t11 (37)\t\t\t\nGGO + cons\t6 (21)\t3 (13)\t\t10 (33)\t\t\t\nNodules\t0\t1 (4)\t\t2 (7)\t\t\t\nRadiographic pattern\t\t\t.53\t\t.50\t.49\t\nAIP/ARDS\t12 (46)\t11 (52)\t\t8 (30)\t\t\t\nCOP\t12 (46)\t8 (38)\t\t14 (52)\t\t\t\nFibrosis\t2 (8)\t0\t\t2 (7)\t\t\t\nCOP + fibrosis\t0\t1 (5)\t\t1 (4)\t\t\t\nHP\t0\t1 (5)\t\t2 (7)\t\t\t\nSharp border\t17 (59)\t4 (17)\t.004\t12 (40)\t.20\t.13\t\nData are presented as n (%).\n\na p values from Fisher's exact tests.\n\nAbbreviations: AIP/ARDS, acute interstitial pneumonia/acute respiratory distress syndrome; cons, consolidation; COP, cryptogenic organizing pneumonia; GGO, ground‐glass opacity; HP, hypersensitivity pneumonitis; ICI, immune checkpoint inhibitor; RT, radiotherapy.\n\nTable 4 Factors associated with higher‐grade (grade 3–4) pneumonitis\n\nVariables\tOverall cohort\tRT + ICI\t\nGrade 1–2\tGrade 3–4\tp value\tGrade 1–2\tGrade 3–4\tp value\t\nn (%)\t53 (65)\t29 (35)\t\t20 (67)\t10 (33)\t\t\nAgea\t69 (45–84)\t68 (48–80)\t.77\t69 (56–82)\t66 (49–77)\t.57\t\nECOG performance scoreb\t\t\t.01\t\t\t.56\t\n0\t13 (24)\t1 (3)\t\t4 (20)\t1 (10)\t\t\n1\t38 (72)\t24 (83)\t\t15 (75)\t7 (70)\t\t\n2\t2 (4)\t4 (14)\t\t1 (5)\t2 (20)\t\t\nSmoking historyb\t\t\t.007\t\t\t.10\t\nCurrent smoker\t6 (11)\t7 (24)\t\t3 (15)\t5 (50)\t\t\nFormer smoker\t35 (66)\t22 (76)\t\t14 (70)\t5 (50)\t\t\nNever smoker\t12 (23)\t0\t\t3 (15)\t0\t\t\nPack‐year smokeda\t30 (0–110)\t40 (10–100)\t.03\t32 (0–110)\t50 (10–100)\t.14\t\nHistory of autoimmune diseasea\t2 (4)\t3 (10)\t.37\t1 (5)\t1 (10)\t.56\t\nPretreatment lung functiona\t\t\t\t\t\t\t\nFEV1, L\t\t\t\t\t\t.70\t\n% FEV1 predicted\t\t\t\t\t\t.38\t\nFVC, L\t\t\t\t\t\t.53\t\n% FVC predicted\t\t\t\t\t\t.53\t\nHistologya\t\t\t.84\t\t\t.65\t\nAdenocarcinoma\t32 (60)\t16 (55)\t\t10 (50)\t3 (30)\t\t\nSquamous cell carcinoma\t15 (28)\t9 (31)\t\t8 (40)\t5 (50)\t\t\nOther\t6 (11)\t4 (14)\t\t2 (10)\t2 (20)\t\t\nInitial stageb\t\t\t.79\t\t\t.44\t\nI\t3 (6)\t0\t\t1 (5)\t0\t\t\nII\t4 (8)\t3 (10)\t\t2 (10)\t2 (20)\t\t\nIII\t29 (55)\t16 (55)\t\t12 (60)\t7 (70)\t\t\nIV\t17 (32)\t10 (35)\t\t5 (25)\t1 (10)\t\t\nRadiation dosimetrya\t(n = 39)\t(n = 20)\t\t\t\t\t\nV20 (% total lung)\t25 (17–41)\t26 (14–35)\t0.99\t24 (17–37)\t21 (14–32)\t.67\t\nMLD (Gy)\t15.0 (8.9–21.7)\t15.7 (8.6–20.0)\t.56\t13.2 (8.9–18.9)\t15.0 (8.6–18.4)\t.53\t\nType of ICIb\t(n = 34)\t(n = 19)\t.74\t\t\t.46\t\nNivolumab\t17 (50)\t12 (63)\t\t9 (45)\t4 (40)\t\t\nPembrolizumab\t5 (15)\t1 (5)\t\t3 (15)\t0\t\t\nIpilimumab‐nivolumab\t5 (15)\t2 (11)\t\t1 (5)\t2 (20)\t\t\nDurvalumab\t7 (20)\t4 (21)\t\t7 (35)\t4 (40)\t\t\nBilateral CT changesb\t13 (24)\t18 (62)\t.002\t4 (20)\t6 (60)\t.04\t\nMultifocal CT changesb\t32 (60)\t28 (97)\t<.001\t12 (60)\t10 (100)\t.03\t\nInvolving three or more lobesb\t19 (36)\t20 (69)\t.006\t5 (25)\t6 (60)\t.11\t\nInvolving ≥25% lung volumeb\t15 (28)\t20 (69)\t<.001\t5 (25)\t5 (50)\t.23\t\nGGO componentb , c\t24 (45)\t22 (76)\t.01\t10 (50)\t7 (70)\t.44\t\nAIP/ARDS patternb\t15 (28)\t16 (55)\t.01\t4 (20)\t4 (40)\t.18\t\nSharp borderb\t28 (53)\t21 (72)\t.10\t13 (65)\t5 (50)\t.46\t\na Median (range). p values from Wilcoxon rank sum tests.\n\nb Number of patients (%). p values from Fisher's exact tests.\n\nc Including cases with GGO or GGO plus consolidations.\n\nAbbreviations: AIP/ARDS, acute interstitial pneumonia/acute respiratory distress syndrome; ECOG, Eastern Cooperative Oncology Group; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; GGO, ground‐glass opacity; ICI, immune checkpoint inhibitor; MLD, mean lung dose; RT, radiotherapy; V20, volume of lung receiving at least 20 Gy.\n\nIn aggregate, pneumonitis CT morphology in the RT + ICI group had features of both RT‐pneumonitis and ICI‐pneumonitis. Forty‐seven percent of pneumonitis in the RT + ICI group was bilateral, 37% involved three or more lobes of the lung, 34% involved ≥25% lung volume, and 40% had sharp borders. Similar to RT‐pneumonitis, pneumonitis after RT + ICI involved fewer lobes than ICI‐pneumonitis (p = .01) and trended toward lower likelihood of bilateral involvement (p = .06), involving lower volume of the lung (p = .07) and higher likelihood of having sharp borders (p = .13) than pneumonitis from ICI alone.\n\nFactors Associated with Higher‐Grade Pneumonitis\n\nTo explore the clinical and morphologic features associated with pneumonitis severity, we performed univariable analyses by dichotomizing pneumonitis severity into lower grade (grade 1–2) and higher grade (grade 3–4, Table 4). In the entire cohort, patients with grade 3–4 pneumonitis had worse baseline Eastern Cooperative Oncology Group performance score (p = .01), higher likelihood of being current or former smokers (100% vs. 77%; p = .007), higher pack‐year smoking history (median 40 vs. 30 pack‐years; p = .03), and lower FEV1 (median 1.48 vs. 1.94 L; p = .03; median 67% vs. 79% predicted; p = .01) and FVC (median 2.41 vs. 2.73 L; p = .04; median 79% vs. 91% predicted; p = .03) when compared with patients with grade 1–2 pneumonitis. In evaluating morphologic features among all patients, patients with grade 3–4 pneumonitis were more likely to have bilateral changes (62% vs. 24%; p = .002), multifocal involvement (97% vs. 60%; p < .001), involvement of three or more lobes (69% vs. 36%; p = .006), involvement of 25% or greater volume of the lung (69% vs. 28%; p < .001), demonstrating GGO component (76% vs. 45%; p = .01), and having an AIP/ARDS pattern (55% vs. 28%; p = .01) when compared with patients with grade 1–2 pneumonitis. Among the subset of patients who received both thoracic RT and ICIs, patients with grade 3–4 pneumonitis trended toward having more extensive smoking history (100% vs. 85% being current or former smokers; p = .10; median 50 vs. 32 pack‐years smoked; p = .14), and were more likely to have bilateral (60% vs. 20%; p = .04) and multifocal (100% vs. 60%; p = .03) CT changes compared with patients with grade 1–2 pneumonitis. Grade 3–4 pneumonitis was not associated with age, histology, stage, lung V20, MLD, or the type of ICI in either the overall cohort or the RT + ICI group.\n\nRadiomics and Machine Learning\n\nWe developed an exploratory ML model to classify pneumonitis etiology based on quantitative radiomic features alone, without the input of CT morphologic features, prior RT field, or the timing of onset. Supplemental online Table 3 lists the seven radiomic features selected for the model. Similar to morphologic exams, pneumonitis after RT + ICI exhibited intermediate radiomic features compared with the RT alone and ICI alone groups. Two radiomic features were similar between pure RT‐pneumonitis and pneumonitis after receipt of RT + ICI, which were significantly or near significantly different from ICI‐pneumonitis. Conversely, four radiomic features were similar between pure ICI‐pneumonitis and pneumonitis after receipt of RT + ICI, which were significantly or near significantly different from RT‐pneumonitis. Supplemental online Figure 1A–D demonstrates the differences in contralateral neighboring gray tone difference matrix (NGTDM) contrast in the same patients as Figure 1A–D. NGTDM contrast measures differences in CT density between each voxel and its surrounding voxels, and higher values suggest greater tissue heterogeneity and pathology [26, 27]. ICI‐pneumonitis (supplemental online Fig. 1B) had higher NGTDM contrast values than RT‐pneumonitis (supplemental online Fig. 1A), which was recapitulated by the difference between two patients with pneumonitis after RT + ICI (supplemental online Fig. 1D vs. 1C).\n\nFigure 2A demonstrates the receiver‐operating characteristics of the final ML model in the RT or ICI alone groups, with an area under the curve of 0.76 (95% confidence interval, 0.63–0.90). To test whether this model could identify the predominant etiology of pneumonitis after RT + ICI, we applied the ML model to the RT + ICI group of patients and compared the model prediction in each case to the attribution determined by the multidisciplinary consensus. As shown in Figure 2B, the height of each bar represents the likelihood of ICI being the predominant etiology of pneumonitis in each patient, as predicted by the ML model. The patients for whom ICI was the most likely etiology by consensus also tended to have higher likelihood predicted by the ML model (black bars clustering toward the right side of the graph), while those less likely to be caused by ICI (more likely RT) by consensus also had lower likelihood predicted by the model (gray bars clustering toward the left side of the graph).\n\nFigure 2 Radiomics‐based machine learning model for distinguishing ICI‐ from RT‐pneumonitis. (A): Receiver‐operating characteristics (ROC) of the model in patients who received RT or ICI alone. The gray areas indicate 95% confidence intervals of the ROC. (B): Model prediction of the likelihood (least to most likely from 0 to 1) of ICI etiology in each patient (individual bars) who developed pneumonitis after RT + ICI (n = 30). The color of each bar represents the attribution by multidisciplinary consensus (gray for RT etiology, black for ICI etiology). Abbreviations: ICI, immune checkpoint inhibitor; ML, machine learning; RT, radiotherapy.\n\nDiscussion\n\nTo our knowledge, this is the first study in which pneumonitis due to different etiologies, including RT, ICI, and potentially combination of the two in patients who received both, are systematically compared. Our findings have potential implications in directing the treatment for pneumonitis in patients with NSCLC, as well as in understanding the pathogenesis of pneumonitis in patients who receive both RT and ICI. First, RT‐ and ICI‐pneumonitis share similar CT elements (both commonly presenting as GGOs and/or consolidations) and patterns (often AIP/ARDS or COP) but differ in their spatial distribution in that ICI‐pneumonitis tends to be bilateral, more likely to involve more lobes of the lung, and less likely to have sharp borders. Second, as a group, patients who develop pneumonitis after receipt of both RT and ICI exhibit an intermediate phenotype between RT‐ and ICI‐pneumonitis in both morphologic and radiomic features, suggesting that both RT and ICI may contribute to the development of pneumonitis in this group. However, it should be noted that this is a heterogeneous group with some patients more closely resembling RT‐pneumonitis and others ICI‐pneumonitis (Fig. 1 and supplemental Fig. 1). Therefore, one etiology may play a more significant role in the development of pneumonitis than the other in a particular patient. The biologic underpinning of such differences in pneumonitis pathogenesis remains to be determined. Nevertheless, treatment of pneumonitis after RT + ICI may need to be individualized to take into account of the predominant etiology.\n\nThe number of patients who develop pneumonitis after RT and ICIs is increasing because of the expanding indications for both thoracic RT and ICIs in patients with NSCLC [7, 14, 28]. The incidence of pneumonitis in patients with locally advanced NSCLC after definitive chemoradiotherapy and ICIs may be as high as 34% [29]. The treatment algorithms and natural histories differ dramatically between RT‐ and ICI‐pneumonitis. Patients with RT‐pneumonitis are often treated with a lower dose of steroids (40–60 mg prednisone per day) for a shorter duration of time, whereas those with ICI‐pneumonitis require high‐dose steroids (1–2 mg prednisone per kg per day) for a prolonged period [13]. High‐grade, steroid refractory ICI‐pneumonitis can develop in as many as 18% of patients and may require intravenous immunoglobulin or other immunosuppressive agents such as mycophenolate mofetil or infliximab [13, 30]. In addition, patients with ICI‐pneumonitis are at a higher risk of recrudescence when rechallenged with ICIs, while ICI rechallenge might be less problematic in patients whose pneumonitis is mainly due to RT [31]. Therefore, identifying the predominant etiology responsible for pneumonitis development after RT + ICI may help to triage patients toward the best treatment pathway.\n\nDespite the clinical need to better define pneumonitis etiology, there is no consensus to guide the distinction of pneumonitis etiology after receipt of both RT and ICIs. Traditional clinical factors, such as the timing of onset and RT dose distribution are two of the most commonly used criteria, but it requires multidisciplinary input from all members of the treatment team, and the results can still be ambiguous in many cases [9, 12]. In our own cohort, initial classification of pneumonitis etiology by two of the authors was only concordant in 63% of cases, even with the full medical, imaging, and treatment history available, which may be partly due to contributions from both RT and ICIs in pneumonitis development. The morphologic features identified in this study, namely laterality, number of lobes involved, and sharp border, may help refine the attribution of the predominant pneumonitis etiology in patients receiving RT + ICI, thereby facilitating treatment decision‐making in this patient population.\n\nRadiomics and ML may play an increasingly active role in assisting human readers and evaluating CT scans in patients with NSCLC. Our results demonstrate the feasibility of using unbiased radiomic features, instead of qualitative morphologic features, to distinguish pneumonitis etiology. Previous studies have shown promising results of radiomics in predicting pneumonitis risk after RT or ICI [18, 19, 20, 21]. However, these studies did not differentiate between RT‐ and ICI‐pneumonitis and did not include patients treated with RT + ICI. In this study, we identified high post‐treatment NGTDM contrast in the contralateral lung as a potential biomarker for ICI‐pneumonitis. NGTDM contrast may help differentiate normal versus malignant tissues and predict treatment response in NSCLC, head and neck cancer, rectal cancer, and multiple myeloma [26, 27, 34, 35, 36]. Interestingly, in a retrospective study of 43 patients with triple‐negative breast cancer, higher NGTDM contrast on mammography was associated with a higher number of tumor‐infiltrating lymphocytes [27]. Lymphocytes are central to the pathogenesis of ICI‐pneumonitis. The link between NGTDM contrast and lymphocyte infiltration may provide a plausible mechanism for the morphologic findings of pneumonitis after ICIs or RT + ICI [37, 38].\n\nThis study also contributes to our understanding of the risk factors for severe pneumonitis. Grade 3–4 pneumonitis was associated with worse baseline performance status, greater smoking history, and lower pretreatment lung function, in particular, FEV1 and FVC. This is consistent with previous findings that pretreatment FEV1 is associated with severe radiation pneumonitis [5, 39]. Radiation dose to the lung, in particular V20 and MLD, were not associated with pneumonitis severity in our cohort of patients who received RT or RT + ICI, possibly because of the small sample size and heterogeneity in disease stage. Among the imaging features, bilateral and multifocal involvement were significantly associated with severe pneumonitis in both the overall cohort and among patients who received RT + ICI. Similarly, previous studies have identified bilateral involvement as a risk factor for both fatal RT‐pneumonitis and steroid refractory ICI‐pneumonitis [30, 40]. These clinical and imaging risk factors may assist in the identification of patients with NSCLC with pneumonitis who may be at high risk of clinical deterioration and may require treatment intensification for pneumonitis.\n\nThe main caveat of this study is the small cohort size. However, the size of our study population is on par with previous reports in this area [3, 5, 9]. As such, we were not able to perform multivariable analysis on the risk factors for higher‐grade pneumonitis because of the small sample size. Future prospective studies with larger patient cohorts should be conducted to independently validate the imaging biomarkers and risk factors identified in this study. Further research is also needed to better characterize the temporal evolution of the imaging findings of pneumonitis, which may serve as early biomarkers for patients who are at risk of clinical deterioration and may require escalation of pneumonitis treatments. Finally, mechanistic studies combining imaging and serum biomarkers, such as interleukin‐8 and chemotactic cytokine ligand 2, may elucidate the underlying etiology of pneumonitis after RT + ICI and identify novel therapeutic targets [39, 40, 41, 42, 43].\n\nConclusion\n\nIn a cohort of patients with NSCLC treated with definitive dose of thoracic RT and/or ICIs, RT‐pneumonitis is more likely to be unilateral, involve fewer lobes of the lung, and have sharp border, whereas ICI‐pneumonitis tends to be bilateral and involve more lobes and is less likely to have sharp border. Patients who develop pneumonitis after both RT and ICI have heterogeneous morphologic presentations, with features overlapping with both RT‐ and ICI‐pneumonitis. Poor performance status, greater smoking history, lower pretreatment lung function, and bilateral and multifocal involvement on CT are risk factors associated with severe pneumonitis. Lastly, an exploratory radiomics‐based ML model can identify the predominant pneumonitis etiology in patients who received RT + ICI with good concordance with the clinical impression of a multidisciplinary group of physicians. Future studies with larger patient cohorts are needed to validate these findings.\n\nAuthor Contributions\n\nConception/design: Xuguang Chen, Khinh Ranh Voong\n\nProvision of study material or patients: Russell K. Hales, Patrick M. Forde, Jarushka Naidoo, Khinh Ranh Voong\n\nCollection and/or assembly of data: Xuguang Chen, Khadija Sheikh, Erica Nakajima, Cheng Ting Lin, Junghoon Lee\n\nData analysis and interpretation: Xuguang Chen, Khadija Sheikh, Cheng Ting Lin, Chen Hu\n\nManuscript writing: Xuguang Chen, Khinh Ranh Voong\n\nFinal approval of manuscript: Xuguang Chen, Khadija Sheikh, Erica Nakajima, Cheng Ting Lin, Junghoon Lee, Chen Hu, Russell K. Hales, Patrick M. Forde, Jarushka Naidoo, Khinh Ranh Voong\n\nDisclosures\n\nJunghoon Lee: Canon Medical Systems (RF); Chen Hu: Merck (H); Russell K. Hales: Genentech (RF); Patrick M. Forde: Bristol‐Myers Squibb, AstraZeneca, Kyowa‐Kirin, Novartis (RF); Bristol‐Myers Squibb, AstraZeneca, Novartis, Merck, EMD, AbbVie, Inivata (H); Jarushka Naidoo: Merck, AstraZeneca (RF); Merck, AstraZeneca, Bristol‐Myers Squibb (C/A); Merck, AstraZeneca, Bristol‐Myers Squibb (H). The other authors indicated no financial relationships.\n\n(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board\n\nSupporting information\n\nSee http://www.TheOncologist.com for supplemental material available online.\n\nSupplementary Figure 1 RT vs. ICI‐pneumonitis have different NGTDM Contrast values. Magnified view of the lung contralateral to the primary tumor on CT scans at the time of pneumonitis. Panels A‐D correspond to Figure 1A‐1D, respectively. Neighborhood gray tone difference matrix (NGTDM) Contrast values: A, 0.06; B, 0.21; C, 0.04; D, 0.16.\n\nClick here for additional data file.\n\nSupplementary Table 1 CT Scan Parameters (Median [Range])\n\nSupplementary Table 2. Radiomic Features Extracted from Each CT Set\n\nSupplementary Table 3. Select Radiomic Features of RT vs ICI‐Pneumonitis (Mean ± Standard Deviation)\n\nClick here for additional data file.\n\nAcknowledgment\n\nOpen access funding enabled and organized by Projekt DEAL.\n\nOpen access funding enabled and organized by Projekt DEAL.\n==== Refs\nReferences\n\n1 KoEC, RabenD, FormentiSC. The integration of radiotherapy with immunotherapy for the treatment of non‐small cell lung cancer. Clin Cancer Res 2018;24 :5792–5806.29945993\n2 LiM, GanL, SongA et al. Rethinking pulmonary toxicity in advanced non‐small cell lung cancer in the era of combining anti‐PD‐1/PD‐L1 therapy with thoracic radiotherapy. Biochim Biophys Acta Rev Cancer 2019 ; 1871:323–330.\n3 NishinoM, RamaiyaNH, AwadMM et al. PD‐1 inhibitor‐related pneumonitis in advanced cancer patients: Radiographic patterns and clinical course. Clin Cancer Res 2016;22 :6051–6060.27535979\n4 NaidooJ, WangX, WooKM et al. Pneumonitis in patients treated with anti‐programmed death‐1/programmed death ligand 1 therapy. J Clin Oncol 2017;35 :709–717.27646942\n5 ThomasR, ChenYH, HatabuH et al. Radiographic patterns of symptomatic radiation pneumonitis in lung cancer patients: Imaging predictors for clinical severity and outcome. Lung Cancer 2020;145 :132–139.32447116\n6 GomezDR, BlumenscheinGRJr, LeeJJ et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non‐small‐cell lung cancer without progression after first‐line systemic therapy: A multicentre, randomised, controlled, phase 2 study. Lancet Oncol 2016;17 :1672–1682.27789196\n7 FriedesC, MaiN, HazellS et al. Consolidative radiotherapy in oligometastatic lung cancer: Patient selection with a prediction nomogram. Clin Lung Cancer 2020;21 :e622–e632.32624411\n8 VoongKR, HazellSZ, FuW et al. Relationship between prior radiotherapy and checkpoint‐inhibitor pneumonitis in patients with advanced non‐small‐cell lung cancer. Clin Lung Cancer 2019;20 :e470–e479.31031204\n9 CousinF, DesirC, Ben MustaphaS et al. Incidence, risk factors, and CT characteristics of radiation recall pneumonitis induced by immune checkpoint inhibitor in lung cancer. Radiother Oncol 2021;157 :47–55.33453313\n10 BarrónF, SánchezR, Arroyo‐HernándezM et al. Risk of developing checkpoint immune pneumonitis and its effect on overall survival in non‐small cell lung cancer patients previously treated with radiotherapy. Front Oncol 2020;10 :570233.33117699\n11 ParkH, HatabuH, RicciutiB et al. Immune‐related adverse events on body CT in patients with small‐cell lung cancer treated with immune‐checkpoint inhibitors. Eur J Radiol 2020;132 :109275.32949913\n12 VoongKR, NaidooJ. Radiation pneumonitis after definitive chemoradiation and durvalumab for non‐small cell lung cancer. Lung Cancer 2020;150 :249–251.32958455\n13 DarnellEP, MooradianMJ, BaruchEN et al. Immune‐related adverse events (irAEs): Diagnosis, management, and clinical pearls. Curr Oncol Rep 2020;22 :39.32200442\n14 AntoniaSJ, VillegasA, DanielD et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med 2018;379 :2342–2350.30280658\n15 BrahmerJ, ReckampKL, BaasP et al. Nivolumab versus docetaxel in advanced squamous‐cell non‐small‐cell lung cancer. N Engl J Med 2015;373 :123–135.26028407\n16 LambinP, LeijenaarRTH, DeistTM et al. Radiomics: The bridge between medical imaging and personalized medicine. Nat Rev Clin Oncol 2017;14 :749–762.28975929\n17 KocherM, RugeMI, GalldiksN et al. Applications of radiomics and machine learning for radiotherapy of malignant brain tumors. Strahlenther Onkol 2020;196 :856–867.32394100\n18 ColenRR, FujiiT, BilenMA et al. Radiomics to predict immunotherapy‐induced pneumonitis: Proof of concept. Invest New Drugs 2018;36 :601–607.29075985\n19 CunliffeA, ArmatoSG, CastilloR et al. Lung texture in serial thoracic computed tomography scans: Correlation of radiomics‐based features with radiation therapy dose and radiation pneumonitis development. Int J Radiat Oncol Biol Phys 2015;91 :1048–1056.25670540\n20 LunaJM, ChaoHH, DiffenderferES et al. Predicting radiation pneumonitis in locally advanced stage II‐III non‐small cell lung cancer using machine learning. Radiother Oncol 2019;133 :106–112.30935565\n21 MoranA, DalyME, YipSSF et al. Radiomics‐based assessment of radiation‐induced lung injury after stereotactic body radiotherapy. Clin Lung Cancer 2017;18 :e425–e431.28623121\n22 ParkKJ, ChungJY, ChunMS et al. Radiation‐induced lung disease and the impact of radiation methods on imaging features. Radiographics 2000;20 :83–98.10682774\n23 ChoiYW, MundenRF, ErasmusJJ et al. Effects of radiation therapy on the lung: Radiologic appearances and differential diagnosis. Radiographics 2004;24 :985–997; discussion 998.15256622\n24 van GriethuysenJJM, FedorovA, ParmarC et al. Computational radiomics system to decode the radiographic phenotype. Cancer Res 2017;77 :e104–e107.29092951\n25 SheikhK, LeeSH, ChengZ et al. Predicting acute radiation induced xerostomia in head and neck cancer using MR and CT Radiomics of parotid and submandibular glands. Radiat Oncol 2019;14 :131.31358029\n26 YuH, CaldwellC, MahK et al. Coregistered FDG PET/CT‐based textural characterization of head and neck cancer for radiation treatment planning. IEEE Trans Med Imaging 2009;28 :374–383.19244009\n27 YuH, MengX, ChenH et al. Correlation between mammographic radiomics features and the level of tumor‐infiltrating lymphocytes in patients with triple‐negative breast cancer. Front Oncol 2020;10 :412.32351879\n28 GomezDR, TangC, ZhangJ et al. Local consolidative therapy vs. maintenance therapy or observation for patients with oligometastatic non‐small‐cell lung cancer: Long‐term results of a multi‐institutional, phase II, randomized study. J Clin Oncol 2019;37 :1558–1565.31067138\n29 AntoniaSJ, VillegasA, DanielD et al. Durvalumab after chemoradiotherapy in stage III non‐small‐cell lung cancer. N Engl J Med 2017;377 :1919–1929.28885881\n30 BalajiA, HsuM, LinCT et al. Steroid‐refractory PD‐(L)1 pneumonitis: Incidence, clinical features, treatment, and outcomes. J Immunother Cancer 2021;9 :e001731.33414264\n31 DolladilleC, EderhyS, SassierM et al. Immune checkpoint inhibitor rechallenge after immune‐related adverse events in patients with cancer. JAMA Oncol 2020;6 :865–871.32297899\n32 LovinfosseP, PolusM, Van DaeleD et al. FDG PET/CT radiomics for predicting the outcome of locally advanced rectal cancer. Eur J Nucl Med Mol Imaging 2018;45 :365–375.29046927\n33 ChenS, HarmonS, PerkT et al. Using neighborhood gray tone difference matrix texture features on dual time point PET/CT images to differentiate malignant from benign FDG‐avid solitary pulmonary nodules. Cancer Imaging 2019;19 :56.31420006\n34 EkertK, HinterleitnerC, BaumgartnerK et al. Extended texture analysis of non‐enhanced whole‐body MRI image data for response assessment in multiple myeloma patients undergoing systemic therapy. Cancers (Basel) 2020;12 :761.\n35 SureshK, NaidooJ, ZhongQ et al. The alveolar immune cell landscape is dysregulated in checkpoint inhibitor pneumonitis. J Clin Invest 2019;129 :4305–4315.31310589\n36 ReussJE, SureshK, NaidooJ. Checkpoint inhibitor pneumonitis: Mechanisms, characteristics, management strategies, and beyond. Curr Oncol Rep 2020;22 :56.32415399\n37 RobnettTJ, MachtayM, VinesEF et al. Factors predicting severe radiation pneumonitis in patients receiving definitive chemoradiation for lung cancer. Int J Radiat Oncol Biol Phys 2000;48 :89–94.10924976\n38 KefferS, GuyCL, WeissE. Fatal radiation pneumonitis: Literature review and case series. Adv Radiat Oncol 2019;5 :238–249.32280824\n39 PetitSF, van ElmptWJ, OberijeCJ et al. [18F]fluorodeoxyglucose uptake patterns in lung before radiotherapy identify areas more susceptible to radiation‐induced lung toxicity in non‐small‐cell lung cancer patients. Int J Radiat Oncol Biol Phys 2011;81 :698–705.20884128\n40 CastilloR, PhamN, AnsariS et al. Pre‐radiotherapy FDG PET predicts radiation pneumonitis in lung cancer. Radiat Oncol 2014;9 :74.24625207\n41 ChaudhuriAA, BinkleyMS, RigdonJ et al. Pre‐treatment non‐target lung FDG‐PET uptake predicts symptomatic radiation pneumonitis following Stereotactic Ablative Radiotherapy (SABR). Radiother Oncol 2016;119 :454–460.27267049\n42 YueJ, McKeeverM, SioTT et al. Association of lung fluorodeoxyglucose uptake with radiation pneumonitis after concurrent chemoradiation for non‐small cell lung cancer. Clin Transl Radiat Oncol 2017;4 :1–7.29594201\n43 YuH, WuH, WangW et al. Machine learning to build and validate a model for radiation pneumonitis prediction in patients with non‐small cell lung cancer. Clin Cancer Res 2019;25 :4343–4350.30992302\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1083-7159",
"issue": "26(10)",
"journal": "The oncologist",
"keywords": "Immune checkpoint inhibitor; Immune-related adverse event; Immune-related pneumonitis; Non-small cell lung carcinoma; Radiation pneumonitis",
"medline_ta": "Oncologist",
"mesh_terms": "D002289:Carcinoma, Non-Small-Cell Lung; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D008175:Lung Neoplasms; D011014:Pneumonia; D012189:Retrospective Studies",
"nlm_unique_id": "9607837",
"other_id": null,
"pages": "e1822-e1832",
"pmc": null,
"pmid": "34251728",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article",
"references": "19244009;30935565;33453313;33117699;32280824;31031204;25670540;30280658;32958455;10682774;27789196;27646942;29594201;28975929;28885881;31358029;31420006;20884128;32624411;10924976;28623121;32213834;30992302;32297899;29046927;27535979;29075985;15256622;29945993;32415399;27267049;32200442;33414264;29092951;32949913;31310589;30826426;26028407;32351879;32394100;24625207;32447116;31067138",
"title": "Radiation Versus Immune Checkpoint Inhibitor Associated Pneumonitis: Distinct Radiologic Morphologies.",
"title_normalized": "radiation versus immune checkpoint inhibitor associated pneumonitis distinct radiologic morphologies"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-082366",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IPILIMUMAB"
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{
"abstract": "OBJECTIVE\nTo investigate the complications and clinical outcome of children with acute myeloid leukemia (AML) undergoing mitoxantrone-cytarabine-etoposide (MAE) induction therapy.\n\n\nMETHODS\nA total of 170 children with AML were given MAE induction therapy, and the complications and remission rate were analyzed after treatment.\n\n\nRESULTS\nThe male/female ratio was 1.33:1 and the mean age was 7.4 years (range 1-15 years). Leukocyte count at diagnosis was 29.52×109/L [range (0.77-351)×109/L]. Of all children, 2 had M0-AML, 24 had M2-AML, 2 had M4-AML, 48 had M5-AML, 3 had M6-AML, 7 had M7-AML, 69 had AML with t(8;21)(q22;q22), and 15 had AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22). The most common complication was infection (158/170, 92.9%). Among these 158 patients, 22 (13.9%) had agranulocytosis with pyrexia (with no definite focus of infection), and 136 (86.1%) had definite focus of infection (including bloodstream infection). Other complications included non-infectious diarrhea, bleeding, and drug-induced hepatitis. Treatment-related mortality was observed in 10 children, among whom 8 had severe infection, 1 had multiple organ failure, and 1 had respiratory failure. Remission rate was evaluated for 156 children and the results showed a complete remission rate of 85.3%, a partial remission rate of 4.5%, and a non-remission rate of 10.3%.\n\n\nCONCLUSIONS\nInduction therapy with the MAE regimen helps to achieve a good remission rate in children with AML after one course of treatment. Infection is the main complication and a major cause of treatment-related mortality.",
"affiliations": "Department of Pediatric Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China. xfzhu@ihcams.ac.cn.",
"authors": "Chen|Xiao-Yan|XY|;Ruan|Min|M|;Zhao|Bei-Bei|BB|;Wang|Shu-Chun|SC|;Chen|Xiao-Juan|XJ|;Zhang|Li|L|;Guo|Ye|Y|;Yang|Wen-Yu|WY|;Zou|Yao|Y|;Chen|Yu-Mei|YM|;Zhu|Xiao-Fan|XF|",
"chemical_list": "D003561:Cytarabine; D005047:Etoposide; D008942:Mitoxantrone",
"country": "China",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1008-8830",
"issue": "21(1)",
"journal": "Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics",
"keywords": null,
"medline_ta": "Zhongguo Dang Dai Er Ke Za Zhi",
"mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D002675:Child, Preschool; D003561:Cytarabine; D004334:Drug Administration Schedule; D005047:Etoposide; D005260:Female; D006801:Humans; D007223:Infant; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008942:Mitoxantrone; D012074:Remission Induction",
"nlm_unique_id": "100909956",
"other_id": null,
"pages": "24-28",
"pmc": null,
"pmid": "30675859",
"pubdate": "2019-01",
"publication_types": "D016428:Journal Article",
"references": "24677028;23255301;15514380;20406937;27276561;14586478;27895058;19357394;15310780;16983120;26304895;23471307;29550834;19620491",
"title": "Mitoxantrone-cytarabine-etoposide induction therapy in children with acute myeloid leukemia: a single-center study of complications and clinical outcomes.",
"title_normalized": "mitoxantrone cytarabine etoposide induction therapy in children with acute myeloid leukemia a single center study of complications and clinical outcomes"
} | [
{
"companynumb": "CN-PFIZER INC-2019042739",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYTARABINE"
},
"drugadditional": null,
... |
{
"abstract": "Thyroid storm is a potentially lethal complication of hyperthyroidism with increased thyroid hormones and exaggerated symptoms of thyrotoxicosis. First-line therapy includes methimazole (MMI) or propylthiouracil (PTU) to block production of thyroid hormones as a bridge toward definitive surgical treatment. Untreated thyroid storm has a mortality rate of up to 30%; this is particularly alarming when patients cannot tolerate or fail pharmacotherapy, especially if they cannot undergo thyroidectomy. Therapeutic plasma exchange (TPE) is an ASFA category III indication for thyroid storm, meaning the optimum role of this therapy is not established, and there are a limited number of cases in the literature. Yet TPE can remove T3 and T4 bound to albumin, autoantibodies, catecholamines and cytokines and is likely beneficial for these patients. We report a patient with thyroid storm who could not tolerate PTU, subsequently failed therapy with MMI, and was not appropriate for thyroidectomy. TPE was therefore performed daily for 4 days (1.0 plasma volume with 5% albumin replacement and 2 U of plasma). Over the treatment course, the patient's thyroid hormones normalized and symptoms of thyroid storm largely resolved; his T3 decreased from 2.27 to 0.81 ng/mL (normal 0.8-2.0), T4 decreased from 4.8 to 1.7 ng/mL (0.8-1.8), heart rate normalized, altered mental status improved, and he converted to normal sinus rhythm. He was ultimately discharged in euthyroid state. He experienced no side effects from his TPE procedures. TPE is a safe and effective treatment for thyroid storm when conventional treatments are not successful or appropriate.",
"affiliations": "Transfusion Medicine, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Transfusion Medicine, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Hemapheresis and Transfusion Support (HATS), Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland.;Transfusion Medicine, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.",
"authors": "McGonigle|Andrea M|AM|http://orcid.org/0000-0002-2977-2499;Tobian|Aaron A R|AAR|;Zink|Jennifer L|JL|;King|Karen E|KE|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/jca.21560",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0733-2459",
"issue": "33(1)",
"journal": "Journal of clinical apheresis",
"keywords": "hyperthyroidism; methimazole (MMI); propylthiouracil (PTU); therapeutic apheresis; thionamide; thyrotoxicosis",
"medline_ta": "J Clin Apher",
"mesh_terms": "D001071:Appointments and Schedules; D006801:Humans; D008297:Male; D010951:Plasma Exchange; D016879:Salvage Therapy; D013958:Thyroid Crisis; D016896:Treatment Outcome",
"nlm_unique_id": "8216305",
"other_id": null,
"pages": "113-116",
"pmc": null,
"pmid": "28608527",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Perfect storm: Therapeutic plasma exchange for a patient with thyroid storm.",
"title_normalized": "perfect storm therapeutic plasma exchange for a patient with thyroid storm"
} | [
{
"companynumb": "PHHY2018US036602",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHIMAZOLE"
},
"drugadditional": "3",
"drug... |
{
"abstract": "BACKGROUND\nRadiation recall (RR) is an acute inflammatory reaction confined to previously irradiated areas after the administration of various pharmacological agents. A diverse range of chemotherapies has been associated with RR but no case series with targeted therapies (TT) has been reported.\n\n\nMETHODS\nFrom a database of 346,933 cancer patients ≥18 years treated at Institut Gustave Roussy between June 1986 and August 2012, clinical data and the pattern of treatment of TT-induced RR were collected. Results were compared with those of prior TT-induced RR publications.\n\n\nRESULTS\nSixteen patients with different tumour types were diagnosed with RR observed in the heart, bladder, salivary glands, skin and gastrointestinal tract. The median duration of RR was 1.7 weeks (range: 0.1-13.7) and median time to onset from TT to RR was 16.9 weeks (range: 1-86.9). TT consisted of inhibitors of the mammalian target of rapamycin (mTOR) (n=5), endothelial growth factor receptor (EGFR) (n=2), integrin (n=2), histone deacetylase (HDAC) (n=2), cell division cycle 7 (CDC7) (n=1), insulin-like growth factor 1 receptor (IGFR1) (n=1), cyclin-dependent kinase (CDK) (n=1), BRAF (n=1) and a vascular disrupting agent (VDA) (n=1). Thirteen incriminated TT (81%) were evaluated during early clinical trials and RR led to discontinuation of TT in six patients. All patients had previously received radiotherapy at a median biologically effective dose (BED) of 47 Gy (range: 20-70). The median interval from radiation to TT was 30 months (range: 0.3-363). Immunohistochemical analysis of skin biopsy specimens did not show any transforming growth factor-beta (TGF-β) activation. TT-induced RR characteristics in our population were comparable to those of the nine other cases previously reported in the literature.\n\n\nCONCLUSIONS\nThis is the largest case series ever reported on TT-induced RR. RR could be a potential dose-limiting toxicity in early clinical trials. Research is warranted to further understand the exact pathophysiology of this rare but clinically relevant phenomenon.",
"affiliations": "Department of Radiation Oncology, Institut Gustave Roussy, Villejuif, France. antonin.levy@igr.fr",
"authors": "Levy|Antonin|A|;Hollebecque|Antoine|A|;Bourgier|Céline|C|;Loriot|Yohann|Y|;Guigay|Joël|J|;Robert|Caroline|C|;Delaloge|Suzette|S|;Bahleda|Rastislav|R|;Massard|Christophe|C|;Soria|Jean-Charles|JC|;Deutsch|Eric|E|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-8049",
"issue": "49(7)",
"journal": "European journal of cancer (Oxford, England : 1990)",
"keywords": null,
"medline_ta": "Eur J Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D004358:Drug Therapy; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D017063:Outcome Assessment, Health Care; D011855:Radiodermatitis; D011879:Radiotherapy Dosage; D012189:Retrospective Studies",
"nlm_unique_id": "9005373",
"other_id": null,
"pages": "1662-8",
"pmc": null,
"pmid": "23312391",
"pubdate": "2013-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Targeted therapy-induced radiation recall.",
"title_normalized": "targeted therapy induced radiation recall"
} | [
{
"companynumb": "FR-PFIZER INC-2020385133",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TEMSIROLIMUS"
},
"drugadditional": null,
... |
{
"abstract": "To determine the maximum tolerated dose, toxicities, and response of sirolimus combined with oral metronomic therapy in pediatric patients with recurrent and refractory solid and brain tumors.\n\n\n\nPatients younger than 30 years of age with recurrent, refractory, or high-risk solid and brain tumors were eligible. Patients received six-week cycles of sirolimus with twice daily celecoxib, and alternating etoposide and cyclophosphamide every three weeks, with Bayesian dose escalation over four dose levels (NCT01331135).\n\n\n\nEighteen patients were enrolled: four on dose level (DL) 1, four on DL2, eight on DL3, and two on DL4. Diagnoses included solid tumors (Ewing sarcoma, osteosarcoma, malignant peripheral nerve sheath tumor, rhabdoid tumor, retinoblastoma) and brain tumors (glioblastoma multiforme [GBM], diffuse intrinsic pontine glioma, high-grade glioma [HGG], medulloblastoma, ependymoma, anaplastic astrocytoma, low-grade infiltrative astrocytoma, primitive neuroectodermal tumor, nongerminomatous germ cell tumor]. One dose-limiting toxicity (DLT; grade 4 neutropenia) was observed on DL2, two DLTs (grade 3 abdominal pain and grade 3 mucositis) on DL3, and two DLTs (grade 3 dehydration and grade 3 mucositis) on DL4. The recommended phase II dose of sirolimus was 2 mg/m2 (DL3). Best response was stable disease (SD) in eight patients, and partial response (PR) in one patient with GBM. A patient with HGG was removed from the study with SD and developed PR without further therapy. Western blot analysis showed inhibition of phospho-S6 kinase in all patients during the first cycle of therapy.\n\n\n\nThe combination of sirolimus with metronomic chemotherapy is well tolerated in children. A phase II trial of this combination is ongoing.",
"affiliations": "Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia.;Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia.;Samuel Oschkin Comprehensive Cancer Institute, Los Angeles, California.;Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia.;Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia.;Emory University School of Medicine, Atlanta, Georgia.;Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, Massachusetts.;Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia.;Emory University School of Medicine, Atlanta, Georgia.;Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, Arizona.;Division of Pediatric Hematology/Oncology and Bone Marrow Transplantation, Nemours Children's Specialty Care and Wolfson Children's Hospital, Jacksonville, Florida.",
"authors": "Qayed|Muna|M|;Cash|Thomas|T|0000-0002-1128-784X;Tighiouart|Mourad|M|;MacDonald|Tobey J|TJ|;Goldsmith|Kelly C|KC|;Tanos|Rachel|R|;Kean|Leslie|L|;Watkins|Benjamin|B|;Suessmuth|Yvonne|Y|;Wetmore|Cynthia|C|;Katzenstein|Howard M|HM|0000-0002-5314-2972",
"chemical_list": "D005047:Etoposide; D003520:Cyclophosphamide; D000068579:Celecoxib; D020123:Sirolimus",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.28134",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "67(4)",
"journal": "Pediatric blood & cancer",
"keywords": "metronomic; pediatric; recurrent; refractory; sirolimus",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D059250:Administration, Metronomic; D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D001932:Brain Neoplasms; D000068579:Celecoxib; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide; D004305:Dose-Response Relationship, Drug; D005047:Etoposide; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms; D020123:Sirolimus; D055815:Young Adult",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e28134",
"pmc": null,
"pmid": "31876107",
"pubdate": "2020-04",
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"title": "A phase I study of sirolimus in combination with metronomic therapy (CHOAnome) in children with recurrent or refractory solid and brain tumors.",
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"abstract": "A cystic artery aneurysm is a rare cause of hemobilia. Herein, we report two cases of acute cholecystitis with a ruptured cystic artery pseudoaneurysm. Two patients (a 69-year-old man and an 83-year-old man) were admitted to our hospital because of acute cholecystitis with gallstone impaction in the neck. Percutaneous transhepatic gallbladder drainage (PTGBD) was performed for both patients. After a few days of PTGBD, gallbladder hemorrhage was observed. Abdominal angiography showed cystic artery aneurysm. A transcatheter arterial embolization was therefore performed, followed by an open cholecystectomy.",
"affiliations": "Department of Gastroenterology, Tokyo Dental College, Ichikawa General Hospital.",
"authors": "Kaida|Shogo|S|;Arahata|Kyouko|K|;Itou|Asako|A|;Takarabe|Sakiko|S|;Kimura|Kayoko|K|;Kishikawa|Hiroshi|H|;Nishida|Jiro|J|;Fujiyama|Yoshiki|Y|;Takigawa|Yutaka|Y|;Matsui|Junichi|J|",
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"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D017541:Aneurysm, False; D017542:Aneurysm, Ruptured; D002764:Cholecystitis; D004621:Embolization, Therapeutic; D042882:Gallstones; D006801:Humans; D008297:Male; D014057:Tomography, X-Ray Computed",
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"title": "Two cases of cystic artery pseudoaneurysm rupture due to acute cholecystitis with gallstone impaction in the neck.",
"title_normalized": "two cases of cystic artery pseudoaneurysm rupture due to acute cholecystitis with gallstone impaction in the neck"
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"abstract": "Acute pancreatitis is commonly caused by gallstones or alcohol abuse. Also, this complication has rarely been associated with other etiologies like drugs in some reports. We report the case of a 43-year-old man with 10-days history of taking Tadalafil for erectile dysfunction. The patient was presented to the emergency room with manifestations of acute pancreatitis. This diagnosis was confirmed after clinical examination, laboratory tests, and radiologic evaluation. Other probable etiological factors were ruled out. A total score of seven using Naranjo Adverse Drug Reaction Probability Scale clarifies a probable diagnosis of drug-induced acute pancreatitis in this case. The reported case of acute pancreatitis was most likely induced with Tadalafil.",
"affiliations": "Clinical Research Development Center, Imam Khomeini and Mohammad Kermanshahi Hospitals, Kermanshah University of Medical Sciences, Kermanshah, Iran.;School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.;School of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran.;School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran. Haidari.dart@yahoo.com.",
"authors": "Navabi|Seyed Jafar|SJ|;Khosravifar|Mina|M|;Navabi|Seyed Mohammad|SM|;Heydari|Ruhollah|R|",
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"keywords": "Acute pancreatitis; Adverse drug reaction; Erectile dysfunction; Tadalafil",
"medline_ta": "Clin J Gastroenterol",
"mesh_terms": "D000328:Adult; D007172:Erectile Dysfunction; D006801:Humans; D008297:Male; D010195:Pancreatitis; D058986:Phosphodiesterase 5 Inhibitors; D000068581:Tadalafil; D014057:Tomography, X-Ray Computed",
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"title": "Acute pancreatitis induced by Tadalafil: a case report.",
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"abstract": "BACKGROUND\nIntrahepatic cholangiocarcinoma is an aggressive tumor originating in the epithelium of the bile duct, often associated with distant dissemination. The prognosis is poor and treatment is challenging due to low response rate to standard chemotherapy and lack of targeted therapies.\n\n\nMETHODS\nHere we report the case of a 74-year-old white woman affected by intrahepatic cholangiocarcinoma with metastatic involvement of spleen, lung, peritoneum, and intra-abdominal lymph nodes. As first-line chemotherapy, she was given cisplatin-gemcitabine chemotherapy. The treatment was well tolerated with the exception of grade 1 constipation and a single episode of grade 4 thrombocytopenia occurring after the fourth course. After the first three courses of chemotherapy a computed tomography scan evaluation demonstrated no change; her CA19-9 levels were slightly decreased. However, after the sixth course of chemotherapy a computed tomography scan revealed a dimensional enlargement of the lung metastases; her CA19-9 levels increased. She was then treated with gemcitabine alone. After 2 months of gemcitabine monotherapy a significant regression of lung and spleen metastases, as well a CA19-9 level reduction, occurred. Eight months after the start of gemcitabine monotherapy no signs of progression were reported.\n\n\nCONCLUSIONS\nTreatment of metastatic intrahepatic cholangiocarcinoma with gemcitabine as maintenance therapy after first-line chemotherapy could be continued until clear evidence of disease progression since delayed responses are possible.",
"affiliations": "Department of Clinical Medicine and Surgery, Oncology Division, University of Naples Federico II, Naples, Italy.;Department of Clinical Medicine and Surgery, Oncology Division, University of Naples Federico II, Naples, Italy.;Department of Experimental and Clinical Medicine, University of Catanzaro Magna Grecia, Catanzaro, Italy.;Department of Clinical Medicine and Surgery, Oncology Division, University of Naples Federico II, Naples, Italy. robianco@unina.it.",
"authors": "Marciano|Roberta|R|;Servetto|Alberto|A|;Bianco|Cataldo|C|;Bianco|Roberto|R|",
"chemical_list": "D003841:Deoxycytidine; C056507:gemcitabine; D002945:Cisplatin",
"country": "England",
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"doi": "10.1186/s13256-017-1443-8",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 144310.1186/s13256-017-1443-8Case ReportDelayed response to maintenance therapy after first-line chemotherapy in metastatic intrahepatic cholangiocarcinoma: a case report Marciano Roberta roberta.marciano@unina.it 1Servetto Alberto albeservetto@gmail.com 1Bianco Cataldo bianco@unicz.it 2Bianco Roberto robianco@unina.it 11 0000 0001 0790 385Xgrid.4691.aDepartment of Clinical Medicine and Surgery, Oncology Division, University of Naples Federico II, Naples, Italy 2 0000 0001 2168 2547grid.411489.1Department of Experimental and Clinical Medicine, University of Catanzaro Magna Grecia, Catanzaro, Italy 26 9 2017 26 9 2017 2017 11 27331 1 2017 3 9 2017 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nIntrahepatic cholangiocarcinoma is an aggressive tumor originating in the epithelium of the bile duct, often associated with distant dissemination. The prognosis is poor and treatment is challenging due to low response rate to standard chemotherapy and lack of targeted therapies.\n\nCase presentation\nHere we report the case of a 74-year-old white woman affected by intrahepatic cholangiocarcinoma with metastatic involvement of spleen, lung, peritoneum, and intra-abdominal lymph nodes. As first-line chemotherapy, she was given cisplatin-gemcitabine chemotherapy. The treatment was well tolerated with the exception of grade 1 constipation and a single episode of grade 4 thrombocytopenia occurring after the fourth course. After the first three courses of chemotherapy a computed tomography scan evaluation demonstrated no change; her CA19-9 levels were slightly decreased. However, after the sixth course of chemotherapy a computed tomography scan revealed a dimensional enlargement of the lung metastases; her CA19-9 levels increased. She was then treated with gemcitabine alone. After 2 months of gemcitabine monotherapy a significant regression of lung and spleen metastases, as well a CA19-9 level reduction, occurred. Eight months after the start of gemcitabine monotherapy no signs of progression were reported.\n\nConclusions\nTreatment of metastatic intrahepatic cholangiocarcinoma with gemcitabine as maintenance therapy after first-line chemotherapy could be continued until clear evidence of disease progression since delayed responses are possible.\n\nKeywords\nIntrahepatic cholangiocarcinomaMaintenance chemotherapyGemcitabinehttp://dx.doi.org/10.13039/501100005010Associazione Italiana per la Ricerca sul CancroIG-15388Bianco Roberto issue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nIntrahepatic cholangiocarcinomas (ICCs) comprise all tumors originating in the bile duct epithelium within the liver and are the second most common primary liver malignancy. ICC is a relatively rare malignancy with an age-adjusted incidence rate between 0.4/100,000 and 1.8/100,000 per year throughout Europe [1]. The overall survival (OS) is approximately 6 months from the time of diagnosis, since the majority of patients (90%) are not eligible for curative resection. The main risk factors for ICC are primary sclerosing cholangitis, human immunodeficiency virus (HIV) infection, diabetes, tobacco smoking, cirrhosis, and hepatitis C infection [2–5]. For patients with unresectable disease but in the absence of systemic dissemination, palliative chemoradiotherapy or palliative ablation and chemoembolization are major options. For metastatic disease chemotherapy is increasingly being applied. The gemcitabine/cisplatin combination therapy is currently the best option for metastatic ICC [6]. The alternatives are represented by fluoropyrimidine-based or other gemcitabine-based chemotherapy regimens. Here we report the case of a patient with metastatic ICC which showed a delayed and durable response to continuation maintenance therapy with gemcitabine.\n\nCase presentation\nIn September 2015 a 74-year-old white woman presented with abdominal pain, pyrosis, and weight loss. Her medical history included cholecystectomy for cholelithiasis in 2010. Her blood analyses were normal. A physical examination was unremarkable. A computed tomography (CT) scan showed an intrahepatic neoplastic lesion of 38 mm localized in the gallbladder bed associated with multiple spleen, pulmonary, and peritoneal metastases. Serum levels of CA19-9 were increased (1100 U/mL; reference range less than 37 U/mL). She was then referred to our oncology division. The Eastern Cooperative Oncology Group (ECOG) performance status (PS) was equal to 0; a physical examination found only mild abdominal tenderness. In October 2015 an ultrasound-guided biopsy was performed on the intrahepatic lesion. Pathological analysis revealed the presence of bile duct adenocarcinoma cells; immunohistochemistry showed strong expression for CK19. A pulmonary biopsy on one of the secondary lesions confirmed the diagnosis of lung metastasis. From November 2015 to January 2016 she underwent first-line chemotherapy with cisplatin (25 mg per square meter of body surface area) followed by gemcitabine (1000 mg per square meter), each administered on days 1 and 8 every 3 weeks [6]. After three courses of treatment, a CT scan showed a condition of stable disease assessed by Response Evaluation Criteria in Solid Tumors (RECIST) evaluation criteria. Her serum levels of CA19-9 were slightly decreased to 576 U/mL. No signs of bone marrow toxicity were observed; grade 1 of gastrointestinal toxicity was recorded (nausea and vomiting). She was then treated with an additional three courses of cisplatin-gemcitabine. A following CT scan revealed a dimensional increase of lung metastases with a 10% increase by RECIST criteria, whereas no changes were observed in the other lesions; her CA19-9 serum levels were increased to 753 U/mL. Grade 4 thrombocytopenia was observed soon after the fourth cycle of chemotherapy; the doses were then reduced by 10%. Grade 1 constipation and nausea were reported for the remaining courses. Her PS had not deteriorated; her liver and renal functions were normal. We then decided to treat her with gemcitabine alone as maintenance therapy starting in April 2016, with the following schedule: 1000 mg per square meter, administered on days 1, 8, and 15 every 4 weeks. After the second cycle, grade 3 thrombocytopenia and lower limb lymphedema were observed and the doses were reduced by 20%. In August 2016 a CT scan revealed a significant dimensional regression of lung lesions (50% reduction as assessed by RECIST evaluation criteria) and a complete regression of spleen lesions (Fig. 1 a–c); her CA19-9 serum levels were decreased to 536 U/mL. She continued maintenance therapy with gemcitabine alone for 10 months until February 2017 when a CT scan showed lung disease progression and new liver lesions (Fig. 1 d). At the same time, her CA19.9 serum level increased to 1265 U/mL (Fig. 1 e).Fig. 1 Computed tomography scans and CA19-9 serum level evaluation during treatment. a Basal computed tomography scan evaluation; spleen and lung lesions are evident. b Computed tomography evaluation after six courses of cisplatin-gemcitabine; no significant changes in lung and spleen lesion were observed. c Computed tomography evaluation after 4 months of gemcitabine maintenance therapy revealed a complete remission of spleen lesions and a significant regression of lung metastases. d Computed tomography evaluation showing disease progression after 10 months of maintenance therapy. e CA19-9 serum levels through time since first diagnosis\n\n\n\n\nDiscussion\nWhile an accepted modality in other cancer types, such as lung cancer, maintenance therapy in gastrointestinal malignancies is not routinely used. In the setting of metastatic colorectal cancer, maintenance therapy has been recently evaluated in phase III randomized trials. For example, combination therapy incorporating capecitabine and bevacizumab, as maintenance treatment after induction therapy with capecitabine, oxaliplatin, and bevacizumab (CAPOX-B), significantly improved progression-free survival (PFS) with excellent tolerability, although the incidence of hand-foot syndrome was increased [7]. Maintenance capecitabine monotherapy has also been evaluated after induction therapy with oxaliplatin and infusional 5-fluorouracil (FOLFOX-4) in patients with metastatic colorectal cancer with very low incidence of side effects [8]. Little data are available for metastatic pancreatic cancer and no data for bile duct cancers. Maintenance therapy with gemcitabine after chemoradiation has been proposed for patients with locally advanced pancreatic cancer and, despite the limitation of a retrospective analysis, an increase in OS is suggested [9]. Reure and colleagues reported a retrospective series of patients with metastatic pancreatic cancer treated with maintenance capecitabine without signs of progression after first-line leucovorin, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) chemotherapy with a median OS of 17 months and a median PFS of 5 months [10]. Doherty et al. have recently reported retrospective data suggesting a survival benefit for patients affected by biliary tract cancer receiving nine or more cycles of chemotherapy, with manageable toxicity [11]. Here we describe the case of a women affected by metastatic ICC treated with first-line cisplatin-gemcitabine chemotherapy. In the phase III randomized trial by Valle and colleagues, the combination of cisplatin-gemcitabine was compared to gemcitabine in patients with locally advanced or metastatic biliary tract cancer [6]. The cisplatin-gemcitabine group achieved a significantly better tumor control rate (81.4 versus 71.8%, p = 0.049), an increased median PFS (8.0 months versus 5.0 months, p < 0.001), and an improved median OS (11.7 months versus 8.1 months, p < 0.001) with more incidence of bone marrow toxicity (mainly neutropenia in the combination arm). In our case, our patient achieved disease stabilization as best overall response after the first three courses of chemotherapy, with a dimensional increase in lung metastases after the sixth course, although it was not sufficient to qualify for progression. Maintenance therapy with gemcitabine was well tolerated and, surprisingly, resulted in a significant clinical delayed response, with a dimensional regression of both lung and spleen metastases. Usually, traditional chemotherapy is associated with rapid but transient rather than delayed durable response, the latter being frequently observed for novel immunotherapy drugs. It could be hypothesized that, in our case, the chemotherapy treatment had unmasked tumor antigens and the antigen release induced an immune-mediated antitumor response, without any significant change in white blood cell (WBC), neutrophil, monocyte, and lymphocytes counts. Recent data suggest that the anticancer effect of chemotherapy is also due to the interaction with innate and adaptive immune system, with various complex mechanisms [12]. This new evidence represents the rationale to design clinical trials testing the combination of cytotoxic agents and immune checkpoint inhibitors.\n\nConclusions\nOur case suggests that treatment of metastatic ICC with first-line chemotherapy could be continued until clear evidence of disease progression since delayed responses are possible. With this in mind, gemcitabine monotherapy appears to be a reasonable option if well tolerated and a good performance status (PS) is maintained through the treatment.\n\nAbbreviations\nCTComputed tomography\n\nICCIntrahepatic cholangiocarcinoma\n\nOSOverall survival\n\nPFSProgression-free survival\n\nPSPerformance status\n\nRECISTResponse Evaluation Criteria in Solid Tumors\n\nAcknowledgements\nNone.\n\nFunding\nThis study was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) Investigator Grant 2015-2017 (IG-15388) to RB\n\nAvailability of data and materials\nNot applicable.\n\nAuthors’ contributions\nRM and AS conducted the chart review and literature search; CB and RB prepared drafts of the manuscript for this case report; all authors contributed to editing the manuscript. All authors reviewed and approved the final manuscript for submission.\n\nEthics approval and consent to participate\nThe Federico II University Ethic Committee does not require approval for case reports publication.\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. Blechacz B Cholangiocarcinoma: Current Knowledge and New Developments Gut Liver 2017 11 1 13 26 10.5009/gnl15568 27928095 \n2. Shaib YH Davila JA McGlynn K El-Serag HB Rising incidence of intrahepatic cholangiocarcinoma in the United States: a true increase? J Hepatol. 2004 40 472 7 10.1016/j.jhep.2003.11.030 15123362 \n3. Wideroff L Gridley G Mellemkjaer L Cancer incidence in a population-based cohort of patients hospitalized with diabetes mellitus in Denmark J Natl Cancer Inst. 1997 89 1360 5 10.1093/jnci/89.18.1360 9308706 \n4. Donato F Gelatti U Tagger A Intrahepatic cholangiocarcinoma and hepatitis C and B virus infection, alcohol intake, and hepatolithiasis: a case-control study in Italy Cancer Causes Control. 2001 12 959 64 10.1023/A:1013747228572 11808716 \n5. Welzel TM Graubard BI El-Serag HB Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a population-based case-control study Clin Gastroenterol Hepatol. 2007 5 1221 8 10.1016/j.cgh.2007.05.020 17689296 \n6. Valle J Wasan H Palmer DH Cunningham D Anthoney A Maraveyas A Madhusudan S Iveson T Hughes S Pereira SP Roughton M Bridgewater J ABC-02 Trial Investigators Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer N Engl J Med 2010 362 14 1273 81 10.1056/NEJMoa0908721 20375404 \n7. Simkens LH van Tinteren H May A ten Tije AJ Creemers GJ Loosveld OJ de Jongh FE Erdkamp FL Erjavec Z van der Torren AM Tol J Braun HJ Nieboer P van der Hoeven JJ Haasjes JG Jansen RL Wals J Cats A Derleyn VA Honkoop AH Mol L Punt CJ Koopman M Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch colorectal cancer group Lancet 2015 385 9980 1843 52 10.1016/S0140-6736(14)62004-3 25862517 \n8. Petrioli R Paolelli L Marsili S Civitelli S Francini E Cioppa T Roviello F Nettuno R Intrivici C Tanzini G Lorenzi M Francini G FOLFOX-4 stop and go and capecitabine maintenance chemotherapy in the treatment of metastatic colorectal cancer Oncology 2006 70 5 345 50 10.1159/000098107 17179728 \n9. Brunner TB Tinkl D Grabenbauer GG Meyer T Brueckl WM Sauer R Maintenance chemotherapy after chemoradiation improves survival of patients with locally advanced pancreatic carcinoma: a retrospective analysis of prospectively recruited patients Strahlenther Onkol 2006 182 4 210 5 10.1007/s00066-006-1524-x 16622622 \n10. Reure J Follana P Gal J Evesque L Cavaglione G Saint A François E Effectiveness and tolerability of maintenance capecitabine administrated to patients with metastatic pancreatic cancer treated with first-line FOLFIRINOX Oncology 2016 90 5 261 6 10.1159/000444854 27097162 \n11. Doherty MK McNamara MG Aneja P McInerney E Moignard S Horgan AM Jiang H Panzarella T Jang R Dhani N Hedley D Knox JJ Long term responders to palliative chemotherapy for advanced biliary tract cancer J Gastrointest Oncol 2017 8 2 352 60 10.21037/jgo.2017.03.06 28480074 \n12. Bracci L Schiavoni G Sistigu A Belardelli F Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer Cell Death Differ 2014 21 1 15 25 10.1038/cdd.2013.67 23787994\n\n",
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"issn_linking": "1752-1947",
"issue": "11(1)",
"journal": "Journal of medical case reports",
"keywords": "Gemcitabine; Intrahepatic cholangiocarcinoma; Maintenance chemotherapy",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001650:Bile Duct Neoplasms; D001653:Bile Ducts, Intrahepatic; D018281:Cholangiocarcinoma; D002945:Cisplatin; D003841:Deoxycytidine; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008198:Lymph Nodes; D008207:Lymphatic Metastasis; D060046:Maintenance Chemotherapy; D009362:Neoplasm Metastasis; D010534:Peritoneal Neoplasms; D013160:Splenic Neoplasms; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "273",
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"title": "Delayed response to maintenance therapy after first-line chemotherapy in metastatic intrahepatic cholangiocarcinoma: a case report.",
"title_normalized": "delayed response to maintenance therapy after first line chemotherapy in metastatic intrahepatic cholangiocarcinoma a case report"
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"abstract": "Herein, we report a case of antibody-mediated rejection (ABMR) due to anti-HLA-DQ antibody after pregnancy and delivery in a female kidney transplant recipient. A 34-year-old female recipient was admitted at 2 years after delivery for an examination of an elevated serum creatinine (S-Cr) level. The patient had received a living kidney transplantation from her mother at 22 years of age, and her kidney graft function was almost stable. The episode biopsy showed peritubular capillaritis and transplant capillaropathy with C4d immunoreactivity in the peritubular capillaries. Additional examination revealed expression of a donor-specific antibody (DSA) against HLA-DQ5, leading to the diagnosis of chronic active ABMR. Intravenous immunoglobulin, plasma exchange, and rituximab were administered, and her S-Cr level was maintained stable. This case demonstrates a possible relationship between pregnancy/delivery and development of ABMR due to a de novo DSA in a female kidney transplant recipient.",
"affiliations": "Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.;Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.;Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.;Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.;Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.;Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.;Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.;Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.;Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.;Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.;Department of Urology, The Jikei University School of Medicine, Tokyo, Japan.;Department of Urology, The Jikei University School of Medicine, Tokyo, Japan.;Department of Urology, The Jikei University School of Medicine, Tokyo, Japan.;Department of Urology, The Jikei University School of Medicine, Tokyo, Japan.;Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.;Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.;Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.;Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.;Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.",
"authors": "Sagasaki|Makoto|M|;Nakada|Yasuyuki|Y|;Yamamoto|Izumi|I|;Kawabe|Mayuko|M|;Yamakawa|Takafumi|T|;Katsumata|Haruki|H|;Mafune|Aki|A|;Katsuma|Ai|A|;Kobayashi|Akimitsu|A|;Koike|Kentaro|K|;Koike|Yusuke|Y|;Miki|Jun|J|;Yamada|Hiroki|H|;Kimura|Takahiro|T|;Tanno|Yudo|Y|;Ohkido|Ichiro|I|;Tsuboi|Nobuo|N|;Yamamoto|Hiroyasu|H|;Yokoo|Takashi|T|",
"chemical_list": "D006683:HLA-DQ Antigens; C410042:HLA-DQ5 antigen; D016756:Immunoglobulins, Intravenous; D007166:Immunosuppressive Agents; D007518:Isoantibodies; D010446:Peptide Fragments; D000069283:Rituximab; D015935:Complement C4b; C032261:complement C4d",
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"keywords": "anti-HLA-DQ antibody; antibody-mediated rejection; donor-specific antibody; living related kidney transplantation; pregnancy and delivery",
"medline_ta": "Nephrology (Carlton)",
"mesh_terms": "D000328:Adult; D001706:Biopsy; D015935:Complement C4b; D005260:Female; D006084:Graft Rejection; D006085:Graft Survival; D006683:HLA-DQ Antigens; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents; D007518:Isoantibodies; D007668:Kidney; D016030:Kidney Transplantation; D019520:Living Donors; D036801:Parturition; D010446:Peptide Fragments; D010951:Plasma Exchange; D011247:Pregnancy; D000069283:Rituximab; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "9615568",
"other_id": null,
"pages": "81-84",
"pmc": null,
"pmid": "29968405",
"pubdate": "2018-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Antibody-mediated rejection due to anti-HLA-DQ antibody after pregnancy and delivery in a female kidney transplant recipient.",
"title_normalized": "antibody mediated rejection due to anti hla dq antibody after pregnancy and delivery in a female kidney transplant recipient"
} | [
{
"companynumb": "PHHY2018JP164466",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo evaluate clinical data, electroencephalogram, etiology, classification, treatment, morbidity, and mortality in acute refractory status epilepticus.\n\n\nMETHODS\nFifteen patients, mean age of 41.3 years-old, six males, with refractory status epilepticus, were retrospectively studied. All of them were followed by serial electroencephalogram or continuous electroencephalographic monitoring.\n\n\nRESULTS\nThe most common comorbidity was hypertension. Seven (46.7%) patients were diagnosed with previous symptomatic focal epilepsy. More than one etiology was identified in 40.0% of the cases. Status epilepticus partial complex was the most common (n=14, 93.3%), and discrete seizures were the most observed initial ictal pattern. Continuous intravenous midazolam was used in nine (60.0%) patients and continuous thiopental in three (20.0%). Nine (60.0%) participants died, one (6.6%) had neurological sequelae, and five (33.3%) presented no neurological sequelae.\n\n\nCONCLUSIONS\nHigher mortality rate was associated with advanced age and periodic lateralized epileptiform discharges. Midazolam proved to be a safe drug. The refractory status epilepticus is related to high mortality.",
"affiliations": "Hospital São Paulo, Escola Paulista de Medicina, Federal University of São Paulo, São Paulo SP, Brazil. paulo.neuroped@gmail.com",
"authors": "Liberalesso|Paulo Breno Noronha|PB|;Garzon|Eliana|E|;Yacubian|Elza M T|EM|;Sakamoto|Américo C|AC|",
"chemical_list": "D000927:Anticonvulsants; D008874:Midazolam",
"country": "Brazil",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "0004-282X",
"issue": "71(3)",
"journal": "Arquivos de neuro-psiquiatria",
"keywords": null,
"medline_ta": "Arq Neuropsiquiatr",
"mesh_terms": "D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants; D002648:Child; D002675:Child, Preschool; D004569:Electroencephalography; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008874:Midazolam; D008875:Middle Aged; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D012640:Seizures; D012737:Sex Factors; D013226:Status Epilepticus; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "0125444",
"other_id": null,
"pages": "153-8",
"pmc": null,
"pmid": "23563714",
"pubdate": "2013-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Higher mortality rate is associated with advanced age and periodic lateralized epileptiform discharges in patients with refractory status epilepticus.",
"title_normalized": "higher mortality rate is associated with advanced age and periodic lateralized epileptiform discharges in patients with refractory status epilepticus"
} | [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MIDAZOLAM\\MIDAZOLAM HYDROCHLORIDE"
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{
"abstract": "The incidence of endometrial carcinoma is rising and the patients with distant metastases have a poor prognosis, especially when progression of disease occurs after systemic treatment with hormonal therapy or chemotherapy. Pazopanib, a multi-targeted inhibitor of several oncogenic receptor tyrosine kinases, has been investigated in patients with chemotherapy-resistant endometrial carcinoma or patients for whom chemotherapy is contraindicated. In this report we will describe a spectacular response to pazopanib in a patient with recurrent metastatic endometrial carcinoma.",
"affiliations": "First auteur: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands Second auteur: Gynaecological Oncology, Amsterdam Medical Centre, Amsterdam, the Netherlands.",
"authors": "van der Steen|M J|MJ|;de Waal|Y R P|YR|;Westermann|A|A|;Tops|B|B|;Leenders|W|W|;Ottevanger|P B|PB|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib",
"country": "Netherlands",
"delete": false,
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"issn_linking": "0300-2977",
"issue": "74(9)",
"journal": "The Netherlands journal of medicine",
"keywords": null,
"medline_ta": "Neth J Med",
"mesh_terms": "D034861:Abdominal Wall; D020533:Angiogenesis Inhibitors; D018269:Carcinoma, Endometrioid; D059186:Chemoradiotherapy, Adjuvant; D016889:Endometrial Neoplasms; D005260:Female; D006801:Humans; D007044:Hysterectomy; D007191:Indazoles; D007412:Intestinal Fistula; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010052:Ovariectomy; D011743:Pyrimidines; D012074:Remission Induction; D058994:Salpingectomy; D012983:Soft Tissue Neoplasms; D013449:Sulfonamides",
"nlm_unique_id": "0356133",
"other_id": null,
"pages": "410-413",
"pmc": null,
"pmid": "27905309",
"pubdate": "2016-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "An impressive response to pazopanib in a patient with metastatic endometrial carcinoma.",
"title_normalized": "an impressive response to pazopanib in a patient with metastatic endometrial carcinoma"
} | [
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"companynumb": "PHHY2016NL159399",
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"occurcountry": "NL",
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"activesubstancename": "PAZOPANIB"
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"abstract": "BACKGROUND\nSerotonin syndrome is a potentially life-threatening adverse drug reaction that most commonly results from adverse interactions between drugs. Because serotonin syndrome can be fatal and is often difficult to diagnose, it is vital for health professionals to know about this reaction. We report a typical case of transient serotonin syndrome secondary to tramadol-Citalopram combination. This case report highlights the value of awareness of the early and subtle signs of serotonin syndrome.\n\n\nMETHODS\nA 44-year-old female with past medical history of chronic pancreatitis, back pain, and major depression was brought to the emergency room (ER) with altered mental status, jerky movements in extremities, generalized weakness, and vomiting.\n\n\nCONCLUSIONS\nMost physicians are aware of serotonin syndrome secondary to antidepressants but do not think about other classes of medications such as analgesics. Clinicians should also be aware of the possibility of serotonin syndrome when encountering a patient taking serotonergic drugs who presents with characteristic symptoms of serotonin syndrome.",
"affiliations": "Department of Internal Medicine, Baystate Medical Center, Springfield, USA.;Department of Pulmonary and Critical Care, University of Arkansas for Medical Sciences, Little Rock, USA.;Department of Internal Medicine, Nishter Medical College, Multan, Pakistan.;Department of Internal Medicine, Fatima Jinnah Medical College, Lahore, Pakistan.",
"authors": "Shakoor|Muhammad|M|;Ayub|Samia|S|;Ahad|Abdul|A|;Ayub|Zunaira|Z|",
"chemical_list": "D000701:Analgesics, Opioid; D017367:Serotonin Uptake Inhibitors; D014147:Tramadol",
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.892264",
"fulltext": null,
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"issn_linking": "1941-5923",
"issue": "15()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D059350:Chronic Pain; D003865:Depressive Disorder, Major; D004347:Drug Interactions; D005260:Female; D006801:Humans; D020230:Serotonin Syndrome; D017367:Serotonin Uptake Inhibitors; D014147:Tramadol",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "562-4",
"pmc": null,
"pmid": "25540831",
"pubdate": "2014-12-19",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16140178;19956471;12422548;9034418;20433130;15190240;23224488;17015284;18006535;12771076;10818650;17259690;8238650",
"title": "Transient serotonin syndrome caused by concurrent use of tramadol and selective serotonin reuptake inhibitor.",
"title_normalized": "transient serotonin syndrome caused by concurrent use of tramadol and selective serotonin reuptake inhibitor"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/15/0045507",
"fulfillexpeditecriteria": "2",
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"patient": {
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"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CITALOPRAM HYDROBROMIDE"
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"drugadditio... |
{
"abstract": "Present report describes a 46 year old male patient with a diagnosis of major depression who developed tardive dyskinesia during bupropion therapy. Our patient had no history of neuroleptic use and his laboratory and neurologic examinations were normal. He had no family history of neurologic diseases. Although bupropion induced dyskinesia has been previously reported in the literature, it is rare and our case is the first case regarding tardive dyskinesia.",
"affiliations": "İzzet Baysal Teaching and Research Hospital for Psychiatry, Bolu, Turkey.;İzzet Baysal Teaching and Research Hospital for Psychiatry, Bolu, Turkey.;İzzet Baysal Teaching and Research Hospital for Psychiatry, Bolu, Turkey.;Department of Psychiatry, Afşin State Hospital, K. Maraş, Turkey.",
"authors": "Tuman|Taha Can|TC|;Çakır|Uğur|U|;Yıldırım|Osman|O|;Camkurt|Mehmet Akif|MA|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.9758/cpn.2017.15.2.194",
"fulltext": "\n==== Front\nClin Psychopharmacol NeurosciClin Psychopharmacol NeurosciClinical Psychopharmacology and Neuroscience1738-10882093-4327Korean College of Neuropsychopharmacology 2844957110.9758/cpn.2017.15.2.194cpn-15-194Case ReportTardive Dyskinesia Associated with Bupropion Tuman Taha Can 1Çakır Uğur 1Yıldırım Osman 1Camkurt Mehmet Akif 21 İzzet Baysal Teaching and Research Hospital for Psychiatry, Bolu, \nTurkey2 Department of Psychiatry, Afşin State Hospital, K. Maraş, \nTurkeyAddress for correspondence: Taha Can Tuman, MD, İzzet Baysal Teaching and Research Hospital for Psychiatry, Bolu, Turkey, Tel: +90-5342200749, Fax: +90-3742752423, E-mail: tahacantuman@hotmail.com5 2017 31 5 2017 15 2 194 196 13 5 2016 04 6 2016 10 6 2016 Copyright © 2017, Korean College of Neuropsychopharmacology2017This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Present report describes a 46 year old male patient with a diagnosis of major depression who developed tardive dyskinesia during bupropion therapy. Our patient had no history of neuroleptic use and his laboratory and neurologic examinations were normal. He had no family history of neurologic diseases. Although bupropion induced dyskinesia has been previously reported in the literature, it is rare and our case is the first case regarding tardive dyskinesia.\n\nMovement disordersBupropionDepression\n==== Body\nINTRODUCTION\nBupropion extended-release (XL) is an important pharmacological option except nicotine for the treatment of smoking cessation. It is thought to act on nicotine addiction by blocking dopamine reward pathway and reducing withdrawal symptoms that arise due to noradrenaline pathway Furthermore, bupropion is used for the treatment of major depression because of it acts as noradrenaline dopamine reuptake inhibitor.1–3) The most common side effects with the use of bupropion can be listed as insomnia, headache, dry mouth, rash, nausea, sweating and hypertension.4) Hypomania, psychotic relapse and visual hallusinations may also occur via use of bupropion.5,6)\n\nAccording to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), tardive dyskinesia is characterized by choreiform or atetoid involuntary movements at least continuing several weeks due to neuroleptic use at least several months. These involuntary movements are often seen on face, arms, legs, jaws and tongues.7) Additionally, tardive dyskinesia may develop with drugs except neuroleptics.8) Here, we report an adult patient who developed tardive dyskinesia during treatment with bupropion. Informed consent was obtained from the patient.\n\nCASE\nForty-six year old man was admitted to our psychiatry outpatient unit with complaints of malaise, unwillingness, fatigue, lack of energy, lack of sexual desire, hypersomnia. His physical and laboratory examination (complete blood count, thyroid function, B12 and folate tests) were normal. The patient received 15 points in the Hamilton Rating Scale for Depression (HAM-D) scale. Bupropion XL 150 mg per day treatment was started to the patient with a diagnosis of major depression according to the DSM-5. After a month, due to continued complaints of depression, bupropion XL dose was increased to 300 mg per day. After two months of dose increase, the patient was admitted to our outpatient unit with complaints of involuntary movements on his tongue and lips. We noted the patient to have repetative buccolingual dyskinesia. Involuntary movements was more pronounced when patient became anxious. His neurologic and laboratory examination were normal. He had never been exposed neuroleptic medication in patients’ history. There was no familly history of neurological disorders. Any pathology was not detected with cranial magnetic resonance imaging. The patient received 7 points in the Abnormal Involuntary Movement Scale (AIMS). Bupropion XL dose was decreased to 150 mg per day. After a month, due to continued involuntary movements, bupropion was stopped. Lorazepam 1 mg per day was started for his tardive dyskinesia symtoms. Involuntary movements disappeared five months after discontinuation of bupropion. Naranjo Adverse Drug Reaction Probability Scale was evaluated as 7 points, a probable adverse effect associated with bupropion.9)\n\nDISCUSSION\nTo our knowledge, this is the first case report regarding tardive dyskinesia associated with bupropion XL in a patient with no history of neuroleptic use or neurologic disorders. Anormal involuntary movements apperared two months after bupropion dose was increased to 300 mg per day and disappeared five months after discontinuation of bupropion with simultaneous use of lorazepam. In literature, there has been three reported cases of dyskinesia associated with bupropion. In first case, 70 year old woman with bipolar disorder, dyskinesia developed 2 days after bupropion IR 75 mg per day was added to her lithium treatment.10) In second case, 63 year old man with major depression, dyskinesia developed one week after bupropion XL dose was increased to 300 mg per day and this patient had a history of neuroleptic medication.11) In third case, 64 year old woman with major depression, dyskinesia developed one week after bupropion dose was increased to 300 mg per day.12) In all three cases, dyskinesia developed acutely. Patients were elderly in previous three cases therefore early stages of Parkinson disease or other neurologic disorders has been associated with dyskinesias after initiation of bupropion. According to DSM-5, dyskinesia associated with bupropion in our patient noted as tar-dive because of involuntary movements occured two months after bupropion dose was increased to 300 mg per day and disappeared five months after discontinuation of bupropion. Also, our patient was 46 years old so he was quite young for onset of neurologic diseases compared with other cases in literature and there was no history of neuroleptic use in our patient.\n\nInvoluntary movements may occur with short term use of drugs as bromocriptine and L-Dopa or lasting than a few weeks in which case the condition is called acute dyskinesia, if these movements develop with use of drugs for at least a few months and lasting a few weeks is called tar-dive dyskinesia according to DSM-5.7,13) In some patients acute dyskinesia may develop after reduction or discontinuation in dosage of drugs which is called withdrawal dyskinesia lasting less than 4–8 weeks. If dyskinesia persists for longer than this time is called tardive dyskinesia.7) Yet, there is no effective and safety treatment and main treatment strategy is preventive approaches for tardive dyskinesia and it causes permanent disability, therefore tardive dyskinesia is important to early diagnosis of tardive dyskinesia in clinical practice.14,15)\n\nNeuroleptic induced tardive dyskinesia develops via dopamin receptor hypersensitivity, reduction in GABA cycle and increased glutamate and aspartate levels after D2 receptor blokage.16) The mechanism of tardive dyskinesia associated with bupropion is still unclear. Excessive dopaminergic transmission in striatum caused by bupropion could be the underlying mechanism of bupropion associated tardive dyskinesia.13) Other prodopaminergic agents such as modafinil, methylphenidate, levodopa, amphetamine and other stimulants have been reported to be associated with involuntary movements.13,17–19)\n\nFinally, clinicians should be careful about tardive dyskinesia associated bupropion when they used this drug even if the patient is not elderly. Our findings must be supported by further studies. New studies may contribute to understand the mechanism of bupropion associated tar-dive dyskinesia.\n\n* Part of the case was reported as a poster at the 50th National Psychiatry Congress (12.11.-16.11.2014, Rixos Sungate Hotel, Antalya, Turkey).\n==== Refs\nREFERENCES\n1 Benowitz NL Pharmacology of nicotine: addiction, smoking-induced disease, and therapeutics Annu Rev Pharmacol Toxicol 2009 49 57 71 10.1146/annurev.pharmtox.48.113006.094742 18834313 \n2 Richmond R Zwar N Review of bupropion for smoking cessation Drug Alcohol Rev 2003 22 203 220 10.1080/09595230100100642 12850907 \n3 Glynn DA Cryan JF Kent P Flynn RA Kennedy MP Update on smoking cessation therapies Adv Ther 2009 26 369 382 10.1007/s12325-009-0022-9 19399385 \n4 Dwoskin LP Rauhut AS King-Pospisil KA Bardo MT Review of the pharmacology and clinical profile of bupropion, an antidepressant and tobacco use cessation agent CNS Drug Rev 2006 12 178 207 10.1111/j.1527-3458.2006.00178.x 17227286 \n5 Aggarwal A Sharma RC Bupropion-induced mania and hypomania: a report of two cases J Neuropsychiatry Clin Neurosci 2011 23 E51 E52 10.1176/jnp.23.2.jnpe51 21677230 \n6 Golden RN James SP Sherer MA Rudorfer MV Sack DA Potter WZ Psychoses associated with bupropion treatment Am J Psychiatry 1985 142 1459 1462 10.1176/ajp.142.12.1459 3934991 \n7 American Psychiatric Association Desk reference to the diagnostic criteria from DSM-5 Arlington, VA American Psychiatric Association Publishing 2013 \n8 Kenney C Hunter C Davidson A Jankovic J Metoclopramide, an increasingly recognized cause of tardive dyskinesia J Clin Pharmacol 2008 48 379 384 10.1177/0091270007312258 18223146 \n9 Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 245 10.1038/clpt.1981.154 7249508 \n10 Gardos G Reversible dyskinesia during bupropion therapy J Clin Psychiatry 1997 58 218 10.4088/JCP.v58n0507a 9184616 \n11 Kohen I Sarcevic A Mirtazapine in bupropion-induced dyskinesias: a case report Mov Disord 2006 21 584 585 10.1002/mds.20818 16511872 \n12 Ferentinos P Christodoulou C Rizos E Douzenis A Lykouras L Mixed-type (limb-truncal and orofacial) bupropion-associated dyskinesia J Clin Psychopharmacol 2010 30 644 646 10.1097/JCP.0b013e3181ee28e5 20841971 \n13 Damier P Drug-induced dyskinesias Curr Opin Neurol 2009 22 394 399 10.1097/WCO.0b013e32832d9dc4 19491677 \n14 Kang NR Kim MD Tardive dyskinesia: treatment with aripiprazole Clin Psychopharmacol Neurosci 2011 9 1 8 10.9758/cpn.2011.9.1.1 23430384 \n15 Egan MF Apud J Wyatt RJ Treatment of tardive dyskinesia Schizophr Bull 1997 23 583 609 10.1093/schbul/23.4.583 9365997 \n16 Sachdev PS The current status of tardive dyskinesia Aust N Z J Psychiatry 2000 34 355 369 10.1080/j.1440-1614.2000.00737.x 10881961 \n17 Heinrich TW A case report of methylphenidate-induced dyskinesia Prim Care Companion J Clin Psychiatry 2002 4 158 159 10.4088/PCC.v04n0408a 15014725 \n18 Luborzewski A Regen F Schindler F Anghelescu I Modafinil-induced reversible hyperkinetic nondystonic movement disorder in a patient with major depressive disorder J Neuropsychiatry Clin Neurosci 2006 18 248 249 10.1176/jnp.2006.18.2.248 16720809 \n19 Jiménez-Jiménez FJ García-Ruiz PJ Molina JA Drug- induced movement disorders Drug Saf 1997 16 180 204 10.2165/00002018-199716030-00004 9098656\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1738-1088",
"issue": "15(2)",
"journal": "Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology",
"keywords": "Bupropion; Depression; Movement disorders",
"medline_ta": "Clin Psychopharmacol Neurosci",
"mesh_terms": null,
"nlm_unique_id": "101207332",
"other_id": null,
"pages": "194-196",
"pmc": null,
"pmid": "28449571",
"pubdate": "2017-05-31",
"publication_types": "D002363:Case Reports",
"references": "9098656;18223146;16511872;9365997;15014725;12850907;21677230;3934991;19399385;10881961;17227286;23430384;20841971;9184616;7249508;19491677;18834313;16720809",
"title": "Tardive Dyskinesia Associated with Bupropion.",
"title_normalized": "tardive dyskinesia associated with bupropion"
} | [
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"activesubstancename": "BUPROPION"
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"abstract": "Given the current understanding of bleomycin-induced pneumonitis (BIP), the use of tumor necrosis factor alpha (TNF-α) inhibitors such as infliximab for late-stage disease appears to be of limited benefit. Further research regarding prevention and management of advanced BIP is required.",
"affiliations": "Department of Intensive Care Medicine Frankston Hospital Frankston Victoria Australia.;Pharmacy Department Frankston Hospital Frankston Victoria Australia.;Department of Intensive Care Medicine Frankston Hospital Frankston Victoria Australia.;Department of Intensive Care Medicine Frankston Hospital Frankston Victoria Australia.",
"authors": "Ge|Victor|V|0000-0001-6050-0478;Banakh|Iouri|I|;Tiruvoipati|Ravindranath|R|;Haji|Kavi|K|",
"chemical_list": null,
"country": "England",
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"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.1790CCR31790Case ReportCase ReportsBleomycin‐induced pulmonary toxicity and treatment with infliximab: A case report GE et al.Ge Victor http://orcid.org/0000-0001-6050-0478vge@phcn.vic.gov.au \n1\nBanakh Iouri \n2\nTiruvoipati Ravindranath \n1\n\n3\nHaji Kavi \n1\n\n3\n\n1 \nDepartment of Intensive Care Medicine\nFrankston Hospital\nFrankston\nVictoria\nAustralia\n\n2 \nPharmacy Department\nFrankston Hospital\nFrankston\nVictoria\nAustralia\n\n3 \nSchool of Public Health\nFaculty of Medicine, Nursing and Health Sciences\nMonash University\nClayton\nVictoria\nAustralia\n* Correspondence\n\nVictor Ge, Department of Intensive Care Medicine, Frankston Hospital, Frankston, Victoria Australia.\n\nEmail: vge@phcn.vic.gov.au\n04 9 2018 10 2018 6 10 10.1002/ccr3.2018.6.issue-102011 2014 06 7 2018 08 8 2018 © 2018 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Key Clinical Message\nGiven the current understanding of bleomycin‐induced pneumonitis (BIP), the use of tumor necrosis factor alpha (TNF‐α) inhibitors such as infliximab for late‐stage disease appears to be of limited benefit. Further research regarding prevention and management of advanced BIP is required.\n\nbleomycininfliximabintensive carepulmonary toxicityrespiratory failuretreatment outcome source-schema-version-number2.0component-idccr31790cover-dateOctober 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.5.0.1 mode:remove_FC converted:15.10.2018\n\n\nGe \nV \n, \nBanakh \nI \n, \nTiruvoipati \nR \n, \nHaji \nK \n. Bleomycin‐induced pulmonary toxicity and treatment with infliximab: A case report . Clin Case Rep . 2018 ;6 :2011 –2014 . 10.1002/ccr3.1790\n==== Body\n1 INTRODUCTION\nBleomycin is a chemotherapy agent commonly used for the treatment of Hodgkin's lymphoma and embryonal carcinomas.1, 2 A broad spectrum of bleomycin‐induced pulmonary toxicities have been well described as a complication of such therapy, the most common variant of which is bleomycin‐induced pneumonitis (BIP).1, 2 BIP is a serious side effect that occurs in 10% of patients receiving bleomycin and carries a mortality risk of 10%‐20%.2, 3 Survival of patients with respiratory failure requiring intensive care unit (ICU) admission is uncertain. Case reports in the published literature suggest that outcomes are often dismal.4, 5, 6, 7\n\n\nThe mechanism of bleomycin toxicity is unclear and likely multifactorial. Oxidative damage, release of inflammatory cytokines, a deficiency of the bleomycin hydroxylase enzyme in the lungs and genetic predisposition have been described.1 The time to onset of BIP can vary significantly.3 Some patients develop BIP soon after the first dose, whereas other patients may tolerate months of treatment before the condition occurs.3 There is little evidence to guide management of BIP, and permanent discontinuation of bleomycin is currently the mainstay of treatment.1 Administration of glucocorticoids may be of benefit; however, patients with acute inflammatory disease appear to respond better than those with indolent, progressive onset of fibrotic BIP.3 In 2015, we trialed the tyrosine kinase inhibitor imatinib as an anti‐inflammatory and an antifibrotic agent in a patient with severe BIP.4 The choice of such therapy was based on a published case of BIP, which was reversed by treatment with imatinib.8 However, our patient did not respond as hoped and eventually died, an outcome consistent with most other cases of severe BIP treated with imatinib.9, 10 Other potential treatments of note are the anti‐tumor necrosis factor alpha (TNF‐α) agents such as infliximab. In animal studies, TNF‐α has been observed to play a key role in the pathophysiology of BIP.11 infliximab has shown a protective property against pulmonary fibrosis in mice, and rat models of bleomycin and methotrexate induced lung injury, by suppressing TNF‐α mediated cytokine expression and eosinophil recruitment.12, 13, 14 To our knowledge, there is no literature pertaining to the use of infliximab to treat BIP in humans. In this case report we present what we believe is the first documented use of infliximab to treat a critically ill patient with corticosteroid refractory BIP.\n\n2 CASE REPORT\nA 45‐year‐old woman with a history of stage IV Hodgkin's Lymphoma, which was diagnosed 6 months prior and treated with six cycles of Adriamycin (Doxorubicin), Bleomycin, Vinblastine, and Dacarbazine (ABVD) chemotherapy. Her other past medical history included depression and gastro‐esophageal reflux.\n\nThe patient initially presented to a rural emergency department 2 weeks after her sixth and final scheduled cycle of ABVD. She complained of increasing dyspnoea and paroxysmal nonproductive cough over the past several days. She denied fever, coryzal symptoms, or chest pain. She was tachypneic with a respiratory rate of 44 breaths per minute. Her oxygen saturation was 94% receiving supplemental oxygen of 10 L/min. Her blood and urine laboratory results were unremarkable with the exception of liver function derangement (alkaline phosphatase of 164 units/L and gamma glutamyl transferase of 282 units/L) which was pre‐existing. Her electrocardiogram demonstrated sinus rhythm without any ischemic changes. The chest x‐ray revealed widespread bilateral pulmonary infiltrates. The patient was treated for a suspected community acquired pneumonia. She was therefore treated with Ceftriaxone (1 g once daily), intravenous Azithromycin (500 mg once daily), and Oseltamivir (75 mg twice daily). She also received intravenous Hydrocortisone (100 mg four times daily). Due to nausea, Ceftriaxone was replaced by intravenous Moxifloxacin. As she was immunosuppressed, oral Trimethoprim/Sulfamethoxazole was added to empirically treat Pneumocystis jeroveci pneumonia (PJP). Blood and urine cultures revealed no growth of micro‐organisms. On day 2 and day 3, her condition deteriorated with fever, increased work of breathing and worsening hypoxia, which resulted in intubation and mechanical ventilation. Her repeat chest x‐ray revealed worsening bilateral pulmonary infiltrates. Due to limited resources at the rural hospital, she was subsequently transferred to our ICU.\n\nIn ICU, the antibiotic therapy was escalated to Cefepime and Vancomycin. Moxifloxacin was ceased, and Oseltamivir was later empirically changed to Aciclovir to cover herpes infection. Cisatracurium infusion was added to sedation in order to improve oxygenation and assist ventilation. Other therapies included Furosemide for suspected fluid overload and nebulised Iloprost for further improvement in her gas exchange.\n\nThe patient had a mild neutrophilic leucocytosis. Her procalcitonin levels were persistently normal. Repeated sputum and blood cultures, respiratory swabs, PJP serology, mycoplasma serology, respiratory viral polymerase chain reaction (PCR), hepatitis B serology, hepatitis C serology, and aspergillus (Galactomannan) were negative. Urinary Legionella pneumophilia serogroup 1 antigen and urinary pneumococcal antigens from the previous hospital and from our hospital were not detected.\n\nA fiberoptic bronchoscopy, performed by the treating intensivist, revealed mild inflammation at the carina and mucoid sputum in left bronchial tree. Washings from the alveolar bronchial lavage were negative for bacterial, acid‐fast bacilli, and fungal cultures, Mycoplasma, PJP, herpes simplex and zoster, cytomegalovirus PCRs and for cytology.\n\nA computed tomography and pulmonary angiogram (Figure 1) revealed diffuse ground‐glass appearance and consolidation of both lungs. Small segmental emboli in the right upper lobe and lateral basal right lower lobe branches were also detected. However, the thrombus load was not radiologically or echocardiographically significant enough to cause right heart strain or to warrant thrombolysis. Nonetheless, the pulmonary emboli were treated medically with subcutaneous enoxaparin.\n\nFigure 1 \nCT chest demonstrating extensive consolidation and ground glass opacification\n\nWith exclusion of infection and in consultation with our hematology team, there was an increasing suspicion of BIP. On day 4 of admission to ICU, pulsed intravenous methylprednisolone was commenced at a dose of 1 g daily for three consecutive days followed by a maintenance dose of 1 mg/kg daily for the remainder of admission. However, on day 6 of ICU admission, the patient's condition further deteriorated with worsening hypoxia (PaO2/FiO2 <100), poor ventilation, and increasing bilateral opacities on chest x‐ray. In light of persisting respiratory failure with no appreciable response to treatment and no identifiable infective cause, there was an increasing certainty surrounding the diagnosis of BIP.\n\nGiven its documented success in attenuating bleomycin‐induced pulmonary fibrosis in animal models, a single dose of infliximab was administered intravenously at a dose of 5 mg/kg. The patient was monitored for, and did not develop signs of an acute infusion reaction or hypersensitivity. She also did not appear to develop any observable acute adverse effects subsequent to treatment with Infliximab.\n\nOver the following week, the patient demonstrated no clinical improvement despite treatment. The patient was not considered to be suitable for extracorporeal oxygenation or lung transplantation due to the irreversible nature of lung injury. It was agreed that the prospects of recovery were exceedingly poor, and all parties including the family were of the view that ongoing treatment and attempts at therapy would be futile. The decision was made for palliation and comfort care. The patient passed away shortly after the withdrawal of ventilation and active treatment on day thirteen of ICU admission.\n\nDuring patient's admission, our ICU maintained consultation with specialist inpatient hematology, respiratory, infectious diseases, and general medical units regarding alternative diagnoses and approaches to management. Imaging studies were discussed with experienced radiologists at multidisciplinary meetings. In the setting of severe disease unresponsive to antimicrobial and glucocorticoid therapy, all teams were of the impression that the clinical, laboratory, and radiological features were most consistent with a diagnosis of fibrotic BIP. For this reason it was decided not to perform a postmortem lung biopsy. We note a number of cases in the literature where a confident clinical diagnosis of BIP has been made in the absence of tissue biopsy.15, 16\n\n\n3 DISCUSSION\nBleomycin‐induced pneumonitis is challenging to manage because it is a difficult condition to diagnose, patients often present late in the disease process and evidence to guide treatment is lacking. Beyond prompt discontinuation of bleomycin and a trial of glucocorticoids, there are no proven effective therapies for severe BIP requiring ICU admission. Hence, early identification is an important factor in successful treatment, because once fibrosis progresses to acute respiratory compromise the condition is almost exclusively irreversible.17, 18\n\n\nStudies have shown that inflammatory mediators, such as tumor necrosis factor alpha (TNF‐α) are heavily implicated in the pathophysiology of BIP.11, 19 In these studies, administration of bleomycin resulted in elevated levels of the TNF‐α ligand in mice, and deletion of TNF receptors prevented mice from developing bleomycin‐induced fibrosis.11, 19 In more recent animal trials, the TNF‐α inhibitor infliximab has demonstrated an ability to protect against BIP in mice11 and rats,14 a response attributed to its anti‐inflammatory and antifibrotic properties. Compared to administration of bleomycin alone, pretreatment with infliximab resulted in significantly reduced serum levels of inflammatory biomarkers and histological evidence of fibrosis in postmortem rat lung samples.14\n\n\nOur patient presented with acute, progressive, and severe disease. Therefore, we believed there was at least a partially inflammatory component of lung injury which may have responded to Infliximab. The fact that she did not improve with either glucocorticoid therapy or Infliximab, in the setting of six complete cycles of ABVD chemotherapy leads us to think this to be a BIP of mostly chronic fibrotic etiology. We note that infliximab has not been studied in human (or animal) models of late, severe pulmonary fibrosis.14\n\n\nTyrosine kinase inhibitors such as imatinib and Transforming growth factor beta (TGF‐β) inhibitors such as pirfenidone have had mixed results in the management of BIP.4, 15, 20, 21 Treatment success is mostly seen when these agents are commenced early in the inflammatory phase of BIP, reducing the likelihood of progression to end‐stage pulmonary fibrosis. Treatment with TGF‐β inhibitors also requires prolonged therapy of 6‐12 months, and usually in combination with oral corticosteroids.15, 20, 21 For this reason pirfenidone was unlikely to have provided benefit to our patient with severe, acute respiratory failure. However, the identification of agents that may assist in active prevention of BIP highlights the importance of regular monitoring and early identification of pneumonitis. Treatment with the aforementioned therapies may be associated with greater success in humans when administered in the early stages of, or prior to the development of BIP and subsequent fibrosis.\n\nThe current evidence also suggests that high concentration oxygen supplementation is associated with poorer outcomes in patients with BIP.1, 2 Therefore, future management strategies may consider reducing direct pulmonary oxygen administration via ventilation to reduce oxidative stress in combination with antifibrotic therapies. Furthermore, preventative strategies such as patient age selection, cumulative dose reduction particularly in renally impaired patients, avoidance of concurrent mediastinal radiation therapy, as well as close monitoring of pulmonary function should be considered.1, 2, 3, 22, 23, 24\n\n\n4 CONCLUSION\nGiven the current understanding of BIP, the use of TNF‐α inhibitors such as infliximab for late‐stage disease appears to be of limited benefit. Further research regarding prevention and management of advanced BIP is required.\n\nCONFLICT OF INTEREST\nThere are no competing interests.\n\nAUTHOR CONTRIBUTIONS\nVG: Preparing manuscript. IB: Preparing manuscript. RT: Revising manuscript. KH: Revising manuscript.\n==== Refs\nREFERENCES\n1 \n\nSleijfer \nS \n. Bleomycin‐induced pneumonitis . Chest . 2001 ;120 (2 ):617 ‐624 .11502668 \n2 \nBleomycin product information document submitted to Therapeutic Goods of Australia, Aspen Pharma Pty Ltd, Published on June 26, 2006 . https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2009-PI-00895-3&d=2018042816114622483. Accessed June 24, 2018.\n3 \n\nReinert \nT \n, \nSerodio da Rocha Baldotto \nC \n, \nPereira Nunes \nF \n, \nAlves de Souza Scheliga \nA \n. Bleomycin‐induced lung injury . J Cancer Res . 2013 ;480608 :9 .\n4 \n\nBanakh \nI \n, \nLam \nA \n, \nTiruvoipati \nR \n, \nCarney \nI \n, \nBotha \nJ \n. imatinib for bleomycin induced pulmonary toxicity: a case report and evidence‐base review . Clin Case Rep . 2016 ;4 (5 ):486 ‐490 .27190613 \n5 \n\nBrugge \nSS \n, \nClaasen \nHR \n, \nDawson \nL \n. Drug induced lung injury‐a case of fatal Bleomycin interstitial pneumonitis . Netherlands J Critical Care . 2013 ;17 :25 ‐29 .\n6 \n\nOliveira \nC \n, \nCosta \nG \n, \nOliveira \nD \n, \nTroster \nE \n, \nVaz \nF \n. Pulmonary toxicity induced by bleomycin in a patient with Hodgkin lymphoma . Crit Care . 2005 ;9 (2 ):91 .\n7 \n\nPatil \nN \n, \nPaulose \nRM \n, \nUdupa \nKS \n, \nRamakrishna \nN \n, \nAhmed \nT \n. Pulmonary toxicity of bleomycin – a case series from a tertiary care center in Southern India . J Clin Diag Res \n2016 ;10 (4 ):FR01 ‐FR03 .\n8 \n\nCarnevale‐Schianca \nF \n, \nGallo \nS \n, \nRota‐Scalabrini \nD \n, et al. Complete resolution of life‐threatening bleomycin‐induced pneumonitis after treatment with imatinib mesylate in a patient with Hodgkin's lymphoma: hope for severe chemotherapy‐induced toxicity? \nJ Clin Oncol . 2011 ;29 :e691 ‐e693 .21709191 \n9 \n\nJabbar \nL \n, \nVarghese \nST \n, \nVenugopal \nPP \n. Bleomycin induced lung injury. MIMS institute of emergency medicine website ; August 21, 2014 \nhttp://www.emergencymedicinemims.com/cmsPage.php?case=32. Accessed June 28, 2018.\n10 \n\nScherrer \nM \n, \nBechir \nM \n. Extracorporeal membrane oxygenation in presence of severe chemotherapy‐induced (bleomycin, etoposide and ifosfomide) interstitial fibrosis . SOJ Anesthesiol Pain Manag . 2014 ;1 :1 ‐4 .\n11 \n\nPiguet \nPF \n, \nCollart \nMA \n, \nGrau \nGE \n, \nKapanci \nY \n, \nVassalli \nP \n. Tumor necrosis factor/cachectin plays a key role in bleomycin‐induced pneumopathy and fibrosis . J Exp Med . 1989 ;170 :655 ‐663 .2475571 \n12 \n\nKurt \nA \n, \nTumkaya \nL \n, \nTurut \nH \n, et al. Protective effects of infliximab on lung injury induced by Methotrexate . Arch Bronconeumol . 2015 ;51 (11 ):551 ‐557 .26071367 \n13 \n\nZhang \nK \n, \nGharaee‐Kermani \nM \n, \nMcGarry \nB \n, \nRemick \nD \n, \nPhan \nSH \n. TNF‐alpha‐mediated lung cytokine networking and eosinophil recruitment in pulmonary fibrosis . J Immunol . 1997 ;158 (2 ):954 ‐959 .8993016 \n14 \n\nAltintas \nN \n, \nErboga \nM \n, \nAktas \nC \n, et al. Protective effect of Infliximab, a Tumor Necrosis Factor‐alfa inhibitor, on Bleomycin‐induced lung fibrosis in rats . Inflammation . 2016 ;39 (1 ):65 ‐78 .26253295 \n15 \n\nVaidya \nPJ \n, \nSandeepa \nHS \n, \nSingh \nT \n, et al. Combined prednisolone and pirfenidone in bleomycin‐induced lung disease . J Cancer Res Ther . 2016 ;12 (3 ):1198 ‐1202 .28054535 \n16 \n\nRashid \nRS \n. Bleomycin lung: a case report . BMJ Case Rep . 2008 ;2009 (bcr11 ):1175 .\n17 \n\nLiu \nT \n, \nDe Los Santos \nFG \n, \nPhan \nSH \n. The Bleomycin model of pulmonary fibrosis . Methods Mol Biol . 2017 ;1627 :27 ‐42 .28836192 \n18 \n\nFyfe \nA \n, \nMcKay \nP \n. Toxicities associated with bleomycin . J R Coll Physicians Edinb . 2010 ;40 (3 ):213 ‐215 .21127762 \n19 \n\nOrtiz \nLA \n, \nLasky \nJ \n, \nHamilton \nRF \nJr\n, et al. Expression of TNF and the necessity of TNF receptors in bleomycin‐induced lung injury in mice . Exp Lung Res . 1998 ;24 :721 ‐743 .9839161 \n20 \n\nBendstrup \nE \n, \nHyldgaard \nC \n, \nAgerbæk \nM \n, \nAndersen \nCU \n, \nHilberg \nO \n. No effect of pirfenidone treatment in fulminant bleomycin‐induced pneumonitis . Respir Med Case Rep . 2014 ;12 :47 ‐49 .26029540 \n21 \n\nSakamoto \nK \n, \nIto \nS \n, \nHashimoto \nN \n, \nHasegawa \nY \n. Pirfenidone as salvage treatment for refractory bleomycin‐induced lung injury: a case report of seminoma . BMC Cancer . 2017 ;17 (1 ):526 .28784103 \n22 \n\nCalzas Rodríguez \nJ \n, \nCarmen Juarez Morales \nMD \n, \nCasero \nMA \n. Death by bleomycin pulmonary toxicity in ovarian dysgerminoma with pathologic complete response to chemotherapy: a case report . Respir Med Case Rep . 2016 ;18 :48 ‐50 .27330950 \n23 \n\nDelanoy \nN \n, \nPécuchet \nN \n, \nFabre \nE \n, et al. Bleomycin‐induced pneumonitis in the treatment of ovarian sex cord‐stromal tumors: a systematic review and meta‐analysis . Int J Gynecol Cancer . 2015 ;25 (9 ):1593 ‐1598 .26308607 \n24 \n\nShippee \nBM \n, \nBates \nJS \n, \nRichards \nKL \n. The role of screening and monitoring for bleomycin pulmonary toxicity . J Oncol Pharm Pract . 2016 ;22 (2 ):308 ‐312 .25736276\n\n",
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"abstract": "A review of the medical literature failed to reveal clear, agreed-upon guidelines for practitioners on the postoperative provision of full agonist opioids for patients maintained on buprenorphine. Some controversy appears to exist about whether to maintain patients on their buprenorphine regimen up to the time of surgery. We describe the surgical outcomes and pain assessments for a series of five patients who underwent seven major surgical procedures. The patients were maintained on stable doses of sublingual buprenorphine. Postoperative pain was adequately controlled using full agonist opioids according to self-report and physician assessment. The observations from this case series lend support to the practice of maintaining stable buprenorphine dosing for patients who require major surgery.",
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"abstract": "BACKGROUND Nonsteroidal anti-inflammatory drugs (NSAIDs) and analgesics are the most commonly used drugs and are increasingly available over-the-counter (OTC). In certain groups of patients, including kidney transplant recipients, their use may be complicated by adverse effects or drug interactions. The aim of our study was to assess the causes and frequency of OTC NSAIDs or analgesics use, as well as the awareness of related side effects. MATERIAL AND METHODS We enrolled 94 randomly selected kidney transplant recipients, who represented 5% of all kidney transplant recipients at our center. An anonymous survey consisting of 23 multiple-choice questions was administered voluntarily and anonymously. RESULTS In all, 63% of study patients confirmed taking the OTC painkillers; 22% of these patients took these drugs at least several times a week, and 4% took these drugs daily. For 38% of the study kidney transplant recipients, NSAIDs or analgesics were reported to be the only way to manage their pain. In addition, 30% of study patients were unaware of the risks associated with these drugs, despite the fact that 89% of the study patients consider physicians the best source of information. CONCLUSIONS Our study found that 63% of kidney transplant recipients regularly took OTC painkillers and 30% were unaware of the potential adverse effects. This necessitates continuous, ongoing education of kidney transplant recipients about the risks of OTC NSAIDs or analgesics use.",
"affiliations": "Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland.;Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland.;Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland.;Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland.;Department of Internal Diseases with the Dialysis Unit, West Hospital of St. John Paul II, Grodzisk Mazowiecki, Poland.;Department and Clinic of General and Transplantation Surgery, Medical University of Warsaw, Warsaw, Poland.;Department and Clinic of General and Transplantation Surgery, Medical University of Warsaw, Warsaw, Poland.;Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland.;Department of General, Vascular and Transplant Surgery, Medical University of Warsaw, Transplantation Institute, , Poland.;Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland.",
"authors": "Mulka-Gierek|Maria|M|;Foroncewicz|Bartosz|B|;Pączek|Leszek|L|;Wawiórko|Elżbieta|E|;Kamińska|Joanna|J|;Kosieradzki|Maciej|M|;Małkowski|Piotr|P|;Małczuk|Bianka|B|;Nazarewski|Sławomir|S|;Mucha|Krzysztof|K|",
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"fulltext": "\n==== Front\nAnn TransplantAnn. TransplantAnnals of TransplantationAnnals of Transplantation1425-95242329-0358International Scientific Literature, Inc. 2949702810.12659/AOT.905856905856Original PaperNonsteroidal Anti-Inflammatory Drugs and Analgesics Use by Kidney Transplant Recipients Mulka-Gierek Maria 1ABCDEFForoncewicz Bartosz 1CDEPączek Leszek 12DEWawiórko Elżbieta 13BKamińska Joanna 4BKosieradzki Maciej 5BMałkowski Piotr 56EMałczuk Bianka 1ENazarewski Sławomir 7BMucha Krzysztof 12ABCDEF\n1 Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland\n2 Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland\n3 Department of Clinical Nursing, Medical University of Warsaw, Warsaw, Poland\n4 Department of Internal Diseases with The Dialysis Unit, West Hospital of St. John Paul II, Grodzisk Mazowiecki, Poland\n5 Department and Clinic of General and Transplantation Surgery, Medical University of Warsaw, Warsaw, Poland\n6 Department of Surgical and Transplantation Nursing, Faculty of Health Science, Warsaw Medical University, Warsaw, Poland\n7 Department of General, Vascular and Transplant Surgery, Medical University of Warsaw, Warsaw, PolandCorresponding Author: Krzysztof Mucha, e-mail: kjmucha@gmail.comA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\n2018 02 3 2018 23 153 159 20 6 2017 31 10 2017 © Ann Transplant, 20182018This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Background\nNonsteroidal anti-inflammatory drugs (NSAIDs) and analgesics are the most commonly used drugs and are increasingly available over-the-counter (OTC). In certain groups of patients, including kidney transplant recipients, their use may be complicated by adverse effects or drug interactions. The aim of our study was to assess the causes and frequency of OTC NSAIDs or analgesics use, as well as the awareness of related side effects.\n\nMaterial/Methods\nWe enrolled 94 randomly selected kidney transplant recipients, who represented 5% of all kidney transplant recipients at our center. An anonymous survey consisting of 23 multiple-choice questions was administered voluntarily and anonymously.\n\nResults\nIn all, 63% of study patients confirmed taking the OTC painkillers; 22% of these patients took these drugs at least several times a week, and 4% took these drugs daily. For 38% of the study kidney transplant recipients, NSAIDs or analgesics were reported to be the only way to manage their pain. In addition, 30% of study patients were unaware of the risks associated with these drugs, despite the fact that 89% of the study patients consider physicians the best source of information.\n\nConclusions\nOur study found that 63% of kidney transplant recipients regularly took OTC painkillers and 30% were unaware of the potential adverse effects. This necessitates continuous, ongoing education of kidney transplant recipients about the risks of OTC NSAIDs or analgesics use.\n\nMeSH Keywords\nAnalgesicsAnti-Inflammatory Agents, Non-SteroidalAwarenessData CollectionKidney TransplantationNonprescription Drugs\n==== Body\nBackground\nPain adversely impacts the quality of life [1,2], and thus, people search for effective methods of controlling pain. Nonsteroidal anti-inflammatory drugs (NSAIDs) or analgesics are the most frequently used pain relievers [3]. These drugs are becoming increasingly available over-the-counter (OTC) and are widely advertised to be safe and effective for the treatment of common illnesses [4–6]. However, when used inappropriately, these drugs may cause adverse effects, including gastrointestinal bleeding, or nephro-, hepato-, myelo-, or oto-toxicity [7–10]. Children and elderly are particularly vulnerable to the adverse effects associated with these drugs. Moreover, chronic diseases, dehydration, overdosing, or concomitant medication with other nephro- or hepato-toxic agents, including immunosuppression, may additionally predispose patients to the adverse effects of these drugs [11]. Patients after solid organ transplantation belong to the high toxicity-risk group [12]. However, it is not clear how many transplant patients regularly take or abuse OTC NSAIDs and analgesics. Since many transplant centers have no structured education programs with respect to OTC NSAIDs and analgesics use, kidney transplant recipients are advised on an individual patient-physician basis.\n\nThe purpose of this study was to assess in kidney transplant recipients the frequency of use and the reasons for using OTC NSAIDs or analgesics, as well as patient awareness of related adverse effects.\n\nMaterial and Methods\nThis was a retrospective, descriptive, and quantitative study using a 23-questions survey (Appendix 1). The study design did not require approval from the local ethics committee. Participation in this study was voluntary and anonymous, therefore, written informed consent was not obtained from the patients. In all, 94 study participants (5%) were randomly selected from 1,905 kidney transplant recipients who remained under post-transplant care at our department. The patients were approached by a registered nurse during routine outpatient visits and completed the survey in her presence. To reduce the likelihood of hypothesis guessing, the interviewees were kept blind to the research hypotheses.\n\nResults\nThe characteristics of study participants are presented in Table 1. The survey revealed that 63% of patients used NSAIDs or analgesic drugs. Of these patients, 64% purchased these drugs OTC. Figure 1 presents the frequency of NSAIDs or analgesics use, whereas Figure 2 depicts the time from the last dose to the time of the survey. The study results showed that 8% of kidney transplant recipients indicated that they suffered from everyday pain, located in different parts of their body; and 23% reported pain more than once a month, thus explaining the observed high frequency of drug use. What should be noted is that less than 4% of these patients complained about pain localized near their transplant organ. Since the period after kidney transplantation covered a wide span (2–23 years), we used the U Mann-Whitney test with correction for continuity in our analysis. It revealed that the frequency of drug consumption did not change significantly over time. Moreover, gender and increasing age had no statistically significant impact on the frequency of drug use.\n\nFigure 3 shows the reasons indicated by the study group that they used OTC NSAIDs or analgesics; reasons included headaches, join pain, toothaches, or menstrual pains. The most frequently used OTC drugs contained acetaminophen, metamizole sodium, and ibuprofen (Figure 4). Thirty-one patients (33%) took drugs other than those presented in Figure 4, in a combination with pseudoephedrine, caffeine, or codeine. Interestingly, 63% of the study participants also used such drugs before their transplantation. These results suggest that the majority of patients with chronic kidney disease regularly take this type of medication. However, a different study design would be needed to further analyze this study result in more detail.\n\nIn our study, 82% of kidney transplant recipients confirmed reading the drug information leaflet before drug use. Most of the patients understood the risks associated with taking OTC NSAIDs or analgesics. However, 30% of the kidney transplant recipients surveyed doubted that such effects happen. Figure 5 shows the potential side effects most commonly reported by the survey respondents. Their knowledge was based mainly on what they read in the leaflets provided with the OTC drugs.\n\nThe survey revealed that 89% of kidney transplant recipients identified doctors as the preferred and most reliable source of information about NSAIDs and analgesics. However, it was price, previous experience, and easy dosing that influenced the choice of the drug purchased. Half of the study cohorts indicated that advertisements did not influence their decision to buy certain drugs. In all, 38% of kidney transplant recipients in our study used only analgesics to treat their pain symptoms. Massages, physical therapy, or even waiting out the pain where mentioned as means of pain control.\n\nDiscussion\nThe results of our study indicated that the use of nonprescription analgesics is common among kidney transplant recipients. We found that 63% of kidney transplant recipients took OTC NSAIDs or analgesics. Moreover, one-third of kidney transplant recipients were unaware of the adverse effects associated with these drugs. Therefore, we suggest that the toxicity of these drugs should always be a clinical suspicion, especially if specific symptoms, such as edema, increased blood pleasure, decreased glomerular filtration rate, or increased serum creatinine, occur. It is also reasonable to encourage all transplant practitioners to provide continuous education to their patients regarding the use of these OTC agents. This could prevent or at least diminish uncontrolled drugs use, avoid possible drug interactions, and reduce related adverse effects and unnecessary healthcare costs. Transplant recipients are a non-homogenous group of patients with multiple comorbidities and variable pre-transplant medical histories. Immunosuppression used after transplantation may cause indirect and drug-related side effects. Additional use of NSAIDs or analgesic drugs may result in overlapping symptoms. Therefore, educational programs for such patients are needed.\n\nIn is important to note that cultural or country association is related to prescription strategies by physicians or OTC purchases by patients, as well as the intensity of follow-up by healthcare workers, including patient education on supplementary medication. Each country in the European Union independently determines how medicines are sold and how patients are educated. In many countries, a pharmacy monopoly persists, but it is also common for OTC drugs sales to take place in supermarkets, petrol stations, or kiosks. In the UK, simple analgesic compounds, up to 16 tablets, requires government approval to be available outside the pharmacy. In Ireland, medications available outside of pharmacies include paracetamol, acetylsalicylic acid, and ibuprofen in restricted doses and tablet numbers. In recent years, liberalization rather than tightening of these drug rules has occurred [13].\n\nOTC medicines and dietary supplements are often believed by consumers to be risk-free and used without consulting a physician [14]. It was previously reported that every eighth renal transplant recipient uses some form of complementary and alternative medicine. Of these, some herbal or Chinese medicines can interfere with immunosuppressive treatment [15]. In a previous study, we found that 30% of liver or renal transplant recipients used more than one dietary supplement or herbal supplement. In addition, patient awareness of the possible side effects and interactions with immunosuppressive drugs was poor [12,16]. Given the sales volume of OTC painkillers all over the world, one can speculate that the incidence rate of related adverse effects is much higher than that of dietary or herbal supplements. Accordingly, the costs of adverse effects management are also higher. This suggests appropriate patient education is needed.\n\nIt is estimated that one-third of the world population uses OTC medicines. Among the most frequently used are those containing acetaminophen or acetylsalicylic acid [3,17,18]. Unfortunately, our findings in a kidney transplant recipient population were consistent with this data. Also, the location of the pain in our patients was similar to the pain reported in the general population. The increasing consumption of OTC NSAIDs and analgesics worldwide is partially related to effective advertising. For many people, advertisements represent the primary source of information about drugs and treatment options. Limiting advertising as a method to reduce NSAIDs and analgesics use, and the costs of related adverse effects is a matter for debate. Our results suggest that price, dosing, and patient experience, and not advertisements, contributed the most to the choice of drug purchased. Interestingly, in our study, the majority of kidney transplant recipients believed that doctors were the most reliable source of knowledge about these drugs and expected them to be a source for patient education. But recent reports identified specific areas of patient education where doctors consider nurses more competent. However, in practice, the medical information from doctors and nurses should supplement each other [19]. Therefore, we emphasize the importance of cooperation between nurses and doctors in the education of their patients. This could prevent or at least diminish uncontrolled OTC drug use, avoid possible drug interactions, reduce related adverse effects and unnecessary healthcare costs.\n\nConclusions\nNSAIDs and analgesics are commonly used by kidney transplant recipients. However, a high proportion of kidney transplant recipients remain unaware of potentially dangerous drug interactions. The results of our study showed that dosing, previous experience, and price contributed the most to patient’s OTC drug choice. Thus, appropriate education on these drugs should be provided by health professionals to minimize adverse effects and healthcare costs rather than limiting advertising and drug availability [20].\n\nSource of support: Departmental sources\n\nAppendix 1\nFigure 1 The frequency of the over-the-counter nonsteroidal anti-inflammatory drugs or analgesics use by kidney transplant recipients.\n\nFigure 2 The time from the last dose of over-the-counter nonsteroidal anti-inflammatory drugs or analgesics to survey.\n\nFigure 3 The reason to use over-the-counter nonsteroidal anti-inflammatory drugs or analgesics.\n\nFigure 4 The most frequently consumed over-the-counter nonsteroidal anti-inflammatory drugs or analgesics by kidney transplant recipients.\n\nFigure 5 The awareness of related side effects of over-the-counter nonsteroidal anti-inflammatory drugs and analgesics.\n\nTable 1 Characteristics of 94 kidney transplant recipients.\n\nGender (male/female)\t53/41\t\nTime from transplantation to survey (years)\t23 to 2\t\nPrimary kidney disease:\t\nGlomerulonephritis\t43\t\nAutosomal recessive polycystic kidney disease\t17\t\nUnknown etiology\t12\t\nDiabetic kidney disease\t9\t\nReflux nephropathy\t4\t\nNephroangiosclerosis\t2\t\nIgA Nephropathy\t2\t\nNephrolithiasis\t1\t\nAlport syndrome\t1\t\nAmyloidosis\t1\t\nMixed connective tissue disease\t1\t\nBilateral renal artery stenosis\t1\n==== Refs\nReferences\n1 Gibson SJ Weiner DK Pain in older person IASP Press 2005 \n2 www.painineurope.com\n\n\n3 Kaufman DW Kelly JP Rosenberg L Recent patterns of medication use in the ambulatory adult population of the United States: The Slone survey JAMA 2002 287 337 44 11790213 \n4 Hersh EV Moore PA Ross GL Over-the-counter analgesics and antipyretics: A critical assessment Clin Ther 2000 22 500 48 10868553 \n5 Shi CW Bayard MA Abuse of over-the-counter medications among teenagers and young adults J Am Fam Physician 2011 84 745 50 \n6 Nuki G Doherty M Richette P Current management of gout: Practical messages from EULAR 2016 guidelines Pol Arch Intern Med 2017 127 4 267 77 28430170 \n7 Kwiecień S Magierowska K Śliwowski Z New insight into the mechanisms of gastroduodenal injury induced by nonsteroidal anti-inflammatory drugs: Practical implications Pol Arch Med Wewn 2015 125 191 98 25666703 \n8 Mucha K Foroncewicz B Koziak K The effects of indomethacin on angiogenic factors mRNA expression in renal cortex of healthy rats J Physiol Pharmacol 2007 58 165 78 \n9 Scanzello CR Moskowitz NK Gibofsky A The post-NSAID era: What to use now for the pharmacologic treatment of pain and inflammation in osteoarthritis Curr Rheumatol Rep 2008 10 49 56 18457612 \n10 Mosleh W Farkouh ME Balancing cardiovascular and gastrointestinal risks in patients with osteoarthritis receiving nonsteroidal anti inflammatory drugs Pol Arch Med Wewn 2016 126 68 75 26810416 \n11 Lanas A Pervez-Aisa MA Feu F A nationwide study of mortality associated with hospital admission due to severe gastrointestinal events and those associated with nonsteroidal antiinflammatory drug use Am J Gastroenterol 2005 100 1685 93 16086703 \n12 Mulka-Gierek M Foroncewicz B Florczak M The use of nonsteroidal anti-inflammatory drugs and analgesics by liver transplant recipients J Clin Nurs 2016 25 1001 5 26880399 \n13 Report on OTC drugs use in Poland (with commentaries) http://www.federacja-konsumentow.org.pl [in Polish] \n14 Fourrier-Réglat A Lacoin L Pariente A When patients report diseases that prescribers seem unaware of: discordance between patient and physician reporting of risk-related previous history in NSAID users from the CADEUS study Clin Pharmacol Ther 2010 88 668 75 20861835 \n15 Hess S De Geest S Halter K Prevalence and correlates of selected alternative and complementary medicine in adult renal transplant patients Clin Transplant 2009 23 56 62 18786136 \n16 Foroncewicz B Mucha K Florczak M Dietary supplements and herbal preparations in renal and liver transplant recipients Transplant Proc 2011 43 2935 37 21996193 \n17 Hudec R Kriska M Bozekova L Foltan V Comparison of NSAID consumption in Slovakia, Finland and Norway Bratisl Lek Listy 2008 109 370 73 18837248 \n18 Koffeman AR Valkhoff VE Celik S High-risk use of over-the-counter non-steroidal anti-inflammatory drugs: A population-based cross-sectional study Br J Gen Pract 2014 64 191 98 24686873 \n19 Roumie CL Griffin MR Over-the-counter analgesics in older adults: A call for improved labelling and consumer education Drugs Aging 2004 21 485 98 15182214 \n20 Amoako EP Richardson-Campbell L Kennedy-Malone L Self-medication with over -the-counter drugs among elderly adults J Gerontol Nurs 2003 29 10 15\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1425-9524",
"issue": "23()",
"journal": "Annals of transplantation",
"keywords": null,
"medline_ta": "Ann Transplant",
"mesh_terms": "D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D005260:Female; D007722:Health Knowledge, Attitudes, Practice; D006306:Health Surveys; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D004366:Nonprescription Drugs; D010146:Pain; D012189:Retrospective Studies; D066027:Transplant Recipients",
"nlm_unique_id": "9802544",
"other_id": null,
"pages": "153-159",
"pmc": null,
"pmid": "29497028",
"pubdate": "2018-03-02",
"publication_types": "D016428:Journal Article",
"references": "18457612;22010610;17440234;16086703;24686883;18837248;15182214;11790213;26810416;21996193;13677155;25666703;10868553;26880399;20861835;18786136;28430170",
"title": "Nonsteroidal Anti-Inflammatory Drugs and Analgesics Use by Kidney Transplant Recipients.",
"title_normalized": "nonsteroidal anti inflammatory drugs and analgesics use by kidney transplant recipients"
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"abstract": "Milk-alkali syndrome (MAS) is characterized by the triad of hypercalcemia, metabolic alkalosis, and acute kidney injury. Once thought to be a rare condition, there has been a resurgence of cases due to the consumption of calcium-containing supplements for osteoporosis prevention and dyspepsia in the general population. We describe the case of a female who presented with acute encephalopathy, hypercalcemia, and new-onset seizure. An extensive hypercalcemia workup and ruling out of other causes led to the diagnosis of MAS from excessive intake of calcium carbonate. Brain magnetic resonance imaging revealed signal abnormalities in the occipital and posterior parietal lobes that were indicative of posterior reversible encephalopathy syndrome. The patient's encephalopathy resolved after treatment of her hypercalcemia with fluid resuscitation and cessation of her calcium supplements. We present our case to highlight this unusual presentation of MAS, challenges in diagnosis, and briefly discuss the pathophysiology underlying hypercalcemia-induced encephalopathy.",
"affiliations": "Grand Strand Medical Center, 809 82nd Pkwy, Myrtle Beach, SC 29572, United States.;Grand Strand Medical Center, 809 82nd Pkwy, Myrtle Beach, SC 29572, United States.;Grand Strand Medical Center, 809 82nd Pkwy, Myrtle Beach, SC 29572, United States.",
"authors": "Vu|Khiem|K|;Becker|Gregory|G|;Eagerton|Donald|D|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1016/j.bonr.2020.100278",
"fulltext": "\n==== Front\nBone Rep\nBone Rep\nBone Reports\n2352-1872 Elsevier \n\nS2352-1872(20)30038-3\n10.1016/j.bonr.2020.100278\n100278\nArticle\nA 39 year-old woman with milk-alkali syndrome complicated by posterior reversible encephalopathy syndrome\nVu Khiem khiem.vu@hcahealthcare.coma⁎ Becker Gregory ab Eagerton Donald ac a Grand Strand Medical Center, 809 82nd Pkwy, Myrtle Beach, SC 29572, United States\nb Carolina Health Specialists - Pulmonary Care Center, 906 Medical Circle, Myrtle Beach, SC 29572, United States\nc Carolina Health Specialists - Endocrinology, 945 82nd Pkwy, Myrtle Beach, SC 29572, United States\n⁎ Corresponding author. khiem.vu@hcahealthcare.com\n04 5 2020 \n6 2020 \n04 5 2020 \n12 10027827 11 2019 22 4 2020 1 5 2020 © 2020 The Author(s)2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Milk-alkali syndrome (MAS) is characterized by the triad of hypercalcemia, metabolic alkalosis, and acute kidney injury. Once thought to be a rare condition, there has been a resurgence of cases due to the consumption of calcium-containing supplements for osteoporosis prevention and dyspepsia in the general population. We describe the case of a female who presented with acute encephalopathy, hypercalcemia, and new-onset seizure. An extensive hypercalcemia workup and ruling out of other causes led to the diagnosis of MAS from excessive intake of calcium carbonate. Brain magnetic resonance imaging revealed signal abnormalities in the occipital and posterior parietal lobes that were indicative of posterior reversible encephalopathy syndrome. The patient's encephalopathy resolved after treatment of her hypercalcemia with fluid resuscitation and cessation of her calcium supplements. We present our case to highlight this unusual presentation of MAS, challenges in diagnosis, and briefly discuss the pathophysiology underlying hypercalcemia-induced encephalopathy.\n\nKeywords\nMilk-alkali syndromePRESPosterior reversible encephalopathy syndromeHypercalcemiaSeizure\n==== Body\n1 Introduction\nMilk-alkali syndrome (MAS) was first described in the 1930s and is recognized by the classic triad of hypercalcemia, metabolic alkalosis, and acute kidney injury (Medarov, 2009; Patel et al., 2013). It is due to the overconsumption of calcium and absorbable antacids (i.e. calcium carbonate). The incidence of MAS substantially decreased by the 1980s due to the advent of histamine-2 receptor blockers and proton pump inhibitors for peptic ulcer disease. In the last several years however, there has been a resurgence of cases due to the widespread use of calcium carbonate for treatment of osteoporosis or dyspepsia (Beall et al., 2006; Yang et al., 2013; Manne, 2016; Tal and Powers, 1996; Kolnick et al., 2011; Etemadi and Bosselmann, 2018). In fact, MAS was found to be the third most common cause of hospitalization for hypercalcemia in an academic hospital, after hyperparathyroidism and malignancy (Beall and Scofield, 1995). It remains a diagnosis of exclusion after obtaining a compatible patient history and ruling out alternative causes of hypercalcemia. The signs and symptoms of MAS parallel those of hypercalcemia; in severe cases (Ca >14 mg/dL), manifestations include lethargy, nausea, vomiting, constipation, or cardiac arrhythmias. There have been rare descriptions of potentially life-threatening central nervous system (CNS) manifestations such as hypertensive encephalopathy or seizures (Dinnerstein et al., 2008; Nardone et al., 2016; Kashouty et al., 2011; Juvarra et al., 1985). In fact, a few cases of hypercalcemia associated with posterior reversible encephalopathy syndrome (PRES) have recently been reported (Choudhary and Rose, 2005; Camara-lemarroy et al., 2014; Chan et al., 2019; Moussawi et al., 2018). Although the mechanism underlying this association remains elusive, it is thought to involve reversible vasoconstriction, neuronal excitotoxicity, or inflammatory responses (Chan et al., 2019; Moussawi et al., 2018; Chen et al., 2004).\n\n2 Case report\nA 39 year-old female with a history of pre-eclampsia presented with acute changes in mental status. Two days before presentation, the patient had symptoms of general malaise, posterior headache, and multiple episodes of vomiting. She decided to take a nap at home, but 15 min later, her family members found her confused, actively vomiting, and speaking nonsensically.\n\nThe patient was brought to our emergency department. On initial evaluation, her blood pressure was 240/144 mmHg and heart rate was 140 bpm. The patient was awake but inattentive with frequent bouts of nonpurposeful and repeated speech, and left gaze palsy. After undergoing emergent head computed tomography (CT) scan, she developed two witnessed tonic clonic seizures with shaking of her left arm, and additional vomiting. Due to worsening hypoxia and unresponsiveness, the patient was intubated and transferred to the neurological intensive care unit (NICU).\n\nUpon further history, the patient had been taking calcium carbonate (1.5 g daily) for the past five years for dyspepsia. Due to worsening dyspepsia symptoms, she had been increasing her intake in excess of 6.0 g during the week prior to presentation. Other than pre-eclampsia with two previous pregnancies (two and five years ago), the patient had no other past medical history and was not on any other home medications. She had no prior history of seizure, head trauma, hypertension, cancer, atherosclerotic disease, kidney disease, or neurological disease. She reported consuming up to six alcoholic beverages daily but denied any other recreational drugs.\n\nInitial laboratory studies were notable for elevated calcium of 15 mg/dL (corrected for a mildly decreased albumin of 3.7 g/dL), creatinine 2.96 mg/dL, serum bicarbonate 34 mmol/L, white blood cell count of 12,000 cells/mm3, potassium 2.5 mEq/L, and magnesium 1.2 mg/dL. Arterial blood gas analysis revealed pH of 7.384, pO2 70.0 mmHg, and pCO2 46.4 mmHg. A pregnancy test was negative. Creatine kinase, serum alcohol, urinalysis, urine culture, blood culture, head CT, and head/neck CT angiography were unremarkable. Lumbar puncture was performed and other than a mildly elevated cerebrospinal fluid (CSF) glucose of 86 mg/dL and protein of 53 mg/dL, CSF was negative for bacteria, herpes simplex virus I and II DNA, and enterovirus RNA. However, brain magnetic resonance imaging (MRI) without contrast showed mild FLAIR signal abnormalities and cortical swelling of both occipital and posterior parietal lobes, consistent with PRES (Fig. 1, Fig. 2). Electroencephalogram (EEG) revealed diffuse disorganization with occasional admixed synchronous and asynchronous delta activity of both hemispheres, attributable to a post-ictal state.Fig. 1 Brain MRI demonstrating mild cortical fluid-attenuated inversion recovery (FLAIR) abnormalities in the occipital and posterior parietal lobes symmetrically.\n\nFig. 1Fig. 2 Brain MRI demonstrating mild cortical restricted diffusion within the occipital and posterior parietal lobes on diffusion-weighted imaging (DWI).\n\nFig. 2\n\nA hypercalcemia workup was performed. Parathyroid hormone (PTH) was at the lower range of normal (24.7 pg/mL). Serum thyroid stimulating hormone, phosphate, cortisol, alkaline phosphatase, serum and urine protein electrophoresis (with urine immunofixation), 25-hydroxyvitamin D, and vitamin A were within normal limits. Levels of 1,25-dihydroxyvitamin D and PTH-related peptide were appropriately suppressed at 5.9 pg/mL and <2.0 pmol/L, respectively. A random urinary calcium/creatinine ratio was >0.7, consistent with hypercalciuria (see Table 1 for reference ranges for biochemical data). After excluding primary hyperparathyroidism, malignancy, and other causes of hypercalcemia, we diagnosed the patient with milk-alkali syndrome due to calcium carbonate overingestion.Table 1 Reference intervals of selected biochemical data compared with patient's values.\n\nTable 1Parameter\tReference range\tPatient's value\t\nTotal calcium\t8.5–10.1 mg/dL\t15.0 mg/dL\t\nPTH\t18.5–88 pg/mL\t24.7 pg/mL\t\nPTH-related peptide\t<2.5 pmol/L\t<2.0 pmol/L\t\n1,25-Dihydroxyvitamin D\t19.9–79.3 pg/mL\t5.9 pg/mL\t\nUrinary calcium/creatinine\t<0.14\t>0.70\t\npH\t7.35–7.45\t7.384\t\npO2\t80.0–100.0 mmHg\t70.0 mmHg\t\npCO2\t35.0–45.0 mmHg\t46.4 mmHg\t\nBicarbonate\t21–32 mmol/L\t34 mmol/L\t\n\n\nThe patient's hypercalcemia, hypertension, and other lab abnormalities resolved with fluid resuscitation, pamidronate, calcitonin, and medical management of hypertension and seizures. She was extubated by day 5 and upon regaining her normal mental status, was able to confirm her medical history and details of her present illness. Other than residual dysmetria on finger-to-nose exam and difficulty with fine motor tasks, the patient had an otherwise normal neurological exam with intact speech, executive functioning, and no other motor or sensory deficits. She had no additional seizures throughout her hospital stay and was counseled on the nature of her diagnosis and alternative medications for dyspepsia.\n\n3 Discussion\nMilk-alkali syndrome, originally named in association with the use of milk and absorbable antacids for treatment of peptic ulcer disease, is experiencing a resurgence in recent years. This is partly due to the use of calcium-containing supplements for treatment or prevention of osteoporosis, and treatment of dyspepsia. Among patients hospitalized for hypercalcemia in an academic medical center, MAS was estimated to be the third most common cause behind primary hyperparathyroidism and cancer (Beall and Scofield, 1995). The diagnosis relies on excluding other causes of hypercalcemia, such as thyrotoxicosis, malignancy, hyperparathyroidism, granulomatous diseases, adrenal insufficiency, rhabdomyolysis, and certain medications. Despite our patient's PTH level technically remaining in the low-normal range, the diagnosis of milk-alkali syndrome was reached with a high degree of certainty given the compatible history of calcium carbonate overingestion during the few days prior to admission, the acute nature of her symptoms, and the characteristic triad of hypercalcemia, metabolic alkalosis, and acute kidney injury seen in MAS. Moreover, cases of PTH-independent hypercalcemia are almost always correlated with PTH levels below 20–25 pg/mL (Haden et al., 2000). Primary hyperparathyroidism typically presents in post-menopausal women with minimal to no symptoms, with labs showing an increased serum 1,25-dihydroxyvitamin D (Kinoshita et al., 2005; Moosgaard et al., 2006; Silverberg et al., 1999); the lack of these characteristics further argued against primary hyperparathyroidism.\n\nOur case was complicated by the development of new-onset seizure and brain MRI findings suggestive of posterior reversible encephalopathy syndrome. PRES is a clinical syndrome consisting of headache, acute encephalopathy, visual disturbances, seizure activity, and vasogenic edema predominantly affecting the parietal and occipital lobes. It typically develops in the setting of severe hypertension, pre-eclampsia, and certain immunosuppressive agents (Camara-lemarroy et al., 2014; Chen et al., 2004; Mckinney et al., 2007; Bhagavati and Choi, 2008). Management involves blood pressure control and addressing suspected triggers. Several reports have pointed to hypercalcemia, regardless of the cause, as an additional risk factor associated with PRES (Choudhary and Rose, 2005; Camara-lemarroy et al., 2014; Chan et al., 2019; Moussawi et al., 2018). The exact mechanism remains uncertain, but several lines of evidence point to reversible vasoconstriction in the posterior cerebral arteries, neuronal excitotoxicity, inflammatory responses, or hypertensive encephalopathy (Chan et al., 2019; Moussawi et al., 2018; Chen et al., 2004).\n\nAlthough hypercalcemia is considered to be a risk factor for PRES, it is difficult to ascertain whether it was the definitive cause in our patient. On presentation, there were concurrent findings of malignant hypertension and hypomagnesemia; these are considered risk factors for PRES but are also known to be direct manifestations of hypercalcemia (Moussawi et al., 2018). Alcohol consumption, as in our patient, is also thought to be a culprit in recent reports (Mckinney et al., 2007; Bhagavati and Choi, 2008; Ishikawa et al., 2013). Furthermore, due to the shared cellular processes of vasospasm and membrane instability that underlie both eclampsia and PRES (Moussawi et al., 2018), we speculate whether our patient's history of pre-eclampsia conferred additional risk. The pathophysiology of PRES is an evolving area that will be better elucidated with further clinical experience and investigation.\n\nDeclaration of competing interest\nThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\n\nAcknowledgements\nWe thank the service of our resident physicians, teaching faculty (critical care, endocrinology, neurology), and nursing staff at Grand Strand Medical Center in the care of this patient. Most of all, we thank the patient and her family for consenting to the presentation of her case.\n\nHCA disclaimer\nThis research was supported (in whole or in part) by HCA and/or an HCA affiliated entity. The views expressed in this publication represent those of the author(s) and do not necessarily represent the official views of HCA or any of its affiliated entities.\n==== Refs\nReferences\nBeall D.P. Scofield R.H. Milk-alkali syndrome associated with calcium carbonate consumption. Report of 7 patients with parathyroid hormone levels and an estimate of prevalence among patients hospitalized with hypercalcemia Medicine (Baltimore) 74 2 1995 89 96 7891547 \nBeall D.P. Henslee H.B. Webb H.R. Scofield R.H. Milk-alkali syndrome: a historical review and description of the modern version of the syndrome Am J Med Sci 331 5 2006 233 242 16702792 \nBhagavati S. Choi J. Atypical cases of posterior reversible encephalopathy syndrome. Clinical and MRI features Cerebrovasc. Dis. 26 5 2008 564 566 18936538 \nCamara-lemarroy C.R. Gonzalez-moreno E.I. Ortiz-corona Jde J. Posterior reversible encephalopathy syndrome due to malignant hypercalcemia: physiopathological considerations J. Clin. Endocrinol. Metab. 99 4 2014 1112 1116 24476076 \nChan T.L.H. Mayich M. Budhram A. Sallam Y. Becker W.J. Teaching images in headache: concurrent hypercalcemia-induced reversible cerebral vasoconstriction syndrome and posterior reversible encephalopathy syndrome Headache 59 6 2019 933 935 30985912 \nChen T.H. Huang C.C. Chang Y.Y. Chen Y.F. Chen W.H. Lai S.L. Vasoconstriction as the etiology of hypercalcemia-induced seizures Epilepsia 45 5 2004 551 554 15101837 \nChoudhary M. Rose F. Posterior reversible encephalopathic syndrome due to severe hypercalcemia in AIDS Scand. J. Infect. Dis. 37 6–7 2005 524 526 16012020 \nDinnerstein E. Mcdonald B.C. Cleavinger H.B. Thadani V.M. Jobst B.C. Mesial temporal sclerosis after status epilepticus due to milk alkali syndrome Seizure 17 3 2008 292 295 17804261 \nEtemadi T.R. Bosselmann H.S. Hypercalcaemia due to the milk-alkali syndrome Ugeskr Laeg 180 7 2018 \nHaden S.T. Brown E.M. Hurwitz S. Scott J. El-hajj fuleihan G. The effects of age and gender on parathyroid hormone dynamics Clin. Endocrinol. 52 3 2000 329 338 \nIshikawa H. Natsume N. Matsui K. Tsuda H. Acute alcohol withdrawal accompanied by posterior reversible encephalopathy syndrome Psychiatry Clin. Neurosci. 67 3 2013 189 \nJuvarra G. Bettoni L. Olivieri M.F. Bortone E. Cavatorta A. Hypercalcemic encephalopathy in the course of hyperthyroidism Eur. Neurol. 24 2 1985 121 127 3979417 \nKashouty R. Yono N. Al samara M. Status epilepticus secondary to milk-alkali syndrome induced by hypercalcemia (oral antacids) Seizure 20 8 2011 659 661 21514851 \nKinoshita Y. Taguchi M. Takeshita A. Miura D. Tomikawa S. Takeuchi Y. 1,25-Dihydroxyvitamin D suppresses circulating levels of parathyroid hormone in a patient with primary hyperparathyroidism and coexistent sarcoidosis J. Clin. Endocrinol. Metab. 90 12 2005 6727 6731 16159932 \nKolnick L. Harris B.D. Choma D.P. Choma N.N. Hypercalcemia in pregnancy: a case of milk-alkali syndrome J. Gen. Intern. Med. 26 8 2011 939 942 21347876 \nManne J.R. STriking resemblance: calcium-alkali syndrome Am. J. Med. 129 8 2016 816 818 27154772 \nMckinney A.M. Short J. Truwit C.L. Posterior reversible encephalopathy syndrome: incidence of atypical regions of involvement and imaging findings AJR Am. J. Roentgenol. 189 4 2007 904 912 17885064 \nMedarov B.I. Milk-alkali syndrome Mayo Clin. Proc. 84 3 2009 261 267 19252114 \nMoosgaard B. Vestergaard P. Heickendorff L. Melsen F. Christiansen P. Mosekilde L. Plasma 25-hydroxyvitamin D and not 1,25-dihydroxyvitamin D is associated with parathyroid adenoma secretion in primary hyperparathyroidism: a cross-sectional study Eur. J. Endocrinol. 155 2 2006 237 244 16868136 \nMoussawi K. Meltzer E.I. Levin S.N. Prasad S. Paraneoplastic PRES from lymphoma induced hypercalcemia: case report and review of the literature eNeurologicalSci 13 2018 24 25 30456318 \nNardone R. Brigo F. Trinka E. Acute symptomatic seizures caused by electrolyte disturbances J Clin Neurol 12 1 2016 21 33 26754778 \nPatel A.M. Adeseun G.A. Goldfarb S. Calcium-alkali syndrome in the modern era Nutrients 5 12 2013 4880 4893 24288027 \nSilverberg S.J. Shane E. Jacobs T.P. Siris E. Bilezikian J.P. A 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery N. Engl. J. Med. 341 17 1999 1249 1255 10528034 \nTal A. Powers K. Milk-alkali syndrome induced by 1,25(OH)2D in a patient with hypoparathyroidism J. Natl. Med. Assoc. 88 5 1996 313 314 8667442 \nYang J.D. Lawson P. Beland S. Severe hypercalcemia from the milk-alkali syndrome Am. J. Med. 126 9 2013 e1 e2\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2352-1872",
"issue": "12()",
"journal": "Bone reports",
"keywords": "Hypercalcemia; Milk-alkali syndrome; PRES; Posterior reversible encephalopathy syndrome; Seizure",
"medline_ta": "Bone Rep",
"mesh_terms": null,
"nlm_unique_id": "101646176",
"other_id": null,
"pages": "100278",
"pmc": null,
"pmid": "32455151",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports",
"references": "10718831;8667442;3979417;23830540;27154772;17885064;17804261;30456318;7891547;30985912;10528034;16702792;18936538;21347876;23581872;16012020;19252114;16868136;29465034;15101837;16159932;21514851;24476076;26754778;24288027",
"title": "A 39 year-old woman with milk-alkali syndrome complicated by posterior reversible encephalopathy syndrome.",
"title_normalized": "a 39 year old woman with milk alkali syndrome complicated by posterior reversible encephalopathy syndrome"
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"abstract": "BACKGROUND Splenic cysts are rare. Most are due to previous trauma, infection, or infarction. They are generally handled by laparoscopic surgical removal if they are larger than 5 cm. However, very large cysts may require splenectomy. Another factor in the choice of therapy is the patient's underlying condition. We present the case of a giant splenic cyst in a woman 1 year after a renal transplant. CASE REPORT A 28-year-old woman presented with acute abdominal pain and nausea. One year before, she had received an ABO-identical living donor renal transplantation from her father, and was maintained on oral tacrolimus and prednisolone. A CT scan with contrast showed enteric ileus and an abnormal position of the spleen, which was involved by a cyst measuring 12×12.5×9 cm. A nasogastric tube, and later a small bowel tube, were inserted to decompress the ileus. The patient underwent laparotomy 11 days after admission. We confirmed an internal hernia with volvulus due to migration of the spleen; however, there was no evidence of necrosis. The patient was treated with splenectomy and reduction of the hernia. There were no complications. CONCLUSIONS This was a very unusual emergency following renal transplantation. Splenectomy has been performed in the past for immunosuppression in cases of donor ABO-incompatibility. We therefore considered that it would be more expedient to remove the spleen than to remove the cyst and perform splenopexy.",
"affiliations": "Department of Transplant Surgery, University Hospital Kyoto Prefectural University of Medicine, Kyoto City, Kyoto, Japan.;Department of Transplant Surgery, University Hospital Kyoto Prefectural University of Medicine, Kyoto City, Kyoto, Japan.;Department of Transplant Surgery, University Hospital Kyoto Prefectural University of Medicine, Kyoto City, Kyoto, Japan.;Department of Transplant Surgery, University Hospital Kyoto Prefectural University of Medicine, Kyoto City, Kyoto, Japan.;Department of Transplant Surgery, University Hospital Kyoto Prefectural University of Medicine, Kyoto City, Kyoto, Japan.;Department of Transplant Surgery, University Hospital Kyoto Prefectural University of Medicine, Kyoto City, Kyoto, Japan.",
"authors": "Matsuyama|Takehisa|T|;Nakao|Toshimasa|T|;Harada|Shumpei|S|;Nakamura|Tsukasa|T|;Nobori|Shuji|S|;Ushigome|Hidetaka|H|",
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"doi": "10.12659/AJCR.916845",
"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 3137169510.12659/AJCR.916845916845ArticlesA Case of Small Intestinal Ileus Due to Wandering Spleen with a Large Cyst Matsuyama Takehisa ABCDEFNakao Toshimasa BCDHarada Shumpei BCDNakamura Tsukasa EFNobori Shuji EFGUshigome Hidetaka DEFGDepartment of Transplant Surgery, University Hospital Kyoto Prefectural University of Medicine, Kyoto City, Kyoto, JapanAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\nCorresponding Author: Takehisa Matsuyama, e-mail: tm0904@koto.kpu-m.ac.jp2019 02 8 2019 20 1138 1140 06 4 2019 05 6 2019 © Am J Case Rep, 20192019This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Female, 28\n\nFinal Diagnosis: Ileus due to wandering spleen with a cyst\n\nSymptoms: Acute abdominal pain\n\nMedication: —\n\nClinical Procedure: Tube decompression • laparotomy\n\nSpecialty: Abdominal Surgery • Transplant Surgery\n\nObjective:\nRare disease\n\nBackground:\nSplenic cysts are rare. Most are due to previous trauma, infection, or infarction. They are generally handled by laparoscopic surgical removal if they are larger than 5 cm. However, very large cysts may require splenectomy. Another factor in the choice of therapy is the patient’s underlying condition. We present the case of a giant splenic cyst in a woman 1 year after a renal transplant.\n\nCase Report:\nA 28-year-old woman presented with acute abdominal pain and nausea. One year before, she had received an ABO-identical living donor renal transplantation from her father, and was maintained on oral tacrolimus and prednisolone. A CT scan with contrast showed enteric ileus and an abnormal position of the spleen, which was involved by a cyst measuring 12×12.5×9 cm. A nasogastric tube, and later a small bowel tube, were inserted to decompress the ileus. The patient underwent laparotomy 11 days after admission. We confirmed an internal hernia with volvulus due to migration of the spleen; however, there was no evidence of necrosis. The patient was treated with splenectomy and reduction of the hernia. There were no complications.\n\nConclusions:\nThis was a very unusual emergency following renal transplantation. Splenectomy has been performed in the past for immunosuppression in cases of donor ABO-incompatibility. We therefore considered that it would be more expedient to remove the spleen than to remove the cyst and perform splenopexy.\n\nMeSH Keywords:\nHerniaIleusIntestinal VolvulusSpleen\n==== Body\nBackground\nSplenic cysts are unusual. Approximately 25% are primary (i.e., containing an epithelial lining), and can be congenital or the result of parasitic infestation or neoplasm. Secondary cysts are usually due to trauma, and can also be associated with infection and prior splenic infarct. Cysts larger than 5 cm are generally removed laparoscopically [1]. Very large cysts, or cysts in patients with comorbidities, present more of a challenge. Successful laparoscopic cystectomy has been performed in a pregnant patient [2]. A cyst in a wandering spleen is also quite challenging; with its associated risk of splenic torsion, it is usually treated with splenectomy [3–5].\n\nCase Report\nA 28-year-old woman presented with acute lower abdominal pain and nausea. Her past history was significant for a live donor renal transplant from her father 1 year prior to presentation. Physical examination revealed a mass in the mid-lower abdomen. There was no rebound tenderness. She denied recent trauma. Laboratory tests revealed dehydration but normal renal function. A contrast-enhanced abdominal CT (Figure 1) showed evidence of ileus, and a wandering spleen with a large cyst (12×12.5×9 cm) was identified in the lower abdomen. We first inserted a nasogastric (NG) tube, which was then substituted with a 16-Fr small bowel tube to decompress the small intestine, and then started infusion of fluids and electrolytes. Tacrolimus and prednisolone were administered intravenously. The abdominal distention and pain gradually resolved, and C-reactive protein (CRP) improved from 44.4 nmol/L on admission to 6.29 nmol/L 10 days later. Laparotomy was performed under general anesthesia via a midline lower abdominal incision on POD 11. A wandering spleen with giant cyst was confirmed (Figure 2) and was noted to compress the small intestine. A small amount of ascites was noted. We drew fluid from the giant cyst by fine-needle aspiration to reduce its volume. An internal hernia was present, with small bowel incarcerated between the spleen and splenic hilum (Figure 3). There was no evidence of intestinal ischemia. We performed a splenectomy and reduced the internal hernia. The histopathological diagnosis was epithelial cyst of the spleen. The postoperative course was uneventful and she left the hospital 7 days after the operation.\n\nDiscussion\nThe spleen is fixed by the gastrosplenic, splenorenal, phrenosplenic, and splenocolic ligaments. Wandering spleen occurs when these ligaments are not fully developed or are abnormally attached [6]. The male-to-female ratio is 1: 4 and occurrence is highest in young people aged less than 40 years [7]. In the case of splenic infarction, splenectomy is indicated, but splenopexy is an option if the spleen is not ischemic. To date, few studies have reported a wandering spleen with giant cyst [6], and the approach to treatment is controversial. In the present case, no splenic infarction was identified on CT, and the kidney graft she received 1 year previously required protection. Accordingly, we inserted a long tube for decompression and corrected her dehydration. Eleven days after admission, she underwent elective surgery. The size of the incision was not conducive to splenopexy, so we performed splenectomy. The postoperative course was uneventful.\n\nSplenectomy in liver transplantation has been controversial; it is usually avoided in deceased donor transplants due to an increased risk of sepsis, but is often used with living donor transplantation to reduce portal venous pressure, especially in small-sized grafts, without increasing the risk of sepsis [7].\n\nIn renal transplantation, splenectomy, or its medical equivalent, rituximab, has been employed to reduce de novo [8] or pre-existing [9,10] HLA antibody production. An inhibitory effect for rituximab or splenectomy has not been found against de novo Ab production [3], while different, desensitizing procedures (plasmapheresis, IVIg) to remove pre-existing antibodies have been shown to be equally effective as rituximab or splenectomy [9], although early death rates in ABO-incompatible recipients were higher [10].\n\nConclusions\nHere, we present an unusual case of wandering spleen with a large cyst causing internal herniation and ileus of the small bowel in a living related-donor renal transplant patient. Given the need for immunosuppression and the need to protect the graft from the risks of a long operation, the decision to remove the spleen was based on limiting the extent of surgery.\n\nWe thank Libby Cone, MD, MA, from DMC Corp. (www.dmed.co.jp) for editing drafts of this manuscript.\n\nConflict of interest\n\nNone.\n\nFigure 1. Contrast-enhanced CT (coronal). A thinned wandering spleen with a giant cyst in the pelvic cavity (yellow arrow) is surrounded by a distended small bowel and compresses the bladder in the left lower pelvis. A functioning transplanted kidney is present in the left iliac fossa (red arrow).\n\nFigure 2. The spleen with cyst.\n\nFigure 3. Internal hernia was confirmed.\n==== Refs\nReferences:\n1. Craig DH Campbell DC Powell MS Laparoscopic splenectomy for giant splenic cyst Am Surg 2015 81 E390 91 26672576 \n2. Kapp J Lewis T Glasgow S Spleen preserving management of a non-parasitic splenic cyst in pregnancy Ann R Coll Surg Engl 2016 98 e114 17 27167310 \n3. Flippin JA Fisher P Long J Splenic torsion presenting as splenic vein thrombosis J Pediatr Surg Case Rep 2017 18 13 15 \n4. Samarasinghe RN Protyniak B Bethel CAI Wandering spleen and splenic torsion associated with upper respiratory tract infection J Pediatr Surg Case Rep 2013 1 129 31 \n5. Güngör Ş Öztürk M Varol Fİ Torsion of a wandering spleen in an adolescent with Gaucher disease Turk J Gastroenterol 2017 28 303 6 28699604 \n6. Baglaj M Czernik J Epidermoid cyst in a wandering spleen Pediatr Surg Int 1998 14 113 15 9880716 \n7. Liu HT Lau KK Wandering spleen: An unusual association with gastric volvulus Am J Roentgenol 2007 188 W328 30 17376999 \n8. Badawy A Hamaguchi Y Satoru S Evaluation of safety of concomitant splenectomy in living donor liver transplantation: A retrospective study Transpl Int 2017 30 914 23 28512755 \n9. Ashimine S Watarai Y Yamamoto T Neither pre-transplant rituximab nor splenectomy affects de novo HLA antibody production after renal transplantation Kidney Int 2014 85 425 30 23945498 \n10. Macklin P Morris PJ Knight SR A systematic review of the use of rituximab for desensitization in renal transplantation Transplantation 2014 98 794 805 25321163\n\n",
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"mesh_terms": "D015746:Abdominal Pain; D000328:Adult; D003560:Cysts; D005260:Female; D006801:Humans; D045823:Ileus; D007421:Intestine, Small; D016030:Kidney Transplantation; D013156:Splenectomy; D050805:Wandering Spleen",
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"references": "17376999;23945498;25321163;26672576;27167310;28512755;28699604;9880716",
"title": "A Case of Small Intestinal Ileus Due to Wandering Spleen with a Large Cyst.",
"title_normalized": "a case of small intestinal ileus due to wandering spleen with a large cyst"
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"abstract": "Children with homozygous familial hypercholesterolemia are at risk for early cardiovascular events secondary to coronary artery disease. Current medical therapy does not ameliorate this risk. Liver transplantation offers the most effective option to reduce circulating levels of low-density lipoprotein cholesterol and thereby reduce risk of cardiovascular events. Angiographic evidence of regression of coronary artery disease is presented.",
"affiliations": "Texas Children's Hospital Heart Center, Pediatric Cardiology, Houston, TX; Department of Pediatrics, Baylor College of Medicine, Houston, TX. Electronic address: cecephus@texaschildrens.org.;Texas Children's Hospital Heart Center, Pediatric Cardiology, Houston, TX; Department of Pediatrics, Baylor College of Medicine, Houston, TX.;Texas Children's Hospital Heart Center, Pediatric Cardiology, Houston, TX; Department of Pediatrics, Baylor College of Medicine, Houston, TX.;Margaret M and Albert B Alkek Department of Medicine, Cardiology, Baylor College of Medicine, Houston, TX.;Texas Children's Hospital Heart Center, Pediatric Cardiology, Houston, TX; Department of Pediatrics, Baylor College of Medicine, Houston, TX.",
"authors": "Cephus|Constance E|CE|;Qureshi|Athar M|AM|;Sexson Tejtel|S Kristen|SK|;Alam|Mahboob|M|;Moodie|Douglas S|DS|",
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"issue": "13(6)",
"journal": "Journal of clinical lipidology",
"keywords": "Angiogram; Cardiac catheterization; Coronary atherosclerosis; Genetic; LDL receptor; Liver transplantation; Pediatric; Regression; Treatment",
"medline_ta": "J Clin Lipidol",
"mesh_terms": "D000328:Adult; D006328:Cardiac Catheterization; D002675:Child, Preschool; D003324:Coronary Artery Disease; D005260:Female; D006801:Humans; D006938:Hyperlipoproteinemia Type II; D016031:Liver Transplantation; D008297:Male; D010375:Pedigree; D011973:Receptors, LDL; D055815:Young Adult",
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"title": "Coronary artery disease in a child with homozygous familial hypercholesterolemia: Regression after liver transplantation.",
"title_normalized": "coronary artery disease in a child with homozygous familial hypercholesterolemia regression after liver transplantation"
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"abstract": "Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disease frequently associated with ovarian teratomas. In cases where an ovarian teratoma is identified, treatment involves prompt removal of the ovarian teratoma, resulting in significant clinical improvement and decreased incidence of relapse. We present the case of a 14-year-old female patient admitted for progressively worsening psychiatric and neurological status, diagnosed with anti-NMDAR encephalitis, and negative initial imaging for ovarian pathology. She was in the hospital for 8 months requiring admission to the intensive care unit and multiple courses of immunotherapy before clinical improvement. Three months after discharge, she was readmitted with clinical relapse and repeat imaging showed an ovarian teratoma. Removal of the teratoma resulted in sustained clinical improvement with return to baseline and no further relapse. Our case report highlights the importance of maintaining a high suspicion for an underlying ovarian teratoma in a female patient with anti-NMDAR encephalitis, even when initial imaging is negative. Currently, there are limited data on recommendations for repeat imaging. Therefore, we recommend repeat imaging in patients resistant to multiple lines of treatment or presenting with clinical relapse.",
"affiliations": "Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA cwalker0812@gmail.com.;Pathology, Children's Hospital of Michigan, Detroit, Michigan, USA.;Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA.",
"authors": "Walker|Christopher A|CA|http://orcid.org/0000-0002-6513-0901;Poulik|Janet|J|;D'Mello|Rahul J|RJ|http://orcid.org/0000-0001-8343-0572",
"chemical_list": "D016194:Receptors, N-Methyl-D-Aspartate",
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"issue": "14(7)",
"journal": "BMJ case reports",
"keywords": "epilepsy and seizures; neurological injury; paediatric intensive care; radiology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000293:Adolescent; D060426:Anti-N-Methyl-D-Aspartate Receptor Encephalitis; D005260:Female; D006801:Humans; D007167:Immunotherapy; D009364:Neoplasm Recurrence, Local; D010051:Ovarian Neoplasms; D016194:Receptors, N-Methyl-D-Aspartate; D013724:Teratoma",
"nlm_unique_id": "101526291",
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"title": "Anti-NMDA receptor encephalitis in an adolescent with a cryptic ovarian teratoma.",
"title_normalized": "anti nmda receptor encephalitis in an adolescent with a cryptic ovarian teratoma"
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"abstract": "Epidermal growth factor receptor (EGFR) is the most common driver gene involved in non small cell lung cancer (NSCLC) growth, being found in approximately 10-15% of Caucasian and 40% of Asian patients. A wide variety of pathogenic mutations, deletions, insertions and duplications have been described in EGFR exons 18-21. The presence of the most common among them (e.g. exon 21 L851R and exon 19 deletions) is associated to response to first and second generation EGFR tyrosine kinase inhibitors (TKIs), which have demonstrated clear superiority over chemotherapy in terms of both progression free survival (PFS) and overall survival (OS) in all treatment lines. However, scarcity of data exists in literature about the response of rarer EGFR alterations to first and second generation TKIs, most works consisting in sporadic case reports and small case series. In this review we aim to discuss the available evidence about this topic, in order to derive suggestions for clinical practice. Furthermore, we report seven cases of patients with lung tumors harboring uncommon EGFR mutations, treated in our Institution with first or second generation TKIs.",
"affiliations": "Medical Oncology Department, Fondazione IRCCS Istituto Nazionale di Tumori, via G. Venezian 1, 20133, Milan, Italy.;Medical Oncology Department, Fondazione IRCCS Istituto Nazionale di Tumori, via G. Venezian 1, 20133, Milan, Italy.;Medical Oncology Department, Fondazione IRCCS Istituto Nazionale di Tumori, via G. Venezian 1, 20133, Milan, Italy.;Medical Oncology Department, Fondazione IRCCS Istituto Nazionale di Tumori, via G. Venezian 1, 20133, Milan, Italy.;Medical Oncology Department, Fondazione IRCCS Istituto Nazionale di Tumori, via G. Venezian 1, 20133, Milan, Italy.;Medical Oncology Department, Fondazione IRCCS Istituto Nazionale di Tumori, via G. Venezian 1, 20133, Milan, Italy.;Medical Oncology Department, Fondazione IRCCS Istituto Nazionale di Tumori, via G. Venezian 1, 20133, Milan, Italy.;Medical Oncology Department, Fondazione IRCCS Istituto Nazionale di Tumori, via G. Venezian 1, 20133, Milan, Italy.;Medical Oncology Department, Fondazione IRCCS Istituto Nazionale di Tumori, via G. Venezian 1, 20133, Milan, Italy; Medical Oncology Department, University of Milan, via Festa del Perdono 7, 20122, Milan, Italy.;Medical Oncology Department, Fondazione IRCCS Istituto Nazionale di Tumori, via G. Venezian 1, 20133, Milan, Italy.;Medical Oncology Department, Fondazione IRCCS Istituto Nazionale di Tumori, via G. Venezian 1, 20133, Milan, Italy. Electronic address: giuseppe.lorusso@istitutotumori.mi.it.",
"authors": "Galli|Giulia|G|;Corrao|Giulia|G|;Imbimbo|Martina|M|;Proto|Claudia|C|;Signorelli|Diego|D|;Ganzinelli|Monica|M|;Zilembo|Nicoletta|N|;Vitali|Milena|M|;de Braud|Filippo|F|;Garassino|Marina Chiara|MC|;Lo Russo|Giuseppe|G|",
"chemical_list": "D054316:Biomarkers, Pharmacological; D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors",
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"title": "Uncommon mutations in epidermal growth factor receptor and response to first and second generation tyrosine kinase inhibitors: A case series and literature review.",
"title_normalized": "uncommon mutations in epidermal growth factor receptor and response to first and second generation tyrosine kinase inhibitors a case series and literature review"
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"abstract": "We report the first description of oculocardiac reflex elicited with injection of local anesthetic in an empty orbit, and highlight clinical indicators for patients that may be at risk for an exaggerated oculocardiac reflex. We describe a patient with prior head and eye trauma treated for anophthalmic socket reconstruction at an outpatient eye surgery center. Injection of local anesthetic into the empty orbit induced an extended sinus arrest. This exaggerated response was avoided in a subsequent surgery by pretreatment with high-dose anticholinergics.",
"affiliations": null,
"authors": "Nicholson|David|D|;Kossler|Andrea|A|;Topping|Katie|K|;Stary|Creed M|CM|",
"chemical_list": "D000779:Anesthetics, Local",
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000000609",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2325-7237",
"issue": "9(12)",
"journal": "A & A case reports",
"keywords": null,
"medline_ta": "A A Case Rep",
"mesh_terms": "D000328:Adult; D000779:Anesthetics, Local; D006801:Humans; D008297:Male; D009915:Orbit; D012024:Reflex, Oculocardiac",
"nlm_unique_id": "101637720",
"other_id": null,
"pages": "337-338",
"pmc": null,
"pmid": "28767475",
"pubdate": "2017-12-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Exaggerated Oculocardiac Reflex Elicited by Local Anesthetic Injection of an Empty Orbit: A Case Report.",
"title_normalized": "exaggerated oculocardiac reflex elicited by local anesthetic injection of an empty orbit a case report"
} | [
{
"companynumb": "US-GLENMARK PHARMACEUTICALS-2018GMK030744",
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"activesubstancename": "LIDOCAINE"
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"abstract": "Antiepileptic Drugs (AEDs) are commonly associated with haematological disorders, including anaemia, thrombocytopenia, neutropenia and even bone marrow failure. Fatal disorders like aplastic anaemia are uncommon. On exploring through the literature, older AEDs are more associated with haematological alterations than newer AEDs, and careful monitoring is warranted especially with phenytoin, carbamazepine and valproate. The exact cause of these alterations is not established, though immune mechanisms and pharmacology of individual drugs are the proposed mechanisms, a further research along this path is underway. Of worth mentioning here, this predilection of older AEDs towards haematological disorders is pronounced in children compared to adults. We present here a case of congenital heart disease with history of brain abscess and seizures, on carbamazepine who presented to our hospital with toothache. Routine screening prior to tooth extraction revealed thrombocytopenia. Further evaluation revealed the association of carbamazepine and thrombocytopenia, which mandated discontinuation of drug and switching patient to alternative AED.",
"affiliations": "Intern, Department of General Medicine, Kasturba Medical College, Manipal, Karnataka, India.;Junior Resident, Department of General Medicine, Kasturba Medical College, Manipal, Karnataka, India.;Junior Resident, Department of General Medicine, Kasturba Medical College, Manipal, Karnataka, India.;Associate Professor, Department of General Medicine, Kasturba Medical College, Manipal, Karnataka, India.;Professor, Department of General Medicine, Kasturba Medical College, Manipal, Karnataka, India.",
"authors": "Kumar|Ruhi|R|;Chivukula|Sridhar|S|;Katukuri|Goutham Reddy|GR|;Chandrasekhar|U K|UK|;Shivashankar|K N|KN|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.7860/JCDR/2017/26271.10659",
"fulltext": null,
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"issn_linking": "0973-709X",
"issue": "11(9)",
"journal": "Journal of clinical and diagnostic research : JCDR",
"keywords": "Antiepileptic drugs; Cyanotic congenital heart disease; Haematological alterations",
"medline_ta": "J Clin Diagn Res",
"mesh_terms": null,
"nlm_unique_id": "101488993",
"other_id": null,
"pages": "OD12-OD13",
"pmc": null,
"pmid": "29207763",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports",
"references": "19344362;23121994",
"title": "Carbamazepine Induced Thrombocytopenia.",
"title_normalized": "carbamazepine induced thrombocytopenia"
} | [
{
"companynumb": "IN-VALIDUS PHARMACEUTICALS LLC-IN-2017VAL001651",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "CARBAMAZEPINE"
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"abstract": "Topiramate is a neuromodulatory agent increasingly prescribed for a number of neurological and non-neurological indications. Topiramate-treated patients are at risk for nephrolithiasis due to hypocitraturia and high urine pH. However, the prevalence of symptomatic stone disease in TPM users is generally perceived to be low. This study was undertaken to assess in topiramate-treated patients the prevalence of symptomatic nephrolithiasis (by history) and of asymptomatic nephrolithiasis by computed tomography (CT) scan. Topiramate users were identified from a database of patients with neurological disorders at a single university hospital. Among 75 topiramate-treated adult patients with a median daily dose of 300 mg and median treatment duration of 48 months, the prevalence of symptomatic nephrolithiasis was 10.7%. In a subset of topiramate-treated patients and no history of symptomatic stone disease, the prevalence of asymptomatic nephrolithiasis detected by CT scan was 20%. The prevalence of symptomatic nephrolithiasis with long-term topiramate use is higher than reported in short-term studies. Furthermore, clinical prevalence is underestimated due to asymptomatic nephrolithiasis.",
"affiliations": "Department of Internal Medicine, Charles and Jane Pak Center for Mineral Metabolism & Clinical Research, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-8885, USA. Naim.Maalouf@utsouthwestern.edu",
"authors": "Maalouf|Naim M|NM|;Langston|Joshua P|JP|;Van Ness|Paul C|PC|;Moe|Orson W|OW|;Sakhaee|Khashayar|K|",
"chemical_list": "D018696:Neuroprotective Agents; D000077236:Topiramate; D005632:Fructose",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00240-010-0347-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-5623",
"issue": "39(4)",
"journal": "Urological research",
"keywords": null,
"medline_ta": "Urol Res",
"mesh_terms": "D000328:Adult; D005260:Female; D005632:Fructose; D006801:Humans; D008297:Male; D008875:Middle Aged; D053040:Nephrolithiasis; D018696:Neuroprotective Agents; D015995:Prevalence; D011446:Prospective Studies; D012189:Retrospective Studies; D000077236:Topiramate",
"nlm_unique_id": "0364311",
"other_id": null,
"pages": "303-7",
"pmc": null,
"pmid": "21165738",
"pubdate": "2011-08",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "10227615;11948006;15538246;20089492;17363756;9858083;10227614;16393234;9353451;17391164;12939417;16043677;15833090;18664832;15318111;17877442;15926010;12172346;12350390;16997051;15365138;14982912;16703004;16539889",
"title": "Nephrolithiasis in topiramate users.",
"title_normalized": "nephrolithiasis in topiramate users"
} | [
{
"companynumb": "US-GLENMARK PHARMACEUTICALS-2017GMK028082",
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
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"abstract": "Dofetilide's hepatotoxicity is not well described. In this case report, we describe acute hepatocellular jaundice related to dofetilide use in a 33-year-old male being treated for atrial fibrillation. Both viral and ischemic causes of hepatocellular damage were ruled out as unlikely in this case. This case report outlines a rare yet probable report of idiosyncratic dofetilide-induced liver injury.",
"affiliations": "State University of New York Upstate Medical University, Syracuse, NY, USA.;State University of New York Upstate Medical University, Syracuse, NY, USA.;State University of New York Upstate Medical University, Syracuse, NY, USA.",
"authors": "Rose|Patrick Gary|PG|;Seabury|Robert|R|;Cwikla|Gregory|G|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/0018578717738079",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0018-5787",
"issue": "53(1)",
"journal": "Hospital pharmacy",
"keywords": "adverse drug reactions; adverse drug reactions reporting/monitoring; cardiac agents; cardiovascular; gastrointestinal disorders",
"medline_ta": "Hosp Pharm",
"mesh_terms": null,
"nlm_unique_id": "0043175",
"other_id": null,
"pages": "55-58",
"pmc": null,
"pmid": "29434388",
"pubdate": "2018-02",
"publication_types": "D016428:Journal Article",
"references": "24099014;11085972;8801060;11766306;24935270",
"title": "Acute Hepatocellular Jaundice After Dofetilide Initiation: A Case Report.",
"title_normalized": "acute hepatocellular jaundice after dofetilide initiation a case report"
} | [
{
"companynumb": "US-TARO PHARMACEUTICALS USA.,INC-2018SUN00359",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "WARFARIN"
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{
"abstract": "A 72-year-old man presented with anorexia and 15-kg weight loss over 3 years. Endoscopy revealed yellow, shaggy mucosa alternating with erythematous, eroded mucosa in the duodenum. Biopsy specimens showed massive infiltration of periodic acid-Schiff-positive macrophages in the lamina propria, consistent with Whipple's disease. The patient was treated with intravenous ceftriaxone for four weeks, followed by oral trimethoprim-sulfamethoxazole. His condition improved, and he gradually gained weight. Although the endoscopic findings improved with continuous trimethoprim-sulfamethoxazole administration, macrophage infiltration of the duodenal mucosa persisted. However, the patient has been symptom-free for eight years.",
"affiliations": "Department of Internal Medicine, Okayama Saiseikai General Hospital, Japan.;Department of Internal Medicine, Okayama Saiseikai General Hospital, Japan.;Department of Internal Medicine, Okayama Saiseikai General Hospital, Japan.;Department of Internal Medicine (Nephrology), Kanto Rosai Hospital, Japan.;Department of Internal Medicine, Okayama Saiseikai General Hospital, Japan.;Department of Internal Medicine, Okayama Saiseikai General Hospital, Japan.;Department of Internal Medicine, Okayama Saiseikai General Hospital, Japan.;Department of Internal Medicine, Okayama Saiseikai General Hospital, Japan.;Department of Internal Medicine, Okayama Saiseikai General Hospital, Japan.;Department of Internal Medicine, Okayama Saiseikai General Hospital, Japan.;Department of Internal Medicine, Okayama Saiseikai General Hospital, Japan.;Department of Internal Medicine, Okayama Saiseikai General Hospital, Japan.",
"authors": "Saito|Hiroaki|H|;Shiode|Junji|J|;Ohya|Shogen|S|;Yao|Atsushi|A|;Saito|Shunsuke|S|;Fujii|Masakuni|M|;Itoh|Mamoru|M|;Ishiyama|Shuhei|S|;Fujiwara|Akiko|A|;Nasu|Junichiro|J|;Yoshioka|Masao|M|;Yamamoto|Kazuhide|K|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002443:Ceftriaxone; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.9631-17",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2943415210.2169/internalmedicine.9631-17Case ReportWhipple's Disease with Long-term Endoscopic Follow-up Saito Hiroaki 12Shiode Junji 1Ohya Shogen 13Yao Atsushi 4Saito Shunsuke 1Fujii Masakuni 1Itoh Mamoru 1Ishiyama Shuhei 1Fujiwara Akiko 1Nasu Junichiro 1Yoshioka Masao 1Yamamoto Kazuhide 1\n1 Department of Internal Medicine, Okayama Saiseikai General Hospital, Japan\n2 Saito Clinic, Japan\n3 Kawaguchi-Medical Clinic, Japan\n4 Department of Internal Medicine (Nephrology), Kanto Rosai Hospital, JapanCorrespondence to Dr. Hiroaki Saito, gentetu3110@gmail.com\n\n9 2 2018 15 6 2018 57 12 1707 1713 7 6 2017 15 10 2017 Copyright © 2018 by The Japanese Society of Internal Medicine2018The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).A 72-year-old man presented with anorexia and 15-kg weight loss over 3 years. Endoscopy revealed yellow, shaggy mucosa alternating with erythematous, eroded mucosa in the duodenum. Biopsy specimens showed massive infiltration of periodic acid-Schiff-positive macrophages in the lamina propria, consistent with Whipple's disease. The patient was treated with intravenous ceftriaxone for four weeks, followed by oral trimethoprim-sulfamethoxazole. His condition improved, and he gradually gained weight. Although the endoscopic findings improved with continuous trimethoprim-sulfamethoxazole administration, macrophage infiltration of the duodenal mucosa persisted. However, the patient has been symptom-free for eight years. \n\nWhipple's diseaseTropheryma whippleiendoscopymacrophage\n==== Body\nIntroduction\nWhipple's disease is a systemic inflammatory condition resulting from infection with the bacterium Tropheryma whipplei. It typically involves the duodenum and small intestine, causing severe malabsorption. It can also affect many organs, including the heart and brain, and is occasionally fatal (1). Whipple's disease is rare, with only about 1,000 cases reported to date (2), some of which have been reported in Japan. We herein report the endoscopic and histopathologic findings over eight years in a patient with Whipple's disease.\n\nCase Report\nA 72 year-old-man had a history of anorexia and general malaise beginning in the summer of 2005. Although he consulted a local doctor and was treated with intravenous feeding, his symptoms gradually worsened. He lost 15 kg over 3 years and became unable to walk. He consulted our hospital for further investigations and was admitted in April 2008.\n\nThe patient had a history of abdominal surgery for intestinal volvulus at the age of 14 years. Physical examination findings on admission were as follows: height, 173 cm; body weight, 49.2 kg; body mass index, 16.4 kg/m2; body temperature, 36.9℃, blood pressure, 124/86 mmHg; and pulse, 60 beats/minute. He was alert, and a neurological examination showed normal findings. His respiratory and cardiac sounds and abdominal findings were normal. His laboratory data on admission are summarized in Table 1. He demonstrated hypoalbuminemia and high levels of C-reactive protein, soluble interleukin-2 receptor (sIL-2R), and interleukin-6 (IL-6).\n\nTable 1. Laboratory Data on Admission.\n\nWBC\t5,030\t/µL\tCl\t104\tmmol/L\t\nNeu\t71.6\t%\tAST\t33\tIU/L\t\nEos\t1.2\t%\tALT\t31\tIU/L\t\nBaso\t0.4\t%\tALP\t146\tIU/L\t\nLym\t25.0\t%\tγ-GTP\t11\tIU/L\t\nMono\t1.8\t%\tChE\t64\tIU/L\t\nRBC\t237×104\t/µL\tLDH\t201\tIU/L\t\nHgb\t6.6\tg/dL\tT-bil\t0.4\tmg/dL\t\nHct\t20.3\t%\tD-bil\t0.1\tmg/dL\t\nPLT\t16.5×104\t/µL\tBUN\t11.5\tmg/dL\t\nTP\t4.9\tg/dL\tCr\t0.69\tmg/dL\t\nAlb\t2.1\tg/dL\tCEA\t1.1\tng/mL\t\nCRP\t2.75\tmg/dL\tCA19-9\t8.2\tU/mL\t\nNa\t133\tmmol/L\tsIL-2R\t1,950\tU/mL\t\nK\t3.8\tmmol/L\tIL-6\t20.7\tpg/mL\t\nWBC: white blood cells, Neu: neutrophils, Eos: eosinophils, Baso: basophils, Lym: lymphocytes, Mono: monocytes, RBC: red blood cells, Hgb: hemoglobin, Hct: hematocrit, PLT: platelets, TP: total protein, Alb: albumin, CRP: C-reactive protein, Na: sodium, K: potassium, Cl: chloride, AST: aspartate aminotransferase, ALT: alanine aminotransferase, ALP: alkaline phosphatase, γ-GTP: gamma-glutamyl transpeptidase, ChE: cholinesterase, LDH: lactic acid dehydrogenase, T-bil: total bilirubin, D-bil: direct bilirubin, BUN: blood urea nitrogen, Cr: creatinine, CEA: carcinoembryonic antigen, CA: cancer antigen, sIL: soluble interleukin, IL: interleukin\n\nAbdominal computed tomography showed thickening of the small intestinal mucosa and lymphadenopathy in the abdominal cavity. Although upper gastrointestinal endoscopy showed yellow-white, shaggy mucosa in the duodenum, biopsy specimens did not reveal any specific findings.\n\nAfter admission, he was treated with intravenous hyperalimentation, but his symptoms worsened. Because of the high sIL-2R and IL-6 levels and abdominal lymphadenopathy, we suspected Castleman's disease and started oral prednisolone 25 mg daily. His appetite improved and his weight increased, so he was discharged from the hospital on day 33. However, he lost his appetite again and was readmitted 1 month later.\n\nWe performed repeat upper gastrointestinal endoscopy, which revealed yellow, shaggy mucosa alternating with erythematous, eroded mucosa in the duodenum (Fig. 1). Biopsy specimens revealed massive infiltration of periodic acid-Schiff (PAS)-positive macrophages in the lamina propria of the duodenum, while electron microscopy revealed bacillus-like bodies in the lamina propria (Fig. 2). We recognized these characteristic endoscopic and pathologic findings of Whipple's disease and started treatment with ceftriaxone (CTRX) 2 g daily.\n\nFigure 1. Upper gastrointestinal endoscopy on readmission. Yellow, shaggy mucosa alternating with erythematous, eroded mucosa in the duodenum.\n\nFigure 2. Histopathologic findings. (a) (b) Hematoxylin and Eosin staining [(a) ×40, (b) ×400]. Foamy macrophages are present in the epithelial villi of the duodenal mucosa (arrow). (c) Periodic acid-Schiff (PAS) staining (×400). Numerous PAS-positive macrophages are observed infiltrating the lamina propria of the duodenum. (d) Electron micrograph of the duodenal mucosa (×20,000) showing numerous rod-shaped bacilli with distinctive trilaminar cell walls characteristic of Tropheryma whipplei.\n\nHis appetite gradually increased and his general condition improved after starting treatment. We performed additional gastrointestinal endoscopy on day 17, which showed remarkable improvement, although the yellow, shaggy mucosa remained. He remained symptom-free, so we switched to oral trimethoprim-sulfamethoxazole (TMP-SMX) 1,920 mg daily, and the patient was discharged from the hospital on day 32.\n\nHe continued oral TMP-SMX after discharge and remained symptom-free and gradually gained weight. His course after starting treatment is shown in Fig. 3. We have followed him with yearly upper gastrointestinal endoscopy, the findings of which are shown in Fig. 4. Although the changes in the duodenal mucosa improved during the early stages of treatment, PAS-positive macrophage infiltration of the lamina propria has persisted, even eight years after starting treatment (Fig. 5). Although the clinical significance of these findings is not clear, we have continued TMP-SMX to prevent disease recurrence.\n\nFigure 3. Clinical course after first admission. CTRX: ceftriaxone, PSL: prednisolone, TMP-SMX: trimethoprim-sulfamethoxazole\n\nFigure 4. Upper gastrointestinal endoscopy on follow-up. Changes in the duodenal mucosa were improved in the early stage of treatment and never recurred. CTRX: ceftriaxone\n\nFigure 5. Histopathologic findings at the 8-year follow-up. (a) Microscopy of the duodenal mucosa with Hematoxylin and Eosin staining (×100). Numerous foamy macrophages are noted. (b) Periodic acid-Schiff (PAS) staining (×100). Numerous PAS-positive macrophages are observed.\n\nDiscussion\nWhipple's disease is a multisystem inflammatory condition resulting from infection with the bacterium T. whipplei. Whipple's disease is rare, with a prevalence thought to be less than 0.1% (3). The disorder mostly affects middle-aged white men and is very rare in Asian countries. The Japanese case reports of Whipple's disease from 1970 to 2016 that we searched in PubMed MEDLINE and Japanese Medical Abstract Society databases are summarized in Table 2. 12 cases (including our case) have been reported in the literature (4-14). Four additional cases have been reported in abstract form only (15-18). In most of the Japanese cases, the patients were middle-aged (over 50 years of age), but there have also been a few reports involving younger patients.\n\nTable 2. Cases of Whipple’s Disease in Japan Reported in the Literature.\n\nReference\tAge (y)\n/Sex\tAffected organs\tDiagnostic Tools\tTreatment\tPrognosis\t\nPAS\tEM\tPCR\t\n(4)\t45/M\tGI, Heart, Joints, LN\t+\t-\t/\tTetracycline\tAlive (2m)\t\n(5)\t56/M\tGI, Heart, Joints, LN\t+\t+\t/\tObservation\tDead (2y)\t\n(6)\t52/M\tGI\t+\t+\t+\tCTRX, TMP-SMX\tAlive (1y)\t\n(7)\t54/M\tGI, LN\t+\t-\t-\tCTRX, TMP-SMX\tAlive (2y)\t\n(8)\t50/M\tGI, Brain\t+\t+\t+\tCTRX, PCG, TMP-SMX\tAlive (10y)\t\n(9)\t36/F\tGI, Heart, Brain\t+\t/\t+\tCTRX, TMP-SMX\tAlive (1y)\t\n(10)\t54/F\tGI, Heart, LN, Spleen\t+\t/\t+\tCTRX, TMP-SMX\tAlive (2y)\t\n(11)\t24/F\tGI\t-\t-\t+\tCTRX, TMP-SMX\tAlive (8m)\t\n(12)\t76/M\tGI, LN\t+\t/\t/\tCTRX, TMP-SMX\tAlive (1.5y)\t\n(13)\t7X/M\tGI\t+\t+\t/\tCTRX, TMP-SMX, CFPN-PI\tAlive (2m)\t\n(14)\t50/M\tGI\t+\t+\t+\tCTRX, TMP-SMX\tAlive (2m)\t\nCurrent case\t72/M\tGI, LN\t+\t+\t/\tCTRX, TMP-SMX\tAlive (8y)\t\nM: male, F: female, GI: gastrointestinal tract, LN: lymph node, PAS: periodic acid-Schiff staining, EM: electron microscopy, PCR: polymerase chain reaction, +: positive, -: negative, /: no result, CTRX: ceftriaxone, PCG: penicillin G, TMP-SMX: trimethoprim-sulfamethoxazole, CFPN-PI: cefcapene pivoxil, m: month, y: year\n\nWhipple's disease was first described by George H. Whipple in 1907 (19). In 1949, PAS-positive macrophages were found to have infiltrated the lamina propria of the small intestine in patients with the disease (20). The bacterium in the macrophages was first detected by electron microscopy in 1961 (21), while the 16S ribosomal RNA of T. whipplei was identified in 1992 (22). The first successful cultivation of the Whipple bacillus was performed in 2000 (23).\n\nThe route of infection for T. whipplei is unknown, but the bacterium is thought to exist in the general environment. Studies using polymerase chain reaction have found T. whipplei DNA in sewage plant effluent and human stool (1). It is known that patients with the disease have a higher frequency of human leukocyte antigen (HLA)-B27 than the general population, but no causal association between the presence of HLA-B27 and infection susceptibility has been demonstrated (24).\n\nWhipple's disease is characterized by two stages: a prodromal stage and a much later steady-state stage. The prodromal stage is marked by protean symptoms and nonspecific chronic findings, mainly arthralgia and arthritis. The steady-state stage is typified by weight loss and/or diarrhea; occasionally, there are other manifestations, as many organs can be involved (1,2). Our patient's anorexia and weight loss were consistent with the typical gastrointestinal symptoms of the steady-state stage. Involvement of the abdominal lymph nodes, especially the mesenteric and periaortic nodes is not uncommon, but peripheral lymphadenopathy is rare (1). Our patient had abdominal lymphadenopathy that responded to antibiotic therapy and disappeared.\n\nGiven the broad differential diagnoses and the disease's rarity in Japan, Whipple's disease can be difficult to diagnose (6,9). The differential diagnoses include inflammatory rheumatic diseases, malabsorption with small intestine involvement (e.g., celiac disease, sarcoidosis, and lymphoma), Addison's disease, and connective tissue disorders (1). In our patient, we considered the possibility of lymphoma (Castleman's disease) because of the abdominal lymphadenopathy and high levels of sIL-2R and IL-6; therefore, we started oral prednisolone. However, Whipple's disease is thought to progress rapidly when patients receive immunosuppressive therapy, such as corticosteroids or tumor necrosis factor antagonists (25). In our patient, the oral prednisolone may have caused an exacerbation of the symptoms of Whipple's disease.\n\nThe endoscopic examination of patients with classic Whipple's disease reveals pale yellow, shaggy mucosa alternating with eroded, erythematous, or mildly friable mucosa in the duodenum and/or jejunum (1,24). It is reported that high-magnification endoscopy and narrow-band imaging observation can help visualize the mucosal characteristics typical of Whipple's disease, including edematous and engorged duodenal villi (26).\n\nMassive infiltration of PAS-positive macrophages in the lamina propria of the duodenum or jejunum is the most notable pathophysiologic characteristic of the disease (27). Several studies have also demonstrated a defective macrophage function in patients with Whipple's disease. Moos et al. showed that T. whipplei triggers the differentiation of monocytes to alternative-activated macrophages (M2 macrophages); this subclass of macrophages may aid in the survival and replication of T. whipplei (27,28). The sensitivity of the PAS staining of small bowel biopsies ranges from 71% to 78% for diagnosing Whipple's disease. In addition, Mycobacterium avium complex, which also stains PAS-positive, should be considered as a possible differential diagnosis (29).\n\nThe confirmation of T. whipplei by electron microscopy or DNA identification by polymerase chain reaction (PCR) is mandatory for a definitive diagnosis (30). T. whipplei has a unique trilamellar cell wall that can be detected via electron microscopy, and this is regarded as an important diagnostic finding. However, it requires a longer detection time. PCR has become the second cornerstone in the diagnosis of Whipple's disease in recent years and should be carried out along with a histological examination. Conventional PCR comprises the detection of the specific 16S rRNA of the bacterium. More recent methods using quantitative real-time PCR have demonstrated higher sensitivity, but they are only available in special centers (28).\n\nIn Japan, PAS staining of the intestinal mucosa is positive in almost all cases; however, electron microscopy and PCR are added for the confirmation of a diagnosis (Table 2). Recently, PCR has been used to make a diagnosis in most cases, and there have been several reports describing the usefulness of PCR in making a diagnosis (10,11,14). PCR is rapid, specific, and sensitive (10), so we should recognize it as an indispensable tool for obtaining a definitive diagnosis. In our patient, although we recognized characteristic findings on PAS staining and electron microscopy, specification of the bacteria using PCR was not performed, which should be regarded as a limitation of this case.\n\nWithout treatment, Whipple's disease is fatal. The recommended treatment is 160 mg TMP and 800 mg SMX twice a day for 1 to 2 years, which is usually preceded by the parenteral administration of streptomycin (1 g daily) with penicillin G (1.2 million U daily) or CTRX (2 g daily) for 2 weeks (1,24,30). In order to prevent nervous system recurrence, antibiotics capable of crossing the blood-brain barrier are desirable, although this recommendation is not based on data from any therapeutic trial. In most of the cases reported in Japan, CTRX and TMP-SMX were administered for treatment (Table 2).\n\nThe clinical course after starting treatment is generally good in most Japanese cases, but there are few reports that include long-term follow-up. Therefore, we believe that our ability to perform long-term follow-up in the present patient is particularly meaningful. We performed repeated follow-up gastrointestinal endoscopy, confirming that the changes in the duodenal mucosa improved in the early stage of treatment, whereas macrophage infiltration in the lamina propria of the duodenum persisted. Uryu et al. reported a case with neurologic recurrence of Whipple's disease, where the accumulation of macrophages in the lamina propria of the duodenum continued for six years, even after the symptoms had disappeared (9). Although the relevance of this finding to the clinical course and risk of recurrence is unknown, it may suggest that macrophage replication and the anti-inflammatory function of the lamina propria remain abnormal. For this reason, our patient has continued receiving oral TMP-SMX with careful follow-up.\n\nIn summary, we herein described a patient with Whipple's disease who was successfully treated with antibiotic therapy. Although his clinical symptoms and endoscopic findings rapidly improved, the accumulation of macrophages in the lamina propria of the duodenum persisted. This finding suggests a lack of an anti-inflammatory function may improve the survival of T. whipplei, and as such, a long-term follow-up is indicated.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Fenollar F , Puéchal X , Raoult D \nWhipple's disease . N Engl J Med \n356 : 55 -66 , 2007 .17202456 \n2. Puéchal X \nWhipple disease and arthritis . Curr Opin Rheumatol \n13 : 74 -79 , 2001 .11148719 \n3. Enzinger FM , Helwig EB \nWhipple's disease: a review of the literature and report fifteen patients . Virchows Arch Pathol Anat Physiol Klin Med \n336 : 238 -269 , 1963 .\n4. Naramoto J , Tamechika Y , Niizeki H , et al \nA case of Whipple disease with non-specific multiple ulcer of the intestine . I to Cho (Stomach and Intestine) \n11 : 227 -231 , 1976 (in Japanese, Abstract in English).\n5. Tsuru T , Hamada T , Honda M , et al \nAn autopsy case of Whipple disease . Saishin Igaku \n34 : 1993 -1997 , 1979 (in Japanese).\n6. Yogi T , Hokama A , Kinjo F , et al \nWhipple's disease: the first Japanese case diagnosed by electron microscopy and polymerase chain reaction . Intern Med \n43 : 566 -570 , 2004 .15335181 \n7. Kawasaki K , Kobayashi H , Kurahara K , et al \nWhipple's disease with findings of NBI magnifying observation and capsule endoscopy, report of a case . I to Cho (Stomach and Intestine) \n46 : 311 -319 , 2011 (in Japanese, Abstract in English).\n8. Watanabe D , Kakimoto T , Kodama K , et al \nWhipple's disease . Nihon Shokakibyo Gakkai Zasshi (Jpn J Gastro-enterol) \n110 : 998 -1006 , 2013 (in Japanese, Abstract in English).\n9. Uryu K , Sakai T , Yamamoto T , et al \nCentral nervous system relapse of Whipple's disease . Intern Med \n51 : 2045 -2050 , 2012 .22864135 \n10. Yajima N , Wada R , Kimura S , et al \nWhipple disease diagnosed with PCR using formalin-fixed paraffin-embedded specimens of the intestinal mucosa . Intern Med \n52 : 219 -222 , 2013 .23318851 \n11. Kono M , Yamamoto K , Nagamatsu M , et al \nUse of polymerase chain reaction in the diagnosis of Whipple's disease . J Infect Chemother \n21 : 885 -888 , 2015 .26390825 \n12. Domori K , Sato A , Nakajima N , et al \nWhipple's disease with typical endoscopic features report of clinically diagnosed case . I to Cho (Stomach and Intestine) \n50 : 1443 -1449 , 2015 (in Japanese, Abstract in English).\n13. Hirano A , Hirai F , Takada Y , et al \nWhipple's disease diagnosed based on imaging, reported of a case . I to Cho (Stomach and Intestine) \n51 : 1626 -1634 , 2016 (in Japanese, Abstract in English).\n14. Nagasue T , Kurahara K , Yaita H , et al \nWhipple's disease diagnosed using electron microscopy and polymerase chain reaction . Nihon Shokakibyo Gakkai Zasshi (Jpn J Gastro-enterol) \n113 : 1894 -1900 , 2016 (in Japanese, Abstract in English).\n15. Suehara M , Niiyama T , Higuchi I , et al \nThe first Japanese case of CNS Whipple's disease . Clinical Neurology \n39 : 252 , 1999 (Abstract in Japanese).\n16. Minagawa K , Aramaki K , Kikuchi H , et al \nA case of Whipple disease with clincal features of polyarteritis nodosa . Ryumachi \n43 : 464 , 2003 (Abstract in Japanese).\n17. Iwamura S , Uchita K , Kono N , et al \nA Japanese case of Whipple disease diagnosed by immunohistochemistry . Nihon Shokakibyo Gakkai Zasshi (Jpn J Gastro-enterol) \n103 : A839 , 2006 (Abstract in Japanese).\n18. Tatsuki M , Ishige W , Hatori R , et al \nWhipple disease of child which diagnosed electron microscopy and PCR . Nihon Shounika Gakkai Zasshi (Jpn J Gastro-enterol) \n117 : 329 , 2013 (Abstract in Japanese).\n19. Whipple GH \nA hitherto undescribed disease characterized anatomically by deposits of fat and fatty acids in the intestinal and mesenteric lymphatic tissues . Bull Johns Hopkins Hosp \n18 : 382 -391 , 1907 .\n20. Black-Schaffer B \nThe tinctorial demonstration of a glycoprotein in Whipple's disease . Proc Soc Exp Biol Med \n72 : 225 -227 , 1949 .15391722 \n21. Chears WC Jr, Ashworth CT \nElectron microscopic study of the intestinal mucosa in Whipple's disease. Demonstration of encapsulated bacilliform bodies in the lesion . Gastroenterology \n41 : 129 -138 , 1961 .13692693 \n22. Relman DA , Schmidt TM , MacDermott RP , Falkow S \nIdentification of the uncultured bacillus of Whipple's disease . N Engl J Med \n327 : 293 -301 , 1992 .1377787 \n23. Raoult D , Birg M , La Scola B , et al \nCultivation of the bacillus of Whipple's disease . N Engl J Med \n342 : 620 -625 , 2000 .10699161 \n24. Marth T , Raoult D \nWhipple's disease . Lancet \n361 : 239 -246 , 2003 .12547551 \n25. Mahnel R , Kalt A , Ring S , Stallmach A , Strober W , Marth T \nImmunosuppressive therapy in Whipple's disease patients is associated with the appearance of gastrointestinal manifestations . Am J Gastroenterol \n100 : 1167 -1173 , 2005 .15842595 \n26. Neumann H , Mönkemüller K , Neurath MF , et al \nAdvanced endoscopic imaging using narrow-band imaging for diagnosis of Whipple's disease . Endoscopy \n44 (Suppl ): E101 , 2012 .22473576 \n27. Moos V , Schmidt C , Geelhaar A , et al \nImpaired immune functions of monocytes and macrophages in Whipple's disease . Gastroenterology \n138 : 210 -220 , 2010 .19664628 \n28. Obst W , von Arnim U , Malfertheiner P \nWhipple's disease . Viszeralmedizin \n30 : 167 -172 , 2014 .26288590 \n29. Ramzan NN , Loftus E Jr, Burgart LJ , et al \nDiagnosis and monitoring of Whipple disease by polymerase chain reaction . Ann Intern Med \n126 : 520 -527 , 1997 .9092317 \n30. Keinath RD , Merrell DE , Vlietstra R , Dobbins WO 3rd \nAntibiotic treatment and relapse in Whipple's disease. Long-term follow-up of 88 patients . Gastroenterology \n88 : 1867 -1873 , 1985 .2581843\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "57(12)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "Tropheryma whipplei; Whipple's disease; endoscopy; macrophage",
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D002443:Ceftriaxone; D004386:Duodenum; D004724:Endoscopy; D005500:Follow-Up Studies; D006801:Humans; D007413:Intestinal Mucosa; D008264:Macrophages; D008297:Male; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D008061:Whipple Disease",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1707-1713",
"pmc": null,
"pmid": "29434152",
"pubdate": "2018-06-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11148719;23318851;23739732;17202456;27829601;26288590;10699161;2581843;22864135;13692693;15842595;9092317;22473576;26390825;15335181;1377787;12547551;15391722;19664628",
"title": "Whipple's Disease with Long-term Endoscopic Follow-up.",
"title_normalized": "whipple s disease with long term endoscopic follow up"
} | [
{
"companynumb": "PHHY2018JP044820",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CEFTRIAXONE"
},
"drugadditional": "3",
"drug... |
{
"abstract": "BACKGROUND\nAlemtuzumab is a monoclonal antibody approved for relapsing-remitting multiple sclerosis (RRMS). The only report of Serum Sickness (SS) in a MS patient occurred during treatment with natalizumab. Non-protein drugs, such as some antibiotics, may induce \"SS-like\" reactions (SSLR), whose clinical and laboratory features may partially overlap with the traditional SS.\n\n\nOBJECTIVE\nTo report a case of SS/SSLR in a RRMS patient treated with alemtuzumab.\n\n\nMETHODS\nA 42-year-old-woman with RRMS developed SS/SSLR in the first week after the first alemtuzumab treatment. Concomitant medications included trimethoprim-sulfamethoxazole at low dose. Intravenous methylprednisolone therapy led to clinical resolution and normalization of serum inflammatory markers.\n\n\nCONCLUSIONS\nSS/SSLR should be considered in patients treated with alemtuzumab developing delayed fever, rash and arthralgia and differentiated with Infusion Associated Reactions (IARs) and infections.",
"affiliations": "Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Italy. Electronic address: lapucci.caterina@alice.it.;Department of Hematology, Ospedale Policlinico San Martino IRCCS, Genoa, Italy.;Division of Infectious Diseases, University of Genova (DISSAL) and Ospedale Policlinico San Martino, Genoa, Italy.;Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Italy.;Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Italy; Ospedale Policlinico San Martino IRCCS, Genoa, Italy; Center of Excellence for Biomedical Research (CEBR), University of Genoa, Genoa, Italy.;Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Italy; Ospedale Policlinico San Martino IRCCS, Genoa, Italy; Center of Excellence for Biomedical Research (CEBR), University of Genoa, Genoa, Italy.;Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Italy; Ospedale Policlinico San Martino IRCCS, Genoa, Italy; Center of Excellence for Biomedical Research (CEBR), University of Genoa, Genoa, Italy.",
"authors": "Lapucci|C|C|;Gualandi|F|F|;Mikulska|M|M|;Palmeri|S|S|;Mancardi|G|G|;Uccelli|A|A|;Laroni|A|A|",
"chemical_list": "D005938:Glucocorticoids; D007155:Immunologic Factors; D000074323:Alemtuzumab; D008775:Methylprednisolone",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.msard.2018.09.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2211-0348",
"issue": "26()",
"journal": "Multiple sclerosis and related disorders",
"keywords": "Alemtuzumab; Arthralgia; Monoclonal antibodies; Multiple Sclerosis; Serum sickness; Serum sickness like reaction",
"medline_ta": "Mult Scler Relat Disord",
"mesh_terms": "D000328:Adult; D000074323:Alemtuzumab; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007155:Immunologic Factors; D008775:Methylprednisolone; D020529:Multiple Sclerosis, Relapsing-Remitting; D012713:Serum Sickness",
"nlm_unique_id": "101580247",
"other_id": null,
"pages": "52-54",
"pmc": null,
"pmid": "30223229",
"pubdate": "2018-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Serum sickness (Like Reaction) in a patient treated with alemtuzumab for multiple sclerosis: A case report.",
"title_normalized": "serum sickness like reaction in a patient treated with alemtuzumab for multiple sclerosis a case report"
} | [
{
"companynumb": "IT-SA-2018SA266461",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
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"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo obtain information on the acceptable doses of the antiepileptic drug (AED) retigabine (RTG), the maximum tolerated dose (MTD), drug interactions, safety and tolerability, and preliminary evidence of efficacy when administered as adjunctive therapy and as monotherapy.\n\n\nMETHODS\nStudy 202 was an open-label, add-on study in patients with partial or generalized epilepsy treated with valproic acid (VPA), carbamazepine (CBZ), phenytoin (PHT), or topiramate (TPM) as monotherapy. Following baseline assessments, patients entered a dose titration phase of 28 â 56 days. The initial daily RTG dose was 100 or 200 mg (2 or 3 Ã daily). The RTG dose was increased every 1 - 2 weeks by 50 - 200 mg to a maximum of 1,600 mg/day. Once the RTG MTD had been attained, patients entered a 14-day maintenance period. Following this, the patient's background AED dose could be reduced, with the possibility of achieving RTG monotherapy. The final dosing regimen attained was maintained for an additional 14 days. Patients who completed study 202 could choose to continue treatment with RTG (with or without other AEDs) in study 208, the long-term extension of study 202. Safety assessments included adverse event (AE) monitoring, clinical laboratory evaluations, electrocardiograms, and physical and neurologic examinations. Patients' seizure diaries to assess the frequency and type of seizures, the percentage change in seizure rate, and the responder rate (>= 50% reduction in seizure rate from baseline) were evaluated.\n\n\nRESULTS\n60 patients (mean age 37.2, range 16 - 64 years) were enrolled in study 202, and 47 (78%) continued treatment with RTG in the extension study (208). In study 202, the most commonly reported AEs were: dizziness (53%), asthenia (42%), somnolence (33%), nausea (27%), speech disorder (27%), and tremor (27%). In the extension study, AEs were similar and included dizziness, somnolence, diplopia, feeling \"drunk\", confusion, fatigue, and dysarthria. The median percent reductions in 28-day seizure rate, relative to baseline in Studies 202 and 208, were ~ 20% and 47%, respectively. RTG did not alter the pharmacokinetics of the four monotherapy AEDs investigated. CBZ and PHT increased RTG clearance by 27% and 36%, respectively, whereas TPM and VPA had no effect on RTG clearance.\n\n\nCONCLUSIONS\nStudies 202 and 208 provided critical information on RTG safety and tolerability, and reductions in seizure rates towards the design and conduct of subsequent pivotal clinical trials. Likewise, information regarding the appropriate dosage of RTG with VPA, CBZ, PHT, or TPM was obtained, which permitted the subsequent pivotal trials to be performed appropriately. *Currently at Shire Pharmaceuticals, Behavioral Health Business Unit, Wayne, PA, USA **Currently at University of Pennsylvania, Department of Neurology, Philadelphia, PA, USA.",
"affiliations": null,
"authors": "Sachdeo|Rajesh|R|;Partiot|Arnaud|A|;Biton|Victor|V|;Rosenfeld|William E|WE|;Nohria|Virinder|V|;Tompson|Debra|D|;DeRossett|Sarah|S|;Porter|Roger J|RJ|",
"chemical_list": "D000927:Anticonvulsants; D002219:Carbamates; D010655:Phenylenediamines; C101866:ezogabine",
"country": "Germany",
"delete": false,
"doi": "10.5414/CP202081",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0946-1965",
"issue": "52(6)",
"journal": "International journal of clinical pharmacology and therapeutics",
"keywords": null,
"medline_ta": "Int J Clin Pharmacol Ther",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants; D002219:Carbamates; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004828:Epilepsies, Partial; D004829:Epilepsy, Generalized; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D061214:Patient Safety; D010655:Phenylenediamines; D012107:Research Design; D018570:Risk Assessment; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States; D055815:Young Adult",
"nlm_unique_id": "9423309",
"other_id": null,
"pages": "509-18",
"pmc": null,
"pmid": "24755135",
"pubdate": "2014-06",
"publication_types": "D017427:Clinical Trial, Phase II; D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A novel design for a dose finding, safety, and drug interaction study of an antiepileptic drug (retigabine) in early clinical development.",
"title_normalized": "a novel design for a dose finding safety and drug interaction study of an antiepileptic drug retigabine in early clinical development"
} | [
{
"companynumb": "US-JNJFOC-20140701273",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CARBAMAZEPINE"
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... |
{
"abstract": "Tumor lysis syndrome TLS is commonly seen during the treatment of rapidly proliferating. However TLS is rarely reported in Non-small cell Lung Cancer. This may because of low proliferative rate and chemo-resistant nature of NSCLC. We are reporting a case of tumor lysis without concomitant syndrome in a patient with adenocarcinoma of Lung.",
"affiliations": "Division of Pulmonary and Critical Care, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York, USA.;Division of Pulmonary and Critical Care, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York, USA.;Division of Pulmonary and Critical Care, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York, USA.;Department of Radiology, Jacobi Medical Center, Albert Einstein College of Medicine, Bronx, New York, USA.;Division of Pulmonary and Critical Care, Jacobi Medical Center, Albert Einstein College of Medicine, Bronx, New York, USA.",
"authors": "Chopra|Amit|A|;Marak|Creticus|C|;Alappan|Narendra Kumar|NK|;Alterman|Daniel|D|;Shim|Chang|C|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.rmcr.2013.08.002",
"fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(13)00032-410.1016/j.rmcr.2013.08.002Case ReportTumor lysis without syndrome in adenocarcinoma of the lung: Case report Chopra Amit dr.amitchopra@gmail.coma∗Marak Creticus cmarak@montefiore.orgaAlappan Narendra Kumar NALAPPA@montefiore.orgaAlterman Daniel daniel.alterman@nbhn.netbShim Chang Chang.shim@nbhn.netca Division of Pulmonary and Critical Care, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York, USAb Department of Radiology, Jacobi Medical Center, Albert Einstein College of Medicine, Bronx, New York, USAc Division of Pulmonary and Critical Care, Jacobi Medical Center, Albert Einstein College of Medicine, Bronx, New York, USA∗ Corresponding author. Tel.: +1 646 266 9476. dr.amitchopra@gmail.com07 9 2013 2013 07 9 2013 10 34 36 16 6 2013 15 8 2013 21 8 2013 © 2013 The Authors2013This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).Tumor lysis syndrome TLS is commonly seen during the treatment of rapidly proliferating. However TLS is rarely reported in Non-small cell Lung Cancer. This may because of low proliferative rate and chemo-resistant nature of NSCLC. We are reporting a case of tumor lysis without concomitant syndrome in a patient with adenocarcinoma of Lung.\n\nKeywords\nTumor lysisAdenocarcinomaCyst\n==== Body\n1 Introduction\nTumor lysis syndrome (TLS) is a well-recognized fatal complication seen during the treatment of the rapidly proliferating and chemo-sensitive tumors such as lymphomas and leukemias [1,2], but rarely seen with solid tumor like lung cancer. Tumor lysis syndrome complicating chemotherapy for non-small cell lung cancer is very rare and to date there have been only four such cases that have been reported in literature [10–13].\n\n2 Case report\nA 59-year old African American male former heavy smoker (40 pack years) with no significant past medical history presented to our hospital with non-productive cough and shortness of breath on exertion of three months duration. He did not report any history of hemoptysis, weight lost, night sweats or fever. His vitals were stable and thorough physical examination did not reveal any abnormal findings. Chest X-ray (Fig. 1) revealed collapse of the right upper lobe (RUL). CT scan of the chest (Fig. 2A and B) showed a 4 × 3.7 × 4 cm3 mass with areas of calcification abutting and compressing the right upper lobe bronchus with atelectasis of the RUL. Flexible bronchoscopy revealed an endobronchial lesion which completely occluded the right upper lobe bronchus and partially occluded the bronchus intermedius. Endobronchial biopsy and brushing taken from the mass was positive for a poorly differentiated primary lung adenocarcinoma that stained positive for AE1/AE3, CK 7, TTF1, CD45 and Napsin A. Test for EGFR mutation was negative but tests for p53 and Ki-67 were positive. His hospital stay was complicated by development of focal seizure and weakness involving the right upper extremity. Magnetic resonance imaging (MRI) of brain revealed multiple ring enhancing lesions consistent with brain metastasis. Positron emission tomography showed increased uptake in right upper lobe and right hilar lymph node but no evidence of metastasis elsewhere. He received 6 cycles of combination chemotherapy consisting of carboplatin, paclitaxel and bevacizumab; whole brain radiation was given for his brain metastasis. Repeat CXR (Fig. 3) and CT scan (Fig. 4) after three months of initiation of chemotherapy showed re-expansion of the right upper lobe and replacement of the mass with large air filled cystic space that communicated with right main stem bronchus and bronchus intermedius. Repeat laboratory investigation revealed WBC of 14,500 cell/μl, serum creatinine of 0.9 mg/dL, serum potassium of 4.1 mEq/dL, serum calcium of 9.8 mg/dl, serum phosphate 4 mEq/dL, serum uric acid level of 5.4 mg/dl (normal range 3.5–7.2 mg/Dl) and serum LDH level of 187 IU/L (71–200 IU/L). This was consistent with complete lysis of the lung tumor without the metabolic derangements of tumor lysis syndrome. He was initially maintained on bevacizumab but later switched to erlotinib (EGFR inhibitor) due to hemoptysis. Most recent CT scan after 18 months of chemotherapy (Fig. 5) showed a further decrease in the size of the cystic lesion. Except for recurrent seizures he continues to do well after almost 30 months of his diagnosis with metastatic lung cancer.\n\n3 Discussion\nTumor lysis syndrome results from lysis of the rapidly proliferating malignant cells after the administration of cytotoxic chemotherapy. The release of the cellular contents result in metabolic derangements such as hyper-uricemia, hyperkalemia, elevated LDH levels, hyperphosphatemia, acute renal failure and hypocalcaemia that characterize tumor lysis syndrome [2].\n\nTLS commonly occurs with hematological malignancies but is rare with solid tumors due to relatively low proliferative index and marginal response to chemotherapy. Solid tumors that are known to cause TLS include breast carcinoma [3], medullo-blastoma [4], ovarian cancer [5], rhabdomyosarcoma [6] and neuro-blastoma [7]. Typically these tumors are bulky with multiple metastatic foci and generally are sensitive to initial chemotherapy. TLS rarely occurs with small cell lung cancer [7–9] which is more chemo-sensitive, but occurrence of TLS with NSCLC is extremely rare. This may be due to low proliferative rate and chemo-resistance of NSCLC. There have been only four case reports of TLS with NSCLC, and one of them died of acute spontaneous tumor lysis syndrome without chemotherapy.\n\nStage IV NSCLC is associated with poor prognosis. In patients with good performance status chemotherapy improves survival by only 4 months with 1-year survival of 10–20% and 5-year survival of <5% [14]. Additionally expression of biomarker ki-67 in tumor like our patient is associated with poor outcome [15].\n\nIn this case report we describe a unique case of lung cancer with complete lysis of the tumor resulting from chemotherapy leaving a large cystic lesion in the lung. He did not have metabolic derangements to suggest TLS. The possible explanation for the absence of TLS despite complete lysis of the tumor is that the size of the tumor was not large and bulky enough to cause the syndrome. However it is still possible that he might have had milder form of the TLS which was missed due to absence of symptoms. To our knowledge, this is the first case of lung cancer with complete lysis of the tumor without tumor lysis syndrome.\n\nDisclosures\nThe study was performed at Jacobi Medical Center.\n\nThis manuscript is not under consideration in any other journal.\n\nThe authors declare that there was no funding for this study.\n\nAll authors have read the manuscript and agree to the content.\n\nConflict of interest\nNone.\n\nFig. 1 CXR: Frontal view showing RUL collapse (s sign of gold).\n\nFig. 2 CT chest. 2A (left) coronal section 2B (cross-sectional image) of the chest showing RUL mass abutting right upper lobe bronchus and right main stem causing right upper lobe collapse.\n\nFig. 3 CXR Re-expansion of the RUL.\n\nFig. 4 CT chest showing large air filled cyst communicating with right main stem bronchus.\n\nFig. 5 CT chest: Cyst is smaller in size.\n==== Refs\nReferences\n1 Hande K.R. Garrow G.C. Acute tumor lysis syndrome in patients with high grade non-Hodgkin's lymphoma Am J Med 94 1993 133 139 8430709 \n2 Zusman J. Brown D. Nesbit M. Hyperphosphatemia, hyperphosphaturia and hypocalcemia in acute lymphoblastic leukemia N Engl J Med 289 1973 1335 1340 4518614 \n3 Sklarin N. Markham M. Spontaneous recurrent tumor lysis syndrome in breast cancer Am J Clin Oncol 18 1995 71 73 7847263 \n4 Tomlinson G. Solberg L. Acute tumor lysis syndrome with metastatic medulloblastoma Cancer 53 1984 1783 1785 6199103 \n5 Bilgrami S. Fallon B. Tumor lysis syndrome after combination chemotherapy for ovarian cancer Med Pediatr Oncol 21 1993 521 524 8341221 \n6 Gold J. Malamud S. LaRosa F. Osband M. Adoptive chemoimmunotherapy using ex vivo activated memory T-cells and cyclophosphamide: tumor lysis syndrome of a metastatic soft tissue sarcoma Am J Hematol 44 1993 42 47 8342564 \n7 Kalemkerian G. Darwish B. Varterasian M. Tumor lysis syndrome in small cell carcinoma and other solid tumors Am J Med 103 1997 363 367 9375703 \n8 Beriwal S. Singh S. Garcia J. Tumor lysis syndrome in extensive-stage small-cell lung cancer Am J Clin Oncol (CCT) 25 5 2002 474 475 \n9 Marinella M.A. Fatal tumor lysis syndrome and gastric hemorrhage associated with metastatic small-cell lung carcinoma Med Pediatr Oncol 32 1999 464 465 10358713 \n10 Persons D.A. Garst J. Vollmer R. Crawford J. Tumor lysis syndrome and acute renal failure after treatment of non-small-cell lung carcinoma with combination irinotecan and cisplatin Am J Clin Oncol 21 1998 426 429 9708649 \n11 Feld J. Mehta H. Burkes R.L. Acute spontaneous tumor lysis syndrome in adenocarcinoma of the lung: a case report Am J Clin Oncol 23 2000 491 493 11039510 \n12 Ajzensztejn D. Hegde V.S. Lee S.M. Tumor lysis syndrome after treatment with docetaxel for non-small-cell lung cancer J Clin Oncol 24 2006 2389 2391 16710040 \n13 Honda K. Saraya T. Tamura M. Fujiwara M. Goto H. Tumor lysis syndrome and acquired ichthyosis occurring after chemotherapy for lung adenocarcinoma J Clin Oncol 29 35 December 10 2011 e859 e860 22042943 \n14 Socinski M.A. Crowell R. Hensing T.E. Langer CJ. Lilenbaum L. Sanger AB. Treatment of non-small cell lung cancer, stageIV: ACCP evidence-based clinical practice guidelines (2nd edition) Chest 132 3 suppl. 2007 277S 289S 17873174 \n15 Martin B. Paesmans M. Mascaux C. Berghmans T. Lothaire P. Meert A.P. Ki-67 expression and patients survival in lung cancer: systematic review of the literature with meta-analysis Br J Cancer 91 2004 2018–202\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-0071",
"issue": "10()",
"journal": "Respiratory medicine case reports",
"keywords": "Adenocarcinoma; Cyst; Tumor lysis",
"medline_ta": "Respir Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101604463",
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"pages": "34-6",
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"title": "Tumor lysis without syndrome in adenocarcinoma of the lung: Case report.",
"title_normalized": "tumor lysis without syndrome in adenocarcinoma of the lung case report"
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"abstract": "A 54-year-old male patient with acute lymphoblastic leukemia was referred to the Department of Oral Medicine. He had a primary refractory disease and was treated according to HOVON71 and HAM protocol. Sixteen days after the start of the HAM protocol the patient developed palatal dark red/brownish lesion and maxillary vestibular exophytic lesion. Biopsy specimens from oral lesions were taken and microbiologic evaluation confirmed the presence of Aspergillus fumigatus and Rhizopus genus. The treatment of the patient consisted of the inferior maxillectomy and intravenous posaconazole and amphotericine B for the following 28 days. Since the coinfection with Aspergillus and Rhizopus is extremely rarely seen in the oral cavity, a diagnostic and therapeutic dilemma easily presents itself.",
"affiliations": "Department of Oral Medicine School of Dental Medicine University of Zagreb and Department of Oral Diseases University Hospital Centre Zagreb, Zagreb, Croatia.;Department of Otolaryngology, Head and Neck Surgery University Hospital Centre Zagreb, Zagreb, Croatia.;Department of Oral Medicine School of Dental Medicine University of Zagreb and Department of Oral Diseases University Hospital Centre Zagreb, Zagreb, Croatia.;Department of Otolaryngology, Head and Neck Surgery University Hospital Centre Zagreb, Zagreb, Croatia.;Department of Oral Medicine School of Dental Medicine University of Zagreb and Department of Oral Diseases University Hospital Centre Zagreb, Zagreb, Croatia.;Department of Oral Medicine School of Dental Medicine University of Zagreb and Department of Oral Diseases University Hospital Centre Zagreb, Zagreb, Croatia.;Department of Oral Medicine School of Dental Medicine University of Zagreb and Department of Oral Diseases University Hospital Centre Zagreb, Zagreb, Croatia.;Department of Oral Surgery School of Dental Medicine University of Zagreb and Department of Oral Surgery University Hospital Centre Zagreb, Zagreb, Croatia.",
"authors": "Vučićević Boras|Vanja|V|;Jurlina|Martin|M|;Brailo|Vlaho|V|;Đurić Vuković|Katarina|K|;Rončević|Pavle|P|;Bašić Kinda|Sandra|S|;Vidović Juras|Danica|D|;Gabrić|Dragana|D|",
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"fulltext": "\n==== Front\nActa Stomatol CroatActa Stomatol CroatASCActa Stomatologica Croatica0001-70191846-0410University of Zagreb School of Dental Medicine, and Croatian Dental Society - Croatian Medical Association ASC_53(3)_274-27710.15644/asc53/3/9Case ReportOral Mucormycosis and Aspergillosis in the Patient with Acute Leukemia Vučićević Boras Vanja 1Jurlina Martin 2Brailo Vlaho 1Đurić Vuković Katarina 2Rončević Pavle Bašić Kinda Sandra Vidović Juras Danica 1Gabrić Dragana 31 Department of Oral Medicine School of Dental Medicine University of Zagreb and Department of Oral Diseases University Hospital Centre Zagreb, Zagreb, Croatia2 Department of Otolaryngology, Head and Neck Surgery University Hospital Centre Zagreb, Zagreb, Croatia3 Department of Oral Surgery School of Dental Medicine University of Zagreb and Department of Oral Surgery University Hospital Centre Zagreb, Zagreb, CroatiaAddress for correspondence: Assist. Prof Danica Vidović Juras, DMD, MSc, PhD, Department of Oral Medicine, School of Dental Medicine, University of Zagreb, Gundulićeva 5, 10 000 Zagreb, Tel: 00385 4802 124, dvjuras@gmail.com9 2019 9 2019 53 3 274 277 23 11 2018 28 8 2019 2019University of Zagreb School of Dental MedicineThis is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (CC BY-NC-ND) 4.0 License.A 54-year-old male patient with acute lymphoblastic leukemia was referred to the Department of Oral Medicine. He had a primary refractory disease and was treated according to HOVON71 and HAM protocol. Sixteen days after the start of the HAM protocol the patient developed palatal dark red/brownish lesion and maxillary vestibular exophytic lesion. Biopsy specimens from oral lesions were taken and microbiologic evaluation confirmed the presence of Aspergillus fumigatus and Rhizopus genus. The treatment of the patient consisted of the inferior maxillectomy and intravenous posaconazole and amphotericine B for the following 28 days. Since the coinfection with Aspergillus and Rhizopus is extremely rarely seen in the oral cavity, a diagnostic and therapeutic dilemma easily presents itself.\n\nKey words: \nLeukemiaImmunosuppressionMucormycosisAspergillosisMouth\n==== Body\nIntroduction\nInvasive fungal infections are the major cause of infection-related mortality in hematopoietic stem cells recipients. Although mucormycosis and aspergillosis are the most frequent fungal infections, coinfection in the same host occurs rarely (1). Furthermore, they can be frequently fatal in immunocompromised patients. Treatment options usually combine medical and surgical approaches, often including extended necrosectomies. Nevertheless, the prognosis of generalized fungal infections is very poor (2).\n\nThere have been several case reports describing combined aspergillosis and mucormycosis in various parts of the body, usually with a fatal outcome (3). However, one case report depicts a patient with relapsed acute myeloid leukemia with a combined Aspergillus and Mucorales infection (lungs, brain, spleen and bone) who has been a long time survivor (4). The aforementioned coinfection rarely occurs in healthy individuals. The case of a 22- year- old, otherwise healthy US Marine who sustained extensive soft tissue injuries was published (5). Additionally, Pozo-Laderas et al. (6) published a case of a 17- year- old immunocompetent male who developed this coinfection 11 days after a motorcycle accident.\n\nThe coinfection of mucormycosis and aspergillosis should be considered in immunosuppressed patients in order to establish early management that will lead to the improved prognosis of the patient (1).\n\nCase report\nA 54-year-old male patient was referred to the Department of Oral Medicine due to the dark red/brownish lesions on the left side of the palate (Figure 1) and vestibular exophytic, later ulcerative, lesion in the area of the teeth 25-27 (Figure 2). The lesion was well demarcated from the surrounding tissue, asymmetric and without hemorrhage.\n\nFigure 1 Palatal mucormycosis and aspergillosis: the dark red/brownish lesions on the left side of the palate\n\nFigure 2 Vestibular mucormycosis and aspergillosis: the vestibular ulcerative lesion in the area of the teeth 25-27\n\nHe was diagnosed in December 2017 with acute lymphoblastic leukemia (Ph negative and pre-B). He had primary refractory disease and was treated according to protocols HOVON71 (7) and HAM (high dose of cytosine arabinoside and mitoxantrone). During HAM protocol induced aplasia, the patient developed neutropenic colitis and Aspergillus niger was identified in his stool samples. At the time of the oral examination, the patient was treated with intravenous levofloxacin, acyclovir, metronidazole, collistine, meropenem and tigecycline.\n\nOral lesions appeared sixteen days after the start of the HAM protocol. The patient noticed a swelling of his left cheek. The abovementioned oral lesions were identified upon examination. The orthopantomograph (Figure 3) showed a radiopaque lesion within the left maxillary sinus. Teeth 23, 26 and 27 were avital and tooth 24 was vital. Increased loosening of these teeth was noticed. A severe form of periodontal disease was present. The patient had no pain in that area, except sometimes on palpation. No evident pathological periapical pathology within teeth could be noticed. A CT finding showed a non-homogenous bony structure within the maxillary alveolar ridge.\n\nFigure 3 Orthopantomograph showed a radiopaque lesion within the left maxillary sinus\n\nIncisional biopsy of a vestibular lesion was taken. Histopathology showed tissue necrosis together with adipose tissue abundant with fungal hyphae and spores. Microbiological evaluation confirmed the presence of Aspergillus fumigatus and Rhizopus genus.\n\nIntravenous posaconazole and amphotericine B were given for the following 28 days and inferior maxillectomy was performed. The maxillary defect was to be reconstructed after the completion of hematological treatment. Meanwhile, the patient was given an obturator. Due to poor general condition of the patient, further treatment of leukemia by the transplantation of alogenous stem cells was not possible. Therefore, the treatment with blinatumomab was initiated. Unfortunately, in June 2018, the patient died due to severe hemorrhagic shock and cardiopulmonary arrest.\n\nSince the coinfection with Aspergillus and Rhizopus extremely rarely occurs in the oral cavity, it leads easily to the diagnostic and therapeutic dilemma.\n\nDiscussion\nAcute invasive fungal infections in the paranasal sinuses and surrounding tissues are progressive and carry a high death rate in an immunocompromised patient (8). Gode et al. (8) described 37 patients with acute invasive fungal rhinosinusitis and reported that the palatal involvement was significantly associated with death rate.\n\nThere are only a few case reports about a concomitant aspergillosis and zygomicosis infection in the orofacial region (1, 2, 9).\n\nTorres-Damas et al. (1) reported a case of a 78-year-old male patient with type 2 diabetes and ketoacidosis who presented with a swelling of the right side of his face, right facial paralysis, ptosis and a necrotic ulcer on the right palate due to the Aspergillus fumigatus and mucormycosis. Chermetz et al. (2) reported the case of a 17-year-old girl with combined aspergillosis and mucormycosis of the right side of her face with frontal maxillary area and upper airway involvement after the treatment of a recurrent glioma.\n\nMaiorano et al. (9) reported a case of aspergillosis and mucormycosis in the patient with stage-IV Castleman disease who presented with a palatal ulceration that progressively involved the palatal mucosa and bone, the paranasal sinuses and the orbit.\n\nAlthough invasive fungal infections are the major cause of infection-related mortality in hematopoietic stem cells recipients, in this particular patient invasive fungal infection occurred prior to the hematopoietic stem cell transplantation, during the period of post-chemotherapy aplasia.\n\nDifferential diagnosis of such cases includes malignancy and because of that, biopsy is mandatory. Due to high frequency of fungal infections in immunocompromised patients, microbiological testing and identification of a causative organism should be performed.\n\nTreatment of these lesions includes surgical resection of the affected tissues as well as intravenous antifungals. Posaconazole or Amphotericin BS is the drug of choice. Caspofungine can be added in resistant cases. Nevertheless, the duration of the treatment is long (median 180 days) and the outcome is unpredictable, favorable in only 40-60% of the cases.\n\nThis case report highlights the importance of considering the coinfection with Aspergillus and Rhizopus genera in the orofacial area in patients with leukemia.\n==== Refs\nReferences\n1 Torres-Damas W Yumpo-Cárdenas D Mota-Anaya E \nCoinfection of rhinocerebral mucormycosis and sinus aspergillosis. \nRev Peru Med Exp Salud Publica . 2015 ;32 (4 ):813 –7 . 10.17843/rpmesp.2015.324.1777 26732934 \n2 Chermetz M Gobbo M Rupel K Ottaviani G Tirelli G Bussani R \nCombined Orofacial Aspergillosis and Mucormycosis: Fatal Complication of a Recurrent Paediatric Glioma-Case Report and Review of Literature. \nMycopathologia . 2016 ;181 (9-10 ):723 –33 . 10.1007/s11046-016-0021-8 27350324 \n3 Mölle M Blaschke-Hellmessen R Schuler U Nowak R Ehninger G \nDisseminated aspergillosis and mucormycosis. A case report. \nMycoses . 1996 ;39 \nSuppl 1 :59 –64 .8767273 \n4 Davoudi S Anderlini P Fuller GN Kontoyiannis DP \nA long-term survivor of disseminated Aspergillus and mucorales infection: an instructive case. \nMycopathologia . 2014 ;178 (5-6 ):465 –70 . 10.1007/s11046-014-9785-x 25086667 \n5 Radowsky JS Strawn AA Sherwood J Braden A Liston W \nInvasive mucormycosis and aspergillosis in a healthy 22-year-old battle casualty: case report. \nSurg Infect (Larchmt) . 2011 ;12 (5 ):397 –400 . 10.1089/sur.2010.065 22004440 \n6 Pozo-Laderas JC Pontes-Moreno A Robles-Arista JC Bautista-Rodriguez MD Candau-Alvarez A Caro-Cuenca MT \nMixed invasive fungal infection due to Rhizomucor pusillus and Aspergillus niger in an immunocompetent patient. \nRev Iberoam Micol . 2015 ;32 (1 ):46 –50 . 10.1016/j.riam.2013.03.002 23583263 \n7 Daenen S van der Holt B Dekker A Willemze R Rijneveld A Biemond B \nIntensive chemotherapy to improve outcome in patients with acute lymphoblastic leukemia over the age of 40: a phase II study for efficacy and feasibility by HOVON. \nLeukemia . 2012 ;26 :1726 –9 . 10.1038/leu.2012.53 22358264 \n8 Gode S Turhal G Ozturk K Aysel A Midilli R Karci B \nAcute invasive fungal rhinosinusitis: Survival analysis and the prognostic indicators. \nAm J Rhinol Allergy . 2015 ;29 (6 ):e164 –9 . 10.2500/ajra.2015.29.4245 26637563 \n9 Maiorano E Favia G Capodiferro S Montagna MT Lo Muzio L \nCombined mucormycosis and aspergillosis of the oro-sinonasal region in a patient affected by Castleman disease. \nVirchows Arch . 2005 ;446 (1 ):28 –33 . 10.1007/s00428-004-1126-x 15480762\n\n",
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"journal": "Acta stomatologica Croatica",
"keywords": "Aspergillosis; Immunosuppression; Leukemia; Mouth; Mucormycosis",
"medline_ta": "Acta Stomatol Croat",
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"title": "Oral Mucormycosis and Aspergillosis in the Patient with Acute Leukemia.",
"title_normalized": "oral mucormycosis and aspergillosis in the patient with acute leukemia"
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"abstract": "Rheumatoid arthritis is a systemic inflammatory disease which causes symmetric polyarthritis. Lungs are common site for extra-articular involvement. Rheumatoid lung nodules occur in about 32% of patients with rheumatoid arthritis. The appearance of a lung nodule, along with the blood vessel supplying it, is called \"feeding-vessel\" sign on computed tomography. It is most commonly seen in infections. However, it can also be present in metastases and pulmonary vasculitis. We describe a woman with long-standing rheumatoid arthritis with subcutaneous and pulmonary nodules. Computed tomography of the chest showed \"feeding-vessel\" sign. There was no evidence of infection, malignancy, or vasculitis. She was treated for rheumatoid lung nodulosis with rituximab with which she improved remarkably. To the best of our knowledge, \"feeding-vessel\" sign in rheumatoid lung nodules has never been reported before. This case highlights the fact that \"feeding-vessel\" sign is not specific for pulmonary infections. It can rarely be seen in rheumatoid lung nodulosis.",
"affiliations": "Department of Rheumatology, Fortis Hospital, Sector 62, Noida, Uttar Pradesh, 201301, India. ash.blueney@gmail.com.;Department of Radiology, Fortis Flt Lt Rajan Dhall Hospital, New Delhi, India.;Department of Rheumatology, Fortis Flt Lt Rajan Dhall Hospital, New Delhi, India.",
"authors": "Sharma|Ashish|A|http://orcid.org/0000-0002-4810-8921;Kasetty|Abhinetri|A|;Kumar|Ashok|A|",
"chemical_list": "D000069283:Rituximab",
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"keywords": "Feeding-vessel sign; Lung nodules; Rheumatoid arthritis; Rituximab",
"medline_ta": "Clin Rheumatol",
"mesh_terms": "D001172:Arthritis, Rheumatoid; D005260:Female; D006801:Humans; D008168:Lung; D008171:Lung Diseases; D012218:Rheumatoid Nodule; D000069283:Rituximab",
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"references": "3873887",
"title": "Rheumatoid lung nodules with \"feeding-vessel\" sign.",
"title_normalized": "rheumatoid lung nodules with feeding vessel sign"
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"abstract": "OBJECTIVE\nTo examine the outcome in 155 consecutive patients with Wegener's granulomatosis (WG) followed up for a median of 7 years.\n\n\nMETHODS\nTreatment was adapted to the activity and extent of disease, with regular evaluation by an interdisciplinary team accompanied by group education about vasculitis.\n\n\nRESULTS\nThe estimated median survival time was 21.7 years (95% confidence interval [95% CI] 15.60-27.86). Twenty-two patients died; 19 deaths were attributable to WG and/or its treatment. Significant predictors of survival at diagnosis were age >50 years (hazard ratio [HR] 5.45, 95% CI 1.97-15.02), kidney involvement with impaired renal function (HR 5.42, 95% CI 1.76-16.68), and lung involvement (HR 3.75, 95% CI 1.26-11.16). At some stage, 142 patients received prednisone and cyclophosphamide (CYC), usually as daily CYC plus mesna as uroprotection, 50 patients received trimethoprim/sulfamethoxazole, and 45 received methotrexate. Complete remission was achieved in 83 of the 155 patients. One or more relapses occurred in 99 patients after either complete or partial remission. CYC-induced cystitis and myelodysplastic syndrome occurred in 17 and 11 patients, respectively. A cumulative dose of 100 gm or more of CYC resulted in a 2-fold greater risk of CYC-related morbidity than with lower CYC doses. Serious infections occurred in 41 patients.\n\n\nCONCLUSIONS\nAn interdisciplinary approach to the care of 155 WG patients resulted in a median survival of >21 years. Kidney or lung involvement at diagnosis was predictive of a >3-fold higher mortality. Although CYC remains essential in the treatment of WG, it was administered as briefly as possible and under close surveillance to avoid permanent CYC-related morbidity, which can lead to serious therapeutic problems in chronic relapsing WG.",
"affiliations": "Medical University of Lübeck, and Rheumaklinik Bad Bramstedt GmbH, Bad Bramstedt, Germany.",
"authors": "Reinhold-Keller|E|E|;Beuge|N|N|;Latza|U|U|;de Groot|K|K|;Rudert|H|H|;Nölle|B|B|;Heller|M|M|;Gross|W L|WL|",
"chemical_list": "D016756:Immunoglobulins, Intravenous; D003520:Cyclophosphamide; D011241:Prednisone; D008727:Methotrexate",
"country": "United States",
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"issue": "43(5)",
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"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D015331:Cohort Studies; D003520:Cyclophosphamide; D003556:Cystitis; D005260:Female; D014890:Granulomatosis with Polyangiitis; D006801:Humans; D016756:Immunoglobulins, Intravenous; D008134:Long-Term Care; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D010348:Patient Care Team; D011241:Prednisone; D016896:Treatment Outcome",
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"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "An interdisciplinary approach to the care of patients with Wegener's granulomatosis: long-term outcome in 155 patients.",
"title_normalized": "an interdisciplinary approach to the care of patients with wegener s granulomatosis long term outcome in 155 patients"
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"abstract": "Cerebral venous thrombosis (CVT) is an uncommon cause of stroke that mainly affects young adults with known risk factors of prothrombotic conditions, pregnancy, infection, malignancy, and drugs. Dutasteride is a 5α-reductase inhibitor that is used for benign prostate hypertrophy and androgenetic alopecia. To date, CVT caused by dutasteride use has not been reported. A 25-year-old male presented with headache and diplopia. He had taken 0.5 mg of dutasteride every other day for 9 months to treat alopecia. A headache developed 7 months after he started taking medication, and horizontal diplopia occurred 1 month after the onset of headache. Fundus examination showed bilateral papilledema. Brain magnetic resonance imaging showed thrombosis in the left sigmoid and transverse sinuses. Headache and diplopia improved after discontinuing dutasteride and starting anticoagulation. The results from this case report indicated dutasteride as a potential cause of CVT. Presumably, the increased estrogen level due to dutasteride use caused the formation of a thrombus.",
"affiliations": "Department of Neurology, Gangnam Severance Hospital, Severance Institute for Vascular and Metabolic Research, Yonsei University College of Medicine, Seoul, Korea.;Department of Neurology, Gangnam Severance Hospital, Severance Institute for Vascular and Metabolic Research, Yonsei University College of Medicine, Seoul, Korea.;Department of Neurology, Gangnam Severance Hospital, Severance Institute for Vascular and Metabolic Research, Yonsei University College of Medicine, Seoul, Korea.;Department of Neurology, Gangnam Severance Hospital, Severance Institute for Vascular and Metabolic Research, Yonsei University College of Medicine, Seoul, Korea.;Department of Neurology, Gangnam Severance Hospital, Severance Institute for Vascular and Metabolic Research, Yonsei University College of Medicine, Seoul, Korea. kylee@yuhs.ac.",
"authors": "Choi|Bo Kyu|BK|https://orcid.org/0000-0002-0796-4043;Cheon|Kyeongyeol|K|https://orcid.org/0000-0002-2999-3945;Cho|Bang Hoon|BH|https://orcid.org/0000-0003-1730-4345;Jung|Jae Wook|JW|https://orcid.org/0000-0002-9219-8522;Lee|Kyung Yul|KY|https://orcid.org/0000-0001-5585-7739",
"chemical_list": "D058891:5-alpha Reductase Inhibitors; D000068538:Dutasteride",
"country": "Korea (South)",
"delete": false,
"doi": "10.3349/ymj.2020.61.6.553",
"fulltext": "\n==== Front\nYonsei Med J\nYonsei Med. J\nYMJ\nYonsei Medical Journal\n0513-5796 1976-2437 Yonsei University College of Medicine \n\n10.3349/ymj.2020.61.6.553\nCase Report\nNeurology & Neurosciences\nCerebral Venous Sinus Thrombosis Associated with Dutasteride Use\nhttps://orcid.org/0000-0002-0796-4043Choi Bo Kyu https://orcid.org/0000-0002-2999-3945Cheon Kyeongyeol https://orcid.org/0000-0003-1730-4345Cho Bang-Hoon https://orcid.org/0000-0002-9219-8522Jung Jae Wook https://orcid.org/0000-0001-5585-7739Lee Kyung-Yul Department of Neurology, Gangnam Severance Hospital, Severance Institute for Vascular and Metabolic Research, Yonsei University College of Medicine, Seoul, Korea.\nCorresponding author: Kyung-Yul Lee, MD, PhD, Department of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul 06273, Korea. Tel: 82-2-2019-3325, Fax: 82-2-3462-5904, kylee@yuhs.ac\n01 6 2020 \n25 5 2020 \n61 6 553 555\n28 2 2020 23 4 2020 24 4 2020 © Copyright: Yonsei University College of Medicine 20202020Yonsei University College of MedicineThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Cerebral venous thrombosis (CVT) is an uncommon cause of stroke that mainly affects young adults with known risk factors of prothrombotic conditions, pregnancy, infection, malignancy, and drugs. Dutasteride is a 5α-reductase inhibitor that is used for benign prostate hypertrophy and androgenetic alopecia. To date, CVT caused by dutasteride use has not been reported. A 25-year-old male presented with headache and diplopia. He had taken 0.5 mg of dutasteride every other day for 9 months to treat alopecia. A headache developed 7 months after he started taking medication, and horizontal diplopia occurred 1 month after the onset of headache. Fundus examination showed bilateral papilledema. Brain magnetic resonance imaging showed thrombosis in the left sigmoid and transverse sinuses. Headache and diplopia improved after discontinuing dutasteride and starting anticoagulation. The results from this case report indicated dutasteride as a potential cause of CVT. Presumably, the increased estrogen level due to dutasteride use caused the formation of a thrombus.\n\nAlopeciavenous thrombosis5-alpha reductase inhibitors\n==== Body\nINTRODUCTION\nCerebral venous thrombosis (CVT) is less frequent than other types of strokes and has a different clinical presentation and etiologies.\n\nNumerous conditions are known to cause CVT, such as prothrombotic conditions, infection, inflammatory disease, hematologic disease, malignancy, pregnancy, puerperium state, and drugs.1 Therefore, thorough etiologic investigations are needed to determine the cause of CVT. However, its underlying risk factors are not found in approximately 13% of adult patients with CVT.2 Finasteride, a 5α-reductase inhibitor, is used to treat benign prostate hypertrophy as well as androgenetic alopecia, and it has been reported to induce CVT as a complication.3 Dutasteride is a new 5α-reductase inhibitor with the same indication as finasteride. Herein, we report a case of CVT caused by dutasteride use. Informed consent was obtained from the patient.\n\nCASE REPORT\nA 26-year-old male was admitted to the neurology department due to headache and horizontal diplopia. He had no previous illness or trauma history and was non-smoker. The patient had been taking 0.5 mg of dutasteride every other day for 9 months to treat alopecia. He did not take any medication except dutasteride. A headache developed 7 months after he began taking the medication, and horizontal diplopia occurred 1 month after the onset of headache. Pulsatile headache with dizziness initially started from the occipital area and progressed to the bi-frontal and temporal areas. The patient complained of horizontal diplopia when he looked laterally to either side. Neurologic examination showed no weakness, ataxia, sensory disturbance, or visual field defect.\n\nInitial fundus examination showed bilateral papilledema and retinal hemorrhage (Fig. 1A). To determine the cause of intracranial hypertension, brain magnetic resonance imaging (MRI) was performed on the day of admission, and it revealed thrombosis in the left jugular vein, sigmoid, and transverse sinuses (Fig. 1B). The patient showed no fever or specific findings based on blood tests for infectious conditions, including white blood cell count, erythrocyte sedimentation rate, and C-reactive protein. In addition, autoimmune antibodies, D-dimer, fibrinogen, antithrombin III, protein C, protein S, prothrombin time, activated partial thromboplastin time, and platelet count were normal. Serum estradiol level, which was measured 4 days after the discontinuation of dutasteride, was 14.2 pg/mL (normal range for male, 11.3–43.2).\n\nThere was no specific drug history to explain cerebral venous thrombosis other than dutasteride use. Therefore, dutasteride was discontinued, and intravenous anticoagulation was started to treat CVT. In addition, mannitol was used due to the bilateral papilledema for 10 days. We also used 250 mg of acetazolamide twice a day to alleviate intracranial hypertension for 5 months. After 1 week of intravenous anticoagulation, 7.5 mg of warfarin was given daily. After 6 weeks of oral anticoagulation treatment, the patient's symptoms were relieved, and bilateral papilledema was improved (Fig. 1C). Follow-up brain MRI performed at 9 months after anticoagulation treatment showed resolution of sinus thrombosis in the left sigmoid and transverse sinuses (Fig. 1D). Oral anticoagulation treatment was discontinued after follow-up MRI, and the patient had no symptoms since then.\n\nDISCUSSION\nSeveral types of drugs can cause CVT. Oral contraceptives are known to increase the risk of sinus thrombosis due to their prothrombic effects. In addition, asparaginase, cisplatin, methotrexate, lithium, and steroids can cause CVT.4 In several case reports, finasteride was found to cause CVT. Finasteride is a competitive inhibitor of type II 5α-reductase and an intracellular enzyme that converts the androgen testosterone into 5α-dihydrotestosterone. As a result of this mechanism, finasteride could increase serum estrone and estradiol levels and elevate the risk of CVT.56\n\nIn the present case, the patient also took dutasteride, a selective inhibitor of the type I and II isoforms of 5α-reductase, which is more widely expressed and found in the skin, liver, and kidneys. The patient did not have other prothrombotic conditions, such as infection, inflammatory disease, malignancy, or hematologic disease, and was not using any medications that could cause CVT, except dutasteride. Previous studies did not show consistent evidence of a significant association between dutasteride therapy and risk of cardiovascular adverse events.78\n\nIn this case, symptoms including headache, dizziness, and horizontal diplopia, which indicate intracranial hypertension, occurred progressively and were relieved with anticoagulation treatment, as in the previously reported CVT cases. Although there have been several studies that reported cases of CVT caused by specific drugs, dutasteride has not yet been reported to cause CVT. The present case indicates that the risk of CVT should be considered when dutasteride is prescribed for alopecia, benign prostate hyperplasia, or prostate cancer. In addition, a detailed history should be taken for patients who present with headache and other neurologic symptoms.\n\nThe authors have no potential conflicts of interest to disclose.\n\nAUTHOR CONTRIBUTIONS:\nConceptualization: Kyung-Yul Lee.\n\nData curation: Bo Kyu Choi, Jae Wook Jung, and Kyeongyeol Cheon.\n\nInvestigation: Bo Kyu Choi.\n\nMethodology: Bo Kyu Choi.\n\nSupervision: Bang-Hoon Cho, and Kyung-Yul Lee.\n\nValidation: Bo Kyu Choi, Bang-Hoon Cho, and Kyung-Yul Lee.\n\nWriting—original draft: Bo Kyu Choi.\n\nWriting—review & editing: Kyeongyeol Cheon, Bang-Hoon Cho, Jae Wook Jung, and Kyung-Yul Lee.\n\nApproval of final manuscript: all authors.\n\n\n\n\nFig. 1 (A) Initial fundus photograph shows bilateral papilledema and retinal hemorrhage. (B) Initial brain magnetic resonance imaging (MRI) shows thrombosis (arrows) in the left jugular vein, sigmoid, and transverse sinuses. (C) The papilledema is apparently improved after 6 weeks of anticoagulation treatment. (D) Follow-up MRI performed after 9 months of anticoagulation treatment shows resolution of sinus thrombosis in the left sigmoid and transverse sinuses.\n==== Refs\n1 Saposnik G Barinagarrementeria F Brown RD Jr Bushnell CD Cucchiara B Cushman M Diagnosis and management of cerebral venous thrombosis: a statement for healthcare professionals from the American Heart Association/American Stroke Association Stroke 2011 42 1158 1192 21293023 \n2 Ferro JM Canhão P Stam J Bousser MG Barinagarrementeria F ISCVT Investigators Prognosis of cerebral vein and dural sinus thrombosis: results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT) Stroke 2004 35 664 670 14976332 \n3 Tsuji Y Nakayama T Bono K Kitamura M Imafuku I Two cases of stroke associated with the use of finasteride, an approved drug for male-pattern hair loss in Japan Rinsho Shinkeigaku 2014 54 423 428 24943080 \n4 Gulati D Strbian D Sundararajan S Cerebral venous thrombosis: diagnosis and management Stroke 2014 45 e16 e18 24357654 \n5 Yao S Till C Kristal AR Goodman PJ Hsing AW Tangen CM Serum estrogen levels and prostate cancer risk in the prostate cancer prevention trial: a nested case-control study Cancer Causes Control 2011 22 1121 1131 21667068 \n6 Kang DW Jeong HG Kim HR Park CY Pyun JM Kim DY Finasteride induced cerebral venous thrombosis J Korean Neurol Assoc 2015 33 238 240 \n7 Skeldon SC Macdonald EM Law MR Huang A Paterson JM Mamdani MM The cardiovascular safety of dutasteride J Urol 2017 197 1309 1314 27866006 \n8 Loke YK Ho R Smith M Wong O Sandhu M Sage W Systematic review evaluating cardiovascular events of the 5-alpha reductase inhibitor-Dutasteride J Clin Pharm Ther 2013 38 405 415 23815285\n\n",
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"issue": "61(6)",
"journal": "Yonsei medical journal",
"keywords": "5-alpha reductase inhibitors; Alopecia; venous thrombosis",
"medline_ta": "Yonsei Med J",
"mesh_terms": "D058891:5-alpha Reductase Inhibitors; D000328:Adult; D002550:Cerebral Veins; D000068538:Dutasteride; D005654:Fundus Oculi; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D012307:Risk Factors; D012851:Sinus Thrombosis, Intracranial",
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"pages": "553-555",
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"pubdate": "2020-06",
"publication_types": "D002363:Case Reports",
"references": "24357654;27866006;14976332;23815285;24943080;21667068;21293023",
"title": "Cerebral Venous Sinus Thrombosis Associated with Dutasteride Use.",
"title_normalized": "cerebral venous sinus thrombosis associated with dutasteride use"
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"abstract": "BACKGROUND\nNiemann-Pick disease type C (NPC) is a lysosomal storage disorder with severe prognosis. Disease-specific therapy is crucial to prevent disease progression; however, diagnosing NPC is quite difficult because of remarkably variable clinical presentations. The NPC Suspicion Index (NPC-SI) was developed to overcome this problem. Identifying preclinical cases is important for prevention and therapy. Here, we report three newly diagnosed NPC cases, one typical juvenile-onset case and the cases of two sisters with symptoms neurologically/psychiatrically indistinguishable from dystonia and schizophrenia, respectively.\n\n\nMETHODS\nIn Case 1, a 25-year-old man presented with a 14-year history of intellectual disability, clumsiness, spastic ataxia, dysphagia, and frequent falls. Neurological examination revealed vertical supranuclear gaze palsy and involuntary movements. Ultrasonography revealed mild splenomegaly, and filipin staining of skin fibroblasts was positive with a variant staining pattern. NPC1 gene analysis showed compound heterozygous mutations, including c.1421C > T (p.P474L), a known causative mutation, and c.3722 T > C (p.L1241S), a new mutation. In Case 2, a 28-year-old woman, the proband, who had marked splenomegaly in her childhood, survived well, contrary to the expected severe prognosis of infantile NPC. She had minor neuropsychiatric symptoms including auditory hallucinations, nocturnal urination, and sleep paralysis. At the age of 28 years, she presented with a 1-year history of orofacial and oromandibular painful dystonia. The patient's 35-year-old sister (Case 3) was diagnosed with schizophrenia. In both cases, filipin staining of skin fibroblasts was positive with variant staining patterns, as well as elevated levels of urinary bile acids. NPC1 gene analysis showed compound heterozygous mutations including c.3011C > T (p.S1004 L), a known causative mutation, and c.160_161insG (p.D54GfsX4), a new mutation. Their mother, who was under therapy with modafinil for narcolepsy, shared the latter mutation.\n\n\nCONCLUSIONS\nMarked clinical variability was observed in our three cases. NPC could masquerade as a pure neuropsychiatric disorder such as dystonia or schizophrenia. Abdominal ultrasonography, history evaluation, and neurological examination were quite important in the diagnostic process.",
"affiliations": "Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, 187-8551, Kodaira, Tokyo, Japan.;Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, 187-8551, Kodaira, Tokyo, Japan.;Division of Child Neurology, Institute of Neurological Science, Tottori University Faculty of Medicine, Yonago, Tottori, Japan.;Division of Child Neurology, Institute of Neurological Science, Tottori University Faculty of Medicine, Yonago, Tottori, Japan.;Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, Yonago, Tottori, Japan.;Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, Yonago, Tottori, Japan.;Department of Pediatrics, Akita University Graduate School of Medicine, Akita, Akita, Japan.;Department of Pediatrics, Akita University Graduate School of Medicine, Akita, Akita, Japan.;Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Miyagi, Japan.;Advanced Clinical Research Center, Institute for Neurological Disorders, Kawasaki, Kanagawa, Japan.;Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, 187-8551, Kodaira, Tokyo, Japan.;Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, 187-8551, Kodaira, Tokyo, Japan.;Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, 187-8551, Kodaira, Tokyo, Japan. yutakahashi@ncnp.go.jp.",
"authors": "Kawazoe|Tomoya|T|;Yamamoto|Toshiyuki|T|;Narita|Aya|A|;Ohno|Kousaku|K|;Adachi|Kaori|K|;Nanba|Eiji|E|;Noguchi|Atsuko|A|;Takahashi|Tsutomu|T|;Maekawa|Masamitsu|M|;Eto|Yoshikatsu|Y|;Ogawa|Masafumi|M|;Murata|Miho|M|;Takahashi|Yuji|Y|http://orcid.org/0000-0002-6881-5586",
"chemical_list": "D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein",
"country": "England",
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"doi": "10.1186/s12883-018-1124-2",
"fulltext": "\n==== Front\nBMC NeurolBMC NeurolBMC Neurology1471-2377BioMed Central London 112410.1186/s12883-018-1124-2Case ReportPhenotypic variability of Niemann-Pick disease type C including a case with clinically pure schizophrenia: a case report Kawazoe Tomoya tomoya.kawazoe@gmail.com 1Yamamoto Toshiyuki yamamoto@ncnp.go.jp 1Narita Aya aya.luce@nifty.com 2Ohno Kousaku ohno@sanmedia.or.jp 2Adachi Kaori adachika@med.tottori-u.ac.jp 3Nanba Eiji enanba@med.tottori-u.ac.jp 3Noguchi Atsuko atsuko@doc.med.akita-u.ac.jp 4Takahashi Tsutomu tomy@med.akita-u.ac.jp 4Maekawa Masamitsu m-maekawa@hosp.tohoku.ac.jp 5Eto Yoshikatsu yosh@sepia.ocn.ne.jp 6Ogawa Masafumi rakutei321@yahoo.co.jp 1Murata Miho mihom@ncnp.go.jp 1http://orcid.org/0000-0002-6881-5586Takahashi Yuji yutakahashi@ncnp.go.jp 11 0000 0004 1763 8916grid.419280.6Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, 187-8551, Kodaira, Tokyo, Japan 2 0000 0001 0663 5064grid.265107.7Division of Child Neurology, Institute of Neurological Science, Tottori University Faculty of Medicine, Yonago, Tottori Japan 3 0000 0001 0663 5064grid.265107.7Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, Yonago, Tottori Japan 4 0000 0001 0725 8504grid.251924.9Department of Pediatrics, Akita University Graduate School of Medicine, Akita, Akita Japan 5 0000 0004 0641 778Xgrid.412757.2Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Miyagi Japan 6 Advanced Clinical Research Center, Institute for Neurological Disorders, Kawasaki, Kanagawa Japan 17 8 2018 17 8 2018 2018 18 11722 3 2018 13 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\nNiemann-Pick disease type C (NPC) is a lysosomal storage disorder with severe prognosis. Disease-specific therapy is crucial to prevent disease progression; however, diagnosing NPC is quite difficult because of remarkably variable clinical presentations. The NPC Suspicion Index (NPC-SI) was developed to overcome this problem. Identifying preclinical cases is important for prevention and therapy. Here, we report three newly diagnosed NPC cases, one typical juvenile-onset case and the cases of two sisters with symptoms neurologically/psychiatrically indistinguishable from dystonia and schizophrenia, respectively.\n\nCase presentation\nIn Case 1, a 25-year-old man presented with a 14-year history of intellectual disability, clumsiness, spastic ataxia, dysphagia, and frequent falls. Neurological examination revealed vertical supranuclear gaze palsy and involuntary movements. Ultrasonography revealed mild splenomegaly, and filipin staining of skin fibroblasts was positive with a variant staining pattern. NPC1 gene analysis showed compound heterozygous mutations, including c.1421C > T (p.P474L), a known causative mutation, and c.3722 T > C (p.L1241S), a new mutation. In Case 2, a 28-year-old woman, the proband, who had marked splenomegaly in her childhood, survived well, contrary to the expected severe prognosis of infantile NPC. She had minor neuropsychiatric symptoms including auditory hallucinations, nocturnal urination, and sleep paralysis. At the age of 28 years, she presented with a 1-year history of orofacial and oromandibular painful dystonia. The patient’s 35-year-old sister (Case 3) was diagnosed with schizophrenia. In both cases, filipin staining of skin fibroblasts was positive with variant staining patterns, as well as elevated levels of urinary bile acids. NPC1 gene analysis showed compound heterozygous mutations including c.3011C > T (p.S1004 L), a known causative mutation, and c.160_161insG (p.D54GfsX4), a new mutation. Their mother, who was under therapy with modafinil for narcolepsy, shared the latter mutation.\n\nConclusions\nMarked clinical variability was observed in our three cases. NPC could masquerade as a pure neuropsychiatric disorder such as dystonia or schizophrenia. Abdominal ultrasonography, history evaluation, and neurological examination were quite important in the diagnostic process.\n\nKeywords\nNiemann-Pick disease type CSchizophreniaDystoniaMiglustatNPC1 mutationissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nNiemann-Pick disease type C (NPC, MIM# 257220) is an autosomal recessive lysosomal storage disease caused by NPC1 (95%) or NPC2 (5%) gene mutations. If untreated, the prognosis of NPC is severe, with most patients with infantile-, juvenile-, and adult-onset NPC dying by the age of 10 years, before the age of 30 years, and in their mid-30s, respectively [1].\n\nDisease-specific therapies with miglustat [2] or intrathecal 2-hydroxypropyl-β-cyclodextrin [3] are available; therefore, early and accurate diagnosis is critical. However, establishing the diagnosis of NPC is challenging because of its clinical variability. In order to facilitate diagnosis, the NPC Suspicion Index (NPC-SI) was developed, which includes seven key discriminatory features: splenomegaly, neonatal jaundice, gelastic cataplexy, vertical supranuclear gaze palsy (VSGP), cognitive decline, psychotic symptoms, and family history [4]. NPC-SI assists in the identification of neurologically advanced cases with the key clinical features; however, especially in adult cases, an initial diagnosis of psychiatric illness, such as schizophrenia or depression, is usually made and NPC diagnosis is delayed by several years until the appearance of neurological complications [5]. Here, we report three cases of NPC; one juvenile-onset sporadic case and two adult sister cases. The latter two were diagnosed at clinical stages with minimum neurological complications, resulting in early therapeutic interventions.\n\nCase presentation\nThe case profiles are summarized in Table 1.Table 1 Case profiles\n\n\tCase 1\tCase 2\tCase 3\t\nAge at onset (years)\t11\t27\t22\t\nInitial symptom\tIntellectual disability\tPainful dystonia\tSchizophrenia\t\nAge at diagnosis (years)\t25\t28\t35\t\nVisceral signs\t\n Splenomegaly\tMild\tMild\tMild\t\n Neonatal jaundice\t+\tNone\tNone\t\nNeurological signs\t\n VSGP\t+\tNone\tNone\t\n Dysphagia\t+\tNone\tNone\t\n Spastic ataxia\t+\tNone\tNone\t\n IVM\tChorea, athetosis, dystonia, myoclonus\tDystonia\tNone\t\nPsychiatric signs\t\n Cognitive decline\t+\tNone\tNone\t\n Psychotic symptoms\t+\t+\t+\t\nNPC-SI a\t\n Percentile\t98%\t18%\t32%\t\n RPS\t183\t47\t67\t\nFilipin pattern\tVariant\tVariant\tVariant\t\nASM activity\t221\t213\t165\t\n(nmol/mg protein/h)\t99% of control\t95% of control\t73% of control\t\nPhenotype (cDx)\tJuvenile\tAdult\tAdult\t\nNPC1 gene mutations\t\n Father\tc.1421C > T\tc.3011C > T\tc.3011C > T\t\n(p.P474L)\t(p.S1004 L)\t(p.S1004 L)\t\n Mother\tc.3722 T > C\tc.160_161insG\tc.160_161insG\t\n(p.L1241S)\t(p.D54GfsX4)\t(p.D54GfsX4)\t\nBrain MRI\tSl. atrophic\tNormal\tSl. atrophic\t\nHypoperfusion on ECD-SPECT\tFrontal\tFrontal\tFrontal\t\nCSF Analysis\t\n p-Tau (< 55)\t59 pg/mL\t47 pg/mL\t36 pg/mL\t\n h-Tau (< 300)\t371 pg/mL\t214 pg/mL\t188 pg/mL\t\nCupper\t\n Serum Cu (> 68)\t76 μg/dL\t82 μg/dL\t88 μg/dL\t\n Serum Cp (> 21)\t22 mg/dL\t18 mg/dL\t22 mg/dL\t\n Urine Cu (> 20)\tNA\tNA\t32 μg/day\t\nUrine bile acid b\t\n SNAG-Δ5-CT (< 11)\tNA\t13 ng/mL\t92 ng/mL\t\n SNAG-Δ5-CA (< 282)\tNA\t42 ng/mL\t317 ng/mL\t\n SNAG-Δ5-CG (< 258)\tNA\t69 ng/mL\t481 ng/mL\t\nAbbreviations: ASM Acid sphingomyelinase; cDx Clinical diagnosis; Cp Ceruloplasmin; CSF Cerebrospinal fluid; Cu Copper; ECD-SPECT Technetium-99 m ethyl cysteinate dimer-single photon emission computed tomography; h-Tau Human tau protein; IVM Involuntary movements; MRI Magnetic resonance imaging; NA Not assessed; NPC-SI Niemann-Pick disease type C-suspicion index; p-Tau Phosphorylated tau protein; RPS Risk prediction score; VSGP Vertical supranuclear gaze palsy\n\na) Hendriksz CJ, et al. J Rare Disord. 2015 [4]. b) Maekawa M, et al. Steroids. 2013 [7]\n\n\n\nCase 1\nA 25-year-old man presented with a 14-year history of intellectual disability (since 11 years of age), clumsiness (12 years), spastic ataxia (16 years), slow and slurred speech (17 years), schizophrenic delusions (18 years), dysphagia (19 years), and frequent falls (21 years). He had prolonged neonatal jaundice, for which exploratory laparotomy and simultaneous cholecystectomy were performed at that time. He was also diagnosed with Crohn’s disease at the age of 16 years. Neurological examination at presentation revealed VSGP and involuntary movements including choreoathetosis, dystonia, and myoclonus. Ultrasonography revealed unpalpable mild splenomegaly. The NPC-SI was 98% with a risk prediction score (RPS) of 183 (high likelihood of NPC when the NPC-SI is more than 14% and the RPS is more than 40). Filipin staining of skin fibroblasts showed a variant pattern (Fig. 1). Gene analysis of NPC1 using genomic DNA extracted from the patient’s blood via Sanger sequencing revealed compound heterozygous mutations, including the known c.1421C > T (p.P474L) mutation [6] from the father and a novel c.3722 T > C (p.L1241S) mutation from the mother. We deposited the latter mutation to the Leiden Open Variation Database (LOVD); the individual number of this data entry is 00165102. Oral intake of miglustat for 12 months did not relieve his symptoms. The treatment had to be discontinued because the patient had succumbed to a vegetative state following massive pneumonia secondary to severe ileus due to Crohn’s disease.Fig. 1 Filipin staining of skin fibroblasts. a Positive typical (classical) control from a patient with Niemann-Pick disease type C. b Negative control from a healthy volunteer. All cases were positive with a variant staining pattern. c Case 1. d Case 2. e Case 3\n\n\n\nCase 2\nThe proband, a 28-year-old woman, presented with a 1-year history of orofacial and oromandibular dystonic movements. The woman had no neonatal jaundice; however, at the age of 1 year, marked hepatomegaly (2 cm) and splenomegaly (7 cm) were noted. Vacuolated lymphocytes were observed in her blood and cerebrospinal fluid, and many foam cells were observed in the bone marrow. The enzymatic activity of acid sphingomyelinase in skin fibroblasts had decreased to 17 nmol/mg/h (118 ± 53). As there was relatively conserved enzymatic activity (more than 10% of control), a diagnosis of infantile-onset NPC was considered. However, contrary to the expected severe prognosis of known infantile cases, she survived well with minimal neurological symptoms. The patient developed auditory hallucinations, nocturnal urination, and sleep paralysis at the ages of 3, 6, and 9 years, respectively. These symptoms gradually subsided by the age of 12 years. She had an eating disorder between the ages of 17–19 years, and excessive daytime sleepiness appeared at the age of 19 years. Orofacial and oromandibular dystonic movements with facial pain appeared at the age of 27 years. Modafinil 300 mg/day was not effective for sleepiness, and medications such as amitriptyline 10 mg/day, zonisamide 100 mg/day, trihexyphenidyl 2 mg/day, and L-dopa 50 mg/day were not effective for the painful dystonia. Only clonazepam 2 mg/day minimally relieved the symptoms. At the age of 28 years, when she was referred to our hospital, she was neurologically intact except for the dystonia. Ultrasonography detected mild unpalpable splenomegaly. The NPC-SI was 18% with an RPS of 47. Filipin staining of the skin fibroblasts was positive with a variant staining pattern (Fig. 1). The urinary levels of bile acids [7] were partially elevated (Table 1). NPC1 gene analysis showed compound heterozygous mutations including the known c.3011C > T (p.S1004 L) mutation [8] from the father and a new mutation of c.160_161insG (p.D54GfsX4) from the mother. Oral intake of miglustat for more than 12 months was not effective for the painful dystonia.\n\nCase 3\nThe elder sister of the patient in Case 2 was clinically diagnosed with schizophrenia, with good response to antipsychotic medications and was later found to have NPC. She was examined at the age of 8 years, when her younger sister was suspected to have NPC; however, she was neurologically intact with no splenomegaly at that time. By the age of 22 years, she began showing signs of schizophrenia; an official diagnosis confirmed the disease at the age of 25 years. She responded well to risperidone 3 mg/day. When we examined her at the age of 35 years, she was neurologically intact. Moreover, in this Case, ultrasonography detected mild unpalpable splenomegaly. Given the family history of Case 2, the NPC-SI was 32% with an RPS of 67. NPC1 gene analysis detected the same mutations with those observed in Case 2. We deposited the new mutation to LOVD; the individual numbers are 00165175 (Case 2) and 00165176 (Case 3). Oral intake of miglustat for 20 months improved her psychotic symptoms, and her attending psychiatrist diagnosed complete remission of schizophrenia.\n\nDiscussion and conclusions\nThis case series highlights that patients with NPC may exhibit remarkable phenotypic variability, which in our cases ranged from juvenile-onset progressive neuropsychiatric deterioration to adult psychiatric symptoms clinically indistinguishable from schizophrenia. The phenotypic variability is further supported by previous studies reporting that a substantial number of patients with NPC do not exhibit cardinal symptoms such as VSGP and dysphagia [9, 10]. Phenotypic heterogeneity was even observed in a case of monozygotic twins [11]. Meanwhile, the international study on genetic screening for psychiatric patients with neurological symptoms or splenomegaly, known as the ZOOM study, demonstrated that 3 of 250 participants harbored pathogenic mutations in NPC1 [12]. Of note, the patient in Case 3 did not show any neurological symptoms at the time of NPC diagnosis. Therefore, the phenotypes of NPC must be more diverse than previously thought, and patients with mild clinical manifestations may remain undiagnosed. Based on these observations, we would like to emphasize that NPC should be considered in the differential diagnosis of a wide variety of disease entities, including juvenile-onset multi-systemic neurological disorders and adult psychiatric disorders such as schizophrenia.\n\nIt is of vital importance to accurately diagnose NPC because disease-modifying therapies are available. Furthermore, it is imperative to diagnose it in the early stages, particularly in cases with mild neurological symptoms, because of the severe prognosis of adult NPC, which results in death at a mean age of 38 years [9] or 33 years [10], and the difficulty in ameliorating the neurological symptoms even with miglustat, when the disease is at an advanced stage. In contrast, the appearance of psychotic symptoms consistent with schizophrenia or depression precedes the appearance of neurological complications by several years in more than half of the cases [13], and the effectiveness of miglustat in alleviating the psychotic symptoms [14] has been reported, further corroborating the importance of early detection. For this purpose, the NPC-SI was invented and revised based on the cardinal features of NPC [4]. The NPC-SI in this study varied greatly, depending on the extent to which the key features were detected at the time of diagnosis. The NPC-SI showed that there was high likelihood of NPC in all cases, with the recommendation that the patients should be referred to the NPC referral center (institute) for immediate testing, highlighting the clinical usefulness of the NPC-SI. The fact that the mean RPS of adult cases was as high as 179 [15] implies that most cases were diagnosed at a stage of fully present clinical manifestations. To benefit from the NPC-SI, it is imperative to enhance the awareness of its usefulness in daily clinical settings, particularly in adult neurology.\n\nIn Japan, the current initial diagnostic workup for NPC includes a combination of serum oxysterol (7-ketocholesterol) and urinary bile acids, followed by more specific diagnostic procedures including skin biopsy with filipin staining and NPC1 or NPC2 gene analysis. In our cases, mild elevation of urine bile acids in Cases 2 and 3 was informative in the initial workup, whereas the oxysterol value in Case 2 was normal (could not be tested in Cases 1 and 3). Additionally, in line with previous reports, cerebrospinal tau proteins were elevated in Case 1 [16] and the laboratory values of copper metabolism slightly deviated or were close to the lower limit of the normal levels [17]. Recently, it has been reported that plasma oxysterol (cholestane-3β,5α,6β-triol) is informative in the detection of NPC [18]. Additionally, lysosphingolipids have been proposed as a potential biomarker for NPC [19]. Establishing excellent biomarkers for NPC is highly warranted considering that skin biopsy and genetic analyses are time-consuming and expensive procedures.\n\nFinally, we would like to focus on the narcolepsy experienced by the mother of Cases 2 and 3, who shared the c.160_161insG (p.D54GfsX4) mutation. In addition to gelastic cataplexy as one of the key discriminatory features of NPC, sleep problems, such as excessive daytime sleepiness, are known to be related to NPC, presumably via dysfunction of the locus coeruleus [20]. Regarding partial manifestations in people with NPC1 gene heterozygosity, a previous report of a family whose proband developed late infantile NPC with compound heterozygous mutations of NPC1 described that the heterozygous asymptomatic carriers of NPC mutations, the oldest sister and parents, had foam cells in their bone marrow smears [21]. Likewise, it is possible that the haploinsufficiency of the NPC1 gene identified in our pedigree could also cause mild tissue changes resulting in manifesting carriers. Accumulation of familial histories and genetic evidence is necessary to analyze the relationship between narcolepsy and NPC1 mutation carriers. We hypothesize that NPC1 might be an extremely rare candidate gene for familial narcolepsy syndrome.\n\nIn conclusion, the cases described in this report highlight the clinical variability of NPC and reinforce the importance of early diagnosis of this rare disease to initiate disease-modifying therapy. We would like to emphasize that the exploration of disease-suggestive findings by use of the NPC-SI in patients with schizophrenia would enhance the diagnostic accuracy of NPC.\n\nAbbreviations\nNPCNiemann-Pick disease type C\n\nNPC-SINPC suspicion index\n\nRPSRisk prediction score\n\nVSGPVertical supranuclear gaze palsy\n\nAcknowledgements\nWe are grateful to the patients and their families for their invaluable cooperation and for providing blood samples. We thank Prof. Hasegawa T (Department of Pediatrics, Keio University School of Medicine) for the childhood clinical information of Case 2. We also thank Dr. Tajima H (Department of Pediatrics, Nippon Medical School) and Dr. Asayama K (Department of Neuropsychiatry, Nippon Medical School) for referring the patient of Case 2 and providing clinical information including on oxysterol.\n\nFunding\nThis work was partially supported by Grants-in-Aid for Scientific Research (16 K20900) from the Japan Society for the Promotion of Science. Moreover, a part of this work was supported by a grant from the AMED - Project for Baby and Infant Research of Health and Development to Adolescent and Young adult, 2017–2018.\n\nAvailability of data and materials\nThe datasets obtained and/or analyzed during the current study are available from the corresponding author on reasonable request. The datasets of the new mutations are accessible from the publicly available repository, LOVD [22].\n\nAuthors’ contributions\nTK (Cases 1–3), TY (Cases 2 and 3) and MO (Case 1) examined the patients. TK and YT were major contributors in writing the manuscript. AN performed the filipin staining in all cases. KA and EN analyzed the NPC1 gene for Case 1. KO organized the filipin staining and gene analysis. AN and TT analyzed the NPC1 gene for Cases 2 and 3. MM performed the urinary bile acid analysis. YE performed the oxysterol analysis. MM and YT organized the study. All authors have made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data; have been involved in drafting the manuscript or revising it critically for important intellectual content, and have given final approval of the version to be published. Each author has participated sufficiently in the work, takes public responsibility for appropriate portions of the content, and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent for publication of clinical details was obtained from the patients (Cases 2 and 3) or from the family (Case 1).\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. Vanier MT Niemann-Pick disease type C Orphanet J Rare Disord 2010 5 16 10.1186/1750-1172-5-16 \n2. Patterson MC Vecchio D Prady H Abel L Wraith JE Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study Lancet Neurol 2007 6 765 772 10.1016/S1474-4422(07)70194-1 17689147 \n3. Ory DS Ottinger EA Farhat NY King KA Jiang X Weissfeld L Intrathecal 2-hydroxypropyl-β-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1-2 trial Lancet 2017 390 1758 1768 10.1016/S0140-6736(17)31465-4 28803710 \n4. Hendriksz CJ Pineda M Fahey M Walterfang M Stampfer M Runz H The Niemann-Pick disease type C suspicion index: development of a new tool to aid diagnosis J Rare Disord 2015 1 1 9 \n5. Nia S Psychiatric signs and symptoms in treatable inborn errors of metabolism J Neurol 2014 261 Suppl 2 S559 S568 10.1007/s00415-014-7396-6 25145892 \n6. Tarugi P Ballarini G Bembi B Battisti C Palmeri S Panzani F Niemann-Pick type C disease: mutations of NPC1 gene and evidence of abnormal expression of some mutant alleles in fibroblasts J Lipid Res 2002 43 1908 1919 10.1194/jlr.M200203-JLR200 12401890 \n7. Maekawa M Misawa Y Sotoura A Yamaguchi H Togawa M Ohno K LC/ESI-MS/MS analysis of urinary 3β-sulfooxy-7β-N-acetylglucosaminyl-5-cholen-24-oic acid and its amides: new biomarkers for the detection of Niemann-Pick type C disease Steroids 2013 78 967 972 10.1016/j.steroids.2013.05.017 23751200 \n8. Sun X Marks DL Park WD Wheatley CL Puri V O'Brien JF Niemann-Pick C variant detection by altered sphingolipid trafficking and correlation with mutations within a specific domain of NPC1 Am J Hum Genet 2001 68 1361 1372 10.1086/320599 11349231 \n9. Sévin M Lesca G Baumann N Millat G Lyon-Caen O Vanier MT The adult form of Niemann-Pick disease type C Brain 2007 130 120 133 10.1093/brain/awl260 17003072 \n10. Imrie J Heptinstall L Knight S Strong K Observational cohort study of the natural history of Niemann-Pick disease type C in the UK: a 5-year update from the UK clinical database BMC Neurol 2015 15 257 10.1186/s12883-015-0511-1 26666848 \n11. Benussi A Alberici A Premi E Bertasi V Cotelli MS Turla M Phenotypic heterogeneity of Niemann-Pick disease type C in monozygotic twins J Neurol 2015 262 642 647 10.1007/s00415-014-7619-x 25536905 \n12. Bauer P Balding DJ Klünemann HH Linden DE Ory DS Pineda M Genetic screening for Niemann-Pick disease type C in adults with neurological and psychiatric symptoms: findings from the ZOOM study Hum Mol Genet 2013 22 4349 4356 10.1093/hmg/ddt284 23773996 \n13. Maubert A Hanon C Sedel F Psychiatric disorders in adult form of Niemann-Pick disease type C Encephale 2016 42 208 213 10.1016/j.encep.2015.11.003 26727648 \n14. Szakszon K Szegedi I Magyar A Oláh E Andrejkovics M Balla P Complete recovery from psychosis upon miglustat treatment in a juvenile Niemann-Pick C patient Eur J Paediatr Neurol 2014 18 75 78 10.1016/j.ejpn.2013.08.002 24119781 \n15. Wraith JE Sedel F Pineda M Wijburg FA Hendriksz CJ Fahey M Niemann-Pick type C suspicion index tool: analyses by age and association of manifestations J Inherit Metab Dis 2014 37 93 101 10.1007/s10545-013-9626-y 23793527 \n16. Mattsson N Zetterberg H Bianconi S Yanjanin NM Fu R Månsson JE Gamma-secretase-dependent amyloid-beta is increased in Niemann-Pick type C: a cross-sectional study Neurology 2011 76 366 372 10.1212/WNL.0b013e318208f4ab 21205675 \n17. Sakiyama Y Narita A Osawa S Nanba E Ohno K Otsuka M Abnormal copper metabolism in Niemann–Pick disease type C mimicking Wilson's disease Neurol Clin Neurosci 2014 2 193 200 10.1111/ncn3.122 \n18. Hammerschmidt TG de Oliveira Schmitt Ribas G Saraiva-Pereira ML Bonatto MP Kessler RG FTS S Molecular and biochemical biomarkers for diagnosis and therapy monitorization of Niemann-Pick type C patients Int J Dev Neurosci 2017 66 18 23 10.1016/j.ijdevneu.2017.11.007 29197565 \n19. Pettazzoni M Froissart R Pagan C Vanier MT Ruet S Latour P LC-MS/MS multiplex analysis of lysosphingolipids in plasma and amniotic fluid: a novel tool for the screening of sphingolipidoses and Niemann-Pick type C disease PLoS One 2017 12 e0181700 10.1371/journal.pone.0181700 28749998 \n20. Nevsimalova S Malinova V Cataplexy and sleep disorders in Niemann-Pick type C disease Curr Neurol Neurosci Rep 2015 15 522 10.1007/s11910-014-0522-0 25434476 \n21. Harzer K Beck-Wödl S Bauer P Niemann-Pick disease type C: new aspects in a long published family - partial manifestations in heterozygotes JIMD Rep 2014 12 25 29 10.1007/8904_2013_240 23821321 \n22. Fokkema IF Taschner PE Schaafsma GC Celli J Laros JF den Dunnen JT LOVD v.2.0: the next generation in gene variant databases Hum Mutat 2011 32 557 563 10.1002/humu.21438 21520333\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2377",
"issue": "18(1)",
"journal": "BMC neurology",
"keywords": "Dystonia; Miglustat; NPC1 mutation; Niemann-Pick disease type C; Schizophrenia",
"medline_ta": "BMC Neurol",
"mesh_terms": "D000328:Adult; D000073537:Biological Variation, Population; D002352:Carrier Proteins; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008562:Membrane Glycoproteins; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C; D012559:Schizophrenia",
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"pubdate": "2018-08-17",
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"title": "Phenotypic variability of Niemann-Pick disease type C including a case with clinically pure schizophrenia: a case report.",
"title_normalized": "phenotypic variability of niemann pick disease type c including a case with clinically pure schizophrenia a case report"
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"abstract": "An increasing number of patients are requiring multiple retransplants. We assessed outcomes of third and fourth kidney transplants, to aid decision making on the most suitable donor type.\n\n\n\nData were collected retrospectively for 2561 transplants, including 69 third and 8 fourth, performed from 2000 to 2017. Demographics and outcomes for the combined third/fourth group were compared to first and second transplants. Within the third/fourth kidney transplant group, comparisons were made between deceased donors (n = 39), live donor HLA-compatible (n = 23) and -incompatible (n = 13) transplants, as well as between standard (n = 25) and extended-criteria (n = 14) deceased donor transplants.\n\n\n\nPatient survival did not differ significantly by transplant number (P = 0.532), whereas death-censored graft survival declined progressively, from 89% at 5 years in first, 85% in second and 74% in the third/fourth transplant group (P < 0.001). Within the combined third/fourth transplant subgroup, 5-year graft survival was found to be 100% in recipients of HLA-compatible live donors, compared to 75% in deceased donors and 53% in HLA-incompatible live donors, although this difference did not reach statistical significance (P = 0.083). No significant difference in patient survival (P = 0.356) or complication rates (P = 0.757) were detected between these groups. For recipients of deceased donors in the third/fourth transplant group, there were no significant differences between standard versus extended-criteria donors for any of the outcomes considered.\n\n\n\nDespite variable functional outcomes, third and fourth kidney transplant recipients experience comparable patient survival rates to first and second transplants, regardless of the donor type. In selected patients, HLA-incompatible live donors and extended-criteria deceased donors should be considered.",
"affiliations": "Department of Nephrology and Transplantation, Guy's and St Thomas' NHS Foundation Trust, Great Maze Pond, London, United Kingdom.;Department of Nephrology and Transplantation, Guy's and St Thomas' NHS Foundation Trust, Great Maze Pond, London, United Kingdom.;Institute of Translational Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.;Department of Nephrology and Transplantation, Guy's and St Thomas' NHS Foundation Trust, Great Maze Pond, London, United Kingdom.;Department of Nephrology and Transplantation, Guy's and St Thomas' NHS Foundation Trust, Great Maze Pond, London, United Kingdom.;Department of Nephrology and Transplantation, Guy's and St Thomas' NHS Foundation Trust, Great Maze Pond, London, United Kingdom.;Clinical Transplantation Laboratory, Viapath, Guy's and St Thomas' NHS Foundation Trust, Great Maze Pond, London, United Kingdom.;Department of Nephrology and Transplantation, Guy's and St Thomas' NHS Foundation Trust, Great Maze Pond, London, United Kingdom.;Department of Nephrology and Transplantation, Guy's and St Thomas' NHS Foundation Trust, Great Maze Pond, London, United Kingdom.;Department of Nephrology and Transplantation, Guy's and St Thomas' NHS Foundation Trust, Great Maze Pond, London, United Kingdom.;Department of Nephrology and Transplantation, Guy's and St Thomas' NHS Foundation Trust, Great Maze Pond, London, United Kingdom.;Department of Nephrology and Transplantation, Guy's and St Thomas' NHS Foundation Trust, Great Maze Pond, London, United Kingdom.;Department of Nephrology and Transplantation, Guy's and St Thomas' NHS Foundation Trust, Great Maze Pond, London, United Kingdom.",
"authors": "Dabare|Dilan|D|;Kassimatis|Theodoros|T|;Hodson|James|J|;Khurram|Muhammad Arslan|MA|;Papadakis|Georgios|G|;Rompianesi|Gianluca|G|;Shaw|Olivia|O|;Karydis|Nikolaos|N|;Callaghan|Chris|C|;Olsburgh|Jonathon|J|;Mamode|Nizam|N|;Kessaris|Nicos|N|;Loukopoulos|Ioannis|I|",
"chemical_list": "D000017:ABO Blood-Group System; D006680:HLA Antigens; D007166:Immunosuppressive Agents; D007518:Isoantibodies",
"country": "United States",
"delete": false,
"doi": "10.1097/TP.0000000000002428",
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"issue": "103(7)",
"journal": "Transplantation",
"keywords": null,
"medline_ta": "Transplantation",
"mesh_terms": "D000017:ABO Blood-Group System; D000328:Adult; D001787:Blood Group Incompatibility; D002423:Cause of Death; D046148:Donor Selection; D005260:Female; D006084:Graft Rejection; D006085:Graft Survival; D006680:HLA Antigens; D006648:Histocompatibility; D006801:Humans; D007166:Immunosuppressive Agents; D007518:Isoantibodies; D016030:Kidney Transplantation; D019520:Living Donors; D008297:Male; D008875:Middle Aged; D012086:Reoperation; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D014019:Tissue Donors; D016896:Treatment Outcome",
"nlm_unique_id": "0132144",
"other_id": null,
"pages": "1494-1503",
"pmc": null,
"pmid": "30130325",
"pubdate": "2019-07",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Outcomes in Third and Fourth Kidney Transplants Based on the Type of Donor.",
"title_normalized": "outcomes in third and fourth kidney transplants based on the type of donor"
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"companynumb": "NVSC2020GB071077",
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"occurcountry": "GB",
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"abstract": "Hashimoto's encephalopathy (HE) is an autoimmune encephalopathy that presents with various clinical symptoms, including cognitive deterioration, convulsive seizures, and personality changes. HE is associated with thyroid autoimmunity; however, few cases have been reported to develop as paraneoplastic syndrome. Herein, we report the case of a 73-year-old woman with onset of rapidly progressive dementia. Brain magnetic resonance imaging showed diffuse T2 hyperintensity areas involving the bilateral cerebral white matter, right midbrain tegmental area, left cerebral peduncle, and right middle cerebellar peduncle without clear diffusion hyperintensities and gadolinium enhancement. Her neurological symptoms worsened rapidly, and she presented with the apallic syndrome. Electroencephalogram showed periodic synchronous discharge, suggestive of Creutzfeldt-Jakob disease. However, a brain biopsy revealed infiltration of atypical lymphoid cells expressing CD20, and the anti-NH2 terminal of the α-enolase antibody was detected, diagnosing the complication with lymphomatosis cerebri and HE. High-dose intravenous methylprednisolone therapy and oral prednisolone with whole cranial irradiation enabled her to have simple conversations and consume food orally; however, severe cognitive impairment persisted. Although HE is a rare complication of malignant lymphoma, clinicians should be aware that it could be strongly suspected if the clinical symptoms worsen in the absence of imaging changes.",
"affiliations": "Department of Internal Medicine, Fujiyoshida Municipal Medical Center, Fujiyoshida, Japan.;Department of Internal Medicine, Fujiyoshida Municipal Medical Center, Fujiyoshida, Japan.;Department of Internal Medicine, Fujiyoshida Municipal Medical Center, Fujiyoshida, Japan.;Division of Neurology, Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan.;Division of Neurology, Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan.;Faculty of Nursing and Social Welfare Science, Fukui Prefectural University, Fukui, Japan.;Department of Internal Medicine, Fujiyoshida Municipal Medical Center, Fujiyoshida, Japan.",
"authors": "Amano|Ryota|R|;Tsukada|Setsuro|S|;Kosuge|Shota|S|;Yano|Satoshi|S|;Ono|Kenjiro|K|;Yoneda|Makoto|M|;Taki|Katsumi|K|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fneur.2021.701178",
"fulltext": "\n==== Front\nFront Neurol\nFront Neurol\nFront. Neurol.\nFrontiers in Neurology\n1664-2295\nFrontiers Media S.A.\n\n10.3389/fneur.2021.701178\nNeurology\nCase Report\nCase Report: Paraneoplastic Hashimoto's Encephalopathy Associated With Lymphomatosis Cerebri With Periodic Synchronous Discharges Resembling Creutzfeldt–Jakob Disease\nAmano Ryota 1 *\n\nTsukada Setsuro 1\nKosuge Shota 1\nYano Satoshi 2\nOno Kenjiro 2\n\nYoneda Makoto 3\nTaki Katsumi 1\n\n1Department of Internal Medicine, Fujiyoshida Municipal Medical Center, Fujiyoshida, Japan\n2Division of Neurology, Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan\n3Faculty of Nursing and Social Welfare Science, Fukui Prefectural University, Fukui, Japan\nEdited by: Jorge Matias-Guiu, Complutense University of Madrid, Spain\n\nReviewed by: Julián Benito León, University Hospital October 12, Spain; Leonid Pavlovich Churilov, Saint Petersburg State University, Russia\n\n*Correspondence: Ryota Amano d10sm003@yahoo.co.jp\nThis article was submitted to Multiple Sclerosis and Neuroimmunology, a section of the journal Frontiers in Neurology\n\n10 8 2021\n2021\n12 70117827 4 2021\n31 5 2021\nCopyright © 2021 Amano, Tsukada, Kosuge, Yano, Ono, Yoneda and Taki.\n2021\nAmano, Tsukada, Kosuge, Yano, Ono, Yoneda and Taki\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.\nHashimoto's encephalopathy (HE) is an autoimmune encephalopathy that presents with various clinical symptoms, including cognitive deterioration, convulsive seizures, and personality changes. HE is associated with thyroid autoimmunity; however, few cases have been reported to develop as paraneoplastic syndrome. Herein, we report the case of a 73-year-old woman with onset of rapidly progressive dementia. Brain magnetic resonance imaging showed diffuse T2 hyperintensity areas involving the bilateral cerebral white matter, right midbrain tegmental area, left cerebral peduncle, and right middle cerebellar peduncle without clear diffusion hyperintensities and gadolinium enhancement. Her neurological symptoms worsened rapidly, and she presented with the apallic syndrome. Electroencephalogram showed periodic synchronous discharge, suggestive of Creutzfeldt–Jakob disease. However, a brain biopsy revealed infiltration of atypical lymphoid cells expressing CD20, and the anti-NH2 terminal of the α-enolase antibody was detected, diagnosing the complication with lymphomatosis cerebri and HE. High-dose intravenous methylprednisolone therapy and oral prednisolone with whole cranial irradiation enabled her to have simple conversations and consume food orally; however, severe cognitive impairment persisted. Although HE is a rare complication of malignant lymphoma, clinicians should be aware that it could be strongly suspected if the clinical symptoms worsen in the absence of imaging changes.\n\nHashimoto's encephalopathy\nlymphomatosis cerebri\nanti-NH2-terminal of α-enolase antibody\nperiodic synchronous discharge\nCreutzfeldt–Jakob disease\n==== Body\nIntroduction\n\nHashimoto's encephalopathy (HE), a steroid-responsive disorder, is an autoimmune encephalopathy associated with Hashimoto's thyroiditis in the euthyroid state (1, 2). As HE presents a variety of clinical symptoms, clinicians sometimes misdiagnose it as other neurological diseases, such as seizures, Alzheimer's disease, limbic encephalitis, psychiatric diseases, or Creutzfeldt–Jakob disease (CJD) (3–6). At present, elevation of serum anti-thyroid autoantibodies, such as the anti-thyroid peroxidase (TPO) antibody and/or anti-thyroglobulin (Tg) antibody, is useful and essential for the diagnosis of HE; however, the anti-TPO antibody or anti-Tg antibody is known to be detected in approximately 10% of normal adults (7–9). The specificity of serum diagnosis of HE by anti-thyroid autoantibodies is low. However, Yoneda et al. reported that the serum anti-NH2 terminal of the α-enolase (NAE) antibody is a specific biomarker for HE (with specificity of 91% and sensitivity of 50%) (10, 11). Therefore, serum diagnosis of HE has recently become easier.\n\nLymphomatosis cerebri (LC), a rare variant of primary central nervous system lymphoma (PCNSL) that represents 2–3% of all brain tumors (12), was initially described in 1999 (13). Only less than 50 LC cases have been reported by 2019 (14). PCNSL is generally easy to diagnose with the mass formation in the brain with homogeneous contrast effects on gadolinium-enhanced MRI (15). In contrast, diagnosing LC is challenging as it shows diffuse T2 high-intensity signals without obvious contrast effect or mass formation even if a contrast effect is present (16).\n\nAs HE sometimes shows diffuse non-specific T2 high-intensity signals in the bilateral cerebral white matter on brain MRI (3), it is often impossible to discriminate between HE and LC using only image findings. However, HE is an autoimmune disease, whereas LC is a malignant neoplastic disease; therefore, HE and LC are completely different diseases, and to the best of our knowledge, LC-related HE has not been reported before. Herein, we report a case of paraneoplastic encephalopathy with anti-NAE antibody complicated with LC, which was diagnosed using brain biopsy. The clinical presentation was similar to that of CJD and responded to steroid therapy. We believe that, similar to this case, HE develops as a paraneoplastic neurological syndrome of LC.\n\nCase Presentation\n\nA 73-year-old woman with a history of type 2 diabetes and non-tuberculous mycobacterial infection presented to our hospital with subacute progressive dementia characterized by nausea, dizziness, headaches, loss of recent memory, and behavioral changes for 3 months. On admission, her vital signs were within the normal range. Neurological examinations confirmed disturbance of consciousness [Glasgow Coma Scale (GCS) score of 14 (E4V4M6)], increased deep tendon reflex in the left upper limb and bilateral lower limbs, positive pathological reflexes (Babinski and Chaddock reflexes), cerebellar ataxia in the right upper limb, apathy, perseveration, acalculia, and finger agnosia. We did not observe cranial nerve palsies, muscle weakness, or sensory disturbances.\n\nInitial laboratory tests did not reveal any specific abnormalities. Complete blood count, liver function, and renal function were within the reference range (RR). Thyroid function was in a euthyroid state, and no elevation of serum anti-TPO antibody and anti-Tg antibody was observed in electrochemiluminescence immunoassay (<9.0 and <10.8 IU/ml, respectively; RR <16.0 and <28.0 IU/ml, respectively). The concentrations of lactate dehydrogenase (LDH) and soluble interleukin-2 receptor (sIL-2R) were not elevated (134 IU/L and 206 U/ml, respectively; RR = 100–220 IU/L and 121–613 U/ml, respectively), and human immunodeficiency virus was negative. Cerebrospinal fluid (CSF) analyses showed elevated total protein levels (TP = 52 mg/dl, RR = 10–40 mg/dl) and slightly high levels of sIL-2R (61 U/ml, RR <60.4 U/ml); however, the LDH concentration was 42 U/ml (RR = 8–50 U/ml). CSF analyses also demonstrated normal cell counts (1 leucocyte/μl) without atypia and no amplification of polymerase chain reaction for the John Cunningham (JC) virus. Brain MRI on initial presentation revealed diffuse non-enhancing T2/fluid-attenuated inversion recovery hyperintense lesions in the bilateral cerebral white matter, left temporal pole, and right middle cerebellar peduncle (Figures 1A–F). On diffusion-weighted imaging (DWI), these lesions showed faintly high intensities; however, they could be explained by T2 shine-through (Figures 1G–I).\n\nFigure 1 (A–F) Contrast-enhanced brain MRI taken on admission shows diffuse T2/fluid-attenuated inversion recovery (FLAIR) hyperintense lesions in bilateral cerebral white matter, left temporal pole, and right middle cerebellar peduncle without gadolinium enhancement. (G–I) On diffusion-weighted imaging (DWI), these lesions show faintly high intensities that can be explained by T2 shine-through.\n\nHer cognitive impairments progressively worsened 1 month after admission. She simultaneously presented with a GCS score of E1M1V4 and the apallic syndrome. Despite our best efforts, we could not obtain any specific findings to confirm the diagnosis. One and a half months after admission, her electroencephalogram (EEG) showed bilateral periodic synchronous discharge (PSD), typically suggestive of CJD (Figure 2). To confirm the diagnosis as “CJD,” we measured the CSF total tau protein and 14-3-3 protein levels. However, no elevation of the concentrations of these proteins in the CSF was observed (total tau = 708 pg/ml, RR <1,300 pg/ml; 14-3-3 protein <500 μg/ml, RR <500 μg/ml). Only a half-day after initiating high-dose methylprednisolone (mPSL) therapy (1,000 mg/day), her consciousness improved rapidly; therefore, we treated her with an additional 2 days of high-dose mPSL therapy. She maintained a good state of consciousness during the 3 days of therapy. However, her consciousness worsened soon after high-dose mPSL therapy. These clinical characteristics suggest a lower possibility of CJD.\n\nFigure 2 Electroencephalography (EEG) study 1.5 months after admission shows periodic synchronous discharge (PSD) suggesting Creutzfeldt–Jakob disease (CJD).\n\nTo pathologically evaluate the abnormalities seen on MRI, we performed a brain biopsy of the left frontal lobe. Pathological findings revealed infiltration of atypical lymphoid cells with large and irregularly shaped nuclei (Figure 3A). These atypical lymphoid cells were positive for cluster differentiation (CD) 20, with 80–90% of the Ki-67 proliferation index (Figures 3B,C). A few CD3-positive reactive T cells were also observed and did not show irregularities (Figure 3D). Moreover, the CSF data were reexamined when the brain biopsy showed clearer abnormalities (cell count = 10 leucocytes/μl, TP = 68 mg/dl, sIL-2R = 121 U/ml, LDH = 66 U/ml) than before. Based on these pathological findings, CSF abnormalities, and the distribution of white matter lesions on MRI, we diagnosed her with primary central nervous system B cell lymphoma of the LC type.\n\nFigure 3 Pathological findings. Brain biopsy from the left frontal lobe. (A) Hematoxylin and eosin staining. (B) CD20 immunohistochemical staining. (C) Ki-67 immunohistochemical staining. (D) CD3 immunohistochemical staining.\n\nTo treat LC, we administered two courses of high-dose mPSL (1,000 mg/day for 3 days), followed by 60 mg (2 mg/kg) prednisolone (PSL) for 63 days with a taper of every 5 mg for 7 days and whole cranial irradiation. Contrast-enhanced MRI performed 1 month after brain biopsy revealed a spotty gadolinium enhancement in the left periventricular white matter without high intensity on DWI (Figures 4A–C). Two months after the treatment initiation, the anti-NAE antibody was detected in the serum before mPSL treatment, revealing the presence of HE. We performed thyroid sonography, and it was characterized by isoechogenicity, very slightly internal heterogeneity, no diffuse goiter, and a few cysts (Supplementary Figure 1). Moreover, a second check showed the serum anti-TPO antibody and anti-Tg antibody to be within the RR in chemiluminescent immunoassay (0.72 and <0.50 IU/ml, respectively; RR <4.11 and <5.61 IU/ml, respectively). At that time, she recovered from the apallic syndrome, had simple conversations, and consumed food orally. However, her consciousness worsened again when PSL was reduced to 15 mg/day. No evident new abnormality, including aggravation of LC, was found on the re-performed contrast-enhanced MRI. After another high-dose mPSL therapy, her consciousness improved; therefore, we considered the re-exacerbation of her consciousness as due to HE relapse, even though we performed a third check of the serum anti-TPO and anti-Tg antibodies, which were within the RR in chemiluminescent immunoassay (0.44 and <0.50 IU/ml, respectively). Although her consciousness improved, severe cognitive impairment persisted, and she still needed careful assistance for all her daily living activities. The clinical timeline is shown in Supplementary Figure 2.\n\nFigure 4 (A,B) Contrast-enhanced brain MRI recorded 1 month after brain biopsy shows a spotty gadolinium enhancement in the left periventricular white matter (arrow) and post-biopsy scar (arrowhead) (A) with T2 hyperintensities (B). (C) This lesion does not show abnormal hyperintensities on diffusion-weighted imaging (DWI).\n\nDiscussion\n\nWe present a case of a rare complication of the anti-NAE antibody-related autoimmune encephalopathy and LC showing a CJD-like clinical presentation and PSD on EEG. Since the detection of the anti-NAE antibody and the presence of PSD on EEG suggested the same mechanisms of encephalopathy as HE, we diagnosed this anti-NAE antibody-related autoimmune encephalopathy as that.\n\nEEG is occasionally used in neurological disorders associated with convulsive seizures and impaired consciousness. PSD on EEG can be observed particularly in diseases such as CJD, subacute sclerosing panencephalitis (SSPE), and Alzheimer's disease (17, 18). The EEG of HE shows a variety of abnormal findings in ~90% of cases, and the basal waves tend to slow activities. However, some HE cases present PSD on EEG and require differentiation from CJD, similar to our case (6, 19, 20).\n\nAs LC has been recently reported as a new disease concept, a variant type of PCNSL, as reported by Bakshi et al., it is often overlooked as another disease (13). As far as we investigated in PubMed using the term “lymphomatosis cerebri,” only 71 cases in 43 articles were reported until 2020, and no complications with HE were found (13, 14, 16, 21–60).\n\nIn these reports, seven mentioned the use of EEG for LC (13, 27, 32, 48). Most of these cases have reported generalized diffuse slowing activities with non-specific abnormalities (13, 27, 32). Deutsch et al. reported that four cases of LC on EEG were observed only with diffuse slowing without PSD, and they described that the presence of PSD could be an important differential point between LC and CJD (27). However, Revero et al. reported a case showing PSD in the “T” cell type of LC (48). In the present case, although the possibility of the B cell type of LC-derived PSD could not be ruled out, it was appropriate that PSD was derived from the anti-NAE antibody-related autoimmune encephalopathy diagnosed as HE.\n\nAt present, it is said that the positive serum levels of the anti-thyroid antibodies are essential for HE diagnosis (61). In our case, although repetitive measurements of the anti-thyroid autoantibodies in different ways were performed three times, all of these were negative. Admittedly, the presence of Hashimoto's thyroiditis could not be denied from the slight heterogeneity based on the thyroid ultrasonographic findings, but, to our knowledge, no report has made the diagnosis of HE only from the ultrasonographic findings without positive anti-thyroid autoantibodies. Moreover, unless the paraneoplastic syndrome exists, the neoplasm and autoimmune encephalopathy rarely co-occur. Therefore, the possibility of the thyroid autoimmunity causing the autoimmune encephalopathy was very low. Strictly speaking, the term HE might not be used for this case. At present, paraneoplastic encephalopathy with anti-NAE antibody may be more appropriate. However, the presence of anti-NAE antibodies has high specificity (~90%) for the serum diagnosis of HE (10, 11). Hence, because of the detection of the anti-NAE antibody and PSD on EEG, the same mechanisms of autoimmune encephalopathy were suspected as the anti-thyroid autoantibody-positive “normal” HE. Although anti-thyroid autoantibodies were not detected, the detection of anti-NAE antibodies permitted the diagnosis of HE or some autoimmune encephalopathy extremely similar to HE, and continued steroid treatment led to the improvement of clinical symptoms.\n\nIn our case, the possibility that the primary intracerebral inflammation by HE caused secondary oncogenesis of lymphocytes was low. If HE caused malignant lymphoma, the anti-thyroid autoantibodies should have been detected similar to normal HEs. Patients with malignant lymphomas have a potential risk of various autoimmune diseases (62, 63). Furthermore, the clinical presentation of malignant lymphoma sometimes develops from complicated autoimmune disorders before the tumor itself (64). Although the mechanisms of anti-NAE antibody production are not clear, our case might have developed as a paraneoplastic neurological syndrome of LC.\n\nThe elevation of sIL-2R levels in PCNSL is well-known. For diffuse large B cell lymphoma of PCNSL, Sasagawa et al. reported that the cutoff value of sIL-2R in the CSF was 60.4 U/ml (sensitivity = 94.7%, specificity = 84.6%) (65). It might not have been typical that the concentrations of initial sIL-2R in the CSF in our case were only slightly high; although, its elevation may be observed non-specifically in neurosarcoidosis and meningitis (66). Currently, the levels of IL-10 in the CSF have been reported as a more useful biomarker for the initial screening of PCNSL (cutoff = 3 pg/ml, sensitivity = 94.7%, specificity = 100%) (65). If the levels of IL-10 in the CSF were measured during the first screening, LC could have been diagnosed earlier.\n\nConclusion\n\nIn conclusion, we report a case of a rare complication of HE and LC presenting with CJD-like clinical presentation and PSD. Although the initial presentation of subacute progressive dementia and EEG features was consistent with CJD, the CSF abnormalities, particularly total tau protein and 14-3-3 protein, and steroid responsiveness were not typical of CJD. Physicians should be aware of the possibility of PCNSLs and assess the total tau protein, 14-3-3 protein, sIL-2R, and IL-10 in the CSF at the first screening. Moreover, when the clinical presentation worsens without the aggravation of image findings, physicians should consider the complications of HE. Accurate and early diagnosis and appropriate treatment can improve the clinical outcomes.\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/s.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by Fujiyoshida Municipal Medical Center. The patient provided their written informed consent to participate in this study. Written informed consent was obtained from the individual's next of kin for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nRA, ST, SK, SY, and KO were the attending physicians of the patient, collected the patient data, and decided on a treatment policy. MY measured the anti-NAE antibody levels. KT assessed thyroidal function and proposed critical opinion regarding thyroid disease. RA and KT wrote the first version of this manuscript and played major roles in the conception of the manuscript. All authors have read and approved the final version of the manuscript.\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\nPublisher's Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n\nThe authors thank Shogo Imae and Reina Kawanami, Department of Neurosurgery, Fujiyoshida Municipal Medical Center, Japan, for performing the brain biopsy. Moreover, Katsuya Sato, Department of Locomotive Rehabilitation Science, Nagasaki University Graduate School of Biomedical Sciences, Japan, was gratefully acknowledged for measuring total tau protein and 14-3-3 protein. The authors would like to thank Editage (www.editage.com) for English language editing.\n\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fneur.2021.701178/full#supplementary-material\n\nClick here for additional data file.\n\nSupplementary Figure 1 B-mode of ultrasonographic image of the thyroid gland.\n\nClick here for additional data file.\n\nClick here for additional data file.\n==== Refs\nReferences\n\n1. Brain WR Jellinek EH Ball K . Hashimoto's disease and encephalopathy. Lancet. (1966) 2 :512–4. 10.1016/S0140-6736(66)92876-5 4161638\n2. Shaw PJ Walls TJ Newman PK Cleland PG Cartlidge NE . 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Spectrum and frequency of autoimmune derangements in lymphoproliferative disorders: analysis of 637 cases and comparison with myeloproliferative diseases. Br J Haematol. (1987) 67 :235–9. 10.1111/j.1365-2141.1987.tb02333.x 3499930\n63. Nicholson AG Wotherspoon AC Jones AL Sheppard MN Isaacson PG Corrin B . Pulmonary B-cell non-Hodgkin's lymphoma associated with autoimmune disorders: a clinicopathological review of six cases. Eur Respir J. (1996) 9 :2022–5. 10.1183/09031936.96.09102022 8902461\n64. Kawahigashi T Kitagawa I Tanaka E . Angioimmunoblastic T-cell lymphoma accompanied by pure red cell aplasia: a case report. World J Clin Oncol. (2020) 11 :405–11. 10.5306/wjco.v11.i6.405 32874954\n65. Sasagawa Y Akai T Tachibana O Iizuka H . Diagnostic value of interleukin-10 in cerebrospinal fluid for diffuse large B-cell lymphoma of the central nervous system. J Neurooncol. (2015) 121 :177–83. 10.1007/s11060-014-1622-z 25258254\n66. Petereit HF Reske D Tumani H Jarius S Markus Leweke F Woitalla D . Soluble CSF interleukin 2 receptor as indicator of neurosarcoidosis. J Neurol. (2010) 257 :1855–63. 10.1007/s00415-010-5623-3 20556411\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-2295",
"issue": "12()",
"journal": "Frontiers in neurology",
"keywords": "Creutzfeldt–Jakob disease; Hashimoto's encephalopathy; anti-NH2-terminal of α-enolase antibody; lymphomatosis cerebri; periodic synchronous discharge",
"medline_ta": "Front Neurol",
"mesh_terms": null,
"nlm_unique_id": "101546899",
"other_id": null,
"pages": "701178",
"pmc": null,
"pmid": "34447347",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "10026390;21686648;21382094;17611716;4161638;27502482;30008825;22426596;32296938;18509825;28427529;32713909;31857546;26147788;30682517;31882532;15791573;19846119;2168432;21365456;3499930;19389079;23743243;18516979;32874954;32999225;26073248;25812125;23568984;29187687;25199185;17495760;31061303;26415875;8902461;20304432;22849990;27268005;32911305;7544989;23185172;17210623;21927864;30627096;22806340;28982392;17493046;32315551;24240797;24097320;1351187;28176503;15259624;28781271;30732171;24379950;20345746;25258254;9543128;1992366;28484400;20556411;24847165;27038652;17335908",
"title": "Case Report: Paraneoplastic Hashimoto's Encephalopathy Associated With Lymphomatosis Cerebri With Periodic Synchronous Discharges Resembling Creutzfeldt-Jakob Disease.",
"title_normalized": "case report paraneoplastic hashimoto s encephalopathy associated with lymphomatosis cerebri with periodic synchronous discharges resembling creutzfeldt jakob disease"
} | [
{
"companynumb": "JP-PRA-000147",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "PREDNISOLONE"
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"abstract": "Erythropoietic protoporphyria (EPP) is an inherited metabolic disorder of heme synthesis resulting from overproduction of protoporphyrin IX (PPIX), which can lead to progressive liver disease characterized by recurrent EPP crises and end-stage liver disease. We used the Australian Transplant Registry to identify 5 patients referred for liver transplantation between 2008 and 2017. A total of 4 patients had EPP secondary to ferrochelatase deficiency, and 1 patient had X-linked EPP. No patient had follow-up with a specialist prior to the diagnosis of progressive liver disease. There were 3 patients who underwent orthotopic liver transplantation, whereas 2 died while on the transplant waiting list. Parenteral PPIX-lowering therapy was used in 4 patients and was effective in 3 patients, although 2 of these had rebound porphyria and worsening liver function following a decrease in the intensity of therapy. Early disease recurrence in the allograft following transplantation occurred in 2 patients requiring red cell exchange (RCE) to successfully attain and maintain low PPIX levels, but RCE was associated with hemosiderosis in 1 patient. Allogeneic stem cell transplantation (AlloSCT) was performed in 2 patients. One failed engraftment twice, whereas the second rejected the first graft but achieved full donor chimerism with a second graft and increased immunosuppression. In conclusion, our observations suggest that progressive liver disease needs parenteral PPIX-lowering treatment with the intensity adjusted to achieve a target Erc-PPIX level. Because EPP liver disease is universally recurrent, AlloSCT should be considered in all patients with adequate immunosuppression to facilitate engraftment. RCE appears to be effective for recurrent EPP liver disease but is associated with an increased risk of iron overload.",
"affiliations": "Department of Gastroenterology and Liver Transplant, Austin Hospital, Melbourne, Australia.;Department of Gastroenterology and Liver Transplant, Austin Hospital, Melbourne, Australia.;Department of Gastroenterology, Eastern Health, Melbourne, Australia.;Department of Gastroenterology and Liver Transplant, Austin Hospital, Melbourne, Australia.;Department of Clinical Hematology, Austin Hospital, Melbourne, Australia.;Department of Clinical Hematology, Austin Hospital, Melbourne, Australia.;Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Australia.;AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, Australia.;Department of Cancer Care Services, Royal Brisbane and Women's Hospital, Brisbane, Australia.;Department of Cancer Care Services, Royal Brisbane and Women's Hospital, Brisbane, Australia.;Department of Gastroenterology and Liver Transplant, Austin Hospital, Melbourne, Australia.;Department of Gastroenterology and Liver Transplant, Austin Hospital, Melbourne, Australia.",
"authors": "Ardalan|Zaid S|ZS|0000-0001-6952-0985;Chandran|Sujievvan|S|;Vasudevan|Abhinav|A|;Angus|Peter W|PW|;Grigg|Andrew|A|;He|Simon|S|;Macdonald|Graeme A|GA|;Strasser|Simone I|SI|;Tate|Courtney J|CJ|;Kennedy|Glen A|GA|;Testro|Adam G|AG|;Gow|Paul J|PJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/lt.25632",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1527-6465",
"issue": "25(11)",
"journal": "Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society",
"keywords": null,
"medline_ta": "Liver Transpl",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D064591:Allografts; D018450:Disease Progression; D058625:End Stage Liver Disease; D005260:Female; D006084:Graft Rejection; D006801:Humans; D007223:Infant; D008099:Liver; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D046351:Protoporphyria, Erythropoietic; D012008:Recurrence; D012042:Registries; D033581:Stem Cell Transplantation; D014184:Transplantation, Homologous; D014850:Waiting Lists; D055815:Young Adult",
"nlm_unique_id": "100909185",
"other_id": null,
"pages": "1620-1633",
"pmc": null,
"pmid": "31469227",
"pubdate": "2019-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Management of Patients With Erythropoietic Protoporphyria-Related Progressive Liver Disease.",
"title_normalized": "management of patients with erythropoietic protoporphyria related progressive liver disease"
} | [
{
"companynumb": "PHHY2019AU227614",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALEMTUZUMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "To our knowledge, 5 cases of disseminated microsporidiosis with Encephalitozoon species have been reported worldwide in transplant recipients. George et al. present the first such case in Australia, to be reported and treated with good clinical recovery.",
"affiliations": "Department of Nephrology, Royal Adelaide Hospital, Adelaide, South Australia. docbibin@yahoo.com",
"authors": "George|Bibin|B|;Coates|Toby|T|;McDonald|Stephen|S|;Russ|Graeme|G|;Cherian|Sajiv|S|;Nolan|James|J|;Brealey|John|J|",
"chemical_list": "D000890:Anti-Infective Agents; D007166:Immunosuppressive Agents; D015766:Albendazole",
"country": "Australia",
"delete": false,
"doi": "10.1111/j.1440-1797.2012.01580.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1320-5358",
"issue": "17 Suppl 1()",
"journal": "Nephrology (Carlton, Vic.)",
"keywords": null,
"medline_ta": "Nephrology (Carlton)",
"mesh_terms": "D015766:Albendazole; D000890:Anti-Infective Agents; D001706:Biopsy; D016819:Encephalitozoon; D016890:Encephalitozoonosis; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D008854:Microscopy, Electron; D008875:Middle Aged; D013902:Radiography, Thoracic; D016896:Treatment Outcome",
"nlm_unique_id": "9615568",
"other_id": null,
"pages": "5-8",
"pmc": null,
"pmid": "22497646",
"pubdate": "2012-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Disseminated microsporidiosis with Encephalitozoon species in a renal transplant recipient.",
"title_normalized": "disseminated microsporidiosis with encephalitozoon species in a renal transplant recipient"
} | [
{
"companynumb": "AU-PFIZER INC-2020000114",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE"
},
"druga... |
{
"abstract": "Amantadine is commonly used to treat Parkinson's disease. A case of myoclonus and asterixis was associated with amantadine is reported.\nAn 80-year-old man with Parkinson's disease diagnosed in 2015 was started on amantadine for treatment of progressive tremor and orofacial dyskinesias induced by levodopa. He took amantadine 100mg orally daily for 7 days, then increased to 100mg twice a day thereafter. The patient complained of \"worsening tremor\" after 9 days and amantadine was decreased to 100mg daily. After 1 month on this dose, the patient reported that his \"tremor\" persisted and experienced visual hallucinations. His examination demonstrated diffuse myoclonus throughout his extremities and trunk, as well as asterixis when attempting to stand or holding his arms antigravity. Laboratory testing for renal and hepatic failure was unrevealing. Amantadine was reduced to 50mg daily for 4 days and then discontinued. Myoclonus resolved 3 days after discontinuation of amantadine.\nWhile amantadine-induced myoclonus is rare, health care providers should be vigilant in monitoring for signs and symptoms of myoclonus following amantadine initiation.",
"affiliations": "19980San Francisco Veterans Affairs Health Care System, CA, USA.;19980San Francisco Veterans Affairs Health Care System, CA, USA.;8785University of California San Francisco, CA, USA.;Parkinson's Disease, Research, Education and Clinical Center, 19980San Francisco Veterans Affairs Health Care System, CA, USA.",
"authors": "Poon|Linda H|LH|https://orcid.org/0000-0002-6536-3238;Lee|Audrey J|AJ|;Vuong|Mai|M|;Zuzuarregui|Jose Rafael|JR|",
"chemical_list": "D007980:Levodopa; D000547:Amantadine",
"country": "United States",
"delete": false,
"doi": "10.1177/0897190021997003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0897-1900",
"issue": "34(5)",
"journal": "Journal of pharmacy practice",
"keywords": "Parkinson’s disease; amantadine; myoclonus",
"medline_ta": "J Pharm Pract",
"mesh_terms": "D000369:Aged, 80 and over; D000547:Amantadine; D006212:Hallucinations; D006801:Humans; D007980:Levodopa; D008297:Male; D009207:Myoclonus; D010300:Parkinson Disease",
"nlm_unique_id": "8900945",
"other_id": null,
"pages": "814-817",
"pmc": null,
"pmid": "33622074",
"pubdate": "2021-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Amantadine Associated Myoclonus: Case Report and Review of the Literature.",
"title_normalized": "amantadine associated myoclonus case report and review of the literature"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2021SP000930",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AMANTADINE HYDROCHLORIDE"
},
"... |
{
"abstract": "BACKGROUND\nMycobacterium goodii is an infrequent human pathogen which has been implicated in prosthesis related infections and penetrating injuries. It is often initially misidentified as a gram-positive rod by clinical microbiologic laboratories and should be considered in the differential diagnosis.\n\n\nMETHODS\nWe describe here the second reported case of M. goodii endocarditis. Species level identification was performed by 16S rDNA (ribosomal deoxyribonucleic acid) gene sequencing. The patient was successfully treated with mitral valve replacement and a prolonged combination of ciprofloxacin and trimethoprim/sulfamethoxazole.\n\n\nCONCLUSIONS\nConfirmation of the diagnosis utilizing molecular techniques and drug susceptibility testing allowed for successful treatment of this prosthetic infection.",
"affiliations": "Texas Heart Institute, 6770 Bertner Avenue, Houston, Tx, 77030, USA.;Yale School of Medicine, 333 Cedar St, New Haven, CT, 06510, USA. m.grant@yale.edu.",
"authors": "Parikh|Rohan B|RB|;Grant|Matthew|M|",
"chemical_list": "D000900:Anti-Bacterial Agents; D004269:DNA, Bacterial; D004275:DNA, Ribosomal; D012336:RNA, Ribosomal, 16S",
"country": "England",
"delete": false,
"doi": "10.1186/s12941-017-0190-4",
"fulltext": "\n==== Front\nAnn Clin Microbiol AntimicrobAnn. Clin. Microbiol. AntimicrobAnnals of Clinical Microbiology and Antimicrobials1476-0711BioMed Central London 19010.1186/s12941-017-0190-4Case ReportMycobacterium goodii endocarditis following mitral valve ring annuloplasty Parikh Rohan B. rparikh@texasheart.org 1Grant Matthew m.grant@yale.edu 21 0000 0001 2296 6154grid.416986.4Texas Heart Institute, 6770 Bertner Avenue, Houston, Tx 77030 USA 2 0000000419368710grid.47100.32Yale School of Medicine, 333 Cedar St, New Haven, CT 06510 USA 21 3 2017 21 3 2017 2017 16 1427 7 2016 15 3 2017 © The Author(s) 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\n\nMycobacterium goodii is an infrequent human pathogen which has been implicated in prosthesis related infections and penetrating injuries. It is often initially misidentified as a gram-positive rod by clinical microbiologic laboratories and should be considered in the differential diagnosis.\n\nCase presentation\nWe describe here the second reported case of M. goodii endocarditis. Species level identification was performed by 16S rDNA (ribosomal deoxyribonucleic acid) gene sequencing. The patient was successfully treated with mitral valve replacement and a prolonged combination of ciprofloxacin and trimethoprim/sulfamethoxazole.\n\nConclusion\nConfirmation of the diagnosis utilizing molecular techniques and drug susceptibility testing allowed for successful treatment of this prosthetic infection.\n\nKeywords\nMycobacterium goodiiEndocarditisGene sequencingProstheses related infectionsissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\n\nMycobacterium goodii is a rapidly growing non-tuberculous mycobacterium (NTM) belonging to the Mycobacterium smegmatis [1] group. Its importance has become increasingly appreciated as a pathogen over the last 20 years, with a predilection towards infecting tissues at the site of penetrating injuries. Antibacterial treatment strategies against this pathogen are diverse but reported case cure rates are high. Here we describe what the authors believe to be the second reported case of M. goodii endocarditis ever reported (first time involving a ring annuloplasty).\n\nCase presentation\nA 67-year-old Caucasian man, retired financier, with a history of severe mitral regurgitation status post ring annuloplasty repair complicated by right sided hemothorax requiring two reoperations to achieve hemostasis, presented to an outside hospital 3 weeks postoperatively with fever, loss of appetite, and gait disturbance.\n\nOn examination the patient vital signs were normal, lungs were clear, a mild 1/6 systolic murmur was appreciated at the apex, and a drain was in place for a groin seroma related to recent left heart catheterization. He had an unsteady gait and exhibited mild left lower extremity weakness (4/5). His brain magnetic resonance imaging showed multiple ring-enhancing lesions in the pons and posterior fossa suggestive of septic emboli. Transthoracic echocardiography showed moderate mitral regurgitation without any vegetation. Blood cultures grew gram-positive rods suspicious for Actinomyces spp. and he was started on vancomycin and ampicillin/sulbactam. He developed a morbilliform cutaneous eruption felt to be related to the ampicillin and was switched to vancomycin/ceftriaxone. A computed tomography scan of the chest (Fig. 1) was done which showed bilateral infiltrates and mild pleural effusions.Fig. 1 Computed tomography of chest showing bilateral infiltrates and bilateral pleural effusion\n\n\n\n\nThe patient was then transferred to our hospital on day 14 for further management. A transesophageal echocardiogram (TEE) (Fig. 2) showed vegetations on the P3 annulus and evidence of ring dehiscence in A2, A3, and P3 areas. He completed penicillin desensitization and was successfully narrowed to penicillin G to be optimally treated for presumptive actinomycotic endocarditis and both vancomycin and ceftriaxone were stopped. On hospital day 18 he underwent mitral valve replacement with a bioprosthetic valve (27 mm. St. Jude prosthesis). Intraoperatively, vegetations were confirmed on the mitral valve and tissue cultures from the explanted native mitral valve suggested a rapid growing mycobacterium rather than an Actinomyces spp. Empiric treatment with meropenem (1 g IV thrice a day)/amikacin (1 g IV per day)/clarithromycin (500 mg oral twice a day)/ciprofloxacin (400 mg IV twice a day) was initiated pending final confirmation and susceptibility testing. On day 21 it was confirmed that the gram-positive isolate was a 100% match to the M. goodii strain (American Type Culture Collection or ATCC #700504) using 16S sequencing (MicroSeq 500 bp 16S rDNA kit), but M. smegmatis could not be ruled out due to a high-level sequence homology [99.5% match to M. smegmatis type strain (ATCC 19420) with two mismatches]. Serial blood cultures sterilized on hospital day 26 and he was transferred to a nursing facility after repeat TEE showed a normally functioning prosthetic mitral valve.Fig. 2 Trans-esophageal echocardiogram showing mitral valve vegetation in the mid-esophageal plane\n\n\n\n\nOn the day following discharge into the rehabilitation facility, the patient developed a maculopapular eruption involving his flanks and back, which progressed to involve his anterior trunk and all four limbs. He presented to the infectious diseases clinic 3 days after discharge where the rash was suspected of being related to the meropenem and tigecycline was substituted; however, he had an acute anaphylactoid reaction (involving dyspnea and hypotension) during the loading dose of tigecycline (100 mg once) which was subsequently replaced with linezolid (600 mg oral twice a day). His susceptibility reports returned which showed the mycobacterium was susceptible to trimethoprim–sulfamethoxazole, amikacin, doxycycline, ciprofloxacin, imipenem, linezolid and resistant to clarithromycin. In accordance, his regimen was changed to ciprofloxacin (500 mg oral twice a day)/trimethoprim–sulfamethoxazole (1 DS tablet oral twice a day).\n\nThe patient was ultimately treated with a total of 6 months of therapy. He followed up in infectious diseases clinic on days 61 and 135 and was contacted by phone 137 weeks post valve replacement and there were no complaints or signs of intervening relapse, was highly active and back to all his prior recreational activities.\n\nDiscussion\nA broad literature search was done from PubMed, Scopus and OvidSP databases containing the search terms M. goodii to try and identify all human infections with this organism. M. goodii was proposed as a new rapidly growing species related to M. smegmatis based on gene sequencing work by Brown et al. [1] in 1999 in continuation to the work done by Wallace et al. [2]. We have summarized to the best of our knowledge all the published reports about M. goodii infections (Table 1) after Brown [1]. A total of 45 cases (including our patient) have been reported to date. Eleven (25%) cases were wound/bone infections due to trauma. Twenty-two (49%) cases were iatrogenic, with eighteen (38%) involving infection of prosthetic materials. Eight (18%) cases were pulmonary, which were strongly associated with histological findings of lipoid or granulomatous pneumonias. Four (9%) cases had unclear clinical diagnosis but were confirmed to be M. goodii microbiologically.Table 1 Selected M. goodii reported human cases after Brown et al.\n\nInfection type\tAge\tSex\tComorbidities\tTreatment\tMicrobial susceptibility\t\nMitral valve endocarditis complicating ring annuloplasty\t67\tM\tNone\tMitral valve replacement, ciprofloxacin + TMP/SMX (6 months)\tSusceptible to TMP/SMX, amikacin, doxycycline, ciprofloxacin, imipenem, linezolid\nResistant to clarithromycin\t\nProsthetic mitral valve endocarditis [8]\t76\tF\tNone mentioned\tMitral valve replacement, tigecycline + ciprofloxacin (2 weeks) doxycycline + ciprofloxacin (11 weeks)\tResistant to cefotaxime, erythromycin, clarithromycin\t\nPacemaker site infection [9]\t23\tM\tPartial AV canal defect repair at 5 years of age\tPacemaker retained, ofloxacin + amikacin (1 month), doxycycline (6 months)\tResistant to clarithromycin\t\nPacemaker pocket infection [10]\t85\tM\tIschemic cardiomyopathy\tPacemaker replacement, TMP/SMX (8 weeks)\tSusceptible to TMP/SMX, minocycline, imipenem\t\nPacemaker pocket and bloodstream infection [11]\t82\tM\tNone mentioned\tPacemaker removal, amikacin + minocycline\tResistant to clarithromycin, cefoxitin, clindamycin, vancomycin\t\nPacemaker pocket infection [12]\t74\tF\tBicuspid aortic valve, hypothyroidism, diabetes mellitus, gastro-esophageal reflux disease, asthma\tPacemaker removal, ciprofloxacin + doxycycline (6 months)\tSusceptible to amikacin, ciprofloxacin, doxycycline, imipenem, linezolid, tobramycin and trimethoprim/sulfamethoxazole Resistant to clarithromycin\t\nVentriculo-peritoneal shunt infection [13]\t60\tF\tAllergy to sulfa drugs\tVentriculoperitoneal shunt removal, imipenem + moxifloxacin (5 weeks), moxifloxacin monotherapy (3 additional months)\tResistant to azithromycin, clarithromycin\t\nHernia mesh infection with abdominal wall abscess [14]\t65\tM\tNone mentioned\tMesh removal, TMP/SMX\tResistant to cefoxitin, clarithromycin\t\nHernia mesh infection [15]\t64\tM\tNone mentioned\tPatch removal. Antibacterial treatment not specified\tSusceptible to ciprofloxacin, doxycycline and TMP/SMX\t\nSkin graft infection [16]\t6\tM\tNone mentioned\tTMP/SMX + linezolid (6 months)\tResistant to clarithromycin, amoxicillin/clavulanate\t\nProsthetic total knee joint infection [17]\t44\tM\tNicotine dependence, significant ethanol use\tRemoval of prosthesis, TMP/SMX (stopped after 1 week by patient), minocycline + ciprofloxacin (6 months)\tResistant to clindamycin\t\nProsthetic total knee joint infection [15]\t75\tF\tNone mentioned\tProsthesis replaced\tSusceptible to ciprofloxacin, doxycycline and TMP/SMX\t\nProsthetic total hip joint infection [15]\t64\tM\tNone mentioned\tProsthesis replaced\tSusceptible to ciprofloxacin, doxycycline and TMP/SMX\t\nOlecranon bursitis following corticosteroid injections [18]\t60\tM\tDiabetes mellitus\tDoxycycline + ciprofloxacin (10 weeks)\tResistant to clarithromycin\t\nPostcataract endophthalmitis [19]\t67\tM\tNone mentioned\tPars plana vitrectomy + lens removal, intravitreal amikacin × 2 doses\tNone reported\t\nAspiration pneumonia [20]\t15\tF\tRickettsial infection\tLaparoscopic Heller myotomy with fundoplication, ciprofloxacin + doxycycline (12 months)\tResistant to clarithromycin\t\nComplicated parapneumonic effusion [21]\t66\tM\tNone mentioned\tNone mentioned\tNone mentioned\t\n\n\n\nSince there is no available clinical trial or prospective data to guide therapy for this infection, we extrapolated a treatment approach from the accumulated experience with other more common rapid growing NTM species to treat our patient with this incredibly rare disease. Our empiric regimen selection was further made challenging by the development of a second drug eruption and an anaphylactoid infusional reaction, both of which required cessation of drugs and subsequent drug substitution.\n\nConclusions\nRapid growing mycobacteria should be suspected in trauma or prosthetic related infections not responding to initial empiric therapies. Molecular techniques are rapid and reliable for confirmation of rapid growing mycobacterial infections and are recommended by the Infectious Diseases Society of America guidelines [3]. Once rapid growing mycobacteria are suspected, 16S ribosomal sequencing should be used if available for species level identification. 16S rRNA gene sequences contain hypervariable regions that can provide species-specific signature sequences useful for identification of bacteria [4]. Since M. goodii has the ability to form biofilms [5], prosthesis removal is indicated to achieve cure if feasible. Macrolides should not be included in the empirical/definitive treatment since it has been shown that the organism has intrinsic macrolide resistance conferred by novel rRNA methylase genes erm(38) and erm(39) [6, 7]. This has also been seen widely in the susceptibility testing for the organism. The organism is usually susceptible to sulfonamides, amikacin, doxycycline, imipenem, fluoroquinolones and they should be optimized for dose and duration according to the severity and comorbidities.\n\nAbbreviations\nATCCAmerican Type Culture Collection\n\nrDNAribosomal deoxyribonucleic acid\n\nTEEtransesophageal echocardiogram\n\nAuthors’ contributions\nRP authored the main text and conducted the literature review. MG was the consultant physician, oversaw the management of this patient and edited/revised several versions of the case report and literature review. Both the authors read and approved the final manuscript.\n\nAcknowledgements\nWe thank David Ryan Peaper for providing the details about the bacterial identification process and Dr. Elise M Meoli for providing the transesophageal echocardiography images.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAvailability of data and materials\nThe production of this manuscript did not involve the production of any data sets.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report.\n\nConsent for publication\nThe patient in the case report provided both verbal and written consent to access his entire medical record as well as verbally consented to publishing his case in a de-identified manner.\n\nEthics approval and consent to participate\nThe study contains exclusively de-identified patient data from a single case report and a retrospective review of previously published human cases, therefore poses no hazard directly or indirectly to any living persons and is exempt from ethics approval.\n==== Refs\nReferences\n1. Brown BA Springer B Steingrube VA Wilson RW Pfyffer GE Garcia MJ Menendez MC Rodriguez-Salgado B Jost KC Jr Chiu SH Mycobacterium wolinskyi sp. nov. and Mycobacterium goodii sp. nov., two new rapidly growing species related to Mycobacterium smegmatis and associated with human wound infections: a cooperative study from the International Working Group on Mycobacterial Taxonomy Int J Syst Bacteriol 1999 49 Pt 4 1493 1511 10.1099/00207713-49-4-1493 10555330 \n2. Wallace RJ Nash DR Tsukamura M Blacklock ZM Silcox VA Human disease due to Mycobacterium smegmatis J Infect Dis 1988 158 1 52 59 10.1093/infdis/158.1.52 3392420 \n3. Griffith DE Aksamit T Brown-Elliott BA Catanzaro A Daley C Gordin F Holland SM Horsburgh R Huitt G Iademarco MF An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases Am J Respir Crit Care Med 2007 175 4 367 416 10.1164/rccm.200604-571ST 17277290 \n4. Kolbert CP Persing DH Ribosomal DNA sequencing as a tool for identification of bacterial pathogens Curr Opin Microbiol 1999 2 3 299 305 10.1016/S1369-5274(99)80052-6 10383862 \n5. Esteban J Martin-de-Hijas NZ Kinnari TJ Ayala G Fernandez-Roblas R Gadea I Biofilm development by potentially pathogenic non-pigmented rapidly growing mycobacteria BMC Microbiol 2008 8 184 10.1186/1471-2180-8-184 18928544 \n6. Nash KA Andini N Zhang Y Brown-Elliott BA Wallace RJ Jr Intrinsic macrolide resistance in rapidly growing mycobacteria Antimicrob Agents Chemother 2006 50 10 3476 3478 10.1128/AAC.00402-06 17005837 \n7. Nash KA Intrinsic macrolide resistance in Mycobacterium smegmatis is conferred by a novel erm gene, erm(38) Antimicrob Agents Chemother 2003 47 10 3053 3060 10.1128/AAC.47.10.3053-3060.2003 14506008 \n8. Jonsson G Rydberg J Sturegard E Christensson B A case of Mycobacterium goodii prosthetic valve endocarditis in a non-immunocompromised patient: use of 16S rDNA analysis for rapid diagnosis BMC Infect Dis 2012 12 301 10.1186/1471-2334-12-301 23151090 \n9. Marchandin H Battistella P Calvet B Darbas H Frapier JM Jean-Pierre H Parer S Jumas-Bilak E Van de Perre P Godreuil S Pacemaker surgical site infection caused by Mycobacterium goodii J Med Microbiol 2009 58 Pt 4 517 520 10.1099/jmm.0.006759-0 19273649 \n10. Chrissoheris MP Kadakia H Marieb M Libertin C Pacemaker pocket infection due to Mycobacterium goodii : case report and review of the literature Conn Med 2008 72 2 75 77 18306833 \n11. Toda H Sato K Iimori M Yamazumi T Furuta I Satoh A Katsukawa C A case of Mycobacterium goodii infection wifh isolation from blood and a pacemaker lead Kansenshogaku Zasshi 2006 80 3 262 266 10.11150/kansenshogakuzasshi1970.80.262 16780134 \n12. Yoo DK, Hosseini-Moghaddam SM. Pacemaker pocket infection due to Mycobacterium goodii, a rapidly growing mycobacteria. BMJ Case Reports. 2017. doi:10.1136/bcr-2016-218323\n13. Uche C Silibovsky R Jungkind D Measley R Ventriculoperitoneal shunt-associated Mycobacterium goodii infection Infect Dis Clin Pract 2008 16 2 129 130 10.1097/IPC.0b013e318142cbae \n14. Sohail MR Smilack JD Hernia repair mesh-associated Mycobacterium goodii infection J Clin Microbiol 2004 42 6 2858 2860 10.1128/JCM.42.6.2858-2860.2004 15184492 \n15. Ferguson DD Gershman K Jensen B Arduino MJ Yakrus MA Cooksey RC Srinivasan A Mycobacterium goodii infections associated with surgical implants at Colorado hospital Emerg Infect Dis 2004 10 10 1868 1871 10.3201/eid1010.040402 15504281 \n16. Hougas JE Bruneteau RJ Varman M Mycobacterium goodii infection of skin graft in an immunocompetent child Infect Dis Clin Pract 2011 19 2 146 147 10.1097/IPC.0b013e3182002df1 \n17. Ahmad S Khakoo RA Left knee prosthesis-related Mycobacterium goodii infection Int J Infect Dis 2010 14 12 e1115 e1116 10.1016/j.ijid.2010.02.2245 21071255 \n18. Friedman ND Sexton DJ Bursitis due to Mycobacterium goodii , a recently described, rapidly growing mycobacterium J Clin Microbiol 2001 39 1 404 405 10.1128/JCM.39.1.404-405.2001 11136814 \n19. Spencer TS Teske MP Bernstein PS Postcataract endophthalmitis caused by Mycobacterium goodii J Cataract Refract Surg 2005 31 6 1252 1253 10.1016/j.jcrs.2004.11.035 16039508 \n20. Martinez-Gonzalez D Franco J Navarro-Ortega D Munoz C Marti-Obiol R Borras-Salvador R Achalasia and Mycobacterium goodii pulmonary infection Pediatr Infect Dis J 2011 30 5 447 448 10.1097/INF.0b013e3182024c1c 21076363 \n21. Buijtels PC Petit PL Verbrugh HA van Belkum A van Soolingen D Isolation of nontuberculous mycobacteria in Zambia: eight case reports J Clin Microbiol 2005 43 12 6020 6026 10.1128/JCM.43.12.6020-6026.2005 16333092\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1476-0711",
"issue": "16(1)",
"journal": "Annals of clinical microbiology and antimicrobials",
"keywords": "Endocarditis; Gene sequencing; Mycobacterium goodii; Prostheses related infections",
"medline_ta": "Ann Clin Microbiol Antimicrob",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D016000:Cluster Analysis; D004269:DNA, Bacterial; D004275:DNA, Ribosomal; D017548:Echocardiography, Transesophageal; D004697:Endocarditis, Bacterial; D006321:Heart; D006801:Humans; D008297:Male; D058386:Mitral Valve Annuloplasty; D009161:Mycobacterium; D009165:Mycobacterium Infections, Nontuberculous; D010802:Phylogeny; D012336:RNA, Ribosomal, 16S; D013902:Radiography, Thoracic; D012092:Replantation; D017422:Sequence Analysis, DNA; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "101152152",
"other_id": null,
"pages": "14",
"pmc": null,
"pmid": "28327156",
"pubdate": "2017-03-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16333092;17005837;16039508;10383862;18306833;23151090;21071255;21076363;15504281;17277290;11136814;16780134;18928544;15184492;14506008;28073877;3392420;10555330;19273649",
"title": "Mycobacterium goodii endocarditis following mitral valve ring annuloplasty.",
"title_normalized": "mycobacterium goodii endocarditis following mitral valve ring annuloplasty"
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"abstract": "Tenofovir disoproxil fumarate (TDF) is recommended as first-line agents in chronic hepatitis B (CHB) patients for its high antiviral effects and high barrier to resistance. It is controversial whether the rtA194T mutation truly confers resistance against TDF. We present here a 62-year-old CHB patient who occurred rtL180M, rtM204V and rtA194T mutants after lamivudine (LAM) monotherapy for 9 years. TDF was introduced in replacement of LAM and led to Hepatitis B Virus (HBV) DNA undetectable in 1 month, maintained in the follow up of 52 weeks. These observations suggest that rtA194T mutation emerges under LAM monotherapy and remains sensitive to TDF.",
"affiliations": "Department of Infectious Diseases, Research Laboratory of Clinical Virology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.;Department of Infectious Diseases, Research Laboratory of Clinical Virology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.;Department of Infectious Diseases, Research Laboratory of Clinical Virology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.",
"authors": "Li|Jing|J|;Zhang|Donghua|D|;Zhang|Xinxin|X|",
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"doi": "10.2147/IDR.S295060",
"fulltext": "\n==== Front\nInfect Drug Resist\nInfect Drug Resist\nidr\nidr\nInfection and Drug Resistance\n1178-6973\nDove\n\n295060\n10.2147/IDR.S295060\nCase Report\nThe Occurrence of rtA194T Mutant After Long-Term Lamivudine Monotherapy Remains Sensitive to Tenofovir Disoproxil Fumarate: A Case Report\nLi et al\nLi et al\nLi Jing 1\nZhang Donghua 1\nZhang Xinxin 12\n1 Department of Infectious Diseases, Research Laboratory of Clinical Virology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China\n2 Sino-French Research Centre for Life Sciences and Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China\nCorrespondence: Xinxin Zhang Department of Infectious Diseases, Research Laboratory of Clinical Virology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin Second Road, Shanghai, 200025, People’s Republic of ChinaTel +86 21-64370045 ext 681088 Email zhangx@shsmu.edu.cn\n15 3 2021\n2021\n14 10131017\n03 12 2020\n03 3 2021\n© 2021 Li et al.\n2021\nLi et al.\nThis work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).\nAbstract\n\nTenofovir disoproxil fumarate (TDF) is recommended as first-line agents in chronic hepatitis B (CHB) patients for its high antiviral effects and high barrier to resistance. It is controversial whether the rtA194T mutation truly confers resistance against TDF. We present here a 62-year-old CHB patient who occurred rtL180M, rtM204V and rtA194T mutants after lamivudine (LAM) monotherapy for 9 years. TDF was introduced in replacement of LAM and led to Hepatitis B Virus (HBV) DNA undetectable in 1 month, maintained in the follow up of 52 weeks. These observations suggest that rtA194T mutation emerges under LAM monotherapy and remains sensitive to TDF.\n\nKeywords\n\nhepatitis B\ntenofovir disoproxil fumarate\nresistance\nrtA194T mutant\ncase report\n==== Body\nIntroduction\n\nChronic Hepatitis B (CHB) is a major problem for global public health. Antiviral treatment improves liver histology and reduces risks of liver-related fibrosis, hepatocellular carcinoma (HCC), and mortality.1 Currently, tenofovir disoproxil fumarate (TDF) is recommended as first-line nucleos(t)ide analogue (NA) treatment in patients with CHB for its high antiviral effects and high genetic barriers to drug resistance.2 Additionally, TDF is effective in patients harboring lamivudine (LAM)-resistant mutations.3 Although TDF-resistance can be found in anti-HIV treatment,4,5 TDF resistance was not detected in CHB patients after long-term TDF treatment.6 The rtA194T Hepatitis B Virus (HBV) polymerase mutation was firstly identified, along with LAM resistance-associated mutations (rtL180M and rtM204V), in two HIV/HBV-coinfected patients treated with long-term TDF and LAM therapy. Meanwhile, phenotypic analyses revealed that constructs harboring rtA194T together with rtL180M and rtM204V displayed a 10-fold reduction in TDF susceptibility.7 In addition, Samad Amini-Bavil-Olyaee demonstrated that clones harboring rtA194T showed partial resistance (a fivefold to sevenfold increase in the EC50) to TDF in vitro, irrespective of additional mutations.8 However, Delaney WE had not found a clear association between rtA194T and viral load by using transfected-HepG2 cell culture.9 It appears that the potential impact of rtA194T mutation on TDF susceptibility remains unclear and therefore deserves further study. Here, we report a case of a CHB patient who developed rtM204V, rtL180M and rtA194T mutations in association with viral breakthrough on LAM monotherapy and was rescued by TDF.\n\nCase Presentation\n\nA 62-year-old man was diagnosed with HBV-related HCC in June 2010 and then received LAM antiviral treatment followed by surgery. At the time of diagnosis, HBV DNA level was almost 10,000 copies/mL by self-reports, the patient was hepatitis B surface antigen (HBsAg) positive, hepatitis B e antigen (HBeAg) negative, anti-HBe positive, and without co-infection by hepatitis C virus (HCV) or human immunodeficiency virus (HIV). Two months later (August 2010), the detectable level of HBV DNA was <1000 copies/mL (Roche Diagnostics, Mannheim, Germany, detection threshold, 1000 copies/mL), HBsAg was 454.12 IU/mL (Roche Diagnostics GmBH, Mannheim, Germany), serum alanine aminotransferase (ALT) was 24 IU/L (normal level: 10–64 IU/L), aspartate aminotransferase (AST) was 24 IU/L (normal level: 8–40 IU/L), total bilirubin (TBil) was 22.3μmol/L (normal level: 4.7–24μmol/L), direct bilirubin was 4.0 μmol/L (normal level: 0–6.8μmol/L), indirect bilirubin (IBil) was 18.3μmol/L, AFP was 13.05 ng/mL (normal level: <8.04 ng/mL). No HBV resistance mutations were detected using direct sequencing of the reverse transcriptase region of HBV polymerase gene. Ultrasonography (US) of liver showed that this patient had fatter liver and gallbladder stone. During follow-up of 8 years, the detectable level of HBV DNA was <500 IU/mL (Shanghai KEHUA Bio-engineering Co., LTD; detection threshold, 500IU/mL), ALT and AST were normal and IBil mildly elevated (35.4μmol/L). In November 2019, the HBV load rebounded to 4920 IU/mL (Roche COBAS TaqMan HBV test, Roche Diagnostics, Mannheim, Germany, detection threshold, 20 IU/mL), HBsAg was 20.40 IU/mL, quantification of anti-HBc (qAnti-HBc) was 3323.12 IU/mL, ALT and AST were normal, IBil was 23.4 μmol/L, estimated glomerular filtration rate (eGFR) was 94.1, complete blood count was normal, AFP was 2.46 ng/mL. Subsequently, TDF was introduced in replacement of LAM. Further genotypic drug resistance testing found the emergence of rtL180M, rtM204V and rtA194T mutations (confirmed by a second sequencing). US showed that this patient had fatter liver and gallbladder stone. Transient elastography (FibroScan) revealed that controlled attenuation parameter (CAP) was 252dB/m and liver stiffness measurement (LSM) was 8.8 kPa. After 1 month (December 2019), HBV DNA was undetectable (Roche COBAS TaqMan HBV test, Roche Diagnostics, Mannheim, Germany, detection threshold, 20 IU/mL) and HBsAg was 18.27 IU/mL, qAnti-HBc was 2801.62 IU/mL. Sequencing of uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) revealed that the patient was a heterozygous individual with a TA insertion in TATA box of promoter region as A(TA)6/(TA)7TAA. In April 2020, HBV DNA was undetectable (Roche COBAS TaqMan HBV test), HBsAg was 21.37 IU/mL, qAnti-HBc was 1640.44 IU/mL, and ALT was 33 IU/L, AST was 27 IU/L, IBil was 28.7 μmol/L, eGFR was 93.6, complete blood count was normal, AFP was 2.38 ng/mL. In June 2020, HBV DNA was also undetectable (Roche COBAS TaqMan HBV test), HBsAg was 21.30 IU/mL, qAnti-HBc was 1808.99 IU/mL, and ALT and AST were normal, IBil was 45.2 μmol/L. In December 2020, HBV DNA remained undetectable (Roche COBAS TaqMan HBV test), HBsAg was 20.96 IU/mL, and ALT was 24 IU/L, IBil was 38.2 μmol/L. The evolution of viral load and HBV genotypic patterns were presented in Figure 1, and the unified unit of HBV DNA was IU/mL (1 IU/mL=5.6 copies/mL).10Figure 1 Evolution of HBV DNA (log10 IU/mL), ALT levels (IU/mL), HBV genotypic patterns, and antiviral regimen for the patient.\n\nAbbreviations: LAM, lamivudine; TDF, tenofovir disoproxil fumarate; rt, reverse transcriptase; L180M, from leucine to methionine at amino-acid 180; M204V, from methionine to valine at amino-acid 204; A194T, from aspartate to tyrosine at amino-acid 194.\n\nDiscussion\n\nWhether the rtA194T mutation conferring resistance against TDF is still controversial and more clinical evidences are needed to reveal the true relevance of the rtA194T mutation. In this case, we report the occurrence of rtA194T mutant during the long-term LAM monotherapy in a CHB patient who remains sensitive to TDF.\n\nProlonged LAM therapy is associated with the emergence of LAM-resistant mutations, from 24% in 1 year to 70% in 5 years.11,12 Three mutations associated with LAM resistance have been mostly described: rtM204V/I in C domain, rtV173L and rtL180M in B domain.13 In the present case, no drug-resistant HBV variants were detected at the initiation of antiviral treatment in this patient. However, HBV load rebounded to 4920 IU/mL from <500 IU/mL at the ninth years of LAM monotherapy. Subsequently, TDF was introduced as rescue therapy to replace LAM. The HBV load decreased to undetectable level in 1 month and maintained in follow-up of 52 weeks, which suggested that the patient was sensitive to TDF. Interestingly, genotypic drug resistance testing showed that rtA194T mutation was present in this patient, along with rtL180M and rtM204V mutations. It is coincided with an in vitro study that the rtA194T mutation did not confer to TDF as a single mutation or in a LAM-resistant viral background, using a HepG2 cell system.9 But these results do not agree with the previous study that a clear association between rtA194T and viral load rebound reported by Sheldon.7 The discrepancy might be explained by differences among clinical data in patients. HBV rtA194T mutant emerged prior TDF treatment in this case, whereas Sheldon reported that rtA194T mutation occurred under the treatment with TDF for 11.2±6.7 months in two HIV/HBV-coinfected patients. Also, the HIV infection may influence the association between rtA194T mutation and TDF resistance. In addition, only one patient had a transient viral increase and the other one had continuous viral decrease after the occurrence of rtA194T mutant under TDF treatment in his study.\n\nFurthermore, previous studies reported that rtA194T mutant can be observed in treatment-naïve patients.14–16 Nevertheless, HBV DNA could be detected in a patient again at 3 month after TDF treatment, which can be explained by short follow-up and nonoptimal compliance in this study.14 Apart from rtL180M, rtM204V and rtA194T mutations, rtM187V and rtV207L were also detected. RtV207L has been previously reported in LAM-resistance patients,17 but clinical implication needs to be further investigated. Notedly, close virological monitoring is necessary, because CHB patients with HBeAg negative may be at particular risk to rtA194T mutations on account of precore (PC) and basic core promoter (BCP) substitutions enhancing the reduced replicative capacity of rtA194T mutants.8 PC mutations occur frequently among patients infected with genotype D HBV and BCP mutations are more prevalent in genotype A and C.18,19 However, G1896A or A1762T/G1764A mutations were not found in this patient with genotype C HBV by DNA sequencing, while A1727T, C1730G and C1799G mutations were found in BCP region, which were reported to be associated significantly with cirrhosis.20\n\nThe patient was diagnosed as Gilbert syndrome based on mild prolonged indirect hyperbilirubinemia and A(TA)7TAA genotype.21 Individuals with Gilbert syndrome may be susceptible to these drugs that require glucuronidation for metabolism, such as menthol, estradiol benzoate, ethinyl estradiol, lamotrigine, tolbutamide, rifamycin SV, acetaminophen, nonsteroidal inflammatory drugs, statins and gemfibrozil,22 human immunodeficiency virus (HIV) protease inhibitors.23 Indinavir and atazanavir (HIV protease inhibitors) can induce hyperbilirubinemia by inhibiting UGT1A1.24 Hyperbilirubinemia associated with the use of nucleoside/nucleotide reverse transcriptase inhibitors is uncommon.25 TDF as one of nucleotide reverse transcriptase inhibitors, to our knowledge, no previous study has shown that TDF has notable toxicity to patient with Gilbert syndrome. And in our study, the TBil level of patient did not increase obviously after receiving TDF treatment. However, both chronic liver disease and Gilbert syndrome may potentiate the hyperbilirubinemia. Therefore, the regular clinical and laboratory follow-up is essential.\n\nIn conclusion, our case reported that the emergence of rtA194T mutants within the HBV polymerase after LAM treatment is sensitive to TDF rescue therapy. The potential impact of this mutation on TDF susceptibility deserves to be elucidated by long-term observation of large cohorts.\n\nAcknowledgement\n\nThis work was supported by National Key Grant 2017ZX10202202.\n\nEthics and Consent Statement\n\nWritten informed consent was obtained from the patient for the publication of this case report and the study was approved by the institutional review board of Ruijin Hospital in accordance with the Declaration of Helsinki.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n==== Refs\nReferences\n\n1. Ganem D, Prince AM. Hepatitis B virus infection–natural history and clinical consequences. N Engl J Med. 2004;350 (11 ):1118–1129. doi:10.1056/NEJMra031087 15014185\n2. Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67 :1560–1599.29405329\n3. Fung S, Kwan P, Fabri M, et al. Randomized comparison of tenofovir disoproxil fumarate vs emtricitabine and tenofovir disoproxil fumarate in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology. 2014;146 (4 ):980–988. doi:10.1053/j.gastro.2013.12.028 24368224\n4. Kabbara WK, Ramadan WH. Emtricitabine/rilpivirine/tenofovir disoproxil fumarate for the treatment of HIV-1 infection in adults. J Infect Public Health. 2015;8 (5 ):409–417. doi:10.1016/j.jiph.2015.04.020 26001757\n5. Behrens G, Rijnders B, Nelson M, et al. Rilpivirine versus efavirenz with emtricitabine/tenofovir disoproxil fumarate in treatment-naïve HIV-1-infected patients with HIV-1 RNA ≤100,000 copies/mL: week 96 pooled ECHO/THRIVE subanalysis. AIDS Patient Care STDS. 2014;28 (4 ):168–175. doi:10.1089/apc.2013.0310 24660840\n6. Liu Y, Corsa AC, Buti M, et al. No detectable resistance to tenofovir disoproxil fumarate in HBeAg+ and HBeAg- patients with chronic hepatitis B after 8 years of treatment. J Viral Hepat. 2017;24 (1 ):68–74. doi:10.1111/jvh.12613 27658343\n7. Sheldon J, Camino N, Rodés B, et al. Selection of hepatitis B virus polymerase mutations in HIV-coinfected patients treated with tenofovir. Antivir Ther (Lond). 2005;10 :727–734.\n8. Amini-Bavil-Olyaee S, Herbers U, Sheldon J, Luedde T, Trautwein C, Tacke F. The rtA194T polymerase mutation impacts viral replication and susceptibility to tenofovir in hepatitis B e antigen-positive and hepatitis B e antigen-negative hepatitis B virus strains. Hepatology. 2009;49 (4 ):1158–1165. doi:10.1002/hep.22790 19263474\n9. Delaney WE, Ray AS, Yang H, et al. Intracellular metabolism and in vitro activity of tenofovir against hepatitis B virus. Antimicrob Agents Chemother. 2006;50 (7 ):2471–2477. doi:10.1128/AAC.00138-06 16801428\n10. Liaw YF, Leung N, Kao JH, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update. Hepatol Int. 2008;2 (3 ):263–283. doi:10.1007/s12072-008-9080-3 19669255\n11. Liaw YF, Leung NW, Chang TT, et al. Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. Gastroenterology. 2000;119 (1 ):172–180. doi:10.1053/gast.2000.8559 10889166\n12. Dienstag JL, Goldin RD, Heathcote EJ, et al. Histological outcome during long-term lamivudine therapy. Gastroenterology. 2003;124 (1 ):105–117. doi:10.1053/gast.2003.50013 12512035\n13. Zoulim F, Locarnini S. Optimal management of chronic hepatitis B patients with treatment failure and antiviral drug resistance. Liver Int. 2013;33 (Suppl 1 ):116–124. doi:10.1111/liv.12069 23286855\n14. Dupouey J, Gerolami R, Solas C, Colson P. Hepatitis B virus variant with the a194t substitution within reverse transcriptase before and under adefovir and tenofovir therapy. Clin Res Hepatol Gastroenterol. 2012;36 (2 ):e26–e28. doi:10.1016/j.clinre.2012.01.003 22342116\n15. Dos Santos M, Pacheco SR, Stocker A, et al. Mutations associated with drug resistance and prevalence of vaccine escape mutations in patients with chronic hepatitis B infection. J Med Virol. 2017;89 (10 ):1811–1816. doi:10.1002/jmv.24853 28500726\n16. Pastor R, Habersetzer F, Fafi-Kremer S, et al. Hepatitis B virus mutations potentially conferring adefovir/tenofovir resistance in treatment-naive patients. World J Gastroenterol. 2009;15 (6 ):753–755. doi:10.3748/wjg.15.753 19222103\n17. Alvarado-Esquivel C, de la Ascensión Carrera-gracia M, Conde-González CJ, et al. Genotypic resistance to lamivudine among hepatitis B virus isolates in Mexico. J Antimicrob Chemother. 2006;57 (2 ):221–223. doi:10.1093/jac/dki457 16373428\n18. Chu CJ, Keeffe EB, Han SH, et al. Hepatitis B virus genotypes in the United States: results of a nationwide study. Gastroenterology. 2003;125 (2 ):444–451. doi:10.1016/S0016-5085(03)00895-3 12891547\n19. Chu CJ, Keeffe EB, Han SH, et al. Prevalence of HBV precore/core promoter variants in the United States. Hepatology. 2003;38 (3 ):619–628. doi:10.1053/jhep.2003.50352 12939588\n20. Yin J, Xie J, Liu S, et al. Association between the various mutations in viral core promoter region to different stages of hepatitis B, ranging of asymptomatic carrier state to hepatocellular carcinoma. Am J Gastroenterol. 2011;106 (1 ):81–92. doi:10.1038/ajg.2010.399 20959817\n21. Erlinger S, Arias IM, Dhumeaux D. Inherited disorders of bilirubin transport and conjugation: new insights into molecular mechanisms and consequences. Gastroenterology. 2014;146 (7 ):1625–1638. doi:10.1053/j.gastro.2014.03.047 24704527\n22. Strassburg CP. Hyperbilirubinemia syndromes (Gilbert-Meulengracht, Crigler-Najjar, Dubin-Johnson, and Rotor syndrome). Best Pract Res Clin Gastroenterol. 2010;24 (5 ):555–571. doi:10.1016/j.bpg.2010.07.007 20955959\n23. Thoguluva Chandrasekar V, John S. Gilbert Syndrome. StatPearls; 2021.\n24. Rotger M, Taffe P, Bleiber G, et al. Gilbert syndrome and the development of antiretroviral therapy-associated hyperbilirubinemia. J Infect Dis. 2005;192 (8 ):1381–1386. doi:10.1086/466531 16170755\n25. Korenblat KM, Berk PD. Hyperbilirubinemia in the setting of antiviral therapy. Clin Gastroenterol Hepatol. 2005;3 (4 ):303–310. doi:10.1016/S1542-3565(05)00083-2 15822033\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1178-6973",
"issue": "14()",
"journal": "Infection and drug resistance",
"keywords": "case report; hepatitis B; resistance; rtA194T mutant; tenofovir disoproxil fumarate",
"medline_ta": "Infect Drug Resist",
"mesh_terms": null,
"nlm_unique_id": "101550216",
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"pages": "1013-1017",
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"pmid": "33758517",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "10889166;12891547;24368224;24660840;19263474;16170755;12512035;12939588;15014185;16801428;19669255;16373428;20955959;26001757;20959817;16218172;22342116;28500726;24704527;19222103;27658343;23286855;29405329;15822033",
"title": "The Occurrence of rtA194T Mutant After Long-Term Lamivudine Monotherapy Remains Sensitive to Tenofovir Disoproxil Fumarate: A Case Report.",
"title_normalized": "the occurrence of rta194t mutant after long term lamivudine monotherapy remains sensitive to tenofovir disoproxil fumarate a case report"
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"abstract": "Dupilumab an inhibitor of the interleukin (IL)-4R-alpha subunit is used for the treatment of allergic diseases. The patient was a 49-year-old man who received dupilumab for the treatment of severe atopic dermatitis. He presented hyperthyroidism with elevated thyroglobulin and anti-thyroid antibody negativity at 4 months after the initiation of therapy. On scintigraphy, the thyroid radioiodine uptake was low. Ultrasonography showed a diffuse hypoechoic area in the thyroid gland. A pathological study revealed lymphocytic infiltration. The administration of dupilumab was continued because of his atopic dermatitis that showed an excellent response. The patient`s hyperthyroidism changed to hypothyroidism 3 weeks later. Six months later his thyroid function normalized without any treatment. We herein describe the case of a patient with atopic dermatitis who developed painless thyroiditis under treatment with dupilumab. To the best of our knowledge, this is the first report of this event in the literature.\nDupilumab, a fully human monoclonal antibody that blocks interleukin-4 and interleukin-13, has been shown to be effective in the treatment atopic dermatitis and asthma with eosinophilia. Painless thyroiditis is characterized by transient hyperthyroidism and hypothyroidism and recovery without anti-thyroid treatment. This is the first report of painless thyroiditis as an adverse effect of dupilumab, although conjunctivitis and nasopharyngitis are the main adverse effects of dupilumab.",
"affiliations": "Division of Endocrinology and Metabolism, Department of Internal Medicine.;Division of Endocrinology and Metabolism, Department of Internal Medicine.;Department of Pediatrics, Aichi Medical University School of Medicine, Nagakute, Japan.;Department of Otolaryngology, Aichi Medical University School of Medicine, Nagakute, Japan.;Department of Dermatology, Aichi Medical University School of Medicine, Nagakute, Japan.;Division of Endocrinology and Metabolism, Department of Internal Medicine.;Division of Endocrinology and Metabolism, Department of Internal Medicine.;Division of Endocrinology and Metabolism, Department of Internal Medicine.;Division of Endocrinology and Metabolism, Department of Internal Medicine.;Department of Otolaryngology, Aichi Medical University School of Medicine, Nagakute, Japan.;Department of Hematology, Aichi Medical University School of Medicine, Nagakute, Japan.",
"authors": "Narantsatsral|Daramjav|D|;Junko|Takagi|T|;Hideyuki|Iwayama|I|;Daisuke|Inukai|I|;Hiroyuki|Takama|T|;Yuka|Nomura|N|;Syo|Hirase|H|;Hiroyuki|Morita|M|;Kazuo|Otake|O|;Tetsuya|Ogawa|O|;Akiyoshi|Takami|T|",
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"fulltext": "\n==== Front\nEndocrinol Diabetes Metab Case Rep\nEndocrinol Diabetes Metab Case Rep\nEDM\nEndocrinology, Diabetes & Metabolism Case Reports\n2052-0573 Bioscientifica Ltd Bristol \n\n10.1530/EDM-20-0030\nEDM200030\nAdult\nMale\nAsian - Japanese\nJapan\nThyroid\nThyroid\nThyroxine (T4)\nThyroiditis\nAtopic dermatitis*\nHyperthyroidism\nHypothyroidism\nHypothyroidism\nHyperthyroidism\nNeck pain/discomfort\nOedema\nFatigue\nGoitre\nHypertension\nTachycardia\nThyroglobulin\nThyroid antibodies\nThyroid scintigraphy\nThyroid ultrasonography\nC-reactive protein\nImmunoglobulin G4\nBiopsy\nFT3\nFT4\nTSH\nDupilumab*\nDermatology\nUnusual Effects of Medical Treatment\nUnusual Effects of Medical Treatment\nPainless thyroiditis in a dupilumab-treated patient\nD Narantsatsral and othersDupilumab related painless thyroiditisNarantsatsral Daramjav 1 Junko Takagi 1 Hideyuki Iwayama 2 Daisuke Inukai 3 Hiroyuki Takama 4 Yuka Nomura 1 Syo Hirase 1 Hiroyuki Morita 1 Kazuo Otake 1 Tetsuya Ogawa 3 Akiyoshi Takami 5 1 Division of Endocrinology and Metabolism, Department of Internal Medicine\n2 Department of Pediatrics, Aichi Medical University School of Medicine, Nagakute, Japan\n3 Department of Otolaryngology, Aichi Medical University School of Medicine, Nagakute, Japan\n4 Department of Dermatology, Aichi Medical University School of Medicine, Nagakute, Japan\n5 Department of Hematology, Aichi Medical University School of Medicine, Nagakute, Japan\nCorrespondence should be addressed to D Narantsatsral; Email: daramjav.narantsatsral.026@mail.aichi-med-u.ac.jp\n16 6 2020 \n2020 \n2020 20-003008 5 2020 26 5 2020 © 2020 The authors2020The authors This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License..Summary\nDupilumab an inhibitor of the interleukin (IL)-4R-alpha subunit is used for the treatment of allergic diseases. The patient was a 49-year-old man who received dupilumab for the treatment of severe atopic dermatitis. He presented hyperthyroidism with elevated thyroglobulin and anti-thyroid antibody negativity at 4 months after the initiation of therapy. On scintigraphy, the thyroid radioiodine uptake was low. Ultrasonography showed a diffuse hypoechoic area in the thyroid gland. A pathological study revealed lymphocytic infiltration. The administration of dupilumab was continued because of his atopic dermatitis that showed an excellent response. The patient`s hyperthyroidism changed to hypothyroidism 3 weeks later. Six months later his thyroid function normalized without any treatment. We herein describe the case of a patient with atopic dermatitis who developed painless thyroiditis under treatment with dupilumab. To the best of our knowledge, this is the first report of this event in the literature.\n\nLearning points:\nDupilumab, a fully human monoclonal antibody that blocks interleukin-4 and interleukin-13, has been shown to be effective in the treatment atopic dermatitis and asthma with eosinophilia.\n\nPainless thyroiditis is characterized by transient hyperthyroidism and hypothyroidism and recovery without anti-thyroid treatment.\n\nThis is the first report of painless thyroiditis as an adverse effect of dupilumab, although conjunctivitis and nasopharyngitis are the main adverse effects of dupilumab.\n\nPatient Demographics\nAdultMaleAsian - JapaneseJapanClinical Overview\nThyroidThyroidThyroxine (T4)ThyroiditisAtopic dermatitis*HyperthyroidismHypothyroidismDiagnosis and Treatment\nHypothyroidismHyperthyroidismNeck pain/discomfortOedemaFatigueGoitreHypertensionTachycardiaThyroglobulinThyroid antibodiesThyroid scintigraphyThyroid ultrasonographyC-reactive proteinImmunoglobulin G4BiopsyFT3FT4TSHDupilumab*Related Disciplines\nDermatologyPublication Details\nUnusual effects of medical treatmentJune2020\n==== Body\nBackground\nAutoimmune thyroiditis is characterized with the release of thyroid hormone resulting in transient hyperthyroidism, frequently followed by a hypothyroid phase before recovery of normal thyroid function. Approximately 5–20% of patients with painless thyroiditis have the characteristic sequence of hyperthyroidism. Painless thyroiditis is associated with specific human leukocyte antigen (HLA) haplotypes, most often HLA-DR3. Medical treatment as interferon alpha, lithium, tyrosine kinase inhibitors, and immune checkpoint inhibitors are possible triggers for painless thyroiditis. Dupilumab is a block of the shared receptor component for interleukin (IL) 4 and IL-13, key drivers of type 2 inflammation in diseases such as atopic dermatitis, asthma, and allergic rhinitis and several adverse effects have been reported in patients treated with dupilumab; however, there are no previous reports on endocrine dysfunction. This is the first report of a patient with painless thyroiditis that appeared in dupilumab treatment.\n\nCase presentation\nThe patient was a 49-year-old man with atopic dermatitis since childhood. The patient had no significant medical history and no family history of thyroid disease including Hashimoto thyroiditis. In May 2019, he was treated with an injection of a 600 mg loading dose of dupilumab followed by the injection of dupilumab (300 mg) every 2 weeks for the treatment of severe atopic dermatitis. At 8 weeks after the initiation of dupilumab, he complained of leg edema, fatigue, and neck discomfort. There was no fever and any symptoms of virus infection. He showed mild hypertension (140/82 mmHg), with tachycardia (108 beats/min), and painless goiter.\n\nInvestigation\nIn the ninth week of dupilumab treatment, laboratory studies revealed the following findings: CRP: 0.06 mg/dL; IgG4: 34.2 mg/dL (Normal range:11–121); TSH: 0.072 IU/mL; free T3: 4.28 pg/mL; free T4: 1.51 ng/dL; and thyroglobulin: 113.7 ng/mL. A test for anti-thyroid antibodies was negative (Table 1). Thyroid ultrasonography showed an enlarged thyroid gland, with a diffuse hypoechoic area (size: 2.8 × 3.4 × 4.1 mm) in the left lobe and smaller lesion with similar characteristics in the right lobe without elevated blood flow, suggesting on-going thyroiditis (Fig. 1A and B). In addition, I131-scintigraphy showed a low uptake in the thyroid gland (Fig. 2A and B). The pathological examination of a biopsy specimen of the lesion in left lobe revealed lymphocyte infiltration indicating destructive thyroiditis.\nFigure 1 The enlarged thyroid gland, with a diffuse hypoechoic area in the left lobe.\n\n\nFigure 2 I131-scintigrapy revealed a low uptake in the thyroid gland.\n\n\nTable 1 The laboratory result in the present case.\n\nTest\tDay 1\tDay 32\tDay 52\tDay 80\tDay 115\tDay 208\tNormal range\t\nfT3, pg/mL\t4.28\t2.2\t2.46\t2.65\t2.58\t2.56\t2.1–3.1\t\nfT4 ng/dL\t1.51\t0.62\t0.8\t0.93\t1.01\t0.75\t0.75–1.42\t\nTSH, IU/mL\t0.043\t4.356\t8.078\t4.407\t4.549\t3.297\t0.45–3.72\t\nTg, ng/mL\t113.7\t34.33\t42.53\t22.2\t18.31\t14.2\t<33.7\t\nTPOAb, IU/mL\t13.8\t12.0\t10.3\t8.7\t9.7\t11.2\t<16\t\nTRAb, IU/L\t0.3\t0.4\t0.4\t0.3\t0.4\t0.5\t<21\t\nCRP, mg/dL\t0.06\t\t\t\t\t\t<30\t\nIgG4, mg/dL\t34.2\t\t\t\t\t\t11–121\t\nBlood examination indicated transient hyperthyroidism, followed by hypothyroidism, and recovery.\n\n\n\n\nTreatment\nWe did not start any anti-thyroid drugs since the clinical examinations indicated painless thyroiditis and his complains gradually disappeared, accompanied by a decrease of T3 and T4. No therapeutic intervention was required for the patient, and the thyroid dysfunction spontaneously improved through the period of hypothyroidism.\n\nOutcome and follow-up\nDupilumab was continued because the patient`s atopic dermatitis showed an excellent response to atopic dermatitis. Follow-up laboratory tests revealed that the function gradually changed to low and transient hypothyroidism (TSH: 8.078 IU/mL; free T3: 2.46 pg/mL; free T4: 0.80ng/dL) 4 months after the initiation of dupilumab. On ultrasonography, a hypoechoic region in the thyroid became invisible 2 months later. His thyroid function normalized without any treatment.\n\nDiscussion\nPainless thyroiditis is characterized by transient hyperthyroidism, which is sometimes followed by hypothyroidism, and then recovery, as was observed in our patient. Polymorphism in the Interleukin 4 gene is related to autoimmune thyroiditis (1). In addition, the IL4-positive lymphocyte count is reported to be increased in patients with autoimmune thyroiditis and concurrent non-endocrine disorders (2). IL4 seems to be involved in the pathophysiology of autoimmune thyroiditis. Dupilumab is a human monoclonal IgG4 antibody that inhibits interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling by binding to the IL-4Rα subunit. The blocking of IL-4Rα with dupilumab inhibits IL-4 and IL-13 cytokine-induced inflammatory responses, including the release of proinflammatory cytokines, chemokines, nitric oxide and IgE. The clinical indications of dupilumab include atopic dermatitis, chronic rhinosinusitis with nasal polyposis, and asthma. However, its mechanism of action in asthma has not been definitively established. The adverse effects of dupilumab include local injection-site reactions, conjunctivitis, headache, and nasopharyngitis (3). Dry eye syndrome, eosinophilic granulomatosis with polyangiitis, eosinophilic pneumonitis, significant cardiovascular event, and vasculitis are rare (4, 5). A meta-analysis of eight randomized controlled trials that was published in January 2018 showed that patients treated with dupilumab had a higher risk of injection-site infection (13.2%) in comparison to placebo-treated patients (6.5%) (5), and that among patients with atopic dermatitis, dupilumab-treated patients had a higher incidence of conjunctivitis than placebo-treated patients (5). However previous studies of patients with asthma and chronic sinusitis with nasal polyposis reported that dupilumab-treated patients and placebo-treated patients showed similar incidence of conjunctivitis (6, 7, 8). In a report on patients with chronic sinusitis with nasal polyposis, dupilumab-treated patients and placebo-treated patients showed a similar incidence of injection-site infection (8, 9). Dupilumab moderately increased the risk of injection-site reaction and conjunctivitis in adults with moderate-to-severe atopic dermatitis. This could indicate that dupilumab has another mechanism of action in atopic dermatitis. Painless thyroiditis is diagnosed based on an increased thyroglobulin level, a low radioactive iodine uptake, an increased FT4 level, and a suppressed TSH level. This disorder can occur in patients with autoimmune thyroiditis as a process of the destruction of thyroid tissue. Cytokines, antiviral agents, molecular-targeted therapeutic agents, and immune checkpoint inhibitors including interferon alpha, interleukin-2, tyrosine kinase inhibitors, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), are also known to cause painless thyroiditis. However, dupilumab is an IL-4 and IL-13 inhibitor and is not recognized as a risk factor for thyroiditis or any endocrine disease. Th1 cells and their producing cytokines such as IL-2 play pivotal roles in the development of painless thyroiditis. Dupilumab suppresses Th2 cells through inhibition of IL-4 and IL-13, which leads to the relative dominance of Th1 cells, which may have contributed to the development of painless thyroiditis in the current patient, although this is highly speculative. This may be supported by a previous report (10) in which an increase in the Th1/Th2 ratio, but not in the total number of Th1 cells, was associated with Hashimoto’ thyroiditis. In summary, this is the first report of painless thyroiditis related to dupilumab treatment in patients with atopic dermatitis; however, the mechanism underlying this adverse effect is unknown and a single report is not enough to conclude. The investigation is required to clear the mechanisms for the development of silent thyroiditis after dupilumab treatment. Further studies to explore this phenomenon are warranted. The observation of the thyroid function may be useful for patients undergoing treatment with dupilumab.\n\nDeclaration of interest\nThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this case report.\n\nFunding\nThis researcher did not receive any specific grant from any funding agency in the public, commercial or not for profit sector.\n\nPatient consent\nWe obtained written informed consent from the patients.\n\nAuthor contribution statement\nBoth authors contributed equally to the manuscript.\n==== Refs\nReferences\n1 Hunt PJ Marshall SE Weetman AP Bell JI Wass JA Welsh KI \nCytokine gene polymorphisms in autoimmune thyroid disease\n. Journal of Clinical Endocrinology and Metabolism \n2000 \n85 \n1984 –1988\n. (10.1210/jcem.85.5.6588 )10843185 \n2 Santaguida MG Nardo S Del Duca SC Lococo E Virili C Gargano L Lenti L Centanni M \nIncreased interleukin-4-positive lymphocytes in patients with Hashimoto’s thyroiditis and concurrent non-endocrine autoimmune disorders\n. Clinical and Experimental Immunology \n2011 \n165 \n148 –154\n. (10.1111/j.1365-2249.2011.04419.x )21623768 \n3 Lee JH Son SW Cho SH \nA comprehensive review of the treatment of atopic eczema\n. Allergy, Asthma and Immunology Research \n2016 \n8 \n181 –190\n. (10.4168/aair.2016.8.3.181 )\n4 Mitchell K Levitt J \nAlopecia areata after dupilumab for atopic dermatitis\n. JAAD Case Reports \n2018 \n4 \n143 –144\n. (10.1016/j.jdcr.2017.11.020 )29387767 \n5 Barnes AC Blandford AD Perry JD \nCicatricial ectropion in a patient treated with dupilumab\n. American Journal of Ophthalmology Case Reports \n2017 \n7 \n120 –122\n. (10.1016/j.ajoc.2017.06.017 )29260094 \n6 Ou Z Chen C Chen A Yang Y Zhou W \nAdverse events of dupilumab in adults with moderate-to-severe atopic dermatitis: a meta-analysis\n. International Immunopharmacology \n2018 \n54 \n303 –310\n. (10.1016/j.intimp.2017.11.031 )29182975 \n7 Bachert C Mannent L Naclerio RM Mullol J Ferguson BJ Gevaert P Hellings P Jiao L Wang L Evans RR , \nEffect of subcutaneous Dupilumab on nasal polyp burden in patients with chronic sinusitis and nasal polyposis: a randomized clinical trial\n. JAMA \n2016 \n315 \n469 –479\n. (10.1001/jama.2015.19330 )26836729 \n8 Wenzel S Ford L Pearlman D Spector S Sher L Skobieranda F Wang L Kirkesseli S Rocklin R Bock B , \nDupilumab in persistent asthma with elevated eosinophil levels\n. New England Journal of Medicine \n2013 \n368 \n2455 –2466\n. (10.1056/NEJMoa1304048 )23688323 \n9 Bachert C Joseph Kh Desrosiers M Hellings PW Amin N Lee SE Mullol J Greos LS Bosso JV Laidlaw TM , \nEfficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebocontrolled, parallel-group phase 3 trials\n. Lancet \n2019 \n394 \n1638 –1650\n. (10.1016/S0140-6736(19)31881-1 )31543428 \n10 Colin IM Isaac J Dupret P Ledant T D’Hautcourt JL \nFunctional lymphocyte subset assessment of the Th1/Th2 profile in patients with autoimmune thyroiditis by flow cytometric analysis of peripheral lymphocytes\n. Journal of Biological Regulators and Homeostatic Agents \n2004 \n18 \n72 –76\n.15323363\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2052-0573",
"issue": "2020()",
"journal": "Endocrinology, diabetes & metabolism case reports",
"keywords": "2020; Adult; Asian - Japanese; Atopic dermatitis*; Biopsy; C-reactive protein; Dermatology; Dupilumab*; FT3; FT4; Fatigue; Goitre; Hypertension; Hyperthyroidism; Hypothyroidism; Immunoglobulin G4; Japan; June; Male; Neck pain/discomfort; Oedema; TSH; Tachycardia; Thyroglobulin; Thyroid; Thyroid antibodies; Thyroid scintigraphy; Thyroid ultrasonography; Thyroiditis; Thyroxine (T4); Unusual effects of medical treatment",
"medline_ta": "Endocrinol Diabetes Metab Case Rep",
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"title": "Painless thyroiditis in a dupilumab-treated patient.",
"title_normalized": "painless thyroiditis in a dupilumab treated patient"
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"abstract": "Hemophagocytic lymphohistiocytosis (HLH) is a severe complication after allogeneic hematopoietic cell transplantation (HCT) and can cause graft failure or multi-organ failure. Here, we report two children with refractory HCT-associated HLH treated with ruxolitinib. In the first patient, ruxolitinib resolved fever, cytopenia and hyperferritinemia. In another patient, although severe hepatic failure, which developed and worsened before the administration of ruxolitinib, was irreversible, rapid improvement in fever, leukopenia and hyperferritinemia was observed. Of note, multiplex cytokine profiling showed amelioration of cytokine storm in both patients. Ruxolitinib may be an encouraging option for HCT-associated HLH.",
"affiliations": "Department of Pediatrics, St. Luke's International Hospital, 9-1 Akashicho, Chuo-ku, Tokyo, 104-0044, Japan.;Department of Pediatrics, St. Luke's International Hospital, 9-1 Akashicho, Chuo-ku, Tokyo, 104-0044, Japan.;Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan.;Department of Pediatrics, St. Luke's International Hospital, 9-1 Akashicho, Chuo-ku, Tokyo, 104-0044, Japan.;Department of Pediatrics, St. Luke's International Hospital, 9-1 Akashicho, Chuo-ku, Tokyo, 104-0044, Japan.;Department of Pediatrics, St. Luke's International Hospital, 9-1 Akashicho, Chuo-ku, Tokyo, 104-0044, Japan.;Center for Medical Sciences, St Luke's International University, Tokyo, Japan.;Department of Hematology, St. Luke's International Hospital, Tokyo, Japan.;Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan.;Department of Pediatrics, St. Luke's International Hospital, 9-1 Akashicho, Chuo-ku, Tokyo, 104-0044, Japan. hasedai1313@gmail.com.",
"authors": "Ono|Rintaro|R|;Ashiarai|Miho|M|;Hirabayashi|Shinsuke|S|;Mizuki|Kazuyoshi|K|;Hosoya|Yosuke|Y|;Yoshihara|Hiroki|H|;Ohtake|Junya|J|;Mori|Shinichiro|S|;Manabe|Atsushi|A|;Hasegawa|Daisuke|D|http://orcid.org/0000-0002-9446-9568",
"chemical_list": "D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; C540383:ruxolitinib",
"country": "Japan",
"delete": false,
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"issue": "113(2)",
"journal": "International journal of hematology",
"keywords": "Cytokine profiling; Hematopoietic cell transplantation; Hemophagocytic lymphohistiocytosis; Ruxolitinib",
"medline_ta": "Int J Hematol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002675:Child, Preschool; D019468:Disease Management; D004198:Disease Susceptibility; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D051359:Lymphohistiocytosis, Hemophagocytic; D008297:Male; D009570:Nitriles; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; D011720:Pyrazoles; D011743:Pyrimidines; D014184:Transplantation, Homologous; D016896:Treatment Outcome",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "297-301",
"pmc": null,
"pmid": "32979171",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ruxolitinib for hematopoietic cell transplantation-associated hemophagocytic lymphohistiocytosis.",
"title_normalized": "ruxolitinib for hematopoietic cell transplantation associated hemophagocytic lymphohistiocytosis"
} | [
{
"companynumb": "JP-PFIZER INC-2021226572",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "Crizotinib is an orally active multi-target tyrosine kinase inhibitor which is the standard of care in patients with anaplastic lymphoma kinase translocated non-small-cell lung cancer. Common adverse events in clinical trials with crizotinib included visual disorders, nausea-vomiting, diarrhea and elevated transaminases. Less common toxicities are emerging, such as bradycardia and QT interval prolongation. We report on a case of a presyncopal episode which occurred under crizotinib and metoclopramide treatment.",
"affiliations": "Cardiology Unit, IRCCS, Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture (PZ), Italy.",
"authors": "Gallucci|Giuseppina|G|;Tartarone|Alfredo|A|;Lombardi|Lucia|L|;Aieta|Michele|M|",
"chemical_list": "D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; D008787:Metoclopramide",
"country": "England",
"delete": false,
"doi": "10.1586/14737140.2015.1045493",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1473-7140",
"issue": "15(7)",
"journal": "Expert review of anticancer therapy",
"keywords": "cardiotoxicity; crizotinib; drug interactions; metoclopramide; non-small-cell lung cancer",
"medline_ta": "Expert Rev Anticancer Ther",
"mesh_terms": "D000230:Adenocarcinoma; D000077192:Adenocarcinoma of Lung; D000971:Antineoplastic Combined Chemotherapy Protocols; D001919:Bradycardia; D000077547:Crizotinib; D006339:Heart Rate; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008787:Metoclopramide; D008875:Middle Aged; D011720:Pyrazoles; D011725:Pyridines",
"nlm_unique_id": "101123358",
"other_id": null,
"pages": "761-3",
"pmc": null,
"pmid": "25961872",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "When crizotinib-induced bradycardia becomes symptomatic: role of concomitant drugs.",
"title_normalized": "when crizotinib induced bradycardia becomes symptomatic role of concomitant drugs"
} | [
{
"companynumb": "PHHY2015IT086464",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CRIZOTINIB"
},
"drugadditional": null,
"drug... |
{
"abstract": "OBJECTIVE\nTo describe 4 cases of cytomegalovirus (CMV) corneal endotheliitis occurring after Descemet membrane endothelial keratoplasty (DMEK).\n\n\nMETHODS\nThis is a retrospective, interventional case series. Case records of 4 patients (one eye each) diagnosed with CMV corneal endotheliitis after DMEK were reviewed retrospectively. Presenting clinical features, treatment, and outcomes were examined.\n\n\nRESULTS\nPatients' age ranged from 68 to 77 years. Three patients underwent DMEK for failed corneal grafts and 1 for pseudophakic bullous keratopathy. Time from DMEK to presentation ranged from 5 to 15 weeks. Presenting features included corneal edema, pigmented keratic precipitates, mild anterior chamber inflammation, and raised intraocular pressure. Two cases were initially misdiagnosed as graft rejection and treated with corticosteroids. Both worsened, and delayed diagnoses of CMV corneal endotheliitis were made. The two other cases were diagnosed correctly at initial presentation. All cases were confirmed by anterior chamber paracentesis and polymerase chain reaction testing for CMV. All cases were treated initially with topical ganciclovir gel and oral valganciclovir. Three cases showed clinical resolution. Final corrected visual acuity ranged from 20/25 to 20/40. One case failed to respond to topical ganciclovir gel, oral valganciclovir, and intravenous ganciclovir and foscarnet. This patient declined further systemic treatment and was maintained on topical ganciclovir only but subsequently showed spontaneous resolution 3 months later.\n\n\nCONCLUSIONS\nCMV corneal endotheliitis may occur after DMEK and can closely mimic graft rejection. Polymerase chain reaction testing of aqueous humor is advised for suspect cases. A high index of suspicion is important for prompt diagnosis and initiation of appropriate antiviral treatment.",
"affiliations": "Corneal and External Eye Disease Department, Singapore National Eye Centre, Singapore.;Corneal and External Eye Disease Department, Singapore National Eye Centre, Singapore.",
"authors": "Tan|Tien-En|TE|;Tan|Donald Tiang Hwee|DTH|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/ICO.0000000000001847",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-3740",
"issue": "38(4)",
"journal": "Cornea",
"keywords": null,
"medline_ta": "Cornea",
"mesh_terms": "D000368:Aged; D003316:Corneal Diseases; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D057111:Descemet Stripping Endothelial Keratoplasty; D004728:Endothelium, Corneal; D015828:Eye Infections, Viral; D005260:Female; D006801:Humans; D008297:Male; D011183:Postoperative Complications; D012189:Retrospective Studies",
"nlm_unique_id": "8216186",
"other_id": null,
"pages": "413-418",
"pmc": null,
"pmid": "30614903",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cytomegalovirus Corneal Endotheliitis After Descemet Membrane Endothelial Keratoplasty.",
"title_normalized": "cytomegalovirus corneal endotheliitis after descemet membrane endothelial keratoplasty"
} | [
{
"companynumb": "SG-TEVA-2019-SG-1055571",
"fulfillexpeditecriteria": "1",
"occurcountry": "SG",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISOLONE ACETATE"
},
"drugadditional": "1",... |
{
"abstract": "Dystrophic epidermolysis bullosa is a rare inherited disease caused by mutations in the COL7A1 gene. Its recessive variant (recessive dystrophic epidermolysis bullosa) is characterized by the absence or considerably reduced expression of type VII collagen, which leads to marked fragility of the skin and mucous membranes and subsequent blister formation, whether spontaneously or following minimal injury. There have been very few reports of this disease in pregnant women. We present 2 cases of pregnant women with recessive dystrophic epidermolysis bullosa managed in our High-Risk Pregnancy Unit at Hospital Universitario La Paz, Madrid, Spain. Both patients underwent full-term cesarean delivery, with no further complications for mother or child. Although recessive dystrophic epidermolysis bullosa increases the risk of maternal complications, a patient is not advised against pregnancy. With adequate monitoring, these patients can fulfil their desire to become mothers.",
"affiliations": "Unidad de Medicina Materno-Fetal, Servicio de Obstetricia, Hospital Universitario La Paz, Madrid, España. Electronic address: F.Boria.Alegre@gmail.com.;Servicio de Dermatología, Hospital Universitario La Paz, Madrid, España.;Unidad de Medicina Materno-Fetal, Servicio de Obstetricia, Hospital Universitario La Paz, Madrid, España.;Unidad de Medicina Materno-Fetal, Servicio de Obstetricia, Hospital Universitario La Paz, Madrid, España.;Servicio de Dermatología, Hospital Universitario La Paz, Madrid, España.",
"authors": "Boria|F|F|;Maseda|R|R|;Martín-Cameán|M|M|;De la Calle|M|M|;de Lucas|R|R|",
"chemical_list": null,
"country": "Spain",
"delete": false,
"doi": "10.1016/j.ad.2017.06.024",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2173-5778",
"issue": "110(1)",
"journal": "Actas dermo-sifiliograficas",
"keywords": "Complicaciones del embarazo; Dystrophic epidermolysis bullosa; Embarazo; Epidermolysis bullosa; Epidermólisis bullosa; Epidermólisis bullosa distrófica; Female; Mujer; Pregnancy; Pregnancy complications",
"medline_ta": "Actas Dermosifiliogr (Engl Ed)",
"mesh_terms": "D000328:Adult; D016108:Epidermolysis Bullosa Dystrophica; D005260:Female; D006801:Humans; D011247:Pregnancy; D011248:Pregnancy Complications",
"nlm_unique_id": "101777537",
"other_id": null,
"pages": "50-52",
"pmc": null,
"pmid": "29203033",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Recessive Dystrophic Epidermolysis Bullosa and Pregnancy.",
"title_normalized": "recessive dystrophic epidermolysis bullosa and pregnancy"
} | [
{
"companynumb": "PHHY2019ES112814",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IRON"
},
"drugadditional": null,
"drugadmini... |
{
"abstract": "We experienced a case of endocrine therapy-resistant recurrent breast cancer with liver and bone metastases, treated with S-1 as first-line chemotherapy and maintaining a good quality of life. The patient was a 31-year-old premenopausal woman. She was diagnosed with cancer of the left breast(T1(18mm), N0, M(-))and underwent breast-conserving surgery, sentinel lymph node biopsy, and radiation therapy in August 2002. As there was hormone sensitivity, she was treated with LHRH analog for 3 years and tamoxifen for 5 years as adjuvant therapy. After her first childbirth, she had a recurrence of liver and bone metastases. After treatment with endocrine therapy failed, an oral administration of S-1 was initiated as first-line chemotherapy considering her QOL. She received 8 months of S-1 therapy with no severe adverse reactions and maintained a high quality of life. Treatment with S-1 is thought to be useful for first-line chemotherapy if the treatment demonstrates a therapeutic equivalence with taxane on patients' overall survival.",
"affiliations": "Dept. of Breast Surgery, Sagara Hospital, Hakuaikai Medical Corporation, Japan.",
"authors": "Tamada|Shugo|S|;Sagara|Yasuaki|Y|;Baba|Shinichi|S|;Sagara|Yoshiaki|Y|;Yotsumoto|Daisuke|D|;Matsukata|Ayami|A|;Andou|Mitsutake|M|;Sagara|Yoshiatsu|Y|;Rai|Yoshiaki|Y|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "38(4)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000328:Adult; D000964:Antimetabolites, Antineoplastic; D001859:Bone Neoplasms; D001943:Breast Neoplasms; D004338:Drug Combinations; D005260:Female; D006801:Humans; D008113:Liver Neoplasms; D010094:Oxonic Acid; D011788:Quality of Life; D005641:Tegafur; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "635-7",
"pmc": null,
"pmid": "21498994",
"pubdate": "2011-04",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "A patient with of metastatic breast cancer with a well-controlled quality of life using S-1 therapy as first-line chemotherapy.",
"title_normalized": "a patient with of metastatic breast cancer with a well controlled quality of life using s 1 therapy as first line chemotherapy"
} | [
{
"companynumb": "JP-MYLANLABS-2016M1031117",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": "3",
... |
{
"abstract": "A 30 year-old man with acute myeloblastic leukaemia and secondary myelodysplastic syndrome developed graft-versus-host disease. The patient was treated with ruxolitinib. After being treated for 3 months with ruxolitinib, an inhibitor of Janus kinase, he developed Aspergillus retinal necrosis resistant to common treatment. Treatment with Janus kinase inhibitors may lead to an increased incidence of opportunistic infections. Janus kinase inhibitor administration may result in poor treatment efficacy.",
"affiliations": "Sección de Uveítis, Departamento de Oftalmología, Hospital Universitario Virgen del Rocío, Sevilla, España. Electronic address: antoniomoruno_89@hotmail.com.;Sección de Retina Quirúrgica, Departamento de Oftalmología, Hospital Universitario Virgen del Rocío, Sevilla, España.;Sección General, Departamento de Oftalmología, Hospital Universitario Virgen del Rocío, Sevilla, España.;Sección General, Departamento de Oftalmología, Hospital Universitario Virgen del Rocío, Sevilla, España.;Sección de Córnea, Departamento de Oftalmología, Hospital Universitario Virgen del Rocío, Sevilla, España.;Sección de Retina Médica, Departamento de Oftalmología, Hospital Universitario Virgen del Rocío, Sevilla, España.",
"authors": "Moruno-Rodríguez|A|A|;Sánchez-Vicente|J L|JL|;Rueda-Rueda|T|T|;Lechón-Caballero|B|B|;Muñoz-Morales|A|A|;López-Herrero|F|F|",
"chemical_list": "D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; C540383:ruxolitinib",
"country": "Spain",
"delete": false,
"doi": "10.1016/j.oftal.2018.12.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2173-5794",
"issue": "94(5)",
"journal": "Archivos de la Sociedad Espanola de Oftalmologia",
"keywords": "Acute myeloblastic leukaemia; Aspergillus; Enfermedad injerto contra huésped; Graft-versus-host disease; Leucemia mieloblástica aguda; Myelodysplastic syndrome; Necrosis retiniana; Retinal necrosis; Ruxolitinib; Síndrome mielodisplásico",
"medline_ta": "Arch Soc Esp Oftalmol (Engl Ed)",
"mesh_terms": "D000328:Adult; D001228:Aspergillosis; D001231:Aspergillus flavus; D001234:Aspergillus niger; D015821:Eye Infections, Fungal; D017809:Fatal Outcome; D006086:Graft vs Host Disease; D006801:Humans; D007511:Ischemia; D015470:Leukemia, Myeloid, Acute; D008297:Male; D009190:Myelodysplastic Syndromes; D009336:Necrosis; D009570:Nitriles; D009894:Opportunistic Infections; D011720:Pyrazoles; D011743:Pyrimidines; D012160:Retina; D012171:Retinal Vessels",
"nlm_unique_id": "101715860",
"other_id": null,
"pages": "237-241",
"pmc": null,
"pmid": "30712951",
"pubdate": "2019-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Invasive aspergillosis manifesting as retinal necrosis in a patient treated with ruxolitinib.",
"title_normalized": "invasive aspergillosis manifesting as retinal necrosis in a patient treated with ruxolitinib"
} | [
{
"companynumb": "ES-CHEPLA-C20200265",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "GANCICLOVIR"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nComplications with high-dose steroid administration for spinal cord injury are documented in adult patients. Our purpose was to determine the incidence of early complications of this therapy in pediatric patients with spinal cord injuries.\n\n\nMETHODS\nAn IRB-approved retrospective review was performed for patients treated for spinal cord injury at a level 1 pediatric trauma center between 2003 and 2011. Demographic data, injury characteristics, and surgical interventions were documented. Complications were divided into 4 categories: infectious, gastrointestinal (GI), hyperglycemia/endocrine, and wound healing problems. Complication rates were compared using a Student's t test and Fischer's exact test.\n\n\nRESULTS\nThirty-four spinal cord injury patients were identified. Twenty-three patients (mean age 6.6 y) in the treatment group received high-dose steroid treatment and 11 patients (mean age 8.4 y) did not and comprised the control group. No statistical difference was detected between the 2 groups regarding age, mechanism of injury, rate of surgical intervention, level of injury, and injury severity. Hyperglycemia was the most common complication and was present in all patients in both the treatment and control groups. The overall infection rate was 64% in the control group compared with 26% in the treatment (P<0.05). The control group demonstrated a significantly increased rate of respiratory tract infections [45% control vs. 9% treatment (P<0.05)]. No surgical patients developed a wound infection. One treatment group patient experienced a GI bleed.\n\n\nCONCLUSIONS\nThis is the largest study evaluating the complications associated with high-dose steroid administration for spinal trauma in a pediatric population. Hyperglycemia was found in all spinal cord injury patients, regardless of steroid treatment. Paradoxically, infection rates were noted to be higher in the control group. GI and wound problems were not significantly different. Larger, multicenter prospective studies are needed to better understand the risks in pediatric SCI patients.",
"affiliations": "*Tripler Army Medical Center, Orthopedic Surgery Service, Honolulu, HI †Department of Orthopedics, Texas Scottish Rite Hospital for Children and Children's Medical Center, Dallas, TX ‡Center for Policy & Public Administration, Principal Outcomes Consultant, Draper, UT.",
"authors": "Cage|Jason M|JM|;Knox|Jeffrey B|JB|;Wimberly|Robert L|RL|;Shaha|Steve|S|;Jo|ChanHee|C|;Riccio|Anthony I|AI|",
"chemical_list": "D005938:Glucocorticoids",
"country": "United States",
"delete": false,
"doi": "10.1097/BPO.0000000000000364",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0271-6798",
"issue": "35(7)",
"journal": "Journal of pediatric orthopedics",
"keywords": null,
"medline_ta": "J Pediatr Orthop",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D005767:Gastrointestinal Diseases; D005938:Glucocorticoids; D006801:Humans; D006943:Hyperglycemia; D015994:Incidence; D007223:Infant; D007275:Injections, Intravenous; D008297:Male; D012189:Retrospective Studies; D013119:Spinal Cord Injuries; D014193:Trauma Centers; D014481:United States",
"nlm_unique_id": "8109053",
"other_id": null,
"pages": "687-92",
"pmc": null,
"pmid": "25494031",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Complications Associated With High-dose Corticosteroid Administration in Children With Spinal Cord Injury.",
"title_normalized": "complications associated with high dose corticosteroid administration in children with spinal cord injury"
} | [
{
"companynumb": "US-TEVA-651941USA",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nAortic dissection is a very rare but life-threatening condition associated with a high mortality. Unexpected sudden cardiac death due to aortic rupture following laparoscopic appendectomy is very rare and may be difficult to diagnose. However, early diagnosis of aortic dissection is essential for the timely treatment and outcome of aortic dissection.\n\n\nMETHODS\nA 50-year-old man underwent a laparoscopic appendectomy. Postoperatively, the patient complained of dyspnea and chest pain. In 25 minutes after arrival in the postanesthesia care unit (PACU), the patient was in asystole. Then, he underwent cardiopulmonary resuscitation (CPR) according to advanced cardiac life support (ACLS) protocol using 1 mg of epinephrine, one 200J DC shock for ventricular fibrillation (V-fib). After that, his noninvasive blood pressure (NIBP) was 80/40 mm Hg, pulse rate (PR) was 140 beats/min, and peripheral oxygen saturation (SpO2) was 84%. His electrocardiogram (ECG) finding was atrial fibrillation (A-fib). After 20 minutes, the patient developed asystole rhythm again and CPR was restarted. He remained severely hypotensive despite vasopressors and died after 5 hours CPR. A forensic autopsy was performed postmoterm and thoracic and abdominal aortic dissection along the root of ascending aorta was present and massive hematoma within right and left thorax was present.\n\n\nCONCLUSIONS\nAcute aortic disease can be difficult to recognize; therefore, diagnosis is sometimes delayed or missed. It is important to recognize the atypical symptoms of aortic dissection and maintain a broad differential diagnosis if patients complained of abdominal pain.",
"affiliations": "Department of Anesthesia and Pain Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Incheon.;Division of Critical Care Medicine, Department of Internal Medicine, Myongji Hospital, Seonam University College of Medicine, Goyang-si.;Department of Anesthesia and Pain Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Incheon.;Department of Anesthesia and Pain Medicine, St. Paul's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.",
"authors": "Joo|Chunghee|C|;Min|Joo-Won|JW|;Noh|Giyong|G|;Seo|Jaeho|J|",
"chemical_list": "D014662:Vasoconstrictor Agents; D004837:Epinephrine",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000012823",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 30334980MD-D-18-0331610.1097/MD.0000000000012823128233300Research ArticleClinical Case ReportA case report of unexpected sudden cardiac death due to aortic rupture following laparoscopic appendectomy Joo Chunghee MDa∗Min Joo-Won MD, PhDbNoh Giyong MDaSeo Jaeho MDcNA. a Department of Anesthesia and Pain Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Incheonb Division of Critical Care Medicine, Department of Internal Medicine, Myongji Hospital, Seonam University College of Medicine, Goyang-sic Department of Anesthesia and Pain Medicine, St. Paul's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.∗ Correspondence: Chunghee Joo, Department of Anesthesia and Pain Medicine, Incheon St. Mary's hospital, College of Medicine, The Catholic University of Korea, 56, Dongsu-ro, Bupyeong-gu, Incheon 21431, Republic of Korea (e-mail: tommy234@hanmail.net).10 2018 19 10 2018 97 42 e1282323 5 2018 20 9 2018 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc/4.0Abstract\nIntroduction:\nAortic dissection is a very rare but life-threatening condition associated with a high mortality. Unexpected sudden cardiac death due to aortic rupture following laparoscopic appendectomy is very rare and may be difficult to diagnose. However, early diagnosis of aortic dissection is essential for the timely treatment and outcome of aortic dissection.\n\nCase presentation:\nA 50-year-old man underwent a laparoscopic appendectomy. Postoperatively, the patient complained of dyspnea and chest pain. In 25 minutes after arrival in the postanesthesia care unit (PACU), the patient was in asystole. Then, he underwent cardiopulmonary resuscitation (CPR) according to advanced cardiac life support (ACLS) protocol using 1 mg of epinephrine, one 200J DC shock for ventricular fibrillation (V-fib). After that, his noninvasive blood pressure (NIBP) was 80/40 mm Hg, pulse rate (PR) was 140 beats/min, and peripheral oxygen saturation (SpO2) was 84%. His electrocardiogram (ECG) finding was atrial fibrillation (A-fib). After 20 minutes, the patient developed asystole rhythm again and CPR was restarted. He remained severely hypotensive despite vasopressors and died after 5 hours CPR. A forensic autopsy was performed postmoterm and thoracic and abdominal aortic dissection along the root of ascending aorta was present and massive hematoma within right and left thorax was present.\n\nConclusion:\nAcute aortic disease can be difficult to recognize; therefore, diagnosis is sometimes delayed or missed. It is important to recognize the atypical symptoms of aortic dissection and maintain a broad differential diagnosis if patients complained of abdominal pain.\n\nKeywords\nacute aortic dissectionacute aortic syndromeappendectomycardiopulmonary resuscitationOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nAortic dissection is a very rare but life-threatening condition associated with a high mortality.[1] The incidence of acute aortic dissection is 2.53/1,000,000 per year.[1] Because acute aortic disease can be difficult to recognize, diagnosis is sometimes delayed or missed.[2] Furthermore, acute aortic dissection can result in catastrophic complications or sudden diagnosed and untreated, which is associated with a high mortality rate of 1% to 2% per hour.[3] Therefore, it is important to diagnose acute aortic dissection fast and accurately.\n\nWe report a rare case of unexpected sudden cardiac death due to aortic rupture following laparoscopic appendectomy.\n\n2 Case report\nA 50-year-old male patient with acute right lower quadrant pain was admitted to our hospital for emergency laparoscopic appendectomy under general anesthesia. He suffered from right ureter stone 2 years ago. Except that, the patient was in good health. The patient suffered from acute right lower quadrant stabbing pain from 11 am. The physical examination was remarkable for tenderness on the right lower quadrant area. The patient's preoperative chest X-ray finding, laboratory finding, and electrocardiogram were all within normal range. His preoperative blood pressure (BP) was 125/79 mm Hg, and pulse rate (PR) was 80 beats/min. General anesthesia was induced with 350 mg of thiopental, 80 mg of succinylcholine, and 50 μg of fentanyl. Tracheal intubation was done without difficulty on a single try. And then anesthesia was maintained with 6vol % of desflurane. The patient was monitored with noninvasive blood pressure (NIBP), ECG (lead II), pulse oximetry, and capnography. During the operation, BP, PR, and SpO2 were maintained at 110 to 150/65 to 90 mm Hg, 80 to 110 beats/min, and 99% to 100%, respectively. And there was no problem during appendectomy. When the anesthesia was over, NIBP was 120/70 and PR was 100 beats/min. On arrival in the postanesthesia care unit (PACU), the patient complained of severe dyspnea and chest pain, which was persisted and worsened. At that time, NIBP was 100/60, PR was 100 beats/min, but SpO2 was 85% to 94%. Respiratory rate was 30 breaths/min. Thus naloxone 0.2 mg was administered. In 25 minutes after arrival in the PACU, the patient was in asystole. And then he underwent cardiopulmonary resuscitation according to ACLS protocol using 1 mg of epinephrine, one 200J DC shock for V-fib. After that, his NIBP was 80/40 mm Hg, PR was 140 beats/min, and SpO2 was 84%. His ECG finding was A-fib. After 20 minutes, the patient developed asystole rhythm again and CPR was restarted. He remained severely hypotensive despite vasopressors, and died after 5 hours CPR. Because the patient's vital signs abruptly worsened, we could not perform additional evaluation such as chest X-ray, transthoracic echocardiography, thoracic computed tomography (CT) scan, etc. Then, a forensic autopsy was performed postmortem and thoracic and abdominal aortic dissection along the root of ascending aorta was present and massive hematoma within right and left thorax was present. And there was acute inflammation of appendix. Other findings were essentially normal. The patient had no family history of vascular disease or clinical features of connective tissue disease. He has no marfanoid habitus. This is the second case in the literature of acute aortic dissection occurring after laparoscopic appendectomy. This case was approved by Ethics Review Committee and the Institutional Review Board (OC18ZESI0062). Informed written consent was obtained from the patient's elder brother for publication of this case report and accompanying images.\n\n3 Discussion\nAortic dissection is a very rare but life-threatening condition associated with a high mortality. The incidence of aortic dissection is 2.53/100,000 per year.[1] The risk factors for aortic dissection include hypertension, connective tissue disease, atherosclerosis, Marfan syndrome, Ehlers--Danlos syndrome, other connective tissue disorders, Turner syndrome, biscuspid aortic valve, aortic coarctation, cocaine use, pregnancy, and trauma.[4–10]\n\nIn this case, 2 scenarios are possible; the dissection was present before the operation. Aortic dissection occurs when the intimal layer tears due to sudden shear stress.[11] Especially, uncontrolled high BP is the major risk factor for aortic dissection. If the force of the blood pressing against the aortic wall is too high, it can lead to a tear of the wall. If the patient who underwent laparoscopic appendectomy had a cardiovascular problem with preexisting ascending aorta tear, this give rise to aortic dissection. Therefore, during induction of anesthesia for aortic dissection, smooth and deep induction is needed.[12] But in our case, we could not be suspicious of acute aortic dissection because the patient has no past history of cardiovascular disease. In a previous case,[13] a 43-year old woman with Marfan syndrome was diagnosed as dilated ascending aorta with a circular shape intimal flap at the root level, which resulted in death within 20 seconds of examination of subsequent transesophageal echocardiography (TEE). That was a very rare case of death, which could be related to TEE and deep sedation might be required to prevent the increase of BP.\n\nAcute aortic dissection was most common cause of sudden unexpected death of aortic disease and a very catastrophic cardiovascular disease, which is associated with high mortality if undiagnosed and untreated. And acute aortic disease can be difficult to recognize or missed; therefore, diagnosis is sometimes delayed or missed. In a retrospective study of forensic autopsy cases, 26 patients were clinically misdiagnosed with acute myocardial infarction (9 cases), coronary artery disease (6 cases), cholecystitis (4 cases), acute gastroenteritis (3 cases), renal/urinary calculi (3 cases), and acute pancreatitis (3 cases). Of this study, 22 cases were type A aortic dissection (84.6%) and 4 cases (15.4%) were type B dissection.[14] Classical symptom of aortic dissection is usually sudden chest pain or back pain, but they are atypical and nonspecific symptoms of aortic dissections. In several reported case reports, presenting symptom of aortic dissection was acute abdominal pain,[15–17] but its incidence was rare (4.6%) by Upchurch et al.[18]\n\nTo be diagnosed with acute appendicitis and aortic dissection together at the same time is extremely rare. Looking for the literature, there was only 1 case report of missed diagnosis of acute standard type A aortic dissection presenting with abdominal pain in the setting of acute appendicitis.[19] In that case, the patient who underwent laparoscopic appendectomy distressed pulmonary edema in the PACU and he was diagnosed for acute aortic dissection by means of chest CT and transthoracic echocardiogram and because his vital sign were stable compared with our patient.\n\nUnlike previous descriptions, a new aortic dissection due to lengthy CPR is a possible scenario of this case.\n\nCardiac injury is a rare complication from standard CPR with only a few cases reported.[20–22] Because the patient had received CPR for a long time, it might have injured the preexisting dilated aorta or ingenerated new aortic dissection. However, isolated aortic rupture or vascular injury as a result of CPR is rare, and its reported incidence was 1%.[23] And in our patient, there was an injury including, bilateral rib fractures and ruptured pericardium, but this occurs during the late phase of CPR at autopsy finding. Therefore, CPR after operation was not the cause of the acute aortic dissection.\n\nIn conclusion, this case is a second unfortunate case of unexpected sudden cardiac death due to aortic rupture following laparoscopic appendectomy. And it is important to recognize the atypical symptoms of aortic dissection and maintain a broad differential diagnosis if patients complained abdominal pain.\n\nAuthor contributions\nConceptualization: Chunghee Joo, Joo-Won Min.\n\nData curation: Chunghee Joo, Joo-Won Min, Giyong Noh, Jaeho Seo.\n\nInvestigation: Joo-Won Min, Giyong Noh.\n\nWriting – original draft: Chunghee Joo, Joo-Won Min.\n\nWriting – review & editing: Chunghee Joo.\n\nAbbreviations: ACLS = advanced cardiac life support, A-fib = atrial fibrillation, BP = blood pressure, CPR = cardiopulmonary resuscitation, ECG = electrocardiogram, HR = heart rate, NIBP = noninvasive blood pressure, PACU = postanesthesia care unit, PR = pulse rate, SpO2 = peripheral oxygen saturation, TEE = transesophageal echocardiography, V-fib = ventricular fibrillation.\n\nThe authors report no conflicts of interest.\n==== Refs\nReferences\n[1] Melvinsdottir IH Lund SH Agnarsson BA \nThe incidence and mortality of acute thoracic aortic dissection: results from a whole nation study . Eur J Cardiothorac Surg \n2016 ;50 :1111–7 .27334108 \n[2] Chua M Ibrahim I Neo X \nAcute aortic dissection in the ED: risk factors and predictors for missed diagnosis . Am J Emerg Med \n2012 ;30 :1622–6 .22306397 \n[3] Shirakabe A Hata N Yokoyama S \nDiagnostic score to differentiate acute aortic dissection in the emergency room . Circ J \n2008 ;72 :986–90 .18503227 \n[4] Gawinecka J Schonrath F von Eckardstein A \nAcute aortic dissection: pathogenesis, risk factors and diagnosis . Swiss Med Wkly \n2017 ;147 :w14489.28871571 \n[5] Bondy CA \nAortic dissection in Turner syndrome . Curr Opin Cardiol \n2008 ;23 :519–26 .18839441 \n[6] Girdauskas E Disha K Borger MA \nRisk of proximal aortic dissection in patients with bicuspid aortic valve: how to address this controversy? \nInteract Cardiovasc Thorac Surg \n2014 ;18 :355–9 .24336701 \n[7] Tretter JT Jones TK McElhinney DB \nAortic wall injury related to endovascular therapy for aortic coarctation . Circ Cardiovasc Interv \n2015 ;8 :e002840.26291468 \n[8] Shah R Berzingi C Fan TH \nCocaine-induced acute aortic dissection . J Emerg Med \n2015 ;49 :e87–89 .25912879 \n[9] Gelpi G Pettinari M Lemma M \nShould pregnancy be considered a risk factor for aortic dissection? Two cases of acute aortic dissection following cesarean section in non-Marfan nor bicuspid aortic valve patients . J Cardiovasc Surg (Torino) \n2008 ;49 :389–91 .\n[10] Zalzstein E Hamilton R Zucker N \nAortic dissection in children and young adults: diagnosis, patients at risk, and outcomes . Cardiol Young \n2003 ;13 :341–4 .14694954 \n[11] Shi Y Zhu M Chang Y \nThe risk of Stanford type-A aortic dissection with different tear size and location: a numerical study . Biomed Eng Online \n2016 ;15 suppl 2 :128.28155679 \n[12] Totonchi Z Givtaj N Sakhaei M \nAnesthetic management in a patient with type A aortic dissection and superior vena cava syndrome . Res Cardiovasc Med \n2015 ;4 :e27424.26436073 \n[13] Kim CM Yu SC Hong SJ \nCardiac tamponade during transesophageal echocardiography in the patient of circumferential aortic dissection . J Korean Med Sci \n1997 ;12 :266–8 .9250927 \n[14] Li Y Li L Mu HS \nAortic dissection and sudden unexpected deaths: a retrospective study of 31 forensic autopsy cases . J Forensic Sci \n2015 ;60 :1206–11 .25771939 \n[15] Lin LF Tung JN \nAn uncommon cause of acute abdomen: aortic dissection complicated by superior mesenteric artery occlusion . J Dig Dis \n2009 ;10 :74–5 .19236551 \n[16] Besli GE Durakbasa CU Yildirim S \nAcute aortic dissection mimicking acute abdomen in a 14-year-old boy . Pediatr Int \n2015 ;57 :1169–71 .26420506 \n[17] Telci O Ozkok A Tekce G \nAortic dissection presenting with abdominal pain . Intern Med \n2012 ;51 :1439.22687860 \n[18] Upchurch GR JrNienaber C Fattori R \nAcute aortic dissection presenting with primarily abdominal pain: a rare manifestation of a deadly disease . Ann Vasc Surg \n2005 ;19 :367–73 .15735946 \n[19] Nwiloh J Chiegboka GT \nMissed diagnosis of acute Stanford Type A aortic dissection presenting with abdominal pain in the setting of acute appendicitis . Niger J Cardiovasc Thorac Surg \n2017 ;2 :21.\n[20] Bodily K Fischer RP \nAortic rupture and right ventricular rupture induced by closed chest cardiac massage . Minn Med \n1979 ;62 :225–7 .440243 \n[21] Fosse E Lindberg H \nLeft ventricular rupture following external chest compression . Acta Anaesthesiol Scand \n1996 ;40 :502–4 .8738698 \n[22] Baldwin JJ Edwards JE \nClinical conference: rupture of right ventricle complicating closed chest cardiac massage . Circulation \n1976 ;53 :562–4 .1248089 \n[23] Bode G Joachim H \n[Differential diagnosis of accident and resuscitation traumas] . Z Rechtsmed \n1987 ;98 :19–32 .3591013\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0025-7974",
"issue": "97(42)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000784:Aneurysm, Dissecting; D001019:Aortic Rupture; D001062:Appendectomy; D016887:Cardiopulmonary Resuscitation; D016757:Death, Sudden, Cardiac; D004837:Epinephrine; D006801:Humans; D010535:Laparoscopy; D008297:Male; D008875:Middle Aged; D014662:Vasoconstrictor Agents",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e12823",
"pmc": null,
"pmid": "30334980",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case report of unexpected sudden cardiac death due to aortic rupture following laparoscopic appendectomy.",
"title_normalized": "a case report of unexpected sudden cardiac death due to aortic rupture following laparoscopic appendectomy"
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"companynumb": "KR-IMPAX LABORATORIES, LLC-2018-IPXL-03615",
"fulfillexpeditecriteria": "1",
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"drug": [
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"activesubstance": {
"activesubstancename": "EPINEPHRINE"
},
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{
"abstract": "Pegylated asparaginase (PEG-Asp), a key component in the treatment of acute lymphoblastic leukemia (ALL), is associated with coagulopathy and an increased risk of venous thromboembolism (VTE). PEG-Asp also lowers antithrombin (AT) levels. Between April 2014 and October 2017, 75 adult ALL patients were identified to have received at least one dose of PEG-Asp. Patients were assigned to the AT group if a physician monitored AT levels with an intention to correct low AT levels (<60%). Incidence of VTE was not significantly different, with 17% (8/47) of the AT patients and 11% (3/28) of the control patients experiencing a VTE event (p = .52). The occurrence of coagulopathies was not significantly different. Within the AT group, 37 patients (78%) received AT, and median AT% prior to supplementation was 49%. The median number of AT doses received was 2 (range 0-12) and the mean cost of AT per patient was $11,847.",
"affiliations": "a Department of Pharmacy , City of Hope National Medical Center , Duarte , CA , USA.;a Department of Pharmacy , City of Hope National Medical Center , Duarte , CA , USA.;b Department of Hematology & Hematopoietic Cell Transplantation , City of Hope National Medical Center , Duarte , CA , USA.;a Department of Pharmacy , City of Hope National Medical Center , Duarte , CA , USA.;c Department of Information Sciences , City of Hope National Medical Center , Duarte , CA , USA.;b Department of Hematology & Hematopoietic Cell Transplantation , City of Hope National Medical Center , Duarte , CA , USA.",
"authors": "Chen|Jason|J|0000-0001-6523-7621;Ngo|Dat|D|;Aldoss|Ibrahim|I|;Shayani|Sepideh|S|;Tsai|Ni-Chun|NC|;Pullarkat|Vinod|V|",
"chemical_list": "D000970:Antineoplastic Agents; D000991:Antithrombins; D015415:Biomarkers; D011092:Polyethylene Glycols; C042705:pegaspargase; D001215:Asparaginase",
"country": "United States",
"delete": false,
"doi": "10.1080/10428194.2018.1519811",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "60(5)",
"journal": "Leukemia & lymphoma",
"keywords": "Antithrombin; acute lymphoblastic leukemia; asparaginase; venous thromboembolism",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D000991:Antithrombins; D001215:Asparaginase; D015415:Biomarkers; D001777:Blood Coagulation; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D012307:Risk Factors; D054556:Venous Thromboembolism; D055815:Young Adult",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "1187-1192",
"pmc": null,
"pmid": "30322332",
"pubdate": "2019-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Antithrombin supplementation did not impact the incidence of pegylated asparaginase-induced venous thromboembolism in adults with acute lymphoblastic leukemia.",
"title_normalized": "antithrombin supplementation did not impact the incidence of pegylated asparaginase induced venous thromboembolism in adults with acute lymphoblastic leukemia"
} | [
{
"companynumb": "US-SHIRE-US201842703",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEGASPARGASE"
},
"drugadditional": "3",
... |
{
"abstract": "A 46-year-old female was treated with a regimen of paclitaxel and carboplatin (TC therapy) as adjuvant chemotherapy for Stage IC ovarian adenocarcinoma. There was no severe toxicity except for grade 3 neutropenia during the first four cycles of TC therapy. However, she developed acute pancreatitis at 14 days after fifth cycle. TC therapy is commonly associated with adverse effects such as myelosuppression, hypersensitivity, alopecia, and peripheral neuropathy, but acute pancreatitis has rarely been reported. Ovarian cancer patients often present with nausea and abdominal pain, which are the same symptoms of pancreatitis. It is very important to keep in mind that acute pancreatitis may be concealed in these common symptoms of ovarian cancer during and after TC therapy. Because acute pancreatitis is fatal complication and quitting the drug usually leads to complete cure. The authors report an uncommon case in which TC therapy may have caused acute pancreatitis.",
"affiliations": null,
"authors": "Shintani|D|D|;Yoshida|H|H|;Imai|Y|Y|;Fujiwara|K|K|",
"chemical_list": "D016190:Carboplatin; D017239:Paclitaxel",
"country": "China",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0392-2936",
"issue": "37(2)",
"journal": "European journal of gynaecological oncology",
"keywords": null,
"medline_ta": "Eur J Gynaecol Oncol",
"mesh_terms": "D000208:Acute Disease; D000230:Adenocarcinoma; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D017024:Chemotherapy, Adjuvant; D005260:Female; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms; D017239:Paclitaxel; D010195:Pancreatitis; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8100357",
"other_id": null,
"pages": "286-7",
"pmc": null,
"pmid": "27172765",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute pancreatitis induced by paclitaxel and carboplatin therapy in an ovarian cancer patient.",
"title_normalized": "acute pancreatitis induced by paclitaxel and carboplatin therapy in an ovarian cancer patient"
} | [
{
"companynumb": "JP-PFIZER INC-2016265928",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
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{
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"activesubstancename": "APREPITANT"
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... |
{
"abstract": "BACKGROUND\nTreatment of pleural infection with instillation of sequential intrapleural tissue plasminogen activator (tPA) and human recombinant deoxyribonuclease (DNase) twice daily for a total of 6 doses has been shown to decrease surgical referral and improve radiographic imaging. This labor-intensive regimen was empirically chosen. Thus, it remains unclear whether the 2 drugs can be administered immediately one after the other (concurrent administration) instead of instilling them separately with a 1-hour to 2-hour interval in between (sequential administration). The aim of this study was to compare the efficacy and safety of sequential versus concurrent tPA/DNase therapy in patients with pleural infection.\n\n\nMETHODS\nThis was a prospective observational study. Consecutive patients with pleural infection who received concurrent and sequential tPA/DNase were included. The initiation and number of doses of tPA/DNase therapy were based on the amount of pleural fluid drainage, clinical response and radiographic findings.\n\n\nRESULTS\nA total of 38 patients with pleural infection received tPA/DNase treatment: 18 in the sequential group and 20 in the concurrent group. Treatment was successful in 77.7% in the sequential group and 75% in concurrent group (P=0.57). There was no statistically significant difference between the 2 treatment groups (sequential and concurrent) in median pleural fluid drainage (P=0.45), median volume of pleural effusion estimated on chest computed tomography scan (P=0.4) or median hemithorax occupied by effusion on chest radiography (P=0.83) following intrapleural therapy. One patient required a blood transfusion for gradual pleural blood loss in each treatment group. Pain needing escalation of analgesia affected 3 patients in each arm but none required cessation of therapy.\n\n\nCONCLUSIONS\nA simpler regimen of concurrent administration of intrapleural tPA/DNase as compared with sequential intrapleural therapy is safe, effective, and represents a viable option for the management of pleural infection.",
"affiliations": "Department of Thoracic Surgery and Interventional Pulmonology, Beth Israel Deaconess Medical Center, Harvard Medical School.;Division of Pulmonary, Allergy and Critical Care, Duke University School of Medicine, Durham, NC.;Department of Thoracic Surgery and Interventional Pulmonology, Beth Israel Deaconess Medical Center, Harvard Medical School.;Department of Internal Medicine, Boston University School of Medicine.;Department of Pulmonary and Critical Care Medicine, Massachusetts General Hospital Harvard Medical School, Boston, MA.;Section of Interventional Pulmonology, Clinica Alemana, Universidad Del Desarrollo, Santiago, Chile.;Department of Pulmonary and Critical Care Medicine, Massachusetts General Hospital Harvard Medical School, Boston, MA.;Department of Thoracic Surgery and Interventional Pulmonology, Beth Israel Deaconess Medical Center, Harvard Medical School.;Department of Pulmonary and Critical Care Medicine, Massachusetts General Hospital Harvard Medical School, Boston, MA.;Department of Thoracic Surgery and Interventional Pulmonology, Beth Israel Deaconess Medical Center, Harvard Medical School.;Department of Thoracic Surgery and Interventional Pulmonology, Beth Israel Deaconess Medical Center, Harvard Medical School.",
"authors": "Kheir|Fayez|F|;Cheng|George|G|;Rivera|Estefania|E|;Folch|Alejandro|A|;Folch|Erik|E|;Fernandez-Bussy|Sebastian|S|;Keyes|Colleen|C|;Parikh|Mihir|M|;Channick|Colleen|C|;Chee|Alex|A|;Majid|Adnan|A|",
"chemical_list": "D004338:Drug Combinations; D005343:Fibrinolytic Agents; D003851:Deoxyribonucleases; D010959:Tissue Plasminogen Activator",
"country": "United States",
"delete": false,
"doi": "10.1097/LBR.0000000000000461",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1948-8270",
"issue": "25(2)",
"journal": "Journal of bronchology & interventional pulmonology",
"keywords": null,
"medline_ta": "J Bronchology Interv Pulmonol",
"mesh_terms": "D000280:Administration, Inhalation; D000368:Aged; D000369:Aged, 80 and over; D003851:Deoxyribonucleases; D004334:Drug Administration Schedule; D004338:Drug Combinations; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D008297:Male; D008875:Middle Aged; D010995:Pleural Diseases; D011446:Prospective Studies; D010959:Tissue Plasminogen Activator; D016896:Treatment Outcome",
"nlm_unique_id": "101496866",
"other_id": null,
"pages": "125-131",
"pmc": null,
"pmid": "29346247",
"pubdate": "2018-04",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Concurrent Versus Sequential Intrapleural Instillation of Tissue Plasminogen Activator and Deoxyribonuclease for Pleural Infection.",
"title_normalized": "concurrent versus sequential intrapleural instillation of tissue plasminogen activator and deoxyribonuclease for pleural infection"
} | [
{
"companynumb": "IL-ROCHE-2079798",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "BACKGROUND\nChronic hepatitis C is a leading cause of severe liver disease. Protease inhibitors used to treat these patients are known to have many drug interactions, although there is limited data available between boceprevir and warfarin. This case report is the first in vivo drug interaction reported in the literature.\n\n\nMETHODS\nA 73-year-old African American man was diagnosed with hepatitis C in 2004, and had decided to not initiate therapy. In 2006, he was diagnosed with deep vein thrombosis and pulmonary embolism and was started on warfarin. His international normalized ratio had been stable on a dose of 13.75 mg to 20mg/week over a period of 6 years. A liver biopsy in 2012 revealed marked fibrosis, leading the patient to start hepatitis C treatment with peginterferon alfa-2a, ribavirin and boceprevir. Three weeks after starting boceprevir, his international normalized ratio became subtherapeutic at 1.2. Upon increasing the warfarin dose by 16%, his international normalized ratio remained at 1.2 6 days later. Two months after initiating boceprevir, he reached a therapeutic international normalized ratio. His warfarin dose had been increased by 75% from his dose prior to starting boceprevir, from 15 mg/week to 26.25mg/week. His hepatitis C treatment was discontinued at week 39 of the intended 48 weeks of treatment due to severe thrombocytopenia. Upon discontinuation of boceprevir, his warfarin dose was prophylactically decreased by 17%, which resulted in a subtherapeutic international normalized ratio of 1.48 1 week later. The warfarin dose was subsequently increased by 10% which resulted, 2 weeks later, in a therapeutic international normalized ratio of 2.8. Once stabilized, his new warfarin dose was 23.75 mg/week, 37% higher than his original maintenance dose of 15 mg/week prior to starting boceprevir.\n\n\nCONCLUSIONS\nThe co-administration of boceprevir and warfarin resulted in a subtherapeutic international normalized ratio. Upon starting boceprevir, his warfarin dose was increased by 75% over 2 months to achieve a therapeutic international normalized ratio. After discontinuing boceprevir, his maintenance dose of warfarin was 37% greater than his original dose. This is an original case report which demonstrates the significant effects of this drug interaction and the importance of monitoring international normalized ratio.",
"affiliations": "Clinical Pharmacist, Critical Care, VA New Jersey Healthcare System, East Orange, NJ, USA. atsiattalos@gmail.com.",
"authors": "Tsiattalos|Andrew S|AS|;Patel|Anita|A|",
"chemical_list": "D000925:Anticoagulants; D014859:Warfarin; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide; D011392:Proline",
"country": "England",
"delete": false,
"doi": "10.1186/1752-1947-8-433",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 303210.1186/1752-1947-8-433Case ReportWarfarin and boceprevir interaction causing subtherapeutic international normalized ratio: a case report Tsiattalos Andrew S atsiattalos@gmail.com Patel Anita anita.patel@va.gov Clinical Pharmacist, Critical Care, VA New Jersey Healthcare System, East Orange, NJ USA Clinic for Anticoagulation, Philadelphia VA Medical Center, Clinical Pharmacy Specialist, Philadelphia, PA USA 17 12 2014 2014 8 4333 6 2014 29 10 2014 © Tsiattalos and Patel; licensee BioMed Central. 2014This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Introduction\nChronic hepatitis C is a leading cause of severe liver disease. Protease inhibitors used to treat these patients are known to have many drug interactions, although there is limited data available between boceprevir and warfarin. This case report is the first in vivo drug interaction reported in the literature.\n\nCase presentation\nA 73-year-old African American man was diagnosed with hepatitis C in 2004, and had decided to not initiate therapy. In 2006, he was diagnosed with deep vein thrombosis and pulmonary embolism and was started on warfarin. His international normalized ratio had been stable on a dose of 13.75mg to 20mg/week over a period of 6 years. A liver biopsy in 2012 revealed marked fibrosis, leading the patient to start hepatitis C treatment with peginterferon alfa-2a, ribavirin and boceprevir. Three weeks after starting boceprevir, his international normalized ratio became subtherapeutic at 1.2. Upon increasing the warfarin dose by 16%, his international normalized ratio remained at 1.2 6 days later. Two months after initiating boceprevir, he reached a therapeutic international normalized ratio. His warfarin dose had been increased by 75% from his dose prior to starting boceprevir, from 15mg/week to 26.25mg/week. His hepatitis C treatment was discontinued at week 39 of the intended 48 weeks of treatment due to severe thrombocytopenia. Upon discontinuation of boceprevir, his warfarin dose was prophylactically decreased by 17%, which resulted in a subtherapeutic international normalized ratio of 1.48 1 week later. The warfarin dose was subsequently increased by 10% which resulted, 2 weeks later, in a therapeutic international normalized ratio of 2.8. Once stabilized, his new warfarin dose was 23.75mg/week, 37% higher than his original maintenance dose of 15mg/week prior to starting boceprevir.\n\nConclusions\nThe co-administration of boceprevir and warfarin resulted in a subtherapeutic international normalized ratio. Upon starting boceprevir, his warfarin dose was increased by 75% over 2 months to achieve a therapeutic international normalized ratio. After discontinuing boceprevir, his maintenance dose of warfarin was 37% greater than his original dose. This is an original case report which demonstrates the significant effects of this drug interaction and the importance of monitoring international normalized ratio.\n\nKeywords\nHCVHepatitis C virusHCCHepatocellular carcinomaINRInternational normalized ratioissue-copyright-statement© The Author(s) 2014\n==== Body\nIntroduction\nChronic hepatitis C virus (HCV) is an infection that affects approximately 2.7 to 3.9 million people in the USA with an estimated mortality rate of 12,000 deaths per year according to the US Centers for Disease Control and Prevention\n[1]. HCV is a progressive disease and a leading cause of cirrhosis, end-stage liver disease, hepatocellular carcinoma (HCC), and liver transplantation. In acute cases of HCV infection, 75 to 85% will become persistent, of which 20% will develop cirrhosis after approximately 20-30 years\n[1].\n\nThere are reportedly six different genotypes of HCV in the world, with genotype 1 being the most common in the USA\n[1]. With the advent of HCV protease inhibitors in addition to the standard regimen of pegylated interferon and ribavirin, sustained virological response rates in patients with chronic HCV genotype 1 have improved from nearly 40 to 50% to approximately 60 to 80%\n[2].\n\nBoceprevir is a protease inhibitor indicated for the treatment of chronic HCV genotype 1. The mechanism of action is a selective inhibition of the HCV NS3/4A serine protease\n[3]. Dosing is 800mg every 8 hours, and the duration of triple therapy with peginterferon and ribavirin is dependent on the patient’s response to treatment, which can vary between 24 to 48 weeks of treatment\n[2, 3]. There are many drug–drug interactions with boceprevir, although to the best of our knowledge there have not been any documented reports of an interaction with warfarin. Here we present a probable interaction between boceprevir and warfarin.\n\nCase presentation\nThe patient is a 73-year-old, 79kg African American man with a past medical history of diabetes, hypertension, and microscopic hematuria. He was diagnosed with HCV genotype 1a infection in 2004. At that time, he was not interested in being treated with interferon and ribavirin given poor response rates and profound adverse effects. In June 2006, he was diagnosed with deep vein thrombosis and pulmonary embolism, for which he was started on warfarin and referred to the anticoagulation clinic for drug monitoring. The duration of warfarin therapy was determined to be indefinite by his primary care team. His target international normalized ratio (INR) is 2 to 3, which had been stable on a warfarin dose of 13.75mg to 20mg/week, over a period of 6 years.\n\nHe underwent a transjugular liver biopsy in April 2012 due to possible cirrhosis and for guidance of possible HCV treatment. The biopsy showed mild fatty infiltration of his liver and received a grade of stage F4 with marked bridging fibrosis. At this time, he was interested in HCV treatment. It was decided that he would begin treatment with peginterferon alfa-2a weekly and ribavirin twice daily for the first 4 weeks. Boceprevir would be added at week five to be given every 8 hours for 44 weeks. He was informed that treatment could be discontinued if he did not demonstrate a positive and safe response to therapy. Counseling on medication adverse effects and required laboratory monitoring were reviewed with him.\n\nHCV therapy with peginterferon alfa-2a and ribavirin began on 1 August 2012. At this time, his INR was stable on a weekly warfarin dose of 15mg for the previous 4 months. Boceprevir was scheduled to start on 29 August, although he started it on 31 August. On the day prior to starting boceprevir, his INR was 2.5. Five days after starting boceprevir, his INR remained therapeutic at 2.5. On 19 September, almost 3 weeks later, his INR decreased to 1.2. He denied any missed doses of warfarin or changes in consumption of vitamin K foods. His warfarin dose was increased by 16% and 6 days later, on 25 September, his INR remained subtherapeutic at 1.2. However, the day before this visit, he had eaten a large portion of collard greens, a high vitamin K food. The anticoagulation provider believed this may have contributed to the low INR. Therefore, the provider instructed the patient to take a booster dose and remain on the same weekly dose of 17.5mg/week. At his following week’s appointment, his INR was still subtherapeutic at 1.3 without any vitamin K intake or missed doses of warfarin reported. He continued to come to the anticoagulation clinic every 7 to 10 days for INR monitoring and subsequent dose increases; see Table \n1 for more details. The majority of his INRs were checked on a point-of-care (POC) device. Periodically, his INRs were also checked in the laboratory through a venipuncture blood draw. On two occasions, both a POC and a laboratory INR were taken on the same day and results correlated very well with one another.Table 1 \nWarfarin dosing relative to initiation and discontinuation of boceprevir\n\n\nDate\tWeekly ribavirin dose (mg)\tWeekly warfarin dose (mg)\tPOC-INR, LAB-INR*\tImportant notes\t\n11/07/2012\t\t15\t1.9\t\t\n01/08/2012\t1200\t15\t2.8\tPEG-INF and RBV started\t\n15/08/2012\t1200\t15\t1.9\t\t\n30/08/2012\t1200\t15\t2.5\t\t\n31/08/2012\t1200\t-----\t-----\tBoceprevir started\t\n05/09/2012\t1200\t15\t2.5\t\t\n19/09/2012\t1000\t15\t1.2\t\t\n25/09/2012\t1000\t17.5\t1.2\tConsumed high vitamin K food on 24/09/12\t\n01/10/2012\t600\t17.5\t1.3\tEpoetin alfa and vitamin B12 added\t\n10/10/2012\t600\t20\t1.3\t\t\n16/10/2012\t200\t23.75\t1.48*\t\t\n24/10/2012\t200\t26.25\t2.2\t\t\n31/10/2012\t200\t26.25\t1.72*\t\t\n07/11/2012\t200\t27.5\t2.0\t\t\n14/11/2012\t200\t26.25\t1.8 1.82*\tPatient took less warfarin than instructed.\t\n27/11/2012\t400\t27.5\t2.24*\t\t\n12/12/2012\t600\t27.5\t2.0 2.02*\t\t\n26/12/2012\t800\t28.75\t2.1\t\t\n16/01/2013\t800\t28.75\t1.7\t\t\n30/01/2013\t800\t31.25\t2.0\tConsumed high vitamin K food twice in past week\t\n13/02/2013\t600\t31.25\t3.3\t\t\n27/02/2013\t200\t30\t2.4\tIron added\t\n13/03/2013\t400\t30\t2.9\tRecent suprapubic abscess; completing amoxicillin/clavulanate, which started 07/03/13\t\n27/03/2013\t200\t30\t2.2\t\t\n10/04/2013\t200\t30\t2.4\t\t\n24/04/2013\t400\t30\t3.6\tNew facial abscess, starting 10-day course clindamycin\t\n08/05/2013\t400\t28.75\t2.5\tHCV medications DISCONTINUED due to low platelets\t\n16/05/2013\t\t23.75\t1.48*\t\t\n29/05/2013\t\t26.25\t2.8\t\t\n12/06/2013\t\tUnknown\t2.2\tHospitalized at outside hospital for UTI and bacteremia from 04/06/–07/06/13, ciprofloxacin added\t\n19/06/2013\t\t25\t3.1\t\t\n26/06/2013\t\t25\t3.7\t\t\n10/07/2013\t\t25\t3.2\tPatient took more warfarin than instructed\t\n24/07/2013\t\t23.25\t2.4\t\t\n15/08/2013\t\t23.75\t2.4\t\t\n10/09/2013\t\t23.75\t3.0\t\t\n10/10/2013\t\t23.75\t2.5\t\t\n06/11/2013\t\t23.75\t3.2\t\t\n\nAbbreviations:\nHCV hepatitis C virus, INR international normalized ratio, LAB laboratory, PEG-INF peginterferon alfa-2a, POC point-of-care, RBV ribavirin, UTI urinary tract infection. *Laboratory INR.\n\n\n\nHe finally reached a therapeutic INR on 24 October 2012, almost 2 months after starting boceprevir. His original warfarin dose was increased by 75% from 15mg/week to 26.25mg/week. In the subsequent weeks, his INR trended downward due to an increased consumption of vitamin K foods, for which his dose was further increased to 30mg/week. At this point, his original dose had doubled in order to maintain a therapeutic INR. For approximately 2 months thereafter, he remained stable on 30mg/week of warfarin. On 24 April 2013, his INR increased to 3.6 while on 30mg/week of warfarin probably due to a decrease in vitamin K food intake. At this point, his warfarin dose was reduced and his INR returned to his therapeutic target by his next anticoagulation clinic visit on 8 May 2013.\n\nHis HCV treatment was discontinued prematurely at week 39 of the intended 48 weeks, due to severe thrombocytopenia. He had close follow-up in the Hepatitis C clinic including complete blood count (CBC) monitoring every 2 weeks. During his last week of therapy, his platelet count decreased from 129,000 to 12,000. Of note, his therapy had been complicated by multiple significant adverse events including severe anemia with a hemoglobin nadir of 7.8, and the development of two abscesses, a suprapubic and a facial abscess. The suprapubic abscess was treated with a course of amoxicillin/clavulanic acid and the facial abscess was treated with clindamycin. Amoxicillin/clavulanic acid may increase the risk of bleeding when given with warfarin but neither antibiotic should significantly affect the INR\n[4]. His anemia had been difficult to manage as he was unable to tolerate normal dosing ranges of ribavirin. Approximately 7 weeks after starting ribavirin, his dose was reduced to 1000mg/day. Two weeks later, it was reduced again to 600mg/day and eventually down to 200mg/day. He continued to have CBC monitoring by the Hepatitis C clinic with continual ribavirin adjustments. His maintenance dose fluctuated from 200 to 800mg/day, significantly less than his starting dose. Due to his anemia, he required epoetin alfa supplementation throughout his treatment course and was placed on ferrous sulfate and cyanocobalamin. Fortunately, his HCV viral load had been undetectable since week 10 of therapy. He did not experience any bleeding throughout his entire course. Given the severity of his adverse events along with his improved viral load, it was decided to discontinue HCV therapy as overall risks outweighed benefits.\n\nUpon discontinuing boceprevir, his warfarin dose was prophylactically decreased by 17% anticipating that his INR may start increasing. However, at his 1 week follow-up visit, this caused his INR to decrease to 1.48. The warfarin dose was subsequently increased by 10% which resulted, 2 weeks later, in a therapeutic INR of 2.8. Over the following several weeks, his warfarin dose was continuously adjusted. Upon stabilization of his INR, his warfarin dosing needs decreased to 23.75mg/week. This is a 21% reduction from his dose requirement of 26.25mg/week while on boceprevir, and a 37% increase from his original maintenance dose of 15mg/week prior to starting boceprevir.\n\nDiscussion\nBoceprevir is a HCV NS3/4A protease inhibitor approved by the US Food and Drug Administration in 2011, for the treatment of chronic HCV genotype 1 infection in combination with peginterferon and ribavirin\n[3]. Boceprevir is extensively metabolized in the liver, undergoing both oxidation and reduction\n[3, 4]. Despite a lack of in vivo interaction studies between boceprevir and warfarin, the manufacturer suggests warfarin concentrations may be decreased or elevated by boceprevir, and the INR should be monitored closely\n[3]. In vitro studies indicate boceprevir is primarily metabolized by hepatic aldo-keto reductase and partially metabolized by CYP3A4/5, and it is a potent inhibitor of CYP3A4/5\n[4, 5]. Other major CYP450 enzymes, such as CYP1A2, 2C8, 2C9, and 2C19, have not been found to be inhibited by boceprevir, although little to no induction has been seen\n[6].\n\nWarfarin, an oral anticoagulant, consists of a racemic mixture of active enantiomers. Elimination occurs almost exclusively by metabolism through CYP450 isozymes. The S-enantiomer, which is more potent than the R-enantiomer, is predominantly metabolized by the CYP2C9 isozyme, whereas the R-enantiomer is primarily metabolized by CYP1A2 and CYP3A4. Inhibitors and inducers of CYP2C9, CYP1A2, and CYP3A4 are likely to result in increased and decreased concentrations of warfarin, respectively\n[7]. Because boceprevir is a known inhibitor of CYP3A4, it is expected to increase concentrations of warfarin, although there is a possibility that boceprevir could also induce CYP1A2 and CYP2C9 which would result in reduced concentrations of warfarin\n[4–6].\n\nAlthough in vivo studies between boceprevir and warfarin have not been reported, other interactions between similar drugs have been documented. In one case report, a patient starting telaprevir, along with ribavirin and peginterferon alfa-2a, required an increase in the weekly warfarin dose by 50% above baseline to re-attain a target INR\n[8]. Similar to boceprevir, telaprevir has been shown in in vitro studies to inhibit the metabolism of other drugs, specifically substrates of CYP3A as well as P-glycoprotein\n[8]. In both case reports including the one currently being presented, telaprevir and boceprevir have demonstrated an inhibition in warfarin activity, contrary to findings from in vitro studies indicating such protease inhibitors act primarily as inhibitors of metabolism resulting in increased pharmacological activity\n[4, 8].\n\nAdministration of human immunodeficiency virus (HIV) protease inhibitors has shown interactions with warfarin similar to those described in this case report between boceprevir and warfarin. HIV protease inhibitors shown to inhibit the activity of warfarin include lopinavir/ritonavir, nelfinavir/ritonavir, and saquinavir\n[9]. Although these agents are primarily known as CYP450 inhibitors, as in the case of boceprevir, they have demonstrated the ability to decrease warfarin’s activity\n[9].\n\nAt each anticoagulation visit, our patient was assessed for multiple factors that could contribute to variations in INR. These factors included: changes in health, diet, alcohol use, tobacco use, renal function, and liver function. Adherence to prescribed warfarin regimen and changes to medications were also assessed at each visit. He denied any missed doses of warfarin at each of his anticoagulation clinic visits. If he had any potential contributing factors to fluctuations in INR other than the addition of boceprevir, it is documented under “Important notes” in Table \n1.\n\nHe was newly started with peginterferon alfa-2a and ribavirin 30 days prior to starting boceprevir. A literature review has shown evidence that interferon may potentiate the effect of warfarin, although this was not the effect seen in our case report\n[10]. In the case of warfarin and ribavirin, a drug interaction search using Micromedex® indicates there are no known drug interactions\n[11]. Upon literature review, a case report by Schulman reports an inhibition of warfarin activity by ribavirin\n[12]. In Schulman’s report, the interaction occurred immediately after initiation of the antiviral therapy\n[12]. However, in our case report, the INR did not decline until 7 weeks after ribavirin was started. Furthermore, the dose of ribavirin was changed frequently in the patient due to his anemia. Despite ongoing ribavirin dose changes, his INR did not change significantly; see Table \n1 for details. In another study, ribavirin has been found to induce factor VII messenger ribonucleic acid (mRNA) in patients with hemophilia resulting in a reduction in bleeding episodes\n[13]. Due to the lack of clear evidence of boceprevir inducing CYP450 enzymes responsible for warfarin metabolism, it is possible that the inhibition of warfarin activity may be due to other unknown causes, such as in the case of ribavirin inducing factor VII mRNA.\n\nApproximately 1 month after starting boceprevir, our patient was also started on epoetin alfa and cyanocobalamin which are not known to interact with warfarin and are unlikely causes for his decrease in INR\n[7, 11]. Of note, he did consume high vitamin K food beyond his normal intake, prior to his 25 September 2012 visit, at which his INR was subtherapeutic. High vitamin K-rich food can decrease the INR and therefore, may have been a contributing factor to his low INR\n[7]. However, his INR was also low at his 19 September, 1 and 10 October visits at which times he states he did not consume high vitamin K food. The Naranjo probability scale for this case report indicates a possible relationship between the interaction of boceprevir and warfarin\n[14]. Ruling out other contributing factors, it appears his trend of subtherapeutic INRs was due to the addition of boceprevir to his medication regimen.\n\nConclusions\nIn this article, we present a case of a patient whose INR decreased significantly after the start of boceprevir. His original warfarin dose was increased by 75% before reaching therapeutic INR 2 months after starting boceprevir. From our literature search, this is the first documented case report regarding this drug interaction. Anticoagulation providers should be aware of this possible interaction and how it can have significant effects on INR and, subsequently, warfarin dosing. Close monitoring is recommended when boceprevir is added to a medication regimen for a patient also on warfarin.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nAT analyzed and interpreted the literature for pertinent drug interactions and was a major contributor in writing the manuscript. AP was directly involved in the management of the patient’s ambulatory care and was a major contributor in writing the manuscript. Both authors read and approve the final manuscript.\n==== Refs\nReferences\n1. Centers for Disease Control and Prevention: Hepatitis C information for health professionals.http://www.cdc.gov/hepatitis/HCV (accessed 5 June 2013)\n2. Ghany MG Nelson DR Strader DB Thomas DL Seeff LB An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases Hepatology 2011 54 1433 1444 10.1002/hep.24641 21898493 \n3. Victrelis (Boceprevir) Package Insert. Whitehouse Station, NJ: Merck & Company Incorporated; 2011.\n4. Rangnekar A Fontana R Managing drug-drug interactions with boceprevir and telaprevir Clin Liver Dis 2012 1 2 36 40 10.1002/cld.10 \n5. Chu X Cai X Cui D Tang C Ghosai A Chan G Green MD Kuo Y Liang Y Maciolek CM Palamanda J Evers R Prueksaritanont T In vitro assessment of drug-drug interaction potential of boceprevir associated with drug metabolizing enzymes and transporters Drug Metab Dispos 2013 41 3 668 681 10.1124/dmd.112.049668 23293300 \n6. Kiser JJ Burton JR Anderson PL Everson GT Review and management of drug interactions with boceprevir and telaprevir Hepatology 2012 55 5 1620 1628 10.1002/hep.25653 22331658 \n7. Coumadin (Warfarin) Package Insert. Princeton, NJ: Bristol-Myers Squibb; 2011.\n8. Gatti D Cha A Apparent interaction between telaprevir and warfarin in a patient with chronic hepatitis C viral infection Am J Health-Syst Pharm 2012 69 2062 2065 10.2146/ajhp120220 23172264 \n9. Liedtke M Rathbun R Drug interactions with antiretrovirals and warfarin Expert Opin Drug Saf 2010 9 2 215 223 10.1517/14740330903493458 20095918 \n10. Adachi Y Yokoyama Y Nanno T Yamamoto T Potentiation of warfarin by interferon BMJ 1995 311 292 10.1136/bmj.311.7000.292a 7543311 \n11. Warfarin: Drug Interactions. Micromedex 2.0. Greenwood Village, CO: Truven Health Analytics, Inc; http://www.micromedexsolutions.com. (accessed 14 October 2014)\n12. Schulman S Inhibition of warfarin activity by ribavirin Ann Pharmacother 2002 36 72 74 10.1345/aph.1A181 11816263 \n13. Yamamoto K Honda T Matsushita T Kojima T Takamatsu J Anti-HCV agent, ribavirin, elevates the activity of clotting factor VII in patients with hemophilia: a possible mechanism of decreased events of bleeding in patients with hemophilia by ribavirin J Thromb Haemost 2006 4 469 470 10.1111/j.1538-7836.2006.01761.x 16420581 \n14. Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA Janecek E Domecq C Greenblatt DJ A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 245 10.1038/clpt.1981.154 7249508\n\n",
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"medline_ta": "J Med Case Rep",
"mesh_terms": "D000368:Aged; D000925:Anticoagulants; D004347:Drug Interactions; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D011392:Proline; D014859:Warfarin",
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"title": "Warfarin and boceprevir interaction causing subtherapeutic international normalized ratio: a case report.",
"title_normalized": "warfarin and boceprevir interaction causing subtherapeutic international normalized ratio a case report"
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"abstract": "Patients with locally advanced cervical cancer (LACC) are at risk of para-aortic lymph node (PALN) metastasis. Pelvic concurrent chemoradiotherapy, the current standard treatment for LACC, has a PALN failure rate of 9% according to the Radiation Therapy Oncology Group Trial 90-01, suggesting that it may not completely eliminate all microscopic tumors in the PALNs. To minimize the toxicities associated with conventional prophylactic extended-field radiotherapy, our institute use prophylactic semiextended field radiotherapy that includes only the PALNs below the level of the renal vessels. Use of intensity-modulated radiotherapy (IMRT) is another means of reducing the incidence of toxicity. This study evaluated the safety and efficacy of prophylactic semiextended field IMRT (SEF-IMRT) and concurrent cisplatin chemotherapy in patients with LACC.We retrospectively assessed survival and toxicity in 76 patients with stage IB2-IVA cervical cancer and negative PALNs who received prophylactic SEF-IMRT and concurrent weekly cisplatin (40 mg/m) between 2004 and 2013. The region targeted by SEF-IMRT included the PALNs below the level of the renal vessels, and the prescribed dose was 50.4 Gy in 28 fractions. Brachytherapy was administered at a dose of 30 Gy in 6 fractions. Survival outcomes were calculated by using the Kaplan-Meier method, and acute and late toxicities were scored according to the Common Terminology Criteria for Adverse Events, version 3.0.All patients completed the planned SEF-IMRT, as well as brachytherapy. Acute grade ≥3 gastrointestinal, genitourinary, and hematologic toxicities were observed in 2, 0, and 41 patients, respectively. The median follow-up time after SEF-IMRT was 55 (range, 11-124) months. Eight patients developed out-field distant recurrences without PALN failure, and 1 patient experienced out-field PALN failure with simultaneous distant metastasis. No patients had late genitourinary toxicities, and 3 patients had late grade 3 gastrointestinal toxicities. The 5-year overall survival, disease-free survival, local failure-free survival, regional failure-free survival, PALN failure-free survival, and distant metastasis-free survival rates were 85.0%, 84.4%, 96.0%, 97.3%, 98.6%, and 88.4%, respectively.For patients with LACC, prophylactic PALN irradiation up to the level of the renal vessels reduced PALN recurrence and resulted in favorable outcomes with few severe toxicities.",
"affiliations": "Department of Radiation Oncology, MacKay Memorial Hospital Department of Medicine, MacKay Medical College, Taipei Department of Radiation Oncology, Changhua Christian Hospital, Changhua Department of Medical Research, MacKay Memorial Hospital MacKay Junior College of Medicine, Nursing and Management Department of Obstetrics and Gynecology Department of Radiology, Mackay Memorial Hospital, Taipei, Taiwan.",
"authors": "Lee|Jie|J|;Lin|Jhen-Bin|JB|;Sun|Fang-Ju|FJ|;Chen|Yu-Jen|YJ|;Chang|Chih-Long|CL|;Jan|Ya-Ting|YT|;Wu|Meng-Hao|MH|",
"chemical_list": "D000970:Antineoplastic Agents; D002945:Cisplatin",
"country": "United States",
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"doi": "10.1097/MD.0000000000006158",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 28272204MD-D-16-0657910.1097/MD.0000000000006158061585700Research ArticleObservational StudySafety and efficacy of semiextended field intensity-modulated radiation therapy and concurrent cisplatin in locally advanced cervical cancer patients An observational study of 10-year experienceLee Jie MDab∗Lin Jhen-Bin MDcSun Fang-Ju MSdeChen Yu-Jen MD, PhDabChang Chih-Long MD, PhDbfJan Ya-Ting MDgWu Meng-Hao MDab∗Staege. Martin S. a Department of Radiation Oncology, MacKay Memorial Hospitalb Department of Medicine, MacKay Medical College, Taipeic Department of Radiation Oncology, Changhua Christian Hospital, Changhuad Department of Medical Research, MacKay Memorial Hospitale MacKay Junior College of Medicine, Nursing and Managementf Department of Obstetrics and Gynecologyg Department of Radiology, Mackay Memorial Hospital, Taipei, Taiwan.∗ Correspondence: Meng-Hao Wu and Jie Lee, Department of Radiation Oncology, MacKay Memorial Hospital, Taipei, Taiwan (e-mails: radionc1@gmail.com; sinus125125@gmail.com).3 2017 10 3 2017 96 10 e615831 10 2016 23 1 2017 26 1 2017 Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc.2017This is an open access article distributed under the Creative Commons Attribution-No Derivatives 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\nPatients with locally advanced cervical cancer (LACC) are at risk of para-aortic lymph node (PALN) metastasis. Pelvic concurrent chemoradiotherapy, the current standard treatment for LACC, has a PALN failure rate of 9% according to the Radiation Therapy Oncology Group Trial 90–01, suggesting that it may not completely eliminate all microscopic tumors in the PALNs. To minimize the toxicities associated with conventional prophylactic extended-field radiotherapy, our institute use prophylactic semiextended field radiotherapy that includes only the PALNs below the level of the renal vessels. Use of intensity-modulated radiotherapy (IMRT) is another means of reducing the incidence of toxicity. This study evaluated the safety and efficacy of prophylactic semiextended field IMRT (SEF-IMRT) and concurrent cisplatin chemotherapy in patients with LACC.\n\nWe retrospectively assessed survival and toxicity in 76 patients with stage IB2–IVA cervical cancer and negative PALNs who received prophylactic SEF-IMRT and concurrent weekly cisplatin (40 mg/m2) between 2004 and 2013. The region targeted by SEF-IMRT included the PALNs below the level of the renal vessels, and the prescribed dose was 50.4 Gy in 28 fractions. Brachytherapy was administered at a dose of 30 Gy in 6 fractions. Survival outcomes were calculated by using the Kaplan–Meier method, and acute and late toxicities were scored according to the Common Terminology Criteria for Adverse Events, version 3.0.\n\nAll patients completed the planned SEF-IMRT, as well as brachytherapy. Acute grade ≥3 gastrointestinal, genitourinary, and hematologic toxicities were observed in 2, 0, and 41 patients, respectively. The median follow-up time after SEF-IMRT was 55 (range, 11–124) months. Eight patients developed out-field distant recurrences without PALN failure, and 1 patient experienced out-field PALN failure with simultaneous distant metastasis. No patients had late genitourinary toxicities, and 3 patients had late grade 3 gastrointestinal toxicities. The 5-year overall survival, disease-free survival, local failure-free survival, regional failure-free survival, PALN failure-free survival, and distant metastasis-free survival rates were 85.0%, 84.4%, 96.0%, 97.3%, 98.6%, and 88.4%, respectively.\n\nFor patients with LACC, prophylactic PALN irradiation up to the level of the renal vessels reduced PALN recurrence and resulted in favorable outcomes with few severe toxicities.\n\nKeywords\ncervical cancerextended field radiotherapyintensity-modulated radiation therapyOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nLocally advanced cervical cancer is commonly treated via definitive chemoradiotherapy (CCRT) consisting of pelvic radiotherapy and cisplatin. The incidence of para-aortic lymph node (PALN) metastasis in cervical cancer is 10% to 25%,[1–3] and the pattern of lymphatic spread in cervical cancer—from the low pelvis to the high pelvic lymph nodes (PLNs) and the PALNs—appears orderly.[4,5] In the Radiation Therapy Oncology Group (RTOG) trial 90–01, pelvic CCRT had better 8-year overall survival (OS) and disease-free survival (DFS) rates than did extended field radiotherapy (EFRT) alone.[6] However, the 8-year PALN failure rate was 9% in the pelvic CCRT arm compared with only 4% in the EFRT arm. This finding suggests that pelvic CCRT does not completely eradicate all microscopic tumors in the PALNs, particularly in patients with risk factors. Risk factors for PALN failure after pelvic radiotherapy include International Federation of Gynecology and Obstetrics (FIGO) stage III–IVA, positive PLNs, and a high squamous cell carcinoma antigen (SCC-Ag) level.[7–9]\n\nThe RTOG 79–20 trial demonstrated that prophylactic EFRT improved survival and decreased the number of distant metastases compared with pelvic radiotherapy.[10] However, there were more late major gastrointestinal complications in the EFRT arm (8%) than in the pelvic radiotherapy arm (4%), which approached statistical significance (P = 0.06). In the study by Haie et al,[11] severe gastrointestinal complications were significantly more frequent in patients receiving EFRT than in those receiving pelvic radiotherapy, and EFRT did not reduce the number of overall distant metastases or improve local control or survival with no evidence of disease. In addition, the patients in trials in which EFRT was delivered via a conventional technique often experienced severe complications including gastrointestinal toxicities.[10–17] Therefore, the use of prophylactic EFRT in patients without evidence of PALN involvement appears controversial.\n\nTo reduce toxicity, our institutions used semiextended field radiotherapy (SEFRT) that excluded the upper parts of the PALN chain in patients with LACC. Intensity-modulated radiotherapy (IMRT) is another means of decreasing toxicity. The aim of this study was to review our results assessing acute and late toxicity and disease outcomes in patients with LACC treated via SEFRT using the IMRT technique (SEF-IMRT).\n\n2 Methods and materials\n2.1 Patient characteristics\nThis retrospective study was approved by our institutional review board. Patients with biopsy-confirmed FIGO stage IB–IVA cervical cancers treated via definitive CCRT with a curative aim at our institute between October 2004 and May 2014 were retrospectively reviewed. Patients were included in the study if they had received SEF-IMRT and regular follow-ups, were not pregnant at the time of diagnosis, and had complete medical records. The exclusion criteria were as follows: (a) pathologically proven small cell carcinoma because it has a more aggressive clinical course than cervical squamous cell carcinoma or adenocarcinoma; (b) history of previous malignancy; (c) Eastern Cooperative Oncology Group score ≥2; (d) evidence of PALN metastasis; and (e) previous surgery, chemotherapy, or radiotherapy. The pretreatment workup included comprehensive documentation of the patient's medical history, a gynecologic pelvic examination, cystoscopy, proctoscopy, chest x-ray or computed tomography (CT), abdominopelvic CT, a complete blood cell count, and blood chemistry profiles. Magnetic resonance imaging and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) were not routinely used in the workup. Clinical stage was determined by consensus of the gynecologic oncologist, radiologist, and radiation oncologist in a multidisciplinary conference. The lymph nodes were classified as metastatic based on the radiographic findings (>1.0 cm in the short axis dimension) at the time of diagnosis or the radiologist's and oncologist's interpretation of the appearance of the nodes. None of the patients had their PALNs assessed surgically.\n\n2.2 Radiotherapy\nAll patients underwent CT simulation in the supine position and were immobilized by using alpha cradles. Radiopaque markers were placed on the gross cervical cancer during a gynecologic examination before CT simulation. Planning CT images with a maximum slice thickness of 3 mm were acquired throughout the entire abdomen and pelvis. The gross tumor volume consisted of the primary tumor and regional lymph nodes, as defined by the locations of the radiopaque markers on the primary tumor and CT scans. The clinical target volume (CTV) included the gross disease, cervix, parametrium, uterus, superior third to half of the vagina, presacral region, regional lymph nodes (common, internal, and external iliac lymph nodes), and para-aortic nodes to the level of the renal vessels. A planning target volume (PTV) with a uniform 0.5- to 0.7-cm margin was added to the CTV.\n\nAll patients received IMRT consisting of 6 to 9 coplanar fields using 6- or 10-MV photons (Eclipse Treatment Planning System; Varian Medical Systems Inc., Palo Alto, CA). We prescribed a radiation dose of 50.4 Gy in 28 fractions for SEF-IMRT. The target planning constraints were as follows: (a) >95% of the PTV receives >95% of the prescription dose, (b) <1% of the PTV receives <93% of the prescription dose, (c) <10% of the PTV receives >110% of the prescription dose, and (d) the maximum dose to the PTV is <115% of the prescription dose. The normal tissue planning constraints were as follows: (a) <50% of the volume of the rectum receives >45 Gy, (b) <50% of the volume of the bladder receives >45 Gy, (c) <40% of the volume of the non-rectal bowel receives >30 Gy, (d) the spinal cord receives a maximum dose <45 Gy, and (e) the kidney receives a mean dose <16 Gy. No special constraints were applied to the adjacent bone or bone marrow. Following SEF-IMRT, the dose to the involved pelvic lymph nodes was boosted to 59.4 Gy via the IMRT technique.\n\nAfter adequate tumor regression, high-dose-rate intracavitary brachytherapy was performed using an iridium-192 remote after-loading technique, either concurrently with SEF-IMRT once per week or twice per week followed by an SEF-IMRT course. The standard prescribed dose for each brachytherapy was 5.0 Gy to point A for 6 sessions. We considered reducing the number of fractions per session (n = 5) in patients with grade ≥3 gastrointestinal or genitourinary toxicities or who were >70 years. The total prescribed point A doses (external beam radiotherapy + brachytherapy) of a radiobiological equivalent dose in 2-Gy fractions ranged from 80.8 to 87.1 Gy.\n\n2.3 Chemotherapy\nChemotherapy consisted of weekly cisplatin (40 mg/m2; maximum, 70 mg) delivered concurrently with external beam radiotherapy. Chemotherapy was administered as a half dose if the white blood cell count was < 2.0×109/L, the absolute neutrophil count (ANC) was between 1.0 × 109 and 1.5 × 109/L, or the platelet count was between 5.0 × 107 and 7.5 × 107/L. Chemotherapy was omitted if the ANC was <1.0 × 109/L, the platelet count was <5.0 × 107/L, or creatinine clearance was <50 mL/min. None of the patients underwent platelet transfusions or granulocyte/monocyte colony-stimulating factor treatments.\n\n2.4 Follow-up\nDuring CCRT, the patients received weekly clinical assessments, pelvic examinations, complete blood counts, and renal and liver function tests. After completion of CCRT, a radiation oncologist and a gynecologic oncologist evaluated the patients every 3 months for the first 2 years, and every 6 months thereafter. The 3-month evaluations consisted of a physical and pelvic examination, a Pap smear, and a tumor marker (SCC-Ag) measurement. For the first 2 years, the 6-month evaluations consisted of a blood count and renal and liver function tests. A radiographic examination was carried out every 3 to 6 months. Routine urine and stool examinations were performed every 6 to 12 months to assess the possibility of late complications. Toxicity was assessed at the time of each evaluation according to the Common Terminology Criteria for Adverse Events, version 3.0.\n\n2.5 Statistical analysis\nAll statistical analyses were conducted by using Statistical Package for the Social Sciences for Windows software, version 21.0 (IBM, Armonk, NY). Patterns of failure, OS, and DFS were evaluated. The sites of failure were recorded as local, regional, PALN, or distant. In-field failure in SEF-IMRT was defined as disease in the pelvic area and the PALNs within the treatment field, and out-field failure was defined as disease outside the treatment field, especially in the PALNs located above the level of the renal vessels. Survival was defined from the date of SEF-IMRT initiation to the date of the last follow-up or death. Time to recurrence was measured from the date of SEF-IMRT initiation to the date of the first failure. Survival data were analyzed by using the Kaplan–Meier method. A univariate analysis was performed using the log-rank test to identify parameters associated with treatment outcome, and a multivariate analysis was performed using a Cox regression model. A P value ≤0.05 was considered statistically significant.\n\n3 Results\n3.1 Patient compliance and treatment-related toxicities\nA total of 90 patients fulfilled our inclusion criteria. After exclusion of patients with a pathologically proven small cell carcinoma (n = 5), a previous history of malignancy (n = 5), or an Eastern Cooperative Oncology Group score ≥2 (n = 4), 76 remained eligible for analysis. Patient and tumor characteristics are summarized in Table 1. All patients completed the planned SEF-IMRT and brachytherapy. The acute and late toxicities in the patients are summarized in Table 2. Acute gastrointestinal and genitourinary toxicities of grade ≥3 were observed in 2 and 0 patients, respectively. Forty-one (53.9%) patients developed grade ≥3 hematologic toxicities (n = 31, leukopenia; n = 5, thrombocytopenia; n = 5, anemia).\n\nTable 1 Characteristics of patients and tumors.\n\nTable 2 Acute and late toxicity.\n\nThe total length of the treatment including brachytherapy ranged from 48 to 79 (median, 62) days. The median number concurrent cisplatin courses was 5 (range, 1–6). Chemotherapy was omitted because of toxic effects (10 patients), refusal to continue (4 patients), or diminished performance status (3 patients). The chemotherapy dose was reduced in 18 (23%) patients during the treatment course owing to hematologic toxicity. Six patients had ≥2-day breaks in treatments lasting >9 weeks because of acute toxicities (n = 4, diarrhea; n = 2, urinary tract infection). Treatment breaks occurred mainly between 6 and 9 weeks.\n\nAfter a median follow-up duration of 55 (range, 11–124) months, 3 patients had late grade 3 gastrointestinal complications, and no patients had a late grade 3 genitourinary toxicity. Among the former, 1 patient had a small bowel perforation at 56.9 months, 1 had a stricture of the rectosigmoid junction at 41.8 months, and 1 had proctitis at 8.9 months after completion of CCRT; all complications required surgical intervention.\n\n3.2 Treatment outcomes\nThe median follow-up time for surviving patients was 55 (range, 11–124) months. The 5-year OS, DFS, local failure-free survival, regional failure-free survival, PALN failure-free survival, and distant metastasis-free survival (DMFS) rates were 85.0%, 84.4%, 96.0%, 97.3%, 98.6%, and 88.4%, respectively. The Kaplan–Meier plots of the 5-year OS and DFS rates are shown in Fig. 1. During the follow-up period, 65 (85.5%) patients had no recurrence, and 11 (14.5%) patients had treatment failure at the time of analysis as follows: 3 (3.9%), in-field local recurrence; 2 (2.6%), in-field regional recurrence; and 9 (11.8%), out-field distant metastasis (Table 3). Only 1 patient experienced out-field PALN failure, and this patient also had simultaneous distant metastasis (mediastinal and left supraclavicular lymph nodes). No patients had in-field PALN failure.\n\nFigure 1 Kaplan–Meier survival curves for the 76 patients analyzed in this study. (A) Overall survival. (B) Disease-free survival.\n\nTable 3 Failure patterns of patients with cervical cancer receiving SEF-IMRT.\n\nThe results of the univariate analysis are shown in Table 4. The risk factors associated with death and disease relapse were examined via multivariate analysis (Table 5). The independent risk factors for disease relapse were stage III–IVA disease (P = 0.011; hazard ratio, 5.9; 95% confidence interval, 1.5–23.5). The 5-year DFS rate differed significantly between patients with stage I–II versus stage III–IV disease (92.1% vs 57.9%, respectively; P = 0.003).\n\nTable 4 Univariate analysis of prognostic factors on overall survival, disease-free survival, distant metastasis free survival and para-aortic metastasis free survival.\n\nTable 5 Multivariate analysis of prognostic factors on overall survival and disease-free survival.\n\n4 Discussion\nTo our knowledge, this is the first study reporting the safety and outcomes of SEF-IMRT for patients with LACC. This retrospective study found that patients receiving SEF-IMRT along with weekly cisplatin had favorable treatment compliance and tolerable toxicities. The outcomes were also favorable, and the main failure sites of SEF-IMRT were distant.\n\nThe lymphatic spread of cervical cancer is contiguous. The disease initially involves the lower PLNs, and then progresses to the upper PLNs followed by the PALNs.[5] Patients with LACC are at risk of PALN metastasis, and the current standard treatment for these patients is pelvic CCRT. The reported rate of PALN failure for pelvic CCRT in the RTOG 90–01 trial was 9% (95% confidence interval, 4–13%),[6] which suggests that pelvic CCRT might not completely eliminate all microscopic tumors in the PALNs, particularly in high-risk subjects.[6,8,9] Beadle et al[18] described detailed patterns of regional failure; the most common site of regional recurrence was marginal, usually just above the superior boundary of the pelvic field. Hence, modification of the treatment field might improve treatment outcomes without significantly increasing the occurrence of severe toxicities.\n\nPrevious studies of EFRT using conventional techniques reported conflicting data for OS and incidence of distant metastases and significant increases in the incidence of severe toxicities.[10,11] Kuku et al[19] found that EFRT was a significant predictor of severity and chronicity of ongoing disease in patients who developed radiation-induced bowel injuries after treatment for cervical cancer. Given the severe toxicities, the use of EFRT in patients without evidence of PALN involvement remains controversial. Based on the results of this study, we suggest that modifying the radiation field to exclude the PALNs above the level of the renal vessels could reduce toxicity without compromising treatment outcomes.\n\nIMRT is a promising modality for reducing toxicity and improving the therapeutic ratio. Jensen et al[20] studied the effects of IMRT on 21 patients, 14 and 20 of whom had positive PALNs and PLNs, respectively. In that study, the reported probabilities of acute grade ≥3 hematologic, gastrointestinal, and genitourinary toxicities were 57.1%, 19.0%, and 0%, respectively, and the 18-month cumulative incidence of any late grade ≥3 toxicity was 4.8%. In a prospective study evaluating extended field IMRT with concurrent cisplatin in 32 patients with stage IB2–IIIB cervical cancer with positive PLNs and negative PALNs, acute grade ≥3 gastrointestinal, genitourinary, and hematologic toxicities occurred in 2 (6.3%), 1 (3.1%), and 18 (56.3%) patients, respectively.[21] One (3.1%) patient had a late grade 3 gastrointestinal complication, and 1 (3.1%) experienced genitourinary toxicity. The 3-year actuarial OS, DFS, and DMFS rates were 87%, 82%, and 79%, respectively. These findings show that EF-IMRT is a safe and effective modality. When the radiation field of SEF-IMRT excludes the upper part PALNs, as done in the above-mentioned studies, less toxicity with comparable treatment outcomes can be expected.\n\nProphylactic SEFRT using a conventional technique had favorable PALN control and survival outcomes in a retrospective study by Choi et al[22] of patients with cervical cancer and PALN metastasis. In that study, a prescribed dose of 45 Gy in 25 fractions was delivered by using a 4-field (anterior–posterior, posterior–anterior, and 2 lateral fields) box technique. Seventy-seven (74.8%) patients received SEFRT with concomitant chemotherapy and 26 (25.2%) patients received SEFRT alone. The 5-year OS and recurrence-free survival rates were 82% and 76%, respectively, and the rate of late grade 3 gastrointestinal complications was 2.9%. Comparisons between the study by Choi et al[22] and our study are not straightforward because some patients in our study were PLN-negative and all patients received IMRT at a prescribed dose of 50.4 Gy in 28 fractions and concurrent weekly cisplatin.\n\nIn our study, the 5-year OS, DFS, local failure-free survival, regional failure-free survival, PALN failure-free survival, and DMFS rates were 85.0%, 84.4%, 96.0%, 97.3%, 98.6%, and 88.4%, respectively. The patterns of failure were similar to those in previous EFRT and SEFRT studies, with most distant failures.[20–22] No patients had late genitourinary complications, and 3 (3.9%) had late grade 3 gastrointestinal toxicities. Although PLN status has been frequently reported as a major risk factor for death and disease relapse in patients with LACC,[1,7–9,23] our study does not support this premise. If the patients in our study were stratified according to risk of LACC, as done by Liang et al,[9] the 5-year PALN failure-free survival rates would be 100% and 97.4% (P = 0.34), and the 5-year DMFS rates would be 100% and 87.2% (P = 0.01), for low and high risk, respectively. The results of our study show that SEF-IMRT with concurrent cisplatin eliminates microscopic tumors in the lower PALNs and provides favorable treatment outcomes with acceptable acute and late toxicities. The predominant failures are distant, and thus studies investigating the effectiveness of intensified systemic therapy are warranted.\n\nThe present study had some limitations. This study excluded patients with small cell carcinoma of the uterine cervix because it has a more aggressive clinical course and the number of patients was low. Hence, the impact of the radiation field on treatment in patients with small cell carcinoma could not be elaborated in the present study and needs further investigation.\n\nThe major weakness of this study is that lymph node status was mainly evaluated via CT rather than FDG-PET, which is a useful tool for assessing metastatic nodes.[23,24] However, pretreatment FDG-PET performed to detect tumor-containing lymph nodes cannot exclude the existence of micrometastases in the PALNs because of the limited resolution of the gamma camera.[25,26] In addition, a prospective study reported that detection of PALNs via FDG-PET had no survival benefits, although FDG-PET decreased the need for extended-field CCRT.[27,28] In that study, the PALN failure rate for patients (n = 63) receiving pelvic CCRT but not pretreatment FDG-PET was 15.9% compared with 1.3% in the present study. FDG-PET might have revealed PLNs and PALNs in some of the patients in our study, and the treatment outcomes and policies might have differed if pretreatment FDG-PET had been performed in all patients. Thus, future SEF-IMRT studies evaluating the treatment outcomes of LACC patients with PLNs detected via FDG-PET are needed.\n\nIn conclusion, our results suggest that prophylactic SEF-IMRT reduces PALN recurrence and provides favorable treatment outcomes with acceptable acute and late toxicities in patients with LACC without PALN involvement, and is hence the recommended treatment for patients at risk of PALN metastasis.\n\nAbbreviations: ANC = absolute neutrophil count, CCRT = concurrent chemoradiotherapy, CT = computed tomography, CTV = clinical target volume, DFS = disease-free survival, DMFS = distant metastasis-free survival, EFRT = extended field radiotherapy, FDG-PET = 18F-fluorodeoxyglucose positron emission tomography, FIGO = International Federation of Gynecology and Obstetrics, IMRT = intensity-modulated radiotherapy, LACC = locally advanced cervical cancer, OS = overall survival, PALN = para-aortic lymph node, PLN = pelvic lymph nodes, PTV = planning target volume, RTOG = Radiation Therapy Oncology Group, SCC-Ag = squamous cell carcinoma antigen, SEF-IMRT = semiextended field intensity-modulated radiotherapy, SEFRT = semiextended field radiotherapy.\n\nJL conceived and designed the study, collected, analyzed, and interpreted the data, prepared the draft, and gave final approval of the version to be submitted. JBL and FJS collected the data, undertook data analysis and interpretation, and performed the statistical analysis. YJC, CLC, and YTJ also performed the statistical analysis and carried out clinical revision of the data. MHW critically reviewed the intellectual content and gave final approval of the version to be submitted. All authors read and approved the final manuscript.\n\nThe authors have no conflicts of interest to disclose\n==== Refs\nReferences\n[1] Gouy S Morice P Narducci F \nNodal-staging surgery for locally advanced cervical cancer in the era of PET . Lancet Oncol \n2012 ;13 :e212 –20 .22554549 \n[2] Gouy S Morice P Narducci F \nProspective multicenter study evaluating the survival of patients with locally advanced cervical cancer undergoing laparoscopic para-aortic lymphadenectomy before chemoradiotherapy in the era of positron emission tomography imaging . J Clin Oncol \n2013 ;31 :3026 –33 .23857967 \n[3] Vandeperre A Van Limbergen E Leunen K \nPara-aortic lymph node metastases in locally advanced cervical cancer: comparison between surgical staging and imaging . Gynecol Oncol \n2015 ;138 :299 –303 .26007204 \n[4] Berman ML Keys H Creasman W \nSurvival and patterns of recurrence in cervical cancer metastatic to periaortic lymph nodes (a Gynecologic Oncology Group study) . Gynecol Oncol \n1984 ;19 :8 –16 .6469092 \n[5] Liu Z Hu K Liu A \nPatterns of lymph node metastasis in locally advanced cervical cancer . Medicine \n2016 ;95 :e4814 .27684810 \n[6] Eifel PJ Winter K Morris M \nPelvic irradiation with concurrent chemotherapy versus pelvic and para-aortic irradiation for high-risk cervical cancer: an update of radiation therapy oncology group trial (RTOG) 90-01 . J Clin Oncol \n2004 ;22 :872 –80 .14990643 \n[7] Hong JH Tsai CS Lai CH \nRisk stratification of patients with advanced squamous cell carcinoma of cervix treated by radiotherapy alone . Int J Radiat Oncol, Biol Phys \n2005 ;63 :492 –9 .15925454 \n[8] Huang EY Wang CJ Chen HC \nMultivariate analysis of para-aortic lymph node recurrence after definitive radiotherapy for stage IB–IVA squamous cell carcinoma of uterine cervix . Int J Radiat Oncol Biol Phys \n2008 ;72 :834 –42 .18439764 \n[9] Liang JA Chen SW Chang WC \nRisk stratification for failure in patients with advanced cervical cancer after concurrent chemoradiotherapy: another way to optimise treatment results . Clin Oncol (Royal College of Radiologists (Great Britain)) \n2008 ;20 :683 –90 .\n[10] Rotman M Pajak TF Choi K \nProphylactic extended-field irradiation of para-aortic lymph nodes in stages IIB and bulky IB and IIA cervical carcinomas. Ten-year treatment results of RTOG 79-20 . JAMA \n1995 ;274 :387 –93 .7616634 \n[11] Haie C Pejovic MH Gerbaulet A \nIs prophylactic para-aortic irradiation worthwhile in the treatment of advanced cervical carcinoma? Results of a controlled clinical trial of the EORTC radiotherapy group . Radiother Oncol \n1988 ;11 :101 –12 .3281186 \n[12] Malfetano JH Keys H Cunningham MJ \nExtended field radiation and cisplatin for stage IIB and IIIB cervical carcinoma . Gynecol Oncol \n1997 ;67 :203 –7 .9367709 \n[13] Grigsby PW Heydon K Mutch DG \nLong-term follow-up of RTOG 92-10: cervical cancer with positive para-aortic lymph nodes . Int J Radiat Oncol Biol Phys \n2001 ;51 :982 –7 .11704321 \n[14] Sood BM Gorla GR Garg M \nExtended-field radiotherapy and high-dose-rate brachytherapy in carcinoma of the uterine cervix: clinical experience with and without concomitant chemotherapy . Cancer \n2003 ;97 :1781 –8 .12655536 \n[15] Chung YL Jian JJ Cheng SH \nExtended-field radiotherapy and high-dose-rate brachytherapy with concurrent and adjuvant cisplatin-based chemotherapy for locally advanced cervical cancer: a phase I/II study . Gynecol Oncol \n2005 ;97 :126 –35 .15790448 \n[16] Uno T Mitsuhashi A Isobe K \nConcurrent daily cisplatin and extended-field radiation therapy for carcinoma of the cervix . Int J Gynecol Cancer \n2008 ;18 :80 –4 .17466053 \n[17] Ring KL Young JL Dunlap NE \nExtended-field radiation therapy with whole pelvis radiotherapy and cisplatin chemosensitization in the treatment of IB2-IIIB cervical carcinoma: a retrospective review . Am J Obstet Gynecol \n2009 ;201 :109.e101 –6 .19398095 \n[18] Beadle BM Jhingran A Yom SS \nPatterns of regional recurrence after definitive radiotherapy for cervical cancer . Int J Radiat Oncol Biol Phys \n2010 ;76 :1396 –403 .19581056 \n[19] Kuku S Fragkos C McCormack M \nRadiation-induced bowel injury: the impact of radiotherapy on survivorship after treatment for gynaecological cancers . Brit J Cancer \n2013 ;109 :1504 –12 .24002603 \n[20] Jensen LG Hasselle MD Rose BS \nOutcomes for patients with cervical cancer treated with extended-field intensity-modulated radiation therapy and concurrent cisplatin . Int J Gynecol Cancer \n2013 ;23 :119 –25 .23262521 \n[21] Liang JA Chen SW Hung YC \nLow-dose, prophylactic, extended-field, intensity-modulated radiotherapy plus concurrent weekly cisplatin for patients with stage IB2–IIIB cervical cancer, positive pelvic lymph nodes, and negative para-aortic lymph nodes . Int J Gynecol Cancer \n2014 ;24 :901 –7 .23975081 \n[22] Choi J Yoon HI Lee J \nOptimal extent of prophylactic irradiation of paraaortic lymph nodes in patients with uterine cervical ancer . PloS One \n2015 ;10 :e0145158 .26659867 \n[23] Kidd EA Siegel BA Dehdashti F \nLymph node staging by positron emission tomography in cervical cancer: relationship to prognosis . J Clin Oncol \n2010 ;28 :2108 –13 .20308664 \n[24] Grigsby PW Siegel BA Dehdashti F \nLymph node staging by positron emission tomography in patients with carcinoma of the cervix . J Clin Oncol \n2001 ;19 :3745 –9 .11533097 \n[25] Tsai CS Chang TC Lai CH \nPreliminary report of using FDG-PET to detect extrapelvic lesions in cervical cancer patients with enlarged pelvic lymph nodes on MRI/CT . Int J Radiat Oncol Biol Phys \n2004 ;58 :1506 –12 .15050330 \n[26] Sakurai H Suzuki Y Nonaka T \nFDG-PET in the detection of recurrence of uterine cervical carcinoma following radiation therapy—tumor volume and FDG uptake value . Gynecol Oncol \n2006 ;100 :601 –7 .16257440 \n[27] Tsai CS Lai CH Chang TC \nA prospective randomized trial to study the impact of pretreatment FDG-PET for cervical cancer patients with MRI-detected positive pelvic but negative para-aortic lymphadenopathy . Int J Radiat Oncol Biol Phys \n2010 ;76 :477 –84 .19464824 \n[28] Lin SY Tsai CS Chang YC \nThe role of pretreatment FDG-PET in treating cervical cancer patients with enlarged pelvic lymph node(s) shown on MRI: a phase 3 randomized trial with long-term follow-up . Int J Radiat Oncol Biol Phys \n2015 ;92 :577 –85 .25936817\n\n",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D002294:Carcinoma, Squamous Cell; D059248:Chemoradiotherapy; D002945:Cisplatin; D005260:Female; D006801:Humans; D008875:Middle Aged; D010349:Patient Compliance; D050397:Radiotherapy, Intensity-Modulated; D012189:Retrospective Studies; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms",
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"title": "Safety and efficacy of semiextended field intensity-modulated radiation therapy and concurrent cisplatin in locally advanced cervical cancer patients: An observational study of 10-year experience.",
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"abstract": "Azathioprine hypersensitivity syndrome is a rare but potentially severe side effect of azathioprine use. It has a variable and non-specific presentation making it difficult to distinguish from sepsis or disease relapse. High clinical suspicion is therefore required for recognition and prompt cessation of azathioprine for symptom resolution. Herewith two cases of severe azathioprine hypersensitivity syndrome are described, one in association with Sweet syndrome. Both presented with vague symptoms 2 weeks after commencing azathioprine for antineutrophil cytoplasmic antibody vasculitis. The differentials of sepsis and disease relapse were considered prior to cessation of azathioprine which resulted in a dramatic improvement in both cases. These cases highlight the diagnostic challenge azathioprine hypersensitivity syndrome presents. It should be suspected when there is a temporal relationship to drug initiation, with absence of infection or serological evidence of disease relapse.",
"affiliations": "Medicine, Cairns Base Hospital, Cairns, Queensland, Australia tahlia.mckenzie@health.qld.gov.au.;Nephrology, Cairns Hospital, Cairns, Queensland, Australia.;Nephrology, Cairns Hospital, Cairns, Queensland, Australia.;Pharmacy, Cairns Base Hospital, Cairns, Queensland, Australia.",
"authors": "McKenzie|Tahlia|T|http://orcid.org/0000-0002-5969-2449;Dheda|Shyam|S|;Mantha|Murty|M|;Larsen|Catherine|C|",
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"mesh_terms": "D019268:Antibodies, Antineutrophil Cytoplasmic; D001379:Azathioprine; D004342:Drug Hypersensitivity; D063926:Drug Hypersensitivity Syndrome; D006801:Humans; D007166:Immunosuppressive Agents; D016463:Sweet Syndrome",
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"title": "Azathioprine hypersensitivity syndrome: report of two cases.",
"title_normalized": "azathioprine hypersensitivity syndrome report of two cases"
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"dru... |
{
"abstract": "BACKGROUND\nIn preclinical models, the proton pump inhibitor pantoprazole enhances the antitumor activity of chemotherapeutic agents by improving drug distribution and by inhibiting autophagy.\n\n\nMETHODS\nPatients with advanced solid tumors (n = 24) received doxorubicin 60 mg/m(2) and escalating doses of pantoprazole (80, 160, 240 and 360 mg) administered intravenously prior to doxorubicin. Blood samples were collected for pharmacokinetic studies. An optional biopsy was performed to evaluate doxorubicin concentration and pharmacodynamic markers of drug activity.\n\n\nRESULTS\nTwenty-four patients participated in the study (17 in the dose escalation phase and 7 in the dose expansion). Three patients experienced a dose limiting toxicity (grade 3 fatigue in the three cases), one patient at dose level 3 (pantoprazole 240 mg) and two patients at dose level 4 (pantoprazole 360 mg). Dose level 4 was considered to exceed the maximum tolerated dose. The recommended phase II dose was pantoprazole 240 mg and doxorubicin 60 mg/m(2). The most commonly observed toxicities included fatigue, neutropenia and leukopenia. Two patients achieved a confirmed partial response. Median maximum serum concentration of pantoprazole was 84.3 μM at 1-2 h after injection of pantoprazole 240 mg. No drug-drug interaction was observed. A single on-treatment tumor biopsy showed a sharply decreasing gradient in doxorubicin concentration and associated activity markers with increasing distance from tumor blood vessels.\n\n\nCONCLUSIONS\nAdministration of high doses of pantoprazole in combination with doxorubicin is feasible. The recommended phase II dose of pantoprazole, 240 mg, will be evaluated in combination with docetaxel as first line in patients with castration-resistant prostate cancer.",
"affiliations": "Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Department of Medicine, University of Toronto, 610 University Avenue, M5G 2 M9, Toronto, ON, Canada.",
"authors": "Brana|Irene|I|;Ocana|Alberto|A|;Chen|Eric X|EX|;Razak|Albiruni R A|AR|;Haines|Christine|C|;Lee|Carol|C|;Douglas|Sarah|S|;Wang|Lisa|L|;Siu|Lillian L|LL|;Tannock|Ian F|IF|;Bedard|Philippe L|PL|",
"chemical_list": "D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D004317:Doxorubicin; D000077402:Pantoprazole",
"country": "United States",
"delete": false,
"doi": "10.1007/s10637-014-0159-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-6997",
"issue": "32(6)",
"journal": "Investigational new drugs",
"keywords": null,
"medline_ta": "Invest New Drugs",
"mesh_terms": "D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D004317:Doxorubicin; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D000077402:Pantoprazole; D066066:Response Evaluation Criteria in Solid Tumors",
"nlm_unique_id": "8309330",
"other_id": null,
"pages": "1269-77",
"pmc": null,
"pmid": "25213162",
"pubdate": "2014-12",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article",
"references": "8066425;19436029;17473214;3971478;20382705;17545622;23348047;11836511;16361566;17050865;17429391;10734021;20687211;23680920;19097774;16862189;9584137;18679668;21537144;10430072;24141627;16495919;14505800;8408728;15547183;8302842;11948144;21629657;22577347;12435274;21406549;7517642;17288875;2545340;22534666;8387903;3698008;8048479",
"title": "A phase I trial of pantoprazole in combination with doxorubicin in patients with advanced solid tumors: evaluation of pharmacokinetics of both drugs and tissue penetration of doxorubicin.",
"title_normalized": "a phase i trial of pantoprazole in combination with doxorubicin in patients with advanced solid tumors evaluation of pharmacokinetics of both drugs and tissue penetration of doxorubicin"
} | [
{
"companynumb": "CA-PFIZER INC-2014269429",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "Checkpoint inhibitors such as nivolumab represent a novel class of agents that are being increasingly used in the treatment of various cancers. Their toxicities represent unique challenges to the oncologists prescribing them, patients' primary care physicians and other specialists who may encounter these patients during consultations. It is important for physicians to remain vigilant and include autoimmune toxicities in the list of potential differential diagnoses in patients receiving novel cancer therapeutics who present with unusual toxicities. We report the unusual case of a 68-year-old woman with advanced lung cancer on the novel chemotherapeutic Nivolumab whom we suspect developed autoimmune myocarditis with significant cardiac conduction disease as an unintended, and as of yet unrecognised, side effect from this medication.",
"affiliations": "Department of Internal Medicine, University of Florida, Gainesville, Florida, USA.;Department of Internal Medicine, University of Florida, Gainesville, Florida, USA.;Department of Cardiovascular Medicine, University of Florida, Gainesville, Florida, USA.;Department of Oncology, University of Florida, Gainesville, Florida, USA.",
"authors": "Gibson|Robert|R|;Delaune|Jess|J|;Szady|Anita|A|;Markham|Merry|M|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000077594:Nivolumab",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2016()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D001145:Arrhythmias, Cardiac; D001327:Autoimmune Diseases; D002289:Carcinoma, Non-Small-Cell Lung; D003937:Diagnosis, Differential; D004562:Electrocardiography; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D009205:Myocarditis; D000077594:Nivolumab",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "27440853",
"pubdate": "2016-07-20",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25034862;22658127;22491251;26629425;11209085;25482239;20525992;7584144;23724846;25399552;26885708;21639810;24188664;14595408;10956283;25991832;15936612;25901283;23824828;24904570;25927979;25823918;20410257;22658128",
"title": "Suspected autoimmune myocarditis and cardiac conduction abnormalities with nivolumab therapy for non-small cell lung cancer.",
"title_normalized": "suspected autoimmune myocarditis and cardiac conduction abnormalities with nivolumab therapy for non small cell lung cancer"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2016-BI-53886BI",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FONDAPARINUX"
},
... |
{
"abstract": "OBJECTIVE\nReal-world secukinumab gastrointestinal-related adverse events (GIRAE) data during treatment for AS and PsA are lacking. We aimed to obtain this through baseline evaluation of pre-existing IBD rates and predictors of GIRAE.\n\n\nMETHODS\nPatient electronic and paper records commencing secukinumab from 10 UK hospitals between 2016 and 2019 were reviewed. GIRAE after initiation were defined as: definite [objective evidence of IBD (biopsy proven), clear temporal association, resolution of symptoms on drug withdrawal, no alternative explanation felt more likely], probable (as per definite, but without biopsy confirmation) or possible (gastrointestinal symptoms not fulfilling definite or probable criteria).\n\n\nRESULTS\nData for all 306 patients started on secukinumab were analysed: 124 (40.5%) AS and 182 (59.5%) PsA. Twenty-four of 306 (7.8%) experienced GIRAE after starting secukinumab. Amongst patients who developed GIRAE, four (1.3%) had definite, seven (2.3%) probable and 13 (4.2%) possible IBD. All definite cases were patients with AS and stopped secukinumab; two had pre-existing IBD and two (0.7%) were de novo cases of which one required surgical intervention. Seven patients (2.3%) had pre-existing diagnoses of IBD prior to initiation, of which five patients experienced GIRAE.\n\n\nCONCLUSIONS\nAbsolute rates of new IBD in patients starting secukinumab are low. The majority of patients developing new GIRAE did not develop objective evidence of IBD or stop therapy. For patients with pre-existing IBD and AS the risk of GIRAE is much higher, and prescribing alternatives should be considered.",
"affiliations": "Department of Academic Rheumatology, King's College London, London.;Department of Academic Rheumatology, King's College London, London.;Department of Rheumatology, Brighton and Sussex University Hospital, Brighton.;Department of Rheumatology, Frimley Park Hospital, Frimley.;Department of Rheumatology, Brighton and Sussex University Hospital, Brighton.;Department of Rheumatology, Brighton and Sussex University Hospital, Brighton.;Department of Rheumatology, East Surrey Hospital, Redhill.;Department of Rheumatology, Frimley Park Hospital, Frimley.;Department of Rheumatology, Royal Berkshire NHS Foundation Trust, Reading.;Department of Rheumatology, St George's University Hospitals NHS Foundation Trust, London.;Department of Rheumatology, Croydon University Hospital, Croydon.;Department of Rheumatology, Croydon University Hospital, Croydon.;Department of Rheumatology, Croydon University Hospital, Croydon.;Department of Rheumatology, Croydon University Hospital, Croydon.;Department of Rheumatology, East Surrey Hospital, Redhill.;Department of Rheumatology, St George's University Hospitals NHS Foundation Trust, London.;Centre for Rheumatic Diseases, King's College London, London, UK.",
"authors": "Onac|Ioana A|IA|;Clarke|Benjamin D|BD|;Tacu|Cristina|C|;Lloyd|Mark|M|;Hajela|Vijay|V|;Batty|Thomas|T|;Thoroughgood|Jamie|J|;Smith|Sandra|S|;Irvine|Hannah|H|;Hill|Diane|D|;Baxter|Grace|G|;Horwood|Natalie|N|;Mahendrakar|Suma|S|;Rajak|Rizwan|R|;Griffith|Sian|S|;Kiely|Patrick D W|PDW|0000-0002-8091-2717;Galloway|James|J|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/rheumatology/keab193",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1462-0324",
"issue": "60(11)",
"journal": "Rheumatology (Oxford, England)",
"keywords": "ankylosing spondylitis; anti-IL-17; biologic therapy; bowel inflammation; gastrointestinal side effects; inflammatory bowel disease; psoriatic arthritis; real-world data; screening; secukinumab",
"medline_ta": "Rheumatology (Oxford)",
"mesh_terms": null,
"nlm_unique_id": "100883501",
"other_id": null,
"pages": "5233-5238",
"pmc": null,
"pmid": "33677579",
"pubdate": "2021-11-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Secukinumab as a potential trigger of inflammatory bowel disease in ankylosing spondylitis or psoriatic arthritis patients.",
"title_normalized": "secukinumab as a potential trigger of inflammatory bowel disease in ankylosing spondylitis or psoriatic arthritis patients"
} | [
{
"companynumb": "NVSC2021GB069898",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SECUKINUMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "Since the introduction of combined antiretroviral therapy, human immunodeficiency virus (HIV) infection is no longer a contraindication for solid organ transplantation. In HIV/hepatitis C virus (HCV)-coinfected patients undergoing liver transplantation, HCV-related cirrhosis, drug-drug interactions, and calcineurin inhibitors-related toxicity affect clinical outcomes. Therapeutic drug monitoring can be useful to assess antiretroviral over- or underexposure in this cohort. We report the clinical characteristics along with antiretroviral trough levels of maraviroc, darunavir, and etravirine in 3 HIV/HCV-coinfected liver transplant recipients who developed post-transplant liver cirrhosis.",
"affiliations": "Infectious Diseases Department, Santa Maria della Misericordia University Hospital, Udine, Italy.",
"authors": "Righi|E|E|;Londero|A|A|;Pea|F|F|;Bonora|S|S|;Nasta|P|P|;Della Siega|P|P|;Delle Foglie|P|P|;Villa|G|G|;Giglio|O|O|;Dal Zoppo|S|S|;Baccarani|U|U|;Bassetti|M|M|",
"chemical_list": "D044966:Anti-Retroviral Agents; D003510:Cyclohexanes; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; D014230:Triazoles; C451734:etravirine; D000077592:Maraviroc; D000069454:Darunavir",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12339",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "17(1)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "HIV/HCV coinfection; antiretrovirals; c-ART; cirrhosis; liver transplant; therapaeutic drug monitoring",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D044966:Anti-Retroviral Agents; D060085:Coinfection; D003510:Cyclohexanes; D000069454:Darunavir; D016903:Drug Monitoring; D005260:Female; D015658:HIV Infections; D006526:Hepatitis C; D006801:Humans; D008103:Liver Cirrhosis; D016031:Liver Transplantation; D008297:Male; D000077592:Maraviroc; D008875:Middle Aged; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; D014230:Triazoles",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "147-53",
"pmc": null,
"pmid": "25620392",
"pubdate": "2015-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Antiretroviral blood levels in HIV/HCV-coinfected patients with cirrhosis after liver transplant: a report of three cases.",
"title_normalized": "antiretroviral blood levels in hiv hcv coinfected patients with cirrhosis after liver transplant a report of three cases"
} | [
{
"companynumb": "IT-GILEAD-2015-0142373",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": null,
"drugadditional": null,
"drugadministrationroute": null,
"drugauthori... |
{
"abstract": "Hydroxychloroquine (HCQ) is largely prescribed as an immunomodulator to prevent systemic diseases flares in patients with systemic lupus erythematous, rheumatoid arthritis, Sjogren's disease. Among reported side effects, HCQ can accumulate in lysosomes and induced phospholipidosis. Here, we report an HCQ-induced podocytopathy mimicking Fabry disease (FD). They share the same histological lesions: cytoplasmic vacuolisation of the podocytes and zebra bodies on light and electronic microscopy. FD has been ruled out by measuring enzymatic activity and genetic test. The persistence of proteinuria after immunological remission of a systemic disease treated with HCQ could suggest this HCQ-induced podocytopathy.",
"affiliations": "Nephrology, Assistance Publique - Hôpitaux de Paris, Paris, France.;Pathology, Assistance Publique - Hôpitaux de paris, Paris, France.;Nephrology, Assistance Publique - Hôpitaux de Paris, Paris, France.",
"authors": "Serre|Justine|J|;Buob|David|D|;Boffa|Jean-Jacques|JJ|",
"chemical_list": "D018501:Antirheumatic Agents; D006886:Hydroxychloroquine",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-228876",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(5)",
"journal": "BMJ case reports",
"keywords": "pathology; proteinurea; renal system; unwanted effects/adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D018501:Antirheumatic Agents; D003937:Diagnosis, Differential; D000795:Fabry Disease; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine; D008181:Lupus Nephritis; D008297:Male; D009404:Nephrotic Syndrome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31088818",
"pubdate": "2019-05-13",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24855048;28499424;17623715;12673565;23573895;30143072;26120446;12068025;15605079;29661770;17060007",
"title": "Hydroxychloroquine-induced podocytopathy mimicking Fabry disease.",
"title_normalized": "hydroxychloroquine induced podocytopathy mimicking fabry disease"
} | [
{
"companynumb": "FR-MYLANLABS-2019M1110046",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "THALIDOMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nIntussusception, which is common in pediatric patients but rare in adults with leukemia, usually presents with an intralumenal lesion as a lead point in adults.\n\n\nMETHODS\nWe herein report the case of a 38-year-old female who developed right lower quadrant abdominal pain and fever on day 16 of chemotherapy. Abdominal computed tomography showed ileocecal intussusception. The patient underwent surgery, and the definitive pathological diagnosis was typhlitis leading to intussusception. Albeit very rare in adults, typhlitis-induced intussusception should be suspected in those with leukemia presenting with abdominal pain.",
"affiliations": "Division of Colorectal Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan City, 704, Taiwan. buoy2610@gmail.com.;Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.",
"authors": "Chan|Ren-Hao|RH|http://orcid.org/0000-0001-8584-0778;Chen|Ya-Ping|YP|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00384-019-03395-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0179-1958",
"issue": "34(10)",
"journal": "International journal of colorectal disease",
"keywords": "Acute lymphoblastic leukemia; Intussusception; Typhlitis",
"medline_ta": "Int J Colorectal Dis",
"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D007443:Intussusception; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D014057:Tomography, X-Ray Computed; D053706:Typhlitis",
"nlm_unique_id": "8607899",
"other_id": null,
"pages": "1815-1818",
"pmc": null,
"pmid": "31512021",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11427847;16990978;19152443;20138300;21913980;22928122;25593499;2662787;27840762;28104979;28246114;6607636;8470658",
"title": "Intussusception caused by typhlitis: a rare complication in a patient with acute lymphoblastic leukemia after chemotherapy.",
"title_normalized": "intussusception caused by typhlitis a rare complication in a patient with acute lymphoblastic leukemia after chemotherapy"
} | [
{
"companynumb": "TW-PFIZER INC-2019469603",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "We report a case of a 54-year-old woman presented at the emergency service with complaints of transitory visual obscurations for four days, and headache, nausea and occasional vomiting in the last two months. She had been diagnosed of colorectal cancer one year ago and she was on treatment with oxaliplatin on a FOLFOX schedule. On ophthalmic examination, the vision was of 20/20 in both eyes and bilateral disc swelling was noted. The neurologic examination was normal. Magnetic resonance revealed no changes. A diagnostic lumbar puncture demonstrated an elevated opening pressure of 290 mm H2O with normal compounds. Due to the suspicion of ocular toxicity, oxaliplatin treatment was stopped. Treatment with oral acetazolamide was started and maintained for one month. In three weeks ocular and systemic symptoms totally disappeared and disc swelling gradually improved in the following months. Ocular toxicity has been reported as an infrequent adverse effect of oxaliplatin, but intracranial idiopathic pressure has not yet been described. Findings in this case suggest that oxaliplatin could be the cause for these symptoms. As the use of oxaliplatin is increasing as first-line treatment in colorectal cancer, we have to be alert to its potential toxicity.",
"affiliations": "Department of Ophthalmology, Centro Hospitalar entre Douro e Vouga , Santa Maria da Feira , Portugal and.",
"authors": "Painhas|Teresa|T|;Amorim|Manuela|M|;Soares|Raquel|R|;Duarte|Lilianne|L|;Salgado-Borges|José|J|",
"chemical_list": "D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin",
"country": "England",
"delete": false,
"doi": "10.3109/15569527.2014.944647",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-9527",
"issue": "34(3)",
"journal": "Cutaneous and ocular toxicology",
"keywords": "Chemotherapeutic drugs; intracranial hypertension; oxaliplatin; papilledema",
"medline_ta": "Cutan Ocul Toxicol",
"mesh_terms": "D000970:Antineoplastic Agents; D015179:Colorectal Neoplasms; D005260:Female; D006801:Humans; D008875:Middle Aged; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D011559:Pseudotumor Cerebri; D014786:Vision Disorders",
"nlm_unique_id": "101266892",
"other_id": null,
"pages": "237-41",
"pmc": null,
"pmid": "25198406",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Idiopathic intracranial hypertension and oxaliplatin: a causal association?",
"title_normalized": "idiopathic intracranial hypertension and oxaliplatin a causal association"
} | [
{
"companynumb": "PT-FRESENIUS KABI-FK201504403",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,... |
{
"abstract": "BACKGROUND\nOptimal anticoagulation strategy remains uncertain in patients with heparin-induced thrombocytopenia (HIT) and undergoing left ventricular assist device (LVAD) implantation. We describe our protocol of abciximab and heparin in these patients.\n\n\nMETHODS\nOur protocol is to administer abciximab, 0.25 mg/kg loading dose, followed by continuous infusion of 0.125 μg · kg-1 · min-1 throughout cardiopulmonary bypass. Full-dose heparin is then given with subsequent additional doses to maintain an activated clotting time of 400 seconds or longer. The abciximab infusion is stopped 15 minutes after heparin reversal with protamine, and platelets are transfused.\n\n\nRESULTS\nSix patients underwent LVAD implantation with this protocol in our program. HIT was confirmed in 4 patients was suspected in 2, which was negative after the operation. One patient received a HeartMate XVE (Thoratec Corp, Pleasanton, CA) and the others received HeartMate II (Thoratec Corp). There were no thromboembolic complications. One patient required chest reexploration for bleeding and temporary right VAD support. Postoperative anticoagulation with argatroban was restarted on median postoperative day 3 (range, days 1 to 6) and warfarin was started on day 5 (range, days 3 to 12). Median postoperative intensive care unit stay was 9 days (range, 5 to 76 days), and hospital stay was 22 days (range, 18 to 132 days). After the initial LVAD implantation, 1 patient required HeartMate XVE LVAD exchange to HeartMate II and subsequent heart transplant, both of which were performed with the abciximab/heparin protocol. A HeartMate II device was explanted in another patient after myocardial recovery. The remaining 4 patients are alive on device support.\n\n\nCONCLUSIONS\nThis is the first report of a novel abciximab/heparin protocol for LVAD implantation in patients with HIT. The preliminary results suggest the feasibility and safety of this protocol.",
"affiliations": "Department of Anesthesiology, Buddhist Tzu Chi General Hospital, Tzu Chi University, Hualien, Taiwan; Division of Cardiothoracic Surgery, Department of Surgery, New York Presbyterian Hospital, Columbia University Medical Center, New York, New York.;Division of Cardiology, New York Presbyterian Hospital, Columbia University Medical Center, New York, New York.;Division of Hematology, Department of Medicine, New York Presbyterian Hospital, Columbia University Medical Center, New York, New York.;Division of Hematology, Department of Medicine, New York Presbyterian Hospital, Columbia University Medical Center, New York, New York.;Department of Pharmacy, New York Presbyterian Hospital, Columbia University Medical Center, New York, New York.;Division of Cardiothoracic Surgery, Department of Surgery, New York Presbyterian Hospital, Columbia University Medical Center, New York, New York.;Division of Cardiothoracic Surgery, Department of Surgery, New York Presbyterian Hospital, Columbia University Medical Center, New York, New York.;Division of Cardiothoracic Surgery, Department of Surgery, New York Presbyterian Hospital, Columbia University Medical Center, New York, New York.;Division of Cardiothoracic Surgery, Department of Surgery, New York Presbyterian Hospital, Columbia University Medical Center, New York, New York.;Division of Cardiology, New York Presbyterian Hospital, Columbia University Medical Center, New York, New York.;Division of Cardiology, New York Presbyterian Hospital, Columbia University Medical Center, New York, New York.;Division of Cardiothoracic Surgery, Department of Surgery, New York Presbyterian Hospital, Columbia University Medical Center, New York, New York.;Division of Cardiothoracic Surgery, Department of Surgery, New York Presbyterian Hospital, Columbia University Medical Center, New York, New York. Electronic address: hirofu2@hotmail.com.",
"authors": "Lee|Chia-Ling|CL|;Colombo|Paolo C|PC|;Eisenberger|Andrew|A|;Diuguid|David|D|;Jennings|Douglas L|DL|;Han|Jiho|J|;Salna|Michael P|MP|;Takeda|Koji|K|;Kurlansky|Paul A|PA|;Yuzefpolskaya|Melana|M|;Garan|Arthur R|AR|;Naka|Yoshifumi|Y|;Takayama|Hiroo|H|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000925:Anticoagulants; D007140:Immunoglobulin Fab Fragments; D006493:Heparin; D000077284:Abciximab",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.athoracsur.2017.06.031",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-4975",
"issue": "105(1)",
"journal": "The Annals of thoracic surgery",
"keywords": null,
"medline_ta": "Ann Thorac Surg",
"mesh_terms": "D000077284:Abciximab; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D000925:Anticoagulants; D002985:Clinical Protocols; D004359:Drug Therapy, Combination; D005260:Female; D006333:Heart Failure; D006353:Heart-Assist Devices; D006493:Heparin; D006801:Humans; D007140:Immunoglobulin Fab Fragments; D008297:Male; D008875:Middle Aged; D019919:Prosthesis Implantation; D012189:Retrospective Studies; D013921:Thrombocytopenia",
"nlm_unique_id": "15030100R",
"other_id": null,
"pages": "122-128",
"pmc": null,
"pmid": "28987395",
"pubdate": "2018-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Abciximab/Heparin Therapy for Left Ventricular Assist Device Implantation in Patients With Heparin-Induced Thrombocytopenia.",
"title_normalized": "abciximab heparin therapy for left ventricular assist device implantation in patients with heparin induced thrombocytopenia"
} | [
{
"companynumb": "TW-PFIZER INC-2017551996",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": "1",
... |
{
"abstract": "Pyridoxine-dependent epilepsy (PDE) is a recessive genetic disease characterized by epileptic encephalopathy with therapeutic response to pharmacological doses of pyridoxine and resistance to anti-epileptic treatments. The recent discovery in 2006 of the genetic defect antiquitin (ALDH7A1, OMIM #266100) has helped to understand the underlying mechanism, which is the accumulation of neurotoxic intermediates in the lysine catabolic pathway. The goal of the new therapeutic approach, termed triple therapy (TT) (pyridoxine, lysine-restricted diet and arginine supplementation), is to improve epilepsy control and neurocognitive development in patients with PDE. We present the 3-year treatment outcome for a child with PDE on pyridoxine treatment (started at age 5 months), lysine-restricted diet (started at age 17 months) and arginine supplementation therapy (started at age 19 months). The TT was well-tolerated with good compliance. No adverse events were reported. We observed a neurodevelopmental improvement, significantly fewer seizures, and a reduction of pipecolic acid (PA) as a biomarker of the illness. Our results show an improving clinical evolution, supporting and extending previous studies reporting efficacy of TT.",
"affiliations": "Service de Néonatologie, Hôpital Estaing, Centre Hospitalier Universitaire de Clermont-Ferrand, Clermont-Ferrand, France.;Service de Génétique Médicale, Hôpital Estaing, Centre Hospitalier Universitaire de Clermont-Ferrand, Clermont-Ferrand, France.;Service de Génétique Médicale, Hôpital Estaing, Centre Hospitalier Universitaire de Clermont-Ferrand, Clermont-Ferrand, France.;Centre de Référence Des Maladies Héréditaires du Métabolisme, Pôle Enfant, Centre Hospitalier Universitaire de Lille-Hôpital Jeanne de Flandre, Lille, France.;Service de Biochimie-Hormonologie, Centre Hospitalier Universitaire de Paris-Hôpital Robert Debré, Paris, France.;Service de Néonatologie, Hôpital Estaing, Centre Hospitalier Universitaire de Clermont-Ferrand, Clermont-Ferrand, France. gremerand@chu-clermontferrand.fr.",
"authors": "Minet|Perrine|P|;Sarret|Catherine|C|;Miret|Ania|A|;Mention|Karine|K|;Benoist|Jean François|JF|;Remerand|Ganaelle|G|http://orcid.org/0000-0002-7162-5871",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.1007/s13760-020-01467-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-9009",
"issue": "121(6)",
"journal": "Acta neurologica Belgica",
"keywords": "Arginine supplementation; Lysine-restricted diet; Pyridoxine-dependent epilepsy; Triple therapy",
"medline_ta": "Acta Neurol Belg",
"mesh_terms": null,
"nlm_unique_id": "0247035",
"other_id": null,
"pages": "1669-1675",
"pmc": null,
"pmid": "33113107",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
"references": "13133562;32187681;25639976",
"title": "Clinical and biochemical outcome of a patient with pyridoxine-dependent epilepsy treated by triple therapy (pyridoxine supplementation, lysine-restricted diet, and arginine supplementation).",
"title_normalized": "clinical and biochemical outcome of a patient with pyridoxine dependent epilepsy treated by triple therapy pyridoxine supplementation lysine restricted diet and arginine supplementation"
} | [
{
"companynumb": "FR-STRIDES ARCOLAB LIMITED-2022SP000165",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROCORTISONE"
},
"drugadditio... |
{
"abstract": "We describe an outbreak caused by KPC-2- and IMP-10-producing Serratia marcescens isolates in a Brazilian teaching hospital. Tigecycline was the only active antimicrobial agent tested. The blaIMP-10 gene was located in a new class 1 integron, named In990, carried by a nonconjugative plasmid, in contrast to blaKPC-2.",
"affiliations": "Laboratório de Pesquisa em Ciências da Saúde, Universidade Federal da Grande Dourados (UFGD), Dourados, Mato Grasso do Sul, Brazil.;Laboratório ALERTA, Disciplina de Infectologia, Departamento de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil.;Laboratório ALERTA, Disciplina de Infectologia, Departamento de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil.;Hospital Universitário de Dourados, Universidade Federal da Grande Dourados (UFGD), Dourados, Mato Grosso do Sul, Brazil.;Laboratório ALERTA, Disciplina de Infectologia, Departamento de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil.;Laboratório ALERTA, Disciplina de Infectologia, Departamento de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil.;Laboratório de Pesquisa em Ciências da Saúde, Universidade Federal da Grande Dourados (UFGD), Dourados, Mato Grasso do Sul, Brazil Hospital Universitário de Dourados, Universidade Federal da Grande Dourados (UFGD), Dourados, Mato Grosso do Sul, Brazil Fundação Osvaldo Cruz, Campo Grande, Mato Grosso do Sul, Brazil.;Laboratório ALERTA, Disciplina de Infectologia, Departamento de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil.;Laboratório de Pesquisa em Ciências da Saúde, Universidade Federal da Grande Dourados (UFGD), Dourados, Mato Grasso do Sul, Brazil simonesimionatto@ufgd.edu.br.",
"authors": "Silva|Kesia Esther|KE|;Cayô|Rodrigo|R|;Carvalhaes|Cecilia Godoy|CG|;Patussi Correia Sacchi|Flávia|F|;Rodrigues-Costa|Fernanda|F|;Ramos da Silva|Ana Carolina|AC|;Croda|Julio|J|;Gales|Ana Cristina|AC|;Simionatto|Simone|S|",
"chemical_list": "D000900:Anti-Bacterial Agents; D015780:Carbapenems; D004269:DNA, Bacterial; D000078304:Tigecycline; D001618:beta-Lactamases; D008911:Minocycline",
"country": "United States",
"delete": false,
"doi": "10.1128/JCM.00727-15",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0095-1137",
"issue": "53(7)",
"journal": "Journal of clinical microbiology",
"keywords": null,
"medline_ta": "J Clin Microbiol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D001938:Brazil; D015780:Carbapenems; D002675:Child, Preschool; D003428:Cross Infection; D004269:DNA, Bacterial; D004196:Disease Outbreaks; D005260:Female; D005798:Genes, Bacterial; D006784:Hospitals, Teaching; D006801:Humans; D007223:Infant; D032023:Integrons; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D008911:Minocycline; D008969:Molecular Sequence Data; D010957:Plasmids; D017422:Sequence Analysis, DNA; D016868:Serratia Infections; D012706:Serratia marcescens; D000078304:Tigecycline; D018440:beta-Lactam Resistance; D001618:beta-Lactamases",
"nlm_unique_id": "7505564",
"other_id": null,
"pages": "2324-8",
"pmc": null,
"pmid": "25878341",
"pubdate": "2015-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "15484794;6387733;15561846;17080370;19664012;19141739;17470660;21976608;21856046;23100344;23891221;23891433;24000225;24449769;24808234;24798249;11083759;14693513",
"title": "Coproduction of KPC-2 and IMP-10 in Carbapenem-Resistant Serratia marcescens Isolates from an Outbreak in a Brazilian Teaching Hospital.",
"title_normalized": "coproduction of kpc 2 and imp 10 in carbapenem resistant serratia marcescens isolates from an outbreak in a brazilian teaching hospital"
} | [
{
"companynumb": "BR-PFIZER INC-2015232645",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "COLISTIN"
},
"drugadditional": null,
... |
{
"abstract": "Acute massive pulmonary embolism (PE) is a life-threatening condition that requires prompt and aggressive interventions, including anticoagulation, catheter-directed thrombolysis (CDT), mechanical thrombectomy, or surgical thromboembolectomy. The aim of this study was to evaluate the treatment outcome in patients with massive PE who were treated with either ultrasound-accelerated thrombolysis using the EkoSonic Endovascular System (EKOS) or CDT intervention. During a recent 10-year period, the clinical records of all patients with massive PE undergoing catheter-directed interventions were evaluated. Patients were divided into two treatment groups: EKOS versus CDT interventions. Comparisons were made with regard to the treatment outcome between the two groups. Twenty-five patients underwent 33 catheter-directed interventions for massive PE during the study period. Among them, EKOS or CDT was performed in 15 (45%) and 18 (55%) procedures, respectively. In the EKOS group, complete thrombus removal was achieved in 100% cases. In the CDT cohort, complete or partial thrombus removal was accomplished in 7 (50%) and 2 (14%) cases, respectively. Comparing treatment success based on thrombus removal, EKOS treatment resulted in an improved treatment outcome compared with the CDT group (p < .02). The mean time of thrombolysis in EKOS and CDT group was 17.4 +/- 5.23 and 25.3 +/- 7.35 hours, respectively (p = .03). The mortality rate in the EKOS and CDT group was 9.1% and 14.2%, respectively (not significant). Treatment-related hemorrhagic complication rates in the EKOS and CDT group were 0% and 21.4%, respectively (p = .02). A significant reduction in Miller scores was noted in both groups following catheter-based interventions. No significant difference in relative Miller score improvement was observed between groups. Ultrasound-accelerated thrombolysis using the EkoSonic system is an effective treatment modality in patients with acute massive PE. When compared with CDT, this treatment modality provides similar treatment efficacy with reduced thrombolytic infusion time and treatment-related complications.",
"affiliations": "Division of Vascular Surgery and Endovascular Therapy, Michael E, DeBakey Department of Surgery, Baylor College of Medicine, 1709 Dryden Road, Suite 1500, Houston, TX 77030, USA. plin@bcm.edu",
"authors": "Lin|Peter H|PH|;Annambhotla|Suman|S|;Bechara|Carlos F|CF|;Athamneh|Husam|H|;Weakley|Sarah M|SM|;Kobayashi|Katsuhiro|K|;Kougias|Panagiotis|P|",
"chemical_list": "D005343:Fibrinolytic Agents",
"country": "England",
"delete": false,
"doi": "10.2310/6670.2009.00063",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1708-5381",
"issue": "17 Suppl 3()",
"journal": "Vascular",
"keywords": null,
"medline_ta": "Vascular",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002404:Catheterization; D005260:Female; D005343:Fibrinolytic Agents; D006470:Hemorrhage; D006801:Humans; D007261:Infusions, Intra-Arterial; D008297:Male; D008875:Middle Aged; D011655:Pulmonary Embolism; D012189:Retrospective Studies; D015912:Thrombolytic Therapy; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D014464:Ultrasonic Therapy",
"nlm_unique_id": "101196722",
"other_id": null,
"pages": "S137-47",
"pmc": null,
"pmid": "19919804",
"pubdate": "2009",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Comparison of percutaneous ultrasound-accelerated thrombolysis versus catheter-directed thrombolysis in patients with acute massive pulmonary embolism.",
"title_normalized": "comparison of percutaneous ultrasound accelerated thrombolysis versus catheter directed thrombolysis in patients with acute massive pulmonary embolism"
} | [
{
"companynumb": "US-ROCHE-1562640",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": null,
"drug... |
{
"abstract": "Denosumab is an antiresorptive drug with demonstrated efficacy in the treatment of osteoporosis. However, discontinuation of this agent is associated with increased bone turnover and rapid bone loss, and more recently, with the development of vertebral fractures (VF) in some patients. Therefore, the aim of the study was to analyze the clinical characteristics, bone metabolism parameters and evolution of a group of patients who developed vertebral fractures after denosumab discontinuation. In addition, we reviewed the literature on this subject.\n\n\n\nDuring a period of 28 months (September 2015-January 2018) 7 women presenting spontaneous vertebral fractures after denosumab discontinuation were attended in the Rheumatology Department of our centre. We analyzed their clinical characteristics, bone metabolism parameters and evolution and reviewed the literature related to this subject.\n\n\n\nThe patients had received denosumab during 24-58 months (median 38), and developed a median of 5 VF per patient at 8-20 months (median 10) since the last dose of denosumab. Only 2 patients presented previous VF, and most (5 patients) received previous bisphosphonate treatment. After VF all restarted antiosteoporotic treatment with no further fractures during follow-up (median 19 months).\n\n\n\nIn this short series, previous bisphosphonate treatment does not seem to be a protective factor for the development of VF. The possible development of VF following discontinuation of denosumab must be taken into account in the clinical practice of physicians and dentists. Nonetheless, further studies are needed to improve the identification of patients at risk and the most adequate sequential treatment options.",
"affiliations": "Department of Rheumatology, Hospital Clinic, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain. Electronic address: hflorez@clinic.cat.;Department of Rheumatology, Hospital Clinic, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain.;Department of Rheumatology, Hospital Clinic, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain.;Department of Rheumatology, Hospital Clinic, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain.;Department of Rheumatology, Hospital Clinic, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain.",
"authors": "Florez|Helena|H|;Ramírez|Julio|J|;Monegal|Ana|A|;Guañabens|Núria|N|;Peris|Pilar|P|",
"chemical_list": "D050071:Bone Density Conservation Agents; D000069448:Denosumab",
"country": "United States",
"delete": false,
"doi": "10.1016/j.semarthrit.2019.02.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0049-0172",
"issue": "49(2)",
"journal": "Seminars in arthritis and rheumatism",
"keywords": "Denosumab treatment; Drug holidays; Osteoporosis; Rebound; Vertebral fractures",
"medline_ta": "Semin Arthritis Rheum",
"mesh_terms": "D000368:Aged; D050071:Bone Density Conservation Agents; D000069448:Denosumab; D005260:Female; D006801:Humans; D008875:Middle Aged; D058866:Osteoporotic Fractures; D016103:Spinal Fractures; D028761:Withholding Treatment",
"nlm_unique_id": "1306053",
"other_id": null,
"pages": "197-203",
"pmc": null,
"pmid": "30826108",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Spontaneous vertebral fractures after denosumab discontinuation: A case collection and review of the literature.",
"title_normalized": "spontaneous vertebral fractures after denosumab discontinuation a case collection and review of the literature"
} | [
{
"companynumb": "ES-AMGEN-ESPSP2018074525",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DENOSUMAB"
},
"drugadditional": null,
... |
{
"abstract": "We hereby report a case of advanced and recurrent colon cancer with long-term survival after 7 repeated surgical resections. A 73-year-old woman initially underwent right hemicolectomy and partial hepatectomy for an ascending colon cancer with synchronous liver metastasis. Pathological diagnosis of the tumors were moderately differentiated adenocarcinoma and metastasis to the liver compatibly. Final clinical stage was diagnosed as fT3N2M1(H1), fStage Ⅳ. But she was interrupted oxaliplatin-based adjuvant chemotherapy after 6 courses of CAPOX because of adverse drug reaction. One year after first operation, partial resection of right lung was performed for lung metastasis. Two years after first operation, 2nd resection of liver was performed for 2 liver metastatic lesions. Three years after first operation, 3rd partial liver resection, 2nd and 3rd partial lung resections were performed for metachronous metastases during 1 year. After 3 years recurrence free period, she complained of an induration of right neck and diagnosed as neck and supra clavicular lymph nodes metastases. Lymph nodes resection was performed. After the last operation, she has no sign of cancer recurrence for 1 year and 7 months, eventually she has been alive for 7 years and 7 months after the initial operation.",
"affiliations": "Dept. of Surgery, Tokyo Women's Medical University, Medical Center East.",
"authors": "Kuhara|Kotaro|K|;Shiozawa|Shunichi|S|;Yokomizo|Hajime|H|;Usui|Takebumi|T|;Shimojima|Yukio|Y|;Nakayasu|Yasuyo|Y|;Kono|Teppei|T|;Tsuchiya|Akira|A|;Asaka|Shinichi|S|;Yoshimatsu|Kazuhiko|K|;Shimakawa|Takeshi|T|;Katsube|Takao|T|;Ohigashi|Seiji|S|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "47(13)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D003110:Colonic Neoplasms; D005260:Female; D006498:Hepatectomy; D006801:Humans; D008113:Liver Neoplasms; D009364:Neoplasm Recurrence, Local",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1833-1835",
"pmc": null,
"pmid": "33468844",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Advanced and Recurrent Colon Cancer with Long-Term Survival after Seven Repeated Surgical Resections.",
"title_normalized": "a case of advanced and recurrent colon cancer with long term survival after seven repeated surgical resections"
} | [
{
"companynumb": "JP-PFIZER INC-2021118500",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": "3",
... |
{
"abstract": "Antibiomania is a rare but recognized side effect with yet unclear definite pathogenesis although multiple hypotheses have been proposed. The novelty of this case is the suspected pharmacodynamic drug-drug interaction between clarithromycin and amoxicillin-clavulanic acid.\n\n\n\nWe present the occurrence of a brief manic episode concerning a 50-year-old man with no psychiatric history, first started on amoxicillin-clavulanic acid therapy and then switched to clarithromycin for left basal pneumonia. Shortly after the antibiotic prescription, he presented psychiatric symptomatology (logorrhea, elevated mood, irritability, increase in physical activity and delusions). The antibiotic was stopped and the patient received lorazepam (2.5 mg p.o.) to treat psychomotor agitation. Approximately 12 h after clarithromycin cessation, amelioration was already observed, supporting the diagnosis of a clarithromycin-induced manic episode. Amoxicillin-clavulanic acid was then reintroduced because of the pneumonia and psychiatric symptoms reemerged. This second antibiotic was also stopped, and 1 week later, the patient was symptom-free.\n\n\n\nThe emergence of psychiatric side effects related to antibiotherapy, which is a common treatment, can greatly impact a patient's quality of life. Early recognition and intervention could substantially influence the administered medical care and recovery. Moreover, given the widespread use of antibiotics including in combination, we thought our case report might be clinically useful as a clinical reminder relevant to the use of antibiotic combinations.",
"affiliations": "Departments of Emergency and Psychiatry, Emergency Psychiatric Unit (UAUP), Geneva University Hospitals (HUG), Geneva, Switzerland. meszaros.edith.paula@gmail.com.;Department of Psychiatry, Faculty of Medicine, University of Geneva (UNIGE), Rue Gabrielle-Perret-Gentil 4, 1205, Geneva, Switzerland.;Department of Psychiatry, Faculty of Medicine, University of Geneva (UNIGE), Rue Gabrielle-Perret-Gentil 4, 1205, Geneva, Switzerland.;Unit of Psychopharmacology, Department of Pharmacology and Toxicology, Geneva University Hospitals (HUG), Geneva, Switzerland.;Department of Psychiatry, Faculty of Medicine, University of Geneva (UNIGE), Rue Gabrielle-Perret-Gentil 4, 1205, Geneva, Switzerland.;Department of Psychiatry, Faculty of Medicine, University of Geneva (UNIGE), Rue Gabrielle-Perret-Gentil 4, 1205, Geneva, Switzerland.;Departments of Emergency and Psychiatry, Emergency Psychiatric Unit (UAUP), Geneva University Hospitals (HUG), Geneva, Switzerland.",
"authors": "Meszaros|Edith Paula|EP|;Stancu|Catheline|C|;Costanza|Alessandra|A|0000-0001-6387-6462;Besson|Marie|M|;Sarasin|François|F|;Bondolfi|Guido|G|0000-0002-4352-5531;Ambrosetti|Julia|J|0000-0002-5775-4589",
"chemical_list": "D000900:Anti-Bacterial Agents; D019980:Amoxicillin-Potassium Clavulanate Combination; D017291:Clarithromycin",
"country": "England",
"delete": false,
"doi": "10.1186/s12888-021-03397-7",
"fulltext": "\n==== Front\nBMC Psychiatry\nBMC Psychiatry\nBMC Psychiatry\n1471-244X\nBioMed Central London\n\n3397\n10.1186/s12888-021-03397-7\nCase Report\nAntibiomania: a case report of clarithromycin and amoxicillin-clavulanic acid induced manic episodes separately\nMeszaros Edith Paula meszaros.edith.paula@gmail.com\n\n1\nStancu Catheline catheline.stancu@unige.ch\n\n2\nhttps://orcid.org/0000-0001-6387-6462\nCostanza Alessandra alessandra.costanza@unige.ch\n\n2\nBesson Marie marie.besson@hcuge.ch\n\n3\nSarasin François francois.sarasin@unige.ch\n\n24\nhttps://orcid.org/0000-0002-4352-5531\nBondolfi Guido guido.bondolfi@unige.ch\n\n25\nhttps://orcid.org/0000-0002-5775-4589\nAmbrosetti Julia julia.ambrosetti@hcuge.ch\n\n1\n1 grid.150338.c 0000 0001 0721 9812 Departments of Emergency and Psychiatry, Emergency Psychiatric Unit (UAUP), Geneva University Hospitals (HUG), Geneva, Switzerland\n2 grid.8591.5 0000 0001 2322 4988 Department of Psychiatry, Faculty of Medicine, University of Geneva (UNIGE), Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland\n3 grid.150338.c 0000 0001 0721 9812 Unit of Psychopharmacology, Department of Pharmacology and Toxicology, Geneva University Hospitals (HUG), Geneva, Switzerland\n4 grid.150338.c 0000 0001 0721 9812 Department of Emergency, Emergency Medicine Unit, Geneva University Hospitals (HUG), Geneva, Switzerland\n5 grid.150338.c 0000 0001 0721 9812 Department of Psychiatry, Service of Liaison Psychiatry and Crisis Intervention (SPLIC), Geneva University Hospitals (HUG), Geneva, Switzerland\n11 8 2021\n11 8 2021\n2021\n21 3991 10 2020\n28 7 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nAntibiomania is a rare but recognized side effect with yet unclear definite pathogenesis although multiple hypotheses have been proposed. The novelty of this case is the suspected pharmacodynamic drug-drug interaction between clarithromycin and amoxicillin-clavulanic acid.\n\nCase presentation\n\nWe present the occurrence of a brief manic episode concerning a 50-year-old man with no psychiatric history, first started on amoxicillin-clavulanic acid therapy and then switched to clarithromycin for left basal pneumonia. Shortly after the antibiotic prescription, he presented psychiatric symptomatology (logorrhea, elevated mood, irritability, increase in physical activity and delusions). The antibiotic was stopped and the patient received lorazepam (2.5 mg p.o.) to treat psychomotor agitation. Approximately 12 h after clarithromycin cessation, amelioration was already observed, supporting the diagnosis of a clarithromycin-induced manic episode. Amoxicillin-clavulanic acid was then reintroduced because of the pneumonia and psychiatric symptoms reemerged. This second antibiotic was also stopped, and 1 week later, the patient was symptom-free.\n\nConclusion\n\nThe emergence of psychiatric side effects related to antibiotherapy, which is a common treatment, can greatly impact a patient’s quality of life. Early recognition and intervention could substantially influence the administered medical care and recovery. Moreover, given the widespread use of antibiotics including in combination, we thought our case report might be clinically useful as a clinical reminder relevant to the use of antibiotic combinations.\n\nKeywords\n\nAntibiomania\nAmoxicillin-clavulanic acid\nClarithromycin\nAntibiotics\nMania\nCase report\nAdverse effects\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nThe term antibiomania first appeared in 2002, referring to manic symptomatology induced by antibiotics [1]. Despite numerous case reports, specific knowledge about this phenomenon is still lacking. Because its impact on the patient’s quality of life is relevant, it would be useful to know more about the individual susceptibility and arrive at a clinical consensus about managing these cases. The problem with reporting only this side effect to authorities in charge is that the clinical details are left out, hence the importance of published case reports [1].\n\nTwo systematic literature reviews [1, 2] synthetized most existent data on antibiomania by including 47 spontaneous case reports and 143 cases reported to the Food and Drug Administration (FDA) and World Health Organization (WHO). These authors reported that clarithromycin, ciprofloxacin, and ofloxacin were the most common causative antibiotics [1, 2]. The key diagnostic feature for antibiomania is considered to be the close temporal relationship between the administration of the antibiotic and the emergence of manic symptoms. The first and the most important intervention was the discontinuation of the causative agent, which leads to the remission of the symptoms without the addition of antimanic agents in 18 cases (39%) [2]. Concerning putative etiopathogenetic underlying mechanisms of antibiomania, several theories have been put forward. The main hypothesis assumed that most antibiotics such as clarithromycin, fluoroquinolones, and beta-lactam antibiotics, antagonize postsynaptic GABA-A receptors in neurons and may cause an increase in neuron excitability [3–5].\n\nThis case report is aimed to describe a patient presenting with a first manic episode while being on antibiotics for a pneumonia, in order to remind fellow practitioners about the possible psychiatric adverse effects of antibiotics having a major impact on a patient’s quality of life. The early recognition of this phenomenon is important for an optimized medical care.\n\nCase presentation\n\nA 50-year-old male patient with no somatic or psychiatric history was diagnosed with left basal pneumonia at a hospital consultation and was started on amoxicillin-clavulanic acid (1 g t.i.d.), a beta-lactamase inhibitor antibiotic. Then, he was discharged. Due to persistent respiratory symptoms, the patient returned to the hospital the day after, and the treatment was switched to a macrolide antibiotic, clarithromycin (500 mg b.i.d.).\n\nTwo days after the second antibiotic prescription, his family members noted a progressive change in his behavior, with unusual logorrhea, irritability, increased physical activity, elevated mood, and ideas of being in contact with God. Due to these sudden changes, the family brought him back to the hospital. He was transferred to the emergency department (ED) of the University Hospital of Geneva (HUG), 2 days after modifying the antibiotic therapy. There were no known allergies, no tobacco, alcohol, illicit substance or daily medication intake (including steroids), and the patient had never taken antibiotics before.\n\nAt our first psychiatric evaluation, the patient reported that during the night after the introduction of the first antibiotic (amoxicillin-clavulanic acid), he had the feeling of dying and developed auditory hallucinations, as he was hearing God who was talking to him and saying he was chosen for a special mission. The psychiatric examination revealed a familiar attitude, a lightly increased psychomotor activity, irritability, logorrhea, elevated mood, difficulty falling asleep, as well as auditory hallucinations and mystic mood-congruent delusions that were, however, partially criticized. The antibiotic was immediately stopped and the patient received lorazepam (2.5 mg p.o.) as a treatment for psychomotor agitation. We chose to begin the psychopharmacotherapy very gradually, without immediate recourse to antipsychotic treatment, because the patient was partially nosognosic and the increased psychomotor agitation as well the irritability was foregrounded. Moreover, 12 h after clarithromycin cessation, amelioration was rapidly observed with the progressively gained insight of delusions and cessation of auditory hallucinations. The patient agreed that if his clinical conditions symptomatology did not improve, antipsychotic treatment would be necessary. These symptoms lasted in total about 36 h. The Young Mania Rating Scale (YMRS) score at the moment of the evaluation was 28, the equivalent of a manic episode [6].\n\nThe patient spent one night at the psychiatric ED observation unit of the HUG. After the above initial described amelioration during the first 12 h after the clarithromycin cessation, diminution of other manic symptoms was observed. Only logorrhea was still present. The YMRS score was 13, the equivalent of hypomanic symptomatology [6]. We discharged the patient with two tablets of lorazepam (1 mg p.o.). Considering the rapid amelioration of his symptoms by the antibiotics cessation and the only utilization of benzodiazepines, we chose not to initiate antipsychotics. We advised the patient to consult his family doctor in a few days and come back for a psychiatric evaluation 1 week later. Given the course of the clinical presentation the diagnosis of clarithromycin-induced manic episode was retained, and amoxicillin-clavulanic acid (625 mg b.i.d.) (Augmentin®) was then reintroduced for the pneumonia.\n\nInvestigations were completed with blood tests, which were in normal range except for high C-reactive protein at 200 mg/L without leukocytosis, rapid nasopharyngeal test for influenza A, B, and RSV, as well as cerebral scan, lumbar puncture and EEG. None of the results were contributive.\n\nSince the patient was 50 years old, without psychiatric history, considering the close temporal relationship between the clarithromycin intake and the manic episode in addition to the rapid amelioration after clarithromycin cessation, the diagnostic of clarithromycin-induced manic episode was retained at this point as an exclusion diagnostic. We considered this event to be a probable adverse drug reaction based on the WHO-UMC system for standardized case causality assessment [7], and the Naranjo algorithm, which showed a score of 5, indicative of a probable causal reaction [8].\n\nOne week later, at the psychiatric follow-up evaluation, the patient presented the subjective impression of a mildly elevated mood and talkativeness and an YMRS score of 3, the equivalent of a euthymic state.\n\nIn fact, the patient reported a worsening of the psychiatric symptomatology the evening after the reintroduction of amoxicillin-clavulanic acid. As he left the hospital, he took two doses of 625 mg as prescribed. At midnight, he started hearing voices again, he felt persecuted and anxious. He was again partially nosognosic. The next day, he presented symptoms similar to the first manic episode, with logorrhea, difficulties sleeping, familiar attitude, and dysphoria. The patient took the two tablets of lorazepam (1 mg) he received (one during the night after leaving ED and one the next day). He called his family doctor, who recommended the cessation of the antibiotic and concluded an adverse reaction to amoxicillin-clavulanic acid. This evolution then oriented towards a pharmacodynamic drug-drug interaction between clarithromycin and amoxicillin-clavulanic acid, leading to antibiomania.\n\nThis case was reported to the national pharmacovigilance center, and the need for local ethics committee approval was waived.\n\nDiscussion\n\nAntibiomania can affect a wide age-range of the cases (from 3 to 77 years old, mean 40 years old), mostly arises in the absence of psychiatric history, and two-thirds of the patients are male [2]. The duration of the symptomatology lasted on average 3 days for the cases induced by clarithromycin in the published reports reviewed by Abouesh and colleagues [1]. Even though the exact incidence remains unknown, antibiomania is still a clinically rare phenomenon if we consider the significant augmentation in the worldwide consumption of antibiotics, which increased by 36% between 2000 and 2010 [9]. For this reason, although antiobiomania is reported in the literature to be a rare effect, many more cases should be described given the extremely common use of antibiotics.\n\nThe case of the patient presented here indicates an association between the prescription of amoxicillin-clavulanic acid and clarithromycin and the onset of manic symptoms, which is supported by the close chronology between the two antibiotics treatments and the development of a manic symptomatology, as well as by the data from the literature. In a systematic review of 47 cases, macrolides were found to be the incriminating agents in 18 cases, the same number of cases being induced by antituberculars, seven by quinolones, and two by beta-lactams [2]. In another review of spontaneous reports, also using data from World Health Organization (WHO), it was found that out of 82 cases, clarithromycin was implicated in 23 (27.6%), ciprofloxacin in 12 (14.4%), ofloxacin in ten (12%), isoniazid in five (6%), and amoxicillin-clavulanic acid in two (2.4%) cases [1]. The same review analyzed 21 reports of antimicrobial-induced mania found in the literature: six cases implicated clarithromycin, 13 implicated isoniazid, and one case each implicating erythromycin and amoxicillin.\n\nIn summary, macrolides, quinolones, and antitubercular drugs seem to be the most frequent group of antibiotics associated with mania. They all share a decrease in gamma aminobutyric acid (GABA) [2]. The systematic review realized by Lambrichts and colleagues [2], summarizes several etiopathogenetic hypotheses: quinolones competitively inhibit binding of GABA to their receptor sites; isoniazid, an antitubercular drug, inhibits the enzyme called glutamic acid decarboxylase (GAD); and clarithromycin, a macrolide antibiotic, antagonizes postsynaptic GABA-A receptors in neurons and may cause an increase of neuron excitability. Interestingly enough, even though the frequency of antibiomania is much lower for beta-lactams, they could also present a concentration-dependent GABA antagonism. In our case, the patient could have presented two separate manic episodes with two different antibiotics. However, because of the common mechanism of increasing neuron excitability and the almost concomitant assumption, a pharmacodynamic drug-drug interaction between amoxicillin-clavulanic acid and clarithromycin was also suspected. These hypotheses could explain the pharmacodynamic drug-drug interaction between amoxicillin-clavulanic acid and clarithromycin in the present case [5].\n\nIn addition to the action on GABA neurotransmission, there are other hypotheses to explain antibiomania. These hypotheses implicate an increased concentration of cortisol, prostaglandin E1 (PGE1), pro-inflammatory cytokines, or C-reactive protein, as well as the glutaminergic pathways, abnormalities in mitochondrial function induced by antibiotics and finally, associations between antibiotic administration and changes in the composition of microbiota in the gastrointestinal tract [2]. Further research is needed to clarify all the implicated mechanisms.\n\nThe respective role of each antibiotic during the episode is hard to elucidate, since the patient experienced auditory hallucinations after amoxicillin intake, which continued together with manic clinical signs with clarithromycin and the second course of amoxicillin. Nevertheless, a pharmacodynamic drug-drug interaction between the two antibiotics can be hypothesized since they are both known to trigger such an episode. A limitation of this case report is the lack of medical evaluation of the symptoms induced by the second course of amoxicillin because the patient did not return to the hospital.\n\nPresumably, the patient presented here experienced psychiatric symptoms on two occasions, with two different antibiotics, highlighting the relevance of the individual biological susceptibility. There is a clear need for a close follow-up of the patients, especially at the first administration of antibiotics.\n\nThis case report needs to be interpreted in the light of two main limitations. First, there are already existing reports of cases of mania which develop after antibiotic use. Nevertheless, important knowledge is still lacking about this syndrome. Second, a rechallenge to verify our hypothesis of a pharmacodynamic drug-drug interaction between the two antibiotics was not done.\n\nConclusion\n\nDespite being a rare phenomenon, these clinical presentations and their differential diagnosis deserve greater attention, both for doctors working in primary care and mental health professionals. The emergence of psychiatric side effects related to antibiotherapy, which is a very commonly utilized treatment, can greatly impact on a patient’s quality of life. Early recognition and intervention could substantially influence the administered medical care and recovery. Moreover, given the widespread use of antibiotics, including in combination, we believe that our case report can be a clinically useful reminder relevant to antibiotic-combination treatments.\n\nAbbreviations\n\nb.i.d. bis in die (twice a day)\n\nED Emergency Department\n\nEEG Electroencephalography\n\nFDA Food and Drug Administration\n\nGABA Gamma Aminobutyric Acid\n\nHUG University Hospitals of Geneva\n\nPGE1 Prostaglandin E1\n\np.o. per os\n\nRSV Respiratory-Syncytial-Virus\n\nt.i.d. ter in die (three times a day)\n\nWHO World Health Organization\n\nYMRS Young Mania Rating Scale\n\nAcknowledgements\n\nWe would like to thank the patient for agreeing to describe his case.\n\nConflicts of interest disclosure\n\nNone declared.\n\nAuthors’ contributions\n\nEM and CS contributed to the conception and the design of this case report, and wrote the first draft of the manuscript. AC, MB, FS, JA, and GB substantively revised the manuscript and added relevant data and references. All authors have approved the submitted version.\n\nFunding\n\nThis work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nAvailability of data and materials\n\nData sharing is not applicable to this article as no datasets were generated or analysed.\n\nDeclarations\n\nEthics approval and consent to participate\n\nWritten informed consent was obtained from the patient described in the case report. The need for local ethics committee approval was waived. The present study was conducted in compliance with the Helsinki Declaration of 1975, as revised in October 2013 [10].\n\nConsent for publication\n\nWritten informed consent was obtained from the patient for publication of this Case report. A copy of the written consent is available for review by the Editor of this journal.\n\nCompeting interests\n\nAll authors declare that they have no competing interests.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Abouesh A Stone C Hobbs WR Antimicrobial-induced mania (Antibiomania): a review of spontaneous reports J Clin Psychopharmacol 2002 22 1 71 81 10.1097/00004714-200202000-00012 11799346\n2. Lambrichts S Van Oudenhove L Sienaer P Antibiotics and mania: a systematic review J Affect Disord 2017 219 149 156 10.1016/j.jad.2017.05.029 28550767\n3. Bichler EK Elder CC Garcia PS Clarithromycin increases neuronal excitability in CA3 pyramidal neurons through a reduction in GABAergic signalling J Neurophysiol 2017 117 1 93 103 10.1152/jn.00134.2016 27733592\n4. Lode H Potential interactions of the extended-spectrum fluoroquinolones with the CNS Drug Saf 1999 21 2 123 135 10.2165/00002018-199921020-00005 10456380\n5. Payne LE Gagnon DJ Riker RR Cefepime-induced neurotoxicity: a systematic review Crit Care 2017 21 1 276 10.1186/s13054-017-1856-1 29137682\n6. Young RC Biggs JT Ziegler VE Meyer DA A rating scale for mania: reliability, validity and sensitivity B J Psych Int 1978 133 5 429 435\n7. World Medical Association. WHO-UMC system for standardised case causality assessment. https://www.who.int/medicines/areas/quality_safety/safety_efficacy/WHOcausality_assessment.pdf. Accessed on 1 May 2020.\n8. Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA Janecek E Domecq C Greenblatt DJ A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 2 239 245 10.1038/clpt.1981.154 7249508\n9. Van Boeckel TP Gandra S Ashok A Caudron Q Grenfell BT Levin SA Global antibiotic consumption 2000 to 2010: an analysis of national pharmaceutical sales data Lancet Infect Dis 2014 14 8 742 750 10.1016/S1473-3099(14)70780-7 25022435\n10. World Medical Association World medical association declaration of Helsinki: ethical principles for medical research involving human subjects JAMA. 2013 310 20 2191 2194 10.1001/jama.2013.281053 24141714\n\n",
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"abstract": "OBJECTIVE\nThis study was performed to evaluate the Australian experience with cisplatin-based treatment of ovarian germ cell tumors (OGCT) with respect to survival and toxicity of treatment.\n\n\nMETHODS\nA retrospective review was undertaken based on a standardized questionnaire, which was sent to all major gynecologic oncology centers in Australia.\n\n\nRESULTS\nData on 58 patients were obtained. Overall survival at 5 years for all patients was 87%. There was one death from disease among 14 patients with dysgerminoma, and four deaths from disease among 44 patients with nondysgerminomas. Cisplatin-based chemotherapy was associated with a low incidence of serious complications, with only one treatment-related death (from bleomycin-induced respiratory failure).\n\n\nCONCLUSIONS\nOur large series demonstrates that cisplatin-based chemotherapy is highly effective for patients with OGCT. Although direct comparisons cannot be made, the survival of our patients with advanced tumors was comparable to that seen in male germ cell tumors, rather than inferior as is commonly believed. Future studies should aim to refine treatment to minimize toxicity, while further increasing curability.",
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"abstract": "Pharmacologic management for ulcerative colitis (UC) has recently been expanded to include anti- tumor necrosis factor (TNF) therapy for severe disease. Infliximab, a chimeric monoclonal antibody directed again TNF α was first tested in patients with Crohn's disease. In addition to serious infections, malignancy, drug induced lupus and other autoimmune diseases, serum sickness-like reactions, neurological disease, and infusion reactions further complicate the use of Infliximab. We report a case of prolonged fever after Infliximab infusion to treat steroid refractory UC.",
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"abstract": "Neonatal renal vein thrombosis (NRVT) is a rare thromboembolic complication in the neonatal period, and sequelae from renal dysfunction can cause significant morbidity. The authors retrospectively reviewed 10 patients with NRVT treated at their institution. The majority of the cohort were male (n = 9), preterm (n = 6), and had unilateral NRVT (n = 6). Six patients received thrombolysis and/or anticoagulation, and 4 patients received supportive care only. Two of the 6 patients treated with anticoagulation who had bilateral NRVT and anuria received thrombolysis with low-dose tissue plasminogen activator. Thrombolysis was not associated with any major adverse events, and both patients had marked improvement of renal function. Eight patients subsequently developed renal atrophy (3 received anticoagulation, 2 received thrombolysis with anticoagulation, and 3 received supportive care). Anticoagulation/thrombolysis did not appear to prevent renal atrophy. The role of thrombolysis needs to be further studied and considered in the setting of bilateral NRVT and acute renal failure.",
"affiliations": "a Department of Pediatrics, New York Medical College , Valhalla , NY , USA.;b Department of Pediatrics and Adolescent Medicine, Mayo Clinic , Rochester , MN , USA.;b Department of Pediatrics and Adolescent Medicine, Mayo Clinic , Rochester , MN , USA.;b Department of Pediatrics and Adolescent Medicine, Mayo Clinic , Rochester , MN , USA.;b Department of Pediatrics and Adolescent Medicine, Mayo Clinic , Rochester , MN , USA.",
"authors": "Bidadi|Behzad|B|;Nageswara Rao|Amulya A|AA|;Kaur|Dominder|D|;Khan|Shakila P|SP|;Rodriguez|Vilmarie|V|",
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"abstract": "BACKGROUND\nDihydropyrimidine dehydrogenase (DPD) enzyme is responsible for the elimination of approximately 80% of administered dose of 5-FU. DPD deficiency has been associated with severe 5-FU toxicity. Syndrome of DPD deficiency manifests as diarrhea, stomatitis, mucositis, and neurotoxicity and in some cases death. This is a true pharmacogenetic syndrome, with symptoms being unrecognizable until exposure to the drug.\n\n\nMETHODS\nA 75-year-old patient with metastatic pancreatic adenocarcinoma developed grade 4 thrombocytopenia, grade 3 coagulopathy, and grade 3 neurologic toxicity with a fatal outcome following administration of 5-FU. Due to pancytopenia, DPD activity could not be determined in peripheral blood mononuclear cells (PBMC) using a previously described radioassay. Therefore, screening and genotypic analysis of homozygous and heterozygous, known and unknown sequence variants, in the DPYD gene were performed using DHPLC as previously described. All DPYD sequence variants identified by DHPLC were confirmed by DNA sequencing using a dideoxynucleotide chain termination method and capillary electrophoresis on an ABI 310 Automated DNA Sequencer.\n\n\nRESULTS\nGenotyping analysis of the DPYD gene revealed the presence of the heterozygous mutation, IVS14 + 1 G > A, DPYD*2A.\n\n\nCONCLUSIONS\nGenotypic analysis using DHPLC can be employed to screen DPD deficiency in a patient with severe neutropenia. The mutation IVS14 + 1 G > A, DPYD*2A, is the most common mutation associated with DPD deficiency. A G > A base change at the splice recognition sequence of intron 14, leads to exon skipping and results in a 165-bp deletion in the DPD mRNA. We have previously demonstrated that a homozygote DPYD*2A genotype results in complete deficiency while the heterozygous DPYD*2A genotype results in partial deficiency of DPD.",
"affiliations": "Yale University School of Medicine, Section of Medical Oncology, 333 Cedar Street; FMP 116, New Haven, CT 06520, USA. wasif.saif@yale.edu",
"authors": "Saif|M W|MW|;Ezzeldin|Hany|H|;Vance|Katisha|K|;Sellers|Sandra|S|;Diasio|Robert B|RB|",
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"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D054067:Dihydropyrimidine Dehydrogenase Deficiency; D042943:Dihydrouracil Dehydrogenase (NADP); D017809:Fatal Outcome; D005472:Fluorouracil; D006801:Humans; D008297:Male; D009154:Mutation; D010190:Pancreatic Neoplasms; D017422:Sequence Analysis, DNA",
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"references": null,
"title": "DPYD*2A mutation: the most common mutation associated with DPD deficiency.",
"title_normalized": "dpyd 2a mutation the most common mutation associated with dpd deficiency"
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"companynumb": "US-MYLANLABS-2016M1025855",
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"abstract": "In 2010, the American College of Medical Toxicology established its Case Registry, the Toxicology Investigators Consortium (ToxIC). ToxIC is a prospective registry, which exclusively compiles suspected and confirmed toxic exposure cases cared for at the bedside by medical toxicologists at its participating sites. The Registry aims to fulfill two important gaps in the field: a real-time toxicosurveillance system to identify current poisoning trends and a powerful research tool in toxicology. ToxIC allows extraction of information from medical records making it the most robust multicenter database on chemical toxicities in existence. All cases seen by medical toxicologists at participating institutions were entered in a database. Information characterizing patients entered in 2011 was tabulated. 2010 data was also included so that cumulative total numbers could be described as well. The current report is a summary of the data collected in 2011 in comparison to 2010 entries and also includes cumulative data through December 31st, 2011. During 2011, 28 sites with 49 specific institutions contributed a total of 6,456 cases to the Registry. The total number of cases entered into the registry at the end of 2011 was 10,392. Emergency departments remained the most common source of consultations in 2011, accounting for 53 % of cases. The most common reason for consultation was for pharmaceutical overdoses, which occurred in 48 % of patients, including intentional (37 %) and unintentional (11 %) exposures. The most common classes of agents were sedative-hypnotics (1,492 entries in 23 % of cases), non-opioid analgesics (1,368 cases in 21 % of cases), opioids (17 %), antidepressants (16 %), stimulants/sympathomimetics (12 %), and ethanol (8 %). N-acetylcysteine was the most commonly administered antidote during 2011, similar to 2010, followed by the opioid antagonist naloxone, sodium bicarbonate, physostigmine and flumazenil. Anti-crotalid Fab fragments (CroFab) were administered in 106 out of 131 cases in which an envenomation occurred. There were 35 deaths recorded in the Registry during 2011. The most common associated agents, including when reported as sole agent or in combination with other agents, were opioids and analgesics (acetaminophen, aspirin, NSAIDS) with ten and eight deaths, respectively. Oxycodone was reported in six of the ten opioid-related deaths and heroin in three. Acetaminophen was the most common single agent reported overall being identified in all eight of the death cases attributed to analgesics. There were significant trends identified during 2011. Cases involving designer drugs including psychoactive bath salts and synthetic cannabinoids increased substantially from 2010 to 2011. The psychoactive bath salts were responsible for a large increase in stimulant/sympathomimetic-related cases reported to the Registry in 2011 with overall numbers doubling from 6 % of all Registry entries in 2010 to 12 % in 2011. Entries involving psychoactive drugs of abuse also increased twofold from 2010 to 2011 jumping 3 to 6 %, primarily due to increasing frequency of synthetic cannabinoid (\"K2\") related intoxications as 2011 progressed. The 2011 Registry included over 600 ADR's (10 % of Registry Cases) with 115 agents causing at least 2 ADR's. This is up from only 3 % of cases (116 total cases) in 2010. The ToxIC Case Registry continues to grow. At the end of 2011, over 10,000 cases had been entered into the Registry. As demonstrated by the trends identified in psychoactive bath salt and synthetic cannabinoid reports, the Registry is a valuable toxicosurveillance and research tool. The ToxIC Registry is a unique tool for identifying and characterizing confirmed cases of significant or potential toxicity or complexity to require bedside consultation by a medical toxicologist.",
"affiliations": "University of Rochester Medical Center & Strong Memorial Hospital, Rochester, NY, USA. Timothy_Wiegand@URMC.Rochester.edu",
"authors": "Wiegand|Timothy J|TJ|;Wax|Paul M|PM|;Schwartz|Tayler|T|;Finkelstein|Yaron|Y|;Gorodetsky|Rachel|R|;Brent|Jeffrey|J|;|||",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D000928:Antidepressive Agents; D011619:Psychotropic Drugs; D000082:Acetaminophen; D010098:Oxycodone; D000111:Acetylcysteine",
"country": "United States",
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"doi": "10.1007/s13181-012-0264-9",
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"issn_linking": "1556-9039",
"issue": "8(4)",
"journal": "Journal of medical toxicology : official journal of the American College of Medical Toxicology",
"keywords": null,
"medline_ta": "J Med Toxicol",
"mesh_terms": "D000082:Acetaminophen; D000111:Acetylcysteine; D000293:Adolescent; D000328:Adult; D000368:Aged; D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D000928:Antidepressive Agents; D002648:Child; D002675:Child, Preschool; D016208:Databases, Factual; D062787:Drug Overdose; D004636:Emergency Service, Hospital; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010098:Oxycodone; D011446:Prospective Studies; D011619:Psychotropic Drugs; D012042:Registries; D019966:Substance-Related Disorders; D055815:Young Adult",
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"pages": "360-77",
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"pubdate": "2012-12",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "21956161;22068919",
"title": "The Toxicology Investigators Consortium Case Registry--the 2011 experience.",
"title_normalized": "the toxicology investigators consortium case registry the 2011 experience"
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"abstract": "To evaluate whether combined surfactant with inhaled nitric oxide (iNO) use will prevent newborns with hypoxemic respiratory failure (HRF) from developing an Oxygenation Index (OI) > 40.\n\n\n\n100 term newborns with acute HRF (OI ≥ 20) were randomized to: Surfactant+iNO: received iNO plus up to two doses of surfactant or iNO-Controls: received iNO+placebo. Main outcome was the development of severe HRF (OI > 40) despite iNO use.\n\n\n\nBaseline mean ± SD OI was 37.4 ± 14 for the Surfactant+iNO group and 38.2 ± 16 for the controls. Infants receiving surfactant+iNO improved their oxygenation faster, resulting in lower OI at 24 h: 12.9 ± 9 vs 18.7 ± 11 of controls, p < 0.05; and a lower proportion developing OI > 40: 24%(12/50) vs 50%(25/50) of controls, p < 0.02. Fewer infants receiving surfactant+iNO presented the combined outcome of death or ECMO: 16%(8/50) compared to 36%(18/50) of controls, p < 0.05.\n\n\n\nEarly use of combined surfactant+iNO improves oxygenation preventing the progression to severe HRF. This may reduce mortality and ECMO need.\n\n\n\nISRCTN13727958.",
"affiliations": "Department of Neonatology, Division of Pediatrics, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile. alvgonza@med.puc.cl.;Hospital Guillermo Grant Benavente and Department of Pediatrics, Faculty of Medicine, Universidad de Concepción, Concepción, Chile.;Hospital Luis Tisné, Santiago, Chile.;Department of Neonatology, Division of Pediatrics, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.;Hospital San José, Santiago, Chile.;Department of Neonatology, Division of Pediatrics, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.;Department of Neonatology, Division of Pediatrics, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.",
"authors": "González|Alvaro|A|http://orcid.org/0000-0002-0442-9109;Bancalari|Aldo|A|;Osorio|Waldo|W|;Luco|Matías|M|;González|Agustina|A|;Pérez|Héctor|H|;Kattan|Javier|J|",
"chemical_list": "D013501:Surface-Active Agents; D009569:Nitric Oxide",
"country": "United States",
"delete": false,
"doi": "10.1038/s41372-020-00777-x",
"fulltext": null,
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"issn_linking": "0743-8346",
"issue": "41(1)",
"journal": "Journal of perinatology : official journal of the California Perinatal Association",
"keywords": null,
"medline_ta": "J Perinatol",
"mesh_terms": "D000280:Administration, Inhalation; D006801:Humans; D006976:Hypertension, Pulmonary; D007231:Infant, Newborn; D009569:Nitric Oxide; D012131:Respiratory Insufficiency; D013501:Surface-Active Agents; D017211:Treatment Failure",
"nlm_unique_id": "8501884",
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"pages": "32-38",
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"pmid": "32792635",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "27940508;1928459;8545223",
"title": "Early use of combined exogenous surfactant and inhaled nitric oxide reduces treatment failure in persistent pulmonary hypertension of the newborn: a randomized controlled trial.",
"title_normalized": "early use of combined exogenous surfactant and inhaled nitric oxide reduces treatment failure in persistent pulmonary hypertension of the newborn a randomized controlled trial"
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"companynumb": "CL-SYNEX-T202004384",
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"activesubstancename": "PORACTANT ALFA"
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"abstract": "How to cite this article: Mahendran AJ, Gupta N, Agrawal S, Ish P. Colistin-induced Acquired Bartter-like Syndrome: A Rare Cause of Difficult Weaning. Indian J Crit Care Med 2020;24(8):739-740.",
"affiliations": "Department of Pulmonary, Critical Care and Sleep Medicine, Vardhaman Mahavir Medical College and Safdarjung Hospital, New Delhi, India.;Department of Pulmonary, Critical Care and Sleep Medicine, Vardhaman Mahavir Medical College and Safdarjung Hospital, New Delhi, India.;Department of Pulmonary, Critical Care and Sleep Medicine, Jodhpur, Rajasthan, India.;Department of Pulmonary, Critical Care and Sleep Medicine, Vardhaman Mahavir Medical College and Safdarjung Hospital, New Delhi, India.",
"authors": "Mahendran|A J|AJ|;Gupta|Nitesh|N|;Agrawal|Sumita|S|;Ish|Pranav|P|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.5005/jp-journals-10071-23551",
"fulltext": "\n==== Front\nIndian J Crit Care Med\nIndian J Crit Care Med\nIJCCM\nIndian Journal of Critical Care Medicine : Peer-reviewed, Official Publication of Indian Society of Critical Care Medicine\n0972-5229 1998-359X Jaypee Brothers Medical Publishers \n\n10.5005/jp-journals-10071-23551\nLetter to the Editor\nColistin-induced Acquired Bartter-like Syndrome: A Rare Cause of Difficult Weaning\nMahendran AJ 1 Gupta Nitesh 2 Agrawal Sumita 3 Ish Pranav 4 1,2,4 Department of Pulmonary, Critical Care and Sleep Medicine, Vardhaman Mahavir Medical College and Safdarjung Hospital, New Delhi, India\n3 Department of Pulmonary, Critical Care and Sleep Medicine, Jodhpur, Rajasthan, India\nNitesh Gupta, Department of Pulmonary, Critical Care and Sleep Medicine, Vardhaman Mahavir Medical College and Safdarjung Hospital, New Delhi, India, Phone: +91 9873096364, e-mail: niteshgupta2107@gmail.com\n8 2020 \n24 8 739 740\nCopyright © 2020; Jaypee Brothers Medical Publishers (P) Ltd.2020© The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted use, distribution, and non-commercial 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.How to cite this article: Mahendran AJ, Gupta N, Agrawal S, Ish P. Colistin-induced Acquired Bartter-like Syndrome: A Rare Cause of Difficult Weaning. Indian J Crit Care Med 2020;24(8):739–740.\n\nKeywords\nBartters syndromeColistinColistin nephrotoxicityIntensive careMechanical VentilationWeaning failure\n==== Body\nSir,\n\nIn the late 20th century, polymyxin group of drugs, especially colistin, reemerged after 4 decades to curb the emerging pandemic of highly resistant bacteria. Although acute kidney injury (AKI), proteinuria, and tubulopathy are all known complications, disorders involving the tubulo-interstitium that lead to electrolyte and acid–base disorders are increasingly recognized.1 The occurrence of such disturbances in the intensive care unit set up causes undesired complications, deviating from the natural course and expected outcome of the primary disease.\n\nA 65-year-old male patient, known case of hypertension, COPD, and Parkinson's disease, on irregular treatment and follow-up, presented with history of progressive worsening of respiratory distress and productive cough for 1 week. On presentation, he had features suggestive of hypercapnic respiratory failure leading to altered sensorium with leukocytosis suggestive of infective exacerbation of COPD. He was intubated and put on invasive mechanical ventilation. On day 9, he developed ventilator-associated pneumonia, endotracheal aspirate isolating Acinetobacter baumanii. Antibiotics were upgraded to cefoperazone/sulbactam (2 g 12 hourly) and colistin (2 million units 8 hourly) based on culture sensitivity. There was significant fall in procalcitonin levels. But spontaneous breath trial (SBT) failed after 30 minutes with worsening respiratory acidosis, desaturation, and hypotension. Evaluation showed hypovolemic hypotension that was fluid responsive, despite persistent polyuria. Investigations revealed he had hypokalemia, hyponatremia, hypocalcemia, and hypomagnesaemia. Excess renal loss of the electrolytes evidenced by high fractional excretion of sodium (FeNa) and transtubular potassium gradient (TTKG). There was concomitant polyuria, despite being hypovolemic. Despite the parenteral correction of the electrolytes, there was recurrence and weaning was difficult. On stopping colistin on day 9, the parameters started to reverse after 3 days and on day 4 of stopping the drug, the patient was extubated. Unfortunately, he developed grade III bed sores during the course of illness, which was infected and cultured Klebsiella spp., sensitive to colistin only. In view of worsening general parameters secondary to sepsis with rising procalcitonin levels, he was restarted on colistin again on day 27 of admission. The electrolyte abnormalities and polyuria with hypovolemic hypotension recurred, which persisted until stopping colistin. Despite corrections given repeatedly, there was an episode of supraventricular tachycardia (SVT) which was reverted with adenosine. During the episode, very low level of serum magnesium was documented. Magnesium replacement was done, and there was no recurrence. A course of 10 day colistin was given with repeated electrolyte corrections and volume replacements, and the patient was successfully discharged on day 42 after resolution of the abnormalities.\n\nThe diagnosis of Bartter syndrome is a diagnosis of exclusion. It is a differential for metabolic alkalosis with hypokalemia and normal blood pressure more commonly seen in surreptitious vomiting and diuretic use.2 Both these were not present in our patient. Metabolic alkalosis with hypokalemia is a common occurrence in hyperaldosteronism which invariably is associated with hypertension and normovolemic state. In our case, the patient had hypovolemic hypotension with polyuria, which excluded the possibility.\n\nReviewing the literature, previous case reports are found which shows similar presentation.3–5 The duration of use of the drug appears to have little impact. Nevertheless, in all cases, the disorder was completely reversible. None of the cases had any underlying renal dysfunction.\n\nThere is increased and inevitable use of colistin in the ongoing battle against drug-resistant bacteria. As the patient stay increases in the hospital, there is increasing contributing factors for difficult weaning. Apart from the primary disease process and comorbidities, polypharmacy and antibiotic-induced adverse reactions contribute significantly as evidenced by hypokalemia due to Bartter-like syndrome leading to difficult weaning in our case. A high index of suspicion for Bartter-like syndrome while using colistin can help in early diagnosis and appropriate treatment decisions.\n\nSource of support: Nil\n\nConflict of interest: None\n==== Refs\nReferences\n1. Ordooei Javan A Shokouhi S Sahraei Z. A review on colistin nephrotoxicity. Eur J Clin Pharmacol 2015 71 7 801 810 DOI: 10.1007/s00228-015-1865-4 26008213 \n2. da Silva Cunha T Heilberg IP. Bartter syndrome: causes, diagnosis, and treatment. Int J Nephrol Renov Dis 2018 11 291 301 DOI: 10.2147/IJNRD.S155397 \n3. Tabish M Mahendran M Ray A Vikram NK. Colistin-induced acquired bartter-like syndrome: an unusual cause of meltdown. BMJ Case Rep 2020 13 2 e232630. DOI: 10.1136/bcr-2019-232630 \n4. Cakir U Alan S Zeybek C Erdeve O Atasay B Yalcinkaya F et al. Acquired bartter-like syndrome associated with colistin use in a preterm infant. Ren Fail 2013 35 3 411 413 DOI: 10.3109/0886022X.2012.761084 23342992 \n5. Kamal Eldin T Tosone G Capuano A Orlando R. Reversible hypokalemia and Bartter-like syndrome during prolonged systemic therapy with colistimethate sodium in an adult patient. Drug Saf Case Rep 2017 4 1 10 DOI: 10.1007/s40800-017-0052-1 28699114\n\n",
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"issue": "24(8)",
"journal": "Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine",
"keywords": "Bartters syndrome; Colistin; Colistin nephrotoxicity; Intensive care; Mechanical Ventilation; Weaning failure",
"medline_ta": "Indian J Crit Care Med",
"mesh_terms": null,
"nlm_unique_id": "101208863",
"other_id": null,
"pages": "739-740",
"pmc": null,
"pmid": "33024390",
"pubdate": "2020-08",
"publication_types": "D016428:Journal Article",
"references": "28699114;30519073;32029515;23342992;26008213",
"title": "Colistin-induced Acquired Bartter-like Syndrome: A Rare Cause of Difficult Weaning.",
"title_normalized": "colistin induced acquired bartter like syndrome a rare cause of difficult weaning"
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"activesubstancename": "COLISTIMETHATE SODIUM"
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"abstract": "The use of \"bath salts\" or other new psychoactive substances, otherwise known as \"legal highs\", is increasing. Illicit drug use during pregnancy is not uncommon. Nevertheless, literature reporting bath salts and their effect on pregnancy is scant. Besides, there seems to be no literature about bath salts and conduct of general anesthesia. This case report describes a general anesthetic for the surgical delivery of an infant to a woman under the acute influence of bath salts and methamphetamines.",
"affiliations": "Department of Anesthesiology and Pain Medicine, University of California Davis, Sacramento, CA 95817, USA.",
"authors": "Schloemerkemper|Nina|N|",
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"country": "China",
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"doi": "10.7555/JBR.32.20180023",
"fulltext": "\n==== Front\nJ Biomed ResJ Biomed ResJBRJournal of Biomedical Research1674-83012352-4685Editorial Department of Journal of Biomedical Research 2997062210.7555/JBR.32.20180023Case ReportPsychotic due to bath salts and methamphetamines: emergency cesarean section under general anesthesia Psychotic due to bath salts and methamphetaminesSchloemerkemper Nina Department of Anesthesiology and Pain Medicine, University of California Davis, Sacramento, CA 95817, USA.nschloemerkemper@ucdavis.eduCorresponding author: Nina Schloemerkemper, Dr. med., FRCA, FRCA, Department of Anesthesiology and Pain Medicine, University\nof California Davis, 4150 V Street, PSSB Suite 1200, Sacramento, CA 95817, USA. Tel/Fax: +1-916-734-5048/+1-916-734-7980; E-mail: nschloemerkemper@ucdavis.edu26 7 2018 15 5 2018 32 4 311 313 27 2 2018 5 4 2018 10 4 2018 © 2018 by the Journal of Biomedical Research. All rights reserved2018The Journal of Biomedical ResearchThis is an open access article under the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited.\nThe use of “bath salts” or other new psychoactive substances, otherwise known as “legal highs”, is increasing. Illicit drug use during pregnancy is not uncommon. Nevertheless, literature reporting bath salts and their effect on pregnancy is scant. Besides, there seems to be no literature about bath salts and conduct of general anesthesia. This case report describes a general anesthetic for the surgical delivery of an infant to a woman under the acute influence of bath salts and methamphetamines.\n\nbath saltspsychoactive substancelegal highdesigner drugmethamphetaminegeneral anesthesiacesarean section\n==== Body\nIntroduction\nIn pregnancy, the prevalence of illicit drug abuse is estimated to be around 11% with marijuana being the most frequent used[1]. There is no data about the prevalence of bath salt use during pregnancy. Literature about the effects of psychoactive drugs during pregnancy is limited[2]. In addition, there is no published information to date about general anesthesia in patients under the influence of bath salts. The abuse of bath salts is increasing[2‒5]. In the United Kingdom, a prevalence of at least 3% was reported in the 16‒24 year age group[4]. The US National Institute on Drug Abuse published data indicating that approximately 0.8% of 12th graders abuse bath salts (https://www.drugabuse.gov/drugs-abuse/synthetic-cathinones-bath-salts). New psychoactive substances seem to be most commonly used by individuals also involved with other substance abuse[4]. In addition, bath salts are frequently mixed in with other drugs like 3,4-methylenedioxymethamphetamine (MDMA, commonly known as ecstasy) (https://www.drugabuse.gov/national-survey-drug-use-health). Gaps in knowledge about new psychoactive substances and the need for research have become apparent[4,6].\n\n\nThis report describes a successful general anesthetic for an uncooperative and violent patient under the influence of methamphetamines and bath salts presenting for cesarean section.\n\nCase report\nOur patient in her early 20’s had a history of substance-induced psychosis. She had used methamphetamines for several years and admitted continued use throughout pregnancy. She presented near term with premature rupture of membranes, and was clearly psychotic as well as verbally and physically abusive. The patient admitted recent use of methamphetamines which was confirmed in a urine toxicology screen. Because of concern for self-harm, she was placed on involuntary psychiatric hold. On exam, the fetus was found to be in breech presentation. Considering the acute intoxication (at that time thought to be solely due to methamphetamines), aggressive behavior and paranoid delusions, the decision was made to perform a cesarean section rather than attempting external cephalic version followed by induction of labor. A relative was identified as surrogate decision maker, who agreed with the plan for a cesarean section under either general or regional anesthesia. During reassessment, the patient was increasingly agitated and threatening. In order to protect her own safety as well as that of the fetus, the decision was made to perform a cesarean section immediately.\n\nThe patient’s aggression made restraint by security personnel necessary for placement of an intravenous cannula. Immediately, 2 mg of midazolam were given, followed by incremental injection of a total of 120 mcg of dexmedetomidine over approximately 8 minutes. The patient became less agitated and appeared intermittently sleepy. Nevertheless, she still displayed bursts of aggression and required continued restraints on her way to the operating room and prior to induction.\n\nBecause of the patient’s physical outbursts, it became clear that regional anesthesia was not an option and general anesthesia was chosen. Routine anesthesia monitors were used. The baby’s status was unknown because the aggression and then time constraints made it impossible to apply fetal monitors. The first recorded vital signs of the mother in the operating room were a blood pressure of 124/88 mmHg and a pulse of 86. After skin preparation, draping and pre-oxygenation, general anesthesia was induced with 400 mg (5.5 mg/kg) propofol and succinylcholine. A higher than usual induction dose of propofol was chosen as the patient was still hypervigilant during pre-oxygenation. Tracheal intubation was uneventful. The patient was hemodynamically stable and anesthesia was maintained with inhalational sevoflurane in O2/N2O at standard end-tidal levels.\n\n\nA low-transverse cesarean section was performed. The amniotic fluid was clear and a vigorous baby was delivered one minute after incision. Apgar scores were 6 and 8 at 1 and 5 minutes, respectively. A cord blood gas unfortunately clotted.\n\nAfter administration of pitocin (rate: 30 IU over 1 hour), methergine 0.2 mg intramuscular (IM) and hemabate 250 mcg IM, and the placement of a B-Lynch suture the uterine tone was adequate. The overall estimated blood loss was 800 mL.\n\nIn addition to the medication mentioned above, the patient received midazolam 2 mg, fentanyl 150 mcg, ketorolac 30 mg, hydromorphone 2 mg and lactated Ringer’s 1,500 mL solution after delivery of the baby. The patient was slow to wake up from anesthesia but was successfully and uneventfully extubated approximately 70 minutes after surgery end with additional personnel in attendance due to concern for repeated aggression. Fortunately, this was not the case and the post-partum course was uneventful as her psychosis resolved. On further questioning, the patient admitted to having been high on bath salts in addition to methamphetamines.\n\nDiscussion\nBath salts, or “synthetic cathinones”, are a subgroup of “new psychoactive substances” that are also called “designer drugs”. Originally derived from the Catha edulis (Khat) plant, they are β-keto analogues of amphetamines[5,7]. Bath salts act by inhibiting re-uptake or increasing release of noradrenaline, dopamine, and serotonin to various degrees[7]. The signs and symptoms of bath salt intoxication are nonspecific, although agitation, psychosis and violent behavior are common[5,7‒8]. Symptoms can be mild, but serious clinical courses have been described including seizures, respiratory failure, hyperpyrexia, compartment syndrome, rhabdomyolysis, renal failure, disseminated intravascular coagulation, and even death[4‒5,7]. Urine toxicology screening as well as gas chromatography and immunoassays are possible diagnostic tools although impractical: the results take several days to come back[6‒7,9]. Clinicians therefore rely on the patient’s history. Unfortunately, most often patients are not asked about the use of bath salts[10]. Our patient was not specifically asked either and only revealed the information once the acute phase of her intoxication had passed. At the time of her emergency surgery, we were therefore unaware of the same day use of bath salts.\n\n\nSedation of a combative patient may be necessary. However, drugs commonly used can cause hemodynamic instability and hypoventilation, both of which can impair placental blood flow and oxygen transfer to the fetus. Although the use of benzodiazepines has been reported in acute intoxications[7], we were hesitant to give more benzodiazepines due to concern for respiratory depression during transfer to the operating room. One concern was also the respiratory effort of the newborn. In a prior case report, 0.025 mg/kg of midazolam given intravenously before a cesarean section did not have any adverse effects on the newborn[11]. Our patient received 2 mg of midazolam prior to the cord being clamped. This dose was slightly higher (0.028 mg/kg) than in the study mentioned above but did not seem to have an obvious negative impact on the newborn.\n\n\nIn order to minimize midazolam administration, we used dexmedetomidine as an adjunct. Considering that acute consumption of methamphetamine and bath salts causes an increase in sympathetic activity, an alpha2 receptor agonist may be a logical choice. A placental transfer rate of 0.76 shows that dexmedetomidine does cross the placenta but had no negative impact on APGAR scores[12‒13].\n\n\nThis patient received an unusually large dose of propofol for induction. This was an ad-hoc decision by the anesthesia provider due to the apparent resistance of the patient to the sedative medication that had already been administered.\n\n\nIn patients known to have ingested bath salts, it has been recommended to avoid the administration of fentanyl due to possible serotonergic effects[7]. This theoretical interaction was not supported by our clinical experience.\n\n\nSpecial attention should be placed on the potential for rhabdomyolysis, hyperthermia and hyponatremia that can occur during intoxication[7]. It would have been clinically informative to obtain a maternal arterial blood gas as the ingestion of synthetic cathinones has been associated with acidosis in 43% of patients[14].\n\n\nConclusion\nDrug abuse during pregnancy is not uncommon. Health care providers are commonly not aware which substances their patients are using. Unfortunately, timely screening tests for bath salts are not available[9], making diagnosis difficult. Due to their increased use, bath salts should be considered in the differential, particularly if a patient presents in a psychotic and aggressive state[2].\n\n\nWhile literature is lacking regarding the newer recreational drugs and their interaction with anesthetic drugs, we present a successful general anesthetic for an uncooperative and violent patient under the influence of methamphetamines and baths salts presenting for cesarean section. The patient was hemodynamically stable and the baby was born with APGAR scores of 6 and 8 suggesting successful management of mother and fetus in the difficult setting of unknown substance abuse.\n==== Refs\nReferences\n1 \nChang JC , \nHolland CL , \nTarr JA , \n\nPerinatal illicit drug and marijuana use [J]. \nAm J Health Promot , \n2017, \n 31 (1 ): 35 ‒42 .\n26559718 \n2 \nGray BA , \nHolland C . \nImplications of psychoactive ‘bath salts’ use during pregnancy [J]. \nNurs Womens Health , \n2014 , 18 (3 ): 220 ‒230 \n.\n24939199 \n3 \nPalamar JJ , \nSu MK , \nHoffman RS . \nCharacteristics of novel psychoactive substance exposures reported to New York City Poison Center, 2011‒2014 [J].\nAm J Drug Alcohol Abuse , \n2016 , 42 (1 ):\n 39 ‒47 \n.\n26678258 \n4 \nMdege ND , \nMeader N , \nLloyd C , \n\nThe novel psychoactive substances in the UK project: empirical and conceptual review work to produce research recommendations [M]. \nSouthampton (UK): NIHR Journals Library , \n2017 .\n\n5 \nBaumann MH , \nBukhari MO , \nLehner KR , \n\nNeuropharmacology of 3,4-methylenedioxypyrovalerone (MDPV), its metabolites, and related analogs [J].\nCurr Top Behav Neurosci , \n2017 , 32 : 93 ‒117 \n.\n27830575 \n6 \nScherbaum N , \nSchifano F , \nBonnet U . \nNew psychoactive substances (NPS) - a challenge for the addiction treatment services [J].\nPharmacopsychiatry , \n2017 , 50 (3 ): 116 ‒122 \n.\n28444659 \n7 \nDignam G , \nBigham C . \nNovel psychoactive substances: a practical approach to dealing with toxicity from legal highs [J].\nBJA Educ , \n2017 , 17 (5 ): 172 ‒177 .\n\n8 \nBaumann MH , \nSolis E Jr, \nWatterson LR , \n\nBaths salts, spice, and related designer drugs: the science behind the headlines [J].\nJ Neurosci , \n2014 , 34 (46 ): 15150 ‒15158 \n.\n25392483 \n9 \nDasgupta A . \nChallenges in laboratory detection of unusual substance abuse: issues with magic mushroom, peyote cactus, khat, and solvent abuse [J]. \nAdv Clin Chem , \n2017 , 78 : 163 ‒186 \n.\n28057187 \n10 \nVazirian M , \nJerry JM , \nJames J , \n\nBath salts in the emergency department: a survey of emergency clinicians’ experience with bath salts-intoxicated patients [J].\nJ Addict Med , \n2015 , 9 (2 ): 94 ‒98 \n.\n25525943 \n11 \nSenel AC , \nMergan F . \nPremedication with midazolam prior to caesarean section has no neonatal adverse effects [J]. \nBraz J Anesthesiol , \n2014 , 64 (1 ): 16 ‒21 .\n24565384 \n12 \nYu M , \nHan C , \nJiang X , \n\nEffect and placental transfer of dexmedetomidine during caesarean section under general anaesthesia [J].\nBasic Clin Pharmacol Toxicol , \n2015 , 117 (3 ): 204 ‒208 \n.\n25652672 \n13 \nLi C , \nLi Y , \nWang K , \n\nComparative evaluation of remifentanil and dexmedetomidine in general anesthesia for cesarean delivery [J].\nMed Sci Monit , \n2015 , 21 : 3806 ‒3813 \n.\n26638888 \n14 \nFroberg BA , \nLevine M , \nBeuhler MC , \n\nAcute methylenedioxypyrovalerone toxicity [J].\nJ Med Toxicol , \n2015 , 11 (2 ): 185 ‒194 \n.\n25468313 \n15 \nYee LM , \nWu D . \nFalse-positive amphetamine toxicology screen results in three pregnant women using labetalol [J].\nObstet Gynecol , \n2011 , 117 (2 Pt 2 ): 503 ‒506 \n.\n21252805\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1674-8301",
"issue": "32(4)",
"journal": "Journal of biomedical research",
"keywords": "bath salts; cesarean section; designer drug; general anesthesia; legal high; methamphetamine; psychoactive substance",
"medline_ta": "J Biomed Res",
"mesh_terms": null,
"nlm_unique_id": "101551157",
"other_id": null,
"pages": "311-313",
"pmc": null,
"pmid": "29970622",
"pubdate": "2018-07-23",
"publication_types": "D016428:Journal Article",
"references": "21252805;24565384;24939199;25392483;25468313;25525943;25652672;26559718;26638888;26678258;27830575;28057187;28444659",
"title": "Psychotic due to bath salts and methamphetamines: emergency cesarean section under general anesthesia.",
"title_normalized": "psychotic due to bath salts and methamphetamines emergency cesarean section under general anesthesia"
} | [
{
"companynumb": "US-TEVA-2018-US-966582",
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SEVOFLURANE"
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"drugadditional": null,
... |
{
"abstract": "Amyloidosis is a heterogeneous group of protein deposition diseases with more than 40 known clinical presentations. Localized amyloidosis occurs when the protein deposits exist in a singular location. Patients with diabetes mellitus who inject insulin at the same site can develop localized insulin-derived amyloidosis (AIns) at the injection site, which can be confused clinically with lipoma, lipohyperplasia, lipoatrophy, and fat necrosis. Histologic examination is performed to confirm localized AIns. We report a case of a patient with a long history of type 2 diabetes who presented with a subcutaneous mass in the abdomen at a preferred insulin injection site. Examination by light microscopy revealed diffuse deposition of eosinophilic material. Two of the tissue fragments contained numerous 30-40 μm spherical bodies within the eosinophilic material. The bodies had dark centers with peripheral eosinophilic material. Polarized sections stained with Congo red showed apple green birefringence, a characteristic of amyloid. Immunohistochemistry was positive for insulin antibodies in the dark spherules and the surrounding matrix. Proteomic analysis by mass spectrometry showed that the Congo red-positive material was insulin. Electron microscopy showed a background matrix consisting of nonbranching protein fibrils measuring 8.8-16.1 nm, consistent with amyloid; the spherules contained dark globular proteins in the center surrounded by nonbranching fibrillary proteins. Because these spherules were positive for insulin by immunohistochemistry and showed amyloid ultrastructurally, we refer to them as amyloid insulin bodies. The identification of AIns, specifically with amyloid insulin bodies, is important for diagnosis and treatment and may further our understanding of amyloidogenesis.",
"affiliations": "Western University, London, Ontario, Canada.;Department of Pathology, Dr. G.B. Cross Memorial Hospital, Clarenville, Newfoundland, Canada.;Department of Pathology, Dynacare Laboratory and Health Services Centre, Brampton, Ontario, Canada.",
"authors": "Katzman|Benjamin D|BD|;Traum|Peter|P|;Medline|Paul B|PB|",
"chemical_list": "D007004:Hypoglycemic Agents; D007328:Insulin",
"country": "United States",
"delete": false,
"doi": "10.1097/DAD.0000000000001052",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0193-1091",
"issue": "40(7)",
"journal": "The American Journal of dermatopathology",
"keywords": null,
"medline_ta": "Am J Dermatopathol",
"mesh_terms": "D000005:Abdomen; D000368:Aged; D003924:Diabetes Mellitus, Type 2; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents; D007279:Injections, Subcutaneous; D007328:Insulin; D058225:Plaque, Amyloid",
"nlm_unique_id": "7911005",
"other_id": null,
"pages": "527-530",
"pmc": null,
"pmid": "29135508",
"pubdate": "2018-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "New Histologic Finding of Amyloid Insulin Bodies at an Insulin Injection Site in a Patient With Diabetes.",
"title_normalized": "new histologic finding of amyloid insulin bodies at an insulin injection site in a patient with diabetes"
} | [
{
"companynumb": "CA-SA-2018SA305411",
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INSULIN HUMAN"
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"drugadditional": "3",
"... |
{
"abstract": "Pulmonary abscess is a distinctly uncommon complication of pneumococcal pneumonia in immunocompetent adults that has recently been reported to occur following administration of non-steroidal anti-inflammatory drugs (NSAIDs). We report herein the case of a 24-year-old patient with no predisposing risk factor who developed a lung abscess after NSAIDs exposure, further illustrating this potentially severe complication of NSAIDs use, especially in the absence of associated antibiotic therapy.",
"affiliations": "Service de Réanimation Médicale, Hôpital Henri Mondor, Assistance Publique, Hôpitaux de Paris, Créteil, France.",
"authors": "Gibelin|Aude|A|;de Prost|Nicolas|N|;Brun-Buisson|Christian|C|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2013()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002637:Chest Pain; D016724:Empyema, Pleural; D005260:Female; D005334:Fever; D006801:Humans; D008169:Lung Abscess; D011018:Pneumonia, Pneumococcal; D012307:Risk Factors; D055815:Young Adult",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "23964048",
"pubdate": "2013-08-20",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22044658;8995086;19331665;3924256;8358116;6859981;20724739",
"title": "Lung abscess complicating pneumococcal pneumonia: a causal role of non-steroidal anti-inflammatory drugs?",
"title_normalized": "lung abscess complicating pneumococcal pneumonia a causal role of non steroidal anti inflammatory drugs"
} | [
{
"companynumb": "FR-PFIZER INC-2015301557",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
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"drugadditional": null,
... |
{
"abstract": "A 9-year-old boy developed progressive anthracycline-induced cardiomyopathy three months after completion of chemotherapy for osteosarcoma. Five months after completion of chemotherapy, at the age of 10 years, heart transplantation was performed. At 29 months since transplantation, the patient remains free of rejection and recurrence of osteosarcoma. (Level of Difficulty: Intermediate.).",
"affiliations": "New Children's Hospital and Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.;New Children's Hospital and Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.;New Children's Hospital and Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.;New Children's Hospital and Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.;New Children's Hospital and Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.;Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.;Heart and Lung Center, Cardiac Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.;New Children's Hospital and Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.;New Children's Hospital and Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.",
"authors": "Kaskinen|Anu K|AK|;Helle|Emmi|E|;Pihkala|Jaana|J|;Jahnukainen|Timo|T|;Kanerva|Jukka|J|;Mäyränpää|Mikko I|MI|;Lemström|Karl|K|;Mattila|Ilkka|I|;Ojala|Tiina|T|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jaccas.2021.07.004",
"fulltext": "\n==== Front\nJACC Case Rep\nJACC Case Rep\nJACC Case Reports\n2666-0849\nElsevier\n\nS2666-0849(21)00675-6\n10.1016/j.jaccas.2021.07.004\nImaging Vignette\nClinical Vignette\nHeart Transplantation for Early-Onset Anthracycline-Induced Cardiomyopathy Within 5 Months of Chemotherapy Completion\nKaskinen Anu K. MD, PhD anu.kaskinen@helsinki.fi\na∗\nHelle Emmi MD, PhD ab\nPihkala Jaana MD, PhD a\nJahnukainen Timo MD, PhD a\nKanerva Jukka MD, PhD a\nMäyränpää Mikko I. MD, PhD c\nLemström Karl MD, PhD de\nMattila Ilkka MD, PhD a\nOjala Tiina MD, PhD ae\na New Children’s Hospital and Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland\nb Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland\nc Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland\nd Heart and Lung Center, Cardiac Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland\ne Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland\n∗ Address for correspondence: Dr Anu Kaskinen, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Biomedicum Helsinki 2U E104b, 00029 HUS Helsinki, Finland. anu.kaskinen@helsinki.fi\n03 11 2021\n03 11 2021\n03 11 2021\n3 15 16771679\n28 4 2021\n16 6 2021\n1 7 2021\n© 2021 The Authors\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nA 9-year-old boy developed progressive anthracycline-induced cardiomyopathy three months after completion of chemotherapy for osteosarcoma. Five months after completion of chemotherapy, at the age of 10 years, heart transplantation was performed. At 29 months since transplantation, the patient remains free of rejection and recurrence of osteosarcoma. (Level of Difficulty: Intermediate.)\n\nCentral Illustration\n\nKey Words\n\nacute heart failure\ncancer\ncardiac transplantation\ncardiomyopathy\npediatric surgery\nAbbreviations and Acronyms\n\nACM, anthracycline-induced cardiomyopathy\nEF, ejection fraction\nEMB, endomyocardial biopsy\nFS, fractional shortening\nHF, heart failure\nHTx, heart transplantation\nLV, left ventricle/ventricular\n==== Body\npmcA 9-year-old boy with high-grade osteosarcoma in the left humerus without metastases received treatment according to a 9-month-long EURAMOS-1 (European and American Osteosarcoma Study) protocol with good response (1). Radical surgery was performed, and no recurrence was detected. Anthracycline-induced mild left ventricular (LV) dysfunction (ejection fraction [EF] 55%, fractional shortening [FS] 28%) was observed in cardiac screening performed according to the EURAMOS-1 protocol after 300 mg/m2 cumulative dose of doxorubicin (Figure 1A) and at completion of treatment (LV EF/FS 52%/28%, cumulative doxorubicin dose of 450 mg/m2) (1). Three months after completing chemotherapy, the patient presented to the emergency department with acute heart failure (HF). Echocardiography showed biventricular dysfunction: LV 3D-EF 20%, LV FS 10%, LV global longitudinal strain −3%, tricuspid annular plane systolic excursion 13 mm, right ventricular fractional area change 22%, and pericardial effusion (Figures 1A to 1C).Figure 1 Clinical Parameters of Heart Function, Echocardiogram Findings at ACM Presentation, and Findings of the Explanted Heart\n\n(A) Left ventricular (LV) function as fractional shortening, left ventricular end-diastolic dimension (LVEDD), and cumulative doxorubicin dosage from start of osteosarcoma treatment as weeks. Echocardiogram images of parasternal (B) short axis and (C) long axis at presentation of anthracycline-induced cardiomyopathy (ACM) showing LV end-diastolic dimension 50 mm (+2.0 SD), and 4–8 mm of pericardial effusion. In Herovici staining of the explanted heart (D) (original magnification ×40) (E, ×200) LV wall revealed chicken wire–type interstitial fibrosis characteristic of AMC. (F) Explanted heart showing remarkable dilatation of both ventricles. EURAMOS-1 = European and American Osteosarcoma Study; HTx = heart transplantation; LVAD = left ventricular assist device.\n\nBased on the clinical evaluation, early-onset anthracycline-induced cardiomyopathy (ACM) was diagnosed. Despite intensive care, HF progressed, and a CentriMag LV assist device with Berlin Heart cannulas was implemented. During this operation, an endomyocardial biopsy (EMB) was taken to confirm the diagnosis. RV function was supported pharmacologically.\n\nThe risk for osteosarcoma tumor recurrence, secondary malignancy, or death was estimated at 5% to 10% (1). On the basis of an international transplantation network consultation and multidisciplinary team evaluation, the patient was listed for urgent heart transplantation (HTx) after 2 weeks of intensive care.\n\nSix weeks after listing, a HTx was successfully performed (see Figures 1D to 1F for explanted heart findings). The immunosuppressive therapy comprised tacrolimus, azathioprine, and steroids, with tacrolimus later replaced by cyclosporine because of septal hypertrophy. EMBs at 17 days and 1, 3, 6, 9, 12, and 24 months after HTx have revealed no rejection. At 29 months since HTx, the patient continues to thrive with no oncologic recurrence.\n\nDiscussion\n\nApproximately 2% of patients receiving anthracyclines present with congestive HF (2). The cardiotoxicity risk is dose dependent and is higher in younger patients (2). According to the International Society of Heart and Lung Transplantation guidelines from 2006, no arbitrary time for observation before HTx is necessary; instead, HTx can be considered based on individual assessment. This is supported by findings of cancer recurrence not increasing after pediatric HTx (3). The Pediatric Heart Transplant Study group, capturing data on approximately 80% of pediatric transplantation candidates worldwide, does not report time from completion of malignancy treatment to HTx in ACM (3). Notably, before this case, only two cases of early HTx <1 year after treatment of malignancy have been reported (3).\n\nThe osteosarcoma was initially treated according to the EURAMOS-1 protocol, wherein anthracyclines may be continued if FS is ≥28% and EF is ≥50% (1). It remains unknown whether the patient’s outcome would have been improved by increasing echocardiographic sensitivity with strain imaging to detect ACM and by early initiation of cardioprotective treatment.\n\nThis case demonstrates HTx as a successful treatment option just 5 months after completion of chemotherapy in severe ACM with end-stage heart failure. When HTx is considered shortly after chemotherapy completion, individual assessment of life expectancy and recurrence risk remains essential.\n\nFunding Support and Author Disclosures\n\nOpen access was funded by the Helsinki University Library. This work was financially supported by the Foundation for Pediatric Research, Helsinki, Finland, and by the Academy of Finland, Helsinki, Finland. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.\n\nThe authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.\n==== Refs\nReferences\n\n1 Smeland S. Bielack S.S. Whelan J. Survival and prognosis with osteosarcoma: outcomes in more than 2000 patients in the EURAMOS-1 (European and American Osteosarcoma Study) cohort Eur J Cancer 109 2019 36 50 30685685\n2 Saleh Y. Abdelkarim O. Herzallah K. Abela G.S. Anthracycline-induced cardiotoxicity: mechanisms of action, incidence, risk factors, prevention, and treatment. Heart Fail Rev 26 5 2021 1159 1173 32410142\n3 Bock M. Pahl E. Rusconi P. Cancer recurrence and mortality after pediatric heart transplantation for anthracycline cardiomyopathy: a report from the Pediatric Heart Transplant Study (PHTS) Group Pediatr Transplant 21 5 2017 e12923\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2666-0849",
"issue": "3(15)",
"journal": "JACC. Case reports",
"keywords": "ACM, anthracycline-induced cardiomyopathy; EF, ejection fraction; EMB, endomyocardial biopsy; FS, fractional shortening; HF, heart failure; HTx, heart transplantation; LV, left ventricle/ventricular; acute heart failure; cancer; cardiac transplantation; cardiomyopathy; pediatric surgery",
"medline_ta": "JACC Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101757292",
"other_id": null,
"pages": "1677-1679",
"pmc": null,
"pmid": "34766017",
"pubdate": "2021-11-03",
"publication_types": "D016428:Journal Article",
"references": "30685685;32410142",
"title": "Heart Transplantation for Early-Onset Anthracycline-Induced Cardiomyopathy Within 5 Months of Chemotherapy Completion.",
"title_normalized": "heart transplantation for early onset anthracycline induced cardiomyopathy within 5 months of chemotherapy completion"
} | [
{
"companynumb": "FI-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-338516",
"fulfillexpeditecriteria": "1",
"occurcountry": "FI",
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"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
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"dru... |
{
"abstract": "Multiple idiopathic cervical root resorption is an aggressive form of external root resorption that occurs at the cementoenamel junction and can affect multiple teeth (a minimum of 3) throughout the entire dentition. Most of the individuals affected are healthy with noncontributory medical histories. The resorption is usually detected as an incidental finding on radiographs or during dental examination. This case report describes an adult female with multiple cervical root resorptions who had been treated with chemotherapy for ovarian cancer at 16 years old. Nine years later, a total of 12 teeth were diagnosed with cervical root resorption. All of the known causative factors for external cervical resorption were discarded. To our knowledge, this is the first case reported of multiple cervical root resorption related to chemotherapy.",
"affiliations": "University of Barcelona, Barcelona, Spain. Electronic address: marc.llavayol@gmail.com.;University of Barcelona, Barcelona, Spain.;University of Barcelona, Barcelona, Spain; IDIBELL Institute, Barcelona, Spain.;University of Barcelona, Barcelona, Spain; IDIBELL Institute, Barcelona, Spain.",
"authors": "Llavayol|Marc|M|;Pons|Montserrat|M|;Ballester|Maria Lluisa|ML|;Berástegui|Esther|E|",
"chemical_list": "D017329:Triptorelin Pamoate; D001761:Bleomycin; D017373:Cyproterone Acetate; D005047:Etoposide; D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.joen.2018.12.012",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0099-2399",
"issue": "45(3)",
"journal": "Journal of endodontics",
"keywords": "Chemotherapy; cone-beam computed tomography; external cervical resorption; multiple idiopathic cervical root resorption",
"medline_ta": "J Endod",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001761:Bleomycin; D002945:Cisplatin; D054893:Cone-Beam Computed Tomography; D017373:Cyproterone Acetate; D003757:Dental Implantation; D003793:Dental Restoration, Permanent; D005047:Etoposide; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms; D012391:Root Resorption; D017329:Triptorelin Pamoate",
"nlm_unique_id": "7511484",
"other_id": null,
"pages": "349-353",
"pmc": null,
"pmid": "30803545",
"pubdate": "2019-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Multiple Cervical Root Resorption in a Young Adult Female Previously Treated with Chemotherapy: A Case Report.",
"title_normalized": "multiple cervical root resorption in a young adult female previously treated with chemotherapy a case report"
} | [
{
"companynumb": "ES-ACCORD-135480",
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{
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"activesubstance": {
"activesubstancename": "CISPLATIN"
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"druga... |
{
"abstract": "Cytoreductive nephrectomy has long been used to improve disease control in metastastic Renal Cell Carcinoma (mRCC). However, based on the results of the CARMENA and SURTIME trials, cytoreductive nephrectomy is no longer the standard of care in patients requiring upfront systemic treatment and it should be avoided in most poor-risk patients. Nevertheless, it should still be considered in patients responding to systemic therapy and good-risk patients not requiring systemic treatment. This case series of the phase 2 CABOPRE trial suggests neoadjuvant cabozantinib may be able to induce rapid and significant responses in some intermediate-risk advanced renal cell carcinoma patients facilitating resectability.",
"affiliations": "Medical Oncology Department, Hospital Universitario 12 de Octubre, Comunidad de Madrid, Madrid, Spain.;Medical Oncology Department, Hospital Universitario 12 de Octubre, Comunidad de Madrid, Madrid, Spain.;Urology Department, Hospital Universitario 12 de Octubre, Comunidad de Madrid, Madrid, Spain.;Medical Oncology Department, Hospital Universitario Ramón y Cajal, Comunidad de Madrid, Madrid, Spain.;Medical Oncology Department, Hospital Universitario HM Sanchinarro, Comunidad de Madrid, Madrid, Spain.;Medical Oncology Department, Hospital Universitario 12 de Octubre, Comunidad de Madrid, Madrid, Spain.;Medical Oncology Department, Hospital Universitario 12 de Octubre, Comunidad de Madrid, Madrid, Spain.;Urology Department, Hospital Universitario 12 de Octubre, Comunidad de Madrid, Madrid, Spain.;Medical Oncology Department, Hospital Universitario 12 de Octubre, Comunidad de Madrid, Madrid, Spain.",
"authors": "de Velasco|Guillermo|G|;Carril-Ajuria|Lucia|L|;Guerrero-Ramos|Felix|F|;Alonso-Gordoa|Teresa|T|;Rodríguez-Moreno|Juan F|JF|;Carretero|Alberto|A|;Martin-Soberon|Maricruz|M|;de la Rosa-Kehrmann|Federico|F|;Castellano|Daniel|D|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.18632/oncotarget.27807",
"fulltext": "\n==== Front\nOncotarget\nOncotarget\nImpact Journals LLC\nOncotarget\n1949-2553 Impact Journals LLC \n\n27807\n10.18632/oncotarget.27807\nCase Report\nA case series of advanced renal cell carcinoma patients treated with neoadjuvant cabozantinib prior to cytoreductive nephrectomy within the phase 2 CABOPRE trial\nde Velasco Guillermo 1 Carril-Ajuria Lucia 1 Guerrero-Ramos Felix 2 Alonso-Gordoa Teresa 3 Rodríguez-Moreno Juan F. 4 Carretero Alberto 1 Martin-Soberon Maricruz 1 de la Rosa-Kehrmann Federico 2 Castellano Daniel 1 1Medical Oncology Department, Hospital Universitario 12 de Octubre, Comunidad de Madrid, Madrid, Spain\n2Urology Department, Hospital Universitario 12 de Octubre, Comunidad de Madrid, Madrid, Spain\n3Medical Oncology Department, Hospital Universitario Ramón y Cajal, Comunidad de Madrid, Madrid, Spain\n4Medical Oncology Department, Hospital Universitario HM Sanchinarro, Comunidad de Madrid, Madrid, Spain\nCorrespondence to: Guillermo de Velasco, email: gdvelasco.gdv@gmail.com\n24 11 2020 \n24 11 2020 \n11 47 4457 4462\n18 9 2020 27 10 2020 Copyright: © 2020 de Velasco et al.This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Cytoreductive nephrectomy has long been used to improve disease control in metastastic Renal Cell Carcinoma (mRCC). However, based on the results of the CARMENA and SURTIME trials, cytoreductive nephrectomy is no longer the standard of care in patients requiring upfront systemic treatment and it should be avoided in most poor-risk patients. Nevertheless, it should still be considered in patients responding to systemic therapy and good-risk patients not requiring systemic treatment.\n\nThis case series of the phase 2 CABOPRE trial suggests neoadjuvant cabozantinib may be able to induce rapid and significant responses in some intermediate-risk advanced renal cell carcinoma patients facilitating resectability.\n\nkidney cancerrenal cell carcinomaneoadjuvant treatmentcabozantinibtrial\n==== Body\nINTRODUCTION\nSystemic treatment (ST) has been the cornerstone of advanced renal cell carcinoma (aRCC) but CN has also long been used to improve disease control [1–5]. Currently, the role of CN for aRCC patients has yet to be defined. The SURTIME and the CARMENA trials provided new data but the definitive role of CN remains unclear [6, 7]. The SURTIME trial, suggested the non-inferiority of deferred CN compared to upfront CN [7]. The CARMENA trial demonstrated the non-inferiority of sunitinib alone compared to immediate CN followed by sunitinib [6]. These results support that CN should no longer be the standard of care in patients requiring ST upfront and suggest that surgery should be avoided in IMDC International Metastatic RCC database Consortium-(IMDC)-poor risk patients. Nevertheless, CN could remain as an option for selected patients responding to ST and good-risk patients not requiring ST [8].\n\nWithin this context the CABOPRE trial (EudraCT Number: 2018-001201-93) was designed as an open-arm phase II trial, to assess the efficacy and safety of cabozantinib 60 mg/daily, given as perioperative treatment for aRCC patients in potential candidates to CN. The primary endpoint was objective response rate (ORR) by RECIST 1.1 (Response Criteria Evaluation Criteria in Solid Tumors) at 12 weeks. The goal of this case series is to illustrate the preliminary experience of the CABOPRE trial with some illustrative cases of aRCC treated with neoadjuvant (NA) cabozantinib prior to CN.\n\nPatient 1: Tumour thrombus downsize in a locally advanced (LA) RCC patient treated with NA cabozantinib\nA 60 year-old man with no relevant medical history, presented in the Emergency Department (ED) with back pain and hematuria in March of 2019. A thoracoabdominal-pelvic (TAP) computed tomography (CT) scan revealed a left renal mass of 9 cm with renal vein and inferior cave vein (ICV) invasion, paraaortic lymph nodes and small bilateral lung metastases. A CT guided biopsy of the renal mass revealed a Fuhrman grade 3 clear cell RCC (ccRCC).\n\nThe patient was classified as intermediate-risk by IMDC and was enrolled in the CABOPRE trial. The patient underwent three cycles of full dose cabozantinib (60 mg/d) with acceptable tolerance and achieving a significant downsizing of the tumor thrombus and renal mass (Figure 1). Radical nephrectomy and IVC/renal vein thrombectomy were successfully performed, confirming a pT3bNxMx ccRCC with IVC/left renal vein extension. The patient restarted cabozantinib at a dose of 40 mg daily after surgery and has remained progression free to date (follow-up 12 months). The benefits of tumor thrombus reduction are well known, reducing surgical morbidity and mortality and enabling a complete surgical resection of both the primary tumor and the tumor thrombus which is key to improve survival outcomes [9].\n\nFigure 1 (A) baseline CT scan and (B) the reassessment CT scan at 12 weeks of treatment, showing the tumor thrombus downsizing (arrows) and the left kidney mass response (from 89 to 75 mm). (C) last reassessment CT scan where the patient remains progression free.\n\nPatient 2: Rapidly progressive aRCC during cabozantinib break despite initial response\nA 46 year-old woman current smoker and with no other relevant medical history presented in the ED in May 2019 with a palpable abdominal mass and intense right clavicle pain. A TAP CT scan was performed showing a large left renal mass of ~17.5 cm in its long axis and revealing mediastinal/ retroperitoneal lymph node and bone metastasis (right clavicle), as well as left lung nodules suspicious of metastases. CT guided biopsy confirmed Fuhrman grade 3 ccRCC. The patient was classified as intermediate-risk by IMDC and met all criteria of the CABOPRE trial. She underwent three cycles before surgery and required dose reduction to 40 mg daily from the third cycle due to grade 2 mucositis. No other toxicity was reported, and the reassessment CT scan demonstrated a significant response of both the renal mass and the mediastinal and retroperitoneal lymph nodes metastatic disease (Figure 2). Radical nephrectomy with left adrenalectomy and lymphadenectomy was performed in October 2019 without acute complications. Unfortunately, the CT scan performed 12 weeks later revealed lymph node, lung and hepatic progression.\n\nFigure 2 (A) baseline CT scan and (B) the reassessment CT scan showing the response achieved after 12 weeks of treatment with cabozantinib at different levels (mediastinal lymph nodes, left kidney mass and retroperitoneal lymph nodes).\n\nTiming of CN is not defined. Median time to response to cabozantinib is around 1.9 months [10]. Thus, our trial was designed for 12 weeks of neoadjuvant cabozantinib before CN. Regrettably, not all patients who respond to systemic therapy may benefit from CN. In fact, our patient presented progressive disease after 3 cycles of the ipilimumab/nivolumab combination. A third line therapy with a TKI again (Axitinib) was attempted without benefit. Cancer treatment was finally stopped, and the patient is currently under best supportive care.\n\nPatient 3: Resectable kidney mass after response to NA cabozantinib, but unfortunately medically inoperable\nA 59 year-old man current smoker and with chronic obstructive pulmonary disease (COPD), presented in the ED with sharp left costal pain. A thoracic radiography demonstrated cannonball metastases with a pleural thickening of 6 cm on the upper left lobe, a right renal mass of 16 cm and right iliac metastasis with soft tissue extension. Bronchoscopy was performed and the biopsies revealed a Fuhrman grade 2 ccRCC. The patient was classified as intermediate-risk by IMDC and was included in our study. The patient underwent three cycles of cabozantinib with good tolerance and achieving partial response by RECIST 1.1 (Figure 3). After multidisciplinary team discussion, although resectable, the patient was finally considered inoperable due to worsening of his COPD. Cabozantinib was continued at 60 mg/day. Unfortunately, two months later the patient presented clinical progression with tumoral hypercalcemia and radiological progression with kidney mass enlargement and new bone lesions on the reassessment CT scan. In this case the response was deeper in the metastases than in the primary as predictable. The key point that illustrates this case is whether a CN would have impacted the prognosis of this patient.\n\nFigure 3 (A) baseline CT scan and (B) response after 12 weeks of neoadjuvant treatment with cabozantinib with significant reduction of the mass in the superior right lobe (SRL) from 43.4 to 30 mm and of the right kidney mass from 116.3 to 80 mm.\n\nPatient 4: Maintained disease control with cabozantinib allows successful CN and lung metastasectomy approach\nA 60 year-old man with a medical history of hypertension, type 2 diabetes mellitus and coronary artery disease, was diagnosed of a left kidney renal mass by ultrasound due to intermittent hematuria. A TAP CT scan was then performed demonstrating a left kidney mass of 66.8 mm and small bilateral lung nodules, being the largest of 12 mm. CT guided biopsy of both the left kidney mass and the lung nodule revealed a Fuhrman grade 1 ccRCC. The patient received 12 weeks of cabozantinib requiring dose reduction to 40 mg daily after the first cycle due to grade 2 asthenia. The reassessment CT scan showed a reduction of both the primary tumor and the lung metastasis but without achieving PR by RECIST 1.1 criteria (–16%) (Figure 4). Left kidney CN was performed successfully on December 2019. Cabozantinib at dose of 40 mg daily was reinitiated three weeks later. Two months later the treatment was discontinued due to poor tolerability (dysphonia, diarrhea and anxiety) and maximal benefit achieved with stability of the target lung nodule metastasis. The patient is currently waiting for surgical resection of the only solitary lung visible metastasis which has been delayed due to the COVID19 pandemic.\n\nFigure 4 (A) baseline CT scan and (B) response obtained after three months of neoadjuvant cabozantinib, with a reduction of the left kidney mass from 66.8 to 55.5 mm and of the SRL nodule from 12.1 to 10.8 mm. (C) Last reassessment CT scan, after CN, showing only stability of the remaining solitary lung metastases which is pending surgery.\n\nDISCUSSION\nCabozantinib is a multi-kinase inhibitor (vascular endothelial growth factor receptor 2, tyrosine-protein kinases (TKI) MET and AXL) that has shown better disease control rate (DCR) and response rate (RR) than first generation TKIs such as sunitinib (i.e., DCR of 75% vs 47% and RR of 20% vs 9% respectively, CABOSUN trial) [10]. These results anticipated an increased RR when given prior to nephrectomy, which added to the short time-to-response reported with this drug, make it suitable for perioperative treatment. Here, we have reported the outcomes of four patients treated in the CABOPRE study as preliminary data of the trial. Remarkably, although all these patients were intermediate-risk and most of them had high tumor burden and high number of comorbidities, the tumor shrinkage was remarkable. Two (Patients 2–3) of the four cases achieved partial response by RECIST 1.1. criteria, and the other two patients presented a significant response. Patient 1 presented a significant downsizing of the tumor thrombus which facilitated surgical resectability and decreased risk of postoperative complications, and patient 4 achieved a sustained stability enabling a successful CN which will be followed by lung metastasectomy. Surprisingly, there is still no single predictive biomarker developed for RCC. This perioperative treatment with active drugs allows better selection of patients for CN and precludes a perfect window of opportunity for translational research in order to optimize treatment in the near future (multiple translation studies are ongoing).\n\nOn the downside, these preliminary results raise concerns about the breaks, either surgery-related or due to toxicity, and disease progression, as well as the perfect timing for delayed CN. Recently, the combination of immune checkpoint inhibitors (IO) with either TKI or double IO-IO has shown an improvement in RR and overall survival [4, 5]. CN may still have a role, especially with these novel combos since the response of the primary tumor is usually less intense than of the metastases [11].\n\nIn conclusion, cabozantinib as perioperative treatment can induce rapid and remarkable responses in intermediate-risk patients facilitating resectability in advanced or metastatic ccRCC patients. These preliminary results are promising, and definitive results and biomarkers of this trial are awaited. Final results will be reported as a global efficacy data including the CN rate and the relationship with tumor-shinkrage.\n\n\nAuthor contributions\n\n\nConception and design: all authors. Acquisition of data: all authors. Analysis an interpretation of data: all authors. Drafting of the manuscript: de Velasco G, Carril-Ajuria L. Critical revision: all authors. Statistical analysis: N/A. Obtaining funding: de Velasco G. Administrative, technical or material support: all authors. Supervision: de Velasco G, Castellano D.\n\nACKNOWLEDGMENTS\nAcknowledgments to all investigators of CABOPRE Trial (J.F. Rodriguez-Moreno, H.U. HM Sanchinarro; T. Alonso-Gordoa, H. U. Ramón y Cajal; A. Pinto, H. U. la Paz; A. Lopez Martin, H. U. Severo Ochoa; X. García del Muro, Institut Català d’Oncologia; E. Esteban, Hospital Universitario Central de Asturias; I. Durán, H.U. de Valdecilla).\n\n\nCONFLICTS OF INTEREST\n\n\nGdV reports honoraria/consulting role/research funding: Pfizer, Novartis, Ipsen, Bristol-Myers Squibb, Bayer, Roche, Astellas, MSD. Merk, Jannsen. Also, from Ipsen, which contributed financially to the design and conduction of the trial (initiated investigated research; grant from Ipsen). DC reports consulting or advisory role for Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Ipsen, Janssen Oncology, Lilly, MSD Oncology, Novartis, P LCA, FGR, TAG, JRM, AGC, MM, FRK, DC : declare no conflicts of interest. fizer, Pierre Fabre, Roche/Genentech, Sanofi. LCA, FGR, TAG, JRM, AGC, MM, and FRK: declare no conflicts of interest.\n\n\nFUNDING\n\n\nSponsorship by ONCOSUR. Initiated study with a grant from Ipsen. GdV is funded by the Carlos III Institute of Health, Ministry of Economy and Competitiveness (Spain), reference FSI17/1728.\n==== Refs\nREFERENCES\n1. \n\nEscudier \nB \n, \nPorta \nC \n, \nSchmidinger \nM \n, \nRioux-Leclercq \nN \n, \nBex \nA \n, \nKhoo \nV \n, \nGrünwald \nV \n, \nGillessen \nS \n, \nHorwich \nA \n; ESMO Guidelines Committee . 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Updated European Association of Urology Guidelines on Renal Cell Carcinoma: Immune Checkpoint Inhibition Is the New Backbone in First-line Treatment of Metastatic Clear-cell Renal Cell Carcinoma\n.\nEur Urol . 2019 ; 76 :151 –156\n. 10.1016/j.eururo.2019.05.022 .\n31151678 \n4. \n\nMotzer \nRJ \n, \nTannir \nNM \n, \nMcDermott \nDF \n, \nArén Frontera \nO \n, \nMelichar \nB \n, \nChoueiri \nTK \n, \nPlimack \nER \n, \nBarthélémy \nP \n, \nPorta \nC \n, \nGeorge \nS \n, \nPowles \nT \n, \nDonskov \nF \n, \nNeiman \nV \n, et al; CheckMate 214 Investigators . Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma\n.\nN Engl J Med . 2018 ; 378 :1277 –1290\n. 10.1056/NEJMoa1712126 .\n29562145 \n5. \n\nRini \nBI \n, \nPlimack \nER \n, \nStus \nV \n, \nGafanov \nR \n, \nHawkins \nR \n, \nNosov \nD \n, \nPouliot \nF \n, \nAlekseev \nB \n, \nSoulières \nD \n, \nMelichar \nB \n, \nVynnychenko \nI \n, \nKryzhanivska \nA \n, \nBondarenko \nI \n, et al; KEYNOTE-426 Investigators . Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma\n.\nN Engl J Med . 2019 ; 380 :1116 –1127\n. 10.1056/NEJMoa1816714 .\n30779529 \n6. \n\nMéjean \nA \n, \nRavaud \nA \n, \nThezenas \nS \n, \nColas \nS \n, \nBeauval \nJB \n, \nBensalah \nK \n, \nGeoffrois \nL \n, \nThiery-Vuillemin \nA \n, \nCormier \nL \n, \nLang \nH \n, \nGuy \nL \n, \nGravis \nG \n, \nRolland \nF \n, et al. 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Deferred Cytoreductive Nephrectomy in Patients with Newly Diagnosed Metastatic Renal Cell Carcinoma\n.\nEur Urol . 2020 ; 78 :615 –623\n. 10.1016/j.eururo.2020.04.038 .\n32362493 \n9. \n\nQuencer \nKB \n, \nFriedman \nT \n, \nSheth \nR \n, \nOklu \nR \n. Tumor thrombus: incidence, imaging, prognosis and treatment\n.\nCardiovasc Diagn Ther . 2017 ; 7 :S165 –S177\n. 10.21037/cdt.2017.09.16 .\n29399520 \n10. \n\nChoueiri \nTK \n, \nHessel \nC \n, \nHalabi \nS \n, \nSanford \nB \n, \nMichaelson \nMD \n, \nHahn \nO \n, \nWalsh \nM \n, \nOlencki \nT \n, \nPicus \nJ \n, \nSmall \nEJ \n, \nDakhil \nS \n, \nFeldman \nDR \n, \nMangeshkar \nM \n, et al. Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): Progression-free survival by independent review and overall survival update\n.\nEur J Cancer . 2018 ; 94 :115 –125\n. 10.1016/j.ejca.2018.02.012 .\n29550566 \n11. \n\nAlbiges \nL \n, \nTannir \nN \n, \nBurotto \nM \n, \nMcDermott \nDF \n, \nPlimack \nER \n, \nBarthélémy \nP \n, \nPorta \nCG \n, \nPowles \nTB \n, \nDonskov \nF \n, \nGeorge \nS \n, \nKollmannsberger \nC \n, \nGurney \nH \n, \nGrimm \nMO \n, et al\n711P Nivolumab + ipilimumab (N+I) vs sunitinib (S) for first-line treatment of advanced renal cell carcinoma (aRCC) in CheckMate 214: 4-year follow-up and subgroup analysis of patients (pts) without nephrectomy\n.\nAnn Oncol . 2020 ; 31 :S559 –60\n. 10.1016/j.annonc.2020.08.783 .\n\n",
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"title": "A case series of advanced renal cell carcinoma patients treated with neoadjuvant cabozantinib prior to cytoreductive nephrectomy within the phase 2 CABOPRE trial.",
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"abstract": "A 78 year-old woman with life-threatening angiotensin-converting enzyme inhibitor (ACE-i) induced angioedema was unresponsive to conventional treatment with corticosteroids, antihistamines and epinephrine. She was successfully treated with icatibant licensed for treatment of hereditary angioedema knowing that both conditions involve bradykinin induced activation of bradykinin B2 receptors. Randomised, controlled trials are warranted to document the efficacy of icatibant in ACE-i angioedema.",
"affiliations": "Øre-næse-hals Afdeling F, Odense Universitetshospital, 5000 Odense C, Denmark. Soeren.Fast@ouh.regionsyddanmark.dk",
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{
"abstract": "BACKGROUND\nAcute kidney injury (AKI) occurs frequently after liver transplantation and is associated with significant morbidity and mortality. Recent evidence has linked the predominant usage of 'chloride-liberal' intravenous fluids, such as 0.9% saline to the development of renal dysfunction in general critically ill patients. We compared the effects of perioperative fluid types on AKI in liver transplant recipients.\n\n\nMETHODS\nAn observational analysis of liver transplant recipients over a 33-month period, between January 2010 and September 2013, was performed. Intensive care unit database and patient records were analyzed for determinants of early postoperative AKI. Univariate and multivariate regression analysis was carried out using a two-tailed P value less than 0.05 to establish significance. The institutional Research Ethics Committee approved the study methodology (RAC no. 2131 073).\n\n\nRESULTS\nOne hundred and fifty-eight liver transplants were performed, AKI developed in 57 (36.1%) patients: 39 (68.4%) fully recovered, 13 (22.8%) developed chronic renal failure and 10 (17.5%) required long-term hemodialysis. On univariate regression analysis, AKI was significantly associated with greater than 3,200 ml of chloride-liberal fluids infused within the first postoperative day (HR 5.9, 95% CI 2.64, 13.2, P < 0.001), greater than 1,500 ml colloids received in the operating room (hazard ratio (HR) 1.97, 95% CI 1.01, 3.8, P = 0.046), vasopressor requirement for 48 hours posttransplant (HR 3.34, 95% CI 1.55, 7.21, P = 0.002), hyperchloremia at day 2 (HR 1.09, 95% CI 1.01, 1.18, P = 0.015) and preoperative model for end-stage liver disease (MELD) score (HR 1.08, 95% CI 1.03, 1.13, P < 0.001). After stepwise multivariate regression, infusion of greater than 3,200 ml of chloride-liberal fluids (HR 6.25, 95% CI 2.69, 14.5, P < 0.000) and preoperative MELD score (HR 1.08, 95% CI 1.02, 1.15, P = 0.004) remained significant predictors for AKI.\n\n\nCONCLUSIONS\nIn a sample of liver transplant recipients, infusion of higher volumes of chloride-liberal fluids and preoperative status was associated with an increased risk for postoperative AKI.",
"affiliations": "Department of Adult Critical Care Medicine, King Faisal Specialist Hospital and Research Centre, At Takhassusi, Al Madhar Ash Shamali, Riyadh, 12713, Saudi Arabia. ashmohnad@hotmail.com.;Department of Adult Critical Care Medicine, King Faisal Specialist Hospital and Research Centre, At Takhassusi, Al Madhar Ash Shamali, Riyadh, 12713, Saudi Arabia. salahuddin.nawal@gmail.com.;Department of Nursing Services, King Faisal Specialist Hospital and Research Centre, At Takhassusi, Al Madhar Ash Shamali, Riyadh, 12713, Saudi Arabia. a.m.haz@live.com.;Department of Adult Critical Care Medicine, King Faisal Specialist Hospital and Research Centre, At Takhassusi, Al Madhar Ash Shamali, Riyadh, 12713, Saudi Arabia. mjoseph@kfshrc.edu.sa.;Department of Adult Critical Care Medicine, King Faisal Specialist Hospital and Research Centre, At Takhassusi, Al Madhar Ash Shamali, Riyadh, 12713, Saudi Arabia. bbohlega@kfshrc.edu.sa.;Organ transplant Centre, King Faisal Specialist Hospital and Research Centre, At Takhassusi, Al Madhar Ash Shamali, Riyadh, 12713, Saudi Arabia. sallam-h@hotmail.com.;Organ transplant Centre, King Faisal Specialist Hospital and Research Centre, At Takhassusi, Al Madhar Ash Shamali, Riyadh, 12713, Saudi Arabia. yelsheikh@kfshrc.edu.sa.;Organ transplant Centre, King Faisal Specialist Hospital and Research Centre, At Takhassusi, Al Madhar Ash Shamali, Riyadh, 12713, Saudi Arabia. dbroering@kfshrc.edu.sa.",
"authors": "Nadeem|Ashraf|A|;Salahuddin|Nawal|N|;El Hazmi|Alyaa|A|;Joseph|Mini|M|;Bohlega|Balsam|B|;Sallam|Hend|H|;Sheikh|Yasser|Y|;Broering|Dieter|D|",
"chemical_list": "D002712:Chlorides; D012965:Sodium Chloride",
"country": "England",
"delete": false,
"doi": "10.1186/s13054-014-0625-7",
"fulltext": "\n==== Front\nCrit CareCritical Care1364-85351466-609XBioMed Central London 2540750462510.1186/s13054-014-0625-7ResearchChloride-liberal fluids are associated with acute kidney injury after liver transplantation Nadeem Ashraf ashmohnad@hotmail.com Salahuddin Nawal salahuddin.nawal@gmail.com El Hazmi Alyaa a.m.haz@live.com Joseph Mini mjoseph@kfshrc.edu.sa Bohlega Balsam bbohlega@kfshrc.edu.sa Sallam Hend sallam-h@hotmail.com Sheikh Yasser yelsheikh@kfshrc.edu.sa Broering Dieter dbroering@kfshrc.edu.sa Department of Adult Critical Care Medicine, King Faisal Specialist Hospital and Research Centre, At Takhassusi, Al Madhar Ash Shamali, Riyadh 12713 Saudi Arabia Department of Nursing Services, King Faisal Specialist Hospital and Research Centre, At Takhassusi, Al Madhar Ash Shamali, Riyadh 12713 Saudi Arabia Organ transplant Centre, King Faisal Specialist Hospital and Research Centre, At Takhassusi, Al Madhar Ash Shamali, Riyadh 12713 Saudi Arabia 19 11 2014 19 11 2014 2014 18 6 62510 6 2014 28 10 2014 © Nadeem et al.; licensee BioMed Central Ltd. 2014This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Introduction\nAcute kidney injury (AKI) occurs frequently after liver transplantation and is associated with significant morbidity and mortality. Recent evidence has linked the predominant usage of ‘chloride-liberal’ intravenous fluids, such as 0.9% saline to the development of renal dysfunction in general critically ill patients. We compared the effects of perioperative fluid types on AKI in liver transplant recipients.\n\nMethods\nAn observational analysis of liver transplant recipients over a 33-month period, between January 2010 and September 2013, was performed. Intensive care unit database and patient records were analyzed for determinants of early postoperative AKI. Univariate and multivariate regression analysis was carried out using a two-tailed P value less than 0.05 to establish significance. The institutional Research Ethics Committee approved the study methodology (RAC no. 2131 073).\n\nResults\nOne hundred and fifty-eight liver transplants were performed, AKI developed in 57 (36.1%) patients: 39 (68.4%) fully recovered, 13 (22.8%) developed chronic renal failure and 10 (17.5%) required long-term hemodialysis. On univariate regression analysis, AKI was significantly associated with greater than 3,200 ml of chloride-liberal fluids infused within the first postoperative day (HR 5.9, 95% CI 2.64, 13.2, P <0.001), greater than 1,500 ml colloids received in the operating room (hazard ratio (HR) 1.97, 95% CI 1.01, 3.8, P = 0.046), vasopressor requirement for 48 hours posttransplant (HR 3.34, 95% CI 1.55, 7.21, P = 0.002), hyperchloremia at day 2 (HR 1.09, 95% CI 1.01, 1.18, P = 0.015) and preoperative model for end-stage liver disease (MELD) score (HR 1.08, 95% CI 1.03, 1.13, P <0.001).\n\nAfter stepwise multivariate regression, infusion of greater than 3,200 ml of chloride-liberal fluids (HR 6.25, 95% CI 2.69, 14.5, P <0.000) and preoperative MELD score (HR 1.08, 95% CI 1.02, 1.15, P = 0.004) remained significant predictors for AKI.\n\nConclusions\nIn a sample of liver transplant recipients, infusion of higher volumes of chloride-liberal fluids and preoperative status was associated with an increased risk for postoperative AKI.\n\nissue-copyright-statement© The Author(s) 2014\n==== Body\nIntroduction\nAcute kidney injury (AKI) occurs both frequently after liver transplantation, reportedly in 29 to 60% recipients [1-3] and, irrespective of severity, confers an increased risk of death [4]. This increase in risk of mortality extends from the early postoperative period (28 days) and up to one year after transplantation [1]. The National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) long-term follow-up study ascribed a 2.66 hazard ratio (HR) directly attributable to renal dysfunction developing after liver transplantation [5].\n\nPreviously described risk factors for AKI in liver recipients are greater severity of illness pretransplant (higher model for end-stage liver disease (MELD) scores, intensive care unit (ICU) admission, and coagulopathy), vasopressors, and greater transfusions in the immediate perioperative period [5-13]. However, very little is known about the effects of intravenous fluid selection (chloride-liberal versus chloride-restrictive) or the effects of fluid balance on the risk of renal injury. An overall fluid overload state leads to renal congestion, compromised renal blood flow and reductions in glomerular filtration rate (GFR) [14]. In critically ill patients, a positive fluid balance has been associated with increased mortality [15,16] and poorer outcomes once AKI develops [17-19]. Recent evidence has highlighted the possible nephrotoxic effects of ‘chloride-liberal’ fluids (0.9% saline). Animal and human controlled studies have shown that infusions of chloride-liberal or solutions with supraphysiological chloride concentrations cause vasoconstriction of renal afferent arterioles, cortical hypoperfusion and decreased GFR [20-22]. In a recent pre- and postintervention study, restriction to chloride-restrictive fluids was associated with lower AKI and need for renal replacement therapy (RRT) as compared to chloride-liberal fluids [23]. Therefore, perioperative intravenous fluid selection and volume may prove to be a modifiable risk factor for the prevention of AKI. No similar data exists for liver transplant recipients. These patients clearly are at an increased risk of renal injury with mortal consequences. We hypothesized that AKI occurring in the early postoperative period after liver transplant may be associated with the use of chloride-liberal fluids and overall fluid overload causing renal congestion.\n\nMaterial and methods\nThis study is reported following the STROBE statement checklist for observational studies [24]. All studies at our institution require ethical approval; the Office of Research Affairs (ORA) and ORA Research Ethics Committee approved the study (RAC no. 2131 073). Patient consent was waived by the Research Ethics Committee.\n\nStudy design and setting\nThis was an observational study of liver transplant recipients carried out at a tertiary care, university hospital over a 33-month period between January 2010 and September 2013.\n\nOperational definitions\nAKI was defined according to the risk, injury, failure, loss, end-stage renal failure (RIFLE) classification [25] of renal dysfunction, that is using both increases in creatinine from preoperative values and urine output measured as urine volume in milliliters/patient’s baseline weight in kilograms/hour. Serum creatinine values were measured preoperatively and daily for up to the third postoperative day. Serum creatinine was measured using the COBAS Integra Creatinine plus ver. 2 assay (Roche Diagnostics Corp, Basel, Switzerland). This is an enzymatic method based on the determination of hydrogen peroxide after conversion of creatinine with the aid of creatininase, creatinase, and sarcosine oxidase. Patients were screened for the development of postoperative AKI on a daily basis until the third day.\n\nProlonged ICU stay was defined a priori as a cutoff value of the mean (or median for skewed data) ICU days after transplantation. Delayed weaning from mechanical ventilation was defined as <3 > days of invasive ventilation.\n\nChloride-liberal fluids were fluids containing supraphysiological concentrations of chloride (0.9% saline, 20% and 5% albumin); chloride-restrictive fluids were fluids with chloride concentrations closer to plasma (0.45% saline, Ringer’s lactate).\n\nParticipants\nConsecutive adult liver transplant recipients within the specified study period were included. Patients undergoing multiorgan transplantation were excluded.\n\nCrystalloids used in the study patients were: lactated Ringer’s (sodium chloride, potassium chloride, sodium lactate and calcium chloride) injection, 0.9% sodium chloride injection, USP, 0.45% sodium chloride injection, USP, manufactured by Baxter Healthcare Corp, Deerfield IL, USA. Colloids used were: human albumin 5% and 20% manufactured by Biotest Pharma GmbH, Dreieich, Germany.\n\nVariables\nThe primary outcome variable was the development of postoperative AKI. Other outcome variables studied were delayed weaning from mechanical ventilation, prolonged ICU stay (as defined above), ICU mortality, and 28-day mortality. Other variables collected were recipient demographic data, etiology of cirrhosis, comorbidities, posttransplant acute physiologic and chronic health evaluation II (APACHE II) scores, routine hematological, biochemical and organ dysfunction/physiological (AKI, vasopressors, RRT, mechanical ventilation) data, fluid balance, fluids and blood products received at admission to ICU and daily up to day 3 posttransplantation.\n\nData sources/measurement\nIn our ICU, patient data is routinely entered into an ICU database. Data entry is by a critical care nurse dedicated to the database. Patient data required for the study and missing from the database was extracted by the research team (AH, HS, BB, AN) from the patient’s electronic medical records and laboratory computerized results.\n\nStatistical analysis\nContinuous data was tested for normality: measures of central tendency were compared as means ± standard deviations (SD) using the Student’s t test for normally distributed variables and as medians (interquartile range, IQR) using the Mann-Whitney U test for skewed data. Categorical variables were compared using the chi-square test or the Fisher exact test for n <5. Fluid volumes were dealt with as continuous variables while fluid types were classified into either ‘chloride-liberal’ or ‘chloride-restrictive’ and correspondingly dealt with as continuous variables. Logistic regression analysis was performed to determine the predictive ability of variables for AKI, prolonged ICU stay and prolonged mechanical ventilation. Univariate and multivariate techniques were used, and for multivariate regression, a backward mode with a threshold 0.15 was used for elimination. Multivariate associations were reported as odds ratios (OR) with 95% confidence intervals (CIs). A two-sided P value of <0.05 was considered as statistically significant. All analyses were carried out using IBM SPSS version 22.0 (IBM Corp, Armonk, NY, USA).\n\nResults\nParticipants and descriptive data\nOne hundred and fifty-eight liver transplants were performed during the study period. Of these, 104 (65.8%) were living donor-related transplants, 53 (33.5%) cadaveric and 1 (0.6%) was a retransplant. Mean age of transplant recipients was 52.3 ± 13.3 years and 66 (42%) were female, mean body mass index (BMI) was 26.8 ± 6 (range 14, 49). Mean MELD score at time of transplantation was 19.4 ± 7.7 (range 6, 45), with mean baseline creatinine 88.7 micromol/L ± 56 (range 27, 350). Transplant recipients had end-stage liver disease caused by: hepatitis C in 60 (38%) patients, hepatitis B in 34 (21.5%), cryptogenic liver disease in 41 (25.9%), autoimmune disease in 9 (5.7%) and others (bilharziasis, congenital hepatic cirrhosis, Budd-Chiari, Wilson’s disease) in 14 (9%) recipients. Fifty-two (32.9%) patients had hepatocellular carcinomas.\n\nAll patients were transferred to the ICU posttransplant. On arrival, transplant recipients were in a positive fluid balance of 8.48 ± 2.3 liters fluid, having received 1.7 ± 0.26 L packed red cells, 3.8 ± 0.143 L blood products (plasma, cryoprecipitate, platelets) and a mean of 7.8 ± 6.3 L crystalloids of which 5.6 ± 4.0 L were chloride-liberal and 2.4 ± 1.4 L were chloride-restrictive fluids. Mean APACHE II score was 15.9 ± 5.4 (range 4, 48), serum procalcitonin level 2.4 ngm/ml (IQR 3.1), proBNP 476 pg/mL (IQR 2,510) and 120 (76%) patients were on a norepinephrine infusion. Seventy-eight (49.4%) had pleural effusions; pleural drainage by pigtail catheters was carried out in 23 out of 78 patients (29.4%). In the first 72 hours of ICU stay, transplant recipients were in a cumulative positive fluid balance of 12.7 ± 7.8 L with 9 ± 6 L crystalloids, 6.4 ± 3.5 L colloids (5%, 20% albumin) and 25 ± 11.9 L chloride-liberal (0.9% saline, 5% albumin, 20% albumin) received. Blood products transfused were 4 L (IQR 4.8). There was no significant difference between the mean serum chloride levels in the chloride-liberal group compared to the chloride-restrictive group, 114 ± 5.8 versus 113 ± 5.9, P >0.05. No significant correlation was found between the mean serum chloride concentrations and the cumulative volumes of chloride-liberal fluids given, P >0.05 (see Table 1 and Figure 1).Table 1 \nChemical compositions of fluids used in liver transplant recipients\n\n\n\nFluid-type\n\t\nComposition per 1 liter\n\t\nManufacturer\n\t\n\ncrystalloids\n\t\t\t\n0.9% Sodium chloride, USP\t154 mEq Sodium\tBaxter Healthcare Corp, Deerfield, IL, USA\t\n154 mEq Chloride\t\n0.45% Sodium chloride, USP\t77 mEq Sodium\tBaxter Healthcare Corp, Deerfield, IL, USA\t\n77 mEq Chloride\t\nLactated Ringer’s injection, USP\t130 mEq Sodium\tBaxter Healthcare Corp, Deerfield, IL, USA\t\n4 mEq Potassium\t\n3 mEq Calcium\t\n109 mEq Chloride\t\n28 mEq Sodium lactate\t\n\nColloids\n\t\t\t\nHuman albumin 5% biotest\tPlasma protein 50gm (96% albumin), caprylate (4 mmol/l), N-acetyl-DL-tryptophanate (4 mmol/l), sodium ions (145 mmol/l), water for injections ad 1,000 ml\tBiotest Pharma GmbH\t\nDreieich, Germany\t\nHuman albumin 20% biotest (given diluted in 0.9% normal saline)\t200 g/l (at least 95% is human albumin)\tBiotest Pharma GmbH\t\nDreieich, Germany\t\nFigure 1 \nRelative volumes of chloride-liberal fluids received by liver transplant recipients with and without acute kidney injury (AKI).\n\n\n\n\nMedian ICU length of stay was five days (IQR 6), mean 8.4 ± 12.5 days. Patients were ventilated for a median of two days (IQR 2) with nine (5.7%) patients subsequently undergoing tracheostomy. ICU mortality was 8.2% (13 patients); 28-day survival was 140 (88.6%). Eight (5%) recipients were readmitted to the ICU for the following: respiratory failure two, sepsis three, bleeding three. Mean time to readmission was 3.5 ± 1.1 days (2, 5).\n\nOutcomes\nAKI developed in 58 (36.4%) patients; classified as risk in 30 (52%), injury in 12 (21%) and failure in 16 (27%) patients. Ninety percent (53 patients) developed AKI within the first two postoperative days. All liver transplant patients, both the group that developed AKI and those that did not were on the calcineurin inhibitor, tacrolimus. Drug levels were routinely monitored and dosing adjusted accordingly. Thirty-nine (68.4%) patients recovered fully, 13 (22.8%) developed chronic renal failure and 10 (17.5%) required long-term hemodialysis. AKI was significantly associated with ICU mortality, P = 0.001 and 28-day mortality, P <0.001. Mean serum chloride levels on the second postoperative day were significantly greater in patients who developed AKI compared to those who did not; 114 ± 7.2 versus 112 ± 4.4, P = 0.01. The mean chloride levels on days one and three were not significantly different. There were no significant associations between mean serum chloride levels and the severity of renal failure (see Table 2).Table 2 \nCharacteristics of liver transplant patients grouped by acute kidney injury according to the RIFLE classification\n\n\n\t\nNo AKI\n(n = 101)\n\t\nAKI\n(n =57)\n\t\nP\nvalue\n\t\n\nAge, years\n\t51 ± 14.2\t54 ± 11.3\t0.13\t\n\nBMI\n\t26.4 ± 6\t27.7 ± 6.6\t0.19\t\n\nPretransplant creatinine, micromol/L\n\t76.2 ± 40.2\t110.8 ± 72.6\t0.001\t\n\nPretransplant MELD score\n\t19.2 ± 5.4\t21.8 ± 9.1\t0.001\t\n\nVolume of chloride-liberal fluids, liters (IQR)\n\t\t\t\t\nOperating room\t4.7 (5.7)\t6 (6.8)\t0.23\t\n24 hours\t2.1 (1.2)\t3.8 (2.7)\t<0.001\t\n48 hours\t0.64 (1.06)\t1.7 (1.5)\t0.007\t\n72 hours\t0.35 (0.65)\t1.07 (0.87)\t0.55\t\n\nVolume of chloride-restrictive fluids, liters (IQR)\n\t\t\t\t\nOperating room\t2 (2)\t2 (1.2)\t0.46\t\n24 hours\t1.9 (1.28)\t1.8 (1.4)\t0.32\t\n48 hours\t2.0 (0.76)\t1.9 (1.6)\t0.86\t\n72 hours\t1.3 (1.0)\t1.6 (1.1)\t0.67\t\n\nVolume of colloids, liters (IQR)\n\t\t\t\t\nOperating room\t1.5 (1)\t2.1 (2.5)\t0.013\t\n24 hours posttransplant\t1.2 (1.03)\t1.9 (1.4)\t0.001\t\n48 hours posttransplant\t0.45 (0.85)\t0.95 (0.71)\t0.016\t\n72 hours posttransplant\t0.35 (0.65)\t1.0 (0.87)\t0.05\t\n\nVolume of packed RBC transfusions, liters (IQR)\n\t\t\t\t\nOperating room\t1.5 (1.2)\t2.2 (1.9)\t0.022\t\n24 hours\t0.76 (0.44)\t1.14 (5.8)\t0.19\t\n48 hours\t0.53 (0.38)\t0.72 (0.53)\t0.08\t\n72 hours\t0.38 (0.71)\t0.38 (0.06)\t0.89\t\n\nVolume of blood products transfused, liters (IQR)\n\t\t\t\t\nOperating room\t3.2 (2.3)\t3.8 (3.2)\t0.17\t\n24 hours\t0.95 (2.1)\t2.1 (4.8)\t0.14\t\n48 hours posttransplant\t0.72 (0.53)\t0.97 (1.2)\t0.63\t\n72 hours posttransplant\t0.63 (1.5)\t0.51 (0.32)\t0.78\t\n\nVolume of crystalloids infused, liters (IQR)\n\t\t\t\t\nOperating room\t6 (5.6)\t6 (6)\t0.8\t\n24 hours\t2.5 (1.3)\t3.1 (1.9)\t0.15\t\n48 hours\t2.1 (0.72)\t2.4 (1.4)\t0.22\t\n72 hours\t1.6 (0.96)\t1.7 (1.1)\t0.30\t\n\nFluid balance, liters (IQR)\n\t\t\t\t\nOperating room\t6.4 (4.7)\t6.7 (5.4)\t0.76\t\n24 hours\t2.9 (2.6)\t3.7 (4.8)\t0.09\t\n48 hours\t1.6 (1.5)\t1.7 (2.4)\t0.06\t\n72 hours\t0.947 (2.07)\t0.623 (1.54)\t0.93\t\n\nSerum lactate, mmol/L\t\t\t\t\nDay 1\t4.2 ± 2.9\t4.8 ± 3.9\t0.26\t\nDay 2\t1.8 ± 1.1\t2.1 ± 1.6\t0.09\t\nDay 3\t1.4 ± 0.5\t1.9 ± 0.3\t0.046\t\n\nSerum sodium, mmol/L\t\t\t\t\nDay 1\t146 ± 5.2\t146.5 ± 5.0\t0.57\t\nDay 2\t143 ± 5.7\t145 ± 3\t0.016\t\nDay 3\t144 ± 2.3\t146 ± 2.6\t0.002\t\n\nSerum chloride, mmol/L\t\t\t\t\nDay 1\t114 ± 5.7\t113 ± 5.9\t0.76\t\nDay 2\t112 ± 4.4\t114 ± 7.2\t0.01\t\nDay 3\t110 ± 4.6\t111 ± 4.8\t0.18\t\n\nVasopressor requirement\n\t\t\t\t\nAt admission\t73 (72%)\t47 (82.5%)\t0.25\t\nDay 1\t3 (3%)\t1 (1.8%)\t0.64\t\nDay 2\t15 (14.8%)\t21 (36.8%)\t0.002\t\nDay 3\t4 (4%)\t8 (14%)\t0.056\t\n\nDays on mechanical ventilation\n\t2.3 ± 3.6\t6 ± 7.1\t0.001\t\n\nLength of ICU stay after transplant\n\t5.5 ± 4.7\t13.4 ± 19\t0.003\t\nAKI, acute kidney injury; BMI, body mass index; ICU, intensive care unit; IQR, interquartile range; MELD, model for end-stage liver disease; RIFLE, risk, injury, failure, loss, end-stage renal failure.\n\n\n\nUnivariate outcome data\nOn univariate regression analysis, AKI was significantly associated with greater than 3,200 ml of chloride-liberal fluids infused within the first postoperative day (HR 5.9, 95% CI 2.64, 13.2, P <0.001), greater than 1,500 ml colloids received in the OR (HR 1.97, 95% CI 1.01, 3.8, P = 0.046), vasopressor requirement for 48 hours posttransplant (HR 3.34, 95% CI 1.55, 7.21, P = 0.002), hyperchloremia at day 2 (HR 1.09, 95% CI 1.01, 1.18, P = 0.015) and preoperative MELD score (HR 1.08, 95% CI 1.03, 1.13, P = 0.001).\n\nDelayed weaning from mechanical ventilation was associated with higher volumes of chloride-liberal fluids, P = 0.02, higher colloid volumes, P = 0.015, blood products transfused, P = 0.017 and a cumulative positive fluid balance, P = 0.026. Higher pretransplant MELD scores, P = 0.001, male gender, P = 0.015, transplant for hepatocellular carcinoma, P = 0.014, crystalloid volume received in the first 72 hours, P = 0.034, need for vasopressors at 48 hours, P <0.001 and 72 hours, P = 0.031, AKI, P <0.001 and pleural effusion, P = 0.001 were significantly associated with a prolonged ICU admission. Drainage of effusion was significantly associated with a reduced ICU stay, P = 0.007 (see Tables 3 and 4).Table 3 \nDemographic, fluids and outcome variables in liver transplant patients grouped by ICU length of stay\n\n\n\t\n<5 days ICU stay (n = 78)\n\t\n≥5 days ICU stay (n = 80)\n\t\nP\nvalue\n\t\n\nMale gender\n\t25 (32%)\t41 (51.2%)\t0.015\t\n\nHCC\n\t33 (42.3%)\t19 (23.1.7%)\t0.014\t\n\nPretransplant MELD score\n\t17 ± 5.9\t21.3 ± 8\t0.001\t\n\nVolume of crystalloids received by 72 hours\nml (IQR)\n\t1,675 (1,055)\t1,520 (1,066)\t0.034\t\n\nVolume of colloids received by\nml (IQR)\n\t\t\t\t\n24 hours posttransplant\t1,247 (1,263)\t1,700 (1,188)\t0.046\t\n48 hours posttransplant\t650 (713)\t950 (1095)\t0.015\t\n\nUndrained pleural effusion posttransplant\n\t28 (35.8%)\t50 (62.5%)\t0.001\t\n\nVasopressors requirement\n\t\t\t\t\n48 hours posttransplant\t8 (10.3%)\t28 (35%)\t0.001\t\n72 hours posttransplant\t2 (2.6%)\t10 (12.5%)\t0.031\t\n\nAKI\n\t17 (22%)\t40 (50%)\t<0.001\t\n\nEarly complications\n\t43 (55.1%)\t50 (62.5%)\t0.035\t\nAKI, acute kidney injury; HCC, hepatocellular carcinoma; ICU, intensive care unit; IQR, interquartile range; MELD, model for end-stage liver disease.\n\nTable 4 \nPerioperative fluids in patients after liver transplant grouped by delayed weaning from mechanical ventilation\n\n\n\t\n<3 days mechanical ventilation (n = 104)\n\t\n≥3 days mechanical ventilation (n = 54)\n\t\nP\nvalue\n\t\n\nVolume of blood products,*\nml (IQR)\n\t\t\t\t\nOperating room\t4,030 (2391)\t5,321 (4607)\t0.015\t\n24 hours posttransplant\t920 (1551)\t3,028 (3893)\t0.017\t\n48 hours posttransplant\t415 (470)\t827 (1194)\t0.048\t\n\nVolume of colloids, ml (IQR)\n\t\t\t\t\nOperating room\t1,500 (1875)\t2,421 (850)\t0.032\t\n24 hours posttransplant\t1,842 (1019)\t2,315 (1205)\t<0.001\t\n48 hours posttransplant\t625 (669)\t1,193 (933)\t<0.001\t\n72 hours posttransplant\t675 (881)\t700 (883)\t0.015\t\n\nVolume of chloride-liberal fluids, ml (IQR)\n\t\t\t\t\nOperating room\t5,000 (7813)\t7,000 (8434)\t0.027\t\n24 hours posttransplant\t3,397 (2868)\t3,725 (2473)\t0.020\t\n\nFluid balance at 48 hours posttransplant, ml\n\t1,725 (1186)\t2,257 (2102)\t0.026\t\n\n*Includes packed cells, fresh frozen plasma, platelets, cryoprecipitate. IQR, interquartile range.\n\n\n\nMultivariate analysis\nAfter adjusting for covariates, infusion of greater than 3,200 ml of chloride-liberal fluids (HR 6.25, 95% CI 2.69, 14.5, P <0.001) and preoperative MELD score (HR 1.08, 95% CI 1.02, 1.15, P = 0.004) remained significant predictors for AKI. Prolonged ICU stay was predicted by male gender, P = 0.014, vasopressors = 0.003 and the development of AKI, P = 0.013 (see Table 5).Table 5 \nRegression analysis for variables associated with acute kidney injury post-liver transplantation\n\n\n\t\nHazard ratio\n\t\n95% CI\n\t\nP\nvalue\n\t\n\nUnivariate analysis\n\t\t\t\t\nMELD score\t1.08\t1.03,1013\t0.001\t\nAPACHE II score at admission to ICU\t1.08\t1.03,1.15\t0.018\t\nColloids ≥1,500 ml received in OR\t1.97\t1.01,3.8\t0.046\t\nChloride-liberal fluids ≥3,200 ml received within the first 24 hours posttransplant\t5.9\t2.64,13.2\t0.000\t\nVasopressors requirement at 2 days posttransplant\t3.34\t1.55,7.21\t0.002\t\nSerum chloride level at day 2\t1.09\t1.01,1.18\t0.015\t\n\nMultivariate analysis\n\t\t\t\t\nChloride-liberal fluids ≥3,200 ml received within the first 24 hours posttransplant\t6.25\t2.69,14.5\t<0.001\t\nPreoperative MELD score\t1.08\t1.02,1.15\t0.004\t\nAPACHE II, acute physiology and chronic health evaluation II; CI, confidence interval; ICU, intensive care unit; MELD, model for end-stage liver disease; OR, operating room.\n\n\n\nDiscussion\nIn this observational study, we found that liver transplant recipients were more likely to develop AKI if they received larger volumes of chloride-liberal (hyperchloremic) fluids. This association was significant, after adjusting for baseline variables, for both 5% albumin in 0.9% saline and only 0.9% saline infusions. Patients who developed AKI had significantly higher serum chloride levels compared to transplant recipients that did not develop AKI.\n\n‘Normal’ saline or 0.9% saline contains supraphysiological levels of chloride (154 mmol/L as compared to Hartmann’s solution, Ringer’s lactate or Plasma-Lyte 148, all of which contain chloride concentrations that are lower (94 to 111 mmol/L). Five percent albumin is available either as salt-poor or in sodium chloride (chloride concentration 128 mmol/L). Intravenous infusions of chloride-liberal fluids have been associated with hyperchloremia and metabolic acidosis when administered in large volumes [26].\n\nOur results show a detrimental effect on renal function with use of chloride-liberal fluids in the immediate postoperative period (up to 48 hours). Support for our findings comes from animal studies that have demonstrated reductions in GFRs, renal arteriolar vasoconstriction [27], and human volunteer studies that have shown reduced renal cortical tissue perfusion, renal blood flow velocity after infusions of hyperchloremic solutions. [28]. In controlled trials, chloride-liberal fluids compared to chloride-poor fluids have been linked to longer time to micturition [21], lower urine output [29] and in a recent observational study of over 31,000 postoperative patients, 0.9% saline compared to ‘balanced’ crystalloids increased the risk of acute renal failure requiring dialysis [30]. Yunos et al., in a pre- and postintervention study on 1,530 critically ill patients found that a chloride-restrictive fluid strategy resulted in a significant reduction in AKI, need for RRT and increase in creatinine as compared to a control group given chloride-liberal fluids [23].\n\nPossible explanations for this renal ‘toxicity’ of chloride-liberal fluids come from animal studies that have demonstrated renal vasoconstriction [22] and thromboxane release after chloride infusions [20]. Chloride infusions increase delivery to the macula densa that stimulates glomerulotubular feedback leading to afferent arteriole constriction, mesangial contraction and resultant decrease in GFR [31].\n\nPatients in our study received both 5% albumin in saline and 20% albumin in saline. Though it is possible that the observed renal dysfunction resulted from hyperoncotic albumin, the data on 20% albumin is so far inconclusive. A recent cohort study on 1,000 patients found a higher risk of renal injury and failure with the use of hyperoncotic albumin (OR 5.99) [32], however, a contradictory result was reported from two meta-analyses that concluded no harmful effects of hyperoncotic resuscitation [33,34]. The SAFE study that compared albumin and saline found no difference in adverse outcomes [35].\n\nFluid overload leads to organ dysfunction due to interstitial edema and visceromegaly. The limited accommodative capacity of the encapsulated kidney causes increased interstitial hydrostatic pressures with reduced renal perfusion and filtration [36]. Additionally, a fluid overload state contributes to third spacing, ascitic fluid accumulation and abdominal compartment syndrome [37]. Cumulative fluid overload has been linked to poor outcomes in all groups (pediatric, septic, postoperative) of critically ill patients with prolonged days on mechanical ventilation, ICU stay and mortality [16,17,38-43]. Recovery of renal function in patients on RRT is also determined by overall fluid balance [17,38,42]. In our study, a cumulative positive fluid balance increased the duration of stay in ICU.\n\nA limitation of our study is that the observational design does not establish a causal relationship of hyperchloremic fluid excess with the development of AKI in liver transplant recipients. These associations may be subject to bias from selection, confounding or random error. We attempted to control for confounders by using regression analysis. Another limitation is the external validity or generalizability of our results to other liver transplant recipients since we collected data only from a single institution.\n\nConclusions\nIn summary, large infusions of chloride-liberal fluids may predict a higher risk of AKI in liver transplant recipients. Our findings support the hypothesis that ‘routine’ intravenous fluids may not be routine and in themselves be associated with organ dysfunction. Our results can be used to build hypotheses for further controlled trials.\n\nKey messages\nChloride-liberal fluids may cause renal dysfunction\n\nLarge volumes (>3,200 ml) of chloride-liberal fluids infused in the first 24 hours after liver transplantation were associated with a higher risk of AKI.\n\n\n\nAbbreviations\nAKIacute kidney injury\n\nAPACHE IIacute physiologic and chronic health evaluation II\n\nBMIbody mass index\n\nCIconfidence interval\n\nGFRglomerular filtration rate\n\nHRhazard ratio\n\nICUintensive care unit\n\nIQRinterquartile range\n\nMELDmodel for end-stage liver disease\n\nORodds ratio\n\nRIFLErisk, injury, failure, loss, end-stage renal failure\n\nRRTrenal replacement therapy\n\nSDstandard deviation\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nAN participated in the design of the study, collected the data, analyzed and interpreted the data, drafted the manuscript, and revised the manuscript critically for important intellectual content. NS conceived the study, participated in the design of the study, made the figures and table, analyzed and interpreted the data, drafted the manuscript, and revised the manuscript critically for important intellectual content. AH, MJ, HAS and BB participated in the design of the study, collected the data, and participated in the coordination of the study. YS and DB participated in the design and coordination of the study and participated in the critical review of the final manuscript. All authors have given final approval of the version to be published.\n\nAcknowledgements\nThere was no special funding for the study. The design, collection, analysis and interpretation of data, plus writing and publication of the manuscript were done by the authors without participation or influence from any of the funding sources.\n==== Refs\nReferences\n1. 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Sanchez EQ Gonwa TA Levy MF Goldstein RM Mai ML Hays SR Melton LB Saracino G Klintmalm GB Preoperative and perioperative predictors of the need for renal replacement therapy after orthotopic liver transplantation Transplantation 2004 78 1048 1054 10.1097/01.TP.0000137176.95730.5B 15480173 \n10. Bilbao I Charco R Balsells J Lazaro JL Hidalgo E Llopart L Murio E Margarit C Risk factors for acute renal failure requiring dialysis after liver transplantation Clin Transpl 1998 12 123 129 \n11. Lima EQ Zanetta DM Castro I Massarollo PC Mies S Machado MM Yu L Risk factors for development of acute renal failure after liver transplantation Ren Fail 2003 25 553 560 10.1081/JDI-120022546 12911159 \n12. Lebron Gallardo M Herrera Gutierrez ME Seller Perez G Curiel Balsera E Fernandez Ortega JF Quesada Garcia G Risk factors for renal dysfunction in the postoperative course of liver transplant Liver Transpl 2004 10 1379 1385 10.1002/lt.20215 15497160 \n13. Cabezuelo JB Ramirez P Rios A Acosta F Torres D Sansano T Pons JA Bru M Montoya M Bueno FS Robles R Parrilla P Risk factors of acute renal failure after liver transplantation Kidney Int 2006 69 1073 1080 10.1038/sj.ki.5000216 16528257 \n14. Herrler T Tischer A Meyer A Feiler S Guba M Nowak S Rentsch M Bartenstein P Hacker M Jauch KW The intrinsic renal compartment syndrome: new perspectives in kidney transplantation Transplantation 2010 89 40 46 10.1097/TP.0b013e3181c40aba 20061917 \n15. Alsous F Khamiees M DeGirolamo A Amoateng-Adjepong Y Manthous CA Negative fluid balance predicts survival in patients with septic shock: a retrospective pilot study Chest 2000 117 1749 1754 10.1378/chest.117.6.1749 10858412 \n16. Payen D de Pont AC Sakr Y Spies C Reinhart K Vincent JL A positive fluid balance is associated with a worse outcome in patients with acute renal failure Crit Care 2008 12 R74 10.1186/cc6916 18533029 \n17. Bouchard J Soroko SB Chertow GM Himmelfarb J Ikizler TA Paganini EP Mehta RL Fluid accumulation, survival and recovery of kidney function in critically ill patients with acute kidney injury Kidney Int 2009 76 422 427 10.1038/ki.2009.159 19436332 \n18. Bagshaw SM Brophy PD Cruz D Ronco C Fluid balance as a biomarker: impact of fluid overload on outcome in critically ill patients with acute kidney injury Crit Care 2008 12 169 10.1186/cc6948 18671831 \n19. Reydellet L Blasco V Mercier MF Antonini F Nafati C Harti-Souab K Leone M Albanese J Impact of a goal-directed therapy protocol on postoperative fluid balance in patients undergoing liver transplantation: A retrospective study Ann Fr Anesth Reanim 2014 33 e47 e54 10.1016/j.annfar.2013.12.016 24456618 \n20. Bullivant EM Wilcox CS Welch WJ Intrarenal vasoconstriction during hyperchloremia: role of thromboxane Am J Physiol 1989 256 F152 F157 2912160 \n21. Williams EL Hildebrand KL McCormick SA Bedel MJ The effect of intravenous lactated Ringer's solution versus 0.9% sodium chloride solution on serum osmolality in human volunteers Anesth Analg 1999 88 999 1003 10320158 \n22. Wilcox CS Regulation of renal blood flow by plasma chloride J Clin Invest 1983 71 726 735 10.1172/JCI110820 6826732 \n23. Yunos NM Bellomo R Hegarty C Story D Ho L Bailey M Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults JAMA 2012 308 1566 1572 10.1001/jama.2012.13356 23073953 \n24. von Elm E Altman DG Egger M Pocock SJ Gotzsche PC Vandenbroucke JP Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies BMJ 2007 335 806 808 10.1136/bmj.39335.541782.AD 17947786 \n25. Bellomo R Ronco C Kellum JA Mehta RL Palevsky P Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group Crit Care 2004 8 R204 R212 10.1186/cc2872 15312219 \n26. Wakim KG “Normal” 0.9 per cent salt solution is neither “normal” nor physiological JAMA 1970 214 1710 10.1001/jama.1970.03180090074027 5536543 \n27. Wan L Bellomo R May CN Bolus hypertonic or normal saline resuscitation in gram-negative sepsis: systemic and regional haemodynamic effects in sheep Crit Care Resusc 2011 13 262 270 22129288 \n28. Chowdhury AH Cox EF Francis ST Lobo DN A randomized, controlled, double-blind crossover study on the effects of 2-L infusions of 0.9% saline and plasma-lyte® 148 on renal blood flow velocity and renal cortical tissue perfusion in healthy volunteers Ann Surg 2012 256 18 24 10.1097/SLA.0b013e318256be72 22580944 \n29. Wilkes NJ Woolf R Mutch M Mallett SV Peachey T Stephens R Mythen MG The effects of balanced versus saline-based hetastarch and crystalloid solutions on acid–base and electrolyte status and gastric mucosal perfusion in elderly surgical patients Anesth Analg 2001 93 811 816 10.1097/00000539-200110000-00003 11574338 \n30. Shaw AD Bagshaw SM Goldstein SL Scherer LA Duan M Schermer CR Kellum JA Major complications, mortality, and resource utilization after open abdominal surgery: 0.9% saline compared to Plasma-Lyte Ann Surg 2012 255 821 829 10.1097/SLA.0b013e31825074f5 22470070 \n31. Salomonsson M Gonzalez E Kornfeld M Persson AE The cytosolic chloride concentration in macula densa and cortical thick ascending limb cells Acta Physiol Scand 1993 147 305 313 10.1111/j.1748-1716.1993.tb09503.x 8386427 \n32. Schortgen F Girou E Deye N Brochard L The risk associated with hyperoncotic colloids in patients with shock Intensive Care Med 2008 34 2157 2168 10.1007/s00134-008-1225-2 18685828 \n33. Wiedermann CJ Dunzendorfer S Gaioni LU Zaraca F Joannidis M Hyperoncotic colloids and acute kidney injury: a meta-analysis of randomized trials Crit Care 2010 14 R191 10.1186/cc9308 21029460 \n34. Jacob M Chappell D Conzen P Wilkes MM Becker BF Rehm M Small-volume resuscitation with hyperoncotic albumin: a systematic review of randomized clinical trials Crit Care 2008 12 R34 10.1186/cc6812 18318896 \n35. Finfer S Bellomo R Boyce N French J Myburgh J Norton R A comparison of albumin and saline for fluid resuscitation in the intensive care unit N Engl J Med 2004 350 2247 2256 10.1056/NEJMoa040232 15163774 \n36. Stone HH Fulenwider JT Renal decapsulation in the prevention of post-ischemic oliguria Ann Surg 1977 186 343 355 10.1097/00000658-197709000-00012 407854 \n37. Vidal MG Ruiz Weisser J Gonzalez F Toro MA Loudet C Balasini C Canales H Reina R Estenssoro E Incidence and clinical effects of intra-abdominal hypertension in critically ill patients Crit Care Med 2008 36 1823 1831 10.1097/CCM.0b013e31817c7a4d 18520642 \n38. Bellomo R Cass A Cole L Finfer S Gallagher M Lee J Lo S McArthur C McGuiness S Norton R Myburgh J Scheinkestel C Su S An observational study fluid balance and patient outcomes in the Randomized Evaluation of Normal vs Augmented Level of Replacement Therapy trial Crit Care Med 2012 40 1753 1760 10.1097/CCM.0b013e318255d9a0 22610181 \n39. Boyd JH Forbes J Nakada TA Walley KR Russell JA Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality Crit Care Med 2011 39 259 265 10.1097/CCM.0b013e3181feeb15 20975548 \n40. Brandstrup B Tonnesen H Beier-Holgersen R Hjortso E Ording H Lindorff-Larsen K Rasmussen MS Lanng C Wallin L Iversen LH Gramkow CS Okholm M Blemmer T Svendsen PE Rottensten HH Thage B Riis J Jeppesen IS Teilum D Christensen AM Graungaard B Pott F Effects of intravenous fluid restriction on postoperative complications: comparison of two perioperative fluid regimens: a randomized assessor-blinded multicenter trial Ann Surg 2003 238 641 648 10.1097/01.sla.0000094387.50865.23 14578723 \n41. Gillespie RS Seidel K Symons JM Effect of fluid overload and dose of replacement fluid on survival in hemofiltration Pediatr Nephrol 2004 19 1394 1399 10.1007/s00467-004-1655-1 15517417 \n42. Heung M Wolfgram DF Kommareddi M Hu Y Song PX Ojo AO Fluid overload at initiation of renal replacement therapy is associated with lack of renal recovery in patients with acute kidney injury Nephrol Dial Transplant 2012 27 956 961 10.1093/ndt/gfr470 21856761 \n43. Wiedemann HP Wheeler AP Bernard GR Thompson BT Hayden D deBoisblanc B Connors AF Jr Hite RD Harabin AL Comparison of two fluid-management strategies in acute lung injury N Engl J Med 2006 354 2564 2575 10.1056/NEJMoa062200 16714767\n\n",
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"mesh_terms": "D058186:Acute Kidney Injury; D000328:Adult; D000368:Aged; D002712:Chlorides; D005260:Female; D005440:Fluid Therapy; D006801:Humans; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012965:Sodium Chloride",
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"pubdate": "2014-11-19",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "10858412;24456618;12827563;12911159;14578723;15163774;15312219;15480173;15497160;5536543;407854;6826732;2912160;8386427;9575400;10320158;15517417;16528257;16714767;17112880;17109735;17947786;18520642;18318896;18533029;18671831;18685828;19399734;19436332;20061917;20486907;21029460;21094830;20975548;21127462;22129288;21856761;22470070;22610181;22580944;23073953;23146506;11574338",
"title": "Chloride-liberal fluids are associated with acute kidney injury after liver transplantation.",
"title_normalized": "chloride liberal fluids are associated with acute kidney injury after liver transplantation"
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"abstract": "DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) syndrome is a potentially fatal and probably underrecognized complication of allopurinol. We present the case of a 33 year old male with this condition who required intensive care support and subsequently improved following corticosteroid therapy. We review the literature considering optimal strategies for treatment and prevention of this condition. We believe that acute physicians clinicians should have greater awareness of this complication of allopurinol therapy.",
"affiliations": "Department of Acute Medicine, Manchester Royal Infirmary,Oxford Road, Manchester, M13 9WL.",
"authors": "Cooksley|Timothy|T|;Iqbal|Javaid|J|;Robertson|Claire|C|;Bright|John|J|",
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"issue": "9(3)",
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"nlm_unique_id": "101553725",
"other_id": null,
"pages": "122-3",
"pmc": null,
"pmid": "21597594",
"pubdate": "2010",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "DRESS Syndrome caused by allopurinol.",
"title_normalized": "dress syndrome caused by allopurinol"
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"companynumb": "PT-TEVA-2019-PT-1009837",
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"abstract": "Therapeutic plasma exchange (TPE) is a procedure for removal of plasma and its components while leaving behind cellular elements via an apheresis device. It is used in multiple conditions one among which is systemic lupus erythematosus (SLE). Adverse reactions from TPE range from mild hypotension and fever to life-threatening cardiovascular compromise. We report the case of sudden hemodynamic collapse following TPE for a neuropsychiatric lupus flare in a patient on losartan. A 62-year-old Caucasian female with a history of drug-induced lupus presented to the hospital with symptoms of a neuropsychiatric lupus flare. She was initiated on TPE with 5% albumin based on recommendations by her rheumatologist. Shortly after TPE, she became hypotensive with poor response to fluid boluses, requiring pressor support and intubation. These symptoms resolved within 24 hours on supportive measures. This was believed to be due to losartan use on the day of TPE. The medication was discontinued and she had further sessions of TPE with no complications. Angiotensin-converting enzyme (ACE) inhibitors have previously been associated with flushing and hypotension in patients undergoing TPE. Patients undergoing TPE have an activation of the prekallikrein and bradykinin system on contact with the extracorporeal membranes. ACE inhibitors potentiate this reaction by inhibiting bradykinin catabolism. Angiotensin receptor blockers (ARBs) have also been postulated to cause elevated bradykinin levels although data pertaining to the use of ARBs in TPE is limited. We hope to highlight this rare interaction in our case and emphasize the need for further data with regard to the same.",
"affiliations": "Internal Medicine, Upstate Medical University, Syracuse, USA.;Internal Medicine, Upstate Medical University, Syracuse, USA.;Medicine, Upstate Medical University, Syracuse, USA.",
"authors": "Ashok Kumar|Prashanth|P|;Paulraj|Shweta|S|;Udekwu|Adaora|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.7028",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.7028\nInternal Medicine\nMiscellaneous\nHematology\nHemodynamic Collapse Following Therapeutic Plasma Exchange in a Patient Receiving an Angiotensin Receptor Blocker\nMuacevic Alexander Adler John R Ashok Kumar Prashanth 1 Paulraj Shweta 1 Udekwu Adaora 2 \n1 \nInternal Medicine, Upstate Medical University, Syracuse, USA \n\n2 \nMedicine, Upstate Medical University, Syracuse, USA \n\nPrashanth Ashok Kumar ashokkup@upstate.edu\n18 2 2020 \n2 2020 \n12 2 e70289 2 2020 13 2 2020 Copyright © 2020, Ashok Kumar et al.2020Ashok Kumar et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/27982-hemodynamic-collapse-following-therapeutic-plasma-exchange-in-a-patient-receiving-an-angiotensin-receptor-blockerTherapeutic plasma exchange (TPE) is a procedure for removal of plasma and its components while leaving behind cellular elements via an apheresis device. It is used in multiple conditions one among which is systemic lupus erythematosus (SLE). Adverse reactions from TPE range from mild hypotension and fever to life-threatening cardiovascular compromise. We report the case of sudden hemodynamic collapse following TPE for a neuropsychiatric lupus flare in a patient on losartan. A 62-year-old Caucasian female with a history of drug-induced lupus presented to the hospital with symptoms of a neuropsychiatric lupus flare. She was initiated on TPE with 5% albumin based on recommendations by her rheumatologist. Shortly after TPE, she became hypotensive with poor response to fluid boluses, requiring pressor support and intubation. These symptoms resolved within 24 hours on supportive measures. This was believed to be due to losartan use on the day of TPE. The medication was discontinued and she had further sessions of TPE with no complications. Angiotensin-converting enzyme (ACE) inhibitors have previously been associated with flushing and hypotension in patients undergoing TPE. Patients undergoing TPE have an activation of the prekallikrein and bradykinin system on contact with the extracorporeal membranes. ACE inhibitors potentiate this reaction by inhibiting bradykinin catabolism. Angiotensin receptor blockers (ARBs) have also been postulated to cause elevated bradykinin levels although data pertaining to the use of ARBs in TPE is limited. We hope to highlight this rare interaction in our case and emphasize the need for further data with regard to the same.\n\ntherapeutic plasma exchangealbuminangiotensin receptor blockersace inhibitorsdrug-related side effects and adverse reactionshypotensionThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nTherapeutic plasma exchange (TPE) is a procedure where plasma and its components are removed from the patient with the cellular components left untouched as blood passes through an apheresis device [1]. It was first employed in 1952 to treat hyper-viscosity in multiple myeloma [2]. TPE is ideal for removal of toxic substances such as antibodies, toxins or abnormal proteins. Conditions such as Guillain-Barre syndrome, myasthenia gravis, monoclonal gammopathies, thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome, idiopathic thrombocytopenia, and rheumatologic diseases like systemic lupus erythematosus (SLE) have seen the use of TPE [3]. One volume exchange roughly removes plasma equivalent to 65% of the intravascular space. The plasma removed is replaced with either albumin or fresh frozen plasma (FFP) [4].\n\nAdverse reactions from TPE can range from the more common reactions such as mild hypotension, fever, chills to rare life-threatening complications such as cardiovascular and respiratory compromise. The estimated overall incidence is around 9% with a range of 1.5%-25% [3,5]. Reports have shown that patients taking angiotensin-converting enzyme (ACE) inhibitors who undergo TPE, especially with albumin replacement are at an increased risk of serious reactions like sudden hypotensive episodes [6].\n\nWe report a rare case of sudden hemodynamic collapse in a patient on losartan undergoing TPE with albumin for a neuropsychiatric lupus flare.\n\nCase presentation\nA 62-year-old Caucasian female with a history of recurrent and resistant SLE, Crohn’s disease, hypertension, hyperlipidemia, coronary artery disease, and stroke was hospitalized for a neuropsychiatric flare of lupus. She presented with manic features like tangential, pressured speech, and agitation with difficulty in redirection. She was hemodynamically stable, not requiring oxygen support, alert and oriented on admission. Basic laboratory tests including blood counts, complete metabolic panel, and infectious work up including urinalysis and chest X-ray (CXR) were negative.\n\nTen years prior, she developed drug-induced lupus after the use of infliximab for Crohn’s disease which resolved on discontinuing the medication. Her disease was stable up until two years ago, since when she has had recurrent episodes of lupus-associated serositis causing severe cardiorespiratory symptoms. She continued to have recurrent exacerbations despite therapy with steroids, hydroxychloroquine, mycophenolate, belimumab, and cyclosporine. Two weeks prior to her presentation, she developed aphasia, seizures, and mania which improved with steroids and plasma exchange. She was started on antiepileptics, mood stabilizers, and antipsychotics. She underwent extensive rheumatologic and neurologic work up including magnetic resonance imaging (MRI) of the brain, lumbar puncture, and electroencephalography (EEG) which were unremarkable. She was evaluated by her rheumatologist on the day of admission and had been recommended initiation of plasmapheresis as she had failed multiple treatment regimens in the past.\n\nHer home medications included amlodipine and losartan for hypertension among several others. All her home medications were resumed on admission. She had received 25 mg of losartan along with her usual morning medications. A few hours later, she was started on single volume TPE with 5% albumin as replacement fluid. Shortly after TPE, she decompensated becoming severely hypotensive. Her blood pressure did not respond to fluid resuscitation and she required both epinephrine and norepinephrine support. She had to be intubated for respiratory compromise. Blood gases revealed hypoxia and labs were unremarkable except for hypocalcemia. With supportive measures, she improved in 24 hours, was extubated and no longer required vasopressor support. Losartan was discontinued following the episode. Through her hospital course, she received four more sessions of TPE with 5% albumin and tolerated it well without any complications. She was also treated with rituximab resulting in improvement of her neuropsychiatric symptoms.\n\nDiscussion\nOur case is a rare presentation of severe hemodynamic decompensation following TPE with albumin. Severe reactions following plasma exchange is an uncommon occurrence [5,6].\n\nOwen et al., in their study, analyzed 299 patients undergoing TPE and found that 4.7% received ACE inhibitors and all of them had reactions characterized by flushing and hypotension. They also mention that patients receiving ACE inhibitors and undergoing TPE with albumin have a 100% risk of having such a reaction [6]. The vasodilatory and blood pressure lowering effect of bradykinin is already well established [7]. It is also equally well known that ACE inhibitors are associated with elevated levels of bradykinin [8]. Perseghin et al. studied the bradykinin levels in volunteers following donor plasmapheresis and found the levels to be higher in those who were receiving an ACE Inhibitor. They observed that patients on ACE inhibitors showed greater variations in systolic blood pressure than those who were not on it [9]. It is hypothesized that blood comes in contact with extracorporeal membranes in procedures like TPE that carry a negative or sometimes, a positive charge. Charged materials through Factor 12, also called Hageman factor may cause activation of the prekallikrein and bradykinin system. It is postulated that this interaction may be responsible for life-threatening reactions like cardiovascular compromise. ACE inhibitors having a synergistic action on the bradykinin pathway may increase the likelihood of such reactions. Thus, a plausible hypothesis for such a catastrophic reaction as seen in our patient may be due to elevated levels of bradykinin [9].\n\nStudies have shown that hypotensive reactions are more common when albumin is used as the replacement fluid. The choice of whether to use 5% albumin or FFP is disease specific. FFP is used in coagulopathies like TTE and hemolytic uremic syndrome where clotting factors have clinical benefits. Albumin is used in all other conditions due to the lower possibility of allergic reactions and antibody development. Albumin preparations were found to contain variable amounts of kallikrein activating substances. Rapid infusion of albumin containing kallikrein activators may lead to sudden surges in bradykinin levels. This in combination with drugs that inhibit bradykinin catabolism, brews the perfect recipe for causing hemodynamic compromise. Strauss et al. recommend stopping ACE inhibitors 24-48 hours prior to TPE depending on the half-life of the medication; whereas, Owen et al. recommend a period of 24 hours [2,6]. Longer acting drugs may need a period of up to 72 hrs [10].\n\nWhile ARBs, in the ideal sense, do not cause bradykinin elevation, literature shows that ARBs like losartan cause elevated bradykinin levels. By blocking the receptor, ARBs cause a reactive increase in angiotensin II, ultimately leading to increased bradykinin levels. It is also not uncommon to see patients with ACE inhibitor-induced angioedema develop similar reactions to ARBs [11-13]. Data with regard to ARBs and TPE is lacking with no case reports or trials and thus entails further research.\n\nConclusions\nARBs and ACE inhibitors are one of the most commonly used classes of drugs for hypertension. There is no policy with regard to patients on ARBs and ACE inhibitors undergoing plasma exchange in most hospitals. On most occasions, hospitalists and primary care physicians manage a patient’s medications. Given the lack of awareness on this interaction, there is an increased risk of adverse events, as seen in our case, in patients needing TPE. Through our case, we hope to increase the awareness regarding this rare interaction and stress on the need for more data and research, especially on ARBs and plasma exchange.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Therapeutic plasma exchange - a brief review of indications, urgency, schedule, and technical aspects Transfus Apher Sci 1 2019 Pham HP Staley EM Schwartz J 237 246 58 2019 31085053 \n2 An overview of current management J Clin Apher Strauss RG Ciavarella D Gilcher RO Kasprisin DO Kiprov DD Klein HG McLeod BC 189 194 8 1993 8113206 \n3 Therapeutic plasma exchange - an emerging treatment modality in patients with neurologic and non-neurologic diseases J Clin Diagn Res Bobati SS Naik KR 35 37 11 2017 \n4 Evidence-based guideline update: plasmapheresis in neurologic disorders Neurology Cortese I Chaudhry V So YT Cantor F Cornblath DR Rae-Grant A 294 300 76 2011 21242498 \n5 Therapeutic plasma exchange: complications and management Am J Kidney Dis Mokrzycki MH Kaplan AA 817 827 23 1994 8203364 \n6 Atypical reactions associated with use of angiotensin-converting enzyme inhibitors and apheresis Transfusion Owen HG Brecher ME 891 894 34 1994 7940662 \n7 Hypertension and the bradykinin system Curr Hypertens Rep Sharma JN 178 181 11 2009 19442326 \n8 Unraveling the pivotal role of bradykinin in ACE inhibitor activity Am J Cardiovasc Drugs Taddei S Bortolotto L 309 321 16 2016 27260014 \n9 Bradykinin production during donor plasmapheresis procedures Vox Sang Perseghin P Capra M Baldini V Sciorelli G 24 28 81 2001 11520412 \n10 Contraindication of angiotensin-converting enzyme (ACE) inhibitors for patients receiving therapeutic plasma exchanges Nephrol Nurs J Perkins KA 571 574 35 2008 https://www.ncbi.nlm.nih.gov/pubmed/19260608 19260608 \n11 Angiotensin II receptor blocker-associated angioedema: on the heels of ACE inhibitor angioedema Pharmacotherapy Abdi R Dong VM Lee CJ Ntoso KA 1173 1175 22 2002 12222553 \n12 Effects of losartan on angiotensin and bradykinin peptides and angiotensin-converting enzyme J Cardiovasc Pharmacol Campbell DJ Kladis A Valentijn AJ 233 240 26 1995 7475048 \n13 Angiotensin-converting enzyme inhibitors in hypertension: to use or not to use? J Am Coll Cardiol Messerli FH Bangalore S Bavishi C Rimoldi SF 1474 1482 71 2018 29598869\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "12(2)",
"journal": "Cureus",
"keywords": "ace inhibitors; albumin; angiotensin receptor blockers; drug-related side effects and adverse reactions; hypotension; therapeutic plasma exchange",
"medline_ta": "Cureus",
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"pages": "e7028",
"pmc": null,
"pmid": "32211262",
"pubdate": "2020-02-18",
"publication_types": "D002363:Case Reports",
"references": "21242498;19442326;7475048;29598869;28969140;11520412;7940662;31085053;12222553;8113206;27260014;8203364;19260608",
"title": "Hemodynamic Collapse Following Therapeutic Plasma Exchange in a Patient Receiving an Angiotensin Receptor Blocker.",
"title_normalized": "hemodynamic collapse following therapeutic plasma exchange in a patient receiving an angiotensin receptor blocker"
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"abstract": "Streptococcus intermedius occasionally causes brain abscesses that can be life-threatening, requiring prompt antibiotic and neurosurgical treatment. The source is often dental, and it may spread to the eye or the brain parenchyma. We report the case of a 34-year-old man with signs of apical periodontitis, endophthalmitis, and multiple brain abscesses caused by Streptococcus intermedius. Initial treatment with meropenem and vancomycin was unsuccessful due to subtherapeutic concentrations, despite recommended dosages. Adequate concentrations could be reached only after increasing the dose of meropenem to 16 g/day and vancomycin to 1.5 g × 4. The patient exhibited high creatinine clearance consistent with augmented renal clearance, although iohexol and cystatin C clearances were normal. Plasma free vancomycin clearance followed that of creatinine. A one-day dose of trimethoprim-sulfamethoxazole led to an increase in serum creatinine and a decrease in both creatinine and urea clearances. These results indicate that increased tubular secretion of the drugs was the cause of suboptimal antibiotic treatment. The patient eventually recovered, but his left eye needed enucleation. Our case illustrates that augmented renal clearance can jeopardize the treatment of serious bacterial infections and that high doses of antibiotics are needed to achieve therapeutic concentrations in such cases. The mechanisms for regulation of kidney tubular transporters of creatinine, urea, vancomycin, and meropenem in critically ill patients are discussed.",
"affiliations": "Department of Neurosurgery and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.;Department of Clinical Chemistry and Clinical Pharmacology and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.;Department of Infectious Diseases, and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.;Department of Clinical Chemistry and Clinical Pharmacology and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.;Department of Infectious Diseases, and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.;Department of Infectious Diseases, Kalmar County Hospital, Kalmar, Sweden.;Department of Neurosurgery and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.;Department of Infectious Diseases, and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.;Department of Clinical Chemistry and Clinical Pharmacology and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.",
"authors": "Fransson|Marcus|M|;Helldén|Anders|A|;Östholm Balkhed|Åse|Å|;Nezirević Dernroth|Dženeta|D|;Ha|Maria|M|;Haglund|Mats|M|;Milos|Peter|P|;Hanberger|Håkan|H|;Kågedal|Bertil|B|",
"chemical_list": null,
"country": "Switzerland",
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"doi": "10.3389/fphar.2021.728075",
"fulltext": "\n==== Front\nFront Pharmacol\nFront Pharmacol\nFront. Pharmacol.\nFrontiers in Pharmacology\n1663-9812\nFrontiers Media S.A.\n\n728075\n10.3389/fphar.2021.728075\nPharmacology\nOriginal Research\nCase Report: Subtherapeutic Vancomycin and Meropenem Concentrations due to Augmented Renal Clearance in a Patient With Intracranial Infection Caused by Streptococcus intermedius\nFransson et al.\nSubtherapeutic Vancomycin and Meropenem Concentrations\nFransson Marcus 1 †\n\nHelldén Anders 2 †\n\nÖstholm Balkhed Åse 3\n\nNezirević Dernroth Dženeta 2\n\nHa Maria 3\n\nHaglund Mats 4\n\nMilos Peter 1\n\nHanberger Håkan 3\n\nKågedal Bertil 2 *\n\n1 Department of Neurosurgery and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden\n2 Department of Clinical Chemistry and Clinical Pharmacology and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden\n3 Department of Infectious Diseases, and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden\n4 Department of Infectious Diseases, Kalmar County Hospital, Kalmar, Sweden\nEdited by: Jeffrey Lipman, The University of Queensland, Australia\n\nReviewed by: Tony Whitehouse, Queen Elizabeth Hospital Birmingham, United Kingdom\n\nAndrew Udy, The Alfred Hospital, Australia\n\n*Correspondence: Bertil Kågedal, bertil.kagedal@liu.se\n† These authors have contributed equally to this work and share first authorship\n\nThis article was submitted to Renal Pharmacology, a section of the journal Frontiers in Pharmacology\n\n06 10 2021\n2021\n12 72807520 6 2021\n01 9 2021\nCopyright © 2021 Fransson, Helldén, Östholm Balkhed, Nezirević Dernroth, Ha, Haglund, Milos, Hanberger and Kågedal.\n2021\nFransson, Helldén, Östholm Balkhed, Nezirević Dernroth, Ha, Haglund, Milos, Hanberger and Kågedal\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.\nStreptococcus intermedius occasionally causes brain abscesses that can be life-threatening, requiring prompt antibiotic and neurosurgical treatment. The source is often dental, and it may spread to the eye or the brain parenchyma. We report the case of a 34-year-old man with signs of apical periodontitis, endophthalmitis, and multiple brain abscesses caused by Streptococcus intermedius. Initial treatment with meropenem and vancomycin was unsuccessful due to subtherapeutic concentrations, despite recommended dosages. Adequate concentrations could be reached only after increasing the dose of meropenem to 16 g/day and vancomycin to 1.5 g × 4. The patient exhibited high creatinine clearance consistent with augmented renal clearance, although iohexol and cystatin C clearances were normal. Plasma free vancomycin clearance followed that of creatinine. A one-day dose of trimethoprim–sulfamethoxazole led to an increase in serum creatinine and a decrease in both creatinine and urea clearances. These results indicate that increased tubular secretion of the drugs was the cause of suboptimal antibiotic treatment. The patient eventually recovered, but his left eye needed enucleation. Our case illustrates that augmented renal clearance can jeopardize the treatment of serious bacterial infections and that high doses of antibiotics are needed to achieve therapeutic concentrations in such cases. The mechanisms for regulation of kidney tubular transporters of creatinine, urea, vancomycin, and meropenem in critically ill patients are discussed.\n\nsuboptimal antibiotic treatment\ntubular cell membrane transporters\nglomerular filtration rate\naugmented renal clearance\nvancomycin clearance\niohexol clearance\ncreatinine clearance\nurea clearance\n==== Body\npmcIntroduction\n\nAugmented renal clearance (ARC), defined as a measured creatinine clearance >130 ml/min/1.73 m2, is increasingly being recognized in critically ill patients. The condition can lead to subtherapeutic concentrations of renally excreted drugs. The case-patient presented with low serum creatinine concentrations and high creatinine clearance, leading to the diagnosis of ARC. The pathophysiology of ARC is unknown, but high cardiac output, increased tubular creatinine secretion, and hormonal effects have been suggested. ARC may jeopardize the treatment of life-threatening deep bacterial infections with, for instance, members of the Streptococcus anginosus group. We report a patient with S. intermedius infection, endogenous endophthalmitis, and septic embolization to the CNS, arising from a dental infection. Increased drug elimination due to ARC resulted in subtherapeutic antibiotic drug concentrations until high doses were administered. The purpose of this case report is to illustrate the possible causes for rapid elimination of the drugs.\n\nCase Description\n\nA 34-year-old man presented at the emergency room with 1-day history of headache, fever, photosensitivity, and visual impairment. On examination, he was awake but slightly disoriented (Glasgow Coma Scale 14). The following were observed: CRP: 50 mg/L, lumbar puncture: 25 cm H2O opening pressure (Lee and Lueck, 2014), CSF: white cell count of 7210 × 106/L (6380 × 106/L polymorphonuclear), lactate 8.2 mmol/L, and albumin 880 mg/L. Meningitis was diagnosed and treatment started with meropenem 2 g × 3, acyclovir 800 mg × 3, and betamethasone 8 mg × 4. CT brain showed no sign of abscess or empyema; bilateral diffuse low-density areas were observed in the frontal and temporal lobes, indicating edema (Figure 1A). Methods, reference values, and drug target values are given in Table 1.\n\nFIGURE 1 Computer tomography showing hypodense areas bilaterally in the temporal lobes indicating edema (arrows) (A). MRI of the brain with T1WI with gadolinium contrast (B), apparent diffusion coefficient (ADC) image (C), and diffusion-weighted imaging (DWI) (D). Multiple peripherally contrast-enhancing lesions with perilesional edema were found both supra- and infratentorial (B). A thin ependymal contrast enhancement is found. Diffusion imaging (C,D) show reduced signaling in the parenchymal lesions and in the content of the posterior horns, indicating multiple abscesses and ventriculitis.\n\nTABLE 1 Definitions, methods, and reference values.\n\nClinical investigation and analysis\tReference intervals, target values\tMethods and references\t\nClinical evaluation\t\n Glasgow Coma Scale (GCS)\t3–15\tDefinition: The GCS is the summation of scores for eye, verbal, and motor responses Teasdale and Jennett (1974) and Teasdale and Jennett (1976). The minimum score is 3, which indicates deep coma or a brain dead state. The maximum is 15, which indicates a fully awake patient\t\n Lumbar puncture opening pressure\t6–25 cm H2O\tNormal range: Whiteley et al. (2006) and Lee and Lueck (2014). The patient should be placed in lateral decubitus position\t\n Quantiferon\tNegative\tQuantiferon is a test for presence of active or latent tuberculosis Sotgiu et al. (2019)\t\nCerebrospinal fluid, CSF\t\n CSF--albumin\t<320 mg/L\tReference interval: personal information from neurochemistry laboratory, Mölndal\t\nMethod: Immunoturbidimetric determination using the cobas c501/701 instruments. Calibrated against ERM-DA470k/IFCC reference material\t\n CSF--lactate\t<2,1 mmol/L\tReference interval: Lindgren et al. (2019)\t\nMethod: Enzymatic determination using the cobas c501/701 instruments\t\n CSF--WBC\t0–5 × 106/L\tReference interval: Traditional\t\nMethod: Cell counts by manual microscopy or phase contrast microscopy using the Fuchs-Rosenthal or Bürker chambers\t\n CSF vancomycin\t6–19 mg/L\tTarget value: Albanèse et al. (2000) and Shokouhi and Alavi Darazam (2014)\t\nMethod: The spectrophotometric homogenous enzyme immune technique used for serum was validated for use as the method for CSF in a correlation study with an HPLC method Marks et al. (2019)\t\nPlasma or serum and urine\t\n P--C-reactive protein\t<10 mg/L\tMethod: Particle enhanced Immunoturbidimetric determination using the instruments cobas c501/701. Calibrated against ERM-DA470k/IFCC reference material\t\n P--Creatinine\t61–108 µmol/L\tReference interval: Erlandsen and Randers (2018)\t\nMethod: Enzyme method using cobas c 501/701 instruments from Roche Diagnostics\t\nCreatinine was calibrated using the calibrator for automated systems (C.f.a.s) traceable to the IDMS reference creatinine method\t\n U--Creatinine\t5–22 mmol/24 h\tReference values: Junge et al. (2004)\t\nMethod: Enzyme method using cobas c 501/701 instruments from Roche Diagnostics. The method is standardized against the ID/MS calibrator for automated systems (C.f.a.s). The amount excreted per 24 h (mmol/24 h) is calculated as concentration (mmol/L) × volume (L/24 h)\t\n P--Iohexol\t\tMethod: Iohexol analysis was performed on an Acquity UPLC I-Class UHPLC system coupled with a Xevo TQ-S micro Triple Quadrupole Mass Spectrometer (Waters). Iohexol (Nycomed Amersham AB) and d5-iohexol, the internal standard, (ALSACHIM SAS) were simultaneously eluted by a BEH C18 column (Waters) using a gradient of 0.1% formic acid in 2 mM ammonium acetate and methanol. Simultaneous peak integration and quantitation for iohexol were achieved automatically using MassLynx Software\t\n P--Cystatin C\t0.62–1.04 mg/L\tReference interval: Erlandsen and Randers (2018)\t\nMethod: Particle-enhanced turbidimetric analysis according to principles given by Kyhse-Andersen et al. (1994). Calibrator: C.f.a.s. The method is calibrated against ERM-DA471/IFCCs reference material Grubb et al. (2014)\t\n S--Vancomycin, total\t15–20 mg/L\tTarget values: Rybak et al. (2009) and Rybak et al. (2020)\t\nMethod: Spectrophotometric homogenous enzyme immune technique using cobas c 502 instrument from Roche Diagnostics\t\nCalibrator: Preciset TDM I calibrators\t\n S--Vancomycin, free\t10.5–14 mg/L\tTarget value: Can be estimated as 0.7 × mg/L Sokol (1991), Uchino et al. (2000), Fanos and Cataldi (2001), Shibayama et al. (2007), Klein et al. (2011), Pais et al. (2020)\t\nMethod: For ultrafiltration of serum, Nanosep Omega PES (Millipore), with a 10 kDa cutoff was used. For chromatographic analysis, we used a Waters Alliance 2695 HPLC system equipped with a Waters bridge column BEH C18 (2.5 μm × 3 mm x 75 mm). Detection was with a photodiode array detector (Waters), and Chromeleon v.7 was used for data collection and analysis\t\n P--Meropenem\t>8 mg/L\tTarget value: “Total trough concentrations above 8.0 mg/L for meropenem and above 22.5 mg/L for piperacillin were defined as the breakpoints for target attainment” Scharf et al. (2020)\t\nMethod: Total meropenem was analyzed at the Department of Clinical Pharmacology, Karolinska University Hospital, using an accredited LC-MS/MS method\t\nClearances\t\n Creatinine clearance, endogenous\t66–143\tReference interval: Junge et al. (2004)\t\nMethod: Urine collection for 12 h. Collection of urine was from midnight (00.00) until 12.00. Plasma creatinine concentrations used for clearance calculations were from early morning the same day\t\nClearance was calculated according to the formula ClCrea (ml/min) = urinary concentration (mmol/L) × urinary volume (L)/serum concentration (mmol/L) × collection time (min). The clearance values were normalized to standard body surface area of 1.73 m2 calculated from height and weight according to Dubois and Dubois (1989)\t\n Iohexol clearance (GFRiohexol)\t78–122 ml/min/1.73 m2\tReference values: Bäck et al. (1989)\t\nMethod: After injection and 4-points measurements iohexol plasma clearance was calculated according to Bröchner-Mortensen (1972). Clearance day 9 was calculated from the dose (67 ml) given at the Department of Radiology and clearance day 14 from the 5 ml dose used in our standard method Krutzén et al. (1984). The clearance values were normalized to standard body surface area of 1.73 m2 calculated from height and weight according to Dubois and Dubois (1989)\t\n Urea clearance\t9.6–60 ml/min/1.73 m2\tReference values: Koch et al. (1980)\t\nMethod: Urine collection for 12 h. Collection of urine was from midnight (00.00) until 12.00. Plasma urea concentrations used for clearance calculations were from early morning the same day\t\nClearance was calculated according to the formula ClUrea (ml/min) = urinary concentration (mmol/L) × urinary volume (L)/serum concentration (mmol/L) × collection time (min). The clearance values were normalized to standard body surface area of 1.73 m2 calculated from height and weight according to Dubois and Dubois\t\n Vancomycin clearance from total serum concentrations\t50–157 (n = 10) or <118 ml/min/1.73 m2 from intersection at creatinine clearance of 130 ml/min/1.73 m2\tReference intervals: Rodvold et al. (1988)\t\nClearance of healthy subjects\t\nMethod: Blood samples for vancomycin concentrations were collected shortly before the dose, immediately after the two hour infusion, and at 3, 4, and 6 hours after the start of the infusion, and as a trough sample before next dose. Vancomycin clearance calculated using the trapezoidal rule and area under the curve (AUC)\t\nThe clearance values were normalized to standard body surface area of 1.73 m2 calculated from height and weight according to Dubois and Dubois (1989)\t\n Vancomycin clearance from free serum concentrations\tx–y mL/min\tReference intervals: Not available in the literature\t\nx–y mL/min/1.73 m2\tMethod: Vancomycin clearance from free concentrations was obtained and calculated according to the same methods as from total vancomycin in serum\t\nThe clearance values were normalized to standard body surface area of 1.73 m2 calculated from height and weight according to Dubois and Dubois (1989)\t\n Cystatin C clearance (eGFRcystatin C)\tmL/min/1.73 m2\tReference interval: Ca 15% less than iohexol clearance, see Figure 1A in Grubb et al. (2014)\t\nMethod: Grubb et al. (2014) estimated clearance from plasma cystatin C was calculated according to the equation eGFR = 130 × Cystatin C−1.069 × age−0.117 − 7\t\n\nHis visual impairment worsened, perceiving only light and dark with his left eye. On day 7, MRI with contrast enhancement revealed multiple brain abscesses (Figures 1B–D) and reduced diffusion, indicating ventriculitis. Reduced diffusion was also observed in the retina of the left eye, suggesting abscess and retinal detachment.\n\nThe patient was transferred to the university hospital’s neurosurgical intensive care unit. CSF cultures were negative for bacteria, fungi, and neurotropic viruses. The QuantiFERON test and the tests for HIV and toxoplasmosis were also negative. The echocardiography indicated no endocarditis or other abnormality. The MRI showed no signs of thrombosis in the jugular vein, indicative of Lemierre’s syndrome. The intravitreal and subconjunctival injections of vancomycin and ceftazidime, as well as ocular dexamethasone and cyclopentolate, were administered. A puncture of a subcortical abscess in the right frontal lobe and the placement of an external ventricular drainage were performed.\n\nDay 13 dental examination showed apical periodontitis requiring extraction of one mandibular and three maxillary teeth was identified. Two days later, surgical extirpation of a right frontal cortical abscess was performed. No bacterial growth was seen in cultures, but the material from the brain abscess was sent for 16S rRNA sequencing analysis. S. intermedius was detected and confirmed by PCR analysis. The CSF profiles improved, and day 21 MRI showed slight regression of ventriculitis and some abscesses. Intrathecal antibiotics were discontinued, and the ventricular drainage was removed. Ophthalmological examination showed almost complete retinal detachment with rupture. The eye was beyond help and thus enucleated. The patient was discharged after 6 weeks. Fourteen weeks after admission, the patient still acknowledged cognitive and memory impairments; fatigue; changed sense of smell, sound sensitivity, and photosensitivity; recurrent nightmares; and impaired motor function.\n\nAntibiotic Treatment\n\nInitial treatment was meropenem 2 g × 3 and acyclovir 800 mg × 3. This was changed on day 7 to cefotaxime and metronidazole following the finding of multiple intracerebral abscesses (Table 2). To broaden antibacterial coverage, this was reversed the following day to meropenem and metronidazole, with the addition of intravenous vancomycin, and from day 9, intrathecal vancomycin was administered. On suspicion of toxoplasmosis, he received trimethoprim–sulfamethoxazole (TMP-SMX) on day 11, but this was replaced by rifampicin on day 12.\n\nTABLE 2 Antibiotic treatment and drug concentrations in a neurosurgery patient with augmented renal clearance and multiple abscesses in the brain due to S. intermedius infection.\n\nDay (day 1 is first day with symptoms)\t3\t4\t5\t6\t7\t8\t9\t10\t11\t12\t13\t14\t15\t16\t17\t18\t19\t20\t21\t\nMeropenem dosage\t2 g × 3\t→\t→\t→\t\t2 g × 4\t→\t→\t→\t→\t→\t3 g bolus +12 g/day b\t12 g/day b\t16 g/day b\t→\t→\t12 g/day b\t→\t→\t\nMeropenem trough concentration (mg/L) (> 8 mg/L) a\t\t\t\t\t\t\t\t\t\t1.3\t\t\t11\t\t23\t\t31\t17\t\t\nAcyclovir\t800 mg × 3\t→\t→\t→\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nBetamethasone\t8 mg × 4\t→\t→\t→\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nCefotaxime\t\t\t\t\t3 g × 4\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nMetronidazole\t\t\t\t\t1.5 g\t0.5 g × 3\t→\t→\t→\t→\t→\t→\t→\t→\t→\t→\t→\t→\t→\t\nVancomycin dosage\t\t\t\t\t\t2 g bolus + 1.5 g ×3\t1.5 g × 3\t2 g × 3\t→\t2 g × 4\t2 g × 3\t1.5 g × 4\t→\t→\t→\t→\t→\t→\t→\t\nVancomycin trough concentration (mg/L) (15–20 mg) a\t\t\t\t\t\t\t6.5\t9.8\t9.0\t22.3\t11.7\t\t14.6/12.6\t12.0\t\t15.1\t19.6\t18.7\t19.3\t\nTrimethoprim–sulfamethoxazole (TMP-SMX) (16 mg/ml, 80 mg/ml)\t\t\t\t\t\t\t\t\t40 ml × 2\t\t\t\t\t\t\t\t\t\t\t\nTrimethoprim trough concentration (mg/L)\t\t\t\t\t\t\t\t\t\t2.8\t\t\t\t\t\t\t\t\t\t\nSulfamethoxazole trough concentration (mg/L)\t\t\t\t\t\t\t\t\t\t75.8\t\t\t\t\t\t\t\t\t\t\nRifampicin\t\t\t\t\t\t\t\t\t\t450 mg × 2\t→\t600 mg × 2\t→\t\t\t\t\t\t\t\nVancomycin intrathecal dosage (mg single dosage)\t\t\t\t\t\t\t10\t\t10\t10\t\t10\t\t20\t20\t\t20\t\t20\t\nVancomycin intrathecal (CSF) trough concentration (mg/L)\t\t\t\t\t\t\t\t<4\t\t<4\t\t<4\t\t<4\t<4\t11.9\t<4\t12.4\t<4\t\na Reference values.\n\nb Continuous infusion.\n\nDespite doses ranging from 1.5 g × 3 to 2 g × 4, a stable vancomycin target level of 15–20 mg/L (Rybak et al., 2020) was not achieved until 1.5 g × 4 was given (Table 2). Serum and CSF antibiotic concentrations remained undetectable or subtherapeutic until doses higher than those recommended for meningitis were administered.\n\nResearch Investigations\n\nOur patient participated in a prospective observational study on the pharmacokinetics of vancomycin in intensive care patients. Vancomycin clearance was determined over a period of 5 days on three occasions, and iohexol clearance on two (Figure 2). The period included the day when TMP–SMX was administered. ARC was diagnosed since creatinine clearance was above 130 ml/min/1.73 m2 apart from the days immediately following TMP–SMX treatment. Urea clearance was initially 86% above the upper reference limit (Koch et al., 1980) and followed the same pattern as creatinine clearance (Figure 2). However, iohexol and cystatin C clearances were normal.\n\nFIGURE 2 Clearance values in a patient with augmented renal clearance. Black circles: measured creatinine clearance, white circles: measured urea clearance, green triangles: iohexol clearance, yellow rhomboids: cystatin C clearance, red cross: total vancomycin clearance, green squares: free vancomycin clearance. The black horizontal line shows the limit for augmented renal clearance (130 ml/min/1.73 m2) and the red horizontal line shows the upper normal reference for urea clearance (60 ml/min/1.73 m2). Arrow shows the dosage of trimethoprim–sulfamethoxazole (TMP-SMX).\n\nVancomycin clearance calculated from total plasma concentrations was higher than that of iohexol, cystatin C, and creatinine clearances after trimethoprim treatment (Figure 2). The clearance of free vancomycin was even higher, approaching that of creatinine during ARC, indicating that vancomycin underwent both glomerular filtration and tubular secretion. Unfortunately, the total and free vancomycin clearances were not determined each day after TMP–SMX administration, precluding the conclusion regarding the effect of trimethoprim on the systems responsible for the tubular transport of vancomycin.\n\nDiscussion\n\nClinical Observations\n\nThe incidence of brain abscess is 0.3–1.3 per 100,000 people per year, 70% being male with an average age of 34 years (Brouwer et al., 2014a). The pathophysiology of brain abscess varies, with pathogens invading the CNS directly or via the bloodstream. The spread from dental infection is usually direct, causing abscesses in the frontal area. Symptoms are often non-specific, but headache is prominent, and only 50% have fever. Altered consciousness and signs of elevated intracranial pressure may occur. Brain abscesses of dental origin are often caused by mixed infections, for example, anaerobic Gram-positive cocci, and aerobic staphylococci and streptococci (Brouwer et al., 2014b). In this case, S. intermedius, a common commensal in the oral cavity, was detected in samples from the abscess material, as in a recent study reporting the predominance of this agent in brain abscesses (Darlow et al., 2020). The broad-spectrum β-lactam antibiotic meropenem, with good CNS penetration, was given, but despite this, endogenous endophthalmitis was diagnosed a week after admission. A recent case report described how S. constellatus of dental origin caused endophthalmitis and brain abscesses (Chheda et al., 2011), and endogenous endophthalmitis caused by S. intermedius has been described after routine dental practice (Mali et al., 2015).\n\nThe trough values of vancomycin and meropenem were initially far below their suggested therapeutic ranges, although the patient received recommended doses (Table 2), and clearances of creatinine, urea, and free vancomycin were high (Figure 2). The patient’s BMI was 30.9 kg/m2 (height 197 cm, weight 120 kg), with a body surface area of 2.55 m2, but his serum creatinine the first four days after admission was remarkably low [49, 44, 42, and 41 µmol/L (0.55, 0.49, 0.48, and 0.46 mg/dl)]. Despite his serious infection, sarcopenia was judged not responsible as he was not bedridden and sat in a chair during daytime. On treatment with trimethoprim, a well-known inhibitor of tubular creatinine transport (Berglund et al., 1975), creatinine clearance normalized. Apart from the days immediately following TMP–SMX treatment, creatinine clearance was around 70% higher than iohexol and cystatin C, indicating substantial tubular excretion of creatinine (Figure 2). Total vancomycin clearance was around 45% higher than iohexol and cystatin C clearances, and clearance of free vancomycin was even higher at around 90% of that of creatinine. The high clearance of vancomycin and demand for high doses of both vancomycin and meropenem clearly indicated high tubular secretion of these two drugs. Lonsdale et al. (2013) reported a similar case. This case and our case illustrate the phenomenon of contemporary rapid elimination of vancomycin and meropenem in neurosurgical patients with ARC (Lin Wu et al., 2015).\n\nTubular Cell Transport of Creatinine, Urea, Vancomycin, and Meropenem\n\nThe literature regarding the tubular transport of creatinine is extensive (Wang and Kestenbaum, 2018). Creatinine is largely cleared by glomerular filtration, and normally around 10% is actively excreted by tubular transport. In the steady state, the excretion matches muscle production. In humans, creatinine is transported across the basolateral membrane of the proximal tubule by the human organic cation transporter-2 (hOCT2) (Urakami et al., 2004; Motohashi and Inui, 2013). The antiport transporters MATE1 and MATE2-K regulate its transport across the apical membrane into the tubular lumen. Trimethoprim is a known inhibitor of this transport system; hence, the temporary reduction in creatinine clearance to normal after trimethoprim treatment clearly shows that tubular creatinine transport was upregulated in this case (Figure 2).\n\nUrea is also freely filtered in the glomeruli, but the concentrations along the tubular fluid transport system vary greatly due to resorption of water and removal of urea by transporters in the inner medullary collecting duct cells. The urea transporter UT-A1, at the apical membrane, transports urea from the lumen into the cell, while UT-A3 transports urea across the basal membrane to the interstitium. The final elimination of urea in the urine is around 30–50% of the glomerular filtrate in mammals (Klein et al., 2011). Surprisingly, urea clearance was also affected by treatment with trimethoprim in a similar way as creatinine clearance (Figure 2). The significance of this is unclear and, to our knowledge, has not been reported previously.\n\nDrug transport within the tubular cells is the first fundamental stage in the onset of the nephrotoxic process. Knowledge of these concepts is important for the prevention of iatrogenic kidney damage, particularly in patients with underlying disease receiving concomitant treatment with several potentially nephrotoxic drugs (Fanos and Cataldi, 2001). In experimental models of nephrotoxicity, vancomycin crosses the basolateral membrane of the proximal tubular epithelium via the OCT system (Sokol, 1991). The involvement of MATE1 and MATE2-K proteins in the secretion of vancomycin has yet to be demonstrated (Pais et al., 2020). In our patient, vancomycin and creatinine clearances were simultaneously increased, suggesting that these transporters are also involved; otherwise, intracellular accumulation would have led to toxicity.\n\nIn an in vitro study, Shibayama et al. (2007) showed that hOCT1 and hOCT2 transport meropenem but were not able to examine transport across the apical membrane into the lumen. Uchino et al. (2000) reported that Npt1, an inorganic phosphate transporter, participates in the renal secretion of penem antibiotics. While it is known that renal excretion of meropenem is largely through active transport, the mechanism behind the rapid elimination of meropenem in our patient with ARC remains unclear.\n\nOn the Causes of and Factors Contributing to Augmented Renal Clearance\n\nThere is no consensus in the literature regarding the causes of ARC. Recently, Cook and Hatton–Kolpek (2019) addressed the risk factors and potential contributing factors to the emergence of ARC. Chen and Nicolau (2020) published a review on ARC and put forward suggestions on how to identify ARC. There is further no consensus regarding how to define ARC. It should be kept in mind that low–molecular weight endogenous compounds (like creatinine) and drugs (such as vancomycin and meropenem) can be eliminated both by glomerular filtration and tubular secretion. Nevertheless, there is currently a broad consensus in considering the measured creatinine clearance of 130 ml/min/1.73 m2 as the lower limit for the diagnosis of ARC. We therefore fully adopt the definition of ARC as creatinine clearance slightly above the upper normal reference limit for GFR, that is, >130 ml/min/1.73 m2, as suggested by the Australian team and further advocated by them (Silva et al., 2020) and others (Mahmoud and Shen, 2017; Bilbao-Meseguer et al., 2018; Chen and Nicolau, 2020). Thus, creatinine clearance above this limit indicates ARC, caused by either increased glomerular filtration or tubular secretion. Table 3 shows the clearance rates of our patient both in absolute (ml/min) and normalized (mL/min/1.73 m2) terms. The absolute clearance rates however may just signify high clearance rates due to the big size of the patient and does not by itself indicate ARC. It is therefore confusing that some authors equalize high clearance rates in absolute terms with ARC. Neither can demand for high dosage of drugs by itself define ARC. However, the absolute clearance of each patient is the basis for dosage of the drugs.\n\nTABLE 3 Creatinine, urea, iohexol, cystatin C, and vancomycin (total and free) clearances together with plasma concentrations of creatinine, urea, and cystatin C and excretion of creatinine and urea during the 6 days of clearance studies.\n\nVancomycin study day\t1\t2\t3\t4\t5\t6\t\nDay from start of symptoms\t9\t10\t11\t12\t13\t14\t\nPlasma creatinine (µmol/L)\t46\t44\t44\t59\t51\t43\t\nCreatinine clearance (ml/min)\t-\t305\t272\t170\t139\t294\t\nCreatinine clearance (mL/min/1.73 m2)\t-\t214\t190\t119\t97\t206\t\nUrine excretion of creatinine, mmol/24 h\t\t19.2\t17.2\t14.2\t10.2\t18.2\t\nPlasma urea (mmol/L)\t\t2.1\t2.6\t3.5\t2.5\t2.4\t\nUrea clearance (ml/min)\t\t179\t119\t71\t71\t111\t\nUrea clearance (mL/min/1.73 m2)\t\t125\t84\t50\t50\t78\t\nUrine excretion of urea, mmol/24 h\t\t536\t447\t360\t256\t384\t\nIohexol clearance, mL/min\t177 a\t-\t-\t-\t-\t189\t\nIohexol clearance (mL/min/1.73 m2)\t119 a\t-\t-\t-\t-\t129\t\nPlasma cystatin C (mg/L)\t-\t0.79\t0.61\t0.79\t0.64\t0.7\t\nCystatin C clearance (ml/min)\t-\t154\t206\t153\t195\t174\t\nCystatin C clearance (mL/min/1.73 m2)\t-\t104\t139\t104\t132\t119\t\nVancomycin clearance (ml/min)\t190\t-\t237\t-\t-\t199\t\nVancomycin clearance (mL/min/1.73 m2)\t128\t-\t160\t-\t-\t136\t\nFree vancomycin clearance (ml/min)\t251\t-\t281\t-\t-\t254\t\nFree vancomycin clearance (mL/min/1.73 m2)\t169\t-\t190\t-\t-\t174\t\na Calculated from iohexol given at the Department of Radiology.\n\nOne suggested and cherished cause of ARC is an increased cardiac output that would give increased renal blood flow, and thus increased GFR (Sime et al., 2015; Atkinson, 2018). In our patient, an echocardiogram was performed that showed no signs of endocarditis. At this investigation, the cardiac output was considered normal with normal contractility, and there were no signs of organic heart failure. We have measured GFR with the best available method (iohexol plasma clearance), and thus, we exclude the increased cardiac output with increased GFR as the cause of ARC in our patient. The GFR measured by iohexol clearance was quite normal, and the creatinine clearance after trimethoprim treatment decreased to half its value into the area of normal GFR. A similar result was found with urea clearance. We therefore consider the cause of ARC in our patient to be increased tubular secretion. The next question however is whether this is constitutional in our patient or induced during the current period of illness. We reviewed the earlier medical records of our patient and found seven serum creatinine values with a mean ± SD of 68.1 ± 13.0 µmol/L during the years 2012–2019. The mean serum creatinine of 44.2 ± 5.7 µmol/L during the present hospital stay was significantly lower than that during the earlier period (p < 0.001). Furthermore, after a follow-up of 16 months, his plasma creatinine was 69 µmol/L, creatinine clearance was 110 ml/min/1.73 m2, urea clearance was 48 ml/min/1.73 m2, and iohexol clearance was 88 ml/min/1.73 m2, that is, quite normal results. It therefore seems that during the stay at neurosurgical unit, he had a period of induced increased tubular secretion of creatinine as the dominant cause of ARC. The conclusion of increased tubular secretions in our patient however does not preclude that increased GFR occurs in other patients. In a recent publication, it was shown that 29 patients had ARC as measured by 6-hour creatinine clearance. Of these, 16 patients had hyperfiltration and 13 had not, as measured by iohexol clearance (Collet et al., 2021). Thus, ARC can be due to increased GFR or increased tubular secretion or both. Our study indicates that this may also be true for drugs such as vancomycin and meropenem. To discriminate between these possibilities, employment of a highly standard GFR method is necessary, as well as actual measurement of creatinine or drug clearances that can indicate augmented clearance beyond the patients true GFR.\n\nConclusion\n\nThis case report describes a 34-year-old man with multiple brain abscesses where the clearances of creatinine, urea, and vancomycin were all increased. High demand for meropenem to reach optimal plasma concentration also indicated increased elimination rate. The increased elimination of these compounds was not due to increased GFR as shown by concomitant measured normal iohexol and cystatin C clearances. We therefore infer that the increased clearances were due to increased tubular secretion. For creatinine, this is proven by the fact that during the study period, temporarily given trimethoprim lowered the clearance of creatinine to normal. High clearance of urea that fell into normal was also found after trimethoprim treatment. However, tubular transport and secretion of urea into the urine are quite different from those of creatinine, and there is no information available in the literature on trimethoprim effects on tubular transporters of urea. This is a new finding and needs to be corroborated in larger studies. Anyhow, urea clearance was higher than normal, and this by itself infers increased excretion into the urine by the tubular system. To our knowledge, there is no reliable information available on human tubular transporters of vancomycin. We have no data on vancomycin clearance the immediate days after trimethoprim dosing, so we cannot evaluate the possible effect of trimethoprim on tubular transport of this drug. However, vancomycin clearance as calculated from non–protein-bound vancomycin was high, above normal GFR and 130 ml/min/1.73 m2, set for definition of ARC, and close to the level of creatinine clearance. Thus, our study shows increased tubular secretion of vancomycin, but we cannot indicate the mechanism for its tubular secretion. A limitation of our study is that the clearance rates of meropenem were not actually measured.\n\nWe conclude that tubular secretion is responsible for the clearance rates beyond the true normal GFR. Further studies on tubular secretion are needed to understand the mechanisms for increased tubular secretion of drugs in intensive care patients with ARC. Increased clearances of drugs like vancomycin and β-lactam antibiotics may result in life-threatening subtherapeutic antibiotic concentrations. Finally, dose recommendations for renally excreted drugs in ARC patients should be implemented to prevent treatment failure, increased morbidity, and mortality.\n\nThe contribution with the pharmacokinetic calculations by Olof Breuer, MD, is greatly appreciated.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/supplementary material; further inquiries can be directed to the corresponding author.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by Regionala etikprövningsnämnden i Linköping c/o Medical Faculty Linköpings universitet 58185 Linköping. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nBK, DND, HH, and AH provided study concept, design, and project execution. MF and HH included the patient in the study and MF, AH, ÅÖB, DND, MH (5th author), and MH (6th author) performed data acquisition and processing. BK drafted the manuscript and included the intellectual content and the revisions from MF, AH, ÅÖB, and PM to the final manuscript. All authors revised the manuscript critically for important intellectual content and approved the final version for submission.\n\nFunding\n\nSwedish government funding to university hospitals for research, ALF (LIO-887221), and VINNOVA, collaboration platform for innovation of existing antibiotics (PLATINEA, 2018-03340).\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\nPublisher’s Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n\nAbbreviations\n\nARC, augmented renal clearance; BSA, body surface area; CNS, central nervous system; CRP, C-reactive protein; CSF, cerebrospinal fluid; OCT, organic cationic transporter; hOCT1, human organic cation transporter-1; hOCT2, human organic cation transporter-2; MATE1, multidrug and toxin extrusion 1; MATE2-K, multidrug and toxin extrusion 2-K; MRI, magnetic resonance imaging; HIV, human immunodeficiency virus; TMP-SMX, trimethoprim–sulfamethoxazole; UT-A1, urea transporter A1; UT-A3, urea transporter A3.\n==== Refs\nReferences\n\nAlbanèse J. Léone M. Bruguerolle B. Ayem M. L. Lacarelle B. Martin C. (2000). Cerebrospinal Fluid Penetration and Pharmacokinetics of Vancomycin Administered by Continuous Infusion to Mechanically Ventilated Patients in an Intensive Care Unit. Antimicrob. 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Urea and Creatinine Levels and Clearances: Observations in 25 Healthy Subjects for One Year (Author's Transl). J. Clin. Chem. Clin. Biochem. 18 (7 ), 423–429. 10.1515/cclm.1980.18.7.423 7411024\nKrutzén E. Bäck S. E. Nilsson-Ehle I. Nilsson-Ehle P. (1984). Plasma Clearance of a New Contrast Agent, Iohexol: a Method for the Assessment of Glomerular Filtration Rate. J. Lab. Clin. Med. 104 (6 ), 955–961. 6438261\nKyhse-Andersen J. Schmidt C. Nordin G. Andersson B. Nilsson-Ehle P. Lindström V. (1994). Serum Cystatin C, Determined by a Rapid, Automated Particle-Enhanced Turbidimetric Method, Is a Better Marker Than Serum Creatinine for Glomerular Filtration Rate. Clin. Chem. 40 (10 ), 1921–1926. 10.1093/clinchem/40.10.1921 7923773\nLee S. C. Lueck C. J. (2014). Cerebrospinal Fluid Pressure in Adults. J. Neuroophthalmol 34 (3 ), 278–283. 10.1097/WNO.0000000000000155 25133881\nLin Wu F. L. Liu S. S. Yang T. Y. Win M. F. Lin S. W. Huang C. F. (2015). A Larger Dose of Vancomycin Is Required in Adult Neurosurgical Intensive Care Unit Patients Due to Augmented Clearance. Ther. Drug Monit. 37 (5 ), 609–618. 10.1097/FTD.0000000000000187 25627406\nLindgren C. Koskinen L. O. Ssozi R. Naredi S. (2019). Cerebrospinal Fluid Lactate and Neurological Outcome after Subarachnoid Haemorrhage. J. Clin. Neurosci. 60 , 63–67. 10.1016/j.jocn.2018.10.025 30361053\nLonsdale D. O. Udy A. A. Roberts J. A. Lipman J. (2013). Antibacterial Therapeutic Drug Monitoring in Cerebrospinal Fluid: Difficulty in Achieving Adequate Drug Concentrations. J. Neurosurg. 118 (2 ), 297–301. 10.3171/2012.10.JNS12883 23121433\nMahmoud S. H. Shen C. (2017). Augmented Renal Clearance in Critical Illness: An Important Consideration in Drug Dosing. Pharmaceutics 9 (3 ), 36. 10.3390/pharmaceutics9030036\nMali J. O. Falk N. S. Mali Y. P. Mencias L. (2015). Endogenous Endophthalmitis with Iris Abscess after Routine Dental Cleaning. JAMA Ophthalmol. 133 (5 ), 616–617. 10.1001/jamaophthalmol.2015.12 25719547\nMarks L. Duchein S. González II Suárez H. A. Rivolta S. (2019). Validation of a Immunoassay for the Determination of Vancomycin in Cerebospinal Fluid. Rev. Fac. Cien Med. Univ. Nac Cordoba 76 (2 ), 101–106. 10.31053/1853.0605.v76.n2.23550 31216164\nMotohashi H. Inui K. (2013). Organic Cation Transporter OCTs (SLC22) and MATEs (SLC47) in the Human Kidney. Aaps J. 15 (2 ), 581–588. 10.1208/s12248-013-9465-7 23435786\nPais G. M. Liu J. Zepcan S. Avedissian S. N. Rhodes N. J. Downes K. J. (2020). Vancomycin-Induced Kidney Injury: Animal Models of Toxicodynamics, Mechanisms of Injury, Human Translation, and Potential Strategies for Prevention. Pharmacotherapy 40 (5 ), 438–454. 10.1002/phar.2388 32239518\nRodvold K. A. Blum R. A. Fischer J. H. Zokufa H. Z. Rotschafer J. C. Crossley K. B. (1988). Vancomycin Pharmacokinetics in Patients with Various Degrees of Renal Function. Antimicrob. 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Irlbeck M. (2020). Therapeutic Drug Monitoring of Meropenem and Piperacillin in Critical Illness-Experience and Recommendations from One Year in Routine Clinical Practice. Antibiotics (Basel) 9 (3 ), 131. 10.3390/antibiotics9030131\nShibayama T. Sugiyama D. Kamiyama E. Tokui T. Hirota T. Ikeda T. (2007). Characterization of CS-023 (RO4908463), a Novel Parenteral Carbapenem Antibiotic, and Meropenem as Substrates of Human Renal Transporters. Drug Metab. Pharmacokinet. 22 (1 ), 41–47. 10.2133/dmpk.22.41 17329910\nShokouhi S. Alavi Darazam I. (2014). Determination of Vancomycin Trough Level in Serum and Cerebrospinal Fluid of Patients with Acute Community-Acquired Meningitis: A Prospective Study. J. Infect. 69 (5 ), 424–429. 10.1016/j.jinf.2014.06.010 24973553\nSilva C. M. Udy A. A. Baptista J. P. (2020). Urinary Creatinine Clearance and Pharmacokinetics Studies: If We Can Measure it, Why Do We Estimate it?. Antimicrob. Agents Chemother. 64 (9 ), e00980–20. 10.1128/AAC.00980-20 32571825\nSime F. B. Udy A. A. Roberts J. A. (2015). Augmented Renal Clearance in Critically Ill Patients: Etiology, Definition and Implications for Beta-Lactam Dose Optimization. Curr. Opin. Pharmacol. 24 , 1–6. 10.1016/j.coph.2015.06.002 26119486\nSokol P. P. (1991). Mechanism of Vancomycin Transport in the Kidney: Studies in Rabbit Renal brush Border and Basolateral Membrane Vesicles. J. Pharmacol. Exp. Ther. 259 (3 ), 1283–1287. 1684821\nSotgiu G. Saderi L. Petruccioli E. Aliberti S. Piana A. Petrone L. (2019). QuantiFERON TB Gold Plus for the Diagnosis of Tuberculosis: a Systematic Review and Meta-Analysis. J. Infect. 79 (5 ), 444–453. 10.1016/j.jinf.2019.08.018 31473271\nTeasdale G. Jennett B. (1974). Assessment of Coma and Impaired Consciousness. A Practical Scale. Lancet 2 (7872 ), 81–84. 10.1016/s0140-6736(74)91639-0 4136544\nTeasdale G. Jennett B. (1976). Assessment and Prognosis of Coma after Head Injury. Acta Neurochir (Wien) 34 (1-4 ), 45–55. 10.1007/BF01405862 961490\nUchino H. Tamai I. Yabuuchi H. China K. Miyamoto K. Takeda E. (2000). Faropenem Transport across the Renal Epithelial Luminal Membrane via Inorganic Phosphate Transporter Npt1. Antimicrob. Agents Chemother. 44 (3 ), 574–577. 10.1128/aac.44.3.574-577.2000 10681320\nUrakami Y. Kimura N. Okuda M. Inui K. (2004). Creatinine Transport by Basolateral Organic Cation Transporter hOCT2 in the Human Kidney. Pharm. Res. 21 (6 ), 976–981. 10.1023/b:pham.0000029286.45788.ad 15212162\nWang K. Kestenbaum B. (2018). Proximal Tubular Secretory Clearance: A Neglected Partner of Kidney Function. Clin. J. Am. Soc. Nephrol. 13 (8 ), 1291–1296. 10.2215/CJN.12001017 29490976\nWhiteley W. Al-Shahi R. Warlow C. P. Zeidler M. Lueck C. J. (2006). CSF Opening Pressure: Reference Interval and the Effect of Body Mass index. Neurology 67 (9 ), 1690–1691. 10.1212/01.wnl.0000242704.60275.e9 17101909\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1663-9812",
"issue": "12()",
"journal": "Frontiers in pharmacology",
"keywords": "augmented renal clearance; creatinine clearance; glomerular filtration rate; iohexol clearance; suboptimal antibiotic treatment; tubular cell membrane transporters; urea clearance; vancomycin clearance",
"medline_ta": "Front Pharmacol",
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"nlm_unique_id": "101548923",
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"pages": "728075",
"pmc": null,
"pmid": "34690767",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": "32055559;7411024;30361053;33742973;25627406;32191793;23121433;17329910;32571825;32659898;11760211;4629674;21482882;17101909;961490;24477107;30723936;2520314;32245195;4136544;24973553;25133881;24829272;6438261;3415206;25719547;28926966;32239518;25075836;32179070;31473271;31216164;1684821;26119486;23435786;15212162;10681320;2609107;29441476;23737200;1195454;15149882;19106348;29490976;29573343;10770777;7923773",
"title": "Case Report: Subtherapeutic Vancomycin and Meropenem Concentrations due to Augmented Renal Clearance in a Patient With Intracranial Infection Caused by Streptococcus intermedius.",
"title_normalized": "case report subtherapeutic vancomycin and meropenem concentrations due to augmented renal clearance in a patient with intracranial infection caused by streptococcus intermedius"
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"abstract": "Primary mediastinal large B-cell lymphoma (PMBCL) is an uncommon, but aggressive, type of B-cell lymphoma. Patients with relapsed refractory PMBCL (rrPMBCL) have limited therapeutic options and usually have a relatively poor outcome. Immune checkpoint blockade has become a potential treatment for this disease. We report here a case of a female patient with rrPMBCL who was treated with nivolumab plus gemcitabine, dexamethasone, and cisplatin (GDP) chemotherapy. Complete remission was achieved after four cycles of combined therapy. With continued nivolumab maintenance monotherapy, she has remained in complete remission for longer than 28 months. This is the first report of nivolumab plus GDP chemotherapy inducing complete remission in patient with rrPMBCL. This case supplements the limited literature and provides implications for clinical trial designs regarding the potential use of nivolumab in the treatment of rrPMBCL.",
"affiliations": "Department of Hematology, Yuebei People's Hospital, Shantou University Medical College, Shaoguan, Guangdong Province, China.;Guangdong Women and Children Hospital, Guangzhou, Guangdong, China.;Guangdong Women and Children Hospital, Guangzhou, Guangdong, China.;Department of Hematology, Yuebei People's Hospital, Shantou University Medical College, Shaoguan, Guangdong Province, China.;Guangdong Women and Children Hospital, Guangzhou, Guangdong, China.",
"authors": "Huang|Gang|G|;Huang|Ju|J|;Zhang|Zhili|Z|;Xue|Chongchong|C|;Liu|Yuan|Y|https://orcid.org/0000-0003-4880-5185",
"chemical_list": "D003841:Deoxycytidine; D000077594:Nivolumab; D003907:Dexamethasone; C056507:gemcitabine; D002945:Cisplatin",
"country": "England",
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"doi": "10.1177/0300060520945075",
"fulltext": "\n==== Front\nJ Int Med Res\nJ. Int. Med. Res\nIMR\nspimr\nThe Journal of International Medical Research\n0300-0605 1473-2300 SAGE Publications Sage UK: London, England \n\n10.1177/0300060520945075\n10.1177_0300060520945075\nCase Report\nNivolumab plus gemcitabine, dexamethasone, and cisplatin chemotherapy induce durable complete remission in relapsed/refractory primary mediastinal B-cell lymphoma: a case report and literature review\nHuang Gang 1 Huang Ju 2 Zhang Zhili 2 Xue Chongchong 1 https://orcid.org/0000-0003-4880-5185Liu Yuan 2 \n1 Department of Hematology, Yuebei People’s Hospital, Shantou University Medical College, Shaoguan, Guangdong Province, China\n\n2 Guangdong Women and Children Hospital, Guangzhou, Guangdong, China\nYuan Liu, Medical Genetic Centre, Guangdong Women and Children Hospital, No. 521 Xingnan Rd, Panyu District, Guangzhou, Guangdong 511400, China. Email: yuanliu005@163.com\n12 8 2020 \n8 2020 \n48 8 030006052094507526 2 2020 1 7 2020 © The Author(s) 20202020SAGE PublicationsCreative Commons Non Commercial CC BY-NC: 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).Primary mediastinal large B-cell lymphoma (PMBCL) is an uncommon, but aggressive, type of B-cell lymphoma. Patients with relapsed refractory PMBCL (rrPMBCL) have limited therapeutic options and usually have a relatively poor outcome. Immune checkpoint blockade has become a potential treatment for this disease. We report here a case of a female patient with rrPMBCL who was treated with nivolumab plus gemcitabine, dexamethasone, and cisplatin (GDP) chemotherapy. Complete remission was achieved after four cycles of combined therapy. With continued nivolumab maintenance monotherapy, she has remained in complete remission for longer than 28 months. This is the first report of nivolumab plus GDP chemotherapy inducing complete remission in patient with rrPMBCL. This case supplements the limited literature and provides implications for clinical trial designs regarding the potential use of nivolumab in the treatment of rrPMBCL.\n\nRelapsed refractory primary mediastinal B-cell lymphomanivolumabcheckpoint blockadegemcitabinedexamethasonecisplatinchemotherapyprogrammed cell death 1complete remissiontypesetterts2\n==== Body\nIntroduction\nPrimary mediastinal large B-cell lymphoma (PMBCL) is an uncommon, but aggressive, tumor that accounts for 2% to 3% of non-Hodgkin lymphoma.1 PMBCL is distinguished from diffuse large B-cell lymphoma by virtue of distinct clinical, pathological, and genetic features.2–4 Recently, PMBCL was listed as a separate entity in the latest World Health Organization 2016 classification of hematopoietic and lymphoid tumors.5 PMBCL has a similar clinical presentation as classical Hodgkin lymphoma (cHL), and PMBCL also shares certain features at the molecular level, particularly 9p24.1 alterations and programmed cell death protein ligand 1/ligand 2 (PD-L1/PD-L2) expression.6–8 At present, management and outcome of PMBCL are still critical, and a more serious situation is faced by people who are diagnosed with relapsed and refractory PMBCL (rrPMBCL).1,9 The optimal salvage chemotherapy and autologous stem cell transplant for rrPMBCL are of limited efficacy.1,9\n\nRecently, agents targeting programmed cell death 1 (PD-1) and PD-L1 have been developed in tumor immunotherapy.10 Anti-PD-1 therapy with monoclonal antibodies has been approved for the treatment of several types of solid tumor and cHL. The therapeutic potential of anti-PD-1 therapy in other malignancies is likely to be approved soon. In 2018, a humanized immunoglobulin G1 recombinant monoclonal antibody for the PD-1 receptor pidilizumab was approved by the US Food and Drug Administration (FDA) for treating adult and pediatric patients with rrPMBCL.11 Another agent that targets the PD-1 receptor called nivolumab is a fully humanized immunoglobulin G4 monoclonal antibody that has been granted approval by the US FDA for treating several solid malignancies and cHL. The therapeutic efficacy of nivolumab in patients with rrPMBCL remains unclear.\n\nWe report here a patient with rrPMBCL who received combined treatment with off-label nivolumab and GDP chemotherapy. Complete remission (CR) was achieved after four cycles of such combined treatment. At the time of this submission, the patient has remained in CR for longer than 28 months with continued nivolumab maintenance monotherapy.\n\nCase report\nA 32-year-old woman presented to Yuebei People’s Hospital with intermittent dyspnea and chest pain. A positron emission tomography (PET) scan showed a 10-cm mass in the anterior superior mediastinum with a standardized uptake value of 13.5. The mass showed unclear margins and compressed the ascending aorta and pulmonary trunk. Small pericardial and left pleural effusions were also observed.\n\nThe mass was diagnosed as PMBCL by a subsequent biopsy. Immunohistochemical staining showed that large lymphocytes were positive for CD20, CD79a, Pax-5, BCL-6, CD23, CD30, and multiple myeloma-1, and negative for CD10, CD3, CD5, synaptophysin, chromogranin A, endomysial, terminal deoxynucleotidyl transferase, cytokeratin (CK), CK19, and S-100. Ki-67 was 80% positive and Epstein–Barr encoding region in situ hybridization was negative. She was initially treated with six cycles of front-line chemotherapy, including two cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP), and four cycles of dose-adjusted etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) were administered. The timeline of treatment is shown in Figure 1a. She received tumor resection by thoracoscopic surgery after she continued two cycles of gemcitabine, dexamethasone, cis-platinum, etoposide, and rituximab therapy. Her first CR was achieved in December 2016.\n\nFigure 1. Summary of treatment and monitoring the tumor response. (a) Patient’s timeline chart with the dates of treatment and monitoring the tumor response. (b) Positron emission tomography images. Upper panel: a scan of the relapsed hypermetabolic lesions located at the left lung and right adrenal gland before combined treatment. Lower panel: complete remission was achieved after four cycles of nivolumab plus GDP chemotherapy.\n\nR-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone; DA-EPOCH-R, dose-adjusted etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin, and rituximab; GDPE-R, gemcitabine, dexamethasone, cis-platinum, etoposide, and rituximab; CR, complete remission; PMBCL, primary mediastinal large B-cell lymphoma; DICE, dexamethasone, ifosfamide, cisplatin, and etoposide; IBC, ibrutinib, bendamustine, and cytarabine; GDP, gemcitabine, dexamethasone, and cisplatin.\n\nHowever, 4 months later, a PET-computed tomography (CT) scan showed hypermetabolic lesions located at the left lung and right adrenal gland, but not in the primary mediastinal site (Figure 1b). The patient reported no physical symptoms and received a repeat tissue biopsy, which confirmed a relapse with PMBCL. She was treated with each cycle of a dexamethasone, ifosfamide, cisplatin, and etoposide regimen and ibrutinib, bendamustine, and cytarabine therapy. A chest CT scan showed that the right adrenal gland lesion had partially responded, while the lesions in the left lung had progressed. After those cycles of chemotherapy, the patient showed Grade IV myelosuppression and had to receive blood transfusion treatment. Moreover, a cerebrospinal fluid examination showed the presence of atypical lymphocytes and no symptoms of infection of the central nervous system were observed. Intrathecal chemotherapy (cytarabine 50 mg, methotrexate 10 mg, and dexamethasone 5 mg) was then administered and no atypical lymphocytes were detected by repeated cerebrospinal fluid analysis. These findings highly suggested a potential risk of metastasis of the central nervous system.\n\nBecause the disease had progressed with severe myelosuppression and there were no standard chemotherapy guidelines or alternative treatment options for the patient, other salvage treatments of her refractory disease needed to be considered. After much discussion with the patient and her family, she declined autologous hematopoietic stem cell transplantation and received combined treatment of gemcitabine 1400 mg, dexamethasone 50 mg, and cis-platinum 150 mg (GDP) chemotherapy and the off-label anti-PD1 antibody nivolumab (140 mg). After four cycles of combined treatment, a repeated PET/CT scan showed that she had secondary CR (Figure 1b). She received two more cycles of combined treatment with nivolumab and GDP chemotherapy, and then continued single nivolumab maintenance treatment (100 mg). Since her first dose in May 2017, she received 16 doses of nivolumab. She reported moderate fatigue and pyrexia in 2 to 3 days after each administration of nivolumab. Blood tests indicated normal function of the liver, kidney, and thyroid (Figure 2). She also had normal blood levels of creatinine, albumin, globulin, lactate dehydrogenase, aspartate transaminase, alanine aminotransferase, total bilirubin, and urea nitrogen during the whole process of nivolumab therapy (Figure 2b). Neutrophil and platelet counts were decreased in the first four combined therapies because of toxicity of GDP chemotherapy, but they recovered to normal levels during continued nivolumab maintenance monotherapy (Figure 2c). Furthermore, no adverse signs and symptoms were observed in the lungs, brain, and skin. At the time of this submission, she has remained in CR for longer than 28 months with continued nivolumab maintenance therapy.\n\nFigure 2. Blood test values during the whole treatment process since the first dose of nivolumab. The first four cycles were nivolumab plus GDP chemotherapy, and nivolumab maintenance monotherapy was administered since the fifth cycle. (a) Thyroxine, thyrotropin, FT3, and FT4 levels. (b) Levels of creatinine, albumin, globulin, lactate dehydrogenase, aspartate transaminase, alanine aminotransferase, total bilirubin, and urea nitrogen. (c) Neutrophil and platelet counts.\n\nFT4, free thyroxine; FT3, free triiodothyronine; GDP, gemcitabine, dexamethasone, and cisplatin.\n\nEthics approval was obtained from the ethical committee of Yuebei People’s Hospital. Written informed consent was obtained from the patient for analysis of the samples and publication.\n\nDiscussion\nTreatment and outcome are critical in managing PMBCL. Because there is no established standard approach, the first-line treatment of PMBCL is generally the same as that for diffuse large B-cell lymphoma, including R-CHOP and DA-EPOCH-R. Relapse of PMBCL usually occurs in the first 6 to 12 months after completion of front-line therapy, with a lower incidence (approximately 10%–30%) than diffuse large B-cell lymphoma.1,9 There are various second-line immunochemotherapy regimens for patients with rrPMBCL, including the rituximab, ifosfamide, carboplatin, and etoposide regimen, the rituximab, dexamethasone, cytarabine, and cisplatin regimen, and rituximab-GDP.12 Because of a lack of standard guidelines or treatment options for PMBCL, the outcome greatly depends on the patients’ response to the regimen. This response remains poor, despite these second-line salvage chemotherapies and subsequent autologous hematopoietic stem cell transplantation.9,12\n\nIn recent years, strategies focusing on the checkpoint blockade have been developed in tumor immunotherapy.10 Therapeutic antibodies targeting the PD-1–PD-L1 axis possess clinical activity and an acceptable safety profile in treating a growing list of solid tumors and B-cell lymphomas.13 Based on a clinical study of 53 patients with rrPMBCL, pidilizumab was approved by the US FDA for treatment of adult and pediatric patients with rrPMBCL in 2018.11 Another antibody, nivolumab, has been granted approval for treating several solid malignancies and cHL. However, studies regarding application of nivolumab for PMBCL are limited. Only five reports have described using nivolumab for treatment of PMBCL/rrPMBCL (Table 1) as follows. In a phase I study published in 2016, two patients with PMBCL were recruited and treated with nivolumab at doses of 1 or 3 mg/kg every 2 weeks after previous systemic treatments.14 No objective responses were observed in this previous study. In another phase I study, one patient with PMBCL received combined therapy of nivolumab and ipilimumab, and died during the therapeutic process.15 Recently, two reports showed the potential therapeutic efficiency of nivolumab for patients with refractory PMBCL/rrPMBCL who showed failure with conventional immunochemotherapy.16,17 Both of these two cases had immune-related adverse effects during the antibody treatment process. One patient with high-grade neutropenia had nivolumab stopped temporarily and was treated with intravenous immunoglobulin.16 The other patient with zoster reactivation was controlled by administration of valacyclovir.17 Recently, Zinzani and colleagues showed that combined treatment of nivolumab and brentuximab vedotin had promising antitumor activity and a manageable safety profile in patients with rrPMBCL.18 In this phase II study, 30 patients were recruited and treated with nivolumab 3 mg/kg and brentuximab vedotin 1.8 mg/kg every 3 weeks. The objective response rate was 73%, and 37% achieved CR and 37% achieved partial remission. Of 30 patients, 25 of them had drug-related adverse events and the most common were neutropenia, thrombocytopenia, and peripheral neuropathy.18 In the present case, we attempted several available approaches in treating the patient’s relapsed disease, but failed to control the progress of the mass. After much discussion with the patient and her family, we considered an off-label nivolumab and GDP chemotherapy as salvage treatment for the patient. In September 2017, her second CR was achieved after four cycles of combined treatment. Currently, with continued nivolumab maintenance monotherapy, the patient has remained in CR for longer than 28 months.\n\nTable 1. Reports regarding application of nivolumab in primary mediastinal large B-cell lymphoma/relapsed and refractory primary mediastinal large B-cell lymphoma.\n\nReports\tNumber \nof cases\tDose\tCombined \ntreatment\tAdverse events\tResponse \n(yes/no)\t\nLesokhin AM \net al., 201614\t2\t1 or 3 mg/kg\t–\t–\tNo\t\nAnsell S et al., \n201615\t1\t3 mg/kg\tIpilimumab\t–\tNo\t\nWright Z \net al., 201716\t1\t–\tNo\tHigh-grade neutropenia\tYes\t\nYassin R et al., \n201917\t1\t3 mg/kg\tNo\tZoster reactivation\tYes\t\nZinzani, \nPL et al., 201918\t30\t240 mg\tBrentuximab \nvedotin\tNeutropenia, \nthrombocytopenia, \nand peripheral neuropathy \n(83% of patients)\t73% of \npatients\t\nPresent case\t1\t2–3 mg/kg\tGDP \nchemotherapy\tMild fatigue and pyrexia\tYes\t\nNote: – means not indicated in the report.\n\nImmune-related adverse events that are associated with checkpoint blockade often start within the first few weeks to months after treatment, but can occur any time and in any organ. The most common immune-related adverse events are hypothyroidism, nausea, diarrhea, pyrexia, and fatigue.19,20 In the present case, we were concerned about immune-related organ damage since the first dose of nivolumab. The patient reported moderate fatigue and pyrexia after each administration of nivolumab, and soon recovered within 2 to 3 days. Blood testing was performed during the whole therapeutic process and the data were reviewed and analyzed. Blood levels of thyroxine, thyrotropin, free triiodothyronine, and free thyroxine indicated no thyroiditis (Figure 2a). Our patient also showed normal metabolic data during the whole process of nivolumab therapy (Figure 2b). Neutrophil and platelet counts were decreased in the first four combined therapies because of toxicity of GDP chemotherapy but they then recovered to normal levels during continued nivolumab maintenance monotherapy (Figure 2c).\n\nUnlike other lymphomas, prognostic biomarkers are largely lacking in PMBCL.12 Some serum molecules, such as CCL17 and CD163, are considered as potential biomarkers for predicting and monitoring responses and detection of relapses in patients with Hodgkin lymphoma.12,21 The role of serum biomarkers in PMBCL remains to be investigated. Radiological imaging should only be used in patients who have new clinical symptoms or signs suggestive of relapse, but not in asymptomatic patients.9,22\n\nTo the best of our knowledge, this is the first reported case of nivolumab plus GDP chemotherapy that induced CR with no severe immune-related organ damage in a patient with rrPMBCL. We also report the longest follow-up observation of successful application of nivolumab in a patient with rrPMBCL.\n\nThis report supplements the limited literature of nivolumab for treatment of PMBCL/rrPMBCL and provides implications for clinical trial design regarding the potential use of nivolumab in treatment of rrPMBCL. Further investigation needs to be performed for potential application of single or combined use of nivolumab for patients with rrPMBCL who experience failure with conventional therapeutic approaches.\n\nDeclaration of conflicting interest\nThe authors declare that there is no conflict of interest.\n\nFunding\nThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\n\nORCID iD\nYuan Liu https://orcid.org/0000-0003-4880-5185\n==== Refs\nReferences\n1 Martelli M Ferreri A Di Rocco A , et al\nPrimary mediastinal large B-cell lymphoma.\n\nCrit Rev Oncol Hematol \n2017 ; \n113 : 318 –327\n.28318892 \n2 Savage KJ Monti S Kutok JL , et al\nThe molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma.\n\nBlood \n2003 ; \n102 : 3871 –3879\n.12933571 \n3 Rosenwald A Wright G Leroy K , et al\nMolecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma.\n\nJ Exp Med \n2003 ; \n198 : 851 –862\n.12975453 \n4 Mottok A Wright G Rosenwald A , et al\nMolecular classification of primary mediastinal large B-cell lymphoma using routinely available tissue specimens.\n\nBlood \n2018 ; \n132 : 2401 –2405\n.30257882 \n5 Swerdlow SH Campo E Pileri SA , et al\nThe 2016 revision of the World Health Organization classification of lymphoid neoplasms.\n\nBlood \n2016 ; \n127 : 2375 –2390\n.26980727 \n6 Xu-Monette ZY Zhou J andYoung KH. \nPD-1 expression and clinical PD-1 blockade in B-cell lymphomas.\n\nBlood \n2018 ; \n131 : 68 –83\n.29118007 \n7 Van Roosbroeck K Ferreiro JF Tousseyn T , et al\nGenomic alterations of the JAK2 and PDL loci occur in a broad spectrum of lymphoid malignancies.\n\nGenes Chromosomes Cancer \n2016 ; \n55 : 428 –441\n.26850007 \n8 Twa DD Chan FC Ben-Neriah S , et al\nGenomic rearrangements involving programmed death ligands are recurrent in primary mediastinal large B-cell lymphoma.\n\nBlood \n2014 ; \n123 : 2062 –2065\n.24497532 \n9 Cwynarski K Marzolini MAV Barrington SF , et al\nThe management of primary mediastinal B-cell lymphoma: a British Society for Haematology Good Practice Paper\n. Br J Haematol \n2019 ; \n185 : 402 –409\n.30609016 \n10 Ribas A andWolchok JD. \nCancer immunotherapy using checkpoint blockade.\n\nScience \n2018 ; \n359 : 1350 –1355\n.29567705 \n11 Hematology/Oncology (Cancer) Approvals & Safety Notifications. Available online . 2018 URL: www.fda.gov/drugs/informationondrugs/approveddrugs/ucm610670.htm\nhttps: //www.fda.gov/drugs/informationondrugs/approveddrugs/ucm610670.htm\n12 Lees C Keane C Gandhi MK , et al\nBiology and therapy of primary mediastinal B-cell lymphoma: current status and future directions\n. Br J Haematol \n2019 ; \n185 : 25 –41\n.30740662 \n13 Goodman A Patel SP andKurzrock R. \nPD-1-PD-L1 immune-checkpoint blockade in B-cell lymphomas.\n\nNat Rev Clin Oncol \n2017 ; \n14 : 203 –220\n.27805626 \n14 Lesokhin AM Ansell SM Armand P , et al\nNivolumab in patients with relapsed or refractory hematologic malignancy: preliminary results of a phase Ib study.\n\nJ Clin Oncol \n2016 ; \n34 : 2698 –2704\n.27269947 \n15 Ansell S Gutierrez ME Shipp MA , et al\nA phase 1 study of nivolumab in combination with ipilimumab for relapsed or refractory hematologic malignancies (CheckMate 039)\n. Blood \n2016 ; \n128 : 183 –183\n.\n16 Wright Z andBrown A. \nHigh-grade neutropenia in a patient successfully treated with nivolumab for refractory primary mediastinal B-cell lymphoma.\n\nBlood Adv \n2017 ; \n1 : 1306 –1308\n.29296772 \n17 Yassin R Hajeer A Alshieban S , et al\nHLA genotype and response to nivolumab therapy in relapsed refractory primary mediastinal B-cell lymphoma.\n\nCurr Res Transl Med \n2019 ; \n67 : 31 –33\n.30448276 \n18 Zinzani PL Santoro A Gritti G , et al\nNivolumab combined with brentuximab vedotin for relapsed/refractory primary mediastinal large B-cell lymphoma: efficacy and safety from the Phase II CheckMate 436 Study\n. J Clin Oncol \n2019 ; \n37 : 3081 –3089\n.31398081 \n19 Postow MA Sidlow R andHellmann MD. \nImmune-related adverse events associated with immune checkpoint blockade.\n\nN Engl J Med \n2018 ; \n378 : 158 –168\n.29320654 \n20 Zinzani PL Ribrag V Moskowitz CH , et al\nSafety and tolerability of pembrolizumab in patients with relapsed/refractory primary mediastinal large B-cell lymphoma.\n\nBlood \n2017 ; \n130 : 267 –270\n.28490569 \n21 Jones K Vari F Keane C , et al\nSerum CD163 and TARC as disease response biomarkers in classical Hodgkin lymphoma.\n\nClin Cancer Res \n2013 ; \n19 : 731 –742\n.23224400 \n22 Cheson BD Fisher RI Barrington SF , et al\nRecommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification.\n\nJ Clin Oncol \n2014 ; \n32 : 3059 –3068\n.25113753\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0300-0605",
"issue": "48(8)",
"journal": "The Journal of international medical research",
"keywords": "Relapsed refractory primary mediastinal B-cell lymphoma; checkpoint blockade; chemotherapy; cisplatin; complete remission; dexamethasone; gemcitabine; nivolumab; programmed cell death 1",
"medline_ta": "J Int Med Res",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D003841:Deoxycytidine; D003907:Dexamethasone; D005260:Female; D006801:Humans; D009364:Neoplasm Recurrence, Local; D000077594:Nivolumab; D016896:Treatment Outcome",
"nlm_unique_id": "0346411",
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"pmid": "32783492",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "24497532;30740662;12933571;30448276;26980727;30609016;29567705;29118007;12975453;30257882;27269947;31398081;28318892;26850007;23224400;25113753;29320654;29296772;28490569;27805626",
"title": "Nivolumab plus gemcitabine, dexamethasone, and cisplatin chemotherapy induce durable complete remission in relapsed/refractory primary mediastinal B-cell lymphoma: a case report and literature review.",
"title_normalized": "nivolumab plus gemcitabine dexamethasone and cisplatin chemotherapy induce durable complete remission in relapsed refractory primary mediastinal b cell lymphoma a case report and literature review"
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"abstract": "BACKGROUND Trazodone is widely used in the treatment of depression, anxiety, and insomnia. It is thought to have a safe cardiac profile due to the relative lack of anticholinergic effects. Publications about cardiac toxicities of trazodone are scant. CASE REPORT A 55-year-old woman presented with acute disorder of consciousness secondary to an intentional trazodone overdose. She was found to have seizure activity without cerebral edema. The initial electrocardiogram was unremarkable, with a normal QTc interval. She eventually developed QTc prolongation that evolved into ventricular tachycardia, and then into a transient right bundle-branch block, left anterior fascicular block, and variable degrees of atrioventricular nodal blocks at 12-24 h after ingestion. She then developed generalized tonic-clonic seizures, cardiogenic shock, and respiratory arrest. She was intubated and treated with antiepileptics, norepinephrine, and dopamine infusion. QTc interval prolongation gradually resolved and the various forms of heart block did not recur after at 24-36 h. She did not require transcutaneous pacing, and was successfully extubated with intact neurological function. CONCLUSIONS Fatal arrhythmias can occur in trazodone overdose. Close monitoring and supportive care are crucial for patient survival.",
"affiliations": "Department of Medical Education, Dignity Health St. Mary Medical Center, Long Beach, CA, USA.;Section of Cardiology, Department of Internal Medicine, Dignity Health St. Mary Medical Center, Long Beach, CA, USA.",
"authors": "Soe|Kyaw Khaing|KK|;Lee|Mark Young|MY|",
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"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 3187941510.12659/AJCR.919833919833ArticlesArrhythmias in Severe Trazodone Overdose Soe Kyaw Khaing ABCEF1Lee Mark Young ABCEF23\n1 Department of Medical Education, Dignity Health St. Mary Medical Center, Long Beach, CA, U.S.A.\n2 Section of Cardiology, Department of Internal Medicine, Dignity Health St. Mary Medical Center, Long Beach, CA, U.S.A.\n3 Department of Cardiology and Electrophysiology, Long Beach Memorial Medical Center, Long Beach, CA, U.S.A.Authors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\nCorresponding Author: Kyaw Khaing Soe, e-mail: kyawkhaings@gmail.com2019 27 12 2019 20 1949 1955 02 9 2019 16 10 2019 © Am J Case Rep, 20192019This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Female, 55-year-old\n\nFinal Diagnosis: Trazodone overdose\n\nSymptoms: Altered mental status • seizure • shock • arrhythmia\n\nMedication: —\n\nClinical Procedure: —\n\nSpecialty: Toxicology\n\nObjective:\nRare disease\n\nBackground:\nTrazodone is widely used in the treatment of depression, anxiety, and insomnia. It is thought to have a safe cardiac profile due to the relative lack of anticholinergic effects. Publications about cardiac toxicities of trazodone are scant.\n\nCase Report:\nA 55-year-old woman presented with acute disorder of consciousness secondary to an intentional trazodone overdose. She was found to have seizure activity without cerebral edema. The initial electrocardiogram was unremarkable, with a normal QTc interval. She eventually developed QTc prolongation that evolved into ventricular tachycardia, and then into a transient right bundle-branch block, left anterior fascicular block, and variable degrees of atrioventricular nodal blocks at 12–24 h after ingestion. She then developed generalized tonic-clonic seizures, cardiogenic shock, and respiratory arrest. She was intubated and treated with antiepileptics, norepinephrine, and dopamine infusion. QTc interval prolongation gradually resolved and the various forms of heart block did not recur after at 24–36 h. She did not require transcutaneous pacing, and was successfully extubated with intact neurological function.\n\nConclusions:\nFatal arrhythmias can occur in trazodone overdose. Close monitoring and supportive care are crucial for patient survival.\n\nMeSH Keywords:\nArrhythmias, CardiacAtrioventricular BlockBundle-Branch BlockDrug OverdoseLong QT SyndromeTrazodone\n==== Body\nBackground\nDepression is a major public health problem and is the leading cause of disability in the United States and worldwide [1]. Depression has significant potential morbidity and mortality, contributing to suicide, with nearly 800 000 people committing suicide every year [2]. Trazodone is a serotonin antagonist and reuptake inhibitor that is widely used for the treatment of depression, anxiety, and insomnia. Trazodone was the second most prescribed medication for sleep and the sixth most prescribed psychiatric medication in 2016 [3]. Trazodone possesses minimal anticholinergic properties, and thus is generally regarded as having less cardiotoxic potential than other antidepressants. Although trazodone was initially thought to have a safe cardiac profile, there has been increasing concern about its cardiotoxicity, as cardiac arrhythmias in trazodone overdose cases became known [4]. Here, we report the case of a patient who intentionally overdosed on trazadone who developed QTc prolongation, wide-complex tachycardia, and variable heart blocks arrhythmias as a result of trazodone cardiotoxicity.\n\nCase Report\nThe patient was a 55-year-old woman with no known chronic illness who was brought in by ambulance for altered mentation. She was last seen conversing normally on the day before hospital admission. At about midnight, the patient reportedly told her son that she had ingested a large amount of trazodone, apparently in an attempt to commit suicide. The exact dosage was unknown, but she said she took all that remained of a bottle of trazodone (50 milligrams, 90 tablets when full). The bottle was not full when she took it and the possible ingested dose could have been 2000–4500 milligrams. According to the son, the patient was initially well but acutely decompensated, with what he described as staggering movement, loss of balance, and complete unresponsiveness, with purposeless shaking and twitching. Paramedics were called, and upon arrival the patient was found minimally responsive and notably hypertensive and tachycardic. No seizures were observed and she was brought to the Emergency Department of our center. She arrived approximately 3–4 h after ingestion, and her initial vitals were: blood pressure 228/120 mmHg, heart rate beats 105 per minute, axillary temperature 37.1°C, respiratory rate 14 breaths per minute, and oxygen saturation 95% on room air. On examination, she had spontaneous eye opening but was without any response to verbal stimuli. Nonspecific eye twitching was noted and she did not blink to threat. She grimaced to painful stimuli but did not localize pain. There was rigidity in the proximal muscle groups but flaccidity in the distal muscle groups. Periods of purposeful-seeming movements, grabbing at the blanket and attempting to cover herself were noted. Gag and cough reflexes were intact, without any concern for airway compromise at that time. A computed tomography of the brain was negative for acute pathology, ruling out head injury, acute intracranial bleed, or any other space-occupying lesions. Due to high suspicion of subclinical seizure activity, the patient was loaded with intravenous levetiracetam 1 gram twice daily. There was minimal improvement after administration of the antiepileptics. She was given intravenous hydralazine 10 mg twice to reduce the systolic blood pressure to below 180 mmHg. Her status did not change noticeably for the next few hours, as she remained nonverbal, with occasionally purposeful-appearing movements punctuated by minimal responsiveness and staring into space. Initial electrocardiogram showed sinus rhythm, U waves, QTc interval of 390 ms, without evidence of heart block (Figure 1). Initial laboratory results were significant for hypokalemia, with potassium of 2.7, which was treated with slow intravenous infusion of potassium chloride; however, her serum magnesium and phosphorous levels were normal. Serum alcohol level, salicylate, and acetaminophen levels were undetectable and a urine toxicology screen was also negative.\n\nThere was little neurological improvement on reassessment the following morning. Approximately 12 h after ingestion, a significant widening of the QTc interval was observed on telemetry. A repeat electrocardiogram showed the QTc interval increased to 519 ms and P pulmonale (Figure 2). A repeated electrolyte panel showed a potassium level of 3.4, for which further intravenous potassium chloride therapy was given. At about 15 h after ingestion, telemetry showed abrupt onset of a wide-complex tachycardia at a rate of 126 per min (Figure 3). The patient was found unresponsive by the registered nurse, but still with a thready pulse and without any spontaneous breathing, triggering code blue activation. The patient was emergently intubated, after which she developed generalized tonic-clonic seizure which was quickly terminated with intravenous pushes of lorazepam. The patient became hypotensive and the rhythm switched to sinus bradycardia at a rate of 40 beats per min, with right bundle-branch block and left anterior fascicular block (Figure 4). She also developed first-degree heart block, Wenckebach phenomenon, wandering pacemaker, and a junctional rhythm (Figures 5–7). She was given intravenous pushes of atropine and epinephrine. Chest compression was not started because her pulse was palpable throughout the course. She was also not cardioverted since the wide-complex tachycardia episode was brief and the rhythm transitioned to brady-arrhythmia. With a provisional diagnosis of cardiogenic shock in the setting of bradycardia and heart blocks, intravenous infusion of norepinephrine and then dopamine were started. She was also loaded with intravenous phenytoin and transferred to the Intensive Care Unit (ICU).\n\nThe right bundle-branch block and the left anterior fascicular block quickly resolved after a few hours (Figure 8). The norepinephrine and dopamine infusion were eventually titrated off within 12 h after the event. Creatinine kinase levels were elevated, peaking at 5590, with a CKMB index of 0.4. Troponin levels were elevated, peaking at 4, which was interpreted as a type II myocardial infarct in the setting of arrhythmia with cardiogenic shock secondary to substance overdose. Transthoracic echocardiogram was done while she was intubated, and her left ventricular ejection fraction was 65–70%, without any wall-motion abnormalities. No further ischemic work-up was warranted at this time. The patient was eventually extubated on the next day. The ICU course was pertinent for aspiration pneumonia in the right lower lobe, which likely happened during her seizures. Her mental status eventually improved and she was responding appropriately to questions over the next few days. She became hypertensive afterwards, with her systolic blood pressure hovering around 150, but she refused treatment. She confirmed not taking any additional medications in this suicide attempt and did not know the exact number of trazadone pills she took. She was subsequently transferred to an inpatient psychiatric facility to continue treatment of her major depression with suicide attempt.\n\nDiscussion\nTrazodone was developed in Italy in 1966. The U.S. Food and Drug Administration (FDA) approved its use for major depression treatment in 1981 [5]. Trazodone is both a selective serotonin reuptake inhibitor (SSRI) and a 5HT2 receptor antagonist, and the net result of this action on serotonergic transmission and its role in the antidepressant effect of trazodone is unknown [5]. QT prolongation was described in several case reports of trazodone overdose [4,6]. Atrioventricular nodal blockage was also described previously [4]. The cellular mechanisms of trazodone cardiotoxicity were explained in a study in which trazodone dose-dependently decreased the maximum upstroke velocity (Vmax), inhibited all of the major ion channels, (IKr, IKs, INa, and ICa), and prolonged the action potential (AP) duration, triggering ventricular arrhythmias in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) [7]. Trazodone has also been implicated in Torsades de pointes in patients with deliberate trazodone overdose [8,9]. Our patient presented with wide-complex tachycardia, transient right bundle-branch block, left anterior fascicular block, and variable degrees of atrioventricular nodal block, which eventually resolved. The rhythm was not consistent with Torsades in our case, and our patient did not require pacer placement for her bradyarrhythmia.\n\nIn our patient, hypotension was likely due to cardiogenic shock in the setting of severe arrhythmia burden, and vasopressors were eventually titrated off as her rhythm improved. It is also noted that severe hypotension can persist without significant arrhythmias and might need intensive care admission and pressor administration [10].\n\nSerotonin syndrome was reported in trazodone overdose with concomitant intake of other serotonergic agents [11–13]. Serotonin syndrome is classically described as hyperthermia, tachycardia, hypertension, altered mental status, agitation, diaphoresis, tremor, myoclonus, and hyperreflexia. Our patient confirmed that she did not take any drugs other than trazadone in her suicide attempt She did not exhibit agitation, tremor, or myoclonus, and there was also no hyperthermia on presentation until she developed aspiration pneumonia and became febrile. She was only briefly hypotensive during her arrhythmias due to the cardiogenic shock and she did have elevated blood pressure afterwards, which could have been pre-existing prior to drug overdose. Nevertheless, we could not rule out the likelihood of serotonergic activity from acute trazodone overdose, which could possibly explain the development of seizures [14].\n\nThere have been case reports of trazodone overdose in which patients developed hyponatremia because of a syndrome of inappropriate antidiuretic hormone secretion, seizure, and cerebral edema [15]. Our patient’s sodium level had been normal throughout, and repeated CT head scans were negative for cerebral edema. As stated above, her seizures could have been due to serotonin syndrome, but also possibly could have resulted from acute cerebral ischemic insult from the cardiogenic shock caused by trazodone cardiotoxicity.\n\nIn our case, there was evidence of an empty bottle of trazodone, and the patient also said she took the medication, which confirmed the diagnosis. The serum trazodone level could not be determined, which is a limitation of this case report.\n\nConclusions\nTrazodone overdose can induce life-threatening electrophysiological abnormalities of the heart, even in those without previous cardiac comorbidity. There is no antidote for trazodone overdose, and supportive care is the mainstay of therapy. It is important to closely monitor for rhythm disturbances and manage these accordingly.\n\nDepartment and Institution where work was done\n\nDepartment of Internal Medicine, St. Mary Medical Center (Dignity Health), Long Beach, CA, U.S.A.\n\nConflict of interest\n\nNone.\n\nFigure 1. Initial electrocardiogram on presentation. Sinus rhythm without QT prolongation.\n\nFigure 2. Sinus tachycardia with QTc interval widening.\n\nFigure 3. Wide-complex tachycardia, followed by seizure activity.\n\nFigure 4. Sinus bradycardia with intermittent ventricular escape with right bundle-branch morphology and left anterior fascicular block.\n\nFigure 5. Wandering pacemaker with different P wave morphologies.\n\nFigure 6. Junctional rhythm with occasional P wave.\n\nFigure 7. Gradual PR interval prolongation with a drop beat. Wenckebach phenomenon.\n\nFigure 8. Resolution of right bundle-branch block and left anterior fascicular block.\n==== Refs\nReferences:\n1. US Burden of Disease Collaborators The state of US health, 1990–2010: Burden of diseases, injuries, and risk factors JAMA 2013 310 6 591 608 23842577 \n2. World Health Organization Depression, Fact sheets 22 3 2018 Available from: URL: https://www.who.int/news-room/fact-sheets/detail/depression \n3. Grohol JM Top 25 psychiatric medications for 2016 Psych Central Last updated: 05 Jul 2019. Available from: URL: https://psychcentral.com/blog/top-25-psychiatric-medications-for-2016/ \n4. Service JA Waring WS QT Prolongation and delayed atrioventricular conduction caused by acute ingestion of trazodone Clin Toxicol (Phila) 2008 46 1 71 73 18167038 \n5. U.S. Food and Drug Administration Trazodone chloride (DESYREL) Revised: 6/2017. Reference ID: 4119349. Available from: URL: https://www.access-data.fda.gov/drugsatfda_docs/label/2017/018207s032lbl.pdf \n6. Dattilo PB Nordin C Prolonged QT associated with an overdose of trazodone J Clin Psychiatry 2007 68 8 1309 10 17854263 \n7. Lee S Lee HA Kim SJ Kim KS Cellular mechanisms for trazodone-induced cardiotoxicity Hum Exp Toxicol 2016 35 5 501 10 26187900 \n8. Chung KJ Wang YC Liu BM Supernaw RB Management of ventricular dysrhythmia secondary to trazadone overdose J Emerg Med 2008 35 171 74 17976767 \n9. De Meester A Carbutti G Gabriel L Jacques JM Fatal overdose with trazodone: Case report and literature review Acta Clin Belg 2001 56 4 258 61 11603256 \n10. Camacho LD Stearns J Amini R Management of trazodone overdose with severe hypotension Case Rep Emerg Med 2019 2019 2470592 31467734 \n11. Little K Lin CM Reynolds PM Delayed serotonin syndrome in the setting of a mixed fluoxetine and serotonin antagonist overdose Am J Case Rep 2018 19 604 7 29795058 \n12. Kaneda Y Ohmori T Okabe H Possible mild serotonin syndrome related to co-prescription of tandospirone and trazodone Gen Hosp Psychiatry 2001 23 2 98 101 11354048 \n13. McCue RE Joseph M Venlafaxine- and trazodone-induced serotonin syndrome Am J Psychiatry 2001 158 12 2088 89 11729039 \n14. Almallouhi E Rahwan M Dainton H Bonilha L Focal seizure as a manifestation of serotonin syndrome: Case report Avicenna J Med 2019 9 119 21 31404205 \n15. Avila JD Fatal cerebral edema, seizures, and hyponatremia after trazodone overdose Clin Neuropharmacol 2017 40 5 221 23 28816830\n\n",
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"mesh_terms": "D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D002037:Bundle-Branch Block; D004298:Dopamine; D062787:Drug Overdose; D004562:Electrocardiography; D005260:Female; D006801:Humans; D008133:Long QT Syndrome; D008875:Middle Aged; D009638:Norepinephrine; D012640:Seizures; D017180:Tachycardia, Ventricular; D014196:Trazodone",
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"title": "Arrhythmias in Severe Trazodone Overdose.",
"title_normalized": "arrhythmias in severe trazodone overdose"
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"abstract": "Most patients suffering from trigeminal neuralgia (TN) benefit from medical therapy, for example carbamazepin, gabapentin, and pregabalin, individually or in combination. Nonetheless, some patients experience severe and intractable pain despite such medication, or the medication eliminates their pain but they experience intolerable side effects sufficient to warrant discontinuation. Intravenous magnesium and lidocaine have been used for management of intractable neuropathic pain. We treated nine patients with TN by using an intravenous infusion of a combination of 1.2 g magnesium and 100 mg lidocaine for 1 hour, once a week for 3 weeks. All patients experienced sound pain relief after the combined intravenous infusion therapy. Two patients experienced short and mild dizziness after the therapy, but no severe side effects were reported.",
"affiliations": "Multidisciplinary Pain Centre, School of Medicine, Aichi Medical University, 21 Karimata, Nagakutecho, Aichigun, Aichi, 480-1195, Japan, arainon@aichi-med-u.ac.jp.",
"authors": "Arai|Young-Chang P|YC|;Hatakeyama|Noboru|N|;Nishihara|Makoto|M|;Ikeuchi|Masahiko|M|;Kurisuno|Makoto|M|;Ikemoto|Tatsunori|T|",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12393768;19378524;21179603;15155309;19284488;15781543;9842827;18503343;21904467;17592992;19594762;22183181;14979299;19496957",
"title": "Intravenous lidocaine and magnesium for management of intractable trigeminal neuralgia: a case series of nine patients.",
"title_normalized": "intravenous lidocaine and magnesium for management of intractable trigeminal neuralgia a case series of nine patients"
} | [
{
"companynumb": "PHHY2014JP078465",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LIDOCAINE"
},
"drugadditional": null,
"druga... |
{
"abstract": "High-risk (HR) neuroblastoma remains a very challenging disease to treat and long-term cure is only possible with intensive, multimodal treatment including chemotherapy, high-dose therapy, radiotherapy, surgery, and immunotherapy. As a result, treatment-related morbidity and late effects are common in survivors. This report outlines a case series of six patients who developed a chronic productive cough following treatment for HR neuroblastoma. High-resolution computed tomography scanning confirmed the diagnosis of bronchiectasis. Two of the patients who have undergone immunological testing demonstrate hypogammaglobulinaemia and impaired vaccine response. Persistent cough in patients treated for neuroblastoma warrants investigation and consideration of immunological referral.",
"affiliations": "Department of Paediatric Oncology, Children's Hospital for Wales, Heath Park, Cardiff, UK.;Department of Paediatric Oncology, Children's Hospital for Wales, Cardiff, UK.;Department of Paediatric Respiratory Medicine, Children's Hospital for Wales, Cardiff, UK.;Department of Paediatric Oncology, Bristol Children's Hospital, Bristol, UK.",
"authors": "Adams|Madeleine|M|;Traunecker|Heidi|H|;Doull|Iolo|I|;Cox|Rachel|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.26509",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "64(10)",
"journal": "Pediatric blood & cancer",
"keywords": "bronchiectasis; hypogammaglobulinaemia; neuroblastoma",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D001987:Bronchiectasis; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D009447:Neuroblastoma",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28296062",
"pubdate": "2017-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bronchiectasis following treatment for high-risk neuroblastoma: A case series.",
"title_normalized": "bronchiectasis following treatment for high risk neuroblastoma a case series"
} | [
{
"companynumb": "GB-MYLANLABS-2017M1063847",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BUSULFAN"
},
"drugadditional": "3",
... |
{
"abstract": "Malignant glioblastoma multiform (GBM) is the most common primary malignancy of the brain in the U.S. Temozolomide (TMZ) is the cornerstone of management along with surgical resection and radiotherapy. Because of the reduction in the CD4+ lymphocyte count as a side effect of TMZ use, this patient population is under risk for opportunistic infections like Pneumocystis jiroveci. A male patient with newly diagnosed glioblastoma multiform presented with non-productive cough and chest pain. Before presentation, the patient received the standard therapy including surgical resection, radiation and TMZ. Computerized tomography of the chest showed a very large cavitary lesion in the upper segment of the right lower lobe and multiple nodular lesions with some starting to cavitate. Cytology of the bronchioalveolar lavage with special stain showed large, broad based budding yeast-like cells, morphologically consistent with blastomyces and macrophages filled with yeast-like forms, morphologically consistent with histoplasma. The patient was treated with intraconazole intended for 12 months. To the best of our knowledge, our case represents the first documented case of lung infection with both blastomyces and histoplasma in a patient after receiving TMZ for newly diagnosed GBM.",
"affiliations": "Department of Internal Medicine, University of South Dakota Sanford School of Medicine.;Department of Internal Medicine, University of South Dakota Sanford School of Medicine.",
"authors": "Jbeli|Aiham H|AH|;Yu|John|J|",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D000077204:Temozolomide",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0038-3317",
"issue": "69(10)",
"journal": "South Dakota medicine : the journal of the South Dakota State Medical Association",
"keywords": null,
"medline_ta": "S D Med",
"mesh_terms": "D018906:Antineoplastic Agents, Alkylating; D001759:Blastomycosis; D001932:Brain Neoplasms; D017024:Chemotherapy, Adjuvant; D003606:Dacarbazine; D005909:Glioblastoma; D006660:Histoplasmosis; D006801:Humans; D008172:Lung Diseases, Fungal; D008297:Male; D008875:Middle Aged; D009894:Opportunistic Infections; D018714:Radiotherapy, Adjuvant; D000077204:Temozolomide",
"nlm_unique_id": "101265265",
"other_id": null,
"pages": "447-450",
"pmc": null,
"pmid": "28806010",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Blastomycosis and Histoplasmosis in a Patient with Glioblastoma Receiving Temozolomide.",
"title_normalized": "blastomycosis and histoplasmosis in a patient with glioblastoma receiving temozolomide"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2018US-167788",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TEMOZOLOMIDE"
},
"dr... |
{
"abstract": "X-linked carriers of chronic granulomatous disease (CGD) may become phenotypically affected if substantial skewing from lyonisation occurs. We describe a 73-year-old female carrier with an overt CGD phenotype due to skewed lyonisation, complicated by macrophage activation syndrome (MAS)/haemophagocytic lymphohistiocytosis (HLH) secondary to Burkholderiacepacia complex septicaemia that was successfully treated with a combination of three antibiotics, an antifungal, granulocyte colony stimulating factor, intravenous immune globulin (IVIG) and ciclosporin. Fully phenotypic immunodeficiency is possible in X-linked CGD carriers when skewed lyonisation occurs, rendering such patients to all the same sequelae of CGD such as MAS/HLH. MAS/HLH should be thoroughly excluded when evaluating 'cepacia syndrome' in non-CGD patients.",
"affiliations": "Immunology, Campbelltown Hospital, Campbelltown, New South Wales, Australia.;Immunopathology, Children's Hospital at Westmead, Westmead, New South Wales, Australia.;Immunology, Campbelltown Hospital, Campbelltown, New South Wales, Australia.",
"authors": "Urriola|Nicolás|N|;Williams|Andrew|A|;Keat|Karuna|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-230434",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(8)",
"journal": "BMJ case reports",
"keywords": "immunology; pneumonia (respiratory medicine)",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000208:Acute Disease; D000368:Aged; D019121:Burkholderia Infections; D042602:Burkholderia cepacia complex; D005260:Female; D006105:Granulomatous Disease, Chronic; D006801:Humans; D051359:Lymphohistiocytosis, Hemophagocytic; D055501:Macrophage Activation Syndrome; D018805:Sepsis; D013577:Syndrome; D049951:X Chromosome Inactivation",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31473638",
"pubdate": "2019-08-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11978610;21116026;11568995;21195301;18356119;16937360;19411195;25394312;23652865;25422023;6420530;24078260;30706673;26090111;10833131;24016250;17446299;22119934;21225928;19058215;25760962;26155526;22551926;15361735;14697745;23401277;20553438;11261321",
"title": "Macrophage activation syndrome/haemophagocytic lymphohistiocytosis secondary to Burkholderia cepacia complex septicaemia in an elderly female carrier of X-linked chronic granulomatous disease with extreme lyonisation: 'cepacia syndrome' revisited.",
"title_normalized": "macrophage activation syndrome haemophagocytic lymphohistiocytosis secondary to burkholderia cepacia complex septicaemia in an elderly female carrier of x linked chronic granulomatous disease with extreme lyonisation cepacia syndrome revisited"
} | [
{
"companynumb": "AU-AMGEN-AUSSP2019156002",
"fulfillexpeditecriteria": "2",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AZITHROMYCIN ANHYDROUS"
},
"drugadditional": ... |
{
"abstract": "OBJECTIVE\nAlthough immune checkpoint inhibitor (ICI) myocarditis carries a high reported mortality, increasing reports of smoldering myocarditis suggest a clinical spectrum of disease. Endomyocardial biopsy (EMB) remains the gold standard for diagnosis of ICI myocarditis, but different pathologic diagnostic criteria exist. The objective of this study was to classify the spectrum of ICI myocarditis and myocardial inflammation by pathology findings on EMB and correlate this with clinical outcomes.\n\n\nRESULTS\nAll patients who had EMB at MD Anderson Cancer Center between January 2018 and August 2019 for suspected ICI myocarditis were retrospectively reviewed. A grading system (Grades 0-2) based on the degree of inflammatory infiltrate was developed by pathologists. Cardiovascular outcomes and treatment were compared between grades of pathology. We identified 28 patients who had EMB for suspected ICI myocarditis, of which 18 were positive for myocarditis/inflammation. There were four deaths (two in Grade 2 and two in Grade 1), but only one was attributable to myocarditis. Grade 2 patients had no myocarditis-associated deaths despite having the highest troponin T values (median 2063 pg/mL). Four patients with Grade 1 myocardial inflammation continued ICI without any immunomodulation, and all were alive without adverse cardiovascular events at follow-up.\n\n\nCONCLUSIONS\nWe defined an EMB grading system for ICI myocarditis encompassing a spectrum of histologic findings of inflammatory infiltrates. A subset of low-grade myocardial inflammation patients were able to continue ICI without immunosuppressive therapy. Further studies are needed to identify low-risk patients who can be safely treated with ICI.",
"affiliations": "Department of Cardiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Texas Heart Institute, Houston, TX, USA.;University of Texas Health Science Center, Houston, TX, USA.;Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Cardiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Cardiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Cardiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.;University of Texas Health Science Center, Houston, TX, USA.;University of Texas Health Science Center, Houston, TX, USA.;Department of Cardiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.",
"authors": "Palaskas|Nicolas L|NL|;Segura|Ana|A|;Lelenwa|Laura|L|;Siddiqui|Bilal A|BA|;Subudhi|Sumit K|SK|;Lopez-Mattei|Juan|J|;Durand|Jean B|JB|;Deswal|Anita|A|;Zhao|Bihong|B|;Maximilian Buja|L|L|;Iliescu|Cezar|C|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ejhf.2265",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1388-9842",
"issue": "23(10)",
"journal": "European journal of heart failure",
"keywords": "Endomyocardial biopsy; Immune checkpoint inhibitor; Myocarditis",
"medline_ta": "Eur J Heart Fail",
"mesh_terms": null,
"nlm_unique_id": "100887595",
"other_id": null,
"pages": "1725-1735",
"pmc": null,
"pmid": "34114291",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Immune checkpoint inhibitor myocarditis: elucidating the spectrum of disease through endomyocardial biopsy.",
"title_normalized": "immune checkpoint inhibitor myocarditis elucidating the spectrum of disease through endomyocardial biopsy"
} | [
{
"companynumb": "US-ROCHE-2960287",
"fulfillexpeditecriteria": "1",
"occurcountry": null,
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ATEZOLIZUMAB"
},
"drugadditional": "3",
"dru... |
{
"abstract": "We herein report three cases of Parkinson's disease associated with difficulty in eyelid opening, referred to as apraxia of eyelid opening (AEO), which improved after aripiprazole treatment. In case 1, aripiprazole was administered as a psychiatric treatment. It proved to be effective in AEO with blepharospasm. In case 2 and case 3, the patients experienced AEO without blepharospasm, and a significant improvement was observed after aripiprazole treatment. In this study, the aripiprazole dosage ranged between 3 and 9 mg/day. This is the first report of aripiprazole as a potentially effective treatment for AEO in Parkinson's disease.",
"affiliations": "The Department of Neurology, Kumamoto Kinoh Hospital, Japan.",
"authors": "Tokisato|Kaori|K|;Fukunaga|Kimiko|K|;Tokunaga|Makoto|M|;Watanabe|Susumu|S|;Nakanishi|Ryoji|R|;Yamanaga|Hiroaki|H|",
"chemical_list": "D000068180:Aripiprazole",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.54.4279",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0918-2918",
"issue": "54(23)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D001072:Apraxias; D000068180:Aripiprazole; D001764:Blepharospasm; D005143:Eyelids; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease; D016896:Treatment Outcome",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "3061-4",
"pmc": null,
"pmid": "26631893",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Aripiprazole Can Improve Apraxia of Eyelid Opening in Parkinson's Disease.",
"title_normalized": "aripiprazole can improve apraxia of eyelid opening in parkinson s disease"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2016RR-111372",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HALOPERIDOL"
},
"dru... |
{
"abstract": "Atrial fibrillation (AF) is the most common type of arrhythmia. Warfarin reduces the incidence and mortality of strokes in patients with AF. Edoxaban reduces the bleeding risk in patients with AF. This study evaluates the efficacy and safety of edoxaban versus warfarin in preventing clinical events in patients with AF through a meta-analysis of randomized controlled trials (RCTs). RCTs were retrieved from medical literature databases. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated to compare the primary and safety endpoints. In total, five articles (10 trial comparisons) containing 24,836 patients were retrieved. Of these patients, 16,268 (65.5%) received edoxaban and 8,568 (34.5%) received warfarin. Compared with warfarin, edoxaban significantly reduced the incidence of cardiovascular death (CVD), major bleeding, and non-major bleeding (RR: 0.86, 95% CI: 0.80-0.93, I2 : 0.0%; RR: 0.65, 95% CI: 0.59-0.71, I2 : 75.6%; and RR: 0.80, 95% CI: 0.77-0.84, I2 : 79.3%, respectively). Edoxaban did not increase the incidence of stroke, systemic embolic events, myocardial infarction, and adverse events compared with warfarin (RR: 1.00, 95% CI: 0.90-1.11, I2 : 42.8%; RR: 1.00, 95% CI: 0.67-1.49, I2 : 0.0%; RR: 1.08, 95% CI: 0.93-1.27, I2 : 0.0%; RR: 1.00, 95% CI: 0.91-1.10, I2: 46.4%, respectively). This meta-analysis indicated that compared with warfarin, edoxaban can significantly reduce the incidence of CVD and major and non-major bleeding. The anticoagulant effect and safety of edoxaban may be better than those of warfarin.",
"affiliations": "Department of Cardiology, the First People's Hospital of Yulin, the Sixth Affiliated Hospital of Guangxi Medical University; Guangxi-China.;Department of Cardiology, the First People's Hospital of Yulin, the Sixth Affiliated Hospital of Guangxi Medical University; Guangxi-China.;Department of Cardiology, the First People's Hospital of Yulin, the Sixth Affiliated Hospital of Guangxi Medical University; Guangxi-China.;Department of Cardiology, the First People's Hospital of Yulin, the Sixth Affiliated Hospital of Guangxi Medical University; Guangxi-China.",
"authors": "Liang|Xiangwen|X|;Xie|Wenchao|W|;Lin|Zhihai|Z|;Liu|Ming|M|",
"chemical_list": "D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D011725:Pyridines; D013844:Thiazoles; D014859:Warfarin; C552171:edoxaban",
"country": "Turkey",
"delete": false,
"doi": "10.14744/AnatolJCardiol.2020.18049",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2149-2263",
"issue": "25(2)",
"journal": "Anatolian journal of cardiology",
"keywords": null,
"medline_ta": "Anatol J Cardiol",
"mesh_terms": "D000925:Anticoagulants; D001281:Atrial Fibrillation; D065427:Factor Xa Inhibitors; D006801:Humans; D011725:Pyridines; D020521:Stroke; D013844:Thiazoles; D016896:Treatment Outcome; D014859:Warfarin",
"nlm_unique_id": "101652981",
"other_id": null,
"pages": "77-88",
"pmc": null,
"pmid": "33583814",
"pubdate": "2021-02",
"publication_types": "D016428:Journal Article; D017418:Meta-Analysis; D000078182:Systematic Review",
"references": "27614940;21094542;25911527;6161558;27590218;24493817;11848460;22711103;27284259;29509959;26093875;19132230;20694273;27989309;25179572;28892643;25370585;21136011;23991658;16706956;28668628;20807664;31040359;28426737;26399866;21747126;29760204;12756461;24251359;22664798;1462916;24322553;25687352;28387109;26167638;11740689;26204447;28611377",
"title": "The efficacy and safety of edoxaban versus warfarin in preventing clinical events in atrial fibrillation: A systematic review and meta-analysis.",
"title_normalized": "the efficacy and safety of edoxaban versus warfarin in preventing clinical events in atrial fibrillation a systematic review and meta analysis"
} | [
{
"companynumb": "PT-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-023251",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MICONAZOLE"
},
"drugadd... |
{
"abstract": "Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS) is the second most common heritable autoinflammatory disease, typically presenting in pre-school aged children with fever episodes lasting 1-3 weeks. Systemic symptoms can include rash, myalgia, ocular inflammation, and serositis.\n\n\n\nHere we report an unusual presentation of TRAPS in a 7 month old girl who presented with only persistent fever. She was initially diagnosed with incomplete Kawasaki Disease and received IVIG and infliximab; however, her fevers quickly recurred. Subsequent testing revealed a urinary tract infection, but she did not improve despite appropriate therapy. As fever continued, she developed significant abdominal distension with imaging concerning for appendicitis, followed by hyperthermia and hemodynamic instability. Given her protracted clinical course and maternal history of a poorly defined inflammatory condition, an autoinflammatory disease was considered. Therapy with anakinra was initiated, resulting in rapid resolution of fever and normalization of inflammatory markers. She was found to have a previously unreported mutation, Thr90Pro, in the TNFRSF1A gene associated with TRAPS. This novel mutation was also confirmed in the patient's mother and maternal uncle.\n\n\n\nThis report reviews a severe case of TRAPS in infancy associated with a novel mutation, Thr90Pro, in the TNFRSF1A gene, and emphasizes that autoinflammatory disease should be considered in the differential of infants with fever of unknown origin.",
"affiliations": "Department of Pediatrics, Division of Allergy, Immunology, Rheumatology and Kawasaki Disease, University of California San Diego and Rady Children's Hospital, 9500 Gilman Drive #0760, La Jolla, San Diego, CA, 92093, USA.;Department of Pediatrics, University of California San Diego and Rady Children's Hospital, San Diego, CA, USA.;Department of Pediatrics, Division of Allergy, Immunology, Rheumatology and Kawasaki Disease, University of California San Diego and Rady Children's Hospital, 9500 Gilman Drive #0760, La Jolla, San Diego, CA, 92093, USA. lbroderick@ucsd.edu.",
"authors": "Radhakrishna|Suhas M|SM|;Grimm|Amy|A|;Broderick|Lori|L|",
"chemical_list": "D005819:Genetic Markers; D047888:Receptors, Tumor Necrosis Factor, Type I; C506235:TNFRSF1A protein, human",
"country": "England",
"delete": false,
"doi": "10.1186/s12887-017-0856-2",
"fulltext": "\n==== Front\nBMC PediatrBMC PediatrBMC Pediatrics1471-2431BioMed Central London 85610.1186/s12887-017-0856-2Case ReportNovel mutation identified in severe early-onset tumor necrosis factor receptor-associated periodic syndrome: a case report Radhakrishna Suhas M. sradh@ucsd.edu 1Grimm Amy aegrimm@ucsd.edu 23Broderick Lori lbroderick@ucsd.edu 11 0000 0001 2107 4242grid.266100.3Department of Pediatrics, Division of Allergy, Immunology, Rheumatology and Kawasaki Disease, University of California San Diego and Rady Children’s Hospital, 9500 Gilman Drive #0760, La Jolla, San Diego, CA 92093 USA 2 0000 0001 2107 4242grid.266100.3Department of Pediatrics, University of California San Diego and Rady Children’s Hospital, San Diego, CA USA 3 Allegro Pediatrics, Bellevue, WA USA 20 4 2017 20 4 2017 2017 17 10821 5 2016 1 4 2017 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nTumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS) is the second most common heritable autoinflammatory disease, typically presenting in pre-school aged children with fever episodes lasting 1–3 weeks. Systemic symptoms can include rash, myalgia, ocular inflammation, and serositis.\n\nCase presentation\nHere we report an unusual presentation of TRAPS in a 7 month old girl who presented with only persistent fever. She was initially diagnosed with incomplete Kawasaki Disease and received IVIG and infliximab; however, her fevers quickly recurred. Subsequent testing revealed a urinary tract infection, but she did not improve despite appropriate therapy. As fever continued, she developed significant abdominal distension with imaging concerning for appendicitis, followed by hyperthermia and hemodynamic instability. Given her protracted clinical course and maternal history of a poorly defined inflammatory condition, an autoinflammatory disease was considered. Therapy with anakinra was initiated, resulting in rapid resolution of fever and normalization of inflammatory markers. She was found to have a previously unreported mutation, Thr90Pro, in the TNFRSF1A gene associated with TRAPS. This novel mutation was also confirmed in the patient’s mother and maternal uncle.\n\nConclusions\nThis report reviews a severe case of TRAPS in infancy associated with a novel mutation, Thr90Pro, in the TNFRSF1A gene, and emphasizes that autoinflammatory disease should be considered in the differential of infants with fever of unknown origin.\n\nElectronic supplementary material\nThe online version of this article (doi:10.1186/s12887-017-0856-2) contains supplementary material, which is available to authorized users.\n\nKeywords\nAutoinflammatory diseasePeriodic fever syndromeTumor necrosis factor receptor associated periodic syndromeKawasaki diseaseAnakinraCase reporthttp://dx.doi.org/10.13039/100000071National Institute of Child Health and Human Development5K08HD075830Broderick Lori issue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nAutoinflammatory diseases, also known as periodic fever syndromes, are caused by dysregulation of the innate immune response with inappropriate activation of interleukin-1 and tumor necrosis factor pathways [1]. These differ from typical autoimmune disorders in that they are not mediated by autoantibodies and are often monogenically inherited. The diagnosis of an autoinflammatory disease should be considered in the setting of recurrent fever without a source. Family history of recurrent fevers or inflammatory symptoms may lend support to the diagnosis.\n\nIn Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS), the average age of onset is 3 years of age, but onset has been reported as early as 4 days [2] and up to the sixth decade of life. Flares, lasting from 5 days to several weeks, may occur spontaneously or in relation to a trigger such as a minor illness. Symptoms include fever, migrating myalgia, arthralgia or arthritis, rash, and serous membrane inflammation that manifests as chest and abdominal pain [1]. Arthralgia is more common than arthritis, and affects large joints as well as wrists and temporomandibular joints. Centrifugal migratory erythematous rashes are present in the majority of cases, but other patterns, including urticaria, are possible. Periorbital edema is also common and can be associated with uveitis or conjunctivitis. Secondary AA amyloidosis is the most severe long term complication of TRAPS, affecting 10–20% of untreated patients [3]. Morbidity and mortality associated with amyloidosis is generally due to nephrotic syndrome and renal failure [1], but other organ systems can be affected.\n\nTRAPS is due to mutations in TNFRSF1A that encodes the Tumor Necrosis Factor (TNF)-∝ receptor, and is inherited in an autosomal dominant fashion. Mutations are primarily single nucleotide missense mutations in exons 2, 3, 4 and 6 that affect the three-dimensional structure of the receptor. Normally, binding of TNF-∝ to the TNF receptor leads to downstream signaling of pathways for inflammation, apoptosis and cellular regulation. The mechanism by which mutations in TNFRSF1A lead to uncontrolled inflammation in TRAPS is not entirely known. Proposed etiologies include decreased levels of circulating inhibitor soluble TNFR1, constitutive activation of the receptor, decreased TNF mediated apoptosis, and intracellular oxidative stress due to misfolding of the receptor in the endoplasmic reticulum [1].\n\nCase presentation\nThe patient presented at 7 months of age with seven days of fever, vomiting, diarrhea, and faint erythematous papular rash. She was born prematurely at 32 weeks and had delayed gross motor development compared to her fraternal twin. Laboratory tests showed c-reactive protein (CRP) 25.7 mg/dl, erythrocyte sedimentation rate (ESR) 50 mm, white blood cell count 19.6 103/μL, hemoglobin 9.9 g/dL, and platelets 508 × 103/μL. Liver enzymes and urinalysis were normal. Initial echocardiogram showed borderline dilated left anterior descending coronary artery (Z-score 2). Therefore, two doses of IVIG and aspirin were given for presumed incomplete Kawasaki Disease (KD). Though fever resolved with the second dose of IVIG, a dose of infliximab (10 mg/kg) was given due to borderline dilation of multiple coronary arteries on repeat echocardiogram (Z-scores 2.05–2.3). CRP improved to 3.4 mg/dl and she was discharged on low-dose aspirin.\n\nThree days after discharge, the fever recurred to 103 °F without rash or other systemic symptoms. Laboratory testing again showed significant inflammation (CRP 26.2 mg/dl, ESR >140 mm). Urine culture grew E.coli, but she remained febrile despite appropriate intravenous antibiotics. Echocardiogram was normal. She subsequently developed diarrhea and abdominal distention, and abdominal CT showed a calcified appendicolith with regional ileus concerning for acute appendicitis. Appendectomy was deferred as she developed fever to 107 °F and hypotension requiring intensive care support. The fever persisted despite broadened antibiotic coverage.\n\nFurther investigation into our patient’s family history revealed that her mother and maternal uncle had previously been diagnosed with systemic juvenile arthritis due to recurrent attacks of fever, arthritis, rash, serositis, and conjunctivitis since infancy (Fig. 1). For them, several treatments were partially successful including etanercept and anakinra; infliximab caused severe flare of disease in the mother. By mother’s history, the patient’s maternal grandfather also suffered from similar attacks since childhood, but remained untreated and died at age 52 of complications of systemic amyloidosis.Fig. 1 Family pedigree. Arrow indicates proband\n\n\n\n\nGiven this family history of chronic recurrent inflammatory disease, the diagnosis of TRAPS was considered and treatment with anakinra was initiated at 4 mg/kg/day. Her fever resolved within 48 h of initiating treatment. In addition, her abdominal distension improved and CRP normalized over two weeks (Fig. 2). Genetic testing (MNG Laboratories) confirmed a novel mutation at position 268A > C, causing the substitution of threonine to proline at amino acid 90, in the TNFRSF1A gene. At 15 months of age, the patient remains in remission on anakinra 2 mg/kg daily, with no evidence of subclinical inflammation. A trial of withdrawal of anakinra resulted in rapid elevation of serum inflammatory markers and return of fever. Gross motor development has also progressed to an age-appropriate level.Fig. 2 Daily maximum temperature curve superimposed with CRP values over the period from initial presentation to resolution of symptoms. Administration of therapies is indicated by arrows\n\n\n\n\n\nAffected and unaffected relatives (Fig. 1) were sequenced to query this mutation, and informed consent was obtained under an IRB approved protocol to Sanger sequence exon 3 of the TNFRSF1A gene (Additional file 1). Only the patient’s mother and maternal uncle were confirmed to share the same point mutation. No DNA was available from the deceased grandfather. Once an accurate diagnosis was established, the mother was treated with canakinumab with resolution of symptoms and normalization of inflammatory labs.\n\nDiscussion and conclusions\nAutoinflammatory diseases may present a diagnostic challenge to the pediatrician given their rarity, chronic recurrent nature of flares, and overlapping signs and symptoms with other disorders and amongst themselves. The increasing spectrum of autoinflammatory disorders has recently been reviewed [4–6]. For the clinician, a detailed history can provide invaluable information to differentiate between autoinflammatory disorders, as well as immunodeficiency or infection which also present in childhood, thereby reducing further delays in diagnosis and unnecessary diagnostic investigations. Extremes of hyperthermia may also be indicative of an underlying inflammatory condition, or condition affecting hypothalamic temperature regulation (i.e., malignant hyperthermia, spinal cord injury), rather than an infectious process [7–10]. Beyond the numeric temperature, recognition of characteristic patterns, such as duration of febrile attacks, and associated symptoms such as rashes, serositis, and arthritis, is often the key to diagnosing patients early [6]. A suspected diagnosis should be confirmed with genetic testing when possible. For our patient, a family history of a poorly defined inflammatory condition was crucial in making the correct diagnosis and initiating timely therapy. The mutation identified in this family, Thr90Pro in the TNFRSF1A gene, has not previously been reported in TRAPS.\n\nThis case demonstrates an unusual presentation of TRAPS in a young infant without the characteristic symptoms or history of recurrent fever episodes typically seen in older children and adults, and further emphasizes the importance of an accurate history in patients with fevers of unknown origin in order to pursue an appropriate clinical evaluation. Our patient had findings suggesting incomplete KD, urinary tract infection (UTI), and appendicitis, but these alternative diagnoses can be reconciled with the diagnosis of TRAPS. Transient coronary arteritis has been reported to occur in other autoinflammatory diseases [11, 12, 13]. Furthermore, the development of distinct autoinflammatory syndromes in patients with a history of KD has also been described [14] and it has been postulated that such immune dysregulation may also predispose patients to KD. The E.coli UTI may have served as the trigger for a TRAPS flare. Finally, sterile acute peritonitis is common in TRAPS and other autoinflammatory diseases and can mimic appendicitis such that one third of TRAPS patients undergo unnecessary appendectomy [1].\n\nWith the increasing availability of targeted biologic anti-cytokine treatments, new recommendations for the management of these unique patients have been proposed [15]. For TRAPS, treatment options include short-term glucocorticoids, with or without nonsteroidal anti-inflammatory drugs, anti-TNF therapy with etanercept, and IL-1 blockade, such as anakinra, as used in our patient. Notably, infliximab (Remicade), a monoclonal antibody directed against TNF-∝, has been shown to potentially trigger TRAPS flares [16], and its use is not recommended. Once on therapy, routine monitoring for subclinical inflammation as well as proteinuria, a manifestation of renal amyloidosis, is advised. As in this case, early diagnosis, treatment and close monitoring promote control of systemic inflammation, prevent long-term organ damage associated with systemic AA amyloidosis, and dramatically improve quality of life.\n\nAdditional file\n\nAdditional file 1: This file contains the Sanger sequencing protocol. (DOCX 36 kb)\n\n\n\n\nAbbreviations\nCRPC-reactive protein\n\nESRErythrocyte sedimentation rate\n\nKDKawasaki Disease\n\nTRAPSTumor Necrosis Factor Receptor-Associated Periodic Syndrome\n\nUTIUrinary tract infection\n\nThe authors would like to thank Dr. Hal M. Hoffman for thoughtful comments during the writing of this manuscript.\n\nFunding\nThe work was supported by NIH NICHD (5K08HD075830) and Arthritis National Research Foundation (both to L.B.)\n\nAvailability of data and materials\nWe have submitted the novel mutation identified to INFEVERS: The registry of Hereditary Auto-inflammatory Disorders Mutations http://fmf.igh.cnrs.fr/ISSAID/infevers/. No additional datasets were generated during the current study.\n\nAuthors’ Contributions\nSMR: Clinical care of patient, contributed to original report, edited and approved final draft. AG: Clinical care of patient, contributed to original report, edited and approved final draft. LB: Clinical care of patient, performed in vitro work and sequence analysis, contributed to original report, edited and approved final draft. All authors approved the final manuscript as submitted.\n\nCompeting interests\nSuhas M. Radhakrishna and Amy Grimm: None; Lori Broderick: current grant support from NIH NICHD (5K08HD075830) and Arthritis National Research Foundation; participation in advisory boards for SOBI, Inc. and Novartis (both subsequent to involvement with this case).\n\nConsent for publication\nSigned informed consent from adults greater than 18 years of age, and parent informed consent with child assent (for patients under 18 years of age) was obtained for publication. It was specifically discussed with the family that the details of the case were described including the pedigree, but no images or names are used. The family agreed to this publication of her this case report, with mother acting as surrogate for the patient (a minor).\n\nEthical approval and consent to participate\nSigned informed consent from adults greater than 18 years of age, and parent informed consent with child assent (for patients under 18 years of age) was obtained to perform DNA sequence analysis from all subjects from whom samples were obtained. The genetic study was approved by the Institutional Review Board of University of California, San Diego.\n\nDeclarations\nCARE guidelines and methodology were adhered to in the construction of this manuscript.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Rigante D Lopalco G Vitale A Key facts and hot spots on tumor necrosis factor receptor-associated periodic syndrome Clin Rheumatol 2014 33 9 1197 1207 10.1007/s10067-014-2722-z 24935411 \n2. Savage T Loftus BG Tormey V McDermott MF Moylett E Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) or familial Hiberian fever: presentation in a four-day-old infant J Clin Rheumatol 2008 14 6 342 345 10.1097/RHU.0b013e31817d109b 18690165 \n3. Obici L Merlini G Amyloidosis in autoinflammatory syndromes Autoimmun Rev 2012 12 1 14 17 10.1016/j.autrev.2012.07.016 22878269 \n4. Lachman HJ Autoinflammatory syndromes as a cause of fever of unknown origin Clin Med 2015 15 3 295 298 10.7861/clinmedicine.15-3-295 \n5. Broderick L De Nardo D Franklin BS Hoffman HM Latz E The inflammasomes and autoinflammatory syndromes Annu Rev Pathol 2015 10 395 424 10.1146/annurev-pathol-012414-040431 25423351 \n6. Rigante D Vitale A Lucherini OM Cantarini L The heredity autoinflammatory disorders uncovered Autoimmun Rev 2014 13 9 892 900 10.1016/j.autrev.2014.08.001 25149390 \n7. Good GR DiNubile MJ Cyclic fever in Hodgkin's disease (Pel–Ebstein fever) N Engl J Med 1995 332 436 10.1056/NEJM199502163320705 7824016 \n8. Shah NT Habtegebriel YA Bloomfield DA Extreme hyperpyrexia of uncertain origin J Emerg Med 2016 51 3 e33 e35 10.1016/j.jemermed.2016.02.030 27364825 \n9. Rosenberg H Pollock N Schiemann A Bulger T Stowell K Malignant hyperthermia: a review Orphanet J Rare Dis 2015 10 93 10.1186/s13023-015-0310-1 26238698 \n10. Drewry AM Fuller BM Bailey TC Hotchkiss RS Body temperature patterns as a predictor of hospital-acquired sepsis in afebrile adult intensive care unit patients: a case-control study Crit Care 2013 17 5 R200 10.1186/cc12894 24028682 \n11. Binstadt BA Levine JC Nigrovic PA Coronary artery dilation among patients presenting with systemic-onset juvenile idiopathic arthritis Pediatrics 2005 116 1 e89 e93 10.1542/peds.2004-2190 15930186 \n12. Thors VS Vastert SJ Wulffraat N Periodic fever in MVK deficiency: a patient initially diagnosed with incomplete kawasaki disease Pediatrics 2014 133 2 e461 e465 10.1542/peds.2012-1372 24470648 \n13. Hodgson KA Crawford NW Akikusa JD Recurrent fevers in children: TRAPS for young players BMJ Case Rep 2014 24729107 \n14. Broderick L Tremoulet AH Burns JC Bastian JF Hoffman HM Recurrent fever syndromes in patients after recovery from Kawasaki syndrome Pediatrics 2011 127 2 489 493 10.1542/peds.2010-1218 \n15. ter Haar NM Oswald M Jeyaratnam J Recommendations for the management of autoinflammatory diseases Ann Rheum Dis 2015 74 9 1636 1644 10.1136/annrheumdis-2015-207546 26109736 \n16. Nedjai B Hitman GA Quillinan N Proinflammatory action of the anti-inflammatory drug infliximab in tumor necrosis factor receptor-associated periodic syndrome Arthritis Rheum 2009 60 2 619 625 10.1002/art.24294 19180495\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2431",
"issue": "17(1)",
"journal": "BMC pediatrics",
"keywords": "Anakinra; Autoinflammatory disease; Case report; Kawasaki disease; Periodic fever syndrome; Tumor necrosis factor receptor associated periodic syndrome",
"medline_ta": "BMC Pediatr",
"mesh_terms": "D000328:Adult; D019943:Amino Acid Substitution; D005260:Female; D005334:Fever; D005819:Genetic Markers; D056660:Hereditary Autoinflammatory Diseases; D006801:Humans; D007223:Infant; D008297:Male; D017354:Point Mutation; D047888:Receptors, Tumor Necrosis Factor, Type I",
"nlm_unique_id": "100967804",
"other_id": null,
"pages": "108",
"pmc": null,
"pmid": "28427379",
"pubdate": "2017-04-20",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D052061:Research Support, N.I.H., Extramural",
"references": "22878269;24470648;26031984;25423351;24935411;18690165;24028682;7824016;19180495;15930186;26238698;25149390;24729107;26109736;27364825;21220401",
"title": "Novel mutation identified in severe early-onset tumor necrosis factor receptor-associated periodic syndrome: a case report.",
"title_normalized": "novel mutation identified in severe early onset tumor necrosis factor receptor associated periodic syndrome a case report"
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"companynumb": "US-AMGEN-USASP2017169214",
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"activesubstancename": "ETANERCEPT"
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