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"abstract": "BACKGROUND\nRecently, gadolinium from linear GBCAs has been reported to deposit in various regions of the body. Besides gadolinium, other lanthanides are used in medical care. In the current study, we investigated deposition of lanthanum in two patients who received lanthanum carbonate as a phosphate binder due to chronic kidney injury and compared it to additionally found Gd deposition.\n\n\nMETHODS\nTissue specimens of two patients with long-term application of lanthanum carbonate as well as possible GBCA application were investigated. Spatial distribution of gadolinium and lanthanum was determined by quantitative laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) imaging of tissue sections. The deposition of gadolinium and lanthanum in different organs was compared, and the ratio of Gd concentration to La concentration (Gd-to-La-ratio) was investigated on an individual pixel base within the images.\n\n\nRESULTS\nDeposition of Gd and La was found in all investigated tissues of both patients. Gd and La exhibited high spatial correlation for all samples, with the main deposition being located in the middle coat (tunica media) of blood vessels. The Gd-to-La-ratio was similar in the tissues investigated (between 8 ± 4 (mean ± standard deviation) and 10 ± 2), except for the thyroid vasculature and surrounding tissue (90 ± 17) as well as the cerebellum (270 ± 18). Here, the ratio was significantly increased towards higher Gd concentration.\n\n\nCONCLUSIONS\nThe results of this study demonstrate long-term deposition of La and comparable localization of additionally found Gd in various tissues of the body. La deposition was relatively low, considering the total administered amount of lanthanum carbonate of up to 11.5 kg, indicating a low absorption and/or high excretion of lanthanum. However, the total amount of deposited La is significant and raises questions about possible adverse side effects. The ratio-approach allows for the usage of the additionally generated Gd data, without detailed knowledge about possible GBCA applications. The significantly decreased Gd-to-La-ratio in the brain might be explained by the lanthanum being released and taken up as free La3+ ion in the stomach that impedes a crossing of the blood-brain-barrier while the intravenously injected GBCAs might dechelate first when they have already crossed the blood-brain-barrier.",
"affiliations": "Institute of Inorganic and Analytical Chemistry, University of Münster, 48149 Münster, Germany.;Diagnostic Imaging Research Unit (DIRU), Clinic for Diagnostic Imaging, University of Zurich, CH-8057 Zurich, Switzerland.;Department of Diagnostic and Interventional Radiology and Neuroradiology, University Clinic Essen, University Duisburg-Essen, 45147 Essen, Germany; Department of Diagnostic and Interventional Neuroradiology, University Clinic Bonn, 53127 Bonn, Germany.;Institute of Inorganic and Analytical Chemistry, University of Münster, 48149 Münster, Germany; European Virtual Institute for Speciation Analysis (EVISA), 48149 Münster, Germany.;Department of Medicine D, University Hospital Münster, Division of General Internal Medicine, Nephrology and Rheumatology, 48149 Münster, Germany.;Department of Neurosurgery, University Hospital Münster, 48149 Münster, Germany.;Department of Pathology, University Hospital Münster, 48149 Münster, Germany.;Department of Neuropathology, University Hospital Münster, 48149 Münster, Germany.;Department of Neuropathology, University Hospital Münster, 48149 Münster, Germany.;Institute of Inorganic and Analytical Chemistry, University of Münster, 48149 Münster, Germany. Electronic address: uk@uni-muenster.de.",
"authors": "Bücker|Patrick|P|;Richter|Henning|H|;Radbruch|Alexander|A|;Sperling|Michael|M|;Brand|Marcus|M|;Holling|Markus|M|;Van Marck|Veerle|V|;Paulus|Werner|W|;Jeibmann|Astrid|A|;Karst|Uwe|U|",
"chemical_list": "D003287:Contrast Media; C119467:lanthanum carbonate; D007811:Lanthanum; D005682:Gadolinium",
"country": "Germany",
"delete": false,
"doi": "10.1016/j.jtemb.2020.126665",
"fulltext": null,
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"issn_linking": "0946-672X",
"issue": "63()",
"journal": "Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)",
"keywords": "Bioimaging; Gadolinium-Based contrast agent; LA-ICP-MS; Lanthanide deposition; Lanthanum carbonate; Phosphate binder",
"medline_ta": "J Trace Elem Med Biol",
"mesh_terms": "D003287:Contrast Media; D005682:Gadolinium; D006801:Humans; D007811:Lanthanum; D007834:Lasers; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D014018:Tissue Distribution",
"nlm_unique_id": "9508274",
"other_id": null,
"pages": "126665",
"pmc": null,
"pmid": "33152670",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Deposition patterns of iatrogenic lanthanum and gadolinium in the human body depend on delivered chemical binding forms.",
"title_normalized": "deposition patterns of iatrogenic lanthanum and gadolinium in the human body depend on delivered chemical binding forms"
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"companynumb": "DE-TAKEDA-2020TUS049988",
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"abstract": "Angiotensin receptor blockers (ARBs) plus calcium channel blockers (CCBs) are a widely used combination therapy for hypertensive patients. In order to determine which combination was better as the next-step therapy for standard-dose combination of ARBs and CCBs, a combination with high-dose CCBs or a triple combination with diuretics, the authors conducted a prospective, randomized, open-label trial to determine which of the following combination is better as the next-step treatment: a combination with high-dose CCBs or a triple combination with diuretics. Hypertensive outpatients who did not achieve their target blood pressure (BP) with usual dosages of ARBs and amlodipine 5 mg were randomly assigned to treatment with irbesartan 100 mg/amlodipine 10 mg (Group 1: n = 48) or indapamide 1 mg in addition to ARBs plus amlodipine 5 mg (Group 2: n = 46). The primary end point was changes in the systolic BP (SBP) and diastolic BP (DBP) after the 12-week treatment period, while secondary end points were changes in BP after the 24-week treatment period and laboratory values. At 12 weeks, the SBP/DBP significantly decreased from 152.1/83.4 mm Hg to 131.5/76.1 mm Hg in Group 1 and 153.9/82.1 mm Hg to 132.7/75.9 mm Hg in Group 2. Although both groups produced a similar efficacy in reducing the SBP/DBP (-19.2/-9.2 mm Hg in Group 1 and -21.6/-8.8 mm Hg in Group 2; SBP P = .378, DBP P = .825), high-dose CCBs combined with ARBs controlled hypertension without elevation of serum uric acid. These results will provide new evidence for selecting optimal combination therapies for uncontrolled hypertensive patients.",
"affiliations": "Division of Cardiology, Nephrology, Pulmonology and Neurology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan.;Division of Cardiology, Nephrology, Pulmonology and Neurology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan.;Division of Community Medicine and Epidemiology, Department of Health Science, Asahikawa Medical University, Asahikawa, Japan.;Department of Internal Medicine, Fukagawa Municipal Hospital, Fukagawa, Japan.;Department of Internal Medicine, Asahikawa Rehabilitation Hospital, Asahikawa, Japan.;Department of Cardiology, Asahikawa Kosei General Hospital, Asahikawa, Japan.;Department of Cardiology, Hokkaido Kitami Hospital, Kitami, Japan.;Department of Internal Medicine, Asahikawa Rehabilitation Hospital, Asahikawa, Japan.;Department of Internal Medicine, Asahikawa Rehabilitation Hospital, Asahikawa, Japan.;Department of Cardiology, Municipal Ashibetsu Hospital, Ashibetsu, Japan.;Division of Cardiology, Nephrology, Pulmonology and Neurology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan.;Division of Cardiology, Nephrology, Pulmonology and Neurology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan.",
"authors": "Nakagawa|Naoki|N|0000-0002-5398-3667;Sato|Nobuyuki|N|;Saijo|Yasuaki|Y|;Morimoto|Hideo|H|;Koyama|Satoshi|S|;Ogawa|Yuji|Y|;Uekita|Kazumi|K|;Maruyama|Junichi|J|;Ohta|Takafumi|T|;Nakamura|Yasuhiro|Y|;Takeuchi|Toshiharu|T|;Hasebe|Naoyuki|N|;|||",
"chemical_list": "D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D013777:Tetrazoles; D017311:Amlodipine; D014527:Uric Acid; D007190:Indapamide; D000077405:Irbesartan",
"country": "United States",
"delete": false,
"doi": "10.1111/jch.13977",
"fulltext": null,
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"issn_linking": "1524-6175",
"issue": "22(9)",
"journal": "Journal of clinical hypertension (Greenwich, Conn.)",
"keywords": "antihypertensive agents; blood pressure variability; combination therapy",
"medline_ta": "J Clin Hypertens (Greenwich)",
"mesh_terms": "D017311:Amlodipine; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001185:Artificial Intelligence; D001794:Blood Pressure; D004359:Drug Therapy, Combination; D006801:Humans; D006973:Hypertension; D007190:Indapamide; D000077405:Irbesartan; D011446:Prospective Studies; D013777:Tetrazoles; D016896:Treatment Outcome; D014527:Uric Acid",
"nlm_unique_id": "100888554",
"other_id": null,
"pages": "1577-1584",
"pmc": null,
"pmid": "32762115",
"pubdate": "2020-09",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Assessment of suitable antihypertensive therapies: Combination with high-dose amlodipine/irbesartan vs triple combination with amlodipine/irbesartan/indapamide (ASAHI-AI study).",
"title_normalized": "assessment of suitable antihypertensive therapies combination with high dose amlodipine irbesartan vs triple combination with amlodipine irbesartan indapamide asahi ai study"
} | [
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"companynumb": "JP-PFIZER INC-2021368013",
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"occurcountry": "JP",
"patient": {
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AMLODIPINE BESYLATE"
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"abstract": "Pyogenic granuloma (PG) is a granulomatous elevated lesion that occurs on the skin and mucous membranes. We herein report two cases of intra-oral PG that developed during the administration of ramucirumab for gastric cancer. Case 1 involved a 55-year-old man with a 6-mm tumor on the right tongue, and case 2 involved a 67-year-old man with a 5-mm tumor on the upper lip. The imbalance in angiogenesis caused by ramucirumab and the deterioration in the local oral environment were suggested to have caused the PG. Medical and dental collaboration is essential during the administration of ramucirumab.",
"affiliations": "Section of Dentistry and Oral Surgery, Gunma Prefectural Cancer Center, Japan.;Department of Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Japan.;Department of Oral and Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Japan.;Section of Gastroenterology, Gunma Prefectural Cancer Center, Japan.;Section of Gastrointestinal Surgery, Gunma Prefectural Cancer Center, Japan.;Section of Pathology, Gunma Prefectural Cancer Center, Japan.;Department of Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Japan.",
"authors": "Aragaki|Tadanobu|T|;Tomomatsu|Nobuyoshi|N|;Michi|Yasuyuki|Y|;Hosaka|Hisashi|H|;Fukai|Yasuyuki|Y|;Iijima|Misa|M|;Yoda|Tetsuya|T|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C543333:ramucirumab",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.6650-20",
"fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918\n1349-7235\nThe Japanese Society of Internal Medicine\n\n33678742\n10.2169/internalmedicine.6650-20\nCase Report\nRamucirumab-related Oral Pyogenic Granuloma: A Report of Two Cases\nAragaki Tadanobu 12\nTomomatsu Nobuyoshi 2\nMichi Yasuyuki 3\nHosaka Hisashi 4\nFukai Yasuyuki 5\nIijima Misa 6\nYoda Tetsuya 2\n1 Section of Dentistry and Oral Surgery, Gunma Prefectural Cancer Center, Japan\n2 Department of Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Japan\n3 Department of Oral and Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Japan\n4 Section of Gastroenterology, Gunma Prefectural Cancer Center, Japan\n5 Section of Gastrointestinal Surgery, Gunma Prefectural Cancer Center, Japan\n6 Section of Pathology, Gunma Prefectural Cancer Center, Japan\nCorrespondence to Dr. Tadanobu Aragaki, t.aragaki@gunma-cc.jp\n\n8 3 2021\n15 8 2021\n60 16 26012605\n5 11 2020\n13 1 2021\nCopyright © 2021 by The Japanese Society of Internal Medicine\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ The Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).\nPyogenic granuloma (PG) is a granulomatous elevated lesion that occurs on the skin and mucous membranes. We herein report two cases of intra-oral PG that developed during the administration of ramucirumab for gastric cancer. Case 1 involved a 55-year-old man with a 6-mm tumor on the right tongue, and case 2 involved a 67-year-old man with a 5-mm tumor on the upper lip. The imbalance in angiogenesis caused by ramucirumab and the deterioration in the local oral environment were suggested to have caused the PG. Medical and dental collaboration is essential during the administration of ramucirumab.\n\nramucirumab\npyogenic granuloma\nVEGFR2\noral management\nmedical and dental collaboration\n==== Body\npmcIntroduction\n\nPyogenic granuloma (PG) is a granulomatous, elevated lesion that occurs on the skin and mucous membranes (1). Clinically, this lesion grows without pain, and frequently appears as a hemorrhagic, red-purple, venous or perforating tumor mass (2). It may grow rapidly, and needs to be differentiated from malignant tumors. PGs are commonly found in the face and limbs. In the oral region, the gingiva, lip, and tongue are common sites (1,3).\n\nPG arises from various stimuli, including chronic low-grade irritation, traumatic injury, hormones, and drugs (1). The pathogenesis of pyogenic granuloma at the molecular level is unclear, but may be considered as resulting from the imbalance of angiogenesis enhancers and inhibitors (4).\n\nIt has been reported that PG and angioma can develop during the administration of ramucirumab, an angiogenesis inhibitor (5-7). Most of these reports describe skin lesions, and to our knowledge, no detailed studies have been published on oral lesions, especially from the point of view of histopathology. Therefore, in this study, we report two cases of PG that occurred in the oral cavity during the administration of ramucirumab. The study protocol adhered to the recommendations in the Declaration of Helsinki and the study was approved by the regional Ethical Review Board of our Institution.\n\nCase Report\n\nCase 1\n\nA 55-year-old man presented to our department with swelling of the right tongue. He was diagnosed with stage IV (T4aN2M1) gastric cardia cancer. Combination chemotherapy with capecitabine+cisplatinum+trastuzumab therapy was started; owing to tumor growth, however, chemotherapy was stopped after eight courses, and new combination chemotherapy with ramucirumab+weekly paclitaxel was initiated. In each four-week course, ramucirumab was administered once every two weeks with paclitaxel for three consecutive weeks, with a one-week break. After four courses of treatment, computed tomography (CT) showed that the tumor had shrunk by more than 30%; this indicated a partial response (PR) to treatment according to the Response Evaluation Criteria in Solid Tumors.\n\nAfter seven courses, a tumor was found on the right tongue. An initial physical examination revealed a 6-mm extroverted, elastic, soft mass (Fig. 1a). The mass was painless and involved the upper and lower canines and premolars. Hemorrhaging was also observed from the gingiva of the lower anterior region, and the crown of the right upper second molar was missing. On panoramic imaging, the upper right maxillary second molar had a residual root (Fig. 1b). The patient had no family dentist and had not received dental care for more than three years. Daily prevention at home was performed only once a day.\n\nFigure 1. Clinical and imaging characteristics of case 1. (a) Macroscopic findings. A pedunculated tumor of approximately 6 mm can be seen on the right side of the tongue. Slight bleeding is seen from the left lower anterior gingiva. (b) Panoramic image: Moderate marginal alveolar bone resorption is seen. The upper right maxillary second molar had a residual root (*).\n\nThe tumor showed rapid growth and was therefore resected under local anesthesia; no abnormal bleeding was observed. Histopathological findings of oral specimens obtained from the tongue tumor revealed local proliferation of vascular endothelial cells in the connective tissue (Fig. 2a). Expanded capillaries and surrounding endothelial cells were also observed (Fig. 2b). For immunostaining, heat-induced antigen retrieval was performed by incubating the sections with 10 mM Tris base containing 1 mM ethylenediaminetetraacetic acid (pH 9.0). In order to detect vascular endothelial growth factor receptor-2 (VEGFR2), CD31, D2-40, and Ki-67, a section was incubated with anti-VEGFR2 rabbit monoclonal antibody (clone 55B11; Cell Signaling Technology, Danvers, USA), anti-CD31 (clone 1aA10; Novocastra Laboratories, Newcastle upon Tyne, UK), anti D2-40 (clone D2-40; Nichirei Bioscience, Tokyo, Japan), and Ki-67 (MIB-1; Dako, Glostrup, Denmark), followed by incubation with an anti-rabbit peroxidase polymer (Nichirei Bioscience). Based on the immunostaining results, most blood vessels were considered to be CD31- and VEGFR2-positive and D2-40-negative; Ki-67, a proliferation marker, was also found to be strongly expressed in the nuclei of endothelial cells (Fig. 2c-f). After treatment at our department, ramucirumab was discontinued due to cancer progression on CT. The patient subsequently received other drugs but died six months after visiting our department; the oral lesions did not recur after the discontinuation of ramucirumab.\n\nFigure 2. Histopathological characteristics of case 1. (a, b) Hematoxylin and Eosin staining. a: ×100, b: ×400. A large number of capillaries showing foliar compaction can be seen beneath the mucous membrane. Hemorrhaging and slight inflammatory cell infiltration can be seen in the stroma. No malignant cells are observed; the findings are consistent with those of pyogenic granuloma. (c, d) Endothelial cells positive for CD31 (c) and negative for D2-40 (d) can be seen. (e) Strong immunostaining for vascular endothelial growth factor receptor-2 (VEGFR2) can be seen in almost all vascular endothelial cells. (f) Cell proliferation marker Ki-67 is also frequently detected.\n\nCase 2\n\nA 67-year-old man was admitted to our department owing to a tumor on the upper lip. He had been diagnosed with stage IIIB (cT3N3aM0) gastric cancer six years previously, and distal gastrectomy had been performed at the gastrointestinal surgery department of our hospital; S-1 was administered for 1 year as postoperative adjuvant chemotherapy. Four years later, magnetic resonance imaging showed cancerous peritonitis; S-1 was therefore restarted. Owing to the evidence of lesions on a CT examination three months later, XELOX therapy was started. Since disease progression was observed after 22 courses, combination chemotherapy was started with ramucirumab+nab-paclitaxel. In each four-week course, ramucirumab was administered once every two weeks along with nab-paclitaxel for three consecutive weeks and a one-week break. At the end of six courses, CT showed no obvious change in the tumor size and increased ascites; this indicated stable disease (SD) according to the Response Evaluation Criteria in Solid Tumors.\n\nDuring the fifth course, a tumor appeared on the upper lip. The lip tumor fell off spontaneously but subsequently recurred and increased in size; the patient was therefore referred to our department during the seventh course. On an initial physical examination, a 5-mm elastic soft mass was observed on the right upper lip. In addition, the crown of the upper left central incisor was fractured (Fig. 3a). Oral care was found to be poor, and the periodontal pocket was deep overall, reaching 6 mm at the right maxillary canine. The left maxillary central incisor and lateral incisors showed moderate instability; the mandibular partial denture was not sufficiently stable. Panoramic imaging showed multiple residual roots, with a fracture at the upper right first molar (Fig. 3b). The patient's family had a dental clinic, but he had not undergone intensive treatment after the initiation of anticancer drug therapy. A benign tumor was diagnosed at the upper lip and was excised under local anesthesia; the fractured piece of the upper left central incisor was also removed simultaneously. No abnormal bleeding was observed from the sutures nine days later.\n\nFigure 3. Clinical and imaging characteristics of case 2. (a) Macroscopic findings: a 5-mm extroverted, elastic, soft mass can be seen on the upper right lip. (b) Panoramic image: Moderate to high marginal alveolar bone resorption can be seen. A horizontal root fracture can be seen in the upper first molar (*); both maxillary sinuses are deformed.\n\nThe histopathological findings of the oral specimens obtained from the lip tumor revealed local proliferation of vascular endothelial cells in the connective tissue (Fig. 4a). Expanded capillaries and surrounding endothelial cells were also observed (Fig. 4b). Based on the immunostaining results, most blood vessels were considered to be CD31- and VEGFR2-positive and D2-40-negative; Ki-67, a proliferation marker, was also found to be strongly expressed in the nuclei of endothelial cells (Fig. 4c-f).\n\nFigure 4. Histopathological characteristics of case 2. (a, b) Hematoxylin and Eosin staining. a: ×100, b: ×400. A large number of capillaries showing foliar compaction can be seen beneath the mucous membrane. Hemorrhaging and slight inflammatory cell infiltration can be seen in the stroma. No malignant cells are observed; the findings are consistent with those of pyogenic granuloma. (c, d) CD31 (c) and D2-40 (d) immunostaining: endothelial cells are positive for CD31 and negative for D2-40. (e) Vascular endothelial growth factor receptor-2 (VEGFR2) immunostaining. Strong staining can be seen in almost all vascular endothelial cells. (f) The Ki-67 cell proliferation marker is also frequently detected in vascular endothelial cells.\n\nAfter starting treatment, the patient presented with a generalized pruritic skin rash; difluprednate ointment was prescribed. At the same time as the visit to our department, pruritus was observed on the back; a 1-cm tumor also appeared, which required resection at a nearby dermatology clinic. A histopathological examination showed capillary lobular growth with vascular endothelial cell proliferation, suggestive of a pyogenic granuloma. Since exacerbation of the cancerous peritonitis was confirmed on CT after 12 courses, ramucirumab+paclitaxel therapy was discontinued at 6 months after the initial visit to our department, and nivolumab therapy was started. After resection, there was no evidence of recurrence of the oral or skin tumors.\n\nDiscussion\n\nTo our knowledge, this is the first report concerning the histopathological examination of oral PG in patients receiving ramucirumab. The causes of PG were considered to be the systemic deterioration of the angiogenic balance by ramucirumab and the locally deteriorated oral environment (4). Angiogenesis is an important characteristic of cancer; malignant tumors create new vascular networks to meet their increased demand for oxygen and nutrients and to achieve efficient removal of metabolic waste. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) have been identified as major regulators of angiogenesis (8,9). VEGFR2 is a major mediator of VEGF-induced angiogenesis and exhibits the most potent tyrosine kinase activity; it is being investigated as a target of anti-angiogenic therapy for cancer (10).\n\nRamucirumab is a fully human IgG1 monoclonal antibody that selectively binds to the extracellular domain of VEGFR2 (9,11). It is mainly used as a second-line treatment for advanced cancers, such as gastric, colorectal, and non-small-cell lung cancers (11). The Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma trial, which was the first randomized phase III study on advanced gastric cancer, revealed that ramucirumab therapy was beneficial in terms of the overall survival compared with placebo in a second-line treatment setting (8,12). The combination of ramucirumab with paclitaxel significantly increases the overall survival compared with placebo plus paclitaxel in advanced gastric or gastro-esophageal junction adenocarcinoma patients (11,12). Various adverse events have been reported in relation to ramucirumab, including hypertension, deep vein thrombosis, headaches, anorexia, vomiting, and dyspnea (8,11). Interestingly, there are several reports on PGs and hemangiomas occurring in patients receiving ramucirumab. Lim et al. first reported the development of an angioma during the administration of ramucirumab in 2015 (5); several cases have been reported since then, including sporadic and multiple occurrences (5-7); tumors appeared at a minimum of two months and a maximum of six months after starting ramucirumab (5-7). The pathogenesis of ramucirumab-related PG remains unknown. Ibe et al. reported on a case of PG of the fingers, where strongly positive immunostaining was observed for VEGFR2; they hypothesized that following ramucirumab administration, a small wound triggered VEGFR2 overexpression owing to a mutation in KDR (p.T771R), which is a driver of vascular lesions (6).\n\nPG in our two cases developed during the administration of ramucirumab. The tumor appeared during the fourth and sixth course in cases 1 and 2, respectively. From the clinical course, ramucirumab appeared to be involved in the formation of PG. The first case in the oral cavity was sporadic. However, in the second case, PG also developed in the skin of the back; it was therefore considered to be a case of multiple PG. On immunostaining, both cases tested positive for VEGFR2 and CD31, which are expressed in blood vessels; they tested negative for D2-40, which is expressed in lymphatic vessels. The expression of the growth factor Ki-67 was also observed. These results showed that the overexpression of VEGFR2 caused the excessive proliferation of small blood vessels, leading to PG.\n\nThe findings from these cases suggest that the oral environment was also involved in PG formation. The oral cavity is easily damaged by caries, periodontal disease, defective teeth or bite, food, and poor oral cleaning. In these two cases, the oral environment was poor, and dental care was insufficient. In addition to the administration of ramucirumab, intraoral stimulation by the residual roots and sharp edges of the dentures were also suspected of having induced the development of PGs.\n\nA limitation of this study is that the frequency of ramucirumab-related PG and the difference in characteristics from other PGs were not determined. Further large-scale studies are needed to elucidate the characteristics and etiology of oral PG in patients treated with ramucirumab. Among the oral adverse events caused by specific drugs used in anticancer treatment, everolimus-related stomatitis and medication-related osteonecrosis of the jaw due to bone resorption inhibitors, such as bisphosphonates and denosumab, are well known. The frequency of ramucirumab-related PG is unknown, but the use of ramucirumab is increasing; the incidence of oral PG is therefore expected to increase in the future. Medical and dental interprofessional collaboration is essential for investigating the possibility of oral PG development during the administration of ramucirumab.\n\nIn conclusion, we encountered two cases of ramucirumab-related oral PG. The deterioration in the local angiogenic balance caused by ramucirumab and the poor oral environment contributed to the formation of PG. Oncologists and dentists should carefully consider the development of oral symptoms and their management.\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Jafarzadeh H , Sanatkhani M , Mohtasham N . Oral pyogenic granuloma: a review. J Oral Sci 48 : 167-175, 2006.17220613\n2. Wollina U , Langner D , Franca K , Gianfaldoni S , Lotti T , Tchernev G . Pyogenic granuloma - a common benign vascular tumor with variable clinical presentation: new findings and treatment options. Open Access Maced J Med Sci 5 : 423-426, 2017.28785323\n3. Harris MN , Desai R , Chuang TY , Hood AF , Mirowski GW . Lobular capillary hemangiomas: an epidemiologic report, with emphasis on cutaneous lesions. J Am Acad Dermatol 42 : 423-426, 2000.\n4. Yuan K , Jin YT , Lin MT . The detection and comparison of angiogenesis-associated factors in pyogenic granuloma by immunohistochemistry. J Periodontol 71 : 701-706, 2000.10872949\n5. Lim YH , Odell ID , Ko CJ , Choate KA . Somatic p.T771R KDR (VEGFR2) mutation arising in a sporadic angioma during ramucirumab therapy. JAMA Dermatol 151 : 1240-1243, 2015.26422291\n6. Ibe T , Hamamoto Y , Takabatake M , Kamoshida S . Development of pyogenic granuloma with strong vascular endothelial growth factor receptor-2 expression during ramucirumab treatment. BMJ Case Rep 12 : e231464, 2019.\n7. Kosumi H , Nishie W , Sugai T , et al . Ramucirumab-induced multiple haemangiomas of the skin: two case reports. Acta Derm Venereol 98 : 454-455, 2018.29327066\n8. Hironaka S . Anti-angiogenic therapies for gastric cancer. Asia Pac. J Clin Oncol 15 : 208-217, 2019.\n9. Takahashi S . Vascular endothelial growth factor (VEGF), VEGF receptors and their inhibitors for antiangiogenic tumor therapy. Biol Pharm Bull 34 : 1785-1788, 2011.22130231\n10. Ferrara N , Hillan KJ , Gerber HP , Novotny W . Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 3 : 391-400, 2004.15136787\n11. Spratlin JL , Mulder KE , Mackey JR . Ramucirumab (IMC-1121B): a novel attack on angiogenesis. Future Oncol 6 : 1085-1094, 2010.20624120\n12. Fuchs CS , Tomasek J , Yong CJ , et al ; REGARD Trial Investigators. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 383 : 31-39, 2014.24094768\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "60(16)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "VEGFR2; medical and dental collaboration; oral management; pyogenic granuloma; ramucirumab",
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D017789:Granuloma, Pyogenic; D006801:Humans; D008046:Lip; D008297:Male; D008875:Middle Aged; D009061:Mouth Mucosa",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "2601-2605",
"pmc": null,
"pmid": "33678742",
"pubdate": "2021-08-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20624120;24094768;17220613;10827405;29327066;22130231;15136787;10872949;26422291;28785323;31776151;31111678",
"title": "Ramucirumab-related Oral Pyogenic Granuloma: A Report of Two Cases.",
"title_normalized": "ramucirumab related oral pyogenic granuloma a report of two cases"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-311202",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"dr... |
{
"abstract": "Thrombophilia is a prothrombotic state that can be caused by genetic disorders, such as the factor-V-Leiden or prothrombin mutation, as well as by acquired changes like oestrogen-induced APC resistance and the antiphospholipid syndrome. Pregnancy induces multiple procoagulant changes in the haemostatic system, increasing the risk of venous thromboembolism in women with a thrombophilia even further. Additionally, thrombophilias are suggested to be associated with a number of pregnancy complications such as recurrent miscarriage, stillbirth, preeclampsia and HELLP syndrome. Increased local activation of coagulation may directly influence trophoblast expansion and invasion, causing thereby an impaired trophoblast development and insufficient widening of spiral arteries in the first trimenon, which results in placenta-mediated pregnancy complications like preeclampsia or HELLP syndrome. Besides, macro- and microthrombosis in the vessels of placental stemm villi and spiral arteries may lead to multiple infarctions with release of necrotic trophoblast fragments and inflammatory cytokines playing an important role in the pathogenesis of recurrent pregnancy loss and stillbirth. For women with a known thrombophilia it is recommended to carry out either only postpartal or combined ante- and postpartal thrombosis prophylaxis with low-molecular weight heparins (LMWH) depending on the individual risk stratification. The effectiveness of the LMWH administration for prevention of thrombophilia-induced pregnancy complications and improvement of the pregnancy outcome is currently a matter of debate. Furthermore, an additional application of acetyIsalicylic acid (ASA) should be considered in the management of women with the antiphospholipid antibody syndrome. In the current article we present the case of a 28-year-old woman with the heterozygous prothrombin mutation, HELLP syndrome, a late miscarriage and a stillbirth in the anamnesis, who delivered 3 healthy babies under antenatal LMWH prophylaxis combined with intensive interdisciplinary prenatal care.",
"affiliations": "Gynecology und Obstetrics, Universitätsklinikum Magdeburg, Magdeburg.;Gynecology und Obstetrics, Universitätsklinikum Magdeburg, Magdeburg.;Gynecology und Obstetrics, Universitätsklinikum Magdeburg, Magdeburg.",
"authors": "Findeklee|S|S|;Costa|S D|SD|;Tchaikovski|S N|SN|",
"chemical_list": "D005343:Fibrinolytic Agents; D006495:Heparin, Low-Molecular-Weight",
"country": "Germany",
"delete": false,
"doi": "10.1055/s-0034-1385856",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0948-2393",
"issue": "219(1)",
"journal": "Zeitschrift fur Geburtshilfe und Neonatologie",
"keywords": null,
"medline_ta": "Z Geburtshilfe Neonatol",
"mesh_terms": "D000328:Adult; D003937:Diagnosis, Differential; D005260:Female; D005343:Fibrinolytic Agents; D017359:HELLP Syndrome; D006495:Heparin, Low-Molecular-Weight; D006801:Humans; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D011256:Pregnancy Outcome; D019851:Thrombophilia; D016896:Treatment Outcome",
"nlm_unique_id": "9508901",
"other_id": null,
"pages": "45-51",
"pmc": null,
"pmid": "25734477",
"pubdate": "2015-02",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Thrombophilia and HELLP syndrome in pregnancy - case report and overview of the literature.",
"title_normalized": "thrombophilia and hellp syndrome in pregnancy case report and overview of the literature"
} | [
{
"companynumb": "PHHY2016DE005745",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OXYTOCIN"
},
"drugadditional": null,
"druga... |
{
"abstract": "OBJECTIVE\nCoadministration of morphine with oral gabapentin has been shown to increase plasma gabapentin concentrations. This study evaluated whether there was any interaction between gabapentin enacarbil (GEn), which is a prodrug of gabapentin, and morphine in terms of pharmacokinetics, pharmacodynamics, safety, and tolerability.\n\n\nMETHODS\nThis randomized, double-blind, 3-treatment crossover study included nonelderly, healthy male subjects. The study subjects received (in random order and with a minimum 7-day washout between treatments) the following: morphine placebo + GEn 600 mg; morphine 60 mg + GEn 600 mg; and morphine 60 mg + GEn placebo. Morphine/morphine placebo was administered in fasted conditions, and GEn/GEn placebo was administered 2 hours later with food. The primary end points were AUC and C(max) for gabapentin, morphine, and morphine-6-glucuronide. Pharmacodynamic measures were limited to subject assessment of somnolence, dizziness, and nausea conducted by using a visual analog scale (VAS). Safety monitoring included adverse event reporting, clinical laboratory tests, vital signs, pulse oximetry, and 12-lead ECGs.\n\n\nRESULTS\nOf the 18 enrolled subjects (mean age, 36 years), 15 (83%) completed the study. Sixteen received GEn, 15 received morphine, and 18 received the combination. Compared with the single treatments, the 90% CIs for the ratio of the geometric means for both AUC and C(max) were all within 0.8 to 1.25, the accepted range for bioequivalence. Ratios of geometric mean (90% CIs) values were as follows: gabapentin, AUC of 1.10 (1.035-1.162) and C(max) of 1.02 (0.920-1.126); morphine, AUC of 1.06 (1.014-1.098) and C(max) of 1.05 (0.967-1.134); and morphine-6-glucuronide, AUC of 0.992 (0.929-1.058) and C(max) of 0.953 (0.855-1.062). Mean changes from predose VAS scores were generally small and suggested a slight increase in dizziness after GEn and slight increases in dizziness, somnolence, and nausea after morphine. Trends were noted suggesting slightly greater score changes from predose with the combination treatment than with either drug given alone for somnolence and dizziness. Adverse events were generally mild; there were no serious adverse events or subject withdrawals due to adverse events. Headache and nausea were among the most commonly reported events for the combination and morphine treatments (headache, 27% and 28%; nausea, 13% and 11%, respectively). There were fewer adverse events with GEn alone than with either of the combination regimens.\n\n\nCONCLUSIONS\nNo significant pharmacokinetic interaction between the 2 drugs was seen in this study. The VAS data suggest that the potential exists for increased adverse effects when GEn and morphine are coadministered. ClinicalTrials.gov identifier: NCT01476124.",
"affiliations": "GlaxoSmithKline, Uxbridge, United Kingdom. Electronic address: chao.c.chen@gsk.com.;GlaxoSmithKline, Stevenage, United Kingdom.;GlaxoSmithKline, Research Triangle Park, North Carolina.;GlaxoSmithKline, Research Triangle Park, North Carolina.;GlaxoSmithKline, Stevenage, United Kingdom.",
"authors": "Chen|Chao|C|;Upward|James|J|;Arumugham|Thangam|T|;Stier|Brendt|B|;Davy|Maria|M|",
"chemical_list": "C493250:1-(((alpha-isobutanoyloxyethoxy)carbonyl)aminomethyl)-1-cyclohexaneacetic acid; D000588:Amines; D000701:Analgesics, Opioid; D002219:Carbamates; D003509:Cyclohexanecarboxylic Acids; D011355:Prodrugs; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D009020:Morphine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0149-2918",
"issue": "37(2)",
"journal": "Clinical therapeutics",
"keywords": "combination; gabapentin enacarbil; morphine; pharmacodynamics; pharmacokinetics",
"medline_ta": "Clin Ther",
"mesh_terms": "D000328:Adult; D000588:Amines; D000701:Analgesics, Opioid; D002219:Carbamates; D018592:Cross-Over Studies; D003509:Cyclohexanecarboxylic Acids; D004244:Dizziness; D004311:Double-Blind Method; D020920:Dyssomnias; D004562:Electrocardiography; D000077206:Gabapentin; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D009020:Morphine; D009325:Nausea; D011355:Prodrugs; D055815:Young Adult; D005680:gamma-Aminobutyric Acid",
"nlm_unique_id": "7706726",
"other_id": null,
"pages": "349-57",
"pmc": null,
"pmid": "25467190",
"pubdate": "2015-02-01",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Gabapentin enacarbil and morphine administered in combination versus alone: a double-blind, randomized, pharmacokinetic, and tolerability comparison.",
"title_normalized": "gabapentin enacarbil and morphine administered in combination versus alone a double blind randomized pharmacokinetic and tolerability comparison"
} | [
{
"companynumb": "GB-GLENMARK PHARMACEUTICALS INC, USA.-2015GMK016545",
"fulfillexpeditecriteria": "2",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GABAPENTIN"
},
"dru... |
{
"abstract": "Post-transplantation primary central nervous system lymphoma is an uncommon and fatal post-transplant lymphoproliferative disorder. Such lymphomas have been described in only a few case series in the literature. The incidence of this condition is rising with improved survival after organ transplantation. A case of post-transplantation primary central nervous system lymphoma in a young Chinese woman with systemic lupus erythematosus is described here. She presented with right-sided weakness and memory loss after tooth extraction 2 weeks before admission. Contrast computed tomography of the brain demonstrated a contrast rim-enhancing lesion over the left frontal lobe. With a history of recent dental procedure, long-term immunosuppressive therapy and computed tomography findings, cerebral abscess was highly suspected. Emergency operation was performed. Histopathology showed post-transplantation primary central nervous system lymphoma, with cells positive for B-cell marker CD20. Immunosuppressant was stopped and she was treated with radiotherapy and rituximab (anti-CD20 monoclonal antibody). She remained disease-free at 16 months. Post-transplantation primary central nervous system lymphoma is rare with variable presentation and radiological features. We believe rituximab may have a role in the treatment of such lymphomas.",
"affiliations": "Department of Neurosurgery, Princess Margaret Hospital, Lai Chi Kok, Hong Kong.;Department of Neurosurgery, Princess Margaret Hospital, Lai Chi Kok, Hong Kong.;Department of Neurosurgery, Princess Margaret Hospital, Lai Chi Kok, Hong Kong.;Department of Neurosurgery, Princess Margaret Hospital, Lai Chi Kok, Hong Kong.",
"authors": "Tse|Teresa P K|TP|;Chan|Allan N L|AN|;Chan|Tony K T|TK|;Po|Y C|YC|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "China",
"delete": false,
"doi": "10.12809/hkmj134095",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1024-2708",
"issue": "20(6)",
"journal": "Hong Kong medical journal = Xianggang yi xue za zhi",
"keywords": "Central nervous system neoplasms; Immunosuppressive agents; Lupus erythematosus, systemic",
"medline_ta": "Hong Kong Med J",
"mesh_terms": "D000328:Adult; D001932:Brain Neoplasms; D003937:Diagnosis, Differential; D005260:Female; D005625:Frontal Lobe; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008180:Lupus Erythematosus, Systemic; D008223:Lymphoma; D011183:Postoperative Complications",
"nlm_unique_id": "9512509",
"other_id": null,
"pages": "541-4",
"pmc": null,
"pmid": "25488034",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Post-transplantation primary central nervous system lymphoma in a patient with systemic lupus erythematosus and prolonged use of immunosuppressant.",
"title_normalized": "post transplantation primary central nervous system lymphoma in a patient with systemic lupus erythematosus and prolonged use of immunosuppressant"
} | [
{
"companynumb": "HK-ALKEM LABORATORIES LIMITED-HK-ALKEM-2021-06519",
"fulfillexpeditecriteria": "1",
"occurcountry": "HK",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
... |
{
"abstract": "OBJECTIVE\nThe aim of this study was to determine if the use of tranexamic acid (TXA) in long-segment spinal fusion surgery can help reduce perioperative blood loss, transfusion requirements, and morbidity.\n\n\nMETHODS\nIn this retrospective single-center study, the authors included 119 consecutive patients who underwent thoracolumbar fusion spanning at least 4 spinal levels from October 2016 to February 2019. Blood loss, transfusion requirements, perioperative morbidity, and adverse thrombotic events were compared between a cohort receiving intravenous TXA and a control group that did not.\n\n\nRESULTS\nThere was no significant difference in any measure of intraoperative blood loss (1514.3 vs 1209.1 mL, p = 0.29) or transfusion requirement volume between the TXA and control groups despite a higher number of pelvic fusion procedures in the TXA group (85.9% vs 62.5%, p = 0.003). Postoperative transfusion volume was significantly lower in TXA patients (954 vs 572 mL, p = 0.01). There was no difference in the incidence of thrombotic complications between the groups.\n\n\nCONCLUSIONS\nTXA appears to provide a protective effect against blood loss in long-segment spine fusion surgery specifically when pelvic dissection and fixation is performed. TXA also seems to decrease postoperative transfusion requirements without increasing the risk of adverse thrombotic events.",
"affiliations": "Departments of1Neurological Surgery and.;Departments of1Neurological Surgery and.;Departments of1Neurological Surgery and.;Departments of1Neurological Surgery and.;Departments of1Neurological Surgery and.;Departments of1Neurological Surgery and.;2Anesthesiology and Pain Management, UT Southwestern Medical Center Dallas, Texas.;Departments of1Neurological Surgery and.",
"authors": "Pernik|Mark N|MN|;Dosselman|Luke J|LJ|;Aoun|Salah G|SG|;Walker|Adrienne D|AD|;Hall|Kristen|K|;Peinado Reyes|Valery|V|;McDonagh|David L|DL|;Bagley|Carlos A|CA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1547-5646",
"issue": null,
"journal": "Journal of neurosurgery. Spine",
"keywords": "DVT = deep venous thrombosis; EBL = estimated blood loss; LOS = length of stay; PRBC = packed red blood cell; TXA = tranexamic acid; long-segment fusion; operative blood loss; operative transfusion; spine surgery safety; tranexamic acid",
"medline_ta": "J Neurosurg Spine",
"mesh_terms": null,
"nlm_unique_id": "101223545",
"other_id": null,
"pages": "1-7",
"pmc": null,
"pmid": "31978874",
"pubdate": "2020-01-24",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The effectiveness of tranexamic acid on operative and perioperative blood loss in long-segment spinal fusions: a consecutive series of 119 primary procedures.",
"title_normalized": "the effectiveness of tranexamic acid on operative and perioperative blood loss in long segment spinal fusions a consecutive series of 119 primary procedures"
} | [
{
"companynumb": "US-PFIZER INC-2020051251",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRANEXAMIC ACID"
},
"drugadditional": "3",
... |
{
"abstract": "This is a case presentation describing a high insulin requirement that suddenly resolved in a patient with acute lymphoblastic leukemia treated with stem cell transplantation complicated by chronic graft-versus-host disease. The patient was diagnosed with acquired partial lipodystrophy that did not require alternative therapies such as leptin or insulin-like growth factor 1.",
"affiliations": "Department of Pediatric Endocrinology, UCLA Mattel Children's Hospital, Los Angeles, California.;Department of Pediatric Endocrinology, Children's Hospital of Los Angeles, Los Angeles, California.;Department of Biomathematics, UCLA David Geffen School of Medicine, Los Angeles, California.;Department of Pediatric Endocrinology, UCLA Mattel Children's Hospital, Los Angeles, California.;Department of Pediatric Hematology-Oncology, UCLA Mattel Children's Hospital, Los Angeles, California.;Department of Pediatric Hematology-Oncology, UCLA Mattel Children's Hospital, Los Angeles, California.;Florida Hospital, Orlando, Florida.",
"authors": "Kimura|Leslie|L|;Alvarez|Griselda|G|;Li|Ning|N|;Pawlikowska-Haddal|Anna|A|;Moore|Theodore B|TB|;Casillas|Jacqueline|J|;Lee|Kuk-Wha|KW|",
"chemical_list": "D007004:Hypoglycemic Agents; D007328:Insulin",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.26427",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "64(7)",
"journal": "Pediatric blood & cancer",
"keywords": "acute lymphoblastic lymphoma (ALL); hypertriglyceridemia; stem cell transplant",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D002648:Child; D002908:Chronic Disease; D005260:Female; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015228:Hypertriglyceridemia; D007004:Hypoglycemic Agents; D007328:Insulin; D008060:Lipodystrophy; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28371314",
"pubdate": "2017-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Temporary resolution of insulin requirement in acquired partial lipodystrophy associated with chronic graft-versus-host disease.",
"title_normalized": "temporary resolution of insulin requirement in acquired partial lipodystrophy associated with chronic graft versus host disease"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2017SP011095",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional"... |
{
"abstract": "Endometriosis is a rare cause of large bowel obstruction and has been infrequently reported in patients with inflammatory bowel disease. We present an unusual case of a young woman with ulcerative colitis, who presented with a large bowel obstruction with colonic stricture and peripancreatic mass concerning for malignancy. The evaluation revealed endometriosis, and her large bowel obstruction was successfully managed with leuprolide and colonic stenting.",
"affiliations": "Division of Community Internal Medicine, Mayo Clinic, Jacksonville, FL.;Division of Gastroenterology, Mayo Clinic, Jacksonville, FL.;Division of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, FL.;Division of Gastroenterology, Mayo Clinic, Jacksonville, FL.;Division of Gastroenterology, Mayo Clinic, Jacksonville, FL.;Division of Gastroenterology, Mayo Clinic, Jacksonville, FL.",
"authors": "Moktan|Varun P|VP|0000-0001-9875-9450;Koop|Andree H|AH|;Olson|Matthew T|MT|;Lewis|Michele D|MD|;Gomez|Victoria|V|;Farraye|Francis A|FA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.14309/crj.0000000000000638",
"fulltext": "\n==== Front\nACG Case Rep J\nACG Case Rep J\nACGCRJ\nACGCRJ\nAC9\nACG Case Reports Journal\n2326-3253\nWolters Kluwer Maryland, MD\n\nACGCR-20-1008\n10.14309/crj.0000000000000638\n00013\nCase Report\nInflammatory Bowel Disease\nAn Unusual Cause of Large Bowel Obstruction in a Patient With Ulcerative Colitis\nhttp://orcid.org/0000-0001-9875-9450\nMoktan Varun P. MD 1\nKoop Andree H. MD 2koop.andree@mayo.edu\n\nOlson Matthew T. MD 3methaion@gmail.com\n\nLewis Michele D. MD, MMSc 2lewis.michele@mayo.edu\n\nGomez Victoria MD 2gomez.victoria@mayo.edu\n\nFarraye Francis A. MD, MSc 2farraye.francis@mayo.edu\n\n1 Division of Community Internal Medicine, Mayo Clinic, Jacksonville, FL\n2 Division of Gastroenterology, Mayo Clinic, Jacksonville, FL\n3 Division of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, FL\nCorrespondence: Varun P. Moktan, MD (Moktan.varun@mayo.edu).\n7 2021\n20 7 2021\n8 7 e0063819 8 2020\n30 3 2021\n© 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.\n\nABSTRACT\n\nEndometriosis is a rare cause of large bowel obstruction and has been infrequently reported in patients with inflammatory bowel disease. We present an unusual case of a young woman with ulcerative colitis, who presented with a large bowel obstruction with colonic stricture and peripancreatic mass concerning for malignancy. The evaluation revealed endometriosis, and her large bowel obstruction was successfully managed with leuprolide and colonic stenting.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\n\nIntestinal endometriosis can mimic several gastrointestinal (GI) diseases, including irritable bowel syndrome, diverticulitis, colitis, Crohn's disease, and malignancy; it has rarely been reported in patients with inflammatory bowel disease (IBD).1,2 We report a case of large bowel obstruction and peripancreatic mass because of endometriosis in a middle-aged woman with ulcerative colitis (UC) who was successfully treated with leuprolide and colonic stenting.\n\nCASE REPORT\n\nA 39-year-old African American woman presented with epigastric pain associated with nausea and anorexia for 5 days and no bowel movement or flatus for 1 day. She had been diagnosed with moderately severe UC on a flexible sigmoidoscopy 9 years earlier which showed discrete ulceration in the colon and pathology showing chronic inflammation. She had been taking prednisone and Asacol. She also had a hysterectomy for heavy menstrual bleeding and endometriosis 8 years earlier. A surveillance colonoscopy performed 3 months earlier was limited by an acute angulation at the hepatic flexure. Biopsy information was not available.\n\nOn physical examination, she was afebrile, with a heart rate of 52 beats per minute and blood pressure of 111/77 mm Hg. She had moderate tenderness in the epigastrium without rebound or guarding. Laboratory studies revealed a white blood cell count of 6.8 × 109 cells/L, hemoglobin 12.2 g/dL, platelet count 427 × 109/L, and normal liver enzymes and lipase. C-reactive protein was <3.0 mg/L. Abdominal and pelvic computed tomography (CT) with contrast showed a stricture and wall thickening extending from the hepatic flexure into the transverse colon, with upstream dilatation consistent with large bowel obstruction (Figure 1). There was an infiltrative soft-tissue mass extending from the stricture and encasing the gastroepiploic vessels near the pancreatic head, measuring 33 × 29 mm in the greatest cross-section. Upper endoscopic ultrasound demonstrated an irregular 5-cm partially calcified hypoechoic and heterogeneous perigastric mass within the peritoneal space. CT-guided needle biopsy of the mass revealed endometrial type stroma and glands consistent with endometriosis (Figure 2).\n\nFigure 1. Abdominal and pelvic computed tomography scan in the coronal plane demonstrating large bowel obstruction (inferior yellow arrow) in the ascending colon from a mass at the hepatic flexure (superior yellow arrow) with extension cranially to encase the gastroepiploic vessels.\n\nFigure 2. Hematoxylin and eosin stain at 10× magnification demonstrating endometrial glands (yellow arrow) and stroma (green arrow) consistent with endometriosis.\n\nAfter consultation with gynecology and colorectal surgery, the patient pursued conservative treatment with intramuscular leuprolide. One week later, she developed recurrent and was readmitted. CT imaging showed persistent obstruction at the hepatic flexure, and a colonic stent was placed to relieve the large bowel obstruction and to allow further time for treatment response to leuprolide while planning for surgery. Colonoscopy was notable for intrinsic, severe stenosis at the hepatic flexure, which could not be traversed with an adult colonoscope (Figure 3). A 22-mm diameter by 90-mm length uncovered self-expanding colonic metal stent (Wallflex stent; Boston Scientific Corporation, Boston, MA) was successfully placed through the stricture (Figure 4). No biopsies were collected.\n\nFigure 3. A benign-appearing, intrinsic moderate stenosis measuring 8 mm (inner diameter, length unclear) was found in the proximal transverse colon.\n\nFigure 4. Abdominal x-ray demonstrating a 22 × 90-mm uncovered self-expanding metal stent (yellow arrow) placed through the stricture at the transverse colon.\n\nTwo months later, she underwent repeat abdominal imaging, which did not show any interval change in the pericolonic mass in response to the leuprolide. Given concern for external compression on the colon, she underwent a diagnostic laparoscopy with excision of the endometrioid nodules with peritoneal and omental biopsies. Pathology confirmed endometriosis and was negative for malignancy. She met again with colorectal surgery and was recommended total colectomy because she was at high risk of both large bowel and stent perforation. Surgical scheduling has not yet been completed.\n\nDISCUSSION\n\nThe GI tract is the most common location of extrapelvic endometriosis, estimated to occur in 4%–37% of women with endometriosis, with the most common site of involvement being the sigmoid colon, followed by the proximal colon, small intestine, and appendix.3 Through an inflammatory reaction, endometriosis can lead to fibrosis and scarring, leading to narrowing of the lumen and obstruction.4,5\n\nAs previously noted, endometriosis can mimic other GI diseases, including malignancy, irritable bowel syndrome, diverticulitis, and even mucosal changes suggestive of IBD.6,7 Endoscopic, histopathologic, and surgical analyses are required to otherwise differentiate between nonspecific symptoms. In addition, cyclical abdominal pain in relation to menstrual cycles cannot solely differentiate endometriosis from underlying GI symptoms in patients with IBD.8\n\nEndometriosis and IBD can coexist and have been reported in patients with both UC and Crohn's disease.9 The literature discussing associations between IBD and endometriosis is scarce; however, 1 study suggests an increased incidence of IBD among women with endometriosis. The authors hypothesize that endometriosis should be classified as an autoimmune disorder because it both involves alterations in cell-mediated and humoral immunity.10 Another study found that women who use oral contraceptive pills, not necessarily for endometriosis, have an increased risk of developing Crohn's disease.11\n\nIntestinal endometriosis may be missed endoscopically because of the focality of lesions and involvement of the serosa and muscularis propria with sparing of the mucosa.2,12,13 Our patient had a stricture of the large intestine in continuity with a peripancreatic endometrial implant. Initially, this was concerning for malignancy, especially in the setting of UC which is associated with an increased risk of colorectal cancer.14 Providers should consider endometriosis among the differential diagnosis in premenopausal women with IBD and unexplained symptoms and/or findings including obstruction.\n\nThe treatment of choice for symptomatic intestinal endometriosis is generally surgery; however, hormonal therapy is also used to control symptoms.3 Large bowel obstruction from colonic endometriosis has been treated with colonic stenting previously as a bridge to surgery.15,16 For benign colonic obstruction, American guidelines recommend dilation with or without steroid injection, electroincision, and placement of either decompression tube or expandable stent.17 European guidelines support using stents as a bridge to elective surgery, specifically for left-sided obstructing colon cancer as an alternative to emergency resection.18 Our patient was treated with leuprolide, a gonadotropin-releasing hormone analog, which decreases steroidogenesis leading to atrophy of endometrial implants. Leuprolide has been used similarly in patients with endometriosis and ureteral obstruction.19\n\nIn conclusion, we present a rare case of a young woman with UC, found to have a large bowel obstruction from endometriosis and treated successfully with leuprolide and colonic stenting. Endometriosis should be considered on the differential diagnosis of young women with abdominal symptoms, including those with known IBD.\n\nDISCLOSURES\n\nAuthor contributions: All authors contributed equally to this manuscript. FA Farraye is the article guarantor.\n\nFinancial disclosure: V. Gómez conducts consulting work for Olympus Corporation of the Americas. All other authors have no reported conflicts.\n\nPrevious presentation: This case was accepted at the Digestive Disease Week; May 2-5, 2020; Virtual.\n\nInformed consent was obtained for this case report.\n==== Refs\nREFERENCES\n\n1. Chapron C Marcellin L Borghese B Santulli P . Rethinking mechanisms, diagnosis and management of endometriosis. Nat Rev Endocrinol. 2019;15 (11 ):666–82.31488888\n2. Yantiss RK Clement PB Young RH . Endometriosis of the intestinal tract: A study of 44 cases of a disease that may cause diverse challenges in clinical and pathologic evaluation. Am J Surg Pathol. 2001;25 (4 ):445–54.11257618\n3. Charatsi D Koukoura O Ntavela IG . Gastrointestinal and urinary tract endometriosis: A review on the commonest locations of extrapelvic endometriosis. Adv Med. 2018;2018 :3461209.30363647\n4. Molina GA Ramos DR Yu A . Endometriosis mimicking a cecum mass with complete bowel obstruction: An infrequent cause of acute abdomen. Case Rep Surg. 2019;2019 :7024172.30838152\n5. Allan Z . A case of endometriosis causing acute large bowel obstruction. Int J Surg Case Rep. 2018;42 :247–9.29294460\n6. Rana R Sharma S Narula H Madhok B . A case of recto-sigmoid endometriosis mimicking carcinoma. Springerplus. 2016;5 :643.27330909\n7. Langlois NE Park KG Keenan RA . Mucosal changes in the large bowel with endometriosis: A possible cause of misdiagnosis of colitis? Hum Pathol. 1994;25 (10 ):1030–4.7927307\n8. Lim SM Nam CM Kim YN . The effect of the menstrual cycle on inflammatory bowel disease: A prospective study. Gut Liver. 2013;7 (1 ):51–7.23423645\n9. Lee KK Jharap B Maser EA Colombel JF . Impact of concomitant endometriosis on phenotype and natural history of inflammatory bowel disease. Inflamm Bowel Dis. 2016;22 (1 ):159–63.26332310\n10. Jess T Frisch M Jorgensen KT Pedersen BV Nielsen NM . Increased risk of inflammatory bowel disease in women with endometriosis: A nationwide Danish cohort study. Gut. 2012;61 (9 ):1279–83.22184069\n11. Cornish J Tan E Simillis C . The risk of oral contraceptives in the etiology of inflammatory bowel disease: A meta-analysis. Am J Gastroenterol. 2008;103 (9 ):2394–400.18684177\n12. Ong SY Johnston M Crowley P Froomes P . Education and imaging. Gastrointestinal: Refractory ulcerative colitis complicated by colonic stricturing endometriosis. J Gastroenterol Hepatol. 2012;27 (1 ):181.22188028\n13. Casiraghi S Baggi P Lanza P . Simultaneous diagnosis of acute Crohn's disease and endometriosis in a patient Affects HIV. Case Rep Gastrointest Med. 2018;2018 :1509167.29854490\n14. Rubin DT Ananthakrishnan AN Siegel CA Sauer BG Long MD . ACG clinical guideline: Ulcerative colitis in adults. Am J Gastroenterol. 2019;114 (3 ):384–413.30840605\n15. Whelton C Bhowmick A . Acute endometrial bowel obstruction: A rare indication for colonic stenting. Int J Surg Case Rep. 2013;4 (2 ):160–3.23276756\n16. Navajas-Laboa M Orive-Calzada A Landaluce A . Colonic obstruction caused by endometriosis solved with a colonic stent as a bridge to surgery. Arab J Gastroenterol. 2015;16 (1 ):33–5.25791032\n17. Harrison ME Anderson MA Appalaneni V . The role of endoscopy in the management of patients with known and suspected colonic obstruction and pseudo-obstruction. Gastrointest Endosc. 2010;71 (4 ):669–79.20363408\n18. van Hooft JE Veld JV Arnold D . Self-expandable metal stents for obstructing colonic and extracolonic cancer: European Society of Gastrointestinal Endoscopy (ESGE) guideline—Update 2020. Endoscopy. 2020;52 (5 ):389–407.32259849\n19. Vilos GA Marks-Adams JL Vilos AG Oraif A Abu-Rafea B Casper RF . Medical treatment of ureteral obstruction associated with ovarian remnants and/or endometriosis: Report of three cases and review of the literature. J Minim Invasive Gynecol. 2015;22 (3 ):462–8.25533869\n\n",
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"title": "An Unusual Cause of Large Bowel Obstruction in a Patient With Ulcerative Colitis.",
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"abstract": "A 23-year-old woman with preexisting Graves' disease who received thiamazole treatment presented with fever, dysphagia, hyperthyroidism and leukopenia. With suspicion of thyreotoxicosis accompanied by drug-induced agranulocytosis she was successfully managed by plasmapheresis, G‑CSF administration and inhibition of periphereal conversion of thyroid hormones. In due course she underwent thyroidectomy. Thiamazole is frequently associated with drug-induced agranulocytosis. Long-term therapy with thiamazole requires critical evaluation and alternatives should be considered early. Plasmapheresis is an adequate treatment option to achieve normal thyroid hormonal status.",
"affiliations": "Klinik und Poliklinik für Innere Medizin A, Universitätsmedizin Greifswald, Ferdinand-Sauerbruch-Str., 17475, Greifswald, Deutschland. georg.beyer@uni-greifswald.de.;Klinik und Poliklinik für Hals-, Nasen- und Ohrenkrankheiten, Kopf- und Halschirurgie, Universitätsmedizin Greifswald, Greifswald, Deutschland.;Klinik und Poliklinik für Innere Medizin A, Universitätsmedizin Greifswald, Ferdinand-Sauerbruch-Str., 17475, Greifswald, Deutschland.;Klinik und Poliklinik für Innere Medizin A, Universitätsmedizin Greifswald, Ferdinand-Sauerbruch-Str., 17475, Greifswald, Deutschland.;Klinik und Poliklinik für Allgemeine Chirurgie, Universitätsmedizin Greifswald, Greifswald, Deutschland.;Institut für Pathologie, Universitätsmedizin Greifswald, Greifswald, Deutschland.;Klinik und Poliklinik für Innere Medizin A, Universitätsmedizin Greifswald, Ferdinand-Sauerbruch-Str., 17475, Greifswald, Deutschland.;Klinik und Poliklinik für Innere Medizin B, Universitätsmedizin Greifswald, Greifswald, Deutschland.;Klinik und Poliklinik für Innere Medizin A, Universitätsmedizin Greifswald, Ferdinand-Sauerbruch-Str., 17475, Greifswald, Deutschland.;Klinik und Poliklinik für Innere Medizin A, Universitätsmedizin Greifswald, Ferdinand-Sauerbruch-Str., 17475, Greifswald, Deutschland.",
"authors": "Beyer|G|G|;Küster|I|I|;Budde|C|C|;Wilhelm|E|E|;Hoene|A|A|;Evert|K|K|;Stracke|S|S|;Friesecke|S|S|;Mayerle|J|J|;Steveling|A|A|",
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"title": "Hyperthyroid and acute tonsillitis in a 23-year-old woman.",
"title_normalized": "hyperthyroid and acute tonsillitis in a 23 year old woman"
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"abstract": "Hemophiliacs infected with human immunodeficiency virus with a history of hypersensitivity reaction to a combination product of trimethoprim and sulfamethoxazole were desensitized orally. Six of the seven patients included in the study successfully completed the desensitization protocol and received trimethoprim-sulfamethoxazole for 5 to 7 months after desensitization (mean length of treatment, 5.7 months) for prophylaxis of Pneumocystis carinii pneumonia. The small number of patients and the short follow-up allow us to suggest that oral desensitization may be an effective and inexpensive means to treat hemophiliacs infected with human immunodeficiency virus with trimethoprim-sulfamethoxazole as prophylaxis against Pneumocystis carinii pneumonia.",
"affiliations": "Department of Pediatrics, University of Arkansas for Medical Science, Little Rock.",
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"title": "Trimethoprim-sulfamethoxazole oral desensitization in hemophiliacs infected with human immunodeficiency virus with a history of hypersensitivity reactions.",
"title_normalized": "trimethoprim sulfamethoxazole oral desensitization in hemophiliacs infected with human immunodeficiency virus with a history of hypersensitivity reactions"
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"abstract": "Lung cancer is one of the major causes of death in the world. Small cell carcinoma is the most aggressive type and can spread rapidly. The association of a small cell carcinoma with hepatic hilar metastasis and biliary obstruction is rare. Endoscopic ultrasound allows the aspiration of a cytology sample from adenopathies for diagnostic purpose. We present the case of a patient with lung cancer, with lymph node metastasis to the hepatic hilum and extrinsic biliary tree compression. Endoscopic ultrasound allowed the definitive diagnosis of hepatic hilar metastasis of a lung small cell carcinoma. To the author's knowledge it was the first time that endoscopic ultrasound was used for the diagnosis of hepatic hilar lymph node metastasis of lung cancer.",
"affiliations": "Department of Gastroenterology, Institute of CUF - ManoPh; Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal.;Department of Gastroenterology, Santo António Hospital, Porto Hospital Center, Porto, Portugal.;Department of Pneumology, Hospital de Braga, Braga, Portugal.;Department of Gastroenterology, Institute of CUF - ManoPh; Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal.",
"authors": "Castro-Pocas|Fernando M|FM|;Araújo|Tarcísio P|TP|;Ferreira|Maria L|ML|;Saraiva|Miguel M|MM|",
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"fulltext": "\n==== Front\nEndosc UltrasoundEndosc UltrasoundEUSEndoscopic Ultrasound2303-90272226-7190Medknow Publications & Media Pvt Ltd India 27824020EUS-7-27910.4103/2303-9027.193570Case ReportThe role of endoscopic ultrasound in a case of lung cancer with jaundice Castro-Poças Fernando M. 12Araújo Tarcísio P. 3Ferreira Maria L. 4Saraiva Miguel M. 121 Department of Gastroenterology, Institute of CUF – ManoPh, Porto, Portugal2 Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal3 Department of Gastroenterology, Santo António Hospital, Porto Hospital Center, Porto, Portugal4 Department of Pneumology, Hospital de Braga, Braga, PortugalAddress for correspondence Dr. Fernando M. Castro-Poças, Department of Gastroenterology, Institute of CUF – ManoPh, Porto, Portugal. E-mail: castro.pocas@sapo.ptJul-Aug 2018 08 11 2016 7 4 279 281 25 1 2015 23 2 2016 Copyright: © 2016 Spring Media Publishing Co. Ltd2016This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Lung cancer is one of the major causes of death in the world. Small cell carcinoma is the most aggressive type and can spread rapidly. The association of a small cell carcinoma with hepatic hilar metastasis and biliary obstruction is rare. Endoscopic ultrasound allows the aspiration of a cytology sample from adenopathies for diagnostic purpose. We present the case of a patient with lung cancer, with lymph node metastasis to the hepatic hilum and extrinsic biliary tree compression. Endoscopic ultrasound allowed the definitive diagnosis of hepatic hilar metastasis of a lung small cell carcinoma. To the author's knowledge it was the first time that endoscopic ultrasound was used for the diagnosis of hepatic hilar lymph node metastasis of lung cancer.\n\nEndoscopic ultrasonographyhilar lymph nodesjaundicelung cancersmall cell carcinoma\n==== Body\nINTRODUCTION\nLung cancer is the leading cause of cancer mortality in the world. Neuroendocrine tumors comprise from typical carcinoid with low malignancy and slow growth to the highly aggressive small cell carcinoma. At the time of diagnosis, approximately 30% of patients have the disease limited to the hemithorax, supraclavicular lymph nodes, or mediastinal tumors. This histological type accounts for about 20% of all lung tumors that metastasizes early, with the sites of metastasis being most frequently the liver, bones, brain, and adrenal gland. The association of a small cell carcinoma with jaundice is rare. In certain situations it is vital to exclude other causes of adenopathies besides lung cancer. The endoscopic ultrasound may have a fundamental role in this setting, allowing sample collection for a definitive diagnosis.\n\nCASE REPORT\nA 61-year-old male presented right chest pain, exacerbated by inspiration, with evolution of a month and progressive worsening. He denied weight loss, cough, sputum, or dyspnea. The past medical history revealed tobacco consumption (50 packs per year), with no other relevant history. Thoracic-abdominal-pelvic computed tomography (CT) showed in the right lung upper lobe (RUL) a 10 × 7.8 cm lesion (greater dimensions), in contact with pleura and a mediastinal adenopathy with 2 cm of greater diameter.\n\nSubsequently, a positron emission tomography was performed, in which hypermetabolism of 18-fluorodeoxyglucose was observed in the RUL and right tracheobronchial lymph node. These findings were consistent with lung cancer and lymph node metastasis. Transthoracic biopsy of lung mass was performed and the histological examination revealed a non-small cell lung carcinoma (NSCLC).\n\nThe endobronchial ultrasound with biopsy of mediastinal lymphadenopathy showed a neuroendocrine SCLC. The diagnosis of lung cancer mixed cellularity (T3N2M0; tumor, node, and metastasis (TNM) classification) was assumed.\n\nThe patient initiated treatment with etoposide, carboplatin, and radiotherapy. Reassessment after 6 months with CT showed onset of abdominal lymphadenopathy (celiac trunk) and slight increase in the mediastinal lymphadenopathy (2 × 3.5 cm). They were considered metastasis of lung cancer and the patient initiated second-line chemotherapy with paclitaxel. Nevertheless, the disease maintained progression with increased mediastinal lymphadenopathy.\n\nThen, the patient initiated third line chemotherapy with topotecan. The thoracic adenopathy stabilized, but progression of the disease occurred with onset of multiple lymph nodes involving the hepatic hilum [Figure 1], causing moderate dilatation of the main bile duct and of right and left hepatic duct.\n\nFigure 1 Computed tomography. Lymph nodes involving the hepatic hilum\n\nTo exclude other causes of hepatic hilar adenopathy, and given the lack of response to chemotherapy and radiotherapy, a fine-needle aspiration (25-G) guided by endoscopic ultrasound of the hepatic hilar lymph nodes was performed [Figure 2a and b]. Cytology revealed the presence of a small cell carcinoma [Figure 3a–d]. The immunocytochemical study showed positivity to chromogranin, synaptophisin, and thyroid transcription factor-1 (TTF-1). He underwent endoscopic retrograde cholangiopancreatography (ERCP), in which a stenosis of the distal third of the main biliary duct was identified. Sphincterotomy and placement of a metallic biliary stent with 10 Fr were performed.\n\nFigure 2 Endoscopic ultrasound. (a) Hilar lymph node; and (b) fine-needle aspiration\n\nFigure 3 Cytological examination. (a) Lymph node containing metastatic small cell carcinoma (Diff-Quick stain, ×400); (b) histological small cell pattern in a cell block section (H and E stain, ×250); (c) thyroid transcription factor-1 (TTF-1) immunohistochemical staining, nuclear positivity (×250); (d) Synaptophysin positivity, that confirms neuroendocrine differentiation (×250)\n\nA palliative radiotherapy of the hilar lymph nodes and subsequent etoposide cycle was performed; however, without response. The patient was admitted 1 month after for worsening of general condition with prostration, and died during that hospitalization.\n\nDISCUSSION\nThis article describes the case of an obstruction of the biliary tract, secondary to extrinsic compression caused by hepatic hilar lymphadenopathy. The tumors more frequently associated with malignant biliary obstruction are the gastric, colon, and breast. Reports of cases of jaundice secondary to a small cell carcinoma metastasis are rare.[123456]\n\nThe endoscopic ultrasound has been used to diagnose causes of enlarged lymph nodes, allowing the distinction between malignant and nonmalignant causes of hepatic hilum adenopathies, such as infectious disease.[7]\n\nThe endoscopic ultrasound is a safe, minimum invasive, and accessible method to diagnose and evaluate the hepatic hilum, even in malignant diseases.[78]\n\nIn this case, following a suspected obstruction of the biliary tract by an adenopathy, a diagnostic puncture was performed by endoscopic ultrasound, establishing the diagnosis. Obstruction of biliary tree caused by the spread of the tumor was resolved with a stent placement. The treatment with chemotherapy was ineffective. Unfortunately, the outcome was fatal.\n\nThe endoscopic ultrasonography has successfully been used in many cases for the diagnosis of mediastinal lymph node metastasis in lung cancer; but to the author's knowledge, it was the first time it was used for the diagnosis of hepatic hilar lymph node metastasis of lung cancer.[9]\n\nOur approach supports the progressive use of endoscopic ultrasound in the evaluation of the liver and hilum pathology. Probably in a near future, the endoscopic ultrasound will be used more frequently in the evaluation and therapy of this pathology. In that context, some authors have characterized the anatomy of the hepatic hilum by endoscopic ultrasonography and the possibility of using that region as a landmark to study the liver anatomy segmentation.[10]\n==== Refs\nREFERENCES\n1 Johnson DH Hainsworth JD Greco FA Extrahepatic biliary obstruction caused by small-cell lung cancer Ann Intern Med 1985 102 487 90 2983594 \n2 Martin A Castagliuolo I Mastropaolo G Cholestatic jaundice as the presenting symptom of small-cell lung cancer Ital J Gastroenterol 1990 22 36 9 \n3 Kotan C Er M Ozbay B Extrahepatic biliary obstruction caused by small-cell lung cancer: A case report Acta Chir Belg 2001 101 190 2 11680063 \n4 Sakar A Kara E Aydede H A case of a small-cell lung carcinoma presenting with jaundice due to pancreatic metastasis Tuberk Toraks 2005 53 181 4 16100657 \n5 Obara M Satoh H Yamashita YT Metastatic small-cell lung cancer causing biliary obstruction Med Oncol 1998 15 292 4 9951697 \n6 Jeong IB Kim SM Lee TH Pancreatic metastasis and obstructive jaundice in small-cell lung carcinoma Korean J Intern Med 2006 21 132 5 16913445 \n7 Saieg MA Yazawa F Horta M The utility of endoscopic ultrasound guided fine needle aspiration in the diagnosis of infectious diseases — report of three cases Case Rep Infect Dis 2013 2013 512182 \n8 Fritscher-Ravens A Broering DC Sriram PV EUS-guided fine-needle aspiration cytodiagnosis of hilar cholangiocarcinoma: A case series Gastrointest Endosc 2000 52 534 40 11023576 \n9 Eloubeidi MA Cerfolio RJ Chen VK Endoscopic ultrasound-guided fine needle aspiration of mediastinal lymph node in patients with suspected lung cancer after positron emission tomography and computed tomography scans Ann Thorac Surg 2005 79 263 8 15620955 \n10 Bhatia V Hijioka S Hara K Endoscopic ultrasound description of liver segmentation and anatomy Dig Endosc 2014 26 482 90 24355092\n\n",
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"abstract": "Fluoroquinolones (FQs) are a frequently prescribed class of antibacterial agents. FQs are widely used but may carry serious side effects particularly pronounced in older adults, and the Food and Drug Administration recently suggested FQs should not be routinely used in certain conditions if alternative options are available. Research has demonstrated that the risk of tendinitis and tendon rupture associated with FQs is one of the highest in older adults who are concurrently treated with steroids. Health care providers and pharmacists involved in the treatment of older adults should be aware of this potential drug interaction, which may lead to serious side effects and safety concerns.",
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"abstract": "We report the case of a 50-year-old woman with anorexigen-induced pulmonary arterial hypertension treated with epoprostenol, who presented with Trousseau's sign, leading to the diagnosis of severe hypocalcemia for which substitution was started (initially orally, followed by intravenous substitution). After further analysis, we assume that epoprostenol-induced diarrhea caused malabsorption (as other reasons were excluded), leading to nutritional osteomalacia with secondary hyperparathyroidism. We discovered that even more severe hypocalcemia was induced by the treatment with the anti-osteoporotic drug denosumab, which was started after the diagnosis of osteoporosis on bone densitometry. In our opinion, clinicians have to be aware that in patients with malabsorption, antiresorptive therapy can induce dangerous and even life-threatening hypocalcemia, even in patients with normal renal function.",
"affiliations": "Department of Respiratory Diseases, KU Leuven - University of Leuven and University Hospitals Leuven, Leuven, Belgium.;Department of Respiratory Diseases, KU Leuven - University of Leuven and University Hospitals Leuven, Leuven, Belgium.;Department of Endocrinology, KU Leuven - University of Leuven and University Hospitals Leuven, Leuven, Belgium.;Department of Endocrinology, KU Leuven - University of Leuven and University Hospitals Leuven, Leuven, Belgium.;Department of Respiratory Diseases, KU Leuven - University of Leuven and University Hospitals Leuven, Leuven, Belgium.;Department of Respiratory Diseases, KU Leuven - University of Leuven and University Hospitals Leuven, Leuven, Belgium.",
"authors": "De Muynck|Benedicte|B|;Leys|Mathias|M|;Cuypers|Joke|J|;Vanderschueren|Dirk|D|;Delcroix|Marion|M|;Belge|Catharina|C|",
"chemical_list": "D000959:Antihypertensive Agents; D001067:Appetite Depressants; D050071:Bone Density Conservation Agents; D000069448:Denosumab; D011464:Epoprostenol",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000481713",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-7931",
"issue": "95(2)",
"journal": "Respiration; international review of thoracic diseases",
"keywords": "Denosumab; Epoprostenol; Hypocalcemia; Malabsorption; Nutritional osteomalacia; Pulmonary arterial hypertension",
"medline_ta": "Respiration",
"mesh_terms": "D000959:Antihypertensive Agents; D001067:Appetite Depressants; D050071:Bone Density Conservation Agents; D000069448:Denosumab; D003967:Diarrhea; D011464:Epoprostenol; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary; D006996:Hypocalcemia; D008875:Middle Aged",
"nlm_unique_id": "0137356",
"other_id": null,
"pages": "139-142",
"pmc": null,
"pmid": "29485420",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hypocalcemia after Denosumab in a Pulmonary Hypertension Patient Receiving Epoprostenol.",
"title_normalized": "hypocalcemia after denosumab in a pulmonary hypertension patient receiving epoprostenol"
} | [
{
"companynumb": "BE-AMGEN-BELSP2017174452",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "EPOPROSTENOL"
},
"drugadditional": null,
... |
{
"abstract": "A patient in Virginia, USA, who had previously undergone multiple kidney transplantations showed signs of Bordetella hinzii bacteremia and meningitis. This emerging pathogen has been increasingly identified as a clinically significant pathogen in immunosuppressed and, less frequently, immunocompetent patients. This patient was treated and recovered without further issue.",
"affiliations": null,
"authors": "Pechacek|Joseph|J|;Raybould|Jillian|J|;Morales|Megan|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.3201/eid2709.210350",
"fulltext": "\n==== Front\nEmerg Infect Dis\nEmerg Infect Dis\nEID\nEmerging Infectious Diseases\n1080-6040\n1080-6059\nCenters for Disease Control and Prevention\n\n34424178\n21-0350\n10.3201/eid2709.210350\nDispatch\nDispatch\nBordetella hinzii Meningitis in Patient with History of Kidney Transplant, Virginia, USA\nBordetella hinzii Meningitis in Patient with History of Kidney Transplant, Virginia, USA\nMeningitis in Patient with History of Transplant\nPechacek Joseph\nRaybould Jillian\nMorales Megan\nVirginia Commonwealth University Medical Center, Richmond, Virginia, USA\nAddress for correspondence: Joseph Pechacek, National Institutes of Health, BG 10-CRC Rm 4-4179, 10 Center Dr, Bethesda, MD 20814, USA; email: joseph.pechacek@gmail.com\n9 2021\n27 9 24592461\nA patient in Virginia, USA, who had previously undergone multiple kidney transplantations showed signs of Bordetella hinzii bacteremia and meningitis. This emerging pathogen has been increasingly identified as a clinically significant pathogen in immunosuppressed and, less frequently, immunocompetent patients. This patient was treated and recovered without further issue.\n\nKeywords:\n\nmeningitis/encephalitis\ntransplantation\nbacteremia\nBordetella hinzii\nbacteria\nVirginia\nUnited States\n==== Body\nBordetella is a genus consisting mostly of strictly aerobic, small, gram-negative coccobacilli known to house the causative agent of pertussis and kennel cough in dogs (Bordetella pertussis) and cats (B. bronchiseptica). Over the past several decades, more human-derived clinical isolates have been identified, causing a range of pathologies. As our ability to rapidly and precisely identify clinical isolates grows, characterizing these rarer causes of human disease and their clinical significance and means of treatment has become vital.\n\nB. hinzii was initially discovered in poultry isolates as a respiratory colonizer and cause of respiratory infection; subsequently, it was discovered to cause clinically significant infection in 1994 in a patient with advanced AIDS (1). Since this characterization, B. hinzii has been implicated as the cause of a range of clinical symptoms, including bacteremia (1–3), pulmonary disease (4–6), endocarditis (7), chronic cholangitis (8), and soft tissue abscess (9,10). We describe a case of meningitis in an immunocompromised patient that was caused by B. hinzii.\n\nCase Report\n\nA 44-year-old man sought care in the emergency department of Virginia Commonwealth University Medical Center (Richmond, VA, USA) in June 2020 after experiencing 3 days of severe, diffuse headache, and subjective fevers; maximum measured temperature was 37.9°C. In 1986, the patient had undergone a living related donor kidney transplant for end-stage renal disease related to focal segmental glomerulosclerosis. He underwent another living related donor transplant in 1999 and a deceased-donor transplant in 2010 after the previous allografts failed. His most recent transplant, which occurred 10 years before the illness documented in this study, was performed with thymoglobulin induction and had been maintained with an immunosuppressive regimen of tacrolimus (goal trough of 5–7 ng/mL at the time of this hospitalization), 180 mg mycophenolic acid (2×/d), and 10 mg prednisone (1×/d). His medical history was further notable for seizure disorder and an allergy to penicillin, which manifested as severe urticaria.\n\nHe appeared stable in the emergency department; vital signs were temperature 37.5°C, pulse rate 90 bpm, respiratory rate 17 breaths/min, blood pressure 141/85 mm Hg, and oxyhemoglobin saturation 99% on room air. He reported neck stiffness associated with his headaches. When asked about animal exposures, he noted that he works in a warehouse and was regularly exposed to wild birds and rodents. Physical examination revealed discomfort but no signs of toxicity or neurologic deficits; cranial nerves were intact, and speech, motor abilities, and sensation were unremarkable. Complete blood count revealed a leukocyte count of 8.4 × 109/L, hemoglobin of 11 g/dL, and platelet count of 163 × 109/L. Additional bloodwork showed a glomerular filtration rate of 30 mL/min, which was consistent with the patient’s baseline given his history of chronic kidney disease. Noncontrasted computed tomography of the head demonstrated no acute pathology. Cerebrospinal fluid (CSF) was clear and colorless, and analysis indicated neutrophilic pleocytosis (Table 1). The patient was given 2 g intravenous (IV) ceftriaxone, a loading dose of 2 g IV vancomycin, and IV acyclovir. Ceftriaxone was rapidly replaced with 2 g meropenem given the patient’s immunosuppressed status and to empirically treat for the possibility of Listeria.\n\nTable 1 Cerebrospinal fluid sample laboratory results in case of Bordetella hinzii meningitis in transplant patient, Virginia, USA*\n\nCharacteristic\tHospital admission\tHospital day 9\t\nLeukocytes\t852/mm3\t26/mm3\t\nPMNs\t86%\t3%\t\nMonocytes\t27%\t1%\t\nLymphocytes\t5%\t96%\t\nErythrocytes\t<1 per mm3\t4 per mm3\t\nProtein\t149 mg/dL†\t72 mg/dL†\t\nGlucose\t58 mg/dL‡\t58 mg/dL§\t\nOpening pressure\tND\t39 cm H2O\t\n*ND, not done; PMNs, polymorphonuclear leukocytes. †No serum protein available for comparison. ‡Serum glucose 108mg/dL. §Serum glucose 89mg/dL.\n\nAdditional CSF analysis was negative for cytomegalovirus PCR, enterovirus PCR, adenovirus PCR, herpes simplex virus 1 and 2 PCR, and cryptococcal antigen. Because of concerns about possible viral meningitis, we tested nasopharyngeal swab specimens by using the BioFire FilmArray 2.0 respiratory pathogen PCR panel (bioMérieux, https://www.biomerieux.com); results were negative. Acyclovir was stopped after CSF specimens tested negative for herpes simplex virus by PCR, and the patient continued on vancomycin and meropenem. On the second day of hospitalization, blood cultures taken at admission grew gram-negative rods; CSF culture grew gram-negative rods on the fourth day. Blood cultures drawn after antibiotics were administered showed no growth. Vancomycin was stopped on day 3 after cultures showed growth of only gram-negative organisms, which by that time had been identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry as Bordetella spp. and subsequently B. hinzii. Oral ciprofloxacin (500 mg every 12 h) was added on day 6 of hospitalization because B. hinzii isolates have been reported to be sensitive to fluoroquinolones (9).\n\nAround day 6 of hospitalization, the patient again began to experience intermittent headaches, although of lesser intensity than his initial symptoms. He underwent a second lumbar puncture on day 9, which revealed improving neutrophilic pleocytosis (Table 1). CSF cultures from this lumbar puncture remained negative.\n\nThe patient was discharged after demonstrating substantial improvement. However, because results of antibiotic sensitivity tests were still pending at that time, he was discharged on renally dosed IV meropenem (2 g every 12 h) and oral ciprofloxacin (500 mg every 12 h) for a planned total antibiotic duration of 21 days. Results of sensitivity testing of the B. hinzii isolates from blood and CSF samples returned after the patient was discharged revealed susceptibility to meropenem but only intermediate susceptibility to ciprofloxacin (Table 2). At follow-up 7 days after completion of therapy, the patient felt well and appeared to have clinically recovered.\n\nTable 2 Antibiotic susceptibility of Bordetella hinzii isolate from blood and cerebrospinal fluid in transplant patient, Virginia, USA*\n\nAntibiotic\tEtest MIC from blood\tEtest MIC from CSF\t\nCeftazidime\t4 μg/mL\t2 μg/mL\t\nCiprofloxacin\t2 μg/mL\t2 μg/mL\t\nImipenem\t2 μg/mL\t1 μg/mL\t\nMeropenem\t0.125 μg/mL\t0.125 μg/mL\t\nPiperacillin\t1 μg/mL\t1 μg/mL\t\nTobramycin\t8 μg/mL\t4 μg/mL\t\nTrimethoprim/sulfamethoxazole\t0.125 μg/mL\t0.064 μg/mL\t\n*Etest, bioMérieux (https://www.biomerieux.com). CSF, cerebrospinal fluid.\n\nConclusions\n\nSince its discovery as a cause of bacteremia in a patient with advanced AIDS in 1994 (1), B. hinzii has been implicated in a growing range of clinical syndromes as an opportunistic agent in immunocompromised and immunocompetent persons. It remains an infrequently isolated pathogen; further research and characterization is required. Its relatively recent recognition as an infective agent in humans is likely in part due to the increasingly common use of advanced identification techniques; in the past, B. hinzii might have been identified only at the genus level (11) or misidentified as a different, related bacterium (1)\n\nB. hinzii is known to be found in the respiratory tracts of poultry as a colonizer and cause of respiratory infection (12). Exposure to poultry is an established risk factor for B. hinzii infection, especially in immunosuppressed populations (6). It is unclear whether this case-patient’s exposure to wild birds in his workplace constitutes a similar risk. Although B. avium is known to infect a range of wild and domesticated birds (13), whether B. hinzii affects birds other than poultry is not known. After the identification of B. hinzii from the respiratory tract of laboratory mice (14), rodents have also been proposed as potential reservoirs for this pathogen, and it has been isolated from wild mice (11) and rabbits (12). Definitive evidence of spread from an infected or colonized animal to a human has yet to be discovered.\n\nThe clinical isolates in this study were notable for sensitivity to carbapenems, piperacillin, and trimethoprim/sulfamethoxazole, which is in accordance with susceptibilities noted in other case reports on this species (9). We further noted an intermediate sensitivity to ciprofloxacin. Previous reports have indicated that levofloxacin might have a more favorable MIC for B. hinzii than ciprofloxacin (9).\n\nBecause B. hinzii is an emerging pathogen, its virulence factors require further research to be fully identified. Although the more classic B. pertussis (as well as B. parapertussis and B. bronchiseptica) rely on filamentous hemagglutinin and adenylate cyclase toxin as virulence factors, these proteins are absent in B. hinzii (12). These proteins are thought to assist in tracheal and pulmonary colonization in the more classic Bordetella spp. (15), so their absence from B. hinzii might begin to explain its propensity to cause syndromes atypical for bacteria of this genus.\n\nIn summary, we describe an unusual occurrence of B. hinzii–caused meningitis in an immunosuppressed patient. The clinical isolates in this study were sensitive to carbapenems, piperacillin, and trimethoprim/sulfamethoxazole but showed only intermediate sensitivity to ciprofloxacin. Clinicians should be aware of the possibility of human infection with this emerging pathogen, particularly in immunocompromised patients.\n\nDr. Pechacek is an infectious diseases clinical fellow at the National Institute of Allergy and Infectious Diseases, National Institutes of Health. His current research interests include infections in immunodeficient populations, especially with primary immunodeficiency.\n\nSuggested citation for this article: Pechacek J, Raybould J, Morales M. Bordetella hinzii meningitis in transplant patient, Virginia, USA. Emerg Infect Dis. 2021 Sep [date cited]. https://doi.org/10.3201/eid2709.210350\n==== Refs\nReferences\n\n1. CooksonBT, VandammeP, CarlsonLC, LarsonAM, SheffieldJV, KerstersK, et al. Bacteremia caused by a novel Bordetella species, “B. hinzii”. J Clin Microbiol. 1994;32 :2569–71. 10.1128/jcm.32.10.2569-2571.1994 7814500\n2. KattarMM, ChavezJF, LimayeAP, Rassoulian-BarrettSL, YarfitzSL, CarlsonLC, et al. Application of 16S rRNA gene sequencing to identify Bordetella hinzii as the causative agent of fatal septicemia. J Clin Microbiol. 2000;38 :789–94. 10.1128/JCM.38.2.789-794.2000 10655386\n3. HristovAC, AuwaerterPG, RomagnoliM, CarrollKC. Bordetella hinzii septicemia in association with Epstein-Barr virus viremia and an Epstein-Barr virus-associated diffuse large B-cell lymphoma. Diagn Microbiol Infect Dis. 2008;61 :484–6. 10.1016/j.diagmicrobio.2008.03.013 18482816\n4. FunkeG, HessT, von GraevenitzA, VandammeP. Characteristics of Bordetella hinzii strains isolated from a cystic fibrosis patient over a 3-year period. J Clin Microbiol. 1996;34 :966–9. 10.1128/jcm.34.4.966-969.1996 8815118\n5. Palacián RuizMP, Vasquez MartinezMA, Lopez CallejaAI. Respiratory infection caused by Bordetella hinzii. Arch Bronconeumol. 2013;49 :409–10.23755859\n6. FabreA, DupinC, BénézitF, GoretJ, PiauC, JouneauS, et al. Opportunistic pulmonary Bordetella hinzii infection after avian exposure. Emerg Infect Dis. 2015;21 :2122–6. 10.3201/eid2112.150400 26584467\n7. GonzálezMM, RomanoMPC, de Guzmán García MongeMT, MartínBB, GarcíaAS. Bordetella hinzii endocarditis, a clinical case not previously described. Eur J Case Rep Intern Med. 2019;6 :000994.30931262\n8. ArvandM, FeldhuesR, MiethM, KrausT, VandammeP. Chronic cholangitis caused by Bordetella hinzii in a liver transplant recipient. J Clin Microbiol. 2004;42 :2335–7. 10.1128/JCM.42.5.2335-2337.2004 15131227\n9. NegishiT, MatsumotoT, ShinagawaJ, KasugaE, HoriuchiK, NatoriT, et al. A case of cervical subcutaneous abscess due to Bordetella hinzii. Diagn Microbiol Infect Dis. 2019;95 :114865. 10.1016/j.diagmicrobio.2019.07.003 31405631\n10. KampmeierS, RennebaumF, SchmidtH, RiegelA, HerrmannM, SchaumburgF. Peripancreatic abscess supported by Bordetella hinzii. New Microbes New Infect. 2020;34 :100650. 10.1016/j.nmni.2020.100650 32025312\n11. JiyipongT, MorandS, JittapalapongS, RaoultD, RolainJ-M. Bordetella hinzii in rodents, Southeast Asia. Emerg Infect Dis. 2013;19 :502–3. 10.3201/eid1903.120987 23750354\n12. RegisterKB, KunkleRA. Strain-specific virulence of Bordetella hinzii in poultry. Avian Dis. 2009;53 :50–4. 10.1637/8388-070108-Reg.1 19432003\n13. HarringtonAT, CastellanosJA, ZiedalskiTM, ClarridgeJEIII, CooksonBT. Isolation of Bordetella avium and novel Bordetella strain from patients with respiratory disease. Emerg Infect Dis. 2009;15 :72–4. 10.3201/eid1501.071677 19116056\n14. HayashimotoN, YasudaM, GotoK, TakakuraA, ItohT. Study of a Bordetella hinzii isolate from a laboratory mouse. Comp Med. 2008;58 :440–6.19004369\n15. MattooS, CherryJD. Molecular pathogenesis, epidemiology, and clinical manifestations of respiratory infections due to Bordetella pertussis and other Bordetella subspecies. Clin Microbiol Rev. 2005;18 :326–82. 10.1128/CMR.18.2.326-382.2005 15831828\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1080-6040",
"issue": "27(9)",
"journal": "Emerging infectious diseases",
"keywords": "Bordetella hinzii; United States; Virginia; bacteremia; bacteria; meningitis/encephalitis; transplantation",
"medline_ta": "Emerg Infect Dis",
"mesh_terms": "D001884:Bordetella; D006801:Humans; D016030:Kidney Transplantation; D008581:Meningitis; D014768:Virginia",
"nlm_unique_id": "9508155",
"other_id": null,
"pages": "2459-2461",
"pmc": null,
"pmid": "34424178",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "31405631;10655386;23750354;18482816;19432003;26584467;15831828;32025312;15131227;19116056;7814500;8815118;30931262;19004369;23755859",
"title": "Bordetella hinzii Meningitis in Patient with History of Kidney Transplant, Virginia, USA.",
"title_normalized": "bordetella hinzii meningitis in patient with history of kidney transplant virginia usa"
} | [
{
"companynumb": "US-ACCORD-238591",
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"actiondrug": "5",
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"activesubstancename": "PREDNISONE ACETATE"
},
"drugadditional": "3",
... |
{
"abstract": "A toddler presented with a 5-month history of recurrent episodes of cough, wheezing and fever. Before referral, the toddler had been initially diagnosed as having bronchial asthma and later as having pulmonary tuberculosis. On examination, the patient was febrile and had severe respiratory distress. Chest radiograph and high-resolution CT of the chest revealed collapse of the entire left lung with diffuse bronchiectasis along with a grossly hyperinflated right lung. CT virtual bronchoscopy did not reveal any foreign body. The parents denied any history suggestive of foreign body aspiration and refused consent for rigid bronchoscopy. Nine days after admission, chest physiotherapy was inadvertently prescribed to the patient. Within an hour, the patient experienced acute respiratory deterioration and died. Autopsy revealed a piece of betel nut in the right main bronchus; it had got dislodged from its initial site in the left main bronchus following the chest physiotherapy session.",
"affiliations": "Department of Pediatrics, Seth GS Medical College & KEM Hospital, Mumbai, Maharashtra, India.;Department of Pathology (Cardiovascular & Thoracic Division), Seth GS Medical College & KEM Hospital, Mumbai, Maharashtra, India.;Department of Pediatrics, Seth GS Medical College & KEM Hospital, Mumbai, Maharashtra, India.",
"authors": "Karande|Sunil|S|;Vaideeswar|Pradeep|P|;Muranjan|Mamta|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D001114:Areca; D001344:Autopsy; D001980:Bronchi; D001987:Bronchiectasis; D001995:Bronchography; D001999:Bronchoscopy; D003371:Cough; D017809:Fatal Outcome; D005334:Fever; D005547:Foreign Bodies; D006801:Humans; D007223:Infant; D001261:Pulmonary Atelectasis; D053120:Respiratory Aspiration; D012135:Respiratory Sounds; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26598528",
"pubdate": "2015-11-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10216624;12112794;12962459;16947011;16983595;17033800;17101364;20014614;20113989;20426892;20802055;21409389;22688368;22940892;23234818;23962764;2496870;25402832;25475887;25753164;28386831",
"title": "Muddy clinical waters: a missed betel nut in the bronchus.",
"title_normalized": "muddy clinical waters a missed betel nut in the bronchus"
} | [
{
"companynumb": "IN-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2016-BI-07468BI",
"fulfillexpeditecriteria": "1",
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BUDESONIDE"
},
... |
{
"abstract": "BACKGROUND\nThe pneumonia severity index (PSI) accounts for many comorbidities, but not immunosuppression.\n\n\nOBJECTIVE\nTo document the utility of the PSI to predict mortality in immunocompromised patients (IP) with community-acquired pneumonia (CAP).\n\n\nMETHODS\nCharts of 284 patients with immunosuppression and CAP were reviewed, and these patients were compared with a contemporary sample of non-IP with CAP. The ability of the PSI to predict mortality was assessed by using multiple logistic regression. Discrimination of the PSI was studied by using the concordance index.\n\n\nRESULTS\nThirty-nine of 284 IP died. Mortality varied according to the etiology of the immunosuppression. Patients with HIV, solid organ transplantation or treatment with immunosuppressive drugs (n=118) had a low in-hospital mortality (4.3%) and were classified as low risk. IP with hematological malignancies, chemotherapy, chest radiation or marrow transplantation (n=166) had a high mortality (20%) and were classified as high risk. Compared with non-IP, low-risk IP had similar PSI-controlled mortality (OR=0.9, P=0.80), whereas high-risk IP had significantly greater mortality (OR=2.8, P<0.0001). The concordance index revealed similar discrimination for the PSI in low-risk IP (0.77) and in non-IP (0.7), but inferior discrimination in high-risk patients (0.6).\n\n\nCONCLUSIONS\nPatients with CAP and immunosuppression can be divided into low-risk and high-risk groups. The low-risk IP have mortality similar to non-IP and can be risk stratified by using the PSI.",
"affiliations": "Department of Medicine, University of Toronto, Toronto, Canada.",
"authors": "Sanders|K M|KM|;Marras|Theodore K|TK|;Chan|Charles K N|CK|",
"chemical_list": null,
"country": "Egypt",
"delete": false,
"doi": "10.1155/2006/195464",
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"issn_linking": "1198-2241",
"issue": "13(2)",
"journal": "Canadian respiratory journal",
"keywords": null,
"medline_ta": "Can Respir J",
"mesh_terms": "D000368:Aged; D015331:Cohort Studies; D017714:Community-Acquired Infections; D005260:Female; D006760:Hospitalization; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D008875:Middle Aged; D009864:Ontario; D018410:Pneumonia, Bacterial; D012189:Retrospective Studies; D012720:Severity of Illness Index; D015996:Survival Rate",
"nlm_unique_id": "9433332",
"other_id": null,
"pages": "89-93",
"pmc": null,
"pmid": "16550266",
"pubdate": "2006-03",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "11172189;11401897;11502651;12114367;12684306;15045044;346201;6878708;2690289;2225971;7903922;7800006;7551387;7472683;8538233;8722930;8995086;9250232;9361163;9737840;9769267;10207470;10321679;10424512;10790680;10987697;10987698;11112115",
"title": "Pneumonia severity index in the immunocompromised.",
"title_normalized": "pneumonia severity index in the immunocompromised"
} | [
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"companynumb": "CA-TEVA-786498ACC",
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"occurcountry": "CA",
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"actiondrug": "5",
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"activesubstancename": "PREDNISONE"
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{
"abstract": "Imiquimod has immune-stimulant properties that can precipitate autoimmune conditions like eczema, psoriasis and lichenoid conditions. We report two cases here where imiquimod induced florid lichen sclerosus in one patient and lichen planus in another. In both patients the condition was so aggressive and unresponsive to steroid treatment that circumcision was necessary.",
"affiliations": "Countess of Chester Hospital NHS Foundation Trust, Chester CH21UL, UK. colm.omahony@coch.nhs.uk",
"authors": "O'Mahony|C|C|;Yesudian|P D|PD|;Stanley|M|M|",
"chemical_list": "D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D000077271:Imiquimod",
"country": "England",
"delete": false,
"doi": "10.1258/ijsa.2009.009154",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0956-4624",
"issue": "21(3)",
"journal": "International journal of STD & AIDS",
"keywords": null,
"medline_ta": "Int J STD AIDS",
"mesh_terms": "D000276:Adjuvants, Immunologic; D000328:Adult; D000634:Aminoquinolines; D002944:Circumcision, Male; D003218:Condylomata Acuminata; D006801:Humans; D000077271:Imiquimod; D008010:Lichen Planus; D018459:Lichen Sclerosus et Atrophicus; D008297:Male",
"nlm_unique_id": "9007917",
"other_id": null,
"pages": "219-21",
"pmc": null,
"pmid": "20215634",
"pubdate": "2010-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Imiquimod use in the genital area and development of lichen sclerosus and lichen planus.",
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"abstract": "A 55-year-old woman came to our attention in April 2020 referring haematuria, frequency and urgency. The patient referred previous treatment with leuprorelin 3.75 mg/2 ml for breast cancer three years ago. Urine culture was performed and resulted always negative for pathogens. Cystoscopy revealed a whitish plaque lesion on the fundus, dome, trigone, and left lateral wall of the bladder. Histology of the biopsy confirmed the diagnosis of leukoplakia of the bladder. The plan is to follow her up repeating a cystoscopy every three months and biopsy in 6 months. Literature search revealed very little information on pathogenesis and prognosis of this condition due to its rare occurrence. The main objective of our case study was to describe individual situation of a woman affected by diffuse leukoplakia of the bladder ostium-sparing with a previous treatment with leuprorelin 3.75 mg/2 ml for breast cancer and to show safety of follow-up by cystoscopy and biopsy.\nWe showed a case of a woman treated with leuprorelin and with diffuse leukoplakia of the bladder. We support the recommended long-term follow-up and surveillance based on the literature review by cystoscopy with or without biopsy.",
"affiliations": "Urology Department, IRCCS CROB, Rionero in Vulture (PZ), Italy.;Urology Department, IRCCS CROB, Rionero in Vulture (PZ), Italy.;Anatomical Pathology Department, IRCCS CROB, Rionero in Vulture (PZ), Italy.;Anatomical Pathology Department, IRCCS CROB, Rionero in Vulture (PZ), Italy.;Anatomical Pathology Department, IRCCS CROB, Rionero in Vulture (PZ), Italy.;Urology Department, IRCCS CROB, Rionero in Vulture (PZ), Italy.;Anatomical Pathology Department, IRCCS CROB, Rionero in Vulture (PZ), Italy.",
"authors": "Nacchia|Antonio|A|https://orcid.org/0000-0002-3985-1991;di Giacomo|Ferdinando|F|;Di Cerbo|Arcangelo|A|;Di Somma|Massimo Dante|MD|;Patitucci|Giuseppe|G|;Disabato|Giuseppe|G|;Vita|Giulia|G|",
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"doi": "10.1155/2021/9970711",
"fulltext": "\n==== Front\nCase Rep Urol\nCase Rep Urol\nCRIU\nCase Reports in Urology\n2090-696X\n2090-6978\nHindawi\n\n10.1155/2021/9970711\nCase Report\nDiffuse Leukoplakia of the Bladder Ostium-Sparing in Patient Treated with Leuprorelin for Breast Cancer\nhttps://orcid.org/0000-0002-3985-1991\nNacchia Antonio antonionacchia7@gmail.com\n1\ndi Giacomo Ferdinando 1\nDi Cerbo Arcangelo 2\nDi Somma Massimo Dante 2\nPatitucci Giuseppe 2\nDisabato Giuseppe 1\nVita Giulia 2\n1Urology Department, IRCCS CROB, Rionero in Vulture (PZ), Italy\n2Anatomical Pathology Department, IRCCS CROB, Rionero in Vulture (PZ), Italy\nAcademic Editor: Tun-Chieh Chen\n\n2021\n27 7 2021\n2021 997071117 3 2021\n5 6 2021\n17 7 2021\nCopyright © 2021 Antonio Nacchia et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nCase\n\nA 55-year-old woman came to our attention in April 2020 referring haematuria, frequency and urgency. The patient referred previous treatment with leuprorelin 3.75 mg/2 ml for breast cancer three years ago. Urine culture was performed and resulted always negative for pathogens. Cystoscopy revealed a whitish plaque lesion on the fundus, dome, trigone, and left lateral wall of the bladder. Histology of the biopsy confirmed the diagnosis of leukoplakia of the bladder. The plan is to follow her up repeating a cystoscopy every three months and biopsy in 6 months. Literature search revealed very little information on pathogenesis and prognosis of this condition due to its rare occurrence. The main objective of our case study was to describe individual situation of a woman affected by diffuse leukoplakia of the bladder ostium-sparing with a previous treatment with leuprorelin 3.75 mg/2 ml for breast cancer and to show safety of follow-up by cystoscopy and biopsy.\n\nConclusions\n\nWe showed a case of a woman treated with leuprorelin and with diffuse leukoplakia of the bladder. We support the recommended long-term follow-up and surveillance based on the literature review by cystoscopy with or without biopsy.\n==== Body\n1. Introduction\n\nLeukoplakia vesicae (LV), also known as keratinizing squamous metaplasia, is a rare histological change of the bladder predisposing the individual to a possible high risk of bladder carcinoma in the background of prolonged exposure to a chronic irritant [1, 2]. It is rarely encountered in urological practice with an incidence of 1 : 10000. In areas where schistosomiasis is uncommon, it usually occurs due to chronic irritation of the inflamed bladder mucosa by bacteria. Risk factors include chronic catheterization, neurogenic bladder, vitamin A deficiency, urinary fistulas, and bladder outlet obstruction [3, 4]. Literature search revealed few reported cases of LV. We are reporting one case of this histological change in the bladder not secondary to chronic irritation due to infection. The main objective of our case study was to describe individual situation of a woman affected by diffuse leukoplakia of the bladder ostium-sparing with previous treatment with leuprorelin 3.75 mg/2 ml for breast cancer and to show safety of follow-up by cystoscopy and biopsy.\n\n2. Case Report\n\nA 55-year-old woman presented gross haematuria for several days. She had history of storage lower urinary tract symptoms (LUTS) since undergoing quadrantectomy surgery for breast cancer 3 years previously. She referred previous treatment with leuprorelin 3.75 mg/2 ml. She was an ex-smoker with a cigarette consumption of maximum ten a day. She interrupted smoking when she was diagnosed breast cancer. She referred past episodes of haematuria and storage LUTS that she always treated with antibiotics even if urine culture was negative. In April 2020, she came to our ambulatory of urology. She showed us a recent urine culture negative for infections and urinary cytology negative for malignant cells. Cystoscopy was performed, and it demonstrated an extensive whitish plaque area on the fundus, the dome, left emi-trigone, and left bladder wall. It extended near the left ureteric orifice without interesting it (Figure 1). Right orifice was completely spared (Figure 2). The efflux from both the ureteric orifices was normal. The mucosa underneath the plaques was inflamed (Figure 3). Multiple biopsies were performed. A net margin separated sane mucosa from pathological plagues. The histology of the affected area revealed keratinizing squamous metaplasia and focal low grade epithelial dysplasia (Figure 4). With these collected data, the main objective of our case study was to describe individual situation of a woman affected by diffuse leukoplakia of the bladder ostium-sparing with previous treatment with leuprorelin 3.75 mg/2 ml for breast cancer and to show safety of follow-up by cystoscopy and biopsy.\n\n3. Discussion\n\nA women of 55 years old came to our attention for LUTS, especially urgency and frequency, associated with haematuria in April 2020. Urine culture was negative. Urinary cytology was negative for malignant cells. Cystoscopy was performed showing a diffuse white plague ostium-sparing. Left orifice was circumferentially spared by LV (Figure 1). Dedicated informed consent for surgery and for this article was given by subject, and her anonymity is totally preserved. Multiple biopsies were performed with a LV diagnosis. According to some evidences in literature [1–3], the patient was managed with medical treatment. Antibiotics, pain killers, and antimuscarinics were given to manage her storage LUTS. She repeated a cystoscopy at six months from first cystoscopy in October 2020, and mapping of the bladder was performed in December 2020 confirming keratinizing squamous metaplasia (Figures 4 and 5).\n\nLeukoplakia signifies “white plaque”: the pathogenesis being cornification of normally noncornifying membrane due to a chronic inflammation (Figure 6) triggered by various risk factors [5]. It is encountered in urological practice with an incidence of 1 : 10000 and with the highest incidence in women between 50 and 70 years old [1, 5]. Trigone is the commonest site of occurrence sparing the ureteric orifice as in our case, but the condition can also be seen in the other walls of the bladder. Risk factors include chronic catheterization, neurogenic bladder, vitamin A deficiency, urinary fistulas, and bladder outlet obstruction [3].\n\nThe etiology is not known exactly, but according to Eyup et al. [2], possible hypotheses are embryological dispersal of ectoderm or spontaneous transformation or secondary epithelial response to appropriate stimuli.\n\nDiagnosis is histological. Microscopically, the normal urothelium is replaced by squamous epithelium with an overlying layer of keratin (Figures 5 and 7). It is considered as a risk factor for squamous cell carcinoma. Based on available literature, the current recommendation is for close cystoscopic monitoring annually to look for any subsequent malignant changes [4].\n\nNo consensus on management and treatment is actually available. Antibiotics are the most common therapy used in clinical practice, and they may help symptomatic remission, but efficacy is not durable. Transurethral resection of the bladder therapy significantly relieves urinary symptoms in women with LV. Improvement of quality of life has a success rate of 57.6%. Considering the very low complication rate, our study supports transurethral resection as an alternative treatment for patients who are resistant to medical therapy [6]. Recently, Benelli et al. [7] manage a man affected by LV with hyaluronic acid instillations with resolution of clinical symptoms. It could be considered the starting point and the gold standard in the follow-up of our patient. However, at present, further studies are required to formulate an adequate policy for therapeutic management of this unusual lesion of the bladder mucosa [7].\n\nThe woman of this case report was previously treated with leuprorelin 3.75 mg/2 ml for breast cancer. Leuprorelin is in the gonadotropin-releasing hormone (GnRH) analogue family of medications. There are two works evaluating the efficacy of the GnRH-analogue, leuprolide acetate, on NK cell activity. The first one suggests an increased NK cell activity in peripheral blood samples determined by 51Cr release assay [8], and the second one reported that NK cell cytotoxicity from control and patients was significantly decreased with leuprolide acetate [9]. These findings suggest a direct immunomodulatory role of GnRH on NK cell activity.\n\nThere is a report where the immunomodulation exerted by GnRH on freshly isolated primary peritoneal macrophages is clearly observed. In this work, the authors found that the production of nitric oxide, costimulated with lipopolysaccharide (LPS) and interferon-γ (IFNy), and the activity of NF-κB were suppressed by GnRH exposure. These results demonstrate that GnRH participates in macrophage function and indicate that the NF-κB signaling pathway may be responsible for GnRH-mediated immune modulation [9].\n\nIn some studies, leuprorelin was associated with interstitial lung diseases, granulomas, or other kinds of cutaneous eruptions (erythematous macules, infiltrated plaques, subcutaneous nodules, and sterile abscesses) [10–14], but no case reports of LV associated with leuprorelin are reported, so our manuscript should be considered innovative as first article on this topic. Possible association between leuprorelin treatment and LV could be related to alterations on immune system as proposed for interstitial lung disease by Shioi et al. [10]. This possible explanation about immune reactivity was supported for granulomas leuprorelin-related by Yasukawa et al. too [12]. However, etiology and pathogenesis about this association are actually not clear and should be clarified in the future.\n\nData Availability\n\nThe data that support the findings of this study are available from the corresponding author, A.N., upon reasonable request.\n\nAdditional Points\n\nLearning Points. LV is a rare condition which aetiology is not known exactly. Leuprorelin was associated with interstitial lung diseases, granulomas, or other kinds of cutaneous eruptions (erythematous macules, infiltrated plaques, subcutaneous nodules, and sterile abscesses). Leuprorelin use could be associated with LV too through immune system pathways. Recommended long-term follow-up and surveillance by cystoscopy with or without biopsy are safety and should be performed in LV.\n\nConflicts of Interest\n\nThere are no financial conflicts of interest to disclose by all authors.\n\nFigure 1 Whitish plaque extended near the left ureteric orifice without interesting it.\n\nFigure 2 Right orifice was completely spared by plaques.\n\nFigure 3 The mucosa underneath the plaques was inflamed.\n\nFigure 4 Replacement of the urothelium with stratified keratinized squamous epithelium.\n\nFigure 5 Hyperkeratotic, acanthotic squamous epithelium lining the lumen of the bladder with papillomatosis.\n\nFigure 6 Loose subepithelial connective tissue rich in small vessels with chronic inflammation infiltrate.\n\nFigure 7 Staining for Ki67 (cell proliferation index) limited to the basal layer of the epithelium supports the benign nature of leukoplakia.\n==== Refs\n1 Roehrborn C. G. Teigland C. M. Spence H. M. Progression of leukoplakia of the bladder to squamous cell carcinoma 19 years after complete urinary diversion The Journal of Urology 1988 140 3 603 604 10.1016/S0022-5347(17)41733-2 2-s2.0-0023788491 3411683\n2 Eyup G. Banu Y. Cengiz M. Extensive bilateral renal pelvis, ureter and bladder leukoplakia-case report International Journal of Urology 2002 9 11 653 655 12534913\n3 Amin M. B. McKenney J. K. Paner G. P. ICUD-EAU International consultation on bladder cancer 2012: pathology European Urology 2013 63 16 35 10.1016/j.eururo.2012.09.063 2-s2.0-84870478491 23083804\n4 Pandey T. Pandey S. Goel A. Aggarwal A. Leukoplakia of the urinary bladder: keratinising squamous metaplasia BMJ Case Reports 2018 2018, article 227019 10.1136/bcr-2018-227019 2-s2.0-85052656465\n5 Kasianandan A. Kannan K. Leukoplakia of the bladder: a case report and literature review International Urogynecology Journal 2012 23 1 131 133 10.1007/s00192-011-1491-3 2-s2.0-84860674633 21732098\n6 Wang H. Chong T. Tang X. Y. Zhang W.-B. Transurethral resection in women with symptomatic keratinizing squamous metaplasia of urinary bladder: a retrospective study of 92 cases May 2020 12 2 137 142 Epub 2019 Nov 24 10.1111/luts.12294 31762198\n7 Benelli A. Varca V. Vaccaro C. Keratinizing squamous metaplasia of the bladder: our experience and current approaches Urologia 2020 87 2 97 100 Epub 2018 Dec 3 10.1177/0391560318810197 30509153\n8 Tanaka T. Umesaki N. Novel intermittent GnRHa therapy for patients with endometriosis Nihon Rinsho 2001 59 Supplement 1 124 128 11235149\n9 Kang M.-G. Gwak D.-W. Cho H.-J. Min Y.-S. Park J.-S. Effect of leuprorelin in bulbar function of spinal and bulbar muscular atrophy patients: observational study for 1 year Journal of Neurology 2021 10.1007/s00415-021-10503-y 33675422\n10 Shioi K. Yoshida M. Sakai N. Interstitial pneumonitis induced by bicalutamide and leuprorelin acetate for prostate cancer International Journal of Urology 2003 10 11 625 626 10.1046/j.1442-2042.2003.00705.x 2-s2.0-0344736923 14633092\n11 Maeda K. Osafune T. Masuda Y. Drug-induced interstitial lung disease during combined androgen blockade with bicalutamide and leuprorelin acetate for prostate cancer Nihon Hinyokika Gakkai Zasshi 2019 110 1 36 40 10.5980/jpnjurol.110.36 31956217\n12 Yasukawa K. Sawamura D. Sugawara H. Leuprorelin acetate granulomas: case reports and review of the literature The British Journal of Dermatology 2005 152 5 1045 1047 10.1111/j.1365-2133.2005.06341.x 2-s2.0-18944374005 15888168\n13 Kluger N. Hahtola S. Lempinen T. Granulomes cutanes apres injections sous-cutanees d’acetate de leuproreline Presse Médicale 2017 46 10 966 968 Epub 2017 Sep 14 10.1016/j.lpm.2017.08.004 2-s2.0-85029431017 28919272\n14 de Salins C. A. Kupfer-Bessaguet I. Fleuret C. Fixed drug eruption induced by leuprorelin Annales de Dermatologie et de Vénéréologie 2015 142 12 780 781 Epub 2015 Aug 4 10.1016/j.annder.2015.06.016 2-s2.0-84949627441 26249532\n\n",
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"title": "Diffuse Leukoplakia of the Bladder Ostium-Sparing in Patient Treated with Leuprorelin for Breast Cancer.",
"title_normalized": "diffuse leukoplakia of the bladder ostium sparing in patient treated with leuprorelin for breast cancer"
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"abstract": "In the global phase 3 RAINBOW study, ramucirumab plus paclitaxel significantly improved overall survival compared with placebo plus paclitaxel in patients with advanced gastric or gastro-oesophageal junction (GEJ) adenocarcinoma. RAINBOW-Asia, a bridging study with similar design to RAINBOW, aimed to evaluate the efficacy and safety of ramucirumab plus paclitaxel for advanced gastric or GEJ adenocarcinoma in Asian, predominantly Chinese, patients.\n\n\n\nRAINBOW-Asia was a randomised, double-blind, placebo-controlled, phase 3 trial done at 32 centres in China, Malaysia, the Philippines, and Thailand. Adult patients (≥18 years) with metastatic or locally advanced, unresectable gastric or GEJ adenocarcinoma who previously received fluoropyrimidine-platinum-based chemotherapy were randomly assigned with a centralised interactive web response system in a 2:1 ratio to receive ramucirumab 8 mg/kg or placebo intravenously on days 1 and 15 plus paclitaxel 80 mg/m2 intravenously on days 1, 8, and 15 of every 28-day cycle. Randomisation was stratified by Eastern Cooperative Oncology Group performance status and presence of peritoneal metastases. The co-primary endpoints were progression-free survival and overall survival. Efficacy analyses were done in the intention-to-treat population, and safety analysis included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02898077, and has been completed.\n\n\n\nBetween March 2, 2017, and June 30, 2020, 440 patients were randomly assigned to receive ramucirumab plus paclitaxel (n=294) or placebo plus paclitaxel (n=146). Median progression-free survival was 4·14 months (95% CI 3·71-4·30) in the ramucirumab plus paclitaxel group compared with 3·15 months (2·83-4·14) in the placebo plus paclitaxel group (hazard ratio [HR] 0·765, 95% CI 0·613-0·955, p=0·0184). Median overall survival was 8·71 months (95% CI 7·98-9·49) in the ramucirumab plus paclitaxel group and 7·92 months (6·31-9·10) in the placebo plus paclitaxel group (HR 0·963, 95% CI 0·771-1·203, p=0·7426). The most common grade 3 or worse treatment-emergent adverse events were decreased neutrophil count (159 [54%] of 293 patients in the ramucirumab plus paclitaxel group vs 56 [39%] of 145 in the placebo plus paclitaxel group), decreased white blood cell count (127 [43%] vs 42 [29%]), anaemia (46 [16%] vs 24 [17%]), hypertension (21 [7%] vs nine [6%]), and febrile neutropenia (18 [6%] vs one [<1%]).\n\n\n\nThese findings, along with the results from RAINBOW, support the use of ramucirumab plus paclitaxel as second-line therapy in a predominantly Chinese population with advanced gastric or GEJ adenocarcinoma.\n\n\n\nEli Lilly and Company, USA.\n\n\n\nFor the Chinese translation of the abstract see Supplementary Materials section.",
"affiliations": "Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.;Department of Gastroenterology, Harbin Medical University Cancer Hospital, Harbin, China.;Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China.;Department of Medical Oncology, Jiangsu Cancer Hospital, Nanjing, China.;Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.;Department of Medical Oncology, Fudan University Zhongshan Hospital, Shanghai Medical College, Shanghai, China.;Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.;Cancer Center of Nanjing Bayi Hospital, Nanjing Chinese Medicine University, Nanjing, China.;Gastroenterology and Urology Department, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China.;The Comprehensive Cancer Center of Drum Tower Hospital, Clinical Cancer Institute of Nanjing University, Nanjing, China.;Medical Oncology, Tianjin Cancer Hospital, Tianjin, China.;Gastroenterology and Urology Department, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China.;Radiotherapy and Oncology Department, Hospital Umum Sarawak, Kuching, Malaysia.;Division of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.;Lilly China Drug Development and Medical Affairs Center, Eli Lilly and Company, Shanghai, China.;Lilly China Drug Development and Medical Affairs Center, Eli Lilly and Company, Shanghai, China.;Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China. Electronic address: linshenpku@163.com.",
"authors": "Xu|Rui-Hua|RH|;Zhang|Yanqiao|Y|;Pan|Hongming|H|;Feng|Jifeng|J|;Zhang|Tao|T|;Liu|Tianshu|T|;Qin|Yanru|Y|;Qin|Shukui|S|;Yin|Xianli|X|;Liu|Baorui|B|;Ba|Yi|Y|;Yang|Nong|N|;Voon|Pei Jye|PJ|;Tanasanvimon|Suebpong|S|;Zhou|Chan|C|;Zhang|Wan Li|WL|;Shen|Lin|L|",
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"title": "Efficacy and safety of weekly paclitaxel with or without ramucirumab as second-line therapy for the treatment of advanced gastric or gastroesophageal junction adenocarcinoma (RAINBOW-Asia): a randomised, multicentre, double-blind, phase 3 trial.",
"title_normalized": "efficacy and safety of weekly paclitaxel with or without ramucirumab as second line therapy for the treatment of advanced gastric or gastroesophageal junction adenocarcinoma rainbow asia a randomised multicentre double blind phase 3 trial"
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"abstract": "To assess the safety and efficacy of local intra-gestational sac methotrexate injection followed by dilation and curettage (D&C) in treating cesarean scar pregnancies (CSP).\n\n\n\nMedical records of CSP patients treated with local intra-gestational sac methotrexate injection followed by dilation and curettage were analyzed at the Maternal and Child Hospital of Guangxi Zhuang Autonomous Region, China.\n\n\n\nThirty-one patients were included in this study. The mean gestational age, sac diameter and thickness of the uterine scar were 49.6 ± 7.7 days, 1.8 ± 0.6 cm and 0.30 ± 0.15 cm, respectively. The median pretreatment serum β-human chorionic gonadotropin (β-HCG) level was 40,887 mIU/mL, with the 25th and 75th percentiles at 19,852 and 74,552, respectively. The median blood loss during D&C was 20 mL with the 25th and 75th percentiles at 10 mL and 50 mL. Following D&C, a Foley's balloon catheter compression was implanted in 26 (83.9%) patients due to active uterine bleeding. All patients had a β-HCG regression time of ≤ 4 weeks after D&C. While 30 patients (96.8%) had a uterine recovery time of ≤ 4 weeks, and 29 patients (93.5%) had resumption of menstruation of less than 6 weeks. Three patients (9.7%) had complications. One of them suffered from massive vaginal bleeding and underwent s blood transfusion. There were no other complications, such as pelvic infection and uterine rupture during the procedures. And no patient was converted to surgical resection or uterine artery embolization. Overall, 30 patients (96.8%) were treated successfully.\n\n\n\nLocal intra-gestational sac methotrexate injection followed by D&C with the aid of a Foley's balloon catheter compression appears to be a safe and effective treatment for CSP. Further randomized controlled trials are suggested to confirm these findings.",
"affiliations": "Department of Obstetrics and Gynecology, Maternal and Child Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530003, China. tankailiang2012@163.com.;Department of Obstetrics and Gynecology, Maternal and Child Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530003, China.;Department of Obstetrics and Gynecology, Maternal and Child Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530003, China.;Department of Obstetrics and Gynecology, Maternal and Child Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530003, China.;Department of Obstetrics and Gynecology, Maternal and Child Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530003, China.;Department of Obstetrics and Gynecology, Maternal and Child Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530003, China.;Department of Obstetrics and Gynecology, Maternal and Child Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530003, China.;Department of Obstetrics and Gynecology, Maternal and Child Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530003, China.;Department of Obstetrics and Gynecology, Maternal and Child Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530003, China.;Department of Obstetrics and Gynecology, Maternal and Child Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530003, China.",
"authors": "Tan|Kai-Liang|KL|http://orcid.org/0000-0002-0917-7158;Jiang|Li|L|;Chen|Yu-Mei|YM|;Meng|Ying|Y|;Lv|Bang-Quan|BQ|;Wei|Liu-Fei|LF|;Peng|Xiao-Zhu|XZ|;Ling|Yu-Ying|YY|;Lan|Jing|J|;Wei|Jin-Ying|JY|",
"chemical_list": "D008727:Methotrexate",
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"issue": "302(2)",
"journal": "Archives of gynecology and obstetrics",
"keywords": "Cesarean scar pregnancy; Dilation and curettage; Intra-gestational sac; Local injection; Methotrexate",
"medline_ta": "Arch Gynecol Obstet",
"mesh_terms": "D000328:Adult; D002585:Cesarean Section; D002921:Cicatrix; D004107:Dilatation and Curettage; D005260:Female; D058746:Gestational Sac; D006801:Humans; D008727:Methotrexate; D011247:Pregnancy; D016896:Treatment Outcome",
"nlm_unique_id": "8710213",
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"pages": "439-445",
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"pmid": "32474696",
"pubdate": "2020-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "15027012;12666214;16919632;11169360;25371837;24282376;25670903;26885053;26372348;25126192;25336858;26522097;20708532;22178164;26770522;23157046;24289991;3314739;15193489;26520674;25491022;28599886;25346492;27125412",
"title": "Local intra-gestational sac methotrexate injection followed by dilation and curettage in treating cesarean scar pregnancy.",
"title_normalized": "local intra gestational sac methotrexate injection followed by dilation and curettage in treating cesarean scar pregnancy"
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"abstract": "Oocyte and embryo cryopreservation, using controlled ovarian stimulation (COS), are common fertility preservation methodologies in breast cancer patients receiving gonadotoxic neo (adjuvant) chemotherapy (CT). The effects of COS and peak estradiol levels on CT-induced side effects are unknown.\nEighteen patients with stage II and III breast cancer underwent oocyte or embryo cryopreservation at Leiden University Medical Center before receiving docetaxel, adriamycin, and cyclophosphamide (TAC) CT (COS group). A control group (N=18) was retrospectively selected from breast cancer patients, aged between 18 and 40, who underwent TAC CT without fertility preservation. CT -induced toxicity in the 2 groups was compared using χ2 analysis. Associations between peak estradiol levels and distinct stimulation protocols and side effects in the COS group were investigated by using regression analysis.\nPatient characteristics between both groups were similar, except for a lower age in the COS group vs the control group (30.5 vs 35.2 years, P=0.005). No differences were seen in grade III/IV side effects between both groups. In the COS group, an increase in thrombopenia grade I/II was seen, while grade I/II stomatitis and constipation were significantly lower in the COS group as compared with the control group (P=0.006 and P=0.008, respectively). In the COS group, no association was found between the peak estradiol levels and distinct stimulation protocols and side effects of CT.\nCOS prior to TAC CT was not associated with an increase in grade III/IV side effects. Interestingly, COS may have a protective effect on mucositis and constipation. Moreover, the peak estradiol levels and distinct stimulation protocols had no effect on grade III/IV side effects in our study.",
"affiliations": "Department of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands, j.r.kroep@lumc.nl.;Department of Gynecology, Leiden University Medical Center, Leiden, the Netherlands.;Department of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands, j.r.kroep@lumc.nl.;Department of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands, j.r.kroep@lumc.nl.;Department of Medical Oncology, OLVG Hospital, Amsterdam, the Netherlands.;Department of Medical Oncology, Alrijne Hospital, Leiden, the Netherlands.;Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands.;Department of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands, j.r.kroep@lumc.nl.",
"authors": "de Groot|Stefanie|S|;Louwé|Leoni A|LA|;Ramautar|Ashna Ie|AI|;Portielje|Johanneke Ea|JE|;Ogilvie|Aernout C|AC|;Batman|Erdogan|E|;Fiocco|Marta|M|;Kroep|Judith R|JR|",
"chemical_list": null,
"country": "New Zealand",
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"doi": "10.2147/CMAR.S151905",
"fulltext": "\n==== Front\nCancer Manag ResCancer Manag ResCancer Management and ResearchCancer Management and Research1179-1322Dove Medical Press 10.2147/CMAR.S151905cmar-10-3931Original ResearchEffects of controlled ovarian stimulation on toxicity of TAC chemotherapy in early breast cancer patients de Groot Stefanie 1Louwé Leoni A 2Ramautar Ashna IE 1Portielje Johanneke EA 13Ogilvie Aernout C 4Batman Erdogan 5Fiocco Marta 67Kroep Judith R 1\n1 Department of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands, j.r.kroep@lumc.nl\n2 Department of Gynecology, Leiden University Medical Center, Leiden, the Netherlands\n3 Department of Medical Oncology, Haga Hospital, Den Haag, the Netherlands\n4 Department of Medical Oncology, OLVG Hospital, Amsterdam, the Netherlands\n5 Department of Medical Oncology, Alrijne Hospital, Leiden, the Netherlands\n6 Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands\n7 Mathematical Institute, Leiden University, Leiden, the NetherlandsCorrespondence: Judith R Kroep, Department of Medical Oncology, Leiden University Medical Center, Albinusdreef 2, Leiden, PO Box 9600, 2300RC Leiden, the Netherlands, Tel +31 71 526 3464, Email j.r.kroep@lumc.nl2018 26 9 2018 10 3931 3935 © 2018 de Groot et al. This work is published and licensed by Dove Medical Press Limited2018The 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.Background\nOocyte and embryo cryopreservation, using controlled ovarian stimulation (COS), are common fertility preservation methodologies in breast cancer patients receiving gonadotoxic neo (adjuvant) chemotherapy (CT). The effects of COS and peak estradiol levels on CT-induced side effects are unknown.\n\nPatients and methods\nEighteen patients with stage II and III breast cancer underwent oocyte or embryo cryopreservation at Leiden University Medical Center before receiving docetaxel, adriamycin, and cyclophosphamide (TAC) CT (COS group). A control group (N=18) was retrospectively selected from breast cancer patients, aged between 18 and 40, who underwent TAC CT without fertility preservation. CT -induced toxicity in the 2 groups was compared using χ2 analysis. Associations between peak estradiol levels and distinct stimulation protocols and side effects in the COS group were investigated by using regression analysis.\n\nResults\nPatient characteristics between both groups were similar, except for a lower age in the COS group vs the control group (30.5 vs 35.2 years, P=0.005). No differences were seen in grade III/IV side effects between both groups. In the COS group, an increase in thrombopenia grade I/II was seen, while grade I/II stomatitis and constipation were significantly lower in the COS group as compared with the control group (P=0.006 and P=0.008, respectively). In the COS group, no association was found between the peak estradiol levels and distinct stimulation protocols and side effects of CT.\n\nConclusion\nCOS prior to TAC CT was not associated with an increase in grade III/IV side effects. Interestingly, COS may have a protective effect on mucositis and constipation. Moreover, the peak estradiol levels and distinct stimulation protocols had no effect on grade III/IV side effects in our study.\n\nKeywords\nchemotherapytoxicityfertility preservationcontrolled ovarian hyperstimulation\n==== Body\nIntroduction\nPremenopausal breast cancer patients who receive chemotherapy (CT) have a risk of decreased ovarian reserve, premature ovarian failure, and infertility after treatment.1–3 Therefore, discussion of and referral for fertility preservation in patients who wish to have a child in the future is an essential part of the treatment plan.4–7 As mortality rates have declined over time in this patient group and patients often postpone their first pregnancy,2,8 oocyte and embryo cryopreservation are commonly used fertility preservation options.9 Both approaches require controlled ovarian stimulation (COS) for ~2 weeks. Conventional ovarian stimulation protocols cause high serum levels of estradiol.10,11 To block or to decrease estradiol during COS, new protocols with tamoxifen and aromatase inhibitors in combination with low levels of follicle-stimulating hormone (FSH) are developed.10,12 Studies have shown that COS for fertility preservation with tamoxifen or aromatase inhibitors in patients with breast cancer are unlikely to increase recurrence risk.13–16 The effects of COS and the additional hormonal alterations on toxicity of CT have not been studied. Preclinical evidence shows that sex hormones may interfere with side effects of CT.17,18 Therefore, we conducted a retrospective case–control study of the effects of COS on CT-induced toxicity in early breast cancer patients undergoing oocyte and embryo cryopreservation for fertility preservation prior to neo (adjuvant) docetaxel, adriamycin, and cyclophosphamide (TAC) CT.\n\nPatients and methods\nStudy population\nEligible patients with early breast cancer stage, Ic, II and III, and underwent oocyte or embryo cryopreservation at the gynecology department of the Leiden University Medical Center (LUMC) between 2009 and 2015. All patients received TAC CT (docetaxel 75 mg/m2 IV, adriamycin 50 mg/m2 IV, and cyclophosphamide 500 mg/m2 IV, day 1, q3 weeks) and were treated in 6 hospitals in the Netherlands. The control group was selected from all patients in the LUMC who underwent TAC CT between 2009 and 2015 without oocyte or embryo cryopreservation and with the age at diagnosis between 18 and 40 years. The retrospective study was conducted according with the Declaration of Helsinki and the Dutch “Code of Good Conduct,” and was approved by the Ethics Committee of the LUMC. Patient consent was assumed as per the no-objection rule of the “Code of Good Conduct” (https://www.federa.org/codes-conduct).\n\nStimulation protocols\nThe following stimulation protocols were used: 1) COS protocol with FSH, tamoxifen, and gonadotropin-releasing hormone (GnRH) antagonist; 2) protocol with FSH and a GnRH antagonist alone; and 3) protocol with FSH and a GnRH agonist. Patient received the distinct COS protocols depending on hormone receptor status of the tumor and timing of start in the follicular or luteal phase of the menstrual cycle. Typically, patients received COS on the second or third day of the menstrual bleeding with an average dose of 150 U of FSH subcutaneously with or without 60 mg tamoxifen daily. Until E2 >250 pg/mL and/or the largest ovarian follicles reach 17–18 mm in diameter by ultrasound examination, the stimulation was followed by an human chorionic gonadotropin (HCG) injection (subcutaneous ovitrelle 0.25 mg/d). The oocyte retrieval was performed 36 hours later.\n\nToxicity\nSide effects and hematological toxicity were graded according to the Common Terminology Criteria for Adverse Events version 4.03. Each side effect, documented by the physician, was scored once per patient at maximum during the course, and the highest grade of occurrence was scored.\n\nBlood sampling and assay methods\nDuring the monitoring phase of the COS, venous blood samples were drawn in a serum-separating tube with intervals of 1–4 days. Serum estradiol levels were analyzed by electrochemiluminescence immunoassay (Modular Analytics E 170 Roche Diagnostics, Basel, Switzerland). All samples were analyzed by the accredited clinical laboratory of the LUMC.\n\nStatistical analysis\nFor the primary endpoint, toxicity due to CT was compared between both groups using chi-square and logistic regression analysis. For the secondary endpoints, peak estradiol serum levels and distinct stimulation protocols were associated with grade III/IV toxicity in the COS group by using regression analysis. Univariate and multivariate odds ratios along with their 95% confidence intervals were estimated. All tests were 2-tailed, and P-values <0.05 were considered significant. All data were analyzed using Statistical Package for Social Sciences software™ 20.0 (IBM Corporation, Armonk, NY, USA).\n\nResults\nPatient characteristics\nEighteen patients received COS prior to neo (adjuvant) CT. Ten patients received a COS protocol with tamoxifen and GnRH antagonist, four patients a protocol with a GnRH antagonist alone, and four patients a protocol with a GnRH agonist alone. Eight patients in the COS group received 2 subsequent cycles of COS, whereas 10 patients received 1 cycle of COS. The control group (N=18) consisted of patients who received neo (adjuvant) TAC CT between 2009 and 2016 and were between 18 and 40 years old. Patient characteristics between both groups were similar, except for a lower age in the COS group vs the control group (30.5 vs 35.2 years, P=0.005). Two patients did not receive all 6 cycles of TAC in the COS group. One patient switched after one TAC cycle due to neutropenic enterocolitis (typhlitis) to 3 3-weekly cycles AC followed by 9 weekly cycles of paclitaxel, and 1 patient chose to stop after 4 cycles of TAC without a medical necessity to discontinue the CT. Patient characteristics at diagnosis are summarized in Table 1.\n\nToxicity\nThe observed grade III/IV side effects were neutropenic fever, neutropenic enterocolitis, fatigue, and pneumonia. No difference were seen in grade III/IV side effects between both groups. The incidence of side effects that occurred in both groups is given in Table 2. In the COS group an increase in thrombopenia grade I/II was seen; 4 patients had a grade I and 1 patient had a grade II thrombopenia. Grade I/II stomatitis and constipation occurrence was significantly lower in the COS group as compared to the control group (P=0.008 and P=0.006, respectively). These results remained significant in multivariate analysis when adjusting for age (P=0.018 and P=0.020, respectively). No grade V toxicity occurred during the CT in either group.\n\nEstradiol levels and toxicity\nIn the COS group, no association was found between the peak estradiol levels and distinct stimulation protocols and grade III/IV side effects of CT. The mean peak estradiol serum levels in the protocol with tamoxifen was 8,046 pmol/L (N=10) and in the protocol without tamoxifen 5,717 pmol/L (N=8); the peak estradiol levels per protocol are given in Table 3. The peak estradiol levels were not significantly different (P=0.351).\n\nDiscussion\nThis study shows that COS prior to TAC CT is not associated with an increase or decrease in grade III/IV side effects in breast cancer patients treated with neo (adjuvant) TAC CT. To the best knowledge of the authors, this is the first study on effects of COS on CT -induced side effects.\n\nCOS for fertility preservation prior to TAC CT appears to be safe in terms of toxicity in breast cancer patients, as it did not increase grade III/IV side effects. However, we found a significant increase in grade I/II thrombopenia in the COS group. Because thrombocytopenia grade II (<75.0×102/L blood platelets) might require delay and/or dose reduction of the CT, these results need to be validated in a larger study.\n\nInterestingly, COS had a protective effect on mucositis and constipation. The protective effect of COS on occurrence of mucositis during CT treatment may be due to the hormonal alterations caused by COS. Analogously, estrogen treatment had a beneficial effect on recurrent aphthous mouth ulcers in premenopausal healthy women19 and on oral discomfort in postmenopausal women.20 Additionally, the estrogen receptor has been detected in the oral mucosa.21,22 Thus, decrease in occurrence of mucositis in the COS group may be due to a transient increase of estradiol levels due to COS and its effects on the oral mucosa. The beneficial effect on constipation may be caused by the hormonal alternations as well. Researchers found a beneficial effect of estrogen on stool consistency and ease of passage in healthy postmenopausal women.23 However, this effect might also be due to variable antiemetics protocols used in the different hospitals, as antiemetics can cause constipation.24\n\nAs an alternative for COS, ovarian tissue cryopreservation is an option for breast cancer patients under the age of 35 years with CT resulting in >50% loss of ovarian reserve.25 Although, it does not require COS and can be performed without delaying the start of CT, ovarian tissue cryopreservation requires surgery and is still in the experimental stage. The success rate for pregnancy has been estimated between 11% and 30%;26 however, presumably, the success rate cannot be accurately determined yet.27 Our study results support the usage of COS prior to CT because of the absence of a significant effect on grade III/IV side effects during CT. Moreover, patients with a mutation of BRCA1/2 might choose preimplantation genetic diagnosis, which requires COS and an in vitro fertilization procedure.28\n\nIt seems important to emphasize that the sample size of our study was small. Therefore, the results need to be validated in a larger cohort. Another limitation of our study was the significant difference in age between the COS and control group. We cannot rule out that this difference might be related to our results, although we used the same inclusion criteria for age in both groups. Moreover, in this retrospective study, the estradiol levels of the patients in the control group were unknown, and these levels may be valuable for the comparison between both groups in a future study.\n\nConclusion\nIn conclusion, COS prior to TAC CT is not associated with an increase in grade III/IV side effects. COS may increase grade I/II thrombocytopenia and may have a protective effect on mucositis and constipation.\n\nAcknowledgments\nThe authors gratefully acknowledge the physicians R Oosterkamp (Medisch Centrum Haaglanden), M Bos (Reinier de Graaf Hospital), G Jonkers (Alrijne Hospital), and MM Geenen (Sint Lukas Andreas Hospital); PC de Jong (St. Antonius Hospital); G Sonke (Anthoni van Leeuwenhoek Hospital); and AH Jonkoop (Isala).\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nTable 1 Patient characteristics\n\nCharacteristics\tOS (n=18)\tControl (n=18)\tP-value\t\nMedian age (range), years\t35.2 (22–38)\t30.5 (25–40)\t0.005\t\nT-classification\t\t\t0.32\t\n T1\t10 (55.6%)\t7 (38.8%)\t\t\n T2–T4\t8 (44.4%)\t11 (61.1%)\t\t\nN-classification\t\t\t0.73\t\n N0\t12 (66.7%)\t11 (61.1%)\t\t\n N+\t6 (33.3%)\t7 (38.9%)\t\t\nHR status\t\t\t0.49\t\n ER and PR negative\t6 (33.3%)\t8 (42.1%)\t\t\n ER and/or PR positive\t12 (66.7%)\t10 (58.8%)\t\t\nHER-2 status\t\t\t0.29\t\n Negative\t17 (94.4%)\t15 (83.3%)\t\t\n Positive\t1 (5.6%)\t3 (16.7%)\t\t\nRadiotherapy before CT\t\t\t0.49\t\n No\t12 (66.7%)\t14 (77.8%)\t\t\n Yes\t6 (33.3%)\t4 (22.2%)\t\t\nMedication\t\t\t\t\n Tamoxifen + GnRH antagonist\t10 (55.6%)\t\t\t\n GnRH agonist\t4 (22.2%)\t\t\t\n GnRH antagonist\t4 (22.2%)\t\t\t\nNumber of cycles\t\t\t\t\n 1\t10 (55.6%)\t\t\t\n 2\t8 (44.4%)\t\t\t\nAbbreviations: CT, chemotherapy; ER, estrogen receptor; GnRH, gonadotropin-releasing hormone; HR, hormone receptor; OS, ovarian stimulation; PR, progesterone receptor.\n\nTable 2 Grade I/II and grade III/IV toxicity during 6 cycles of TAC in both arms\n\nAdverse event\tOS\tControl\tP-value\tOR (95% CI)\tP-value, OR (95% CI), multivariate\t\nAny grade\t\t\t\t\t\t\n Fatigue\t13\t14\t0.700\t0.74 (0.16–3.38)\t\t\n Mucositis\t5\t13\t0.008\t0.15 (0.03–0.06)\t0.018, 0.13 (0.03–0.70)\t\n Neuropathy\t5\t7\t0.480\t0.60 (0.15–2.45)\t\t\n Diarrhea\t8\t4\t0.157\t2.80 (0.66–11.9)\t\t\n Nausea\t12\t13\t0.717\t0.77 (019–3.19)\t\t\n Vomiting\t7\t5\t0.362\t1.66 (0.41–6.71)\t\t\n Eye complaints\t5\t9\t0.171\t0.39 (0.10–1.54)\t\t\n Constipation\t7\t15\t0.006\t0.13 (0.27–0.61)\t0.020, 0.13 (0.022–0.721)\t\n Anemia\t11\t13\t0.480\t0.60 (0.15–2.45)\t\t\n Thrombopenia\t5\t0\tNA\tNA\t\t\n Leukopenia\t7\t4\t0.278\t2.23 (0.52–9.59)\t\t\n Neutropenia\t6\t3\t0.248\t2.50 (0.52–12.1)\t\t\nGrade III/IV\t\t\t\t\t\t\n Total grade III/IV\t6\t5\t0.717\t1.30 (0.31–5.39)\t\t\n Febrile neutropenia\t5\t2\t0.206\t3.08 (0.51–18.5)\t\t\nNotes: All side effects were scored according CTCAE4.03. Each side effect was scored maximal once per patient during the course (the highest grade of occurrence was scored). The multivariate model has been adjusted for age.\n\nAbbreviations: CTCAE, Common Terminology Criteria for Adverse Events; NA, not applicable; OR, odds ratio; OS, ovarian stimulation; TAC, docetaxel, adriamycin, and cyclophosphamide.\n\nTable 3 The peak estradiol levels of distinct stimulation protocols\n\nProtocol\tN\tMean levels of estradiol (pmol/L)\t\nTamoxifen + GnRH antagonist\t10 (55.6%)\t8,046 (4,565–11,527)\t\nGnRH agonist\t4 (22.2%)\t6,869 (3,758–9,979)\t\nGnRH antagonist\t4 (22.2%)\t4,566 (2,170–6,962)\t\nAbbreviation: GnRH, gonadotropin-releasing hormone.\n==== Refs\nReferences\n1 Turan V Oktay K Sexual and fertility adverse effects associated with chemotherapy treatment in women Expert Opin Drug Saf 2014 13 6 775 783 24784147 \n2 Partridge AH Winer EP Long-term complications of adjuvant chemotherapy for early stage breast cancer Breast Dis 2004 21 55 64 15687723 \n3 Gadducci A Cosio S Genazzani AR Ovarian function and childbearing issues in breast cancer survivors Gynecol Endocrinol 2007 23 11 625 631 17926162 \n4 Garvelink MM Ter Kuile MM Louwe LA Hilders CG Stiggelbout AM A Delphi consensus study among patients and clinicians in the Netherlands on the procedure of informing young breast cancer patients about fertility preservation Acta Oncol 2012 51 8 1062 1069 23050612 \n5 Garvelink MM ter Kuile MM Fischer MJ Development of a decision aid about fertility preservation for women with breast cancer in the Netherlands J Psychosom Obstet Gynaecol 2013 34 4 170 178 24188788 \n6 Canada AL Schover LR The psychosocial impact of interrupted childbearing in long-term female cancer survivors Psychooncology 2012 21 2 134 143 22271533 \n7 Loren AW Mangu PB Beck LN Fertility preservation for patients with cancer: American Society of Clinical Oncology clinical practice guideline update J Clin Oncol 2013 31 19 2500 2510 23715580 \n8 Cossetti RJ Tyldesley SK Speers CH Zheng Y Gelmon KA Comparison of breast cancer recurrence and outcome patterns between patients treated from 1986 to 1992 and from 2004 to 2008 J Clin Oncol 2015 33 1 65 73 25422485 \n9 Lobo RA Potential options for preservation of fertility in women N Engl J Med 2005 353 1 64 73 16000356 \n10 Oktay K Hourvitz A Sahin G Letrozole reduces estrogen and gonadotropin exposure in women with breast cancer undergoing ovarian stimulation before chemotherapy J Clin Endocrinol Metab 2006 91 10 3885 3890 16882752 \n11 Casper RF Mitwally MF Use of the aromatase inhibitor letrozole for ovulation induction in women with polycystic ovarian syndrome Clin Obstet Gynecol 2011 54 4 685 695 22031258 \n12 Jenninga E Kroep JR Hilders CG Louwe LA Verburg HJ Nortier JW Fertility preservation in female oncology patients Ned Tijdschr Geneeskd 2008 152 45 2437 2441 Dutch 19051792 \n13 Kim J Turan V Oktay K Long-term safety of letrozole and gonadotropin stimulation for fertility preservation in women with breast cancer J Clin Endocrinol Metab 2016 101 4 1364 1371 26751194 \n14 Oktay K Buyuk E Libertella N Akar M Rosenwaks Z Fertility preservation in breast cancer patients: a prospective controlled comparison of ovarian stimulation with tamoxifen and letrozole for embryo cryopreservation J Clin Oncol 2005 23 19 4347 4353 15824416 \n15 Azim AA Costantini-Ferrando M Oktay K Safety of fertility preservation by ovarian stimulation with letrozole and gonadotropins in patients with breast cancer: a prospective controlled study J Clin Oncol 2008 26 16 2630 2635 18509175 \n16 Turan V Bedoschi G Moy F Oktay K Safety and feasibility of performing two consecutive ovarian stimulation cycles with the use of letrozole-gonadotropin protocol for fertility preservation in breast cancer patients Fertil Steril 2013 100 6 1681 1685.e1 24055050 \n17 Altieri P Barisione C Lazzarini E Testosterone antagonizes doxorubicin-induced senescence of cardiomyocytes J Am Heart Assoc 2016 5 1 pii: 0022383 \n18 Imai A Sugiyama M Furui T Tamaya T Ohno T Direct protection by a gonadotropin-releasing hormone analog from doxorubicin-induced granulosa cell damage Gynecol Obstet Invest 2007 63 2 102 106 17028438 \n19 Bishop PM Harris PW Trafford JA Oestrogen treatment of recurrent aphthous mouth ulcers Lancet 1967 1 7504 1345 1347 4165173 \n20 Giuca MR Carli E Pasini M Bonfigli D Cappe MR Evaluation of efficacy of estrogen and phytotherapy in oral cavity alterations of women in menopause Minerva Ginecol 2009 61 1 13 22 19204657 \n21 Valimaa H Savolainen S Soukka T Estrogen receptor-β is the predominant estrogen receptor subtype in human oral epithelium and salivary glands J Endocrinol 2004 180 1 55 62 14709144 \n22 Leimola-Virtanen R Salo T Toikkanen S Pulkkinen J Syrjanen S Expression of estrogen receptor (ER) in oral mucosa and salivary glands Maturitas 2000 36 2 131 137 11006500 \n23 Gonenne J Esfandyari T Camilleri M Effect of female sex hormone supplementation and withdrawal on gastrointestinal and colonic transit in postmenopausal women Neurogastroenterol Motil 2006 18 10 911 918 16961694 \n24 Oncoline. [homepage on the Internet] Cancer clinical practice guidelines “Nausea and vomiting” [updated June 16, 2014] Available from: http://www.oncoline.nl/nausea-and-vomiting Accessed July 1, 2017 \n25 Imbert R Moffa F Tsepelidis S Safety and usefulness of cryopreservation of ovarian tissue to preserve fertility: a 12-year retrospective analysis Hum Reprod 2014 29 9 1931 1940 24958067 \n26 Donnez J Dolmans MM Pellicer A Restoration of ovarian activity and pregnancy after transplantation of cryopreserved ovarian tissue: a review of 60 cases of reimplantation Fertil Steril 2013 99 6 1503 1513 23635349 \n27 Andersen CY Success and challenges in fertility preservation after ovarian tissue grafting Lancet 2015 385 9981 1947 1948 \n28 Quinn GP Vadaparampil ST Jacobsen PB Frozen hope: fertility preservation for women with cancer J Midwifery Womens Health 2010 55 2 175 180 20189137\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1179-1322",
"issue": "10()",
"journal": "Cancer management and research",
"keywords": "chemotherapy; controlled ovarian hyperstimulation; fertility preservation; toxicity",
"medline_ta": "Cancer Manag Res",
"mesh_terms": null,
"nlm_unique_id": "101512700",
"other_id": null,
"pages": "3931-3935",
"pmc": null,
"pmid": "30310313",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "11006500;23050612;24784147;16000356;16961694;20189137;26090642;26746999;14709144;19204657;19051792;18509175;15824416;17028438;25422485;17926162;23715580;22031258;15687723;24958067;24188788;23635349;24055050;22271533;26751194;16882752;4165173",
"title": "Effects of controlled ovarian stimulation on toxicity of TAC chemotherapy in early breast cancer patients.",
"title_normalized": "effects of controlled ovarian stimulation on toxicity of tac chemotherapy in early breast cancer patients"
} | [
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"companynumb": "NL-JNJFOC-20181235808",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
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{
"abstract": "Persistent cytopenia due to poor graft function (PoGF) is a relatively common complication which may affect up to 20% of patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Treatment options for PoGF remain limited, and reinfusion of additional HSC is often the only way to rescue hematopoiesis. Here we describe a retrospective single-center experience with the thrombopoietin-mimetic agent eltrombopag for the treatment of PoGF. Thirteen patients have received eltrombopag for either PoGF (n = 12) or primary graft failure (n = 1). In the 12 PoGF patients eltrombopag was started at the median time of 79 days after HSCT, due to persistent thrombocytopenia, with concomitant anemia and neutropenia in 7 and 3 patients, respectively. The treatment was started at the dose of 50 mg per day, and eventually increased up to 150 mg in case of lack of response. Hematological response was seen in 7 patients, with 6 complete responses. Hematological responses were seen both in patients with evidence of immune-mediated pathophysiology, and with possible infectious/iatrogenic causes. In responding patients, eltrombopag was discontinued in 6/7 patients without further relapse. These results suggest that eltrombopag is safe and possibly effective in the setting of the treatment of PoGF, and pave the way for future prospective studies.",
"affiliations": "Hematology, Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.;Hematology, Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.;Hematology, Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.;Hematology, Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.;Hematology, Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.;Hematology, Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.;Hematology, Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.;Hematology, Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.;Hematology, Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.;Hematology, Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.;Hematology, Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy. amrisita@unina.it.",
"authors": "Marotta|Serena|S|;Marano|Luana|L|;Ricci|Patrizia|P|;Cacace|Fabiana|F|;Frieri|Camilla|C|;Simeone|Luigia|L|;Trastulli|Fabio|F|;Vitiello|Selenia|S|;Cardano|Flora|F|;Pane|Fabrizio|F|;Risitano|Antonio M|AM|0000-0002-4744-5109",
"chemical_list": "D001565:Benzoates; D006834:Hydrazines; D011720:Pyrazoles; C520809:eltrombopag",
"country": "England",
"delete": false,
"doi": "10.1038/s41409-019-0442-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-3369",
"issue": "54(8)",
"journal": "Bone marrow transplantation",
"keywords": null,
"medline_ta": "Bone Marrow Transplant",
"mesh_terms": "D000328:Adult; D000368:Aged; D001565:Benzoates; D005260:Female; D006801:Humans; D006834:Hydrazines; D008297:Male; D008875:Middle Aged; D011720:Pyrazoles; D012189:Retrospective Studies; D013921:Thrombocytopenia",
"nlm_unique_id": "8702459",
"other_id": null,
"pages": "1346-1353",
"pmc": null,
"pmid": "30679824",
"pubdate": "2019-08",
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"abstract": "Human papilloma virus (HPV) infection is documented to be involved in the development of epithelial malignancies, mostly in cervical cancer. Systemic lupus erythematosus (SLE) patients have an increased prevalence of such an infection. We report the case of a 55-year-old female SLE patient who developed multiple in situ squamous cell carcinomas on her fingers, after chronic HPV infection. HPV-33 DNA was isolated from the lesions. The purpose of this case presentation is to raise awareness about HPV-induced malignancies for this high-risk group and propose an early HPV vaccination to efficiently prevent such comorbidities.",
"affiliations": "Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Dessau, Germany.;Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Dessau, Germany.;Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Dessau, Germany.;Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Dessau, Germany.;Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Dessau, Germany.;Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Dessau, Germany.",
"authors": "Nikolakis|Georgios|G|;Karagiannidis|Ioannis|I|;Zampeli|Vasiliki A|VA|;Altenburg|Andreas|A|;Brunner|Martina|M|;Zouboulis|Christos C|CC|",
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"fulltext": "\n==== Front\nCase Rep DermatolCase Rep DermatolCDECase Reports in Dermatology1662-6567S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000442017cde-0007-0329Published online: November, 2015Multiple HPV-Induced Squamous Cell Carcinomas on the Fingers of a Patient with Systemic Lupus Erythematosus: A Case and Review Nikolakis Georgios *Karagiannidis Ioannis Zampeli Vasiliki A. Altenburg Andreas Brunner Martina Zouboulis Christos C. Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Dessau, Germany*Dr. med. Georgios Nikolakis, MD, Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Auenweg 38, DE-06847 Dessau (Germany), E-Mail nikolakisgeorgios@gmail.comSep-Dec 2015 19 11 2015 19 11 2015 7 3 329 334 Copyright © 2015 by S. Karger AG, Basel2015This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Human papilloma virus (HPV) infection is documented to be involved in the development of epithelial malignancies, mostly in cervical cancer. Systemic lupus erythematosus (SLE) patients have an increased prevalence of such an infection. We report the case of a 55-year-old female SLE patient who developed multiple in situ squamous cell carcinomas on her fingers, after chronic HPV infection. HPV-33 DNA was isolated from the lesions. The purpose of this case presentation is to raise awareness about HPV-induced malignancies for this high-risk group and propose an early HPV vaccination to efficiently prevent such comorbidities.\n\nKey Words\nHuman papilloma virusLupus erythematosusSquamous cell carcinomaHPV-33\n==== Body\nIntroduction\nHuman papilloma virus (HPV) infection is currently considered one of the most prevalent sexually transmitted diseases worldwide, leading to a broad palette of different conditions, ranging from common warts to malignancy. Its involvement in cervical carcinogenesis is well established, since it facilitates the evasion of apoptosis from damaged cervical cells. Multiple risk factors are associated with HPV prevalence, among which is the patient's immunocompetence status [1]. Despite the lack of known risk factors for an HPV infection, systemic lupus erythematosus (SLE) patients were found to have a 3-fold increase in HPV infection [2]. Furthermore, infection by high-risk HPV subtypes was more frequently reported in SLE patients [3, 4].\n\nCase Presentation\nA 55-year-old patient presented to our Departments with chronic, erythematous, eczematous, and hyperkeratotic and partially exophytic skin lesions on her fingers (fig. 1). The 2nd finger of the left hand (fig. 1a) and fingers D1–D5 (fig. 1b–d) of the right hand were affected. The lesions observed on the 4th finger of the right hand showed exudative ulceration and nail loss (fig. 1c). The patient underwent a 3-week treatment with fusidic acid and hydrocortisone cream, which did not improve the lesions. The patient was diagnosed with SLE, involving sicca and Raynaud symptoms, arthralgias, and the characteristic butterfly rash, about 20 years ago. Routine laboratory parameters were in the normal range except for lymphocytes 6.3% (range 16–39), neutrophils 82.9% (range 51–74), C-reactive protein 14 mg/l (range 0–5), and GFR-K 67.2 ml/min (range 80–140). Laboratory tests regarding the immunological status are presented: antinuclear antibodies 1:1,280; extractable nuclear antigens, negative; C3 complement 1.02 g/l (range 0.9–1.8); C4 complement 0.274 g/l (range 0.1–0.4); double-stranded DNA antibodies, positive (1:80), and circulating immune complexes, normal. The patient was under treatment with hydroxychloroquine 200 mg daily and 5 mg prednisolone, alternating every other day with 10 mg.\n\nA comprehensive history revealed the removal of bowenoid papulosis by electrocautery from the anogenital and vaginal region 17 years ago. The patient also suffered from perianal condylomata acuminata, removed in 2001 and 2010. Virus typing resulted in the isolation of HPV-6 DNA. Furthermore, 20 years ago, she underwent a total hysterectomy because of a cervical in situ carcinoma.\n\nSwab tests from the right finger D4 were positive for Enterococcus faecalis, ciprofloxacin sensitive as well as positive for Candida parapsilosis. The infection was treated with ciprofloxacin 250 mg twice daily for 10 days and the mycosis with ciclopirox cream twice daily for 3 weeks. An X-ray of the same digit revealed no destruction of the bony tissue and no signs of osteomyelitis.\n\nA punch biopsy from the left finger D2 revealed a widened epithelium with impaired strata formation. Polymorphic cells and nuclei were observed, together with numerous and atypical mitoses (fig. 2a). Immunohistochemistry against the proliferation marker Ki-67 resulted in positive staining of about 60% of the epidermis. No invasion of the proliferating keratinocytes through the basal membrane was reported. These findings were compatible with the diagnosis of a squamous cell carcinoma in situ, or Bowen's disease. Two biopsies from the fingers D2 and D4 of the right hand were subsequently performed with identical histological patterns.\n\nAfter confirmation of the diagnosis, two cycles of photodynamic therapy after previous application of methyl-5-amino-4-oxopentanoate cream were performed without significant improvement in the lesions. Three months after treatment, multiple erosions and ulcerations of the 4th finger of the right hand were present (fig. 2c, d). New biopsies once more confirmed Bowen's disease, whereas clumping cells, koilocytes, focal hypergranulosis, and irregular keratohyalin granules with focal condensation were compatible with a virus infection (fig. 2b). DNA was isolated from the paraffin blocks of the lesional biopsies (QIAamp DNA FFPE Tissue Kit; QIAGEN GmbH, Hilden, Germany). HPV typing was performed through a sensitive line probe assay (INNO-LiPA HPV Genotyping Extra; Innogenetics, Gent, Belgium), using the principle of reverse hybridization. Through detection of specific sequences of the L1 region of the HPV genome, 28 HPV subtypes and, specifically, 15 high-risk subtypes can be identified. In our case, DNA from the high-risk HPV-33 was detected.\n\nAfter confirmation of the HPV infection as a cause for the in situ squamous cell carcinomas, imiquimod 5% was initiated. The therapy led to partial remission of the lesions but had to be stopped because of the intense local reaction on the finger D4 of the right hand. Ingenol mebutate gel 500 µg/g was used off-label for the lesions over 2 days. The therapy led to further remission of the lesions, after their assessment 1 month after therapy.\n\nAfter 3 months, the patient was treated with CO2 laser ablation and curettage in intubation anesthesia at an external department. She received cefuroxim 500 mg twice daily for 10 days, metamizole drops for postinterventional analgesia, and local therapy, initially with povidone iodine gauzes, disinfection with a polyhexanide-containing solution (Sanalind®), and subsequently with polyhexanide in cetearyl alcohol and petrolatum-coated non-adherent gauzes (Adaptic®). The fibrinous layers which remained were efficiently removed with Debrisoft®. Follow-up biopsies 2 months after treatment showed no tumor residues (fig. 2e, f).\n\nDiscussion\nThis is, to the best of our knowledge, the first case reporting multiple HPV-induced in situ squamous cell carcinomas in an SLE patient at this location. HPV-33 is a high-risk subtype for cervical dysplasia. HPV-11 DNA was isolated from a patient with multiple squamous cell carcinomas and nonscarring cutaneous LE [5], while a squamous cell carcinoma was reported in an SLE patient with discoid LE [6]. Most of the clinical studies, prospective and retrospective, were conducted to provide evidence for a correlation between SLE and HPV-induced cervical dysplasia or cancer. Furthermore, HPV-related anal carcinomas were documented for SLE patients under treatment with cyclophosphamide [7].\n\nA recent Danish study of 576 SLE patients investigated the risk of virus-associated malignancies for this patient cohort. Interestingly, as far as HPV-associated malignant and premalignant conditions are concerned, SLE patients were found to have an increased risk of anal cancer, cervix dysplasia/in situ carcinoma, and melanoma skin cancer (standardized incidence ratio 2.0, 95% confidence interval 1.2–3.6) [8].\n\nThe pathophysiology of this susceptibility is not yet elucidated. Healthy immune response to HPV includes the production of specific antibodies and a cell-mediated response after Th1-lymphocyte activation [9]. Patients with SLE are known to have impairments of both cellular and innate immunity, which lead to difficulty in clearing high-risk HPV. Possible mechanisms also include complement deficiency, IgG subclass deficiency, and cytokine receptor polymorphisms [3]. A recent study showed an impairment of Toll-like receptor (TLR) regulation in SLE patients compared to controls with HPV infection. Those patients had significantly lower levels of TLR3 and TLR7 in comparison to controls. HPV-infected SLE patients had lower levels of TLR7 and TLR9, thus facilitating viral persistence [10].\n\nImmunosuppressive agents are involved in the persistence of HPV infection by inhibition of innate immune responses, which are involved in containing the virus [2]. Studies, which have demonstrated a significant correlation between cervical dysplasia in SLE patients who had previously received azathioprine, cyclophosphamide (positive association with duration and cumulative dose), and mycophenolate mofetil, are reported in the literature [9, 11]. Mycophenolate mofetil was shown to reduce the number of B cells and natural killer cells in SLE patients, thus enhancing the risk of an HPV infection [9]. Interestingly, the use of immunosuppressive drugs was not always associated with a higher prevalence of HPV infection, probably because of an inadequate number of cases analyzed or controls [2, 3, 12, 13]. In the study of Klumb et al. [2], SLE patients with mild or no immunosuppressant use were more often diagnosed with an HPV infection, although the difference was not statistically significant. Chronic use of prednisolone and the TLR antagonist hydroxychloroquine, which were also used for the treatment of the patient presented, can decrease TLR7 and TLR9 at the protein level, providing the rationale for a further decrease in the immune response against such a viral infection [10].\n\nConclusion\nSince up to 80% of the female population is predicted to encounter an HPV infection in the first 50 years of their life, early routine vaccination of high-risk patients (routinely before the 11th–12th year of age), such as SLE patients, is of great importance. Both the bivalent and quadrivalent vaccines are composed of noninfectious virus-like particles, which induce an effective T-cell-dependent B-cell response, thus producing high levels of L1-specific neutralizing antibodies and T-cell memory [2]. Recently, a 9-equivalent vaccine was introduced to the market and is recommended for females aged 13–26 years and males aged 13–21 years not previously vaccinated [14]. At the other end of the spectrum, manifestations of SLE or SLE-like symptoms, particularly for patients with a personal or family history of SLE, after vaccination against the HPV virus have recently been reported [15]. Despite this, HPV vaccination of SLE patients might be the most plausible and cost-effective approach to sufficiently control this infection and the consequent development of HPV-induced malignancies.\n\nStatement of Ethics\nAll photos presented in this case report were taken after the patient's informed consent. All photos were taken in the outpatient clinic of the Departments of Dermatology, Venereology, Allergology and Immunology of Dessau Medical Center, Dessau, Germany.\n\nDisclosure Statement\nThe authors have no conflicts of interest to declare.\n\nFig. 1 Skin manifestations on fingers D1 (d), D2 (b) and D4 (c) of the right hand and the second finger (D2) of the left hand (a) during the first presentation of the patient to our Departments.\n\nFig. 2 a Histological examination of the lesions revealed impaired stratification, cell and nucleus polymorphy and atypical mitoses. b Koilocytes and irregular keratohyalin granules, suggesting HPV infection. c, d 3 months after therapy, multiple erosions and ulcerations of D4 of the right hand were still present. e, f Clinical result 8 months after last treatment of the lesions with CO2 laser ablation\n==== Refs\nReferences\n1 Bosch FX Lorincz A Muñoz N Meijer CJLM Shah KV The causal relation between human papillomavirus and cervical cancer J Clin Pathol 2002 55 244 265 11919208 \n2 Klumb E Pinto A Jesus G Araujo M Jascone L Gayer C Ribeiro F Albuquerque E Macedo J Are women with lupus at higher risk of HPV infection? Lupus 2010 19 1485 1491 20605875 \n3 Tam LS Chan AY Chan PK Chang AR Li EK Increased prevalence of squamous intraepithelial lesions in systemic lupus erythematosus: association with human papillomavirus infection Arthritis Rheum 2004 50 3619 3625 15529372 \n4 Blumenfeld Z Lorber M Yoffe N Scharf Y Systemic lupus erythematosus: predisposition for uterine cervical dysplasia Lupus 1994 3 59 61 8025589 \n5 Cohen LM Tyring SK Rády P Callen JP Human papillomavirus type 11 in multiple squamous cell carcinomas in a patient with subacute cutaneous lupus erythematosus J Am Acad Dermatol 1992 26 840 845 1319432 \n6 Simpson JK Medina-Flores R Deng JS Squamous cell carcinoma arising in discoid lupus erythematosus lesions of the ears infected with human papillomavirus Cutis 2010 86 195 198 21140928 \n7 Lydon E Belmont H When rectal bleeding is serious: anal squamous cell carcinoma in two intravenous cyclophosphamide treated systemic lupus erythematosus patients with human papilloma virus infection Lupus 2013 22 1182 1184 23893826 \n8 Dreyer L Faurschou M Mogensen M Jacobsen S High incidence of potentially virus-induced malignancies in systemic lupus erythematosus: a long-term follow-up study in a Danish cohort Arthritis Rheum 2011 63 3032 3037 21953088 \n9 Abud-Mendoza C Cuevas-Orta E Santillan-Guerrero EN Martinez-Martinez MU Hernandez-Castro B Estrada-Capetillo L Gonzalez-Amaro R Baranda L Decreased blood levels of B lymphocytes and NK cells in patients with systemic lupus erythematosus (SLE) infected with papillomavirus (HPV) Arch Dermatol Res 2013 305 117 123 22752509 \n10 Yu SL Chan PK Wong CK Szeto CC Ho SC So K Yu MM Yim SF Cheung TH Wong MC Cheung JL Yeung AC Li EK Tam LS Antagonist-mediated down-regulation of Toll-like receptors increases the prevalence of human papillomavirus infection in systemic lupus erythematosus Arthritis Res Ther 2012 14 R80 22513098 \n11 Tam LS Chan PK Ho SC Yu MY Yim SF Cheung TH Wong MC Cheung JL Li EK Risk factors for squamous intraepithelial lesions in systemic lupus erythematosus: a prospective cohort study Arthritis Care Res (Hoboken) 2011 63 269 276 20890985 \n12 Berthier S Mougin C Vercherin P Desmurs H Gil H de Wazieres B Dupond JL Does a particular risk associated with papillomavirus infections exist in women with lupus? Rev Med Interne 1999 20 128 132 10227090 \n13 Nath R Mant C Luxton J Hughes G Raju KS Shepherd P Cason J High risk of human papillomavirus type 16 infections and of development of cervical squamous intraepithelial lesions in systemic lupus erythematosus patients Arthritis Rheum 2007 57 619 625 17471531 \n14 Petrosky E Bocchini JA Jr Hariri S Chesson H Curtis CR Saraiya M Unger ER Markowitz LE Use of 9-valent human papillomavirus (HPV) vaccine: updated HPV vaccination recommendations of the advisory committee on immunization practices MMWR Morb Mortal Wkly Rep 2015 64 300 304 25811679 \n15 Gatto M Agmon-Levin N Soriano A Manna R Maoz-Segal R Kivity S Doria A Shoenfeld Y Human papillomavirus vaccine and systemic lupus erythematosus Clin Rheumatol 2013 32 1301 1307 23624585\n\n",
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"title": "Multiple HPV-Induced Squamous Cell Carcinomas on the Fingers of a Patient with Systemic Lupus Erythematosus: A Case and Review.",
"title_normalized": "multiple hpv induced squamous cell carcinomas on the fingers of a patient with systemic lupus erythematosus a case and review"
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"affiliations": "Senior Consultant Neurology, Institute of Neurosciences, Indraprastha Apollo Hospitals Delhi, India.;DNB Neurology Resident Institute of Neurosciences, Indraprastha Apollo Hospitals Delhi, India.;DNB Neurology Resident Institute of Neurosciences, Indraprastha Apollo Hospitals Delhi, India.;Consultant Neurocritical Care, Indraprastha Apollo Hospitals Delhi, India.",
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"abstract": "Combination therapy, consisting of immune checkpoint inhibitors and traditional chemotherapeutic agents, has significantly improved the clinical outcomes of non-small cell lung cancer. Therefore, it will be a promising first-line therapy, whereas, there is a prospect that associated kidney injury may increase during treatment. We presented four patients, diagnosed with advanced non-small cell lung cancer, who received combination therapy, consisting of pembrolizumab, cisplatin, and pemetrexed as first-line treatment. All of them had been referred to nephrologists and had undergone renal biopsy. We observed that three of four patients presented a very rapid time course for acute kidney injury development. Notably, the three patients received only one or two cycles of the combined chemotherapy. In a renal biopsy, one patient showed severe acute tubular injury rather than interstitial nephritis. Another patient presented focal segmental glomerular sclerosis concomitant with tubulointerstitial nephritis. However, it was challenging to distinguish which agent was primarily responsible for kidney injury. Regarding the treatment, all the patients discontinued pembrolizumab and received corticosteroid treatment. We adjusted the dose and duration of corticosteroid according to the pathological results and patient conditions. The current cases provide a further understanding of clinical features and appropriate management in patients treated with combination therapy including pembrolizumab.",
"affiliations": "Department of Nephrology, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan. sae-aratani@nms.ac.jp.;Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Address: 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan.;Department of Analytic Human Pathology, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan.;Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Address: 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan.;Department of Nephrology, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan.;Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Address: 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan.;Department of Nephrology, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan.",
"authors": "Aratani|Sae|S|http://orcid.org/0000-0002-5581-2618;Sugano|Teppei|T|;Shimizu|Akira|A|;Seike|Masahiro|M|;Kashiwagi|Tetsuya|T|;Gemma|Akihiko|A|;Sakai|Yukinao|Y|",
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"doi": "10.1002/ccr3.2495",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.2495CCR32495Case ReportCase ReportsvWFpp/ADAMTS13 ratio is a useful marker of postliver transplantation thrombotic microangiopathy: A pediatric case report DUQUENNE et al.Duquenne Lisa https://orcid.org/0000-0002-0425-5719\n1\nlisa.duquenne@student.uclouvain.be Balbeur Samuel \n1\nEverard Emilie \n1\nReding Raymond \n2\nEeckhoudt Stéphane \n3\nBrichard Bénédicte \n4\nGodefroid Nathalie \n5\nDerycke Emilien \n6\nKomuta Mina \n7\nScheers Isabelle \n1\nSmets Françoise \n1\nSokal Etienne \n1\nStéphenne Xavier \n1\n\n1 \nDivision of Paediatric Gastroenterology and Hepatology\nDepartment of Paediatrics\nCliniques Universitaires Saint Luc\nUniversité Catholique de Louvain\nBrussels\nBelgium\n\n2 \nDivision of Paediatric Surgery\nDepartment of Surgery\nCliniques Universitaires Saint Luc\nUniversité Catholique de Louvain\nBrussels\nBelgium\n\n3 \nLaboratory of Haematology\nCliniques Universitaires Saint Luc\nUniversité Catholique de Louvain\nBrussels\nBelgium\n\n4 \nDivision of Paediatric Haematology\nDepartment of Paediatrics\nCliniques Universitaires Saint Luc\nUniversité Catholique de Louvain\nBrussels\nBelgium\n\n5 \nDivision of Paediatric Nephrology\nDepartment of Paediatrics\nCliniques Universitaires Saint Luc\nUniversité Catholique de Louvain\nBrussels\nBelgium\n\n6 \nDivision of Emergency and Intensive Care\nDepartment of Paediatrics\nCliniques Universitaires Saint Luc\nUniversité Catholique de Louvain\nBrussels\nBelgium\n\n7 \nDepartment of Anatomopathology\nCliniques Universitaires Saint Luc\nUniversité Catholique de Louvain\nBrussels\nBelgium\n* Correspondence\n\nLisa Duquenne, Department of Paediatrics, Division of Paediatric Gastroenterology and Hepatology, Cliniques Universitaires Saint‐Luc, Brussels 1200, Belgium.\n\nEmail: lisa.duquenne@student.uclouvain.be\n10 12 2019 1 2020 8 1 10.1002/ccr3.v8.141 46 03 8 2019 17 9 2019 20 9 2019 © 2019 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.Abstract\nvWFpp/ADAMTS13 ratio should be further studied as a useful marker for diagnosis of thrombotic microangiopathy postliver transplantation. Immunosuppressive regimen modification and plasma supplementation can lead to recovery.\n\nvWFpp/ADAMTS13 ratio should be further studied as a useful marker for diagnosis of thrombotic microangiopathy postliver transplantation. Immunosuppressive regimen modification and plasma supplementation can lead to recovery.\n\n\npediatric liver transplantationsirolimustacrolimusthrombotic microangiopathyvWFpp/ADAMTS13 ratio source-schema-version-number2.0cover-dateJanuary 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.7.5 mode:remove_FC converted:25.01.2020\n\n\nDuquenne \nL \n, \nBalbeur \nS \n, \nEverard \nE \n, et al. vWFpp/ADAMTS13 ratio is a useful marker of postliver transplantation thrombotic microangiopathy: A pediatric case report . Clin Case Rep . 2020 ;8 :41 –46 . 10.1002/ccr3.2495\n==== Body\n1 INTRODUCTION\nThrombotic microangiopathy (TMA) is a rare and life‐threatening complication following liver transplantation in children. Recent studies suggest that an elevated vWFpp/ADAMTS13 ratio could be a useful marker for diagnosis of thrombotic microangiopathy. This pediatric case report supports this hypothesis, and we propose, as treatment, immunosuppressive regimen modification and plasma supplementation.\n\n\nThrombotic microangiopathy is a microvascular occlusive disorder characterized by systemic or intrarenal aggregation of platelets leading to thrombocytopenia, mechanical destruction of red blood cells, and ischemic injury to the affected organs. This term includes a spectrum of diseases, all defined by the same histopathological finding: arteriolar and capillary thrombosis with specific abnormalities in the endothelium and vessel wall1, 2 Clinical presentation can be extremely variable. Diagnosis is generally based purely on biochemical findings in the presence of thrombocytopenia and nonimmune microangiopathic hemolytic anemia with schistocytes and negative direct Coombs test2\n\n\nThrombotic microangiopathy is a well‐recognized complication after renal and allogeneic hematopoietic stem cell transplantations. It is also increasingly reported following liver transplantation in adults.2, 3 Though endothelial damage seems a key event in all forms of TMA, so far, the exact pathophysiology of the disease is not completely understood and probably involves multiple mechanisms.2, 3, 4, 5 Early detection and aggressive treatment are vital to reduce significant morbidity and mortality associated with this disease. However, immediate accurate diagnosis is often difficult because of lack of rapid diagnosis test and so far, there is no standardized treatment protocol.2, 3, 4, 5\n\n\nRecent studies suggest that a relative defect in ADAMTS13, a disintegrin and metalloprotease with thrombospondin type 1 domains, could contribute to the pathogenesis.2, 6, 7 We report a pediatric case of TMA following liver transplantation with increased von Willebrand factor pro‐peptide (vWFpp)/ADAMTS13 ratio at diagnosis, successfully treated with immunosuppressive regimen modification and plasma supplementation.\n\n2 CASE PRESENTATION\nThe patient underwent an ABO‐compatible living‐related liver transplantation for genetically proven progressive familial intrahepatic cholestasis type 1 after failure of biliary diversion. She presented liver cirrhosis complicated by portal hypertension, failure to thrive, stunting and disabling pruritus. Post‐transplant immunosuppressive regimen consisted in steroid‐free induction with basiliximab (SimulectR, Novartis, Ixelles), and then tacrolimus (PrograftR, Astellas, Anderlecht) monotherapy, a calcineurin inhibitor (CNI). Tacrolimus blood levels were closely monitored, and drug doses were adjusted.\n\nFive days after surgery, she developed acute cellular rejection with histologic confirmation. An echography was performed, showing no vascular trouble with permeable portal vein, sus‐hepatic veins, and hepatic artery. She was treated with intravenous methylprednisolone (MedrolR, Pfizer) (5 mg/kg/d for three days, then gradually tapered). Seven days postliving donor liver transplantation (LDLT), we observed normalization of transaminases. (Figure 1).\n\nFigure 1 Trends in laboratory date in our patient. The patient had to stay in the pediatric intensive cares for 2 mo after TMA diagnosis. She faced lots of complications which explain the further transfusions and modification of renal function delayed from acute TMA, and not representing TMA relapse. We voluntary chose to not talk about those events in the presentation of this case report to avoid overload information\n\nNine days post‐transplant, colic perforation complicated by peritonitis was diagnosed. Surgical exploration revealed suture line dehiscence at the level of transverse colon. Segmental colonic resection trough laparotomy was performed, and adequate intravenous antibiotic therapy was administered.\n\nAt day 12 post‐transplantation, she developed acute respiratory distress syndrome linked to pleural effusion and diaphragmatic dyskinesia, requiring oxygen therapy and pleural drainage.\n\nFifteen days post‐transplant, blood tests revealed another increase in hepatic enzymes. As rejection was suspected, a new liver biopsy was performed, presenting a well‐delineated coagulation necrosis associated with canalicular damages and severe bilirubinostasis. She was treated with intravenous methylprednisolone bolus (10 mg/kg for 3 days and gradual tapering).\n\nDespite normalization of hepatic function, the patient showed unexplained progressive deterioration of general condition, increased respiratory distress and increased transfusion requirements (transfusions of platelets and red blood cells), requiring a transfer to pediatric intensive cares.\n\nTwenty‐one days post‐transplant, blood analysis revealed schistocytes at 11.5% with negative direct Coombs test. At this time, the patient also had low hemoglobin (6.4 g/dL) and platelet count (20 000/mm4), increased LDH (585 U/L), low haptoglobin (<0.1 g/dL), and elevated urea (87 mg/dL). ADAMTS13 levels were decreased at 11%, and WFpp/ADAMTS13 ratio was increased (48) (Table 1). Chest radiography showed signs of acute respiratory distress syndrome.\n\nTable 1 Post‐transplant evolution of ADAMTS‐13 and von Willebrand factor pro‐peptide (vWfpp)\n\n \tvWFpp (%)a\n\tADAMTS‐13 (%)a\n\tvWFpp/ADAMTS‐13b\n\t\nNormal value\t55‐229\t>40%\t3.66‐14.5\t\n21 days post‐transplant\t528 ↑\t11 ↓\t48 ↑↑\t\n24 days post‐transplant\t291 ↑\t27 ↓\t10.7\t\n27 days post‐transplant\t562 ↑\t59\t9.52\t\n43 days post‐transplant\t733 ↑\t43\t17 ↑\t\n66 days post‐transplant\t419 ↑\t22 ↓\t19 ↑\t\nNote\n↑, Values above normal range; ↓, Values below normal range.\n\na Normal values of Cliniques Universistaires Saint Luc's laboratory.\n\nb Normal values after living donor liver transplantation extrapolated from the article of Takahashi N et al, 2013.7\n\n\nJohn Wiley & Sons, LtdFinally, thrombotic microangiopathy was diagnosed, with acute respiratory distress syndrome as complication.\n\nPotential intercurrent bacterial, fungal, and viral infections were excluded. Unfortunately, no genetic test was performed to exclude other causes of primary TMAs.\n\nWe decided to change immunosuppression, and we switched to sirolimus (RapamuneR, Pfizer, Brussels) and mycophenolate mofetil (CellceptR, Roche, Brussels) associated with methylprednisolone (5 mg/kg/dose). The patient also received fresh frozen plasma (FFP) once a day because of low ADAMTS13 blood levels, and multiple transfusions of platelets and packed red blood cells. We did not opt for therapeutic plasma exchange (as indicated in thrombotic thrombocytopenic purpura) because no autoantibodies against ADAMTS13 were detected in repeated laboratory tests.\n\nLater on, blood parameters improved gradually and 10 days after treatment initiation, the frequency of FFP infusions was reduced and corticosteroid treatment was tapered. FFP administration was stopped 18 days after its initiation.\n\nEight weeks post‐transplant and 6 weeks after initially stopping tacrolimus, we observed normalized ADAMTS13 levels. Because of repeated pneumothorax and the potential impact of sirolimus on pleural scarring and because of persistent signs of cellular rejection on biopsies, we chose to restart tacrolimus and to stop sirolimus, while pursuing mycophenolate mofetil.\n\nFinally, 19 weeks post‐transplant, the child's renal and hepatic functions had fully recovered. She was in good general condition and was discharged from hospital.\n\n3 DISCUSSION\nThe case we presented supports the recent hypothesis that an increased vWFpp/ADAMTS13 ratio could be an early marker of postliver transplantation TMA (p‐LT TMA) in addition to the existing diagnostic criteria for TMA. Plasma supplementation and switch of immunosuppression (switch from CNIs‐based immunosuppressive regimen to sirolimus and mycophenolate mofetil) were proposed and were successful in this patient.\n\nTMA is a rare, life‐threatening, and not fully understood complication after liver transplantation that needs prompt treatment.8, 9, 10, 11 However, the immediate accurate diagnosis of p‐LT TMA can be extremely difficult for multiples reasons: There is no current widely available rapid diagnostic test in suspected cases, patients can develop only minimal hematologic disorder or organ involvement, and differential diagnosis is required to distinguish p‐LT TMA from liver graft failure and disseminated intravascular coagulation.3, 12\n\n\nIt was the first case of TMA following living donor liver transplantation observed in the institution of Saint Luc in our cohort of more than 1000 operated children. This diagnosis was difficult because of its rareness, and the complexity of the multiple concomitant disorders encountered in this patient.\n\nThere are several distinct pathophysiologic mechanisms leading to TMA: ADAMTS13 deficiency‐mediated TMA, also called thrombotic thrombocytopenic purpura, defined by activity of ADAMTS13 below 5 to 10% (according to the authors) that can be congenital or due to the presence of an inhibitor or autoantibody (and so defined as acquired); Shiga toxins or Streptococcus pneumoniae‐related hemolytic‐uremic syndrome; alternative complement pathway dysregulation‐mediated TMA; drug‐mediated TMA; etc1, 13, 14 It is important to distinguish the etiologies in order to initiate appropriate treatment.1, 13\n\n\nUnderlying mechanisms of TMA remain largely unexplored. In the field of p‐LT TMA, different risk factors have been linked: ischemia‐reperfusion injury, immunosuppressive medications particularly CNIs (cyclosporine A and tacrolimus), interfering disease and relative ADAMTS13 deficiency.2\n\n\nCalcineurin inhibitors administration as a risk factor is not a new concept5, 15, 16 but has recently been discussed.17 Their disease triggering effects have been linked to their ability to cause endothelial dysfunction resulting in vasoconstriction and increased platelet aggregation, possibly through the inhibition of prostacyclin.2, 5 However, CNIs are extensively used in transplanted patients and only a limited number of them will develop TMA, which can suggest the presence of another underlying factor.17 Likewise, CNIs withdrawal does not always guarantee a recovery.2, 17 mTOR inhibitors (as sirolimus) have also been reported to be implicated in the pathogenesis of TMA, probably due to their antiangiogenic properties.2 However, they are also used as rescue medication in cases of CNI‐induced TMA.8, 16, 17\n\n\nRecent studies suggest that a relative defect in ADAMTS13 could contribute to the pathogenesis, more precisely an imbalance between ADAMTS13 and unusually large vWF multimers (UL‐vWFM).2, 6, 7 vWFpp is synthesized in endothelial cells and cleaved to form vWF. During endothelial damage, vWF is released into plasma as UL‐vWFM, the highly active form of vWF, which is essential for platelet aggregation at sites with a high degree of shear stress.6, 18 ADAMTS13 is a disintegrin and metalloprotease, which splits von Willebrand factor (vWF) multimers into small and inactive fragments, limiting platelet thrombus formation under normal conditions. Therefore, when ADAMTS13 activity is reduced, blood levels of UL‐vWFM increase and lead to excessive platelet clumping.2, 6, 7, 18, 19\n\n\nADAMTS13 deficiency seems to play a special role in TMA occurring after transplantation of the liver more than other solid organs.2, 20 Indeed, ADAMTS13 is synthesized in the liver. Consequently, graft dysfunction could lead to decrease its level which could lead to the fact that TMA tends to occur earlier after transplantation of the liver than other solid organs.2 Furthermore, we know that patients with cirrhosis have complex alterations in the hemostatic system. In particular, they have abnormally high plasma levels of vWF and low ADAMTS13 activity to compensate thrombocytopenia and thrombocytopathia21\n\n\nTakahashi et al found that vWFpp/vWF ratio and vWFpp/ADAMTS13 ratio were significantly higher in the weeks following LDLT compared with pretransplant values and to healthy patients.7 They also highlighted that the vWFpp/vWF ratio was significantly higher in those who developed TMA, and the vWFpp/ADAMTS13 ratio significantly higher in nonsurvivors compared with survivors. These results suggest that a prothrombotic state exists in the recipients, and that pLT‐TMA would occur when the production of ADAMTS13 cannot meet the demand to cleave the oversynthesized UL‐vWFM released by the injured endothelium.2, 6, 7 Thus, recent studies suggest that a highly elevated vWFpp/ADAMTS13 ratio is a more useful marker, reflecting the prothrombotic state after LDLT, for the diagnosis of TMA and for poor outcome prediction compared with the independent values of ADAMTS13, vWF, and vWFpp7, 11, 19However, it should be noted that other studies showed some patients with p‐LT TMA had normal ADAMTS13 absolute values.2 Banno et al also proved with ADAMTS13‐deficient mice that complete deficiency in ADAMTS13 is not sufficient to cause a TMA. These authors suggest that other triggers, such as genetic defects or environmental factors (oxidative stress, complement dysfunction, and infection), are needed to provoke the disease.22 The frequent occurrence of p‐LT TMA concomitantly with other acute events such as infection or acute rejection (as in the situation of our patient) also supports this hypothesis.2, 4\n\n\nIn the case of our patient, ADAMTS 13’s value was superior to 10% and no antibodies were detected, excluding acquired thrombotic thrombocytopenic purpura. We found an increased vWFpp/ADAMTS‐13 ratio at the diagnosis, supporting its recent interest as a marker to identify TMA.\n\nThere is currently no available standard protocol for the treatment of post‐transplant TMA, probably because etiologies are multiple and clinical presentation is variable and heterogeneous. The treatment choice is controversial and can include supportive care, for example, transfusion of packed red blood cells and folic acid supplementation, replenishment of coagulation factors to substitute the deficient ADAMTS13 with plasma infusion/exchange and conversion or discontinuation of CNIs.2, 4\n\n\nAlthough CNIs administration as main risk factor is recently discussed, the majority of authors agreed on modification of offending medication (CNIs discontinuation, dose reduction, or conversion) as first line of treatment.2, 4, 17 If possible, the CNI should be substituted by an immunosuppressive agent not linked with TMA, such as mycophenolate mofetil.2 However, clinicians must also consider the fact that CNIs modification may increase the risk of acute rejection.2\n\n\nIn this case, the switch for mycophenolate mofetil and sirolimus successfully addressed pLT‐TMA. However, because of secondary effects of sirolimus and persistent signs of cellular rejection, tacrolimus was reintroduced after TMA resolution. As the risk of developing TMA concerns especially the days following liver transplantation,2, 20 resuming tacrolimus was the option presenting the lowest risk. No signs of TMA relapse were observed.\n\nA new medication is also studied in this indication: eculizumab, an anti‐C5 agent, that has already proven its efficacy as treatment and prevention of recurrent alternative complement pathway dysregulation‐mediated TMA. Its efficacy has already been documented in several cases of resistant medication‐associated TMA after renal transplantation with no evidence of genetic defects.14, 17 But this medication is currently extremely expensive, and some controversial results can be found in the literature.14, 17 Consequently, this option of treatment has to be further investigated and, in the meantime, has to be reserved to refractory patients.\n\nTherapeutic plasma exchange is not indicated in the treatment of pLT‐TMA since no autoantibodies were detected.2, 18 Conversely, as we suppose that the pathogenesis of pLT‐TMA is linked to an imbalance between oversynthesized vWFpp and ADAMTS13 consumption, we consider the benefit of administration of plasma infusion to compensate a lack of ADAMTS13.\n\nIn this case, we finally managed to cure the patient from TMA after switching the immunosuppressive regimen to mycophenolate mofetil and sirolimus, and administering FFP.\n\n4 CONCLUSION\nAfter pediatric liver transplantation, it is necessary to consider the possibility of TMA, with its variable clinical presentations in view of the poor prognosis without early detection and aggressive treatment.2, 4, 5 The pathogenesis leading to the onset of this TMA is certainly multifactorial. Based on our experience and on previous studies, we suggest the vWFpp/ADAMTS13 ratio as an early marker to identify TMA in addition to the existing diagnostic criteria for TMA.\n\nAs a treatment, we propose switching immunosuppressive regimen to a non‐CNI and plasma supplementation to compensate insufficient production of ADAMTS 13.\n\nHowever, further studies including larger cohorts of patients are necessary to confirm these approaches and to determine precise cutoff of vWFpp/ADAMTS13 ratio. Continuing investigations to increase understanding of the underlying physiopathology is essential to improve the prognosis and the care of these patients.\n\nAUTHOR CONTRIBUTION STATEMENTS\nL. Duquenne: wrote the manuscript and validated the final section of the manuscript. X. Stéphenne: drafted initial sections of the manuscript, was in charge of the patient, and validated the final section of the manuscript. S. Balbeur: drafted initial sections of the manuscript and approved final section of the manuscript. E. Everard: drafted initial sections of the manuscript and approved final section of the manuscript. N. Godefroid: offered precious advices to write this manuscript and approved final section of the manuscript. B. Brichard: offered precious advices to write this manuscript and approved final section of the manuscript. É. Derycke: was in charge of the patient in the pediatric intensive care unit and validated the final section of the manuscript. R. Reding: served as a surgeon that operated the patient and validated the final section of the manuscript. S. Eeckhoudt: performed laboratory tests and validated the final section of the manuscript. É. Sokal, F. Smets, and I. Scheers: were in charge of the patient and validated the final section of the manuscript. All authors: provided critical feedback and helped shape the manuscript.\n\nCONFLICT OF INTEREST\nNone.\n\nINFORMED CONSENT STATEMENT\nInformed written consent was obtained from the patient for publication of this report and any accompanying images.\n==== Refs\nREFERENCES\n1 \n\nGeorge \nJN \n, \nNester \nCM \n. Syndromes of thrombotic microangiopathy . New Engl J Med . 2014 ;371 (7 ):654 ‐666 .25119611 \n2 \n\nVerbiest \nA \n, \nPirenne \nJ \n, \nDierickx \nD \n. De novo thrombotic microangiopathy after non‐renal solid organ transplantation . Blood Rev . 2014 ;28 (6 ):269 ‐279 .25266355 \n3 \n\nNishi \nH \n, \nHanafusa \nN \n, \nKondo \nY \n, et al. Clinical outcome of thrombotic microangiopathy after living‐donor liver transplantation treated with plasma exchange therapy . Clin J Am Soc Nephrol . 2006 ;1 (4 ):811 ‐819 .17699291 \n4 \n\nShindoh \nJ \n, \nSugawara \nY \n, \nAkamatsub \nN \n, et al. Thrombotic microangiopathy after living‐donor liver transplantation . Am J Transplant . 2012 ;12 (3 ):728 ‐736 .22070669 \n5 \n\nNwaba \nA \n, \nMacQuillan \nG \n, \nAdams \nLA \n, et al. Tacrolimus‐induced thrombotic microangiopathy in orthotopic liver transplant patients: case series of four patients . Int Med J . 2013 ;43 (3 ):328 ‐333 .\n6 \n\nNakanuma \nS \n, \nMiyashita \nT \n, \nHayashi \nH \n, et al. Von Willebrand Factor deposition and ADAMTS‐13 consumption in allograft tissue of thrombotic microangiopathy‐like disorder after living donor liver transplantation: A case report . Transplantation Proceeding . 2017 ;49 (7 ):1596 ‐1603 .\n7 \n\nTakahashi \nN \n, \nWada \nH \n, \nUsui \nM \n, et al. Behavior of ADAMTS13 and Von Willebrand factor levels in patients after living donor liver transplantation . Thromb Res . 2013 ;131 :225 ‐229 .23266519 \n8 \n\nCzubkowski \nP \n, \nPawłowska \nJ \n, \nJankowska \nI \n, et al. Successful sirolimus rescue in tacrolimus‐induced thrombotic microangiopathy after living‐related liver transplantation . Pediatr Transplant . 2012 ;16 (6 ):E261 ‐E264 .22066835 \n9 \n\nLee \nCH \n, \nChen \nCL \n, \nLin \nCC \n, et al. Plasma exchange therapy for thrombotic thrombocytopenic purpura in pediatric patients with liver transplantation . Transplant Proceed . 2008 ;40 (8 ):2554 ‐2556 .\n10 \n\nTakatsuki \nM \n, \nUemoto \nS \n, \nKurokawa \nT \n, \nKoshiba \nT \n, \nInomata \nY \n, \nTanaka \nK \n. Idiopathic thrombocytopenic purpura after a living‐related liver transplantation . Transplantation . 1999 ;67 :479 ‐481 .10030298 \n11 \n\nHori \nT \n, \nKaido \nT \n, \nOike \nF \n, et al. Thrombotic microangiopathy‐like disorder after living‐donor liver transplantation: A single‐center experience in Japan . World J Gastroenterol . 2011 ;17 (14 ):1848 ‐1857 .21528059 \n12 \n\nPlautz \nWE \n, \nRaval \nJS \n, \nDyer \nMR \n, \nRollins‐Raval \nMA \n, \nZuckerbraun \nBS \n, \nNeal \nMD \n. ADAMTS13: origins, applications, and prospects . 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World J Transplantation . 2018 ;8 (5 ): 122 ‐141 .\n18 \n\nLong \nZX \n. ADAMTS13 and von willebrand factor in thrombotic thrombocytopenic purpura . Ann Rev Med . 2015 ;66 (1 ):211 ‐225 .25587650 \n19 \n\nAkyol \nO \n, \nAkyol \nS \n, \nChen \nCH \n. Update on ADAMTS13 and VWF in cardiac and hematological disorders . Clin Chim Acta . 2016 ;463 :109 ‐118 .27746209 \n20 \n\nKo \nS \n, \nOkano \nE \n, \nKanehiro \nH \n, et al. Plasma ADAMTS13 activity may predict early adverse events in living donor liver transplantation: observations in 3 cases . Liver transplant . 2006 ;12 (5 ):859 ‐869 .\n21 \n\nLisman \nT \n, \nBongers \nTN \n, \nAdelmeijer \nJ \n, et al. Elevated levels of von Willebrand Factor in cirrhosis support platelet adhesion despite reduced functional capacity . Hepatology . 2006 ;44 (1 ):53 ‐31 .16799972 \n22 \n\nBanno \nF \n, \nKokame \nK \n, \nOkuda \nT \n, et al. Complete deficiency in ADAMTS13 is prothrombotic, but it alone is not sufficient to cause thrombotic thrombocytopenic purpura . Blood . 2006 ;107 (8 ):3161 ‐3166 .16368888\n\n",
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"issn_linking": "2050-0904",
"issue": "8(1)",
"journal": "Clinical case reports",
"keywords": "pediatric liver transplantation; sirolimus; tacrolimus; thrombotic microangiopathy; vWFpp/ADAMTS13 ratio",
"medline_ta": "Clin Case Rep",
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"pages": "41-46",
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"publication_types": "D002363:Case Reports",
"references": "22070669;23266519;28447417;25266355;22066835;16799972;15147429;23441660;21902819;30211021;16528712;27746209;10030298;25119611;28651806;25587650;17699291;16368888;21528059;10354295;18929799;30208220",
"title": "vWFpp/ADAMTS13 ratio is a useful marker of postliver transplantation thrombotic microangiopathy: A pediatric case report.",
"title_normalized": "vwfpp adamts13 ratio is a useful marker of postliver transplantation thrombotic microangiopathy a pediatric case report"
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"abstract": "As several sedative-hypnotics are distributed illegally and are available domestically through media like the internet, their abuse is becoming a serious social problem. In the present study, four legal cases involving abuse of diazepam, midazolam, and/or zolpidem were proved by hair analysis using a simultaneous quantification method for the determination of diazepam (and its metabolites), lorazepam, midazolam, and zolpidem, which are often illegally abused in Korea, in hair that was developed and validated. Drugs and metabolites in hair were extracted using methanol followed by solid-phase extraction. The extracts were derivatized with N-methyl-N-(trimethylsilyl)trifluoroacetamide (MSTFA) and analyzed using gas chromatography-mass spectrometry in selected ion monitoring mode. The validation parameters of the method, including selectivity, linearity, limits of detection and quantification (LOQ), recovery, intra- and interassay precision and accuracy, and processed sample stability, were satisfactory. Moreover, the developed method was successfully applied to actual cases. In case 1, which involved a pop singer who was detained for suspected drug abuse, the concentrations of diazepam and nordiazepam were 5.7 and 2.0 ng/mg in nonpigmented hair and 6.6 and 1.8 ng/mg in pigmented hair, respectively. In case 2, 0.4 ng/mg zolpidem was detected in hair from a drug abuser who purchased illegally through the internet, and 0.2 ng/mg midazolam was detected in hair from an illegal drug seller in case 3. In case 4, diazepam (lower than the LOQ), nordiazepam (0.7 ng/mg), and zolpidem (0.7 ng/mg) were detected in hair from a medical doctor who abused drugs using forged prescriptions.",
"affiliations": "National Forensic Service, , Yangcheon-gu, Seoul, Republic of Korea.",
"authors": "Lee|Sooyeun|S|;Han|Eunyoung|E|;In|Sanghwan|S|;Choi|Hwakyung|H|;Chung|Heesun|H|;Chung|Kyu Hyuck|KH|",
"chemical_list": "D006993:Hypnotics and Sedatives; D013287:Illicit Drugs; D011725:Pyridines; D000077334:Zolpidem; D008140:Lorazepam; D003975:Diazepam; D008874:Midazolam",
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"doi": "10.1093/anatox/35.5.312",
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"issn_linking": "0146-4760",
"issue": "35(5)",
"journal": "Journal of analytical toxicology",
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"medline_ta": "J Anal Toxicol",
"mesh_terms": "D000328:Adult; D003975:Diazepam; D008401:Gas Chromatography-Mass Spectrometry; D006197:Hair; D006801:Humans; D006993:Hypnotics and Sedatives; D013287:Illicit Drugs; D057230:Limit of Detection; D008140:Lorazepam; D008297:Male; D008874:Midazolam; D008875:Middle Aged; D011725:Pyridines; D015813:Substance Abuse Detection; D055815:Young Adult; D000077334:Zolpidem",
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"title": "Determination of illegally abused sedative-hypnotics in hair samples from drug offenders.",
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"abstract": "Intraventricular masses are a relatively rare condition ranging from asymptomatic to potentially life-threatening situations.\nHerein, we report a case of a 49-year-old woman under investigation for a massive right ventricular (RV) mass who underwent complete investigation for possible differential diagnosis, in the suspect of RV tumour. Multimodality imaging with cardiac computed tomography and magnetic resonance imaging showed the presence of a massive thrombus partially obliterating the right ventricle. Surgical removal of the mass showed a large area of stratified thrombosis with an underlying area of endocardial fibrosis. The patient has been then discharged in good clinical condition and with lifetime oral anticoagulation.\nMassive RV thrombosis is a rare yet potentially fatal condition. Invasive management is preferable and lifetime anticoagulation is required to reduce possible downstream thrombotic complications.",
"affiliations": "Cardiovascular Department, Azienda Sanitaria Universitaria Integrata and University of Trieste, Via Pietro Valdoni 7, 34100 Trieste, Italy.;Department of Radiology, Azienda Sanitaria Universitaria Integrata and University of Trieste, Trieste, Italy.;Department of Pathology, Azienda Sanitaria Universitaria Integrata and University of Trieste, Trieste, Italy.;Cardiovascular Department, Azienda Sanitaria Universitaria Integrata and University of Trieste, Via Pietro Valdoni 7, 34100 Trieste, Italy.",
"authors": "Artico|Jessica|J|https://orcid.org/0000-0001-7112-4607;Belgrano|Manuel|M|https://orcid.org/0000-0002-2054-8984;Bussani|Rossana|R|https://orcid.org/0000-0001-8241-9726;Sinagra|Gianfranco|G|",
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"doi": "10.1093/ehjcr/ytab156",
"fulltext": "\n==== Front\nEur Heart J Case Rep\nEur Heart J Case Rep\nehjcr\nEuropean Heart Journal: Case Reports\n2514-2119\nOxford University Press\n\n10.1093/ehjcr/ytab156\nytab156\nCase Report\nAcademicSubjects/MED00200\nThe curious case of a massive right heart thrombosis: a case report\nhttps://orcid.org/0000-0001-7112-4607\nArtico Jessica 1\nhttps://orcid.org/0000-0002-2054-8984\nBelgrano Manuel 2\nhttps://orcid.org/0000-0001-8241-9726\nBussani Rossana 3\nSinagra Gianfranco 1\n1 Cardiovascular Department, Azienda Sanitaria Universitaria Integrata and University of Trieste, Via Pietro Valdoni 7, 34100 Trieste, Italy\n2 Department of Radiology, Azienda Sanitaria Universitaria Integrata and University of Trieste, Trieste, Italy\n3 Department of Pathology, Azienda Sanitaria Universitaria Integrata and University of Trieste, Trieste, Italy\nDastidar Amardeep Ghosh Handling Editor\nPodlesnikar Tomaz Editor\nDastidar Amardeep Ghosh Editor\nCarazo Carlos Minguito Editor\nRanganathan Deepti Editor\nCorresponding author. Tel: +39 040 399 4698, Email: jessica.artico@hotmail.it\n7 2021\n24 7 2021\n24 7 2021\n5 7 ytab15624 7 2020\n08 10 2020\n29 3 2021\n© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com\n\nAbstract\n\nBackground\n\nIntraventricular masses are a relatively rare condition ranging from asymptomatic to potentially life-threatening situations.\n\nCase summary\n\nHerein, we report a case of a 49-year-old woman under investigation for a massive right ventricular (RV) mass who underwent complete investigation for possible differential diagnosis, in the suspect of RV tumour. Multimodality imaging with cardiac computed tomography and magnetic resonance imaging showed the presence of a massive thrombus partially obliterating the right ventricle. Surgical removal of the mass showed a large area of stratified thrombosis with an underlying area of endocardial fibrosis. The patient has been then discharged in good clinical condition and with lifetime oral anticoagulation.\n\nDiscussion \n\nMassive RV thrombosis is a rare yet potentially fatal condition. Invasive management is preferable and lifetime anticoagulation is required to reduce possible downstream thrombotic complications.\n\nIntraventricular masses\nRight ventricular thrombus\nAnticoagulation\nCardiac tumour\nCase report\n==== Body\nLearning points\n\nIntraventricular masses are rare. Presentation ranges from asymptomatic to potentially life-threatening situations.\n\nPotential differential diagnosis between cardiac tumours, endomyocardial fibrosis, and thrombi are essential.\n\nMultimodality imaging complemented with clinical information and genetic data is crucial for driving effective treatment.\n\nIntroduction\n\nIntraventricular masses are a challenging clinical scenario of either benign or severe origin.1,2 Intraventricular masses may be due to several aetiologies: from potentially benign conditions, such as thrombi or benign neoplasm, to malignant neoplasm, metastatic tumours, or endomyocardial fibrosis (EMF). These aetiologies carry different prognostic burden.1,2\n\nThe diagnostic pathway and management rely on clinical aspects and multimodality imaging for a proper diagnosis. Here, we report a case of a right ventricular (RV) mass in a patient with an important thrombophilic state.\n\nTimeline\n\nTimeline\tEvent\t\n1 year before\tPulmonary embolism\t\nDay 0\tHospitalization for worsening dyspnoea\t\nDay 1\tEchocardiogram and computed tomography scan\t\nDay 2–5\tTumour markers and positron emission tomography scan\t\nDay 7\tCardiac magnetic resonance imaging showed the presence of a massive thrombus partially obliterating the right ventricle\t\nDay 10\tSurgery with implantation of mechanical tricuspid valve\t\nDay 11–17\tRehabilitation\t\nDay 18\tDischarge\t\n\nCase presentation\n\nA 49-year-old woman was admitted to the emergency room because of worsening dyspnoea. Past medical history revealed hypertension, diabetes, severe obesity (body mass index 39.7 kg/m2), and asthma. She had no history of miscarriages or pre-eclampsia. Approximately 1 year earlier, the patient was treated with warfarin for 6 months for an episode of pulmonary embolism and worsening heart failure, with a normal echocardiogram and no RV thrombus. She has a significant family history for thromboembolism: a cousin, carrier of MethyleneTetraHydroFolate Reductase (MTHFR) heterozygous mutation 677 C>T and prothrombin heterozygous mutation 20210 G>A, suffered a pulmonary embolism and has an inferior vena cava filter. A detailed pedigree is shown in Figure 1. Her 7-year-old daughter and her sister, both with no history of thromboembolic disease, are carriers of the same mutation.\n\nFigure 1 Patient’s family pedigree.\n\nAt admission, the patient was severely symptomatic for exertional dyspnoea. Physical examination showed no signs of overt RV failure and muffled heart sounds. Her blood tests revealed normal full blood count, blood group 0+, and elevated BNP (1543 pg/mL, normal values <100 pg/mL), and the electrocardiogram showed signs of RV overload (tall R wave in V1 and V2). The patient was haemodynamically stable; her blood pressure was 100/60 mmHg, and her heart rate 89 b.p.m.\n\nThe echocardiogram showed normal left ventricular size and function, dilated right atrium (End Systolic Area (ESA): 40 cm2), enlarged right ventricle with qualitatively reduced function, and an intraventricular mass partially obliterating the ventricular cavity, normal pulmonary valve function, and estimated systolic pulmonary arterial pressure of 26 mmHg. At first, to rule out the hypothesis of cardiac neoplasm, the patient underwent a computed tomography (CT) scan, which revealed large hypodense mass with no enhancement compatible with a massive thrombus involving the right ventricle, the right atrium, and the superior vena cava (Figure 2), though with no evidence of pulmonary embolism and no mediastinal lymphadenopathy. Neoplastic markers were negative besides elevated Ca 125 (113.3 U/mL—normal values 0–35 U/mL). Positron emission tomography (PET) did not detect any lesion with increased metabolism. Thus, the initial suspicion of neoplasm was excluded.\n\nFigure 2 Three-dimensional computed tomography reconstruction of the right ventricular outflow tract partially obliterated by the massive thrombosis originating from the right atrium (A). Different reconstruction highlights the subvalvular stenosis of the right ventricular outflow tract with an area of 0.95 cm2 without the pulmonary artery’s involvement (B).\n\nLower limbs and abdomen ultrasounds showed no deep vein thrombosis and normal cave-portal system. However, at that stage, the diagnosis of EMF could not have been excluded.\n\nThe cardiac magnetic resonance imaging (MRI) showed normal left ventricle and confirmed the presence of a large hypointense mass in T1 with no gadolinium enhancement compatible with a massive thrombus partially obliterating the right heart and involving the RV apex on top of possible endocardial fibrosis (Figures 3 and 4 and Video 1) suggesting underlying obliterative cardiomyopathy or spontaneous massive thrombosis of the right ventricle. The RV function was qualitatively reduced as well.\n\nFigure 3 T1-weighted image early after gadolinium administration in four-chamber view shows hypointense masses occupying the right ventricular apex and the right atrium’s posterior aspect. The insert shows the T1-weighted image 10 min after gadolinium administration in right ventricular three-chamber view. The hypointensity of the core of the mass persists, whereas there is late gadolinium enhancement along the endocardial border.\n\nFigure 4 Four-chamber view showing that the right ventricle is partially obliterated.\n\nDue to ineffective treatment with heparin and anticoagulants for 10 days, the patient required surgical debulking of the right cavities and a mechanical tricuspid valve replacement (ON-X 27–33). Histology revealed a large area of stratified thrombosis, with an underlying area of endocardial fibrosis, caused either by primary fibrosis or direct compression on the ventricular wall by the thrombus, although not meeting the criteria for EMF (Figure 5).\n\nFigure 5 Azan–Mallory staining of the surgical specimen. A large thrombus is tightly attached to the ventricular myocardium, which appears severely permeated by fibrotic tissue branches. Several blood cells (white arrows) are trapped within the thrombus. The black arrows show numerous apoptotic/necrotic myocytes with loss of the contractile apparatus.\n\nDespite multimodality imaging raised the suspicion for cardiac thrombus, definite diagnosis have been reached only after histology.\n\nImmediately after surgery, the patient rapidly recovered and progressively normalized the RV systolic function.\n\nA complete thrombophilia screening showed MTHFR heterozygous mutation for polymorphism 677 C>T and 1298 A>C and elevated factor VIII activity (187%—normal values 50–150, confirmed 6 months after the acute phase) in the absence of other thrombophilic mutations (Table 1).\n\nTable 1 Thrombophilic essays and most relevant laboratory findings performed during the index hospitalization\n\nEssay\tValue\tNormal range\t\nHaemoglobin (g/dL)\t14.8\t13–16\t\nPlatelets (×103/mm3)\t318\t200–400\t\nEosinophil (×103/mm3)\t0.02\t0.1–0.4\t\nCreatinin (mg/dL)\t1.3\t0.9–1.1\t\nANA, Extractable nuclear antigen (ENA), anti-DsDNA, anti-mitochondria, Antineutrophil Cytoplasmic Antibodies (ANCA), anti-smooth muscle (anti-SM), Anti-Liver-Kidney Microsomal (anti-LKM), anti-TG, reumathoid factor\tNegative\t\nC3 (mg/dL)\t141\t90–180\t\nC4 (mg/dL)\t40\t10–40\t\nIgM (mg/dL)\t59\t40–230\t\nIgG (mg/dL)\t1071\t700–1600\t\nIgA (mg/dL)\t185\t70–400\t\nIgE (mg/dL)\t55\t0–55\t\nOmocystein (µmol/L)\t11\t<15\t\nLp(a) (mg/dL)\t82\t<30\t\nhsPCR (mg/L)\t10.6\t1–3\t\nProtein C (%)\t89\t70–140\t\nProtein S (%)\t91\t55–124\t\nLAC Dilute Russell's viper venom time (dRVVT) (ratio)\t1.15\t<1.2\t\nLAC SCT (ratio)\t0.87\t<1.2\t\nFactor VIII (%)\t187\t50–150\t\nFactor IX (%)\t98\t65–150\t\nFactor XI (%)\t122\t65–150\t\nFactor XII (%)\t89\t50–150\t\nProthrombin 20210 mutation\tAbsent\t\nFactor V Leiden mutation\tAbsent\t\nMTHFR 677 C > T mutation\tPresent (heterozygous)\t\nMTHFR 1298 A > C mutation\tPresent (heterozygous)\t\nBold values are those above reference range.\n\nThe patient has been discharged from the hospital in good conditions with lifetime oral anticoagulant therapy with warfarin aiming a target INR between 2.5 and 3.5 due to the high thrombophilic profile and the mechanical tricuspid valve replacement.\n\nDiscussion\n\nThough of different origin, intraventricular thrombi and neoplastic lesions may present with downstream thromboembolism (Table 2).6,7 In the case presented above, the clinical and echocardiographic suspicion of intraventricular neoplasm presenting with pulmonary embolism was very high at admittance. However, based on the imaging analysis performed (CT-scan, PET, and MRI), which displayed a massive thrombus with a large fibrotic area underneath, the clinical hypothesis of a massive ventricular thrombosis rose dramatically. However, even after the cardiac MRI, a diagnosis of EMF could not be invariably excluded, requiring histological analysis for a precise diagnosis of a spontaneous massive RV thrombosis.\n\nTable 2 Main differential characteristics for cardiac masses\n\n\tThrombus\tSarcoma\tMyxoma\tRhabdomyoma\tFibroelastoma\tFibroma\tLipoma\t\nAge at presentation\tAdulthood\tYoung adults\tYoung adults\tChildhood\tElderly\tChildhood\tAll ages\t\nMost common location\tApex (RV or LV)\tAny chamber (angiosarcoma originates in the right atrium)\tInteratrial septum\tVentricular walls, AV valves, outflow tract\tValves\tVentricles\tAny chamber + pericardium\t\nNumber\tSingle or multiples\tMultiples\tSolitary\tMultiples\tSolitary\tSolitary\tSingle or multiples\t\nMorphology\tExuberant size, jagged edges\tHeterogeneous with epicardial, endocardial and intracavitary extension\tCauliflower-like, attached to the septum\tPedunculated\tSmall (<1 cm), rare calcifications\tLarge size, calcified\tVery large, broad base\t\nEchocardiogram\tAssociated with regional wall motion abnormalities, useful contrast images\tMultilobate masses with ill-defined margins\tMobile, narrow stalk\tHyperechogenic masses\tSparkling edged mass\tSmall, mobile, pedunculated valvular mass + calcifications\tHypoechogenic mass\t\nCardiac MRI\tAcute: intermediate T1 and T2; chronic: low T1 and high T2\tHeterogeneous T1 and T2\tHeterogeneous, high T2\tIsointense on T1; high T2\tN/A\tIsointense T1, low T2\tHomogeneous increased T1\t\nCT\tAbsence of enhancement\tLow attenuation\tHeterogeneous\tHypodense\tN/A\tLow attenuation + calcification\tHomogeneous fat attenuation\t\nAdapted from Refs.1–5\n\nAV, atrioventricular; CT, computed tomography; LV, left ventricle; MRI, magnetic resonance imaging; RV, right ventricle.\n\nMassive RV thrombosis is a rare yet potentially fatal condition. Although intraventricular thrombi are usually secondary to severe ventricular dysfunction, a thrombophilic state may lead to their formation regardless of ventricular function. In patients with preserved ventricular function, intraventricular thrombosis may be secondary to acquired hypercoagulability, inherited protein defects, or pathological conditions, leading to augmented clotting formation.8 Heterozygous MTHFR mutations, present in up to 45% of the population,9 are per se mildly associated with an elevated risk of thrombosis (odds ratio for venous thrombosis 1.27).7 On the other hand, elevated levels of factor VIII procoagulant activity (FVIII:C), a fundamental cofactor for activated factor IX (FIXa), have not been unquestionably associated with an increased risk for either venous or arterial thromboembolism.10\n\nFor many years, FVIII deficient patients with haemophilia A had significant bleeding diathesis. Poles apart, novel evidence demonstrated the flipside; indeed elevated levels of FVIII might facilitate a pro-thrombotic state.10 Individuals with factor VIII levels >150 IU/dL had a three-fold increased risk of thrombosis than those with levels <100 IU/dL and each 10 IU/dL increment lead to a 10% risk increase for venous thromboembolism (VTE),11 and recurrent VTE.12\n\nFurthermore, AB0 blood group significantly influences plasma levels of the complex FVIII-von Willebrand factor (VWF). Individuals with blood group 0 have ∼25–30% reduction of procoagulant activity of the factor VIII:C.10 Therefore, in our patient, 0+ serogroup, factor VIII activity was consistent with an even higher activation compared to the non-0 individuals.\n\nMany cases of VTE or PE due to FVIII:C hyperactivity have been reported,11,12 however, to the best of our knowledge, massive thrombosis of the right ventricle and atrium has never been described so far. Elevated factor VIII levels are associated with decreased Protein S and Protein C activity and enhance thrombin formation. Synergic effects of MTHFR mutations and elevated factor VIII activity may explain the severe pro-thrombotic state, which led to massive RV thrombosis. Therefore, routine screening of thrombophilic mutation also might include factor VIII hyperactivity in selected cases.\n\nInterestingly, no pregnancy disorders or other embolic events have been reported, besides the pulmonary embolic event, suggesting a relatively recent onset, or worsening, of the hypercoagulable state, apparently without significant triggers. Conversely, right atrial enlargement and endocardial fibrosis were compatible with a long-standing thrombotic process. Lifelong oral anticoagulants with VKAs (due to the mechanical prosthetic valve) are required and, in those cases, international normalised ratio (INR) should be maintained among 3–4 to avoid any possible thrombotic recurrence or prosthetic valve blockade. No data are available for novel oral anticoagulants in patients with elevated factor VIII activity and MTHFR mutations. However, whenever feasible, anticoagulation with VKAs may be preferable.\n\nConclusions\n\nIntraventricular masses are rare conditions ranging from EMF, cardiac tumours, or thrombi, with different prognostic burden. Multimodality imaging is crucial for the diagnosis. Thrombophilic screening might reveal important findings driving effective management of these patients.\n\nLead author biography\n\nDr Jessica Artico received her MD degree at the University of Udine, Italy. After that, she moved to the University of Trieste for her Cardiology training and attended the Policlinico San Donato Milanese, Milan, Italy, and the St Bartholomew’s Hospital in London for more training in advanced cardiac imaging. Her main focus is on advanced imaging and cardiomyopathies.\n\nSupplementary material\n\nSupplementary material is available at European Heart Journal - Case Reports online.\n\nSlide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.\n\nConsent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.\n\nConflict of interest: None declared.\n\nFunding: None declared.\n\nSupplementary Material\n\nytab156_Supplementary_Data Click here for additional data file.\n\nAcknowledgements\n\nWe thank the patient for her willingness to share the case and Dr Giulia De Angelis for the passionate care of the patient during the hospitalization. We are really thankful to Mr Josef Huntington for his support and the language revision.\n==== Refs\nReferences\n\n1 MaleszewskiJJ, AnavekarNS, MoynihanTJ, KlarichKW. Pathology, imaging, and treatment of cardiac tumours. Nat Rev Cardiol 2017;14 :536–549.28436488\n2 BassoC, RizzoS, ValenteM, ThieneG. Cardiac masses and tumours. Heart 2016;102 :1230–1245.27277840\n3 KirkpatrickJN, WongT, BednarzJE, SpencerKT, SugengL, WardRP, DeCaraJM, WeinertL, KrauszT, LangRM. Differential diagnosis of cardiac masses using contrast echocardiographic perfusion imaging. J Am Coll Cardiol 2004;43 :1412–1419.15093876\n4 MousaviN, CheezumMK, AghayevA, PaderaR, VitaT, SteignerM, HultenE, BittencourtMS, DorbalaS, Di CarliMF, KwongRY, DunneR, BlanksteinR. Assessment of cardiac masses by cardiac magnetic resonance imaging: histological correlation and clinical outcomes. J Am Heart Assoc 2019;8 :e007829.30616453\n5 GulatiG, SharmaS, KothariSS, JunejaR, SaxenaA, TalwarKK. Comparison of echo and MRI in the imaging evaluation of intracardiac masses. Cardiovasc Interv Radiol 2004;27 :459–469.\n6 De StefanoV, RossiE, PaciaroniK, LeoneG. Screening for inherited thrombophilia: indications and therapeutic implications. Haematologica 2002;87 :1095–1108.12368166\n7 NakashimaMO, RogersHJ. Hypercoagulable states: an algorithmic approach to laboratory testing and update on monitoring of direct oral anticoagulants. Blood Res 2014;49 :85–94.25025009\n8 WallerBF, GriderL, RohrTM, McLaughlinT, TaliercioCP, FettersJ. Intracardiac thrombi: frequency, location, etiology, and complications: a morphologic review–part I. Clin Cardiol 1995;18 :477–479.7586767\n9 ConnorsJM. Thrombophilia testing and venous thrombosis. N Engl J Med 2017;377 :1177–1187.28930509\n10 JenkinsPV, RawleyO, SmithOP, O'DonnellJS. Elevated factor VIII levels and risk of venous thrombosis. Br J Haematol 2012;157 :653–663.22530883\n11 KosterT, BlannAD, BrietE, VandenbrouckeJP, RosendaalFR. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 1995;345 :152–155.7823669\n12 KyrlePA, MinarE, HirschlM, BialonczykC, StainM, SchneiderB et al High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Engl J Med 2000;343 :457–462.10950667\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2514-2119",
"issue": "5(7)",
"journal": "European heart journal. Case reports",
"keywords": "Anticoagulation; Cardiac tumour; Case report; Intraventricular masses; Right ventricular thrombus",
"medline_ta": "Eur Heart J Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101730741",
"other_id": null,
"pages": "ytab156",
"pmc": null,
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"pubdate": "2021-07",
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"title": "The curious case of a massive right heart thrombosis: a case report.",
"title_normalized": "the curious case of a massive right heart thrombosis a case report"
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"abstract": "OBJECTIVE\nPseudomyogenic hemangioendothelioma is a rare endothelial tumor. Previous genetic investigations have shown that the tumors carry either a SERPINE1-FOSB or an ACTB-FOSB fusion gene. The aim of the study was to identify FOSB fusions linked with pseudomyogenic hemangioendothelioma.\n\n\nMETHODS\nRNA sequencing, reverse transcription polymerase chain reaction (RT-PCR) and Sanger sequencing analyses were performed on a pseudomyogenic hemangioendothelioma.\n\n\nRESULTS\nAn in-frame fusion was found between exon 4 of WWTR1 from 3q25 and exon 2 of FOSB from 19q13. The fusion gene not only places FOSB under the control of the WWTR1 promoter, but is predicted to encode a chimeric WWTR1-FOSB transcription factor.\n\n\nCONCLUSIONS\nFOSB may be fused with SERPINE1, ACTB, or WWTR1 in pseudomyogenic hemangioendotheliomas. The resulting overexpression of FOSB fusion is a potentially useful marker that could be helpful in the diagnosis of these tumors.",
"affiliations": "Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway ioannis.panagopoulos@rr-research.no.;Department of Pathology, the Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.;Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.;Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.",
"authors": "Panagopoulos|Ioannis|I|;Lobmaier|Ingvild|I|;Gorunova|Ludmila|L|;Heim|Sverre|S|",
"chemical_list": "C064269:FOSB protein, human; D016760:Proto-Oncogene Proteins c-fos; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C551991:WWTR1 protein, human",
"country": "Greece",
"delete": false,
"doi": "10.21873/cgp.20134",
"fulltext": null,
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"issn_linking": "1109-6535",
"issue": "16(4)",
"journal": "Cancer genomics & proteomics",
"keywords": "FOSB; Pseudomyogenic hemangioendothelioma; RNA sequencing; WWTR1; WWTR1-FOSB fusion gene",
"medline_ta": "Cancer Genomics Proteomics",
"mesh_terms": "D000328:Adult; D005260:Female; D006390:Hemangioendothelioma; D006801:Humans; D016760:Proto-Oncogene Proteins c-fos; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins",
"nlm_unique_id": "101188791",
"other_id": null,
"pages": "293-298",
"pmc": null,
"pmid": "31243110",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11118213;21263239;21536240;24374978;24950227;25043949;25621995;27515856;28009608;30256258;30459475;8474434;8800467",
"title": "Fusion of the Genes WWTR1 and FOSB in Pseudomyogenic Hemangioendothelioma.",
"title_normalized": "fusion of the genes wwtr1 and fosb in pseudomyogenic hemangioendothelioma"
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{
"abstract": "Mycophenolate mofetil (MMF) is an immunosuppressive drug currently used to treat Systemic Lupus Erythematosus (SLE). In addition to clinical efficacy, MMF use is also supported by a favorable profile of tolerance, with main side effects being nausea, diarrhea, headache, and, less frequently, leucopoenia. Acne is a relatively frequent adverse reaction to MMF that requires specific treatment and drug suspension.\nHerein, we describe four cases of MMF-induced acne, none reporting past medical history of acne. The patients were diagnosed with SLE and lupus nephritis and treated with MMF. They developed papulo-pustular and nodular skin lesions consistent with acne. The lesions occasionally showed the appearance of macrocomedones or of unusual, nodular, oedematous lesions in gluteal region, or they had abscess-like features. Culture test demonstrated the presence of Staphylococcus Aureus. They resolved after MMF withdrawal and therapy with tetracycline and local pseudomonic-acid.\nStaphylococcus Aureus skin-localized infections inducing inflammatory/infectious acne may be a relatively frequent side-effect of MMF therapy in SLE. As soon as generalized, severe infections, due to Staphylococcus Aureus, may also occur in patients treated with MMF and even if antibiotics therapy is usually relatively effective, at least temporary MMF suspension may be suggested.",
"affiliations": "Lupus Clinic, Sezione di Reumatologia, Dipartimento di Medicina Interna, Sapienza Università di Roma, Rome, Italy.;Lupus Clinic, Sezione di Reumatologia, Dipartimento di Medicina Interna, Sapienza Università di Roma, Rome, Italy.;Lupus Clinic, Sezione di Reumatologia, Dipartimento di Medicina Interna, Sapienza Università di Roma, Rome, Italy.;Lupus Clinic, Sezione di Reumatologia, Dipartimento di Medicina Interna, Sapienza Università di Roma, Rome, Italy.;Lupus Clinic, Sezione di Reumatologia, Dipartimento di Medicina Interna, Sapienza Università di Roma, Rome, Italy.;Lupus Clinic, Sezione di Reumatologia, Dipartimento di Medicina Interna, Sapienza Università di Roma, Rome, Italy.;Lupus Clinic, Sezione di Reumatologia, Dipartimento di Medicina Interna, Sapienza Università di Roma, Rome, Italy.",
"authors": "Perricone|Carlo|C|;Ceccarelli|Fulvia|F|;Spinelli|Francesca Romana|FR|;Truglia|Simona|S|;Priori|Roberta|R|;Valesini|Guido|G|;Conti|Fabrizio|F|",
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"doi": "10.31138/mjr.29.4.217",
"fulltext": "\n==== Front\nMediterr J Rheumatol\nMediterr J Rheumatol\nMJR\nMediterranean Journal of Rheumatology\n2529-198X The Mediterranean Journal of Rheumatology (MJR) \n\n10.31138/mjr.29.4.217\nmjr-29-4-217\nCase Report\nManagement of mycophenolate mofetil-induced acne in patients with Systemic Lupus Erythematosus: report of four cases and review of the literature\nPerricone Carlo Ceccarelli Fulvia Spinelli Francesca Romana Truglia Simona Priori Roberta Valesini Guido Conti Fabrizio Lupus Clinic, Sezione di Reumatologia, Dipartimento di Medicina Interna, Sapienza Università di Roma, Rome, Italy\nCorresponding author: Carlo Perricone, MD, PhD, Rheumatology, Department of Internal Medicine, Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy, Tel. +39 06 49974673, E-mail: carlo.perricone@gmail.com\n12 2018 \n18 12 2018 \n29 4 217 220\n31 7 2018 30 11 2018 03 12 2018 © 2018 The Mediterranean Journal of Rheumatology (MJR)2018This work is licensed under and Creative Commons Attribution-NonCommercial 4.0 International License.Background:\nMycophenolate mofetil (MMF) is an immunosuppressive drug currently used to treat Systemic Lupus Erythematosus (SLE). In addition to clinical efficacy, MMF use is also supported by a favorable profile of tolerance, with main side effects being nausea, diarrhea, headache, and, less frequently, leucopoenia. Acne is a relatively frequent adverse reaction to MMF that requires specific treatment and drug suspension.\n\nInvestigations:\nHerein, we describe four cases of MMF-induced acne, none reporting past medical history of acne. The patients were diagnosed with SLE and lupus nephritis and treated with MMF. They developed papulo-pustular and nodular skin lesions consistent with acne. The lesions occasionally showed the appearance of macrocomedones or of unusual, nodular, oedematous lesions in gluteal region, or they had abscess-like features. Culture test demonstrated the presence of Staphylococcus Aureus. They resolved after MMF withdrawal and therapy with tetracycline and local pseudomonic-acid.\n\nConclusions:\nStaphylococcus Aureus skin-localized infections inducing inflammatory/infectious acne may be a relatively frequent side-effect of MMF therapy in SLE. As soon as generalized, severe infections, due to Staphylococcus Aureus, may also occur in patients treated with MMF and even if antibiotics therapy is usually relatively effective, at least temporary MMF suspension may be suggested.\n\nAcneMycophenolate mofetilSkinSystemic Lupus Erythematosus\n==== Body\nINTRODUCTION\nMycophenolate mofetil (MMF) is an immunosuppressive drug the efficacy of which has been established in kidney, liver, or heart transplantation. It is converted to mycophenolic acid, and by inhibiting inosine monophosphate dehydrogenase, a lymphocyte specific enzyme, inhibits both T and B lymphocyte proliferation.1 In 1997 MMF (Cellcept®, Roche Pharma) was approved by the FDA to prevent renal allograft rejection, but over the last few years, its use in treating autoimmune disorders, mostly in Systemic Lupus Erythematosus (SLE),2 is becoming more widespread. Initially, MMF in SLE was used for diffuse proliferative lupus glomerulonephritis (World Health Organization [WHO] class-IV). Currently, MMF is also used to control general disease activity and other lupus manifestations including those haematological and cutaneous.3 In addition to clinical efficacy, MMF use is also supported by a favourable profile of tolerance, with main reported side effects being nausea, diarrhoea, headache, and, less frequently, leukopenia. Herein, we describe four cases of MMF-induced acne, none reporting past medical history of symptomatic acne and all of them caused by the presence of Staphylococcus Aureus. Resolution of the infection and MMF treatment suspension may be suggested in patients experiencing this adverse event.\n\nTHE CASES\nPatient 1, M.F., a 25-year-old woman, had been treated with prednisone, cyclosporin-A (CYA) and cyclophosphamide (CYC) for SLE since 1991 and for Lupus nephritis (WHO class-V) since 1999. For the poor control of proteinuria (2 g/24h) with glucocorticoid therapy, she started in 2002 MMF (2 g/daily) with normalization of proteinuria levels. In June 2008, the patient complained of papulopustules and nodules on the vulva and in gluteal region (\nFigure 1) with open and closed comedones. Contemporarily, paronychia and nasal furuncle appeared. Culture tests of two gluteal open comedones and of the nasal furuncle were undertaken and demonstrated the presence of Staphylococcus Aureus (SA) at the gluteal level. Thus, treatment with doxycycline 100 mg/daily together with local mupirocin in the form of 2% ointment applied three times per day was initiated while MMF was suspended producing clinical improvement.\n\nFigure 1. Papulo-pustules and nodules in gluteal region (Patient 1).\n\nPatient 2, F.C., a 33-years-old woman, had been treated since 1998 for SLE and retinal vasculitis using high doses-glucocorticoids, hydroxychloroquine, methotrexate, azathioprine and CYA. Due to several adverse events to such drugs and low benefit, MMF was introduced in November 2005 (2 g/daily) with efficacy on the clinical and laboratory picture. In March 2007, the patient complained of papulopustules and nodules in gluteal region and posterior region of the legs, starting with one single open comedone. Contemporarily, fever and generalized discomfort appeared, and the patient developed severe nodulocystic gluteal acne. Culture tests were undertaken at these regions together with a nasal culture test and demonstrated the presence of SA in the gluteal comedones. Thus, MMF treatment was suspended, while treatment with minocycline 100 mg/daily together with local mupirocin was initiated. Minocycline was interrupted after one week due to dizziness and substituted with Co-trimoxazole 320-1600 mg/daily. After two months, the resolution of the cutaneous lesions was observed.\n\nPatient 3, K.C., a 33-year-old woman, diagnosed of SLE and Lupus nephritis (WHO class-IV-B) in 1998 was treated with CYC, and then with hydroxychloroquine, methotrexate, azathioprine and prednisone. Occasionally, proteinuria was still observed. In January 2006 due to the increase of proteinuria (> 1 g/24h), MMF was started at the dosage of 2 g/daily. After three months of therapy open and closed comedones in mammary, inguinal and gluteal region showing abscess-like features were noted. Culture tests of the comedones were undertaken together with a nasal culture test and SA was demonstrated in the gluteal comedones. Suspension of MMF and treatment with doxycycline 100 mg/daily together with topical mupirocin resulted in clinical improvement.\n\nPatient 4, L.C., a 45-years-old woman, with a diagnosis of SLE and Lupus nephritis (WHO class-III-A), was treated with hydroxychloroquine and intravenous methylprednisone. For the persistence of positive urine protein analysis (> 1g/24h) she started in September 2008 MMF 3 g/daily with benefit on the renal disease. After one year of therapy open and closed comedones localized at the décolleté, arms and gluteal region were observed. Culture tests of the comedones localized at the arms were undertaken together with a nasal culture test. SA was present in both regions. Acne disappeared one month after MMF was suspended and treatment with doxycycline 100 mg/daily and topical mupirocin was started.\n\nMMF was reintroduced in cases 2, 3 and 4 one month after the resolution of the event. The follow-up for cases 3 and 4 is up to two years with no other events. For case 2, MMF was continued till nowadays with clinical benefit and no further events.\n\nDISCUSSION\nAll the patients had a predominance of inflammatory/infectious acne lesions in which SA was isolated from the comedones. The clinical appearance differed from acne vulgaris and from monomorphic papules of corticosteroid-induced acne. Interestingly, the lesions were predominantly painful and occasionally showed the appearance of macrocomedones or of unusual, nodular, oedematous lesions in gluteal region, or abscess-like features. Moreover, the disappearance of the lesions after MMF withdrawal seems suggestive for a role of the drug in their induction. MMF-induced acne seems to be mainly due to immunosuppression and to an infection sustained by SA. Lesions were responsive to tetracycline and local pseudomonic acid together with the interruption of MMF therapy. The fact that SA was isolated in one nasal culture test may suggest that, at least in some cases, this is the source-site of the infection to be reclaimed. Of note, prednisone dosage was 7.5 mg/day in case 1 and 4; 5 mg/day in case 2 and 3 at the time of acne comparison. All the cases had reduced C4 and all but case 4 had reduced C3 at the time of the event. WBC count was within normal values in all cases; nonetheless, all the patients had haematological involvement (lymphopenia) in their clinical history.\n\nNo specific clinical reports of MMF-induced acne have been published yet. Side-effects associated with the immunosuppressive regimen can pose problems for patients with SLE. Skin lesions can be markedly distressing for patients reducing compliance to therapy. The mechanism of this MMF-induced acne is unknown, and the pathogenesis may include direct toxic effects or local immunosuppression. The longest-lasting experience with MMF has been accumulated in patients undergoing renal transplantation. In most of these cases MMF is used in combination with sirolimus to prevent allograft rejection. It has been widely reported that sirolimus frequently induces acne in a high number of patients. It may be supposed that a number of these cases may be due to MMF despite of sirolimus. Schaffellner et al. reported that 12/23 patients assuming sirolimus after renal transplantation showed dermatological side effects, six of which constituted by acne.4 Since 20/23 patients were also assuming MMF, it would be of interest to discriminate whether it was sirolimus or MMF to induce the skin lesions, not excluding the possibility of a synergistic effect. MMF side-effects are indeed well known and even various cutaneous lesions were anecdotally reported. The most common were infectious caused by mucocutaneous candidiasis, CMV syndrome, and Herpes Simplex.5 In a combination therapy with tacrolimus, MMF caused mouth ulceration. After MMF discontinuation, the lesions ameliorated.6 Oral ulcers were also reported by Naranjo et al., where authors concluded MMF was the suspicious drug.7 Indeed, another patient with the same combination therapy reported blisters on one hand and loose toenails; symptoms resolved after MMF therapy interruption. After the therapy with the drug was resumed, hand blisters and loose toenails recurred.8 Similarly, a patient with liver transplantation developed bullous eruption on hands and feet after MMF treatment. MMF was withdrawn and the cutaneous lesions resolved. After restarting therapy with MMF, the lesions recurred on the patient’s hand.9 All these reports sustain the hypothesis that MMF itself induces cutaneous lesions. MMF can reduce the expression of adhesion molecules on endothelial cells, leading to a decreased invasion of leukocytes in the target tissue, e.g. the skin.10 It may be postulated that specific immunosuppression at the skin level may predispose to localized infection. Indeed, MMF has been used for a variety of skin disorders included cutaneous manifestations of SLE, rationale being the reduction, directly induced by MMF, of leukocyte migration to skin.11 However, in patients affected with SLE, the sustaining immunological defect may lead into the development of SA infections; not only skin-localised, but also generalised. Indeed, not only could SA be isolated from the comedones of our patients, but also one patient affected with atopic dermatitis who developed SA septicaemia was already described in the literature.12 Unfortunately, we failed to find any clinical or laboratory feature that may predict the comparison of acne in MMF treated SLE patients.\n\nIn conclusion, acne may be a side-effect of MMF therapy in SLE. Infection with SA must be considered in these cases, and specific antibiotic therapy for reclaim of the germ is strongly suggested. Finally, even if therapy for acne is relatively effective, definitive treatment most often may rely on MMF suspension. It is noteworthy that reintroduction of MMF after SA eradication13 can be safe even in the long-term (up to 10 years of experience), even if the low number of patients evaluated cannot allow to draw definite conclusions.\n\nCONFLICT OF INTEREST\nThe authors declare no conflict of interest.\n\nABBREVIATIONS\nCYCCyclophosphamide\n\nMMFMycophenolate mofetil\n\nSAStaphylococcus Aureus\n\nSLESystemic Lupus Erythematosus\n==== Refs\nREFERENCES\n1. \nAdu D Cross J Jayne DR \n. \nTreatment of systemic lupus erythematosus with mycophenolate mofetil\n. \nLupus \n2001 ;\n10 \n(3 ):\n203 –\n8\n. [10.1191/096120301673517315 ] [PMID: ]11315353 \n2. \nChan TM Li FK Tang CS Wong RW Fang GX Ji YL \n. \nEfficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group\n. N Engl J Med \n2000 ;\n343 \n(16 ):\n1156 –\n62\n. [10.1056/NEJM200010193431604 ] [PMID: ]11036121 \n3. \nAlba P Karim MY Hunt BJ \n. \nMycophenolate mofetil as a treatment for autoimmune haemolytic anaemia in patients with systemic lupus erythematosus and antiphospholipid syndrome\n. \nLupus \n2003 \n;\n12 \n:\n633 \n–\n5\n\n. [10.1191/0961203303lu419cr ] [PMID: ]12945724 \n4. \nSchaffellner S Jakoby E Kniepeiss D Stadlbauer V Duller D Iberer F Tscheliessnigg KH \n. \nCenter experience in liver transplantation (LTX): management of dermal side effects caused by sirolimus\n. \nInt Immunopharmacol \n2005 ;\n5 \n(1 ):\n137 –\n40\n. [10.1016/j.intimp.2004.09.017 ] [PMID: ]15589473 \n5. \nHartmann M Enk A \n. \nMycophenolate mofetil and skin diseases\n. \nLupus \n2005 \n;\n14 \nSuppl 1 \n:\ns58 \n–\n63\n\n. [PMID: ]15803935 \n6. \nApostolou T Tsagalis G Koutroubas G Hadjiconstantinou V Drakopoulos S \n. \nMycophenolate mofetil and oral ulcerations\n. \nTransplantation \n2004 ;\n77 :1911 –2\n. [PMID: ]15223919 \n7. \nNaranjo J Poniachik J Cisco D Contreras J Oksenberg D Valera JM \n. \nOral ulcers produced by mycophenolate mofetil in two liver transplant patients\n\n. \nTransplant Proc. \n2007 \n4 \n;\n39 \n(\n3 \n):\n612 \n–\n4\n\n. [10.1016/j.transproceed.2006.12.028 ] [PMID:\n]17445557 \n8. \nRault R \n. \nMycophenolate-associated onycholysis\n. \nAnn Intern Med \n2000 \n;\n133 \n:\n921 \n–\n2\n\n. [PMID: ]11103069 \n9. \nSemhoun-Ducloux S Ducloux D Miguet JP \n. \nMycophenolate mofetilinduced dyshidrotic eczema\n. \nAnn Intern Med \n2000 \n;\n132 \n:\n417 \n. [PMID: ]10691595 \n10. \nPisoni CN Obermoser G Cuadrado MJ Sanchez FJ Karim Y Sepp NT \n. \nSkin manifestations of systemic lupus erythematosus refractory to multiple treatment modalities: poor results with mycophenolate mofetil\n. \nClin Exp Rheumatol \n2005 ;\n23 \n(3 ):\n393 –\n6\n. [PMID: ]15971430 \n11. \nBoehm I Bieber T \n. \nChilblain lupus erythematosus Hutchinson: successful treatment with mycophenolate mofetil\n. \nArch Dermatol \n2001 ;\n137 \n(2 ):\n235 –\n6\n. [PMID: ]11176709 \n12. \nSatchell AC Barnetson RS \n. \nStaphylococcal septicaemia complicating treatment of atopic dermatitis with mycophenolate\n. \nBr J Dermatol \n2000 ;\n143 :202 –3\n. [PMID: ]10886168 \n13. \nConti F Ceccarelli F Iaiani G Perricone C Giordano A Amori L \n. \nAssociation between Staphylococcus aureus nasal carriage and disease phenotype in patients affected by systemic lupus erythematosus\n. \nArthritis Res Ther \n2016 \n30 \n;\n18 \n:\n177 \n. [\n10.1186/s13075-016-1079-x \n]27475749\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2529-198X",
"issue": "29(4)",
"journal": "Mediterranean journal of rheumatology",
"keywords": "Acne; Mycophenolate mofetil; Skin; Systemic Lupus Erythematosus",
"medline_ta": "Mediterr J Rheumatol",
"mesh_terms": null,
"nlm_unique_id": "101730166",
"other_id": null,
"pages": "217-220",
"pmc": null,
"pmid": "32185330",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports",
"references": "17445557;15589473;10886168;11036121;11103069;12945724;15223919;11176709;15971430;15803935;11315353;10691595;27475749",
"title": "Management of mycophenolate mofetil-induced acne in patients with Systemic Lupus Erythematosus: report of four cases and review of the literature.",
"title_normalized": "management of mycophenolate mofetil induced acne in patients with systemic lupus erythematosus report of four cases and review of the literature"
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"activesubstancename": "HYDROXYCHLOROQUINE"
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"abstract": "BACKGROUND\nMyelosuppression due to pegylated interferon (peg-IFN) is common during treatment for hepatitis C virus. The relationship between infection risk and decreases in leukocyte lines, however, is not well established. The objective of this analysis was to determine the incidence of and risk factors for infections during peg-IFN/ribavirin (RBV) therapy.\n\n\nMETHODS\nA total of 3070 treatment-naive, chronic hepatitis C genotype 1-infected patients were treated for up to 48 weeks with peg-IFN alfa-2b 1.5 µg/kg/week or 1 µg/kg/week, or peg-IFN alfa-2a 180 µg/week plus RBV. On-treatment leukocyte counts were obtained every 2-6 weeks. Dose reduction was required for a neutrophil count <0.75 × 10(9) cells/L, and treatment discontinuation was required for a neutrophil count <0.5 × 10(9) cells/L. Granulocyte colony-stimulating factor was prohibited. Data on infections were captured at each study visit and categorized according to MedDRA version 13.0.\n\n\nRESULTS\nA total of 581 (19%) patients experienced moderate, severe, or life-threatening infections as assessed by the investigator; 648 (21%) patients had at least 1 neutrophil count <0.75 × 10(9) cells/L, but only 242 (8%) sustained an infection and had a neutrophil count <0.75 × 10(9) cells/L at any time while on treatment. Twelve patients had severe or life-threatening infection and grade 3/4 neutropenia, but only 4 had temporally related infections. In a multivariate logistic regression model, nadir lymphocyte count, history of depression, and female sex, but not nadir neutrophil count, were associated with moderate, severe, or life-threatening infection.\n\n\nCONCLUSIONS\nNadir lymphocyte count, not nadir neutrophil count, was independently associated with moderate, severe, or life-threatening infections in the IDEAL study. Clinicians should be aware of their patients' absolute lymphocyte counts during peg-IFN/RBV therapy; peg-IFN dose reductions may be a consideration in patients with significant lymphocytopenia (<0.5 × 10(9) cells/L).",
"affiliations": "Johns Hopkins University School of Medicine, Baltimore, Maryland.",
"authors": "Melia|Michael T|MT|;Bräu|Norbert|N|;Poordad|Fred|F|;Lawitz|Eric J|EJ|;Shiffman|Mitchell L|ML|;McHutchison|John G|JG|;Muir|Andrew J|AJ|;Galler|Greg W|GW|;Nyberg|Lisa M|LM|;Lee|William M|WM|;Schiff|Eugene|E|;Long|Jianmin|J|;Noviello|Stephanie|S|;Brass|Clifford A|CA|;Pedicone|Lisa D|LD|;Sulkowski|Mark S|MS|",
"chemical_list": "D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C417083:peginterferon alfa-2b",
"country": "United States",
"delete": false,
"doi": "10.1093/cid/ciu009",
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"issue": "58(7)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": "hepatitis C virus; infections; interferon; lymphopenia; neutropenia",
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D005260:Female; D006526:Hepatitis C; D006801:Humans; D015994:Incidence; D007239:Infections; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D018655:Lymphocyte Count; D008231:Lymphopenia; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009504:Neutrophils; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012254:Ribavirin; D018570:Risk Assessment; D012307:Risk Factors; D055815:Young Adult",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "960-9",
"pmc": null,
"pmid": "24399086",
"pubdate": "2014-04",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "21094928;16082419;21258094;18458815;16083315;20830784;19210290;12360468;16500782;16890601;12395340;21696307;21449783;19330875;19625712;17241864;21329753;16705570",
"title": "Infections during peginterferon/ribavirin therapy are associated with the magnitude of decline in absolute lymphocyte count: results of the IDEAL study.",
"title_normalized": "infections during peginterferon ribavirin therapy are associated with the magnitude of decline in absolute lymphocyte count results of the ideal study"
} | [
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"abstract": "Primary and secondary malignant tumors of the spine are relatively uncommon in the pediatric population but are associated with high morbidity and significantly decreased quality of life due to pain. Local management of these tumors is often challenging due to the importance of maintaining vertebral mechanical integrity as well as the spinal growth potential. Typically, surgery and/or radiation therapy have been used in the primary management of these tumors. However, treatment options become more limited when there is relapse or refractory disease, with re-resection or additional radiotherapy often not being viable therapies. Vertebroplasty is a currently underutilized modality that might provide significant pain palliation in cases of relapsed cancer in the spine.",
"affiliations": "Division of Interventional Radiology, Department of Medical Imaging, Western University, London, Ontario, Canada.;Division of Hematology, Oncology and BMT, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada.;Department of Radiology, University of British Columbia, Vancouver, British Columbia, Canada.;Department of Radiology, University of British Columbia, Vancouver, British Columbia, Canada.",
"authors": "Cardarelli-Leite|Leandro|L|https://orcid.org/0000-0003-1653-3760;Rassekh|Shahrad Rod|SR|;D'Ortenzio|Robert|R|;Heran|Manraj Kanwal Singh|MKS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.29307",
"fulltext": null,
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"issn_linking": "1545-5009",
"issue": "68(12)",
"journal": "Pediatric blood & cancer",
"keywords": "palliative care; pediatric cancer; rhabdomyosarcoma; spinal tumor; vertebroplasty",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": null,
"nlm_unique_id": "101186624",
"other_id": null,
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"pmc": null,
"pmid": "34453400",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Vertebroplasty as a palliative treatment option for intractable pain in pediatric patients with spinal tumors.",
"title_normalized": "vertebroplasty as a palliative treatment option for intractable pain in pediatric patients with spinal tumors"
} | [
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"companynumb": "CA-LUPIN PHARMACEUTICALS INC.-2022-04298",
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{
"abstract": "The risk of hemorrhage after therapeutic administration of tissue plasminogen activator (tPA) is well known. Cases of postadministration hemorrhage have been reported within many organ systems. We present a case of a 62-year-old female with undiagnosed thyroid goiter who received tPA for acute ischemic stroke and developed acute airway compromise. The surgical airway response team was called due to inability to ventilate or intubate. An incision into the mass during attempted tracheotomy released colloid and blood, decompressing the airway and facilitating ventilation and intubation. Hemithyroidectomy for mass removal was delayed for 3 days to allow normalization of post-tPA coagulopathy.",
"affiliations": "Department of Otolaryngology, New York University, New York, New York, U.S.A.",
"authors": "Gallant|Sara C|SC|;Fritz|Mark A|MA|;Paul|Benjamin C|BC|;Costantino|Peter D|PD|",
"chemical_list": "D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator",
"country": "United States",
"delete": false,
"doi": "10.1002/lary.24841",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0023-852X",
"issue": "125(3)",
"journal": "The Laryngoscope",
"keywords": "airway; goiter; hemorrhage; tPA; thyroid",
"medline_ta": "Laryngoscope",
"mesh_terms": "D000402:Airway Obstruction; D002545:Brain Ischemia; D005260:Female; D005343:Fibrinolytic Agents; D005500:Follow-Up Studies; D006044:Goiter, Nodular; D006406:Hematoma; D006801:Humans; D008875:Middle Aged; D015912:Thrombolytic Therapy; D013965:Thyroidectomy; D010959:Tissue Plasminogen Activator; D014140:Tracheotomy",
"nlm_unique_id": "8607378",
"other_id": null,
"pages": "604-7",
"pmc": null,
"pmid": "25043767",
"pubdate": "2015-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Management of airway compromise following thyroid cyst hemorrhage after thrombolytic therapy.",
"title_normalized": "management of airway compromise following thyroid cyst hemorrhage after thrombolytic therapy"
} | [
{
"companynumb": "US-ROCHE-1447219",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SODIUM CHLORIDE"
},
"drugadditional": null,
... |
{
"abstract": "A 39-year-old woman with systemic lupus erythematosus treated with anti-CD20 monoclonal antibody rituximab was admitted to our hospital with COVID-19 pneumonia. Despite receiving dexamethasone, she developed hypoxaemia and persistent lung opacities. As bronchoalveolar lavage was suggestive of cryptogenic organising pneumonia, high-dose corticosteroid was administered, and she received antimicrobial therapy for opportunistic infections without improvement. Reverse transcription PCR was repeatedly positive for SARS-CoV-2, and virus replication was confirmed in cell cultures. As no anti-SARS-CoV-2 antibodies were detected more than 100 days after symptom onset, she was treated with convalescent plasma with fast clinical improvement, returning home days later. Our case shows that persistent SARS-CoV-2 infection in an immunocompromised patient may be overturned with the appropriate treatment.",
"affiliations": "Departmento de Medicina, Serviço de Medicina Interna, Unidade Local de Saúde de Matosinhos EPE, Senhora da Hora, Portugal sarasofia.pereira@ulsm.min-saude.pt.;Departmento de Medicina, Serviço de Medicina Interna, Unidade Local de Saúde de Matosinhos EPE, Senhora da Hora, Portugal.;Departmento de Medicina, Serviço de Imunohemoterapia, Unidade Local de Saúde de Matosinhos EPE, Senhora da Hora, Portugal.;Departmento de Medicina, Serviço de Medicina Interna, Unidade Local de Saúde de Matosinhos EPE, Senhora da Hora, Portugal.",
"authors": "Moutinho-Pereira|Sara|S|http://orcid.org/0000-0001-8732-5518;Calisto|Raquel|R|;Sabio|Federico|F|;Guerreiro|Luísa|L|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-244853",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(8)",
"journal": "BMJ case reports",
"keywords": "COVID-19; biological agents; respiratory system; systemic lupus erythematosus",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000086382:COVID-19; D005260:Female; D006801:Humans; D007116:Immunization, Passive; D016867:Immunocompromised Host; D008180:Lupus Erythematosus, Systemic; D000086402:SARS-CoV-2",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34433539",
"pubdate": "2021-08-25",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "32878994;33277981;32702095;32503849;29180125;32503854;23851398;32593180;33044747;32492084;32503848;33008453;32557623;33314018;32591357;33009361;33547062;33523609;32959052;16785532;32986807;33232588;34319130;33406353;33176080;32588877;33504483",
"title": "High-titre convalescent plasma therapy for an immunocompromised patient with systemic lupus erythematosus with protracted SARS-CoV-2 infection.",
"title_normalized": "high titre convalescent plasma therapy for an immunocompromised patient with systemic lupus erythematosus with protracted sars cov 2 infection"
} | [
{
"companynumb": "PT-CELLTRION HEALTHCARE HUNGARY KFT-2021PT012015",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadd... |
{
"abstract": "The development of deep venous thrombophlebitis in a lithium-intoxicated patient is described. The sedation, lassitude, and decreased activity of the toxic state are proposed as risk factors for the development of hemostasis and thrombophlebitis. The need for greater awareness of this possible complication in patients who are lithium toxic is advanced.",
"affiliations": null,
"authors": "Lyles|M R|MR|",
"chemical_list": "D016651:Lithium Carbonate; D008094:Lithium",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0027-9684",
"issue": "76(6)",
"journal": "Journal of the National Medical Association",
"keywords": null,
"medline_ta": "J Natl Med Assoc",
"mesh_terms": "D005260:Female; D006801:Humans; D008094:Lithium; D016651:Lithium Carbonate; D008875:Middle Aged; D013924:Thrombophlebitis",
"nlm_unique_id": "7503090",
"other_id": null,
"pages": "633-4",
"pmc": null,
"pmid": "6431115",
"pubdate": "1984-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "1189984;884923;329779;356084;378163;7351009;7352540;7457166",
"title": "Deep venous thrombophlebitis associated with lithium toxicity.",
"title_normalized": "deep venous thrombophlebitis associated with lithium toxicity"
} | [
{
"companynumb": "US-ACTAVIS-2016-01266",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "ACETAZOLAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "A 73-year-old man, without any medical history, had presented with dark urine and pale stool without pain. Diagnostic imaging revealed a tumour in the pancreas with liver metastases. Histopathological examination showed a well-differentiated pancreatic neuroendocrine tumour. After a stable 2.5 years on everolimus, progression of the liver metastases was seen and a switch was made to chemotherapy. Three months later, he developed progressive spinal neurological symptoms. MRI of the spine and brain revealed leptomeningeal contrast-enhancing lesions. Cytopathological examination of the cerebrospinal fluid showed malignant epithelial cells compatible with well-differentiated neuroendocrine tumour. Epithelial cell-adhesion molecule-based flow cytometry of the cerebrospinal fluid confirmed the presence of epithelial tumour cells. Based on these results, the diagnosis of leptomeningeal metastases of an originally well-differentiated neuroendocrine tumour of the pancreas was made.",
"affiliations": "Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands.;Department of Neuro-Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands.;Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.;Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands.",
"authors": "Versluis|J M|JM|;Brandsma|D|D|;van den Berg|J G|JG|;Tesselaar|Met|M|",
"chemical_list": "D007166:Immunosuppressive Agents; D000068338:Everolimus",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-226557",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "endocrine cancer; neuroendocrinology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D002555:Cerebrospinal Fluid; D004358:Drug Therapy; D000068338:Everolimus; D017809:Fatal Outcome; D006801:Humans; D007166:Immunosuppressive Agents; D007414:Intestinal Neoplasms; D008113:Liver Neoplasms; D008279:Magnetic Resonance Imaging; D008297:Male; D008577:Meningeal Neoplasms; D009362:Neoplasm Metastasis; D018358:Neuroendocrine Tumors; D010190:Pancreatic Neoplasms; D013274:Stomach Neoplasms",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30391925",
"pubdate": "2018-11-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "28199314;16030115;16258976;6336971;24867803;23352435;26731013;20598636;22231633;25674288;22089116;19660683;15305414;28076709;15844174;28943940;25312765;27942928;20689429;28178709;18520845",
"title": "Leptomeningeal metastases of a well-differentiated neuroendocrine tumour: a rare entity.",
"title_normalized": "leptomeningeal metastases of a well differentiated neuroendocrine tumour a rare entity"
} | [
{
"companynumb": "NL-TEVA-2019-NL-1014445",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "EVEROLIMUS"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nChildren, adolescents and young adults (CAYA) with perinatally acquired human immunodeficiency virus (PaHIV) need lifelong antiretroviral therapy (ART) to suppress viral load (VL), maintain health and prevent onward transmission. Many struggle with adherence despite multidisciplinary input. We assessed ART adherence outcomes following two novel interventions: percutaneous endoscopic gastrostomy (PEG) and Pill Glide®, a fruit-flavoured lubricant spray aiding tablet swallowing.\n\n\nMETHODS\nRetrospective cohort analysis by database and case-note review of PaHIV CAYA aged < 25 years receiving PEG or Pill Glide® between 1995 and 2017 at a single tertiary centre.\n\n\nRESULTS\nNineteen PEGs were inserted in 15 CAYA at a median age of 17 (IQR 6-22) years, median CD4 count 40 cells/µL (IQR 10-220). A viral load (VL) < 50 copies/mL was achieved in 93% with PEG ART. At last follow-up all were alive, median age 23 years (IQR 22-28). Nine had PEG removed, after a median of 3.3 years (range 0.5-6.8), with a current VL < 50 copies/mL, median CD4 count 940 cells/µL (IQR 261-1353) sustained post PEG removal median was 5.4 years (range 1.5-17.8) previously. From 2017 seven CAYA received Pill Glide®, median age 10 years (IQR 7-14), median CD4 count 898 cells/µL (range 148-1943), 6/7 with a suppressed VL. All reported increased ease in tablet swallowing and transitioned successfully from crushed tablets/liquids to tablets. At follow-up, all patients had a suppressed VL.\n\n\nCONCLUSIONS\nWhilst PEG insertion markedly improved rates of viral suppression in CAYA struggling with ART adherence, the use of novel less invasive aids such as Pill Glide® requires further exploration.",
"affiliations": "Department of Paediatrics, Royal London Hospital, Barts Health NHS Trust, 6c ward, Whitechapel Road, Whitechapel, London, E1 1FR, UK. luca.zombori@nhs.net.;Department of Paediatrics, St. Mary's Hospital, Imperial College Healthcare NHS Trust, London, UK.;Department of Paediatrics, Chelsea and Westminster Hospital, Chelsea and Westminster Hospital, NHS Trust, London, UK.;Department of Paediatrics, St. Mary's Hospital, Imperial College Healthcare NHS Trust, London, UK.;Department of Paediatrics, St. Mary's Hospital, Imperial College Healthcare NHS Trust, London, UK.;Department of Paediatrics, St. Mary's Hospital, Imperial College Healthcare NHS Trust, London, UK.",
"authors": "Zombori|Luca|L|http://orcid.org/0000-0002-0105-3732;Kirkhope|Natalie|N|;Busari|Temitope|T|;Tickner|Neil|N|;Weston|Rosy|R|;Foster|Caroline|C|",
"chemical_list": "D019380:Anti-HIV Agents",
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40261-020-00918-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1173-2563",
"issue": "40(8)",
"journal": "Clinical drug investigation",
"keywords": null,
"medline_ta": "Clin Drug Investig",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents; D018791:CD4 Lymphocyte Count; D015331:Cohort Studies; D005260:Female; D015658:HIV Infections; D006801:Humans; D018445:Infectious Disease Transmission, Vertical; D008297:Male; D010349:Patient Compliance; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D012189:Retrospective Studies; D019562:Viral Load; D055815:Young Adult",
"nlm_unique_id": "9504817",
"other_id": null,
"pages": "765-772",
"pmc": null,
"pmid": "32519251",
"pubdate": "2020-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Novel Adherence Interventions in Perinatally Acquired HIV: PEG Insertion and Pill Glide.",
"title_normalized": "novel adherence interventions in perinatally acquired hiv peg insertion and pill glide"
} | [
{
"companynumb": "GB-GLAXOSMITHKLINE-GB2020GSK151498",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
"drugadditional": nul... |
{
"abstract": "Consensus regarding kidney transplantation feasibility in patients with chronic myeloid leukemia (CML) well controlled by tyrosine kinase inhibitors has not yet been achieved. Here, we report a patient with CML well controlled by tyrosine kinase inhibitors who developed end-stage renal disease during treatment and underwent kidney transplantation. CML activity has been carefully and successfully controlled for 4 years post-transplant. Very cautious dose adjustment and temporary cessation of nilotinib were required because kidney function fluctuated in reference to the doses of nilotinib.",
"affiliations": "Department of Urology, Keio University School of Medicine, Tokyo, Japan. Electronic address: kshino49@yahoo.co.jp.;Department of Urology, Keio University School of Medicine, Tokyo, Japan.;Department of Urology, Keio University School of Medicine, Tokyo, Japan.;Department of Urology, Keio University School of Medicine, Tokyo, Japan.;Department of Urology, Keio University School of Medicine, Tokyo, Japan.;Department of Urology, Keio University School of Medicine, Tokyo, Japan.;Apheresis and Dialysis Center, Keio University School of Medicine, Tokyo, Japan.;Department of Hematology, Keio University School of Medicine, Tokyo, Japan.;Department of Hematology, Keio University School of Medicine, Tokyo, Japan.;Department of Hematology, Keio University School of Medicine, Tokyo, Japan.;Department of Urology, Keio University School of Medicine, Tokyo, Japan.",
"authors": "Shinoda|Kazunobu|K|;Morita|Shinya|S|;Tamaki|Satoshi|S|;Takahashi|Ryohei|R|;Kitaoka|Sotaro|S|;Asanuma|Hiroshi|H|;Yoshida|Tadashi|T|;Okayama|Mikio|M|;Kasahara|Hidenori|H|;Okamoto|Shinichiro|S|;Oya|Mototsugu|M|",
"chemical_list": "D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate; D000069439:Dasatinib",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2019.10.035",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "52(2)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000069439:Dasatinib; D006801:Humans; D000068877:Imatinib Mesylate; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "604-607",
"pmc": null,
"pmid": "32029318",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful Treatment of End-stage Renal Disease in a Patient With Chronic Myeloid Leukemia by Kidney Transplantation and Tyrosine Kinase Inhibitors: A Case Report.",
"title_normalized": "successful treatment of end stage renal disease in a patient with chronic myeloid leukemia by kidney transplantation and tyrosine kinase inhibitors a case report"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-245003",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IMATINIB MESYLATE"
},
... |
{
"abstract": "A significant decrease in cardiovascular mortality has been reported with use of the SGLT2 inhibitor empagliflozin (Jardiance) to treat patients with type 2 diabetes who have established cardiovascular disease. The mechanism of this reduction is unclear, and these results may not apply to patients with type 2 diabetes and less advanced cardiovascular disease. Whether the increase in fractures reported with canagliflozin (Invokana) could also occur with empagliflozin remains to be established. All SGLT2 inhibitors are only modestly effective for treatment of diabetes.",
"affiliations": null,
"authors": null,
"chemical_list": "D001559:Benzhydryl Compounds; D001786:Blood Glucose; D005960:Glucosides; D007004:Hypoglycemic Agents; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D000068896:Canagliflozin; C570240:empagliflozin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-732X",
"issue": "57(1479)",
"journal": "The Medical letter on drugs and therapeutics",
"keywords": null,
"medline_ta": "Med Lett Drugs Ther",
"mesh_terms": "D000818:Animals; D001559:Benzhydryl Compounds; D001786:Blood Glucose; D000068896:Canagliflozin; D002318:Cardiovascular Diseases; D002986:Clinical Trials as Topic; D003924:Diabetes Mellitus, Type 2; D005960:Glucosides; D006801:Humans; D007004:Hypoglycemic Agents; D058028:Research Report; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors",
"nlm_unique_id": "2985240R",
"other_id": null,
"pages": "139-40",
"pmc": null,
"pmid": "26445203",
"pubdate": "2015-10-12",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "SGLT2 inhibitors: new reports.",
"title_normalized": "sglt2 inhibitors new reports"
} | [
{
"companynumb": "US-JNJFOC-20151114703",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CANAGLIFLOZIN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nEarly antithrombotic therapy after bioprosthetic aortic valve replacement (AVR) is controversial. This study aimed to retrospectively compare between warfarin and aspirin treatment in the 3 months after bioprosthetic AVR for elderly patients more than 60 years old, and to determine the optimal antithrombotic therapy.\n\n\nMETHODS\nThis retrospective study included 479 patients in single center from January 1994 to June 2014. Patients were divided into two groups (Wa group, warfarin; As group, aspirin). We searched our computerized clinical database for thromboembolic or bleeding events. Propensity score analysis was conducted to adjust for selection bias.\n\n\nRESULTS\nAll patients, except one patient, were followed-up in the out-patient department for 3 months after the operation. In all, 86 propensity-matched patient-pairs were derived. Early operative outcomes were similar in both the groups. There are one patient of thromboembolic event and three patients of bleeding events, but the prevalence was not significantly different (p >0.999).\n\n\nCONCLUSIONS\nThe incidence of thromboembolic and bleeding events during early 3 months after bioprosthetic AVR were similar in Wa and As groups. If the patient does not have indications of warfarin, early antithrombotic therapy with aspirin only may be easier and more feasible for elderly patients.",
"affiliations": "Department of Thoracic and Cardiovascular Surgery, Gil Medical Center, Gachon University, Incheon, Korea.;Department of Thoracic and Cardiovascular Surgery, Chonnam National University Hospital, College of Medicine, Gwangju, Korea.;Department of Thoracic and Cardiovascular Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Thoracic and Cardiovascular Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Thoracic and Cardiovascular Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Thoracic and Cardiovascular Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Thoracic and Cardiovascular Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.",
"authors": "Lee|Seok In|SI|;Lee|Kyo Seon|KS|;Kim|Joon Bum|JB|;Choo|Suk Jung|SJ|;Chung|Cheol Hyun|CH|;Lee|Jae Won|JW|;Jung|Sung-Ho|SH|",
"chemical_list": "D005343:Fibrinolytic Agents; D014859:Warfarin; D001241:Aspirin",
"country": "Japan",
"delete": false,
"doi": "10.5761/atcs.oa.16-00297",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-1098",
"issue": "23(3)",
"journal": "Annals of thoracic and cardiovascular surgery : official journal of the Association of Thoracic and Cardiovascular Surgeons of Asia",
"keywords": "aortic valve replacement; bioprostheses; oral anticoagulation",
"medline_ta": "Ann Thorac Cardiovasc Surg",
"mesh_terms": "D000368:Aged; D001021:Aortic Valve; D001022:Aortic Valve Insufficiency; D001024:Aortic Valve Stenosis; D001241:Aspirin; D001705:Bioprosthesis; D016009:Chi-Square Distribution; D004334:Drug Administration Schedule; D005260:Female; D005343:Fibrinolytic Agents; D006350:Heart Valve Prosthesis; D019918:Heart Valve Prosthesis Implantation; D006470:Hemorrhage; D006801:Humans; D016015:Logistic Models; D008297:Male; D057216:Propensity Score; D011474:Prosthesis Design; D056910:Republic of Korea; D012189:Retrospective Studies; D012307:Risk Factors; D013923:Thromboembolism; D013997:Time Factors; D016896:Treatment Outcome; D014859:Warfarin",
"nlm_unique_id": "9703158",
"other_id": null,
"pages": "128-134",
"pmc": null,
"pmid": "28367855",
"pubdate": "2017-06-20",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D064888:Observational Study",
"references": "15289387;15867776;20510209;12446543;15383476;22315272;22257078;22921973;24621565;17670662;22922415;24603191;22493097;19262444;17515465",
"title": "Early Antithrombotic Therapy after Bioprosthetic Aortic Valve Replacement in Elderly Patients: A Single-Center Experience.",
"title_normalized": "early antithrombotic therapy after bioprosthetic aortic valve replacement in elderly patients a single center experience"
} | [
{
"companynumb": "KR-SUN PHARMACEUTICAL INDUSTRIES LTD-2018RR-161086",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugad... |
{
"abstract": "BACKGROUND\nWhipple's disease is a rare infectious disease caused by Tropheryma whipplei with protean clinical manifestations. This infection may mimic chronic inflammatory rheumatisms.\n\n\nMETHODS\nWe report two cases of Whipple's disease diagnosed in the context of an inflammatory disease with anti-tumor necrosis factor alpha failure. The first patient was a 58-year-old white man with psoriatic spondylarthritis, who was treated with adalimumab, etanercept, infliximab, tocilizumab and golimumab. The second was a 73-year-old white man with rheumatoid arthritis, who received treatment with infliximab, then etanercept and rituximab.\n\n\nCONCLUSIONS\nWhipple's disease should be suspected in all patients diagnosed with chronic inflammatory rheumatism, partially controlled or not controlled by treatment with tumor necrosis factor alpha blockers, whose condition worsens after treatment.",
"affiliations": "Department of Internal Medicine, Hospital General Universitario de Alicante, c/ Pintor Baeza, 12, 03010, Alicante, Spain. jramosrincon@yahoo.es.;Department of Internal Medicine, Hospital Marina Baixa, Avenida Alcalde Jaume Botella Mayor, 7, Villajoyosa, 03570, Alicante, Spain. pasquau_fra@gva.es.;Department of Internal Medicine, Hospital Marina Baixa, Avenida Alcalde Jaume Botella Mayor, 7, Villajoyosa, 03570, Alicante, Spain. norathais@hotmail.com.;Department of Internal Medicine, Hospital General Universitario de Alicante, c/ Pintor Baeza, 12, 03010, Alicante, Spain. beatrizvn@gmail.com.;Department of Internal Medicine, Hospital Marina Baixa, Avenida Alcalde Jaume Botella Mayor, 7, Villajoyosa, 03570, Alicante, Spain. angelanavarroc@hotmail.com.;Department of Rheumatology, Hospital General Universitario de Alicante, c/ Pintor Baeza, 12, 03010, Alicante, Spain. martinez_agu@gva.es.;Department of Rheumatology, Hospital Marina Baixa, Avenida Alcalde Jaume Botella Mayor, 7, Villajoyosa, 03570, Alicante, Spain. j.rosas.gs@gmail.com.;Department of Gastroenterology, Hospital General Universitario de Alicante, c/ Pintor Baeza, 12, 03010, Alicante, Spain. gutierrez_ana@gva.es.;Department of Internal Medicine, Hospital General Universitario de Alicante, c/ Pintor Baeza, 12, 03010, Alicante, Spain. sanchez_rosmar@gva.es.",
"authors": "Ramos|Jose M|JM|;Pasquau|Francisco|F|;Galipienso|Nora|N|;Valero|Beatriz|B|;Navarro|Angela|A|;Martinez|Agustín|A|;Rosas|José|J|;Gutiérrez|Ana|A|;Sanchez-Martínez|Rosario|R|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D014409:Tumor Necrosis Factor-alpha; D000069283:Rituximab; C529000:golimumab; D000069285:Infliximab; D000068879:Adalimumab; C502936:tocilizumab; D000068800:Etanercept",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-015-0632-6",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 63210.1186/s13256-015-0632-6Case ReportWhipple’s disease diagnosed during anti-tumor necrosis factor alpha treatment: two case reports and review of the literature Ramos Jose M. +34965933000jramosrincon@yahoo.es Pasquau Francisco pasquau_fra@gva.es Galipienso Nora norathais@hotmail.com Valero Beatriz beatrizvn@gmail.com Navarro Angela angelanavarroc@hotmail.com Martinez Agustín martinez_agu@gva.es Rosas José j.rosas.gs@gmail.com Gutiérrez Ana gutierrez_ana@gva.es Sanchez-Martínez Rosario sanchez_rosmar@gva.es Department of Internal Medicine, Hospital General Universitario de Alicante, c/ Pintor Baeza, 12, 03010 Alicante, Spain Department of Medicine, Miguel Hernández University of Elche, Sant Joan d’Alacant, 03550 Spain Department of Internal Medicine, Hospital Marina Baixa, Avenida Alcalde Jaume Botella Mayor, 7, Villajoyosa, 03570 Alicante Spain Department of Rheumatology, Hospital General Universitario de Alicante, c/ Pintor Baeza, 12, 03010 Alicante, Spain Department of Rheumatology, Hospital Marina Baixa, Avenida Alcalde Jaume Botella Mayor, 7, Villajoyosa, 03570 Alicante Spain Department of Gastroenterology, Hospital General Universitario de Alicante, c/ Pintor Baeza, 12, 03010 Alicante, Spain Servicio de Medicina Interna, Hospital General Universitario de Alicante, c/ Pintor Baeza, 12, 03010 Alicante, Spain 28 7 2015 28 7 2015 2015 9 1657 1 2015 3 6 2015 © Ramos et al. 2015This 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\nWhipple’s disease is a rare infectious disease caused by Tropheryma whipplei with protean clinical manifestations. This infection may mimic chronic inflammatory rheumatisms.\n\nCase presentation\nWe report two cases of Whipple’s disease diagnosed in the context of an inflammatory disease with anti-tumor necrosis factor alpha failure. The first patient was a 58-year-old white man with psoriatic spondylarthritis, who was treated with adalimumab, etanercept, infliximab, tocilizumab and golimumab. The second was a 73-year-old white man with rheumatoid arthritis, who received treatment with infliximab, then etanercept and rituximab.\n\nConclusions\nWhipple’s disease should be suspected in all patients diagnosed with chronic inflammatory rheumatism, partially controlled or not controlled by treatment with tumor necrosis factor alpha blockers, whose condition worsens after treatment.\n\nKeywords\nWhipple diseaseInfliximabEtanerceptSpondylarthritisRheumatoid arthritisissue-copyright-statement© The Author(s) 2015\n==== Body\nIntroduction\nWhipple’s disease (WD) is a rare, chronic, systemic infection caused by Tropheryma whipplei, a Gram-positive intracellular bacillus related to actinomycetes. WD is a rare infectious disease with protean clinical manifestations. WD may often manifest itself as chronic seronegative oligoarthritis or polyarthritis, which may mimic various joint diseases (rheumatoid arthritis or spondylarthritis). The organism may be detectable by periodic acid–Schiff (PAS) staining of affected organ tissue, especially small bowel, or with 16S ribosomal ribonucleic acid (rRNA) gene identification by polymerase chain reaction (PCR) amplification [1, 2].\n\nIncreased susceptibility to infections is a major safety concern with tumor necrosis factor alpha (TNF-α) antagonist treatment [3]. Infection should be ruled out in atypical cases by searching for foci [4]. Several authors have shown that treatment with TNF-α blockers seems to increase the risk of exacerbating WD [5] or worsening preexisting WD, triggering visceral disorders [4, 6].\n\nWe describe two cases of patients who were given TNF-α antagonists to treat long-standing joint disease, who then experienced the involvement of several organs leading to the diagnosis of WD. We also review the case reports of WD diagnosed during anti-TNF-α treatment.\n\nCase presentation\nFrom 2000 to 2012, eight cases of WD were diagnosed at two Spanish hospitals (Hospital General Universitario de Alicante, Alicante and Hospital Marina Baixa, Villajoyosa, Alicante), and two cases were associated with use of TNF-α antagonists.\n\nCase report 1\nA 58-year-old white man with inflammatory back pain and large and small joint arthritis had been diagnosed with psoriatic spondylarthritis 9 years ago. Our patient had been treated with adalimumab for 4 months, after that with etarnecept for 8 months, then infliximab for 2 months, tocilizumab for 21 months and golimumab for 1 month, to treat the pain in his back and neck with the consequent difficulty in bending, and arthritis of his knee and interphalangeal joint arthritis. Our patient was admitted to the hospital with abdominal septic shock. A computed tomography (CT) scan showed multiple retroperitoneal lymph nodes. The colonoscopy result was normal and the biopsy result was normal. Three months later, he was admitted again with a fever and heart failure, which was interpreted as a side effect of the golimumab treatment. One year after that, he was admitted to the hospital with abdominal pain, diarrhea and weight loss progressing to a severe wasting syndrome. At this time, he was being treated with 5mg prednisone plus hydroxicloroquine and methotrexate (MTX). Abnormal laboratory test results included a white blood cell (WBC) count of 14,630/mm3, a hemoglobin level of 9.6g/dL and an erythrocyte sedimentation rate (ESR) of 58mm/h. A CT scan showed multiple lymph nodes. Endoscopy showed diffuse intestinal lymphangiectasia (Fig. 1). A duodenal biopsy showed distortion of the villous architecture with abundant macrophages, and bacilliform intracytoplasmic structures that stained positive with PAS with diastase digestion compatible with WD. A PCR assay for detecting T. whipplei was not done. Intravenous ceftriaxone (2g daily for 2 weeks) was commenced followed by trimethoprim and sulphamethoxazole with improved symptoms after 3 weeks; treatment was continued for 18 months. One year later, a new gastroscopy with duodenal biopsy was done. It did not show intestinal lymphangiectasia. A PCR assay result for T. whipplei was negative. There were no relapses after 19 months.Fig. 1 Endoscopy. White lesions compatible with diffuse intestinal lymphangiectasia\n\n\n\nCase report 2\nA 73-year-old white man had been diagnosed with rheumatoid arthritis with migratory arthralgias of the large joints and chronic obstructive pulmonary disease 14 years ago. Our patient had been treated with gold salts, chloroquine and MTX. Fourteen years after diagnosis of his diseases, infliximab was added to the MTX treatment without improvement, so infliximab was suspended 8 months later because there was no improvement of his migratory nondeforming polyarthritis; treatment with MTX was continued. After 5 months infliximab was stopped, and etanercept was added to MTX for 6 months. During treatment with etanercept, he suffered an acute middle cerebral artery ischemic stroke of atherothrombotic origin, and etanercept was stopped. Six months later, rituximab was added for 3 months, without improvement. After that, MTX was stopped and leflunomide (20mg/day) was initiated and from that point, our patient presented with abdominal pain, chronic diarrhea and edema in his lower extremities, a consequence of chronic malabsorption. After 1 year on this treatment, he was admitted to hospital with rectal bleeding, however, the colonoscopy and gastroscopy results were normal and the colon biopsy showed unspecific changes. At that time, our patient was being treated with leflunomide, which was then stopped. Three months after that admission, our patient was admitted with weight loss, abdominal pain and diarrhea. On physical examination, he had hyperpigmentation of the skin but no other abnormalities. Abnormal laboratory test results included a WBC count of 13,800/mm3, a hemoglobin level of 9.2g/dL, mean corpuscular volume (MCV) of 72fl, an albumin level of 1.8g/dL, and an ESR of 13mm/h. A thoracic and abdominal CT scan showed pericardial effusion with calcifications, bronchiectasis in his lower right lung, intestinal bowel with distention and no abdominal lymph nodes. A duodenal biopsy showed altered architecture and intracellular bacilli on PAS stain. T. whipplei was detected from duodenal tissue by PCR assay. A cerebral magnetic resonance imaging scan showed multiple hyperintensive lesions in both cerebral hemispheres, cortical retraction, increased subarachnoid space and ventricular dilatation. The PCR assay result for T. whipplei in his cerebrospinal fluid was negative. Intravenous ceftriaxone (2g daily) was commenced for 2 weeks followed by trimethoprim and sulphamethoxazole with improvement of his symptoms (the diarrhea, malabsorption and pericardial effusion). One year later, a new gastroscopy with duodenal biopsy was done. It showed altered architecture and intracellular bacilli on PAS stain, but the PCR assay result for T. whipplei was negative. Because of mild renal failure, trimethoprim and sulphamethoxazole was changed for doxycycline plus hydroxychloroquine, and normal renal function was recovered.\n\nDiscussion\nWe reviewed database cases recorded in PubMed using the following retrieval scheme: [“Whipple disease” and (“infliximab” or “adalimumab” or “etanercept” or “golimumab” or “tocilizumab”)]. We gathered the following data from the medical cases reported: age, sex, joint diseases, years with joint disease, TNF-α antagonist therapy, days with TNF-α antagonist therapy before WD was diagnosed, symptoms related to WD, organs affected by WD, investigations for diagnosing WD, treatment and outcome of WD.\n\nWe retrieved 14 cases from the PubMed database from January 2004 to December 2014. All the case reports recorded and the two case reports in this manuscript are from European scientists [4–10], except one case from the United States of America [11]. Four case reports were published in a language other than English [7, 8, 10]. Table 1 shows age, sex, joint diseases, years with joint disease, TNF-α antagonist therapy, days with TNF-α antagonist therapy before WD was diagnosed, symptoms related to WD, organs affected by WD, investigations for diagnosing WD, treatment and outcome of WD for 16 WD cases. Out of 16 cases, there were 14 men and two women patients with an age range of 33 to 73 years old. Six patients were diagnosed as ankylosis spondylitis (AS), six as seronegative spondyloarthropathy (SA) (seronegative chronic polyarthritis), two as rheumatoid arthritis (RA), one as Still’s disease (SD), and one as psoriatic arthritis. All patients had osteoarticular (with pain and swelling) involvement and 15 had gastrointestinal involvement (diarrhea, weight loss, abdominal pain, malabsorption, and so on) [4–12]. Moreover, some patients had extra-articular and gastrointestinal involvement, such as vertebra [5], meningitis [6], pericarditis ([6], present report 2 (PR2)), abdominal or thoracic lymph nodes ([4, 6], PR1), gingiva such as scurvy [9] and heart valve involvement [10]. All were diagnosed by histological biopsy, in 14 of 15 cases a PCR assay for DNA detection of T. whipplei was done, and all were positive. The DNA of T. whipplei by PCR assay was detected in duodenal or other gastrointestinal-colonic areas; saliva, blood, feces, bone or cerebrospinal fluid [4–11]. All patients recovered from gastrointestinal involvement when the TNF-α antagonist was stopped and antibiotic treatment was started.Table 1 Features of the patients’ diagnosis of Whipple’s disease after tumor necrosis factor alpha antagonist initiation\n\nAuthors / country / language of publication\tAge / sex\tUnderlying disease previous WD diagnosis / time with that diagnosis\tTNF-α drugs and immunosuppressive treatment\tStart of acute symptoms after TNF-α blockade\tSymptoms after TNF-α blockade\tOrgan involvement\tHistological diagnosisa\n\tResult of PCR for Tropheryma whipplei\n\tTreatment for WD\tOutcome\t\nKneitz et al. (2005) [4] / Germany / English\t34y / M\tSD\tMethotrexate + infliximab (2w)\t2w\tWeight loss, erythema nodosum, diarrhea, lymph node enlargement, and a sigmoidovesical fistula\tSkin, gastroduodenitis and sigmoidovesical\tPositive in fistula and lymph nodes\tPositive in lymph node, small bowel and sigmoidovesical fistula\tSXT (12m)\tResolved within 1 year\t\nKremer et al. (2008) [7] / Germany / German\t47y / M\tSA / 4y\tLeflunomide + adalimumab\t\tFever, weight loss, and severe arthralgia\t\tPositive in duodenal tissue\tPositive in duodenal tissue\tSXT\t\t\nSpoerl et al. (2009) [5] / Switzerland / English\t64y / M\tSA / 5 + 3y\tEtanercept\t4m\tLethargy, night sweats, weight loss\tGastrointestinal and vertebral\tPositive in duodenal tissue and vertebral tissue\tPositive in gastric and vertebral tissue\tCeftriaxone (2w), then, SXT (2y), (12m) then doxycycline + HC (18m)\tNo relapses after 34-month follow-up\t\nAhmadi-Simab et al. (2009) [8] / Germany / German\t33y / F\tAS / 8y\tEtanercept\t12m\tDiarrhea, abdominal pain and weight loss\t\tNegative in duodenal tissue\tPositive in duodenal biopsy\tCeftriaxone (2w) after SXT\t\t\nHoppé et al. (2010) [6] / France / English\t67y / F\tSA / 7y\tInfliximab (4m)\t4m\tChest pain, dyspnea, polyarthritis\t\tPositive in duodenal tissue\tPositive in duodenal tissue. Negative in blood and saliva\tCeftriaxone (2w), then doxycycline (24m)\tResolved within 15d. No relapses after 71-month follow-up\t\nHoppé et al. (2010) [6] / France / English\t40y / M\tAS / 1y\tInfliximab (18m) then etanercept (7m) then adalimumab (1m)\t26m\tDiarrhea, weight loss, fever, arthralgia\tWidespread ileocolitis, gastroduodenitis, meningitis\tPositive in duodenal tissue\tPositive in saliva, feces and cerebrospinal fluid. Negative in blood\tDoxycycline, HC, and SXT (15d), then SXT was replaced by sulfasalazine 4g/day\tResolved within 2 months. No relapses after 17-month follow-up\t\nHoppé et al. (2010) [6] / France / English\t60y / M\tAS / 8y\tEtanercept (9m)\t9m\tFever, night sweats, polyarthritis, chest pain\tPericarditis, mediastinal and abdominal lymphadenopathy, duodenitis\tNegative in duodenal tissue\tPositive in the duodenal sample, saliva, feces, and lymph nodes\tDoxycycline + HC (15m)\tResolved within 7d. No relapses after 30-month follow-up\t\nHoppé et al. (2010) [6] / France / English\t47y / M\tRA / 17y\tInfliximab (36m), then etanercept (42m), then adalimumab (6m), then rituximab, abatacept then infliximab (1m)\t85m\tFever, night sweats, weight loss, polyarthritis, radio carpal arthropathy. transient diplopia, myalgia, subacute depression\tPericarditis, abdominal lymphadenopathy, duodenitis\t\tPositive PCR assay in the duodenal sample, blood, saliva, and feces. Negative PCR assay in cerebrospinal fluid\tDoxycycline + HC (UT)\tResolved within 2m No relapses after 15-month follow-up\t\nHoppé et al. (2010) [6] / France / English\t38y / M\tAS / 9y\tEtanercept (2m)\t9m\tDiarrhea, abdominal pain. weight loss, blurred vision\tHemorrhagic gastroduodenitis, hemorrhagic colitis, mediastinal and cervical lymphadenopathy, splenomegaly, meningitis\tPositive in duodenum and colon\tPositive PCR assay in blood, saliva, cerebrospinal fluid, and feces\tDoxycycline 200mg/day. HC 600mg/day. (UT)\tResolved within 3w. No relapses after 13-month follow-up\t\nHmamouchi et al. (2010) [9] / France / English\t35y / M\tAS / 4y\tEtanercept\t4m\tGingival nodule, purpura, abdominal pain diarrhea, fatigue, weight loss\tGingiva and colitis\tPositive in colon tissue\tPositive in blood, stool, and cerebrospinal fluid\tSXT (NR)\tResolved within 3 months\t\nDaïen et al. (2010) [10] / France / English\t70y / M\tSA / 27y\tEtanercept (18m)\tNR\tFever and dyspnea\tEndocarditis of aortic valve\tNegative in duodenal tissue and, aortic valve\tPositive in aortic valve\tDoxycycline HC + SXT (18m)\tResolved. No relapses after 21-month follow-up\t\nGaddy et al., (2012) [12] / USA / English\t46y / M\tAS / 10y\tPrednisone + MTX + infliximab (24m), then adalimumab\t24m\tFever, migratory arthritis, weight loss, diarrhea\tGastroenteritis\tPositive in duodenal tissue\tPositive in blood and duodenal tissue\tCeftriaxone (x2w) after SXT\tNR\t\nSparsa et al. (2013) [11] / France / French\t53y / M\tSA\tEtanercept (3m), then adalimumab (6m)\t9m\tPolyarthralgia peripheric, arthritis metarsophalangeal\t\tPositive in duodenal tissue biopsy\tPositive in saliva and duodenal tissue\tDoxycycline + HC (18m)\tResolved within 3 weeks. No relapses after 18-month follow-up\t\nSparsa et al. (2013) [11] / France / French\t42y / M\tSA / 2m\tAdalimumab (9m) and then etanercept (4m)\t13m\tPolyarthralgia peripheric\t\tPositive in duodenal and gastric tissue\tPositive in saliva and duodenal tissue\tDoxycycline + HC and then doxycycline alone\tResolved within 3 weeks. No relapses after 17- month follow-up\t\nPresent report\t58y / M\tPsoriatic spondyloarthropathy/ 14y\tAdalimumab (4m), then etanercept (8m), infliximab (2m), tocilizumab (21m), golimumab (1m)\t36m\tAbdominal pain, diarrhea and weight loss\tDuodenitis and abdominal lymph nodes\tPositive in duodenal tissue\tNot done\tCeftriaxone (14d), then SXT during (UT)\tResolved within 3 weeks. No relapses after 9-month follow-up.\t\nPresent report\t78y / M\tRA / 19y\tInfliximab (6m), etanercept (6m), rituximab (3m), leflunomide (24m)\t24m\tAbdominal pain, diarrhea and weight loss\tDuodenitis, and pericardial effusion\tPositive in duodenal tissue\tPositive in duodenal biopsy. Negative in cerebrospinal fluid\tCeftriaxone (14d), then SXT for (12m) then doxycycline + HC\tResolved within 3 weeks. No relapses after 18-month follow-up\t\n(UT) Patient still under treatment\n\n\nTNF-α tumor necrosis factor alpha, WD Whipple’s disease, PCR polymerase chain reaction, y year, SD Still’s disease, w week, SXT cotrimoxazole, m month, SA spondyloarthropathy (seronegative chronic polyarthritis), HC hydroxychlorochine, AS ankylosis spondylitis, RA rheumatoid arthritis, NR not reported, MTX methotrexate\n\n\naHistological diagnosis = intracellular bacilli on periodic acid–Schiff stain\n\n\n\nConclusions\nWD is a systemic infection, which involves many chronic manifestations, especially digestive disorders. Some of the manifestations involved are articular symptoms, which can appear as inflammatory rheumatism, such as rheumatoid arthritis or spondylarthritis. Beside these symptoms, the microorganism responsible for T. whipplei disease has also been found in DNA recovered from articular fluid and bones of these patients [13, 14].\n\nOur two cases illustrate that alternative etiologies in patients with articular symptoms should be considered, most importantly following clinical deterioration by immunomodulatory agents like TNF-α inhibitors. The reflections to be made with respect to the analysis of these two cases are to speculate that these patients either had WD with mainly articular manifestations, which had been considered as a rheumatic disease; or in fact, they had a rheumatic disease, which, through the treatment with TNF drugs, may have reactivated T. whipplei and the appearance, therefore, of its florid symptoms that we managed to diagnose.\n\nTherapies with immunomodulators, TNF-α inhibitors, and corticosteroids may transform an infection with T. whipplei, normally at a subacute stage, into a septic, life-threatening disease. Thus, it seems that TNF-α blockade allowed for rapid dissemination of T. whipplei by inhibiting some important immune defense mechanisms. In the later phase of an infection, the TNF-α blocker contributes to limiting the extent of cell and/or tissue damage by inducing apoptosis and maintaining granuloma formation [15, 16], which are important mechanisms in T. whipplei infections. TNF-α blockade might result in the loss of some of the immunological control mechanisms and, therefore, facilitate rapid bacterial dissemination and severe exacerbation of the disease. This is the situation in the first case.\n\nIn the second case, the TNF-α blockade was used before the gastrointestinal symptoms appeared. However, with anti-TNF-α treatment, our patient had an acute stroke. After stopping the treatment, our patient recovered from his central nervous system symptoms. When the gastrointestinal involvement of WD was discovered, an examination of DNA for T. whipplei was performed but it was negative. In this case, it was not clear that our patient had neurological involvement of WD, and real improvement of WD after stopping the TNF-α blockade treatment was not clear. There are several cases reported of patients with rheumatic diseases and, during follow-up, they were diagnosed with WD [13, 14, 17, 18]. Thus, the case report of a patient with an initial diagnosis of rheumatoid arthritis who developed pericarditis caused by WD (diagnosed by pericardial biopsy) and the patient who had not been treated previously with TNF-α blocker [17].\n\nIn summary, anti-TNF-α treatment seems to increase the risk of exacerbation of WD and WD may mimic a rheumatic disease.\n\nConsent\nWritten informed consent was obtained from the patients 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\nAbbreviations\nASAnkylosis spondylitis\n\nCTComputed tomography\n\nESRErythrocyte sedimentation rate\n\nHCHydroxychlorochine\n\nmmonth\n\nMCVMean corpuscular volume\n\nMTXMethotrexate\n\nNRNot reported\n\nPASPeriodic acid–Schiff\n\nPRPresent report\n\nPCRPolymerase chain reaction\n\nRARheumatoid arthritis\n\nSASpondyloarthropathy (seronegative chronic polyarthritis)\n\nSDStill’s diseases\n\nSXTCotrimoxazole\n\nrRNAribosomal ribonucleic acid\n\nTNF-αTumor necrosis factor alpha\n\nwweek\n\nWBCWhite blood cell\n\nWDWhipple’s disease\n\nyyear\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nAll authors treated the patients during the years 2002 to 2014. Each of them has made substantial contributions to data acquisition and interpretation. All of them have been involved in drafting the manuscript. All authors read and approved the final manuscript.\n\nAcknowledgements\nWe should like to acknowledge the personnel from the Department of Internal Medicine Rheumatology and Gastroenterology of the Hospital General Universitario de Alicante and the Hospital Marina Baixa, Villajoyosa, Alicante (Spain) for attending to the patients.\n==== Refs\nReferences\n1. Fenollar F Puéchal X Raoult D Whipple’s disease N Engl J Med. 2007 356 55 66 10.1056/NEJMra062477 17202456 \n2. Schneider T Moos V Loddenkemper C Marth T Fenollar F Raoult D Whipple’s disease: new aspects of pathogenesis and treatment Lancet Infect Dis. 2008 8 179 90 10.1016/S1473-3099(08)70042-2 18291339 \n3. Rosenblum H Amital H Anti-TNF therapy: safety aspects of taking the risk Autoimmun Rev. 2011 10 563 8 10.1016/j.autrev.2011.04.010 21570495 \n4. Kneitz C Suerbaum S Beer M Müller J Jahns R Tony HP Exacerbation of Whipple’s disease associated with infliximab treatment Scand J Rheumatol. 2005 34 148 51 10.1080/03009740510015230 16095013 \n5. Spoerl D Bär D Cooper J Vogt T Tyndall A Walker UA Multisegmental spondylitis due to Tropheryma whipplei: case report Orphanet J Rare Dis. 2009 4 13 10.1186/1750-1172-4-13 19493331 \n6. Hoppé E Masson C Audran M Drillon M Andreu M Saraux A Whipple’s disease diagnosed during biological treatment for joint disease Joint Bone Spine. 2010 77 335 9 10.1016/j.jbspin.2010.03.015 20471891 \n7. Kremer AE Budenhofer U Beuers U Rust C A 47-year-old dog breeder with chronic polyarthritis, weight loss and high fever Z Gastroenterol 2008 46 431 4 10.1055/s-2007-963690 18461518 \n8. Ahmadi-Simab K Schnitzler P Schnitzler P Whipple’s disease with normal duodenal histology and ankylosing spondylitis Dtsch Med Wochenschr 2009 134 127 30 10.1055/s-0028-1123969 19148854 \n9. Hmamouchi I Costes V Combe B Morel J Scurvy as the presenting illness of Whipple’s disease exacerbated by treatment with etanercept in a patient with ankylosing spondylitis J Rheumatol. 2010 37 1077 8 10.3899/jrheum.091301 20439534 \n10. Daïen CI Cohen JD Makinson A Battistella P Bilak EJ Jorgensen C Whipple’s endocarditis as a complication of tumour necrosis factor-alpha antagonist treatment in a man with ankylosing spondylitis Rheumatology (Oxford) 2010 49 1600 2 10.1093/rheumatology/keq089 20371501 \n11. Sparsa L Fenollar F Gossec L Leone J Pennaforte JL Dougados M Whipple disease revealed by anti-TNFα therapy Rev Med Interne 2013 34 105 9 10.1016/j.revmed.2012.10.371 23199973 \n12. Gaddy JR Khan ZZ Chaser B Scofield RH Whipple’s disease diagnosis following the use of TNF-α blockade Rheumatology (Oxford) 2012 51 946 10.1093/rheumatology/ker387 22179734 \n13. O’Duffy JD Griffing WL Li CY Abdelmalek MF Persing DH Whipple’s arthritis: direct detection of Tropheryma whipplei in synovial fluid and tissue Arthritis Rheum. 1999 42 812 7 10.1002/1529-0131(199904)42:4<812::AID-ANR27>3.0.CO;2-S 10211899 \n14. Weber U Morf MH Gubler JG Altwegg M Maibach RC Spondylodiscitis as the first manifestation of Whipple’s disease: a removal worker with chronic low back pain Clin Rheumatol. 2003 22 443 6 10.1007/s10067-003-0786-2 14677024 \n15. Keane J Gershon S Wise RP Mirabile-Levens E Kasznica J Schwieterman WD Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent New Engl J Med. 2001 345 1098 104 10.1056/NEJMoa011110 11596589 \n16. Cunnane G Doran M Bresnihan B Infections and biological therapy in rheumatoid arthritis Best Pract Res Clin Rheumatol. 2003 17 345 63 10.1016/S1521-6942(02)00107-9 12787529 \n17. Makol A Maleszewski JJ Warrington KJ A case of refractory rheumatoid pericarditis Arthritis Care Res (Hoboken) 2012 64 935 40 10.1002/acr.21645 22337605 \n18. von Gerstenbergk C Lorenz HM Blank N Fever and arthritis: rheumatic or Whipple’s disease? Dtsch Med Wochenschr 2011 136 1656 9 10.1055/s-0031-1281569 21833885\n\n",
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"issn_linking": "1752-1947",
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"journal": "Journal of medical case reports",
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"medline_ta": "J Med Case Rep",
"mesh_terms": "D000068879:Adalimumab; D000368:Aged; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D003937:Diagnosis, Differential; D000068800:Etanercept; D006801:Humans; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D012213:Rheumatic Fever; D000069283:Rituximab; D014409:Tumor Necrosis Factor-alpha; D008061:Whipple Disease",
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"pubdate": "2015-07-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "18461518;18291339;19493331;20439534;20471891;20371501;21570495;21833885;22179734;22337605;12787529;11596589;23199973;14677024;10211899;16095013;17202456;19148854",
"title": "Whipple's disease diagnosed during anti-tumor necrosis factor alpha treatment: two case reports and review of the literature.",
"title_normalized": "whipple s disease diagnosed during anti tumor necrosis factor alpha treatment two case reports and review of the literature"
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"abstract": "Menopausal symptoms may adversely affect quality of life and health in women diagnosed with a gynecologic malignancy. The aim of this study was to determine the incidence of adverse outcomes, including cancer recurrence, venous thromboembolism, and secondary malignancies, among patients with a history of endometrial, ovarian, or cervical cancer prescribed vaginal estrogen for genitourinary syndrome of menopause.\n\n\n\nA retrospective cohort study was performed including women who were diagnosed with endometrial, ovarian, or cervical cancer from January 1, 1991 to December 31, 2017 and subsequently treated with vaginal estrogen for genitourinary syndrome of menopause. Patients were included if not undergoing active cancer treatment and were disease-free based on most recent cancer surveillance visit with physical exam and/or imaging. Demographics, oncologic variables, estrogen use, and adverse outcomes were recorded. Descriptive statistics and univariate analysis were performed.\n\n\n\nOf 244 women who received vaginal estrogen, 52% (n=127) had a history of endometrial, 25.4% (n=62) cervical, 18.9% (n=46) ovarian cancer, and 3.7% (n=9) low malignant potential tumors. The mean age and body mass index were 55.5±12.5 years and 29.2±8.6 mg/kg2, respectively. With a median follow-up of 80.2 months, the incidence of recurrence for endometrial, ovarian, and cervical cancer was 7.1% (n=9), 18.2% (n=10), and 9.7% (n=6), respectively. In patients with endometrial cancer who recurred, the incidence was 2.4% (n=3) for stage I/II and 4.7% (n=6) for stage III/IV disease. Similarly, recurrence rates for ovarian cancer were 4.3% (n=2) for stage I/II and 17.4% (n=8) for stage III/IV disease. All cervical cancer recurrences were in patients with stage I/II disease. Adverse outcomes including breast cancer (1.6%, n=4), secondary malignancy (2.5%, n=6), and venous thromboembolism (2.5%, n=6) were rare.\n\n\n\nIn women with a history of endometrial, ovarian, or cervical cancer prescribed vaginal estrogen use for genitourinary syndrome of menopause, adverse outcomes, including recurrence and thromboembolic events, are infrequent. Vaginal estrogen may be considered safe in gynecologic cancer survivors.",
"affiliations": "Division of Gynecologic Oncology, Cleveland Clinic Foundation, Cleveland, Ohio, USA chambel2@ccf.org.;Women's Health Institute and Department of Obstetrics and Gynecology, Cleveland Clinic, Cleveland, Ohio, USA.;Division of Gynecologic Oncology, Cleveland Clinic Foundation, Cleveland, Ohio, USA.;Department of Urogynecology, Cleveland Clinic, Cleveland, Ohio, USA.;Gynecologic Oncology Division, Ob/Gyn and Women's Health Institute, Cleveland Clinic, Cleveland, Ohio, USA.",
"authors": "Chambers|Laura M|LM|;Herrmann|Alyssa|A|;Michener|Chad M|CM|;Ferrando|Cecile A|CA|;Ricci|Stephanie|S|",
"chemical_list": "D004967:Estrogens",
"country": "England",
"delete": false,
"doi": "10.1136/ijgc-2019-001034",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1048-891X",
"issue": "30(4)",
"journal": "International journal of gynecological cancer : official journal of the International Gynecological Cancer Society",
"keywords": "cervical cancer; female; genitalia; ovarian cancer; quality of life (PRO)/palliative care; uterine cancer",
"medline_ta": "Int J Gynecol Cancer",
"mesh_terms": "D000282:Administration, Intravaginal; D015331:Cohort Studies; D004967:Estrogens; D005260:Female; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms; D012189:Retrospective Studies; D002583:Uterine Cervical Neoplasms; D014594:Uterine Neoplasms",
"nlm_unique_id": "9111626",
"other_id": null,
"pages": "515-524",
"pmc": null,
"pmid": "32075898",
"pubdate": "2020-04",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Vaginal estrogen use for genitourinary symptoms in women with a history of uterine, cervical, or ovarian carcinoma.",
"title_normalized": "vaginal estrogen use for genitourinary symptoms in women with a history of uterine cervical or ovarian carcinoma"
} | [
{
"companynumb": "US-MYLANLABS-2020M1053142",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "Pregabalin (PRG) is indicated for the treatment of neuropathic pain, epilepsy and generalised anxiety disorder. Limited data exists on reference blood concentrations for this drug and levels above which death can be attributed to PRG toxicity. Furthermore, there is increasing evidence that the drug is subject to abuse. This study reviews the post-mortem blood concentrations of PRG analysed in the authors' laboratory between 2012 and 2014 in order to try and assign the likely therapeutic and fatal ranges. PRG was detected in 70 post-mortem blood samples of which 33% were at concentrations considered to be in excess of the reference range (above 17mg/L). PRG concentrations ranged from 0.05mg/L to 226mg/L (median 8.0mg/L) in the group as a whole and in one case a PRG concentration of 76mg/L was determined to be the likely cause of death as no other drugs of significance were involved. The results from this study are consistent with the scientific literature with respect to a high frequency of multidrug use, particularly with opioids/opiates which can increase the probability of a fatal outcome.",
"affiliations": "LGC, Toxicology Department, Queens Road, Teddington, Middlesex TW11 0LY, United Kingdom. Electronic address: Jane.eastwood@lgcgroup.com.;LGC, Toxicology Department, Queens Road, Teddington, Middlesex TW11 0LY, United Kingdom. Electronic address: lizziedavison@hotmail.co.uk.",
"authors": "Eastwood|Jane A|JA|;Davison|Elizabeth|E|",
"chemical_list": "D000069583:Pregabalin",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.forsciint.2016.05.033",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "266()",
"journal": "Forensic science international",
"keywords": "Blood drug concentration; Fatal poisoning; Post-mortem; Pregabalin; Therapeutic",
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D053593:Forensic Toxicology; D006801:Humans; D000069583:Pregabalin; D015813:Substance Abuse Detection; D019966:Substance-Related Disorders",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "197-201",
"pmc": null,
"pmid": "27295075",
"pubdate": "2016-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pregabalin concentrations in post-mortem blood-A two year study.",
"title_normalized": "pregabalin concentrations in post mortem blood a two year study"
} | [
{
"companynumb": "GB-NOVEL LABORATORIES, INC-2016-03165",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OXYCODONE"
},
"drugadditional": ... |
{
"abstract": "OBJECTIVE\nTo report two cases of major depressive disorder in which lamotrigine (LTG) induced anger with murderous impulse.\n\n\nMETHODS\nCase 1 was a 22-year-old man with symptoms of obsessive-compulsive disorder who developed major depressive disorder with antidepressant-induced hypomanic episodes. Case 2 was a 23-year-old woman experiencing an antidepressant-refractory depressive episode for whom remission was achieved by switching to a mood stabilizer and antipsychotics. In both cases LTG was started to treat the depressive episode.\n\n\nRESULTS\nCase 1 manifested with anger and murderous impulse when taking 125 mg/day of LTG. A reduction to 75 mg/day calmed this anger. Case 2 manifested with the same symptom when taking 25 mg/day of LTG, and the symptom immediately disappeared upon stopping LTG.\n\n\nCONCLUSIONS\nUse of LTG for epilepsy in intellectually disabled patients was reported to be associated with onset or exacerbation of aggressive or violent behavior. The two cases would suggest that LTG may cause anger so severe as to be accompanied with murderous impulse when administered to patients with mood disorders. Physicians should be cognizant of this possible, albeit infrequent, adverse effect even in use of LTG for mood disorders.",
"affiliations": "Department of Psychiatry, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke City, Tochigi 329-0498, Japan. Electronic address: saitoshinnosuke@gmail.com.;Department of Psychiatry, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke City, Tochigi 329-0498, Japan.;Department of Psychiatry, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke City, Tochigi 329-0498, Japan.",
"authors": "Saito|Shinnosuke|S|;Shioda|Katsutoshi|K|;Nisijima|Kouichi|K|",
"chemical_list": "D000927:Anticonvulsants; D014227:Triazines; D000077213:Lamotrigine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-8343",
"issue": "36(4)",
"journal": "General hospital psychiatry",
"keywords": "Anger with murderous impulse; Bipolarity; Lamotrigine; Mood disorder",
"medline_ta": "Gen Hosp Psychiatry",
"mesh_terms": "D000328:Adult; D000374:Aggression; D000786:Anger; D000927:Anticonvulsants; D001714:Bipolar Disorder; D003865:Depressive Disorder, Major; D005260:Female; D006801:Humans; D000077213:Lamotrigine; D008297:Male; D014227:Triazines; D055815:Young Adult",
"nlm_unique_id": "7905527",
"other_id": null,
"pages": "451.e1-2",
"pmc": null,
"pmid": "24736088",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Anger with murderous impulse induced by lamotrigine.",
"title_normalized": "anger with murderous impulse induced by lamotrigine"
} | [
{
"companynumb": "JP-WATSON-2015-07409",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "LAMOTRIGINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nMultisystem Inflammatory Syndrome is a rare condition that affects multiple organs following SARS-CoV-2 infection. It was first observed in children, however few cases of adults with Multisystem Inflammatory Syndrome (MIS-A) were published in the US and the UK. We present two cases of Multisystem Inflammatory Syndrome in adults which occurred in Germany.\n\n\nMETHODS\n#1: A 27-year-old male presented with fever (40 °C), right lower abdominal pain, diarrhea and peritonism. #2: A 21-year-old female presented with fever (40 °C) occipital headaches, neck stiffness, and somnolence.\n\n\nRESULTS\n#1: Increased inflammation parameters and elevated Nt-proBNP were found. Abdominal CT showed signs of ileitis terminalis and colitis. Crohn's disease was excluded endoscopically. Echocardiography showed minor pericardial effusion. A SARS-CoV-2 antibody test was positive. #2: Increased inflammation parameters and an increased Nt-proBNP were found. Cranial CT showed pathology. Meningitis was excluded via lumbar puncture. Thoracic CT and abdominal ultrasound showed no signs of infection. Echocardiography showed reduced LVEF (50 %). A SARS-CoV-2 antibody test was positive.\n\n\nRESULTS\n#1: Antibiotic therapy as well as oral prednisolone didn't improve the clinical course. High-dose vasopressor therapy was necessary. The clinical condition improved only after adding hydrocortisone therapy. #2 Despite antibiotic therapy the clinical condition deteriorated. Because of insufficient effect of hydrocortisone, high-dose immunoglobulins were administered. Consequently, symptoms improved and LVEF normalized.\n\n\nCONCLUSIONS\nMultisystem Inflammatory Syndrome presents as a chameleon of symptoms. In the context of the ongoing SARS-CoV-2 pandemic, rising numbers of cases in adults can be expected. In patients with fever, increased inflammation parameters and lack of other explanations, Multisystem Inflammatory Syndrome must be considered. Due to the potential severity of clinical courses and possible cardiac involvement, a therapy with hydrocortisone, ASS and immunoglobulins should be considered early.",
"affiliations": "DRK-Kliniken Berlin-Westend, Klinik für Innere Medizin, Schwerpunkt Kardiologie.;DRK-Kliniken Berlin-Westend, Klinik für Innere Medizin, Schwerpunkt Gastroenterologie.",
"authors": "Rieper|Karl|K|;Sturm|Andreas|A|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1055/a-1404-6763",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-0472",
"issue": "146(9)",
"journal": "Deutsche medizinische Wochenschrift (1946)",
"keywords": null,
"medline_ta": "Dtsch Med Wochenschr",
"mesh_terms": "D000328:Adult; D000086382:COVID-19; D005260:Female; D005858:Germany; D006801:Humans; D008297:Male; D000086402:SARS-CoV-2; D018746:Systemic Inflammatory Response Syndrome; D014057:Tomography, X-Ray Computed; D055815:Young Adult",
"nlm_unique_id": "0006723",
"other_id": null,
"pages": "598-602",
"pmc": null,
"pmid": "33706390",
"pubdate": "2021-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "First Cases of Multisystem Inflammatory Syndrome following SARS-CoV-2 infection in Adults in Germany.",
"title_normalized": "first cases of multisystem inflammatory syndrome following sars cov 2 infection in adults in germany"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2021SP026462",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROCORTISONE"
},
"drugadditio... |
{
"abstract": "Postoperative euglycemic diabetic ketoacidosis (euDKA) associated with sodium-glucose cotransporter-2 (SGLT2) inhibitor use has been well-documented and carries a Food and Drug Administration recommendation to hold SGLT2 inhibitors 3 to 4 days before a planned surgical procedure. Unfortunately, many surgical procedures, such as orthotopic heart transplant (OHT), are unplanned and unpredictable. With the increasing use of SGLT2 inhibitors in diabetic and non-diabetic heart failure patients, new challenges in patient management and perioperative risk have arisen. We report a case in which SGLT2 inhibitor-associated euDKA complicated the postoperative course of a prediabetic patient who had undergone OHT.",
"affiliations": "Department of Medicine, University of California at Los Angeles, Los Angeles, California. Electronic address: BCha@mednet.ucla.edu.;Department of Pharmacy, University of California at Los Angeles, Los Angeles, California.;Division of Cardiology, Department of Medicine, University of California at Los Angeles, Los Angeles, California.;Department of Pharmacy, University of California at Los Angeles, Los Angeles, California.;Division of Cardiology, Department of Medicine, University of California at Los Angeles, Los Angeles, California.",
"authors": "Cha|Beda M|BM|;Davoudi|Roland|R|;DiVita|Michael C|MC|;Fan|Ashley M|AM|;Kamath|Megan Y|MY|",
"chemical_list": "D000077203:Sodium-Glucose Transporter 2 Inhibitors; D012964:Sodium; D005947:Glucose",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2021.08.017",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "53(8)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D003924:Diabetes Mellitus, Type 2; D016883:Diabetic Ketoacidosis; D005947:Glucose; D016027:Heart Transplantation; D006801:Humans; D011236:Prediabetic State; D012964:Sodium; D000077203:Sodium-Glucose Transporter 2 Inhibitors",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "2636-2639",
"pmc": null,
"pmid": "34531071",
"pubdate": "2021-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Sodium-Glucose Cotransporter-2 Inhibitor-Associated Euglycemic Diabetic Ketoacidosis After Orthotopic Heart Transplant in a Prediabetic Patient: A Case Report.",
"title_normalized": "sodium glucose cotransporter 2 inhibitor associated euglycemic diabetic ketoacidosis after orthotopic heart transplant in a prediabetic patient a case report"
} | [
{
"companynumb": "US-TEVA-2021-US-1972584",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "Non-small cell lung cancer (NSCLC) driven by activating mutations in epidermal growth factor receptor (EGFR) constitutes up to 10% of NSCLC cases. According to the NCCN recommendations, all patients (with the exception of smoking patients with squamous cell lung cancer) should be screened for the presence of activating EGFR mutations, i.e. deletion in exon 19 or point mutation L858R in exon 21, in order to select the group that benefits from EGFR tyrosine kinase inhibitors (EGFR TKIs) treatment. Among approved agents there are the 1st generation reversible EGFR TKIs, erlotinib and gefitinib, and the 2nd generation irreversible EGFR TKI, afatinib. The objective response rates to these drugs in randomised clinical trials were in the range of 56-74%, and median time to progression 9-13 months. The most common determinant of resistance to these drugs is the clonal expansion of cancer cells with T790M mutation (Thr790Met) in exon 20 of EGFR. Osimertinib (Tagrisso™), a 3rd generation, irreversible EGFR tyrosine kinase inhibitor, constitutes a novel, highly efficacious treatment for NSCLC patients progressing on EGFR TKIs with T790M mutation confirmed as the resistance mechanism. Resistance mutation can be determined in tissue or liquid biopsy obtained after progression on EGFR TKIs. Osimertinib has a favourable toxicity profile, with mild rash and diarrhoea being the most common. In this article, we present three cases that were successfully treated with osimertinib after progression on 1st and 2nd generation EGFR TKIs.",
"affiliations": "Department of Oncology and Radiotherapy, Medical University of Gdansk, Poland.;Department of Pneumonology and Allergology, Medical University of Gdansk, Poland.;Department of Oncology and Radiotherapy, Medical University of Gdansk, Poland.",
"authors": "Skrzypski|Marcin|M|;Szymanowska-Narloch|Amelia|A|;Dziadziuszko|Rafał|R|",
"chemical_list": null,
"country": "Poland",
"delete": false,
"doi": "10.5114/wo.2017.70116",
"fulltext": "\n==== Front\nContemp Oncol (Pozn)Contemp Oncol (Pozn)WOContemporary Oncology1428-25261897-4309Termedia Publishing House 3059710.5114/wo.2017.70116Case ReportOsimertinib – effective treatment of NSCLC with activating EGFR mutations after progression on EGFR tyrosine kinase inhibitors Skrzypski Marcin 1Szymanowska-Narloch Amelia 2Dziadziuszko Rafał 1\n1 Department of Oncology and Radiotherapy, Medical University of Gdansk, Poland\n2 Department of Pneumonology and Allergology, Medical University of Gdansk, PolandAddress for correspondence: Rafał Dziaduszko, Department of Oncology and Radiotherapy, Medical University of Gdansk, Słodowskiej-Curie 3 A, 80-210 Gdansk, Poland. e-mail: rafald@gumed.edu.pl29 9 2017 2017 21 3 254 258 31 7 2017 10 9 2017 Copyright: © 2017 Termedia Sp. z o. o.2017This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License, allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.Non-small cell lung cancer (NSCLC) driven by activating mutations in epidermal growth factor receptor (EGFR) constitutes up to 10% of NSCLC cases. According to the NCCN recommendations, all patients (with the exception of smoking patients with squamous cell lung cancer) should be screened for the presence of activating EGFR mutations, i.e. deletion in exon 19 or point mutation L858R in exon 21, in order to select the group that benefits from EGFR tyrosine kinase inhibitors (EGFR TKIs) treatment. Among approved agents there are the 1st generation reversible EGFR TKIs, erlotinib and gefitinib, and the 2nd generation irreversible EGFR TKI, afatinib. The objective response rates to these drugs in randomised clinical trials were in the range of 56–74%, and median time to progression 9–13 months. The most common determinant of resistance to these drugs is the clonal expansion of cancer cells with T790M mutation (Thr790Met) in exon 20 of EGFR. Osimertinib (Tagrisso™), a 3rd generation, irreversible EGFR tyrosine kinase inhibitor, constitutes a novel, highly efficacious treatment for NSCLC patients progressing on EGFR TKIs with T790M mutation confirmed as the resistance mechanism. Resistance mutation can be determined in tissue or liquid biopsy obtained after progression on EGFR TKIs. Osimertinib has a favourable toxicity profile, with mild rash and diarrhoea being the most common. In this article, we present three cases that were successfully treated with osimertinib after progression on 1st and 2nd generation EGFR TKIs.\n\nlung cancerchemotherapyTKI inhibitorsosimertinib\n==== Body\nNon-small cell lung cancer (NSCLC) driven by activating mutations in epidermal growth factor receptor (EGFR) constitutes up to 10% of NSCLC cases [1]. According to the NCCN guidelines, all patients (with the exception of smoking patients with squamous cell lung cancer) should be screened for the presence of activating EGFR mutations, i.e. deletion in exon 19 or point mutation L858R in exon 21, in order to select the group that benefits from EGFR tyrosine kinase inhibitors (EGFR TKIs) treatment. Among approved agents there are the 1st generation reversible EGFR TKIs, erlotinib and gefitinib, and the 2nd generation irreversible EGFR TKI, afatinib. The objective response rates to these drugs in randomised clinical trials were in the range of 56–74%, and the median time to progression 9–13 months [2–7]. These two classes of EGFR TKIs inhibit non-selectively both mutated and the wild type EGFR, which explains their main toxicities, i.e. trophic changes of the skin, nails, and the hair as well as gastro-intestinal symptoms, e.g. diarrhoea [8, 9].\n\nThe most common determinant of resistance to these drugs is the clonal expansion of cancer cells with T790M mutation (Thr790Met) in exon 20 of EGFR that is detected in 63-69% of the cases, irrespective of the class of EGFR TKIs used in the first line of treatment [10]. T790M variant decreases the affinity of the 1st and 2nd generation EGFR TKIs to EGFR ATP-binding pocket, which results in enhanced proliferation signalling and prompts disease progression. The efficacy of chemotherapy, e.g. platinum and pemetrexed doublet, after progression on EGFR TKIs is limited. The median progression-free survival in the AURA3 and IMPRESS prospective clinical trials was 4.4 and 5.4 months, respectively [11, 12]. Similarly, patients with EGFR activating mutations seem not to benefit from immune checkpoint inhibitors treatment [13].\n\nOsimertinib (Tagrisso™), a 3rd generation, irreversible EGFR tyrosine kinase inhibitor, is selectively active against EGFR protein with activating mutations, including T790M resistance mutation to the 1st and 2nd generation EGFR TKIs. In the randomized phase III AURA3 trial, the median progression free survival, duration of response, and the rates of objective response were 10.1 months, 9.7 months and 71%, respectively [11, 14]. In comparison to chemotherapy osimertinib was more efficacious also in patients with central nervous system (CNS) involvement. In subgroup analysis, the benefit in patients with CNS metastases was similar to that seen in general population. Median progression free survival was 8.4 months, with the relative risk decrease of 68% (HR = 0.32) [11]. In experimental studies, osimertinib was shown to have a higher blood brain barrier penetrance in comparison to other EGFR TKIs (gefitinib, erlotinib, afatinib, rociletinib) [15].\n\nDue to a strong affinity to the mutated EGFR protein osimertinib is very well tolerated. In AURA3 clinical trial treatment related adverse events in grade 3 or higher were noted in 23% patients treated with osimertinib versus 47% in the group receiving cisplatin doublet [11]. Among the mild toxicities of osimertinib there were diarrhoea (41%; 1% grade ≥ 3), rash (34%; < 1% grade ≥ 3), dryness of skin (23%; 1% grade ≥ 3), and paronychia (22%). In the pooled analysis of the data from prospective trials, the frequency of interstitial lung disease (ILD) among the patients treated with osimertinib was 4% (grade 1, n = 2; grade 3, n = 3; and grade 5, n = 3) [16]. The incidence of this toxicity is similar as in the case of 1st and 2nd generation EGFR TKIs. Prolongation of QT was noted in 4% of patients receiving osimertinib, with only 1 case in grade 3 [11].\n\nAlthough osimertinib is metabolised by CYP3A4, its inhibitors, e.g. itraconazole, do not significantly impact the drug’s turnover [17]. On the other hand, strong inducers of CYP3A, e.g. rifampicin, carbamazepine or St. John’s Wort, may cause significant reduction in osimertinib exposure and therefore their concomitant use should be avoided. Moderate inhibitors of CYP3A, e.g. bosentan, efavirenz, etravirine, modafinil may also increase osimertinib metabolism and should be therefore used with caution. In terms of interactions with commonly used drugs, Tagrisso can be safely combined with gastric acid reducing substances, e.g. omeprazole, as well as with simvastatin [18].\n\nThe presence of T790M mutation can be assessed in biopsied tumour tissue or in plasma through liquid biopsy that allows its detection in circulating cell free DNA (cfDNA). The latter method requires a standard collection of peripheral blood into an EDTA tube (purple or lavender cap tube, used for collecting blood for whole blood count analyses), and isolation of plasma through centrifugation within 3 hours. In Poland, T790M can be assessed in many academic centres and commercial laboratories. The companion diagnostic tests for osimertinib that were used in drug registration trials are Cobas EGFR Mutation Test and Cobas EGFR Mutation Test v2 for liquid biopsy. These real-time PCR based tests allow for detection of 42 mutations in EGFR exons 18, 19, 20 and 21, including T790M mutation. The sensitivity of T790M detection by liquid biopsy in reference to tissue biopsy is in the range of 61–70%, which implies that liquid biopsy negative result necessitates consideration for obtaining tumour tissue biopsy [19, 20]. For example, among 102 patients with the negative result of liquid biopsy, T790M was detected in tumour biopsy in 45 (44%) cases [20]. The median progression-free survival (PFS) in this group was 16.2 months, whereas in the group tested negative by both diagnostic modalities the median PFS was 2.8 months [20]. On the other hand, in phase 1/2 trial there were 21% of objective responses in patients in whom tissue biopsy tested negative for T790M mutation [14]. Most likely, at least in part of this group it would have been possible to detect mutation through liquid biopsy. In order to qualify a patient to osimertinib therapy it is sufficient to detect T790M mutation with one of these methods. Objective response rates to osimertinib of 64% were seen in prospective trials both in tissue and liquid biopsy groups [11, 19]. In cases when both tests have been performed, but only one yielding a positive result, treatment with osimertinib is justified.\n\nThere are other molecular methods for detection of T790M mutation, e.g. Sanger sequencing, next generation sequencing and digital droplet PCR, the latter being the most sensitive. Some of these methods require a threshold value, above which the result is interpreted as “positive”. According to local expertise, these methods may also be used for evaluation of molecular resistance mechanisms in NSCLC patients after progression on 1st line EGFR TKIs.\n\nIn the following section, we present three cases that were successfully treated with osimertinib after progression on 1st and 2nd generation EGFR TKIs.\n\nCase 1\nA 63-year-old male (an ex-smoker that quit 20 years ago, with smoking history of 15 pack-years) was referred to our outpatient clinic with NSCLC diagnosis to assess treatment options. The tumour was located in the right lung and spread to the mediastinal and supraclavicular lymph nodes. The lesion was detected in the chest CT (April, 2015) performed due to recurring mild exertional dyspnoea, decrease in exercise tolerance and dry paroxysmal cough. On histopathological examination of mediastinal lymph nodes biopsy obtained at mediastinoscopy and the right supraclavicular lymph nodes from fine-needle biopsy metastatic lung adenocarcinoma (TTF1+, Napsin A+) was diagnosed (June, 2015). The patient denied any weight loss. His medical history included mild prostatic hyperplasia, past lithotripsy due to urolithiasis, and in his youth hepatitis A. He is a farm worker.\n\nThe results of laboratory testing were within normal limits. The chest CT revealed suspicious additional changes in the lung parenchyma as well as bone lesions suggestive of metastases. In PET scan distant metastases were ruled out, however, due to significant regional spread of tumour (stage IIIB) the patient was not eligible for radical radiotherapy. In parallel to the staging procedures, the status of EGFR activating mutations was assessed and the exon 19 deletion was detected. The patient was therefore started on afatinib 40 mg QD.\n\nAfter 4 weeks of treatment the patient presentedwith a facial rash (grade 1). After 12 weeks of treatment diarrhoea ensued, however, the patient remained professionally active. Diet modification and loperamide as needed were advised. In the chest CT performed after 12 weeks of treatment there was a partial tumour response. With no laboratory abnormalities, the patient continued therapy for 12 months. The rash with no need of treatment persisted.\n\nIn August 2016 the patient experienced a pathological vertebral fracture with no evidence of lung cancer progression on chest imaging and no evidence of disease progression in the brain MRI. However, a few days later there appeared progressive paraparesis. The spine MRI revealed metastases in vertebral bodies of Th1, Th7 and Th8 with protrusion into the epidural space and spinal cord compression. The patient underwent neurosurgery (posterior decompression and C4-Th11 stabilisation), rehabilitation (physiotherapy and kinesitherapy) and palliative radiotherapy (30 Gy in 10 fractions) for affected area. The treatment with afatinib was continued.\n\nIn December 2016 (15th month of afatinib treatment) the chest CT revealed progression of the disease in the lungs. Genetic examination of circulating free DNA (cfDNA) was performed and EGFR T790M mutation was found. In December 2016 the treatment with osimertinib 80 mg QD was initiated. The severity of the neurological deficits was slowly improving and the patient recovered the ability to move his legs. Follow-up chest CT, performed after 2 months of treatment, revealed partial regression. In the following examination further regression was observed, with the sum of measurable dimensions of the lesions reduced in size by 38%. Currently, the patient is still experiencing a clinical benefit after 8 months of osimertinib treatment.\n\nCase 2\nA 68-year-old never-smoking female was referred to our outpatient clinic due to the stage IV lung adenocarcinoma, with involvement of the right supraclavicular lymph nodes and pelvic bones. Microscopic diagnosis was obtained via bronchoscopic biopsy and further confirmed by histologic examination of the tissue material form core needle biopsy of the supraclavicular node. The medical history included hypertension, ventricular extrasystoles, secondary hypothyroidism (after partial thyreoidectomy due to thyroid adenoma), degenerative spine disease and hypercholesterolemia. Cisplatin and pemetrexed were used as the 1st line treatment (from December 2010 to March 2011). Due to progression of the lesion in the right lung, the patient received four cycles of docetaxel (from July 2012 to September 2012) and, subsequently, the palliative radiation to the chest in February 2013.\n\nIn July 2013, the patient was diagnosed with liver metastases. The liver lesion biopsy revealed activating EGFR mutation (exon 19 deletion), and the patient was enrolled in the clinical trial OAM4971G, comparing combination of erlotinib and onartuzumab (monoclonal antibody blocking MET protein signalling) with erlotinib treatment only. During the study the patient developed facial rush (grade 1), recognized as associated with erlotinib treatment. In the chest and abdomen CT (September 2013 and November 2013) tumour partial regression was reported. There were no clinically significant abnormalities in laboratory testing.\n\nIn March 2014 the patient was informed about negative outcome of the clinical trial. Unblinding revealed that the patient was treated in placebo/erlotinib arm, and, therefore continuation of erlotinib 150 mg QD was offered. The patient did not report any further toxicity until April 2015, when G2 paronychia appeared. The skin changes were located around nail folds, mostly of left hand fingers, and required the use of amoxicillin with clavulanic acid.\n\nIn July 2015, after 24 months of erlotinib treatment, the progression of liver metastases was diagnosed. The patient was proposed 3rd line chemotherapy, i.e. paclitaxel 80 mg/m2 weekly over 3 week-period and 1 week-break thereafter. The treatment resulted in partial response that was maintained until April 2016. Because of availability of osimertinib within extended access programme, liver metastasis biopsy was performed, resulting in confirmation of T790M resistance mutation by Cobas test. In the abdomen CT (December 2016), further progression of liver metastatic lesions was confirmed, with lesions’ dimensions of 60 x 67 mm and 24 x 36 mm, respectively.\n\nIn December 2016 the patient began treatment with osimertinib 80 mg QD. In the first follow-up abdomen CT after 8 weeks significant regression of liver metastasis was seen, with reduction of the sum of lesion dimensions by 48%. Currently, after 8 months of treatment the patient is not reporting any side effects. On the last imaging (July 2017) almost complete remission of the liver lesions and full control of the other foci was confirmed, after more than 6 years from the initial diagnosis of the metastatic lung cancer.\n\nCase 3\nIn a never-smoking 52-year-old female, the lung cancer was detected during the diagnostic work-up for exertional dyspnea. In chest CT (April 2014) a tumour in the lower left lobe with accompanying left-sided hydrothorax were reported. Lung adenocarcinoma was diagnosed on histological examination of sections obtained through core needle biopsy, and EGFR activating mutation (deletion in exon 19) was confirmed. In May 2014 gefitinib 250mg QD was initiated, which led to the partial disease response. In June 2015, after around 13 months of treatment, progression in the left lung ensued. In subsequent video-thoracoscopy the metastatic nodules in parietal pleura were biopsied and T790M resistance mutation was confirmed.\n\nIn July 2015 the patient was enrolled into an expansion cohort of phase I trial assessing the clinical activity of rociletinib, a 3rd generation EGFR inhibitor. After 6 months of treatment, the patient reported conjunctivitis, prolongation of QTc in ECG (QTcB up to 482 ms) and hyperglycaemia, deemed as related to rociletinib. After 12 months of treatment in July 2016 multiple brain metastases were diagnosed. The experimental therapy was continued as the patient was benefiting from disease control in the lungs. In September 2016 the vision impairment ensued that required ophtalmological consultation. The surgical treatment was recommended because of the predicted high dynamics of this type of cataract. Due to increasing toxicity of rociletinib and central nervous system progression the patient was ultimately taken off the trial.\n\nIn view of osimertinib availability in extended access program, blood sample was taken to determine the resistance mutation to 1st and 2nd generation TKIs. In examination of plasma cell-free DNA T790M mutation was detected. In September 2016 the treatment with osimertinib 80 mg QD was started.\n\nSince December 2016 the patient was receiving low molecular weight heparin in therapeutic doses, i.e. Clexane 100mg QD, because of the deep vein thrombosis recurrence requiring hospitalization. In the head and chest CT, performed 10 weeks after osimertinib initiation, almost complete remission of CNS metastases and further control of chest lesions were reported. The patient has completed 8 months treatment now and is not reporting any treatment related side effects.\n\nGiven the high clinical efficacy and beneficial toxicity profile of osimertinib, this drug is currently being investigated in the first line of treatment of advanced NSCLC with activating EGFR mutations. The available clinical data suggests high effectiveness of the agent in this setting. Median progression free survival and objective response rates in previously untreated NSCLC patients with activating EGFR mutations in expanded cohort from phase I trial AURA were 19.3 months and 77%, respectively [21]. During American Society of Clinical Oncology Annual Meeting 2017 (ASCO 2017) reports on mechanisms of resistance to osimertinib were presented. Among the most common molecular changes after progression on osimertinib (also detectable in liquid biopsy) was MET amplification, present in 30% of the cases [22]. In three of these patients partial response was attained after administration of MET inhibitor in conjunction with EGFR TKI, which suggests new treatment option for patients with MET amplification as a resistance mechanism. Another group of molecular determinants of resistance to osimertinib includes mutations within EGFR, e.g. C797S, and, in other genes, e.g. PIK3CA E545K, BRAF V600E, or KRAS G12S as well as amplification of HER2 and FGFR1 [23]. In patients with HER2 amplification as a resistance mechanism to EGFR TKIs, the combination of trastuzumab and paclitaxel resulted in partial responses in 41% of the patients [24]. Moreover, in patients with oligo-progression on osimertinib, ablative therapy of up to five metastatic lesions (surgery or stereotactic radiotherapy) was safe and allowed for continuation of TKI treatment [25]. The results of the phase III FLAURA trial, assessing efficacy of osimertinib in comparison to 1st generation EGFR TKIs (gefitinib or erlotinib) in first line of treatment of NSCLC patients with activating EGFR mutations, are soon to be announced.\n\nIn summary, osimertinib provides a novel, highly efficacious treatment for NSCLC patients progressing on EGFR TKIs with T790M mutation confirmed as the resistance mechanism. The drug is also effective in patients with brain metastasis who exhausted possibilities of local ablative therapies. The presence of T790M can be determined in tissue or liquid biopsy obtained after progression on EGFR TKIs. Osimertinib has a favourable toxicity profile, with mild rash and diarrhoea being the most common.\n\nThe authors declare no conflict of interest.\n==== Refs\nReferences\n1 Pardinas JR Xiao L Zhang J Li K Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers J Natl Cancer Inst 2005 97 339 46 15741570 \n2 Mitsudomi T Morita S Yatabe Y Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial Lancet Oncol 2010 11 121 8 20022809 \n3 Zhou C Wu YL Chen G Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study Lancet Oncol 2011 12 735 42 21783417 \n4 Rosell R Carcereny E Gervais R Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial Lancet Oncol 2012 13 239 46 22285168 \n5 Sequist LV Yang JC Yamamoto N Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations J Clin Oncol 2013 31 3327 34 23816960 \n6 Wu YL Zhou C Liam CK First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the phase III, randomized, open-label, ENSURE study Ann Oncol 2015 26 1883 9 26105600 \n7 Kowalski DM Krzakowski M Ramlau R Jaskiewicz P Janowicz-Żebrowska A Erlotinib in salvage treatment of patients with advanced non-small cell lung cancer: results of an expanded access programme in Poland Contemp Oncol (Pozn) 2012 16 170 5 23788872 \n8 Jänne PA Boss DS Camidge DR Phase I dose-escalation study of the pan-HER inhibitor, PF299804, in patients with advanced malignant solid tumors Clin Cancer Res 2011 17 1131 9 21220471 \n9 Yap TA Vidal L Adam J Phase I trial of the irreversible EGFR and HER2 kinase inhibitor BIBW 2992 in patients with advanced solid tumors J Clin Oncol 2010 28 3965 72 20679611 \n10 Jenkins S Chih-Hsin Yang J Jänne PA EGFR mutation analysis for prospective patient selection in two Phase II registration studies of osimertinib J Thorac Oncol 2017 12 1247 56 28527899 \n11 Mok TS Wu Y-L Ahn M-J Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer N Engl J Med 2017 376 629 40 27959700 \n12 Soria JC Wu YL Nakagawa K Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial Lancet Oncol 2015 16 990 8 26159065 \n13 Abbosh C Birkbak NJ Wilson GA Phylogenetic ctDNA analysis depicts early stage lung cancer evolution Nature 2017 545 446 451 28445469 \n14 Jänne PA Yang JC Kim DW AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer N Engl J Med 2015 372 1689 99 25923549 \n15 Ballard P Yates JW Yang Z Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity Clin Cancer Res 2016 22 5130 40 27435396 \n16 Yang JC Ahn MJ Kim DW Osimertinib in Pretreated T790M-Positive Advanced Non-Small-Cell Lung Cancer: AURA Study Phase II Extension Component J Clin Oncol 2017 35 1288 96 28221867 \n17 Dickinson PA Cantarini MV Collier J Frewer P Martin S Pickup K Ballard P Metabolic Disposition of Osimertinib in Rats, Dogs, and Humans: Insights into a Drug Designed to Bind Covalently to a Cysteine Residue of Epidermal Growth Factor Receptor Drug Metab Dispos 2016 44 1201 12 27226351 \n18 Vishwanathan K Effect of food and gastric pH modifiers on the pharmacokinetics of AZD9291 Mol Cancer Ther 2015 Abstract: B153 \n19 Jenkins S Yang JC Ramalingam SS Plasma ctDNA Analysis for Detection of the EGFR T790M Mutation in Patients with Advanced non-small Cell Lung Cancer J Thorac Oncol 2017 12 1061 70 28428148 \n20 Oxnard GR Thress KS Alden RS Association Between Plasma Genotyping and Outcomes of Treatment With Osimertinib (AZD9291) in Advanced Non-Small-Cell Lung Cancer J Clin Oncol 2016 34 3375 82 27354477 \n21 Ramalingam S Yang JC Lee CK LBA1_PR: Osimertinib as first-line treatment for EGFR mutation-positive advanced NSCLC: updated efficacy and safety results from two Phase I expansion cohorts J Thorac Oncol 2016 11 4 Suppl S152 \n22 Piotrowska Z MET amplification (amp) as a resistance mechanism to osimertinib J Clin Oncol 2017 35 suppl abstr. 9020 \n23 Guibert NM Early detection of competing resistance mutations using plasma next-generation sequencing (NGS) in patients (pts) with EGFR-mutant NSCLC treated with osimertinib J Clin Oncol 2017 35 suppl abstr. 11529 \n24 De Langen J Trastuzumab and paclitaxel in patients (pts) with EGFR mutated non-small-cell lung cancer (NSCLC) that express HER2 after progression on EGFR TKI treatment J Clin Oncol 2017 35 suppl abstr. 9042 \n25 Kim C Azuma K Sakai K Local ablative therapy (LAT) for oligoprogressive, EGFR-mutant, non-small cell lung cancer (NSCLC) after treatment with osimertinib J Clin Oncol 2017 35 suppl abstr. e20545\n\n",
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"keywords": "TKI inhibitors; chemotherapy; lung cancer; osimertinib",
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"title": "Osimertinib - effective treatment of NSCLC with activating EGFR mutations after progression on EGFR tyrosine kinase inhibitors.",
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"abstract": "A 70-year-old man diagnosed with pleomorphic malignant fibrous histiocytoma of the left thigh underwent tumor resection. After 10 months, he underwent extended resection due to local recurrence. However, because multiple lung metastases was detected at this time, chemotherapy with ifosfamide and doxorubicin was administered. After three courses of chemotherapy, the lung metastases enlarged and the patient received ifosfamide and etoposide as second line chemotherapy. Even after three courses of second line treatment, the disease progressed, for which docetaxel and gemcitabine were administered as third line chemotherapy. After three courses of third line treatment, multiple lung metastases reduced and were replaced with scar and cystic lesions (reduction ratio 85.9%). After four courses of treatment, the patient developed left pneumothorax. Partial resection of the left upper lobe was performed by thoracoscopic surgery. Histopathological examination revealed rupture of the visceral pleura in a scar lesion leading to air leakage. After 13 courses of treatment, he developed right pneumothorax. Partial resection of the right middle lobe was performed. Histopathological examination revealed a cystic lesion without tumor remnants. After 15 courses of third line treatment, lung metastasis could be controlled. Chemotherapy with docetaxel and gemcitabine resulted in few adverse effects that were within tolerance limits.",
"affiliations": "Dept. of Surgery, Saiseikai Hiroshima Hospital.",
"authors": "Miyahara|Eiji|E|;Itagaki|Tomoko|T|;Kegoya|Yasuhide|Y|;Kameda|Akira|A|;Nitta|Yasuaki|Y|;Oue|Naohide|N|",
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"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D003841:Deoxycytidine; D000077143:Docetaxel; D051677:Histiocytoma, Malignant Fibrous; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D011030:Pneumothorax; D043823:Taxoids; D016896:Treatment Outcome",
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"title": "A case of pleomorphic malignant fibrous histiocytoma with multiple lung metastases with bilateral pneumothorax after chemotherapy.",
"title_normalized": "a case of pleomorphic malignant fibrous histiocytoma with multiple lung metastases with bilateral pneumothorax after chemotherapy"
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"abstract": "Background: Ustekinumab is a monoclonal antibody that inhibits interleukins 12 and 23. It is approved for treatment of Crohn's disease (CD) in adults; however, there is a paucity of data regarding its use in pediatric CD. We describe our experience using ustekinumab in anti-TNF refractory CD pediatric patients. Methods: We performed a retrospective chart review on pediatric patients with CD who were started on ustekinumab from January 2016 to November 2018. We collected patient's clinical history, previous treatment history, surgeries related to CD, disease severity, as measured by abbrPCDAI, and endoscopic severity as recorded by SES-CD before and after ustekinumab. Results: We identified 10 patients with CD who were started on ustekinumab due to non-response to currently approved agents. Seven patients needed augmented maintenance dosing every 4-6 weeks to achieve clinical response or remission. Six of these seven patients had therapeutic drug monitoring during the course of treatment, with five patients showing subtherapeutic drug levels of <4.5 μg/mL while on standard maintenance dosing every 8 weeks, and four patients showing therapeutic drug levels of >4.5 μg/mL on augmented dosing interval. The remaining three patients were on standard maintenance dosing for the duration of treatment. Conclusion: In this retrospective chart review, 7 out of 10 patients with anti-TNF refractory pediatric-onset CD required augmented maintenance doses of ustekinumab to achieve clinical response or remission. A prospective study is needed to define appropriate ustekinumab dosing and interval in management of pediatric CD.",
"affiliations": "Department of Pediatrics, Children's Health Medical Center Dallas, Dallas, TX, 75235, USA.;Department of Pediatrics, Children's Health Medical Center Dallas, Dallas, TX, 75235, USA.;Department of Pediatrics, Children's Health Medical Center Dallas, Dallas, TX, 75235, USA.;Department of Pediatrics, Children's Health Medical Center Dallas, Dallas, TX, 75235, USA.;Department of Pediatrics, Children's Health Medical Center Dallas, Dallas, TX, 75235, USA.;Department of Pediatrics, Children's Health Medical Center Dallas, Dallas, TX, 75235, USA.;Department of Pediatrics, Children's Health Medical Center Dallas, Dallas, TX, 75235, USA.",
"authors": "Do|Phinga|P|0000-0003-2255-9991;Andersen|John|J|;Patel|Ashish|A|;Semrin|Gaith|G|;Sifuentes-Dominguez|Luis|L|;Luu|Phuong|P|;Gurram|Bhaskar|B|0000-0003-3169-2225",
"chemical_list": "D000079424:Tumor Necrosis Factor Inhibitors; D000069549:Ustekinumab",
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"fulltext": "\n==== Front\nF1000Res\nF1000Res\nF1000Research\n2046-1402\nF1000 Research Limited London, UK\n\n10.12688/f1000research.22673.2\nResearch Article\nArticles\nAugmented ustekinumab dosing is needed to achieve clinical response in patients with anti-TNF refractory pediatric Crohn’s disease: a retrospective chart review\n[version 2; peer review: 2 approved]\n\nDo Phinga Formal Analysis Investigation Writing – Original Draft Preparation https://orcid.org/0000-0003-2255-9991\na1\nAndersen John Resources Writing – Review & Editing 12\nPatel Ashish Resources Writing – Review & Editing 12\nSemrin Gaith Resources Writing – Review & Editing 12\nSifuentes-Dominguez Luis Resources Writing – Review & Editing 12\nLuu Phuong Data Curation Resources 1\nGurram Bhaskar Conceptualization Methodology Project Administration Resources Supervision Writing – Review & Editing https://orcid.org/0000-0003-3169-2225\n12\n1 Department of Pediatrics, Children’s Health Medical Center Dallas, Dallas, TX, 75235, USA\n2 Department of Pediatric Gastroenterology, UT Southwestern Medical Center, Dallas, TX, 75235, USA\na phinga.do@utsw.edu\nNo competing interests were disclosed.\n\n9 8 2021\n2020\n9 3167 7 2021\nCopyright: © 2021 Do P et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\n\nBackground: Ustekinumab is a monoclonal antibody that inhibits interleukins 12 and 23. It is approved for treatment of Crohn’s disease (CD) in adults; however, there is a paucity of data regarding its use in pediatric CD. We describe our experience using ustekinumab in anti-TNF refractory CD pediatric patients.\n\nMethods: We performed a retrospective chart review on pediatric patients with CD who were started on ustekinumab from January 2016 to November 2018. We collected patient’s clinical history, previous treatment history, surgeries related to CD, disease severity, as measured by abbrPCDAI, and endoscopic severity as recorded by SES-CD before and after ustekinumab.\n\nResults: We identified 10 patients with CD who were started on ustekinumab due to non-response to currently approved agents. Seven patients needed augmented maintenance dosing every 4-6 weeks to achieve clinical response or remission. Six of these seven patients had therapeutic drug monitoring during the course of treatment, with five patients showing subtherapeutic drug levels of <4.5 μg/mL while on standard maintenance dosing every 8 weeks, and four patients showing therapeutic drug levels of >4.5 μg/mL on augmented dosing interval. The remaining three patients were on standard maintenance dosing for the duration of treatment.\n\nConclusion: In this retrospective chart review, 7 out of 10 patients with anti-TNF refractory pediatric-onset CD required augmented maintenance doses of ustekinumab to achieve clinical response or remission. A prospective study is needed to define appropriate ustekinumab dosing and interval in management of pediatric CD.\n\nUstekinumab\nPediatric Crohn's disease\nanti-TNF-refractory Crohn's disease\nInflammatory bowel disease\nTherapeutic drug monitoring\nClinical response\nThe author(s) declared that no grants were involved in supporting this work.Revised Amendments from Version 1\n\n- Clarified laboratory and methodology used to obtain ustekinumab level - Addressed and highlighted one of the cases as \"very early onset IBD\" - Removed patient's 6's prior brief exposure to ustekinumab from table 2 and highlighted it as a foot note under the table's caption - Clarified each patient's type of anti-TNF failure in more detail in table 1 - Omitted dosing description in the text since the same information was highlighted in table 2 - Details about patients' outcome were moved from the \"discussion\" to \"result\" section - Included the 2 studies below in the discussion section: Real World Experience with Ustekinumab in Children and Young Adults at a Tertiary Care Pediatric Inflammatory Bowel Disease Center. Dayan JR et al. J Pediatr Gastroenterol Nutr. (2019)\n\n Ustekinumab for the treatment of refractory pediatric Crohn's disease: a single-center experience. Cohen A, Ahmed N, Sant'Anna A.. Intest Res. 2020 Apr 22.\n==== Body\npmcIntroduction\n\nTogether, ulcerative colitis and Crohn’s disease (CD) make up inflammatory bowel disease (IBD), an autoimmune-mediated process of unclear etiology. The global incidence of pediatric IBD has been rising rapidly, with the highest incidence of CD being in Europe at 23/100000 person years and North America at 15.2/100000 person years 1– 3 . Earlier onset of IBD is associated with higher impact on growth and development, more aggressive disease course, and increased need for immunomodulators 4. Anti-tumor necrosis factors (anti-TNFs) form the forefront of management of patients with CD who do not respond to steroids and immunomodulatory medications 5.\n\nAmong pediatric patients with CD who are started on anti-TNF treatments, about 10–25% do not respond to it (primary non-responders) 6. Of those who initially respond, loss of response and adverse effects limit duration of therapy. At 1, 3, and 5 years after therapy initiation, the probability of patients remaining on infliximab is only 0.87, 0.74, and 0.67, respectively (secondary non-responders) 7. Thus, there is a significant need for novel therapies for management of CD.\n\nAmong the newer biologics approved for treatment of CD is ustekinumab, a human immunoglobulin G1 kappa monoclonal antibody that binds with high affinity to the p40 subunit of human interleukin (IL)-12 and IL23. Ustekinumab prevents IL12 and IL23 bioactivity by preventing their interaction with their cell surface receptor protein IL12Rb1. Through this mechanism of action, ustekinumab effectively neutralizes IL12 (Th1)- and IL23 (Th17)-mediated cellular responses. It has recently been approved for the treatment of moderate to severe active CD in adults 8. However, data on usage of ustekinumab in management of pediatric Crohn’s disease is limited to small case series 9– 11 . Here we describe our experience on using ustekinumab for management of TNF-refractory pediatric CD.\n\nMethods\n\nWe performed a retrospective chart review on 10 pediatric CD patients who failed anti-TNF therapy and were treated with ustekinumab between January 2016 and November 2018. Ustekinumab levels and antibodies were done either by Miraca or Inform Diagnostics. Both these labs used automated enzyme linked immunosorbent assay (ELISA) assay for simultaneous antibody and drug levels.\n\nThis study was approved by the Institutional Review Board (IRB) of Dallas Children’s Hospital (study #25338). Request for waiver of patient/guardian consent for this study was approved by the IRB.\n\nData collection\n\nWe collected baseline demographic data, disease phenotype based on Paris Classification 12, disease related complications, previous treatment history, and reason for changing therapy.\n\nTo assess clinical response to ustekinumab, we calculated the Abbreviated Pediatric Crohn’s Disease Activity Index (abbrPCDAI) prior to starting therapy, 2–3 months after therapy initiation, and at the last office visit before conclusion of the study 13. When no office visits were available immediately prior to treatment initiation, telephone and email encounters were used to assess patients’ clinical symptoms to calculate abbrPCDAI. Where possible we also calculated the Simple Endoscopic Score for Crohn’s Disease (SES-CD) before and after treatment initiation 14. Body Mass Index (BMI) before and after treatment was collected.\n\nLaboratory measurements, which include hematocrit, C-reactive protein (CRP), and albumin, were also collected before and after treatment initiation. We also looked at the trough ustekinumab levels where available in relation to dose and response to therapy.\n\nData analysis\n\nPatients are categorized as anti-TNF primary non-responders if there’s no clinical response during therapy induction, and secondary non-responders if there’s loss of response during maintenance phase 15. Based on abbrPCDAI, clinical response is defined as ≥15 points reduction, and clinical remission is defined as <10. We define sustained clinical remission as abbrPCDAI of <10 with no subsequent elevation in AbbrPCDAI as of the last visit. Disease severity is categorized as follows: severe >25; moderate 16–25; mild <16. We use the following SES-CD cutoff to define disease severity: remission 0–2; mild 3–6; moderate 7–15; and severe >16 16. Endoscopic response is defined as ≥50% decrease in SES-CD score compared to baseline 17. Based on previous studies we used a target ustekinumab trough level of >4.5 µg/mL 18.\n\nResults\n\nPatients’ age at initial diagnosis ranged from 2 to 14 years (median age of 9.5 years). Age at initiation of ustekinumab ranged from 9 to 19 years (median age of 14.5 years). Duration of disease ranged from 3 to 14 years (median duration of 6.5 years). Table 1 summarizes patients’ demographic, disease phenotype at diagnosis, extraintestinal manifestations, disease related surgeries, treatment history, and reasons for changing therapy to ustekinumab. Of note, patient one was diagnosed at two years of age, putting him in the very early onset IBD (VEO-IBD) category. Even though VEO-IBD is a phenotypically distinct group, there’s still significant overlap in behavior and response to therapy between VEO-IBD and conventional-onset IBD 19. All 10 patients in our cohort were refractory to anti-TNF therapy.\n\nTable 1. Baseline characteristics of patients included in the study.\n\nPatient\tGender\tAge at\ndiagnosis\tCurrent\nage\tAge at\nustekinumab\ninitiation\tParis\nClassification\nat diagnosis\tabbrPCDAI\nat diagnosis\tExtra-intestinal\nmanifestations\tPerianal\ndisease\tSurgery\tPast\nimmunomodulators\tPast\nanti-TNF\ntherapy\tOther past\nbiologics\tReason for switching to\nustekinumab\t\n1\tM\t2\t11\t9\tA1aL3L4aB1pG1\t30\tNone\tYes\tIleocececto-\nmy with\nileostomy\tThiopurines\tInfliximab,\nadalimumab\tNA\tSecondary loss of response to\ninfliximab and adalimumab. No\nlevel or antibody obtained\t\n2\tM\t13\t16\t15\tA1bL3L4aB1G1\t40\tNone\tNo\tNo\tMethotrexate\tInfliximab,\nadalimumab\tVedolizumab\tSecondary anti-TNF\nnon-responder, antibody\ndevelopment leading to\ntransfusion reaction\t\n3\tF\t10\t18\t17\tNA\tNA\tArthritis\tNo\tComplete\ncolectomy\tThiopurines,\nmethotrexate\tInfliximab,\nadalimumab\tNA\tPrimary anti-TNF non-responder.\nNo antibody detected\t\n4\tF\t9\t16\t14\tA1aL3L4aB1G1\t30\tNone\tNo\tDistal loop\nileostomy\tThiopurines,\nmethotrexate\tInfliximab,\nadalimumab\tVedolizumab\tSecondary anti-TNF non-\nresponder. Developed antibody\nto inflximab. Poor response\ndespite good level and no\nantibody to adalimumab\t\n5\tF\t9\t13\t11\tA1aL3aB1pG1\t35\tNone\tYes\tNo\tMethotrexate\tInfliximab,\nadalimumab\tVedolizumab\tPrimary lack of response to\ninfliximab and adalimumab.\nNo inflximab level; therapuetic\nadalimumab level with no\nantibody\t\n6\tM\t11\t17\t14\tA1bL1L4aB1G1\t25\tArthritis\tYes\tNo\tThiopurines,\nmethotrexate\tInfliximab,\nadalimumab,\ncertolizumab\tNA\tSecondary loss of response\nand psoriasis with infliximab\nand adalimumab with antibody\ndevelopment\t\n7\tM\t9\t15\t12\tA1aL3L4aB1pG1\t30\tFever, arthritis,\nepiscleritis\tYes\tNo\tNA\tInfliximab,\nadalimumab\tNA\tClinical secondary loss of\nresponse\t\n8\tM\t14\t19\t17\tA1bL3L4aB2G1\t20\tNone\tNo\tNo\tThiopurines\tAdalimumab\tNA\tSecondary loss of respone. No\nantibody, therapeutic level\t\n9\tF\t7\t21\t19\tA1aL3B1P\t35\tArthritis, fever\tYes\tNo\tThiopurines,\nmethotrexate\tInfliximab,\nadalimumab\tNA\tPrimary non response to\nalalimumab without drug level.\nLymphoma on infliximab\t\n10\tF\t10\t18\t16\tA1bL3L4aB2G1\t45\tArthritis, fever\tYes\tNo\tThiopurines,\nmethotrexate\tInfliximab,\nadalimumab\tVedolizumab\tPsoriasis reaction with infliximab\t\nEIM- extra intestinal manifestations. AbbrPCDAI - abbreviated pediatric Crohn Disease activity index.\n\nTable 2 summarizes the ustekinumab induction and maintenance dose used in these patients. For induction, the dosing varied among patients with 7 out of 10 receiving induction doses per current recommendations 20 The remaining 3 patients received doses as described in Table 2\n\nTable 2. Ustekinumab dosing, interval, levels, duration of therapy, and complications.\n\nPatient\tInduction\n(mg)\tMaintenance\n(mg)\tInitial\ninterval\n(weeks)\tTrough level\n(ug/ml)\tFinal\nmaintenance\ndose (mg)\tFinal\nintervals\n(weeks)\tLast\ntrough\nlevel\n(µg/mL)\tTherapy\nduration\n(weeks)\tComplications\non\nUstekinumab\t\n1\t45x2\t45\t8\tNA\t90\t8\tNA\t142\tNA\t\n2\t520\t90\t8\tundetectable\t90\t4\tNA\t59\tNA\t\n3\t260\t90\t8\t3.6\t90\t4\t8\t63\tinfusion\nreaction\t\n4\t240\t90\t6\t0.8\t90\t4\t7.1\t71\tNA\t\n5\t180\t45x1, then 90\t6\t0.1\t90\t6\t>10\t73\tNA\t\n6 *\t390\t90\t4\t10\t90\t8\tNA\t16\tskin abscess\t\n7\t90x3 Q4\t90\t8\t1.1\t90\t6\tNA\t143\tskin abscess\t\n8\t260\t90\t8\tNA\t90\t8\tNA\t55\tClostridium\ndifficile infection\t\n9\t390\t90\t8\tNA\t90\t8\tNA\t36\tNA\t\n10\t390\t90\t8\tNA\t90\t8\tNA\t25\tNA\t\n*This patient was exposed to ustekinumab 2 years prior for a duration of 4 weeks\n\nPatients on augmented dose\n\nOf the seven patients who received augmented maintenance doses, all seven showed clinical response, as shown in Figure 1 (patients 1–7), and all but one patient achieved sustained clinical remission as assessed by abbrPCDAI. One patient (patient 7) achieved remission after 5 months of specific carbohydrate diet (SCD) and ustekinumab at Q8 maintenance. He remained in remission for the next 17 months, then developed fatigue and bloody stool when diet was liberalized. His symptoms did not respond to reintroduction of SCD. However, he went into clinical remission when ustekinumab maintenance interval was changed to Q6 weeks.\n\nFigure 1. Clinical and endoscopic response.\n\nAbbreviated-pediatric Crohn’s disease activity index in patients with ( A) augmented ustekinumab dosing and ( B) Q8 dosing; ( C) simple endoscopic score-Crohn’s disease (SES-CD) pre and post-ustekinumab initiation.\n\nOnly 4 out of 10 patients had endoscopy before and after ustekinumab treatment. Of these, three patients showed endoscopic response and one showed worsening of SES-CD score ( Figure 1C). Of note, all 3 patients who showed endoscopic response received augmented dose. While no patient showed mucosal remission, mucosal inflammation did improve from severe to mild, severe to moderate, and moderate to mild in three patients.\n\nLaboratory indices also improved in 6 out of 7 patients ( Table 3). The most significant and consistent improvements were seen in CRP and albumin ( Figure 2C–F). BMI improved significantly in patients with pre-treatment BMI below the 2 nd percentile. In patients with normal BMI (5 th to 85 th percentile), the BMI either decreased or showed small numerical improvement ( Figure 2G,H).\n\nTable 3. laboratory and clinical response to ustekinumab.\n\nPatient\tHematocrit\nBefore\tLast\nHematocrit\tCRP\n(mg/dl)\nbefore\tLast\nCRP\n(mg/dl)\tAlbumin\nBefore\tLast\nAlbumin\tBMI %\nbefore\tLast\nBMI %\tabbrPCDAI\npre tx\tabbrPCDAI\n2-3 months\non tx\tabbrPCDAI\nlast\nassessment\tpre tx\nSES-CD\tpost Tx\nSES-CD\t\n1\t37.4\t38\t10.3\t<0.29\t3.4\t3.7\t63\t60\t35\t5\t0\tNA\tNA\t\n2\t41.6\t43\t0.869\t0.516\t3.2\t3.8\t99\t99.3\t20\t5\t0\tNA\tNA\t\n3\t32\t36\t5.61\t<0.29\t2.7\t3.3\t1.31\t38.9\t30\t15\tNA\t10\t12\t\n4\t28.1\t38.2\t5.06\t<0.29\t2.2\t4\t0.15\t65\t40\t30\t5\t20\t5\t\n5\t35.3\t35\t9.91\t1.92\t2.6\t3.1\t1.88\t42.3\t35\t15\t0\t36\t8\t\n6 *\t40.6\t40.6\t0.52\t0.43\t3.3\t4\t79.8\t77.8\t15\t0\tNA\t14\t5\t\n7\t39.1\t37\t1.39\t1.1\t3.4\t4\t57.4\t29.35\t20\t25\t5\tNA\tNA\t\n8\t40.9\t44.7\t1.62\t0.625\t3\t3.2\t19.4\t17\t20\t25\t0\tNA\tNA\t\n9\t36.7\t36.4\t0.4\t<0.29\t3.5\t1.9\t80.4\t61\t45\t50\tNA\tNA\tNA\t\n10\t36.5\t35.7\t0.95\t1.11\t2.7\t3.3\t77.3\t69.7\t5\t0\t30\t16\t17\t\n*Data collected for patient's second time on ustekinumab\n\nFigure 2. Laboratory and BMI response.\n\nHematocrit in patients with ( A) augmented dosing and ( B) Q8 dosing; CRP in patients with ( C) augmented dosing and ( D) Q8 dosing; albumin in patients with ( E) augmented dosing and ( F) Q8 dosing; BMI in patients with ( G) augmented dosing and ( H) Q8 dosing.\n\nAmong the seven patients, five had ustekinumab trough level showing low or undetectable drug level when receiving medication at a 6 or 8 week intervals ( Table 2). Subsequently, four patients had escalation in frequency to Q4 and either achieved remission or clinical improvement. Following this change in interval, repeat drug levels for three patients were all therapeutic at 8, 7.1, and >10 μg/mL. Subsequently one of these three patients’ maintenance interval was decreased to Q6, and by the time of this study’s conclusion, a repeat level has not been obtained. Frequency was increased to Q6 in another patient, resulting in clinical remission. One of the patients was empirically started on a maintenance dose of Q4 interval and had trough levels of >10 μg/mL at 4 weeks. Frequency was subsequently changed to Q8, but a repeat drug level was not obtained ( Table 2).\n\nPatients on standard dose interval\n\nThree of the 10 patients were on standard ustekinumab dosing. One patient had symptomatic duodenal stricture and obstruction, resulting in abdominal pain, vomiting, and weight loss. He underwent endoscopic stricture dilation 2 months prior to initiation of ustekinumab. After ustekinumab was started, he required two subsequent dilations in a 2-month period, but had subsequently been in remission for the next 5 months on high dose steroid. However, this was confounded by his family continuing 60mg prednisone daily for at least 4 months (2 months longer than prescribed). Unfortunately, there was no subsequent follow ups as he had transitioned to adult care. His hematocrit, CRP, and albumin all improved compared to levels prior to ustekinumab, while his BMI decreased slightly. The remaining two patients had disease worsening on ustekinumab, shown by serology and worsening abbrPCDAI. None of these three patients had their levels checked.\n\nComplications observed while on ustekinumab included infusion reactions, such as low-grade fever, joint pain and vomiting within one week of infusion, and infections such as Clostridium difficile, influenza, and pneumonia. Of note, one patient developed perianal abscess within a few weeks of the first ustekinumab induction, requiring hospitalization and resulting in stopping therapy. Upon the second induction more than 1.5 years later, he again developed forearm abscess requiring hospitalization. However, his CD went into remission with ustekinumab. Work-up for immune deficiency was negative. He was later diagnosed with maturity-onset diabetes of the young.\n\nDiscussion\n\nHere we report 10 pediatric patients with CD refractory to currently approved medications including anti-TNFs, immunomodulators and some to vedolizumab, with seven showing a clinical response to ustekinumab treatment. The majority of our patients showed positive response to ustekinumab within the first 2–3 months of therapy and clinical remission by the time this study was concluded. Four of these seven patients had endoscopic data pre- and post-ustekinumab, out of which three showed an improvement as measured by SES-CD. In general, SES-CD score showed higher level of disease activity than abbrPCDAI, which is likely due to poor correlation between these two indices 21. Moreover, abbrPCDAI and SES-CD information were collected at different times in the treatment course, resulting in small differences in disease activities. CRP, albumin, and BMI showed the largest improvement, and hematocrit improved in all but two patients who responded to treatment.\n\nTo achieve clinical response and/or remission, 7 out of 10 patients needed augmented maintenance doses. Of note, one patient’s (patient 7) level of 1.1 μg/mL coincided with disease exacerbation and increase in maintenance frequency to Q6 resulted in clinical remission. However, more data from subsequent follow ups is needed to determine if disease activity corresponds to dosing frequency and trough level since he had no trough level during previous remission on SCD diet.\n\nAmong the three patients on standard dosing for the entire duration of treatment, only one achieved remission. He had ileocolonic as well as symptomatic gastroduodenal CD, which is a relatively rare manifestation and only affects about 2% of CD patients 22. There are currently no well- established treatment protocols for gastroduodenal CD, and despite treatments with corticosteroid, 6-MP, ASA, and anti-TNF agents, 31% of patients eventually require surgery 23. We cannot conclude if patient 8’s clinical improvement was secondary to ustekinumab or corticosteroids.\n\nIn a previous study by Battat et al. over 75% of adult CD patients needed Q4 week dosing for maintenance of clinical response 18. This study also demonstrated a positive association of biomarkers and endoscopic improvement with ustekinumab trough levels >4.5 μg/mL 18. In addition, in a case series of three adult CD patients, Park et al demonstrated an ability to recapture response by dose escalation among patients who lost response to standard ustekinumab dosing regimen 24. Several observational studies in pediatric IBD patients demonstrate ustekinumab’s efficacy in inducing and maintaining remission 20, 25. While the majority of patients in both studies had dose frequency escalation, the decision was made based on patient’s lack of clinical response. Even though ustekinumab concentration and antibody level was measured for more than half of the 52 patients studied by Dayan et al., the author noted that there was no timing consistency for these measurements, and there was no correlation between dosing escalation and clinical remission. In contrast, among the 7 patients who required dose escalation in our study, 6 had subtherapeutic drug level on Q6 and Q8 dosing interval, which corresponded with poorly controlled disease activities. All these patients showed clinical response to changing the dosing interval. On the two patients who were on standard dosing interval (Q8 weeks), therapeutic drug monitoring (TDM) was not performed and thus we cannot determine if treatment failure was due to subtherapeutic dosing or a primary non-response to ustekinumab. This study demonstrates that TDM can be used to guide dose frequency escalation in patients who show no clinical response or lack of clinical response to ustekinumab. A larger, randomized trial is needed to confirm the role of ustekinumab TDM in pediatric CD patients. Thus, based on our experience and existing literature, we recommend proactively checking trough levels 4 weeks after maintenance therapy initiation to guide dosing frequency early in the treatment course or to consider reactively checking levels and augmenting maintenance dosing interval in patients with sub-optimal or poor response to standard dosing.\n\nSerious adverse effects were rare among our patients despite shorter dosing intervals. Only two patients developed recurrent infections and required hospitalization while on ustekinumab. Even though the patient who was hospitalized for abscesses also had other comorbidities such as maturity onset diabetes of the young, acne, skin picking, psoriasis, and was previously hospitalized twice for recurrent abscesses on certolizumab, ustekinumab could not be ruled out as a cause of these infections. We did not observe any serious infections or cancers in the remaining eight patients, suggesting that ustekinumab is relatively well tolerated even at a higher frequency in pediatric patients.\n\nLimitations\n\nOur study is limited by its small size and retrospective nature. Furthermore, induction and maintenance doses were not uniform among all patients. TDM was only performed on six patients, and follow-up trough for five out of those six patients have not been obtained after changes in dosing frequency.\n\nOnly six patients had pre- and post-treatment endoscopy, and two of those patients had intestinal surgeries, which might have altered SES-CD scores. Even though abbrPCDAI and other laboratory workups were helpful to correlate disease activities, fecal calprotectin should be added to further assess inflammation.\n\nConclusion\n\nIn this retrospective chart review, 7 out of 10 patients with anti-TNF refractory pediatric-onset Crohn’s disease required augmented maintenance doses of ustekinumab to achieve clinical response or remission as measured by abbrPCDAI. The remaining three patients on standard maintenance doses either did not respond or had confounding factors affecting clinical response. Further large, randomized studies with closer therapeutic drug monitoring are needed to assess the relationship between dosing interval, trough levels, and clinical response in the pediatric population. Longer follow up is also needed to assess response once ustekinumab has reached therapeutic level.\n\nData availability\n\nUnderlying data\n\nFigshare: Table 1. Baseline characteristics of patients included in the study, https://doi.org/10.6084/m9.figshare.14681013 26.\n\nFigshare: Table 2. Ustekinumab dosing, interval, levels, duration of therapy, and complication, https://doi.org/10.6084/m9.figshare.14681028 27.\n\nFigshare: Table 3 Clinical response of anti-TNF refractory pediatric Crohn Disease patients on ustekinumab.csv, https://doi.org/10.6084/m9.figshare.14681040 28.\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\nAcknowledgements\n\nThe abstract of this work was presented at the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition Annual Meeting (October 17-19, 2019, Chicago, IL; abstract 101).\n\n10.5256/f1000research.57245.r91519\nReviewer response for version 2\nKellermayer Richard 123Referee https://orcid.org/0000-0002-4146-1335\n\n1 Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA\n2 Section of Pediatric Gastroenterology, Texas Children's Hospital, Houston, TX, USA\n3 USDA/ARS Children's Nutrition Research Center, Houston, TX, USA\n31 8 2021 Copyright: © 2021 Kellermayer R\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nVersion 2recommendationapprove\nThe authors have addressed all my concerns appropriately.\n\nIs the work clearly and accurately presented and does it cite the current literature?\n\nPartly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\n\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility?\n\nPartly\n\nIs the study design appropriate and is the work technically sound?\n\nYes\n\nAre the conclusions drawn adequately supported by the results?\n\nYes\n\nAre sufficient details of methods and analysis provided to allow replication by others?\n\nPartly\n\nReviewer Expertise:\n\nInflammatory bowel disease, Crohn's disease, ulcerative colitis, molecular genetics, epigenetics, nutrition, developmental origins of disease, recurrent Clostridioides difficile infection, fecal transplantation, microbiome, microbial therapeutics.\n\nI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.\n\n10.5256/f1000research.25033.r62949\nReviewer response for version 1\nElkadri Abdul 1Referee\n1 Medical College of Wisconsin, Milwaukee, WI, USA\n12 4 2021 Copyright: © 2021 Elkadri A\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nVersion 1recommendationapprove\nThis study reviews retrospectively the experience of one pediatric institution with ustekinumab in Crohn's disease patients. This is an understudied population with paucity of data. Interestingly, it showed good response in 7/10 patients, but also showed that there was a need for shortened intervals of dosing. This shortened interval of dosing was shown previously in one of the adult studies cited and suggests that there needs to be more studies to support this shortened interval. The review is limited by the lack of comprehensive endoscopic data for all patients, and by the lack of comprehensive data for therapeutic drug monitoring to try to prove the hypothesis that shortened intervals lead to remission and clinical response (with resulting increased drug levels). The retrospective nature of this paper makes the data limited in its ability to prove the hypothesis, but the data is still reviewed well and with details all available to show what the authors have stated. The population is somewhat heterogeneous in nature, limiting the ability to identify a subpopulation where the response is higher. \n\nDue to the small number of patients, the manuscript is by default limited to a descriptive review which the authors have done properly in this manuscript. The data needs to be published to expand the available literature on this medication in this population. \n\nThe current version of the manuscript is appropriate for indexing.\n\nIs the work clearly and accurately presented and does it cite the current literature?\n\nYes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\n\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility?\n\nYes\n\nIs the study design appropriate and is the work technically sound?\n\nYes\n\nAre the conclusions drawn adequately supported by the results?\n\nYes\n\nAre sufficient details of methods and analysis provided to allow replication by others?\n\nYes\n\nReviewer Expertise:\n\nPediatric inflammatory bowel Disease\n\nI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.\n\n10.5256/f1000research.25033.r62953\nReviewer response for version 1\nKellermayer Richard 123Referee https://orcid.org/0000-0002-4146-1335\n\n1 Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA\n2 Section of Pediatric Gastroenterology, Texas Children's Hospital, Houston, TX, USA\n3 USDA/ARS Children's Nutrition Research Center, Houston, TX, USA\n18 5 2020 Copyright: © 2020 Kellermayer R\n2020\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nVersion 1recommendationapprove-with-reservations\nPhinga Do and colleagues, with the leadership of Bhaskar Gurram, give a nice summary on 10 pediatric Crohn’s disease patients, refractory to anti-TNF biologic therapy, who were treated with ustekinumab. Such real life observations on the off label use of new biologic agents in pediatric inflammatory bowel disease (IBD) patients are rather important. Their conclusions coincide with our subjective observation that pediatric IBD patients require a more intensified use of ustekinumab than the manufacturer’s guidance, in order to achieve drug levels that have been found to associate with improved outcomes in adult patients. There are a couple of recommendations, which may further improve the manuscript. In the Methods section, please clarify which laboratory and what methodology was used (especially for ustekinumab therapeutic drug monitoring) for the laboratory measurements discussed in the paper.\n\nVery early onset (VEO) IBD is more and more considered a disease category of its own within IBD. Consider excluding the VEO-IBD (patient 1) case from this cohort, or highlight the case as a variant.\n\nExcluding the brief 4 week course of patient 6 from the table and discussion is recommended. The treatment course was too short to make any conclusions. The comment below the figure is important to keep, however, to clarify that patient 6 was exposed to ustekinumab 2 years prior to the treatment course examined.\n\nIn Table 1, or in a separate table, it would be useful to clarify the type of anti-TNF failure for each patient and each anti-TNF biologic, respectively. Primary non-response could be due to rapid antibody development or primary biological non-response. The same is true for secondary non-response (i.e. late development of antibodies, or immune pathway shift). It is fine to state unknown/clinical if level and antibody for the anti-TNF agent was not examined.\n\nIn the results, consider omitting the complicated description of dosing, since Table 2 describes that in detail.\n\nBoth figures are complicated, and the results those depict could be easily described and followed in writing within the Results section. Omitting the figures is recommended.\n\nThe clinical outcomes are difficult to follow based on the separation of the patients by augmented ustekinumab treatment versus not. Separating the patients by responders vs. non-responders, and examining ustekinumab dosing differences between the 2 groups is recommended. If I am not mistaken, and even if the patient 1 (VEO-IBD) case is excluded, there were 7 responders (6 on intensified ustekinumab therapy) and 2 non-responders (all on conventional ustekinumab treatment). These results, if compared by Chi squared testing, significantly favor (p=0.0233) treatment intensification in order to achieve clinical response.\n\nThere are parts of the discussion, which continue specific patient outcome descriptions. This should be moved to the Results section. The discussion should only draw general conclusions from what has been presented in the results and compare the findings to the existing literature.\n\nInclude in the discussion, more recent similar studies, such as the ones below, and highlight the novelties of the case series presented within this work compared to other pediatric cohorts:\n\n Real World Experience With Ustekinumab in Children and Young Adults at a Tertiary Care Pediatric Inflammatory Bowel Disease Center. Dayan JR et al. J Pediatr Gastroenterol Nutr. (2019) 1\n\nUstekinumab for the treatment of refractory pediatric Crohn's disease: a single-center experience. Cohen A, Ahmed N, Sant'Anna A.. Intest Res. 2020 Apr 22. 2\n\nIs the work clearly and accurately presented and does it cite the current literature?\n\nPartly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\n\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility?\n\nPartly\n\nIs the study design appropriate and is the work technically sound?\n\nYes\n\nAre the conclusions drawn adequately supported by the results?\n\nYes\n\nAre sufficient details of methods and analysis provided to allow replication by others?\n\nPartly\n\nReviewer Expertise:\n\nInflammatory bowel disease, Crohn's disease, ulcerative colitis, molecular genetics, epigenetics, nutrition, developmental origins of disease, recurrent Clostridioides difficile infection, fecal transplantation, microbiome, microbial therapeutics.\n\nI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.\n\ndo phinga UT Southwestern, USA\n\n26 5 2021 In the Methods section, please clarify which laboratory and what methodology was used (especially for ustekinumab therapeutic drug monitoring) for the laboratory measurements discussed in the paper. \n\nAll of the tests were done either by Miraca or Inform Diagnostics. Both these labs use Automated ELISA assay for simultaneous antibody and drug levels \n\nVery early onset (VEO) IBD is more and more considered a disease category of its own within IBD. Consider excluding the VEO-IBD (patient 1) case from this cohort, or highlight the case as a variant. \n\nAlthough some patients with VEOIBD might behave differently than conventional-onset IBD patients (onset>10 years of age), there is still significant overlap with their disease behavior and response to therapy. Moreover, although the patient 1 included in the current study had onset at 2 years of age, he was started on ustekinumab at 9 years age. Inflamm Bowel Dis 2021 Feb 16;27(3):295-302. doi: 10.1093/ibd/izaa080. \n\nExcluding the brief 4-week course of patient 6 from the table and discussion is recommended. The treatment course was too short to make any conclusions. The comment below the figure is important to keep, however, to clarify that patient 6 was exposed to ustekinumab 2 years prior to the treatment course examined. \n\nWe will remove this part. Agree that it does not add much aside from noting that there’s prior exposure.\n\nIn Table 1, or in a separate table, it would be useful to clarify the type of anti-TNF failure for each patient and each anti-TNF biologic, respectively. Primary non-response could be due to rapid antibody development or primary biological non-response. The same is true for secondary non-response (i.e. late development of antibodies, or immune pathway shift). It is fine to state unknown/clinical if level and antibody for the anti-TNF agent was not examined. \n\nTable 1 has been modified to include more specific reasons for anti-TNF failure.\n\nIn the results, consider omitting the complicated description of dosing, since Table 2 describes that in detail. \n\nThe results section has been edited to omit dosing descriptions.\n\n \n\nBoth figures are complicated, and the results those depict could be easily described and followed in writing within the Results section. Omitting the figures is recommended. \n\nWe believe that the figures compliment the text and some readers prefer just to look at the tables and pictures. They provide visual aid and show a clear trend of improvement for patients on augmented dosing.\n\nThe clinical outcomes are difficult to follow based on the separation of the patients by augmented ustekinumab treatment versus not. Separating the patients by responders vs. non-responders and examining ustekinumab dosing differences between the 2 groups is recommended. If I am not mistaken, and even if the patient 1 (VEO-IBD) case is excluded, there were 7 responders (6 on intensified ustekinumab therapy) and 2 non-responders (all on conventional ustekinumab treatment). These results, if compared by Chi squared testing, significantly favor (p=0.0233) treatment intensification in order to achieve clinical response. \n\nWe did organize it by responder vs non responder initially but found that organizing by augmented vs standard dosing shows a clearer trend. Moreover, what we want to point out to the readers through this paper is that most pediatric patients in our cohort needed higher dose than the standard dosing. In addition, we cannot say if patient 8 (the one with duodenal stricture) is an ustekinumab responder or not and will require 3 distinct categories (responder, non-responder, and indeterminant). All 7 responders were on augmented dose\n\nThere are parts of the discussion, which continue specific patient outcome descriptions. This should be moved to the Results section. The discussion should only draw general conclusions from what has been presented in the results and compare the findings to the existing literature. \n\nThe text has been reorganized.\n\nInclude in the discussion, more recent similar studies, such as the ones below, and highlight the novelties of the case series presented within this work compared to other pediatric cohorts:\n\nEdited to include these 2 studies.\n\nCompeting interests: No competing interests were disclosed.\n\nCompeting interests: No competing interests were disclosed.\n\nCompeting interests: No competing interests were disclosed.\n\nCompeting interests: None\n==== Refs\n1 Ong C Aw MM Liwanag MJ : Rapid rise in the incidence and clinical characteristics of pediatric inflammatory bowel disease in a South-East Asian cohort in Singapore, 1994-2015. J Dig Dis. 2018;19 (7 ):395–403. 10.1111/1751-2980.12641 29927059\n2 Sýkora J Pomahačová R Kreslová M : Current global trends in the incidence of pediatric-onset inflammatory bowel disease. World J Gastroenterol. 2018;24 (25 ):2741–2763. 10.3748/wjg.v24.i25.274129991879\n3 Pozler O Maly J Bonova O : Incidence of Crohn disease in the Czech Republic in the years 1990 to 2001 and assessment of pediatric population with inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2006;42 (2 ):186–9. 10.1097/01.mpg.0000189328.47150.bc 16456413\n4 Pigneur B Seksik P Viola S : Natural history of Crohn’s disease: comparison between childhood- and adult-onset disease. Inflamm Bowel Dis. 2010;16 (6 ):953–61. 10.1002/ibd.21152 19834970\n5 Ruemmele FM Veres G Kolho KL : Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn’s disease. J Crohns Colitis. 2014;8 (10 ):1179–1207. 10.1016/j.crohns.2014.04.005 24909831\n6 Cameron F Wilson M Basheer N : Anti-TNF therapy for paediatric IBD: the Scottish national experience. Arch Dis Child. 2015;100 (4 ):399–405. 10.1136/archdischild-2013-305812 25678594\n7 Grossi V Lerer T Griffiths A : Concomitant Use of Immunomodulators Affects the Durability of Infliximab Therapy in Children With Crohn’s Disease. Clin Gastroenterol Hepatol. 2015;13 (10 ):1748–1756. 10.1016/j.cgh.2015.04.010 25911120\n8 Feagan BG Sandborn WJ Gasink C : Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease. N Engl J Med. 2016;375 (20 ):1946–1960. 10.1056/NEJMoa1602773 27959607\n9 Bertrand V El Haite A Carré D : Efficiency of Ustekinumab in Crohn’s Disease with Severe Psoriasiform Rash Induced by Biotherapies in an Adolescent. Pediatr Dermatol. 2017;34 (4 ):e214–e215. 10.1111/pde.13138 28436109\n10 Rinawi F Rosenbach Y Assa A : Ustekinumab for Resistant Pediatric Crohn Disease. J Pediatr Gastroenterol Nutr. 2016;62 (4 ):e34–e35. 10.1097/MPG.0000000000000503 25023579\n11 Bishop C Simon H Suskind D : Ustekinumab in Pediatric Crohn Disease Patients. J Pediatr Gastroenterol Nutr. 2016;63 (3 ):348–51. 10.1097/MPG.0000000000001146 26854655\n12 Levine A Griffiths A Markowitz J : Pediatric modification of the Montreal classification for inflammatory bowel disease: the Paris classification. Inflamm Bowel Dis. 2011;17 (6 ):1314–21. 10.1002/ibd.21493 21560194\n13 Shepanski MA Markowitz JE Mamula P : Is an abbreviated Pediatric Crohn's Disease Activity Index better than the original? J Pediatr Gastroenterol Nutr. 2004;39 (1 ):68–72. 10.1097/00005176-200407000-00014 15187784\n14 Daperno M D'Haens G Van Assche G : Development and validation of a new, simplified endoscopic activity score for Crohn's disease: the SES-CD. Gastrointest Endosc. 2004;60 (4 ):505-12. 10.1016/s0016-5107(04)01878-4 15472670\n15 Roda G Jharap B Neeraj N : Loss of Response to Anti-TNFs: Definition, Epidemiology, and Management. Clin Transl Gastroenterol. 2016;7 (1 ):e135. 10.1038/ctg.2015.6326741065\n16 Koutroumpakis E Katsanos KH : Implementation of the simple endoscopic activity score in crohn's disease. Saudi J Gastroenterol. 2016;22 (3 ):183–91. 10.4103/1319-3767.18245527184635\n17 Ferrante M Colombel JF Sandborn WJ : Validation of endoscopic activity scores in patients with Crohn's disease based on a post hoc analysis of data from SONIC. Gastroenterology. 2013;145 (5 ):978–986.e5. 10.1053/j.gastro.2013.08.010 23954314\n18 Battat R Kopylov U Bessissow T : Association Between Ustekinumab Trough Concentrations and Clinical, Biomarker, and Endoscopic Outcomes in Patients With Crohn’s Disease. Clin Gastroenterol Hepatol. 2017;15 (9 ):1427–1434.e2. 10.1016/j.cgh.2017.03.032 28365485\n19 Kerur B Benchimol EI Fiedler K : Natural History of Very Early Onset Inflammatory Bowel Disease in North America: A Retrospective Cohort Study. Inflamm Bowel Dis. 2021;27 (3 ):295–302. 10.1093/ibd/izaa08032386060\n20 Dayan J Dolinger M Benkov K : Real World Experience with Ustekinumab in Children and Young Adults at a Tertiary Care Pediatric Inflammatory Bowel Disease Center. J Pediatr Gastroenterol Nutr. 2019;69 (1 ):61–67. 10.1097/MPG.000000000000236231058718\n21 Turner D Levine A Walters TD : Which PCDAI Version Best Reflects Intestinal Inflammation in Pediatric Crohn Disease? J Pediatr Gastroenterol Nutr. 2017;64 (2 ):254–260. 10.1097/MPG.0000000000001227 27050050\n22 Nugent FW Richmond M Park SK : Crohn’s disease of the duodenum. Gut. 1977;18 (2 ):115–120. 10.1136/gut.18.2.115856671\n23 Murray JJ Schoetz DJ Jr Nugent FW : Surgical management of Crohn's disease involving the duodenum. Am J Surg. 1984;147 (1 ):58–65. 10.1016/0002-9610(84)90035-7 6691553\n24 Park S Evans E Sandborn WJ : Ustekinumab IV 6 mg/kg Loading Dose Re-induction Improves Clinical and Endoscopic Response in Crohn’s disease: A Case Series. Am J Gastroenterol. 2018;113 (4 ):627–629. 10.1038/ajg.2018.22 29610516\n25 Cohen A Najma A Sant'Anna A : Ustekinumab for the Treatment of Refractory Pediatric Crohn’s Disease: a Single-Center Experience. Intest Res. 2021;19 (2 ):217–224. 10.5217/ir.2019.0916432312033\n26 Do P Gurram B Luu P : Table 1. Baseline characteristics of patients included in the study. figshare.Dataset.2020. 10.6084/m9.figshare.14681013\n27 Do P Gurram B Luu P : Table 2. Ustekinumab dosing, interval, levels, duration of therapy, and complication. figshare.Dataset.2020. 10.6084/m9.figshare.14681028\n28 Do P Gurram B Luu P : Table 3 Clinical response of anti-TNF refractory pediatric Crohn Disease patients on ustekinumab.csv. figshare.Dataset.2020. 10.6084/m9.figshare.14681040\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2046-1402",
"issue": "9()",
"journal": "F1000Research",
"keywords": "Clinical response; Inflammatory bowel disease; Pediatric Crohn's disease; Therapeutic drug monitoring; Ustekinumab; anti-TNF-refractory Crohn's disease",
"medline_ta": "F1000Res",
"mesh_terms": "D000328:Adult; D002648:Child; D003424:Crohn Disease; D006801:Humans; D012189:Retrospective Studies; D000079424:Tumor Necrosis Factor Inhibitors; D000069549:Ustekinumab",
"nlm_unique_id": "101594320",
"other_id": null,
"pages": "316",
"pmc": null,
"pmid": "34504690",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Augmented ustekinumab dosing is needed to achieve clinical response in patients with anti-TNF refractory pediatric Crohn's disease: a retrospective chart review.",
"title_normalized": "augmented ustekinumab dosing is needed to achieve clinical response in patients with anti tnf refractory pediatric crohn s disease a retrospective chart review"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-317132",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"dr... |
{
"abstract": "BACKGROUND\nUnresectable cholangiocarcinoma has a poor prognosis and treatment options are limited. Combined systemic and intrahepatic chemotherapy may improve local control and enable downsizing. The aim of this study was to determine the maximum tolerated dose (MTD) of intravenous gemcitabine combined with intravenous cisplatin and hepatic arterial infusion (HAI) with floxuridine (FUDR) in patients with unresectable intrahepatic or hilar cholangiocarcinoma.\n\n\nMETHODS\nTwelve patients were treated within a 3 + 3 dose escalation algorithm with 600, 800, or 1,000 mg/m2 gemcitabine and predefined doses of cisplatin 25 mg/m2 on days 1 and 8, q21, for 4 cycles, and FUDR 0.2 mg/kg on days 1-14 as continuous HAI, q28, for 3 cycles. Safety and toxicity as well as resectability rates after 3 months and preliminary survival data are reported.\n\n\nRESULTS\nThe determined MTD for gemcitabine was 800 mg/m2. Dose limiting toxicities were neutropenic fever and biliary tract infections. In total, 27% of the patients showed partial remission and 73% stable disease. Although none of the patients achieved resectability after 3 months, the 3-year overall survival rate was 33%, median overall survival 23.9 months (range 1-49), and median progression-free survival 10.1 months (range 2-40).\n\n\nCONCLUSIONS\nIntravenous gemcitabine/cisplatin plus HAI-FUDR is feasible and appears effective for disease control. Larger prospective studies evaluating this triplet combination are warranted.",
"affiliations": "Department of Medical Oncology and Hematology, Division of Medical Oncology, University Hospital Zurich, Zurich, Switzerland.;Department of General Surgery and Transplantation, University Hospital Zurich, Zurich, Switzerland.;Department of Medical Oncology and Hematology, Division of Medical Oncology, University Hospital Zurich, Zurich, Switzerland.;Department of Medical Oncology and Hematology, Division of Medical Oncology, University Hospital Zurich, Zurich, Switzerland.;Department of Medical Oncology and Hematology, Division of Medical Oncology, University Hospital Zurich, Zurich, Switzerland.;Department of Medical Oncology and Hematology, Division of Medical Oncology, University Hospital Zurich, Zurich, Switzerland.;Department of Radiology, University Hospital Zurich, Zurich, Switzerland.;Department of Surgery, Kantonsspital Winterthur, Winterthur, Switzerland.;Department of Medical Oncology and Hematology, Division of Medical Oncology, University Hospital Zurich, Zurich, Switzerland.;Department of General Surgery and Transplantation, University Hospital Zurich, Zurich, Switzerland.;Department of Medical Oncology and Hematology, Division of Medical Oncology, University Hospital Zurich, Zurich, Switzerland.;Department of General Surgery and Transplantation, University Hospital Zurich, Zurich, Switzerland.;Department of Medical Oncology and Hematology, Division of Medical Oncology, University Hospital Zurich, Zurich, Switzerland, panagiotis.samaras@uzh.ch.",
"authors": "Pietge|Heike|H|;Sánchez-Velázquez|Patricia|P|;Akhoundova|Dilara|D|;Siebenhüner|Alexander|A|;Winder|Thomas|T|;Bachmann|Helga|H|;Nguyen-Kim|Thi Dan Linh|TDL|;Breitenstein|Stefan|S|;Knuth|Alexander|A|;Petrowsky|Henrik|H|;Pestalozzi|Bernhard|B|;Clavien|Pierre-Alain|PA|;Samaras|Panagiotis|P|",
"chemical_list": "D005467:Floxuridine; D003841:Deoxycytidine; C056507:gemcitabine; D002945:Cisplatin",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000512967",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0030-2414",
"issue": "99(5)",
"journal": "Oncology",
"keywords": "Cholangiocarcinoma; Floxuridine; Hepatic arterial infusion; Intrahepatic chemotherapy; Intrahepatic cholangiocarcinoma; Unresectable cholangiocarcinoma",
"medline_ta": "Oncology",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001650:Bile Duct Neoplasms; D018281:Cholangiocarcinoma; D002945:Cisplatin; D003841:Deoxycytidine; D005260:Female; D005467:Floxuridine; D005500:Follow-Up Studies; D006499:Hepatic Artery; D006801:Humans; D007261:Infusions, Intra-Arterial; D008297:Male; D008875:Middle Aged; D065228:Non-Randomized Controlled Trials as Topic; D011379:Prognosis; D011446:Prospective Studies; D015996:Survival Rate",
"nlm_unique_id": "0135054",
"other_id": null,
"pages": "300-309",
"pmc": null,
"pmid": "33657549",
"pubdate": "2021",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": "20404611;9829747;11391522;27995089;19491285;25379846;28597043;20497401;12376491;31670750;27000463;1303612;6346495;28612017;29233520;7964942;26830685;29234631;29277819;11049044;26695839;22910846;18333200;29327075;15273542;20375404;21730269",
"title": "Combination of HAI-FUDR and Systemic Gemcitabine and Cisplatin in Unresectable Cholangiocarcinoma: A Dose Finding Single Center Study.",
"title_normalized": "combination of hai fudr and systemic gemcitabine and cisplatin in unresectable cholangiocarcinoma a dose finding single center study"
} | [
{
"companynumb": "CH-HQ SPECIALTY-CH-2021INT000184",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "Drug-induced liver injury (DILI) in a patient with multiple comorbidities is often challenging to diagnose because liver injury can be attributed to multiple disease processes. Delayed treatment of DILI could have fatal consequences and, therefore, understanding the features and risks of DILI is crucial. We report a unique case of a patient who was admitted for severe sepsis of unknown etiology. This patient was later found to have miliary tuberculosis (TB) with associated adrenal insufficiency, complicated by acute cholestatic liver injury. Liver injury fully improved after initiation of corticosteroid for the treatment of adrenal insufficiency. The most likely pathophysiology of acute liver injury was DILI, given the clinical course of liver injury and the liver biopsy result of non-caseating granulomas. Although five different antibiotics including ciprofloxacin, metronidazole, vancomycin, imipenem/cilastatin, and cefepime were provided, the timing of liver injury and pharmacology of each drug imply that ciprofloxacin was the most likely antibiotic causing DILI, given the pharmacology of each antibiotics. This case is unique because miliary TB was complicated by adrenal insufficiency and drug-induced cholestatic liver injury, but acute liver injury was fully reversed after corticosteroid treatment. This implies an immune-mediated etiology of DILI, especially ciprofloxacin-induced cholestatic liver injury. DILI is challenging to diagnose in the setting of multiple comorbidities. Therefore, it is crucial that clinicians are to be aware of signs and symptoms of DILI, in that delayed diagnose and treatment may have fatal consequences.",
"affiliations": "Department of Medicine, Elmhurst Hospital Center, Icahn School of Medicine at Mount Sinai, Elmhurst, IL, USA. orlando.machado@mssm.edu.",
"authors": "Lee|S Y|SY|;Schneier|A|A|;Schiano|T|T|;Liu|S J|SJ|;Machado|O N|ON|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000900:Anti-Bacterial Agents",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1128-3602",
"issue": "19(16)",
"journal": "European review for medical and pharmacological sciences",
"keywords": null,
"medline_ta": "Eur Rev Med Pharmacol Sci",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000309:Adrenal Insufficiency; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D056486:Chemical and Drug Induced Liver Injury; D002779:Cholestasis; D015897:Comorbidity; D057210:Delayed Diagnosis; D005260:Female; D006801:Humans; D014391:Tuberculosis, Miliary",
"nlm_unique_id": "9717360",
"other_id": null,
"pages": "3046-9",
"pmc": null,
"pmid": "26367727",
"pubdate": "2015-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Delayed diagnosis of cholestatic drug-induced liver injury treated with corticosteroid for adrenal insufficiency secondary to miliary tuberculosis.",
"title_normalized": "delayed diagnosis of cholestatic drug induced liver injury treated with corticosteroid for adrenal insufficiency secondary to miliary tuberculosis"
} | [
{
"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2015-02326",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN"
},
"drugadditio... |
{
"abstract": "BACKGROUND\nMetformin is prescribed with an increasing frequency for patients with Type II diabetes mellitus; the increasing availability increases the risk of intentional overdoses. Metformin may cause severe lactic acidosis in overdose, especially when accompanied by co-ingestants or other medical conditions that alter lactate handling or metformin elimination. Though the clearance of therapeutic metformin by hemodialysis is known, the clearance in the setting of a large overdose has not been reported.\n\n\nMETHODS\nA 58-year-old man with a history of Type II diabetes, hypertension, bipolar disease, and decreased renal function presented after ingestion of approximately 40 500-mg metformin tablets and 20 240-mg diltiazem sustained-release tablets. Clinical manifestations of poisoning included somnolence, hypotension, bradycardia, severe lactic acidosis, and ultimately death. Gastric decontamination was attempted with gastric lavage, multiple dose activated charcoal, and whole bowel irrigation. Hemodynamic support was provided with pressors, glucagon, insulin, and intra-aortic balloon pump. Due to hypotension, continuous renal replacement therapy, rather than hemodialysis, was initiated. Continuous veno-venous hemodialysis was performed with a blood flow of 180 mL/min and dialysate flow of 2.5 L/h. A Multiflow 60 kidney (Cobe) on a Prisma (Cobe) continuous renal replacement therapy machine was used. The initial metformin level was 110 microg/mL (therapeutic range 1-2 microg/mL). By continuous veno-venous hemodialysis, an absolute clearance of 50.4 mL/min was obtained.\n\n\nCONCLUSIONS\nMetformin was cleared by the continuous veno-venous hemodialysis modality of continuous renal replacement therapy in this metformin overdose. Although a fatal outcome occurred in this patient, its utility in other patients with metformin overdose should be investigated.",
"affiliations": "Department of Emergency Medicine, Brody Medical School at East Carolina University, Greenville, North Carolina 27858, USA.",
"authors": "Barrueto|Fermin|F|;Meggs|William J|WJ|;Barchman|M J|MJ|",
"chemical_list": "D000959:Antihypertensive Agents; D007004:Hypoglycemic Agents; D008687:Metformin; D004110:Diltiazem",
"country": "United States",
"delete": false,
"doi": "10.1081/clt-120004407",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0731-3810",
"issue": "40(2)",
"journal": "Journal of toxicology. Clinical toxicology",
"keywords": null,
"medline_ta": "J Toxicol Clin Toxicol",
"mesh_terms": "D000959:Antihypertensive Agents; D004110:Diltiazem; D017809:Fatal Outcome; D006440:Hemofiltration; D006801:Humans; D007004:Hypoglycemic Agents; D008297:Male; D008657:Metabolic Clearance Rate; D008687:Metformin; D008875:Middle Aged",
"nlm_unique_id": "8213460",
"other_id": null,
"pages": "177-80",
"pmc": null,
"pmid": "12126190",
"pubdate": "2002",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Clearance of metformin by hemofiltration in overdose.",
"title_normalized": "clearance of metformin by hemofiltration in overdose"
} | [
{
"companynumb": "CA-ALKEM LABORATORIES LIMITED-CA-ALKEM-2018-07476",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
... |
{
"abstract": "The authors report significant worsening of a pre-existing neuropathy in six patients who received \"non-toxic\" dosages of known neurotoxic agents. Before treatment, baseline total neuropathy score (TNS) averaged 9.5 (range 0 to 19). After chemotherapy (Taxol [125 to 175 mg/m(2) x 4]; vincristine [2 to 5 mg]; cisplatin [40 mg/m(2) x 8]; and thalidomide [60 g]), the TNS averaged 22 (range 13 to 29). The authors conclude that functionally disabling toxic neuropathy can occur in patients with pre-existing neuropathy at standard doses.",
"affiliations": "Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. vchaudh@jhmi.edu.",
"authors": "Chaudhry|V|V|;Chaudhry|M|M|;Crawford|T O|TO|;Simmons-O'Brien|E|E|;Griffin|J W|JW|",
"chemical_list": "D013792:Thalidomide; D014750:Vincristine; D017239:Paclitaxel; D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": "10.1212/01.wnl.0000043691.53710.53",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3878",
"issue": "60(2)",
"journal": "Neurology",
"keywords": null,
"medline_ta": "Neurology",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D002945:Cisplatin; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008179:Lupus Erythematosus, Discoid; D008223:Lymphoma; D008297:Male; D008875:Middle Aged; D009431:Neural Conduction; D009959:Oropharyngeal Neoplasms; D017239:Paclitaxel; D010523:Peripheral Nervous System Diseases; D012720:Severity of Illness Index; D013792:Thalidomide; D014750:Vincristine",
"nlm_unique_id": "0401060",
"other_id": null,
"pages": "337-40",
"pmc": null,
"pmid": "12552058",
"pubdate": "2003-01-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Toxic neuropathy in patients with pre-existing neuropathy.",
"title_normalized": "toxic neuropathy in patients with pre existing neuropathy"
} | [
{
"companynumb": "US-PFIZER INC-2018067749",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINCRISTINE SULFATE"
},
"drugadditional": "3",... |
{
"abstract": "A 46-year-old woman with a history of end-stage renal disease on chronic haemodialysis presented with 1 week of fever, chills, altered mental status and hand pain. She was febrile and ill-appearing on presentation with a pulse rate of 102 beats per minute. She had a tunnelled dialysis catheter in her right neck. Hand examination demonstrated a swollen, erythematous and tender wrist. Cardiovascular examination demonstrated no murmurs. CT of the hand showed abscesses involving the left forearm. Blood and abscess cultures grew methicillin-resistant Staphylococcus aureus (MRSA). Transesophageal echocardiography (TEE) showed a 1.0×1.0 cm mobile vegetation involving the eustachian valve (EV), confirming EV endocarditis. She remained bacteraemic for 18 days despite being on vancomycin with appropriate blood levels. Vancomycin was switched to daptomycin and ceftaroline, which cleared her cultures. Repeat TEE showed improved vegetation size. Our case highlights the rarity and management of EV endocarditis and the importance of synergy for treatment of persistent MRSA bacteraemia.",
"affiliations": "Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, Michigan, USA dilpat.kumar@med.wmich.edu.;Internal Medicine Department, Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, Michigan, USA.;Internal Medicine, Interfaith Medical Center, Brooklyn, New York, USA.;Medicine, Division of Infectious Diseases, Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, Michigan, USA.",
"authors": "Kumar|Dilpat|D|http://orcid.org/0000-0001-8462-4627;Boyer|James|J|;Fnu|Warsha|W|;Boamah|Harry|H|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "England",
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"abstract": "This was a case report of severe fatigue and bleeding in a 65-year-old man with ischemic heart disease who was wearing a stent and taking multiple medications for hypertension and diabetes. The use of a drug interaction and personalized prescription software (g-Nomic®) revealed potential interactions, involving acetylsalicylic acid and several non-pharmaceutical products including ginger, blueberry extracts, pineapple juice, docosahexaenoic acid and liquorice. Correction of these interactions resulted in complete remission of the reported side effects. This supports the idea that non-pharmaceuticals potentiated the effects of acetylsalicylic acid on haemostasis, producing the bleeding that would have caused fatigue. It is important to use appropriate tools to detect drug interactions that also take into account commonly used non-pharmaceutical products. Drug interactions can be considered illnesses by themselves.",
"affiliations": "Bahía de Cádiz-La Janda Health District, Mobile Emergency Unit of the Andalusian Health Care, Service of Cádiz, Cádiz, Spain.;Eugenomic, Barcelona, Spain.;Biochemistry and Molecular Biology Unit, School of Pharmacy, University of Barcelona, Barcelona, Spain.;Eugenomic, Barcelona, Spain.",
"authors": "Saldarreaga Marin|Abel|A|0000-0003-2341-8648;Cendros|Marc|M|;Ciudad|Carlos J|CJ|0000-0002-7855-392X;Sabater|Ana|A|0000-0002-5359-4995",
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"fulltext": "\n==== Front\nPharmgenomics Pers Med\nPharmgenomics Pers Med\npgpm\nppm\nPharmacogenomics and Personalized Medicine\n1178-7066\nDove\n\n323463\n10.2147/PGPM.S323463\nCase Report\nCase Report: Fatigue and Bleeding in a Polymedicated Patient Using Several Herbal Supplementations, Detected with g-Nomic® Software\nSaldarreaga Marin et al\nSaldarreaga Marin et al\nhttp://orcid.org/0000-0003-2341-8648\nSaldarreaga Marin Abel 1\nCendros Marc 2\nhttp://orcid.org/0000-0002-7855-392X\nCiudad Carlos J 3\nhttp://orcid.org/0000-0002-5359-4995\nSabater Ana 2\n1 Bahía de Cádiz-La Janda Health District, Mobile Emergency Unit of the Andalusian Health Care, Service of Cádiz, Cádiz, Spain\n2 Eugenomic, Barcelona, Spain\n3 Biochemistry and Molecular Biology Unit, School of Pharmacy, University of Barcelona, Barcelona, Spain\nCorrespondence: Ana Sabater Eugenomic, c/ Londres 6, Barcelona, 08029, SpainTel +34-93-292-2963 Email asabater@eugenomic.com\n12 8 2021\n2021\n14 963970\n14 6 2021\n19 7 2021\n© 2021 Saldarreaga Marin et al.\n2021\nSaldarreaga Marin et al.\nhttps://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).\nAbstract\n\nThis was a case report of severe fatigue and bleeding in a 65-year-old man with ischemic heart disease who was wearing a stent and taking multiple medications for hypertension and diabetes. The use of a drug interaction and personalized prescription software (g-Nomic®) revealed potential interactions, involving acetylsalicylic acid and several non-pharmaceutical products including ginger, blueberry extracts, pineapple juice, docosahexaenoic acid and liquorice. Correction of these interactions resulted in complete remission of the reported side effects. This supports the idea that non-pharmaceuticals potentiated the effects of acetylsalicylic acid on haemostasis, producing the bleeding that would have caused fatigue. It is important to use appropriate tools to detect drug interactions that also take into account commonly used non-pharmaceutical products. Drug interactions can be considered illnesses by themselves.\n\nKeywords\n\npharmacogenetics\nSNP\ndrug-drug interaction\ndrug-lifestyle interactions\ndrug-herb\nsoftware\nbleeding\nfatigue\npolymedication\nmedication risk\npharmacogenetics software\npersonalized prescription\n==== Body\nIntroduction\n\nDrug treatment can be affected by significant variability in the degree of response and the occurrence of side effects. Adverse drug reactions are responsible for considerable morbidity and mortality. Sometimes these undesirable effects are intrinsic to the drug, but in many cases they are due to drug-drug interactions.1,2 It is known that drug-drug interactions can trigger adverse effects of medicines that would have been safe if they had not been used in combination. In addition, other substances that are not usually considered pharmaceuticals, like herbal products, may also cause drug-lifestyle interactions. Recognising and managing these interactions can be an invaluable process in achieving safer therapy.\n\nWe present a case of a polymedicated patient who was taking apparently harmless substances and dietary supplements and who presented with bleeding and fatigue. This situation was resolved by identifying and managing drug interactions using g-Nomic® personalised prescription software.\n\nCase Presentation\n\nA 65-year-old Caucasian man with hypertension, type 2 diabetes, elevated LDL-cholesterol and ischemic cardiomyopathy, wearing a stent, presented unexplained fatigue with physical activity and coagulation defects consisting of gingival bleeding and frequent bruising.\n\nAnalytical Explorations\n\nAll biochemical parameters were within the normality except for elevated LDL-c levels. Hepatic and renal functions were normal (Alanine transaminase -ALT 17 U/L, aspartate transaminase AST 21 u/L, gamma-glutamyltransferase 24 U/L, creatinine 0.94 mg/dL, blood urea 35 mg/dL, glucose 95 mg/dL, glycosylated haemoglobin 6.1%). Prothrombin time (seconds): 10.2“ (8.9–13.3). Normalized prothrombin time (INR): 0.90 (0.80–1.20).\n\nAt the moment of the consultation, the patient had the following treatment:\n\nTelmisartan 40mg/d, metformin 850 mg/d, empagliflozin 40mg/d, bisoprolol 2.5/d, atorvastatin 40mg/d, clopidogrel 75mg/d and acetylsalicylic acid (ASA) 100mg/d.\n\nExamination\n\nExcept for fatigue and bleeding, the patient showed good general condition; he was conscious, oriented and collaborative, eupnoeic at rest and afebrile. Cardiopulmonary auscultation and abdominal examination did not result in pathological findings. Basal oxygen saturation: 98%. Blood pressure: 138 mm Hg (systolic)/76 mm Hg (diastolic). Heart rate; 85 bpm. Respiratory rate at rest: 14 bpm. Temperature: 35.8 °C.\n\nThe patient’s medication regime was evaluated using g-Nomic® software3 to check for interactions and possible genetic effects. In Figure 1 it is shown all the initial drugs entered in the personalized prescription software. Figure 1 All initial drugs entered in the personalized prescription software.\n\nIn addition, the same personalized prescription software was used to check for possible substances that could contribute to interactions even if they are not considered drugs per se, referred to in the software as lifestyle habits. After interviewing the patient about them, it was identified that the patient consumed 3 grams of docosahexaenoic acid (DHA) /day, blueberry and ginger extract supplements, and daily consumption of pineapple juice. In addition, the patient quit smoking nine years ago, and since then has been consuming liquorice ever since to support abstinence. Figure 2 shows the list of lifestyle habits that may interact negatively with the patient’s prescription entered into the personalized prescription software. The physician should ask the patient if he/she takes any of these substances on a regular basis in his/her daily life. If so, the doctor should click on the hyperlink to make this lifestyle habits part of the prescription as a whole. Figure 2 Shows the list of all lifestyle habits that could interact with patient's medication, reported by the personalized prescription software.\n\nActions and Outcome\n\nAfter evaluating the possible interactions between medication and lifestyle, some measures were taken to avoid those interactions. Figure 3 shows drug-drug interactions as well as drug- lifestyle interactions. Figure 4 shows the possible interactions due to inhibitions and inductions caused by patient’s polymedication. It is known that substances with inhibitory capacity can also impair enzyme activity even in the absence of loss-of-function variants. Therefore, a person who would be classified as a normal metaboliser based on a genetic test alone would experience a phenoconversion to a poor metaboliser when exposed to a strong inhibitor. Similarly, enzyme inducers can increase enzyme activity beyond what a genetic test might indicate. This reasoning can be extended to drug-herb and drug-lifestyle interactions as potential modulators of drug metabolism and thus drug response. Figure 3 Drug interactions and drug – lifestyle reported by the personalized prescription software.\n\nFigure 4 Pharmacogenetics interactions described by the personalized prescription software.\n\nThe patient was advised to discontinue the consumption of ginger, blueberry extracts and pineapple juice. The dose of omega-3 fatty acids was reduced from 3g/day DHA to 1g/day. Liquorice was maintained, but the patient was told to minimize its use.\n\nAs the patient was already being treated with a beta-blocker to control blood pressure, telmisartan was temporarily discontinued to minimise the side effects of the combination of two antihypertensive drugs.\n\nFigure 5 shows the primary genes to be considered when checking the specific medication for to this clinical case. After assessing all drug interactions, no genetic testing of the patient was considered necessary. Figure 5 Pharmacogenetics markers described by the personalized prescription software.\n\nThe patient was scheduled for a follow-up evaluation two months later.\n\nAt the next visit, there was a clear improvement in both his clinical condition and general wellbeing. The coagulation defects had disappeared with no further gingival bleeding or skin bruising.\n\nBlood pressure was normal (BP: 134/68 mmHg) despite the discontinuation of telmisartan, and it was considered that reinstating the antihypertensive was not justified. Furthermore, glycaemia was also correct (HbA1c: 5.4%) and it was decided to discontinue metformin leaving only Empagliflozin to manage the patient’s diabetes.\n\nThe patient’s general condition and well-being had also increased enormously: he did not complain of fatigue and had started exercising outdoors and working out at the gym three times a week.\n\nDiscussion\n\nDrug interactions seem to have been the cause of the patient’s worsening condition, as the improvement was remarkable after addressing the detected potential risks of interactions.\n\nThe main concern in this patient was the excessive bleeding. Several factors could have contributed to altered haemostasis, including impaired renal function, which could also explain the increased blood pressure. ASA has an anticoagulant action and may also reduce renal function, contributing to both said problems, and its effects could have been potentiated by other substances. Ginger has hypoglycaemic action, but has also been reported to inhibit thromboxane synthesis, so it may potentially interact with acetylsalicylic acid to potentiate the effects of this drug.4 Berries from the Vaccinium genus contain small amounts of salicylates, and berry juice in large quantities (more than 1L/day) or berry extracts may increase the hypoprothrombinaemia effects of acetylsalicylic acid.5 While 1L a day is too large to be a likely cause of interaction, the patient was taking an extract supplement, which usually contains higher amounts of active compounds than those present on juice or the berry itself. Pineapple juice, which the patient consumed daily, contains bromelain, a substance that can inhibit cytochrome P450 2C9,6 which is the main metabolic pathway for acetylsalicylic acid.7 Therefore, regular intake of pineapple juice could have been an additional factor leading to higher exposure to salicylates.\n\nAll of this would contribute to increase the effects of salicylates on both platelet aggregation and blood pressure.\n\nHypoprothrombinaemia may have also been increased by omega-3 fatty acids, as the patient was consuming large doses of DHA.8\n\nFurthermore, liquorice has been reported to reduce the effects of the antihypertensive medication by increasing liquid retention.9\n\nIn this case, none of these products would have been considered dangerous on their own, as they are consumed by a large amount of people without incident. They would have been overlooked unless the personalised prescribing software had reported them as potential risks of interaction with the patients’ medication. The proactive warning prompted the physician to ask the patient about the consumption of these products. Herbal products or extracts used as supplements, such as blueberry extracts, would perhaps have been considered at some point, while consumption habits, such as pineapple juice, would have remained unnoticed.\n\nNo specific cause of the fatigue was identified with certainty, but it was likely to be a side effect of the blood loss.\n\nIn this case, the extracts the patient used, containing blueberry and ginger, could have contributed to bleeding, in addition to DHA and pineapple juice. These substances in combination were considered a likely trigger for the gingival bleeding.9 It is not possible to know the relative contribution of these substances to the interaction, nor if a clinically meaningful interaction would still have happened without the presence of the whole polymedication. Caution is recommended whenever natural products are used in combination with drugs affecting haemostasis.\n\nThe patient’s condition improved as the drug regimen was reduced and simplified, meaning that some drugs may have been unnecessary in the first place. For example, the hypertension could have been secondary to the use of liquorice and salicylate potentiation, and in this case, discontinuation of these substances would have been more helpful in controlling blood pressure than starting telmisartan.\n\nConclusion\n\nThis case report serves to illustrate two concepts: I) the importance of recognizing the interactions of existing compounds in commonly consumed products, in this particular case with anticoagulants. It is therefore advisable to use drug interaction software that take into account lifestyle habits. II) Be aware of the increased risk of drug-drug interactions in patients consuming multiple natural products not considered drugs, which may be the cause of many drug-drug interactions. While being aware of the dangers of polymedication with multiple therapeutic drugs, other substances such as herbal products and dietary supplements, should not be disregarded. Reducing the drug regimen may occasionally lower the amount and severity of drug interactions, provided that the remaining drugs are enough to control the pathology. This work emphasizes the need for personalized approaches for patient empowerment in both clinical settings and home health care.\n\nConsent Form\n\nConsent was obtained from the patient to allow publication of his medical record. The patient was informed that his case of polymedication would be presented as a case report to the scientific community in order to let other healthcare professionals know what his treatment was like and how it has evolved.\n\nThe patient signed a consent form to authorise his doctor to record his medical history for the purpose of a scientific publication on his health conditions. He agreed to have his medical records recorded for the named purpose of a scientific publication. No ethics statement from the institution was required, the sole statement from doctor was needed.\n\nDisclosure\n\nMarc Cendrós and Ana Sabater work for EUGENOMIC S.L. and are directly involved in the development of the g-Nomic® the personalized prescription software, but neither they nor anyone at Eugenomic has had any role in the management and clinical evaluation of this case beyond assisting the medical professionals in using the software. In addition, Mrs Ana Sabater has a patent g-Nomic issued to Eugenomic. The authors declare no other conflicts of interest in this work.\n==== Refs\nReferences\n\n1. NikolicB, JankovicS, StojanovO, PopovicJ. Prevalence and predictors of potential drug-drug interactions. Cent Eur J Med. 2014. doi:10.2478/s11536-013-0272-4\n2. McQuaidKR, LaineL. Systematic review and meta-analysis of adverse events of low-dose aspirin and clopidogrel in randomized controlled trials. Am J Med. 2006;119 (8 ):624–638. doi:10.1016/j.amjmed.2005.10.039 16887404\n3. SabaterA, CiudadCJ, CendrosM, DobrokhotovD, Sabater-TobellaJ. G-nomic: a new pharmacogenetics interpretation software. Pharmgenomics Pers Med. 2019. doi:10.2147/PGPM.S203585\n4. TsaiHH, LinHW, LuYH, ChenYL, MahadyGB. A review of potential harmful interactions between anticoagulant/antiplatelet agents and chinese herbal medicines. PLoS One. 2013. doi:10.1371/journal.pone.0064255\n5. SrinivasNR. Cranberry juice ingestion and clinical drug-drug interaction potentials; review of case studies and perspectives. J Pharm Pharm Sci. 2013;16 (2 ):289. doi:10.18433/j3ng6z 23958198\n6. HidakaM, NagataM, KawanoY, et al. Inhibitory effects of fruit juices on cytochrome P450 2C9 activity in vitro. Biosci Biotechnol Biochem. 2008;72 (2 ):406–411. doi:10.1271/bbb.70511 18256496\n7. AgundezJ, MartinezC, Perez-SalaD, et al. Pharmacogenomics in Aspirin Intolerance. Curr Drug Metab. 2009;10(9):998–1008. doi:10.2174/138920009790711814\n8. CohenMG, RossiJS, GarbarinoJ, et al. Insights into the inhibition of platelet activation by omega-3 polyunsaturated fatty acids: beyond aspirin and clopidogrel. Thromb Res. 2011;128 (4 ):335–340. doi:10.1016/j.thromres.2011.04.023 21621252\n9. Stockley’s herbal medicines interactions: a guide to the interactions of herbel medicines, dietary supplements and nutraceuticals with conventional medicines. Choice Rev. 2010. Availble form: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/204353s020lbl.pdf. Accessed August 2, 2021. doi:10.5860/choice.47-2357\n\n",
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"keywords": "SNP; bleeding; drug-drug interaction; drug-herb; drug-lifestyle interactions; fatigue; medication risk; personalized prescription; pharmacogenetics; pharmacogenetics software; polymedication; software",
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"title": "Case Report: Fatigue and Bleeding in a Polymedicated Patient Using Several Herbal Supplementations, Detected with g-Nomic® Software.",
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"abstract": "A 64-year-old man, with history of micropapillary thyroid cancer and epidermal growth factor receptor-positive lung adenocarcinoma with no evidence of active disease for 3 years after chemotherapy and radiation on erlotinib, presented with fatigue, nausea, lack of appetite, and xeroderma. A screening magnetic resonance image of the patient's head demonstrated a new bilateral pituitary mass. Initial evaluation revealed low morning cortisol, and the patient was diagnosed with adrenal insufficiency. His symptoms rapidly improved with maintenance glucocorticoids. Soon thereafter, the patient developed an acute visual deficit secondary to enlargement of the pituitary mass, and biopsy revealed EGFR T790M positive metastatic lung adenocarcinoma. Hence, we present a rare case of metastatic lung adenocarcinoma to the pituitary causing secondary adrenal insufficiency.",
"affiliations": "Department of Internal Medicine, Sinai Hospital, Baltimore, MD, USA.;University of Maryland Marlene & Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA.;Department of Endocrinology, Sinai Hospital, Baltimore, MD, USA.",
"authors": "Adashek|Michael L|ML|0000-0002-1321-8469;Miller|Kenneth|K|;Silpasuvan|Arit A|AA|",
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"fulltext": "\n==== Front\nCase Rep Oncol MedCase Rep Oncol MedCRIONMCase Reports in Oncological Medicine2090-67062090-6714Hindawi 10.1155/2018/2349021Case ReportEGFR T790M-Positive Lung Adenocarcinoma Metastases to the Pituitary Gland Causing Adrenal Insufficiency: A Case Report http://orcid.org/0000-0002-1321-8469Adashek Michael L. madashek@osteo.wvsom.edu\n1\nMiller Kenneth \n2\nSilpasuvan Arit A. \n3\n\n1Department of Internal Medicine, Sinai Hospital, Baltimore, MD, USA\n2University of Maryland Marlene & Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA\n3Department of Endocrinology, Sinai Hospital, Baltimore, MD, USAAcademic Editor: Giovanni Tallini\n\n2018 31 5 2018 2018 234902125 3 2018 17 5 2018 Copyright © 2018 Michael L. Adashek et al.2018This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.A 64-year-old man, with history of micropapillary thyroid cancer and epidermal growth factor receptor-positive lung adenocarcinoma with no evidence of active disease for 3 years after chemotherapy and radiation on erlotinib, presented with fatigue, nausea, lack of appetite, and xeroderma. A screening magnetic resonance image of the patient's head demonstrated a new bilateral pituitary mass. Initial evaluation revealed low morning cortisol, and the patient was diagnosed with adrenal insufficiency. His symptoms rapidly improved with maintenance glucocorticoids. Soon thereafter, the patient developed an acute visual deficit secondary to enlargement of the pituitary mass, and biopsy revealed EGFR T790M positive metastatic lung adenocarcinoma. Hence, we present a rare case of metastatic lung adenocarcinoma to the pituitary causing secondary adrenal insufficiency.\n==== Body\n1. Introduction\nAdrenal insufficiency (AI) is a broadly encompassing term for inadequate physiologic corticosteroid production. Primary AI is due to adrenal gland inadequacy, whereas secondary AI is due to disruption of the hypothalamus or pituitary in the hypothalamus-pituitary-adrenal (HPA) axis. We present a case of a man who presented with new fatigue, nausea, lack of appetite, and xeroderma who was found to have a new pituitary mass resulting in secondary AI.\n\n2. Case Presentation\n2.1. Presentation\nA 64-year-old man with a medical history of micropapillary thyroid cancer and stage IIIb lung adenocarcinoma with no evidence of active disease for 3 years after chemotherapy and radiation presented with subjective complaints of new onset fatigue, nausea, scalp tenderness, and xeroderma. His medications included gabapentin 300 mg four times a day for chemotherapy-induced neuropathy, erlotinib 150 mg once daily for epidermal growth factor receptor- (EGFR-) positive lung adenocarcinoma, and omeprazole 40 mg once daily for subjective gastroesophageal reflux disease. A screening magnetic resonance image of the head revealed a new hypovascular pituitary mass measuring approximately 1 cm by 0.8 cm (Figure 1(a)).\n\n2.2. Assessment\nOn examination, the patient's vital signs were within normal limits. On physical exam, xeroderma was appreciated in all extremities. Finger size was proportional and no prognathism, acromegaly, or Cushingoid features were appreciated. The cardiopulmonary exam was normal.\n\nInitial lab values demonstrated normal free triiodothyronine (T3) of 2.4 pg/mL (normal range (NR) 1.8–4.2 pg/mL), normal T3 of 86 ng/dL (NR 70–172 ng/dL), and normal free thyroxine of 1.00 ng/dL (NR 0.84–1.68 ng/dL). Prolactin was elevated at 28.9 ng/mL (NR 2.5–17.0 ng/mL). The patient's morning cortisol was immeasurably low at <1.0 mcg/dL (NR > 10 mcg/dL) as was the patient's testosterone level at <20 ng/dL (280–1100 ng/dL). Luteinizing hormone was low at 0.05 mIU/mL (NR 1.8–12.0 mIU/L).\n\nThe patient was started on prednisone 20 mg by mouth daily, at which point he noticed immediate improvement in his energy and appetite as well as decrease in his nausea. For chronic steroid replacement therapy, the patient's treatment was changed from prednisone to hydrocortisone 20 mg of hydrocortisone in the morning and 10 mg in the evening. The patient was additionally instructed about the dangers of adrenal crisis and told to increase his hydrocortisone to 90 mg daily if acutely ill.\n\n2.3. Diagnosis\nWithin a month of initial diagnoses, the patient suffered acute visual bilateral field cut and loss of peripheral vision. A repeat MRI demonstrated rapid enlargement of his pituitary mass, nearly doubled in size and described as a 2.2 cm by 1.2 cm mass impinging on the overlying optic chiasm (Figure 1(b)).\n\nThe patient subsequently underwent transsphenoidal resection of his pituitary mass. Gross histology characterized the mass as firm and fibrous. Macroscopic analysis revealed metastatic lung adenocarcinoma described as adenohypophysis fibrosis. Further histologic analysis revealed positive identification of cytokeratin 7, TTF-1, Ki-67, and epidermal growth factor receptor (EGFR) positive with EGFR gene nucleotide change demonstrating T790M and L858R positivity. This histopathology demonstrated further EGFR mutation of the patient's known history of lung adenocarcinoma which initially was only positive for EGFR mutation L585R.\n\nAfter transsphenoidal resection and subsequent whole-brain radiation, further results demonstrated a continued low morning cortisol at <1.0 mcg/dL (NR > 10 mcg/dL) and testosterone level at <20 ng/dL (280–1100 ng/dL). Luteinizing hormone was low at <0.1 mIU/mL (NR 1.8–12.0 mIU/L) as was follicle-stimulating hormone 0.8 mIU/mL (NR 1.5–12.4 mIU/mL). Free T4 was low at 0.65 ng/dL (NR 0.84–1.68 ng/dL) and thyroid-stimulating hormone was low at 0.019 MCI/mL (NR 0.4–4.0 MCI/mL). Prolactin was lower than previous but still elevated at 14.9 ng/mL (NR 2.5–17.0 ng/mL).\n\n3. Discussion\nAnnually, 200,000 new patients are diagnosed with brain metastasis (BM), making BM the most frequent cause of intercranial neoplasm in adults in the United States. An estimated 20–40% of adult patients with systemic malignancies will develop BM, and of those, a further 20% will become symptomatic over the course of their disease. Lung cancer comprises the majority of these BM cases (50%), followed by breast cancer (20–30%) and melanoma (5–10%) [1]. Complications of brain metastases are one of the chief causes of mortality and morbidity in patients with non-small cell lung cancer [2]. Adrenal insufficiency (AI) secondary to metastatic malignancy is highly unusual and has been reported in under 100 cases in English literature [3].\n\nAdrenal insufficiency (AI) stems from inadequate physiologic steroid production and is most commonly a result of discontinuation of long-term glucocorticoid treatment. The signs of adrenal insufficiency are wide and varied including orthostatic hypotension, altered mental status, nausea and vomiting, abdominal pain, weight loss, and salt craving, many of which can be attributed to fluid losses from reduced mineralocorticoid function [4]. Physical signs of AI can include Cushingoid appearance: thinning skin, striae, obesity, muscle wasting, and psychiatric disturbance, all of which may indicate prior chronic iatrogenic steroid exposure. The treatment is physiologic replacement, with hydrocortisone demonstrating decreased LDL levels compared to prednisone making hydrocortisone the replacement therapy of choice [5]. The patient demonstrated initial rapid symptomatic improvement with physiologic corticosteroid replacement. Of note, AI develops only in patients with bilateral hypothalamic-pituitary-adrenal (HPA) axis involvement. However, HPA metastasis typically results in an excitation of the HPA system leading to increased cortisol levels, making our patient's presentation of AI secondary to pituitary metastases an unusual one [6].\n\nRadiologically, it is difficult to differentiate BM from primary intercranial malignancies. BM is typically found in the cerebral hemispheres (80%), followed by the cerebellum (15%) and brainstem (5%) [7]. Unfortunately, the lifetime risk of BM in non-small cell lung cancer has been estimated at 40% [2], making clinical history one of the greatest prognosticators for BM. Had the patient not been undergoing regular surveillance magnetic resonance imaging of the head, his clinical diagnoses of BM may have been significantly delayed. Symptomatic presence of pituitary BM often presents as medial visual field cut secondary to cranial nerve impingement as seen in this patient.\n\nChemical indications of pituitary BM are severely limited. Pituitary stalk compression, a common side effect of pituitary metastases, may lead to elevated prolactin. Prolactinomas are well known to produce prolactin levels > 200 ng/mL, whereas pituitary stalk compression may present with a prolactin level between the upper limit of normal (13 ng/mL) and <200 ng/mL [8]. Table 1 demonstrates the decrease in prolactin production with relief of pituitary stalk compression after resection of the lung adenocarcinoma metastasis. Values between 20–200 ng/mL may be artificially low due to prolactin levels > 5000 ng/mL resulting in saturation and incorrect analyses of both capture and signal assay antibodies. This “hook effect” can be addressed with 1/100 dilution of the sample [9]. BM can additionally present with central diabetes insipidus with symptoms of both polyuria and hypernatremia, neither of which was seen in this patient.\n\nThe patient's bilateral medial visual field cut indicated acutely symptomatic BM. Initial treatment is both dexamethasone 4–8 mg/day and alleviation of the mass effect through surgical or stereotactic radiotherapy if feasible. The current literature does not recommend prophylactic anticonvulsant therapy [7]. The brain is a singularly difficult target for medical treatment as the blood-brain barrier (BBB) limits the efficacy of many types of chemotherapy, often creating a haven for metastases. However, there is ongoing debate in literature suggesting that the integrity of this BBB is compromised in the setting of these lesions. This patient's symptoms successfully resolved with surgery; however, further positron emission tomography revealed uptake in the area indicative of returning metastatic disease. Although treatments for BM are both variable and highly dependent on tumor type, it has been noted that donepezil has demonstrated to improve cognition, mood, and quality of life in these patients [7].\n\nThe patient demonstrated progression of disease on erlotinib, a 1st-generation EGFR tyrosine kinase inhibitor (TKI). Response rates of EGFR TKIs generally range from 70–80% with longer progression-free survival than previous standard chemotherapy regimens [7]. On average, the progression of disease occurs in 10–14 months due to new resistance mutations associated with EGFR-positive lung adenocarcinoma [10]. Initial screening for EGFR mutation from the lung core needle biopsies was performed with high-affinity class ribonucleotide analogs termed “locked nucleic acid probes” to identify wild-type EGFR and T790M mutations. However, this technique has a minimum sensitivity of 3% for T790M and 10–15% for L585R mutations [11]. There is emerging evidence to suggest that T790M mutation singularly develops during erlotinib treatment of EGFR-positive malignancies [12], and it is unlikely that the initial lung adenocarcinoma expressed T790M as the doubling time of the pituitary tumor was approximately 1 month and would have been visible far sooner on regular screening CT/MRI imaging. The patient's symptomatic pituitary mass was tested for T790M mutation through real-time PCR analysis [13] via the cobas EGFR Mutation Test P120019 (Roche Molecular Systems Inc., CA, USA) [14]. The patient's initial lung biopsy demonstrated the L858R EGFR mutation on exon 21 and when recurred was additionally identified with the T790M mutation on exon 20. This T790M mutation resulted in conformational change, sterically hindering erlotinib from binding to the adenosine triphosphate kinase pocket. Current EGFR TKIs include second-generation agents such as afatinib, dacomitinib, and neratinib or third-generation agents such as osimertinib, rociletinib, or olmutinib. Osimertinib in particular has been approved in T790M-positive non-small cell lung cancers (NSCLC), penetrates the BBB [15], and may offer this patient future benefit.\n\nUnfortunately, neurosurgery could not be delayed due to mass effect of the underlying lung adenocarcinoma metastases on the pituitary and overlying optic chiasm. Had surgery been delayable, a far less invasive diagnostic test for T790M mutation could have been performed. The FDA has approved “liquid biopsy” [13] for EGFR mutations, which involves the testing of circulating cell-free tumor DNA (cfDNA) and has been demonstrated to reveal EGFR mutations not previously detected by biopsy in up to 34% of patients [16]. Moreover, this test can be performed on serum, rather than tumor tissue as previous ribonucleotide analogues have required. Given the rate of disease advancement on erlotinib [10], serial screens of cfDNA may play a future role in preempting changes in TKI treatment regimens before radiologic imaging reflects tumor progression. However, osimertinib has been associated with “pseudoprogression” or temporary paradoxical enlargement of EGFR T790M adenocarcinomas and may have worsened this patient's mass effect rather than relieved it [17].\n\nIn conclusion, physicians caring for patients with prior history of breast or lung cancer should remain vigilant in their history and physical exam for underlying signs of metastatic disease. AI is a rare complication of metastatic disease to the HPA axis and requires physiologic steroid replacement, ideally with hydrocortisone due to its lower LDL profile. Patients should be instructed to assess for signs of adrenal crises as soon as a diagnosis of AI is made as it can be life-threatening. Prolactin elevation < 200 ng/mL may be the first sign of pituitary stalk compression, and when an alarming clinical sign such as medial visual field cuts presents itself, patients should be started on dexamethasone dosing of 4–8 mg daily. The relief of mass effect is key in symptomatic pituitary BM and includes multidisciplinary involvement from specialties such as neurosurgery, as well as both medical oncology and radiation oncology. Given the recent advancements in tumor genomics and genetically targeted treatment modalities, BM pathology should be obtained via minimally invasive techniques provided the BM is not exerting mass effect on adjacent structures and requires surgical intervention. Finally, serum cfDNA may offer accurate nonsurgical screening for EGFR TKI resistance mutations and in turn facilitate changes in therapy to improve long-term patient outcomes.\n\nEthical Approval\nThis paper has been written in keeping with the principles of the Declaration of Helsinki.\n\nConsent\nInformed consent was obtained from the patient for educational use of the abovementioned data and no personal patient information has been disclosed.\n\nConflicts of Interest\nNone of the authors have any financial or personal bias to declare.\n\nFigure 1 Brain magnetic resonance imaging demonstrating enlarging pituitary mass. (a) T1-weighted MRI demonstrating enlarged pituitary gland containing a hypovascular 10.5 × 7.5 mm mass lesion with thickening of the pituitary infundibulum without intracranial hemorrhage or extra-axial fluid collection. (b) Imaging one month later with T1-weighted MRI demonstrating a 22.0 × 12.0 mm bilobed mass with 8 mm suprasellar extension exerting mass effect on overlying optic chiasm.\n\nTable 1 Laboratory results before and after transsphenoidal pituitary metastases resection.\n\nHormone\tNormal limit\tPreresection\tPostresection\t\nThyroxine\t0.84–1.68 ng/dL\t1.00 ng/dL\t0.65 ng/dL\t\nThyroid-stimulating hormone\t0.3–4.0 mIU/L\t0.016 MCI/mL\t0.019 MCI/mL\t\nFollicle-stimulating hormone\t1.6–17.8 mIU/mL\t2.4 mIU/mL\t0.8 mIU/mL\t\nLuteinizing hormone\tNR 1.8–12.0 mIU/L\t0.05 mIU/mL\t<0.1 mIU/mL\t\nTestosterone\t280–1100 ng/dL\t<20 ng/dL\t<20 ng/dL\t\nAdrenocorticotropic hormone\t9–52 pg/mL (2.0–11.0 pmol/L)\t6.0 pg/mL\t<5.0 pg/mL\t\nMorning cortisol\t>10 mcg/dL\t<1.0 mcg/dL\t<1.0 mcg/dL\t\nProlactin\t<12.3 ng/mL (<0.55 nmol/L)\t\n28.9 ng/mL\n\t\n14.9 ng/mL\n==== Refs\n1 Rahmathulla G. Toms S. A. Weil R. J. The molecular biology of brain metastasis Journal of Oncology 2012 2012 16 10.1155/2012/723541 2-s2.0-84859753177 723541 \n2 Li H. Lian J. Han S. Applicability of graded prognostic assessment of lung cancer using molecular markers to lung adenocarcinoma patients with brain metastases Oncotarget 2017 8 41 70727 70735 10.18632/oncotarget.19980 2-s2.0-85030261226 29050314 \n3 Imaoka Y. Kuranishi F. Ogawa Y. Okuda H. Nakahara M. Adrenal failure due to bilateral adrenal metastasis of rectal cancer: a case report International Journal of Surgery Case Reports 2017 31 1 4 10.1016/j.ijscr.2016.12.011 2-s2.0-85008682917 28073054 \n4 Huecker M. R. Dominique E. Adrenal, insufficiency StatPearls 2017 Treasure Island, FL, USA StatPearls Publishing LLC NBK441832 [bookaccession] \n5 Quinkler M. Ekman B. Marelli C. Prednisolone is associated with a worse lipid profile than hydrocortisone in patients with adrenal insufficiency Endocrine Connections 2017 6 1 1 8 10.1530/EC-16-0081 2-s2.0-85026824851 27864317 \n6 Lutz A. Stojkovic M. Schmidt M. Arlt W. Allolio B. Reincke M. Adrenocortical function in patients with macrometastases of the adrenal gland European Journal of Endocrinology 2000 143 1 91 97 10.1530/eje.0.1430091 2-s2.0-0033927341 10870036 \n7 D’Antonio C. Passaro A. Gori B. Bone and brain metastasis in lung cancer: recent advances in therapeutic strategies Therapeutic Advances in Medical Oncology 2014 6 3 101 114 10.1177/1758834014521110 2-s2.0-84899018415 24790650 \n8 Komninos J. Vlassopoulou V. Protopapa D. Tumors metastatic to the pituitary gland: case report and literature review The Journal of Clinical Endocrinology & Metabolism 2004 89 2 574 580 10.1210/jc.2003-030395 2-s2.0-1442352287 14764764 \n9 Melmed S. Casanueva F. F. Hoffman A. R. Diagnosis and treatment of hyperprolactinemia: an endocrine society clinical practice guideline The Journal of Clinical Endocrinology & Metabolism 2011 96 2 273 288 10.1210/jc.2010-1692 2-s2.0-79951685894 21296991 \n10 Wu S. G. Shih J. Y. Management of acquired resistance to EGFR TKI-targeted therapy in advanced non-small cell lung cancer Molecular Cancer 2018 17 1 p. 38 10.1186/s12943-018-0777-1 2-s2.0-85042145569 29455650 \n11 NeoGenomics EGFR T790M germline mutation analysis 2018 May 2018, https://neogenomics.com/test-menu/egfr-t790m-germline-mutation-analysis \n12 Demuth C. Madsen A. T. Weber B. Wu L. Meldgaard P. Sorensen B. S. The T790M resistance mutation in EGFR is only found in cfDNA from erlotinib-treated NSCLC patients that harbored an activating EGFR mutation before treatment BMC Cancer 2018 18 1 p. 191 10.1186/s12885-018-4108-0 2-s2.0-85042105805 29448920 \n13 FDA approves first blood test to detect gene mutations associated with non-small cell lung cancer June 2016, https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm504488.htm \n14 Weber B. Meldgaard P. Hager H. Detection of EGFR mutations in plasma and biopsies from non-small cell lung cancer patients by allele-specific PCR assays BMC Cancer 2014 14 1 294 2407 10.1186/1471-2407-14-294 2-s2.0-84899956118 24773774 \n15 Ballard P. Yates J. W. T. Yang Z. Preclinical comparison of osimertinib with other EGFR-TKIs in EGFR-mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity Clinical Cancer Research 2016 22 20 5130 5140 10.1158/1078-0432.CCR-16-0399 2-s2.0-84991730676 27435396 \n16 Alegre E. Fusco J. P. Restituto P. Total and mutated EGFR quantification in cell-free DNA from non-small cell lung cancer patients detects tumor heterogeneity and presents prognostic value Tumor Biology 2016 37 10 13687 13694 10.1007/s13277-016-5282-9 2-s2.0-84979987432 27473086 \n17 Okauchi S. Osawa H. Miyazaki K. Kawaguchi M. Satoh H. Paradoxical response to osimertinib therapy in a patient with T790M-mutated lung adenocarcinoma Molecular and Clinical Oncology 2017 8 1 175 177 10.3892/mco.2017.1474 29285395\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2018()",
"journal": "Case reports in oncological medicine",
"keywords": null,
"medline_ta": "Case Rep Oncol Med",
"mesh_terms": null,
"nlm_unique_id": "101581035",
"other_id": null,
"pages": "2349021",
"pmc": null,
"pmid": "29955407",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "29455650;29285395;29448920;24773774;24790650;27473086;10870036;27864317;27435396;29050314;21296991;14764764;22481931;28073054",
"title": "EGFR T790M-Positive Lung Adenocarcinoma Metastases to the Pituitary Gland Causing Adrenal Insufficiency: A Case Report.",
"title_normalized": "egfr t790m positive lung adenocarcinoma metastases to the pituitary gland causing adrenal insufficiency a case report"
} | [
{
"companynumb": "US-MYLANLABS-2018M1088127",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ERLOTINIB"
},
"drugadditional": "3",
... |
{
"abstract": "Lithium is a potent psychotherapeutic agent that has gained wide acceptance in paediatrics, especially as adjunct treatment for severe behavioural, anxiety, and attention-deficit hyperactivity disorders, along with bipolar conditions. Its cardiac toxicity has been well-documented in adults; however, information is limited regarding lithium's effects on the heart in children. Therefore, paediatric cardiologists following-up children on lithium therapy should be cognizant of the cardiac side-effects and pathophysiology associated with this drug. In this manuscript, we used an illustrative case of a child who presented with lithium poisoning, in order to highlight adverse clinical manifestations that can arise from this medication. The cardiac cell membrane is thought to be the primary site of lithium's action. Thus, we reviewed lithium's effects on membrane electrogenic pumps and channels involved in the distribution and passage of sodium, potassium, and calcium across the sarcolemma, as these ions, and their associated currents, are the primary determinates of the action potentials underlying auto-rhythmicity and contractile activity of the heart.",
"affiliations": "1Department of Pediatrics,Division of Cardiology,Louisiana State University School of Medicine,New Orleans,Louisiana,United States of America.;1Department of Pediatrics,Division of Cardiology,Louisiana State University School of Medicine,New Orleans,Louisiana,United States of America.;1Department of Pediatrics,Division of Cardiology,Louisiana State University School of Medicine,New Orleans,Louisiana,United States of America.;1Department of Pediatrics,Division of Cardiology,Louisiana State University School of Medicine,New Orleans,Louisiana,United States of America.",
"authors": "Singh|Dhiraj|D|;Akingbola|Akinbolaji|A|;Ross-Ascuitto|Nancy|N|;Ascuitto|Robert|R|",
"chemical_list": "D000928:Antidepressive Agents; D016651:Lithium Carbonate",
"country": "England",
"delete": false,
"doi": "10.1017/S104795111500147X",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1047-9511",
"issue": "26(2)",
"journal": "Cardiology in the young",
"keywords": "Lithium; action potential; cardiac; electrocardiogram; toxicity",
"medline_ta": "Cardiol Young",
"mesh_terms": "D000928:Antidepressive Agents; D001714:Bipolar Disorder; D009202:Cardiomyopathies; D002675:Child, Preschool; D004562:Electrocardiography; D006801:Humans; D016651:Lithium Carbonate; D008297:Male; D012307:Risk Factors",
"nlm_unique_id": "9200019",
"other_id": null,
"pages": "221-9",
"pmc": null,
"pmid": "26365301",
"pubdate": "2016-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Electrocardiac effects associated with lithium toxicity in children: an illustrative case and review of the pathophysiology.",
"title_normalized": "electrocardiac effects associated with lithium toxicity in children an illustrative case and review of the pathophysiology"
} | [
{
"companynumb": "US-WEST-WARD PHARMACEUTICALS CORP.-US-H14001-16-00324",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LITHIUM CARBONATE"
},
... |
{
"abstract": "Rituximab is an anti-CD20 chimeric antibody used to treat autoimmune conditions and B cell neoplasms. We characterized immunoglobulin (Ig) levels and vaccine responses in rituximab-treated B cell non-Hodgkin lymphoma (NHL) patients. Patients with impaired vaccine responses were offered therapy with 20% subcutaneous (subq) Ig.\n\n\n\nPatients with a biopsy-proven diagnosis of B cell NHL who had received rituximab within the past 24 months were eligible for the study and underwent the following immune evaluation: serum IgG, IgM, IgA, IgE, T/B cell lymphocyte panel, and pre/post vaccine IgG titers to diphtheria, tetanus, and streptococcus pneumoniae. Patients were vaccinated with tetanus, diphtheria and pneumococcal polysaccharide vaccine. Patients with abnormal vaccine responses were offered prophylactic subq Ig for 52 weeks.\n\n\n\nFifteen patients with NHL were enrolled in the study. The median IgG was 628 mg/dL [interquartile range, 489-718 mg/dL]. Three (20%) of 15 patients responded to diphtheria vaccination, 1 (6.7%) of 15 responded to tetanus vaccination, and 3 (20%) of 15 responded to vaccination to streptococcus pneumoniae. Thirteen (86.7%) of 15 met criteria for humoral immunodeficiency. Ten patients received subq Ig, and experienced a significant increase in serum IgG (P = .008). There were no serious adverse events, and there was a decrease in nonneutropenic infections while on subq Ig therapy.\n\n\n\nPatients with NHL treated with rituximab may have significant humoral immunodeficiency as defined by abnormal vaccine responses even in the setting of relatively normal IgG levels. For these patients, subq Ig replacement therapy is well-tolerated and efficacious in improving serum IgG, and may decrease reliance on antibiotics for the treatment of nonneutropenic infections.",
"affiliations": "Division of Allergy, Immunology, and Rheumatology, Rochester Regional Health, Rochester, NY; Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY. Electronic address: shahzad.mustafa@rochesterregional.org.;Division of Hematology and Oncology, Rochester Regional Health, Rochester, NY.;Division of Critical Care, Mercy Hospital, Springfield, MO.;Division of Allergy, Immunology, and Rheumatology, Rochester Regional Health, Rochester, NY; Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY.",
"authors": "Mustafa|S Shahzad|SS|;Jamshed|Saad|S|;Vadamalai|Karthik|K|;Ramsey|Allison|A|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D022242:Pneumococcal Vaccines; D000069283:Rituximab",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clml.2020.04.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2152-2669",
"issue": "20(9)",
"journal": "Clinical lymphoma, myeloma & leukemia",
"keywords": "Non-Hodgkin lymphoma; Secondary immunodeficiency; Subcutaneous immunoglobulin; Vaccine responses",
"medline_ta": "Clin Lymphoma Myeloma Leuk",
"mesh_terms": "D000368:Aged; D000074322:Antineoplastic Agents, Immunological; D005260:Female; D006801:Humans; D055104:Infusions, Subcutaneous; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008875:Middle Aged; D022242:Pneumococcal Vaccines; D000069283:Rituximab",
"nlm_unique_id": "101525386",
"other_id": null,
"pages": "e590-e596",
"pmc": null,
"pmid": "32646834",
"pubdate": "2020-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "The Use of 20% Subcutaneous Immunoglobulin Replacement Therapy in Patients With B Cell Non-Hodgkin Lymphoma With Humoral Immune Dysfunction After Treatment With Rituximab.",
"title_normalized": "the use of 20 subcutaneous immunoglobulin replacement therapy in patients with b cell non hodgkin lymphoma with humoral immune dysfunction after treatment with rituximab"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/20/0127428",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugaddit... |
{
"abstract": "OBJECTIVE\nWe present a new and unique association of opsoclonus-myoclonus-ataxia syndrome with neuroblastoma and type 1 diabetes mellitus.\n\n\nMETHODS\nThis 17-month-old child presented with opsoclonus-myoclonus-ataxia syndrome. Investigations revealed a thoracic neuroblastoma. Eleven days later, she re-presented with diabetic ketoacidosis. The neuroblastoma was resected, and she was given immunotherapy. At 12 months' follow-up, her neurological signs and symptoms have significantly improved, but she continues to be insulin dependent.\n\n\nCONCLUSIONS\nThis child expands the clinical spectrum of autoimmune disorders associated with opsoclonus-myoclonus-ataxia syndrome.",
"affiliations": "Department of Neurology, Princess Margaret Hospital, Perth, Western Australia, Australia.;Department of Neurology, Princess Margaret Hospital, Perth, Western Australia, Australia.;Department of Oncology, Princess Margaret Hospital, Perth, Western Australia, Australia.;Department of Endocrinology, Princess Margaret Hospital, Perth, Western Australia, Australia.;Department of Paediatric Surgery, Princess Margaret Hospital, Perth, Western Australia, Australia.;Department of Neurology, Princess Margaret Hospital, Perth, Western Australia, Australia; School of Paediatrics and Child Health, University of Western Australia, Princess Margaret Hospital, Perth, Western Australia, Australia. Electronic address: lakshmi.Nagarajan@health.wa.gov.au.",
"authors": "Ghia|Twinkle|T|;Kanhangad|Manoj|M|;Alessandri|Angela Jane|AJ|;Price|Glynis|G|;Gera|Parshotam|P|;Nagarajan|Lakshmi|L|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0887-8994",
"issue": "55()",
"journal": "Pediatric neurology",
"keywords": "anti-GAD antibodies; neuroblastoma; opsoclonus myoclonus ataxia; type I diabetes mellitus",
"medline_ta": "Pediatr Neurol",
"mesh_terms": "D003922:Diabetes Mellitus, Type 1; D005260:Female; D006801:Humans; D007223:Infant; D009447:Neuroblastoma; D053578:Opsoclonus-Myoclonus Syndrome; D013899:Thoracic Neoplasms",
"nlm_unique_id": "8508183",
"other_id": null,
"pages": "68-70",
"pmc": null,
"pmid": "26778146",
"pubdate": "2016-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Opsoclonus-Myoclonus Syndrome, Neuroblastoma, and Insulin-Dependent Diabetes Mellitus in a Child: A Unique Patient.",
"title_normalized": "opsoclonus myoclonus syndrome neuroblastoma and insulin dependent diabetes mellitus in a child a unique patient"
} | [
{
"companynumb": "AU-BAUSCH-BL-2016-013353",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "A 45-year-old morbidly obese woman (body mass index 51.9) was scheduled for right knee arthroscopic synovectomy. We selected spinal anesthesia in order to avoid difficult ventilation or intubation during anes- thetic induction of general anesthesia. As she strongly requested unawareness during operation, we decided to sedate her with dexmedetomidine(DEX), a sedative drug which has little possibility to cause upper airway obstruction and respiratory depression. Dose of DEX was determined based on total body weight (TBW) instead of ideal body weight To achieve adequate sedation, DEX was titrated by monitoring Ramsay sedation score (RSS), and was discontinued 10 minutes before the end of operation. She was well sedated dur- ing the operation but developed minimal upper airway obstruction and respiratory depression. She showed a good recovery profile when discharged from the oper- ating room. She was very satisfied with the anesthetic management The similar patient's satisfaction was also obtained at the opposite knee joint operation per- formed using the same anesthetic management Conse- quently, DEX infusion based on TBW appears to be suitable to sedate a morbidly obese patient.",
"affiliations": null,
"authors": "Mori|Yuji|Y|;Kawata|Ryuichi|R|;Yoshida|Mitsuyoshi|M|;Uchi|Risa|R|;Hirayama|Kaori|K|;Oshibuchi|Takao|T|;Ohki|Kenii|K|",
"chemical_list": "D000777:Anesthetics; D006993:Hypnotics and Sedatives; D020927:Dexmedetomidine",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-4892",
"issue": "65(7)",
"journal": "Masui. The Japanese journal of anesthesiology",
"keywords": null,
"medline_ta": "Masui",
"mesh_terms": "D000768:Anesthesia, General; D000775:Anesthesia, Spinal; D000777:Anesthetics; D020927:Dexmedetomidine; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives; D008875:Middle Aged; D009767:Obesity, Morbid; D012131:Respiratory Insufficiency",
"nlm_unique_id": "0413707",
"other_id": null,
"pages": "743-746",
"pmc": null,
"pmid": "30358307",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Satisfactory Sedation for a Morbidly Obese Woman by Dexmedetomidine Dosed on the Basis of Total Body Weight under Spinal Anesthesia ; A Case Report.",
"title_normalized": "satisfactory sedation for a morbidly obese woman by dexmedetomidine dosed on the basis of total body weight under spinal anesthesia a case report"
} | [
{
"companynumb": "JP-HQ SPECIALTY-JP-2016INT000884",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DEXMEDETOMIDINE HYDROCHLORIDE"
},
"dru... |
{
"abstract": "A 46-year-old man with HIV infection and AIDS presented with a large perianal ulcerated vegetative lesion that developed over a 1-year period. He had a past history of recurrent genital herpes infection, treated successfully each time with acyclovir. The perianal lesion developed while he was taking prophylactic acyclovir. Clinically, there were features suspicious of a carcinoma and a biopsy was reported as showing dysplasia. Therefore, the lesion was resected in its entirety. Histologically, there were prominent pseudo-epitheliomatous hyperplasia and chronic ulceration associated with herpesvirus infection. There was no evidence of dysplasia or malignancy. It is important to be aware of chronic vegetant herpesvirus infection, as clinical appearances are unusual and some methods of identification, such as smears or biopsy, may not be sufficient for diagnosis. Viral culture or PCR may need to be performed for a definite diagnosis to alleviate prolonged discomfort and avoid unnecessary radical surgery.",
"affiliations": "Anatomical Pathology, Royal Brisbane Hospital, Qld, Australia.",
"authors": "Samaratunga|H|H|;Weedon|D|D|;Musgrave|N|N|;McCallum|N|N|",
"chemical_list": "D000998:Antiviral Agents; D000212:Acyclovir",
"country": "England",
"delete": false,
"doi": "10.1080/00313020120083322",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-3025",
"issue": "33(4)",
"journal": "Pathology",
"keywords": null,
"medline_ta": "Pathology",
"mesh_terms": "D017088:AIDS-Related Opportunistic Infections; D000163:Acquired Immunodeficiency Syndrome; D000212:Acyclovir; D000998:Antiviral Agents; D001005:Anus Neoplasms; D002277:Carcinoma; D003937:Diagnosis, Differential; D004847:Epithelial Cells; D005401:Fissure in Ano; D006561:Herpes Simplex; D006801:Humans; D006965:Hyperplasia; D016867:Immunocompromised Host; D008297:Male; D008875:Middle Aged; D027383:Papillomaviridae",
"nlm_unique_id": "0175411",
"other_id": null,
"pages": "532-5",
"pmc": null,
"pmid": "11827427",
"pubdate": "2001-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Atypical presentation of herpes simplex (chronic hypertrophic herpes) in a patient with HIV infection.",
"title_normalized": "atypical presentation of herpes simplex chronic hypertrophic herpes in a patient with hiv infection"
} | [
{
"companynumb": "AU-RANBAXY-2014R1-83127",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ACYCLOVIR"
},
"drugadditional": null,
... |
{
"abstract": "Background: Ataxia telangiectasia (A-T) is a rare autosomal-recessive multisystem disorder characterized by pronounced cerebellar ataxia, telangiectasia, cancer predisposition and altered body composition. In addition, evidence is rising for endocrine dysfunction. Objectives: To determine the evolution of diabetes and its prevalence in a larger A-T cohort. Methods: A retrospective analysis of the patient charts of 39 subjects from the Frankfurt A-T cohort was performed between August 2002 and 2018 concerning HbA1c and oral glucose tolerance (OGTT). The median follow-up period was 4 years (1-16 years). In addition, in 31 A-T patients aged 1 to 38 years HbA1c and fasting glucose were studied prospectively from 2018 to 2019. Results: In the retrospective analysis, we could demonstrate a longitudinal increase of HbA1c. The prospective analysis showed a significant increase of HbA1c and fasting glucose with age (r = 0.79, p ≤ 0.0001). OGTT has a good sensitivity for insulin resistance screening, whereas HbA1c can be used to evaluate individual courses and therapy response. Seven out of 39 (17.9%) patients suffered from diabetes. Metformin did not always lead to sufficient diabetes control; one patient was treated successfully with repaglinide. Conclusion: Diabetes is a common finding in older A-T patients and often starts in puberty. Our data clearly demonstrate the need for an annual diabetes screening in patients > 12 years.",
"affiliations": "Division of Allergology, Pulmonology and Cystic Fibrosis, Department for Children and Adolescents, Goethe University, Frankfurt, Germany.;Division of Allergology, Pulmonology and Cystic Fibrosis, Department for Children and Adolescents, Goethe University, Frankfurt, Germany.;Division of Pediatric Neurology, Department for Children and Adolescents, Goethe University, Frankfurt, Germany.;Division of Pediatric Neurology, Department for Children and Adolescents, Goethe University, Frankfurt, Germany.;Division of Pediatric Neurology, Department for Children and Adolescents, Goethe University, Frankfurt, Germany.;Division of Allergology, Pulmonology and Cystic Fibrosis, Department for Children and Adolescents, Goethe University, Frankfurt, Germany.;Division of Allergology, Pulmonology and Cystic Fibrosis, Department for Children and Adolescents, Goethe University, Frankfurt, Germany.;Division of Allergology, Pulmonology and Cystic Fibrosis, Department for Children and Adolescents, Goethe University, Frankfurt, Germany.",
"authors": "Donath|Helena|H|;Hess|Ursula|U|;Kieslich|Matthias|M|;Theis|Marius|M|;Ohlenschläger|Ute|U|;Schubert|Ralf|R|;Woelke|Sandra|S|;Zielen|Stefan|S|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fped.2020.00317",
"fulltext": "\n==== Front\nFront Pediatr\nFront Pediatr\nFront. Pediatr.\nFrontiers in Pediatrics\n2296-2360 Frontiers Media S.A. \n\n10.3389/fped.2020.00317\nPediatrics\nOriginal Research\nDiabetes in Patients With Ataxia Telangiectasia: A National Cohort Study\nDonath Helena 1* Hess Ursula 1 Kieslich Matthias 2 Theis Marius 2 Ohlenschläger Ute 2 Schubert Ralf 1 Woelke Sandra 1 Zielen Stefan 1 1Division of Allergology, Pulmonology and Cystic Fibrosis, Department for Children and Adolescents, Goethe University, Frankfurt, Germany\n2Division of Pediatric Neurology, Department for Children and Adolescents, Goethe University, Frankfurt, Germany\nEdited by: Prashant Kumar Verma, All India Institute of Medical Sciences, Rishikesh, India\n\nReviewed by: Luciana Chessa, Sapienza University of Rome, Italy; Nizar Mahlaoui, Assistance Publique Hopitaux De Paris, France\n\n*Correspondence: Helena Donath helena.donath@kgu.deThis article was submitted to Genetic Disorders, a section of the journal Frontiers in Pediatrics\n\n\n09 7 2020 \n2020 \n8 31713 4 2020 18 5 2020 Copyright © 2020 Donath, Hess, Kieslich, Theis, Ohlenschläger, Schubert, Woelke and Zielen.2020Donath, Hess, Kieslich, Theis, Ohlenschläger, Schubert, Woelke and ZielenThis 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.Background: Ataxia telangiectasia (A-T) is a rare autosomal-recessive multisystem disorder characterized by pronounced cerebellar ataxia, telangiectasia, cancer predisposition and altered body composition. In addition, evidence is rising for endocrine dysfunction.\n\nObjectives: To determine the evolution of diabetes and its prevalence in a larger A-T cohort.\n\nMethods: A retrospective analysis of the patient charts of 39 subjects from the Frankfurt A-T cohort was performed between August 2002 and 2018 concerning HbA1c and oral glucose tolerance (OGTT). The median follow-up period was 4 years (1–16 years). In addition, in 31 A-T patients aged 1 to 38 years HbA1c and fasting glucose were studied prospectively from 2018 to 2019.\n\nResults: In the retrospective analysis, we could demonstrate a longitudinal increase of HbA1c. The prospective analysis showed a significant increase of HbA1c and fasting glucose with age (r = 0.79, p ≤ 0.0001). OGTT has a good sensitivity for insulin resistance screening, whereas HbA1c can be used to evaluate individual courses and therapy response. Seven out of 39 (17.9%) patients suffered from diabetes. Metformin did not always lead to sufficient diabetes control; one patient was treated successfully with repaglinide.\n\nConclusion: Diabetes is a common finding in older A-T patients and often starts in puberty. Our data clearly demonstrate the need for an annual diabetes screening in patients > 12 years.\n\nataxia telangiectasiadiabetesHbA1cOGTTdiabetes therapy\n==== Body\nBackground\nAtaxia telangiectasia (A-T) is a rare autosomal recessive multisystem disorder characterized by pronounced cerebellar ataxia, telangiectasia, cancer predisposition, and altered body composition (1–3). The incidence is estimated at 1:40.000–1:200.000 (4).\n\nThe sequence of the Ataxia Telangiectasia Mutated (ATM) gene has been known since 1995. It is located in the region q22-23 of chromosome 11 and encodes a 370 kDa serine/threonine kinase called ATM belonging to the family of signal transduction molecules (5, 6) and is activated in response to DNA double-strand breaks. ATM has over 700 interaction partners, including the tumor suppressor p53 (7, 8). In this way, a large number of processes such as cell cycle checkpoints, DNA repair systems or apoptosis are controlled. Due to the multitude of tasks, the failure of the kinase results in a complex clinical appearance that manifests in various organ systems (9). Many of the clinical alterations observed in A-T patients may be related to the dysfunctional control of reactive oxygen species (ROS) observed when ATM is deficient (10, 11).\n\nMedical care for A-T patients has improved significantly during the last years and new treatment options rise hope to patients and physicians (4). With increasing life expectancy evolving morbidities like liver disease (12), insulin resistance (IR) (13), lipid alterations (14, 15), and cardiovascular disease (16) are coming to the fore as a typical signs of premature aging (17).\n\nWhile gastrointestinal involvement, mainly dysphagia, poor weight gain, and failure to thrive have been characterized well (2, 3, 18–21), hepatic and metabolic disease is an entity taken into consideration only recently, with the clinical improvement and increased survival of A-T patients (12, 15). Recently, it was shown that ATM is also involved in metabolic and cardiovascular complications when disrupted (13, 15, 22, 23). ATM is a critical player in a multitude of cellular pathways for glucose metabolism (24–26). In vitro hyperglycemia led to increased activation of the ATM protein in pancreatic β-cells (27). The absence of ATM leads to dysglycemia and IR with lower Matsuda index when compared to controls while performing an oral glucose tolerance test (OGTT) (28).\n\nATM protein is involved in glucose transport, and lack of ATM can cause IR (24). Cytoplasmic ATM is a major upstream activator of Akt thus contributes to the translocation of cell surface glucose transporter 4 (GLUT4) to cell membrane (24). Early IR and a high prevalence of diabetes type 2 in older A-T patients as well as their family members are well known (23, 29–32). In the last years, it became evident that ATM gene polymorphisms are associated with higher risk of type 2 diabetes (33) and poorer response to metformin treatment (34).\n\nThe aim of this retrospective and in part prospective study was to evaluate our patient cohort for the incidence of IR and diabetes. In addition, we evaluated the therapy efficaciousness of diabetes treatment in seven patients.\n\nMethods\nBetween August 2002 and August 2018 we studied data of 39 classical A-T patients aged 1 to 38 years from the Frankfurt A-T cohort regarding HbA1c and outcome of OGTT. The parameters were taken from the available patient charts. In addition, 31 A-T patients were investigated for HbA1c and fasting glucose prospectively. The parameters were determined in the serum of whole blood.\n\n(Pre-)Diabetes was defined according to recent International Society for Pediatric and Adolescent Diabetes (ISPAD) guidelines as pathological 2 h-postchallenge glucose, fasting glucose ≥ 126 mg/dL or HbA1c ≥ 5.7% (35).\n\nAll patients were clinically and/or genetically diagnosed with A-T according to recent World Health Organization (WHO) recommendations (36). We compared patients <12 years of age (group 1) to patients ≥ 12 years (group 2).\n\nData Ascertainment\nThe data presented were collected from two non-interventional clinical trials at the children's hospital Frankfurt. Both trials were registered at clinicaltrials.gov 2012 (Susceptibility to infections in ataxia telangiectasia; NCT02345135) and 2017 (Susceptibility to Infections, tumor risk, and liver disease in patients with ataxia telangiectasia; NCT03357978). The studies were approved by the responsible ethics committee in Frankfurt (application number 121/12 and 504/15) and conducted following the ethical principles of the Declaration of Helsinki, regulatory requirements and the code of Good Clinical Practice.\n\nStatistical Analysis\nFor statistical analysis GraphPad Prism 5.01 (GraphPad Software, Inc.) was used. Values are presented as arithmetic means with standard deviations (SDs). For comparisons between the two study groups, two-tailed Mann-Whitney-U test was applied. Correlations were analyzed by Spearman's correlation coefficient. P ≤ 0.05 were considered significant.\n\nResults\nRetrospective Trial\nFrom our database, we collected HbA1c of 39 A-T patients who presented in our clinic within this period of time (2002–2018) and had at least one measurement of HbA1c; a total of 73 HbA1c measurements were performed. HbA1c was significantly higher in group 2 compared to group 1 (4.85 ± 0.14 vs. 5.65 ± 0.08%, p ≤ 0.0001). We could show a significant correlation between age and increased HbA1c (r = 0.59, p ≤ 0.0001). Figure 1 shows the progression of HbA1c with age. We evaluated the results of OGTT in 13 older patients (Median age: 17.5 years). As shown in Table 1, 7 out of 13 patients had IR or diabetes. OGTT was more sensitive to detect disturbed glucose metabolism than the corresponding HbA1c. All diabetic patients were ≥ 12 years of age at diagnosis (median age at diagnosis: 21 years). Figure 2 shows OGTT results in six patients who had or developed diabetes. None of the patients had auto antibodies, the family history of diabetes was unremarkable in all cases. None of the patients had systemic steroid intake documented in the patient charts.\n\nFigure 1 HbA1c (n = 3) and age. As depicted here HbA1c is increasing with age. Normal range is up to 5.7% (hatched line).\n\nTable 1 Overview about seven diabetic patient from the Frankfurt A-T cohort.\n\nPatient Number\tAge at OGTT [years]\tResult of OGTT\tCorresponding HbA1c [%]\tAge at diagnosis [years]\tMetformin response\tCause of death\tClinical information\t\n1\t17\tIR\t5.5\t21#\tYes\t-\t- IR with 17 years \n- Metabolic syndrome with diabetes \n- First dietary treatment\t\n2\t19\tDiabetes\t5.79\t19\tYes\t-\t- Overweight\t\n3\t18\tIR\t5.1\t19#\tYes\t-\t- IR at the age of 18 \n- First dietary treatment\t\n4\tn.a.\tn.a.\tn.a.\t22#\tno*\t- Lymphoma (age 26)\t- First dietary treatment \n- Metformin non responder \n- Insulin glargin once daily \n- Repaglinide (3 x 500 mg, 30 min bevor every meal)\t\n5\t16\tnormal\t5.56\t20\tYes\t-\t- Overweight \n- Granuolma\t\n6\t21\tDiabetes\t6\t21\tno*\t- Pneumonia with respiratory failure (age 30)\t- No treatment \n- Recurrent pneumonia\t\n7\t25\tDiabetes\t4.1\t25\tn.a.\t- Pneumonia with respiratory failure (age 25)\t- No data concerning treatment and clinical follow up available\t\nData from the retrospective and prospective trial are shown.\n\n* Metformin was discontinued because of gastrointestinal side effects and poor glycemic control.\n\n#Diagnosed in an outpatient clinic.\n\nn.a., not available.\n\nFigure 2 OGTT in 6 patient with diabetes. IR is defined as 120 min glucose > mg/dl, diabetes is defined as 120 min glucose > 200 mg/dl (hatched lines). N = 3 patients were diagnosed with diabetes (black curves). N = 2 had an IR and developed diabetes (orange curves). N = 1 had a normal OGTT and developed diabetes (green curve).\n\nProspective Trial\nPatient characteristics are shown in Table 2. HbA1c and fasting glucose were significantly increased in group 2 compared to group 1 (HbA1c: group 1: 4.84 ± 0.35, group 2: 5.72 ± 0.6%; p ≤ 0.0001, fasting glucose: group 1: 84.2 ± 10.13 mg/dL, group 2: 103.7 ± 16.8 mg/dL, p ≤ 0.0001). Pathologically increased HbA1c levels were found in 30% (3/10) of older A-T patients. We could establish a significant correlation of HbA1c (r = 0.79, p ≤ 0.0001) and fasting glucose (r = 0.51, p ≤ 0.001) with age. The correlations are shown in Figures 3, 4. 30 % (3/10) of group 2 suffered from diabetes type 2 whereas no patient in group 1 was affected.\n\nTable 2 Patient characteristics.\n\nParameter\tAge <12 years (n = 21)\tAge > 12 years (n = 10)\tP value\t\nSex\t9♀ / 12♂\t5♀/5♂\t\t\nAge [years]\t6.5 ± 2.8\t19.6 ± 3.5\t≤ 0.0001\t\nWeight [kg]\t21.1 ± 5.0\t50.4 ± 16.4\t≤ 0.0001\t\nBMI [kg/m2]\t15.7 ± 1.5\t20.3 ± 4.3\t≤ 0.001\t\nZ-Score BMI\t−0.3 ± 0.8\t−0.9 ± 1.2\tn.s.\t\nAFP [ng/mL] Normal range <7 ng/mL\t313.4 ± 267.2\t540.8 ± 275.8\t≤ 0.05\t\nHbA1c [%] Normal range <5,7%\t4.84 ± 0.35\t5.72 ± 0.6\t≤ 0.0001\t\nFasting glucose [mg/dL]\t84.2 ± 10.13\t103.7 ± 16.8\t≤ 0.0001\t\nDiabetes Type 2\tn = 0\tn = 3\t\t\nData from the prospective trial are shown.\n\nThe values are shown as mean + SD, n.s., not significant.\n\nFigure 3 Correlation of HbA1c and age r = 0.79, p ≤ 0.0001.\n\nFigure 4 Correlation of fasting glucose and age r = 0.51, p ≤ 0.0001.\n\nAll diabetic patients received treatment with metformin (Table 1). Response to metformin was favorable 4/7 patients (57.1%). 2/7 patients did not respond to metformin monotherapy. Due to gastrointestinal side effects, one of these patients discontinued the metformin treatment. After a short period without any treatment, subcutaneous injections of insulin glargin were started. Still, the patient suffered from poorly controlled diabetes marked by a fasting glucose of 250 mg/dL and HbA1c of 7.6% at presentation in our clinic. Due to an advanced neurological deficit we were hesitant to initiate an intensified subcutaneous insulin therapy and therefore decided to treat him with repaglinide orally. Within 8 weeks, HbA1c dropped to 6.2%. The individual course of HbA1c of this patient is shown in Figure 5.\n\nFigure 5 Individual course of HbA1c in a diabetic patient under different treatments. Repaglinide led to an efficacious glycaemia control.\n\nDiscussion\nA-T is a lethal, chronic degenerative disease. Due to the improved treatment options in the recent years, hitherto largely unknown disease features such as endocrine dysfunction, liver disease and cardiovascular diseases are gaining in importance (12, 15, 37, 38). The present work clearly demonstrates the high rate of type 2 diabetes (17.9%) among post-pubertal patients.\n\nDiabetes is one of the leading causes of death worldwide (39). It leads to a high cardiovascular risk, micro-angiopathy, dyslipidemia, nephropathy, neuropathy, and repressed immune system (39). HbA1c values in the upper normal range indicate a high risk for later diabetes (40). In condition of A-T, IR and diabetes have rarely been investigated in clinical settings. In view of the comorbidities (e.g., malnutrition, neurological deficit, and immunodeficiency), consistent diabetes therapy is of particular importance.\n\nIn the cytoplasm of the cells, ATM causes activation of the serine/threonine-specific protein kinase Akt in response to insulin. Akt is an important protein which participates in the signaling cascade for the inhibition of apoptotic signals (41). In response to insulin, protein translation is stimulated, and glucose uptake is controlled by GLUT 4 (24). Mice with a muscle-specific deletion in the GLUT 4 gene develop IR and glucose intolerance (42). Low ATM levels will therefore contribute to the development of IR and glucose intolerance in A-T via the down-regulation of Akt activity in muscle cells (24).\n\nIn 2000, the insulin signaling induced ATM-dependent phosphorylation of 4E-BP1 was reported (46). Ever since, the deficiency in the insulin and insulin-like growth factor 1 (IGF-1) axes has been demonstrated in the absence of ATM (20, 26). Apo E knockout mice without ATM protein showed increased IR and were prone to develop a metabolic syndrome (22).\n\nAdditionally, ATM is a regulator of adipocyte differentiation. In Atm-deficient mice lack of induction of C/EBPα and PPARγ, central transcription factors for adipocyte differentiation, as well a reduced fat mass were reported (43). Of course, fat mass is of particular importance for glucose metabolism and homeostasis. There was no significant difference when comparing fat mass of A-T patients to sex and age matched healthy controls in humans (2). Apparently, the significantly decreased lean mass is a major contributor to the disturbed glycemic control in A-T patients.\n\nApart from that, there have been few reports on endocrine abnormalities in A-T patients (38). While poor weight gain, stunting and delayed pubertal development have been characterized as a typical findings in A-T (2, 3, 19, 20, 38), abnormalities in glucose metabolism, also if known since long time, are hardly described as clinical manifestation (30–32). We have recently reported about liver involvement in A-T and dyslipidemia (12). In synopsis of lipid metabolism disorder and IR, A-T patients suffer from an incomplete metabolic syndrome with increased risk for cardiovascular events (15, 16, 44).\n\nDue to better care, life expectancy of A-T patients has emerged over the last decades (45). Especially in the light of new treatment options such as bone marrow transplantation (46–48), dexamethasone treatment (49–51), and gene therapy (52–54) disease facets with manifestation in the later disease course should be screened and treated. According to our data, diabetes screening is indicated starting for the age of 12 years. HbA1c is an easy to obtain, inexpensive marker that can be used to evaluate individual courses and therapy response. However, OGTT is more sensitive in diagnosing IR than HbA1c and fasting glucose. This shows that the OGTT is still of value and confirms the current recommendation of the English CF society: HbA1c reflects glycemic control over a period of time. The statement about the long-term course of blood glucose has some advantages, but the values of HbA1c in CF patients may still be within the normal range when the OGTT already shows an IR or even diabetes (55). Taken these information into account, we truly believe that both measurements, HbA1c and OGTT, should be applied in A-T patients.\n\nFirst line treatment for insulin-resistant diabetes is metformin (39). However, to our clinical experience, not all A-T patients respond to treatment with metformin. As has been shown in 2011, inhibition of ATM in rat hepatoma cell lines diminished the effect of metformin by reduced phosphorylation and activation of AMP-activated protein kinase (25). Additionally, the gene variant SNP rs11212617 at a locus that includes the ATM was proved to influence the glycemic response to metformin in type 2 diabetes (56). In line with these studies, Connelly et al. reported that the absence of ATM leads to dysglycaemia and IR with lower Matsuda index when compared to controls while performing an OGTT (28). Nevertheless, they could not show altered fasting glucose levels, insulin concentrations or insulinogenic index measurements (28).\n\nIn addition to that, it is important to consider the general condition of the patient with particular attention to the neurological status, body composition, and independence in the patients' everyday life. For instance, subcutaneous injections often present an insurmountable barrier to self-administration due neurological impairment [unpublished clinical observation]. Apart from clinical experience, research on endocrine, and metabolic alterations in A-T is rare (15, 22, 37, 57). No guidelines for treatment of diabetes in this challenging patient group are available.\n\nIn case a patient does not respond adequately to metformin therapy, insulin treatment is recommended. The beneficial effects of insulin as anabolic hormone should be taken into consideration when escalating diabetes therapy (58). Especially in malnourished patients, an amelioration of the nutritional status with weight gain could be achieved with insulin injections. The insulin/IGF-1 axis increases muscle mass and bone density and improves insulin sensitivity as well as enhancement of free fatty acid oxidations in the muscles. Also, it was shown recently that the IGF-1 pathway has beneficial effect on cardiovascular and cerebrovascular disease (59). On the other hand, insulin as anabolic hormone and growth factor may possibly increase the cancer risk in A-T patients (60).\n\nHowever, self-administration of subcutaneous insulin injections are not feasible for older A-T patients with considerable neurological deficit. In case an insulin therapy is initiated, they are dependent on their caregiver. There is a dilemma between the autonomy of patients and the necessary treatment. To improve compliance, a different treatment regimen with oral antidiabetic drugs such as repaglinide may be used in special cases (61). In the Frankfurt A-T cohort, one of our A-T patients with diabetes had poorly controlled serum glucose levels under treatment with insulin glargin. We initiated a treatment with repaglinide. Hereunder, with a very favorable side-effect profile, a good therapeutic success and at the same time excellent compliance was achieved.\n\nThis study has some limitations. Due to the retrospective design, we cannot provide a complete data set for the diagnosis of type 2 diabetes, since many patients of our national cohort are admitted to our center for routine care annually or even every second year only. Still, to our best knowledge, this is the first prospective study on diabetes in 31 A-T patients and seems to confirm our retrospective analysis of longitudinal data sets of our national cohort. Due to the large number of cases, we think we have delivered reliable data that clearly demonstrate the need for an annual diabetes screening in patients ≥ 12 years.\n\nConclusion\nEspecially with advancing age, a diabetes screening should be conducted regularly in A-T patients. IR and diabetes have to be treated in order to stabilize the nutritional status and avert further complications. OGTT has a good sensitivity for IR screening, whereas HbA1c is an inexpensive marker that can be used to evaluate individual courses and therapy response. Metformin should be administered as first line treatment and in non-responders repaglinide was shown to be safe and efficacious for glycemic control.\n\nAt a Glance Commentary\nScientific knowledge on the subject: Little is known about the natural course of diabetes in ataxia telangiectasia (A-T). This is the first longitudinal retrospective and prospective surveillance of diabetes in a larger A-T cohort.\n\nWhat This Study Adds to the Field: Diabetes is a common finding in older A-T patients and normally starts after puberty. There was a significant correlation of HbA1c and fasting glucose with age. OGTT has a good sensitivity for IR screening, whereas HbA1c can be used to evaluate individual courses and therapy response.\n\nData Availability Statement\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\n\nEthics Statement\nThe studies involving human participants were reviewed and approved by Ethikkommitee des Universitätsklinikums Frankfurt. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. 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's Note\nThis manuscript has been released as a pre-print at Research Square, Donath et al. (62).\n\nAuthor Contributions\nHD, SW, UH, SZ, and RS did the study design, data collection and interpreted, and did statistical analysis. MT, MK, UO, HD, SW, UH, and SZ conducted visits. HD and SZ wrote the manuscript. All authors read and approved the final manuscript.\n\nConflict of Interest\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nWe would like to thank our patients and their families who share and support our research.\n\nAbbreviations\nA-TAtaxia telangiectasia\n\nATMAtaxia telangiectasia mutated\n\nROSReactive oxygen species\n\nIRInsulin resistance\n\nOGTTOral glucose tolerance test\n\nGLUT4Cell surface glucose transporter 4\n\nISPADInternational Society For Pediatric And Adolescent Diabetes\n\nWHOWorld Health Organization\n\nSDStandard deviation\n\nIGF-1Insulin-Like Growth Factor 1\n\nSNPSingle nucleotide polymorphism.\n==== Refs\nReferences\n1. Boder E Sedwick RP . Ataxia-telangiectasia; a familial syndrome of progressive cerebellar ataxia, oculocutaneous telangiectasia and frequent pulmonary infection\n. Pediatrics. 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Elevated oxidative stress in patients with ataxia telangiectasia\n. Antioxid Redox Signal. (2002 ) 4 :465 –9\n. 10.1089/15230860260196254 12215213 \n12. Donath H Woelke S Theis M Heß U Knop V Herrmann E . Progressive liver disease in patients with ataxia telangiectasia\n. Front Pediatr. (2019 ) 7 :458 . 10.3389/fped.2019.00458 31788461 \n13. Espach Y Lochner A Strijdom H Huisamen B . ATM protein kinase signaling, type 2 diabetes and cardiovascular disease\n. Cardiovasc Drugs Ther. (2015 ) 29 :51 –8\n. 10.1007/s10557-015-6571-z 25687661 \n14. Mercer JR Cheng K-K Figg N Gorenne I Mahmoudi M Griffin J . DNA damage links mitochondrial dysfunction to atherosclerosis and the metabolic syndrome\n. Circ Res. (2010 ) 15 :1021 –31\n. 10.1161/CIRCRESAHA.110.218966 20705925 \n15. Paulino TL Rafael MN Hix S Shigueoka DC Ajzen SA Kochi C . Is age a risk factor for liver disease and metabolic alterations in ataxia telangiectasia patients?\n\nOrphanet J Rare Dis. (2017 ) 12 :136 . 10.1186/s13023-017-0689-y 28778179 \n16. Andrade IGA Costa-Carvalho BT da Silva R Hix S Kochi C Suano-Souza FI . Risk of atherosclerosis in patients with ataxia telangiectasia\n. Ann Nutr Metab. (2015 ) 66 :196 –201\n. 10.1159/000430790 26045095 \n17. Shiloh Y Lederman HM . Ataxia-telangiectasia (A-T): an emerging dimension of premature ageing\n. Ageing Res Rev. (2017 ) 33 :76 –88\n. 10.1016/j.arr.2016.05.002 27181190 \n18. Lefton-Greif MA Crawford TO Winkelstein JA Loughlin GM Koerner CB Zahurak M . Oropharyngeal dysphagia and aspiration in patients with ataxia-telangiectasia\n. J Pediatr. (2000 ) 136 :225 –31\n. 10.1016/S0022-3476(00)70106-5 10657830 \n19. Ross LJ Capra S Baguley B Sinclair K Munro K Lewindon P . Nutritional status of patients with ataxia-telangiectasia: a case for early and ongoing nutrition support and intervention\n. J Paediatr Child Health. (2015 ) 51 :802 –7\n. 10.1111/jpc.12828 25656498 \n20. Voss S Pietzner J Hoche F Taylor AMR Last JI Schubert R . Growth retardation and growth hormone deficiency in patients with ataxia telangiectasia\n. Growth Factors. (2014 ) 32 :123 –9\n. 10.3109/08977194.2014.939805 25060036 \n21. Stewart E Prayle AP Tooke A Pasalodos S Suri M Bush A . Growth and nutrition in children with ataxia telangiectasia\n. Arch Dis Child. (2016 ) 101 :1137 –41\n. 10.1136/archdischild-2015-310373 27573920 \n22. Schneider JG Finck BN Ren J Standley KN Takagi M Maclean KH . ATM-dependent suppression of stress signaling reduces vascular disease in metabolic syndrome\n. Cell Metab. (2006 ) 4 :377 –89\n. 10.1016/j.cmet.2006.10.002 17084711 \n23. van Os NJH Roeleveld N Weemaes CMR Jongmans MCJ Janssens GO Taylor AMR . Health risks for ataxia-telangiectasia mutated heterozygotes: a systematic review, meta-analysis and evidence-based guideline\n. Clin Genet. (2016 ) 90 :105 –17\n. 10.1111/cge.12710 26662178 \n24. Halaby M-J Hibma JC He J Yang D-Q . ATM protein kinase mediates full activation of akt and regulates glucose transporter 4 translocation by insulin in muscle cells\n. Cell Signal. (2008 ) 20 :1555 –63\n. 10.1016/j.cellsig.2008.04.011 18534819 \n25. Zhou K Bellenguez C Spencer CCA Bennett AJ Coleman RL Tavendale R . Common variants near aTM are associated with glycemic response to metformin in type 2 diabetes\n. Nat Genet. (2011 ) 43 :117 –20\n. 10.1038/ng.735 21186350 \n26. Yang D-Q Halaby M-J Li Y Hibma JC Burn P . Cytoplasmic aTM protein kinase: an emerging therapeutic target for diabetes, cancer and neuronal degeneration\n. Drug Discov Today. (2011 ) 16 :332 –8\n. 10.1016/j.drudis.2011.02.001 21315178 \n27. Sidarala V Kowluru A . Exposure to chronic hyperglycemic conditions results in ras-related c3 botulinum toxin substrate 1 (Rac1)-mediated activation of p53 and aTM kinase in pancreatic β-cells\n. Apoptosis. (2017 ) 22 :597 –607\n. 10.1007/s10495-017-1354-6 28220272 \n28. Connelly PJ Smith N Chadwick R Exley AR Shneerson JM Pearson ER \nRecessive mutations in the cancer gene ataxia telangiectasia mutated (ATM), at a locus previously associated with metformin response, cause dysglycaemia and insulin resistance\n. Diabet Med. (2016 ) 33 :371 –5\n. 10.1111/dme.13037 26606753 \n29. Swift M . Genetics and epidemiology of ataxia-telangiectasia\n. Kroc Found Ser. (1985 ) 19 :133 –46\n.3864935 \n30. Morrell D Chase CL Kupper LL Swift M . Diabetes mellitus in ataxia-telangiectasia, fanconi anemia, xeroderma pigmentosum, common variable immune deficiency, and severe combined immune deficiency families\n. Diabetes. (1986 ) 35 :143 –7\n. 10.2337/diabetes.35.2.143 3943665 \n31. Bar RS Levis WR Rechler MM Harrison LC Siebert C Podskalny J . Extreme insulin resistance in ataxia telangiectasia: defect in affinity of insulin receptors\n. N Engl J Med. (1978 ) 298 :1164 –71\n. 10.1056/NEJM197805252982103 651946 \n32. Blevins LS Gebhart SS . Insulin-resistant diabetes mellitus in a black woman with ataxia-telangiectasia\n. South Med J. (1996 ) 89 :619 –21\n. 10.1097/00007611-199606000-00013 8638204 \n33. Altall RM Qusti SY Filimban N Alhozali AM Alotaibi NA Dallol A . SLC22A1 and ATM genes polymorphisms are associated with the risk of type 2 diabetes mellitus in western saudi arabia: a case-control study\n. Appl Clin Genet. (2019 ) 15 :213 –9\n. 10.2147/TACG.S229952 31814751 \n34. Out M Becker ML van Schaik RH Lehert P Stehouwer CD Kooy A . A gene variant near ATM affects the response to metformin and metformin plasma levels: a post hoc analysis of an RCT\n. Pharmacogenomics. (2018 ) 19 :715 –26\n. 10.2217/pgs-2018-0010 29790415 \n35. Zeitler P Fu J Tandon N Nadeau K Urakami T Barrett T . ISPAD clinical practice consensus guidelines 2014. Type 2 diabetes in the child and adolescent\n. Pediatr Diabetes. (2014 ) 15 Suppl \n20 :26 –46\n. 10.1111/pedi.12179 25182306 \n36. Gathmann B Goldacker S Klima M Belohradsky BH Notheis G Ehl S„ . The german national registry for primary immunodeficiencies (PID)\n. Clin Exp Immunol. (2013 ) 173 :372 –80\n. 10.1111/cei.12105 23607573 \n37. Weiss B Krauthammer A Soudack M Lahad A Sarouk I Somech R . Liver disease in pediatric patients with ataxia telangiectasia: a Novel report\n. J Pediatr Gastroenterol Nutr. (2016 ) 62 :550 –5\n. 10.1097/MPG.0000000000001036 26594831 \n38. Nissenkorn A Levy-Shraga Y Banet-Levi Y Lahad A Sarouk I Modan-Moses D . Endocrine abnormalities in ataxia telangiectasia: findings from a national cohort\n. Pediatr Res. (2016 ) 79 :889 –94\n. 10.1038/pr.2016.19 26891003 \n39. Bundesärztekammer (BÄK) Kassenärztliche Bundesvereinigung (KBV) Arbeitsgemeinschaft der Wis-senschaftlichen Medizinischen Fachgesellschaften (AWMF). Nationale VersorgungsLeitlinie Therapie des Typ-2-Diabetes - Langfassung, 1\n. Auflage. Version 4. 2013 . Zuletzt Geändert (2014 ). Available online at: www.dm-therapie.versorgungsleitlinien.de\n40. Pradhan AD Rifai N Buring JE Ridker PM . Hemoglobin a1c predicts diabetes but not cardiovascular disease in nondiabetic women\n. Am J Med. (2007 ) 120 :720 –7\n. 10.1016/j.amjmed.2007.03.022 17679132 \n41. Viniegra JG Martínez N Modirassari P Hernández Losa J Parada Cobo C Sánchez-Arévalo Lobo VJ \nFull activation of pKB/Akt in response to insulin or ionizing radiation is mediated through aTM\n. J Biol Chem. (2005 ) 280 :4029 –36\n. 10.1074/jbc.M410344200 15546863 \n42. Zisman A Peroni OD Abel ED Michael MD Mauvais-Jarvis F Lowell BB . Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance\n. Nat Med. (2000 ) 6 :924 –8\n. 10.1038/78693 10932232 \n43. Takagi M Uno H Nishi R Sugimoto M Hasegawa S Piao J . ATM regulates adipocyte differentiation and contributes to glucose homeostasis\n. Cell Rep. (2015 ) 10 :957 –67\n. 10.1016/j.celrep.2015.01.027 25683718 \n44. Micol R Ben Slama L Suarez F Le Mignot L Beauté J Mahlaoui N . Morbidity and mortality from ataxia-telangiectasia are associated with aTM genotype\n. J Allergy Clin Immunol. (2011 ) 128 :382 –9\n.e1. 10.1016/j.jaci.2011.03.052 21665257 \n45. Crawford TO Skolasky RL Fernandez R Rosquist KJ Lederman HM . Survival probability in ataxia telangiectasia\n. Arch Dis Child. (2006 ) 91 :610 –1\n.16790721 \n46. Duecker R Baer PC Buecker A Huenecke S Pfeffermann L-M Modlich U . Hematopoietic stem cell transplantation restores naïve t-Cell populations in atm-Deficient mice and in preemptively treated patients with ataxia-Telangiectasia\n. Front Immunol. (2019 ) 10 :2785 . 10.3389/fimmu.2019.02785 31849966 \n47. Pietzner J Baer PC Duecker RP Merscher MB Satzger-Prodinger C Bechmann I . Bone marrow transplantation improves the outcome of atm-deficient mice through the migration of ATM-competent cells\n. Hum Mol Genet. (2013 ) 22 :493 –507\n. 10.1093/hmg/dds448 23100326 \n48. Bakhtiar S Woelke S Huenecke S Kieslich M Taylor AM Schubert R . Pre-emptive allogeneic hematopoietic stem cell transplantation in ataxia telangiectasia\n. Front Immunol. (2018 ) 9 :2495 . 10.3389/fimmu.2018.02495 30420857 \n49. Menotta M Orazi S Gioacchini AM Spapperi C Ricci A Chessa L . Proteomics and transcriptomics analyses of ataxia telangiectasia cells treated with dexamethasone\n. PLoS ONE. (2018 ) 13 :e0195388 . 10.1371/journal.pone.0195388 29608596 \n50. Coker SA Szczepiorkowski ZM Siegel AH Ferrari A Mambrini G Anand R . A study of the pharmacokinetic properties and the in vivo kinetics of erythrocytes loaded with dexamethasone sodium phosphate in healthy volunteers\n. Transfus Med Rev. (2018 ) 32 :102 –10\n. 10.1016/j.tmrv.2017.09.001 29031409 \n51. Menotta M Biagiotti S Orazi S Rossi L Chessa L Leuzzi V . In vivo effects of dexamethasone on blood gene expression in ataxia telangiectasia\n. Mol Cell Biochem. (2018 ) 438 :153 –66\n. 10.1007/s11010-017-3122-x 28744812 \n52. Carranza D Torres-Rusillo S Ceballos-Pérez G Blanco-Jimenez E Muñoz-López M García-Pérez JL . Reconstitution of the ataxia-Telangiectasia cellular phenotype with lentiviral vectors\n. Front Immunol. (2018 ) 9 :2703 . 10.3389/fimmu.2018.02703 30515174 \n53. Cortés ML Oehmig A Saydam O Sanford JD Perry KF Fraefel C . Targeted integration of functional human aTM cDNA into genome mediated by hSV/AAV hybrid amplicon vector\n. Mol Ther. (2008 ) 16 :81 –8\n. 10.1038/sj.mt.6300338 17998902 \n54. Pineda de las Infantas MJ Torres-Rusillo S Unciti-Broceta JD Fernandez-Rubio P Luque-Gonzalez MA Gallo MA . Synthesis of 6,8,9 poly-substituted purine analogue libraries as pro-apoptotic inducers of human leukemic lymphocytes and dAPK-1 inhibitors\n. Org Biomol Chem. (2015 ) 13 :5224 –34\n. 10.1039/C5OB00230C 25856731 \n55. Tommerdahl KL Brinton JT Vigers T Nadeau KJ Zeitler PS Chan CL . Screening for cystic fibrosis-related diabetes and prediabetes: evaluating 1,5-anhydroglucitol, fructosamine, glycated albumin, and hemoglobin a1c\n. Pediatr Diabetes. (2019 ) 20 :1080 –6\n. 10.1111/pedi.12914 31469470 \n56. van Leeuwen N Nijpels G Becker ML Deshmukh H Zhou K Stricker BHC . A gene variant near aTM is significantly associated with metformin treatment response in type 2 diabetes: a replication and meta-analysis of five cohorts\n. Diabetologia. (2012 ) 55 :1971 –7\n. 10.1007/s00125-012-2537-x 22453232 \n57. Ehlayel M Soliman A Sanctis V de . Linear growth and endocrine function in children with ataxia telangiectasia\n. Indian J Endocrinol Metab. (2014 ). 18 (Suppl 1 ):S93-6. 10.4103/2230-8210.145079 25538885 \n58. Steiner DF Chan SJ Terris S Hofmann C \nInsulin as a cellular growth regulator\n. Ciba Found Symp. (1977 ) 217 –28\n. 10.1002/9780470720363.ch11 248001 \n59. Obradovic M Zafirovic S Soskic S Stanimirovic J Trpkovic A Jevremovic D . Effects of iGF-1 on the cardiovascular system\n. Curr Pharm Des. (2019 ) 25 :3715 –25\n. 10.2174/1381612825666191106091507 31692426 \n60. Iqbal MA Siddiqui FA Gupta V Chattopadhyay S Gopinath P Kumar B . Insulin enhances metabolic capacities of cancer cells by dual regulation of glycolytic enzyme pyruvate kinase m2\n. Mol Cancer. (2013 ) 12 :72 . 10.1186/1476-4598-12-72 23837608 \n61. Dimic D Velojic Golubovic M Antic S Radenkovic S . Evaluation of the repaglinide efficiency in comparison to the glimepiride in the type 2 diabetes patients poorly regulated by the metmorfine administration\n. Bratisl Lek Listy. (2009 ) 110 :335 –9\n.19634573 \n62. Donath H Hess U Kieslich M \nDiabetes in Patients with Ataxia telangiectasia: A National Cohort Study . PREPRINT (Version 1). Available online at: 10.21203/rs.3.rs-21121/v1 (accessed April 08, 2020).\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2296-2360",
"issue": "8()",
"journal": "Frontiers in pediatrics",
"keywords": "HbA1c; OGTT; ataxia telangiectasia; diabetes; diabetes therapy",
"medline_ta": "Front Pediatr",
"mesh_terms": null,
"nlm_unique_id": "101615492",
"other_id": null,
"pages": "317",
"pmc": null,
"pmid": "32733823",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "25856731;31849966;7792600;3943665;25538885;15546863;7705845;29031409;26594831;26045095;31692426;23440242;22453232;21315178;26645295;25683718;21186350;8638204;28778179;26891003;28948852;25687661;31469470;27884168;3200306;16790721;28744812;26606753;28220272;18534819;26662178;17998902;10657830;248001;25656498;12215213;17679132;29608596;23607573;23100326;31814751;29790415;30515174;17084711;10932232;13542097;651946;19634573;31788461;27181190;25060036;21665257;30420857;27573920;18813293;20705925;3864935;23837608;25182306;26083028",
"title": "Diabetes in Patients With Ataxia Telangiectasia: A National Cohort Study.",
"title_normalized": "diabetes in patients with ataxia telangiectasia a national cohort study"
} | [
{
"companynumb": "DE-EMD SERONO-E2B_90080394",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "BACKGROUND\nAccidental intra-arterial drug injections usually occur as an iatrogenic complication but it is also found in drug abusers as a result of attempted intravenous (IV) injections. It is estimated that accidental intra-arterial injections are found in 1:3500-1:56000 patients visiting emergency department.\n\n\nMETHODS\nThis was cross sectional study performed in cardiovascular department Lady reading Hospital Peshawar from 1.1.2013 to 31.8.2015. Accidental intra-arterial injection was defined as intravenous injection in upper limb for any illness which is followed by sudden severe pain in limb followed by bluish discoloration of any part of limb. Data was analysed using SPSS-20. Frequency and percentage were calculated for categorical variables like while Means±SD was calculated for numerical variables. Chi square test was used to compare Categorical variables.\n\n\nRESULTS\nTotal 30 patients were studied in whom 17 were male. Mean age of the study population was 43.2±17.9 years. All patients after admission were put on intravenous Heparin alone or in combination with Dexamethason, Beraprost and Nifedifin on discretion of visiting consultant. Injection diclofenac were found more frequently as cause of limb ischemia (43 %). Amputation of digits or part of limb was noted in 7 (23.1 %) cases.\n\n\nCONCLUSIONS\nAccidental intra-arterial injection can lead to limb ischemia and even limb loss so while injecting IV drugs, care should be taken to use venous site away from arterial sites.",
"affiliations": "Cardiovascular Unit, Lady reading hospital Peshawar, Pakistan.;Cardiovascular Unit, Lady reading hospital Peshawar, Pakistan.;Cardiovascular Unit, Lady reading hospital Peshawar, Pakistan.;Cardiovascular Unit, Lady reading hospital Peshawar, Pakistan.;District Headquarter Hospital, Timergara, Pakistan.",
"authors": "Malik|Abdul|A|;Ikramullah|||;Khan|Muhammad Gibran|MG|;Ali Shah|Syed Murad|SM|;Ilyas|Muhammad|M|",
"chemical_list": null,
"country": "Pakistan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1025-9589",
"issue": "29(2)",
"journal": "Journal of Ayub Medical College, Abbottabad : JAMC",
"keywords": "Diclofenac; Heparin; IM, ABI; IV; Intraarterial; Intramuscular",
"medline_ta": "J Ayub Med Coll Abbottabad",
"mesh_terms": "D000328:Adult; D003430:Cross-Sectional Studies; D006801:Humans; D007049:Iatrogenic Disease; D007269:Injections, Intra-Arterial; D007511:Ischemia; D008875:Middle Aged; D010146:Pain; D034941:Upper Extremity",
"nlm_unique_id": "8910750",
"other_id": null,
"pages": "230-233",
"pmc": null,
"pmid": "28718237",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Accidental Intra Arterial Injection And Limb Ischemia.",
"title_normalized": "accidental intra arterial injection and limb ischemia"
} | [
{
"companynumb": "PK-AMNEAL PHARMACEUTICALS-2019AMN00574",
"fulfillexpeditecriteria": "1",
"occurcountry": "PK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RANITIDINE"
},
"drugadditional":... |
{
"abstract": "BACKGROUND\nPatients who refuse allogeneic blood transfusions (alloBT) on the basis of religious doctrine, such as Jehovah's Witnesses (JWs), can pose a challenge when undergoing surgical procedures. During cardiac surgery, special considerations regarding surgical techniques and blood loss minimization strategies can lead to improved outcomes. Limited literature exists to guide the use of four-factor prothrombin complex concentrate (4PCC) in this patient population undergoing cardiac surgery.\n\n\nMETHODS\nThis retrospective, single-center study evaluated the impact of 4PCC on hemoglobin (Hgb) change from baseline to postoperative nadir within a 7-day period among patients who refused alloBT during cardiac surgery. This study identified patients who refused alloBT from January 2011 to June 2017. Multivariable linear regression was used to control for confounding variables to evaluate the effectiveness of 4PCC.\n\n\nRESULTS\nDuring the study timeframe, 79 patients met inclusion criteria, all of whom identified as JWs, and underwent cardiac surgery. Of these, 19 received intraoperative 4PCC. Multivariable linear regression found no difference in Hgb change in patients who received 4PCC vs those who did not. No significant differences were found in mortality, thromboembolic complications, or in-hospital postoperative events.\n\n\nCONCLUSIONS\nIn JWs undergoing cardiac surgery who refuse alloBT, intraoperative use of 4PCC was not associated with a difference in Hgb change within 7 days postoperatively when adjusting for confounding variables. In the event of excessive blood loss, the utilization of 4PCC may provide a viable option in JW patients who undergo cardiac surgery where few options exist to mitigate blood loss.",
"affiliations": "Department of Pharmacy, Houston Methodist Hospital, Houston, Texas.;Department of Pharmacy, Houston Methodist Hospital, Houston, Texas.;Department of Anesthesiology, Houston Methodist Hospital, Houston, Texas.;Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas.;Department of Pharmacy, Houston Methodist Hospital, Houston, Texas.",
"authors": "Harris|Jesse E|JE|http://orcid.org/0000-0002-5586-5648;Varnado|Sara|S|;Herrera|Elizabeth|E|;Salazar|Eric|E|;Colavecchia|Anthony C|AC|",
"chemical_list": "D001779:Blood Coagulation Factors; D006454:Hemoglobins; C025667:prothrombin complex concentrates",
"country": "United States",
"delete": false,
"doi": "10.1111/jocs.14463",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0886-0440",
"issue": "35(4)",
"journal": "Journal of cardiac surgery",
"keywords": "Jehovah's Witness; factor concentrate; four-factor prothrombin complex concentrate; refusal of blood products; transfusion",
"medline_ta": "J Card Surg",
"mesh_terms": "D000368:Aged; D001779:Blood Coagulation Factors; D016063:Blood Loss, Surgical; D001803:Blood Transfusion; D006348:Cardiac Surgical Procedures; D005260:Female; D006454:Hemoglobins; D006801:Humans; D007430:Intraoperative Care; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D011184:Postoperative Period; D012067:Religion; D012189:Retrospective Studies; D016896:Treatment Outcome; D016312:Treatment Refusal",
"nlm_unique_id": "8908809",
"other_id": null,
"pages": "801-809",
"pmc": null,
"pmid": "32048355",
"pubdate": "2020-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Evaluation of postoperative clinical outcomes in Jehovah's Witness patients who receive prothrombin complex concentrate during cardiac surgery.",
"title_normalized": "evaluation of postoperative clinical outcomes in jehovah s witness patients who receive prothrombin complex concentrate during cardiac surgery"
} | [
{
"companynumb": "US-AMGEN-USASP2020162969",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DARBEPOETIN ALFA"
},
"drugadditional": null,
... |
{
"abstract": "Carfilzomib was approved for the treatment of multiple myeloma in 2012 and since then there have been concerns for cardiovascular toxicity from its use. With this study, we aim to further study the hazards and underlying risk factors for cardiovascular adverse events associated with carfilzomib. This study was conducted using Surveillance, Epidemiology, and End Results (SEER)-Medicare data set of multiple myeloma from 2001 to 2015. Data were analyzed for hazards ratio of cardiovascular adverse events between carfilzomib users and nonusers. We identified 7330 patients with multiple myeloma of whom 815 were carfilzomib users. Carfilzomib users had a statistically significant hazard ratio of 1.41 with p < 0.0001 for all cardiovascular adverse events as compared to nonusers. Carfilzomib use was significantly associated with increased risk of heart failure (HR 1.47, p = 0.0002), ischemic heart disease (HR 1.45, p = 0.0002), and hypertension (HR 3.33, p < 0.0001), whereas there was no association between carfilzomib use and cardiac conduction disorders (arrhythmia and heart blocks). Carfilzomib users were at higher risk of new-onset edema (HR 5.09, p < 0.0001), syncope (HR 4.27, p < 0.0001), dyspnea (HR 1.33, p < 0.0001), and chest pain (HR 1.18, p < 0.0001) as compared to carfilzomib nonusers. Age above 75 years, preexisting cardiovascular disease, obesity, and twice a week carfilzomib schedule were significant risk factors associated with cardiovascular adverse events in carfilzomib users. The median time of the onset for all cardiovascular adverse events was 3.1 months. This study has identified a significantly higher likelihood of cardiovascular adverse events in elderly Medicare patients receiving carfilzomib.",
"affiliations": "Division of Hematology and Oncology, Department of Medicine, University of Florida, Gainesville, FL, USA.;Department of Health Services Research, Management and Policy, College of Public Health and Health Professions, University of Florida, Gainesville, FL, USA.;Division of Hematology and Oncology, Department of Medicine, University of Florida, Gainesville, FL, USA.;Department of Health Outcomes and Bioinformatics, College of Medicine, University of Florida, Gainesville, FL, USA.;Division of Hematology/Oncology, Mayo Clinic Alix School of Medicine, Mayo Clinic Florida, Jacksonville, FL, USA.;Bone Marrow Transplant Program, University of Florida Health Cancer Center, Gainesville, FL, USA.;Division of Hematology/Oncology, University of Florida College of Medicine, Gainesville, FL, USA.",
"authors": "Bishnoi|Rohit|R|0000-0001-5976-3510;Xie|Zhigang|Z|;Shah|Chintan|C|;Bian|Jiang|J|;Murthy|Hemant S|HS|;Wingard|John R|JR|;Farhadfar|Nosha|N|0000-0002-2752-9604",
"chemical_list": "D000970:Antineoplastic Agents; D009842:Oligopeptides; D011480:Protease Inhibitors; C524865:carfilzomib",
"country": "United States",
"delete": false,
"doi": "10.1002/cam4.3568",
"fulltext": "\n==== Front\nCancer Med\nCancer Med\n10.1002/(ISSN)2045-7634\nCAM4\nCancer Medicine\n2045-7634 John Wiley and Sons Inc. Hoboken \n\n33169938\n10.1002/cam4.3568\nCAM43568\nOriginal Research\nClinical Cancer Research\nOriginal Research\nReal‐world experience of carfilzomib‐associated cardiovascular adverse events: SEER‐Medicare data set analysis\nBISHNOI et al.Bishnoi Rohit https://orcid.org/0000-0001-5976-3510\n1\nrohit.bishnoi@medicine.ufl.edudocrb29@gmail.com Xie Zhigang \n2\n Shah Chintan \n1\n Bian Jiang \n3\n Murthy Hemant S. \n4\n Wingard John R. \n5\n\n6\n Farhadfar Nosha https://orcid.org/0000-0002-2752-9604\n6\n \n1 \nDivision of Hematology and Oncology\nDepartment of Medicine\nUniversity of Florida\nGainesville\nFL\nUSA\n\n\n2 \nDepartment of Health Services Research, Management and Policy\nCollege of Public Health and Health Professions\nUniversity of Florida\nGainesville\nFL\nUSA\n\n\n3 \nDepartment of Health Outcomes and Bioinformatics\nCollege of Medicine\nUniversity of Florida\nGainesville\nFL\nUSA\n\n\n4 \nDivision of Hematology/Oncology\nMayo Clinic Alix School of Medicine\nMayo Clinic Florida\nJacksonville\nFL\nUSA\n\n\n5 \nBone Marrow Transplant Program\nUniversity of Florida Health Cancer Center\nGainesville\nFL\nUSA\n\n\n6 \nDivision of Hematology/Oncology\nUniversity of Florida College of Medicine\nGainesville\nFL\nUSA\n\n* Correspondence\n\nRohit Bishnoi, Division of Hematology and Oncology, Department of Medicine, University of Florida, PO Box 100278, 1600 SW Archer Rd, Gainesville, FL 32610, USA.\n\nEmail: rohit.bishnoi@medicine.ufl.edu or docrb29@gmail.com\n\n10 11 2020 \n1 2021 \n10 1 10.1002/cam4.v10.170 78\n01 8 2020 23 9 2020 05 10 2020 © 2020 The Authors. Cancer Medicine 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.Abstract\nCarfilzomib was approved for the treatment of multiple myeloma in 2012 and since then there have been concerns for cardiovascular toxicity from its use. With this study, we aim to further study the hazards and underlying risk factors for cardiovascular adverse events associated with carfilzomib. This study was conducted using Surveillance, Epidemiology, and End Results (SEER)‐Medicare data set of multiple myeloma from 2001 to 2015. Data were analyzed for hazards ratio of cardiovascular adverse events between carfilzomib users and nonusers. We identified 7330 patients with multiple myeloma of whom 815 were carfilzomib users. Carfilzomib users had a statistically significant hazard ratio of 1.41 with p < 0.0001 for all cardiovascular adverse events as compared to nonusers. Carfilzomib use was significantly associated with increased risk of heart failure (HR 1.47, p = 0.0002), ischemic heart disease (HR 1.45, p = 0.0002), and hypertension (HR 3.33, p < 0.0001), whereas there was no association between carfilzomib use and cardiac conduction disorders (arrhythmia and heart blocks). Carfilzomib users were at higher risk of new‐onset edema (HR 5.09, p < 0.0001), syncope (HR 4.27, p < 0.0001), dyspnea (HR 1.33, p < 0.0001), and chest pain (HR 1.18, p < 0.0001) as compared to carfilzomib nonusers. Age above 75 years, preexisting cardiovascular disease, obesity, and twice a week carfilzomib schedule were significant risk factors associated with cardiovascular adverse events in carfilzomib users. The median time of the onset for all cardiovascular adverse events was 3.1 months. This study has identified a significantly higher likelihood of cardiovascular adverse events in elderly Medicare patients receiving carfilzomib.\n\nCarfilzomib associated cardiotoxicity has been reported in trials and is a concern with its use. In this study, from SEER‐medicare datasets that represent real‐world scenarios, we identified that the hazard ratio of 1.41 (p < 0.0001) in patients using carfilzomib as compared to non‐users. Carfilzomib use was associated with increased risk of heart failure, ischemic heart disease, and hypertension.\n\n\n\ncardiotoxicitycardiovascular adverse eventscarfilzomibmultiple myelomaproteasome inhibitors source-schema-version-number2.0cover-dateJanuary 2021details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.6 mode:remove_FC converted:24.01.2021Rohit Bishnoi and Zhigang Xie contributed equally to this study.\n==== Body\n1 BACKGROUND\nProteasome inhibitors (PI) comprise an important class of drugs for treating multiple myeloma (MM). Currently, three drugs are approved in this class, bortezomib, carfilzomib, and ixazomib. Carfilzomib is a second‐generation, highly selective and irreversible PI which received accelerated approval by the United States Food and Drug Administration (FDA) in July 2012.\n1\n This approval was based on a phase II study where carfilzomib demonstrated an overall response rate (ORR) of about 23% for relapsed and refractory multiple myeloma (RRMM).\n2\n Since then carfilzomib has been approved for multiple other indications for the treatment of MM. Presently, as per the National Comprehensive Cancer Network (NCCN) guidelines, carfilzomib is recommended for primary therapy of MM in transplant‐eligible as well as transplant‐ineligible patients. In the RRMM, carfilzomib is recommended as a preferred regimen either as a single agent or in combination with other agents.\n\nSince its approval, cardiovascular adverse events (CVAEs) from carfilzomib has been a concern. Initially, carfilzomib associated CVAEs were reported in about 22% patients from the grouped data of four phase II studies in 2013.\n3\n Meta‐analyses of clinical trials have shown that up to 18% of patients experienced CVAEs.\n4\n, \n5\n, \n6\n, \n7\n These studies reported CVAEs with variable rates and the most common CVAEs were hypertension (18.5%) and heart failure (6.7%). Arrhythmia (2.4%) and ischemic events (3.7%) were observed less commonly. Other significant CVAEs were dyspnea (31.9%) and edema (24.7%).\n6\n, \n7\n\n\n\nMultiple studies have tried to identify risk factors for Carfilzomib associated cardiotoxicity. Retrospective studies from single institutions have reported prior cardiac history as a risk factor for carfilzomib associated cardiotoxicity.\n8\n, \n9\n, \n10\n Most of CVAEs have been reported to occur soon after carfilzomib use, rarely beyond 12 cycles and the systolic dysfunction is usually reversible.\n9\n, \n11\n, \n12\n Current evidence is not clear for an association of CVAEs with the dose or the duration of carfilzomib use but re‐challenge with reduced dose has been recommended.\n4\n, \n11\n, \n13\n The prospective observational study by Cornell et al reported that 51% of patients treated with carfilzomib developed CVAEs including heart failure (41%), hypertension (23%), arrhythmia (7%), an acute coronary syndrome in (6%), and also reported chest pain in 9% of patients.\n14\n There was no association between drug dose, infusion time, and concurrent drugs or fluids administered with carfilzomib but elevated natriuretic peptide was associated with increased risk of CVAEs. Similarly, 33% of patients experienced CVAEs in the study by Bruno et al and baseline uncontrolled blood pressure, left ventricular hypertrophy, and higher pulse‐wave velocity were identified as risk factors.\n15\n\n\n\nCardiovascular adverse events remains the drug limiting toxicity of carfilzomib and NCCN also alerts for potential carfilzomib related cardiac and pulmonary toxicity, especially in elderly patients. As the median age for diagnosis of MM is 70 years, nearly two‐thirds of patients have preexisting cardiovascular disease at baseline, hence, at risk of developing carfilzomib associated CVAEs.\n16\n\n\n\nWe have enough scientific evidence about CVAEs from the use of carfilzomib which is mainly obtained through pooled analysis of data from clinical trials. Clinical trials usually exclude patients with preexisting cardiac conditions and the enrolled patients are usually monitored diligently as per clinical trial protocols. Therefore, a clinical trial setting is not the representative of the most commonly encountered scenario in the community clinical practice. This study aims to identify the incidence and risk factors for CVAEs associated with carfilzomib for the treatment of MM using Surveillance Epidemiology and Endpoint Research (SEER)‐Medicare data set, which gives a real‐world experience of carfilzomib.\n\n2 METHODS\nThis study is a retrospective study completed through the SEER‐Medicare data set. The SEER program, supported by the National Cancer Institute (NCI), contains cancer patients’ demographic and tumor characteristics for approximately 34% of the U.S. population. The Medicare data set, maintained by the Centers for Medicare and Medicaid Services, contains health care claims and payment information, for over 97% of the U.S. population aged 65 years or older. We used this linked SEER‐Medicare data set, which captures treatment information after a cancer diagnosis from the Medicare insurance program along with individual patient‐level demographic and survival data from the SEER cancer registry program.\n\n2.1 Study population\nThis study included patients age ≥ 65 years‐old with the diagnosis of MM between 2001 and 2015. To capture the prior history or risk factors for cardiovascular events, only patients who were enrolled in Medicare for at least 1 year before diagnosis were included. Patients were identified using International Classification of Diseases for Oncology, third edition (ICD‐O‐3) codes from the SEER database. We excluded patients with amyloidosis as those patients can have cardiac dysfunction and can be a confounding factor.\n\nICD 9/10 codes were used to identify past medical history and the new cardiovascular diagnosis after treatment with carfilzomib. Basic demographic data were collected for sex, race/ethnicity, Nicotine/tobacco use, obesity, and Charleston comorbidity index (CCI) among others. Various cardiovascular diagnoses including ischemic heart disease, congestive heart failure, conduction disorders (arrhythmia and blocks) were identified using ICD9/10. We also identified hazards of edema, chest pain, dyspnea, and syncope which are reported separately and not included in CVAEs. Treatment details were identified using Healthcare Common Procedure Coding System (HCPCS) and National Drug Code (NDC) drug codes. Data from Medicare claims for linked patients are available for a year after, up to 2016. Details of the diagnostic codes used for study are available as Table S1.\n\nThe primary endpoint of the study was the hazard of the all‐new CVAEs associated with carfilzomib use in the entire study cohort of myeloma patients. The secondary endpoint of the study includes risk factors for CVAEs and hazard of different categories of CVAEs in carfilzomib users. We analyzed the potential risk factors for CVAEs the entire study cohort of myeloma patients and then separately for sub‐group of carfilzomib users. The study focuses mainly on risk factors in carfilzomib users. Impact of carfilzomib use pattern and use of other drugs for treatment of myeloma on were also analyzed. We also calculated the hazard of dyspnea, chest pain, edema, and syncope in carfilzomib users versus nonusers.\n\n2.2 Statistical analysis\nPatients were divided into two cohorts; carfilzomib users and nonusers. Patient‐, disease‐, and treatment‐related factors were compared using the Chi‐square test for categorical and the Kruskal–Wallis test for continuous variables. A Cox proportional‐hazards model was constructed to determine the relationship between CVAEs and carfilzomib therapy and was controlled for various variables including age, sex, race/ethnicity, previous autologous transplant, CCI, preexisting conditions including body mass index (BMI), nicotine/tobacco use, preexisting diabetes, preexisting hypertension, preexisting cardiovascular conditions, and previous anthracycline use. The goodness of fit was assessed using the method of Hosmer and Lemeshow. Within the treatment group, we also used Cox proportional‐hazards models to examine how the preexisting conditions predicted the newly diagnosed CVAEs. Cox models were also adjusted for the aforementioned patients' characteristics. All statistical tests were two‐sided and statistical significance was defined as p < 0.05. Analyses were conducted using SAS version 9.4 software (SAS Institute).\n\n3 RESULTS\n3.1 Patient characteristics\nA total of 7330 patients with multiple myeloma were included in the study; 815 (11.1%) carfilzomib users and 6515 (88.9%) carfilzomib nonusers. Figure 1 shows the flowsheet for the study cohort derivation.\n\nFIGURE 1 Flowsheet detailing cohort derivation from the SEER‐Medicare data set. HCPCS, Healthcare Common Procedure Coding System; HMO, Health Maintenance Organization\n\nBaseline characteristics of the entire cohort including carfilzomib users and nonusers are shown in Table 1. Carfilzomib‐user cohort was younger, white race, had lower CCI compare to nonusers. A higher proportion of carfilzomib users had a history of hypertension or pre‐existing cardiovascular diseases. Furthermore, Carfilzomib use was higher in patients with relapsed myeloma and prior history of stem cell transplant (Table S2). No significant differences were observed between the two groups in terms of sex and pre‐existing history of diabetes. The study model was controlled for these different variables.\n\nTABLE 1 Patient demographics and clinical characteristics of carfilzomib users and non‐users\n\nCharacteristics\tTotal\tCarfilzomib use\t\np‐value\t\nYes\t%\tNo\t%\t\nYear of diagnosis\t\n2001–2012\t4459\t537\t12.0\t3922\t88.0\t0.0001\t\n2013\t1088\t121\t11.1\t967\t88.9\t\n2014\t856\t92\t10.7\t764\t89.3\t\n2015\t927\t65\t7.0\t862\t93.0\t\nAge groups\t\n66–69\t1813\t286\t15.8\t1527\t84.2\t<0.0001\t\n70–74\t2015\t291\t14.4\t1724\t85.6\t\n75–79\t1627\t146\t9.0\t1481\t91.0\t\n80+\t1875\t92\t4.9\t1783\t95.1\t\nSex\t\nMale\t3846\t429\t11.2\t3417\t88.8\t0.9185\t\nFemale\t3484\t386\t11.1\t3098\t88.9\t\nRace/ethnicity\t\nNon‐Hispanic white\t5332\t640\t12.0\t4692\t88.0\t<0.0001\t\nNon‐Hispanic black\t1076\t98\t9.1\t978\t90.9\t\nOther\t400\t29\t7.3\t371\t92.8\t\nHispanic\t522\t48\t9.2\t474\t90.8\t\nMyeloma\t\nNew\t5621\t355\t6.3\t5266\t93.7\t<0.0001\t\nRelapsed\t1709\t460\t26.9\t1249\t73.1\t\nPrevious transplant\t\nNo\t6483\t606\t9.3\t5877\t90.7\t<0.0001\t\nYes\t847\t209\t24.7\t638\t75.3\t\nCharleston comorbidity index\t\n0\t4788\t613\t12.8\t4175\t87.2\t<0.0001\t\n1\t1293\t129\t10.0\t1164\t90.0\t\n2\t631\t41\t6.5\t590\t93.5\t\n3+\t618\t32\t5.2\t586\t94.8\t\nBody mass index\t\nOther\t6775\t693\t10.2\t6082\t89.8\t<0.0001\t\nOverweight\t60\t15\t25.0\t45\t75.0\t\nObesity\t495\t107\t21.6\t388\t78.4\t\nNicotine/tobacco use\t\nNever\t6565\t557\t8.5\t6008\t91.5\t<0.0001\t\nCurrent/former\t765\t258\t33.7\t507\t66.3\t\nPre‐existing diabetes\t\nNo\t4311\t465\t10.8\t3846\t89.2\t0.2795\t\nYes\t3019\t350\t11.6\t2669\t88.4\t\nPre‐existing hypertension\t\nNo\t6682\t584\t8.7\t6098\t91.3\t<0.0001\t\nYes\t648\t231\t35.6\t417\t64.4\t\nPre‐existing cardiovascular conditions\t\nNo\t3452\t302\t8.7\t3150\t91.3\t<0.0001\t\nYes\t3878\t513\t13.2\t3365\t86.8\t\nPrevious anthracycline use\t\nNo\t7177\t755\t10.5\t6422\t89.5\t<0.0001\t\nYes\t153\t60\t39.2\t93\t60.8\t\nJohn Wiley & Sons, Ltd3.2 Risk factors associated with CVAEs in the entire study cohort of myeloma patients, including carfilzomib users and nonusers\nBased on the multivariate analysis, carfilzomib use was independently associated with an increase in the risk of development of CVAEs in the entire study cohort of MM patients. Compared to carfilzomib nonusers, the HR for CVAEs for carfilzomib users was 1.41 (95% CI 1.26–1.58, p < 0.0001). In addition to exposure to carfilzomib, advancing age, male sex, white race, higher CCI, higher BMI, nicotine/tobacco use, preexisting hypertension, and other cardiovascular diagnosis were associated with an increased risk for CVAEs. Pre‐existing diabetes and previous anthracycline use were not associated with higher CVAEs. Please see Table S3 for results of multivariable analysis of the entire study cohort.\n\n3.3 Risk factors associated with CVAEs in sub‐group of carfilzomib users\nBased on the multivariate analysis, age 75–79 years (HR 1.35, p = 0.0394) and above 80 (HR 1.53, p = 0.0118) were associated with a significantly higher risk of CVAEs compared to patients aged 65–69 years. Whereas obesity (HR 1.57, p = 0.0006), pre‐existing hypertension (HR 1.57, p = 0.0006), and preexisting other cardiovascular diagnoses (HR 2.75, p < 0.0001) were also significant risk factors. Patient's sex, race/ethnicity, nicotine/tobacco use, preexisting diabetes, previous anthracycline use, and history of the previous autologous transplant were not associated with higher CVAEs. Please see Figure 2 for details. Among all carfilzomib users, 57.6% (n = 469) were noted to have one or more CVAEs. The median time to onset of these CVAEs was 3.1 months.\n\nFIGURE 2 Adjusted hazard ratios for cardiovascular adverse events in carfilzomib users (n = 815). CI, confidence interval; HR, hazards ratio; NH, non‐Hispanic\n\n3.4 Categories of CVAEs\nThe study cohort was then analyzed for the hazards of various categories of new‐onset CVAEs. Cardiovascular events were categorized into ischemic heart disease, heart failure, conduction disorders (arrhythmia and heart blocks), and hypertension. Carfilzomib use was significantly associated with increased risk of heart failure (HR 1.47, p = 0.0002), ischemic heart disease (HR 1.45, p = 0.0002), and hypertension (HR 3.33, p < 0.0001), whereas there was no association between carfilzomib use and cardiac conduction disorders (arrhythmia and heart blocks). Please see Figure 3 for details.\n\nFIGURE 3 Adjusted hazard ratios of patient using carfilzomib in cardiovascular adverse effects. CI, confidence interval; HR, hazards ratio\n\n3.5 Symptoms\nHazards of certain new‐onset symptoms were also studied in the entire study cohort. Carfilzomib users were at higher risk of new‐onset edema (HR 5.09, p < 0.0001), syncope (HR 4.27, p < 0.0001), dyspnea (HR 1.33, p < 0.0001), and chest pain (HR 1.18, p < 0.0001) as compared to carfilzomib nonusers (Figure 4).\n\nFIGURE 4 Hazards of new‐onset symptoms in carfilzomib users as compared to nonusers. CI, confidence interval; HR, hazards ratio\n\n3.6 Carfilzomib use pattern\nThe SEER‐Medicare data set has limited information about drug doses. We analyzed carfilzomib usage information based on reimbursement patterns. Although, not perfect but this does provide some insight into the pattern of carfilzomib use and associated toxicity. The multivariate logistic regression model was used after controlling various variables as described previously.\n\nThe overall median duration of carfilzomib therapy was 3.6 months and the median number of carfilzomib doses used was 24. The median interval between the two doses was 4.5 days. Patients receiving twice a week carfilzomib were identified as a treatment interval of fewer than 4 days. Carfilzomib was used once a week in 38% of patients while in rest 62% of patients; carfilzomib was used twice a week. Weekly infusion of carfilzomib was associated with a lower risk of cardiovascular toxicity compare to twice‐weekly infusions (HR 0.76, 95% CI: 0.62–0.92, p = 0.0051).\n\nCarfilzomib was used as a single agent in 61% (n = 496) and in combination with other drugs in 39% (n = 319) of patients. When prescribed in combination, carfilzomib was most commonly used with cyclophosphamide in 27.7% (n = 218) followed by daratumumab in 8.3% (n = 68) and Lenalidomide in 2.7% (n = 22). Combination use with Pomalidomide or Thalidomide was minimal. In comparison to single‐agent carfilzomib, combined use with cyclophosphamide, daratumumab, lenalidomide, pomalidomide, or thalidomide was not associated with increased risk for CVAEs.\n\n4 DISCUSSION\nOur study is an extensive review of carfilzomib associated CVAEs using the SEER‐Medicare data set that approximately includes 34% of the U.S. population and represents a commonly encountered patient population as compared to selective patients enrolled through clinical trials. We identified a significantly increased risk of CVAEs with carfilzomib therapy, even after controlling for multiple variables. The incidence of CVAEs (57.6%) was higher as compared to previously reported incidence through pooled analysis but these rates are closer to the prospective study done by Cornell et al to identify the incidence of CVAEs.\n14\n Similar to previous retrospective studies, we found that pre‐existing hypertension and other cardiovascular diagnoses were associated with a higher risk of CVAEs after carfilzomib use. Elderly patients above age 75 years and obesity were at higher risk for CVAEs from carfilzomib use. The majority of MM patients who received carfilzomib had relapsed disease and were likely to have received previous treatments or underwent an autologous transplant. Our study did not find that patients with either relapsed disease or previous autologous transplant had higher CVAEs after carfilzomib use.\n\nAs previously reported in the literature, we also identified highly significant HR for heart failure, ischemic heart disease, and hypertension while there was no association with conduction disorders (arrhythmia and blocks). Conduction disorders have been reported with carfilzomib use, but the literature review was not consistent with this toxicity. Like other studies\n6\n, \n12\n our study also identified that carfilzomib users had significant hazards of new‐onset dyspnea, chest pain, edema, and syncope, as compared to nonusers. Although these symptoms are not specific, we recommend careful monitoring of these symptoms as it might help in the early detection of CVAEs.\n\nOur study did not identify any combination regimens to be associated with a higher risk for CVAEs as compared to the use of carfilzomib alone. Once a week use was associated with lower CVAEs as compared to twice a week use of carfilzomib. A study by Moreau et al reported prolonged progression‐free survival and fewer cardiac failure events with the once weekly schedule as compared to a twice‐weekly schedule.\n17\n Since studies so far have not shown any clear evidence of dose‐dependent cardiovascular toxicity form carfilzomib, this finding suggests that quicker frequency may be related to higher toxicity. Although this finding is significant, we advise caution in clinical interpretation in the absence of exact dosages information, which unfortunately is a known limitation of the SEER‐Medicare data set.\n\nVarious preventative and management strategies have been proposed for carfilzomib‐induced cardiotoxicity by single‐center studies.\n18\n, \n19\n These include baseline cardiac function evaluation, optimizing underlying hypertension and cardiac conditions, careful fluid management, and symptom directed workup while on carfilzomib therapy. Although faster infusion rates of carfilzomib have been reported to be associated with higher CVAEs the prospective observational study by Cornell et al did not find any such association.\n14\n, \n20\n Cautious re‐challenge with a reduced dose of carfilzomib after the resolution of cardiac events has also been recommended. European Myeloma network and the Italian society of arterial hypertension also released a consensus paper with a scoring system based on risk factors and management recommendations for patients using carfilzomib.\n21\n\n\n\nIn summary, with our study results and previous data, we can assertively say that there is enough evidence to strongly associate the significant risk of CVAEs with the use of carfilzomib. As such, there is a need for identifying patients at higher risk, cautious monitoring, prompt identification, and management of carfilzomib associated CVAEs. Patients with pre‐existing cardiovascular conditions should be monitored closely by a multidisciplinary team from cardiology and oncology which is also a recommendation from the International Cardio‐Oncology Society (ICOS).\n22\n This is absolutely necessary until we have a full understanding of all the risk factors, preventative measures, and long‐term toxicity from carfilzomib use.\n\n5 CONCLUSIONS\nThis study from a large SEER‐Medicare data set provides further evidence of carfilzomib‐associated CVAEs and identifies potential risk factors.\n\n5.1 Study limitations\nThis study has an inherent limitation of retrospective design and thus we infer association and not direct causation. Although the SEER database includes data from 19 different geographical areas covering approximately 34% of the U.S. population from diverse demographics and locations it cannot be ascertained that every population group has proper representation. Authors caution that results might be affected by various local risk factors, including access to health care, and should be considered for an individual patient The SEER‐Medicare database does not contain clinical measures of disease severity, information regarding chemotherapy dosage and schedule or management of cardiovascular toxicity. In addition, this study included elderly patients with age ≥ 65 years and prone to reporting bias. Therefore, the results may not be generalizable to younger populations or those not covered by Medicare. We have included nicotine/tobacco use and BMI in analyses based on ICD‐9/10 diagnoses codes from Medicare data. However, the sensitivity of these codes is low. Even considering these limitations, studies from SEER‐Medicare data sets have provided clinically relevant information, which often is not feasible from clinical trials.\n\nCONFLICT OF INTEREST\nThe authors declare that they have no conflict of interest.\n\nETHICS APPROVAL AND CONSENT TO PARTICIPATE\nThe Institution Review Board (IRB) at the University of Florida, Gainesville FL, approved this study and all standard ethical guidelines were followed. A full waiver of informed consent was obtained.\n\nCONSENT TO PUBLICATION\nNot applicable. The manuscript does not contain any individual patients' data.\n\nSupporting information\nTable S1‐S3\n\nClick here for additional data file.\n\n ACKNOWLEDGEMENTS\nNone.\n\nDATA AVAILABILITY STATEMENT\nThe data sets used for the current study are available from SEER‐Medicare. This study used the linked SEER‐Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. The authors acknowledge the efforts of the National Cancer Institute; the Office of Research, Development and Information, CMS; Information Management Services (IMS), Inc.; and the Surveillance, Epidemiology, and End Results (SEER) Program tumor registries in the creation of the SEER‐Medicare database.\n==== Refs\nREFERENCES\n1 \n\nHerndon \nTM \n, \nDeisseroth \nA \n, \nKaminskas \nE \n, et al. U.S. Food and Drug Administration approval: carfilzomib for the treatment of multiple myeloma\n. Clin Cancer Res . 2013 ;19 (17 ):4559 –4563\n.23775332 \n2 \n\nSiegel \nD \n, \nVij \nR \n, \nStewart \nK \n, et al. Results of PX‐171‐003‐A0, part 1 of an open‐label, single‐arm, phase 2 study of carfilzomib in patients with relapsed and refractory multiple myeloma\n. EJC Suppl . 2009 ;7 (2 ):571 .\n3 \n\nSiegel \nD \n, \nMartin \nT \n, \nNooka \nA \n, et al. Integrated safety profile of single‐agent carfilzomib: experience from 526 patients enrolled in 4 phase II clinical studies\n. 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Cardiac complications in relapsed and refractory multiple myeloma patients treated with carfilzomib\n. Blood Cancer J . 2015 ;5 (1 ):e272 .25594159 \n9 \n\nJain \nT \n, \nNarayanasamy \nH \n, \nMikhael \nJ \n, et al. Systolic dysfunction associated with carfilzomib use in patients with multiple myeloma\n. Blood Cancer J . 2017 ;7 (12 ):642 .29234003 \n10 \n\nDimopoulos \nMA \n, \nRoussou \nM \n, \nGavriatopoulou \nM \n, et al. Cardiac and renal complications of carfilzomib in patients with multiple myeloma\n. Blood Adv . 2017 ;1 (7 ):449 –454\n.29296960 \n11 \n\nGrandin \nEW \n, \nKy \nB \n, \nCornell \nRF \n, \nCarver \nJ \n, \nLenihan \nDJ \n. Patterns of cardiac toxicity associated with irreversible proteasome inhibition in the treatment of multiple myeloma\n. J Cardiac Fail . 2015 ;21 (2 ):138 –144\n.\n12 \n\nChari \nA \n, \nHajje \nD \n. Case series discussion of cardiac and vascular events following carfilzomib treatment: possible mechanism, screening, and monitoring\n. BMC Cancer . 2014 ;14 :915 .25471129 \n13 \n\nBringhen \nS \n, \nMilan \nA \n, \nFerri \nC \n, et al. Cardiovascular adverse events in modern myeloma therapy – incidence and risks. A review from the European Myeloma Network (EMN) and Italian Society of Arterial Hypertension (SIIA)\n. Haematologica . 2018 ;103 (9 ):1422 –1432\n.30049825 \n14 \n\nCornell \nRF \n, \nKy \nB \n, \nWeiss \nBM \n, et al. Prospective study of cardiac events during proteasome inhibitor therapy for relapsed multiple myeloma\n. J Clin Oncol . 2019 ;37 (22 ):1946 –1955\n.31188726 \n15 \n\nBruno \nG \n, \nBringhen \nS \n, \nMaffei \nI \n, et al. Cardiovascular organ damage and blood pressure levels predict adverse events in multiple myeloma patients undergoing carfilzomib therapy\n. Cancers . 2019 ;11 (5 ):622 .\n16 \n\nKristin \nD \n, \nKistler \nKR \n, \nFaich \nG \n, \nLanes \nS \n. Cardiac event rates in patients with newly diagnosed and relapsed multiple myeloma in US Clinical Practice\n. Blood . 2012 ;120 (21 ):2916 .\n17 \n\nMoreau \nP \n, \nMateos \nM‐V \n, \nBerenson \nJR \n, et al. Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (A.R.R.O.W.): interim analysis results of a randomised, phase 3 study\n. Lancet Oncol . 2018 ;19 (7 ):953 –964\n.29866475 \n18 \n\nMikhael \nJ \n. Management of carfilzomib‐associated cardiac adverse events\n. Clin Lymphoma Myeloma Leuk . 2016 ;16 (5 ):241 –245\n.26907720 \n19 \n\nLendvai \nN \n, \nTsakos \nI \n, \nDevlin \nSM \n, et al. Predictive biomarkers and practical considerations in the management of carflizomib‐associated cardiotoxity\n. Leuk Lymphoma . 2018 ;59 (8 ):1981 –1985\n.29308691 \n20 \n\nKim \nGY \n, \nAhuja \nT \n, \nPapadopoulos \nJ \n, \nCirrone \nF \n. Cardiotoxicity with carfilzomib at doses greater than 27 mg/m(2): a case series\n. J Oncol Pharm Pract . 2019 ;25 (1 ):229 –233\n.28914153 \n21 \n\nBringhen \nS \n, \nMilan \nA \n, \nD'Agostino \nM \n, et al. Prevention, monitoring and treatment of cardiovascular adverse events in myeloma patients receiving carfilzomib A consensus paper by the European Myeloma Network and the Italian Society of Arterial Hypertension\n. J Intern Med . 2019 ;286 (1 ):63 –74\n.30725503 \n22 \n\nLenihan \nDJ \n, \nFradley \nMG \n, \nDent \nS \n, et al. Proceedings from the global cardio‐oncology summit: the top 10 priorities to actualize for CardioOncology\n. JACC: CardioOncol . 2019 ;1 (2 ):256 –272\n.\n\n",
"fulltext_license": "CC BY",
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"issue": "10(1)",
"journal": "Cancer medicine",
"keywords": "cardiotoxicity; cardiovascular adverse events; carfilzomib; multiple myeloma; proteasome inhibitors",
"medline_ta": "Cancer Med",
"mesh_terms": "D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D066126:Cardiotoxicity; D016208:Databases, Factual; D005260:Female; D006331:Heart Diseases; D006801:Humans; D006973:Hypertension; D015994:Incidence; D008297:Male; D006278:Medicare; D009101:Multiple Myeloma; D009842:Oligopeptides; D011480:Protease Inhibitors; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D018426:SEER Program; D016896:Treatment Outcome; D014481:United States",
"nlm_unique_id": "101595310",
"other_id": null,
"pages": "70-78",
"pmc": null,
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"references": "29234003;29285538;25471129;29991494;29881259;23935022;29296960;31188726;29308691;29465266;30049825;31058856;29866475;25433360;30725503;26907720;25594159;28914153;23775332",
"title": "Real-world experience of carfilzomib-associated cardiovascular adverse events: SEER-Medicare data set analysis.",
"title_normalized": "real world experience of carfilzomib associated cardiovascular adverse events seer medicare data set analysis"
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"companynumb": "US-AMGEN-USASP2020187287",
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"abstract": "Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe, treatable and potentially reversible disorder presenting with memory deficits, psychiatric symptoms and seizures. Initially described in young patients with ovarian teratoma, the disease is meanwhile increasingly recognized also in women without tumors, in men and in children. The presence of anti-glutamate receptor (type NMDA) autoantibodies in serum or cerebrospinal fluid is specific for this novel and widely under-diagnosed disorder. We present a young women presenting with psychotic symptoms, initially treated psychiatrically, but was ultimately discovered to have anti-NMDAR encephalitis. We review this disease state with respect to epidemiology, phenomenology, pathogenesis, and treatment.",
"affiliations": null,
"authors": "Spiegel|David R|DR|;Zaki|Neil|N|",
"chemical_list": "D014150:Antipsychotic Agents; D018967:Risperidone",
"country": "United States",
"delete": false,
"doi": "10.3371/CSRP.SPZA.061213",
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"issue": "9(3)",
"journal": "Clinical schizophrenia & related psychoses",
"keywords": "Anti-N-Methyl-D-Aspartate Receptor Encephalitis; Psychosis; Teratoma",
"medline_ta": "Clin Schizophr Relat Psychoses",
"mesh_terms": "D000328:Adult; D060426:Anti-N-Methyl-D-Aspartate Receptor Encephalitis; D014150:Antipsychotic Agents; D005260:Female; D006801:Humans; D011618:Psychotic Disorders; D018967:Risperidone",
"nlm_unique_id": "101312513",
"other_id": null,
"pages": "135-40",
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"pmid": "23773888",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "A Case of New Onset Psychosis in a Young Woman with Minimal Response to Risperidone, Ultimately Diagnosed with N-Methyl-D-Aspartate Receptor Encephalitis: A Review of this Under-Recognized Condition.",
"title_normalized": "a case of new onset psychosis in a young woman with minimal response to risperidone ultimately diagnosed with n methyl d aspartate receptor encephalitis a review of this under recognized condition"
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"companynumb": "US-JNJFOC-20151016933",
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"abstract": "To investigate the impact of kidney transplantation (KTx) on insulin sensitivity affecting glucose metabolism. 9 nondiabetic patients awaiting living donor KTx were examined prior to transplantation with an oral glucose tolerance test and a 3-h hyperinsulinaemic-euglycaemic clamp. The clamp was repeated 6 months after KTx. Nine age-, gender- and body mass index (BMI)-matched individuals with normal kidney function served as controls. Endogenous glucose production and glucose disappearance rate (N = 6) were measured in a subgroup of patients with corresponding controls. Results presented as mean [range]. Two patients had pretransplant prediabetes, whereas all others had normal glucose tolerance. After KTx, average glucose infusion rate to maintain euglycaemia during clamp declined significantly from 15.1 [9.1-23.7] to 9.8 [2.8-14.6] μmol/kg/min (P < 0.01) with 20.2 [9.9-33.7] μmol/kg/min in controls. Endogenous glucose production increased from 7.0 [4.8-8.5] to 9.4 [7.4-11.8] μmol/kg/min (P < 0.05) with 7.0 [-3.8 to 10.1] μmol/kg/min in controls. Glucose disappearance rate was unchanged (18.1 [12.9-24.5] vs. 17.1 [12.2-22.7] μmol/kg/min, NS) with 22.3 [14.6-34.3] in controls. In conclusion, insulin sensitivity is reduced 6 months after KTx and characterized mainly by impaired suppression of the endogenous glucose production.",
"affiliations": "Department of Nephrology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.;Department of Nephrology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.;Clinical Metabolomics Core Facility, Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.;Department of Nephrology, Odense University Hospital, Odense, Denmark.;Department of Nephrology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.;Department of Endocrinology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.;Department of Nephrology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.",
"authors": "Jørgensen|Morten B|MB|http://orcid.org/0000-0001-9681-3134;Hornum|Mads|M|;van Hall|Gerrit|G|;Bistrup|Claus|C|;Hansen|Jesper M|JM|;Mathiesen|Elisabeth R|ER|;Feldt-Rasmussen|Bo|B|",
"chemical_list": "D001786:Blood Glucose; D007328:Insulin; D005934:Glucagon; D005947:Glucose",
"country": "England",
"delete": false,
"doi": "10.1111/tri.12907",
"fulltext": null,
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"issn_linking": "0934-0874",
"issue": "30(3)",
"journal": "Transplant international : official journal of the European Society for Organ Transplantation",
"keywords": "hyperinsulinaemic-euglycaemic clamp; insulin resistance; kidney transplantation",
"medline_ta": "Transpl Int",
"mesh_terms": "D000328:Adult; D001786:Blood Glucose; D001823:Body Composition; D016022:Case-Control Studies; D005260:Female; D005934:Glucagon; D005947:Glucose; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin; D007333:Insulin Resistance; D016030:Kidney Transplantation; D008066:Lipolysis; D019520:Living Donors; D008297:Male; D008875:Middle Aged; D013997:Time Factors; D055815:Young Adult",
"nlm_unique_id": "8908516",
"other_id": null,
"pages": "295-304",
"pmc": null,
"pmid": "28000288",
"pubdate": "2017-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The impact of kidney transplantation on insulin sensitivity.",
"title_normalized": "the impact of kidney transplantation on insulin sensitivity"
} | [
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"companynumb": "PHHY2017DK022802",
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"occurcountry": "DK",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": "3",
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{
"abstract": "Olmesartan induced enteropathy was first described in 2012. It is a rare adverse effect of this antihypertensive drug. The clinical presentation commonly includes severe chronic diarrhea leading to weight loss and a variable degree of dehydration. Histological findings are most commonly observed in the duodenum and consist of partial or total villous atrophy, increased intraepithelial lymphocytes and inflammation in the lamina propria. Involvement of gastric and colic mucosa has also been described. We report on the case of a 63-year-old man, treated by olmesartan, who presented with severe chronic diarrhea. Biopsies from different levels of the gastrointestinal tract revealed a pandigestive intraepithelial lymphocytosis.",
"affiliations": "Service d'anatomie pathologique, cliniques universitaires Saint-Luc, Tour Franklin -1, 10, avenue Hippocrate, 1200 Bruxelles, Belgique. Electronic address: paulina.henry@jolimont.be.;Service d'anatomie pathologique, cliniques universitaires Saint-Luc, Tour Franklin -1, 10, avenue Hippocrate, 1200 Bruxelles, Belgique.;Service de gastroentérologie, cliniques universitaires Saint-Luc, 10, avenue Hippocrate, 1200 Bruxelles, Belgique.;Service d'anatomie pathologique, cliniques universitaires Saint-Luc, Tour Franklin -1, 10, avenue Hippocrate, 1200 Bruxelles, Belgique.",
"authors": "Henry|Paulina|P|;Dano|Hélène|H|;Piessevaux|Hubert|H|;Jouret-Mourin|Anne|A|",
"chemical_list": "D000959:Antihypertensive Agents; D007093:Imidazoles; D013777:Tetrazoles; C437965:olmesartan",
"country": "France",
"delete": false,
"doi": "10.1016/j.annpat.2018.10.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0242-6498",
"issue": "39(3)",
"journal": "Annales de pathologie",
"keywords": "Atrophie villositaire; Enteropathy; Entéropathie; Hyperlymphocytose intraépithéliale pandigestive; Olmesartan; Panlymphocytosis; Villous atrophy",
"medline_ta": "Ann Pathol",
"mesh_terms": "D000959:Antihypertensive Agents; D002908:Chronic Disease; D003681:Dehydration; D003967:Diarrhea; D005767:Gastrointestinal Diseases; D006801:Humans; D007093:Imidazoles; D007413:Intestinal Mucosa; D008297:Male; D008875:Middle Aged; D035583:Rare Diseases; D013777:Tetrazoles; D015431:Weight Loss",
"nlm_unique_id": "8106337",
"other_id": null,
"pages": "237-240",
"pmc": null,
"pmid": "30712983",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "An unusual case of olmesartan induced enteropathy.",
"title_normalized": "an unusual case of olmesartan induced enteropathy"
} | [
{
"companynumb": null,
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OLMESARTAN MEDOXOMIL"
},
"drugadditional": "1",
"drugadmin... |
{
"abstract": "Checkpoint inhibitors have significantly improved the prognosis of patients with advanced melanoma. These cancer immunotherapy drugs have specific endocrine autoimmune toxicity. We describe a case of an adrenal insufficiency secondary to pembrolizumab, an anti-programmed cell death-1 monoclonal antibody. Moreover, this case of polyendocrinopathy resulting from a pembrolizumab as the adrenal insufficiency occurred after a thyroiditis.\nA 55-year-old female was started on pembrolizumab immunotherapy for a metastatic choroidal melanoma. Five months after initiation, she suffered from thyrotoxicosis. A thyroiditis was diagnosed by iodine-123 thyroid scintigraphy and ultrasonography. Pembrolizumab therapy was maintained. Two weeks later, without any other treatment given, she patient developed hypothyroidism and levothyroxine substitution was started. Pembrolizumab proved to be ineffective and was stopped 9 months after initiation. One month following its discontinuation, the patient was hospitalized in the intensive care unit. Severe hyponatremia (115 mmol/L) associated with hyperkalemia (5.7 mmol/L) led to the early recognition and treatment of an acute adrenal insufficiency. Positive results for adrenal cortex and 21-hydroxylase antibodies were in favor of autoimmune toxicity.\nThis case highlights the diversity of potential endocrine toxicity of checkpoint inhibitors. Because acute adrenal crisis may be associated with substantial morbidity and mortality, physicians must be aware of these rare adverse events to allow an early diagnosis.",
"affiliations": "Department of Endocrinology, Cochin Hospital, Assistance Publique Hôpitaux de Paris, Paris Descartes University, 75014 Paris, France.;Department of Dermatology, Cochin Hospital, Assistance Publique Hôpitaux de Paris, Paris Descartes University, 75014 Paris, France.;Department of Dermatology, Cochin Hospital, Assistance Publique Hôpitaux de Paris, Paris Descartes University, 75014 Paris, France.;Department of Endocrinology, Cochin Hospital, Assistance Publique Hôpitaux de Paris, Paris Descartes University, 75014 Paris, France.;Department of Nuclear Medicine, Cochin Hospital, Assistance Publique Hôpitaux de Paris, Paris Descartes University, 75014 Paris, France.;Department of Endocrinology, Cochin Hospital, Assistance Publique Hôpitaux de Paris, Paris Descartes University, 75014 Paris, France.;Department of Dermatology, Cochin Hospital, Assistance Publique Hôpitaux de Paris, Paris Descartes University, 75014 Paris, France.;Department of Endocrinology, Cochin Hospital, Assistance Publique Hôpitaux de Paris, Paris Descartes University, 75014 Paris, France.",
"authors": "Paepegaey|Anne-Cécile|AC|;Lheure|Coralie|C|;Ratour|Carole|C|;Lethielleux|Gaëlle|G|;Clerc|Jérome|J|;Bertherat|Jérome|J|;Kramkimel|Nora|N|;Groussin|Lionel|L|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1210/js.2017-00170",
"fulltext": "\n==== Front\nJ Endocr SocJ Endocr SocJSJSJournal of the Endocrine Society2472-1972Endocrine Society Washington, DC JS_20170017010.1210/js.2017-00170Case ReportsAdrenalPolyendocrinopathy Resulting From Pembrolizumab in a Patient With a Malignant Melanoma Paepegaey Anne-Cécile 1Lheure Coralie 2Ratour Carole 2Lethielleux Gaëlle 1Clerc Jérome 3Bertherat Jérome 1Kramkimel Nora 2Groussin Lionel 11 Department of Endocrinology, Cochin Hospital, Assistance Publique Hôpitaux de Paris, Paris Descartes University, 75014 Paris, France2 Department of Dermatology, Cochin Hospital, Assistance Publique Hôpitaux de Paris, Paris Descartes University, 75014 Paris, France3 Department of Nuclear Medicine, Cochin Hospital, Assistance Publique Hôpitaux de Paris, Paris Descartes University, 75014 Paris, FranceAddress all correspondence to: Anne-Cécile Paepegaey, MD, Hôpital Cochin, Service des Maladies Endocriniennes et Métaboliques, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France. E-mail: paepegaeyanc@yahoo.fr.01 6 2017 28 4 2017 28 4 2017 1 6 646 649 28 3 2017 25 4 2017 Copyright © 2017 Endocrine SocietyThis article has been published under the terms of the Creative Commons Attribution Non-Commercial, No-Derivatives License (CC BY-NC-ND; https://creativecommons.org/licenses/by-nc-nd/4.0/).Introduction:\nCheckpoint inhibitors have significantly improved the prognosis of patients with advanced melanoma. These cancer immunotherapy drugs have specific endocrine autoimmune toxicity. We describe a case of an adrenal insufficiency secondary to pembrolizumab, an anti-programmed cell death-1 monoclonal antibody. Moreover, this case of polyendocrinopathy resulting from a pembrolizumab as the adrenal insufficiency occurred after a thyroiditis.\n\nParticipant:\nA 55-year-old female was started on pembrolizumab immunotherapy for a metastatic choroidal melanoma. Five months after initiation, she suffered from thyrotoxicosis. A thyroiditis was diagnosed by iodine-123 thyroid scintigraphy and ultrasonography. Pembrolizumab therapy was maintained. Two weeks later, without any other treatment given, she patient developed hypothyroidism and levothyroxine substitution was started. Pembrolizumab proved to be ineffective and was stopped 9 months after initiation. One month following its discontinuation, the patient was hospitalized in the intensive care unit. Severe hyponatremia (115 mmol/L) associated with hyperkalemia (5.7 mmol/L) led to the early recognition and treatment of an acute adrenal insufficiency. Positive results for adrenal cortex and 21-hydroxylase antibodies were in favor of autoimmune toxicity.\n\nConclusion:\nThis case highlights the diversity of potential endocrine toxicity of checkpoint inhibitors. Because acute adrenal crisis may be associated with substantial morbidity and mortality, physicians must be aware of these rare adverse events to allow an early diagnosis.\n\nWe present a case of adrenal insufficiency secondary to pembrolizumab and of polyendocrinopathy secondary to pembrolizumab.\n\npembrolizumabpolyendocrinopathycheckpoint inhibitorsadrenal insufficiencythyroiditis\n==== Body\nCheckpoint inhibitors have transformed the prognosis for patients with advanced melanoma [1]. These immunomodulators restore the activity of cytotoxic T lymphocytes inhibited by cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) as well as programmed cell death protein 1 (PD-1) receptor and its ligands, PD-L1 and PD-L2. They are divided into two categories of agents: CTLA-4 inhibitors (ipilimumab and tremelimumab) and PD-1 inhibitors (nivolumab and pembrolizumab) [2]. Their mechanism of action induces specific autoimmune toxicity. These immune-related adverse events are mainly gastrointestinal, hepatic, dermatologic, and endocrinologic. The exact risk and mechanism of these side effects remain incompletely understood. Ipilimumab is often responsible for pituitary dysfunction, affecting up to 18% of patients in a phase 3 study [3], whereas nivolumab and pembrolizumab are more often providers of thyroid dysfunction. Hypothyroidism occurs in 1.6% to 8.9% of patients on checkpoint inhibitors and hyperthyroidism occurs in 0.4% to 3.5% of patients [4]. Another more rarely described endocrine adverse effect is adrenal insufficiency. Few cases of CTLA-4 inhibitor-induced adrenal insufficiency have been described in phase 2 and 3 studies [5]. PD-1 inhibitor-induced adrenal insufficiency seems rather rare, but a case of nivolumab-induced primary adrenal failure has recently been described in the literature [6]. Here, we describe a case of polyendocrinopathy resulting from pembrolizumab: a thyroiditis followed by a primary adrenal insufficiency.\n\n1. Case report\nA 55-year-old female was started on pembrolizumab immunotherapy for a metastatic choroidal melanoma for which she had already undergone surgery, two different chemotherapy regimens (dacarbazine and fotemustine), and a targeted therapy with a multikinase inhibitor (sorafenib). Before starting pembrolizumab, thyroid function was normal: thyroid-stimulating hormone (TSH) plasma level of 1.8 mIU/L (normal range, 0.4 to 4.0), free thyroxine plasma level of 13.4 pmol/L (normal range, 11.5 to 22.7), and free triiodothyronine plasma level of 4.9 pmol/L (normal range, 3.5 to 6.5). A normal value for serum cortisol (491 nmol/L) was observed in the morning (normal range, 276 to 552).\n\nFour months after starting pembrolizumab, she suffered from palpitations and weight loss. Laboratory data showed a low TSH level of 0.01 mIU/L, an elevated free thyroxine level of 91.8 pmol/L, and an elevated triiodothyronine level of 27.2 pmol/L. Antithyroperoxidase, antithyroglobulin, and TSH receptor antibodies were negative. Thyroiditis was diagnosed based on the absence of iodine-123 uptake on thyroid scan. Thyroid ultrasonography showed a heterogeneous and hypoechoic gland (Fig. 1). Two weeks later, without any treatment added, primary hypothyroidism was observed. Levothyroxine was initiated. Pembrolizumab proved to be inefficient after 10 courses at a dose of 2 mg/kg every 3 weeks and was stopped.\n\nFigure 1. Polyendocrinopathy secondary to pembrolizumab. The dark arrow represents the time in months since the introduction of pembrolizumab. The vertical red arrows represent pembrolizumab injections at a dose of 2 mg/kg. The first CT scan shows the adrenal glands at the time of diagnosis of adrenal insufficiency. The second CT scan shows the adrenal glands 2 months later. I123, iodine-123.\n\nOne month after pembrolizumab discontinuation, the patient was hospitalized in the intensive care unit for general physical health deterioration, hypotension at 86/65 mm Hg, hypothermia, and hypoglycemia at 3.6 mmol/L. A blood test showed a severe hyponatremia at 115 mmol/L associated with hyperkaliemia at 5.7 mmol/L and acute renal failure. Acute adrenal crisis was suspected. Treatment with intravenous hydrocortisone was initiated, and the patient rapidly improved. The diagnosis was confirmed by measurement of an undetectable serum cortisol (<14 nmol/L) unresponsive to the Synacthen test (stimulated cortisol remained undetectable at <14 nmol/L). Adrenocorticotropic hormone level was elevated at 88 pmol/L (normal, <13). Other pituitary axes were tested and were normal with prolactin level at 288.8 mIU/L (normal range, 38 to 430), luteinizing hormone at 32.6 UI/L (normal range for menopause, 16 to 54), follicle-stimulating hormone at 56.9 UI/L (normal range for menopause, 23 to 116), and TSH level at 1.7 mIU/L (normal range, 0.4-4.0) under levothyroxine treatment. A growth hormone deficiency was not ruled out by dynamic testing, but growth hormone at 12.6 mIU/L (normal range, 0.26 to 15.0) and insulin-like growth factor-1 at 65 ng/mL (normal range, 65 to 240) were within the normal range. Aldosterone levels were undetectable. Renin level, after a high dose of glucocorticoid replacement, was at 23 µUI/mL (normal range, 9 to 72). Fludrocortisone was then added to hydrocortisone.\n\nTo rule out adrenal metastasis, an abdominal computed tomography (CT) scan was undertaken, but no increase in the adrenal gland size was found. The 21-hydroxylase and adrenal cortex antibodies had a positive titer of 1.9 UI/L (normal, <1) and 20 (normal, <0), respectively, which led us to the diagnosis of autoimmune adrenalitis. One month later, 21-hydroxylase antibodies were negative, adrenal cortex antibodies remained positive at 5 (normal, <0), and renin level was elevated at 148 µUI/mL (normal range, 9 to 72), which led us to increase the doses of fludrocortisone. Two months later, CT scan was performed and showed atrophied adrenal glands (Fig. 1).\n\n2. Discussion\nHere we report the case of a primary adrenal failure secondary to pembrolizumab. We also report a polyendocrinopathy resulting from pembrolizumab; a transient hyperthyroidism resulting from thyroiditis was followed by this adrenal insufficiency. Establishing the cause of adrenal insufficiency can sometimes be a challenge [7]. In our case, the first step was to distinguish between secondary and primary adrenal insufficiency because there are more cases of hypophysitis than adrenal insufficiency resulting from use of checkpoint inhibitors [4]. Hyperkalemia led us to suspect a primary cause. This hypothesis was confirmed by high adrenocorticotropic hormone levels. The second step was to determine the cause of this primary adrenal insufficiency. Positive antiadrenal antibodies confirmed the autoimmune etiology [7]. The subsequent disappearance of the antibodies may be related to the atrophy of the adrenal cortex observed 2 months later on the CT scan. In the few other cases of primary adrenal insufficiency secondary to immunomodulators described in the literature, anti-21 hydroxylase antibodies and adrenal cortex antibodies were not measured [6, 8, 9]. Thirteen cases have been described secondary to ipilimumab: 11 cases in phase 3 studies and 2 case reports [8, 9]. Four cases have been described secondary to the use of tremelimumab in a phase 3 study [5] and one case was reported with nivolumab [6].\n\nPembrolizumab has been evaluated in 917 melanoma patients included in phase 2 (n = 316) or 3 (n = 556) trials; no case of adrenal insufficiency has been described [1]. As a consequence, we can assume that it is a very rare adverse effect of pembrolizumab or that it is underdiagnosed. However, the subsequent morbidity and mortality resulting from acute adrenal crisis require patients and physicians to be informed of this particular risk.\n\nAnother interesting aspect of this case is the progression of thyroid dysfunction and adrenal insufficiency. Thyroid ultrasonography and iodine-123 thyroid scintigraphy, used when the patient was hyperthyroid, are in favor of inflammatory thyroiditis. This mechanism has already been suggested in an article that described pembrolizumab-induced thyroid dysfunction. Indeed, in this article, thyrotoxicosis was associated with a diffuse increased 18F-fluorodeoxyglucose (FDG) uptake by the thyroid gland, which suggested an inflammatory thyroiditis [10]. In the case report of nivolumab-induced primary adrenal failure, FDG positron emission tomography scan showed uniformly increased FDG activity in both adrenal glands [6]. This suggests a common mechanism of destruction between the two endocrine adverse events.\n\nAnother interesting point is that adrenal failure appeared a month after the last injection of pembrolizumab, which suggests that there can be a persistent effect and that endocrine adverse events must be sought even after discontinuation of treatment. These checkpoint inhibitors have specific immune-related adverse effects. It seems difficult to predict which patients are at risk for endocrine toxicity. But, because our patient had thyroiditis before adrenal insufficiency, it seems important to monitor carefully patients who already had an endocrine adverse event.\n\nIn conclusion, the mechanisms and risk factors predisposing to endocrine toxicity secondary to checkpoint inhibitors are still unclear. Because of increased use of checkpoint inhibitors, these endocrine immune-related adverse events are going to increase. Physicians must be aware of this endocrine toxicity to avoid morbidity and mortality in these fragile patients.\n\nAbbreviations: CTcomputed tomography\n\nCTLA-4cytotoxic T lymphocyte–associated antigen 4\n\nFDGfluorodeoxyglucose\n\nPD-1programmed cell death-1\n\nTSHthyroid-stimulating hormone.\n\n\n\nAcknowledgments\nDisclosure Summary: The authors have nothing to disclose.\n==== Refs\nReferences and Notes\n1. Robert C , Schachter J , Long GV , Arance A , Grob JJ , Mortier L , Daud A , Carlino MS , McNeil C , Lotem M , Larkin J , Lorigan P , Neyns B , Blank CU , Hamid O , Mateus C , Shapira-Frommer R , Kosh M , Zhou H , Ibrahim N , Ebbinghaus S , Ribas A ; KEYNOTE-006 investigators \nPembrolizumab versus ipilimumab in advanced melanoma . N Engl J Med . 2015 ;372 (26 ):2521 –2532 .25891173 \n2. Momtaz P , Postow MA \nImmunologic checkpoints in cancer therapy: focus on the programmed death-1 (PD-1) receptor pathway . Pharm Genomics Pers Med . 2014 ;7 :357 –365 .\n3. Eggermont AMM , Chiarion-Sileni V , Grob J-J , Dummer R , Wolchok JD , Schmidt H , Hamid O , Robert C , Ascierto PA , Richards JM , Lebbé C , Ferraresi V , Smylie M , Weber JS , Maio M , Konto C , Hoos A , de Pril V , Gurunath RK , de Schaetzen G , Suciu S , Testori A \nAdjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial . Lancet Oncol . 2015 ;16 (5 ):522 –530 .25840693 \n4. Abdel-Rahman O , ElHalawani H , Fouad M \nRisk of endocrine complications in cancer patients treated with immune check point inhibitors: a meta-analysis . Future Oncol . 2016 ;12 (3 ):413 –425 .26775673 \n5. Ribas A , Kefford R , Marshall MA , Punt CJA , Haanen JB , Marmol M , Garbe C , Gogas H , Schachter J , Linette G , Lorigan P , Kendra KL , Maio M , Trefzer U , Smylie M , McArthur GA , Dreno B , Nathan PD , Mackiewicz J , Kirkwood JM , Gomez-Navarro J , Huang B , Pavlov D , Hauschild A \nPhase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma . J Clin Oncol . 2013 ;31 (5 ):616 –622 .23295794 \n6. Trainer H , Hulse P , Higham CE , Trainer P , Lorigan P \nHyponatraemia secondary to nivolumab-induced primary adrenal failure . Endocrinol Diabetes Metab Case Rep . 2016 ;2016. doi:10.1530/EDM-16-0108 \n7. Bancos I , Hahner S , Tomlinson J , Arlt W \nDiagnosis and management of adrenal insufficiency . Lancet Diabetes Endocrinol . 2015 ;3 (3 ):216 –226 .25098712 \n8. Bacanovic S , Burger IA , Stolzmann P , Hafner J , Huellner MW \nIpilimumab-iduced adrenalitis: a possible pitfall in 18F-FDG-PET/CT . Clin Nucl Med . 2015 ;40 (11 ):e518 –e519 .26164177 \n9. Min L , Ibrahim N \nIpilimumab-induced autoimmune adrenalitis . Lancet Diabetes Endocrinol . 2013 ;1 (3 ):e15 .24622375 \n10. de Filette J , Jansen Y , Schreuer M , Everaert H , Velkeniers B , Neyns B , Bravenboer B \nIncidence of thyroid-related adverse events in melanoma patients treated with pembrolizumab . J Clin Endocrinol Metab . 2016 ;101 (11 ):4431 –4439 .27571185\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2472-1972",
"issue": "1(6)",
"journal": "Journal of the Endocrine Society",
"keywords": "adrenal insufficiency; checkpoint inhibitors; pembrolizumab; polyendocrinopathy; thyroiditis",
"medline_ta": "J Endocr Soc",
"mesh_terms": null,
"nlm_unique_id": "101697997",
"other_id": null,
"pages": "646-649",
"pmc": null,
"pmid": "29264517",
"pubdate": "2017-06-01",
"publication_types": "D002363:Case Reports",
"references": "26164177;25484597;25891173;25098712;26775673;25840693;27571185;24622375;23295794;27857838",
"title": "Polyendocrinopathy Resulting From Pembrolizumab in a Patient With a Malignant Melanoma.",
"title_normalized": "polyendocrinopathy resulting from pembrolizumab in a patient with a malignant melanoma"
} | [
{
"companynumb": "FR-009507513-1810FRA011896",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "X-linked severe combined immunodeficiency (X-SCID), caused by defects in the common gamma chain, is typically characterized by T and NK cell defects with the presence of B cells. T cell dysfunction and impaired class-switch recombination of B cells mean that patients typically have defects in class-switched immunoglobulins (IgG, IgA, and IgE) with detectable IgM. Here, we describe two patients with X-SCID with IgG1 gammopathy, in whom we identified maternal T and B cell engraftment. Exclusively, maternal B cells were found among the IgD-CD27+ class-switched memory B cells, whereas the patients' B cells remained naïve. In vitro stimulation with CD40L+IL-21 revealed that peripheral blood cells from both patients produced only IgG1. Class-switched maternal B cells had restricted receptor repertoires with various constant regions and few somatic hypermutations. In conclusion, engrafted maternal B cells underwent class-switch recombination and produced immunoglobulin, causing hypergammaglobulinemia in patients with X-SCID.",
"affiliations": "Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.;Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.;Laboratory of Diagnostic Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.;Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.;Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.;Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.;Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.;Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.;Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.;Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.;Department of Community Pediatrics, Perinatal and Maternal Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.;Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.;Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.;Department of Community Pediatrics, Perinatal and Maternal Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan. Electronic address: kimai.ped@tmd.ac.jp.;Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan. Electronic address: hkanegane.ped@tmd.ac.jp.;Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.",
"authors": "Okano|Tsubasa|T|;Nishikawa|Takuro|T|;Watanabe|Eri|E|;Watanabe|Takashi|T|;Takashima|Takehiro|T|;Yeh|Tzu-Wen|TW|;Yamashita|Motoi|M|;Tanaka-Kubota|Mari|M|;Miyamoto|Satoshi|S|;Mitsuiki|Noriko|N|;Takagi|Masatoshi|M|;Kawano|Yoshifumi|Y|;Mochizuki|Yoshiki|Y|;Imai|Kohsuke|K|;Kanegane|Hirokazu|H|;Morio|Tomohiro|T|",
"chemical_list": "D002352:Carrier Proteins; D007074:Immunoglobulin G; D053631:Interleukin Receptor Common gamma Subunit; C029702:prolactin-binding protein",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clim.2017.08.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1521-6616",
"issue": "183()",
"journal": "Clinical immunology (Orlando, Fla.)",
"keywords": "Allotype; Gammopathy; Germinal center; Hypergammaglobulinemia; IL2RG; Maternal engraftment; Memory B cell; Multiple myeloma; Somatic hypermutation; X-linked severe combined immunodeficiency",
"medline_ta": "Clin Immunol",
"mesh_terms": "D001402:B-Lymphocytes; D002352:Carrier Proteins; D005434:Flow Cytometry; D006801:Humans; D017578:Immunoglobulin Class Switching; D007074:Immunoglobulin G; D016130:Immunophenotyping; D066298:In Vitro Techniques; D007223:Infant; D007231:Infant, Newborn; D053631:Interleukin Receptor Common gamma Subunit; D008297:Male; D010265:Paraproteinemias; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes; D053632:X-Linked Combined Immunodeficiency Diseases",
"nlm_unique_id": "100883537",
"other_id": null,
"pages": "112-120",
"pmc": null,
"pmid": "28780374",
"pubdate": "2017-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Maternal T and B cell engraftment in two cases of X-linked severe combined immunodeficiency with IgG1 gammopathy.",
"title_normalized": "maternal t and b cell engraftment in two cases of x linked severe combined immunodeficiency with igg1 gammopathy"
} | [
{
"companynumb": "JP-OTSUKA-2017_019111",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUDARABINE PHOSPHATE"
},
"drugadditional": null... |
{
"abstract": "We present a case of severe rigidity during emergence from general anaesthesia in a 64-year-old man who had suffered from Parkinson's disease for nine years. Controversy still exists over how to optimally manage these patients perioperatively. We successfully managed his Parkinsonism with administration of crushed Sinemet\" and amantadine via a nasogastric tube. This case report serves as a reminder of the importance that patients receive their anti-Parkinsonian medications perioperatively, and highlights the potential benefits of inserting a gastric tube to continue anti-Parkinson's medication dosing during prolonged surgery.",
"affiliations": "Department of Anaesthesia, Gold Coast Hospital, Robina Campus, Gold Coast, Queensland, Australia. Philip.stagg@gmail.com",
"authors": "Stagg|P|P|;Grice|T|T|",
"chemical_list": "D000978:Antiparkinson Agents; D004338:Drug Combinations; C009265:carbidopa, levodopa drug combination; D007980:Levodopa; D000547:Amantadine; D002230:Carbidopa",
"country": "United States",
"delete": false,
"doi": "10.1177/0310057X1103900623",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0310-057X",
"issue": "39(6)",
"journal": "Anaesthesia and intensive care",
"keywords": null,
"medline_ta": "Anaesth Intensive Care",
"mesh_terms": "D000547:Amantadine; D000758:Anesthesia; D000762:Anesthesia Recovery Period; D000768:Anesthesia, General; D000978:Antiparkinson Agents; D002230:Carbidopa; D004338:Drug Combinations; D005593:Fracture Fixation, Internal; D050723:Fractures, Bone; D006801:Humans; D006811:Humerus; D058926:Intraoperative Awareness; D007441:Intubation, Gastrointestinal; D007980:Levodopa; D008297:Male; D008875:Middle Aged; D009127:Muscle Rigidity; D010300:Parkinson Disease; D019990:Perioperative Care",
"nlm_unique_id": "0342017",
"other_id": null,
"pages": "1128-30",
"pmc": null,
"pmid": "22165370",
"pubdate": "2011-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Nasogastric medication for perioperative Parkinson's rigidity during anaesthesia emergence.",
"title_normalized": "nasogastric medication for perioperative parkinson s rigidity during anaesthesia emergence"
} | [
{
"companynumb": "AU-MYLANLABS-2021M1030575",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PROPOFOL"
},
"drugadditional": null,
... |
{
"abstract": "Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne infectious disease caused by the SFTS virus (SFTSV). Clinical symptoms of SFTS often involve encephalopathy and other central neurological symptoms, particularly in seriously ill patients; however, pathogenesis of encephalopathy by SFTSV is largely unknown. Herein, we present case reports of three patients with SFTS, complicated by encephalopathy, admitted to Tokushima University hospital: one patient was a 63-year-old man, while the other two were 83- and 86-year-old women. All of them developed disturbance of consciousness around the 7th day post onset of fever. After methylprednisolone pulse therapy of 500 mg/day, all of them recovered without any neurological sequelae. SFTSV genome was not detected in the cerebrospinal fluid of 2 out of the 3 patients that were available for examination. In these patients, disturbance of consciousness seemed to be an indirect effect of the cytokine storm triggered by SFTSV infection. We propose that short-term glucocorticoid therapy might be beneficial in the treatment of encephalopathy during early phase of SFTSV infection.",
"affiliations": "Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan. Electronic address: shingen@tokushima-u.ac.jp.;Division of Infection Control, Tokushima University Hospital, Tokushima, Japan.;Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.;Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.;Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.;Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.;Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.;Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.;Division of Transfusion Medicine and Cell Therapy, Tokushima University Hospital, Tokushima, Japan.;Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.;National Health Insurance Katsuura Hospital, Tokushima, Japan.;National Health Insurance Katsuura Hospital, Tokushima, Japan.;Mahara Institute of Medical Acarology, Anan, Tokushima, Japan.;Mahara Hospital, Anan, Tokushima, Japan.;Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.",
"authors": "Nakamura|Shingen|S|;Azuma|Momoyo|M|;Maruhashi|Tomoko|T|;Sogabe|Kimiko|K|;Sumitani|Ryohei|R|;Uemura|Munenori|M|;Iwasa|Masami|M|;Fujii|Shiro|S|;Miki|Hirokazu|H|;Kagawa|Kumiko|K|;Hiraga|Takashi|T|;Kondo|Noriyasu|N|;Fujita|Hiromi|H|;Mahara|Fumihiko|F|;Abe|Masahiro|M|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D008775:Methylprednisolone",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jiac.2017.11.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-321X",
"issue": "24(5)",
"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": "Encephalopathy; Severe fever with thrombocytopenia syndrome; Steroid pulse therapy",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D000369:Aged, 80 and over; D000893:Anti-Inflammatory Agents; D001927:Brain Diseases; D002044:Bunyaviridae Infections; D005260:Female; D005334:Fever; D006785:Hospitals, University; D006801:Humans; D008297:Male; D008775:Methylprednisolone; D008875:Middle Aged; D016856:Phlebovirus; D020551:Pulse Therapy, Drug; D013577:Syndrome; D013921:Thrombocytopenia; D017282:Tick-Borne Diseases",
"nlm_unique_id": "9608375",
"other_id": null,
"pages": "389-392",
"pmc": null,
"pmid": "29428565",
"pubdate": "2018-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Steroid pulse therapy in patients with encephalopathy associated with severe fever with thrombocytopenia syndrome.",
"title_normalized": "steroid pulse therapy in patients with encephalopathy associated with severe fever with thrombocytopenia syndrome"
} | [
{
"companynumb": "PHHY2018JP075912",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "1",
... |
{
"abstract": "Originally developed for the treatment of epilepsy, pregabalin has become a compound with a wide spectrum of indications comprising anxiety disorders and chronic pain and is therefore largely prescribed. Thus, it is important for clinicians to be aware of rare, but serious adverse effects. The following report illustrates the case of a 20-year-old male with a severe depressive syndrome following pregabalin medication which even led to a suicide attempt.",
"affiliations": "Department of Psychiatry and Psychotherapy, Friedrich-Alexander University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany.;Department of Neurology, Friedrich-Alexander University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany.;Department of Psychiatry and Psychotherapy, Friedrich-Alexander University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany.;Department of Psychiatry and Psychotherapy, Friedrich-Alexander University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany.;Department of Psychiatry and Psychotherapy, Friedrich-Alexander University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany.",
"authors": "Kustermann|Andreas|A|;Möbius|Cornelia|C|;Oberstein|Timo|T|;Müller|Helge H|HH|;Kornhuber|Johannes|J|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12991-014-0037-8",
"fulltext": "\n==== Front\nAnn Gen PsychiatryAnn Gen PsychiatryAnnals of General Psychiatry1744-859XBioMed Central London 254893343710.1186/s12991-014-0037-8Case ReportDepression and attempted suicide under pregabalin therapy Kustermann Andreas andreas.kustermann@uk-erlangen.de Möbius Cornelia cornelia.moebius@uk-erlangen.de Oberstein Timo timo.oberstein@uk-erlangen.de Müller Helge H helge.mueller@uk-erlangen.de Kornhuber Johannes johannes.kornhuber@uk-erlangen.de Department of Psychiatry and Psychotherapy, Friedrich-Alexander University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany Department of Neurology, Friedrich-Alexander University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany 4 12 2014 4 12 2014 2014 13 3711 8 2014 18 11 2014 © Kustermann 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.Originally developed for the treatment of epilepsy, pregabalin has become a compound with a wide spectrum of indications comprising anxiety disorders and chronic pain and is therefore largely prescribed. Thus, it is important for clinicians to be aware of rare, but serious adverse effects. The following report illustrates the case of a 20-year-old male with a severe depressive syndrome following pregabalin medication which even led to a suicide attempt.\n\nKeywords\nDepressionAnticonvulsantsSuicidePregabalinissue-copyright-statement© The Author(s) 2014\n==== Body\nBackground\nPregabalin is a compound originally developed for treating epilepsy. Meanwhile, it has shown positive effects on neuropathic pain as well as on general anxiety disorder and is therefore largely prescribed by neurologists, psychiatrists and, of course, general practitioners. Apart from the most common side effects such as—among others—drowsiness, increased appetite, and headache, also depressive mood disorders must be kept in mind as side effects of pregabalin and various other antiepileptic drugs. An FDA warning concerning self-harm in patients taking antiepileptic drugs was released in 2008 [1], yet a relevant risk for pregabalin is postulated to be less than 1% [2] (low-risk group of antiepileptic compounds concerning mood disorders). An observational study [2] did not find a significant increase in self-harm within the group of those low-risk compounds; however, a review of the literature indicated that suicidal ideations under pregabalin have recently been reported in one case [3] under a daily dose of 600 mg pregabalin. The following case is startling inasmuch as the patient did not only experience suicidal ideations but did attempt suicide while being prescribed pregabalin.\n\nCase presentation\nThe patient we present is a 20-year-old male admitted to our psychiatric ward in February who reported depressed mood, loss of motivation, hopelessness, anxiety, sleep disturbances, and suicidal thoughts as major depressive symptoms.\n\nRecent brain imaging, as well as routine laboratory analysis upon admission, was unremarkable.\n\nIt was the patient’s first episode of a psychiatric disorder. It originally started with somatic symptoms and their treatment. He suffered from an orofacial dyskinesia of unknown origin, muscular atrophy of the right forearm, and an alar scapula on the left, currently diagnosed as multifocal motoric neuropathia. The orofacial dyskinesia was first treated symptomatically with tiapride starting in July the year before admission, which he tolerated well. Later, the movements were thought to be complex-focal seizures, the medication was switched to pregabalin, 150 mg daily within 2 weeks during his stay in an external clinic in October. The patient reported no further co-medication at that time.\n\nStarting with the first prescription of pregabalin in October, the patient felt increasingly depressed (visual analogue scale 4/10–5/10) and demotivated. Suicidal thoughts first appeared in November. These continued to worsen and led to a suicide attempt in December of the year before admission; he tried to poison himself to death using high doses of ibuprofen and aspirin after consuming alcohol. He could not name any triggering factors and described the incident as a completely unexpected and irrational act. He was seen by his general practitioner and taken care of by his family. He did not receive further inpatient treatment then but was prescribed antidepressants for the emerging mood disorder starting with the sedating mirtazapine 15 mg at night in order to prevent further harmful acts on impulse. Later, the serotonergic drug citalopram was added in order to address the lack of motivation, starting with 10 mg and rising to 20 mg in the morning. Tiapride was also restarted for controlling the dyskinesia.\n\nAfter the patient retrospectively clearly correlated the start of pregabalin therapy with the onset of his depressive symptoms during exploration on our ward, we immediately discontinued the drug. Consequently, he reported a rapid decline in depressive symptoms, his mood remained stable, and he was discharged. Until then, pregabalin was not believed to trigger the patient’s symptoms, and his somatic problems were the focus of investigation and treatment. Thus, there are unfortunately no objective follow-up scales available but only symptom descriptions. His alcohol intake preceding the suicide attempt may be considered a confounding factor. However, casual drinking before taking the drug never caused suicidal thoughts prior to this episode. The depressive symptoms themselves began only when the drug was started; thus, alcohol might have had an aggravating effect.\n\nConclusions\nFor the clinician, the case illustrates that not only suicidal ideations—a known but rare adverse effect of pregabalin—but also suicidal actions under pregabalin therapy have to be kept in mind. The issue that alcohol can reduce one’s inhibitions to actually carry out suicidal ideations should be separately addressed in the dialogue with the patient and the combination with pregabalin should strictly be advised against.\n\nFor theoretical considerations, it is quite surprising that a compound relieving a patient from his anxious distress sometimes does not improve mood and activity but, on the contrary, causes severe depression and self-harm tendencies. Taking into account that certain antiepileptic drugs have been shown to be protective for patients with bipolar disorder concerning suicidality [4], but hazardous for patients with monopolar depression, for example [5], there may be critical patient variables also for pregabalin which remain to be elucidated.\n\nIn the current case, pregabalin has been increased to the daily dose of 150 mg within 2 weeks. In order to prevent more common side effects of the compound such as drowsiness or headache, a low starting dose which is then gently increased often turns out to be helpful. Maybe the initial dosing regimen also plays a role with the depressive side effects.\n\nConcerning the pharmacodynamic side of the mood effects of antiepileptic drugs, serotonergic pathways are discussed [6]. Regarding analgesic efficacy of pregabalin, it has been shown to depend on the descending serotonergic system with spinal 5HT3 receptors [7], so serotonergic effects may also play a role for pregabalin-induced mood alterations.\n\nConsent\nWe thank the patient for providing his written consent to publish this case report.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nAK made substantial contributions to conception and design of the case report and drafted the manuscript. CM and TO contributed to the clinical and rating evaluations of the patient as well as to the revision of the manuscript. HM and JK provided intellectual input and participated in the execution and coordination of the study. All authors read and approved the final manuscript.\n\nAcknowledgements\nWe acknowledge the support by Deutsche Forschungsgemeinschaft and Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) within the funding program Open Access Publishing.\n==== Refs\nReferences\n1. US Food and Drug Administration Antiepileptic drugs and suicidality ᅟ ᅟ \n2. Andersohn F Schade R Willich SN Garbe E Use of antiepileptic drugs in epilepsy and the risk of self-harm or suicidal behavior Neurology 2010 75 335 340 10.1212/WNL.0b013e3181ea157e 20660863 \n3. Mutschler J Grosshans M Herwig U Heekeren K Kawohl W Bruhl A Pregabalin-induced suicidal ideations Pharmacopsychiatry 2011 44 119 10.1055/s-0031-1271689 21318939 \n4. Gibbons RD Hur K Brown CH Mann JJ Relationship between antiepileptic drugs and suicide attempts in patients with bipolar disorder Arch Gen Psychiatry 2009 66 1354 1360 10.1001/archgenpsychiatry.2009.159 19996040 \n5. Arana A Wentworth CE Ayuso-Mateos JL Arellano FM Suicide-related events in patients treated with antiepileptic drugs N Engl J Med 2010 363 542 551 10.1056/NEJMoa0909801 20818889 \n6. Kalinin VV Suicidality and antiepileptic drugs: is there a link? Drug Saf 2007 30 123 142 10.2165/00002018-200730020-00003 17253878 \n7. Bannister K Sikandar S Bauer CS Dolphin AC Porreca F Dickenson AH Pregabalin suppresses spinal neuronal hyperexcitability and visceral hypersensitivity in the absence of peripheral pathophysiology Anesthesiology 2011 115 144 152 10.1097/ALN.0b013e31821f6545 21602662\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1744-859X",
"issue": "13(1)",
"journal": "Annals of general psychiatry",
"keywords": "Anticonvulsants; Depression; Pregabalin; Suicide",
"medline_ta": "Ann Gen Psychiatry",
"mesh_terms": null,
"nlm_unique_id": "101236515",
"other_id": null,
"pages": "37",
"pmc": null,
"pmid": "25489334",
"pubdate": "2014",
"publication_types": "D016428:Journal Article",
"references": "21602662;19996040;21318939;20660863;17253878;20818889",
"title": "Depression and attempted suicide under pregabalin therapy.",
"title_normalized": "depression and attempted suicide under pregabalin therapy"
} | [
{
"companynumb": "DE-JNJFOC-20150321189",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": "3",
"d... |
{
"abstract": "Resistance to linezolid (LZD) in methicillin-resistant Staphylococcus aureus (MRSA) isolates from patients with cystic fibrosis (CF) is due mainly to ribosomal mutations. We report on four CF patients with LZD-resistant MRSA bronchopulmonary infections by strains carrying the cfr gene. Strains from one patient also harbored the G2576U mutation (23S rRNA) and the G139R substitution (L3 protein). All strains belonged to the epidemic clone ST125 MRSA IVc. Our results support the monitoring of LZD resistance emergence in CF and non-CF MRSA isolates.",
"affiliations": "Servicio de Microbiología, Hospital Universitario Ramón y Cajal and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain Red Española de Investigación en Patología Infecciosa (REIPI), Madrid, Spain.;Servicio de Neumología, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain.;Staphylococcus Reference Laboratory, Servicio de Bacteriología, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid, Spain.;Servicio de Neumología, Hospital Universitario Ramón y Cajal, Madrid, Spain.;Servicio de Microbiología, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain.;Servicio de Microbiología, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain.;Servicio de Microbiología, Hospital Universitario Ramón y Cajal and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.;Servicio de Microbiología, Hospital Universitario Ramón y Cajal and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain Red Española de Investigación en Patología Infecciosa (REIPI), Madrid, Spain.;Servicio de Microbiología, Hospital Universitario Ramón y Cajal and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain Red Española de Investigación en Patología Infecciosa (REIPI), Madrid, Spain rosacampo@yahoo.com.;Servicio de Microbiología, Hospital Universitario Ramón y Cajal and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain Red Española de Investigación en Patología Infecciosa (REIPI), Madrid, Spain.",
"authors": "de Dios Caballero|Juan|J|;Pastor|María Dolores|MD|;Vindel|Ana|A|;Máiz|Luis|L|;Yagüe|Genoveva|G|;Salvador|Carme|C|;Cobo|Marta|M|;Morosini|María-Isabel|MI|;del Campo|Rosa|R|;Cantón|Rafael|R|;|||",
"chemical_list": "D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; C539943:CFR protein, Staphylococcus aureus; D012338:RNA, Ribosomal, 23S; D000090822:Ribosomal Protein L3; D012269:Ribosomal Proteins; D000069349:Linezolid",
"country": "United States",
"delete": false,
"doi": "10.1128/AAC.02067-15",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0066-4804",
"issue": "60(3)",
"journal": "Antimicrobial agents and chemotherapy",
"keywords": null,
"medline_ta": "Antimicrob Agents Chemother",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D003550:Cystic Fibrosis; D024881:Drug Resistance, Bacterial; D005260:Female; D006801:Humans; D000069349:Linezolid; D055624:Methicillin-Resistant Staphylococcus aureus; D008826:Microbial Sensitivity Tests; D012338:RNA, Ribosomal, 23S; D000090822:Ribosomal Protein L3; D012269:Ribosomal Proteins; D013203:Staphylococcal Infections; D055815:Young Adult",
"nlm_unique_id": "0315061",
"other_id": null,
"pages": "1878-82",
"pmc": null,
"pmid": "26666940",
"pubdate": "2015-12-14",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "20551409;17469151;22143525;22322352;21918450;18948410;22578666;25155597;16527459;23459489;21792559;20463179;21263048;18669817;25559432;23917314;25583881;22214776;20089543;24820843;25118167;20144045;20841419;12751028;10698988;23929481;26429520",
"title": "Emergence of cfr-Mediated Linezolid Resistance in a Methicillin-Resistant Staphylococcus aureus Epidemic Clone Isolated from Patients with Cystic Fibrosis.",
"title_normalized": "emergence of cfr mediated linezolid resistance in a methicillin resistant staphylococcus aureus epidemic clone isolated from patients with cystic fibrosis"
} | [
{
"companynumb": "ES-MYLANLABS-2016M1018016",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LINEZOLID"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo determine the outcomes in regards to seizure control and foetal malformation in pregnant women with epilepsy not treated with antiepileptic drugs (AEDs).\n\n\nMETHODS\nAnalysis of data from the Australian Register of AEDs in Pregnancy on 148 women with epilepsy who were not receiving AEDs before and during at least the first trimester of pregnancy.\n\n\nRESULTS\nSeizure control was less likely to be maintained in AED-untreated pregnancies. Whether AED therapy had been ceased in preparation for pregnancy, or had not been employed for long periods before pregnancy, made no statistically significant difference to seizure control outcomes, but those who ceased therapy in preparation for pregnancy were more likely to again be taking AED therapy by term. Foetal malformation rates were reasonably similar in untreated pregnancies, and in treated pregnancies if pregnancies exposed to known AED teratogens (valproate and probably topiramate) were excluded from consideration.\n\n\nCONCLUSIONS\nLeaving epilepsy untreated during pregnancy appears disadvantageous from the standpoint of seizure control: it also does not reduce the hazard of foetal malformation unless it avoids valproate or topiramate intake during pregnancy.",
"affiliations": "Department of Medicine and Neurosciences, Royal Melbourne Hospital and University of Melbourne, Parkville, Victoria 3050, Australia. Electronic address: vajda@netspace.net.au.;Department of Medicine and Neurosciences, Royal Melbourne Hospital and University of Melbourne, Parkville, Victoria 3050, Australia.;Department of Medicine and Neurosciences, Royal Melbourne Hospital and University of Melbourne, Parkville, Victoria 3050, Australia.;Royal Brisbane and Women's Hospital and School of Medicine and Biomedical Science, University of Queensland, Brisbane, Queensland 4027, Australia.;Royal Brisbane and Women's Hospital and School of Medicine and Biomedical Science, University of Queensland, Brisbane, Queensland 4027, Australia.",
"authors": "Vajda|F J E|FJ|;O'Brien|T J|TJ|;Graham|J|J|;Lander|C M|CM|;Eadie|M J|MJ|",
"chemical_list": "D000927:Anticonvulsants",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1059-1311",
"issue": "24()",
"journal": "Seizure",
"keywords": "Antiepileptic drugs; Epilepsy; Foetal malformations; Pregnancy; Seizures",
"medline_ta": "Seizure",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D001315:Australia; D004827:Epilepsy; D005260:Female; D006801:Humans; D011247:Pregnancy; D011248:Pregnancy Complications; D012042:Registries; D016896:Treatment Outcome",
"nlm_unique_id": "9306979",
"other_id": null,
"pages": "77-81",
"pmc": null,
"pmid": "25218112",
"pubdate": "2015-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "The outcomes of pregnancy in women with untreated epilepsy.",
"title_normalized": "the outcomes of pregnancy in women with untreated epilepsy"
} | [
{
"companynumb": "AU-JNJFOC-20150113423",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drugadditional": null,
... |
{
"abstract": "Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive Food and Drug Administration (FDA)-approved treatment for unipolar treatment-resistant depression (TRD). rTMS has been utilized clinically to treat bipolar TRD; however, there remains a lack of evidence and support for effectively utilizing this intervention for bipolar TRD. We retrospectively analyzed data from a group of patients who were treated with rTMS for unipolar or bipolar TRD and describe a case example to further delineate management techniques for employing rTMS in the treatment of bipolar TRD.\n\n\n\nRecords of 71 patients treated with rTMS for unipolar (n=54) or bipolar (n=17) TRD between 2008 and 2017 were reviewed. The primary outcome of depression severity, the Quick Inventory of Depressive Symptomatology, was completed at baseline and after every 5 sessions throughout the course of 30 treatments. Secondary outcomes involved a comparison of outcomes and clinical characteristics within and between the bipolar and unipolar TRD groups.\n\n\n\nIn the total sample, patients' depression improved significantly over the course of treatment. Patients with bipolar TRD showed greater response and remission rates over the course of treatment compared with patients with unipolar TRD, but this difference was not statistically significant. Both groups showed a similar pattern of depression response over treatment time. No manic or hypomanic episodes occurred during any patient's course of rTMS treatment. A case example is provided discussing the timing of rTMS in a patient with bipolar depression to decrease the likelihood of treatment-induced hypomania.\n\n\n\nLimitations included the small overall sample size, the smaller size of the patient group with bipolar TRD compared with the group with unipolar TRD, and the naturalistic setting of this study.\n\n\n\nOur data suggest that rTMS may be equally effective and safe for patients with both unipolar and bipolar depression. Patients with bipolar TRD showed a similar response profile over treatment time compared with patients with unipolar TRD.",
"affiliations": null,
"authors": "Phillips|Angela L|AL|;Burr|Robert L|RL|;Dunner|David L|DL|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/PRA.0000000000000447",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1527-4160",
"issue": "26(1)",
"journal": "Journal of psychiatric practice",
"keywords": null,
"medline_ta": "J Psychiatr Pract",
"mesh_terms": "D001714:Bipolar Disorder; D061218:Depressive Disorder, Treatment-Resistant; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017397:Prefrontal Cortex; D012189:Retrospective Studies; D012720:Severity of Illness Index; D050781:Transcranial Magnetic Stimulation; D016896:Treatment Outcome",
"nlm_unique_id": "100901141",
"other_id": null,
"pages": "37-45",
"pmc": null,
"pmid": "31913968",
"pubdate": "2020-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Repetitive Transcranial Magnetic Stimulation in the Treatment of Bipolar Depression: Experience From a Clinical Setting.",
"title_normalized": "repetitive transcranial magnetic stimulation in the treatment of bipolar depression experience from a clinical setting"
} | [
{
"companynumb": "US-009507513-2004USA009178",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MIRTAZAPINE"
},
"drugadditional": null,
... |
{
"abstract": "Posttransplant lymphoproliferative disorders (PTLDs) are lymphoid proliferations or lymphomas that develop as a consequence of immunosuppression after solid organ or bone marrow transplantation and are mostly associated with an Epstein-Barr virus infection. The morphologic categories include different types of benign and malignant lymphoid proliferations. The majority of PTLDs is of B-cell origin with clonal rearrangements of the immunoglobulin genes. The PTLDs in solid organ transplants are reported to be either of host or of donor origin. Donor-related PTLDs frequently involve the allograft. We report a case of a 52-year-old woman recipient who developed simultaneously PTLDs in several organs 5 month after receiving a sex-mismatched renal and pancreas allograft. Immunosuppression regimen comprised antithymocyte globulin, tacrolimus, mycophenolate mofetil, and steroids. Pathologic features appeared as polymorphic PTLDs in the renal allograft, liver, and central nervous system (CNS). Molecular genetic studies revealed different clonal immunoglobulin heavy chain gene rearrangements in all 3 organs as determined by polymerase chain reaction (PCR). Epstein-Barr virus were detected by nested PCR and in situ hybridization in all 3 tumors. The PTLDs in liver and CNS were of host origin whereas the allograft kidney PTLD was found to originate from the male donor as shown by the simultaneous detection of female and male sex chromosomes by PCR and fluorescence in situ hybridization. The recipient died in consequence of the CNS involvement, after intracerebral hemorrhage with uncal and tonsillar herniation.",
"affiliations": "Department of Pathology, Klinikum Darmstadt, Grafenstrasse 9, 64276 Darmstadt, Germany. pathologie-heyny@klinikum-darmstadt.de",
"authors": "Heyny-von Haussen|Roland|R|;Klingel|Karin|K|;Riegel|Werner|W|;Kandolf|Reinhard|R|;Mall|Gerhard|G|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/01.pas.0000202165.67278.b3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0147-5185",
"issue": "30(7)",
"journal": "The American journal of surgical pathology",
"keywords": null,
"medline_ta": "Am J Surg Pathol",
"mesh_terms": "D001402:B-Lymphocytes; D002490:Central Nervous System; D041321:Chromosomes, Human, X; D041322:Chromosomes, Human, Y; D002999:Clone Cells; D020031:Epstein-Barr Virus Infections; D017809:Fatal Outcome; D005260:Female; D004854:Herpesvirus 4, Human; D006801:Humans; D016867:Immunocompromised Host; D017404:In Situ Hybridization, Fluorescence; D007668:Kidney; D016030:Kidney Transplantation; D008099:Liver; D008232:Lymphoproliferative Disorders; D008297:Male; D008875:Middle Aged; D016035:Pancreas Transplantation; D011183:Postoperative Complications; D012737:Sex Factors; D014019:Tissue Donors",
"nlm_unique_id": "7707904",
"other_id": null,
"pages": "900-5",
"pmc": null,
"pmid": "16819335",
"pubdate": "2006-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Posttransplant lymphoproliferative disorder in a kidney-pancreas transplanted recipient: simultaneous development of clonal lymphoid B-cell proliferation of host and donor origin.",
"title_normalized": "posttransplant lymphoproliferative disorder in a kidney pancreas transplanted recipient simultaneous development of clonal lymphoid b cell proliferation of host and donor origin"
} | [
{
"companynumb": "PHHY2018DE171699",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": null,
... |
{
"abstract": "Neurocysticercosis, an infection of the central nervous system with the larval stage of the cestode Taenia solium, is common in developing countries but its occurrence and management in allogeneic hematopoietic stem cell transplantation (HSCT) has not been reported previously, to our knowledge. We report the case of an immigrant female patient who underwent a matched-related allogeneic HSCT for acute lymphoblastic leukemia and was incidentally found to have a solitary viable neurocysticercosis lesion. However, despite severe immunosuppression, the size of the cyst did not increase. More importantly, restoration of the immune system did not induce significant inflammation or seizures. Subsequent follow-up demonstrated complete resolution of the neurocysticercosis lesion. Thus, in the setting of HSCT, an asymptomatic patient with a single neurocysticercosis lesion was successfully managed without the use of anthelmintics, steroids, or anti-epileptics.",
"affiliations": "Hematology Branch, National Heart, Lung, Blood Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA.;Hematology Branch, National Heart, Lung, Blood Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA.;Hematology Branch, National Heart, Lung, Blood Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA.;Hematology Branch, National Heart, Lung, Blood Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA.;Hematology Branch, National Heart, Lung, Blood Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA.;National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland, USA.;Center for Infectious Disease Imaging (CIDI), Radiology and Imaging Sciences, Clinical Center, NIH, Bethesda, Maryland, USA.;National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.;University of Illinois at Chicago, Chicago, Illinois, USA.;Hematology Branch, National Heart, Lung, Blood Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA.;National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.;Hematology Branch, National Heart, Lung, Blood Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA.",
"authors": "Purvey|S|S|;Lu|K|K|;Mukkamalla|S K|SK|;Anandi|P|P|;Dumitriu|B|B|;Kranick|S|S|;Hammoud|D A|DA|;O'Connell|E|E|;Oh|A L|AL|;Barrett|J|J|;Mahanty|S|S|;Battiwalla|M|M|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12392",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "17(3)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "Taenia solium; allogeneic hematopoietic stem cell transplantation; anthelmintics; neurocysticercosis; parasite; tapeworm",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D003560:Cysts; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007165:Immunosuppression Therapy; D020019:Neurocysticercosis; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D014184:Transplantation, Homologous",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "456-62",
"pmc": null,
"pmid": "25850995",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052060:Research Support, N.I.H., Intramural; D016454:Review",
"references": "12781380;14724304;15210888;15259471;3543710;2909643;1940452;1736171;8112262;7936301;7948938;8520442;9153484;9726343;15680651;15728858;15926779;16168934;16170737;16217690;16441247;16498657;16818928;17030744;17061203;17092722;17181420;17889216;18509826;18495737;19270284;19358669;19394828;20045747;20218875;21072231;21797658;22217610;22517102;22222333;22809375;22496318;25092547;25073691;10738675;10796510;10805184;11480424;12467692;12473760",
"title": "Conservative management of neurocysticercosis in a patient with hematopoietic stem cell transplantation: a case report and review.",
"title_normalized": "conservative management of neurocysticercosis in a patient with hematopoietic stem cell transplantation a case report and review"
} | [
{
"companynumb": "US-PFIZER INC-2017182315",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DASATINIB"
},
"drugadditional": null,
... |
{
"abstract": "Amiodarone-induced pulmonary toxicity (APT) is a serious adverse event that can lead to death. The aims of our study are to determine factors associated with mortality and to describe outcome and sequelae of patients with APT.\n\n\nMETHODS\nForty-six patients with APT were divided into two groups according to survival at day 90 for a clinical, functional, biological and radiological comparaison. We then evaluated the evolution of 15 survivors at a median of three months [1-6 months] and/or 12 months [8-36 months].\n\n\nRESULTS\nMortality of APT at day 90 was 37% (17 patients) and was linked to the speed of onset of symptoms and a high HRCT alveolar score. Angiotensin system antagonist treatment was prescribed significantly more in the survival group (p = 0.042, HR 0.34 (95% CI 0.12-0.96)). In surviving patients, dyspnea, vital capacity and HRCT alveolar score improved significantly while HRCT fibrosis score deteriorated gradually during the first six months. At the end of the study, all the surviving patients presented functional and/or radiological sequelae.\n\n\nCONCLUSIONS\nSeverity of APT is linked to the extent and speed of onset of pulmonary damage. After the initial episode, the patients who survived improved slowly but with persistent sequelae.",
"affiliations": "CHRU Tours, Service de Pneumologie, Tours, France.;CHRU Tours, Service de Radiologie, Tours, France.;Université François Rabelais, UMR 1100, F-37032 Tours, France; INSERM, Centre d'Etude des Pathologies Respiratoires, UMR 1100/EA6305, F-37032 Tours, France; CHRU Tours, Service de Réanimation Médicale, Tours, France.;CHRU Tours, Service de Pneumologie, Tours, France; Université François Rabelais, UMR 1100, F-37032 Tours, France; INSERM, Centre d'Etude des Pathologies Respiratoires, UMR 1100/EA6305, F-37032 Tours, France.;CHRU Tours, Service d'anatomopathologie, Tours, France.;CHRU Tours, Service de Pharmacologie Clinique Centre Régional de Pharmacovigilance, Tours, France.;Université François Rabelais, UMR 1100, F-37032 Tours, France; CHRU Tours, Service de Réanimation Médicale, Tours, France.;CHRU Tours, Service de Pneumologie, Tours, France; Université François Rabelais, UMR 1100, F-37032 Tours, France; INSERM, Centre d'Etude des Pathologies Respiratoires, UMR 1100/EA6305, F-37032 Tours, France.;CHRU Tours, Service de Pneumologie, Tours, France; Université François Rabelais, UMR 1100, F-37032 Tours, France; INSERM, Centre d'Etude des Pathologies Respiratoires, UMR 1100/EA6305, F-37032 Tours, France. Electronic address: karoun@orange.fr.",
"authors": "Mankikian|J|J|;Favelle|O|O|;Guillon|A|A|;Guilleminault|L|L|;Cormier|B|B|;Jonville-Béra|A P|AP|;Perrotin|D|D|;Diot|P|P|;Marchand-Adam|S|S|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D005938:Glucocorticoids; D000638:Amiodarone",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0954-6111",
"issue": "108(4)",
"journal": "Respiratory medicine",
"keywords": "Amiodarone; Amiodarone-induced pulmonary toxicity; Drug toxicity; High resolution computer tomography; Pulmonary function tests",
"medline_ta": "Respir Med",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000638:Amiodarone; D000889:Anti-Arrhythmia Agents; D005260:Female; D005500:Follow-Up Studies; D005938:Glucocorticoids; D006760:Hospitalization; D006801:Humans; D053208:Kaplan-Meier Estimate; D008171:Lung Diseases; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012129:Respiratory Function Tests; D012189:Retrospective Studies; D012720:Severity of Illness Index; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8908438",
"other_id": null,
"pages": "638-46",
"pmc": null,
"pmid": "24565600",
"pubdate": "2014-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Initial characteristics and outcome of hospitalized patients with amiodarone pulmonary toxicity.",
"title_normalized": "initial characteristics and outcome of hospitalized patients with amiodarone pulmonary toxicity"
} | [
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"activesubstancename": "AMIODARONE"
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{
"abstract": "Cephalexin is a well tolerated antimicrobial and hepatic injury is an infrequent occurrence with its use. We here describe a 21-year-old female who presented with jaundice and elevated liver enzymes after 4 weeks completion of 10 day course of cephalexin, prescribed prophylactically after mammoplasty. Extensive work up including all causes of hepatitis was within normal limits and she improved with conservative management. This case highlights the need to suspect drug induced liver injury in cases of jaundice and cephalexin use.",
"affiliations": "Department of Internal Medicine, University of Missouri School of Medicine, One Hospital Drive, Columbia, MO 65212, USA.;Division of Gastroenterology, Department of Internal Medicine, University of Missouri School of Medicine, One Hospital Drive, Columbia, MO 65212, USA.;Department of Internal Medicine, University of Missouri School of Medicine, One Hospital Drive, Columbia, MO 65212, USA.",
"authors": "Singla|Atul|A|;Hammad|Hazem T|HT|;Hammoud|Ghassan M|GM|",
"chemical_list": null,
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"doi": "10.4021/gr2010.06.210w",
"fulltext": "\n==== Front\nGastroenterology ResGastroenterology ResElmer PressGastroenterology Research1918-28051918-2813Elmer Press 10.4021/gr2010.06.210wCase ReportUncommon Cause of Acute Drug-induced Liver Injury Following Mammoplasty Cephalexin Induced Liver InjurySingla Atul aHammad Hazem T. bHammoud Ghassan M. ca Department of Internal Medicine, University of Missouri School of Medicine, One Hospital Drive, Columbia, MO 65212, USAb Division of Gastroenterology, Department of Internal Medicine, University of Missouri School of Medicine, One Hospital Drive, Columbia, MO 65212, USAc Corresponding author: Hepatology and Biliary Disease, Division of Gastroenterology, Department of Internal Medicine, University of Missouri School of Medicine, One Hospital Drive, DC043.00, Columbia, MO 65212, USA. Email: hammoudg@health.missouri.edu8 2010 20 7 2010 3 4 171 172 16 6 2010 Copyright 2010, Singla et al.2010This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Cephalexin is a well tolerated antimicrobial and hepatic injury is an infrequent occurrence with its use. We here describe a 21-year-old female who presented with jaundice and elevated liver enzymes after 4 weeks completion of 10 day course of cephalexin, prescribed prophylactically after mammoplasty. Extensive work up including all causes of hepatitis was within normal limits and she improved with conservative management. This case highlights the need to suspect drug induced liver injury in cases of jaundice and cephalexin use.\n\nCephalexinHepatitisDrug-induced\n==== Body\nCase Report\nA 21-year-old previously healthy female with recent history of uneventful mammoplasty presented with one-week history of right upper quadrant abdominal pain, skin rash, muscle aches, jaundice, dark urine and pruritus one month after her surgery. She had received Cephalexin 500 mg capsule three times daily prophylactically for 10 days postoperatively. She had no history of fever, chills, weight loss, joint pains, travel abroad or ill contacts. She denied alcohol intake or exposure to any herbal or over the counter supplements. Her surgical records revealed no hypotensive episodes perioperatively. Physical examination revealed alert young woman with icteric sclera. She had mild tenderness in the right upper quadrant and had no hepatosplenomegaly or ascites. Skin examination revealed a macular rash over the right flank with no vesicles. Laboratory tests were significant for WBC 9300 cells per microliter with 7.2% eosinophils, alanine aminotransferase (ALT) 1280 U/L (normal range 10 - 60 U/L), aspartate aminotransferase (AST) 580 U/L (normal range 10 - 40 U/L), alkaline phosphatase (ALP) 323 U/L (normal range 38 - 126 U/L), gamma glutamyl transpeptidase (GGTP) 323 U/L (normal range 7 - 50 U/L), total bilirubin 4.3 mg/dL with a conjugated fraction of 2.9 mg/dL. Serum total protein, albumin, LDH, amylase, creatinine, TSH and prothrombin time were all normal. Serologic tests for acute viral hepatitis A, B and C, CMV, HSV, and EBV were negative. Her serum autoantibodies and tests for metabolic liver diseases such as hemochromatosis, Wilson disease and alpha-1 antitrypsin deficiency were negative. Ultrasound of the abdomen showed normal echogenicity of the liver. The gall bladder appeared contracted with no stones or evidence of acute cholecystitis. Doppler studies of the portal and hepatic veins were normal. With close follow-up, her abdominal pain and jaundice resolved. Cholestyramine alleviated her pruritus and she had a complete normalization of liver transaminases eight weeks after exposure to cephalexin (Fig. 1). Liver biopsy was not performed.\n\nFigure 1 Changes of aminotransferases and alkaline phosphatase.\n\nDiscussion\nCephalexin is a first generation cephalosporin and a well tolerated antibiotic which has been widely used for variety of skin and soft tissue infections. Gastrointestinal disturbances such as nausea, vomiting, diarrhea and abdominal pain are common. Mild elevations (less than 2 - 3 fold) in serum transaminases are common but severe hepatocellular injury is very rare. Other groups of cephalosporin have been implicated in drug-induced liver injury. Chen et al reported acute hepatitis with cefdinir [1]. Pacik reported two cases of prophylactic cephazolin induced hepatitis after augmentation Mammoplasty [2].\n\nSearch of medical literature in English language from January 1969 to January 2010 including Pubmed, MEDLINE, WHO database, Cochrane database, PDR, Food and drug administration (FDA) website reveals a single case report of cephalexin induced hepatic cholestasis. Skoog et al reported a 51-year-old male who received cephalexin for 10 days and developed dark colored urine and pale colored stools three days after taking cephalexin [3]. Within 24 hours of completing therapy, fever, hives and jaundice ensue. Liver biopsy showed panacinar hepatitis and extensive cholestasis. Our patient was prophylactically treated with cephalexin after mammoplasty and developed jaundice and marked elevation (more than 20 fold) of liver transaminases four weeks after exposure to cephalexin. Extensive history and laboratory tests revealed no risk factors for viral hepatitis or drug-drug interaction. Her liver enzyme elevation, the presence of eosinophilic leukocytosis and skin rash pointed towards hypersensitivity category of idiosyncratic reactions of severe hepatocellular injury. Moreover, the close temporal relationship between completion of cephalexin therapy and onset of symptoms with lack of other causes of hepatitis strongly suggested drug-induced liver injury.\n\nIn general, there are no standard criteria or biochemical tests for diagnosis of drug induced hepatotoxicity. Few models have been developed that attempt to correlate causality of drug toxicity into objective criteria such as the Naranjo Adverse Reactions Probability Scale (NADRPS), Councils for International Organizations of Medical Sciences (CIOMS)\\Roussel-Uclaf Causality Assessment Method (RUCAM) scale, and the Maria & Victorino (M & V) clinical scale [4]. However, none of these models address all risk factors and neither is routinely used in clinical practice. In our patient, NADRPS indicated a ‘robable’ (score = 6) and RUCAM a ‘possible’ (score = 10) relationship between the drug and liver injury. Serum bilirubin more than 3 times the upper limit of normal in association with elevated aminotransferases, is associated with bad prognosis (Hy’s Law) [5]. Fortunately, our patient had a benign course with complete recovery. In conclusion, cephalexin is a well tolerated antimicrobial agent and to our knowledge, severe hepatocellular injury is exceedingly rare if ever reported. Clinicians should be aware of the potential severe hepatotoxicity associated with cephalexin.\n==== Refs\nReferences\n1 Chen J Ahmad J Cefdinir-induced hepatotoxicity: potential hazards of inappropriate antibiotic use J Gen Intern Med 2008 23 11 1914 1916 10.1007/s11606-008-0758-y 18752027 \n2 Pacik PT Augmentation mammaplasty: postoperative cephalosporin-induced hepatitis Plast Reconstr Surg 2007 119 3 1136 1137 10.1097/01.prs.0000253456.58964.6e 17312549 \n3 Skoog SM Smyrk TC Talwalkar JA Cephalexin-induced cholestatic hepatitis J Clin Gastroenterol 2004 38 9 833 10.1097/01.mcg.0000139074.40365.04 15365421 \n4 Tajiri K Shimizu Y Practical guidelines for diagnosis and early management of drug-induced liver injury World J Gastroenterol 2008 14 44 6774 6785 10.3748/wjg.14.6774 19058303 \n5 Reuben A Hy's law Hepatology 2004 39 2 574 578 10.1002/hep.20081 14768020\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1918-2805",
"issue": "3(4)",
"journal": "Gastroenterology research",
"keywords": "Cephalexin; Drug-induced; Hepatitis",
"medline_ta": "Gastroenterology Res",
"mesh_terms": null,
"nlm_unique_id": "101519422",
"other_id": null,
"pages": "171-172",
"pmc": null,
"pmid": "27942299",
"pubdate": "2010-08",
"publication_types": "D002363:Case Reports",
"references": "18752027;17312549;19058303;15365421;14768020",
"title": "Uncommon Cause of Acute Drug-induced Liver Injury Following Mammoplasty.",
"title_normalized": "uncommon cause of acute drug induced liver injury following mammoplasty"
} | [
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"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2021-04015",
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"abstract": "Natalizumab is indicated as monotherapy for the treatment of relapsing-remitting multiple sclerosis; it prevents outbreaks and delays the progression of physical disability. Here, we report the case of a 30-year-old patient with multiple sclerosis receiving natalizumab as monotherapy who subsequently developed self-limited cytomegalovirus disease. Cytomegalovirus infection has been reported during treatment with natalizumab, and in this study, we use new techniques to analyze the possible association of cytomegalovirus infection with natalizumab.\nNatalizumab is a humanized recombinant monoclonal antibody (IgG4k) against α4-integrin which promotes immunocompromise by blocking the adhesion interactions necessary for lymphocyte trafficking.Cytomegalovirus infection has been described during natalizumab treatment, although the pathogenesis and mechanisms are not complete understood.This case highlights the importance of awareness of this association and possible complications.",
"affiliations": "Faculty of Medicine, University Center UNINTA, Sobral, Ceará, Brazil.;Faculty of Medicine, Federal University of Ceará (UFC), Fortaleza, Ceará, Brazil.;Internal Medicine Department, Hospital Regional Norte (HRN), Sobral, Ceará, Brazil.;Internal Medicine Department, Hospital Regional Norte (HRN), Sobral, Ceará, Brazil.",
"authors": "Lima|Marina Rodrigues|MR|;Farias|Luís Arthur Brasil Gadelha|LABG|;da Ponte|Maycon Fellipe|MF|;de Arruda Furtado|Luís Edmundo Teixeira|LET|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.12890/2019_001046",
"fulltext": "\n==== Front\nEur J Case Rep Intern MedEuropean Journal of Case Reports in Internal Medicine2284-2594SMC Media Srl 10.12890/2019_0010461046-1-7000-1-10-20190125ArticlesSelf-Limited Cytomegalovirus Infection During Natalizumab Treatment for Multiple Sclerosis Lima Marina Rodrigues 1Farias Luís Arthur Brasil Gadelha 2da Ponte Maycon Fellipe 3de Arruda Furtado Luís Edmundo Teixeira 3\n1 Faculty of Medicine, University Center UNINTA, Sobral, Ceará, Brazil\n2 Faculty of Medicine, Federal University of Ceará (UFC), Fortaleza, Ceará, Brazil\n3 Internal Medicine Department, Hospital Regional Norte (HRN), Sobral, Ceará, Brazil2019 01 2 2019 6 2 00104603 1 2019 09 1 2019 © EFIM 20192019This article is licensed under a Commons Attribution Non-Commercial 4.0 LicenseNatalizumab is indicated as monotherapy for the treatment of relapsing-remitting multiple sclerosis; it prevents outbreaks and delays the progression of physical disability. Here, we report the case of a 30-year-old patient with multiple sclerosis receiving natalizumab as monotherapy who subsequently developed self-limited cytomegalovirus disease. Cytomegalovirus infection has been reported during treatment with natalizumab, and in this study, we use new techniques to analyze the possible association of cytomegalovirus infection with natalizumab.\n\nLEARNING POINTS\nNatalizumab is a humanized recombinant monoclonal antibody (IgG4k) against α4-integrin which promotes immunocompromise by blocking the adhesion interactions necessary for lymphocyte trafficking.\n\nCytomegalovirus infection has been described during natalizumab treatment, although the pathogenesis and mechanisms are not complete understood.\n\nThis case highlights the importance of awareness of this association and possible complications.\n\nInfectionvirusescytomegalovirusnatalizumabmultiple sclerosis\n==== Body\nINTRODUCTION\nCytomegalovirus (CMV) is a ubiquitous human β-herpesvirus that is prevalent worldwide[1,2]. The outcome of CMV infection depends on the health of the infected individual. The majority of immunocompetent individuals infected with CMV are asymptomatic. However, clinical symptoms such as mononucleosis-like syndrome, which consists of an acute fever with marked lymphocytosis and lymphocytic atypia in 10% of cells, can be observed in some cases[1,3,4].\n\nSome patients, particularly those who are immunosuppressed, may develop infection with severe clinical symptoms. Treatment with natalizumab, which binds to α4-integrins, promotes immunocompromise by blocking the adhesion interactions necessary for lymphocyte trafficking, there by disrupting normal immunovigilance. Although numerous studies have discussed infections associated with natalizumab in the central nervous system (CNS), fewer studies have addressed infectious sequelae in other anatomical sites[5].\n\nHere, we report the case of a 30-year-old male patient with multiple sclerosis (MS) that evolved into CMV infection after treatment with natalizumab, focusing mainly on the clinical aspects, drug mechanisms, and side effects described in the literature.\n\nCASE DESCRIPTION\nA 30-year-old male patient from north-eastern Brazil, diagnosed with MS in 2010, who had a previous history of interferon use and had been treated with natalizumab (300 mg per month) for the previous 2 years (2016–2018), presented with sudden onset of pulsatile holocranial headache and photophobia associated with persistent myalgia and fever, with temperatures ranging from 38.3°C to 38.5°C. In addition, he had difficulty walking, paraesthesia, and an isolated episode of diplopia. He denied urinary complaints, respiratory discomfort, angina, diarrhea or vomiting. The physical examination showed positive Romberg and Babinski signs, with no other significant observations. Red and white cell counts were within the normal range. LDH (1,452 IU/l) and ferritin (1,500 ng/ml) levels were elevated.\n\nCerebral computer tomography (CT) did not reveal new lesions suggestive of disease activity (Fig. 1). Anti-HIV 1 and 2, hepatitis B and C, venereal disease research laboratory (VDRL) and Toxoplasma serologies were negative. Tests for John Cunningham virus (JCV) were also negative. Blood culture was negative. Abdominal ultrasonography revealed homogeneous splenomegaly. An echocardiogram and endoscopy were normal. Other serological tests for mononucleosis-like diseases were requested and CMV immunoglobulin M and G (IgM and IgG) tested positive. The patient was diagnosed with cytomegalovirus disease associated with the use of natalizumab. No severe infections were found and treatment was administered on a symptomatic basis. Upon follow-up, we have determined that the patient has had a complete remission of symptoms.\n\nDISCUSSION and CONCLUSION\nNatalizumab is a humanized recombinant monoclonal antibody (IgG4k) against α4-integrin, and is produced in a mouse cell line through recombinant DNA technology. It is usually prescribed as single-drug therapy for the treatment of relapsing-remitting MS to prevent outbreaks and delay the progression of physical disability[6]. Natalizumab has primarily been associated with progressive multifocal leukoencephalopathy secondary to JCV reactivation[7]. Consequently, clinical and laboratory assessments of a patient’s immune status, including total leukocyte and T-lymphocyte counts, history of opportunistic infection and immunosuppressive therapy, and periodic JCV serological screening is recommended for patients taking this medication[8,9]. Other atypical infections, including herpes simplex, varicella zoster virus encephalitis/meningitis, as well as CMV infection, have also been described[10].\n\nIn addition to the presented case, approximately 112 cases of CMV infection after the use of natalizumab have been described in the literature. Most of the reported patients were immunocompromised; however, several cases in immunocompetent patients have also been described[11]. Other opportunistic infections of concern were found in patients with MS treated with anti-MS drugs such as alemtuzumab, ocrelizumab, fingolimod and mitoxantrone.\n\nIndividual cases of Kaposi sarcoma, cutaneous histoplasmosis and CNS toxoplasmosis have been reported in non-HIV-infected patients with MS receiving fingolimod[12]. CMV was also identified in patients during MS treatment with alemtuzumab, suggesting a similar disease pathogenesis[13].\n\nCMV infection is typically self-limiting and can be successfully treated in healthy patients; however, antiviral drugs have only been administered to patients who are immunosuppressed or have severe or persistent disease[14]. We hypothesize that CMV infection causes a mononucleosis-like disease in patients treated with natalizumab, by similarly disrupting normal immunosurveillance through lymphocyte α4-integrin blockade. However, further studies are needed to confirm the effect of natalizumab on CMV infection susceptibility.\n\nThe case discussed is relevant because it is a rare association of an opportunistic infection related to the use of natalizumab. In addition, it encourages further research to clarify this fact and validate the possible side effects related to this drug that have not been documented.\n\nAcknowledgements\nWe would like to thank the general practitioners from the Hospital Regional Norte, Fortaleza, Ceará, Brazil, for their help in collecting the clinical and therapeutic data from the patient.\n\nConflicts of Interests: The Authors declare that there are no competing interests.\n\nAuthor Contributions: MRL and LABGF conceived and designed the study and wrote the paper. MFP collected the data and performed the analysis. MFP and LETAF performed the analysis and reviewed the manuscript.\n\nFigure 1 Cranial MRI revealing signal changes in the deep white matter at the septal callus interface and bridge to the left, suggestive of demyelinating disease\n==== Refs\nREFERENCES\n1 Taylor GH Cytomegalovirus Am Fam Phys 2003 67 519 524 \n2 Crough T Khanna R Immunobiology of human cytomegalovirus: from bench to bedside Clin Microbiol Rev 2009 22 76 98 19136435 \n3 Kano Y Shiohara T Current understanding of cytomegalovirus infection in immunocompetent individuals J Dermatol Sci 2000 22 196 204 10698156 \n4 Rafailidis PI Mourtzoukou EG Varbobitis IC Falagas ME Severe cytomegalovirus infection in apparently immunocompetent patients: a systematic review Virol J 2008 5 47 18371229 \n5 Gandhi MK Khanna R Human cytomegalovirus: clinical aspects, immuneregulation, and emerging treatments Lancet Infect Dis 2004 4 725 738 15567122 \n6 Polman CH O’Connor PW Havrdova E A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis N Engl J Med 2006 354 899 910 16510744 \n7 Warnke C Olsson T Hartung HP PML: the dark side of immunotherapy in multiple sclerosis Trends Pharmacol Sci 2015 36 799 801 26497099 \n8 Gold R Jawad A Miller DH Expert opinion: guidelines for the use of natalizumab in multiple sclerosis patients previously treated with immunomodulating therapies J Neuroimmunol 2007 187 156 158 17499366 \n9 Fernandez O Best practice in the use of natalizumab in multiple sclerosis Ther Adv Neurol Disord 2013 6 69 79 23483450 \n10 Fine AJ Sorbello A Kortepeter C Scarazzini L Central nervous system herpes simplex and varicella zoster virus infections in natalizumab-treated patients Clin Infect Dis 2013 57 849 852 23728144 \n11 Crespo P Dias N Marques N Saraiva da Cunha J Gastritis as a manifestation of primary CMV infection in an immunocompetent host BMJ Case Rep 2015 2015 pii:bcr2014206991 \n12 Epstein DJ Dunn J Deresinski S Infectious complications of multiple sclerosis therapies: implications for screening, prophylaxis, and management Open Forum Infect Dis 2018 5 8 ofy174 30094293 \n13 Clerico M De Mercanti S Artusi CA Durelli L Naismith R Active CMV infection in two patients with multiple sclerosis treated with alemtuzumab Multiple Sclerosis J 2017 23 874 876 \n14 Goodgame RW Gastrointestinal cytomegalovirus disease Ann Intern Med 1993 119 924 935 8215005\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2284-2594",
"issue": "6(2)",
"journal": "European journal of case reports in internal medicine",
"keywords": "Infection; cytomegalovirus; multiple sclerosis; natalizumab; viruses",
"medline_ta": "Eur J Case Rep Intern Med",
"mesh_terms": null,
"nlm_unique_id": "101648453",
"other_id": null,
"pages": "001046",
"pmc": null,
"pmid": "30931272",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "10698156;12588074;15567122;16510744;17499366;18371229;19136435;23483450;23728144;26150611;26497099;28290755;30094293;8215005",
"title": "Self-Limited Cytomegalovirus Infection During Natalizumab Treatment for Multiple Sclerosis.",
"title_normalized": "self limited cytomegalovirus infection during natalizumab treatment for multiple sclerosis"
} | [
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"companynumb": "BR-BIOGEN-2019BI00725097",
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"abstract": "Sarcomas of the kidney during pregnancy are very rare and should be treated by an interdisciplinary team with respect to the actual trimester. Decisions regarding treatment have to be made with the patient and her family.",
"affiliations": "Institute of Pathology, University Clinic of Münster, Germany. O_Bettendorf@web.de",
"authors": "Bettendorf|Olaf|O|;Bierer|Stefan|S|;Köhler|Gabriele|G|;Piechota|Hans-Jürgen|HJ|;Mesters|Rolf M|RM|;Klockenbusch|Walter|W|",
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"issn_linking": "0302-2838",
"issue": "50(1)",
"journal": "European urology",
"keywords": null,
"medline_ta": "Eur Urol",
"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007680:Kidney Neoplasms; D008279:Magnetic Resonance Imaging; D008297:Male; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D011256:Pregnancy Outcome; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "7512719",
"other_id": null,
"pages": "148-50",
"pmc": null,
"pmid": "16519992",
"pubdate": "2006-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Neoplasia of the kidney--a rare event during pregnancy.",
"title_normalized": "neoplasia of the kidney a rare event during pregnancy"
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"abstract": "Purpose: This report describes a case of metronidazole injection infiltration which contrasts the sole other case report in the literature at this time, as the patient described herein experienced mild signs and symptoms with prompt resolution and no significant sequelae. Summary: The patient experienced metronidazole injection infiltration during administration open to gravity via an 18-gauge peripheral catheter in the left brachial vein. The site was examined at bedside within approximately 30 minutes of the incident and was noted to be slightly edematous, erythemic, and painful in terms of a 5.5 × 6.6-cm area. No blanching, blister formation, induration, skin discoloration, or diminished capillary refill were observed. The event was conservatively managed in the form of catheter discontinuation and marking of the affected area with a patient skin marker, as hyaluronidase was not administered due to a product osmolarity of ~314 mOsM/L and pH of 5.8. A bedside evaluation the next morning revealed full resolution of the previously described symptoms. The patient was discharged from the facility 11 days later without further complications from the infiltration event. Conclusion: We describe a case of metronidazole injection infiltration which did not require pharmacologic or nonpharmacologic interventions and resulted in complete resolution. This case supplements the current literature by contrasting the sole other case report which resulted in profound necrosis near the intravenous access site. This case suggests metronidazole infiltrations may not require clinician alarm or treatment if events occur under circumstances similar to that which is presented.",
"affiliations": "The Ohio State University Wexner Medical Center, Columbus, OH, USA.;CHI Franciscan Health St. Clare Hospital, Lakewood, WA, USA.",
"authors": "North|Andrew M|AM|;Yee|Justin M|JM|",
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"issue": "52(8)",
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"keywords": "case reports; extravasation of diagnostic and therapeutic materials; infiltration; infusions (intravenous); metronidazole",
"medline_ta": "Hosp Pharm",
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"nlm_unique_id": "0043175",
"other_id": null,
"pages": "559-563",
"pmc": null,
"pmid": "29276289",
"pubdate": "2017-09",
"publication_types": "D016428:Journal Article",
"references": "10512506;16839898;6628223;8708844;24420913;4009919;10349613;21734520;4160648;811181;14749578;15728059;17667395;8550135;21255716;9646289;24202118;111645;19410998;24714850",
"title": "A Case of Metronidazole Injection Infiltration Without Sequelae.",
"title_normalized": "a case of metronidazole injection infiltration without sequelae"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2017SP014417",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METRONIDAZOLE"
},
"drugadditio... |
{
"abstract": "BACKGROUND\nGlioblastoma (GB) is the most common malignant primary central nervous system tumor in adults. Standard-of-care therapy includes surgical resection, radiotherapy and temozolomide, but nearly all patients experience disease progression. The purpose of this study was to describe 2 cohorts of patients with recurrent GB submitted to second-line treatment with procarbazine/lomustine/vincristine (PCV) or bevacizumab/irinotecan (BI).\n\n\nMETHODS\nRetrospective analysis of GB patients treated in our center with PCV or BI, after progression with temozolomide, between 2004 and 2012.\n\n\nRESULTS\nAmong 60 patients, 41 were treated with BI and 19 with PCV. According to the Macdonald criteria, the overall response rate in the BI group was 66% (n = 27) while it was 11% (n = 2) in the PCV group. The median progression-free survival was 5 and 3 months in the BI and PCV group, respectively. The median overall survival (OS) since second-line chemotherapy was 9 months in the BI group and 5 months in the PCV group. The latter group had a worse toxicity profile (grade 3-4: 52.6% vs. 22.0%; grade 1-2: 89.5% vs. 68.3%).\n\n\nCONCLUSIONS\nThe BI cohort had higher response rates, almost twice the OS and a lower degree of toxicity in contrast to the PCV group. The small number of patients and historical cohorts limits these comparisons.",
"affiliations": "Department of Neurosurgery, Centro Hospitalar de São João, Porto, Portugal.",
"authors": "Carvalho|Bruno F|BF|;Fernandes|Ana C|AC|;Almeida|Daniela S|DS|;Sampaio|Luísa V|LV|;Costa|Andreia|A|;Caeiro|Claudia|C|;Osório|Lígia|L|;Castro|Lígia|L|;Linhares|Paulo|P|;Damasceno|Margarida|M|;Vaz|Rui C|RC|",
"chemical_list": "D000068258:Bevacizumab; D011344:Procarbazine; D014750:Vincristine; D000077146:Irinotecan; D008130:Lomustine; D002166:Camptothecin",
"country": "Netherlands",
"delete": false,
"doi": "10.1159/000431236",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2296-5270",
"issue": "38(7-8)",
"journal": "Oncology research and treatment",
"keywords": null,
"medline_ta": "Oncol Res Treat",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D001932:Brain Neoplasms; D002166:Camptothecin; D017024:Chemotherapy, Adjuvant; D015331:Cohort Studies; D005260:Female; D005909:Glioblastoma; D006801:Humans; D000077146:Irinotecan; D008130:Lomustine; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011174:Portugal; D015995:Prevalence; D011344:Procarbazine; D012189:Retrospective Studies; D018570:Risk Assessment; D016019:Survival Analysis; D015996:Survival Rate; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "101627692",
"other_id": null,
"pages": "348-54",
"pmc": null,
"pmid": "26278578",
"pubdate": "2015",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Second-Line Chemotherapy in Recurrent Glioblastoma: A 2-Cohort Study.",
"title_normalized": "second line chemotherapy in recurrent glioblastoma a 2 cohort study"
} | [
{
"companynumb": "PT-SUN PHARMACEUTICAL INDUSTRIES LTD-2015R1-106818",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TEMOZOLOMIDE"
},
"dr... |
{
"abstract": "OBJECTIVE\nTo describe a case of cefazolin-induced leukopenia in a critically ill patient who developed this adverse reaction upon rechallenge with cefoxitin.\n\n\nMETHODS\nA 22-year-old male was admitted after a motor vehicle crash. beta-Lactam therapy was initiated with vancomycin, cefepime, and metronidazole and, upon identification of methicillin-sensitive Staphylococcus aureus bacteremia 4 days later, therapy was narrowed to cefazolin 1 g every 12 hours. The dose was adjusted to 1 g every 12 hours during continuous venovenous hemodialysis. Imipenem was given for 2 days, resulting in a total of 18 days of beta-lactam treatment, at which time he developed significant leukopenia (white blood cell [WBC] count 0.9 x 10(3)/microL). Antimicrobial treatment was changed to tigecycline and continued for suspected pleural space infection. The patient's WBC count recovered within 4 days after the change in therapy. He was taken to surgery 8 days after cefazolin was discontinued and received perioperative prophylaxis with cefoxitin (total dose 3 g). Subsequently, the patient again became severely leukopenic (WBC count 2.4 x 10(3)/microL). Within a week after surgery, the patient developed septic shock secondary to multidrug-resistant Escherichia coli bacteremia and died.\n\n\nCONCLUSIONS\nbeta-Lactam-induced leukopenia is a rare but well-described adverse drug reaction. It is a cumulative dose-dependent phenomenon reported to occur most often after 2 weeks of therapy. The mechanism of leukopenia is thought to be secondary to either an immune-mediated response or direct bone marrow toxicity. Rechallenge with a different beta-lactam antibiotic has not been shown to consistently cause recurrent leukopenia. The case described here suggests an immune-related mechanism for the development of leukopenia. Use of the Naranjo probability scale determined the association between cephalosporin use and leukopenia to be probable.\n\n\nCONCLUSIONS\nCefazolin was a probable cause of this patient's leukopenia. It is important for clinicians to recognize beta-lactam-induced leukopenia and maybe recommend use of a drug from a different antibiotic class if continued treatment is indicated.",
"affiliations": "Department of Pharmacy Practice and Pharmacy Administration, Philadelphia College of Pharmacy, University of the Sciences, Philadelphia, PA 19104, USA. c.whitman@usp.edu",
"authors": "Whitman|Craig B|CB|;Joseph|Jomy M|JM|;Sjoholm|Lars O|LO|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002440:Cefoxitin",
"country": "United States",
"delete": false,
"doi": "10.1345/aph.1L183",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "42(9)",
"journal": "The Annals of pharmacotherapy",
"keywords": null,
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D001424:Bacterial Infections; D002440:Cefoxitin; D006801:Humans; D007958:Leukocyte Count; D007970:Leukopenia; D008297:Male",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "1327-32",
"pmc": null,
"pmid": "18648015",
"pubdate": "2008-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cephalosporin-induced leukopenia following rechallenge with cefoxitin.",
"title_normalized": "cephalosporin induced leukopenia following rechallenge with cefoxitin"
} | [
{
"companynumb": "US-PFIZER INC-2015179086",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METOPROLOL"
},
"drugadditional": null,
... |
{
"abstract": "We report the first clinical description of a patient with cancer with a heterozygous germline codon-stop mutation in the TYMS gene. The mutation g.657795_657826del, c.53_84del (NM_001071.2), p.Gln18Argfs*42 causes loss of function of one of the TYMS alleles, resulting in a truncated protein. This gene codifies for the target enzyme of 5-fluorouracil (5-FU), the basic treatment in colorectal cancer. The patient, diagnosed with metastatic colorectal cancer, had diarrhea and neutropenia grade 4 and mucositis and neurological toxicity grade 3 under 5-FU-based therapy and exceeded by more than 50% the average survival after metastasectomy. On the basis of the patient's characteristics and the key role of TYMS in 5-FU activity, we hypothesize that this mutation may contribute to the drug response and toxicities suffered by the patient.",
"affiliations": "Genomic Medicine Group, CIBERER, University of Santiago de Compostela, Santiago de Compostela, Spain. Electronic address: emilia.balboa@usc.es.;Hospital Pharmacy Service, University Hospital Complex of Santiago de Compostela (CHUS), Santiago de Compostela, Spain.;Hospital Pharmacy Service, University Hospital Complex of Santiago de Compostela (CHUS), Santiago de Compostela, Spain.;Genomic Medicine Group, CIBERER, University of Santiago de Compostela, Santiago de Compostela, Spain; Galician Public Foundation for Genomic Medicine, SERGAS, Santiago de Compostela, Spain; Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, KSA.;Galician Public Foundation for Genomic Medicine, SERGAS, Santiago de Compostela, Spain.",
"authors": "Balboa-Beltrán|Emilia|E|;Duran|Goretti|G|;Lamas|María Jesús|MJ|;Carracedo|Angel|A|;Barros|Francisco|F|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D013940:Thymidylate Synthase; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-6196",
"issue": "90(9)",
"journal": "Mayo Clinic proceedings",
"keywords": null,
"medline_ta": "Mayo Clin Proc",
"mesh_terms": "D000964:Antimetabolites, Antineoplastic; D015179:Colorectal Neoplasms; D003967:Diarrhea; D005472:Fluorouracil; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007970:Leukopenia; D008297:Male; D008875:Middle Aged; D052016:Mucositis; D011110:Polymorphism, Genetic; D013940:Thymidylate Synthase",
"nlm_unique_id": "0405543",
"other_id": null,
"pages": "1298-303",
"pmc": null,
"pmid": "26210704",
"pubdate": "2015-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Long Survival and Severe Toxicity Under 5-Fluorouracil-Based Therapy in a Patient With Colorectal Cancer Who Harbors a Germline Codon-Stop Mutation in TYMS.",
"title_normalized": "long survival and severe toxicity under 5 fluorouracil based therapy in a patient with colorectal cancer who harbors a germline codon stop mutation in tyms"
} | [
{
"companynumb": "ES-FRESENIUS KABI-FK201504888",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "IRINOTECAN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nLevetiracetam is used in the treatment of some forms of epilepsy. In renal impairment and patients on chronic haemodialysis, dose adjustment is required. We report a case.\n\n\nMETHODS\nThis case report describes a woman on levetiracetam treatment who presented with generalized tonic-clonic seizures during a haemodialysis session. We report on treatment adjustment and on the impact of dialysis on levetiracetam levels.\n\n\nCONCLUSIONS\nHaemodialysis reduces serum levetiracetam concentration and can lead to subtherapeutic levels. Close monitoring is necessary when dialysis is used on patients receiving anticonvulsant drugs that are extensively eliminated by the procedure.",
"affiliations": "Servicio de Farmacia, Área del Medicamento, Hospital Universitari i Politècnic La Fe, Valencia, Spain.;Unidad de Cuidados Intensivos, Hospital Universitari i Politècnic La Fe, Valencia, Spain.;Servicio de Farmacia, Área del Medicamento, Hospital Universitari i Politècnic La Fe, Valencia, Spain.;Servicio de Farmacia, Área del Medicamento, Hospital Universitari i Politècnic La Fe, Valencia, Spain.;Unidad de Cuidados Intensivos, Hospital Universitari i Politècnic La Fe, Valencia, Spain.;Servicio de Farmacia, Área del Medicamento, Hospital Universitari i Politècnic La Fe, Valencia, Spain.",
"authors": "Company-Albir|M J|MJ|;Ruíz-Ramos|J|J|;Solana Altabella|A|A|;Marqués-Miñana|M R|MR|;Vicent|C|C|;Poveda|J L|JL|",
"chemical_list": "D000927:Anticonvulsants; D000077287:Levetiracetam; D010889:Piracetam",
"country": "England",
"delete": false,
"doi": "10.1111/jcpt.12568",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-4727",
"issue": "42(6)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "dialysis; epilepsy; haemodialysis; levetiracetam; monitoring; pharmacokinetics; seizures",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D004827:Epilepsy; D005260:Female; D006801:Humans; D000077287:Levetiracetam; D010889:Piracetam; D006435:Renal Dialysis; D012640:Seizures",
"nlm_unique_id": "8704308",
"other_id": null,
"pages": "774-775",
"pmc": null,
"pmid": "28555936",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Haemodialysis significantly reduces serum levetiracetam levels inducing epileptic seizures: Case report.",
"title_normalized": "haemodialysis significantly reduces serum levetiracetam levels inducing epileptic seizures case report"
} | [
{
"companynumb": "ES-UCBSA-2017022881",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "1",
... |
{
"abstract": "Atypical femoral fractures are atraumatic or minimally traumatic fractures and rare side effects of bone resorption inhibitors. Bone resorption inhibitors are frequently used in the treatment of prostate cancer.\nA 62-year-old man complained of difficulty in walking and left lower limb pain. Androgen deprivation and denosumab therapy for prostate cancer-induced bone metastasis was initiated 27 months ago. Even though the prostate-specific antigen level did not increase, imaging studies indicated the possibility of bone metastasis. The patient underwent bone biopsy; however, no malignancy was detected. Afterward, he had a fall, causing a complete fracture in his left femur.\nAtypical femoral fractures occasionally mimic typical imaging findings and outcomes of bone metastasis. This case is important for recognizing such cases.",
"affiliations": "Department of Urology Shirakawa Kousei General Hospital Shirakawa Fukushima Japan.;Department of Orthopedic Surgery Shirakawa Kousei General Hospital Shirakawa Fukushima Japan.;Department of Urology Shirakawa Kousei General Hospital Shirakawa Fukushima Japan.;Department of Pathology Shirakawa Kousei General Hospital Shirakawa-shi Fukushima Japan.;Department of Urology Shirakawa Kousei General Hospital Shirakawa Fukushima Japan.",
"authors": "Nezu|Kunihisa|K|https://orcid.org/0000-0002-4238-866X;Endo|Yuji|Y|;Katayama|Hiromichi|H|https://orcid.org/0000-0001-8339-5164;Nozawa|Yoshihiro|Y|;Kyan|Atsushi|A|",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.1002/iju5.12104",
"fulltext": "\n==== Front\nIJU Case Rep\nIJU Case Rep\n10.1002/(ISSN)2577-171X\nIJU5\nIJU Case Reports\n2577-171X John Wiley and Sons Inc. Hoboken \n\n10.1002/iju5.12104\nIJU512104\nCase Report\nCase Reports\nCase of atypical femoral fractures that mimicked the typical imaging findings of prostate cancer‐induced bone metastasis\nFractures mimicking bone metastasisK Nezu et al.Nezu Kunihisa https://orcid.org/0000-0002-4238-866X\n1\n Endo Yuji \n2\n Katayama Hiromichi https://orcid.org/0000-0001-8339-5164\n1\nkataman0924@gmail.com Nozawa Yoshihiro \n3\n Kyan Atsushi \n1\n \n1 \nDepartment of Urology\nShirakawa Kousei General Hospital\nShirakawa\nFukushima\nJapan\n\n\n2 \nDepartment of Orthopedic Surgery\nShirakawa Kousei General Hospital\nShirakawa\nFukushima\nJapan\n\n\n3 \nDepartment of Pathology\nShirakawa Kousei General Hospital\nShirakawa‐shi\nFukushima\nJapan\n\n* Correspondence: Hiromichi Katayama Ph.D., Department of Urology, Shirakawa Kousei General Hospital, 2‐1 Kamiyazirou, Toyochi, Shirakawa, Fukushima 961-0005, Japan. Email: kataman0924@gmail.com\n04 7 2019 \n11 2019 \n2 6 10.1111/iju5.v2.6303 306\n03 3 2019 18 6 2019 © 2019 The Authors. IJU Case Reports published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Urological Association.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Introduction\nAtypical femoral fractures are atraumatic or minimally traumatic fractures and rare side effects of bone resorption inhibitors. Bone resorption inhibitors are frequently used in the treatment of prostate cancer.\n\nCase presentation\nA 62‐year‐old man complained of difficulty in walking and left lower limb pain. Androgen deprivation and denosumab therapy for prostate cancer‐induced bone metastasis was initiated 27 months ago. Even though the prostate‐specific antigen level did not increase, imaging studies indicated the possibility of bone metastasis. The patient underwent bone biopsy; however, no malignancy was detected. Afterward, he had a fall, causing a complete fracture in his left femur.\n\nConclusion\nAtypical femoral fractures occasionally mimic typical imaging findings and outcomes of bone metastasis. This case is important for recognizing such cases.\n\natypical femoral fracturesbone metastasisbone resorption inhibitorsdenosumabprostate cancer source-schema-version-number2.0cover-dateNovember 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.8.4 mode:remove_FC converted:08.06.2020\n\n\nNezu \nK \n, \nEndo \nY \n, \nKatayama \nH \n, \nNozawa \nY \n, \nKyan \nA \n. Case of atypical femoral fractures that mimicked the typical imaging findings of prostate cancer-induced bone metastasis\n. IJU Case Rep . 2019 ; 2 : 303 –6\n.\n==== Body\nAbbreviations & Acronyms\nADTandrogen deprivation therapy\n\nAFFatypical femoral fracture\n\nBRIbone resorption inhibitor\n\nCTcomputed tomography\n\nIMintramedullary\n\nMRImagnetic resonance imaging\n\nPCprostate cancer\n\nPETpositron emission tomography\n\nPSAprostate‐specific antigen\n\nSREskeletal‐related event\n\n\nKeynote message\nAFFs are a rare side effect of BRIs used in the treatment of PC. BRIs are frequently used for bone management of PC. There is clinical significance for recognizing such diagnostic dilemma.\n\n\n\n\nIntroduction\nAFFs are minimally traumatic fractures located along the femoral diaphysis in areas just distal to the lesser trochanter and just proximal to the supracondylar flare.1 AFFs can be caused by obesity, stress, osteoporosis, and low bone turnover. AFFs are a known side effect of BRIs, including bisphosphonates and denosumab.2 AFFs account for 0.3% of all femoral fracture cases and 90% of cases occur in women.3 AFFs are categorized as incomplete or complete fractures and can often progress from incomplete to complete.4 The incidence of AFFs in cancer patients is 0.05 per 100 000 cases per year, with an odds ratio of 300 (patients administered with BRIs vs patients not administered BRIs).5 The incidence of AFF increases when BRIs are administered for longer periods.6\n\n\nPSA levels can be used to detect and monitor PC. Only 1% of PC cases progress when PSA levels are <0.1 ng/mL.7 Metastasis without an elevation in tumor marker levels is atypical.\n\nAmong newly diagnosed PC cases, 6% are metastatic cases and 80% are bone metastasis cases.8 SREs are defined as pathological fractures, spinal cord compression, and radiation therapy‐ or bone surgery‐related events. Bone metastasis causes SRE within 2 years in 41.9% of PC patients.9 BRIs decrease the incidence of SRE by inhibiting bone metastasis;10 however, in rare cases, BRI can cause AFFs.1\n\n\nWe present an AFF that mimicked typical imaging findings and SREs of PC‐induced bone metastasis. Although this is the third case of AFF in PC, to the best of our knowledge, our case report is the first to reveal pathological findings involved with denosumab and contain detailed imaging evaluation such as MRI and PET/CT.\n\nCase presentation\nA 62‐year‐old man was admitted to our hospital for left lower limb pain with no prior history of injury. He reported regularly dismounting a forklift by using his left leg. He was diagnosed with bone‐metastatic PC 24 months prior to admission, with a Gleason score of 4 + 4 and an initial PSA level of 219 ng/mL. Thereafter, he was administered denosumab (120 mg) every 3 months and underwent ADT.\n\nAn X‐ray image of his left femur showed a spike with no clear fracture lines (Fig. 1a). Testing revealed that his PSA was within the normal range at 0.01 ng/mL. However, MRI of his left femur revealed a mass in the bone marrow (Fig. 2a–e), and PET‐CT revealed an accumulation of SUVmax 2.7 (Fig. 2f,g). Therefore, we could not dismiss the possibility of bone metastasis. A bone biopsy was performed 16 days post‐admission (Fig. 1b), and the results revealed no malignancy (Fig. 3). Pathological findings also revealed osteoblasts prominently covering the cancellous bone with almost no osteoclasts (Fig. 3a,b).\n\nFigure 1 (a) X‐ray image of the left femoral region showing hypertrophic bone. (b) X‐ray examination findings following bone biopsy of the left femur. (c) CT image showing that the left femur was completely fractured following a fall from a standing position.\n\nFigure 2 (a) T1‐weighted magnetic resonance image showing that the mass in the left femur demonstrates the same low signal as the surrounding muscle. (b) T2‐weighted magnetic resonance image showing that the mass in the left femur demonstrates the same low signal as the surrounding muscle, but the border is unclear. (c) Contrast‐enhanced T1‐weighted magnetic resonance image showing homogeneously contrasted bone marrow. (d) Diffusion‐weighted magnetic resonance image showing a mildly high signal in the mass in the left femur. (e) The apparent diffusion coefficient of the magnetic resonance image shows a mildly high‐intensity signal. (f) CT image of the left femur: the increase in signal intensity allows for the recognition of the bone marrow. (g) PET‐CT imaging revealing a mild accumulation of SUVmax 2.7 in the portion of the left femur where pain was experienced (shown within the circle).\n\nFigure 3 (a) Bone marrow biopsy specimen (hematoxylin‐eosin staining). Malignancy was not observed. (b) An enlarged image of the bone marrow cancellous bone (shown within the blue square in a). The cancellous bone was completely covered by several osteoblasts (arrow), but few osteoclasts were observed. (c) An enlarged image of the bone marrow showing osteomyelitis, with invasion of lymphocytes, plasma cells, and eosinophils (shown within the red square in a).\n\nThe patient fell from a standing position and completely fractured his left femur 20 days post‐admission (Fig. 1c). On the following day, he underwent IM nailing. He was discharged, with walking sticks, 48 days post‐admission, and denosumab was discontinued. The final diagnosis was AFF based on pathological findings and clinical course 4 months after hospitalization.\n\nDiscussion\nThis case revealed a complete atraumatic, noncomminuted, and transverse fracture of the left femur, which fulfilled all the major diagnostic criteria for AFF (Table S1).1 The clinical course suggested progression from an incomplete to complete fracture. Long‐term use of BRI is recently considered a cause of AFF.2 Our literature review revealed the rarity of AFF cases caused by PC. Only three such cases have been reported to date11, 12 (Table 1), in which all patients received ADT and BRI therapy for more than 2 years.\n\nTable 1 Review of studies of atypical femoral fractures in prostate cancer patients\n\nCase No.\tAuthor\tYear\tAge\tSex\tBone metastasis at diagnosis\tTreatment for PC\tTime between pain and complete AFF, months (location of AFF)\tTime for anti‐resorptive medications, months (medication)\tTreatment for AFF\t\n1\tReddy and Gupta11\n\t2012\t70\tMale\tNo\tADT\t0 (right femoral)\t24 (zoledronic acid)\tIM nailing, teriparatide\t\n2\tAustin et al.12\n\t2017\t86\tMale\tYes\tADT\t5 (right femoral)\t42 (denosumab)\tIM nailing, radiation\t\n3\tOur case\t2019\t62\tMale\tYes\tADT\t2 (left femoral)\t27 (denosumab)\tIM nailing, stop denosumab\t\nJohn Wiley & Sons, LtdThe adequate duration and timing of BRI therapy in PC remain unclear. ADT elevated significant incidence of fractures and osteoporosis in PC patients.13, 14 Combined ADT and BRI may be related to the occurrence of AFF. However, AFF is a very rare disease, and a recent meta‐analysis presented that BRIs were effective in osteoporosis caused by ADT.15 Even if there is a risk of AFF, adequate administration of BRI should be clinically recommended for bone management in PC.\n\nWe could not dismiss the possibility of bone metastasis. The characteristics of the fracture often made it difficult to differentiate developing stress fractures like AFF from malignancies.16, 17, 18 In this case, the result of MRI and PET‐CT also mimics bone metastasis (Fig. 2). Bone biopsy should be considered when image examination cannot confirm diagnosis. Currently, there is no established method of distinguishing bone fracture and metastasis except biopsy, and we hope that unnecessary treatment and biopsy will be prevented by further accumulation of cases.\n\nIn this case, AFF might have been caused by denosumab. Pathological findings were consistent with suppressed bone turnover caused by BRI.19 Low bone turnover can cause micro‐damage accumulation and additional fractures. AFF affects 28% of the contralateral femor.1 Incomplete AFFs often progress to complete fractures. Discontinuation of BRIs is recommended for treatment.\n\nConclusion\nThis is a rare case of AFF related to BRI administration. It was difficult to discriminate between AFF and bone metastasis through X‐ray, MRI, and PET‐CT. When treating bone metastasis by PC with BRIs, the possibility of AFFs should be considered. The incidence of AFFs caused by PC remains unknown, and further study is required to clarify this.\n\nConflict of interest\nThe authors declare no conflict of interest.\n\nSupporting information\n\nTable S1. Major features of the ASBMR† Task Force 2013 Revised Case Definition of AFFs.\n\nClick here for additional data file.\n\n Acknowledgment\nWe thank Editage (www.editage.jp) for English language editing.\n==== Refs\nReferences\n1 \n\nShane \nE \n, \nBurr \nD \n, \nAbrahamsen \nB \n\net al\nAtypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research\n. J. Bone Miner. Res. \n2014 ; 29 : 1 –23\n.23712442 \n2 \n\nBlack \nDM \n, \nAbrahamsen \nB \n, \nBouxsein \nML \n, \nEinhorn \nT \n, \nNapoli \nN \n. Atypical femur fractures ‐ review of epidemiology, relationship to bisphosphonates, prevention and clinical management\n. Endocr. Rev. \n2019 ; 40 : 333 –6\n.30169557 \n3 \n\nSchilcher \nJ \n, \nKoeppen \nV \n, \nAspenberg \nP \n, \nMichaëlsson \nK \n. Risk of atypical femoral fracture during and after bisphosphonate use\n. Acta Orthop. \n2015 ; 86 : 100 –7\n.25582459 \n4 \n\nBanffy \nMB \n, \nVrahas \nMS \n, \nReady \nJE \n, \nAbraham \nJA \n. Nonoperative versus prophylactic treatment of bisphosphonate‐associated femoral stress fractures\n. Clin. Orthop. \n2011 ; 469 : 2028 –34\n.21350886 \n5 \n\nEdwards \nBJ \n, \nSun \nM \n, \nWest \nDP \n\net al\nIncidence of atypical femur fractures in cancer patients: the MD Anderson Cancer Center Experience\n. J. Bone Miner. Res. \n2016 ; 31 : 1569 –76\n.26896384 \n6 \n\nDell \nRM \n, \nAdams \nAL \n, \nGreene \nDF \n\net al\nIncidence of atypical nontraumatic diaphyseal fractures of the femur\n. J. Bone Miner. Res. \n2012 ; 27 : 2544 –50\n.22836783 \n7 \n\nLeibovici \nD \n, \nSpiess \nPE \n, \nAgarwal \nPK \n\net al\nProstate cancer progression in the presence of undetectable or low serum prostate‐specific antigen level\n. Cancer \n2007 ; 109 : 198 –204\n.17171704 \n8 \n\nGandaglia \nG \n, \nKarakiewicz \nPI \n, \nBriganti \nA \n\net al\nImpact of the site of metastases on survival in patients with metastatic prostate cancer\n. Eur. Urol. \n2015 ; 68 : 325 –34\n.25108577 \n9 \n\nOster \nG \n, \nLamerato \nL \n, \nGlass \nAG \n\net al\nNatural history of skeletal‐related events in patients with breast, lung, or prostate cancer and metastases to bone: a 15‐year study in two large US health systems\n. Support. Care Cancer \n2013 ; 21 : 3279 –86\n.23884473 \n10 \n\nMacedo \nF \n, \nLadeira \nK \n, \nPinho \nF \n\net al\nBone metastases: an overview\n. Oncol. Rev. \n2017 ; 11 : 321 .28584570 \n11 \n\nReddy \nSV \n, \nGupta \nSK \n. Atypical femoral shaft fracture in a patient with non‐metastatic prostate cancer on zoledronic acid therapy: effect of therapy or coincidence?\n\nSingapore Med. J. \n2012 ; 53 : e52 –4\n.22434305 \n12 \n\nAustin \nDC \n, \nTorchia \nMT \n, \nKlare \nCM \n\net al\nAtypical femoral fractures mimicking metastatic lesions in 2 patients taking denosumab\n. Acta Orthop. \n2017 ; 88 : 351 –3\n.28077015 \n13 \n\nLassemillante \nAC \n, \nDoi \nSA \n, \nHooper \nJD \n\net al\nPrevalence of osteoporosis in prostate cancer survivors: a meta‐analysis\n. Endocrine \n2014 ; 45 : 370 –81\n.24174178 \n14 \n\nShahinian \nVB \n, \nKuo \nYF \n, \nFreeman \nJL \n\net al\nRisk of fracture after androgen deprivation for prostate cancer\n. N. Engl. J. Med. \n2005 ; 352 : 154 –64\n.15647578 \n15 \n\nPoon \nY \n, \nPechlivanoglou \nP \n, \nAlibhai \nSMH \n\net al\nSystematic review and network meta‐analysis on the relative efficacy of osteoporotic medications: men with prostate cancer on continuous androgen‐deprivation therapy to reduce risk of fragility fractures\n. BJU Int. \n2018 ; 121 : 17 –28\n.28921820 \n16 \n\nO'Sullivan \nGJ \n, \nCarty \nFL \n, \nCronin \nCG \n. Imaging of bone metastasis: an update\n. World J. Radiol. \n2015 ; 7 : 202 –11\n.26339464 \n17 \n\nToro \nG \n, \nOjeda‐Thies \nC \n, \nCalabrò \nG \n\net al\nManagement of atypical femoral fracture: a scoping review and comprehensive algorithm\n. BMC Musculoskelet. Disord. \n2016 ; 17 : 227 .27215972 \n18 \n\nNachtrab \nO \n, \nCassar‐Pullicino \nVN \n, \nLalam \nR \n\net al\nRole of MRI in hip fractures, including stress fractures, occult fractures, avulsion fractures\n. Eur. J. Radiol. \n2012 ; 81 : 3813 –23\n.21531099 \n19 \n\nSchilcher \nJ \n, \nSandberg \nO \n, \nIsaksson \nH \n\net al\nHistology of 8 atypical femoral fractures: remodeling but no healing\n. Acta Orthop. \n2014 ; 85 : 280 –6\n.24786905\n\n",
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"title": "Case of atypical femoral fractures that mimicked the typical imaging findings of prostate cancer-induced bone metastasis.",
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"abstract": "A 65-year-old man was diagnosed with leptomeningeal carcinomatosis based on the findings of cerebrospinal fluid cytology and magnetic resonance imaging(MRI).Treatment with erlotinib and bevacizumab was initiated, and partial improvement in consciousness and MRI findings were obtained.However, it was difficult to continue the treatment because of elevation in levels of liver enzymes and melena.We switched the treatment to afatinib monotherapy, and his consciousness improved immediately.Progression -free survival and overall survival from the initiation of the treatment with afatinib were 7 and 9.4 months, respectively. This clinical course suggests activity of afatinib for central nervous system lesions of EGFRmutated lung cancer.",
"affiliations": "First Dept. of Internal Medicine, Toyama University Hospital.",
"authors": "Tanaka|Hiroaki|H|;Inomata|Minehiko|M|;Hayashi|Ryuji|R|;Shimokawa|Kazuki|K|;Tokui|Kotaro|K|;Okazawa|Seisuke|S|;Kambara|Kenta|K|;Yamada|Toru|T|;Miwa|Toshiro|T|;Kashii|Tatsuhiko|T|;Konishi|Hirofumi|H|;Tobe|Kazuyuki|K|",
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"mesh_terms": "D000230:Adenocarcinoma; D000077192:Adenocarcinoma of Lung; D000077716:Afatinib; D000368:Aged; D000970:Antineoplastic Agents; D056486:Chemical and Drug Induced Liver Injury; D000069347:Erlotinib Hydrochloride; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D055756:Meningeal Carcinomatosis; D011799:Quinazolines; D016896:Treatment Outcome",
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"title": "A Case of Lung Adenocarcinoma Presenting with Leptomeningeal Carcinomatosis Successfully Treated with Afatinib after Erlotinib-Induced Hepatotoxicity.",
"title_normalized": "a case of lung adenocarcinoma presenting with leptomeningeal carcinomatosis successfully treated with afatinib after erlotinib induced hepatotoxicity"
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"abstract": "BACKGROUND\nUrinary lithiasis is one of severe postoperative complications in patients undergoing renal transplantation, possibly leading to anuria, urinary infection, or even acute renal failure. Potassium sodium hydrogen citrate (PSHC), a potassium-bearing citrate, is commonly prescribed to prevent stone formation.\nA 25-year-old man (patient 1) and a 31-year-old man (patient 2) receiving renal transplantation for end-stage renal disease (ESRD) were enrolled in this study. They were given 10 g/day of PSHC granules from the ninth day to the 17th day after surgery. Patient 1 presented chest tightness, nausea, muscle weakness, and ascending paralysis on the 10th day. Patient 2 presented weak waves on EGG on the 17th day. Moreover, their serum potassium concentrations (SPCs) were 7.67 and 6.05 mmol/L, respectively.\n\n\nMETHODS\nAcute hyperkalemia.\n\n\nMETHODS\nHemo-filtration was performed for patient 1, while patient 2 received 10% calcium gluconate 10 mL, 5% NaHCO3 125 mL, and 10% glucose 500 mL with the addition of 10 units of insulin through intravenous drip.\n\n\nRESULTS\nTheir SPCs dropped to the normal range.\n\n\nCONCLUSIONS\nPhysicians should pay close attentions to potential risks caused by PSHC, and monitor the SPCs to minimize the occurrence of hyperkalemia.",
"affiliations": "Department of Nephropathy, The Second Affiliated Hospital, Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, China.",
"authors": "Wang|Lin|L|;Cui|Yinglin|Y|;Zhang|Jianwei|J|;Zhang|Qinsheng|Q|",
"chemical_list": "D004232:Diuretics; D019357:Potassium Citrate",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 29049166MD-D-16-0529010.1097/MD.0000000000006933069335200Research ArticleClinical Case ReportSafety of potassium-bearing citrate in patients with renal transplantation A case reportWang Lin PhDCui Yinglin PhD∗Zhang Jianwei PhDZhang Qinsheng PhDLing. Shizhang Department of Nephropathy, The Second Affiliated Hospital, Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, China.∗ Correspondence: Yinglin Cui, Department of Nephropathy, Henan Hospital of Traditional Chinese Medicine, Zhengzhou 450002, Henan, China (e-mail: dhgdhz@126.com).10 2017 20 10 2017 96 42 e693318 8 2016 20 4 2017 21 4 2017 Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc.2017This 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\nRationale:\nUrinary lithiasis is one of severe postoperative complications in patients undergoing renal transplantation, possibly leading to anuria, urinary infection, or even acute renal failure. Potassium sodium hydrogen citrate (PSHC), a potassium-bearing citrate, is commonly prescribed to prevent stone formation.\n\nPatient concerns:\nA 25-year-old man (patient 1) and a 31-year-old man (patient 2) receiving renal transplantation for end-stage renal disease (ESRD) were enrolled in this study. They were given 10 g/day of PSHC granules from the ninth day to the 17th day after surgery. Patient 1 presented chest tightness, nausea, muscle weakness, and ascending paralysis on the 10th day. Patient 2 presented weak waves on EGG on the 17th day. Moreover, their serum potassium concentrations (SPCs) were 7.67 and 6.05 mmol/L, respectively.\n\nDiagnosis:\nAcute hyperkalemia.\n\nInterventions:\nHemo-filtration was performed for patient 1, while patient 2 received 10% calcium gluconate 10 mL, 5% NaHCO3 125 mL, and 10% glucose 500 mL with the addition of 10 units of insulin through intravenous drip.\n\nOutcomes:\nTheir SPCs dropped to the normal range.\n\nLessons:\nPhysicians should pay close attentions to potential risks caused by PSHC, and monitor the SPCs to minimize the occurrence of hyperkalemia.\n\nKeywords\ncase reporthyperkalemiapotassium sodium hydrogen citraterenal transplantationOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nAllograft urolithiasis is a common postoperative complication among patients receiving renal transplantation, with a reported prevalence rate ranging from 0.2% to 10%.[1–4] The disease shows different manifestations such as oliguria, anuria, and acute renal failure, leading to serious consequences. Renal transplantation patients are at a high risk of allograft urolithiasis, especially early after transplantation due to unrecovered kidney function, hyperparathyroidism, chronic urinary tract infection, etc.[5,6] Currently, the application of alkaline citrate is the major therapeutic strategy for this disease, and this agent plays important roles in preventing stone formation via increasing urinary citrate.[7–9] Potassium sodium hydrogen citrate (PSHC), a potassium-bearing citrate, is widely used to prevent stone formation. Potassium citrate (PC) represents the first-line treatment for uric acid nephrolithiasis because it just causes mild gastrointestinal tract complications under acceptable doses, without adverse effects of calcium salt precipitation.[10]\n\nThe report presented 2 unusual patients suffering from acute hyperkalemia after renal transplantation caused by PSHC granules. The transplanted kidneys for these 2 patients were from cardiac death donors from the distribution of China's Organ Transplant Response System (COTRS) at the Second Affiliated Hospital of Zhengzhou City in June 2015. Data were obtained from the combination of COTRS, pharmacy records, and departmental transplantation database. The main causes of hyperkalemia and related prevention measures were discussed as follows. To our knowledge, acute hyperkalemia caused by PSHC, especially after renal transplantation, was rarely reported in published literature.\n\n2 Case presentation\nWith normal BMI (body mass index, BMI), a 25-year-old man (patient 1, weight: 58 kg) and a 31-year-old man (patients 2, weight: 62 kg) receiving renal transplantation for end-stage renal disease (ESRD) were enrolled in the current study. The 2 patients, following normal operation processes, received the kidneys of cardiac death donors from the Second Affiliated Hospital of Zhengzhou City. General systemic examinations for these 2 patients before surgery showed normal statuses: hematocrit, 0.26 and 0.24; hemoglobin, 87 and 82 g/L; serum albumin, 43 and 40 g/L; total serum proteins, 75.8 and 70.5 mg/L; aspartate aminotransferase, 18 and 20 units/L; alkaline phosphatase, 75.7 units and 78.4 units; and alanine aminotransferase, 24 and 29 units/L. HIV and HbsAg were nonreactive. Preoperative hemodialysis was conducted for more than 6 months for both cases. The electrolyte levels and electrocardiograms (ECGs) of the patients before renal transplantation were normal. During the operation, the first patient lost 1000 mL blood, and received blood transfusion of 400 mL. The second patient needed no blood transfusion. After operations, both of them received immunosuppressive therapy with tacrolimus, mycophenolate mofetil, and prednisolone. The following described the immunosuppressive therapy in detail. Tacrolimus was given at a dose of 0.1 mg/kg/day and then adjusted to maintain target trough level of 7 to 12 ng/mL in the first month, 6 to 10 ng/mL during the second and third months, and 3 to 8 ng/mL for the following time. Mycophenolate mofetil was supplied at a daily dose of 500 mg for 3 days followed by 1 g/day. Prednisolone was provided 250 mg directly after transplantation, followed by 100 mg/day for 3 days, and then reduced to 20 mg per day for the rest of the first month following the operation. Afterwards, it was continued to be given at 10 mg/day for the next 5 months, and reduced to 5 mg/day 6 months after transplantation. Postoperative ECG detection and blood component analyses were performed to monitor the electrolyte levels of the 2 patients. At the fourth day after renal transplantation, both of the patients exhibited normal renal function, with normal blood pressure and serum potassium concentration (SPC). According to doctor's advice and the pH values of their urine, the patients were given recommended doses (10 g/day) of PSHC granules (trade name: Uralyt-U, made in Germany Madausag) from the ninth day to the 17th day after surgery. The daily dose was 4 standard measuring spoon (2.5 g/standard measuring spoon), and supposed to be taken orally 3 times a day after meal. The patients took 1 spoon of Uralyt-U in the morning and at noon, respectively, and 2 spoons in the evening. Both of them showed different symptoms after taking the drug. The first patient presented chest tightness, nausea, muscle weakness, and ascending paralysis at the second day after taking the drug with a cumulative dose of 12.5 g. This patient's blood pressure, heart rate, respiratory rate, and SPCs were 106/51 mm Hg, 46 beats/min, 16 times/min, and 7.67 mmol/L, respectively. The ECG with peaked T waves for patient 1 is shown in Fig. 1. Bedsides, hemo-filtration was performed immediately for patient 1, showing stably improved status, with SPCs dropping to 5.30 mmol/L and discomfort disappearing gradually. On the 17th day with a cumulative dose of 62.5 g, patient 2 had stable vital signs but slightly weakened waves on ECG. SPCs of patient 2 was 6.05 mmol/L. Patient 2 was then given 10% calcium gluconate 10 mL, 5% NaHCO3 125 mL, and 10% glucose 500 mL with the addition of 10 units of insulin through intravenous drip. One hour later, patient 2 recovered well and SPCs dropped to 5.48 mmol/L. The information on SPCs (mmol/L), serum creatinine concentrations (SCrCs, ×10−2 μmol/L), and blood tacrolimus concentrations (BTCs, μg/L) of the 2 cases were recorded along with the process of the treatments after renal transplantation (Fig. 2A, B).\n\nFigure 1 ECG at presentation for the first patient. ECG at presentation shows dramatically peaked T waves. ECG = electrocardiogram.\n\nFigure 2 The changes in the concentrations of SP (mmol/L), BT (mmol/L), and SCr (×10−2 μmol/L) in the 2 patients along with the passage of time after renal transplantation. (A) It shows that hyperkalemia happens on the 18th day for the first patient 1 day after taking the drug with a SP concentration of 7.67 mmol/L; (B) It shows that hyperkalemia happens on the 14th day for the second patient 5 days after taking the drug with a SP concentration of 6.05 mmol/L. BT = blood tacrolimus, SCr = serum creatinine, SP = serum potassium.\n\n3 Discussion\nStone formation, which is caused by metabolic anomalies and side effects of relevant medical treatments, is frequently observed after renal transplantation.[11] Immunosoppressive agents, such as calcineurin inhibitor glucocorticoid, may cause calculi after transplantation, thus leading to hyperuricemia, hyperoxaluria, and hypocitraturia.[12–15] Therefore, to reduce the risk of calculi formation, alkaline citrate is given to the patients to increase urinary citrate excretion and urinary solubility index.[16–19] Currently, several types of potassium-bearing citrates (PC, sodium PC, potassium magnistium citrate, and PSHC) are available. With its alkalinizing effect, PSHC can reduce urinary saturation of calcium, and then decrease ionic calcium concentration, thus preventing stone formation.[20–23] Therefore, this agent is commonly used for the prevention of stone formation among patients undergoing renal transplantation.\n\nFirst, in the present study, we found that in both cases, SPCs increased gradually and hyperkalemia only occurred 1 and 6 days after the treatment with PSHC granules for patient 1 and patient 2, respectively (Fig. 2A, B). The degrees of hyperkalemia in the 2 patients were observed to be directly influenced by PSHC. According to previous studies, single oral potassium at a dose of 0.5 mmol/kg produced a minimal increase in serum potassium, while total doses of approximately 1 mmol/kg increased serum potassium by as much as 1 mmol/L in a healthy man.[24,25] The molecular formula of PSHC is K6Na6H3(C6H5O7)5, with the molecular weight of 1321.06. According to the instructions of PSHC granules, each gram of PSHC contains 4.4 mmol potassium. Patient 1 (weight: 58 kg) presented hyperkalemia after orally taking a cumulative dose of 12.5 g PSHC, equal to 0.95 mmol/kg potassium, while patient 2 (weight: 62 kg) developed hyperkalemia after being given a cumulative dose of 62.5 g PSHC, equal to about 1 mmol/kg. For the patients undergoing renal transplantation, the cumulative doses they taking might be a “heavy” load, increasing the risk of hyperkalemia. In addition to PSHC, some other factors might also contribute to the occurrence of hyperkalemia in the 2 patients, such as the application of calcineurin inhibitors, glucocorticoids, and diuretics.[26–28] In this report, both of the cases received tacrolimus (calcineurin inhibitor) and prednisolone (a type of glucocorticoid) in immunosuppressive treatment that might increase the risk of hyperkalemia. Furthermore, blood transfusion might also stand for a potential risk factor for hyperkalemia. It was reported that supernatant potassium concentration of stored blood was frequently higher than potassium levels in normal human plasma, and that rapid intravenous infusion might allow a mass of potassium into receiver's body in a short time, thus swiftly increasing blood potassium concentration.[29,30] However, the specific mechanisms of blood transfusion inducing hyperkalemia remain unclear. Besides, surgical procedure represented another potential risk factor for hyperkalemia. Hirata et al[31] reported that anesthesia contributed to a sharp potassium increase after kidney transplantation. In a word, the application of PSHC together with the uses of calcineurin inhibitors and glucocorticoids, as well as blood transfusion and invasive surgical procedures might contribute to hyperkalemia in the 2 cases.\n\nSecond, there was a clear correlation between the application of PSHC and the occurrence of hyperkalemia, the situation also applying to other potassium-bearing citrates.[23] The correlation between PC and hyperkalemia-related complications has been investigated in previous studies.[17–19] Hyperkalemic ventricular fibrillation was even observed in patients with fine renal function after ingesting small amounts of PC (40–60 mmol/L).[23,24] It might be not harmless for patients with normal renal function even at an acceptable dosage, although there is 28 mmol potassium in 10-mL PC mixture. The recommended daily dose is up to 40 mL, more than twice the daily intake of PSHC, which means more dangers of hyperkalemia. Therefore, we suggest that more attentions should be given when potassium-bearing citrate is prescribed, especially for the elderly and those with impaired renal functions.\n\nThird, these cases highlighted potentially serious consequences of PSHC application in patients receiving renal transplantation. We would like to emphasize side effects of potassium alkaline citrate, despite its significant advantage in preventing urinary lithiasis.[24] Physicians should evaluate the role of potassium-bearing citrates besides PSHC in patients after renal transplantation, particularly in those with renal insufficiency or combination medication. It has been suggested that when coprescribing medicine, it would be better to avoid using potassium-bearing citrate that may interfere with potassium homeostasis among patients with renal dysfunction.[26,32] If not, oral dose should be reduced according to the severity of renal dysfunction. In a previous study, sodium bicarbonate did not allow additional potassium into blood, and showed an effect equivalent to potassium-bearing citrate in the treatment of urinary stone, suggesting that sodium bicarbonate might be a better choice for patients who could not tolerate PC.[33] At the moment, people can purchase all types of potassium-bearing citrates from counters in any retail pharmacies in communities, while many patients and even physicians pay little attention on this issue.\n\nConsidering the analysis results about the 2 unusual patients in our study, it was not safe to use PSHC or other potassium-bearing citrates (PC, sodium PC, and potassium magnistium citrate) for patients undergoing renal transplantation. Both frequencies and timing of potassium evaluation should be regimented to control the level of serum potassium during the therapy. Besides, the therapy should be better performed in centers with advanced equipment and more experts who make appropriate treatment plans.\n\n4 Conclusion\nThe application of PSHC may increase the risk of hyperkalemia in patients undergoing renal transplantation. Physicians should keep a watchful eye on potential risks caused by potassium-bearing citrates, and monitor SPCs to minimize the rate of drug-induced hyperkalemia.\n\nAbbreviations: BMI = Body mass index, BTCs = Blood tacrolimus concentrations, ECG = Electrocardiograms, ESRD = End-stage renal disease, PSHC = Potassium sodium hydrogen citrate, SCrCs = Serum creatinine concentrations, SPCs = Serum potassium concentrations.\n\nFunding/support: This study was supported by grant from the “National Natural Science Foundation” (No. 81573919).\n\nThe study was approved by the Ethic Committee of the authors’ hospital. Both of the patients had signed written informed consents.\n\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n[1] Ferreira Cassini M Cologna AJ Ferreira Andrade M \nLithiasis in 1,313 kidney transplants: incidence, diagnosis, and management . Transplant Proc \n2012 ;44 :2373 –5 .23026596 \n[2] Romero-Vargas L Barba Abad J Rosell Costa D \nStaghorn stones in renal graft. Presentation on two cases report and review the bibliography . Arch Esp Urol \n2014 ;67 :650 –3 .25241841 \n[3] Mamarelis G Vernadakis S Moris D \nLithiasis of the renal allograft, a rare urological complication following renal transplantation: a single-center experience of 2,045 renal transplantations . Transplant Proc \n2014 ;46 :3203 –5 .25420859 \n[4] Khositseth S Gillingham KJ Cook ME \nUrolithiasis after kidney transplantation in pediatric recipients: a single center report . Transplantation \n2004 ;78 :1319 –23 .15548970 \n[5] Cicerello E Merlo F Mangano M \nUrolithiasis in renal transplantation: diagnosis and management . Arch Ital Urol Androl \n2014 ;86 :257 –60 .25641446 \n[6] Duty BD Conlin MJ Fuchs EF \nThe current role of endourologic management of renal transplantation complications . Adv Urol \n2013 ;2013 :246520 .24023541 \n[7] del Valle EE Spivacow FR Negri AL \nCitrate and renal stones . Medicina \n2013 ;73 :363 –8 .23924538 \n[8] Krieger NS Asplin JR Frick KK \nEffect of potassium citrate on calcium phosphate stones in a model of hypercalciuria . J Am Soc Nephrol \n2015 ;26 :3001 –8 .25855777 \n[9] Aslani A Fattahi F \nFormulation, characterization and physicochemical evaluation of potassium citrate effervescent tablets . Adv Pharm Bull \n2013 ;3 :217 –25 .24312839 \n[10] Cicerello E Merlo F Maccatrozzo L \nUrinary alkalization for the treatment of uric acid nephrolithiasis . Arch Ital Urol Androl \n2010 ;82 :145 –8 .21121431 \n[11] Saxena S Sadideen H Goldsmith D \nTreating stones in transplanted kidneys . Minerva Med \n2013 ;104 :31 –40 .23392536 \n[12] Packham DK Kosiborod M \nPotential new agents for the management of hyperkalemia . Am J Cardiovasc Drugs \n2016 ;16 :19 –31 .26156040 \n[13] Gao J Shen Y Sun N \nTherapeutic effects of potassium sodium hydrogen citrate on melamine-induced urinary calculi in China . Chin Med J \n2010 ;123 :1112 –6 .20529547 \n[14] Elderwy AA Kurkar A Hussein A \nDissolution therapy versus shock wave lithotripsy for radiolucent renal stones in children: a prospective study . J Urol \n2014 ;191 (5 Suppl) :1491 –5 .24679880 \n[15] Heilberg IP Goldfarb DS \nOptimum nutrition for kidney stone disease . Adv Chronic Kidney Dis \n2013 ;20 :165 –74 .23439376 \n[16] Lyons KS McGlinchey P \nHyperkalaemic cardiac arrhythmia due to prolonged ingestion of potassium citrate . Int J Cardiol \n2009 ;131 :e134 –6 .17950945 \n[17] Browning JJ Channer KS \nHyperkalaemic cardiac arrhythmia caused by potassium citrate mixture . Br Med J (Clin Res Ed) \n1981 ;283 :1366 .\n[18] Wilson RG Farndon JR \nHyperkalaemic cardiac arrhythmia caused by potassium citrate mixture . Br Med J (Clin Res Ed) \n1982 ;284 :197 –8 .\n[19] Perez GO Oster JR Pelleya R \nHyperkalemia from single small oral doses of potassium chloride . Nephron \n1984 ;36 :270 –1 .6709118 \n[20] Bollee G Cochat P Daudon M \nRecurrence of crystalline nephropathy after kidney transplantation in APRT deficiency and primary hyperoxaluria . Canad J Kidney Health Dis \n2015 ;2 :31 .26380104 \n[21] Sadaat F Walter E \nStability of citrate and calcium dosing in citrate renal replacement therapy . Intensive Care Med Exp \n2015 ;3 :e23191 .\n[22] Jackson EC Avendt-Reeber M \nUrolithiasis in children: treatment and prevention . Curr Treat Options Pediatr \n2016 :e23492 .\n[23] Song Y Hernandez N Shoag J \nPotassium citrate decreases urine calcium excretion in patients with hypocitraturic calcium oxalate nephrolithiasis . Urolithiasis \n2016 ;44 :145 –8 .26582172 \n[24] Youssef RF Preminger GM Lipkin ME \nPotassium Citrate and Calcium Stones: Benefit or Risk . 2014 ;New York : Springer , 115–130 .\n[25] Doizi S Maalouf N Poindexter J \nPD31-07 comparison of potassium citrate, citric acid and placebo on calcium hposphate stones recurrence: preliminary results . J Urol \n2016 ;195 :e719 –20 .\n[26] Eschmann E Beeler PE Kaplan V \nPatient- and physician-related risk factors for hyperkalaemia in potassium-increasing drug-drug interactions . Eur J Clin Pharmacol \n2014 ;70 :215 –23 .24150532 \n[27] Medford-Davis L Rafique Z \nDerangements of potassium . Emerg Med Clin N Am \n2014 ;32 :329 –47 .\n[28] Ben Salem C Badreddine A Fathallah N \nDrug-induced hyperkalemia . Drug Safety \n2014 ;37 :677 –92 .25047526 \n[29] Rizos CV Milionis HJ Elisaf MS \nSevere hyperkalemia following blood transfusions: is there a link? \nWorld J Nephrol \n2017 ;6 :53 –6 .28101452 \n[30] Vraets A Lin Y Callum JL \nTransfusion-associated hyperkalemia . Transfus Med Rev \n2011 ;25 :184 –96 .21498041 \n[31] Hirata ES Pereira RI Filho GA \nHyperkalemia by Euro-Collins solution in anesthesia for renal transplantation: a case report . Braz J Anesthesiol \n2013 ;63 :429 –32 .24263050 \n[32] Ramirez E Rossignoli T Campos AJ \nDrug-induced life-threatening potassium disturbances detected by a pharmacovigilance program from laboratory signals . Eur J Clin Pharmacol \n2013 ;69 :97 –110 .22648277 \n[33] Pinheiro VB Baxmann AC Tiselius HG \nThe effect of sodium bicarbonate upon urinary citrate excretion in calcium stone formers . Urology \n2013 ;82 :33 –7 .23602798\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0025-7974",
"issue": "96(42)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000328:Adult; D004232:Diuretics; D006801:Humans; D006947:Hyperkalemia; D016030:Kidney Transplantation; D008297:Male; D011183:Postoperative Complications; D019357:Potassium Citrate; D052878:Urolithiasis",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e6933",
"pmc": null,
"pmid": "29049166",
"pubdate": "2017-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "26156040;25855777;24263050;21121431;26582172;22648277;28101452;6799102;6709118;24150532;25047526;23026596;15548970;20529547;23602798;24679880;23439376;25241841;24312839;25420859;6797547;24766936;24023541;25641446;23924538;21498041;23392536;17950945;26380104",
"title": "Safety of potassium-bearing citrate in patients with renal transplantation: A case report.",
"title_normalized": "safety of potassium bearing citrate in patients with renal transplantation a case report"
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"companynumb": "CN-CONCORDIA PHARMACEUTICALS INC.-E2B_00008739",
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"abstract": "BACKGROUND\nMacitentan is a clinically approved endothelin receptor antagonist for the treatment of pulmonary arterial hypertension (PAH). Increasing use of combination drug therapy in PAH means that it is important to recognize potential drug-drug interactions (DDIs) that could affect the efficacy and safety of macitentan in patients with PAH.\n\n\nOBJECTIVE\nTwo Phase 1 studies were conducted to investigate the effect of macitentan at steady-state on the pharmacokinetics of the breast cancer resistance protein (BCRP) substrates, rosuvastatin and riociguat in healthy male subjects. Another objective was to determine the safety and tolerability of concomitant administration of rosuvastatin or riociguat with macitentan.\n\n\nMETHODS\nHealthy male subjects received a single oral dose of rosuvastatin 10 mg (n = 20) or riociguat 1 mg (n = 20) on Day 1 (reference treatment). A loading oral dose of macitentan 30 mg was administered on Day 5 followed by macitentan 10 mg once-daily from Day 6 to Day 15 (riociguat study) or Day 6 to Day 16 (rosuvastatin study). A concomitant oral dose of rosuvastatin 10 mg or riociguat 1 mg was administered on Day 10 (test treatment). Pharmacokinetics were evaluated for 96 h after treatment on Day 1 and for 144 h (riociguat study) or 168 h (rosuvastatin study) after treatment on Day 10. To compare the reference and test treatments, the geometric mean ratio was calculated for the maximum plasma concentration (Cmax), the area under the plasma concentration-time curve (AUC) from zero (pre-dose) to time of the last measured concentration above the limit of quantification (AUC0-t), the AUC from zero to infinity (AUC0-∞) and the terminal elimination half-life (t½) of rosuvastatin, riociguat and riociguat's metabolite, M1. The difference in the time to reach maximum plasma concentration (tmax) was determined by the Wilcoxon test. Trough levels of macitentan and its metabolite, ACT-132577, were measured and safety was monitored throughout.\n\n\nRESULTS\nNinety percent confidence intervals of the geometric mean ratios were within the bioequivalence criteria of 0.80-1.25. There was no significant difference between test and reference tmax. Rosuvastatin or riociguat did not affect the steady-state concentrations of macitentan and ACT-132577. The adverse event profile was consistent with the known safety profiles of the drugs.\n\n\nCONCLUSIONS\nMacitentan 10 mg did not affect the pharmacokinetics of BCRP substrates, rosuvastatin or riociguat in healthy male subjects. EudraCT numbers: 2017-003095-31 and 2017-003502-41.",
"affiliations": "Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland. dcsonka@its.jnj.com.;Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland.;Clinical Research Services Mannheim GmbH, Mannheim, Germany.;Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland.;Aixial s.r.o., Brno, Czech Republic.;Idorsia Pharmaceuticals Ltd., Allschwil, Switzerland.;Janssen Global Clinical Pharmacology, Turnhoutseweg, Beerse, Belgium.",
"authors": "Csonka|Dénes|D|http://orcid.org/0000-0001-7797-2615;Bruderer|Shirin|S|;Schultz|Armin|A|;Soergel|Marianne|M|;Stepanova|Radka|R|;Sabattini|Giancarlo|G|;Perez-Ruixo|Juan Jose|JJ|",
"chemical_list": "C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D009363:Neoplasm Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; C542595:riociguat; C533860:macitentan",
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40261-019-00857-7",
"fulltext": "\n==== Front\nClin Drug InvestigClin Drug InvestigClinical Drug Investigation1173-25631179-1918Springer International Publishing Cham 85710.1007/s40261-019-00857-7Original Research ArticleEffect of Macitentan on the Pharmacokinetics of the Breast Cancer Resistance Protein Substrates, Rosuvastatin and Riociguat, in Healthy Male Subjects http://orcid.org/0000-0001-7797-2615Csonka Dénes +41795146879dcsonka@its.jnj.com 1Bruderer Shirin 1Schultz Armin 2Soergel Marianne 1Stepanova Radka 3Sabattini Giancarlo 4Perez-Ruixo Juan Jose 51 grid.417650.10000 0004 0439 5636Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland 2 grid.491580.1Clinical Research Services Mannheim GmbH, Mannheim, Germany 3 Aixial s.r.o., Brno, Czech Republic 4 Idorsia Pharmaceuticals Ltd., Allschwil, Switzerland 5 Janssen Global Clinical Pharmacology, Turnhoutseweg, Beerse, Belgium 24 9 2019 24 9 2019 2019 39 12 1223 1232 © The Author(s) 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Background\nMacitentan is a clinically approved endothelin receptor antagonist for the treatment of pulmonary arterial hypertension (PAH). Increasing use of combination drug therapy in PAH means that it is important to recognize potential drug–drug interactions (DDIs) that could affect the efficacy and safety of macitentan in patients with PAH.\n\nObjective\nTwo Phase 1 studies were conducted to investigate the effect of macitentan at steady-state on the pharmacokinetics of the breast cancer resistance protein (BCRP) substrates, rosuvastatin and riociguat in healthy male subjects. Another objective was to determine the safety and tolerability of concomitant administration of rosuvastatin or riociguat with macitentan.\n\nMethods\nHealthy male subjects received a single oral dose of rosuvastatin 10 mg (n = 20) or riociguat 1 mg (n = 20) on Day 1 (reference treatment). A loading oral dose of macitentan 30 mg was administered on Day 5 followed by macitentan 10 mg once-daily from Day 6 to Day 15 (riociguat study) or Day 6 to Day 16 (rosuvastatin study). A concomitant oral dose of rosuvastatin 10 mg or riociguat 1 mg was administered on Day 10 (test treatment). Pharmacokinetics were evaluated for 96 h after treatment on Day 1 and for 144 h (riociguat study) or 168 h (rosuvastatin study) after treatment on Day 10. To compare the reference and test treatments, the geometric mean ratio was calculated for the maximum plasma concentration (Cmax), the area under the plasma concentration-time curve (AUC) from zero (pre-dose) to time of the last measured concentration above the limit of quantification (AUC0–t), the AUC from zero to infinity (AUC0–∞) and the terminal elimination half-life (t½) of rosuvastatin, riociguat and riociguat’s metabolite, M1. The difference in the time to reach maximum plasma concentration (tmax) was determined by the Wilcoxon test. Trough levels of macitentan and its metabolite, ACT-132577, were measured and safety was monitored throughout.\n\nResults\nNinety percent confidence intervals of the geometric mean ratios were within the bioequivalence criteria of 0.80–1.25. There was no significant difference between test and reference tmax. Rosuvastatin or riociguat did not affect the steady-state concentrations of macitentan and ACT-132577. The adverse event profile was consistent with the known safety profiles of the drugs.\n\nConclusions\nMacitentan 10 mg did not affect the pharmacokinetics of BCRP substrates, rosuvastatin or riociguat in healthy male subjects.\n\nEudraCT numbers: 2017–003095–31 and 2017–003502–41.\n\nhttp://dx.doi.org/10.13039/100005646Actelion Pharmaceuticalsissue-copyright-statement© Springer Nature Switzerland AG 2019\n==== Body\nKey Points\n\nOral administration of macitentan 10 mg had no effect on the pharmacokinetic profile of orally administered breast cancer resistance protein substrates, rosuvastatin and riociguat, in healthy male subjects.\t\nOral administration of rosuvastatin or riociguat did not affect the steady-state concentrations of macitentan and its active metabolite, ACT-132577.\t\nConcomitant administration of macitentan with rosuvastatin or riociguat was well tolerated and the treatment-emergent adverse event profiles were consistent with the known safety profiles of the drugs.\t\n\n\n\nIntroduction\nPulmonary arterial hypertension (PAH) is a progressive disorder in which abnormal smooth muscle proliferation and excess vasoconstriction result in elevated pulmonary arterial pressure [1]. This is caused by an imbalance in vasoactive substances released by the pulmonary vascular endothelium. Of particular interest is the potent vasoactive peptide, endothelin-1 (ET-1), which has been found in increased quantities in the plasma and endothelium of patients with PAH [2, 3]. ET-1 exerts vasoconstrictor and vasodilatory effects by binding to endothelin receptor (ETR)-A and ETR-B, respectively [4–6].\n\nCombination drug therapy has become increasingly prevalent in the treatment of PAH, and evidence shows that dual combination of PAH-specific therapy delays disease progression in patients [7]. In a registry to evaluate early and long-term PAH disease (REVEAL), 46% of patients were receiving two and 9% of patients were receiving three PAH-specific therapies [8]. Therefore, it is important to recognize potential drug–drug interactions (DDIs) that could affect the efficacy and safety of PAH patient treatment.\n\nMacitentan and its active metabolite, ACT-132577, are dual endothelin receptor antagonists (ERAs) that prevent the binding of ET-1 to ETR-A and ETR-B. Macitentan has a high affinity for the ETRs, with a 50-fold increased selectivity for ETR-A compared to ETR-B [9]. It also has the advantage of having significantly slower dissociation kinetics than other ERAs [10]. Macitentan is approved for the treatment of patients with PAH in the European Union, Canada and the USA. The DDI potential of the approved clinical dose of macitentan (10 mg) is considered to be low and various studies have shown that the pharmacokinetics of macitentan are not affected by commonly prescribed medicines for PAH [11]. More than 99% of macitentan and ACT-132577 are highly bound to plasma proteins [12]. In vitro, macitentan has been shown to inhibit breast cancer resistance protein (BCRP) transporters with a 50% inhibitory concentration of 1.0 μM. BCRP is an efflux pump located in the gut, liver canalicular membrane, and kidney, and is exposed to intracellular drug concentrations in the liver and the kidney. When systemic plasma concentrations of macitentan are corrected for the high plasma protein binding, the resulting unbound plasma concentration is not expected to lead to inhibition of BCRP in the liver or the kidney (unpublished data on file, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland). However, the extent of the effect, if any, that macitentan has on intestinal BCRP is unknown. Inhibition of BCRP at the intestinal level might result in an increase in the rate, and extent of absorption of BCRP substrates, like riociguat and rosuvastatin.\n\nOur aim, therefore, was to investigate the effect of a clinical dose of macitentan 10 mg on BCRP using two BCRP substrates, rosuvastatin [13] and riociguat [14]. Riociguat is also indicated in the treatment of PAH and is currently the only approved therapy for chronic thromboembolic pulmonary hypertension (CTEPH); it may be administered concomitantly with macitentan [15]. We conducted two Phase 1 DDI studies with the primary objective of evaluating the effect of macitentan at steady-state on the pharmacokinetics of rosuvastatin and riociguat in healthy male subjects. The secondary objectives were to evaluate the effect of macitentan at steady-state on the pharmacokinetics of riociguat’s major active metabolite, M1; to evaluate the effect of rosuvastatin and riociguat on the steady-state concentrations of macitentan and its active metabolite, ACT-132577; and to determine the safety and tolerability of concomitant administration of rosuvastatin or riociguat with macitentan.\n\nMethods\nStudy Design\nAn independent ethics committee (Ethik-Kommission bei der Landesärztekammer, Baden–Württemberg, Jahnstrasse 40, 70573 Stuttgart, Germany) and the national health authority of Germany approved the two study protocols. Informed consent was obtained from all study participants. The studies were conducted at Clinical Research Services, Mannheim, Germany in accordance with the Declaration of Helsinki. Both were prospective, open-label, one sequence, two-treatment, Phase 1 studies. The first study was conducted between November 2017 and December 2017 and examined the effect of macitentan at steady-state on the pharmacokinetics of rosuvastatin after a single dose of rosuvastatin (EudraCT number: 2017–003095–31). The second study was conducted between December 2017 and February 2018 and examined the effect of macitentan at steady-state on the pharmacokinetics of riociguat and the riociguat metabolite, M1, after a single dose of riociguat (EudraCT number: 2017–003502–41).\n\nStudy Subjects\nThe studies enrolled healthy, adult males aged 18–55 years (rosuvastatin study) and 18–45 years (riociguat study). Subjects were required to have a body mass index of 18–30 kg/m2, normal systolic and diastolic blood pressure and a normal 12-lead electrocardiogram (ECG). Exclusion criteria included, but were not limited to, known allergic reactions to the study drugs, excipients of the study drugs, or any drug of the same class; any previous exposure to the study drugs (rosuvastatin study) or previous exposure to study drugs within 3 months prior to screening (riociguat study); and a history of any disease or condition that could interfere with the absorption, distribution, metabolism or excretion of the study drugs. Subjects with levels of hepatic aminotransferases, hemoglobin or hematocrit outside the normal range were also excluded. Subjects of Asian race were excluded from the rosuvastatin study because of the differences in the metabolism of statins in Asians compared with Caucasians [16].\n\nStudy Drug\nMacitentan was provided by Actelion Pharmaceuticals Ltd. as film-coated tablets for oral administration, formulated at a strength of 10 mg [12]. The same batch of macitentan was administered to all subjects. Commercially available rosuvastatin (10 mg tablets for oral administration) (Crestor AstraZeneca, GmbH, Wedel, Germany) [17] and riociguat (1 mg tablets for oral administration) (Adempas, Bayer Pharmaceuticals AG, Berlin, Germany) [18] were purchased for use in the studies. The same batch of rosuvastatin or riociguat was used for all subjects.\n\nDosing Schedule\nSubjects received a 10 mg single oral dose of rosuvastatin or a 1 mg single oral dose of riociguat on Day 1 (Fig. 1). A 30 mg (three 10 mg tablets) single oral loading dose of macitentan was administered on Day 5, followed by once-daily 10 mg oral doses of macitentan from Day 6 to Day 15 (riociguat study) or Day 6 to Day 16 (rosuvastatin study). On Day 10, a 10 mg single oral dose of rosuvastatin or a 1 mg single oral dose of riociguat was co-administered with macitentan. The subjects were in a fasted state at drug administration on Day 1, Day 5 and Day 10. Study drugs were administered with water. The intake of fluids was not permitted from 1 h before, until 1 h after, drug administration on Day 1 and Day 10.\n\n\nFig. 1 Study design and dosing schedule of the rosuvastatin and riociguat studies\n\n\n\n\nPharmacokinetic Sampling\nBlood samples were collected for rosuvastatin (5.5 mL), riociguat and M1 (4.9 mL) and macitentan and ACT-132577 (2.7 mL) for pharmacokinetic analysis at the times specified in Table 1. Blood samples were collected for macitentan and ACT-132577 trough concentration (Ctrough) before drug administration and once-daily on Day 5 to Day 16. In the rosuvastatin study, an additional sample was collected on Day 17. Plasma was separated by centrifugation. In the rosuvastatin study, the plasma was mixed with 0.1 M sodium acetate buffer (pH 4.0) to prevent the possible conversion of rosuvastatin 5S–lactone to rosuvastatin.\n\n\nTable 1 Blood sample collection times for rosuvastatin, riociguat and M1 pharmacokinetic analysis\n\nStudy Day\t− 1\t1\t\t2\t3\t4\t5\t\nHours post-dose\tPre-dose\t0.5\t1\t1.5\t2\t2.5\t3\t3.5\t4\t4.5\t5\t5.5\t6\t7\t8\t10\t12\t16\t24\t48\t72\t96\t\nRosuvastatin\tX\tX\tX\tX\tX\tX\tX\tX\tX\tX\tX\tX\tX\tX\tX\tX\tX\tX\tX\tX\tX\tX\t\nRiociguat/M1\tX\tX\tX\tX\tX\tX\tX\t–\tX\t–\tX\t–\tX\t–\tX\tX\tX\tX\tX\tX\tX\tX\t\nStudy Day\t10\t11\t12\t13\t14\t15\t16\t17\t\nHours post-dose\tPre-dose\t0.5\t1\t1.5\t2\t2.5\t3\t3.5\t4\t4.5\t5\t5.5\t6\t7\t8\t10\t12\t16\t24\t48\t72\t96\t120\t144\t168\t\nRosuvastatin\tX\tX\tX\tX\tX\tX\tX\tX\tX\tX\tX\tX\tX\tX\tX\tX\tX\tX\tX\tX\tX\tX\tX\tX\tX\t\nRiociguat/M1\tX\tX\tX\tX\tX\tX\tX\t–\tX\t–\tX\t–\tX\t–\tX\tX\tX\tX\tX\tX\tX\tX\tX\tX\t–\t\nX blood sample collected, – blood sample not collected\n\n\n\n\nBioanalysis\nValidated liquid chromatography with tandem mass spectrometry (MS/MS) methods [19–22] were used for the quantification of rosuvastatin, riociguat, M1, macitentan and ACT-132577 in human plasma samples using their respective stable isotope labelled internal standards. The concentration ranges of the assays were 0.04–25 ng/mL for rosuvastatin, 0.2–100 ng/mL for riociguat and M1 and 1–2000 ng/mL for macitentan and ACT-132577.\n\nRosuvastatin was extracted from acidified plasma samples using liquid-liquid extraction. After evaporation of the organic solvent, the reconstructed sample was injected on a C18 column using an isocratic elution. Subsequent MS/MS analysis was performed using an API 5500 mass detector (Sciex, Concord, Ontario, Canada) in positive electrospray mode.\n\nRiociguat and M1 were extracted from plasma samples using basic liquid-liquid extraction. After evaporation of the organic solvent, the reconstructed sample was injected on a C18 column using an isocratic elution. Subsequent MS/MS analysis was performed using an API 4000 mass detector (Sciex, Concord, Ontario, Canada) in positive electrospray mode.\n\nMacitentan and ACT-132577 were extracted from plasma samples using protein precipitation with acetonitrile/ethanol. The supernatant was injected on a C18 column using a gradient elution. Subsequent MS/MS analysis was performed using an API 5000 mass detector (Sciex, Concord, Ontario, Canada) in positive electrospray mode.\n\nThe quality of each analytical run was controlled by including quality control samples at low, medium and high concentrations. Their measured concentrations were used to determine intra- and inter-run precision and accuracy.\n\nPharmacokinetic Assessments\nThe plasma pharmacokinetic parameters of rosuvastatin, riociguat and M1 were derived by non-compartmental analysis (using Phoenix WinNonlin 6.4 [Certara, Princetion, NJ, USA]) of the plasma concentration-time profiles and included the following: the maximum plasma concentration of analyte (Cmax), the area under the plasma concentration-time curve (AUC) from zero (pre-dose) to time of the last measured concentration above the limit of quantification (AUC0–t), the AUC from zero to infinity (AUC0–∞), the time to reach maximum plasma concentration (tmax) and the terminal elimination half-life (t½).\n\nThe individual plasma concentrations of rosuvastatin, riociguat and M1 were used to directly obtain Cmax and tmax. AUC0–t was calculated according to the linear trapezoidal rule using the measured concentration-time values above the lower limit of quantification (LLOQ). AUC0–∞ was calculated by combining AUC0–t and the extrapolated AUC (AUCextra). AUCextra represents an extrapolated value obtained by Ct/λz where Ct is the last concentration above the LLOQ and λz represents the terminal elimination rate constant determined by log-linear regression analysis of the measured plasma concentrations in the terminal elimination phase. The t½ of rosuvastatin, riociguat and M1 was calculated as follows: t½ = 0.693/λz. The measured individual trough plasma concentrations of macitentan and ACT-132577 were used to directly obtain Ctrough, which was used to determine the attainment of steady-state conditions.\n\nSafety Assessments\nSafety assessments were performed at several time points throughout the study and included the evaluation of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), 12-lead ECG variables, clinical laboratory parameters (biochemistry, hematology, serology and urinalysis), vital signs (blood pressure and pulse), body weight and physical examination findings. An end of study examination was performed 10–12 days after last study drug administration and a follow-up telephone call to record any TEAEs and SAEs was performed 30–32 days after last study drug administration. TEAEs and SAEs were coded according to the Medical Dictionary for Regulatory Activities (version 20.0).\n\nStatistical Analysis\nA formal sample size calculation was not performed; however, based on previous publications, a precision estimate was calculated with an assumed coefficient of variation within subjects of 34% for Cmax rosuvastatin, 21% for AUC rosuvastatin, 20% for Cmax riociguat and 20% for AUC riociguat [23, 24]. It was estimated that, with a sample size of 16 evaluable subjects in each study, the lower and upper bounds of the 90% confidence interval (CI) for the geometric mean ratio would be approximately 0.81 and 1.23 for Cmax rosuvastatin, 0.88 and 1.14 for AUC0–∞ rosuvastatin, 0.88 and 1.13 for Cmax riociguat and, 0.88 and 1.13 for AUC0–∞ riociguat if the estimated ratio was one. It was planned to recruit 20 subjects in each study to ensure 16 subjects with evaluable pharmacokinetic parameters were available for the analysis.\n\nBoth studies had two analysis sets: the all-treated set, which comprised all enrolled subjects who received at least one dose of the study drug, and the per-protocol analysis set, which comprised all subjects in the all-treated set with no major protocol deviations that could affect the evaluation of pharmacokinetic endpoints.\n\nStatistical Analysis System (SAS®) software, version 9.4 (SAS Institute, Cary, NC, US) was used for the statistical analysis and the reporting of clinical and pharmacokinetics data. For the concentration-time profile plots of the pharmacokinetics data, WinNonlin version 6.4 or higher (Certara, Princeton, NJ, US) was used. Descriptive statistics were used to summarize the plasma concentrations per time point and the pharmacokinetic parameters of rosuvastatin, riociguat and M1 and Ctrough of macitentan and ACT-132577. The effect of macitentan on Cmax, AUC0–t, AUC0–∞ and t½ of rosuvastatin, riociguat and M1 was determined using the geometric mean ratio and the 90% CI of the test treatment versus the reference treatment (i.e. rosuvastatin and macitentan:rosuvastatin alone and riociguat and macitentan:riociguat alone). The geometric mean ratios and their 90% CIs were calculated from the corresponding back log-transformed contrasts of the mixed-effect models for Cmax, AUC0–t, AUC0–∞ and t½ of rosuvastatin, riociguat or M1. A 90% CI of 0.80–1.25 indicated bioequivalence. Differences between treatments for tmax were determined using the Wilcoxon signed rank test.\n\nResults\nStudy Population\nThe rosuvastatin and riociguat studies enrolled 20 healthy male subjects each, all of whom received the study drugs and were included in the all-treated analysis set. In the rosuvastatin study, 18 subjects were included in the per-protocol analysis set; one subject discontinued the study due to TEAEs (see safety results) and one subject withdrew consent. In the riociguat study, all 20 subjects were included in the per-protocol analysis set. Demographics and baseline characteristics are summarized in Table 2.Table 2 Demographics and baseline characteristics of the healthy male subjects enrolled in the rosuvastatin and riociguat studies, all-treated sets\n\nCharacteristic\tRosuvastatin study\nN = 20\tRiociguat study\nN = 20\t\nAge, years, mean (SD)\t41.2 (12.5)\t35.8 (7.7)\t\nRace, n (%)\t\n White\t19 (95)\t19 (95)\t\n American Indian or Alaska Native\t1 (5)\t0\t\n Asian\t0\t1 (5)\t\nWeight, kg, mean (SD)\t81.8 (9.1)\t82.4 (10.4)\t\nHeight, cm, mean (SD)\t182.8 (6.3)\t180.0 (7.8)\t\nBMI, kg m2, mean (SD)\t24.8 (2.7)\t25.4 (2.7)\t\nBMI body mass index, SD standard deviation\n\n\n\nBioanalysis\nIntra-run precision and accuracy were evaluated only in case the analytical batch contained a number of quality control samples at each concentration ≥ 3 (for macitentan and ACT-132577 only). Intra-run precision was ≤ 8.1% for ACT-064992 and ≤ 6.9% for ACT-132577. Intra-run accuracy ranged from − 9.8 to 7.4% for ACT-064992 and from − 11.9 to 6.2% for ACT-132577.\n\nInter-run precision was ≤ 6.1% for rosuvastatin, ≤ 5.7% for riociguat, ≤ 5.0% for M1, ≤ 7.7% for macitentan and ≤ 6.2% for ACT-132577. Inter-run accuracy ranged from − 9.3 to 4.0% for rosuvastatin, from − 6.5 to 1.1% for riociguat, from − 3.0 to 2.8% for M1, from − 3.9 to 5.9% for macitentan and from − 4.1 to 3.6% for ACT-132577.\n\nPharmacokinetics\nEffect of Macitentan on Rosuvastatin Pharmacokinetics\nThe concentration-time profiles of rosuvastatin following administration of rosuvastatin 10 mg alone or with macitentan 10 mg were similar (Fig. 2a). The pharmacokinetic parameters of rosuvastatin in the absence and presence of macitentan are summarized in Table 3. Concomitant dosing of macitentan 10 mg did not cause any notable difference in the rate and extent of systemic exposure (Cmax, AUC0–t and AUC0–∞) or t½ of rosuvastatin when compared to treatment with rosuvastatin alone. The geometric mean ratios and their 90% CIs for rosuvastatin pharmacokinetic parameters were all within the 0.80–1.25 limits (Table 3). There was no statistical difference between the two treatments for tmax of rosuvastatin.Fig. 2 a Mean and standard deviation (SD) plasma concentration-time profiles of rosuvastatin following treatment with 10 mg rosuvastatin alone and 10 mg rosuvastatin with 10 mg macitentan, per-protocol set (N = 18). b Mean (SD) plasma concentration-time profiles of riociguat following treatment with 1 mg riociguat alone and 1 mg riociguat with 10 mg macitentan, per-protocol set (N = 20). c Mean (SD) plasma concentration-time profiles of riociguat’s metabolite, M1, following treatment with 1 mg riociguat alone and 1 mg riociguat with 10 mg macitentan, per-protocol set (N = 20)\n\nTable 3 Pharmacokinetic parameters of rosuvastatin following administration of 10 mg rosuvastatin alone and rosuvastatin 10 mg with macitentan 10 mg, per-protocol set (N = 18)\n\nRosuvastatin pharmacokinetic parameter\tGeometric mean (95% CI)a\tGeometric mean ratio (90% CI)b\t\n10 mg rosuvastatin\t10 mg rosuvastatin + 10 mg macitentan\t\nCmax (ng/mL)\t5.14 (3.81, 6.93)\t5.58 (4.25, 7.31)\t1.09 (0.98, 1.21)\t\nAUC0–t (ng∙h/mL)\t47.20 (35.34, 63.04)\t45.71 (33.49, 62.38)\t0.97 (0.88, 1.06)\t\nAUC0–∞ (ng∙h/mL)\t54.27c (41.87, 70.35)\t50.81d (37.66, 68.54)\t0.96e (0.85, 1.08)\t\nt½ (h)\t14.83c (12.73, 17.28)\t16.17c (13.16, 19.87)\t1.14d (0.98, 1.32)\t\ntmax (h)\t4.50 (1.5–5.5)\t4.50 (3.5–5.5)\t0.00 (0.00, 0.75)\t\nAUC(0-t) area under the plasma concentration-time curve from zero (pre-dose) to time of the last measured concentration above the limit of quantification, AUC(0-∞) area under the plasma concentration-time curve from zero to infinity, CI confidence interval, Cmax maximum plasma concentration, h hour, t½ terminal elimination half-life, tmax time to reach maximum plasma concentration\n\naFor tmax, median and range is shown\n\nbFor tmax, median difference and 90% CI is shown\n\ncn = 16\n\ndn = 15\n\nen = 14\n\n\n\nEffect of Macitentan on Riociguat and M1 Pharmacokinetics\nThe concentration-time profiles of riociguat and M1 following administration of riociguat 1 mg alone or with macitentan 10 mg were similar (Fig. 2b, c). The pharmacokinetic parameters of riociguat and M1 in the absence and presence of macitentan are summarized in Tables 4 and 5. Concomitant dosing of macitentan 10 mg resulted in similar systemic exposure (Cmax, AUC0–t and AUC0–∞) and t½ of riociguat and M1 when compared to treatment with riociguat alone. The geometric mean ratios and their 90% CIs for riociguat pharmacokinetic parameters were all within the 0.80–1.25 limits. There was no statistical difference between the two treatments for tmax of riociguat and tmax of M1.Table 4 Pharmacokinetic parameters of riociguat following administration of 1 mg riociguat alone and riociguat 1 mg with macitentan 10 mg, per-protocol set (N = 20)\n\nRiociguat pharmacokinetic parameter\tGeometric mean (95% CI)a\tGeometric mean ratio (90% CI)b\t\n1 mg riociguat\t1 mg riociguat + 10 mg macitentan\t\nCmax (ng/mL)\t47.97 (41.61, 55.29)\t45.96 (40.02, 52.78)\t0.96 (0.90, 1.02)\t\nAUC0–t (ng∙h/mL)\t406.26 (296.39, 556.86)\t386.32 (286.34, 521.22)\t0.95 (0.83, 1.09)\t\nAUC0–∞ (ng∙h/mL)\t411.16 (300.48, 562.60)\t393.25 (292.23, 529.18)\t0.96 (0.84, 1.09)\t\nt½ (h)\t8.22 (6.67, 10.12)\t7.94 (6.37, 9.92)\t0.97 (0.88, 1.06)\t\ntmax (h)\t1.00 (0.5–2.1)\t1.00 (0.5–3.0)\t0.00 (0.00, 0.25)\t\nAUC(0-t) area under the plasma concentration-time curve from zero (pre-dose) to time of the last measured concentration above the limit of quantification, AUC(0-∞) area under the plasma concentration-time curve from zero to infinity, CI confidence interval, Cmax maximum plasma concentration, h hour, t½ terminal elimination half-life, tmax time to reach maximum plasma concentration\n\naFor tmax, median and range is shown\n\nbFor tmax, median difference and 90% CI is shown\n\nTable 5 Pharmacokinetic parameters of riociguat’s metabolite, M1, following administration of riociguat 1 mg alone and riociguat 1 mg with macitentan 10 mg, per–protocol set (N = 20)\n\nM1 pharmacokinetic parameter\tGeometric mean (95% CI)a\tGeometric mean ratio (90% CI)b\t\n1 mg riociguat\t1 mg riociguat + 10 mg macitentan\t\nCmax (ng/mL)\t12.10 (9.28, 15.77)\t11.91 (9.45, 15.00)\t0.98 (0.86, 1.13)\t\nAUC0–t (ng∙h/mL)\t379.90 (325.04, 444.01)\t373.79 (317.46, 440.11)\t0.98 (0.91, 1.06)\t\nAUC0–∞ (ng∙h/mL)\t392.10 (336.30, 457.16)\t381.95 (325.67, 447.96)\t0.97 (0.91, 1.05)\t\nt½ (h)\t15.63 (14.12, 17.30)\t14.94 (13.28, 16.80)\t0.96 (0.87, 1.05)\t\ntmax (h)\t4.00 (3.0–24.0)\t5.00 (2.5–23.9)\t0.50 (− 0.25, 1.00)\t\nAUC(0-t) area under the plasma concentration-time curve from zero (pre-dose) to time of the last measured concentration above the limit of quantification, AUC(0-∞) area under the plasma concentration-time curve from zero to infinity, CI confidence interval, Cmax maximum plasma concentration, h hour, t½ terminal elimination half-life, tmax time to reach maximum plasma concentration\n\naFor tmax, median and range is shown\n\nbFor tmax, median difference and 90% CI is shown\n\n\n\nSteady–state Plasma Concentrations of Macitentan and ACT-132577\nSteady-state conditions for macitentan and ACT-132577 were reached before rosuvastatin or riociguat administration on Day 10. Rosuvastatin or riociguat did not have an effect on the steady-state concentrations of macitentan and ACT-132577 (Fig. 3a, b).Fig. 3 Mean and standard deviation (SD) plasma concentration-time profiles of macitentan and its metabolite, ACT-132577, before and after administration of a rosuvastatin (N = 18) and b riociguat (N = 20) on Day 10, per-protocol sets\n\n\n\nIn the riociguat study, one subject had extremely low concentrations of macitentan and ACT-132577. A careful review of the demographic variables and the clinical and bioanalytical procedures did not provide an explanation for the low levels. A sensitivity analysis of the pharmacokinetic parameters for riociguat and M1 was performed excluding this subject. Results of this analysis were similar to the results including all 20 subjects and the same conclusions were drawn.\n\nSafety\nThere were no TEAEs of severe intensity, no deaths or other SAEs reported during the studies. In addition, there were no clinically significant changes from baseline in laboratory parameters, vital signs or ECG variables. In the rosuvastatin study, one subject discontinued due to the TEAEs toothache and tooth abscess, which were considered by the investigator to be not related to the study drugs. In the riociguat study, there were no TEAEs that lead to discontinuation of study drug.\n\nIn the rosuvastatin study, nine (45%) subjects had at least one TEAE during the study. Headache was the most frequent TEAE, reported by three subjects treated with macitentan alone and four subjects treated with rosuvastatin and macitentan. In the riociguat study, 10 (50%) subjects had at least one TEAE. Headache was also the most frequent TEAE in this study, reported by two subjects treated with riociguat alone, two subjects treated with macitentan alone and six subjects treated with riociguat and macitentan. In both studies, headache was the most frequently reported TEAE considered by the investigator to be related to the study drugs. The TEAE profiles in both studies were consistent with the known safety profiles of the study drugs.\n\nDiscussion and Conclusion\nWe conducted two studies to investigate the effect of concomitant administration of macitentan on the BCRP substrates, rosuvastatin and riociguat. Over 99% of macitentan and ACT-132577 binds to plasma proteins [12]. The resulting unbound plasma concentration of macitentan is not expected to lead to inhibition of BCRP-mediated transport in the liver or the kidney. However, the effect, if any, that macitentan has on intestinal BCRP has remained unknown until now. Our data showed that oral administration of macitentan 10 mg had no effect on the pharmacokinetic profiles of orally administered rosuvastatin 10 mg or riociguat 1 mg. The pharmacokinetic parameters of rosuvastatin [25, 26] and riociguat [27, 28] were consistent with those reported by other groups. In addition, we found that rosuvastatin or riociguat did not affect the steady-state concentrations of macitentan and its active metabolite, ACT-132577. Concomitant administration of macitentan with rosuvastatin or riociguat was well tolerated. There were no SAEs or severe TEAEs during the studies and the TEAE profiles were consistent with the known safety profiles of the drugs.\n\nOur study design conformed to regulatory guidelines on the conduct of DDI studies [29, 30]. A starting dose of macitentan 30 mg followed by 10 mg per day for 5 days ensured rapid attainment of steady-state conditions before administration of rosuvastatin or riociguat. Continued administration of macitentan 10 mg once-daily until Day 15 or Day 16 ensured the maintenance of steady-state conditions during the entire pharmacokinetic sampling period. The usual therapeutic dose of macitentan 10 mg and the recommended start dose of rosuvastatin 10 mg was chosen for the studies [17, 31]. To avoid the risk of hypotension associated with riociguat, a dose of riociguat 1 mg was selected [18]. The doses were in line with those used by other groups in similar DDI studies [32, 33].\n\nOne of the shortcomings of the studies was the small sample size, which limits the interpretation of safety data. However, in both studies, the observed within-subject variability for Cmax and AUC0–∞ was similar or smaller than assumed for the sample size calculation, indicating that the selected sample size was sufficient for the pharmacokinetic purposes of the studies. Another limitation of the study, which could affect the generalizability of the results to the patients with PAH, is that subjects of Asian race were excluded from taking part in the rosuvastatin study because of the differences in the metabolism of statins in Asians compared with Caucasians [26].\n\nDespite these limitations our studies show that there is no pharmacokinetic interaction between macitentan and the BCRP substrates, rosuvastatin and riociguat, in healthy subjects. Given that the pharmacokinetic profile of macitentan in healthy subjects is similar to that in PAH patients, the results presented here can be extrapolated to PAH [34]. Our results also suggest that macitentan can be used in combination with other BCRP substrates. These data will allow for informed decisions on future treatment combinations in patients with PAH and CTEPH.\n\nIn summary, the results from our studies show that at the approved clinical dose of macitentan 10 mg has no effect on the pharmacokinetics of orally administered rosuvastatin or riociguat.\n\nAcknowledgements\nThe sponsor of both studies was Actelion Pharmaceuticals Ltd. Medical writing support was provided by Claire Kilmartin and Rachel Beeby from Trilogy Writing & Consulting GmbH, funded by Actelion Pharmaceuticals Ltd.\n\nAuthor Contributions\nDC was responsible for the pharmacokinetic analysis and interpretation of data; SB was responsible for the study design; AS was responsible for the study implementation and had direct responsibility for patients; MS was responsible for the analysis and interpretation of safety information collected in the study; RS was responsible for the statistical analysis; GS was responsible for the pharmacokinetic analysis; JJPR was responsible for the interpretation of the data. All authors reviewed, contributed to and approved the manuscript.\n\nData Availability Statement\nThe data sharing policy of the Sponsor is available at https://www.janssen.com/clinical–trials/transparency. As noted on this site, requests for access to the study data can be submitted through the Yale Open Data Access (YODA) Project site at http://yoda.yale.edu.\n\nCompliance with Ethical Standards\nEthical Approval\nAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.\n\nInformed Consent\nInformed consent was obtained from all individual participants included in the study.\n\nFunding\nThe studies were funded by Actelion Pharmaceuticals Ltd.\n\nConflict of interest\nDénes Csonka, Shirin Bruderer, Marianne Soergel and Juan Jose Perez Ruixo are employees of Actelion Pharmaceuticals Ltd. Armin Schultz is an employee of the clinical research organization Clinical Research Services Mannheim GmbH, which carried out the studies reported. Radka Stepanova is an employee of the clinical research organization Aixial s.r.o, which performed the biostatistics for the studies reported. Giancarlo Sabattini is an employee of Idorsia Pharmaceuticals Ltd, which collaborated on the studies reported.\n==== Refs\nReferences\n1. Lai YC Potoka KC Champion HC Pulmonary arterial hypertension: the clinical syndrome Circ Res. 2014 115 1 115 130 10.1161/CIRCRESAHA.115.301146 24951762 \n2. Giaid A Yanagisawa M Langleben D Expression of endothelin-1 in the lungs of patients with pulmonary hypertension N Engl J Med. 1993 328 24 1732 1739 10.1056/NEJM199306173282402 8497283 \n3. Rubens C Ewert R Halank M Big endothelin-1 and endothelin-1 plasma levels are correlated with the severity of primary pulmonary hypertension Chest. 2001 120 5 1562 1569 10.1378/chest.120.5.1562 11713135 \n4. Chester AH Yacoub MH The role of endothelin-1 in pulmonary arterial hypertension Glob Cardiol Sci Pract. 2014 2014 2 62 78 25405182 \n5. Arai H Hori S Aramori I Cloning and expression of a cDNA encoding an endothelin receptor Nature. 1990 348 6303 730 732 10.1038/348730a0 2175396 \n6. Sakurai T Yanagisawa M Takuwa Y Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor Nature. 1990 348 6303 732 735 10.1038/348732a0 2175397 \n7. Lajoie AC Bonnet S Provencher S Combination therapy in pulmonary arterial hypertension: recent accomplishments and future challenges Pulmon Circ. 2017 7 2 312 325 10.1177/2045893217710639 \n8. McGoon MD Miller DP REVEAL: a contemporary US pulmonary arterial hypertension registry Eur Respir Rev. 2012 21 123 8 18 10.1183/09059180.00008211 22379169 \n9. Monaco TJ Davila CD Safety, efficacy, and clinical utility of macitentan in the treatment of pulmonary arterial hypertension Drug Des Dev Ther. 2016 10 1675 1682 \n10. Gatfield J Mueller Grandjean C Sasse T Slow receptor dissociation kinetics differentiate macitentan from other endothelin receptor antagonists in pulmonary arterial smooth muscle cells PLoS One. 2012 7 10 e47662 10.1371/journal.pone.0047662 23077657 \n11. Sidharta PN Treiber A Dingemanse J Clinical pharmacokinetics and pharmacodynamics of the endothelian receptor antagonist macitentan Clin Pharmacokinet. 2015 54 457 471 10.1007/s40262-015-0255-5 25860376 \n12. Summary of product characteristics Opsumit® (macitentan) 10 mg tablets, for oral use 2018 London Actelion Registration, Ltd. \n13. Elsby R Hilgendorf C Fenner K Understanding the critical disposition pathways of statins to assess drug–drug interaction risk during drug development: it’s not just about OATP1B1 Clin Pharmacol Ther. 2012 92 5 584 598 10.1038/clpt.2012.163 23047648 \n14. Frey R Becker C Saleh S Clinical pharmacokinetic and pharmacodynamic profile of riociguat Clin Pharmacokinet. 2018 57 6 647 661 10.1007/s40262-017-0604-7 29086344 \n15. Khaybullina D Patel A Zerilli T Riociguat (adempas): a novel agent for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension P T 2014 39 11 749 758 25395817 \n16. Liao JK Safety and efficacy of statins in Asians Am J Cardiol. 2007 99 3 410 414 10.1016/j.amjcard.2006.08.051 17261409 \n17. Crestor [10 mg film-coated tablets summary of product characteristics]. Bedfordshire, UK: AstraZeneca UK. 2018. https://www.medicines.org.uk/emc/product/7559/smpc. Accessed 04 Feb 2019.\n18. Adempas [prescribing information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc. 2018. http://labeling.bayerhealthcare.com/html/products/pi/Adempas_PI.pdf. Accessed 04 Feb 2019.\n19. Borkowski L, Steigerwald K. Validation of determination of rosuvastatin in plasma samples of subjects. ACC GmbH Analytical Clinical Concepts, Schöntalweg 9, 63849 Leidersbach, Germany. 2017.\n20. Borkowski L, Steigerwald K. Validation of quantitative determination of the concentration of riociguat and its metabolite desmethyl-riociguat in plasma samples of subjects. ACC GmbH Analytical Clinical Concepts, Schöntalweg 9, 63849 Leidersbach, Germany. 2018.\n21. Zimmermann T. Validation of an analytical method for the determination of ACT-064992 and its metabolite ACT-132577 in human plasma samples by LC-MS/MS. Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland. 2014.\n22. Steurer A. Supplementary validation of an analytical method for the determination of ACT-064992 and its metabolite ACT-132577 in human plasma samples by LC-MS/MS. Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland. 2016.\n23. Martin P Gillen M Ritter J Effects of fostamatinib on the pharmacokinetics of oral contraceptive, warfarin, and the statins rosuvastatin and simvastatin: results from phase I clinical studies Drugs R D. 2016 16 1 93 107 10.1007/s40268-015-0120-x 26748647 \n24. Frey R Reber M Krätzschmar J Riociguat (BAY 63-2521) and aspirin: a randomized, pharmacodynamic, and pharmacokinetic interaction study Pulm Circ. 2016 6 Suppl 1 S35 S42 10.1086/685014 27162625 \n25. Martin PD Warwick MJ Dane AL A double-blind, randomized, incomplete crossover trial to assess the dose proportionality of rosuvastatin in healthy volunteers Clin Ther. 2003 25 8 2215 2224 10.1016/S0149-2918(03)80214-X 14512129 \n26. Birmingham BK Bujac SR Elsby R Rosuvastatin pharmacokinetics and pharmacogenetics in Caucasian and Asian subjects residing in the United States Eur J Clin Pharmacol. 2015 71 3 329 340 10.1007/s00228-014-1800-0 25630984 \n27. Becker C Frey R Unger S Pharmacokinetic interaction of riociguat with ketoconazole, clarithromycin, and midazolam Pulm Circ. 2016 6 Suppl 1 S49 S57 10.1086/685016 27162627 \n28. Saleh S Frey R Becker C Bioavailability, pharmacokinetics, and safety of riociguat given as an oral suspension or crushed tablet with or without food Pulm Circ. 2016 6 Suppl 1 S66 S74 10.1086/685020 27162630 \n29. European Medicines Agency, Evaluation of Medicines for Human Use, CPMP. Guideline on the investigation of Drug Interactions. CPMP/EWP/560/95 Rev. 1. London: 2012.\n30. US Food and Drug Administration, Center for Drug Evaluation and Research (CDER): Guidance for industry. Drug Interaction Studies—Study design, data analysis, implications for dosing, and labeling recommendations, Rockville MD: February 2012.\n31. OPSUMIT [prescribing information]. South San Francisco, CA: Actelion Pharmaceuticals US, Inc. 2018. https://opsumit.com/opsumit-prescribing-information.pdf. Accessed 04 Feb 2019.\n32. Polli JW Hussey E Bush M Evaluation of drug interactions of GSK1292263 (a GPR119 agonist) with statins: from in vitro data to clinical study design Xenobiotica. 2013 43 6 498 508 10.3109/00498254.2012.739719 23256625 \n33. Becker C Frey R Hesse C Absorption of riociguat (BAY 63-2521): bioavailability, food effects, and dose proportionality Pulm Circ. 2016 6 Suppl 1 S27 S34 10.1086/685018 27096084 \n34. Issac M Dingemanse J Sidharta PN Pharmacokinetics of macitentan in patients with pulmonary arterial hypertension and comparison with healthy subjects J Clin Pharmacol. 2017 57 8 997 1004 10.1002/jcph.888 28378883\n\n",
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"issue": "39(12)",
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"medline_ta": "Clin Drug Investig",
"mesh_terms": "D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D000293:Adolescent; D000328:Adult; D004347:Drug Interactions; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides; D055815:Young Adult",
"nlm_unique_id": "9504817",
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"pages": "1223-1232",
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"pmid": "31552642",
"pubdate": "2019-12",
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"title": "Effect of Macitentan on the Pharmacokinetics of the Breast Cancer Resistance Protein Substrates, Rosuvastatin and Riociguat, in Healthy Male Subjects.",
"title_normalized": "effect of macitentan on the pharmacokinetics of the breast cancer resistance protein substrates rosuvastatin and riociguat in healthy male subjects"
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"companynumb": "CH-ALKEM LABORATORIES LIMITED-CH-ALKEM-2019-08677",
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"abstract": "A 79-year-old woman with a history of osteoporosis treated with alendronate presented to the orthopaedic clinic with persistent left hip pain. X-ray and bone scan revealed an atypical femoral fracture associated with bisphosphonate use. The fracture was repaired with antegrade femoral intramedullary fixation. Her postoperative course was complicated by acute blood loss anaemia requiring several packed red blood cell transfusions and progressive thigh ecchymosis. CT angiography demonstrated extravasation of contrast from the superior gluteal artery (SGA). Subsequent angiography revealed an SGA pseudoaneurysm above the intramedullary nail, which was coil embolised. Iatrogenic SGA injury secondary to femoral intramedullary fixation is a rare complication, with only one previous case reported in the literature. Therefore, successful identification of the injury required attention to patient reported symptoms, neurovascular examinations and laboratory values to determine the cause of the patient's postoperative anaemia. The patient made a full recovery and did not have any long-term adverse effects following the embolisation.",
"affiliations": "Department of Orthopaedic Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.;Department of Orthopaedic Surgery, VCU Health, Richmond, Virginia, USA.;Department of Orthopaedic Surgery, VCU Health, Richmond, Virginia, USA.;Department of Orthopaedic Surgery, VCU Health, Richmond, Virginia, USA.",
"authors": "Ailaney|Nikhil|N|;O'Connell|Robert|R|;Giambra|Laura|L|;Golladay|Gregory|G|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-231490",
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"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(10)",
"journal": "BMJ case reports",
"keywords": "calcium and bone; orthopaedic and trauma surgery; orthopaedics; osteoporosis",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D017541:Aneurysm, False; D050071:Bone Density Conservation Agents; D001858:Bone Nails; D000072226:Computed Tomography Angiography; D004164:Diphosphonates; D005260:Female; D005264:Femoral Fractures; D005594:Fracture Fixation, Intramedullary; D006801:Humans; D007083:Iliac Artery",
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"title": "Superior gluteal artery pseudoaneurysm following intramedullary nailing of an atypical femoral fracture.",
"title_normalized": "superior gluteal artery pseudoaneurysm following intramedullary nailing of an atypical femoral fracture"
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"abstract": "This article aims to present the case of a man affected by SARS CoV-2 and to discuss the association between this manifestation, viral infection and Open Abodmen. A 52 years old Caucasian man, affected by SARS CoV-2 infection, was admitted to the Emergency department of Arcispedale Sant'Anna of Ferrara for epigastralgia followed by syncopal episode, vomiting and diarrhea with bloody stools. The next day the patient underwent colonoscopy, which detected an ulceration proximally to the ileocecal valve without active bleeding. Subsequently an initial non-operative management and two pharyngeal swabs negative, for another rectorrhagia and hypotensive episode, underwent emerging surgery and an Open Abdomen was performed. The patient was discharged in 12th post-surgery day without complications. The IHC analysis with anti-SARS-CoV-2 nucleocapsid-protein revealed the presence of viral protein expression in epithelial cell of ulcerated intestinal mucosa. In this case report, we showed the presence of viral inclusion in small intestinal wall after two negative pharyngeal swabs for SARS-CoV-2 RNA. We can also say that the largest amount of viral inclusions was in the tissue of ulceration of the last ileal loop. This case report showed that SARS-CoV-2 can be unseen also after clinical healing. It's probably can be expelled with stools and rectal swabs search for SARS-Cov-2 RNA after pharyngeal swabs could be mandatory for declare heled a patient. Moreover, damage control surgery and Open Abdomen as a surgical technique can be a valid alternative in case of uncertainty of the bleeding source and when a second surgical look is necessary.",
"affiliations": "Acute Care Surgery Service, S. Anna University Hospital of Ferrara Via Aldo Moro, 8 44124, Cona, Ferrara, Italy.;Department of Medical Sciences, Residency Program in General Surgery, University of Ferrara, Via Aldo Moro, 8 44124, Cona, Ferrara, Italy.;Acute Care Surgery Service, S. Anna University Hospital of Ferrara Via Aldo Moro, 8 44124, Cona, Ferrara, Italy.;Acute Care Surgery Service, S. Anna University Hospital of Ferrara Via Aldo Moro, 8 44124, Cona, Ferrara, Italy.;Department of Translational Medicine and for Romagna, University of Ferrara, Via Aldo Moro, 8 44124, Cona, Ferrara, Italy.",
"authors": "Lacavalla|D|D|;Santandrea|G|G|;Andreotti|D|D|;Stano|R|R|;Occhionorelli|S|S|",
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"fulltext": "\n==== Front\nAnn Med Surg (Lond)\nAnn Med Surg (Lond)\nAnnals of Medicine and Surgery\n2049-0801\nElsevier\n\nS2049-0801(21)00355-1\n10.1016/j.amsu.2021.102405\n102405\nCase Report\nCase report of gastrointestinal localization of SARS-CoV-2 and open abdomen technique in an Italian emergency surgery department for gastrointestinal bleeding\nLacavalla D. d.lacavalla@ospfe.it\na∗\nSantandrea G. sgiorsg@gmail.com\nb\nAndreotti D. ndrdra@unife.it\na\nStano R. r.stano@ospfe.it\na\nOcchionorelli S. savino.occhionorelli@unife.it\nc\na Acute Care Surgery Service, S. Anna University Hospital of Ferrara Via Aldo Moro, 8 44124, Cona, Ferrara, Italy\nb Department of Medical Sciences, Residency Program in General Surgery, University of Ferrara, Via Aldo Moro, 8 44124, Cona, Ferrara, Italy\nc Department of Translational Medicine and for Romagna, University of Ferrara, Via Aldo Moro, 8 44124, Cona, Ferrara, Italy\n∗ Corresponding author. d.lacavalla@ospfe.it\n25 5 2021\n6 2021\n25 5 2021\n66 1024055 2 2021\n10 5 2021\n14 5 2021\n© 2021 The Authors\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nThis article aims to present the case of a man affected by SARS CoV-2 and to discuss the association between this manifestation, viral infection and Open Abodmen. A 52 years old Caucasian man, affected by SARS CoV-2 infection, was admitted to the Emergency department of Arcispedale Sant’Anna of Ferrara for epigastralgia followed by syncopal episode, vomiting and diarrhea with bloody stools. The next day the patient underwent colonoscopy, which detected an ulceration proximally to the ileocecal valve without active bleeding. Subsequently an initial non-operative management and two pharyngeal swabs negative, for another rectorrhagia and hypotensive episode, underwent emerging surgery and an Open Abdomen was performed. The patient was discharged in 12th post-surgery day without complications. The IHC analysis with anti-SARS-CoV-2 nucleocapsid-protein revealed the presence of viral protein expression in epithelial cell of ulcerated intestinal mucosa.\n\nIn this case report, we showed the presence of viral inclusion in small intestinal wall after two negative pharyngeal swabs for SARS-CoV-2 RNA. We can also say that the largest amount of viral inclusions was in the tissue of ulceration of the last ileal loop. This case report showed that SARS-CoV-2 can be unseen also after clinical healing. It's probably can be expelled with stools and rectal swabs search for SARS-Cov-2 RNA after pharyngeal swabs could be mandatory for declare heled a patient. Moreover, damage control surgery and Open Abdomen as a surgical technique can be a valid alternative in case of uncertainty of the bleeding source and when a second surgical look is necessary.\n\nHighlights\n\n• The novel SARS-CoV-2 may result in gastrointestinal (GI) symptoms in up to one-third of patients.\n\n• SARS-CoV-2 is excreted in the faeces, thus raising the possibility of faecal-oral transmission.\n\n• Two pharyngeal swabs for SARS-CoV-2 RNA were performed and were both negative.\n\n• Viral protein expression in epithelial cell of ulcerated intestinal mucosa.\n\n• Open Abodmen Technique is a valid alternative in surgical emergencies.\n\nKeywords\n\nCOVID-19\nRectal swabs\nGastrointestinal bleeding\nDamage control surgery\nCase report\n==== Body\n1 Introduction\n\nSevere Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2, formerly known as 2019-nCoV) belongs to the family of Coronaviridae, a group of enveloped, nonsegmented, positive-sense RNA viruses which appeared in December 2019 In the province of Hubei, China. At a genetic level, 2019-nCoV is closely related to the SARS-CoV and MERS-CoV [1,2]. It is well established that most patients suffering from COVID-19, the disease correlated by SARS-CoV-2, present fever associated with respiratory signs and symptoms, such as dry cough and dyspnea [[3], [4], [5]]; In some series, traditional HCoV account for up to 30% of influenza negative upper respiratory tract infections and up to 8.1% of enteritis [6,7]. Interestingly, the novel SARS-CoV-2 may result in gastrointestinal (GI) symptoms in up to one-third of patients [8,9]. Furthermore, SARS-CoV-2 may present primarily with GI complaints such as diarrhea, abdominal pain, hematochezia and liver injury that may precede typical respiratory presentation [4,10]. Also, Zhang et al. showed that SARS-CoV-2 is excreted in the faeces, thus raising the possibility of faecal-oral transmission [11].Whereas more research is underway to elucidate the transmission mechanism of SARS-CoV-2 by the interaction of SARS-CoV-2 with the small bowel, specifically with the angiotensin-converting enzyme 2 (ACE2) receptors located on the brush border of enterocytes [12]: SARS-CoV-2 S protein binds ACE2 with 10-fold higher affinity than the previous SARS-CoV [13]. Interestingly in SARS-CoV-2, the S-spike that is formed by the S1 and S2 segments and is more disordered than in SARS-CoV, having a solvent-exposed loop (i. e. “crack”) held by polybasic RRAR bonds in between S1 and S2. This “crack” facilitates the influx of human proteases, such as the serine proteases (transmembrane protease serine 2) TMPRSS2 and furin, which cleave this polybasic RRAR site at the junction of S1 and S2 14. This cleavage results in a separation of both arms (i.e. “pinchers”) of the S-spike. S1 contains the receptor-binding domain, which directly binds to the peptidase domain of ACE2. Whereas S2 is responsible for cell membrane fusion [[13], [14], [15]]. As with TMPRSS, the enzyme furin may enable the S-spike to separate into two pinching structures.\n\nThe open abdomen non-trauma patients has been proposed to be effective in preventing or treating deranged physiology in patients with severe injuries or critical illness when no other perceived options exist. Its use, however, remains controversial as it is resource consuming and represents a non-anatomic situation with the potential for severe adverse effects [19].\n\nThis case report [20] aims to present the case of a man affected by SARS CoV-2 infection and gastrointestinal bleeding, and to discuss the association between this manifestation and viral infection. Also we discuss the importance of Open Abdomen technique.\n\n1.1 Presentation of case\n\nA 52 years old Caucasian man, affected by SARS CoV-2 infection in-home therapy with hydroxychloroquine and azithromycin, was admitted to the Emergency department of Arcispedale Sant’Anna of Ferrara, complaining epigastralgia followed by syncopal episode, vomiting and diarrhea with bloody stools.\n\n1.2 The patient's medical history was silent\n\nRectal exploration showed blood traces on the explorer finger. Laboratory exams showed Haemoglobin level 8.7 g/dl, neutrophilic leukocytosis, no CRP elevation.\n\nThe patient underwent blood transfusion in the emergency room and was submitted to urgent oesophagus-gastroscopy, not detecting active bleeding or any abnormalities in the upper digestive tract. Thorax and abdomen contrast-enhanced TC was performed, without showing any abdominal bleeding source, but detecting worsening bilateral interstitial pneumonia. The patient was admitted to COVID-19 Medical ward.\n\nThe next day the patient underwent colonoscopy, which detected an ulceration 5 cm proximally to the ileocecal valve (Fig. 1); endoscopy did not find any active bleeding and ileocolic biopsies were made. Were set therapy with ceftriaxone 2 g/die, tranexamic acid, methylprednisolone 40 mg twice a day and therapy with Mesalazine, associated with proton pump inhibitors. The patient was kept in fasting and parenteral nutrition was set. During hospitalization the patient presented several episodes of rectal bleeding, some of them were followed by symptomatic hypotension, requiring intensive rianimatory evaluation, with the indication of fluid filling and blood transfusion. A non-operative management was initially given. Further colonoscopy and another abdomen contrast-enhanced TC were performed without detecting bleeding source; even arteriography of intestinal vessels was performed and was negative for arterial active bleeding.Fig. 1 First colonscopy: ulceration 5 cm proximally to the ileo-cecal valve.\n\nFig. 1\n\nFour days later video-capsule endoscopy to study small bowel was performed, showing hyperemia of the duodenal bulb, small duodenal ulcer, ulcer covered by fibrin in the last ileal loop and small jejunal and right colon angiodysplasia (Fig. 2). The whole exam was made difficult by the presence of melaena in the intestinal tract.Fig. 2 Colon angiodysplasia.\n\nFig. 2\n\nBlood tumor markers were evaluated (negative). In the suspicion of inflammatory bowel disease, fecal calprotectin was tested, detecting moderately increased levels (maximum 128 mg/kg with a cut-off of 50 mg/kg in our laboratory).\n\nTwo pharyngeal swabs were performed and both of them were negative for SARS CoV-2. No fecal research of SARS CoV-2 RNA was performed and the patient was transferred to Gastroenterology Ward first and then, the day after, to our Emergency Surgery Ward for the persistence of rectorrhagia. At the day of transfer, the patient in our Unit presented further hypotensive episode with hematic stools in the evening. Hemoglobin was 8.5 g/dL (10.5 g/dL in the morning) on the hematic exam. The patient was supported with colloid infusion while waiting for blood transfusion and was taken to the surgery room for emergent surgery. The surgical finding was a small bowel and colon full of blood, Meckel diverticulum, several jejunal diverticula; no blood or effusion in the peritoneal cavity was found. Last ileal loop and cecum with Merkel diverticulum resection with ileal manual anastomosis was performed; laparostomy was made and the patient was transferred to the Intensive Care Unit. Two days later second-look surgery was performed: bowel was vital and well perfused and. Because of the presence of several jejunal diverticula, jejunal resection was decided and manual anastomosis was performed. Laparostomy was closed and the patient returned to Intensive Care Ward.\n\nDuring recovery in Intensive Care Unit, Pseudomonas Aeruginosa was isolated from bronchoaspiration and broncho-alveolar lavage, so therapy with Piperacillin-Tazobactam was set. Postoperative electrocardiogram was done, detecting negative T-waves in precordial leads (V1–V3), associated with hypokalemia (3,3 mEq/l) and hypocalcemia (7,5 mg/dl); Troponin I HS was tested, finding out not significant elevation (25 ng/l). Electrolyte correction was performed; echocardiogram showed no myocardial ischemic abnormalities, mild left ventricular hypertrophy with Ejection Fraction 58%, mild mitral and tricuspidal insufficiency.\n\nThe patient was transferred to Emergency Surgery Ward two days after abdominal closure. Next days of recovery was regular without any complication, with normal blood pressure and stable hemoglobin values.\n\nThe patient was discharged in 12th post-surgery day without complications. Follow up was regular, without complications. The histological examination of small bowel showed intestinal diverticulosis with diverticulitis, chronic inflammation of the lamina propria is associated with focal superficial erosions, vascular ectasias and recent blood extravasations coexist also involving perivisceral adipose tissue and fibrinoleukocytic peritonitis. Abnormally enlarged and tortuous thick-walled veins were seen in the submucosa. IHC analysis with anti-SARS-CoV-2 nucleocapsid-protein revealed the presence of viral protein expression in epithelial cell of ulcerated intestinal mucosa (cytoplasmic staining) and a minority of lymphocytes [18].\n\n2 Discussion\n\nIn this case report, we showed the presence of viral inclusion in small intestinal wall after two pharyngeal swabs for SARS-CoV-2 RNA were performed and were both of them negative.\n\nWe can also say that the largest amount of viral inclusions was in the tissue of ulceration of the last ileal loop.\n\nIt's only a case report. In the past months, most publications on COVID-19 have been observational studies in clinical cohorts, epidemiological investigations and forecasts, and in-silico genomic and structural analyses [16], without showing viral inclusion in vivo.\n\nMany basic virological questions of SARS-CoV-2 remain unanswered. The SARS-CoV-2 use of human ACE2 as an entry receptor, and replication in Calu3 (pulmonary) cells. It also replicated to comparable levels in both Calu3 and Caco2 (intestinal) cells. Among other non-pulmonary cell lines, SARS-CoV-2 showed significant replication in Huh7 (hepatic) and 293T (renal) cells [16].\n\nClinical presentation of COVID-19 is often correlated to nausea, vomiting and abdominal pain or, sometimes, with hematochezia. In this case report, we have described important gastrointestinal bleeding. Also presented by Chen et al., the duration of viral shedding from the faces after negative conversion in pharyngeal swabs was 7 (6–10) days, regardless of COVID‐19 severity and SARS‐CoV‐2 transmission via the fecal-oral route should be seriously considered [17].\n\nThe open abdomen technique is a valid alternative in case of deranged physiology and bowel damage and necessity to perform a second look or delayed anastomosis [19].\n\n3 Conclusion\n\nThis case report [20] showed that SARS-CoV-2 can be unseen also after clinical healing. It's probably can be expelled with stools and rectal swabs search for SARS-Cov-2 RNA after pharyngeal swabs could be mandatory for declare heled a patient. Furthermore, we reiterate how the open abdomen technique is a valid alternative in complex clinical cases.\n\nInformed consent\n\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nProvenance and peer review\n\nNot commissioned, externally peer reviewed.\n\nDeclaration of competing interest\n\nAll authors disclose any financial and personal relationships with other people or organisations that could inappropriately influence this work.\n\nConsent\n\nThe patient gives the informed consent for research on anatomical specimens and the publication of this case report.\n\nEthical approval\n\nCase reports do not need to be approved by the ethics committee\n\nFunding for research\n\nThe authors received no funding sources for this article.\n\nAuthor contribution\n\nD. Lacavalla, G. Santandrea, D. Andreotti, R. Stano, S. Occhionorelli contributed to the writing of the article.\n\nGuarantor\n\nD. Lacavalla accepts full responsibility for the work, had access to the data, and controlled the decision to publish.\n\nAppendix A Supplementary data\n\nThe following is the Supplementary data to this article:Multimedia component 1\n\nMultimedia component 1\n\nAppendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.amsu.2021.102405.\n==== Refs\nReferences\n\n1 Zang R. Castro M.F.G. McCune B.T. TMPRSS2 and TMPRSS4 mediate SARS-CoV-2 infection of human small intestinal enterocytes bioRxiv 2020 10.1101/2020.04.21.054015\n2 Guan W. Ni Z. Hu Y. Clinical characteristics of 2019 novel coronavirus infection in China N. Engl. J. Med. 2020 10.1101/2020.02.06.20020974\n3 Legido-Quigley H. Asgari N. Teo Y.Y. Are high-performing health systems resilient against the COVID-19 epidemic? Lancet 2020 10.1016/S0140-6736(20)30551-1\n4 Wang D. Hu B. Hu C. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan, China JAMA, J. Am. Med. Assoc. 2020 10.1001/jama.2020.1585\n5 Totura A.L. Bavari S. Broad-spectrum coronavirus antiviral drug discovery Expet Opin. Drug Discov. 2019 10.1080/17460441.2019.1581171\n6 Jevšnik M. Steyer A. Pokorn M. The role of human coronaviruses in children hospitalized for acute bronchiolitis, acute gastroenteritis, and febrile seizures: a 2-year prospective study PloS One 2016 10.1371/journal.pone.0155555\n7 Chiu S.S. Hung Chan K. Wing Chu K. Human coronavirus NL63 infection and other coronavirus infections in children hospitalized with acute respiratory disease in Hong Kong, China Clin. Infect. Dis. 2005 10.1086/430301\n8 Zhou P. Lou Yang X. Wang X.G. A pneumonia outbreak associated with a new coronavirus of probable bat origin Nature 2020 10.1038/s41586-020-2012-7\n9 Huang C. Wang Y. Li X. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Lancet 2020 10.1016/S0140-6736(20)30183-5\n10 Song Y. Liu P. Shi X.L. SARS-CoV-2 induced diarrhoea as onset symptom in patient with COVID-19 Gut 2020 10.1136/gutjnl-2020-320891\n11 Zhang W. Du R.H. Li B. Molecular and serological investigation of 2019-nCoV infected patients: implication of multiple shedding routes Emerg. Microb. Infect. 2020 10.1080/22221751.2020.1729071\n12 Mönkemüller K. Fry L. Rickes S. Covid-19, Coronavirus, SARS-CoV-2 and the small bowel Rev. Esp. Enferm. Dig. 2020 10.17235/reed.2020.7137/2020\n13 Wrapp D. Wang N. Corbett K.S. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation Science 80 2020 10.1126/science.aax0902\n14 Hoffmann M. Kleine-Weber H. Schroeder S. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor Cell 2020 10.1016/j.cell.2020.02.052\n15 Yan R. Zhang Y. Li Y. Xia L. Guo Y. Zhou Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2 Science 80 2020 10.1126/science.abb2762\n16 Chu H. Chan J.F.-W. Yuen T.T.-T. Comparative tropism, replication kinetics, and cell damage profiling of SARS-CoV-2 and SARS-CoV with implications for clinical manifestations, transmissibility, and laboratory studies of COVID-19: an observational study The Lancet Microbe 2020 10.1016/s2666-5247(20)30004-5\n17 Chen Y. Chen L. Deng Q. The presence of SARS-CoV-2 RNA in the feces of COVID-19 patients J. Med. Virol. 2020 10.1002/jmv.25825\n18 Rizzo R. Neri L.M. Simioni C. SARS-CoV-2 nucleocapsid-protein and ultrastructural modifications in small bowel of a four week negative COVID-19 patient Clin. Microbiol. Infect. 2021 10.1016/j.cmi.2021.01.012\n19 Coccolini F. Roberts D. Ansaloni L. The open abdomen in trauma and non-trauma patients: WSES guidelines World J. Emerg. Surg. 2018 10.1186/s13017-018-0167-4\n20 Agha R.A. Franchi T. Sohrabi C. The SCARE 2020 guideline: updating consensus surgical CAse REport (SCARE) guidelines Int. J. Surg. 2020 10.1016/j.ijsu.2020.10.034\n\n",
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"title": "Case report of gastrointestinal localization of SARS-CoV-2 and open abdomen technique in an Italian emergency surgery department for gastrointestinal bleeding.",
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"abstract": "Management of multiple sclerosis (MS) before and during pregnancy remains challenging given there are no disease-modifying therapies (DMTs) approved for use during pregnancy, and discontinuation of certain DMTs can lead to rebound relapses. Ocrelizumab is a highly effective therapy for relapsing-remitting MS (RRMS) without reported rebound after discontinuation. However, little is known about the safety of ocrelizumab before or during pregnancy. We report a case of second trimester ocrelizumab exposure in a patient with RRMS transitioning off natalizumab, that resulted in no neonatal B-cell depletion, no infections, and normal infant development, despite suppressed B-cells in the mother at delivery.",
"affiliations": "Department of Pediatrics, University of California San Francisco, 550 16th Street, San Francisco CA 94158, United States. Electronic address: Mary.rolfes@ucsf.edu.;UCSF Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, 675 Nelson Rising Lane, San Francisco CA 94158, United States. Electronic address: Alice.rutatangwa@ucsf.edu.;UCSF Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, 675 Nelson Rising Lane, San Francisco CA 94158, United States. Electronic address: Emmanuelle.waubant@ucsf.edu.;UCSF Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, 675 Nelson Rising Lane, San Francisco CA 94158, United States. Electronic address: kristen.krysko@mail.utoronto.ca.",
"authors": "Rolfes|Mary|M|;Rutatangwa|Alice|A|;Waubant|Emmanuelle|E|;Krysko|Kristen M|KM|",
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"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D001402:B-Lymphocytes; D002648:Child; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D020529:Multiple Sclerosis, Relapsing-Remitting; D011247:Pregnancy; D011262:Pregnancy Trimester, Second",
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"title": "Ocrelizumab exposure in the second trimester of pregnancy without neonatal B-cell depletion.",
"title_normalized": "ocrelizumab exposure in the second trimester of pregnancy without neonatal b cell depletion"
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"abstract": "Chorangiomas of the placenta are often discovered incidentally and, although they are not common (1 in 9000 to 1 in 50 000 placentas), these tumors may be found in 0.5% to 1% of carefully examined placentas. The vast majority are of no clinical importance and complications are seen only in association with tumors measuring more than 4 cm in diameter. In contrast, hemangioendotheliomas are vascular tumors with varying grades of malignant potential and hardly ever involve the placenta. Here we describe a large placental chorangioma causing fetal hydrops and demonstrating distinctive intravascular luminal endothelial proliferation and tufting. To the best of our knowledge, this is probably only the second case of a placental hemangioendothelioma reported in the literature.",
"affiliations": "1 Department of Anatomic and Perinatal Pathology and Cytology, Fernandez Hospital Unit 3, Plot 769, Road No. 44, Jubilee Hills, Hyderabad - 500033, India.;2 Department of Obstetrics, Fernandez Hospital Unit 3, Plot 769, Road No. 44, Jubilee Hills, Hyderabad - 500033, India.;3 Department of Gynaecology, Fernandez Hospital Unit 3, Plot 769, Road No. 44, Jubilee Hills, Hyderabad - 500033, India.",
"authors": "Jaiman|Sunil|S|;Fernandez|Evita|E|;Gundabattula|Sirisha Rao|SR|",
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"title": "Chorangioendothelioma of the Placenta: A Myth or Reality?",
"title_normalized": "chorangioendothelioma of the placenta a myth or reality"
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"abstract": "We studied 232 consecutive children transplanted between 1990 and 2011 with relapse after first hematopoietic cell transplant (HCT). Kaplan-Meier survival and hazard ratios for mortality were calculated for factors known at time of relapse using Cox proportional hazards models. The median (range) age at time of first HCT was 10.9 (0.5-20.9) years, time to relapse was 6.1 (0.2-89.5) months after HCT, and age at relapse was 11.7 (0.7-23.6) years. The 3-year overall survival (OS) after relapse was 13% (95% confidence interval (CI): 9%, 18%).The median (range) follow-up for the 18 surviving patients was 7.2 (3.0-24.4) years after relapse. The remaining 214 died after a median of 3 months (0.02-190.4). OS was not significantly different for patients with ALL as compared to AML. Fifty-one patients proceeded to second transplant of whom nine survive. Factors associated with improved survival included late relapse (>12 months), ALL in first CR at the time of first transplant and chemotherapy-based first conditioning regimens. These results can be used to counsel patients at the time of relapse after first transplant and as a baseline for comparison as to the effectiveness of newer therapies which are greatly needed for treatment of post-transplant relapse.",
"affiliations": "Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA, USA. adahlber@fredhutch.org.;Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA, USA.;Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA, USA.;Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA, USA.;Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA, USA.;Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA, USA.;Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA, USA.;Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA, USA.;Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA, USA.;Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA, USA.;Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA, USA.;Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA, USA.",
"authors": "Dahlberg|Ann|A|;Leisenring|Wendy|W|;Bleakley|Marie|M|;Meshinchi|Soheil|S|;Baker|K Scott|KS|;Summers|Corinne|C|;Hadland|Brandon|B|;Delaney|Colleen|C|;Mallhi|Kanwaldeep|K|;Burroughs|Lauri|L|;Carpenter|Paul|P|;Woolfrey|Ann|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1038/s41409-019-0438-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-3369",
"issue": "54(8)",
"journal": "Bone marrow transplantation",
"keywords": null,
"medline_ta": "Bone Marrow Transplant",
"mesh_terms": "D002648:Child; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D009190:Myelodysplastic Syndromes; D011379:Prognosis; D012008:Recurrence; D016019:Survival Analysis; D019172:Transplantation Conditioning",
"nlm_unique_id": "8702459",
"other_id": null,
"pages": "1337-1345",
"pmc": null,
"pmid": "30670822",
"pubdate": "2019-08",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "25092781;23128573;25781572;8426208;16912228;20813197;24778882;26787415;21105791;25139215;20451454;15322568;19064980;18000167;28408462;20558313;9808546;9166833;17119111;29176353;20592248;14755311;17889352;15637143;25999455;25550214;17003380;23212523;21683798;21212791;24000241;14652854;18724393;20685259;26485444;25662999;19657114;22368272;11877272;27602666;19468273;26684393;15361903",
"title": "Prognosis of relapse after hematopoietic cell transplant (HCT) for treatment of leukemia or myelodysplastic syndrome (MDS) in children.",
"title_normalized": "prognosis of relapse after hematopoietic cell transplant hct for treatment of leukemia or myelodysplastic syndrome mds in children"
} | [
{
"companynumb": "US-OTSUKA-2019_031034",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BUSULFAN"
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"abstract": "OBJECTIVE\nRecently, the osteoporosis treatment has attracted attention, and several drugs have been developed. Among these, bisphosphonates (BPs), parathyroid hormone (PTH) and anti-receptor activator of nuclear factor kappa B ligand (RANKL) monoclonal (MAb) denosumab (DMAb) are the major osteoporosis agents. Several studies demonstrated that the effect of osteoporosis agents is evaluated by lumar or hip dual energy X-ray absorptiometry (DXA). However, private clinic commonly use the radial DXA. On the other hand, rheumatoid arthritis (RA) is sometimes associated with osteoporosis but there is no established treatment approach. In addition, glucocorticoids (GCs) are often used in the treatment of RA and sometimes induce osteoporosis. The present study assessed the effect of DMAb on osteoporosis in patients divided into RA and RA + GC patients by radial DXA.\n\n\nMETHODS\nThe therapeutic effect of denosumab was assessed in female osteoporosis patients using radial dual-energy X-ray absorptiometry (radial DXA) in three groups: those with postmenopausal osteoporosis (PO group), PO with rheumatoid arthritis (RA group), and PO with RA receiving glucocorticoids (RA + GC group).\n\n\nMETHODS\nIn total, 427 PO patients 60 years of age or older with a young adult mean value of <70 %, as determined by radial DXA, were treated with denosumab. The denosumab treatment group comprised a PO group (n = 205), RA group (n = 156), and RA + GC group (n = 66). The control group comprised a PO group (n = 44) and RA group (n = 33) who received oral bisphosphonate. Bone mineral density (BMD) was determined by using radial DXA. The bone turnover marker type I collagen cross-linked N-telopeptide (NTx) was also measured.\n\n\nCONCLUSIONS\nRadial DXA revealed a significant increase in BMD in the denosumab treatment group but not in the bisphosphonate treatment group. The onset of an increase in BMD with denosumab was slower in the RA group than in those without RA. The effect of denosumab in preventing increased NTx levels was smaller in the RA and RA + GC groups than in the PO group. Adherence to denosumab treatment was statistically significantly greater than for bisphosphonate treatment.",
"affiliations": "Matsuno Clinic for Rheumatic Diseases, 7187-2 Kureha, Toyama, Toyama, 930-0138, Japan. info@toyama-ra.com.",
"authors": "Matsuno|Hiroaki|H|http://orcid.org/0000-0002-2195-5717",
"chemical_list": "D005938:Glucocorticoids; D000069448:Denosumab",
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40268-016-0146-8",
"fulltext": "\n==== Front\nDrugs R DDrugs R DDrugs in R&D1174-58861179-6901Springer International Publishing Cham 14610.1007/s40268-016-0146-8Original Research ArticleAssessment of Distal Radius Bone Mineral Density in Osteoporosis Patients Receiving Denosumab, Including Those with Rheumatoid Arthritis and Those Receiving Oral Glucocorticoids http://orcid.org/0000-0002-2195-5717Matsuno Hiroaki +81-764-36-1757info@toyama-ra.com 121 Matsuno Clinic for Rheumatic Diseases, 7187-2 Kureha, Toyama, Toyama 930-0138 Japan 2 Institute of Medical Science, Tokyo Medical University, Tokyo, Japan 20 10 2016 20 10 2016 12 2016 16 4 347 353 © The Author(s) 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Background and Objectives\nRecently, the osteoporosis treatment has attracted attention, and several drugs have been developed. Among these, bisphosphonates (BPs), parathyroid hormone (PTH) and anti-receptor activator of nuclear factor kappa B ligand (RANKL) monoclonal (MAb) denosumab (DMAb) are the major osteoporosis agents. Several studies demonstrated that the effect of osteoporosis agents is evaluated by lumar or hip dual energy X-ray absorptiometry (DXA). However, private clinic commonly use the radial DXA. On the other hand, rheumatoid arthritis (RA) is sometimes associated with osteoporosis but there is no established treatment approach. In addition, glucocorticoids (GCs) are often used in the treatment of RA and sometimes induce osteoporosis. The present study assessed the effect of DMAb on osteoporosis in patients divided into RA and RA + GC patients by radial DXA.\n\nPatients\nThe therapeutic effect of denosumab was assessed in female osteoporosis patients using radial dual-energy X-ray absorptiometry (radial DXA) in three groups: those with postmenopausal osteoporosis (PO group), PO with rheumatoid arthritis (RA group), and PO with RA receiving glucocorticoids (RA + GC group).\n\nMethods\nIn total, 427 PO patients 60 years of age or older with a young adult mean value of <70 %, as determined by radial DXA, were treated with denosumab. The denosumab treatment group comprised a PO group (n = 205), RA group (n = 156), and RA + GC group (n = 66). The control group comprised a PO group (n = 44) and RA group (n = 33) who received oral bisphosphonate. Bone mineral density (BMD) was determined by using radial DXA. The bone turnover marker type I collagen cross-linked N-telopeptide (NTx) was also measured.\n\nResults and Conclusions\nRadial DXA revealed a significant increase in BMD in the denosumab treatment group but not in the bisphosphonate treatment group. The onset of an increase in BMD with denosumab was slower in the RA group than in those without RA. The effect of denosumab in preventing increased NTx levels was smaller in the RA and RA + GC groups than in the PO group. Adherence to denosumab treatment was statistically significantly greater than for bisphosphonate treatment.\n\nissue-copyright-statement© Springer International Publishing Switzerland 2016\n==== Body\nKey Points\n\nUnlike bisphosphonates, the therapeutic effect of denosumab can be assessed using radial dual-energy X-ray absorptiometry (radial DXA) in clinics.\t\nRadial DXA revealed the efficacy of denosumab in rheumatoid arthritis (RA) and RA + glucocorticoid groups that responded poorly to bisphosphonate treatment.\t\nAdherence to denosumab treatment was significantly higher than that for bisphosphonate treatment.\t\n\n\n\nIntroduction\nIn recent years, the treatment of osteoporosis has become a focus of attention, and many therapeutic agents have been developed [1]. Among these, bisphosphonates, parathyroid hormone (PTH) and the anti-receptor activator of nuclear factor-κB ligand (RANKL) monoclonal antibody (MAb) denosumab are major osteoporosis agents. Several studies have demonstrated that the effect of bisphosphonates and PTH is not detected by radial dual-energy X-ray absorptiometry (DXA) (except for one report), during the effect of denosumab is confirmed [2–5]. Radial DXA was selected for use as it determines the bone mineral density (BMD) of cortical bone rather than trabecular bone and age-related bone loss is more common in cortical bone [6]; in addition, radial DXA is more commonly used in clinics [7].\n\nRheumatoid arthritis (RA) is commonly associated with osteoporosis but there is no established treatment approach. Moreover, glucocorticoids are often used as a treatment for RA and sometimes induce osteoporosis.\n\nPatients and Methods\nA case-control study was conducted in which the study population comprised 427 female osteoporosis patients 60 years of age or older who received subcutaneous injection of denosumab 60 mg every 6 months between October 2013 and January 2016 and had a young adult mean (YAM) value of <70 %. To prevent hypocalcemia associated with denosumab treatment, all patients received an oral vitamin D3 preparation (cholecalciferol 0.01 mg/day or eldecalcitol 0.75 μg/day) as per the package insert of denosumab. Assessment was performed separately for the three groups: patients with postmenopausal osteoporosis (PO) (PO group), patients with PO with RA (RA group), and PO patients with RA receiving glucocorticoids (RA + GC group) (glucocorticoids were taken for at least 4 weeks until immediately before the start of the study). Patients with secondary osteoporosis probably due to other diseases such as cancer metastatic to bone and metabolic disorders were excluded from the study. All RA patients studied met the 1987 American College of Rheumatology criteria [8]. The control group consisted of 78 patients retrospectively sampled from those who had received an oral bisphosphonate every 4 weeks (minodronate 50 mg) or once a month (risedronate 75 mg) for the treatment of osteoporosis and provided written informed consent. Patient selection was matched to the denosumab treatment group (age ≥60 years, YAM value <70 %, observation period October 2013 to January 2016). No patient treated with glucocorticoids was in the control group. Similar to the denosumab treatment group, assessment was performed separately for the PO (44 patients) and RA (34 patients) bisphosphonate groups. In the control group, as with the denosumab treatment group, patients with secondary osteoporosis were excluded and patients were eligible for inclusion if they were 60 years of age or older and had a YAM value of <70 %; no patients in the bisphosphonate group had received glucocorticoid treatment.\n\nA total of 427 female osteoporosis patients were treated with denosumab: 205 in the PO group, 156 in the RA group, and 66 in the RA + GC group. All patients in the RA + GC group received glucocorticoids at a dose of ≤5 mg/day (1–5 mg/day). Of the female osteoporosis patients who had received bisphosphonate treatment after providing informed consent for participation in previous clinical studies, 78 could be matched with those in the denosumab treatment group for age and YAM value; 44 and 34 were classified in the PO and RA groups, respectively. However, no patients in the bisphosphonate group had been taking glucocorticoids (Table 1).Table 1 Baseline characteristics\n\n\tDMAb (n = 427)a\n\tBP (n = 78)b\n\t\np value\t\nAge\t69.2 ± 10.3\t67.9 ± 8.4\tNS\t\nWeight (kg)\t57.1 ± 10.8\t56.3 ± 12.7\tNS\t\nBMI (kg/m2)\t26.2 ± 8.6\t28.7 ± 18.4\tNS\t\n% YAM\t54.1 ± 13.0\t56.3 ± 13.8\tNS\t\nNTX (nmolBCE/mmolCr)\t64.7 ± 25.0\t66.2 ± 31.1\tNS\t\nData are presented as mean ± standard error\n\n\nBMI body mass index, BP bisphosphonate-treated group, DMAb denosumab-treated group, nmolBCE/mmolCr nmol Bone Collagen Equivalents/nmol creatinine, NS not statistically significant, PO patients with postmenopausal osteoporosis, RA osteoporosis patients with rheumatoid arthritis, RA + GC osteoporosis patients with rheumatoid arthritis taking glucocorticoids, NTX type I collagen cross-linked N-telopeptide, YAM young adult mean\n\n\naPO (n = 205), RA (n = 156), RA + GC (n = 66)\n\n\nbPO (n = 44), RA (n = 34)\n\n\n\n\nIn accordance with pre-treatment YAM and urine type I collagen cross-linked N-telopeptide (NTx) values, the denosumab group was divided into three subgroups and the bisphosphonate group was divided into two subgroups. There is no statistical difference for YAM between any two groups, and no statistical difference was found for urine NTx among any two groups except for between the PO and RA + GC groups taking denosumab (Fig. 1). It is well-known that glucocorticoids strongly induce bone resorption and subsequently influence the NTx level; the difference in the RA + GC group may be due to this effect.Fig. 1 Patient baseline bone mineral density (a) and urine NTx (b). There is no statistical difference in % YAM among any two groups (a). There is no statistical difference in urine NTx among any two groups except for between the PO and RA + GC groups within the DMAb group (b). Bars indicate the standard deviation. BP bisphosphonate, DMAb denosumab, NTx type I collagen cross-linked N-telopeptide, PO patients with postmenopausal osteoporosis, RA osteoporosis patients with rheumatoid arthritis, RA + GC osteoporosis patients with rheumatoid arthritis taking glucocorticoids, YAM young adult mean\n\n\n\n\nAll RA patients enrolled in the study showed remission or a low 28-joint Disease Activity Score–erythrocyte sedimentation rate (DAS28-ESR) of <3.2 for 4 weeks before the start of denosumab treatment [9]. The dosage of both conventional systemic disease-modifying antirheumatic drugs (csDMARDs) and biological DMARDs (bDMARDs) in addition to glucocorticoids remained unchanged throughout the study period. Those patients who required changes in or discontinuation of antirheumatic therapy with glucocorticoids, csDMARDs, and bDMARDs because of changes in RA status or adverse reactions were excluded from the study. No patients in the bisphosphonate group required changes in their RA treatment. The objective of the present study was to assess the therapeutic effect of denosumab by radial DXA, and those patients who could not meet this objective, or who dropped out for reasons other than those related to the effect of denosumab or the response to denosumab, were excluded. The content of the study was explained to all patients participating in the study and written informed consent was provided in advance. This study was conducted according to the principles of the Declaration of Helsinki.\n\nBMD was determined by radial DXA (DCS-600EXV; Hitachi Aloka Medical, Japan) every 24 weeks after the start of the study. The change in BMD between before treatment and after treatment (∆BMD) was calculated for each patient group to compare the effect of denosumab (Eq. 1): 1 ΔBMD=radial DXA value for each week-radial DXA value at the start of treatment. \n\n\nFor the denosumab treatment group, assessment of a marker of bone turnover was also performed. Levels of the marker of bone resorption, NTx, were measured in the second morning urine (enzyme-linked immunosorbent assay: nmol Bone Collagen Equivalents/nmol creatinine) every 24 weeks after the start of denosumab treatment. Percentage NTx (%NTx) values were calculated to compare the effect of denosumab in the patient groups as follows (Eq. 2): 2 %NTx\\,=\\,NTx value for each week-NTx value at the start of treatmentNTx value at the start of treatment×100. \n\n\nDenosumab continuation was estimated using the Kaplan–Meier method and compared using a log-rank test (Mantel–Cox test). The last observation carried forward method was used in each analysis. Results are expressed as mean ± standard deviation or standard error (SE). This study deals with the treatment plan approved by the Institutional Review Board of Matsubara Mayflower Hospital (No. 177) (Kato city, Hyogo, Japan). Verbal informed consent was obtained from each patient to use their clinical data. All analysis proportions were analyzed for treatment differences with the Chi-square test and continuous variables were compared with Student’s t test. A statistically significant difference was defined as p < 0.05.\n\nResults\nChanges in Bone Mineral Density as Determined by Radial Dual-Energy X-Ray Absorptiometry After Denosumab Treatment\nThere were statistically significant differences in the increase in BMD as determined by radial DXA between denosumab and bisphosphonate treatments (p < 0.01). No increase in BMD was observed in the bisphosphonate treatment group, whereas BMD was found to increase over time in the denosumab treatment group (administration every 6 months). The therapeutic effect of denosumab was noted in each of the PO, RA, and RA + GC groups. However, the effect was slower in onset in the RA and RA + GC groups than in the PO group. At week 52, significant differences were found between the increase in BMD between the PO group and the other groups (Fig. 2).Fig. 2 Changes in BMD after the start of DMAb treatment as determined by radial DXA (∆BMD = [radial DXA value for each week] − [radial DXA value at the start of treatment]). In the PO group, the radial DXA value increased with the number of doses (over time). Treatment with DMAb was also associated with increases in the radial DXA value in the RA and RA + GC groups. However, the efficacy of DMAb in increasing radial DXA values was slower in onset than in the PO group. At week 52 of DMAb treatment, statistically significant differences were found in BMD between the PO and RA or RA + GC groups (p < 0.05). Treatment with bisphosphonate showed no increase in the radial DXA value, and the effect of bisphosphonate was statistically significantly inferior to that of DMAb (p < 0.01). Data are expressed as mean ± standard error. ∆BMD change in bone mineral density, BMD bone mineral density, DMAb denosumab, PO patients with postmenopausal osteoporosis, RA osteoporosis patients with rheumatoid arthritis, RA + GC osteoporosis patients with rheumatoid arthritis taking glucocorticoids, radial DXA radial dual-energy X-ray absorptiometry\n\n\n\n\nAll denosumab-treated patients received oral cholecalciferol or eldecalcitol as a vitamin D3 preparation in accordance with their hepatic or renal condition. There is no statistical difference between patients using cholecalciferol or eldecalcitol in ∆BMD at 102 weeks (3.0 ± 0.6 vs. 3.2 ± 0.8 [mean ± SE]).\n\nChanges in Urinary Type I Collagen Cross-Linked N-Telopeptide Levels After the Start of Denosumab Treatment\nAnalysis of the rate of change (%) in the levels of NTx showed that bone resorption was rapidly inhibited in the PO group after the start of denosumab treatment and that the inhibitory effect lasted until the end of the observation period at week 102. The inhibitory effect of denosumab on bone resorption was smaller in the RA and RA + GC groups than in the PO group. The effect of denosumab in preventing an increase in NTx levels was statistically significantly greater in the PO group than in the other groups up to week 78 (Fig. 3).Fig. 3 Changes in the urinary levels of NTx, a marker of bone turnover, associated with denosumab treatment were marked in the PO group. Up to week 78 of denosumab treatment, urinary NTx levels were statistically significantly lower in the PO group than in the RA and RA + GC groups. %NTx = NTx\\,value\\,for\\,each\\,week-NTx\\,value\\,at\\,the\\,start\\,of\\,treatmentNTx\\,value\\,at\\,the\\,start\\,of\\,treatment×100. Data are expressed as mean ± standard error. NTx type I collagen cross-linked N-telopeptide, PO patients with postmenopausal osteoporosis, RA osteoporosis patients with rheumatoid arthritis, RA + GC osteoporosis patients with rheumatoid arthritis taking glucocorticoids\n\n\n\n\nAdherence to Denosumab or Bisphosphonate Treatment\nFor both denosumab and bisphosphonate treatments, withdrawal from the study was found to occur most frequently at week 24 in the early stages of treatment. Adherence to denosumab treatment was statistically significantly higher than that for bisphosphonate treatment (Fig. 4).Fig. 4 Adherence to DMAb treatment remained higher than that for BP treatment (Kaplan–Meier method). BP bisphosphonate, DMAb denosumab, PO patients with postmenopausal osteoporosis, RA osteoporosis patients with rheumatoid arthritis, RA + GC osteoporosis patients with rheumatoid arthritis taking glucocorticoids\n\n\n\n\nAdverse Reactions\nOne 75-year-old patient in the RA group discontinued treatment with denosumab because of an adverse reaction (osteonecrosis of the jaw [ONJ]). The patient was found to have ONJ during tooth extraction at a dental clinic after 60 weeks of denosumab treatment (after the second administration). However, she had been treated with bisphosphonate for 8 years before the start of denosumab treatment, and therefore it is difficult to determine whether the ONJ was attributable to denosumab or bisphosphonate treatment.\n\nDiscussion\nThe number of patients with osteoporosis has increased with the aging of the population worldwide. Against this backdrop, various therapeutic agents for osteoporosis have recently been developed and applied clinically [1, 10]. Among many treatments for osteoporosis, bisphosphonate, denosumab, and PTH are especially highly evidence based and effective. These agents have been shown to increase the BMD of the lumbar spine and total hip [3–5, 11], although radial DXA has revealed little effect for agents other than denosumab. Given that radial DXA determines cortical BMD and that age-related bone loss is attributed to the porosity of cortical bone, radial DXA is of significance [6]. Most of the clinics at which osteoporosis is often treated use radial DXA to determine BMD. It is likely that medical devices such as central (spine/hip) DXA and computed tomography are not used because of cost and space issues [7]. In this context, it is significant that we assessed the effect of denosumab using radial DXA.\n\nPresentation of beneficial therapeutic effect increases patient enthusiasm for receiving treatment and enhances adherence to the continuation of treatment. However, in treatment with bisphosphonate or PTH, radial DXA is not helpful to assess the therapeutic effect, which hinders further treatment. Because denosumab inhibits bone resorption by penetrating cortical bone through the extracellular fluid [12], its effect can be adequately assessed by radial DXA, which determines cortical BMD [3–5]. Although bisphosphonates are most widely used in the treatment of osteoporosis, it was found that at most only 50 % of patients adhered to treatment for 1 year, partly because of limitations such as the need for bed rest and dietary restrictions other than fluid intake for at least 30 min after taking a bisphosphonate [13]. The result is similar to that obtained for patients receiving bisphosphonates in the present study (Fig. 4). The low adherence to bisphosphonate treatment in our study may be attributable to the inadequate presentation of the therapeutic effect (Figs. 2, 4) in addition to the complex instructions for taking a bisphosphonate.\n\nIn contrast to bisphosphonate treatment, at least 50 % of patients receiving denosumab adhered to the treatment even at week 102. This high adherence to denosumab treatment could be attributable to the simplicity of treatment (subcutaneous administration only every 6 months) and presentation of the preferable therapeutic effect (Figs. 2, 4). In addition, because denosumab is a human MAb prepared using transgenic mice, it is a stable pharmaceutical product with low immunogenicity [14], and therefore causes only slight pain at the time of injection and fewer adverse reactions. These factors may also contribute to the high adherence.\n\nDenosumab also had an effect in the RA and RA + GC groups, although it was slower in onset in these groups than in the PO group (Fig. 2). A possible reason for this is that denosumab had an insufficient inhibitory effect on bone resorption (i.e., lowering of the NTx level) because of increased bone resorption due to the presence of RA or the impact of glucocorticoids in the RA and RA + GC groups (Fig. 3). This is the first reported attempt to assess the effect of denosumab in RA and RA + GC groups using radial DXA. However, a previous report showed that denosumab increases the BMD of both the lumbar spine and total hip; this result may be attributable to the effect of denosumab in reducing bone turnover by lowering the levels of both a marker of bone formation, serum procollagen 1 N-terminal peptide (P1NP), and one of bone resorption, serum C-telopeptide type 1 (sCTx-1) [11]. In the present study, denosumab insufficiently lowered NTx levels in the RA and RA + GC groups. This may be because the presence of RA at the start of treatment affected the levels of the marker of bone turnover; therefore, further investigations are needed to confirm this hypothesis.\n\nIt should also be noted that bisphosphonates have been shown to be effective in improving the BMD for the lumbar spine but not the total hip in osteoporosis patients with RA [15]. This is in marked contrast to the finding that bisphosphonate has an effect on both the lumbar spine and total hip in patients with PO alone [1], suggesting that patients with PO complicated by RA may be more refractory to treatment for osteoporosis. There is also a report showing that bisphosphonate has an effect on the lumbar spine and total hip in osteoporosis patients with RA [16]. However, in this report, bisphosphonate had no effect on the metacarpals, which are mainly composed of cortical bone. In contrast, denosumab had an effect in the RA and RA + GC groups in the present study. In addition, denosumab has recently been shown to be effective in the treatment of bone erosion in patients with RA [17]. The American College of Rheumatology recommends use of alendronate or risedronate in the treatment of glucocorticoid-induced osteoporosis [18]. Our results show that denosumab can also be recommended for osteoporosis in RA patients and for RA patients taking glucocorticoids.\n\nMoreover, one patient experienced ONJ during denosumab treatment; however, it is difficult to determine whether the ONJ is attributable to denosumab or bisphosphonate treatment. Recently, it has been reported that RA is a risk factor for ONJ, and ONJ should be especially mentioned to long-term denosumab or bisphosphonate-treated RA patients (median 69 months, range 20–130 months) [19].\n\nCompliance with Ethical Standards\nFunding\nThis research received no specific grant from any funding agency in the public, commercial or non-profit sectors.\n\nConflict of interest\nThe author declares no conflict of interest associated with this manuscript.\n==== Refs\nReferences\n1. Mandema JW Zheng J Libanati C Perez Ruixo JJ Time course of bone mineral density changes with denosumab compared with other drugs in postmenopausal osteoporosis: a dose-response-based meta-analysis J Clin Endocrinol Metab. 2014 99 10 3746 3755 10.1210/jc.2013-3795 24915115 \n2. Reginster J Minne HW Sorensen OH Hooper M Roux C Brandi ML Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group Osteoporos Int. 2000 11 1 83 91 10.1007/s001980050010 10663363 \n3. Nakamura T Matsumoto T Sugimoto T Hosoi T Miki T Gorai I Clinical Trials Express: fracture risk reduction with denosumab in Japanese postmenopausal women and men with osteoporosis: Denosumab Fracture Intervention Randomized Placebo Controlled Trial (DIRECT) J Clin Endocrinol Metab. 2014 99 7 2599 2607 10.1210/jc.2013-4175 24646104 \n4. Reid IR Miller PD Brown JP Kendler DL Fahrleitner-Pammer A Valter I Denosumab Phase 3 Bone Histology Study Group. Effects of denosumab on bone histomorphometry: the FREEDOM and STAND studies J Bone Miner Res. 2010 25 10 2256 2265 10.1002/jbmr.149 20533525 \n5. Leder BZ Tsai JN Uihlein AV Burnett-Bowie SA Zhu Y Foley K Two years of Denosumab and teriparatide administration in postmenopausal women with osteoporosis (The DATA Extension Study): a randomized controlled trial J Clin Endocrinol Metab. 2014 99 5 1694 1700 10.1210/jc.2013-4440 24517156 \n6. Zebaze RM Ghasem-Zadeh A Bohte A Iuliano-Burns S Mirams M Price RI Intracortical remodelling and porosity in the distal radius and post-mortem femurs of women: a cross-sectional study Lancet. 2010 375 9727 1729 1736 10.1016/S0140-6736(10)60320-0 20472174 \n7. Yamauchi H Fukunaga M Nishikawa A Orimo H Changes in distribution of bone densitometry equipment from 1996 to 2006 in Japan J Bone Miner Metab. 2010 28 1 60 67 10.1007/s00774-009-0099-x 19633809 \n8. Arnett FC Edworthy SM Bloch DA McShane DJ The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis Arthritis Rheum. 1988 31 315 324 10.1002/art.1780310302 3358796 \n9. Matsuno H Okada M Sakai Y Abe C Katayama K Sagawa A The usefulness of a new triple combination treatment utilizing methotrexate, salazosulfapyridine, and bucillamine in rheumatoid arthritis Mod Rheumatol. 2016 26 1 51 56 10.3109/14397595.2015.1059984 26052803 \n10. Albaum JM Youn S Levesque LE Gershon AS Cadarette SM Osteoporosis management among chronic glucocorticoid users: a systematic review J Popul Ther Clin Pharmacol. 2014 21 3 e486 e504 25527817 \n11. Dore RK Cohen SB Lane NE Palmer W Shergy W Zhou L Denosumab RA Study Group Effects of denosumab on bone mineral density and bone turnover in patients with rheumatoid arthritis receiving concurrent glucocorticoids or bisphosphonates Ann Rheum Dis. 2010 69 5 872 875 10.1136/ard.2009.112920 19734132 \n12. Zebaze RM Libanati C Austin M Ghasem-Zadeh A Hanley DA Zanchetta JR Differing effects of denosumab and alendronate on cortical and trabecular bone Bone. 2014 59 173 179 10.1016/j.bone.2013.11.016 24275677 \n13. Cotté FE Fardellone P Mercier F Gaudin AF Roux C Adherence to monthly and weekly oral bisphosphonates in women with osteoporosis Osteoporos Int. 2010 21 1 145 155 10.1007/s00198-009-0930-1 19459025 \n14. Nelson AL Dhimolea E Reichert JM Development trends for human monoclonal antibody therapeutics Nat Rev Drug Discov. 2010 9 10 767 774 10.1038/nrd3229 20811384 \n15. Lems WF Lodder MC Lips P Bijlsma JW Geusens P Schrameijer N Positive effect of alendronate on bone mineral density and markers of bone turnover in patients with rheumatoid arthritis on chronic treatment with low-dose prednisone: a randomized, double-blind, placebo-controlled trial Osteoporos Int. 2006 17 5 716 723 10.1007/s00198-005-0037-2 16463007 \n16. Jensen TW Hansen MS Hørslev-Petersen K Hyldstrup L Abrahamsen B Langdahl B Cimestra Study Group Periarticular and generalised bone loss in patients with early rheumatoid arthritis: influence of alendronate and intra-articular glucocorticoid treatment. Post hoc analyses from the CIMESTRA trial Ann Rheum Dis. 2014 73 6 1123 1129 10.1136/annrheumdis-2012-203171 23661492 \n17. Takeuchi T Tanaka Y Ishiguro N Yamanaka H Yoneda T Ohira T Effect of denosumab on Japanese patients with rheumatoid arthritis: a dose-response study of AMG 162 (Denosumab) in patients with RheumatoId arthritis on methotrexate to Validate inhibitory effect on bone Erosion (DRIVE)-a 12-month, multicentre, randomised, double-blind, placebo-controlled, phase II clinical trial Ann Rheum Dis. 2016 75 6 983 990 10.1136/annrheumdis-2015-208052 26585988 \n18. Grossman JM Gordon R Ranganath VK Deal C Caplan L Chen W American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis Arthritis Care Res (Hoboken). 2010 2 11 1515 1526 10.1002/acr.20295 \n19. Di Fede O Bedogni A Giancola F Saia G Bettini G Toia F BRONJ in patients with rheumatoid arthritis: a multicenter case series Oral Dis. 2016 22 6 543 548 10.1111/odi.12490 27062502\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1174-5886",
"issue": "16(4)",
"journal": "Drugs in R&D",
"keywords": null,
"medline_ta": "Drugs R D",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D001172:Arthritis, Rheumatoid; D015519:Bone Density; D016022:Case-Control Studies; D000069448:Denosumab; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007279:Injections, Subcutaneous; D008875:Middle Aged; D010024:Osteoporosis",
"nlm_unique_id": "100883647",
"other_id": null,
"pages": "347-353",
"pmc": null,
"pmid": "27766589",
"pubdate": "2016-12",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": "25527817;24517156;16463007;19734132;26052803;24646104;23661492;19459025;20811384;26585988;24915115;20533525;20662044;19633809;27062502;24275677;3358796;20472174;10663363",
"title": "Assessment of Distal Radius Bone Mineral Density in Osteoporosis Patients Receiving Denosumab, Including Those with Rheumatoid Arthritis and Those Receiving Oral Glucocorticoids.",
"title_normalized": "assessment of distal radius bone mineral density in osteoporosis patients receiving denosumab including those with rheumatoid arthritis and those receiving oral glucocorticoids"
} | [
{
"companynumb": "JP-AMGEN-JPNSP2016162228",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DENOSUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "To visualize and validate the dynamics of interhemispheric neural propagations induced by single-pulse electrical stimulation (SPES).\n\n\n\nThis methodological study included three patients with drug-resistant focal epilepsy who underwent measurement of cortico-cortical spectral responses (CCSRs) during bilateral stereo-electroencephalography recording. We delivered SPES to 83 electrode pairs and analyzed CCSRs recorded at 268 nonepileptic electrode sites. Diffusion-weighted imaging (DWI) tractography localized the interhemispheric white matter pathways as streamlines directly connecting two electrode sites. We localized and visualized the putative SPES-related fiber activation, at each 1-ms time window, based on the propagation velocity defined as the DWI-based streamline length divided by the early CCSR peak latency.\n\n\n\nThe resulting movie, herein referred to as four-dimensional tractography, delineated the spatiotemporal dynamics of fiber activation via the corpus callosum and anterior commissure. Longer streamline length was associated with delayed peak latency and smaller amplitude of CCSRs. The cortical regions adjacent to each fiber activation site indeed exhibited CCSRs at the same time window.\n\n\n\nOur four-dimensional tractography successfully animated neural propagations via distinct interhemispheric pathways.\n\n\n\nOur novel animation method has the potential to help investigators in addressing the mechanistic significance of the interhemispheric network dynamics supporting physiological function.",
"affiliations": "Department of Pediatrics, Children's Hospital of Michigan, Detroit Medical Center, Wayne State University, Detroit, MI 48201, USA; Department of Neurosurgery, Juntendo University, Tokyo, 1138421, Japan.;Department of Pediatrics, Children's Hospital of Michigan, Detroit Medical Center, Wayne State University, Detroit, MI 48201, USA; Department of Neurosurgery, Yokohama City University, Yokohama, 2360004, Japan.;Department of Pediatrics, Children's Hospital of Michigan, Detroit Medical Center, Wayne State University, Detroit, MI 48201, USA; Department of Neurology, Children's Hospital of Michigan, Detroit Medical Center, Wayne State University, Detroit, MI 48201, USA.;Translational Neuroscience Program, Wayne State University, Detroit, MI 48202, USA.;Department of Pediatrics, Children's Hospital of Michigan, Detroit Medical Center, Wayne State University, Detroit, MI 48201, USA; Department of Epileptology, Tohoku University Graduate School of Medicine, Sendai, 9808575, Japan.;Department of Pediatrics, Children's Hospital of Michigan, Detroit Medical Center, Wayne State University, Detroit, MI 48201, USA; Department of Neurology, Children's Hospital of Michigan, Detroit Medical Center, Wayne State University, Detroit, MI 48201, USA.;Department of Neurosurgery, Children's Hospital of Michigan, Detroit Medical Center, Wayne State University, Detroit, MI 48201, USA.;Department of Pediatrics, Children's Hospital of Michigan, Detroit Medical Center, Wayne State University, Detroit, MI 48201, USA; Department of Neurology, Children's Hospital of Michigan, Detroit Medical Center, Wayne State University, Detroit, MI 48201, USA. Electronic address: easano@med.wayne.edu.",
"authors": "Mitsuhashi|Takumi|T|;Sonoda|Masaki|M|;Jeong|Jeong-Won|JW|;Silverstein|Brian H|BH|;Iwaki|Hirotaka|H|;Luat|Aimee F|AF|;Sood|Sandeep|S|;Asano|Eishi|E|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.clinph.2020.11.030",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1388-2457",
"issue": "132(2)",
"journal": "Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology",
"keywords": "Dynamic tractography; Effective connectivity; Functional brain mapping; Pediatric epilepsy surgery; cortico-cortical evoked potentials (CCEPs); electrocorticography (ECoG)",
"medline_ta": "Clin Neurophysiol",
"mesh_terms": "D000293:Adolescent; D002648:Child; D063132:Connectome; D003337:Corpus Callosum; D056324:Diffusion Tensor Imaging; D000069279:Drug Resistant Epilepsy; D005071:Evoked Potentials; D005260:Female; D006801:Humans; D021621:Imaging, Three-Dimensional; D008297:Male; D065908:Transcranial Direct Current Stimulation; D066127:White Matter",
"nlm_unique_id": "100883319",
"other_id": null,
"pages": "520-529",
"pmc": null,
"pmid": "33450573",
"pubdate": "2021-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Four-dimensional tractography animates propagations of neural activation via distinct interhemispheric pathways.",
"title_normalized": "four dimensional tractography animates propagations of neural activation via distinct interhemispheric pathways"
} | [
{
"companynumb": "US-TEVA-2021-US-1910263",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAMOTRIGINE"
},
"drugadditional": "3",
... |
{
"abstract": "In the LYM-3002 study, the efficacy and safety of frontline bortezomib plus rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) and rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) were compared in transplant-ineligible patients with untreated, newly diagnosed, mantle cell lymphoma. We report the final overall survival and safety outcomes for patients in the long-term follow-up phase after the primary progression-free-survival endpoint was met.\n\n\n\nLYM-3002 was a randomised, open-label, phase 3 study done at 128 clinical centres in 28 countries in Asia, Europe, North America, and South America. Adult patients with confirmed stage II-IV previously untreated mantle cell lymphoma, Eastern Cooperative Oncology Group performance status score of 2 or less, who were ineligible for bone marrow transplantation, were randomly assigned (1:1) to receive six or eight 21-day cycles of VR-CAP (intravenous rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and bortezomib 1·3 mg/m2, plus oral prednisone 100 mg/m2) or R-CHOP (intravenous vincristine 1·4 mg/m2 [2 mg maximum], rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and doxorubicin 50 mg/m2, plus oral prednisone 100 mg/m2). Randomisation was done according to a computer-generated randomisation schedule prepared by the sponsor; permuted blocks central randomisation was used (block size of 4), and was stratified by International Prognostic Index score and disease stage at diagnosis. The primary endpoint of this final analysis was overall survival, which was analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00722137, and is closed to new participants with follow-up completed.\n\n\n\nBetween May 22, 2008, and Dec 5, 2011, 487 patients were enrolled and randomly assigned. 268 patients (140 in the VR-CAP group and 128 in the R-CHOP group) were included in the follow-up analysis, which included patients with data available after the primary analysis clinical cutoff date of Dec 2, 2013. After median follow-up of 82·0 months (IQR 74·1-94·2), median overall survival was significantly longer in the VR-CAP group than in the R-CHOP group (90·7 months [95% CI 71·4 to not estimable] vs 55·7 months [47·2 to 68·9]; hazard ratio 0·66 [95% CI 0·51-0·85]; p=0·001). Three new adverse events were reported since the primary analysis cutoff (one each of grade 4 lung adenocarcinoma and grade 4 gastric cancer in the VR-CAP group, and one case of grade 2 pneumonia in the R-CHOP group). 103 (42%) of 243 patients in the VR-CAP group, and 138 (57%) of 244 in the R-CHOP group died; the most common cause of death was progressive disease.\n\n\n\nCompared with R-CHOP, VR-CAP was associated with significantly longer survival, and had a manageable and expected safety profile. Our results support further assessment of VR-CAP in patients with previously untreated mantle cell lymphoma.\n\n\n\nJanssen Research & Development.",
"affiliations": "Department of Hematology, Copernicus Memorial Hospital, Medical University of Lodz, Łodź, Poland. Electronic address: robaktad@csk.umed.lodz.pl.;Department of Hematology, The First Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou, China.;Department of Hematology, Cherkassy Regional Oncology Center, Cherkassy, Ukraine.;Department of Hematology, UZ Leuven Gasthuisberg Hematologie, Leuven, Belgium.;Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.;Allgemeines Krankenhaus der Stadt Wien, Vienna, Austria.;Department of Internal Medicine I, Division of Oncology, Medical University of Vienna, Vienna General Hospital, Vienna, Austria.;Department of Internal Medicine Hematology and Oncology, Masaryk University Hospital Brno, Brno, Czech Republic.;Hospital Das Clinicas Da Faculdade De Medicina Da USP, São Paulo, Brazil.;Cancer Research Center Rams, N N Blokhin Academy of Medical Science, Moscow, Russia.;Chibanishi General Hospital, Chiba, Japan.;Janssen Pharmaceuticals, Tokyo, Japan.;Janssen Research & Development, Raritan, NJ, USA.;Janssen Research & Development, Raritan, NJ, USA.;Janssen Research & Development, High Wycombe, UK.;Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland.",
"authors": "Robak|Tadeusz|T|;Jin|Jie|J|;Pylypenko|Halyna|H|;Verhoef|Gregor|G|;Siritanaratkul|Noppadol|N|;Drach|Johannes|J|;Raderer|Markus|M|;Mayer|Jiri|J|;Pereira|Juliana|J|;Tumyan|Gayane|G|;Okamoto|Rumiko|R|;Nakahara|Susumu|S|;Hu|Peter|P|;Appiani|Carlos|C|;Nemat|Sepideh|S|;Cavalli|Franco|F|;|||",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D000069286:Bortezomib; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "England",
"delete": false,
"doi": "10.1016/S1470-2045(18)30685-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1470-2045",
"issue": "19(11)",
"journal": "The Lancet. Oncology",
"keywords": null,
"medline_ta": "Lancet Oncol",
"mesh_terms": "D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D001208:Asia; D000069286:Bortezomib; D003520:Cyclophosphamide; D018450:Disease Progression; D004317:Doxorubicin; D005060:Europe; D005260:Female; D006801:Humans; D020522:Lymphoma, Mantle-Cell; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009656:North America; D011241:Prednisone; D000077982:Progression-Free Survival; D000069283:Rituximab; D013997:Time Factors; D014750:Vincristine",
"nlm_unique_id": "100957246",
"other_id": null,
"pages": "1449-1458",
"pmc": null,
"pmid": "30348538",
"pubdate": "2018-11",
"publication_types": "D017428:Clinical Trial, Phase III; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Frontline bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in transplantation-ineligible patients with newly diagnosed mantle cell lymphoma: final overall survival results of a randomised, open-label, phase 3 study.",
"title_normalized": "frontline bortezomib rituximab cyclophosphamide doxorubicin and prednisone vr cap versus rituximab cyclophosphamide doxorubicin vincristine and prednisone r chop in transplantation ineligible patients with newly diagnosed mantle cell lymphoma final overall survival results of a randomised open label phase 3 study"
} | [
{
"companynumb": "PHHY2019PL159740",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": "3",
"drug... |
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