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"abstract": "Background. To demonstrate the clinical features, diagnosis, and treatment of nonsteroidal anti-inflammatory drug- (NSAID-) induced diaphragm disease (DD). Methods. A literature search between January 1973 and August 2015 was undertaken. The clinical data of patients with NSAID-induced DD were recorded and analyzed. Results. 159 patients were included. The ratio of male to female was 1 : 2.3; the mean age was 65 ± 11 years. The most common clinical manifestations were gastrointestinal bleeding and obstruction. 121 (84%) patients took traditional NSAIDs. The durations of NSAIDs use ranged from 2 to 300 months. A majority (59.7%) of DD were seen in the small bowel, were seen secondly in the colon (30.2%), and were mainly located in the ileum (57.9%) and right colon (91.7%), respectively. 80% of patients had multiple diaphragms. 41.5% of small bowel DD were diagnosed preoperatively by capsule endoscopy and/or double-balloon enteroscopy, 52.1% at laparotomy. Nearly 75% of patients underwent surgery, endoscopic balloon dilation was performed in 22 patients, and NSAIDs were withdrawn in 53 patients. Conclusions. NSAID-induced DD is relatively rare. The small bowel is most commonly involved. Preoperative diagnosis of small bowel DD is relatively difficult. Discontinuation of the NSAIDs is recommended, surgical resection is the main treatment presently, and endoscopic balloon dilation should be considered as an alternative therapy.",
"affiliations": "Department of Gastroenterology and Hepatology, Chinese People's Liberation Army General Hospital, Beijing 100853, China.;Department of Gastroenterology and Hepatology, Chinese People's Liberation Army General Hospital, Beijing 100853, China.;Department of Gastroenterology and Hepatology, Chinese People's Liberation Army General Hospital, Beijing 100853, China.;Department of Gastroenterology and Hepatology, Chinese People's Liberation Army General Hospital, Beijing 100853, China.",
"authors": "Wang|Yan-Zhi|YZ|;Sun|Gang|G|;Cai|Feng-Chun|FC|;Yang|Yun-Sheng|YS|",
"chemical_list": null,
"country": "Egypt",
"delete": false,
"doi": "10.1155/2016/3679741",
"fulltext": "\n==== Front\nGastroenterol Res PractGastroenterol Res PractGRPGastroenterology Research and Practice1687-61211687-630XHindawi Publishing Corporation 10.1155/2016/3679741Research ArticleClinical Features, Diagnosis, and Treatment Strategies of Gastrointestinal Diaphragm Disease Associated with Nonsteroidal Anti-Inflammatory Drugs Wang Yan-Zhi Sun Gang Cai Feng-Chun Yang Yun-Sheng \n*\nDepartment of Gastroenterology and Hepatology, Chinese People's Liberation Army General Hospital, Beijing 100853, China*Yun-Sheng Yang: sunny301ddc@126.comAcademic Editor: Philipp Lenz\n\n2016 28 3 2016 2016 367974129 12 2015 7 3 2016 Copyright © 2016 Yan-Zhi Wang et al.2016This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nBackground. To demonstrate the clinical features, diagnosis, and treatment of nonsteroidal anti-inflammatory drug- (NSAID-) induced diaphragm disease (DD). Methods. A literature search between January 1973 and August 2015 was undertaken. The clinical data of patients with NSAID-induced DD were recorded and analyzed. Results. 159 patients were included. The ratio of male to female was 1 : 2.3; the mean age was 65 ± 11 years. The most common clinical manifestations were gastrointestinal bleeding and obstruction. 121 (84%) patients took traditional NSAIDs. The durations of NSAIDs use ranged from 2 to 300 months. A majority (59.7%) of DD were seen in the small bowel, were seen secondly in the colon (30.2%), and were mainly located in the ileum (57.9%) and right colon (91.7%), respectively. 80% of patients had multiple diaphragms. 41.5% of small bowel DD were diagnosed preoperatively by capsule endoscopy and/or double-balloon enteroscopy, 52.1% at laparotomy. Nearly 75% of patients underwent surgery, endoscopic balloon dilation was performed in 22 patients, and NSAIDs were withdrawn in 53 patients. Conclusions. NSAID-induced DD is relatively rare. The small bowel is most commonly involved. Preoperative diagnosis of small bowel DD is relatively difficult. Discontinuation of the NSAIDs is recommended, surgical resection is the main treatment presently, and endoscopic balloon dilation should be considered as an alternative therapy.\n==== Body\n1. Introduction\nSince the synthesis of aspirin in 1899, nonsteroidal anti-inflammatory drugs (NSAIDs) have been one of the most widely prescribed drugs in the world for defervescence, analgesia, and the therapy of inflammatory conditions including osteoarthritis and rheumatoid arthritis [1]. New, promising fields of application in cancer prophylaxis have also arisen [2]. Moreover, their widespread and sometimes uncontrolled use is promoted by their over-the-counter availability in many countries. It is indicated by a 2010 National Health Interview Survey (NHIS) that around 43 million adults (19.0%) in the United States took aspirin at least three times per week for more than 3 months (i.e., regular users), and more than 29 million adults (12.1%) were regular users of NSAIDs. Compared with 2005, this was an overall increase of 57% in aspirin use and 41% in NSAID use [3].\n\nIt has been well known that NSAIDs could cause gastrointestinal (GI) inflammation, ulceration, bleeding, and perforation [4]. But it has not been widely recognized that NSAIDs also can cause other types of lesions, for example, formation of diaphragm-like stricture [5, 6]. Cases of small bowel strictures associated with NSAIDs have been reported since the 1970s [7]. Recurrent small bowel obstruction associated with piroxicam was again reported in 1987 by Sukumar who mentioned diaphragm-like strictures as the cause of the obstruction [8]. However, the “diaphragm disease (DD)” was first termed by Lang et al. in 1988 [9]. In their report, 7 cases of DD were identified, the clinicopathological features and its strong relationship to NSAID were described, and the possible mechanisms were discussed. The first report of NSAID-induced colonic DD was a letter by Sheers and Williams in 1989 [10].\n\nThe relationship between NSAIDs use and GI inflammation and ulceration has been well demonstrated by large studies. However, the current papers about the diaphragm-like stricture induced by NSAIDs are mostly case reports. There are several reviews on NSAID-induced DD, but only involving the small intestine or colon [11, 12]. In this paper we describe the clinical features, diagnosis, and treatment strategies of NSAID-induced DD involving stomach, duodenum, small bowel, and colon and hope to further the clinical awareness of this entity which may become increasingly important in the era of widespread use of NSAIDs.\n\n2. Methods\n2.1. Literature Search and Management Procedure\nA literature search was undertaken using the terms “diaphragm disease” or “diaphragm” or “diaphragm-like stricture” or “diaphragm-like strictures” in combination with “nonsteroidal anti-inflammatory drugs” or “nonsteroidal anti-inflammatory drug” or “NSAIDs” or “NSAID”. PubMed was consulted to search for papers published between January 1973 and August 2015. Titles were reviewed and any papers with nonrelevant titles were excluded. Abstracts of the remaining papers were subsequently systematically reviewed. If there was no abstract, the paper would have been browsed. The paper would have been excluded if the abstract was not related to DD or DD unrelated to NSAIDs or not written in English. All published papers (including articles, reviews, case reports, and letters) referring to NSAIDs-induced DD were included. The references of each paper were consulted and any relevant papers were also reviewed for inclusion. Finally, the remaining 72 papers were included in the present paper. The literature search and management procedure is presented in Figure 1.\n\n2.2. Data Extraction\nClinical data of patients extracted included age at onset; gender; clinical presentation; type, dosage, and duration of NSAIDs use; examination; diagnostic method; location and number of diaphragm-like strictures; management.\n\n2.3. Statistical Analysis\nDescriptive statistics for continuous variables (age, duration of NSAIDs use) and discrete variables (number of diaphragm-like strictures) were presented as mean values ± SD, and minimum and maximum values and categorical variables were presented as percent.\n\n3. Results\n3.1. Age, Gender, and Clinical Manifestations\n159 patients (including our one case) with NSAIDs-induced DD were analyzed. 106 patients were female and only 47 were male; with gender unknown in six cases, the ratio of male to female is 1 : 2.3. The mean age was 65 ± 11 years (age range, 37–90 years).\n\nThe most common clinical manifestations were GI bleeding and obstruction. 102 (65.8%) and 113 (72.9%) patients presented with GI bleeding and obstruction, respectively. The other clinical manifestations were shown in Table 1.\n\n3.2. Type and Duration of NSAIDs Use\n57 patients took various NSAIDs, 87 patients took one kind of NSAID, and the NSAIDs taken in the remaining 15 patients were unspecified. 121 (84%) patients took traditional NSAIDs, including diclofenac used most commonly in 47 cases (slow release agent in 16 cases, suppository in 2 cases). 38 (26.4%) patients took selective cyclooxygenase-2 (COX-2) inhibitors. Details of the other NSAIDs were shown in Table 2. Dramatically, more than 40 tablets of compound aminopyrine phenacetin were taken by mistake while drunk one month prior to the onset in our case.\n\nOf the 138 patients in whom durations of NSAID use were reported, 133 patients had been taking NSAIDs for more than one year. Of the 92 patients in whom durations of NSAID use were specified, the varying durations ranged from 2 to 300 months and the mean duration was 79 ± 71 months.\n\n3.3. Location and Number of Diaphragm-Like Strictures\nThe diaphragms were randomly distributed throughout the whole GI tract (Figure 2), but majority (95, 59.7%) were seen in the small bowel, 48 (30.2%) cases in the colon. Small bowel DD was mainly located in the ileum (55, 57.9%). Colonic DD were seen anywhere along the colon from caecum to rectosigmoid junction, but a majority (44, 91.7%) occurred in the right colon and was mainly located in the ascending colon. Of the 123 patients in whom the number of diaphragms was reported, multiple diaphragms were detected in 98 (80%) patients.\n\n3.4. Diagnosis and Treatment\nExamination methods include endoscopy, gastrointestinal radiology, and laparotomy (Table 3). Gastric and duodenal DD in 7 patients were diagnosed by esophagogastroduodenoscopy (EGD); only one case had DD in duodenum afferent limb diagnosed by double-balloon enteroscopy (DBE). The majority (92%) of colonic DD were diagnosed by colonoscopy. With regard to small bowel DD (Figure 3), preoperative diagnosis was made by CE and/or DBE in 39 (41.5%) patients. In 49 (52.1%) patients, DD was diagnosed by laparotomy. In all 36 patients who underwent CE, retained capsule was retrieved by laparotomy in 31 (86%) patients and by DBE in 4 patients; the capsule was excreted spontaneously in one patient.\n\nOf the 150 patients with the treatment methods available (Figure 4), nearly 75% of patients underwent surgery. Therapeutic endoscopy was performed in 24 cases, including endoscopic balloon dilation in 22 cases (with placement of a metal stent in our case), incise using a standard sphincterotome in 2 cases. NSAIDs were withdrawn in 53 patients, discontinuation of NSAIDs was the only treatment in 18 patients, and the other 35 patients discontinued NSAIDs as part of the treatment regimen. 38 patients underwent combined therapy.\n\n4. Discussion\nGastrointestinal diaphragm-like stricture, also called diaphragm disease, is a relatively rare NSAID-induced complication. It is reported that in 2% of patients taking conventional NSAIDs on a long-term basis, small bowel DD developed [13]. But with the ageing of society, the widespread use of NSAIDs such as aspirin in ischaemic heart disease and arthritis, and increasingly recent recognition, the incidence of DD is on the rise and seems likely to increase in the future; the current actual incidence of DD is still unknown.\n\nDD is probably more common in middle-aged and elderly patients, as they are the most likely to take NSAIDs. The mean age at presentation is 65 ± 11 years in our study. The disease has an obvious female preponderance with ratio of 3 : 1 (2.3 : 1 in our study) presumably due to their higher incidence of chronic diseases requiring long-term analgesic and anti-inflammatory therapy, such as rheumatoid arthritis and osteoarthritis [14]. Clinical manifestations of the DD are nonspecific and insidious, including abdominal pain, vomiting and other obstructive symptoms, loss of blood and protein (overt GI bleeding, anemia, positive fecal occult blood, hypoalbuminemia, and protein-losing enteropathy), diarrhea, constipation, changes in bowel habits, and weight loss [15–17]. Our study demonstrates that the most frequent clinical presentations are GI bleeding and obstructive symptoms as seen in our study (4 cases) and it rarely presented as acute abdomen due to obstruction and/or subsequent perforation [18].\n\nThe exact pathogenesis of NSAID-induced DD remains obscure. However, the mechanisms of gastrointestinal damage (such as ulceration) caused by NSAID have been studied and discussed extensively [19–23]. It has been suggested that mucosal damage, for example, circumferential ulceration, could be the precursor of DD [24, 25]. The subsequent reparative process would cause submucosal inflammation and fibrosis. In the healing phase, submucosal granulation tissue matures into collagenous scar tissue; then these rings of scar tissue contract, like drawstrings across the bowel lumen, eventually form diaphragm-like strictures. Moreover, it is paradoxical that despite the wide use of NSAIDs and the high prevalence of NSAID-induced GI inflammation, these lesions can then progress to diaphragm-like strictures only in a few patients. The exact determinants of susceptibility remain unknown. Recently, it has been found that CYP2C9∗3 SNPs were significantly associated with an increased risk for DD [26].\n\nThe relative risks of the different NSAIDs are not very clear and many studies have shown that selective COX-2 inhibitors may be significantly less injurious to gastrointestinal tract than traditional NSAIDs [26]. As shown in Table 2, 121 (84%) patients took traditional NSAIDs, and 38 (26.4%) patients took selective COX-2 inhibitors. Diclofenac is the most commonly used NSAID in our study, which has raised the question of whether diclofenac has a predisposition to cause DD or if diclofenac is just commonly used. All of the 16 patients known to have taken sustained-released diclofenac have diaphragm formation in the colon. Because these NSAIDs have a longer half-life, they are more likely to reach the colon before they are entirely digested. All NSAIDs were taken orally except in four cases involving suppositories. These may reflect an interaction of local and systemic effects [16].\n\nDosage is one factor affecting the plasma concentration of NSAIDs. In general, DD has been associated with high doses taken daily [9, 27]. Interestingly, our case has no indication for taking NSAID; more than 40 tablets of compound aminopyrine phenacetin were taken by mistake while drunk one month prior to the onset. Another important factor is how long it takes for DD to develop in a patient taking NSAIDs. Most patients take NSAIDs on a long-term basis. The duration of NSAIDs use varies from 2 months to 25 years in our study, but 133 (96%) patients had taken NSAIDs for more than one year. However, two patients have taken NSAIDs for only 2 months.\n\nDiaphragm-like strictures can occur anywhere along the whole gastrointestinal tract. However, the majority of instances are located in small bowel [14]; 1/3 have been found in the colon [16]. In our study, 59.7% of the lesions were seen in the small bowel and 30.2% in the colon. Many reports state that small bowel DD is located predominantly in the ileum [28, 29]. Our study showed that 57.9% of small bowel DD were observed in the ileum. It may be because of the differences in the bacterial flora and immune system between the jejunum and ileum [5]. The terminal ileum is frequently spared [16]. In our study, terminal ileum is involved in only five cases. Colonic DD usually involves the right colon [30–33]. Our study also demonstrates that over 90% of colonic DD occur in the right colon and are mainly located in the ascending colon. The diaphragm in the rectosigmoid junction is the most distal lesion reported to date.\n\nThe diagnosis of DD is frequently made after an extensive workup that includes gastrointestinal radiology, endoscopy, and laparotomy. Blood tests may reveal anemia and hypoalbuminemia. For the diagnosis of DD, conventional gastrointestinal radiological techniques are inaccurate. Plain abdominal X-ray is usually unhelpful. Barium studies may show the diaphragms [27, 34, 35], but they are as easily overlooked as the thin-walled diaphragms resembling exaggerated plicae circulares [36, 37]. CT scanning may show a degree of obstruction but is unable to identify the thin diaphragms.\n\nThe upper gastrointestinal tract and the large bowel can be evaluated by EGD and colonoscopy. In our study, the majority of gastric, duodenal, and colonic DD were diagnosed by EGD and colonoscopy. The advent of CE and DBE may facilitate evaluation of the small bowel. The first diagnosis of NSAID-induced small intestinal DD through CE was reported by Yousfi et al. [38]. CE is diagnostically effective but has a significant risk of capsule retention and precipitating bowel obstruction [9, 15, 27]. Under the circumstances, laparotomy or DBE usually would be required to remove the retained capsule, so it should be used cautiously. In all 36 patients who underwent CE, retained capsule was retrieved by laparotomy in 31 (86%) patients and by DBE in 4 patients. DBE is a valuable and minimally invasive technique for the detection of diaphragm-like stricture, and endoscopic treatment is possible [39–41]. But it is technically difficult, demanding, time consuming, expensive, and not widely available and provides poor anatomical localization of diseased segments [20]. Preoperative diagnosis of small bowel DD is relatively difficult because most conventional gastrointestinal radiological techniques are unable to discern the diaphragms and limitations of endoscopy. In our study, small bowel DD were diagnosed by CE and/or DBE in 39 (41.5%) patients; 52.1% of small bowel DD were diagnosed at laparotomy. During laparotomy, the surgeon has the added advantage that the small bowel can be palpated, and a diaphragm may be felt slightly thickened. But even so, the lesion may be missed as it affects only the mucosa and submucosa leaving an intact muscularis propria and serosa [16, 28, 42], so that meticulous palpation is essential to make the diagnosis. Furthermore, intraoperative enteroscopy has been used to explore and assess the extent of the lesion [17, 28, 29, 38, 43]. Compared with laparotomy, the role of laparoscopy appears to be limited because a diaphragm may be apparent only by slight decrease in extraluminal diameter and serosal discoloration [15], as the bowel may look deceptively normal. In our study, only 3 cases were diagnosed by laparoscopy.\n\nDD is intraluminal characterized by the presence of multiple (occasionally single [43]), thin, concentric, circumferential, and diaphragm-like mucosal projections narrowing the intestinal lumen from an approximately normal diameter to a pinhole causing varying degrees of obstruction and dividing the bowel lumen into a series of short compartments. This may make the bowel manifest as segmentation in gross specimens and resemble a string of sausages [5, 20]. The diaphragm-like strictures were often accompanied with varying degrees of erosion or ulceration [10, 19, 27], as this accounts for the chronic blood loss observed. The histopathologic characteristics of the DD are submucosal fibrosis as observed in our case [44]. Unlike Crohn's disease, DD does not affect the full thickness of the bowel wall. The muscularis propria, serosa, and mesentery usually are spared and the adjacent muscularis mucosae are interrupted and partially incorporated into the fibrotic process [16, 45]. Granulomata, which is the histopathologic characteristics of Crohn's disease, is not identified in DD [46].\n\nThe management of DD in most reported cases is segmental resection of the involved intestine, especially for the patients with DD in the small bowel. Intestinal resection was formerly the only option. Moreover, most patients underwent resection because multiple lesions were located close together along the intestine [15]. Recently, with the development of endoscopic techniques (such as DBE), endoscopic balloon dilation could be considered as an alternative option for DD [47, 48]. Given the histological feature of the DD, the risk of intestinal perforation with endoscopic balloon dilation would be low. In our study, endoscopic balloon dilation was performed in 22 patients. As with any NSAID-induced disease, the discontinuation of the NSAIDs is essential for the treatment of DD. In 18 patients for whom discontinuation of NSAIDs was the only treatment, discontinuation was associated with an improvement in symptoms. The prognosis should be good if the NSAIDs can safely be withdrawn. However, long-term cessation of NSAIDs is frequently impossible for patients with chronic arthritis or requiring antiplatelet therapy [5]. The benefit of continuing with NSAIDs may outweigh the risk of GI injury for some patients, as this needs to be considered on a case-by-case basis [46]. The use of prostaglandin derivatives (such as misoprostol) may protect against NSAID-induced GI damage, so their concomitant use should be considered in patients who are particularly at risk of NSAIDs associated GI complications, but NSAIDs are unable to be withdrawn [49]. In our study, one patient took misoprostol and ornoprostil, respectively. Recurrence of symptoms following surgical resection may occur in up to 50% of patients. This is due to either the surgeon's failure to appreciate the extent of the lesions at the initial operation or a true recurrence due to continued use of NSAIDs [10]. In our study, two patients had a relapsing course, because they resumed or continued to take NSAIDs following surgery. So, follow-up is important for timely identification and treatment of the recurrent diaphragms.\n\n5. Conclusion\nDD is a rare but increasingly recognized complication of NSAID usage. The pathogenesis is certainly multifactorial, but still not entirely clear. It can result in GI bleeding and obstruction. Diagnosis of DD often requires endoscopy, gastrointestinal radiological techniques, and even laparotomy. Management mainly includes discontinuation of NSAIDs, surgical resection, and endoscopic balloon dilatation. Appropriate treatment will vary with each individual. With the prevalence of NSAID usage, clinicians may encounter it more frequently. It should be considered in the differential diagnosis of patients with NSAIDs medication history and present with GI obstruction of unclear etiology as to timely diagnosis and treatment. In the future, further studies are needed to elucidate the incidence and pathogenesis of NSAID-induced DD, the related risk factors, the development of improved diagnostic techniques and treatment, and the possibility of effective medication.\n\nCompeting Interests\nThe authors declare that there are no competing interests regarding the publication of this paper.\n\nFigure 1 Literature search and management procedure.\n\nFigure 2 Location of diaphragm-like stricture. Postoperative ileum proximal to the ileal-sigmoid anastomosis (one case) and bypassed ileal segment (one case). Left colon and other included descending colon (one case), lower sigmoid (one case), rectosigmoid junction (one case), and ileocaecal valve, ascending colon, transverse colon, and descending colon were all involved in one case. Other locations included jejunum and duodenum (3 cases); jejunum, duodenum, and pylorus (one case); terminal ileum, ileocaecal valve, caecum, and ascending colon (one case); terminal ileum and ascending colon (one case); terminal ileum and ileocaecal junction (one case); terminal ileum and ileocaecal valve (one case).\n\nFigure 3 Diagnostic methods. Other methods included autopsy (one case), small bowel enema (one case), and sigmoidoscopy (one case).\n\nFigure 4 Treatment for patients with NSAIDs-induced DD.\n\nTable 1 Clinical manifestations in patients with NSAIDs-induced DD.\n\nClinical manifestations\t(n = 155)\t\nGI obstruction\t113 (72.9%)\t\n Abdominal pain\t64 (56.6%)\t\n Nausea and/or vomiting\t40 (35.4%)\t\n Abdominal distension\t20 (17.7%)\t\nGI bleeding\t102 (65.8%)\t\n Occult bleeding\t73 (71.6%)\t\n Overt bleeding\t22 (21.6%)\t\n OGIB\t16 (15.7%)\t\nOther\t \t\n Weight loss\t28 (18.1%)\t\n Diarrhea\t22 (14.2%)\t\n Hypoalbuminemia\t21 (13.5%)\t\n Constipation\t16 (10.3%)\t\n Acute onset of perforation\t4 (2.6%)\t\nTable 2 Type of NSAIDs used in patients with NSAIDs-induced DD.\n\nNSAIDs\t(n = 144)\t\nTraditional NSAIDs\t121 (84.0%)\t\n Diclofenac\t47 (32.6%)\t\n Aspirin\t36 (25.0%)\t\n Indomethacin\t22 (15.3%)\t\n Ibuprofen\t20 (13.9%)\t\n Naproxen\t11 (7.6%)\t\n Paracetamol\t7 (4.9%)\t\n Azapropazone\t5 (3.5%)\t\n Phenylbutazone\t4 (2.8%)\t\n Loxoprofen\t4 (2.8%)\t\n Sulindac\t3 (2.1%)\t\nSelective COX-2 inhibitor\t38 (26.4%)\t\n Piroxicam\t16 (11.1%)\t\n Rofecoxib\t7 (4.9%)\t\n Meloxicam\t5 (3.5%)\t\n Celecoxib\t4 (2.8%)\t\n Etodolac \t4 (2.8%)\t\n Nabumetone \t2 (1.4%)\t\n Tenoxicam\t1 (0.7%)\t\n Nimesulide \t1 (0.7%)\t\nOther\t \t\n Compound aminopyrine phenacetin\t1 (0.7%)\t\nTable 3 Examination methods.\n\nExamination methods\t(n = 158)\t\nEndoscopy\t \t\n EGD\t69 (43.7%)\t\n Colonoscopy\t72 (45.6%)\t\n Sigmoidoscopy\t9 (5.7%)\t\n CE\t36 (22.8%)\t\n Enteroscopy\t18 (11.4%)\t\nGastrointestinal radiology\t \t\n Barium study\t \t\n Upper gastrointestinal tract series\t17 (10.8%)\t\n Small bowel follow-through/small bowel enema\t59 (37.3%)\t\n Barium enema\t29 (18.4%)\t\n CT\t39 (24.7%)\t\n Plain abdominal X-ray\t23 (14.6%)\t\n Abdominal angiography\t10 (6.3%)\t\n Nuclear tagged red blood cell scan\t5 (3.2%)\t\nLaparotomy\t62 (39.2%)\t\nIntraoperative enteroscopy\t7 (4.4%)\t\nDiagnostic laparoscopy\t5 (3.2%)\n==== Refs\n1 Wallace J. 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Diaphragm disease of the small-bowel: a case report and literature review Digestive Surgery 2002 19 5 410 413 10.1159/000065824 2-s2.0-0036432863 12435916 \n17 Shumaker D. A. Bladen K. Katon R. M. NSAID-induced small bowel diaphragms and strictures diagnosed with intraoperative enteroscopy Canadian Journal of Gastroenterology 2001 15 9 619 623 2-s2.0-0035164089 11573106 \n18 Robinson M. H. E. Wheatley T. Leach I. H. Nonsteroidal antiinflammatory drug-induced colonic stricture—an unusual cause of large bowel obstruction and perforation Digestive Diseases and Sciences 1995 40 2 315 319 10.1007/bf02065416 2-s2.0-0028817598 7851196 \n19 Bjarnason I. Hayllar J. Macpherson A. N. D. J. Russell A. N. T. S. Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine in humans Gastroenterology 1993 104 6 1832 1847 2-s2.0-0027244454 8500743 \n20 Davies N. M. Saleh J. Y. Skjodt N. M. Detection and prevention of NSAID-induced enteropathy Journal of Pharmacy & Pharmaceutical Sciences 2000 3 1 137 155 2-s2.0-0033642896 10954683 \n21 Bjarnason I. Zanelli G. Prouse P. Blood and protein loss via small-intestinal inflammation induced by non-steroidal anti-inflammatory drugs The Lancet 1987 2 8561 711 714 \n22 Bjarnason I. So A. Levi A. J. Intestinal permeability and inflammation in rheumatoid arthritis: effects of non-steroidal anti-inflammatory drugs The Lancet 1984 324 8413 1171 1174 10.1016/s0140-6736(84)92739-9 2-s2.0-0021678277 \n23 Bjarnason I. Williams P. Smethurst P. Peters T. J. Levi A. J. Effect of non-steroidal anti-inflammatory drugs and prostaglandins on the permeability of the human small intestine Gut 1986 27 11 1292 1297 10.1136/gut.27.11.1292 2-s2.0-0022977470 3466837 \n24 Manocha D. John S. Bansal N. Paul M. Unusual case of acute intestinal obstruction Journal of Clinical Medicine Research 2010 2 5 230 232 21629545 \n25 Going J. J. Canvin J. Sturrock R. Possible precursor of diaphragm disease in the small intestine The Lancet 1993 341 8845 638 639 10.1016/0140-6736(93)90407-8 2-s2.0-0027450006 \n26 Ishihara M. Ohmiya N. Nakamura M. Risk factors of symptomatic NSAID-induced small intestinal injury and diaphragm disease Alimentary Pharmacology and Therapeutics 2014 40 5 538 547 10.1111/apt.12858 2-s2.0-84907754172 25041257 \n27 Bjarnason I. Price A. B. Zanelli G. Clinicopathological features of nonsteroidal antiinflammatory drug-induced small intestinal strictures Gastroenterology 1988 94 4 1070 1074 2-s2.0-0023933549 3345876 \n28 Matsuhashi N. Yamada A. Hiraishi M. Multiple strictures of the small intestine after long-term nonsteroidal anti-inflammatory drug therapy American Journal of Gastroenterology 1992 87 9 1183 1186 2-s2.0-0026713924 1519577 \n29 Manetas M. O'Loughlin C. Kelemen K. Barkin J. S. Multiple small-bowel diaphragms: a cause of obscure GI bleeding diagnosed by capsule endoscopy Gastrointestinal Endoscopy 2004 60 5 848 851 10.1016/s0016-5107(04)02174-1 2-s2.0-9244265495 15557976 \n30 Halter F. Weber B. Huber T. Eigenmann F. Paul Frey M. Ruchti C. Diaphragm disease of the ascending colon: assocition with sustained-release diclofenac Journal of Clinical Gastroenterology 1993 16 1 74 80 10.1097/00004836-199301000-00020 2-s2.0-0027446461 8421154 \n31 Nicholson A. A. Bennett J. R. Case report: radiological appearance of colonic stricture associated with the use of nonsteroidal anti-inflammatory drugs Clinical Radiology 1995 50 4 268 269 10.1016/s0009-9260(05)83484-1 2-s2.0-0028951836 7729128 \n32 Hooker G. D. Gregor J. C. Ponich T. P. McLarty T. D. Diaphragm-like strictures of the right colon induced by indomethacin suppositories: evidence of a systemic effect Gastrointestinal Endoscopy 1996 44 2 199 202 10.1016/s0016-5107(96)70144-x 2-s2.0-0029742527 8858332 \n33 Gargot D. Chaussade S. D'Alteroche L. Nonsteroidal anti-inflammatory drug-induced colonic strictures: two cases and literature review The American Journal of Gastroenterology 1995 90 11 2035 2038 2-s2.0-0028882966 7485018 \n34 Levi S. De Lacey G. Price A. B. Gumpel M. J. Levi A. J. Bjarnason I. ‘Diaphragm-like’ strictures of the small bowel in patients treated with non-steroidal anti-inflammatory drugs British Journal of Radiology 1990 63 747 186 189 10.1259/0007-1285-63-747-186 2-s2.0-0025248773 2334829 \n35 Ammori B. J. Laparoscopic pancreas-preserving distal duodenectomy for duodenal stricture related to nonsteroidal antiinflammatory drugs (NSAIDs) Surgical Endoscopy 2002 16 9 1362 1363 10.1007/s00464-001-4145-6 2-s2.0-0036729634 \n36 McCune K. H. Allen D. Cranley B. Small bowel diaphragm disease—strictures associated with non-steroidal anti-inflammatory drugs Ulster Medical Journal 1992 61 2 182 184 2-s2.0-0026496840 1481311 \n37 Scholz F. J. Heiss F. W. Roberts P. L. Thomas C. Diaphragmlike strictures of the small bowel associated with use of nonsteroidal antiinflammatory drugs American Journal of Roentgenology 1994 162 1 49 50 10.2214/ajr.162.1.8273688 2-s2.0-0028084894 8273688 \n38 Yousfi M. M. De Petris G. Leighton J. A. Diaphragm disease after use of nonsteroidal anti-inflammatory agents: first report of diagnosis with capsule endoscopy Journal of Clinical Gastroenterology 2004 38 8 686 691 10.1097/01.mcg.0000135367.66159.87 2-s2.0-4143146308 15319653 \n39 Yamamoto H. Sekine Y. Sato Y. Total enteroscopy with a nonsurgical steerable double-balloon method Gastrointestinal Endoscopy 2001 53 2 216 220 10.1067/mge.2001.112181 2-s2.0-0035127914 11174299 \n40 Yamamoto H. Yano T. Kita H. New system of double-balloon enteroscopy for diagnosis and treatment of small intestinal disorders Gastroenterology 2003 125 5 1556 1557 2-s2.0-0242574410 14628813 \n41 Yamamoto H. Kita H. Sunada K. Clinical outcomes of double-balloon endoscopy for the diagnosis and treatment of small-intestinal diseases Clinical Gastroenterology and Hepatology 2004 2 11 1010 1016 10.1016/S1542-3565(04)00453-7 2-s2.0-9144261189 15551254 \n42 Bjarnason I. Hopkinson N. Zanelli G. Treatment of non-steroidal anti-inflammatory drug induced enteropathy Gut 1990 31 7 777 780 10.1136/gut.31.7.777 2-s2.0-0025300404 1973396 \n43 Lapner M. A. Stephen W. J. Rofecoxib associated with diaphragm disease Canadian Journal of Surgery 2007 50 6 E27 E28 2-s2.0-38449113605 \n44 Munipalle P. C. Little M. Garud T. Henderson D. NSAID-induced diaphragmatic disease of the colon BMJ Case Reports 2013 10.1136/bcr-2012-008448 2-s2.0-84878999848 \n45 Image interpretation session: 1995. Case 4. Small bowel webs due to NSAIDs (‘diaphragm disease’) RadioGraphics 1996 16 1 222 224 10.1148/radiographics.16.1.222 10946706 \n46 Pilgrim S. Velchuru V. Waters G. Tsiamis A. Lal R. Diaphragm disease and small bowel enteropathy due to nonsteroidal anti-inflammatory drugs: a surgical perspective Colorectal Disease 2011 13 4 463 466 10.1111/j.1463-1318.2009.02176.x 2-s2.0-79952520043 20041919 \n47 Kamata Y. Iwamoto M. Nara H. A case of rheumatoid arthritis with protein losing enteropathy induced by multiple diaphragmatic strictures of the small intestine: successful treatment by bougieing under double-balloon enteroscopy Gut 2006 55 9 p. 1372 10.1136/gut.2006.100446 2-s2.0-33747759082 \n48 Mehdizadeh S. Lo S. K. Treatment of small-bowel diaphragm disease by using double-balloon enteroscopy Gastrointestinal Endoscopy 2006 64 6 1014 1017 10.1016/j.gie.2006.05.026 2-s2.0-33751439997 17140921 \n49 McGonigal A. Moffat D. F. Lindop G. B. M. Gilchrist W. J. Nonsteroidal anti-inflammatory drug associated diaphragm disease Postgraduate Medical Journal 1997 73 862 505 506 10.1136/pgmj.73.862.505 2-s2.0-0030766283 9307744\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1687-6121",
"issue": "2016()",
"journal": "Gastroenterology research and practice",
"keywords": null,
"medline_ta": "Gastroenterol Res Pract",
"mesh_terms": null,
"nlm_unique_id": "101475557",
"other_id": null,
"pages": "3679741",
"pmc": null,
"pmid": "27118967",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": "11174299;17625980;8421154;8273688;11573106;6150232;21629545;17140921;8858332;20041919;21812898;23517116;15557976;9394740;2334829;7729128;1973396;3345876;2572870;23709532;24689088;23723142;9307744;10954683;25653559;12435916;15319653;15551254;1519577;10882981;7851196;12072993;10946706;25041257;19148795;9041264;14628813;1481311;3567507;16365236;2888943;8094872;18067698;7485018;8500743;3466837;16905713;15944962;3384981",
"title": "Clinical Features, Diagnosis, and Treatment Strategies of Gastrointestinal Diaphragm Disease Associated with Nonsteroidal Anti-Inflammatory Drugs.",
"title_normalized": "clinical features diagnosis and treatment strategies of gastrointestinal diaphragm disease associated with nonsteroidal anti inflammatory drugs"
} | [
{
"companynumb": "CN-JNJFOC-20180112388",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": "3",
"d... |
{
"abstract": "Therapy-related acute myeloid leukemia (t-AML) refers to a heterogeneous group of myeloid neoplasms that develop in patients following extensive exposure to either cytotoxic agents or radiation. The development of t-AML has been reported following treatment of cancers ranging from hematological malignancies to solid tumors; however, to our knowledge, t-AML has never been reported following treatment of gastric cancer. In this study, we report the development of t-acute promyelocytic leukemia in a cT4N1M0 gastric cancer patient after an approximate 44 mo latency period following treatment with 4 cycles of oxaliplatin (OXP) (85 mg/m(2) on day 1) plus capecitabine (1250 mg/m(2) orally twice daily on days 1-14) in combination with recombinant human granulocyte-colony stimulating factor treatment. Karyotype analysis of the patient revealed 46,XY,t(15;17)(q22;q21)[15]/46,idem,-9,+add(9)(p22)[2]/46,XY[3], which, according to previous studies, includes some \"favorable\" genetic abnormalities. The patient was then treated with all-trans retinoic acid (ATRA, 25 mg/m(2)/d) plus arsenic trioxide (ATO, 10 mg/d) and attained complete remission. Our case illuminated the role of certain cytotoxic agents in the induction of t-AML following gastric cancer treatment. We recommend instituting a mandatory additional evaluation for patients undergoing these therapies in the future.",
"affiliations": "Ying-Cheng Zhang, Yu-Qi Zhou, Bing Yan, Jun Shi, Li-Juan Xiu, Yu-Wei Sun, Xuan Liu, Zhi-Feng Qin, Pin-Kang Wei, Yong-Jin Li, Department of Traditional Chinese Medicine, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.;Ying-Cheng Zhang, Yu-Qi Zhou, Bing Yan, Jun Shi, Li-Juan Xiu, Yu-Wei Sun, Xuan Liu, Zhi-Feng Qin, Pin-Kang Wei, Yong-Jin Li, Department of Traditional Chinese Medicine, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.;Ying-Cheng Zhang, Yu-Qi Zhou, Bing Yan, Jun Shi, Li-Juan Xiu, Yu-Wei Sun, Xuan Liu, Zhi-Feng Qin, Pin-Kang Wei, Yong-Jin Li, Department of Traditional Chinese Medicine, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.;Ying-Cheng Zhang, Yu-Qi Zhou, Bing Yan, Jun Shi, Li-Juan Xiu, Yu-Wei Sun, Xuan Liu, Zhi-Feng Qin, Pin-Kang Wei, Yong-Jin Li, Department of Traditional Chinese Medicine, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.;Ying-Cheng Zhang, Yu-Qi Zhou, Bing Yan, Jun Shi, Li-Juan Xiu, Yu-Wei Sun, Xuan Liu, Zhi-Feng Qin, Pin-Kang Wei, Yong-Jin Li, Department of Traditional Chinese Medicine, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.;Ying-Cheng Zhang, Yu-Qi Zhou, Bing Yan, Jun Shi, Li-Juan Xiu, Yu-Wei Sun, Xuan Liu, Zhi-Feng Qin, Pin-Kang Wei, Yong-Jin Li, Department of Traditional Chinese Medicine, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.;Ying-Cheng Zhang, Yu-Qi Zhou, Bing Yan, Jun Shi, Li-Juan Xiu, Yu-Wei Sun, Xuan Liu, Zhi-Feng Qin, Pin-Kang Wei, Yong-Jin Li, Department of Traditional Chinese Medicine, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.;Ying-Cheng Zhang, Yu-Qi Zhou, Bing Yan, Jun Shi, Li-Juan Xiu, Yu-Wei Sun, Xuan Liu, Zhi-Feng Qin, Pin-Kang Wei, Yong-Jin Li, Department of Traditional Chinese Medicine, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.;Ying-Cheng Zhang, Yu-Qi Zhou, Bing Yan, Jun Shi, Li-Juan Xiu, Yu-Wei Sun, Xuan Liu, Zhi-Feng Qin, Pin-Kang Wei, Yong-Jin Li, Department of Traditional Chinese Medicine, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.;Ying-Cheng Zhang, Yu-Qi Zhou, Bing Yan, Jun Shi, Li-Juan Xiu, Yu-Wei Sun, Xuan Liu, Zhi-Feng Qin, Pin-Kang Wei, Yong-Jin Li, Department of Traditional Chinese Medicine, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.",
"authors": "Zhang|Ying-Cheng|YC|;Zhou|Yu-Qi|YQ|;Yan|Bing|B|;Shi|Jun|J|;Xiu|Li-Juan|LJ|;Sun|Yu-Wei|YW|;Liu|Xuan|X|;Qin|Zhi-Feng|ZF|;Wei|Pin-Kang|PK|;Li|Yong-Jin|YJ|",
"chemical_list": "D014408:Biomarkers, Tumor; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D016179:Granulocyte Colony-Stimulating Factor; D000069287:Capecitabine",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v21.i14.4402",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-9327",
"issue": "21(14)",
"journal": "World journal of gastroenterology",
"keywords": "Acute promyelocytic leukemia; Capecitabine; Chemotherapy; Gastric cancer; Oxaliplatin",
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D014408:Biomarkers, Tumor; D001706:Biopsy; D000069287:Capecitabine; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D007621:Karyotyping; D015473:Leukemia, Promyelocytic, Acute; D008297:Male; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D011237:Predictive Value of Tests; D012074:Remission Induction; D012307:Risk Factors; D013274:Stomach Neoplasms; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "4402-7",
"pmc": null,
"pmid": "25892894",
"pubdate": "2015-04-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "24086938;19687318;17509107;20080465;23066388;15829534;11921273;21869918;22133502;22023492;18373227;23837492;15197216;20237318;20080917;17768113;17210514;16293675;12623843;17057028;18692692;16494624;21127174;9609103;16549810;19465957;17851873;9676019",
"title": "Secondary acute promyelocytic leukemia following chemotherapy for gastric cancer: a case report.",
"title_normalized": "secondary acute promyelocytic leukemia following chemotherapy for gastric cancer a case report"
} | [
{
"companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2015RR-97176",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"dru... |
{
"abstract": "BACKGROUND\nThiopurines (Azathioprine (AZA) and 6-Mercaptopurine (6-MP) are considered a well-established therapy for patients with Inflammatory Bowel Disease (IBD) including ulcerative colitis (UC) and Crohn's Disease (CD). However, nearly 20% of patients discontinue thiopurines due to adverse events. Functional polymorphisms of several enzymes involved in the metabolism of thiopurines have been linked with toxicity. The clinical value of variant carriers such as TPMT, ITPA and GSTs in predicting toxicity and adverse events for IBD patients treated with thiopurines remains to be clarified.\n\n\nOBJECTIVE\nTo determine if variation in TPMT, ITPA and GST genotypes can predict adverse effects such as neutropenia, pancreatitis, liver enzyme elevation, as well as clinical response for patients with IBD treated with thiopurines.\n\n\nMETHODS\nPatients known to have IBD and treated with AZA or 6MP were enrolled. Adverse effects were calculated and their correlation with TPMT, ITPA and GST genotypes was evaluated. Further, the correlation between clinical response and TPMT, ITPA and GST genotypes were assessed.\n\n\nRESULTS\nA total of 53 patients were enrolled. 16/53 patients (28.6%) responded to AZA therapy. 17 patients experienced adverse events with 10 having to discontinue treatment. Three patients (5.4%) developed severe myelosuppression (WBC< 2.0 or neutrophils <1.0). Loss of function TPMT genotype was associated with adverse events (OR 3.64, 95% CI 0.55 - 24.23, p=0.0313). ITPA and GST polymorphisms were not associated with toxicity. GSTM1 deletion was associated with poor clinical response to therapy (OR 3.75, 95% CI 0.940 - 14.97, p=0.1028), however, neither TPMT*3A nor ITPA polymorphisms were associated with clinical response.\n\n\nCONCLUSIONS\nIn addition to TPMT for adverse events, genotyping for GSTM1 appears to predict clinical response in IBD patients treated with thiopurines.",
"affiliations": null,
"authors": "Al-Judaibi|B|B|;Schwarz|U I|UI|;Huda|N|N|;Dresser|G K|GK|;Gregor|J C|JC|;Ponich|T|T|;Chande|N|N|;Mosli|M|M|;Kim|R B|RB|",
"chemical_list": "D005819:Genetic Markers; D007166:Immunosuppressive Agents; D005982:Glutathione Transferase; C117740:glutathione S-transferase M1; D001379:Azathioprine",
"country": "Australia",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2561-8741",
"issue": "23(1)",
"journal": "Journal of population therapeutics and clinical pharmacology = Journal de la therapeutique des populations et de la pharmacologie clinique",
"keywords": null,
"medline_ta": "J Popul Ther Clin Pharmacol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001379:Azathioprine; D003967:Diarrhea; D005260:Female; D005500:Follow-Up Studies; D005819:Genetic Markers; D005982:Glutathione Transferase; D006801:Humans; D007166:Immunosuppressive Agents; D015212:Inflammatory Bowel Diseases; D008297:Male; D008875:Middle Aged; D009325:Nausea; D011237:Predictive Value of Tests; D011446:Prospective Studies; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101530023",
"other_id": null,
"pages": "e26-36",
"pmc": null,
"pmid": "26950049",
"pubdate": "2016",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Genetic Predictors of Azathioprine Toxicity and Clinical Response in Patients with Inflammatory Bowel Disease.",
"title_normalized": "genetic predictors of azathioprine toxicity and clinical response in patients with inflammatory bowel disease"
} | [
{
"companynumb": "GB-ALKEM LABORATORIES LIMITED-GB-ALKEM-2022-01232",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"dru... |
{
"abstract": "Burns patients with psychiatric comorbidities may be at increased risk of harm from drug interactions. We aimed to identify the most common classes of drug involved, the potential clinical effects and any clinical evidence for their occurrence.\n\n\n\nThe International Burn Injury Database was used to identify all admission episodes for patients with a psychiatric comorbidity over a 5-year period at an adult regional burns unit. For this group, all drugs administered were categorised as either a new or continuing medication. Following this, an established online tool was used to screen for potential interactions between drugs. Where one was identified, a retrospective notes review was used to investigate whether it had occurred clinically.\n\n\n\nNinety-one admission episodes were identified and records were available for 60 of these. In total, 145 incidences of severe potential interactions were identified (89 between a new drug and a continuing drug and 56 between two new drugs). The most frequently involved continuing drugs with the potential for interaction were neurotransmitter reuptake-inhibiting antidepressants and mirtazapine, while the most common new drugs identified were ondansetron, fentanyl and tramadol. The most frequently identified potential consequence of interactions were serotonin syndrome, arrhythmias and hypokalaemia. Clinically, there was minimal evidence for any interaction.\n\n\n\nWe have found many potential severe interactions in this patient group and psychotropic drugs were more commonly implicated than other drug classes. However, there was little evidence of the clinical manifestations of interaction. Serious drug interactions in burns patients are likely rare, but clinicians should be aware of the most likely drugs involved and the possible sequelae.",
"affiliations": "Bristol Medical School, University of Bristol, Bristol, United Kingdom.;Department of Plastic Surgery, North Bristol NHS Trust, Bristol, United Kingdom.;Department of Pharmacy, North Bristol NHS Trust, Bristol, United Kingdom.;Department of Plastic Surgery, North Bristol NHS Trust, Bristol, United Kingdom; Restore Burn and Scar Research, United Kingdom. Electronic address: jonathon.pleat@nbt.nhs.uk.",
"authors": "Al-Khalil|Majid|M|;Sack|Anthony|A|;Elson|Rachel|R|;Pleat|Jonathon|J|",
"chemical_list": "D000701:Analgesics, Opioid; D000928:Antidepressive Agents; D012702:Serotonin Antagonists; D017367:Serotonin Uptake Inhibitors; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors; D014147:Tramadol; D017294:Ondansetron; D000078785:Mirtazapine; D005283:Fentanyl",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.burns.2020.01.010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0305-4179",
"issue": "46(5)",
"journal": "Burns : journal of the International Society for Burn Injuries",
"keywords": "Antidepressants; Burn injury; Drug interactions; Mental health; Serotonin syndrome",
"medline_ta": "Burns",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D000928:Antidepressive Agents; D001145:Arrhythmias, Cardiac; D002056:Burns; D015897:Comorbidity; D004347:Drug Interactions; D005260:Female; D005283:Fentanyl; D006801:Humans; D008133:Long QT Syndrome; D008297:Male; D001523:Mental Disorders; D008875:Middle Aged; D000078785:Mirtazapine; D017294:Ondansetron; D012189:Retrospective Studies; D012702:Serotonin Antagonists; D020230:Serotonin Syndrome; D017367:Serotonin Uptake Inhibitors; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors; D016171:Torsades de Pointes; D014147:Tramadol",
"nlm_unique_id": "8913178",
"other_id": null,
"pages": "1043-1050",
"pmc": null,
"pmid": "32057547",
"pubdate": "2020-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A 5-year single-centre retrospective study of potential drug interactions in burns inpatients with psychiatric comorbidities.",
"title_normalized": "a 5 year single centre retrospective study of potential drug interactions in burns inpatients with psychiatric comorbidities"
} | [
{
"companynumb": "GB-FRESENIUS KABI-FK202009547",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ONDANSETRON"
},
"drugadditional": null,
... |
{
"abstract": "A 6-year-old girl had fever, abdominal pain, and severe anicteric hepatitis during intravenous oxacillin therapy for staphylococcal osteomyelitis. She had greatly elevated liver enzymes, prolonged prothrombin time, leukopenia, and eosinophilia. Clinical symptoms resolved and laboratory data returned to normal after withdrawing oxacillin and substituting cefazolin. This hepatotoxicity appears to be specific to oxacillin and not to other beta-lactams. Monitoring liver function tests during oxacillin therapy, especially in patients receiving prolonged treatment, may be warranted.",
"affiliations": "Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA.",
"authors": "Al-Homaidhi|Hossam|H|;Abdel-Haq|Nahed M|NM|;El-Baba|Mohammad|M|;Asmar|Basim I|BI|",
"chemical_list": "D010406:Penicillins; D010068:Oxacillin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0038-4348",
"issue": "95(6)",
"journal": "Southern medical journal",
"keywords": null,
"medline_ta": "South Med J",
"mesh_terms": "D056486:Chemical and Drug Induced Liver Injury; D002648:Child; D005260:Female; D006801:Humans; D010019:Osteomyelitis; D010068:Oxacillin; D010406:Penicillins; D013203:Staphylococcal Infections",
"nlm_unique_id": "0404522",
"other_id": null,
"pages": "650-2",
"pmc": null,
"pmid": "12081223",
"pubdate": "2002-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe hepatitis associated with oxacillin therapy.",
"title_normalized": "severe hepatitis associated with oxacillin therapy"
} | [
{
"companynumb": "US-BAXTER-2021BAX012617",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OXACILLIN SODIUM"
},
"drugadditional": "1",
... |
{
"abstract": "We report a case of a patient with severe hyperacusis, photophobia, and skin hypersensitivity. The patient was initially treated with sound therapy and medical therapy for 4 months and successfully with a selective serotonin reuptake inhibitor (SSRI) and cognitive behavioral therapy which improved her mood and the tolerance for sounds and light.",
"affiliations": "Tinnitus Center, European Hospital, Rome, Italy.;Department of Applied Clinical Sciences and Biotechnology, L'Aquila University, Via Vetoio (Coppito 2), 67100 Coppito, Italy.;Tinnitus Center, European Hospital, Rome, Italy.;Tinnitus Center, European Hospital, Rome, Italy.;Tinnitus Center, European Hospital, Rome, Italy; Department of Applied Clinical Sciences and Biotechnology, L'Aquila University, Via Vetoio (Coppito 2), 67100 Coppito, Italy.",
"authors": "Fioretti|Alessandra Barbara|AB|;Varakliotis|Theodoros|T|;Poli|Otello|O|;Cantagallo|Manuela|M|;Eibenstein|Alberto|A|",
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"fulltext": "\n==== Front\nCase Rep OtolaryngolCase Rep OtolaryngolCRIOTCase Reports in Otolaryngology2090-67652090-6773Hindawi Publishing Corporation 10.1155/2016/2570107Case ReportSevere Hyperacusis, Photophobia, and Skin Hypersensitivity Fioretti Alessandra Barbara \n1\nVarakliotis Theodoros \n2\n\n*\nPoli Otello \n1\nCantagallo Manuela \n1\nEibenstein Alberto \n1\n\n2\n1Tinnitus Center, European Hospital, Rome, Italy2Department of Applied Clinical Sciences and Biotechnology, L'Aquila University, Via Vetoio (Coppito 2), 67100 Coppito, Italy*Theodoros Varakliotis: theo_va@hotmail.comAcademic Editor: Dimitrios G. Balatsouras\n\n2016 15 2 2016 2016 25701077 11 2015 18 1 2016 Copyright © 2016 Alessandra Barbara Fioretti et al.2016This 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.We report a case of a patient with severe hyperacusis, photophobia, and skin hypersensitivity. The patient was initially treated with sound therapy and medical therapy for 4 months and successfully with a selective serotonin reuptake inhibitor (SSRI) and cognitive behavioral therapy which improved her mood and the tolerance for sounds and light.\n==== Body\n1. Introduction\nHyperacusis is defined as “unusual tolerance to ordinary environmental sounds” [1] or as “consistently exaggerated or inappropriate responses to sounds that are neither threatening nor uncomfortably loud to typical person” [2]. Hyperacusis should be distinguished from photophobia (fear of sound) and misophonia (dislike towards specific sounds) [3], which are associated with a strong negative emotional response. It is suggested that the term of hyperacusis, is used for various types of hearing hypersensitivity and not for a specific range of sounds. Recruitment is frequently confused with hyperacusis, it is an increased loudness perception [4] caused by a dysfunction of the outer hair cells (OHC) with cochlear hearing impairment. Recruitment is defined as an abnormal increase in the sensitivity to increasing loudness of sound in the affected ear. This phenomenon of recruitment can be used to distinguish between cochlear and retrocochlear impairment. If the hearing is normal, hypersensitivity is always due to hyperacusis (plus or minus misophonia) and never due to recruitment.\n\nIt is widely noted that patients suffering from tinnitus also present hyperacusis in 40% of cases [5–7]. Instead, in patients that have been diagnosed with hyperacusis, tinnitus has been reported in 86% [8].\n\nHyperacusis may be associated with ear pathologies like Ménière's disease, perilymphatic fistula, sudden sensorineural hearing loss, acoustic trauma, otosclerosis, Bell's facial palsy, and Ramsay Hunt syndrome. In addiction, there is a correlation with CNS disorders like migraine, depression, posttraumatic stress disorders, multiple sclerosis, benign intracranial hypertension, Tay-Sachs syndrome, Williams syndrome, and Lyme's disease.\n\nThe differential diagnosis between recruitment and hyperacusis is based on audiologic routine tests like tonal and speech audiometry, tympanometry, and acoustic middle ear reflex examination. Auditory Brainstem Responses (ABR) are useful for a differential diagnosis for retrocochlear diseases, vestibular schwannoma, and neurovascular conflict, together with MRI and angioMRI. There are also specific tests for hyperacusis such as the determination of the loudness discomfort level (LDL), which is generally considered pathological at a threshold below 90 dB HL [9]. Questionnaires for decreased sound tolerance are useful in the clinical diagnosis and have been developed in these years [10]. With these questionnaires it is possible to evaluate cognitive reactions to hyperacusis, behavioral changes, and emotional responses to external sound [11]. The questionnaire published from Khalfa evaluates also attention, social interaction, and emotions [12].\n\n2. Case Report\nA female patient, 72 years old, came to our attention complaining of a chronic hyperacusis that occurred almost one year ago. During the evaluation, the patient described her hyperacusis as an increased sensibility to environmental sounds. This sensation was accompanied to an intense discomfort after exposure to sounds and to loud voices too. A particular association with a widespread skin hypersensitivity and a visual intolerance to intense light was revealed. Hyperacusis was evaluated with uncomfortable loudness levels (ULL) measured at 0.25 kHz, 0.5 kHz, 1 kHz, 2 kHz, 3 kHz, 4 kHz, and 6 kHz.\n\nShe referred hypertension and hypothyroidism in treatment. In March 2012, an MRI was performed which indicated an expansion of the supratentorial ventricular system prevailing in the frontal region. The left temporal region featured an expanded round cavity with liquid content and thin halo of gliosis, with a simultaneous atrophy of the temporal, limbic, and hippocampal structures more prominent on the left side (Figure 1).\n\nIn May 2012, she was examined at the European Hospital Tinnitus Center for a hearing disorder characterized by hyperacusis and photophobia, photophobia, and skin hypersensitivity. These disorders were associated with agoraphobia, mood deflection, hypomimia, skin hyperaesthesia, and absence of ofthalmological pathologies. In the tests of manual dexterity there were not evident motor disorders. Deambulation was cautious, attitude with the trunk bent forward.\n\nThe onset was rapid, noted in June 2011 as a result of cataract surgery in local anesthesia. The following questionnaires were carried out: Pittsburgh Sleep Quality Index (PSQI): 7 (mild sleep disorder) and hyperacusis questionnaire of Khalfa: 36 (positive for hyperacusis). The tonal audiometry showed a mild sensorineural hearing loss in the high frequencies bilaterally and more marked on the left. The ULL showed abnormal levels of tolerance (severe hyperacusis) at levels of 55–65 dB HL symmetrical in both ears (Figure 2). The impedance test indicated a normal compliance with Jerger tympanogram type A bilaterally. The stapedial reflexes were not performed due to decreased tolerance to sound. The distortion products of otoacoustic emissions (DPOAE) resulted normal bilaterally for 2, 3, and 4 kHz frequencies. A very fast response time should be noted. Our conclusion was that the patient suffered from hyperacusis and misophonia (Jastreboff category 4).\n\nA standard EEG emphasized irritative abnormalities on the frontotemporal lobes, more evident during the hyperpnea, in the context of a dysrhythmic track, unstable and irregular.\n\nIn July 2012, she repeated the MRI which indicated large CSF perivascular space of the anterior perforated substance, in the basal portion of the left lentiform nucleus and occasional dilated CSF perivascular space without pathological significance (Figure 3).\n\nThe psychological assessment revealed deep psychological distress characterized by anxiety and expressed through various physical symptoms. The patient, deeply depressed and sad, has a representation of the world as hostile and threatening, from which she cannot defend herself. The behavior was characterized by pessimism, doubtfulness, passivity, and fear of expressing aggressive or sexual feelings. The subject tends to subordinate her needs to those of others, delegating to them the responsibility for the key areas of her life; she shows submission and lacks in self-confidence.\n\nShe is very self-critical and feels strong guilt emotions. The results of psychological tests are summarized in Table 1 [13–16]. The Millon Clinical Multiaxial Inventory-III was invalid because 17 items were without answer.\n\nThe patient was treated with Pregabalin, Levetiracetam, and bilateral sound generators with initial benefit.\n\nBilateral sound generators were used initially set at just audible level, progressively increasing the level of sound and subsequently changing volume as necessary. The objective was the reduction in anxiety and fear. More specifically for the patient's hyperacusis disorder, a program was proposed for the desensitization of the auditory system (for the reduced tolerance to sounds) and for misophonia another was adviced for active listening to pleasant sounds.\n\nThe psychologist prescribed a psychiatric examination, cognitive behavioral psychotherapy, or psychological counseling for at least 4–6 months but the patient did not follow the recommended psychological therapy. After 4 months, the patient revealed reduced symptoms related to hyperacusis and photophobia but in July 2012 she suspended the pharmacological therapy because she was treated for an invasive ductal cancer (T2 N1 M0) with mastectomy and chemotherapy. In the follow-up after 8 months, at the end of chemotherapy the patient reported a worsening of hyperacusis and photophobia. She started a therapy with a selective serotonin reuptake inhibitor (SSRI) and cognitive behavioral therapy for 4 months which improved her mood and the tolerance for sounds and light. In October 2014, the patient improved hyperacusis and photophobia while skin hypersensitivity disappeared. The score of hyperacusis questionnaire of Khalfa was 14 (negative for hyperacusis). The tonal audiometry showed a mild sensorineural hearing loss in the high frequencies bilaterally. The ULL showed abnormal levels of tolerance (moderate hyperacusis) at levels of 65–75 dB HL symmetrical in both ears at all frequencies (Figure 4).\n\n3. Discussion\nWe described for the first time the association between hyperacusis, skin hypersensitivity, and photophobia in a patient.\n\nThe acoustic cortex is localized on upper temporal gyrus and the somatosensory cortex is situated on postrolandic parietal gyrus. The lesion in left temporal lobe of the patient was causative of abnormal bioelectric discharges recorded with EEG.\n\nProbably the association pathway between acoustic cortex, where the lesion is localized, and somatosensory cortex could explain the diffusion of irritative status such as a deficit of inhibitory action of CNS.\n\nThe locus ceruleus, situated in the brainstem underfloor of IV ventricle, is the main nervous centre of synthesis and release of noradrenaline. It is formed from groups of noradrenergic neuronal cells.\n\nNoradrenaline has an exciting effect in brain and modulates the pain awareness.\n\nDeficit of inhibitory control of CNS on locus ceruleus should have played an important role in all disorders.\n\nFurthermore we have to consider that sensory stimulation like hearing, vision, smell, taste, and touch increases excitation of locus ceruleus neuronal cells.\n\nIn consideration of the age and the depression of the patient, we considered the role of serotonin in the modulation of auditory signals and we prescribed SSRI. As reported by Cruz et al., SSRI may improve the results of auditory processing in elderly patients (Cruz OL, Kasse CA, Sanchez M, Barbosa F, and Barros FA; serotonin reuptake inhibitors in auditory processing disorders in elderly patients: preliminary results. Laryngoscope 2004; 114:1656-9).\n\nThere is a valid hypothesis about nonsyndromic hyperacusis related to the patient. Dysfunction of the medial efferent system might lead to reduced damping of the cochlea. This can happen in case of peripheral lesions and the neuroplasticity of the ascending way. Stress causes the release of endogenous opiates or dynorphins in the inner hair cells (IHC). This could increase the cochlear neurotransmitter glutamate, which might lead to enhanced auditory nerve activity. An auditory signal activates an abnormal process of amplification in subconscious auditory pathways, causing secondary activation of the limbic and autonomic nervous systems.\n\nHwang et al. studied 3 patients with hyperacusis by fMRI and they found that the frontal lobes and parahippocampus might be associated with phobic hypersensitivity to unpleasant sounds in patients with idiopathic hyperacusis [17]. The brain activation studied with fMRI could clarify the areas involved in our patient.\n\nHyperacusis is common among severely affected patients with complex regional pain syndrome related dystonia. Hyperacusis in these patients may reflect the spreading of central sensitization to auditory system [18]. Finally, as reported by Hasson et al., women with high levels of emotional exhaustion become more sensitive to sound after an acute stress task and had reduced thresholds to loudness. Patients with normal ULL but seeking help for hyperacusis should be assessed for emotional exhaustion (plasma cortisol concentration, estradiol) [19].\n\n4. Conclusion\nThere is a close relationship between hyperacusis, hypersensitivity, and pain.\n\nIn this clinical case, the treatment has had an effective equilibrating action. As for chronic pain, a multidisciplinary approach is necessary for effective results. The appropriate hyperacusis sound therapy and counseling protocol must be applied for the desensitization of the auditory system. In case of a multisensory disorder (auditory, visual, and somatosensory) a pharmacological and psychological support is indicated.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 An expanded round cavity with liquid content and thin halo of gliosis was evidenced with MRI (indicated with arrows).\n\nFigure 2 Audiological test with ULL showing severe hyperacusis before the treatment.\n\nFigure 3 A large CSF perivascular space of the anterior perforated substance, in the basal portion of the left lentiform nucleus evidenced by a second MRI (indicated with arrows).\n\nFigure 4 Audiological test with ULL showing moderate hyperacusis after the treatment.\n\nTable 1 Scores obtained by the patient on psychological tests. \n\nSymptom checklist 90-R (SCL-90-R)\t \t \t\n Somatization\t\n1.9\t\n Obsessive-compulsive\t\n1.4\t\n Interpersonal sensitivity\t\n0.2\t\n Depression\t\n1.7\t\n Anxiety\t\n1.8\t\n Anger-hostility\t2\t\n Phobic anxiety\t\n0.1\t\n Paranoid ideation\t0\t\n Psychoticism\t\n1.5\t\n Sleep disorders\t4\t\nEysenck Personality Questionnaire \t \t \t\n Neurocriticism\t22/27\tHigh level\t\n Psychoticism\t8/30\tLow level\t\n Extroversion\t15/25\tMedium level\t\n Lies\t17/23\tHigh level\t\nBeck Depression Inventory (BDI)\t \t \t\n Somatic-affective\t10/27\tDown level\t\n Cognitive\t10/36\tHigh level\t\n Total\t20/63\tHigh level\t\nState Trait Anxiety Inventory, X1 and X2 (STAI X1 and X2)\t \t \t\n State anxiety\t71\tTop level\t\n Trait anxiety\t55\tMedium to high\n==== Refs\n1 Vernon J. A. Pathophysiology of tinnitus: a special case—hyperacusis and a proposed treatment American Journal of Otology 1987 8 3 201 202 2-s2.0-0023339928 3631220 \n2 Klein A. J. Armstrong B. L. Greer M. K. Brown F. R. III Hyperacusis and otitis media in individuals with Williams syndrome Journal of Speech and Hearing Disorders 1990 55 2 339 344 10.1044/jshd.5502.339 2-s2.0-0025332820 2329796 \n3 Jastreboff P. J. Hazell J. W. Tinnitus Retraining Therapy: Implementing the Neurophysiological Model 2004 Cambridge, UK Cambridge University Press 10.1017/cbo9780511544989 \n4 Moore E. C. J. Cochlear Hearing Loss 1998 London, UK Whurr \n5 Sood S. K. Coles R. R. A. Hyperacusis and phonophobia in tinnitus patients British Journal of Audiology 1998 22, article 228 \n6 Bartnik G. Fabijanska A. Rogowski M. Hazell J. W. P. Our experience in treatment of patients with tinnitus and/or hyperacusis using the habituation method Proceedings of the 6th International Tinnitus Seminar 1999 London, UK The Tinnitus and Hyperacusis Centre 416 417 \n7 Jastreboff P. J. Jastreboff M. M. Tinnitus retraining therapy (TRT) as a method for treatment of tinnitus and hyperacusis patients Journal of the American Academy of Audiology 2000 11 3 162 177 2-s2.0-0034055057 10755812 \n8 Anari M. Axelsson A. Eliasson A. Magnusson L. Hypersensitivity to sound. Questionnaire data, audiometry and classification Scandinavian Audiology 1999 28 4 219 230 10.1080/010503999424653 2-s2.0-0032863768 10572967 \n9 Goldstein B. Shulman A. Tinnitus—hyperacusis and the loudness discomfort level test—a preliminary report The International Tinnitus Journal 1996 2 1 83 89 10753346 \n10 Nelting M. Rienhoff N. K. Hesse G. Die Erfassung des subjektiven Leidens uner Hyperakusis mit einem Selbstbeurteilungsbogen zur Geruschόberempfindlichkeit (GÜF) Laryngo-Rhino-Otologie 2002 81 327 334 12001021 \n11 Herráiz C. De Los Santos G. Diges I. Díez R. Aparicio J. M. Assessment of hyperacusis: the self-rating questionnaire on hypersensitivity to sound Acta Otorrinolaringologica Espanola 2006 57 7 303 306 10.1016/s0001-6519(06)78716-7 2-s2.0-34547906518 17036991 \n12 Khalfa S. Dubal S. Veuillet E. Perez-Diaz F. Jouvent R. Collet L. Psychometric normalization of a hyperacusis questionnaire Journal for Oto-Rhino-Laryngology and Its Related Specialties 2002 64 6 436 442 10.1159/000067570 2-s2.0-0036948345 12499770 \n13 Derogatis L. R. Symptom Checklist-90-R: Administration, Scoring, and Procedures Manual 1994 3rd Minneapolis, Minn, USA National Computer Systems \n14 Eysenck H. J. Eysenck S. B. G. Manual of the Eysenck Personality Questionnaire 1975 London, UK Hodder & Stoughton \n15 Spielberger C. D. Gorssuch R. L. Lushene P. R. Vagg P. R. Jacobs G. A. Manual for the State-Trait Anxiety Inventory 1983 Consulting Psychologists Press \n16 Beck A. T. Steer R. A. Brown G. K. Manual for the Beck Depression Inventory-II 1996 San Antonio, Tex, USA Psychological Corporation \n17 Hwang J.-H. Chou P.-H. Wu C.-W. Chen J.-H. Liu T.-C. Brain activation in patients with idiopathic hyperacusis American Journal of Otolaryngology—Head and Neck Medicine and Surgery 2009 30 6 432 434 10.1016/j.amjoto.2008.08.005 2-s2.0-73049111781 \n18 De Klaver M. J. M. van Rijn M. A. Marinus J. Soede W. de Laat J. A. P. M. van Hilten J. J. Hyperacusis in patients with complex regional pain syndrome related dystonia Journal of Neurology, Neurosurgery and Psychiatry 2007 78 12 1310 1313 10.1136/jnnp.2006.111609 2-s2.0-36849077173 \n19 Hasson D. Theorell T. Bergquist J. Canlon B. Acute stress induces hyperacusis in women with high levels of emotional exhaustion PLoS ONE 2013 8 1 e52945 10.1371/journal.pone.0052945 2-s2.0-84871815083\n\n",
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"title": "Severe Hyperacusis, Photophobia, and Skin Hypersensitivity.",
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"abstract": "Nocardiosis is a rare infectious disease entity that mostly affects the lungs, brain, or skin of immunocompromised individuals. Recent reports of pulmonary nocardiosis (PN) in patients with chronic obstructive pulmonary disease (COPD) as the only risk factor suggest a possible association between nocardiosis and COPD. Herein, we present a case of ventilator-dependent PN in a patient with a moderate degree of COPD. A high level of suspicion for PN should be maintained when encountered with COPD patients complaining of symptoms of pneumonia and excessive thirst.",
"affiliations": "Department of Medicine, University of Toledo Medical Center, Toledo, OH 43614, USA.;Department of Medicine, University of Toledo Medical Center, Toledo, OH 43614, USA.;Department of Medicine, Kettering Medical Center, Kettering, OH 45429, USA.;Department of Medicine, University of Toledo Medical Center, Toledo, OH 43614, USA.",
"authors": "Pak|Stella|S|;Mansour|Tarek|T|;Yatsynovich|Yan|Y|;Kobalka|Andrew|A|",
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"fulltext": "\n==== Front\nLung IndiaLung IndiaLILung India : Official Organ of Indian Chest Society0970-21130974-598XMedknow Publications & Media Pvt Ltd India LI-35-5810.4103/lungindia.lungindia_170_17Case ReportVentilator-dependent pulmonary nocardiosis in a patient with chronic obstructive pulmonary disease Pak Stella Mansour Tarek Yatsynovich Yan 1Kobalka Andrew Department of Medicine, University of Toledo Medical Center, Toledo, OH 43614, USA1 Department of Medicine, Kettering Medical Center, Kettering, OH 45429, USAAddress for correspondence: Dr. Stella Pak, Department of Medicine, University of Toledo Medical Center, 3000 Arlington Avenue, Toledo, OH 43614, USA. E-mail: stella.pak@rockets.utoledo.eduJan-Feb 2018 35 1 58 61 Copyright: © 2017 Indian Chest Society2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Nocardiosis is a rare infectious disease entity that mostly affects the lungs, brain, or skin of immunocompromised individuals. Recent reports of pulmonary nocardiosis (PN) in patients with chronic obstructive pulmonary disease (COPD) as the only risk factor suggest a possible association between nocardiosis and COPD. Herein, we present a case of ventilator-dependent PN in a patient with a moderate degree of COPD. A high level of suspicion for PN should be maintained when encountered with COPD patients complaining of symptoms of pneumonia and excessive thirst.\n\nKEY WORDS\nAcute respiratory failurechronic obstructive pulmonary diseasepulmonary nocardiosisventilator\n==== Body\nINTRODUCTION\nNocardia is aerobic Gram-positive bacteria that can cause opportunistic infections through direct inhalation in the lungs, brain, and skin of immunocompromised individuals.[12] Due to its inherent inoculation pathway, 90% of nocardiosis involves the pulmonary system.[1] Pulmonary nocardiosis (PN) has been reported to occur mostly in the following populations: HIV patients, lymphoreticular cancer patients, transplant recipients, alcoholics, and diabetics. Disseminated nocardiosis has been reported to even mimic a metastatic malignancy in the immunosuppressed.[3] However, 4 cases of PN in patients with chronic obstructive pulmonary disease (COPD) as the only risk factors have been reported, suggesting a close association for PN and COPD.[4] Underlying pulmonary disease was the second most common predisposing condition for the development of PN in one cohort of patients.[5] The potential mechanism behind this association is the recurrent or persistent bacterial infection in the respiratory system and long-term exposure to steroid therapy. Recurrent bouts of pulmonary infection can impair ciliary motility and damage the epithelial layer. The resultant dysfunction of protective mechanisms in the airway may facilitate the infection process by Nocardia.[2]\n\nIn the United States, approximately, 500–1000 cases of PN are reported annually. The mortality from PN is about 38.7%, whereas the mortality rate reaches 100% for nocardiosis involving the central nervous system (CNS). If the CNS is not involved, disseminated nocardiosis has a mortality rate of 64%.[6] Herein, we report a case of PN that led to acute respiratory failure complicated by Type II myocardial infarction and pulmonary embolism in a patient with COPD on systemic steroid therapy.\n\nCASE REPORT\nA 65-year-old woman presented with a 3-day duration of worsening confusion, dyspnea, chest pain, wheezing, and cough with yellow and blood-tinged sputum. These symptoms were accompanied by intermittent high fever, excessive thirst, polyuria, diarrhea, and anorexia. Significant medical history included moderate degree of COPD managed with inhaled albuterol 2.5 mg PRN and tiotropium bromide 18 mcg. Her blood pressure, heart rate, respiration rate, temperature, and oxygen saturation at room air were 190/114 mmHg, 149/min, 40/min, 37.4°C, and 64%. Her white blood cell and lactic acid levels were elevated at 13.6 × 109/L (70% granulocytes) and 21.3 mg/dL, respectively. Her sodium level was found to be low at 128 mmol/L. Arterial blood gas showed hypoxemic respiratory failure (pH 7.21, CO243.0 mmHg, O257.6 mmHg, HCO318.8 mmol/L, and O2saturation 85.8%). She was expeditiously placed on 2 L of oxygen, but she continued to complain of worsening dyspnea and desaturated to 84%. In light of rapidly progressing hypoxemic respiratory failure, she was intubated and placed on mechanical ventilation. For acute management of her tachycardia and hypertension, metoprolol was given.\n\nChest X-ray revealed multilobar pneumonia [Figure 1]. Computed tomography (CT) of her chest revealed extensive consolidating pneumonia throughout the lung field bilaterally. This finding was most extensive in the lower lung fields, but there was considerable ground glass infiltrate in the right upper lobe and to a lesser extent, the left upper lobe [Figure 2]. She was started on vancomycin, cefepime, and methylprednisolone for empirical treatment. Her sputum culture grew Nocardia asteroides. The diagnosis of nocardiosis prompted the medical team to obtain a CT of her brain, which showed no signs of abscess or infection. Based on the result from the culture, antibiotic regimen was switched to piperacillin/tazobactam, sulfamethoxazole/trimethoprim, and azithromycin; however, the patient did not show any improvement on the combinative antibiotic therapy. A third antibiotic regimen with levofloxacin, ampicillin-sulbactam, meropenem, and sulfamethoxazole/trimethoprim was tried for a week without success. The fourth combinative antibiotic therapy consisted of vancomycin, imipenem, metronidazole, and sulfamethoxazole/trimethoprim, also with no success.\n\nFigure 1 Roentgenogram of chest demonstrating multilobar pneumonia\n\nFigure 2 Computerized tomography of chest visualizing extensive consolidating pneumonia throughout the lung field bilaterally\n\nDue to lack of improvement, further investigation with bronchoscopy and video-assisted thoracoscopy (VAT) was performed. Bronchoscopy showed an inflamed airway with thin frothy secretions, mainly from the right hemithorax. Bronchoalveolar lavage showed nonspecific acute inflammation and blood. VAT of the right lung showed patchy infiltrates of all 3 lobes, the lower lobe most prominently. A modest amount of serous pleural effusion was also noted. Lung biopsy revealed acute fibrinous and organizing pneumonia [Figure 3] consistent with the diagnosis of multifocal necrotizing pneumonia, and a large thickened vessel with an organizing fibrin thrombus [Figure 4]. Overall, the lung was described as bobby and friable.\n\nFigure 3 Lung biopsy (H and E, ×10 power) showing a large blue sheet of predominantly neutrophilic active pneumonia, and organizing pneumonia consisting of amorphous pink fibrin bands in alveolar spaces\n\nFigure 4 Lung biopsy (H and E, ×20 power) showing a large thickened blood vessel with organizing fibrin thrombus\n\nFollowing the investigation, the patient was treated with imipenem, metronidazole, and sulfamethoxazole/trimethoprim. Three days later, amikacin was added. Over a 1 month period, the patient clinically improved. Repeat blood and sputum cultures were negative for Nocardia. Despite this, three attempted extubations were unsuccessful, and the patient remained ventilator-dependent. A tracheal tube was placed on her 31st day on the ventilator to prevent vocal cord damage and tracheal stricture. The patient failed a swallowing test after tracheal tube placement and subsequently had a percutaneous endoscopic gastrostomy tube inserted for feeding purposes.\n\nDuring her admission, she developed a non-ST elevation myocardial infarction, possibly from demand ischemia. Coronary angiography was deferred due to the severe infection. The patient was started on 6 weeks of clopidogrel. Other cardiovascular conditions included DVT of her right arm resulting in a pulmonary embolism [Figure 5]. She was started on a heparin drip, and later bridged to warfarin. Another complication was persistent hyponatremia secondary to syndrome of inappropriate antidiuretic hormone secretion (SIADH). Throughout admission, her sodium level fluctuated from 120 to 131 mmol/L. She was treated with tolvaptan, furosemide, fluid restriction, and sodium chloride tablets. At the time of discharge, her sodium level was at 130 mmol/L.\n\nFigure 5 Computerized tomography of chest showing pulmonary embolism\n\nTwo days before the patient's discharge, her WBC was still elevated at 17.2 × 109/L, thus her antibiotic regimen was changed to linezolid, tobramycin, and sulfamethoxazole/trimethoprim. On the 60th day of hospitalization, she was discharged to a long-term acute care facility with a peripherally inserted central catheter for continuous antibiotic therapy. The patient expired 9 months following discharge due to failure to thrive.\n\nDISCUSSION\nClinical presentation of PN is nonspecific and can resemble acute exacerbation of COPD. Common symptoms include chest pain, coughing, sputum production, dyspnea, fatigue, and loss of appetite.[5] Common, nonspecific radiographic findings include infiltrates, cavitation, pleural effusion, or bony erosion.[2] The diagnosis of PN can be challenging due to the rarity of the disease entity, radiographic pleomorphism, and lack of pathognomonic clinical signs or serologic markers. Only isolation of the organism through smears or culture is diagnostic.[7] Nocardia species grow on aerobic media over 5–21 days, and can exhibit acid-fast characteristics. Sensitivity of cultures from sputum and bronchoalveolar lavage are approximately 90% and 100%, respectively.[2] This slow method greatly delays the diagnostic process. Improvements on current diagnostic methods are urgently needed.\n\nFollowing a diagnosis of PN, it is critical to start treatment immediately because about 50% of untreated PN can spread to other parts of the body through the blood or lymphatic systems.[7] Treatment of PN consists of systematic antibiotic therapy. Sulfonamide-based antibiotics, such as trimethoprim-sulfamethoxazole, are the first line of treatment. For patients with sulfa allergies or nocardiosis refractory to sulfonamide-based regimen, the following alternative treatment options may be adopted: minocycline, doxycycline, amoxicilline-clavulanate, carbapenem, amikacin, cefuroxime, ceftriaxone, clarithromycin, ofloxacin, linezolid, and inhaled aminoglycoside. The recommended treatment duration is 3–12 months.[28]\n\nSIADH is a known complication from PN, but the treatment of nocardiosis and fluid restriction typically resolves hyponatremia.[9] Proper electrolyte balance is critical to improving patient outcomes.\n\nThe lesson to learn here is that clinicians should be aware of the association between PN and structural lung disease such as COPD, cystic fibrosis, and bronchiectasis. Broader awareness of this association would help reduce misdiagnosis and decrease the mortality rate from PN. Immunocompromised patients on long-term steroid therapy are also very vulnerable to PN.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Sarcinelli-Luz B Marchiori E Zanetti G Mano CM Abdalla F Carvalho JF Pulmonary nocardiosis in the acquired immunodeficiency syndrome, computed tomographic findings: A case report Cases J 2009 2 6642 19829838 \n2 Anderson M Kuzniar TJ Pulmonary nocardiosis in a patient with chronic obstructive pulmonary disease – Case report and literature review Pneumonol Alergol Pol 2012 80 565 9 23109210 \n3 Singh A Chhina D Soni RK Kakkar C Sidhu US Clinical spectrum and outcome of pulmonary nocardiosis: 5-year experience Lung India 2016 33 398 403 27578932 \n4 Arjun R Padmanabhan A Reddy Attunuru BP Gupta P Disseminated nocardiosis masquerading as metastatic malignancy Lung India 2016 33 434 8 27578940 \n5 Castellana G Grimaldi A Castellana M Farina C Castellana G Pulmonary nocardiosis in Chronic Obstructive Pulmonary Disease: A new clinical challenge Respir Med Case Rep 2016 18 14 21 27144111 \n6 Martínez Tomás R Menéndez Villanueva R Reyes Calzada S Santos Durantez M Vallés Tarazona JM Modesto Alapont M Pulmonary nocardiosis: Risk factors and outcomes Respirology 2007 12 394 400 17539844 \n7 Yu S Wang J Fang Q Zhang J Yan F Specific clinical manifestations of Nocardia: A case report and literature review Exp Ther Med 2016 12 2021 6 27698688 \n8 Yaich S Charfeddine K Zaghdane S El Aoud N Masmoudi M Kharrat M Pulmonary nocardiosis in a kidney transplant recipient: A case report and review of the literature J Transplant Technol Res 2011 1 101 [Doi: 10.4172/2161-0991.1000101] \n9 Paritala V Narahari NK Mutnuru PC Vujhini SK Nizami MI Pulmonary nocardiosis with a rare association of syndrome of inappropriate antidiuretic hormone secretion (SIADH) in an immunocompetant male J Med Allied Sci 2016 6 87 91\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0970-2113",
"issue": "35(1)",
"journal": "Lung India : official organ of Indian Chest Society",
"keywords": null,
"medline_ta": "Lung India",
"mesh_terms": null,
"nlm_unique_id": "8405380",
"other_id": null,
"pages": "58-61",
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"pmid": "29319037",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "27698688;27578940;27144111;19829838;23109210;17539844;27578932",
"title": "Ventilator-dependent pulmonary nocardiosis in a patient with chronic obstructive pulmonary disease.",
"title_normalized": "ventilator dependent pulmonary nocardiosis in a patient with chronic obstructive pulmonary disease"
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"companynumb": "US-009507513-1801USA006208",
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"abstract": "Disseminated strongyloidiasis is often fatal, despite treatment with oral albendazole and parenteral ivermectin (IVM). Here, we report elevated plasma IVM and albendazole sulfoxide concentrations in the context of extracorporeal membrane oxygenation and continuous renal replacement therapy in a patient with disseminated strongyloidiasis treated with subcutaneous IVM and nasogastric albenzadole. Despite elevated drug plasma concentrations, live filariform larvae were detected in endotracheal aspirates after 2 weeks of treatment.",
"affiliations": "Department of Medicine, University of British Columbia, Vancouver, Canada.;University of Nebraska Medical Centre, Omaha, Nebraska.;University of Nebraska Medical Centre, Omaha, Nebraska.;Department of Medicine, University of British Columbia, Vancouver, Canada.;Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.;Department of Medicine, University of British Columbia, Vancouver, Canada.;J. D. MacLean Centre for Tropical Diseases, McGill University, Montreal, Canada.;Department of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.;Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.",
"authors": "Boodman|Carl|C|;Chhonker|Yashpal S|YS|;Murry|Daryl J|DJ|;Mah|Allison|A|;Grant|Jennifer|J|;Steiner|Theodore|T|;Libman|Michael|M|;Nishi|Cesilia|C|;Charles|Marthe|M|",
"chemical_list": "D000871:Anthelmintics; D007559:Ivermectin; D015766:Albendazole",
"country": "United States",
"delete": false,
"doi": "10.4269/ajtmh.18-0487",
"fulltext": null,
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"issn_linking": "0002-9637",
"issue": "99(5)",
"journal": "The American journal of tropical medicine and hygiene",
"keywords": null,
"medline_ta": "Am J Trop Med Hyg",
"mesh_terms": "D015766:Albendazole; D000818:Animals; D000871:Anthelmintics; D015199:Extracorporeal Membrane Oxygenation; D006801:Humans; D007559:Ivermectin; D007814:Larva; D008297:Male; D008875:Middle Aged; D006435:Renal Dialysis; D017171:Strongyloides stercoralis; D013322:Strongyloidiasis",
"nlm_unique_id": "0370507",
"other_id": null,
"pages": "1194-1197",
"pmc": null,
"pmid": "30226142",
"pubdate": "2018-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "9533454;16242280;23229490;23068416;1740534;18446504;26486704;20085425;23394259;22188792;29769976;16282302;24269075;3770064;14670741;24778101;29310051;27794473;29346367;21041508;26462990;19052292;22975175;15937753;16533536;20889884;20798874;28320466;25918215",
"title": "Case Report: Ivermectin and Albendazole Plasma Concentrations in a Patient with Disseminated Strongyloidiasis on Extracorporeal Membrane Oxygenation and Continuous Renal Replacement Therapy.",
"title_normalized": "case report ivermectin and albendazole plasma concentrations in a patient with disseminated strongyloidiasis on extracorporeal membrane oxygenation and continuous renal replacement therapy"
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"companynumb": "CA-IMPAX LABORATORIES, LLC-2018-IPXL-03970",
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"activesubstancename": "VANCOMYCIN"
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"abstract": "Adenosine is an endogenous nucleoside that plays a major role in the pathophysiology of airway diseases, such as asthma and chronic obstructive pulmonary disease. It is also an effective drug at terminating supraventricular tachycardia and used for pharmacological stress testing with a relatively safe side effect profile. There is a contraindication for the use of adenosine in patients with asthma and a caution to use in patients with chronic obstructive pulmonary disease. We present a case of a 63-year old female patient who was treated with adenosine and subsequently went into respiratory distress. She was placed on bilevel positive airway pressure and had rapid resolution of symptoms.",
"affiliations": "Beaumont Health- Emergency Department, 18101 Oakwood Blvd, Dearborn, Mi 48124, USA. Electronic address: Malak.abbas@beaumont.org.;Beaumont Health- Emergency Department, 18101 Oakwood Blvd, Dearborn, Mi 48124, USA.;Beaumont Health- Emergency Department, 18101 Oakwood Blvd, Dearborn, Mi 48124, USA.",
"authors": "Abbas|Malak|M|;Verville|Justin|J|;Mroue|Khalil|K|",
"chemical_list": "D000241:Adenosine",
"country": "United States",
"delete": false,
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"issue": "44()",
"journal": "The American journal of emergency medicine",
"keywords": "Adenosine; BIPAP; Bronchoconstriction; COPD; SVT",
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000241:Adenosine; D016084:Bronchoconstriction; D045422:Continuous Positive Airway Pressure; D005260:Female; D006801:Humans; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive",
"nlm_unique_id": "8309942",
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"pmc": null,
"pmid": "33189514",
"pubdate": "2021-06",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Resolution of bronchoconstriction with positive airway pressure after intravenous adenosine.",
"title_normalized": "resolution of bronchoconstriction with positive airway pressure after intravenous adenosine"
} | [
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"abstract": "The involvement of the cervix as a site of relapse for hematologic malignancies is rare. We herein present a case of relapsed B-cell Acute Lymphoblastic Leukemia/Lymphoma (ALL) mimicking advanced cervical cancer. The patient is a 61-year-old female with history B-cell ALL and had multiple relapses confined to the bone marrow and had received several different chemotherapy regimens. She presented with lower abdominal pain after the end of her last cycle for which an MRI abdomen and pelvis was done and it showed the presence of an asymmetrical cervical mass. Further imaging included a PET-CT showing the presence of hypermetabolic cervical mass with left pelvic and retroperitoneal lymph node involvement. She underwent a biopsy of 3 distinct lesions in the cervix and vagina and a diagnosis of relapsed B-cell ALL was confirmed in two out of the three specimens.",
"affiliations": "Department of Internal Medicine, American University of Beirut Medical Center, Lebanon.;Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, USA.;Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, USA.;Department of Hematopathology, The University of Texas MD Anderson Cancer Center, USA.;Department of Hematopathology, The University of Texas MD Anderson Cancer Center, USA.;Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, USA.",
"authors": "Kazma|Jamil|J|;Johnson|Cynae|C|;Jain|Nitin|N|;Gali|Vasantha Lakshmi|VL|;Young|Ken H|KH|;Jazaeri|Amir A|AA|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.gore.2019.08.003",
"fulltext": "\n==== Front\nGynecol Oncol RepGynecol Oncol RepGynecologic Oncology Reports2352-5789Elsevier S2352-5789(19)30078-510.1016/j.gore.2019.08.003Case ReportB-cell acute lymphoblastic leukemia/lymphoma in relapse presenting as a cervical mass: A case report and review of literature Kazma Jamil jamilmkazma@gmail.coma⁎Johnson Cynae bJain Nitin cGali Vasantha Lakshmi dYoung Ken H. dJazaeri Amir A. ba Department of Internal Medicine, American University of Beirut Medical Center, Lebanonb Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, USAc Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, USAd Department of Hematopathology, The University of Texas MD Anderson Cancer Center, USA⁎ Corresponding author at: Department of Internal Medicine, American University of Beirut Medical Center, Riad El Solh 1107 2020, Beirut, Lebanon. jamilmkazma@gmail.com12 8 2019 8 2019 12 8 2019 29 94 97 3 7 2019 7 8 2019 11 8 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).The involvement of the cervix as a site of relapse for hematologic malignancies is rare. We herein present a case of relapsed B-cell Acute Lymphoblastic Leukemia/Lymphoma (ALL) mimicking advanced cervical cancer. The patient is a 61-year-old female with history B-cell ALL and had multiple relapses confined to the bone marrow and had received several different chemotherapy regimens. She presented with lower abdominal pain after the end of her last cycle for which an MRI abdomen and pelvis was done and it showed the presence of an asymmetrical cervical mass. Further imaging included a PET-CT showing the presence of hypermetabolic cervical mass with left pelvic and retroperitoneal lymph node involvement. She underwent a biopsy of 3 distinct lesions in the cervix and vagina and a diagnosis of relapsed B-cell ALL was confirmed in two out of the three specimens.\n\nHighlights\n• The cervix as a site of relapse for hematologic malignancies is rare.\n\n• History of leukemia should raise suspicion of extra-medullary involvement.\n\n• Imaging along with histologic specimen provide a better diagnosis.\n\n\n\nKeywords\nHematologic malignancyDiagnosis - relapseCervical cancer\n==== Body\n1 Case presentation\n61-year-old female, G4 P4, presented to the gynecologic oncology clinic after MRI of the abdomen and pelvis showed an asymmetric soft tissue fullness in the region of the cervix measuring 5.7 × 3.9 cm, and extending toward the left, along with a small volume left pelvic and left retroperitoneal lymphadenopathy suggestive of cervical malignancy.\n\nThe patient had a history of B-cell acute lymphoblastic leukemia/lymphoma (ALL) initially diagnosed 4.5 years prior to presentation, with BCR/ABL negative but positive for extra chromosome 22 diagnosed since July 2014 and has had two relapses. These two relapses were diagnosed after the patient returned complaining of symptoms of back pain and fatigue. Bone marrow biopsies were done in both cases and confirmed the relapse in each. However, there was no evidence of any extramedullary involvement on imaging in both relapses.\n\nImmunohistochemical stains done on the cervical specimens showed patchy CD34, CD20, CD79a, TdT, CD10, MUM-1, Bcl-2, c-myc (70%). Cells were negative for CD99, CD30, EBV, and had a Ki-67 of 80%. She has initially received Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin) + ofatumumab followed by POMP (6-mercaptopurine, vincristine, methotrexate, and prednisone) maintenance on which she relapsed the first time on of October 2016. After that, the patient was started on Mini CVD with Rituximab and Inotuzumab to which she relapsed in June 2018. She was then started on Blinatumomab in August 2018 and had the surveillance imaging six month after treatment due to a complaint of lower abdominal pain and nausea, as shown in Fig. 1. She has no vaginal bleeding, itching, or discharge. She reported no dyspareunia or post-coital bleeding. She has no family history of gynecologic tumors. Her last pap smear was done in 2010, which was normal. She reported a history of one abnormal Pap smear several years ago, colposcopy was negative, and no biopsy was obtained.Fig. 1 MRI abdomen and pelvis showing the cervical mass.\n\nFig. 1\n\nOn speculum examination, there was an abnormally appearing cervix with two polyps at the cervical os, and a raised lesion on the left vaginal sidewall. On bimanual and rectovaginal examination, a mobile, nontender uterus was felt, in addition to a 4 cm cervical mass extending to left parametria and left proximal upper 1/3 of the vagina. Pap smear was collected, and three biopsies obtained from the anterior cervical polyp, 6 o'clock location and vagina respectively. The purpose of the pap smear was to detect high-risk Human Papilloma Virus (HPV) strains.\n\nPET scan was ordered after the visit to the gynecologist, and it showed hypermetabolic cervical mass consistent with primary cervical cancer, multiple left pelvic and retroperitoneal FDG-avid lymphadenopathy consistent with nodal metastasis, in addition to foci of increased FDG uptake along the thoracic and lumbar spine consistent with metastasis as shown in Fig. 2.Fig. 2 PET-CT scan showing hypermetabolic cervical mass with increased FDG-uptake in retroperitoneal and left pelvic lymphnodes.\n\nFig. 2\n\nPathology reported the anterior polyp at the os as a benign endometrial polyp. The other two specimens were reported as recurrent B-lymphoblastic leukemia/lymphoma with Ki67 of 90%. Histologically, the specimens showed medium and large-sized neoplastic cells with regular cytoplasm and irregular nuclear contours, blastoid chromatin, and occasional small nucleoli. Apoptotic bodies and mitotic figures are identified, and no necrosis was seen. Immunohistochemical staining showed positive CD10, CD19, CD34, and TdT. The patient was started on a new chemotherapy regimen HCVD (hyperfractionated-cyclophosphamide, vincristine and dexamethasone) + Venetoclax and has received her first cycle with no complications Fig. 3.Fig. 3 H&E stain of cervical lesion.\n\nFig. 3\n\n2 Discussion\nIn this case report, we present a case of extramedullary B-cell ALL involving the cervix with a presentation similar to locally advanced cervical carcinoma. Hematologic malignancies are rarely found in the female genital tract (FGT). The involvement of FGT accounts for less than 1% of the extranodal lymphoma/leukemia, and of that, the cervix account for less than 0.5% (Komaki et al., 1984; Vang et al., 2001). In particular, the primary sites of extramedullary disease in Acute Lymphocytic Leukemia (ALL) are central nervous system and testes (Geetha et al., 2015).\n\nMoreover, Acute Myeloid Leukemia (AML) and lymphoma, which are more common to occur in the genital tract, have been documented at autopsy, but acute lymphoblastic leukemia with relapse in the uterine cervix has been rarely reported (Lyman and Neuhauser, 2002). Primary hematologic involvement is common in patients with hematopoietic malignancies in the genital tract. These patients usually present with symptoms of abnormal vaginal bleeding, pelvic mass, or discomfort. The average age of presentation is 40 years (Hanley et al., 2009). Our patient had non-specific pelvic pain at the time of imaging that showed the cervical mass, after she finished the last cycle of her chemotherapy.\n\nDue to the rarity of the disease, the diagnostic workup is often challenging. The traditional pap smear has low sensitivity in detecting lymphoma with an interval value ranging from 20 to 30%. This can be attributed to the lack of involvement of the surface epithelium and the misclassification of malignant cells as being benign inflammatory without the appropriate clinical context (Hanley et al., 2009; Zutter and Gersell, 1990). For that reason, a biopsy is almost always necessary in addition to the clinical correlation and past medical history of the patient, especially that such tumors when symptomatic can mimic a primary cervical malignancy. The differential of cervical lymphoma can include several inflammatory diseases such as chronic lymphocytic cervicitis or follicular cervicitis and sarcoma. Also, the presence of plasma cells and macrophages along with the appropriate context, may help in the diagnosis of an inflammatory process and prevent misdiagnosis (Kazi et al., 2013).\n\nCytologic features of chronic or follicular cervicitis include a mixture of small and large lymphocytes, polymorphonuclear cells, plasma cells, in addition to reticular histiocytic cells. However, eosinophils and mast cells are rarely observed (Roberts and Ng, 1975). On the other hand, granulocytic sarcoma which occurs as a consequence of granulocytic leukemia is characterized cytologically by the cells with opaque chromatin, sparse cytoplasm, reniform nuclear shapes and the lack of prominent nucleoli (Spahr et al., 1982; Chorlton et al., 1974).\n\nDetecting extramedullary relapse of acute lymphoblastic leukemia/lymphoma by imaging can be hard but often possible when patients are symptomatic. Relapse may occur at various sites with or without bone marrow involvement. The lack of current surveillance protocols for detecting extramedullary relapse and the fact that long-term follow-up with PET-CT and MRI is not routinely used adds to the burden of early detection of disease. Clinical and laboratory correlation require careful consideration when interpreting radiologic findings as radiologic findings alone can be non-specific especially in the context of previous leukemia, soft tissue masses include differentials of infection, hemorrhage and secondary neoplasms (Clark et al., 2010; Arrigan et al., 2013).\n\nIn patients with a known extrauterine malignancy, the physician should have a high-suspicion of a metastatic disease, in which a tissue biopsy is warranted to achieve an accurate diagnosis. Imaging and physical exam will aid when interpreted in the context of the medical history of the patient, but the biopsy should be done as early as possible to ensure proper management.\n\nAuthor contribution\nJamil Kazma: Writing – Original Draft; Writing, Review & Editing, Cynae Johnson: Investigation, Writing – Review & Editing, Nitin Jain: Resources, Vasantha Lakshmi Gali: Resources, Ken H Young: Resources, Amir A. Jazaeri: Writing – Review & Editing, Supervision.\n\nDeclaration of Competing interest\nWe have no conflict of interest to declare.\n==== Refs\nReferences\nArrigan M. Smyth L. Harmon M. Flynn C. Sheehy N. Imaging findings in recurrent extramedullary leukaemias Cancer Imaging 13 2013 26 35 23439108 \nChorlton I. Karnei R.F. Jr. King F.M. Norris H.J. Primary malignant reticuloendothelial disease involving the vagina, cervix, and corpus uteri Obstet. Gynecol. 44 1974 735 748 4528975 \nClark W.B. Strickland S.A. Barrett A.J. Savani B.N. Extramedullary relapses after allogeneic stem cell transplantation for acute myeloid leukemia and myelodysplastic syndrome Haematologica. 95 2010 860 863 20513805 \nGeetha N. Lali V.S. Mathews A. Prakash N.P. Acute lymphoblastic leukemia presenting with a uterine cervical mass Clin. Cancer Investig. J. 4 2015 280 281 \nHanley K.Z. Tadros T.S. Briones A.J. Birdsong G.G. Mosunjac M.B. Hematologic malignancies of the female genital tract diagnosed on liquid-based pap test: Cytomorphologic features and review of differential diagnoses Diagn. Cytopathol. 37 2009 61 67 18973127 \nKazi S. Szporn A.H. Strauchen J.A. Chen H. Kalir T. Recurrent precursor-B acute lymphoblastic leukemia presenting as a cervical malignancy Int. J. Gynecol. Pathol. 32 2013 234 237 23370653 \nKomaki R. Cox J.D. Hansen R.M. Gunn W.G. Greenberg M. Malignant lymphoma of the uterine cervix Cancer. 54 1984 1699 1704 6383595 \nLyman M.D. Neuhauser T.S. Precursor T-Cell Acute Lymphoblastic Leukemia/Lymphoma Involving the Uterine Cervix, Myometrium, Endometrium, and Appendix 6 2002 125 128 \nRoberts T.H. Ng A.B. Chronic lymphocytic cervicitis: cytologic and histopathologic manifestations Acta Cytol. 19 1975 235 243 1056676 \nSpahr J. Behm F.G. Schneider V. Preleukemic granulocytic sarcoma of cervix and vagina: initial manifestation by cytology Acta Cytol. 26 1982 55 60 6461154 \nVang R. Medeiros L.J. Warnke R.A. Higgins J.P. Deavers M.T. Ovarian non-Hodgkin's lymphoma: a clinicopathologic study of eight primary cases Mod. Pathol. 14 2001 1093 1099 11706069 \nZutter M.M. Gersell D.J. Acute lymphoblastic leukemia. An unusual case of primary relapse in the uterine cervix Cancer. 66 1990 1002 1004 2386910\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2352-5789",
"issue": "29()",
"journal": "Gynecologic oncology reports",
"keywords": "Cervical cancer; Diagnosis - relapse; Hematologic malignancy",
"medline_ta": "Gynecol Oncol Rep",
"mesh_terms": null,
"nlm_unique_id": "101652231",
"other_id": null,
"pages": "94-97",
"pmc": null,
"pmid": "31467959",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports",
"references": "1056676;11706069;12004362;18973127;20513805;23370653;23439108;2386910;4528975;6383595;6461154",
"title": "B-cell acute lymphoblastic leukemia/lymphoma in relapse presenting as a cervical mass: A case report and review of literature.",
"title_normalized": "b cell acute lymphoblastic leukemia lymphoma in relapse presenting as a cervical mass a case report and review of literature"
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{
"abstract": "Agitated delirium presents unique challenges for hospice and palliative care clinicians. Haloperidol, the recommended neuroleptic, may be ineffective at low dose, or poorly tolerated at higher doses.\n\n\nRESULTS\nThis article reports on two patients with refractory agitated delirium. Both developed extrapyramidal symptoms from haloperidol and required rotation to an alternate neuroleptic. Patient #1 received 2000 mg/day oral chlorpromazine. Patient #2 received greater than 200 mg/day sublingual olanzapine. Control of agitation was achieved, though the doses were substantially higher than has previously reported in the literature. Each patient experienced considerable sedation, though this was an acceptable side effect for the family. Each patient was transferred from the acute care hospital to a location of family preference. There they died within a week of transfer.\n\n\nCONCLUSIONS\nAgitated delirium is a palliative care emergency. High doses of neuroleptic medications, with rotation to an alternate neuroleptic when side effects occur with standard haloperidol, may effectively palliate agitated delirium. This remedy can provide the patient with a peaceful dying in a place of their choosing.",
"affiliations": "Palliative Care Physician, Portland, OR, USA paulbbascom@gmail.com.;Portland Veteran's Affairs Medical Center, Oregon Health & Science University, Portland, OR, USA.;Oregon Health & Science University, Portland, OR, USA.",
"authors": "Bascom|Paul B|PB|;Bordley|Jessica L|JL|;Lawton|Andrew J|AJ|",
"chemical_list": "D014150:Antipsychotic Agents; D006220:Haloperidol",
"country": "United States",
"delete": false,
"doi": "10.1177/1049909113507124",
"fulltext": null,
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"issn_linking": "1049-9091",
"issue": "31(8)",
"journal": "The American journal of hospice & palliative care",
"keywords": "agitated delirium; chlorpromazine; end-of-life care; olanzapine; palliative sedation; terminal delirium",
"medline_ta": "Am J Hosp Palliat Care",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D003693:Delirium; D057915:Drug Substitution; D005260:Female; D005770:Gastrointestinal Neoplasms; D015658:HIV Infections; D006220:Haloperidol; D006801:Humans; D008297:Male; D008875:Middle Aged; D011595:Psychomotor Agitation; D013727:Terminal Care",
"nlm_unique_id": "9008229",
"other_id": null,
"pages": "808-11",
"pmc": null,
"pmid": "24081790",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "High-dose neuroleptics and neuroleptic rotation for agitated delirium near the end of life.",
"title_normalized": "high dose neuroleptics and neuroleptic rotation for agitated delirium near the end of life"
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{
"abstract": "The development of drugs directed against tumor necrosis factor (TNF)-α has dramatically modified the therapeutic approach to inflammatory bowel diseases: a larger use of such drugs has also led to a major knowledge about their adverse effects, especially on skin. The aim of this report was to describe a rare steroid-dependent form of leukocytoclastic vasculitis induced by an anti-TNF-α agent in a young woman with ulcerative colitis.\n\n\n\nA young girl with ulcerative colitis developed a form of leukocytoclastic vasculitis induced by an anti-TNF-α agent. Recurrent palpable purpuric lesions on her legs were the main cutaneous manifestation. Skin lesions were steroid-dependent, but improved after withdrawal of the anti-TNF-α agent and second-line immunosuppressant therapy.\n\n\n\nThe need to develop specific recommendations to guide the use of medications for managing skin reactions induced by anti-TNF-α drugs is herein emphasized.",
"affiliations": "Department of Life Sciences and Global Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy.;Department of Life Sciences and Global Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy.;Department of Life Sciences and Global Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy.;Institute of Dermatology, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy.;Università Cattolica Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy.;Institute of Rheumatology, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy.;Department of Life Sciences and Global Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy.;Università Cattolica Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy.;Department of Internal Medicine, Università Cattolica Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy.",
"authors": "Giorgio|Valentina|V|;Blasi|Elisa|E|0000-0001-7482-5345;Rigante|Donato|D|;Guerriero|Cristina|C|;De Simone|Clara|C|;Fedele|Anna Laura|AL|;Stella|Giuseppe|G|;Gasbarrini|Antonio|A|;Scaldaferri|Franco|F|",
"chemical_list": "D000079424:Tumor Necrosis Factor Inhibitors; D014409:Tumor Necrosis Factor-alpha",
"country": "Switzerland",
"delete": false,
"doi": "10.3390/ijerph18136711",
"fulltext": "\n==== Front\nInt J Environ Res Public Health\nInt J Environ Res Public Health\nijerph\nInternational Journal of Environmental Research and Public Health\n1661-7827\n1660-4601\nMDPI\n\n34206410\n10.3390/ijerph18136711\nijerph-18-06711\nCase Report\nAnti-TNF-Related Leukocytoclastic Vasculitis in Ulcerative Colitis: A Case Report\nGiorgio Valentina 1*†\nhttps://orcid.org/0000-0001-7482-5345\nBlasi Elisa 1†\nRigante Donato 12\nGuerriero Cristina 3\nDe Simone Clara 23\nFedele Anna Laura 4\nStella Giuseppe 1\nGasbarrini Antonio 25\nScaldaferri Franco 5\nTchounwou Paul B. Academic Editor\n1 Department of Life Sciences and Global Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; elisa.blasi10@gmail.com (E.B.); donato.rigante@policlinicogemelli.it (D.R.); peppe.stella3@gmail.com (G.S.)\n2 Università Cattolica Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; clara.desimone@policlinicogemelli.it (C.D.S.); antonio.gasbarrini@policlinicogemelli.it (A.G.)\n3 Institute of Dermatology, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; cristina.guerriero@policlinicogemelli.it\n4 Institute of Rheumatology, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; annalaura.fedele@policlinicogemelli.it\n5 Department of Internal Medicine, Università Cattolica Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; franco.scaldaferri@policlinicogemelli.it\n* Correspondence: valentina.giorgio@policlinicogemelli.it\n† These two authors equally contributed to this paper.\n\n22 6 2021\n7 2021\n18 13 671112 5 2021\n17 6 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nBackground: The development of drugs directed against tumor necrosis factor (TNF)-α has dramatically modified the therapeutic approach to inflammatory bowel diseases: a larger use of such drugs has also led to a major knowledge about their adverse effects, especially on skin. The aim of this report was to describe a rare steroid-dependent form of leukocytoclastic vasculitis induced by an anti-TNF-α agent in a young woman with ulcerative colitis. Case presentation: A young girl with ulcerative colitis developed a form of leukocytoclastic vasculitis induced by an anti-TNF-α agent. Recurrent palpable purpuric lesions on her legs were the main cutaneous manifestation. Skin lesions were steroid-dependent, but improved after withdrawal of the anti-TNF-α agent and second-line immunosuppressant therapy. Conclusions: The need to develop specific recommendations to guide the use of medications for managing skin reactions induced by anti-TNF-α drugs is herein emphasized.\n\nleukocytoclastic vasculitis\nulcerative colitis\npurpura\ntumor necrosis factor\n==== Body\n1. Introduction\n\nThe development of drugs directed against tumor necrosis factor (TNF)-α has dramatically modified the therapeutic approach to inflammatory bowel disorders, such as ulcerative colitis: first infliximab and then adalimumab were introduced in the guidelines for the treatment of refractory or difficult-to-treat inflammatory bowel diseases characterized by steroid-dependence and poor response to conventional therapies [1]. Historically, the success reported by adults on TNF inhibitors has also given children with juvenile idiopathic arthritis, uveitis, Behçet’s disease and autoinflammatory diseases the opportunity of antagonizing the effects of TNF at a clinical level [2,3,4,5,6,7,8]. Anti TNF- α, particularly adalimumab, is also used in children affected by skin diseases, like plaque psoriasis, pustular psoriasis, and hidradenitis suppurativa [9,10].\n\nMore recently, a wider use of anti-TNF-α drugs has led to major knowledge about their adverse effects, such as immune reactions that can be associated with infections, skin cancer and lymphoma [11,12].\n\nThe aim of this report was to describe a rare steroid-dependent form of leukocytoclastic vasculitis induced by an anti-TNF-α agent in a young patient with ulcerative colitis.\n\n2. Case Presentation\n\nA 13-year-old girl received the diagnosis of ulcerative pancolitis in another hospital in 2015. The first treatment used was oral mesalazine, but intermittent courses of corticosteroids were also required due to disease persistence with mesalazine only. Thereafter, an association therapy with azathioprine (AZA) was started. When the patient came to our attention in 2016, she was 14 and was in a phase of both clinical and histological remission. One year later, the patient started to complain about recurrent intestinal flares, reaching a PUCAI (Pediatric Ulcerative Colitis Activity Index) score >65, which needed intermittent prednisone/budesonide therapy, although a recurrence of symptoms was noted after their suspension. Our patient did not have any other comorbidity and no autoimmune disorder could be detected in her past history. Laboratory testing showed abnormal c-anti-neutrophil cytoplasmic antibodies (41 AU/mL) in a single determination and mild positivity of anti-nuclear antibodies (1:160, fine speckled pattern). She underwent a colonoscopy in March 2017 that showed an active intestinal disease, extended from the hepatic flexure to a proximal descending colon (Mayo 3 phase). Due to poor disease control in June 2017 the patient was started on infliximab (5 mg/kg of body weight) in addition to oral mesalazine and AZA. Four months later she presented megaloblastic anemia, a potential adverse effect with AZA, despite ongoing acid folic therapy at 5 mg/day. AZA was promptly discontinued with rapid resolution of anemia. Since no remission was reached and a PUCAI score of 30–50 persisted, the patient needed to modify infliximab (IFX) therapy in terms of dosage and frequency of infusions. Initially she received IFX every 2–4–8 weeks at the standard dose of 5 mg/kg. Due to absent clinical response, inadequate IFX blood levels and absence of anti-IFX antibodies, the schedule was changed to 10 mg/kg every 8 weeks. After 4 months, the drug was undetectable and anti-drug antibodies were absent, so the frequency of IFX administrations was shortened to 4 weeks, reaching an adequate level of blood IFX without any anti-drug antibodies. After one year on IFX, the girl developed psoriasis-like lesions on the scalp and trunk combined with a papulo-pustular rash on the abdomen and legs. The latter were biopsied, revealing a likely reaction to IFX. This cutaneous picture was treated with topical corticosteroids and recovered. Later on, the patient presented recurrent palpable purpuric lesions on her legs characterized by reddish-purple spots, some covered with a fibrinous film (Figure 1a). Laboratory tests were performed, showing no anemia and normal white blood cell count; inflammatory markers were normal as well as liver and renal function. The whole autoimmunity panel (p-anti-neutrophil cytoplasmic antibodies, c-anti-neutrophil cytoplasmic antibodies, antinuclear antibodies, anti-extractable nuclear antigen antibodies panel (anti-Sjögren syndrome A and B, Smith antibody and anti-ribonucleoprotein), anti-dsDNA, rheumatoid factor, cryoglobulins, C3c, C4, lupus anticoagulant, anti-cardiolipin and anti-beta 2-glycoprotein-I antibodies) was unrevealing. Screening for infections was unremarkable. Urinalysis was negative for proteinuria and hematuria. The only abnormal finding, but without any pathological meaning, was a mild elevation of total serum IgA (4.9 g/L, n.v. 0.6–3.48). Chest X-ray film, renal ultrasound assessment, whole body-magnetic resonance imaging excluded any extra-intestinal disease and/or joint involvement.\n\nAn alternative biological therapy was needed: vedolizumab was considered, but was disregarded as off-label in pediatrics. Therefore, in October 2019, a switch to adalimumab was established, starting with a dose of 160 mg subcutaneously (sc) followed by 80 mg sc after 2 weeks (induction) and then continued with 40 mg sc every 2 weeks (maintenance), which led to a definite intestinal remission. Unfortunately, skin lesions seemed to persist: in fact, the patient had relapsing phases of psoriasis on the scalp and relapsing palpable purpuric with hemorrhagic bullous lesions on the legs (Figure 1b) combined with dysestesia. A biopsy of these latter lesions revealed leukocytoclastic vasculitis. Electromyography was negative for neuropathy. A colonoscopy was performed and showed an endoscopic intestinal remission.\n\nAccordingly, in consideration of the persistent skin lesions, adalimumab was stopped and the anti-interleukin-12/23 monoclonal antibody ustekinumab (recently introduced in dermatology, especially for psoriasis) started at a dosage of 90 mg every 8 weeks. However, no beneficial effects were seen. In fact, after 15 days from ustekinumab introduction, the purpuric rash turned to necrotic-ulcerative lesions (Figure 1c), and a new punch biopsy was performed, confirming the diagnosis of leukocytoclastic vasculitis.\n\nPrednisone at the dose of 1 mg/kg/day combined with colchicine at the dose of 0.5 mg twice a day were started. After the first three months, colchicine efficacy was lost, and mycophenolate mofetil (500 mg twice a day) and AZA (75 mg/day) were started. Due to poor efficacy, mycophenolate mofetil and AZA were stopped after two weeks. As purpura and ulcerative lesions persisted, the whole autoimmunity panel was repeated but was unremarkable. Therefore, cyclosporin at the dose of 200 mg/day was introduced, finally leading to an overall improvement of the skin picture. The patient is currently well, with non-active scars at her lower limbs (Figure 1d), and keeps on receiving cyclosporine plus low-dose prednisone (17.5 mg/day). A timeline of the patient’s diagnostic process and treatment is shown in Figure 2.\n\n3. Discussion and Conclusions\n\nLeukocytoclastic vasculitis is a hypersensitivity-induced inflammation of vessels in which drugs can be recognized to be causative in approximately 10–24% of cases [13]. Few studies have reported vasculitides induced by anti-TNF-α agents in different populations of patients, mostly including rheumatoid arthritis for adults, but also juvenile idiopathic arthritis in children. In a review by Ramos-Casals et al., 113 cases of vasculitides were reported during therapy with TNF-α inhibitors. The underlying condition was rheumatoid arthritis in 84%, Crohn’s disease in 6%, juvenile idiopathic arthritis in 4%, and other disorders in 6%. Etanercept was involved in 52% of such cases, IFX in 42% and adalimumab in 4%. The characteristics of cutaneous lesions were purpura in 57%, ulcerative lesions in 9%, nodules in 9%, digital vasculitis in 6% and maculo-papular rash in 5%. Moreover, extra-cutaneous manifestations were observed in 24% of patients, mostly peripheral neuropathy and renal vasculitis. The majority of patients (89%) responded to withdrawal of the specific TNF-α inhibitor, while corticosteroids were needed in 25% of them and immunosuppressant agents in 15%. Interestingly, 11% of cases did not require the discontinuation of the biological treatment [14].\n\nIn another study conducted by Saint Marcoux et al. describing 39 cases of vasculitides induced by anti-TNF-α agents, six patients (15%) were able to continue biologic therapy and the resolution of vasculitis was complete [15].\n\nIn a retrospective review by Sokumbi et al., eight patients with anti-TNF-induced vasculitis had a mean time of 6.9 months up to the resolution of vasculitis after discontinuing drugs, but all received prednisone and seven also received immunosuppressant agents [16].\n\nOnly a few cases of anti-TNF-induced vasculitis have been related to inflammatory bowel disease [17,18,19,20,21,22]. Unfortunately, no guidelines are available for the management of this condition.\n\nThe pathogenesis of anti-TNF-related leukocytoclastic vasculitis is also poorly known, though immune complexes including the anti-TNF antibody which precipitate on the walls of little vessels are presumed to induce a local activation of the complement system and a type III hypersensitivity reaction. Other explanations might be a cytokine imbalance due to TNF-α suppression, with predominance of the Th2 pattern, but also drug toxicity, exerting direct vascular damage [14,23,24].\n\nMost patients with only skin involvement can be treated in an outpatient setting, with resolution of symptoms obtained within days to months. Some authors described the possibility to treat this condition by simply withdrawing the anti-TNF-α agent or reducing its dosage. Conversely, the most complicated pictures displaying systemic manifestations and/or extra-intestinal involvement might require a more aggressive treatment.\n\nA recent case reported by Bouhuys et al. described a 16-year-old girl with active ulcerative colitis, who presented anti-neutrophil cytoplasmic antibody-associated leukocytoclastic vasculitis with involvement of peripheral nerves while on therapy with mesalazine and AZA, worsened after the introduction of IFX infusions [25]. While the role of inflammatory bowel disease itself in the development of skin diseases (such as erythema nodosum, pyoderma gangrenosum and psoriasis) is well known [26,27], few cases of leukocytoclastic vasculitis have been reported for young patients with inflammatory bowel disease, occurring during both active colitis and quiescence, but without a relationship with the extension of intestinal involvement [28]: therapy with corticosteroids and immunosuppressant agents usually leads to the resolution of skin lesions in such patients [25,29].\n\nOur patient started to present skin lesions referred to a leukocytoclastic vasculitis 1 year after starting IFX infusions, but also during an active phase disease: lesions persisted after reaching clinical and histological intestinal remission with adalimumab. Only the discontinuation of the biological therapy in association with corticosteroids and immunosuppressants led to the final recovery of cutaneous lesions, supporting the hypothesis of a drug-related skin disease.\n\nHence, in conclusion, considering the lack of medical literature upon this field, more studies and discussion are needed in order to develop specific recommendations guiding the use of corticosteroids and immunosuppressant agents in the management of vasculitides likely induced by anti-TNF drugs.\n\nAuthor Contributions\n\nV.G., E.B. and D.R. drafted the manuscript; V.G., E.B., C.G., C.D.S., A.L.F., G.S. and F.S. performed the diagnosis, managed the patient and co-drafted the manuscript; V.G., E.B., D.R., A.G. and F.S. revised the manuscript and made substantial scientific contributions. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInstitutional Review Board Statement\n\nNot applicable.\n\nInformed Consent Statement\n\nInformed consent was obtained from the subject involved in the study.\n\nData Availability Statement\n\nThe data that support the findings of this study are available from the corresponding author, upon reasonable request.\n\nConflicts of Interest\n\nThe authors report no conflict of interest.\n\nFigure 1 (a) Recurrent palpable purpuric lesions on the legs characterized by reddish-purple spots, some covered with a fibrinous film. (b) Swelling and palpable purpuric lesions on patient’s legs, with some haemorrhagic bullous spots. (c) Necrotic-ulcerative lesions on the legs, which were diagnosed as leukocytoclastic vasculitis at the skin biopsy. (d) Scars due to the purpuric and necrotic-ulcerative lesions on the patient’s legs.\n\nFigure 2 Timeline of patient’s diagnostic process and treatment. ASA, aminosalicylate; AZA, azathioprine; IFX, infliximab; MMF, mycophenolate mofetil.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Turner D. Ruemmele F.M. Orlanski-Meyer E. Griffiths A.M. de Carpi J.M. Bronsky J. Veres G. Aloi M. Strisciuglio C. Braegger C.P. Management of Paediatric Ulcerative Colitis, Part 1: Ambulatory Care-An Evidence-based Guideline from European Crohn’s and Colitis Organization and European Society of Paediatric Gastroenterology, Hepatology and Nutrition J. Pediatr. Gastroenterol. Nutr. 2018 67 257 291 10.1097/MPG.0000000000002035 30044357\n2. Mauro A. Rigante D. Cimaz R. Investigational drugs for treatment of juvenile idiopathic arthritis Expert Opin. Investig. Drugs 2017 26 381 387 10.1080/13543784.2017.1301929\n3. Deitch I. Amer R. Tomkins-Netzer O. Habot-Wilner Z. Friling R. Neumann R. Kramer M. The effect of anti-tumor necrosis factor alpha agents on the outcome in pediatric uveitis of diverse etiologies Graefes Arch. Clin. Exp. Ophthalmol. 2018 256 801 808 10.1007/s00417-018-3928-6 29455252\n4. Lopalco G. Rigante D. Lopalco A. Emmi G. Venerito V. Vitale A. Capozio G. Denora N. Cantarini L. Iannone F. Safety of systemic treatments for Behçet’s syndrome Expert Opin. Drug Saf. 2020 19 1269 1301 10.1080/14740338.2020.1817379 32883123\n5. Federico G. Rigante D. Pugliese A.L. Ranno O. Catania S. Stabile A. Etanercept induces improvement of arthropathy in chronic infantile neurological cutaneous articular (CINCA) syndrome Scand. J. Rheumatol. 2003 32 312 314 10.1080/03009740310003974 14690147\n6. Rigante D. A systematic approach to autoinflammatory syndromes: A spelling booklet for the beginner Expert Rev. Clin. 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Childhood generalized pustular psoriasis: Successful long-term treatment with adalimumab Dermatol. Ther. 2020 33 e13294 10.1111/dth.13294 32134546\n11. Nanau R.M. Cohen L.E. Neuman M.G. Risk of infections of biological therapies with accent on inflammatory bowel disease J. Pharm. Pharm. Sci. 2014 17 485 531 10.18433/J3GG6D 25579431\n12. Lemaitre M. Kirchgesner J. Rudnichi A. Carrat F. Zureik M. Carbonnel F. Dray-Spira R. Association Between Use of Thiopurines or Tumor Necrosis Factor Antagonists Alone or in Combination and Risk of Lymphoma in Patients with Inflammatory Bowel Disease JAMA 2017 318 1679 1686 10.1001/jama.2017.16071 29114832\n13. Gonzalex-Gay M.A. Garcia-Porrua C. Pujol R.M. Clinical approach to cutaneous vasculitis Curr. Opin. Rheumatol. 2005 17 56 61 10.1097/01.bor.0000145519.68725.5a 15604905\n14. Ramos-Casals M. Brito-Zerón P. Muñoz S. Soria N. Galiana D. Bertolaccini L. Cuadrado M.J. Khamashta M.A. Autoimmune diseases induced by TNF-targeted therapies: Analysis of 233 cases Medicine (Baltimore) 2007 86 242 251 10.1097/MD.0b013e3181441a68 17632266\n15. Saint Marcoux B. De Bandt M. Vasculitides induced by TNF-α antagonists: A study in 39 patients in France Jt. Bone Spine 2006 73 710 713 10.1016/j.jbspin.2006.02.010\n16. Sokumbi O. Wetter D.A. Makol A. Warrington K.J. Vasculitis associated with tumor necrosis factor-α inhibitors Mayo Clin. Proc. 2012 87 739 745 10.1016/j.mayocp.2012.04.011 22795634\n17. Bernardes C. Carvalho D. Saiote J. Ramos J. Leukocytoclastic vasculitis complicating adalimumab therapy for Crohn’s disease: Report of three cases Gastroenterol. Hepatol. 2018 41 442 443 10.1016/j.gastrohep.2017.08.004 29054318\n18. Kishimoto K. Kawashima K. Fukunaga M. Kotani S. Sonoyama H. Oka A. Mishima Y. Oshima N. Ishimura N. Ishikawa N. Intermittent Purpura Development Associated with Leukocytoclastic Vasculitis Induced by Infliximab for Crohn’s Disease Intern. Med. 2021 60 385 389 10.2169/internalmedicine.5340-20 32863363\n19. Muñoz Villafranca C. Izu Belloso R.M. Bravo Rodriguez M.T. Basterra Olabarrieta S. Vasculitis por adalimumab en un paciente con enfermedad de Crohn [Adalimumab vasculitis in a patient with Crohn’s disease Gastroenterol. Hepatol. 2013 36 296 297 10.1016/j.gastrohep.2012.10.004 23522950\n20. Cury D.B. de Souza A.W. Vianna G.A. Odashiro D. Farias A. Moss A.C. Cutaneous Vasculitis in a patient with Crohn’s disease treated with adalimumab Inflamm. Bowel Dis. 2017 23 E1 E2 10.1097/MIB.0000000000000982 27893546\n21. Shivaji U.N. Awasthi A.K. Aherne R. Cutaneous vasculitis caused by anti-tumor necrosis factor therapy: A case report Clin. Gastroenterol. Hepatol. 2016 14 e1 e2 10.1016/j.cgh.2015.05.012 25998787\n22. Karoui S. Bibani N. Ben Gorbel I. Serghini M. Mlika M. Braham A. Chelly I. Haouet S. Houmène H. Filali A. Leukocytoclastic vasculitis: A rare adverse effect secondary to infliximab Inflamm. Bowel Dis. 2011 17 E4 E5 10.1002/ibd.21309 20848511\n23. Baert F. Noman M. Vermeire S. Van Assche G. D’ Haens G. Carbonez A. Rutgeerts P. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease N. Engl. J. Med. 2003 348 601 608 10.1056/NEJMoa020888 12584368\n24. Fiorentino D.F. The yin and yang of TNF-α inhibition Arch. Dermatol. 2007 143 233 236 10.1001/archderm.143.2.233 17310003\n25. Bouhuys M. Armbrust W. van Rheenen P.F. Case report: Systemic small-vessel vasculitis in an adolescent with active ulcerative colitis Front. Pediatr. 2021 9 617312 10.3389/fped.2021.617312 33643972\n26. Jose F.A. Garnett E.A. Vittinghoff E. Ferry G.D. Winter H.S. Baldassano R.N. Kirschner B.S. Cohen S.A. Gold B.D. Abramson O. Development of extraintestinal manifestations in pediatric patients with inflammatory bowel disease Inflamm. Bowel Dis. 2009 15 63 68 10.1002/ibd.20604 18626963\n27. Vavricka S.R. Schoepfer A. Scharl M. Lakatos P.L. Navarini A. Rogler G. Extraintestinal manifestations of inflammatory bowel disease Inflamm. Bowel Dis. 2015 21 1982 1992 10.1097/MIB.0000000000000392 26154136\n28. Butts G.T. Bishop P.R. Wyatt J.P. Nowicki M.J. Leukocytoclastic vasculitis in an adolescent with ulcerative colitis: Report of a case and review of the literature SAGE Open Med. Case Rep. 2014 2 2050313X14547609 10.1177/2050313X14547609 27489650\n29. Oh S.J. Choi Y. Kim C.R. Park J.H. Lee J.H. Lee D.Y. Atypical extraintestinal manifestation in a child with ulcerative colitis: Cutaneous leukocytoclastic vasculitis Ann. Dermatol. 2020 32 90 91 10.5021/ad.2020.32.1.90 33911718\n\n",
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"journal": "International journal of environmental research and public health",
"keywords": "leukocytoclastic vasculitis; purpura; tumor necrosis factor; ulcerative colitis",
"medline_ta": "Int J Environ Res Public Health",
"mesh_terms": "D003093:Colitis, Ulcerative; D005260:Female; D006801:Humans; D000079424:Tumor Necrosis Factor Inhibitors; D014409:Tumor Necrosis Factor-alpha; D018366:Vasculitis, Leukocytoclastic, Cutaneous",
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"title": "Anti-TNF-Related Leukocytoclastic Vasculitis in Ulcerative Colitis: A Case Report.",
"title_normalized": "anti tnf related leukocytoclastic vasculitis in ulcerative colitis a case report"
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"abstract": "Drug-induced aHUS is rare; however, early diagnosis is vital to reduce morbidity and mortality. With confirmation of the diagnosis, eculizumab appears to be a viable treatment option to suppress the pro-inflammatory surge. Furthermore, adverse side effects of medications such as carfilzomib and gemcitabine should be considered in the appropriate settings.",
"affiliations": "Division of Hematology and Medical Oncology James Graham Brown Cancer Center University of Louisville School of Medicine Louisville Kentucky.;Division of Hematology and Medical Oncology James Graham Brown Cancer Center University of Louisville School of Medicine Louisville Kentucky.;Department of Medicine University of Louisville School of Medicine Louisville Kentucky.;Department of Pharmacy James Graham Brown Cancer Center University of Louisville Louisville Kentucky.;Department of Pharmacy James Graham Brown Cancer Center University of Louisville Louisville Kentucky.;Department of Pharmacy James Graham Brown Cancer Center University of Louisville Louisville Kentucky.;Department of Pharmacy James Graham Brown Cancer Center University of Louisville Louisville Kentucky.;Division of Hematology and Medical Oncology Roswell Park Cancer Institute Buffalo New York.;Division of Hematology and Medical Oncology The Mark H. Zangmeister Cancer Center Columbus Ohio.;Division of Hematology and Medical Oncology Texas Transplant Physician Group - Methodist Physicians San Antonio Texas.",
"authors": "Gosain|Rahul|R|;Gill|Amitoj|A|;Fuqua|Jacob|J|0000-0002-5100-578X;Volz|Lesley H|LH|;Kessans Knable|Mika R|MR|;Bycroft|Ryan|R|;Seger|Sarah|S|;Gosain|Rohit|R|;Rios|Jorge A|JA|;Chao|Ju-Hsien|JH|",
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"doi": "10.1002/ccr3.1214",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.1214CCR31214Case ReportCase ReportsGemcitabine and carfilzomib induced thrombotic microangiopathy: eculizumab as a life‐saving treatment R. Gosain et al.Gosain Rahul rahul.gosain@louisville.edu \n1\nGill Amitoj \n1\nFuqua Jacob http://orcid.org/0000-0002-5100-578X\n2\nVolz Lesley H. \n3\nKessans Knable Mika R. \n3\nBycroft Ryan \n3\nSeger Sarah \n3\nGosain Rohit \n4\nRios Jorge A. \n5\nChao Ju‐Hsien \n6\n\n1 \nDivision of Hematology and Medical Oncology\nJames Graham Brown Cancer Center\nUniversity of Louisville School of Medicine\nLouisville\nKentucky\n\n2 \nDepartment of Medicine\nUniversity of Louisville School of Medicine\nLouisville\nKentucky\n\n3 \nDepartment of Pharmacy\nJames Graham Brown Cancer Center\nUniversity of Louisville\nLouisville\nKentucky\n\n4 \nDivision of Hematology and Medical Oncology\nRoswell Park Cancer Institute\nBuffalo\nNew York\n\n5 \nDivision of Hematology and Medical Oncology\nThe Mark H. Zangmeister Cancer Center\nColumbus\nOhio\n\n6 \nDivision of Hematology and Medical Oncology\nTexas Transplant Physician Group ‐ Methodist Physicians\nSan Antonio\nTexas\n* Correspondence\n\nRahul Gosain, Division of Hematology and Medical Oncology, James Graham Brown Cancer Center, University of Louisville School of Medicine, 529 S Jackson Street, Louisville, 40202 KY. Tel: 502‐852‐4121; E‐mail: rahul.gosain@louisville.edu\n09 10 2017 12 2017 5 12 10.1002/ccr3.2017.5.issue-121926 1930 29 6 2017 21 8 2017 05 9 2017 © 2017 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Key Clinical Message\nDrug‐induced aHUS is rare; however, early diagnosis is vital to reduce morbidity and mortality. With confirmation of the diagnosis, eculizumab appears to be a viable treatment option to suppress the pro‐inflammatory surge. Furthermore, adverse side effects of medications such as carfilzomib and gemcitabine should be considered in the appropriate settings.\n\nCarfilzomibeculizumabgemcitabinehemolytic–uremic syndromethrombotic microangiopathythrombotic thrombocytopenia purpura source-schema-version-number2.0component-idccr31214cover-dateDecember 2017details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.2.7 mode:remove_FC converted:05.12.2017\n\nClinical Case Reports \n2017 ; 5 (12 ): 1926 –1930 \n\n\n\n[Correction added on 24 November 2017 after first online publication: The title was incorrect and an affiliation inadvertently omitted. Both have been corrected in this version]\n==== Body\nBackground\nHistorically, the presentation of thrombotic microangiopathy (TMA) with acute renal insufficiency, thrombocytopenia, and microangiopathic hemolytic anemia was only associated with thrombotic thrombocytopenic purpura (TTP) or hemolytic–uremic syndrome (HUS). Advances in our understanding of the etiology of TMA have allowed the diseases to be further classified based on causation rather than clinical association. The known etiologies of TMA include infection‐induced– HUS, ADAMTS13 deficiency – TTP, disorders of complement regulation – complement‐associated hemolytic–uremic syndrome also known as atypical hemolytic–uremic syndrome (aHUS), defective cobalamine metabolism – newborn HUS, and Quinine‐induced 1. After one has excluded infection or ADAMTS13 deficiency, another life‐threatening differential diagnosis, aHUS as a possible cause of the patient's presentation, should be considered.\n\naHUS is defined as a non‐Shiga toxin, nonimmune TMA caused by uninhibited continuous activation of the alternative complement system with an overall incidence of 1–3 cases per 100,000 2, 3. It is estimated that less than half of aHUS cases are familial in origin, resulting from genetic or complement abnormalities, whereas other cases are sporadic in nature triggered by infection, malignancy, pregnancy, organ transplantation, or drugs 2. Although a rare entity, multiple mechanisms including acute immunologic reaction, direct toxic effect, acute dose‐related toxicity, or chronic and duration‐dependent toxicity have been proposed for drug‐induced aHUS 4.\n\nCertain chemotherapy agents such as gemcitabine and mitomycin have a higher incidence of drug‐induced aHUS; however, new anticancer drugs including proteasome inhibitors have an increasing number of cases reported as well. Other classes of drugs commonly associated with this presentation are immunosuppressive agents, namely cyclosporine, tacrolimus, and sirolimus or antiplatelet agents including clopidogrel and ticlopidine 1, 2, 4, 5.\n\nGemcitabine is a known nucleoside analogue of cytarabine that was first synthesized in the early 1980s with intent to be used as an antiviral agent, but with in vitro testing, it appeared to be a promising anticancer drug 6. Gemcitabine was first approved in the United Kingdom in 1995 and then followed by US Food and Drug Administration (FDA) in 1996. It is commonly used in first‐ and second‐line treatment for non‐small‐cell lung, bladder, ovarian, pancreatic, and breast cancers 7. Thrombocytopenia and anemia from bone marrow suppression are common side effects of gemcitabine, but the first case of gemcitabine‐induced TMA was reported in 1994 during an ongoing phase II clinical trial for pancreatic adenocarcinoma 8. Fortunately, the incidence of gemcitabine‐induced hemolytic–uremic syndrome has been reported to be between 0.02% and 2.2% 8, 9.\n\nWith an increasing number of FDA‐approved drugs and indications, the total number of drug‐induced aHUS cases is on a rise. Carfilzomib, a selective proteasome inhibitor recently approved for relapsed and refractory multiple myeloma (MM), has also been associated with drug‐induced aHUS similar to its predecessor, bortezomib 10. The ubiquitin–proteasome pathway plays an important role in the cell cycle, and bortezomib was the first proteasome inhibitor to be widely used as part of MM therapy followed by a second‐generation proteasome inhibitor, carfilzomib. Hobeika L et al. reported the first case of carfilzomib‐induced renal thrombotic microangiopathy; however, there was no sign of microangiopathic hemolytic anemia 11. Recently, Lodhi A. et al. documented a case of drug‐induced aHUS associated with carfilzomib meeting all TMA criteria.\n\nThe treatment of TMA traditionally has been plasma exchange (PLEX) and supportive management; unfortunately, most reports state that PLEX has little to no effect on renal function, thrombocytopenia, or anemia 12. With better understanding of underlying pathophysiology for drug‐induced aHUS, early recognition is important, and we propose that eculizumab, a monoclonal antibody that binds to complement protein C5, in addition to supportive care, could be a viable treatment to shorten the course of this complement‐excited state and decrease recovery time in this patient population.\n\nCase Presentation\nPatient 1\nA 54 year old woman diagnosed with pancreatic adenocarcinoma, status postsurgical resection and on cycle 12 day 11 of palliative chemotherapy (gemcitabine and nab‐paclitaxel), presents to the hospital with ongoing headache. The patient was noted to have elevated blood pressure, elevated serum creatinine (Cr) at 2.45 mg/dL (from 1.10 mg/dL), hemoglobin (Hb) of 8.1 g/dL (from 10.5 g/dL), and platelet (Plt) count of 62 × 109/L (from 215 × 109/L). Further work‐up revealed LDH of 419 IU/L and haptoglobin of <10 mg/dL. Peripheral blood smear (PBS) was consistent with 3–5 schistocytes on each high‐power field (HPF). Given the patient's clinical and laboratory data, PLEX was initiated for a presumed diagnosis of TMA. The patient was maintained on PLEX for 7 days along with a nicardipine intravenous drip and four scheduled antihypertensive medications with minimal response in blood pressure, renal function, thrombocytopenia, and anemia. With a further decline in her Plt count, Hb, renal function (Cr of 3.54 mg/dL), and sufficient ADAMTS13 activity (79%), diagnosis of TTP was excluded and eculizumab was initiated. Forty‐eight hours after the first eculizumab dose (900 mg IV), the patient was weaned off nicardipine and her Plt count and Hb stabilized. Her serum creatinine continued to rise and peaked at 3.78 mg/dL 5 days after the first dose. The second dose of eculizumab (900 mg IV) was given 2 days earlier (on the 5th day) in order to saturate the C5 protein and anticipate a response sooner. The patient was discharged and seen in outpatient clinic, prior to her 3rd dose of 900 mg IV eculizumab. Patient was maintained on 900 mg IV eculizumab till week 4 (every week) followed by 1200 mg IV on 5th week every 2 weeks as per the approved dosing schedule. The patient remained on three antihypertensive medications and was noted to have normalization of platelet count, 201 × 109/L (Fig. 1), increase in Hb, 9.6 g/dL, and a decrease in SCr, 2.15 mg/dL (Fig. 2).\n\nFigure 1 Patient 1 Platelet response to PLEX and eculizumab.\n\nFigure 2 Patient 1 Serum Creatinine response to PLEX and eculizumab.\n\nPatient 2\nA 61‐year‐old woman diagnosed with kappa light‐chain multiple myeloma in September 2009 was initially treated with lenalidomide, bortezomib, and dexamethasone. Upon disease progression in 2010, she received cyclophosphamide, bortezomib, and dexamethasone. In 2011, with worsening in her disease status, the patient underwent high‐dose melphalan followed by autologous hematopoietic stem cell infusion. Post‐transplant, the patient received radiotherapy with 20‐Gy over 10 fractions to the lytic lesions in both hips and femur. She remained in remission until 2014, but with disease relapse, she was retreated with bortezomib and dexamethasone. Unfortunately, her disease status worsened, and she was initiated on newly approved carfilzomib and dexamethasone. She was able to attain a partial response. On day five, cycle nine of this treatment, the patient presented to the hospital with chest discomfort and shortness of air that was progressively worsening over 5 days. On presentation, she had elevated blood pressure, Cr of 5.45 mg/dL (from 1.45 mg/dL), Hb of 7.6 g/dL (from 10.3 g/dL), and Plt count of 37 × 109/L (from 174 × 109/L) along with LDH of 867 IU/L and haptoglobin of <10 mg/dL. PBS was consistent with increased schistocytes. She was emergently started on PLEX; however, her renal function continued to rapidly decline requiring hemodialysis (HD). The patient's underlying multiple myeloma disease status and laboratory work‐up including free kappa light chain, serum‐free lambda light chain, and kappa‐to‐lambda ratio remained unchanged. Upon receiving results of ADAMTS13 activity of 100%, the patient initiated eculizumab therapy. Within 2 weeks of initiating 900 mg IV (weekly) eculizumab, her labs normalized (Fig. 3), and her clinical status significantly improved. She was weaned off HD around 6 weeks (Fig. 4) in the outpatient setting. Patient was maintained on 1200 mg IV eculizumab every 2 weeks from 5th week after initial 900 mg IV every week dosing for 4 weeks in outpatient settings.\n\nFigure 3 Patient 2 Platelet response to PLEX and eculizumab.\n\nFigure 4 Patient 2 Serum creatinine response to PLEX and eculizumab.\n\nDiscussion\nAtypical HUS is a form of TMA resulting from dysregulation of the alternative complement pathway. The dysregulation triggers thrombotic changes in small blood vessels causing multi‐organ injury, platelet consumption, and fragmentation of red blood cells (RBC). Clinically, this results in hemolysis with schistocytes seen on PBS, thrombocytopenia, and renal failure 11. Etiology of TMA needs to be distinguished because the treatment approach varies based on their underlying pathophysiology mechanism. TTP is a form of TMA driven by ultra‐large molecular weight multimers of von Willebrand factor due to deficiency of the metalloprotease enzyme, ADAMTS13. HUS is a form of TMA propelled by an infection, and aHUS is driven by uncontrolled complement activation. TMA remains important as TTP has a high rate of response to PLEX, whereas aHUS is refractory to PLEX, and eculizumab is the drug of choice when the diagnosis is confirmed 13, 14 (Fig. 5).\n\nFigure 5 Treatment algorithm for patients presenting with TMA\n14.\n\nMultiple causes including genetic mutations, complement abnormalities, malignancies, pregnancy, organ transplantation, and drugs could induce a pro‐inflammatory state and result in unmonitored activation of the complement system to result in aHUS. This article illustrates an uncommon but a serious complication of two commonly used medications in treating cancer, gemcitabine, and carfilzomib being the underlying cause of aHUS. In the above cases, the patients were actively receiving chemotherapy for their respective malignancies. The incidence of gemcitabine‐induced aHUS is low, but the reported mortality remains as high as 60% 15. It is believed that new onset of hypertension or exacerbation of hypertension is a clue to presence of aHUS, as seen in both of our cases above and many other cases 16. The true incidence of carfilzomib‐induced aHUS remains unknown at this time; however, there have been four case reports prior to our study. One continues to speculate that with increasing use of newer novel agents and physicians being more cognizant of adverse events to these medications, the incidence of drug‐induced aHUS will increase.\n\nWith addition of eculizumab, targeting the complement system is changing the schema of aHUS treatment and the prevention of recurrence. The monoclonal antibody that targets the terminal complement protein C5 shuts off downstream generation of cytotoxic membrane attack complex and inflammatory molecules which produce the clinical consequences of aHUS. This has resulted in a high response rate both in terms of hematologic parameters and recovery of renal function, which is one of the most frequent complications of aHUS 1, 2, 13.\n\nConclusion\nDrug‐induced aHUS is a rare condition; however, early diagnosis is vital as it causes significant morbidity and mortality. With confirmation of the diagnosis, eculizumab appears to be a viable treatment to suppress the pro‐inflammatory surge along with discontinuing the offending agent. Though, the duration of the treatment with eculizumab in this patient population remains unclear. Furthermore, rare adverse reactions of medications such as carfilzomib and gemcitabine should be considered in the appropriate clinical setting.\n\nConflicts of Interest\nRahul Gosain M.D., Amitoj Gill M.D., Jacob Fuqua, Lesley H. Volz Pharm.D., Ryan Bycroft Pharm.D., Sarah Seger Pharm.D., Rohit Gosain M.D., Jorge Rios M.D., and Ju‐Hsien Chao D.O.: declare that there is no conflict of interest regarding the publication of this manuscript. Mika R. Kessans Knable Pharm.D.: Speaker Bureau of Alexion.\n\nAuthorship\nRG, AG, and JF: conceptualized the original article. RG, AG, JF, LV, MK, RB, SS, RG, JR, and JC: participated in the delivery of patient care and article write‐up.\n==== Refs\nReferences\n1 \n\nBesbas , N. \n, \nD. \nKarpman \n, \nD. \nLandau \n, \nC. \nLoirat \n, \nW. \nProesmans \n, \nG. \nRemuzzi \n, et al. 2006 \nA classification of hemolytic uremic syndrome and thrombotic thrombocytopenic purpura and related disorders . Kidney Int. \n70 :423 –431 .16775594 \n2 \n\nNoris , M. \n, and \nG. \nRemuzzi \n. 2009 \nAtypical hemolytic‐uremic syndrome . N. Engl. J. Med. \n361 :1676 –1687 .19846853 \n3 \n\nLoirat , C. \n, and \nV. \nFremeaux‐Bacchi \n. 2011 \nAtypical hemolytic uremic syndrome . Orphanet. J. Rare. Dis. \n6 :60 .21902819 \n4 \n\nAl‐Nouri , Z. L. \n, \nJ. A. \nReese \n, \nD. R. \nTerrell \n, \nS. K. \nVesely \n, and \nJ. N. \nGeorge \n. 2015 \nDrug‐induced thrombotic microangiopathy: a systemic review of published reports . Blood \n125 :616 –618 .25414441 \n5 \n\nRuggenenti , P. \n, \nM. \nNoris \n, and \nG. \nRemuzzi \n. 2001 \nThrombotic microangiopathy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura . Kidney Int. \n60 :831 –846 .11532079 \n6 \n\nSneader , W. \n\n2005 \nDrug discovery: a history . P. 259 \nWiley , New York .\n7 \n\nCasper , E. S. \n, \nM. R. \nGreen \n, \nD. P. \nKelsen \n, \nR.T. \nHeelan \n, \nT.D. \nBrown \n, \nC.D. \nFlombaum \n, et al. 1994 \nPhase II trial of gemcitabine (2,2′‐difluorodeoxycytidine) in patients with adenocarcinoma of the pancreas . Invest. New Drugs \n12 :29 –34 .7960602 \n8 \n\nFung , M. C. \n, \nA. M. \nStorniolo \n, \nB. \nNguyen \n, \nM. \nArning \n, \nW. \nBrookfield \n, and \nJ. \nVigil \n. 1999 \nA review of hemolytic uremic syndrome in patient targeted with gemcitabine therapy . Cancer \n85 :2023 –2032 .10223245 \n9 \n\nDesramé , J. \n, \nC. \nDuvic \n, \nC. \nBredin \n, \nD. \nBechade \n, \nP. \nArtru \n, \nC \nBrezault \n, et al. 2005 \nHemolytic uremic syndrome as a complication of gemcitabine treatment: report of six cases and review of the literature . Rev. Med. Interne \n26 :179 –188 .15777580 \n10 \n\nLodhi , A. \n, \nA. \nKumar \n, \nM. U. \nSaqlain \n, and \nM. \nSuneja \n. 2015 \nThrombotic microangiopathy associated with proteasome inhibitors . Clin. Kidney J. \n8 :632 –636 .26413293 \n11 \n\nOikonomopoulou , K. \n, \nD. \nRicklin \n, \nP. A. \nWard \n, and \nJ. D. \nLambris \n. 2012 \nInteraction between coagulation and complement – their role in inflammation . Semin. Immunopathol. \n34 :151 –165 .21811895 \n12 \n\nNoris , M. \n, \nJ. \nCaprioli \n, \nE. \nBresin \n, et al. 2010 \nRelative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype . Clin. J. Am. Soc. Nephrol. \n5 :1844 –1859 .20595690 \n13 \n\nLegendre , C. M. \n, \nC. \nLicht \n, \nP. \nMuus \n, \nS. \nGreenbaum \n, \nC. \nBedroiant \n, \nC. \nBingham \n, et al. 2013 \nTerminal complement inhibitor eculizumab in atypical hemolytic‐uremic syndrome . N. Engl. J. Med. \n368 :2169 –2181 .23738544 \n14 \n\nCataland , S. R. \n, and \nH. M. \nWu \n. 2014 \nHow I treat: the clinical differentiation and initial treatment of adult patients with atypical hemolytic uremic syndrome . Blood \n123 :16 .\n15 \n\nIzzedine , H. \n, \nC. \nIsnard‐Bagnis \n, \nV. \nLaunay‐Vacher \n, et al. 2006 \nGemcitabine‐induced thrombotic microangiopathy: a systematic review . Nephrol. Dial. Transplant. \n21 :3038 –3045 .16968717 \n16 \n\nAssi , C. \n, \nC. \nLepage \n, \nJ. L. \nJouve \n, \nC. \nSgro \n, and \nL. \nBedenne \n. 2010 \nChronic anemia resistant to erythropoietin in a patient treated with gemcitabine showing a hemolytic uremic syndrome . Gasteroenterol. Clin. Biol. \n34 :640 –642 .\n\n",
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"keywords": "Carfilzomib; eculizumab; gemcitabine; hemolytic–uremic syndrome; thrombotic microangiopathy; thrombotic thrombocytopenia purpura",
"medline_ta": "Clin Case Rep",
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"pages": "1926-1930",
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"title": "Gemcitabine and carfilzomib induced thrombotic microangiopathy: eculizumab as a life-saving treatment.",
"title_normalized": "gemcitabine and carfilzomib induced thrombotic microangiopathy eculizumab as a life saving treatment"
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"abstract": "Linear immunoglobulin (Ig) A bullous dermatosis (LABD) is a rare subepidermal autoimmune blistering disease characterized by linear IgA deposits at the basement membrane zone visualized with direct immunofluorescence (DIF). Most cases of LABD are idiopathic, but some are drug-induced with vancomycin being the most common causative agent. We herein report a patient presenting with blisters and erosive lesions, primarily in the intertriginous and flexor areas, consistent with a diagnosis of piperacillin-tazobactam-induced LABD based on the patient's clinical course and histopathology, DIF, and in vitro T-cell activation assay (TAA) findings. Only one case of piperacillin-tazobactam-induced LABD has been previously reported. In addition to its rarity, our case was also unique in that the skin lesions occurred in the intertriginous and flexor areas, uncommon locations for typical adult patients with LABD, and TAA strongly suggested an association with the causative drug.",
"affiliations": "Department of Dermatology, Taipei Veterans General Hospital, Taipei, Taiwan.;Department of Dermatology, Taipei Veterans General Hospital, Taipei, Taiwan.;Department of Dermatology, Taipei Veterans General Hospital, Taipei, Taiwan.",
"authors": "Ho|Yi-Hsin|YH|;Chiu|Yun-Wen|YW|;Liu|Han-Nan|HN|https://orcid.org/0000-0002-4788-6588",
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"doi": "10.5021/ad.2018.30.5.588",
"fulltext": "\n==== Front\nAnn Dermatol\nAnn Dermatol\nAD\nAnnals of Dermatology\n1013-9087\n2005-3894\nThe Korean Dermatological Association; The Korean Society for Investigative Dermatology\n\n10.5021/ad.2018.30.5.588\nCase Report\nPiperacillin-Tazobactam-Induced Linear IgA Bullous Dermatosis Supported by a T-Cell Activation Assay\nHo Yi-Hsin 12\nChiu Yun-Wen 12\nhttps://orcid.org/0000-0002-4788-6588\nLiu Han-Nan 123\n1 Department of Dermatology, Taipei Veterans General Hospital, Taipei, Taiwan.\n2 Department of Dermatology, National Yang-Ming University, Taipei, Taiwan.\n3 Department of Dermatology, National Defense Medical Center, Taipei, Taiwan.\nCorresponding author: Han-Nan Liu, Department of Dermatology, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei 112, Taiwan. Tel: 886-2-28757188, Fax: 886-2-28757666, hnliu@vghtpe.gov.tw\n10 2018\n28 8 2018\n30 5 588591\n04 8 2017\n07 9 2017\nCopyright © 2018 The Korean Dermatological Association and The Korean Society for Investigative Dermatology\n2018\nThe Korean Dermatological Association and The Korean Society for Investigative Dermatology\nThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.\nLinear immunoglobulin (Ig) A bullous dermatosis (LABD) is a rare subepidermal autoimmune blistering disease characterized by linear IgA deposits at the basement membrane zone visualized with direct immunofluorescence (DIF). Most cases of LABD are idiopathic, but some are drug-induced with vancomycin being the most common causative agent. We herein report a patient presenting with blisters and erosive lesions, primarily in the intertriginous and flexor areas, consistent with a diagnosis of piperacillin-tazobactam-induced LABD based on the patient's clinical course and histopathology, DIF, and in vitro T-cell activation assay (TAA) findings. Only one case of piperacillin-tazobactam-induced LABD has been previously reported. In addition to its rarity, our case was also unique in that the skin lesions occurred in the intertriginous and flexor areas, uncommon locations for typical adult patients with LABD, and TAA strongly suggested an association with the causative drug.\n\nLinear IgA bullous dermatosis\nPiperacillin-tazobactam\nT-cell activation assay\nIndustry-University Cooperative Research Project R11004\n==== Body\nINTRODUCTION\n\nLinear IgA bullous dermatosis (LABD) is a subepidermal autoimmune bullous disease characterized by linear IgA deposition at the basement membrane zone (BMZ). LABD typically presents with a widespread annular eruption of vesicles and tense bullae1. In adults, the skin lesions usually occur on the trunk, extensor extremities, buttocks, face2, and rarely in the intertriginous and flexor areas3. Involvement of the intertriginous and flexor areas is more commonly seen in children4.\n\nLABD is usually idiopathic, but it may be related to infection or medication5. Multiple drugs have been implicated, and vancomycin is the most common offending medication15. Only one case of piperacillin-tazobactam-induced LABD has been previously reported1. Also, to the best of our knowledge, conventional lymphocyte transformation test (LTT) has been performed in only two previous case reports of drug-induced LABD6. Some recent reports have suggested that T-cell activation assays (TAA) are more sensitive than LTT for the detection of drug-specific responses in patients with a diagnosis of drug hypersensitivity78910. We herein report a patient presenting with blisters and erosive lesions, mainly in the intertriginous and flexor areas. The diagnosis of piperacillin-tazobactam-induced LABD was finally made based on the patient's clinical course and histopathology, direct immunofluorescence (DIF), and TAA findings.\n\nCASE REPORT\n\nA 59-year-old Taiwanese male was admitted to the hospital with a diagnosis of right lower lung pneumonia. He had a history of insulin-dependent diabetes mellitus, hypertension, end stage renal disease presumed secondary to diabetic nephropathy, peripheral occlusive arterial disease, chronic osteomyelitis of the left foot, and chronic hepatitis C infection. He had no known history of drug allergy and denied recently taking any new medications.\n\nEmpirical antibiotic therapy was administered soon after admission with cefuroxime for 1 day. The next day cefuroxime was discontinued and moxifloxacin was administered. Moxifloxacin was discontinued after 3 days, and a 10-day course of piperacillin-tazobactam was begun. In addition, a 7-day course of teicoplanin was added 2 days after the start of piperacillin-tazobactam administration for suspected recurrent osteomyelitis of the left foot. An erythematous skin rash first appeared 3 days after the initial dose of piperacillin-tazobactam, and subsequently the patient developed multiple intense pruritic vesicles, bullae, and erosions primarily on the thighs, axillae, groins, finger webs, and popliteal fossae over the next 7 days. Because of a suspected drug eruption, all antibiotics were discontinued.\n\nPhysical examination revealed numerous clear tense bullae with erosions and crusts on the thighs, axillae, groins, finger webs, and popliteal fossae (Fig. 1A~C). Some lesions were arciform in appearance (Fig. 1D). The ocular, nasal, and genital mucosal membranes were spared. A skin biopsy obtained from an intact blister revealed a subepidermal blister with dense neutrophils, nuclear dust, and eosinophils in the dermis (Fig. 2A, B). DIF demonstrated a continuous linear deposition of IgA and a weak linear deposition of C3 along the BMZ (Fig. 2C, D). Type IV collagen staining showed the subepidermal blister to be above the basement membrane. Indirect immunofluorescence examination failed to demonstrate anti-keratinocyte cell surface or anti-basement membrane zone antibodies.\n\nTAA was performed 7 days after discontinuation of all antibiotics. At that time, the skin lesions were in clinical remission. In brief, peripheral blood mononuclear cells were isolated using density gradient centrifugation. The cells were then incubated in culture media containing cefuroxime, moxifloxacin, piperacillin/tazobactam, teicoplanin, or solvent control. Culture supernatants were collected on days 7, 14, and 21, and the levels of cytokines granulysin and granzyme B were measured with Enzyme-Linked Immunosorbent Assay. The levels of granulysin and granzyme B were the highest in the piperacillin/tazobactam culture supernant (granulysin, 6 times higher than the solvent control and granzyme b, 31.2 times higher than the solvent control), followed by moxifloxacin (granulysin, 3.4 times higher than the solvent control and granzyme B, 7.7 times higher than the solvent control). There were no significant increases in the cytokine levels in the cefuroxime and teicoplanin culture supernants.\n\nBased on the timing and duration of antibiotics usage, disease course, histopathological findings, and DIF, we suspected a diagnosis of drug induced-LABD most likely triggered by piperacillin-tazobactam. This was supported by the TAA results suggesting piperacillin/tazobactam as the main culprit drug. After cessation of the antibiotics, oral prednisolone 10 mg three times daily was begun, but was discontinued after one day because the patient developed tarry stools. Topical therapy included antimicrobial barrier dressings to the areas of erosion and clobetasol proprionate (0.05%) ointment to areas of intact erythematous skin. The patient's symptoms improved rapidly. At follow-up two weeks later, there was near complete resolution of all skin lesions.\n\nDISCUSSION\n\nLABD is a rare disease with an incidence of 0.23~2.3 cases per million person-years1. LABD has a bipolar age distribution, afflicting mostly children aged 6 months to 10 years or adults over 60 years old5.\n\nPatients with LABD may have lesions on the skin and/or mucous membranes4, and typically present with a widespread skin eruption of vesicles and bullae on inflamed or non-inflamed skin1. The acute onset of annular or arcuate blisters resembling a string or cluster of pearls has been reported to strongly suggest a diagnosis of LABD34. The trunk, extensor extremities, buttocks, and perioral areas are the most common lesion sites in adults2. Unlike our patient, adult patients usually do not manifest lesions in the body folds and flexor areas3.\n\nLABD is usually idiopathic but may be related to infection or medication5. Vancomycin is the most common medication reported to induce LABD15. Other implicated medications include penicillins, cephalosporins, angiotensin converting enzyme inhibitors, and nonsteroidal anti-inflammatory drugs5. However, penicillins have been rarely implicated in LABD. Piperacillin-tazobactam-induced LABD is less common, and only one case has been previously reported and that patient presented with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) like findings1.\n\nCytotoxic mechanisms are involved in most forms of drug-induced skin disease911. Granulysin, a secretory protein produced by cytotoxic T lymphocytes and natural killer cells, plays a key role in disseminated keratinocyte death in SJS/TEN78 and various cutaneous adverse reactions (CAR)911. Other mediator, such as granzyme B, is expressed in epidermal T cells at the dermoepidermal junction and mediates drug-specific cytotoxicity in T-cell lines and clones derived from patients with different CARs911. Since increased concentrations of granulysin and granzyme B are significantly correlated with CARs789, a positive TAA result has been defined as a 2-fold increase in cytokine expression compared with that of the solvent control8. In our case, the TAA showed a strong reaction to piperacillin-tazobactam and provided evidence useful for identifying the causative drug. Larger studies of similar cases are necessary to justify the use of TAA for the detection of causative drugs.\n\nThe primary treatment of patients with drug-induced LABD is withdrawal of the offending agent5. Other accepted treatments include dapsone, sulfonamides (sulfapyridine and sulfamethoxypyridazine), colchicine, and topical and oral corticosteroids5. In our case, spontaneous resolution of the skin eruption several days after discontinuation of piperacillin-tazobactam strengthened our suspicion that piperacillin-tazobactam was the culprit drug. In conclusion, piperacillin-tazobactam can occasionally induce LABD. Unlike the first case report describing a patient with SJS/TEN-like skin lesions, our case presented with annular or arciform blisters mainly in the intertriginous and flexural areas. If possible, LTT or TAA should be performed to potentially identify the causative drug.\n\nACKNOWLEDGMENT\n\nWe would like to thank Professor Wen-Hung Chung and his team for conducting the T-cell activation assay.\n\nFunding by Industry-University Cooperative Research Project, Taiwan (R11004).\n\nWe received the patient consent form about publishing all photographic materials.\n\nFig. 1 (A~C) Photographs showing numerous clear fluid-filled tense bullae with erosions and crust formation on the axillae, thighs, groins and popliteal fossae; (D) some lesions are arciform in appearance.\n\nFig. 2 Photomicrographs of the patient's cutaneous biopsy specimen demonstrate subepidermal blister with dense neutrophils, nuclear dust, and eosinophils in the dermis (A: H&E, ×40; B: H&E, ×100). Photomicrographs of direct immunofluorescent staining of the skin biopsy specimen demonstrated continuous linear deposition of IgA and weak linear deposition of C3 along the basement membrane zone (C, D: ×100).\n\nCONFLICTS OF INTEREST: The authors have nothing to disclose.\n==== Refs\n1 Adler NR McLean CA Aung AK Goh MS Piperacillin-tazobactam-induced linear IgA bullous dermatosis presenting clinically as Stevens-Johnson syndrome/toxic epidermal necrolysis overlap Clin Exp Dermatol 2017 42 299 302 28084616\n2 Fortuna G Marinkovich MP Linear immunoglobulin A bullous dermatosis Clin Dermatol 2012 30 38 50 22137225\n3 Sakka N Yahia KH Volcon A Brazilai A Baum S Intertriginous linear iga bullous dermatosis treated with colchicine J Dermatol Clin Res 2015 3 1040\n4 Lings K Bygum A Linear IgA bullous dermatosis: a retrospective study of 23 patients in Denmark Acta Derm Venereol 2015 95 466 471 25350667\n5 Jha P Swanson K Stromich J Michalski BM Olasz E A rare case of vancomycin-induced linear immunoglobulin A bullous dermatosis Case Rep Dermatol Med 2017 2017 7318305 28168063\n6 Tomida E Kato Y Ozawa H Hasegawa H Ishii N Hashimoto T Causative drug detection by drug-induced lymphocyte stimulation test in drug-induced linear IgA bullous dermatosis Br J Dermatol 2016 175 1106 1108 26265104\n7 Chung WH Hung SI Yang JY Su SC Huang SP Wei CY Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis Nat Med 2008 14 1343 1350 19029983\n8 Chung WH Pan RY Chu MT Chin SW Huang YL Wang WC Oxypurinol-specific T cells possess preferential TCR clonotypes and express granulysin in allopurinol-induced severe cutaneous adverse reactions J Invest Dermatol 2015 135 2237 2248 25946710\n9 Porębski G Czarnobilska E Bosak M Cytotoxic-based assays in delayed drug hypersensitivity reactions induced by antiepileptic drugs Pol Arch Med Wewn 2015 125 823 834 26445768\n10 Porebski G Pecaric-Petkovic T Groux-Keller M Bosak M Kawabata TT Pichler WJ In vitro drug causality assessment in Stevens-Johnson syndrome - alternatives for lymphocyte transformation test Clin Exp Allergy 2013 43 1027 1037 23957338\n11 Schrijvers R Gilissen L Chiriac AM Demoly P Pathogenesis and diagnosis of delayed-type drug hypersensitivity reactions, from bedside to bench and back Clin Transl Allergy 2015 5 31 26339470\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1013-9087",
"issue": "30(5)",
"journal": "Annals of dermatology",
"keywords": "Linear IgA bullous dermatosis; Piperacillin-tazobactam; T-cell activation assay",
"medline_ta": "Ann Dermatol",
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"nlm_unique_id": "8916577",
"other_id": null,
"pages": "588-591",
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"pubdate": "2018-10",
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"references": "26265104;26445768;28168063;19029983;28084616;26339470;25946710;25350667;22137225;23957338",
"title": "Piperacillin-Tazobactam-Induced Linear IgA Bullous Dermatosis Supported by a T-Cell Activation Assay.",
"title_normalized": "piperacillin tazobactam induced linear iga bullous dermatosis supported by a t cell activation assay"
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"abstract": "Intracerebral hemorrhage after spinal surgery is a rare but dreaded complication. The most commonly described form of intracranial hemorrhage after spinal surgery is remote cerebellar hemorrhage (i.e. anatomically distant from the surgical site) (Brockmann MA, Groden C. Remote cerebellar hemorrhage: a review. The Cerebellum 2006;5:64-8); however subdural, subarachnoid, and intraventricular hemorrhage can also occur in combination or isolated (Kaloostian PE, Kim JE, Bydon A, Sciubba DM, Wolinsky JP, Gokaslan ZL, Witham TF. Intracranial hemorrhage after spine surgery. J Neurosurg Spine 2013;19:370-80; Khalatbari MR, Khalatbari J, Moharamzad Y. Intracranial hemorrhage following lumbar spine surgery. Eur Spine J 2012;21:2092-96). Isolated intraventricular hemorrhage after spinal surgery is extremely rare; to our knowledge, there are only two cases reported in the literature (Kaloostian PE, Kim JE, Bydon A, Sciubba DM, Wolinsky JP, Gokaslan ZL, Witham TF. Intracranial hemorrhage after spine surgery. J Neurosurg Spine 2013;19:370-80; Khalatbari MR, Khalatbari J, Moharamzad Y. Intracranial hemorrhage following lumbar spine surgery. Eur Spine J 2012;21:2092-96). Here, we present a 76-year-old female patient who developed isolated intraventricular hemorrhage after spinal surgery.",
"affiliations": "Department of Radiology, Section of Neuroradiology, Rush University Medical Center, 600 S Paulina St, Chicago, IL 60612. Electronic address: melike_guryildirim@rush.edu.;Department of Radiology, Section of Neuroradiology, Rush University Medical Center, 600 S Paulina St, Chicago, IL 60612.",
"authors": "Guryildirim|Melike|M|;Jhaveri|Miral D|MD|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
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"issn_linking": "0899-7071",
"issue": "40(5)",
"journal": "Clinical imaging",
"keywords": "Dural tear; Intraventricular hemorrhage; Remote cerebellar hemorrhage; Spinal surgery",
"medline_ta": "Clin Imaging",
"mesh_terms": "D000368:Aged; D002533:Cerebral Angiography; D002543:Cerebral Hemorrhage; D002552:Cerebral Ventricles; D005260:Female; D006801:Humans; D008159:Lumbar Vertebrae; D008279:Magnetic Resonance Imaging; D019106:Postoperative Hemorrhage; D013123:Spinal Fusion; D013130:Spinal Stenosis; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8911831",
"other_id": null,
"pages": "889-91",
"pmc": null,
"pmid": "27179960",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Isolated intraventricular hemorrhage after spinal surgery.",
"title_normalized": "isolated intraventricular hemorrhage after spinal surgery"
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"activesubstancename": "FIBRINOGEN HUMAN\\THROMBIN HUMAN"
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"abstract": "Renal congestion contributes to the cardiorenal syndrome. There are some heart failure cases that are refractory to diuretic therapy. If the dose of diuretics is titrated, it leads to irreversible renal dysfunction. Early administration of tolvaptan is effective in treating fluid retention and congestion. However, in case of tolvaptan resistance, starting extracorporeal ultrafiltration (ECUM) at an early stage should be considered. Tolvaptan has been proven efficient, and we believe it should be incorporated with the classical method, ECUM. Herein, we present a case of successful application of ECUM to a heart failure patient refractory to any diuretics and tolvaptan.",
"affiliations": "Seirei Hamamatsu General Hospital, Hamamatsu, Shizuoka, Japan.;Department of Cardiology, Seirei Hamamatsu General Hospital, Hamamatsu, Shizuoka, Japan.;Department of Cardiology, Seirei Hamamatsu General Hospital, Hamamatsu, Shizuoka, Japan.",
"authors": "Nakazawa|Naomi|N|;Nakabayashi|Keisuke|K|http://orcid.org/0000-0003-1770-9238;Oka|Toshiaki|T|",
"chemical_list": "D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D000077602:Tolvaptan",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2016-217301",
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"issue": "2016()",
"journal": "BMJ case reports",
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"mesh_terms": "D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D059347:Cardio-Renal Syndrome; D006332:Cardiomegaly; D003937:Diagnosis, Differential; D004351:Drug Resistance; D017583:Hemodiafiltration; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077602:Tolvaptan; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "27702934",
"pubdate": "2016-10-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19215834;19075105;17291932;24656104;16967294;22676934;20354029;22840531;15846257;12094185;19808361",
"title": "Efficacy of extracorporeal ultrafiltration in patients with diuretic-resistant heart failure.",
"title_normalized": "efficacy of extracorporeal ultrafiltration in patients with diuretic resistant heart failure"
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"companynumb": "JP-MYLANLABS-2017M1024348",
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"abstract": "In France, the Afssaps is the body in charge of the evaluation of pharmacodependance. In order to fulfil its mission, the Afssaps has created a network of 10 Centres for Evaluation and Information on Pharmacodependance (CEIP), coordinated by the Drugs and Psychotropics Unit. Pharmacodependence notifications issued by professionals are collected by each Centre which evaluates them: it is therefore necessary to harmonize case reporting and make it possible to homogeneously evaluate the seriousness of pharmacodependence cases. Nantes CEIP has developed and has been routinely using a tool which evaluates pharmacodependence seriousness by quantifying patient consumption behaviour: the corresponding calculation, interpretation related to 3 patients is presented in this article. The association of clinical data generated by the tool, and official data coming from CEIP's, represents a powerful combination which is now available for pharmacodependence and abuse diagnosis.",
"affiliations": "Centre d'Evaluation et d'Information sur la Pharmacodépendance, Service de Pharmacologie Clinique, CHU Nantes, Nantes, France. caroline.vigneau@chu-nantes.fr",
"authors": "Victorri-Vigneau|Caroline|C|;Jolliet|Pascale|P|",
"chemical_list": null,
"country": "France",
"delete": false,
"doi": "10.2515/therapie:2006089",
"fulltext": null,
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"issn_linking": "0040-5957",
"issue": "61(6)",
"journal": "Therapie",
"keywords": null,
"medline_ta": "Therapie",
"mesh_terms": "D000328:Adult; D011307:Drug Prescriptions; D005260:Female; D005602:France; D006801:Humans; D008297:Male; D008875:Middle Aged; D011358:Product Surveillance, Postmarketing; D019966:Substance-Related Disorders; D011795:Surveys and Questionnaires",
"nlm_unique_id": "0420544",
"other_id": null,
"pages": "517-22",
"pmc": null,
"pmid": "17348608",
"pubdate": "2006",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Scoring pharmacodependence seriousness: a novel CEIP's evaluation tool.",
"title_normalized": "scoring pharmacodependence seriousness a novel ceip s evaluation tool"
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"companynumb": "FR-GLAXOSMITHKLINE-FR2016GSK096892",
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{
"abstract": "Introduction. Immunosuppressant and steroid therapy in systemic lupus erythematosus (SLE) increases the risk of human papillomavirus (HPV) infections, one of which is giant condyloma acuminata (GCA). To our knowledge, there is no report evaluating the correlation between immunosuppressive and steroid therapy in patients with SLE and the prevalence of GCA. Case Report. A 42-year-old female was diagnosed with SLE a year ago and has been treated with steroids and immunosuppressive drugs. In the last few months she presented GCA involving the genital area recurring almost every two months. Type 6 and 11 HPVs were identified in vulva, vagina, and cervix. Methods. PubMed, EBSCO, and Cochrane Library literature were searched from inception to July 2015. Authors screened all titles and abstracts and read full text article, and two case-control studies were found relevant. Results. SLE patients in both studies were under immunosuppressive and steroid therapy. Condyloma acuminata was diagnosed at 108 months (latest) and 1 month (earliest) after SLE. Type 6, 11, 16, 42, and oncogenic group of HPV were identified. Conclusions. GCA is a type of HPV infection seldom observed in SLE patients. Therefore, their correlation is still unclear. Period of time since SLE was diagnosed and GCA varies from months to years. A more thorough physical and laboratory examination leading to HPV and other infectious disease is recommended.",
"affiliations": "Division of Hematology and Medical Oncology, Department of Internal Medicine, Faculty of Medicine, University of Indonesia-Cipto Mangunkusumo Hospital, Jakarta, Indonesia.;Faculty of Medicine, University of Indonesia-Cipto Mangunkusumo Hospital, Jakarta, Indonesia.",
"authors": "Rachman|Andhika|A|0000-0003-3246-3352;Hasan|Nabila|N|0000-0002-8123-2852",
"chemical_list": null,
"country": "Egypt",
"delete": false,
"doi": "10.1155/2016/4710979",
"fulltext": "\n==== Front\nCase Reports ImmunolCase Reports ImmunolCRIICase Reports in Immunology2090-66092090-6617Hindawi Publishing Corporation 10.1155/2016/4710979Case ReportGiant Condyloma Acuminata in Indonesian Females with SLE under Immunosuppressant and Steroid Therapy http://orcid.org/0000-0003-3246-3352Rachman Andhika \n1\n\n*\nhttp://orcid.org/0000-0002-8123-2852Hasan Nabila \n2\n1Division of Hematology and Medical Oncology, Department of Internal Medicine, Faculty of Medicine, University of Indonesia-Cipto Mangunkusumo Hospital, Jakarta, Indonesia2Faculty of Medicine, University of Indonesia-Cipto Mangunkusumo Hospital, Jakarta, Indonesia*Andhika Rachman: andhika_rachman@yahoo.comAcademic Editor: Anne E. Tebo\n\n2016 24 10 2016 2016 47109799 6 2016 27 9 2016 4 10 2016 Copyright © 2016 A. Rachman and N. Hasan.2016This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nIntroduction. Immunosuppressant and steroid therapy in systemic lupus erythematosus (SLE) increases the risk of human papillomavirus (HPV) infections, one of which is giant condyloma acuminata (GCA). To our knowledge, there is no report evaluating the correlation between immunosuppressive and steroid therapy in patients with SLE and the prevalence of GCA. Case Report. A 42-year-old female was diagnosed with SLE a year ago and has been treated with steroids and immunosuppressive drugs. In the last few months she presented GCA involving the genital area recurring almost every two months. Type 6 and 11 HPVs were identified in vulva, vagina, and cervix. Methods. PubMed, EBSCO, and Cochrane Library literature were searched from inception to July 2015. Authors screened all titles and abstracts and read full text article, and two case-control studies were found relevant. Results. SLE patients in both studies were under immunosuppressive and steroid therapy. Condyloma acuminata was diagnosed at 108 months (latest) and 1 month (earliest) after SLE. Type 6, 11, 16, 42, and oncogenic group of HPV were identified. Conclusions. GCA is a type of HPV infection seldom observed in SLE patients. Therefore, their correlation is still unclear. Period of time since SLE was diagnosed and GCA varies from months to years. A more thorough physical and laboratory examination leading to HPV and other infectious disease is recommended.\n==== Body\n1. Introduction\nInfection is an important cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE), including infections in the genitalia, such as infections caused by human papillomavirus (HPV) [1]. In Indonesia, HPV 16 and 18 are equally common in the general population, as they are in cervical cancer [2].\n\nGiant condyloma acuminata (GCA), a type of HPV infection in the genital area, is a benign tumor that grows resembling a cauliflower. Although GCA is benign, it has malignancy tendencies as it can grow up to 10 cm, which is locally invasive and damaging [3]. It is a very rare sexually transmitted infection (STI), with 0.1% incident in general population [4, 5].\n\nSLE is a systemic autoimmune disease characterized by high level of autoantibodies affecting many internal organs and therefore, its clinical manifestation varies. The disease is mainly treated with immunosuppressant and steroid. Some studies reported that immunosuppressant and steroid therapy in SLE patient may increase the risk of developing HPV infection [6]. Santana et al. [7] and Nath et al. [8] did not find the correlation between the use of immunosuppressant and the prevalence of HPV infection. To our knowledge, there is no report in South East Asia that evaluates the correlation between immunosuppressant such as azathioprine, cyclophosphamide, mycophenolate mofetil, and steroid therapy in patients with SLE and the prevalence of giant condyloma acuminata.\n\n2. Case Report\nThe patient, a 42-year-old female, was diagnosed with SLE in 2013 based on the presence of antinuclear antibodies, in addition to discoid rash and arthritis. She is sexually active with one partner, had one child, and had a history of multiple sexual partners. Since then she has been treated with methylprednisolone (32 mg/day) and mycophenolate mofetil (1000 mg/day). After six months of therapy, genital warts first appear in the vulva and anal region (Figure 1) and recurred in two months spreading to the pubic mound, perineum, and anal region (Figure 2(a)). It became progressively hypertrophic, resembling cauliflower. Biopsies were performed showing papillomatosis and hyperkeratosis. Type 6 and 11 HPV were identified in the lesions through RT-PCR. She was treated with excision (Figure 2(b)). The following month, she came with HPV infection in cervical region and was treated with surgical procedure (Figures 3(a) and 3(b)).\n\n3. Clinical Question\nIn this report, author would like to know if immunosuppressant and steroid therapy in patient with SLE induced giant condyloma acuminate and which regimen induces it rapidly.\n\n4. Methods\nElectronic searches of PubMed, EBSCO, and Cochrane Library were conducted from inception to July 2015. Search terms (in English) are “SLE AND condyloma acuminatum AND immunosuppressant AND steroid”. There are only few articles found in literature search. Therefore, first article screening was done by reading all titles and abstracts. Full text articles were assessed for eligibility, and two articles were found relevant (Table 1).\n\n5. Results\nOnly two case-control studies related with immunosuppressant and steroid therapy in SLE and the prevalence of giant condyloma acuminata were found. Both studies have low validity compared to randomized controlled trial (RCT) and systematic reviews.\n\nIn the first study, Lube et al. [9] reported the incident of GCA in childhood systemic lupus erythematosus (C-SLE). The study reported that 289 of 5682 patients in Pediatric Rheumatology Unit were diagnosed with SLE, and 4 of 289 (1.4%) had GCA. All patients were under immunosuppressant and corticosteroid therapy.\n\nIn the second study, Costapinto et al. [10] reported the incident of condyloma acuminata in a 33-year-old Black female who was diagnosed with SLE during her first pregnancy in 2003. In 2004, after seven months of mycophenolate mofetil therapy, she was diagnosed with condyloma acuminata in the genital area. The patient had used steroids and immunosuppressant such as cyclophosphamide and azathioprine since she was 14 years old due to her irregular menstrual cycle. Detailed characteristic of each patient in both studies can be seen in Table 2.\n\n6. Discussion\nThere are not many literatures found discussing the correlation between immunosuppressant and steroid therapy in patients with SLE and the prevalence of condyloma acuminata. It may be due to its low incidence, which is only 0.1% in general population [4, 5]. Thornsberry and English III [11] stated that the incidence of anogenital warts, a symptom of GCA, is approximately 1% in sexually active adults and may be up to 3% in sexually active adolescents. HPV is known as the most common sexually transmitted disease (STD) in United States females and the major risk factor is younger age at first sexual intercourse [12], as observed in cases in both studies, where all patients are sexually active except for one case that has a history of sexual abuse.\n\nSystemic lupus erythematosus is a disease with impaired immune regulation and response. The number of active B cells producing immunoglobulin is increasing in the peripheral blood. B cells in SLE patients are likely to undergo polyclonal B cell activation by a specific antigen. B cells responses are abnormal to signal activity. B cell hyperactivity is characterized by elevated concentrations of interleukins 6 and 10 (IL-6 and IL-10). In addition, the number of activated T cells in peripheral blood is also increasing. In SLE patients, T cells may provide help for increasing the production of antibodies. The phagocytic cells in SLE patients can not bind or process immune complex and thus stimulates the formation of antibodies [13].\n\nNK cells play an important role in the innate immune system. They recognize and kill viruses, such as HPV, and transform cells through two mechanisms, that is, granule-dependent cytotoxicity and apoptosis in target cells. NK cells interact with HPVs and can participate in immune response against HPV-induced lesions by displaying higher cytotoxic activity and cytokine production (TNF-α and IFN-γ) [14, 15]. Meanwhile, Henriques et al. [16] found that numbers of circulating NK cells are lower in patients with SLE when compared to healthy subjects, more notorious in active disease. Thus, patients with SLE can be prone to HPV infections, such as condyloma acuminata. Patients with SLE have more severe tissue damage as a result of continuing abnormalities in immune response and regulation.\n\nTherefore, immunosuppressant and steroid therapy is given. However, the therapy itself is one of the main risk factors for developing HPV infection, especially in the skin area (OR 2.91, 95% CI 1.18–7.14). In addition to SLE (OR 2.16, 95% CI 1.04–4.48) [13]. Mendoza-Pinto et al. [17] found that cumulative glucocorticoid dose in women with SLE may increase the risk of HPV infection. Glucocorticoid such as prednisone suppressed the functions of Toll-like receptor (TLR) stimulated plasmacytoid dendritic cells, thereby reducing the ability to clear HPV infection. Mycophenolic acid was also associated with cervical HPV infection. A Mexican study detected low levels of B and NK cells and an increased risk of HPV infection in SLE patients receiving mycophenolate mofetil [18]. Klumb et al. [19] found that there is a higher cumulative cyclophosphamide dose in SLE patients with HPV infections.\n\nIn both studies [9, 10], all patients have immunosuppressant therapy, such as azathioprine, chloroquine, hydroxychloroquine, intravenous cyclophosphamide, or mycophenolate mofetil, while steroids used are prednisone and methylprednisolone. Therapy was given immediately after SLE was diagnosed. The earliest condyloma acuminata incident was found in the third case with only one-month period after the diagnosis of SLE.\n\nSteroids and immunosuppressants have a mechanism to inhibit B cells, T cells, and inflammatory cytokines, which are very appropriate to be used as the rationales of SLE therapy. Glucocorticoids inhibit the extravasation and infiltration of leucocytes into tissue and inhibit macrophages and lymphocytes (B and T cells) to produce inflammatory cytokines such as TNF-α, IL-1, IL-12, and IFN-γ, while immunosuppressant such as mycophenolate mofetil, which is derived from mycophenolic acid isolated from Penicillium glaucum, inhibits the response of lymphocytes through purine synthesis [20].\n\nThe most frequent types of HPV found in patients with SLE are types 6 and 11, which are low-risk HPVs (LR-HPVs) associated with benign tumor. In addition to types 16 and 18, there are other types of HPV that may be found and also play a role in malignancy, which are considered as high-risk HPVs (HR-HPVs) [21]. In Lube et al.'s study [9], all patients have type 16 and oncogenic group with a risk to dysplasia and cervical cancer.\n\nImmunization can be considered as a primary prevention to HPV spread. At the end of 2008, 70% of women younger than 26 years of age had HPV vaccine and the there was a marked reduction in the incidence of condyloma acuminata (50% compared to 2004–2007) [22]. Gardasil, the currently available quadrivalent HPV vaccine, can increase the NK cell population following immunization [14]. Mok et al. [23] found in their study that the quadrivalent HPV vaccine is well tolerated and reasonably effective in patients with stable SLE and does not induce an increase in lupus activity or flares.\n\nBoth studies [9, 10] showed variety of condyloma therapy, such as the use of trichloroacetic acid, TLR7 agonist, imiquimod 5% cream, podophyllin 2% oil, CO2 laser vaporization, LEEP, and surgical procedure. Aubin et al. [24] distinguish condyloma therapy into three categories: physical destruction, chemical, and immunomodulation. However, no therapy can totally eradicate the disease. One of three patients in Lube et al.'s study showed recurrence [9]. Therapy given in condyloma acuminata is based on location, number, size, availability of medical instrument, and doctor's experience.\n\n7. Conclusions\nGCA is a type of HPV infection which is seldom observed in SLE patients. Period of time since SLE was diagnosed and GCA varies from months to years. The correlation between immunosuppressant and steroid therapy in SLE patients and the prevalence of giant condyloma acuminata is still unclear. Therefore, further study and research with bigger sample are required. Hopefully, the studies can be used as a reference in choosing therapy regimens in patients with SLE or other autoimmune diseases. A more thorough history taking, physical, and laboratory examination leading to HPV and other infectious diseases should be performed as a routine procedure in clinical practice. HPV vaccine, particularly before first sexual intercourse, is recommended in SLE patients prior to administration of immunosuppressive and steroid therapy.\n\nCompeting Interests\nThe authors declare that there is no conflict of interests regarding the publication of this manuscript.\n\nFigure 1 Genital warts in vulvar and anal region.\n\nFigure 2 (a) Recurrence of condyloma acuminata in patient with systemic lupus erythematosus during methylprednisolone and mycophenolate mofetil therapy (b) after surgical procedure.\n\nFigure 3 (a) Recurrence of condyloma acuminata in cervical region (b) after surgical procedure.\n\nTable 1 Literature search.\n\nSource\tKeywords\tResult\t\nPubMed\tSLE AND condyloma acuminatum AND Immunosuppressant AND Steroid\t1\t\nEBSCO\t1\t\nCochrane Library\t0\t\nTable 2 Characteristic of each patient in both studies.\n\nVariable\t Lube et al. [9]\tCostapinto et al. [10]\t\n1\t2\t3\t4\t1\t\n\nDemographic data\n\t \t \t \t \t \t\nAge at SLE diagnosis, years\t12\t8\t14\t15\t33\t\nGender\t♀\t♀\t♀\t♀\t♀\t\nSLE therapy\tChloroquine 5 mg/kg/day;\nprednisone 60 mg/day\tPrednisone 2 mg/kg/day; chloroquine 250 mg/day; IV cyclophosphamide 500–1000 mg/m2\n\tMethylprednisolone 1 g/day; IV cyclophosphamide 750 mg/m2; hydroxychloroquine 300 mg/day; prednisone 2 mg/kg/day\tPrednisone 21 mg/kg/day; chloroquine 250 mg/day\tMycophenolate mofetil 2 g/day\t\nSexual activity\tActive\tActive\tNot active\tActive\tActive\t\nPeriod between SLE and GCA, months\t22\t108\t1\t48\t12\t\nClinical features at GCA\tVulva\tVulva, vagina, anal\tVulva and anal\tVulva\tVulva, vagina, perineum, and anal\t\nHPV type\tHPV DNA of oncogenic group and cervix biopsy\tHPV 16, HPV DNA of oncogenic group and cervix biopsy\tHPV DNA of oncogenic group and HPV 16\tHPV DNA of oncogenic group\tHPV 6, 11, and 42\t\n\n\n\t\n\nTreatments at GCA\n\t \t \t \t \t \t\nSLE therapy\tPrednisone 20 mg/day; azathioprine 150 mg/day; chloroquine 250 mg/day\tPrednisone 20 mg/day; chloroquine 250 mg/day; azathioprine 150 mg/day\tIntravenous cyclophosphamide 750 mg/m2; hydroxychloroquine 300 mg/day; prednisone 2 mg/kg/day\tPrednisone 5 mg/day; chloroquine 250 mg/day\tMycophenolate mofetil 2 g/day\t\nHPV\tLEEP\tCO2 laser vaporization\tSurgical removal\tLEEP\tTrichloroacetic acid; TLR7 agonist imiquimod 5% cream; podophyllin 2% oil; operation\t\nRecurrence of GCA\tYes\t—\t—\t—\t—\t\n♀: female; GCA: giant condyloma acuminata; SLE: systemic lupus erythematosus; LEEP: loop electrosurgical excisional procedure.\n==== Refs\n1 Faco M. M. M. Leone C. Campos L. M. A. Febrônio M. V. Marques H. H. S. Silva C. A. Risk factors associated with the death of patients hospitalized for juvenile systemic lupus erythematosus Brazilian Journal of Medical and Biological Research 2007 40 7 993 1002 10.1590/s0100-879x2006005000110 2-s2.0-34547735947 17653454 \n2 Vet J. N. I. de Boer M. A. van den Akker B. E. W. M. Prevalence of human papillomavirus in Indonesia: a population-based study in three regions British Journal of Cancer 2008 99 1 214 218 10.1038/sj.bjc.6604417 2-s2.0-46349088823 18609756 \n3 Kreuter A. Potthoff A. Brockmeyer N. H. Anal carcinoma in human immunodeficiency virus-positive men: results of a prospective study from Germany British Journal of Dermatology 2010 162 6 1269 1277 10.1111/j.1365-2133.2010.09712.x 2-s2.0-77952737710 20184584 \n4 Ganguly N. Waller S. Stasik C. J. Skikne B. S. Ganguly S. Giant anal condylomatosis after allogeneic bone marrow transplantation: a rare complication of human papilloma virus infection Transplant Infectious Disease 2008 10 1 56 58 10.1111/j.1399-3062.2007.00233.x 2-s2.0-38649098122 17511821 \n5 Daneshpouy M. Socie G. Clavel C. Human papillomavirus infection and anogenital condyloma in bone marrow transplant recipient Transplantation 2001 71 1 167 169 10.1097/00007890-200101150-00030 2-s2.0-0035862983 11211188 \n6 Tam L.-S. Chan P. K. S. Ho S. C. Risk factors for squamous intraepithelial lesions in systemic lupus erythematosus: a prospective cohort study Arthritis Care & Research 2011 63 2 269 276 10.1002/acr.20367 2-s2.0-79551526879 20890985 \n7 Santana I. U. Gomes A. D. N. Lyrio L. D. Rios Grassi M. F. Santiago M. B. Systemic lupus erythematosus, human papillomavirus infection, cervical pre-malignant and malignant lesions: a systematic review Clinical Rheumatology 2011 30 5 665 672 10.1007/s10067-010-1606-0 2-s2.0-79959715790 21072553 \n8 Nath R. Mant C. Luxton J. High risk of human papillomavirus type 16 infections and of development of cervical squamous intraepithelial lesions in systemic lupus erythematosus patients Arthritis Care and Research 2007 57 4 619 625 10.1002/art.22667 2-s2.0-34248526065 17471531 \n9 Lube G. Aikawa N. E. Tacla M. Condyloma acuminatum by human papilloma virus infection in childhood-systemic lupus erythematosus patients Acta Reumatológica Portuguesa 2014 39 2 182 187 25111418 \n10 Costapinto L. Grassi M. F. R. Serravalle K. Travessa A. C. V. Olavarria V. N. O. Santiago M. B. Giant disseminated condylomatosis in SLE Lupus 2012 21 3 332 334 10.1177/0961203311421207 2-s2.0-84856762865 21965277 \n11 Thornsberry L. English J. C. III Evidence-based treatment and prevention of external genital warts in female pediatric and adolescent patients Journal of Pediatric and Adolescent Gynecology 2012 25 2 150 154 10.1016/j.jpag.2011.10.004 2-s2.0-84864331442 22530225 \n12 Hariri S. Unger E. R. Sternberg M. Prevalence of genital human papillomavirus among females in the United States, the National Health and Nutrition Examination Survey, 2003–2006 The Journal of Infectious Diseases 2011 204 4 566 573 10.1093/infdis/jir341 2-s2.0-79960882717 21791659 \n13 Martínez-Martínez M. U. Baranda-Cándido L. Abud-Mendoza C. Cutaneous papillomavirus infection in patients with rheumatoid arthritis or systemic lupus erythematosus. A case-control study Lupus 2013 22 9 948 952 10.1177/0961203313490431 2-s2.0-84880873237 23722231 \n14 Amador-Molina A. Hernández-Valencia J. F. Lamoyi E. Contreras-Paredes A. Lizano M. Role of innate immunity against human papillomavirus (HPV) infections and effect of adjuvants in promoting specific immune response Viruses 2013 5 11 2624 2642 10.3390/v5112624 2-s2.0-84887354774 24169630 \n15 Renoux V. M. Bisig B. Langers I. Human papillomavirus entry into NK cells requires CD16 expression and triggers cytotoxic activity and cytokine secretion European Journal of Immunology 2011 41 11 3240 3252 10.1002/eji.201141693 2-s2.0-80054887028 21830210 \n16 Henriques A. Teixeira L. Inês L. NK cells dysfunction in systemic lupus erythematosus: relation to disease activity Clinical Rheumatology 2013 32 6 805 813 10.1007/s10067-013-2176-8 2-s2.0-84879243720 23377197 \n17 Mendoza-Pinto C. Garcia-Carrasco M. Vallejo-Ruiz V. The impact of glucocorticoids and anti-cd20 therapy on cervical human papillomavirus infection risk in women with systemic lupus erythematosus Clinics 2013 68 12 1475 1480 10.6061/clinics/2013(12)01 2-s2.0-84892764295 24473503 \n18 Abud-Mendoza C. Cuevas-Orta E. Santillán-Guerrero E. N. Decreased blood levels of B lymphocytes and NK cells in patients with systemic lupus erythematosus (SLE) infected with papillomavirus (HPV) Archives of Dermatological Research 2013 305 2 117 123 10.1007/s00403-012-1258-9 2-s2.0-84878853078 22752509 \n19 Klumb E. M. Pinto A. C. Jesus G. R. Are women with lupus at higher risk of HPV infection? Lupus 2010 19 13 1485 1491 10.1177/0961203310372952 2-s2.0-78649243616 20605875 \n20 Katzung B. G. Basic and Clinical Pharmacology 2006 10th New York, NY, USA McGraw-Hill \n21 Maniar K. P. Ronnett B. M. Vang R. Yemelyanova A. Coexisting High-grade Vulvar Intraepithelial Neoplasia (VIN) and Condyloma Acuminatum: independent lesions due to different HPV types occurring in immunocompromised patients American Journal of Surgical Pathology 2013 37 1 53 60 10.1097/pas.0b013e318263cda6 2-s2.0-84871607240 23026935 \n22 Fairley C. K. Hocking J. S. Gurrin L. C. Chen M. Y. Donovan B. Bradshaw C. S. Rapid decline in presentations of genital warts after the implementation of a national quadrivalent human papillomavirus vaccination programme for young women Sexually Transmitted Infections 2009 85 7 499 502 10.1136/sti.2009.037788 2-s2.0-72449210177 19837728 \n23 Mok C. C. Ho L. Y. Fong L. S. To C. H. Immunogenicity and safety of a quadrivalent human papillomavirus vaccine in patients with systemic lupus erythematosus: a case-control study Annals of the Rheumatic Diseases 2013 72 5 659 664 10.1136/annrheumdis-2012-201393 2-s2.0-84875956929 22589375 \n24 Aubin F. Martin M. Puzenat E. Genital human Papillomavirus infection in patients with autoimmune inflammatory diseases Joint Bone Spine 2011 78 5 460 465 10.1016/j.jbspin.2011.03.002 2-s2.0-80053455264 21570889\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6617",
"issue": "2016()",
"journal": "Case reports in immunology",
"keywords": null,
"medline_ta": "Case Reports Immunol",
"mesh_terms": null,
"nlm_unique_id": "101622188",
"other_id": null,
"pages": "4710979",
"pmc": null,
"pmid": "27843658",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": "20605875;21791659;18609756;24473503;17653454;21072553;21570889;17511821;19837728;23377197;24169630;23722231;11211188;25111418;21965277;20890985;17471531;22589375;22530225;20184584;22752509;23026935;21830210",
"title": "Giant Condyloma Acuminata in Indonesian Females with SLE under Immunosuppressant and Steroid Therapy.",
"title_normalized": "giant condyloma acuminata in indonesian females with sle under immunosuppressant and steroid therapy"
} | [
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"companynumb": "ID-JUBILANT CADISTA PHARMACEUTICALS-2016JUB00440",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "METHYLPREDNISOLONE"
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... |
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"abstract": "BACKGROUND\nThe administration of abiraterone acetate (abiraterone) leads to an adrenocorticotropic hormone (ACTH)-driven increase in mineralocorticoid hormones, requiring glucocorticoid supplementation that may stimulate the growth of prostate cancer (PCa). Amiloride is a drug that selectively reduces the aldosterone-sensitive Na+/K+ exchange and could be effective in the management of mineralocorticoid excess syndrome (MCES).\n\n\nMETHODS\nThe efficacy of amiloride + hydrochlorothiazide (HCT) in the clinical management of abiraterone-induced MCES was assessed in 5 consecutive patients with castration-resistant PCa (CRPC). Then, using the in vitro experimental model of PCa cell lines, the possible effects of drugs usually used in the clinical management of CRPC patients on PCa cell viability were investigated.\n\n\nRESULTS\nAmiloride/HCT led to a complete disappearance of all clinical and biochemical signs of abiraterone-induced MCES in the 5 treated patients. The in vitro study showed that abiraterone treatment significantly decreased cell viability of both androgen receptor (AR)-expressing VCaP (vertebral-cancer of the prostate) and LNCaP (lymph node carcinoma of the prostate) cells, with no effect on AR-negative PC-3 cells. Prednisolone, spironolactone, and eplerenone increased LNCaP cell viability, while amiloride reduced it. The non-steroid aldosterone antagonist PF-03882845 did not modify PCa cell viability.\n\n\nCONCLUSIONS\nThe combination of amiloride/HCT was effective in the management of abiraterone-induced MCES. Amiloride did not negatively interfere with the abiraterone inhibition of PCa cell viability in vitro.",
"affiliations": "Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.",
"authors": "Bedussi|Francesca|F|;Galli|Diego|D|;Fragni|Martina|M|;Valcamonico|Francesca|F|;Rossini|Elisa|E|;Dalla Volta|Alberto|A|;Vezzoli|Sara|S|;Roca|Elisa|E|;Ferrari|Vittorio|V|;Lazzari|Barbara|B|;Memo|Maurizio|M|;Sigala|Sandra|S|;Berruti|Alfredo|A|",
"chemical_list": "D000728:Androgens; D000736:Androstenes; D000970:Antineoplastic Agents; D004338:Drug Combinations; D008901:Mineralocorticoids; D006852:Hydrochlorothiazide; C010247:amiloride, hydrochlorothiazide drug combination; D000584:Amiloride; C089740:abiraterone",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000477547",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-7012",
"issue": "100(5-6)",
"journal": "Pharmacology",
"keywords": "Abiraterone; Amiloride; Mineralocorticoid excess syndrome",
"medline_ta": "Pharmacology",
"mesh_terms": "D000584:Amiloride; D000728:Androgens; D000736:Androstenes; D000970:Antineoplastic Agents; D045744:Cell Line, Tumor; D002470:Cell Survival; D004338:Drug Combinations; D006801:Humans; D006852:Hydrochlorothiazide; D008297:Male; D043204:Mineralocorticoid Excess Syndrome, Apparent; D008901:Mineralocorticoids; D011471:Prostatic Neoplasms",
"nlm_unique_id": "0152016",
"other_id": null,
"pages": "261-268",
"pmc": null,
"pmid": "28797006",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Amiloride Is Effective in the Management of Abiraterone-Induced Mineralocorticoid Excess Syndrome without Interfering with Its Antineoplastic Activity.",
"title_normalized": "amiloride is effective in the management of abiraterone induced mineralocorticoid excess syndrome without interfering with its antineoplastic activity"
} | [
{
"companynumb": "IT-MYLANLABS-2018M1007728",
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"abstract": "Results of high-dose chemotherapy (HDCT) protocols for the management of malignant central nervous system (CNS) tumors in infants are mostly reported in high-income countries. We evaluated the feasibility and results of such protocols in a middle-income country (Jordan).\n\n\n\nA retrospective study of infants' charts with CNS tumors between 2006 and 2015 who were treated according to HeadStart (HS) protocols. Data included patients' demographics, chemotherapy complications, and cost.\n\n\n\nWe identified 18 patients with median age 29 months (range, 9-62 months) at diagnosis (12 HS-I and six HS-II). Distribution according to pathology was: atypical teratoid rhabdoid tumors (ATRT) (nine), primitive neuoroectodermal tumors (PNET)/pineoblastoma (five), and medulloblastoma (four). Six patients (33%) had metastatic disease, and 14 (78%) had an incomplete resection. Eleven patients achieved partial or complete remission, two stabilized, and five progressed. Ten patients did not proceed to HDCT due to progression (five), financial reasons (two), failure to collect stem cells (one), and undocumented reasons (two). Seventy-eight chemotherapy cycles were administered (median interval 26 days). Main complications during induction and consolidation were febrile neutropenia (73% and 100%), documented infections (8% and 13%), and mucositis (12% and 88%), respectively. Three patients developed moderate hearing loss. No protocol-related mortality was reported. At the last follow-up, five patients were alive: three with medulloblastoma (19, 29, and 89 months) and two with ATRT (18 and 42 months). Three survivors received focal/craniospinal radiation. The median cost of a complete HS protocol, excluding surgery/radiotherapy, was $103 500 per patient; 39% of the median cost was related to pharmacy expenses.\n\n\n\nThese protocols were manageable in our context of limited health care resources. However, considering the significant costs and the modest survival rate, better selection criteria need to be used to identify patients likely to benefit from this approach.",
"affiliations": "Division of Pediatric Hematology/Oncology, King Hussein Cancer Center, Amman, Jordan.;Pediatric Stem Cell Transplantation Unit, King Hussein Cancer Center, Amman, Jordan.;Division of Pediatric Hematology/Oncology, King Hussein Cancer Center, Amman, Jordan.;Division of Pediatric Hematology/Oncology, King Hussein Cancer Center, Amman, Jordan.;Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Canada.;Division of Pediatric Hematology/Oncology, King Hussein Cancer Center, Amman, Jordan.",
"authors": "Elshahoubi|Alya|A|0000-0002-7435-6291;Khattab|Eman|E|;Halalsheh|Hadeel|H|0000-0003-4803-1976;Khaleifeh|Kawther|K|;Bouffet|Eric|E|;Amayiri|Nisreen|N|0000-0002-7972-5885",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.27464",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "66(1)",
"journal": "Pediatric blood & cancer",
"keywords": "HeadStart protocols; feasibility; low middle income country; value",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D016543:Central Nervous System Neoplasms; D002675:Child, Preschool; D003906:Developing Countries; D005240:Feasibility Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007182:Income; D060828:Induction Chemotherapy; D007223:Infant; D008297:Male; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e27464",
"pmc": null,
"pmid": "30251335",
"pubdate": "2019-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Feasibility of high-dose chemotherapy protocols to treat infants with malignant central nervous system tumors: Experience from a middle-income country.",
"title_normalized": "feasibility of high dose chemotherapy protocols to treat infants with malignant central nervous system tumors experience from a middle income country"
} | [
{
"companynumb": "JO-ADIENNEP-2019AD000014",
"fulfillexpeditecriteria": "1",
"occurcountry": "JO",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": "3",
... |
{
"abstract": "Anti-tumor necrosis factor alpha (anti-TNF) therapy is a standard of care in the management of many inflammatory conditions. However, anti-TNF pharmaceuticals increases the risk of reactivating tuberculosis making screening for latent tuberculosis infection (LTBI) a requirement prior to initiating therapy.\n\n\nMETHODS\nA middle-aged male from China with a past medical history of LTBI and Crohn's disease, previously on infliximab, presented to the United States for a second opinion on his abdominal pain. He also reported new onset visual changes. Ophthalmology evaluation revealed a 4 cm choroid mass of his left eye and a CT scan of the abdomen showed diffuse lymphadenopathy and lesions in his liver, spleen, and lung. He was admitted for treatment of miliary tuberculosis.\n\n\nCONCLUSIONS\nImmunocompromised patients are a unique population that brings challenges to LTBI testing.\n\n\nCONCLUSIONS\nClinicians should know the most up to date screening tools for LTBI and diagnostic workup for active tuberculosis infection.",
"affiliations": "Mayo Clinic Florida Department of Internal Medicine, 4500 San Pablo Rd. South, Jacksonville, FL 32224, USA.;Department of Infectious Disease, 4500 San Pablo Rd. South, Jacksonville, FL 32224, USA.;Department of Hospital Medicine, 4500 San Pablo Rd. South, Jacksonville, FL 32224, USA.",
"authors": "Kase|Adam M|AM|;Libertin|Claudia R|CR|;Roy|Archana|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.jctube.2018.10.002",
"fulltext": "\n==== Front\nJ Clin Tuberc Other Mycobact DisJ Clin Tuberc Other Mycobact DisJournal of Clinical Tuberculosis and Other Mycobacterial Diseases2405-5794Elsevier S2405-5794(18)30059-710.1016/j.jctube.2018.10.002ArticleMiliary tuberculosis presenting as a choroidal mass and a tuberculosis screening review Kase Adam M. kase.adam@mayo.edua⁎Libertin Claudia R. bRoy Archana ca Mayo Clinic Florida Department of Internal Medicine, 4500 San Pablo Rd. South, Jacksonville, FL 32224, USAb Department of Infectious Disease, 4500 San Pablo Rd. South, Jacksonville, FL 32224, USAc Department of Hospital Medicine, 4500 San Pablo Rd. South, Jacksonville, FL 32224, USA⁎ Correspondence author. kase.adam@mayo.edu11 10 2018 12 2018 11 10 2018 13 13 16 1 8 2018 9 10 2018 10 10 2018 © 2018 The Authors. Published by Elsevier Ltd.2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Anti-tumor necrosis factor alpha (anti-TNF) therapy is a standard of care in the management of many inflammatory conditions. However, anti-TNF pharmaceuticals increases the risk of reactivating tuberculosis making screening for latent tuberculosis infection (LTBI) a requirement prior to initiating therapy. Case: A middle-aged male from China with a past medical history of LTBI and Crohn's disease, previously on infliximab, presented to the United States for a second opinion on his abdominal pain. He also reported new onset visual changes. Ophthalmology evaluation revealed a 4 cm choroid mass of his left eye and a CT scan of the abdomen showed diffuse lymphadenopathy and lesions in his liver, spleen, and lung. He was admitted for treatment of miliary tuberculosis. Discussion: Immunocompromised patients are a unique population that brings challenges to LTBI testing. Conclusion: Clinicians should know the most up to date screening tools for LTBI and diagnostic workup for active tuberculosis infection.\n\nKeywords\nMiliary tuberculosisChoroidal massIGRA\n==== Body\n1 Introduction\nMycobacterium tuberculosis (TB) is a worldwide trepidation with about one third of the world's population being infected. The incidence of TB in the United States is 3.0 cases per 100,000 with 9,563 cases being reported in the U.S. for the year of 2015 [1]. There is a growing number of patients being treated with immunomodulators which increases their risk for latent tuberculosis infection (LTBI) activation. Anti-tumor necrosis factor alpha (anti-TNF) pharmaceuticals have shown significant success in multiple inflammatory disorders. These anti-TNF therapies increase risk of infection or reactivation of LTBI. Therefore, appropriate screening for latent and active tuberculosis is essential prior to initiation of anti-TNF therapy.\n\n2 Case description\nA middle-aged Chinese male with a known history of Crohn's disease was treated with nine doses of infliximab in China. He presented to the United States for a second opinion regarding his persistent abdominal pain. In China, his inflammatory bowel disease had resolved and was confirmed by colonoscopy, He had been started on azathioprine, but his symptoms worsened. Repeat colonoscopy showed recurrence of Crohn's disease. He was restarted on infliximab and the patient received four doses. Follow up colonoscopy revealed improvement in colonic mucosa on biopsy but again no resolution of his abdominal pain. He then noticed blurring of vision in the left eye which progressively worsened to loss of vision. Over a month period, his right eye developed visual changes. An ophthalmologist diagnosed a 4 cm choroid mass in the left eye and a normal right eye examination (Fig. 1A). Infliximab was discontinued and anti-tubercular treatment with ethambutol, isoniazid, rifampin and pyrazinamide was initiated in China. After two months of anti-tubercular therapy, he had clinical improvement of his abdominal symptoms, a decrease in size of the left eye choroid mass, and stabilization of his vision loss.Fig. 1 (A) White choroidal mass, left eye. (B) Micronodule left lung base. (C) Diffuse bowel wall thickening. (D) Liver, Kidney and splenic lesions.\n\nFig. 1.\n\nThe patient sought a second opinion regarding Crohn's disease vs. intestinal tuberculosis at our institution. Computed tomography (CT) scans of the chest and abdomen showed multiple subcentimeter lesions in liver, spleen, lung, 4.5 cm mass on pole of left kidney and many subcentimeter lesions in both kidneys, diffuse colitis, hilar and mediastinal lymphadenopathy consistent with miliary tuberculosis (Fig. 1B–D). The patient was admitted to the hospital for further evaluation and treatment for miliary tuberculosis.\n\n3 Discussion\nThis case describes a rare and life threatening complication, primary miliary TB, which presented as an eye choroidal mass after infliximab therapy. Miliary TB is an uncontrolled hematogenous spread of mycobacterium infection. Primary infection could involve multi-organ systems such as lung, liver, spleen, kidney, eye, and intestine, as in our case. The term miliary describes many tiny lesions that resemble small millet seeds. These tiny nodules can easily be missed on chest X-ray as 25–40% of cases have a normal chest x-ray early in the course [1]. In Western countries, the risk of TB reactivation while on infliximab for inflammatory bowel disease is low (0.52%), due to low prevalence of TB in these areas [2]. However, depending on the prevalence of TB in one's country and TNF antagonist used, the relative risk is increased up to 25 times; therefore, appropriate screening and exclusion of active TB is necessary before initiation of infliximab or any immunosuppressant agent [3].\n\nIndividuals who may be at higher risk of reactivating tuberculosis should be tested for latent tuberculosis infection (Fig. 2). These individuals include: health-care workers, previous exposure to someone with active TB disease, individuals from countries where TB is endemic (Asia, Africa, and Latin-America), and high risk settings (nursing homes, prisons, and homeless shelters). The two methods of screening for LTBI include the tuberculin skin test (TST) and Interferon-Gamma Release Assay (IGRAs). The TST and IGRAs provide data to the provider as to if the patient has been exposed to tuberculosis in the past or not. Neither provides information as to whether TB is in latency or active causing disease [4].Fig. 2 Latent tuberculosis infection screening algorithm for immunocompetent patients likely to be infected.\n\nFig. 2.\n\nThe TST was developed in the early 1900′s by Von Pirquet and Mantoux. By inoculating individuals with a purified protein derivative (PPD) a delayed type hypersensitivity reaction ensues as a result of the host's adaptive immunity. The interpretation of the result is structured by the host's response (induration diameter, not to be confused with erythema) and the risk stratification of the patient. A limitation to this screening modality is the test must be read in 48–72 h after inoculation, requiring the patient to return at a later date to be read by trained healthcare personnel. TST is considered positive when an induration diameter of 5 or more millimeters is reached for patients who are likely to be infected and high risk of progression including: HIV infected persons, a recent contact of a person with tuberculosis disease, patients with organ transplants, or persons who are immunosuppressed; 10 or more millimeters for patients who are likely to be infected and have low to intermediate risk of progression which includes recent immigrants (< 5 years) from high prevalence countries, intravenous drug users, and healthcare workers [5].\n\nAfter nearly a century, a new screening test, IGRA, for latent tuberculosis was approved by the FDA in 2001. The IGRAs detect sensitization to mycobacterium tuberculosis by measuring the interferon-γ release in response to antigens representing mycobacterium tuberculosis [6]. Since the first approval of the first IGRA, multiple generations of IGRAs have been approved with the two most widely available including the QuantiFERON-TB Gold-in-Tube (QFT-GIT) and T-SPOT TB test, approved in 2007 and 2008 respectively. The benefits of this screening modality includes: only one office visit required, results available in approximately 24 h, and the test may be used in individuals who have been previously vaccinated with BCG.\n\nPatients who are immunosuppressed or who will initiate anti-TNF therapy are a unique population that brings about challenges to LTBI screening. Exposure to immunosuppressive therapy, such as anti-TNF and corticosteroids in inflammatory bowel disease patients, may cause false negative TST and QuantiFERON-TB in up to 30% of patients [7]. Screening should be initiated with a chest X-ray to determine if there are any abnormal TB-related findings such as cavitary or fibrotic lesions. If such lesions are found further work-up for active TB should be initiated and determine if appropriate LTBI treatment was completed. A normal chest x-ray should be followed by testing with IGRA testing [8]. There is currently not a good screening test for LTBI testing in patients with autoimmune inflammatory disease. The performance data in this group is limited [9]. Because of these high false negative results, some experts recommend a dual testing approach for patients on anti-TNF therapy to increase sensitivity by performing both TST and IGRA (Fig. 3). This dual screening may also be used for patients prior to initiating anti-TNF therapy in order to decrease false negative results [6], [8]. If any of the LTBI screening modalities are positive then the patient is considered to have LTBI and warrant further testing to exclude active infection (Fig. 4). Extrapulmonary TB and disseminated TB are common presentations of reactivated TB after anti-TNF therapy. If clinical suspicion is high, then anti-TNF therapy should be discontinued and anti-tuberculosis therapy should be initiated without waiting for culture or biopsy results. These patients do not have typical signs and symptoms of pulmonary TB.Fig. 3 Latent tuberculosis infection screening algorithm prior to initiated anti-TNF therapy.\n\nFig. 3.Fig. 4 Algorithm after positive latent tuberculosis testing.\n\nFig. 4.\n\nTST and IGRA screening modalities are just that, screening tests to determine if the individual has been infected with tuberculosis. These tests do not provide information as to the status of the infection, i.e. latent or active disease. All individuals with either positive TST or IGRA test without prior anti-tuberculosis therapy must undergo evaluation to determine the status of the infection. The next step in this clinical scenario would be to exclude active TB infection (Fig. 5) [11]. In order to exclude active TB, a chest x-ray is indicated. If the CXR is normal, no sputum cultures are indicated. If the CXR shows radiographic changes that could be consistent with a granulomatous disease, three sputum samples for acid fast bacilli smear microscopy on three different days with sputum cultures need to be obtained. Nucleic acid amplification testing of AFB smear positive specimens, if feasible, should be completed. Of course, the patient must be masked in public areas until results are known. Obtaining three sputum samples daily for three days increases the sensitivity and is the standard in the United States [10]. Because the AFB smear microscopy is known to have poor sensitivity (45–80%) it should be used with nucleic acid amplification test (NAAT) which can confirm positive mycobacterium TB in 50–80% of AFB negative specimens. Other benefits of NAAT include: a positive predictive value of >95% with AFB positive samples compared to a positive predictive value of 50–80% for AFB smear microscopy [12]. Interpreting the NAA testing results should be done in conjunction with the AFB smear microscopy results (Fig. 5) [11]. Despite the benefits that NAAT offers, its sensitivity is not optimum to exclude active tuberculosis in patients with AFB negative smears; only 50–80% of AFB smear-negative specimens that are culture positive are detected [11]. In the end, sputum culture remains the gold standard.Fig. 5 Algorithm to rule out active tuberculosis infection.\n\nFig. 5.\n\nIn conclusion, we present a patient from a highly endemic area for TB who received anti-TNF therapy in absence of exclusion of TB infection, not to mention the determination if he had latent or active disease. This case demonstrated the importance that all patients should be screened for TB prior to the initiation of anti-TNF therapy or immunosuppressive therapy. Once receiving anti-TNF therapy, patients should be monitored closely for signs and symptoms of active TB.\n\n4 Conflicts of interest\nThe authors declare that there are no conflicts of interest regarding publication of this paper.\n==== Refs\nReferences\n1 Bhalla AS Goyal A Guleria R Gupta AK Chest tuberculosis: Radiological review and imaging recommendations Indian J Radiol Imaging 25 3 2015 213 225 26288514 \n2 Wang Q Wen Z Cao Q Risk of tuberculosis during infliximab therapy for inflammatory bowel disease, rheumatoid arthritis, and spondyloarthropathy: a meta-analysis Exp Ther Med 12 3 2016 1693 1704 27588089 \n3 Solovic I Sester M Gomez-Reino JJ Rieder HL Ehlers S Milburn HJ The risk of tuberculosis related to tumour necrosis factor antagonist therapies: a TBNET consensus statement Eur Respir J 36 5 2010 1185 1206 Nov 20530046 \n4 CDC. Tuberculosis. https://www.cdc.gov/tb/publications/ltbi/diagnosis.htm.\n5 CDC Targeted tuberculin testing and treatment of latent tuberculosis infection MMWR 49 2000 (No. RR-6. www.cdc.gov/MMWR/PDF/rr/rr4906.pdf \n6 CDC Updated Guidelines for using Interferon Gamma Release Assays to detect Mycobacterium tuberculosis infection MMWR 59 2010 (No.RR-5. www.cdc.gov/MMWR/pdf/rr/rr5905.pdf \n7 Wang Q Wen Z Cao Q Risk of tuberculosis during infliximab therapy for inflammatory bowel disease, rheumatoid arthritis, and spondyloarthropathy: A meta-analysis Exp Ther Med 12 3 2016 1693 1704 27588089 \n8 Shim TS Diagnosis and treatment of latent tuberculosis infection due to initiation of anti-TNF therapy Tuberc Respir Dis (Seoul) 76 2014 261 268 25024719 \n9 Hsia Elizabeth Schluger Neil Cush JohnJ Interferon-gamma release assay versus tuberculin skin test prior to treatment with golimumab, a human anti-tumor necrosis factor antibody, in patients with rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis Arthritis Rheum 64 7 2012 2068 2077 July 22238071 \n10 Lewinsohn David M. Michael K. Leonard Philip A. LoBue et al. Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and Children. Clin Infect Dis 64 2 2017 111 115 28052967 \n11 CDC Updated Guidelines for the Use of Nucleic Acid Amplification Tests in the Diagnosis of Tuberculosis. MMWR 58 01 2009 7 10 19145221 \n12 Dinnes J Deeks J Kunst H A systematic review of rapid diagnostic tests for the detection of tuberculosis infection Health Technol Assess 11 2007 1 196\n\n",
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"issue": "13()",
"journal": "Journal of clinical tuberculosis and other mycobacterial diseases",
"keywords": "Choroidal mass; IGRA; Miliary tuberculosis",
"medline_ta": "J Clin Tuberc Other Mycobact Dis",
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"nlm_unique_id": "101682877",
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"title": "Miliary tuberculosis presenting as a choroidal mass and a tuberculosis screening review.",
"title_normalized": "miliary tuberculosis presenting as a choroidal mass and a tuberculosis screening review"
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"abstract": "METHODS\nThe cases are presented of two patients with periocular basal cell carcinoma of the eyelid who received topical imiquimod 5%, with a good response. Both had a functional state that contraindicated surgical treatment.\n\n\nCONCLUSIONS\nImiquimod cream 5% was shown to be an effective alternative to surgical treatment of periocular basal cell carcinoma, especially in those cases where surgery is not possible.",
"affiliations": "Servicio de Oftalmología, Hospital Universitario Central de Asturias, Oviedo, Asturias, España. Electronic address: m.c.c.a.carmen@gmail.com.;Servicio de Oftalmología, Hospital Universitario Central de Asturias, Oviedo, Asturias, España.;Servicio de Oftalmología, Hospital Universitario Central de Asturias, Oviedo, Asturias, España.;Servicio de Oftalmología, Hospital Universitario Central de Asturias, Oviedo, Asturias, España.;Servicio de Oftalmología, Hospital Universitario Central de Asturias, Oviedo, Asturias, España.",
"authors": "Costales-Álvarez|C|C|;Álvarez-Coronado|M|M|;Rozas-Reyes|P|P|;González-Rodríguez|C M|CM|;Fernández-Vega|L|L|",
"chemical_list": "D000634:Aminoquinolines; D000970:Antineoplastic Agents; D000077271:Imiquimod",
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"issue": "92(2)",
"journal": "Archivos de la Sociedad Espanola de Oftalmologia",
"keywords": "Basal cell carcinoma; Carcinoma basocelular; Casos desfavorables; Imiquimod; Periocular tumors; Topical treatment; Tratamiento tópico; Tumores perioculares; Unfavourable cases",
"medline_ta": "Arch Soc Esp Oftalmol",
"mesh_terms": "D000163:Acquired Immunodeficiency Syndrome; D000634:Aminoquinolines; D000970:Antineoplastic Agents; D002280:Carcinoma, Basal Cell; D000075204:Contraindications, Procedure; D005142:Eyelid Neoplasms; D039682:HIV-Associated Lipodystrophy Syndrome; D006801:Humans; D000077271:Imiquimod; D008297:Male; D008875:Middle Aged; D019651:Reconstructive Surgical Procedures; D012074:Remission Induction; D012883:Skin Ulcer; D013524:Surgical Flaps",
"nlm_unique_id": "1304603",
"other_id": null,
"pages": "93-96",
"pmc": null,
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"pubdate": "2017-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Topical imiquimod 5% as an alternative therapy in periocular basal cell carcinoma in two patients with surgical contraindication.",
"title_normalized": "topical imiquimod 5 as an alternative therapy in periocular basal cell carcinoma in two patients with surgical contraindication"
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"abstract": "Methylene blue is an intravenously administered agent that may potentiate serotonin syndrome. The usage of methylene blue to evaluate ureters for injuries and patency during urological surgeries is recognized as common practice. However, there is no mention of serotonin syndrome caused by methylene blue in urological literature or for urological surgery. We report the first urological case in order to raise awareness of the risk for serotonin toxicity with utilizing methylene blue.",
"affiliations": "Stony Brook Medicine, 101 Nicolls Road, Stony Brook, NY 11794, USA.;Stony Brook Medicine, Department of Urology, 101 Nicolls Road, Stony Brook, NY 11794, USA.;Stony Brook Medicine, Department of Urology, 101 Nicolls Road, Stony Brook, NY 11794, USA.;Stony Brook Medicine, Department of Anesthesiology, 101 Nicolls Road, Stony Brook, NY 11794, USA.;Stony Brook Medicine, Department of Anesthesiology, 101 Nicolls Road, Stony Brook, NY 11794, USA.;Stony Brook Medicine, Department of Urology, 101 Nicolls Road, Stony Brook, NY 11794, USA.",
"authors": "Kapadia|Kailash|K|;Cheung|Felix|F|;Lee|Wai|W|;Thalappillil|Richard|R|;Florence|F Barry|FB|;Kim|Jason|J|",
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"doi": "10.1016/j.eucr.2016.07.012",
"fulltext": "\n==== Front\nUrol Case RepUrol Case RepUrology Case Reports2214-4420Elsevier S2214-4420(16)30089-410.1016/j.eucr.2016.07.012Functional MedicineMethylene Blue Causing Serotonin Syndrome Following Cystocele Repair Kapadia Kailash kailash.kapadia@stonybrookmedicine.edua∗Cheung Felix bLee Wai bThalappillil Richard cFlorence F. Barry cKim Jason ba Stony Brook Medicine, 101 Nicolls Road, Stony Brook, NY 11794, USAb Stony Brook Medicine, Department of Urology, 101 Nicolls Road, Stony Brook, NY 11794, USAc Stony Brook Medicine, Department of Anesthesiology, 101 Nicolls Road, Stony Brook, NY 11794, USA∗ Corresponding author. kailash.kapadia@stonybrookmedicine.edu30 8 2016 11 2016 30 8 2016 9 15 17 23 7 2016 27 7 2016 © 2016 The Authors2016This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Methylene blue is an intravenously administered agent that may potentiate serotonin syndrome. The usage of methylene blue to evaluate ureters for injuries and patency during urological surgeries is recognized as common practice. However, there is no mention of serotonin syndrome caused by methylene blue in urological literature or for urological surgery. We report the first urological case in order to raise awareness of the risk for serotonin toxicity with utilizing methylene blue.\n\nKeywords\nMethylene blueSerotonin syndromeCystocele repair\n==== Body\nIntroduction\nSerotonin syndrome (SS) results from high levels of serotonin within the nervous system causing a range of symptoms from mild to life-threatening. Most commonly seen medications that may induce SS include selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) in combination with monoamine oxidase inhibitors (MAOIs).1 The three hallmark signs of SS include altered mental status, hyperactive automaticity, and abnormal neuromuscular function.1 Two common criteria used in literature are the Sternbach's criteria and the Hunter's Serotonin Toxicity criteria (Table 1).\n\nCase presentation\nA 74-year-old woman with past medical history notable for Parkinson's disease, depression, anxiety, and pelvic organ prolapse presented with cystocele (Table 2). She was scheduled for repeat cystocele repair, due to worsening of incontinence and pelvic organ prolapse. Her current medications consisted of Ropinirole for her restless leg syndrome, as well as Fluoxetine (SSRI) and Duloxetine (SNRI) for depression and anxiety. At baseline, the patient was alert and oriented with normal mental status.\n\nThe patient underwent general anesthesia (Table 3). There was successful reduction of a large cystocele with cadaveric fascia without any surgical complications. 100 mg of 1% MB was administered at the beginning of the procedure to rule out potential vesical–ureteral injury. Cystoscopy did not demonstrate any injuries and blue-tinged ureteral jets were visualized from both ureteral orifices.\n\nApproximately 1 h post-operatively the patient became agitated and tachycardic to 108 bpm. She was unable to express herself and had uncontrollable movements of all four limbs. She was given her Parkinson's medications, Stalevo® and Ropinirole. Bladder scan demonstrated 450 cc residual urine and a foley catheter was placed. Urinalysis and urine culture were obtained. The patient was transferred to the main hospital emergency room and neurology was consulted.\n\nFive hours post-operatively the patient's heart rate remained elevated along with a mild elevation in temperature (37.6 °C). She was nonverbal with hyperactive delirium. Labs demonstrated elevated AST (44 IU/L) and CPK levels (556 IU/L); critically low lactic acid (4.7 mmol/L); and leukocytosis (17.8 K/μL). She was started on empiric antibiotics, IV fluids, and benzodiazepines for agitation. Head CAT scan and chest X-ray were normal. On neurologic exam, the patient was obtunded and dysarthric with restlessness in all extremities. Reflexes were normal and coordination was unable to be assessed.\n\nThe patient was transferred to the medical intensive care unit. She gradually improved with supportive care over the course of the next 2 days with normalization of her AST and CPK. CPK elevation was presumed to be elevated from agitation. Suspicion for SS was based on the patient being on a serotonergic agent and presentation of altered mental status, agitation, diaphoresis, hyperthermia, and hypertonia. This met Sternbach's criteria for SS (Table 1). Benzodiazepines were discontinued and all anti-psychotic medications were held.\n\nThe following day her mental status improved. Her fever and leukocytosis resolved. Urine culture was negative. Foley catheter was removed and the patient was able to void without difficulty. She was downgraded to regular floor bed and the remainder of the hospital course was uneventful. The patient was discharged on hospital day 7 to a rehabilitation facility.\n\nDiscussion\nMethylene blue (MB) is a MAOI utilized during surgical procedures as a dye or vasopressor demonstrated in the literature to cause SS in high risk patients. The primary risk factor is present use of serotonergic medications. Age is an independent risk factor as elderly patients are more likely to be on anti-depressant medications.2 There are 31 cases of SS reported in literature following MB administration during parathyroidectomies used for visualization of parathyroid tissue.3 There are also cases reported after cardiac surgery where MB is used to treat vasoplegic syndrome.4 While most cases resolve, Top et al reports a fatal case of SS.5 In 2011 the FDA issued a warning regarding the use of MB in patients on psychiatric medications, however incidences of SS continue to appear in literature.6, 7 MB is also used during pelvic and abdominal surgeries to identify potential injury to the ureters or bladder.8 However, only two of these cases were reported and there was no case specific to urology.9, 10\n\nThe diagnosis of SS was evaluated with Sternbach's and Hunter's criteria (Table 1). Our patient was at risk due to her serotonergic medications: fluoxetine and duloxetine. She presented with four clinical features of serotonin toxicity: mental status change (restlessness and confusion), agitation, diaphoresis, and fever. This met Sternbach's criteria, which only required three. Other etiologies such as malignant hyperthermia (MH), neuroleptic malignant syndrome (NMS), and infection were ruled out. She did not meet Hunter's criteria though, which emphasized the presence of clonus.1 Whereas Hunter's criteria had better sensitivity than Sternbach's criteria (84% vs 75%), they have similar specificity (97% and 96% respectively). The high specificity of both criteria yields a high positive predictive value, hence a low false positive rate.\n\nEvaluation of ureteral patency, injury, or identifying the ureteral orifices is common practice during urological surgeries according to the American Urological Association guidelines.11 Urologists often times use marker dyes to identify ureteral injuries, and MB should be used with caution. Other options include indocyanine green and indigo carmine. However, indocyanine green has not been studied for cystoscopy and indigo carmine is no longer readily available due to national supply shortages.12 There have been recent studies looking at alternatives for intraoperative cystoscopy. Phenazopyridine (given orally preoperatively) and sodium fluorescein are other agents used to visualize bilateral ureteral jets.13\n\nConclusion\nThe shortage of indigo carmine has increased the usage of alternatives including MB in urology, which in tandem with the increase in patients on psychiatric mediations, heightens the risk of SS. It is therefore important to raise awareness about this drug interaction within the urological field. It is strongly recommended that physicians take the necessary precautions before utilizing MB on patients on serotonergic medications.\n\nConflict of interest\nThe authors of this case report declare that they have nothing to disclose and no conflict of interests. No outside financial support was received for the preparation of this case report.\n\nTable 1 Diagnostic criteria for serotonin syndrome1\n\nTable 1Sternbach's criteria\tHunter's criteria\t\n1. Patient on serotonergic agent\n\n2. Absence of other causes or etiologies\n\n3. No current use of neuroleptic agent\n\n4. Presence of three of the following:• Mental status change (confusion, hypomania, restlessness, ataxia)\n\n• Agitation\n\n• Myoclonus\n\n• Hyperreflexia\n\n• Diaphoresis\n\n• Shivering\n\n• Tremor\n\n• Diarrhea\n\n• Incoordination\n\n• Fever\n\n\n\n\t1. Patient on serotonergic agent\n\n2. Presence of any of the following:• Spontaneous clonus\n\n• Inducible clonus AND agitation OR diaphoresis\n\n• Ocular clonus AND agitation OR diaphoresis\n\n• Tremor AND hyperreflexia\n\n• Hypertonic AND hyperthermia (>38 °C) AND ocular clonus OR inducible clonus\n\n\n\n\t\nTable 2 Patient history\n\nTable 2Past medical history\tPast surgical history\tHome medications\t\n• Anxiety\n\n• Asthma\n\n• Cystocele\n\n• Depression\n\n• Gastroesophageal Reflux Disease (GERD)\n\n• Gout\n\n• Hypothyroidism\n\n• Hypertension\n\n• Hyperlipidemia\n\n• Incontinence (urinary, stress, urge)\n\n• Nocturia\n\n• Obesity\n\n• Osteoporosis\n\n• Parkinson's\n\n• Obstructive sleep apnea\n\n• Uterovaginal prolapse\n\n\t• Cystocele repair\n\n• Cystoscopy\n\n• Interstim\n\n• Hip replacement\n\n• Hiatal hernia repair\n\n• Abdominoplasty\n\n• Knee replacement\n\n• Total abdominal hysterectomy\n\n• Tonsillectomy/adenoidectomy\n\n\t• Allopurinol 100 mg\n\n• Ascorbic acid 500 mg Q24H\n\n• Aspirin 81 mg Q24H\n\n• Carbidopa/entacapone/levodopa QID (Stalevo)\n\n• Diclofenac topical BID, PRN for pain\n\n• Duloxetine 60 mg Q24Ha\n\n• Ergocalciferol\n\n• Estradiol 1 mg Q24H\n\n• Fluoxetine 10 mg Q24Ha\n\n• Furosemide\n\n• Levocetirizine 5 mg\n\n• Levothyroxine 75 mcg Q24H\n\n• Lisinopril 20 mg Q24H\n\n• Multivitamin Q24H\n\n• Olopatadine nasal BID\n\n• Omeprazole 40 mg Q24H\n\n• Potassium chloride 10 mEq BID\n\n• Ropinirole TID\n\n• Rosuvastatin Q48H\n\n• Ubiquinone 300 mg Q24H\n\n\t\na Warning for serotonin syndrome.\n\nTable 3 General anesthesia course during cystocele repair\n\nTable 3Midazolam 1 mg/mL INJ IV Push\t1 mg\t\nFentanyl 50 mcg/mL IV Pusha\t25 mcg\t\nPropofol 10 mg/mL INJ IV Push\t150 mg\t\nPropofol 20 mg/mL INJ Continuous IV\t252 mg\t\nRocuronium 50 mg/5 mL INJ IV Push\t20 mg\t\nDexamethasone 4 mg/mL INJ IV Push\t4 mg\t\nePHEDrine 5 mg/1 mL NS OR SYRINGE IV Push\t10 mg\t\nOndansetron 2 mg/mL 2 mL INJ IV Push\t4 mg\t\nAcetaminophen (OFIRMEV) 10 mg/mL INJ IVPB\t1 g\t\nMethylene blue 1% 10 mL INJ IV Push\t10 mL\t\nNeostigmine 1:1000 INJ IV Push\t2 mg\t\nGlycopyrrolate 0.2 mg/mL INJ IV Push\t0.4 mg\t\na Warning for serotonin syndrome.\n==== Refs\nReferences\n1 Dunkleyt E.J. Isbister G.K. Sibbrit D. The hunter serotonin toxicity criteria: simple and accurate diagnostic decision rules for serotonin toxicity QJM 96 9 2003 635 642 12925718 \n2 Varma S. Sareen H. Trivedi J.K. The geriatric population and psychiatric medication Mens Sana Monogr 8 1 2010 30 51 21327169 \n3 Shopes E. Gerard W. Baughman J. Methylene blue encephalopathy: a case report and review of published cases AANA J 81 3 2013 215 221 23923673 \n4 Wolvetang T. Janse R. Ter Horst M. Serotonin syndrome after methylene blue administration during cardiac surgery: a case report and review J Cardiothorac Vasc Anesth 2015 \n5 Top W.M. Gilliman P.K. de Langen C.J. Kooy A. Fatal methylene blue associated serotonin toxicity Neth J Med 72 3 2014 179 181 24846936 \n6 FDA Drug Safety Communication: Updated Information about the Drug Interaction between Methylene Blue (Methylthionium Chloride) and Serotonergic Psychiatric Medications. Available from: http://www.fda.gov/Drugs/DrugSafety/ucm276119.htm; 2011. Accessed 11.07.16.\n7 Martino E.A. Winterton D. Nardelli P. The blue coma: the role of methylene blue in unexplained coma after cardiac surgery J Cardiothorac Vasc Anesth 30 2 2016 423 427 26703972 \n8 Hudak S. Coburn M. Renal, Ureter – AUA Core Curriculum 2016 American Urological Association Available from: https://www.auanet.org/university/core_topic.cfm?coreid=87 Accessed 11.07.16 \n9 Francescangeli J. Vaida S. Bonavia A.S. Perioperative diagnosis and treatment of serotonin syndrome following administration of methylene blue Am J Case Rep 17 2016 347 351 27210537 \n10 Nicolaou G. Lee D. Methylene blue-induced serotonin syndrome presenting with ocular clonus and failure of emergence from general anesthesia Can J Anaesth 63 7 2016 896 897 26943644 \n11 Morey A.F. Brandes S. Dugi D.D. Urotrauma: AUA guideline J Urol 192 2 2014 327 335 24857651 \n12 Indigo Carmine Injection 2015 American Society of Health-System Pharmacists website Available from: http://www.ashp.org/menu/DrugShortages/CurrentShortages/Bulletin.aspx?id=861 Accessed 28.06.16 \n13 Doyle P.J. Lipetskaia L. Duecy E. Sodium fluorescein use during intraoperative cystoscopy Obstet Gynecol 125 3 2015 548 550 25730214\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-4420",
"issue": "9()",
"journal": "Urology case reports",
"keywords": "Cystocele repair; Methylene blue; Serotonin syndrome",
"medline_ta": "Urol Case Rep",
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"nlm_unique_id": "101626357",
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"pages": "15-7",
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"pmid": "27617215",
"pubdate": "2016-11",
"publication_types": "D002363:Case Reports",
"references": "26943644;12925718;27130452;23923673;24857651;26703972;25730214;21327169;24846936;27210537",
"title": "Methylene Blue Causing Serotonin Syndrome Following Cystocele Repair.",
"title_normalized": "methylene blue causing serotonin syndrome following cystocele repair"
} | [
{
"companynumb": "US-ZYDUS-012517",
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"occurcountry": "US",
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"activesubstancename": "UBIDECARENONE"
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"abstract": "OBJECTIVE\nTo provide practical guidance by providing weekly descriptions of warfarin requirements for the onset and offset of the rifampin-warfarin interaction.\n\n\nMETHODS\nA retrospective chart review within an outpatient Anticoagulation Clinic (AC). Patients were eligible for the onset phase provided they had known ambulatory-based warfarin steady-state requirements prior to rifampin initiation. For the offset phase, warfarin must be managed by the AC following rifampin discontinuation. Each phase was described separately with warfarin proportionate dose changes (median, IQR) for weeks 1, 2, and 4 as well as the change required to reach warfarin steady state.\n\n\nRESULTS\nTen patients with 11 courses of warfarin-rifampin were included. For onset, clinicians should anticipate proportionate warfarin dose increases of 30-80% from week 1 to week 2 and a further 20-100% from week 2 to 4, with an overall warfarin dose increase of 165% (IQR 99, 227) to reach steady state at 30 days. For offset, clinicians should anticipate proportionate warfarin dose decreases of 15-25% for both week 1 and 2, and a further 20% for both week 3 and 4, resulting in an overall warfarin decrease of 67% (IQR - 70, - 58) to reach steady state at 4 weeks for most patients.\n\n\nCONCLUSIONS\nClose monitoring with at least twice weekly INRs for weeks 1 to 2 of both phases is needed to respond to substantially changing warfarin dose requirements. While inter- and intra-patient variability for proportionate warfarin dose changes for both the onset and offset of this drug interaction exists, our data provides general guidance.",
"affiliations": "University of Alberta, Edmonton, Alberta, Canada.;Pharmacy Services, Alberta Health Services, Edmonton, Alberta, Canada.;Division of Cardiology, University of Alberta, 8425 Aberhart Centre, 11402 University Avenue, Edmonton, AB, T6G 2J3, Canada. tammy.bungard@ualberta.ca.",
"authors": "Yang|Charlotte S|CS|;Boswell|Rosaleen|R|;Bungard|Tammy J|TJ|https://orcid.org/0000-0003-1805-5715",
"chemical_list": "D000904:Antibiotics, Antitubercular; D000925:Anticoagulants; D014859:Warfarin; D012293:Rifampin",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00228-020-03057-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-6970",
"issue": "77(3)",
"journal": "European journal of clinical pharmacology",
"keywords": "Anticoagulation; Drug interaction; Rifampin; Warfarin",
"medline_ta": "Eur J Clin Pharmacol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000554:Ambulatory Care Facilities; D000904:Antibiotics, Antitubercular; D000925:Anticoagulants; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012293:Rifampin; D013997:Time Factors; D014859:Warfarin",
"nlm_unique_id": "1256165",
"other_id": null,
"pages": "341-348",
"pmc": null,
"pmid": "33409685",
"pubdate": "2021-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A case series of the rifampin-warfarin drug interaction: focus on practical warfarin management.",
"title_normalized": "a case series of the rifampin warfarin drug interaction focus on practical warfarin management"
} | [
{
"companynumb": "CA-LUPIN PHARMACEUTICALS INC.-2021-03681",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIFAMPIN"
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"drugadditional":... |
{
"abstract": "BACKGROUND\nGastrointestinal stromal tumours (GISTs) with high-risk features have poor prognosis even if adjuvant treatment is given. Neoadjuvant imatinib may increase the cure rate by shrinking large GISTs and preserve organ function.\n\n\nMETHODS\nWe conducted an Asian multinational phase II study for patients with gastric GISTs ≥10 cm. Patients received neoadjuvant imatinib (400 mg/day) for 6-9 months. The primary end point was R0 resection rate.\n\n\nRESULTS\nA total of 56 patients were enroled in this study. In the full analysis set of 53 patients, neoadjuvant imatinib for ≥6 months was completed in 46 patients. Grade 3-4 neutropenia and rash occurred in 8% and 9%, respectively, but there were no treatment-related deaths. The response rate by RECIST was 62% (95% CI, 48-75%). The R0 resection rate was 91% (48/53) (95% CI, 79-97%). Preservation of at least half of the stomach was achieved in 42 of 48 patients with R0 resection. At the median follow-up time of 32 months, 2-year overall and progression-free survival rates were 98% and 89%, respectively.\n\n\nCONCLUSIONS\nNeoadjuvant imatinib treatment for 6-9 months is a promising treatment for large gastric GISTs, allowing a high R0 resection rate with acceptable toxicity.",
"affiliations": "Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan.;Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-gu, Seoul 03080, South Korea.;Department of Surgery, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama 241-8515, Japan.;Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Seoul 05505, South Korea.;Department of Surgery, Osaka Police Hospital, 10-31, Kitayamacho, Tennoji-ku, Osaka 543-0035, Japan.;Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Seoul 05505, South Korea.;Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan.;Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-gu, Seoul 03080, South Korea.;Department of Surgery, Sendai Open Hospital, 5-22-1, Tsurugaya, Miyagino-ku, Sendai 983-0824, Japan.;Gastric Cancer Center, Kyungpook National University Medical Center, 807 Hoguk-ro, Buk-gu, Daegu 41404, South Korea.;Department of Surgery, Niigata University, 1-754, Asahimachidouri, Niigata 951-8520, Japan.;Departments of Hemato-oncology, Yeungnam Medical Center, 170, Hyeonchung-ro, Nam-gu, Daegu 42415, South Korea.;Department of Surgery, Tokai University, 143, Shimokasuya, Isehara 259-1193, Japan.;Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-gu, Seoul 03080, South Korea.;Clinical Study Support Center, Wakayama Medical University, 811-1, Kimiidera, Wakayama 641-8510, Japan.;Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Seoul 05505, South Korea.;Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan.;Department of Internal Medicine and Cancer Research Institute, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-gu, Seoul 03080, South Korea.;Department of Surgical Pathology, Hyogo College of Medicine, 1-1, Mukogawacho, Nishinomiya 663-8501, Japan.;Medical Research Collaborating Center, Seoul National University Hospital, 101 Daehak-Ro, Jongno-gu, Seoul 03080, South Korea.;National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.;Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Seoul 05505, South Korea.",
"authors": "Kurokawa|Yukinori|Y|;Yang|Han-Kwang|HK|;Cho|Haruhiko|H|;Ryu|Min-Hee|MH|;Masuzawa|Toru|T|;Park|Sook Ryun|SR|;Matsumoto|Sohei|S|;Lee|Hyuk-Joon|HJ|;Honda|Hiroshi|H|;Kwon|Oh Kyoung|OK|;Ishikawa|Takashi|T|;Lee|Kyung Hee|KH|;Nabeshima|Kazuhito|K|;Kong|Seong-Ho|SH|;Shimokawa|Toshio|T|;Yook|Jeong-Hwan|JH|;Doki|Yuichiro|Y|;Im|Seock-Ah|SA|;Hirota|Seiichi|S|;Hahn|Seokyung|S|;Nishida|Toshirou|T|;Kang|Yoon-Koo|YK|",
"chemical_list": "D000970:Antineoplastic Agents; D000068877:Imatinib Mesylate",
"country": "England",
"delete": false,
"doi": "10.1038/bjc.2017.144",
"fulltext": "\n==== Front\nBr J CancerBr. J. CancerBritish Journal of Cancer0007-09201532-1827Nature Publishing Group bjc201714410.1038/bjc.2017.14428535156Clinical StudyPhase II study of neoadjuvant imatinib in large gastrointestinal stromal tumours of the stomach Neoadjuvant imatinib in large gastric GISTKurokawa Yukinori 1*Yang Han-Kwang 2*Cho Haruhiko 3Ryu Min-Hee 4Masuzawa Toru 5Park Sook Ryun 4Matsumoto Sohei 6Lee Hyuk-Joon 2Honda Hiroshi 7Kwon Oh Kyoung 8Ishikawa Takashi 9Lee Kyung Hee 10Nabeshima Kazuhito 11Kong Seong-Ho 2Shimokawa Toshio 12Yook Jeong-Hwan 13Doki Yuichiro 1Im Seock-Ah 14Hirota Seiichi 15Hahn Seokyung 16Nishida Toshirou 17Kang Yoon-Koo 41 Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan2 Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-gu, Seoul 03080, South Korea3 Department of Surgery, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama 241-8515, Japan4 Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Seoul 05505, South Korea5 Department of Surgery, Osaka Police Hospital, 10-31, Kitayamacho, Tennoji-ku, Osaka 543-0035, Japan6 Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan7 Department of Surgery, Sendai Open Hospital, 5-22-1, Tsurugaya, Miyagino-ku, Sendai 983-0824, Japan8 Gastric Cancer Center, Kyungpook National University Medical Center, 807 Hoguk-ro, Buk-gu, Daegu 41404, South Korea9 Department of Surgery, Niigata University, 1-754, Asahimachidouri, Niigata 951-8520, Japan10 Departments of Hemato-oncology, Yeungnam Medical Center, 170, Hyeonchung-ro, Nam-gu, Daegu 42415, South Korea11 Department of Surgery, Tokai University, 143, Shimokasuya, Isehara 259-1193, Japan12 Clinical Study Support Center, Wakayama Medical University, 811-1, Kimiidera, Wakayama 641-8510, Japan13 Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Seoul 05505, South Korea14 Department of Internal Medicine and Cancer Research Institute, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-gu, Seoul 03080, South Korea15 Department of Surgical Pathology, Hyogo College of Medicine, 1-1, Mukogawacho, Nishinomiya 663-8501, Japan16 Medical Research Collaborating Center, Seoul National University Hospital, 101 Daehak-Ro, Jongno-gu, Seoul 03080, South Korea17 National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan* E-mail: ykurokawa@gesurg.med.osaka-u.ac.jp* E-mail: hkyang@snu.ac.kr27 06 2017 23 05 2017 27 6 2017 117 1 25 32 03 01 2017 15 04 2017 26 04 2017 Copyright © 2017 The Author(s)2017The Author(s)This work is licensed under the Creative Commons Attribution-Non-Commercial-Share Alike 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/Background:\nGastrointestinal stromal tumours (GISTs) with high-risk features have poor prognosis even if adjuvant treatment is given. Neoadjuvant imatinib may increase the cure rate by shrinking large GISTs and preserve organ function.\n\nMethods:\nWe conducted an Asian multinational phase II study for patients with gastric GISTs ≥10 cm. Patients received neoadjuvant imatinib (400 mg/day) for 6–9 months. The primary end point was R0 resection rate.\n\nResults:\nA total of 56 patients were enroled in this study. In the full analysis set of 53 patients, neoadjuvant imatinib for ≥6 months was completed in 46 patients. Grade 3–4 neutropenia and rash occurred in 8% and 9%, respectively, but there were no treatment-related deaths. The response rate by RECIST was 62% (95% CI, 48–75%). The R0 resection rate was 91% (48/53) (95% CI, 79–97%). Preservation of at least half of the stomach was achieved in 42 of 48 patients with R0 resection. At the median follow-up time of 32 months, 2-year overall and progression-free survival rates were 98% and 89%, respectively.\n\nConclusions:\nNeoadjuvant imatinib treatment for 6–9 months is a promising treatment for large gastric GISTs, allowing a high R0 resection rate with acceptable toxicity.\n\nGISTimatinibneoadjuvantpreoperativestomachgastric\n==== Body\nGastrointestinal stromal tumour (GIST) is the most common mesenchymal tumour in the gastrointestinal tract, with the majority originating in the stomach (Miettinen and Lasota, 2006a). Surgical resection is the only curative treatment for GIST. Independent prognostic factors for recurrence after resection include tumour size, mitotic count, tumour location, and tumour rupture. GISTs with high-risk features such as large tumour size, high mitotic count, or tumour rupture have poor prognosis after resection (Joensuu, 2008); more than half of the patients with such tumours suffer from recurrence within 5 years after surgery (Joensuu et al, 2012). For such high-risk cases, adjuvant treatment has been attempted to reduce recurrence rate.\n\nGISTs usually demonstrate activating mutations in either KIT or platelet-derived growth factor receptor alpha (PDGFRA) (Rubin et al, 2007). Imatinib, a tyrosine kinase inhibitor of KIT protein, is highly effective against GISTs. A small subset of patients with metastatic GIST may achieve durable complete remission on imatinib. Two phase III studies comparing adjuvant imatinib with surgery alone have been conducted in intermediate- and high-risk GIST patients (Dematteo et al, 2009; Corless et al, 2014; Casali et al, 2015). Both studies demonstrated that adjuvant imatinib prolonged recurrence-free survival, but eventually many patients showed recurrence after termination of adjuvant imatinib. Neoadjuvant imatinib treatment may shrink tumour size remarkably and prevent tumour rupture during surgery, leading to increased proportions of ‘true’ complete resection. Furthermore, neoadjuvant treatment may produce secondary advantages in terms of preserving organ function. For the patients with stomach tumours, complete gastrectomy should be avoided wherever possible due to the significant morbidity associated (Robertson et al, 1994).\n\nSeveral retrospective case series and a very small-scale (n=14) prospective study have assessed the feasibility of neoadjuvant imatinib (Sjölund et al, 2010; Doyon et al, 2012; Tirumani et al, 2014). In addition, one phase II study (RTOG0132) of 8–12 weeks neoadjuvant imatinib for GISTs of 5 cm or larger and another phase II study (APOLLON) of 6 months neoadjuvant imatinib for potentially resectable GISTs showed R0 resection rates of 68% (21/31) and 71% (32/45), respectively (Hohenberger et al, 2012; Wang et al, 2012). As these studies included heterogeneous tumour characteristics (size, risk classification, tumour location), it was difficult to evaluate of the efficacy of neoadjuvant imatinib. We therefore designed this multinational phase II study to investigate the efficacy and safety of neoadjuvant imatinib for 6–9 months only in patients with large (≥10 cm) gastric GISTs.\n\nPatients and methods\nStudy design and patients\nThis study was a phase II, single group, non-randomised study conducted at 25 institutions in Japan and South Korea. We enroled patients with histologically proven primary GISTs located in the stomach. The tumour diameter was required to be 10 cm or larger as identified by abdominal enhanced CT scan. Patients were required to have neither apparent distant metastasis nor peritoneal metastasis. Eligibility criteria also included: age 20–79 years; Eastern Cooperative Oncology Group performance status score of 0 or 1; no previous treatment for the disease, including surgery, chemotherapy, and radiotherapy; adequate oral intake; and adequate organ function. Patients provided written informed consent before enrolment. The study protocol was approved by the institutional review boards of all participating hospitals. This study is registered with UMIN Clinical Trials Registry, number UMIN000003114.\n\nTreatment\nAfter registration, patients received oral imatinib (400 mg/day) once a day for 6 months (24 weeks) as a neoadjuvant treatment. If the tumour response was defined as progressive disease at 1 or 3 months after starting the administration, the protocol treatment was discontinued. If the tumour response was defined as complete response (CR) or partial response (PR) at 6 months after starting the administration, the neoadjuvant imatinib could be continued until 9 months (36 weeks).\n\nSurgery was performed within 1 month of final evaluation of neoadjuvant treatment, and treatment was finally discontinued within 1 week of surgery. Surgical procedures and reconstruction methods were not prescribed by the study protocol, but as a rule R0 (macroscopically and histologically negative margin) resection was the intention. When R1 (histologically positive margin or tumour rupture) or R2 (macroscopically residual tumour) resection was performed, any treatments including continuation of imatinib were allowed after surgery.\n\nAfter R0 resection, patients received imatinib (400 mg/day) once a day for at least 1 year. If the dose of preoperative neoadjuvant imatinib was reduced to 300 mg/day, the postoperative dose was to be started at 300 mg/day. Regardless of the efficacy of neoadjuvant imatinib, postoperative imatinib was begun within 7 days after subjects started to take food orally. The protocol treatment was discontinued if imatinib could not be started within 3 months after surgery due to surgical complications or other reasons.\n\nAssessments\nThe primary end point was the R0 resection rate, and the secondary end points were overall survival, progression-free survival, objective response rate, pathological response rate (only in Japan), stomach preservation rate, treatment completion rate, incidence of adverse events, and imatinib plasma levels. Tumour responses were evaluated in accordance with both the RECIST (version 1.1) and Choi criteria by abdominal enhanced CT at weeks 4, 12, and 24 after starting neoadjuvant imatinib (Choi et al, 2007; Eisenhauer et al, 2009). Confirmation of CR or PR was not needed in this study. These evaluations were performed by physicians and radiologists at each institution. Adverse events were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. After surgery, the presence or absence of recurrence was evaluated by abdominal enhanced CT every 3 months for the first 2 years after surgery and every 6 months for the subsequent 3 years.\n\nGenotyping was carried out using biopsy specimens obtained before neoadjuvant imatinib or surgically resected specimens obtained after neoadjuvant imatinib. Whole-coding regions of KIT and PDGFRA cDNAs or selected regions of KIT genomic DNA (exons 9, 11, 13, 17) and PDGFRA genomic DNA (exons 12, 14, 18) were sequenced as previously described (Hirota et al, 1998; Hirota et al, 2003).\n\nStatistical analysis\nBased on the R0 resection rate of 68% (21/31) in the RTOG0132 study (Wang et al, 2012), the required sample size was estimated with a threshold R0 resection rate of 70% and an expected R0 resection rate of 85%, power of 80%, and a one-sided significant level of 0.05 using the binomial test. Given 10% ineligible patients, the target sample size was determined to be 55 patients.\n\nThe primary outcome was analysed with a one-sample binomial test. For secondary outcomes, we estimated response rates and 95% confidence intervals (CIs) using the Clopper–Pearson exact method. For overall and progression-free survival, we used the Kaplan–Meier method to estimate survival curves and Greenwood's formula to calculate 95% CIs for survival rates. All the analyses were conducted with R, version 3.2.2.\n\nThe full analysis set (FAS) was defined as the eligible patients who started neoadjuvant imatinib. The R0 resection rate was calculated using the number of patients in the FAS as the denominator and the number of patients who underwent R0 resection as the numerator. The stomach preservation rate was calculated using the FAS count as the denominator and the number of the patients who underwent R0 resection and who preserved at least half of the stomach as the numerator. Completion of neoadjuvant imatinib was not considered in the estimation of R0 resection rate or stomach preservation rate. Overall survival was defined as the time from the date of enrolment to the date of death from any cause. Progression-free survival was defined as the time from the date of enrolment to the date of disease progression, R1/2 resection, recurrence after surgery, or death from any cause. For patients who refused to undergo surgery, progression-free survival was not censored and was followed until disease progression.\n\nResults\nPatient background\nBetween February 2010 and September 2014, a total of 56 patients were enroled (Figure 1). Two patients were ineligible, and one patient did not start neoadjuvant imatinib because mutation analysis of the biopsy specimen revealed PDGFRA exon 18 D842V mutation. Efficacy and safety analyses of neoadjuvant imatinib were therefore conducted in the FAS of the remaining 53 patients. The characteristics of these 53 patients are listed in Table 1. Sixty percent of patients were from Japan, and the rest were from South Korea. The median tumour size was 12.0 cm (range, 10.0–23.0 cm; interquartile range (IQR), 10.4–15.7 cm). Genotyping of biopsy and/or surgical specimens showed KIT exon 11 mutation in 47 patients and wild-type KIT and PDGFRA in two patients. Samples from four patients were not available or suitable for the analysis.\n\nFeasibility\nIn total, 46 of 53 patients (87%) completed at least 6 months (24 weeks) of neoadjuvant imatinib therapy. Dose reduction of imatinib during neoadjuvant treatment was required in 14 patients (26%). The reasons of dose reduction were non-haematological toxicity for 10 patients, haematological toxicity for three patients, and other (high imatinib plasma trough level) for one patient. The median duration of neoadjuvant imatinib administration in the FAS was 26.0 weeks (range, 1.7–39.6 weeks; IQR, 24.0–35.9 weeks). All adverse events experienced during neoadjuvant imatinib treatment are shown in Table 2. The most common non-haematological toxicities were oedema of the head and neck (any grade, 72%) followed by rash (any grade, 45%). Grade 3–4 neutropenia and rash occurred in 8% and 9% of patients, respectively. Grade 4 cerebrovascular ischaemia occurred in one patient, and there were no treatment-related deaths. Seven patients discontinued neoadjuvant imatinib due to adverse events (2 rash, 2 interstitial pneumonitis, 2 fever, 1 cerebrovascular ischaemia). In the 46 patients who completed at least 6 months of neoadjuvant imatinib treatment, the mean±s.d. of imatinib plasma trough level at 6 months after starting neoadjuvant imatinib was 1852±1572 ng/ml (range, 436 to 9660 ng/ml) (one missing value).\n\nEfficacy\nA waterfall plot representing the ranked best tumour shrinkage after neoadjuvant imatinib is shown in Figure 2. The median shrinkage rate in the 53 patients was 35.4% (range, 0.0–87.0%), and neoadjuvant imatinib brought favourable shrinkage of tumour even in two patients with wild-type GIST (40.8% and 50.5%). The objective best response rate and the disease control rate evaluated by RECIST in the FAS were 62% (95% CI, 48–75%) and 100% (95% CI, 93–100%), respectively. The objective best response rate and the disease control rate evaluated by the Choi criteria in the FAS were 98% (95% CI, 90–100%) and 100% (95% CI, 93–100%), respectively. Of the 46 patients who completed at least 6 months of neoadjuvant imatinib, the earliest point at which maximal reduction of tumour size was observed was 4 weeks after neoadjuvant imatinib initiation in 1 case (2%), 12 weeks in 9 cases (20%), 24 weeks in 29 (63%) cases, and 36 weeks in 7 (15%) cases.\n\nOf the 53 patients who received neoadjuvant imatinib, 50 proceeded to surgery. Three patients refused to undergo surgery. The surgical data are summarised in Table 3. More than 80% of the patients underwent partial gastrectomy. A quarter of the patients underwent combined resection of other organs, excluding the gallbladder. There was one case with tumour rupture at surgery. R0 resection was achieved in 48 patients, R1 (tumour rupture) in one, and R2 in one. The R0 resection rate in the FAS (the primary end point) was 91% (95% CI, 79–97%). This was much higher than the pre-specified threshold of 70% (one-sided P<0.001). At least half of the stomach was preserved with R0 resection in 79% of cases (95% CI, 66–89%). Operative morbidities of any grade occurred in nine patients (two postoperative bleeding, two wound infection, two anastomotic leakage, one bowel obstruction, one intraabdominal infection, and one pyloric stenosis). There were no treatment-related or in-hospital deaths.\n\nThe pathological findings of 50 patients who underwent surgical resection are shown in Table 3. The median postoperative tumour size was 8.0 cm (range, 4.7–20.0 cm; IQR, 7.5–11.8 cm). Peritoneal metastasis was observed in three patients (6%), but there were no patients with lymph node metastasis. Of the 50 patients, 42 (84%) had tumours with mitotic counts less than five per 50 high-power fields (HPF).\n\nOf the 42 patients who underwent R0 resection after completion of at least 6 months of neoadjuvant imatinib therapy, 40 started adjuvant imatinib. One patient refused to receive imatinib after surgery, and the other patient could not take imatinib due to postoperative morbidity. As a result, 38 of 40 patients (95%) continued adjuvant imatinib therapy at least during the first year after surgery. At the median follow-up of 32 months, the 2-year overall survival rate in the FAS was 98% (95% CI, 95–100% Figure 3A). The 2-year progression-free survival rate in the FAS was 89% (95% CI, 81–98% Figure 3B). Of the 48 patients who underwent R0 resection, tumour recurrence occurred in seven patients. The sites of recurrence were the liver (n=5), peritoneum (n=2), and local (n=2) (two patients had duplicated sites).\n\nDiscussion\nA previous phase III study (Z9001) proved that adjuvant imatinib treatment for 1 year significantly prolonged recurrence-free survival, but eventually 60% of patients with GISTs larger than 10 cm showed recurrence within 3 years (Dematteo et al, 2009). Another phase III study (EORTC62024) comparing 2-year adjuvant imatinib with surgery alone found that nearly half of high-risk GIST patients showed recurrence within 6 years even after 2-year adjuvant imatinib (Casali et al, 2015). These results may indicate that the strategy of adjuvant treatment is insufficient to cure patients with high-risk GISTs. Cure of GISTs can only be obtained by ‘true’ complete resection. However, neoadjuvant imatinib treatment may shrink tumour size remarkably and prevent tumour rupture during surgery, and thus lead to increased rates of complete resection. Indeed, the median shrinkage rate in this study was 35.4%, and no patients showed growth of primary tumours while receiving neoadjuvant treatment. Furthermore, neoadjuvant imatinib could preserve the functioning of tumour-involved organs in many patients. Although our study included only large tumours (median, 12 cm), ∼80% of the patients achieved preservation of at least half of the stomach, and only three patients (6%) underwent total gastrectomy. Our results suggesting that the beneficial effect of neoadjuvant imatinib is inconsistent with the results of a Japanese multi-institutional retrospective study showing that 17 (23%) of 73 patients with large (⩾10 cm) gastric GIST required total gastrectomy (Wada et al, 2014).\n\nThe duration of neoadjuvant imatinib administration is important to obtain sufficient response. In a previous phase II study (RTOG0132) patients received neoadjuvant imatinib for only 8–12 weeks (median, 9.9 weeks), and the R0 resection rate was only 68% (21/31) despite the smaller tumour size (median, 8.7 cm) compared to our study (Wang et al, 2012). In a previous randomised study of first-line imatinib treatment (B2222) for patients with unresectable or metastatic GISTs, 75% of patients who achieved PR needed 5.3 months to obtain their response (Blanke et al, 2008). A Japanese phase II study for patients with unresectable or metastatic GIST also revealed that the cumulative response rate reached a plateau after 200 days (Nishida et al, 2008). Based on these results, we judged that 6 months is the minimum duration of neoadjuvant imatinib therapy needed to obtain a certain volume reduction of GISTs. In another phase II study (APOLLON) evaluating the efficacy of neoadjuvant imatinib for 6 months in patients with various types (size, risk classification, tumour location) of potentially resectable GIST, the R0 resection rate was 71% (32/45) (Hohenberger et al, 2012). The R0 resection rate without tumour rupture (91%) in our study was higher than that in any other neoadjuvant or adjuvant studies (Hohenberger et al, 2012; McCarter et al, 2012; Wang et al, 2012; Casali et al, 2015), although our study included larger GISTs. Thus, we considered that the main reason for the high R0 resection rate were the long duration of neoadjuvant imatinib therapy. However, it is important to consider the risk of tumour progression during long treatments, because one patient whose tumour demonstrated a KIT exon 11 mutation showed new peritoneal metastasis on CT after 8 months of neoadjuvant imatinib in spite of high imatinib plasma trough level (5,284 ng/ml at 6 months).\n\nThis study was originally designed with 2-year progression-free survival rate as the primary end point. In 2012, a phase III study (SSGXVIII/AIO) showed that 3-year adjuvant imatinib improved survival in high-risk GIST patients compared with 1-year adjuvant imatinib (Joensuu et al, 2012). After September 2012, therefore, this study protocol recommended administering adjuvant imatinib for 3 years. This extended treatment duration may have easily affected the initial primary end point of 2-year progression-free survival. Response rate according to RECIST is the most frequently used end point in phase II studies of neoadjuvant treatment for solid tumours, but it may not be appropriate for response evaluation of imatinib for GIST (Benjamin et al, 2007). Thus, the primary end point in this study was changed to R0 resection rate in July 2013 according to the recommendation from the Steering Committees of both the Japanese Study Group on GIST and the Korean GIST Study Group. The prognostic impact of R0 resection in the management of localised GIST has been well recognised (Miettinen and Lasota, 2006b; Dematteo et al, 2008; Joensuu, 2008).\n\nThis study has several limitations. First, it was a single-arm non-randomised study and the follow-up period was short. As many patients developed recurrence after the termination of adjuvant imatinib in previous studies (Corless et al, 2014; Casali et al, 2015; Joensuu et al, 2016), we could not determine the survival benefit of neoadjuvant treatment in this study. Second, subjects were limited to those with GIST of the stomach. Since long-term survival and R0 resection rate strongly depend on GIST location (Dematteo et al, 2008; Joensuu et al, 2012), the selection of only gastric GIST in our study might have contributed to the high R0 resection rate. GIST of the rectum or duodenum may be a good target population for neoadjuvant imatinib, because preservation of organ function is more critical in these patients. However, evaluation of organ function preservation may differ among organs. Furthermore, small bowel GIST may be associated with KIT exon 9 mutation and may require higher dose imatinib. Future studies are warranted to evaluate the benefit of neoadjuvant imatinib in patients with GIST of other organs. Finally, this study did not require mutation analysis before enrolment, but eventually most cases showed KIT exon 11 mutation, which might have led to the high R0 resection rate. The response of imatinib treatment can be predicted by genotyping (Heinrich et al, 2003; Debiec-Rychter et al, 2006). Indeed, one patient skipped treatment after enrolment in this study and went straight to surgery because PDGFRA exon 18 D842V mutation was found before the initiation of neoadjuvant imatinib. However, two patients with wild-type GIST underwent neoadjuvant imatinib for 6–9 months without disease progression followed by R0 resection. Although mutation analysis using biopsy specimens is sometimes difficult or may require much time before results are obtained, we recommend it before starting neoadjuvant imatinib if it is available.\n\nTo our knowledge, this phase II study is the only reported multinational prospective study to prove the efficacy of neoadjuvant imatinib administered for 6–9 months in patients with large gastric GIST. We ultimately obtained a much higher R0 resection rate (91%) than expected. The toxicity was tolerable, and it did not increase postoperative complications. These findings suggest that neoadjuvant imatinib for 6–9 months would be a promising treatment in patients with high-risk GISTs. Neoadjuvant imatinib may provide certain benefit for patients with GIST small in size and a high mitotic count. However, we cannot obtain accurate mitotic counts using preoperative biopsy specimens due to tumour heterogeneity (Yasui et al, 2006; Nishida et al, 2008). We also think that patients with huge tumour may have more benefit from neoadjuvant treatment than those with small GIST, because shrinkage of tumour size by neoadjuvant imatinib may lead to both prevention of tumour rupture during surgery and preservation of stomach function due to avoiding total gastrectomy. The mitotic count in the resected specimens may have decreased as treatment effect, and could potentially affect subsequent decision-making of adjuvant imatinib in clinical practice. Although the lack of reliable mitotic counts may result in overtreatment of some patients, tumour size of 10 cm or larger seemed to be one of the most useful criterion to determine the indication for neoadjuvant imatinib.\n\nIn Japan, this study was supported by Non-Profit Organisation of the Research Group for Rare Neoplasms of Japan (Gran-Japan) and the Japanese Study Group on GIST. In South Korea, this study was supported by the Korean GIST Study Group and Novartis. We thank all the patients and clinicians. We also thank Ms. Yuriko Takeda from the SCCRE Data Centre in Osaka University and Ms. Kahee Kim from the Medical Research Collaborating Center in Seoul National University Hospital for data management.\n\nYukinori Kurokawa has received honoraria from Novartis, Pfizer, and Taiho. Haruhiko Cho has received honoraria from Novartis, Pfizer, and Bayer. Kazuhito Nabeshima has received honoraria from Pfizer. Seiichi Hirota has received honoraria from Novartis. Toshirou Nishida has received honoraria from Novartis, Pfizer, Bayer, and Taiho. Han-Kwang Yang, Min-Hee Ryu, Sook Ryun Park, Hyuk-Joon Lee, Oh Kyoung Kwon, Kyung Hee Lee, Seong-Ho Kong, Jeong-Hwan Yook, Yuichiro Doki, Seock-Ah Im, Seiichi Hirota, Seokyung Hahn, Toshirou Nishida, and Yoon-Koo Kang have received grant support from Novartis. All other authors declare no competing interests.\n\nFigure 1 Study profile. FAS, full analysis set; PDGFRA, platelet-derived growth factor receptor alpha.\n\nFigure 2 Waterfall plot of the ranked best tumour shrinkage after neoadjuvant imatinib.\n\nFigure 3 Kaplan–Meier estimates of (A) overall survival and (B) progression-free survival for 53 patients in the full analysis set.\n\nTable 1 Baseline characteristics of patients in the full analysis set\n \t(n=53)\t\nCountry\t\nJapan\t32 (60%)\t\nKorea\t21 (40%)\t\nAge (years)\t\nMedian\t69\t\nRange\t43–79\t\nIQR\t62–73\t\nSex\t\nMale\t24 (45%)\t\nFemale\t29 (55%)\t\nECOG performance status\t\n0\t28 (53%)\t\n1\t25 (47%)\t\nTumour size (cm)\t\nMedian\t12.0\t\nRange\t10.0–23.0\t\nIQR\t10.4–15.7\t\nSampling method used to obtain tumour tissue\t\nEndoscopic standard biopsy\t24\t\nEUS-FNA\t28\t\nPercutaneous biopsy\t1\t\nGenotyping\t\nKIT exon 11\t47 (89%)\t\nWild-type KIT and PDGFRA\t2 (4%)\t\nNot available\t4 (8%)\t\nAbbreviations: IQR=interquartile range; ECOG=Eastern Cooperative Oncology Group; EUS-FNA=endoscopic ultrasound-guided fine-needle aspiration.\n\nTable 2 Adverse events during neoadjuvant imatinib treatment (n=53)\n \tNo. of patients (%)\t\nEvents\tGrade 1\tGrade 2\tGrade 3\tGrade 4\tAll grade\tGrade 3-4\t\nNeutropenia\t16 (30%)\t18 (34%)\t2 (4%)\t2 (4%)\t38 (72%)\t4 (8%)\t\nLeukopenia\t9 (17%)\t16 (30%)\t2 (4%)\t0\t27 (51%)\t2 (4%)\t\nAnaemia\t29 (55%)\t20 (38%)\t1 (2%)\t0\t50 (94%)\t1 (2%)\t\nAST\t15 (28%)\t0\t0\t0\t15 (28%)\t0\t\nALT\t14 (26%)\t1 (2%)\t0\t0\t15 (28%)\t0\t\nCreatinine\t9 (17%)\t0\t0\t0\t9 (17%)\t0\t\nOedema (head & neck)\t35 (66%)\t3 (6%)\t0\t0\t38 (72%)\t0\t\nRash\t11 (21%)\t8 (15%)\t5 (9%)\t0\t24 (45%)\t5 (9%)\t\nOedema (limb)\t20 (38%)\t1 (2%)\t0\t0\t21 (40%)\t0\t\nAnorexia\t13 (25%)\t3 (6%)\t0\t0\t16 (30%)\t0\t\nNausea\t13 (25%)\t3 (6%)\t0\t0\t16 (30%)\t0\t\nVomiting\t10 (19%)\t2 (4%)\t1 (2%)\t0\t13 (25%)\t1 (2%)\t\nDiarrhoea\t6 (11%)\t3 (6%)\t0\t0\t9 (17%)\t0\t\nAbdominal pain\t8 (15%)\t1 (2%)\t0\t0\t9 (17%)\t0\t\nPneumonitis\t0\t1 (2%)\t1 (2%)\t0\t2 (4%)\t1 (2%)\t\nFever\t1 (2%)\t1 (2%)\t0\t0\t2 (4%)\t0\t\nMucositis\t2 (4%)\t0\t0\t0\t2 (4%)\t0\t\nFebrile neutropenia\t0\t0\t1 (2%)\t0\t1 (2%)\t1 (2%)\t\nHypoxia\t0\t0\t1 (2%)\t0\t1 (2%)\t1 (2%)\t\nCNS ischaemia\t0\t0\t0\t1 (2%)\t1 (2%)\t1 (2%)\t\nDizziness\t0\t0\t1 (2%)\t0\t1 (2%)\t1 (2%)\t\nPruritus\t0\t1 (2%)\t0\t0\t1 (2%)\t0\t\nAdverse events were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. Lower limits of grade 0 for leukopenia and neutropenia were defined as 3,300/mm3 and 2,000/mm3, while those for anaemia were 13.7 g/dl (for men) and 11.6 g/dl (for women).\n\nTable 3 Surgical and pathological findings\n \t(n=50)\t\nOperation time (min)\t\nMedian\t150.5\t\nRange\t63–373\t\nIQR\t101–229.3\t\nBlood loss (ml)\t\nMedian\t50\t\nRange\tLittle – 2200\t\nIQR\tLittle – 272.5\t\nType of gastrectomy\t\nPartial\t42 (84%)\t\nProximal\t5 (10%)\t\nTotal\t3 (6%)\t\nCombined resection of other organs (excluding the gallbladder)\t\nNo\t38 (76%)\t\nYesa\t12 (24%)\t\n Spleen\t9\t\n Distal pancreas\t3\t\n Transverse colon\t2\t\n Liver\t2\t\nCompleteness of surgery\t\nR0\t48 (96%)\t\nR1\t1 (2%)\t\nR2\t1 (2%)\t\nPreservation of at least half of the stomach with R0 resection\t\nYes\t42 (84%)\t\nNo\t8 (16%)\t\nTumour size (cm)\t\nMedian\t8.0\t\nRange\t4.7–20.0\t\nIQR\t7.5–11.8\t\nHistologically confirmed metastasis\t\nNone\t47 (94%)\t\nPeritoneum\t3 (6%)\t\nMitotic count\t\n< 5/50 HPF\t42 (84%)\t\n5–9/50 HPF\t3 (6%)\t\n⩾ 10/50 HPF\t5 (10%)\t\nAbbreviations: IQR=interquartile range; HPF=high-power field.\n\na Some cases were duplicated.\n==== Refs\nBenjamin RS, Choi H, Macapinlac HA, Burgess MA, Patel SR, Chen LL, Podoloff DA, Charnsangavej C (2007 ) We should desist using RECIST, at least in GIST . 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"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0007-0920",
"issue": "117(1)",
"journal": "British journal of cancer",
"keywords": null,
"medline_ta": "Br J Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D018572:Disease-Free Survival; D003875:Drug Eruptions; D005260:Female; D005743:Gastrectomy; D046152:Gastrointestinal Stromal Tumors; D006801:Humans; D000068877:Imatinib Mesylate; D007564:Japan; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009503:Neutropenia; D059351:Organ Sparing Treatments; D056910:Republic of Korea; D013274:Stomach Neoplasms; D047368:Tumor Burden",
"nlm_unique_id": "0370635",
"other_id": null,
"pages": "25-32",
"pmc": null,
"pmid": "28535156",
"pubdate": "2017-06-27",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": "22203182;18774375;18553235;22153892;18235121;22726733;18076015;24155204;14645423;16952042;24638003;8053740;9438854;17090188;23316352;19303137;16624552;19097774;17193820;22453568;18946752;17470866;24238762;17470865;17512858;12949711;20512492;26573069;26527782",
"title": "Phase II study of neoadjuvant imatinib in large gastrointestinal stromal tumours of the stomach.",
"title_normalized": "phase ii study of neoadjuvant imatinib in large gastrointestinal stromal tumours of the stomach"
} | [
{
"companynumb": "PHHY2017JP101744",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IMATINIB"
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"drugadditional": null,
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{
"abstract": "Osteonecrosis of the jaw (ONJ) is a rare but very serious disease that can affect both jaws. It is defined as exposed bone in the maxillofacial region that does not heal within 8 weeks after a health care provider identification. ONJ can occur spontaneously or can be due to drugs like bisphosphonates (BPS) and anti-RANK agents, in patients with no history of external radiation therapy in the craniofacial region. Although in phase 3 trials of tyrosine kinase inhibitors (TKIs) used in thyroid cancer (TC) the ONJ was not reported among the most common side effects, several papers reported the association between ONJ and TKIs, both when they are used alone and in combination with a bisphosphonate. The appearance of an ONJ in a patient with metastatic radio-iodine refractory differentiated TC, treated with zoledronic acid and sorafenib, has put us in front of an important clinical challenge: when a ONJ occurred during TKIs treatment, it really worsens the patients' quality of life. We should consider that in the case of ONJ a TKI discontinuation becomes necessary, and this could lead to a progression of neoplastic disease. The most important aim of this review is to aware the endocrinologists/oncologists dealing with TC to pay attention to this possible side effect of BPS and TKIs, especially when they are used in association. To significantly reduced the risk of ONJ, both preventive measures before initiating not only antiresorptive therapy but also antiangiogenic agents, and regular dental examinations during the treatment should always be proposed.",
"affiliations": "Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Via Paradisa 2, 56124, Pisa, Italy.;Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Via Paradisa 2, 56124, Pisa, Italy.;Department of Surgery, Section of Oral Surgery, University of Pisa, Pisa, Italy.;Department of Surgery, Section of Oral Surgery, University of Pisa, Pisa, Italy.;Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Via Paradisa 2, 56124, Pisa, Italy.;Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Via Paradisa 2, 56124, Pisa, Italy.;Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Via Paradisa 2, 56124, Pisa, Italy.;Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Via Paradisa 2, 56124, Pisa, Italy. rossella.elisei@med.unipi.it.;Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Via Paradisa 2, 56124, Pisa, Italy.",
"authors": "Lorusso|L|L|http://orcid.org/0000-0001-8773-3642;Pieruzzi|L|L|;Gabriele|M|M|;Nisi|M|M|;Viola|D|D|;Molinaro|E|E|;Bottici|V|V|;Elisei|R|R|;Agate|L|L|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.1007/s40618-021-01634-0",
"fulltext": "\n==== Front\nJ Endocrinol Invest\nJ Endocrinol Invest\nJournal of Endocrinological Investigation\n0391-4097\n1720-8386\nSpringer International Publishing Cham\n\n34291429\n1634\n10.1007/s40618-021-01634-0\nShort Review\nOsteonecrosis of the jaw: a rare but possible side effect in thyroid cancer patients treated with tyrosine-kinase inhibitors and bisphosphonates\nhttp://orcid.org/0000-0001-8773-3642\nLorusso L. lorussoloredana@hotmail.it\n\n1\nPieruzzi L. pieruzziletizia@gmail.com\n\n1\nGabriele M. mario.gabriele@unipi.it\n\n2\nNisi M. marco.nisi@unipi.it\n\n2\nViola D. violadavid@hotmail.it\n\n1\nMolinaro E. elemoli@hotmail.com\n\n1\nBottici V. valeriabottici@gmail.com\n\n1\nElisei R. rossella.elisei@med.unipi.it\n\n1\nAgate L. laura.agate@virgilio.it\n\n1\n1 grid.5395.a 0000 0004 1757 3729 Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy\n2 grid.5395.a 0000 0004 1757 3729 Department of Surgery, Section of Oral Surgery, University of Pisa, Pisa, Italy\n21 7 2021\n21 7 2021\n2021\n44 12 25572566\n18 3 2021\n7 7 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.\nOsteonecrosis of the jaw (ONJ) is a rare but very serious disease that can affect both jaws. It is defined as exposed bone in the maxillofacial region that does not heal within 8 weeks after a health care provider identification. ONJ can occur spontaneously or can be due to drugs like bisphosphonates (BPS) and anti-RANK agents, in patients with no history of external radiation therapy in the craniofacial region. Although in phase 3 trials of tyrosine kinase inhibitors (TKIs) used in thyroid cancer (TC) the ONJ was not reported among the most common side effects, several papers reported the association between ONJ and TKIs, both when they are used alone and in combination with a bisphosphonate. The appearance of an ONJ in a patient with metastatic radio-iodine refractory differentiated TC, treated with zoledronic acid and sorafenib, has put us in front of an important clinical challenge: when a ONJ occurred during TKIs treatment, it really worsens the patients’ quality of life. We should consider that in the case of ONJ a TKI discontinuation becomes necessary, and this could lead to a progression of neoplastic disease. The most important aim of this review is to aware the endocrinologists/oncologists dealing with TC to pay attention to this possible side effect of BPS and TKIs, especially when they are used in association. To significantly reduced the risk of ONJ, both preventive measures before initiating not only antiresorptive therapy but also antiangiogenic agents, and regular dental examinations during the treatment should always be proposed.\n\nKeywords\n\nThyroid cancer\nSorafenib adverse event\nZoledronic acid\nTyrosine-kinase inhibitors therapy\nOsteonecrosis of the jaw\nhttp://dx.doi.org/10.13039/501100003407 Ministero dell’Istruzione, dell’Università e della Ricerca PRIN project 2017YTWKWH Università di PisaOpen access funding provided by Università di Pisa within the CRUI-CARE Agreement.\n\nissue-copyright-statement© Italian Society of Endocrinology (SIE) 2021\n==== Body\npmcIntroduction\n\nOsteonecrosis of the jaw (ONJ) is a rare but very serious disease that can affect both jaws. It is a clinical condition characterized by the presence of one or more bone necrotic lesions that are generally exposed in the oral cavity for at least 8 weeks [1, 2]. This pathology is known since the end of the nineteenth century, when it occurred, along with other side effects, in some workers of matches-making factories after the inhalation of pyrophosphate [3, 4]. Subsequently, the association between ONJ and the use of intravenous bisphosphonate was for the first time reported in 2003 [1], and, since then, several other studies confirmed the association of ONJ, not only with systemic but also with orally administered bisphosphonates (BPS) [1, 2, 5]. In 2007 the American Society for Bone and Mineral Research formulated the definition of BPS-related ONJ (BRONJ) [6], but in 2014, since new drugs able to causing ONJ were identified, the special committee of the American Association of Oral and Maxillofacial Surgeons (AAOMS) [7] suggested to change the name from BRONJ to medication-related ONJ (MRONJ). In fact, drugs like anti-vascular endothelial growth factor (VEGF), anti-RANK agents and tyrosine-kinases inhibitors (TKIs) were demonstrated to be responsible of ONJ too, both when they are used alone or in combination with BPS [8–12].\n\nONJ: definition, incidence, and etiology\n\nRecently the International Task Force on Osteonecrosis of the Jaw [13] defined ONJ as exposed bone in the maxillofacial region that does not heal within 8 weeks after identification by a health care provider. MRONJ is the same bone lesion that occurred in patients treated with an antiresorptive agent and/or an anti-angiogenics, and with no history of radiation therapy to the craniofacial region. ONJ/MRONJ can be spontaneous or can follow an alveolar trauma such as dental extraction.\n\nSince oncology patients with bone metastases are exposed to more intensive osteoclast inhibition and to higher BPS doses than those with osteoporosis, the incidence of ONJ is much higher in oncological patients and it ranges from 0 to 12,222 per 100,000 patients-years [14–16]. The prevalence of ONJ in oncological patients treated with intravenous BPS ranges from 0 to 0.186% [17, 18].\n\nAlthough the pathophysiology of ONJ is not well understood, several hypotheses for explaining the development of this avascular necrosis are available in the literature and these include bone turnover suppression, bone infections, impaired vascularization, immune system malfunction, and oral mucosal damages. This could explain that every drug that can interfere with bone turnover and/or with vascularization, could also increase the risk of ONJ. In particular, regarding BPS, they seem to have a high affinity to hydroxyapatite crystals forming the bone, thereby inhibiting the resorptive action of osteoclasts by induced apoptosis. This effect may indirectly cause a lack of the cytokines released from the osteoclast, prevent the bone healing ability, and may, finally, lead to BRONJ [19]. BPS also seem to have an anti-angiogenic effect. In particular, when a nitrogen-containing BPS (i.e. zoledronic acid) are used, the circulating levels of VEGF, an essential mediator of angiogenesis and of osteogenic differentiation and bone formation, decrease [20]. Since the new TKI therapies also act against the VEGF receptor, interfering with the formation of new blood vessels, and reducing the capability of healing when microtrauma occurs, these drugs may eventually lead to the development of ONJ, and, according to the recent review of the international recommendations, they can be considered as a risk factor on the ONJ development [21].\n\nA synergistic effect of BPS and antiangiogenic agents on the bone was recently described by Christodoulou et al [22]. In this retrospective study, the authors confirmed that the prevalence of ONJ was 1.1% for those oncological patients on intravenous BPS alone and that it increased to 16% when BPS were used in addition to antiangiogenic agents (bevacizumab and sunitinib).\n\nInterestingly, very recently, since FDA warned about the increased risk of ONJ in patients receiving lenvatinib, a pharmacovigilance study, aiming to assess the association between lenvatinib and ONJ and to summarize the clinical features of these cases using the FDA Adverse Events reporting System (FAERS), was published [23]. A total of 9800 lenvatinib-related adverse events were reported and 52 of these (0.5%) were ONJ. This pharmacovigilance study confirmed that the incidence of ONJ due to lenvatinib treatment alone is very low, but it may increase when this treatment is associated to other drugs (i.e. BPS, glucocorticoids) and risk factors (i.e. diabetes and dental procedures).\n\nRegarding the timing of ONJ appearance, according to the study of Jung et al [24], among 1569 incident ONJ cases, 53.3% of ONJ occurred after BPS discontinuation, and most ONJ cases occurred within three years from BPS suspension. In another study [25], it was also demonstrated that MRONJs occur earlier in patients treated concomitantly with TKIs and BPS compared to patients treated with BPS only (after a median exposure of 4.5 and 25.0 months, respectively; p = 0.0033).\n\nDiagnosis of ONJ\n\nAccording to the AAOMS [7], a diagnosis of MRONJ can be confirmed when patients meet all the following criteria: (1) current or previous treatment with BPS or antiangiogenic agents; (2) exposed bone or bone that can be probed through a fistula, situated within or outside the mouth, in the maxillofacial region that has persisted for longer than 8 weeks; (3) no history of radiation therapy to the jaws or metastatic disease to the jaws.\n\n“Bone that can be probed through a fistula” is a definition referred to those cases (up to one-quarter of patients) that experiences a non-exposed form of MRONJ [26]. To note that the non-exposed form of MRONJ may remain without a correct diagnosis but it would require the same treatment of the classical form of MRONJ.\n\nThe most common site of MRONJ is the mandible (less frequently the maxilla), and, in less than 5% of patients, MRONJ is observed in both locations.\n\nPatients with MRONJ may remain asymptomatic for long periods of weeks, months, or even years after the appearance of bone necrosis but most frequently this condition becomes symptomatic with inflammation of surrounding tissues, that can be documented by radiological procedures.\n\nThe signs and symptoms of MRONJ are exposed necrotic bone, sinus fistula, difficulties with chewing, eating, and speaking, bad breath, maxillary sinus pain, loose teeth, fracture of the jaw. Figure 1 shows a clinical examination of a mandible and maxilla MRONJ.Fig. 1 clinical examination of oral cavity showing a large gingival lesion with bone exposure in the mandibular body (A), both on the right (B) and on the left (C), and smaller lesions in the maxilla, bilaterally (D): the patient came to our attention complaining bilateral maxillary and mandibular pain with difficulty in feeding\n\nAAOMS proposed 5 different clinical stages for MRONJ, from stage 0 to 3rd stages and “at risk” stage [7]. In particular, in stage 0 all those patients with no clinical evidence of necrotic bone but with non-specific symptoms and/or clinical/radiographic findings can be included; stage 1 includes patients with exposed and necrotic bone, or fistulae that probe to bone, who are asymptomatic with no evidence of significant adjacent or regional soft tissue inflammation or infection; stage 2 includes patients with exposed and necrotic bone, or fistulae that probe to bone, associated with infection, as shown by pain and adjacent or regional soft tissue inflammatory swelling, with or without purulent drainage; stage 3 includes patients with exposed and necrotic bone, or fistulae that probe to bone, with evidence of infection, and one or more of the following: (1) pathologic fracture; (2) exposed necrotic bone extending beyond the region of alveolar bone (ie, inferior border and ramus in the mandible, maxillary sinus and zygoma in the maxilla); (3) extra-oral fistula; (4) oral antral/oral nasal communication, (5) osteolysis extending to the inferior border of the mandible or sinus floor. The so-called “at risk stage” includes all those patients who have been treated with BPS/antiangiogenic agents but who have no apparent necrotic bone.\n\nRadiographic criteria are not included for the diagnosis of MRONJ, but, since many studies [27–29] have suggested that the reason for the refractory behavior of MRONJ is that the diagnosis based on bone exposure is too late, an early radiological identification of MRONJ would be ideal. Therefore, some authors focused their attention to identify, by computer tomography scan (CT), some early bone features typical of stage 0 MRONJ. Trabecular bone density seems to be significantly higher in stage 0 MRONJ patients than in the control group or in the at-risk group, especially in the regions close to the alveolar process [30, 31]. In the same way, several studies [31, 32] confirmed that cortical bone thickness, measured by cone-beam CT, is greater in stage 0 patients and early MRONJ patients than in the control and at-risk groups. This means that measuring trabecular bone CT radiodensity values and cortical bone thickness could be simple quantitative methods to radiologically detect the early stages of MRONJ. Except for these features, in advanced-stage disease, there seems to be no significant relationship between stage and imaging features.\n\nPrevention and therapeutic options of ONJ\n\nThe implementation of dental screening and appropriate dental measures before initiating antiresorptive therapy/antiangiogenic agents reduces the risk of ONJ in several prospective studies, especially when compared to patients who did not undergo dental preventive measures [33–35].\n\nTreatment planning should include clinical examination of the oral cavity and a radiographic assessment, and the identification of both acute infection and sites of potential infection to prevent future sequelae that could be exacerbated once drug therapies begin is fundamental.\n\nIndividuals receiving monthly intravenous BPS or denosumab for the treatment of oncologic disease have an increased risk of developing ONJ following tooth extraction and thus these procedures should be avoided if possible.\n\nRegarding the treatment of ONJ/MRONJ, in 2014, AAOMS [7] provided the indications for the treatment of patients with ONJ/MRONJ according to the stage of the disease. In particular, at risk-patients, since they have no exposed bone, do not require any treatment, but they should be informed of the risks of developing MRONJ, as well as the signs and symptoms of this disease process.\n\nStage 0 MROJ requires symptomatic treatment, and conservatively management of other local factors, such as caries and periodontal disease. Systemic management should include medications for chronic pain and control of infection with antibiotics when indicated. Since there is a potential for progression to a higher stage of disease, these patients should be closely monitored.Stage 1: patients could benefit from medical management including the use of oral antimicrobial rinses, such as chlorhexidine 0.12%, but no immediate operative treatment is required.\n\nStage 2: patients could benefit from the use of both oral antimicrobial rinses in combination with antibiotic therapy. Although local bone and soft tissue infection is not the primary etiology for this condition, the colonization of the exposed bone by sensitive penicillin microbes is a very common occurrence (quinolones, metronidazole, clindamycin, doxycycline, and erythromycin may also be used in those patients who are allergic to penicillin). When systemic antibiotics failure occurred, mainly due to a biofilm formation on the surface of the exposed bone, operative therapy directed at reducing the volume of colonized necrotic bone should be added to antibiotic therapy.\n\nStage 3: patients could benefit from debridement, including resection, in combination with antibiotic therapy, which may offer long-term palliation with a resolution of acute infection and pain. Symptomatic patients with stage 3 disease may require resection and immediate reconstruction with a reconstruction plate or an obturator.\n\nRegardless of the disease stage, the mobile bone should be removed to facilitate soft tissue healing. Moreover, the extraction of symptomatic teeth within exposed necrotic bone should be considered since it is unlikely that the extraction will exacerbate the established necrotic process.\n\nONJ in thyroid cancer patients treated with TKI\n\nIn the last 10 years, for the treatment of thyroid cancer, endocrinologists focused their attention on TKI therapies, small molecules able to inhibit different types of tyrosine kinase receptors, as well as a central mediator of MAPK and PI3K/AKT/mTOR signaling cascades [36]. In particular, sorafenib and lenvatinib were approved for the treatment of differentiated (DTC) and poorly differentiated (PDTC) radioiodine-refractory and progressive thyroid carcinoma [37, 38], while vandetanib and cabozantinib [39, 40] were approved for progressive and metastatic medullary thyroid cancer (MTC). Moreover, a second generation of TKIs have been recently approved for the treatment of thyroid cancer by Food and Drug Administration and are under evaluation by European Medicines Agency (larotrectinib, entrectinib, selpercatinib, and pralsetinib). Although in phase 3 trials of TKI used in thyroid cancer the ONJ was not reported among the most common side effects, as mentioned above, several papers reported the association between ONJ and TKI, both when they are used alone and in combination with BPS [41–45].\n\nSorafenib is an oral multiple TKI that targets the VEGF receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family, which play key roles in tumor progression and angiogenesis. It was approved for advanced hepatocellular carcinoma (HCC), for metastatic renal cell cancer (RCC), radioiodine-refractory and progressive DTC and PDTC. Although in DECISION study [37], a phase 3 study that leads to the approval of sorafenib for the treatment of thyroid cancer, the most frequent oral adverse event was mucositis and no cases of ONJ were reported, in the literature, the association between sorafenib and ONJ was reported in several cases. Osteonecrosis has been reported in two HCC patients after few months of sorafenib treatment only, without any history of BPS treatment: in one case it was an ONJ [42], and in the other, a bilateral osteonecrosis of femoral heads was developed [43]. At variance, several are the reports of the occurrence of ONJ during both sorafenib and BPS therapy in RCC patients. According to these studies, this adverse event occurred after an exposure to sorafenib varying from 5 to 36 months and always when sorafenib was used in combination with BPS for bone metastases control [12, 45]. To our knowledge, no cases of MRONJ in thyroid cancer patients treated with sorafenib are present in the literature.\n\nLenvatinib is another oral TKI with high anti-angiogenic activity, able to inhibit VEGF1-3, FGF1-4, PDGF, KIT, and RET receptors. To date, lenvatinib is approved for the treatment of 131I refractory differentiated thyroid cancer, for HCC, and, in combination with everolimus, for RCC. To date, one single case of MRONJ in thyroid cancer patients treated with lenvatinib is described [41]. In particular, Mauceri et al. [41] described a patient with Hürthle cell thyroid cancer, that, since a metastatic progressive disease occurred after initial standard treatment, started a systemic therapy with lenvatinib. After 12 months of lenvatinib intake, the maxillary left first molar was extracted because of deep caries. Healing of the socket was never achieved and, two months after the dental extraction, intraoral examination revealed clinical signs of MRONJ. Treatment with lenvatinib was discontinued by the oncologist and the patient was treated with a combination of ampicillin and sulbactam (1 g intramuscularly twice daily for 7 days) and metronidazole (500 mg orally three times daily for 7 days). Chlorhexidine 0.2% mouthwash (30 ml swished for up to 60 s, three times daily for 14 days) and sodium hyaluronate (local application three times daily for 14 days) were also used. At the latest follow-up, after 6 months, the patient was asymptomatic and the intraoral fistulas had healed.\n\nCabozantinib is another oral TKI able to inhibit MET, VEGFR2 and RET. It is approved for the treatment of RCC and MTC. Also for cabozantinib a single case of MRONJ occurred in one MTC patient was described [46]. In the paper the authors described the onset of MRONJ in an MTC female patient, enrolled in a double-blind, phase 3 trial, testing the efficacy of orally administered cabozantinib. Three months after the initial intake of cabozantinib, the mandibular left first molar was extracted because of deep caries but no healing of the socket was achieved. Intraoral examination revealed local signs of inflammation and infection, with slight purulent exudation. Orthopantomogram revealed an incomplete bone remodelling of the mandibular left first molar socket and a further assessment by CT scan showed irregularity of the alveolar cortical margin and a sclerotic reaction. Cabozantinib was not discontinued, nor were other prescriptions changed. Since surgical debridement of the socket and antibiotic therapy did not achieve clinical improvement, a segmental ostectomy was performed along with extracting the mandibular left second molar and maintaining antibiotic and antiseptic therapy (oral amoxicillin clavulanate and chlorhexidine 0.2% mouthwash) until mucosal healing had been achieved. Histological assessment of the specimen confirmed the presence of atypical bone necrosis. At a 4‐year follow‐up, the patient remains free of lesions and symptoms.\n\nVery recently, another case of a 61-years old male patient who developed an advanced and unusual case of stage 3 peri-implantitis-induced MRONJ involving the right upper jaw was described by Bennardo et al [47]. For a metastatic RCC, starting from May 2017, the patient received interleukin-2 subcutaneously 3 weeks a month, twice a day for 5 days a week, and then, from June 2017, bevacizumab, every 2 weeks, for 6 months. He also underwent a monthly 4 mg infusion of zoledronic acid for five cycles, which was then replaced, in December 2017, by denosumab every 4 weeks, until September 2019. Moreover, from May to September 2019, he also received nivolumab (10 mg/ml), and then cabozantinib (60 mg). Timing of appearance of ONJ in relation to multidrug therapy was not reported.\n\nTo our knowledge to date, no case of MRONJ was described in thyroid cancer patients treated with vandetanib in combination or not with BPS.\n\nTable 1 summarizes the case reports of MRONJ occurred during TKI treatment used in thyroid cancer or in other solid tumors.Table 1 case reports of osteonecrosis of the jaw described in the literature related to tyrosine kinase (TKI) or to TKI and bisphosphonates (BPS)\n\nTKI\tCase report\tTKI or TKI + BPS\tTiming of ONJ appearance after TKI/TKI + BPS inception\tType of treated tumor/disease\t\nSorafenib\tGuillet et al.* [43]\tTKI alone\tAfter 10 months\tHCC\t\nGaruti et al. [42]\tTKI alone\tAfter 3 months\tHCC\t\nLenvatinib\tMauceri et al. [41]\tTKI alone\tAfter 14 months\tTC\t\nCabozantinib\tMarino et al. [46]\tTKI alone\tAfter 3 months\tTC\t\nBennardo et al. [47]\tMultidrug therapy, including TKI and BPS\tNot known\tRCC\t\nAxitinib\tPatel et al. [50]\tTKI alone (nivolumab and pazopanib in the previous years)\tAfter 6 months\tRCC\t\nImatinib\tOkubo-Sato et al. [51]\tTKI alone\tAfter 10 years\tCML\t\nGupta et al. [52]\tTKI alone\tAfter 2 months\tMPN with hypereosinophilia\t\nViviano et al. [53]\tTKI alone\tAfter 22 months\tGIST\t\nSunitinib\tAshrafi et al. [54]\tTKI and BPS\tAfter 5 months from TKI inception\n\nAfter 2 months from BPS inception\n\n\tRCC\t\nAgrillo et al. [55]\tTKI and BPS (2 cases reported)\tNot known\tRCC\t\nFleissig et al. [56]\tTKI alone\tNot reported\tRCC\t\nNicolatou-Galitis et al. [57]\tTKI + cisplatinum (case 1)\n\nTKI alone (case 2)\n\n\tNot reported\n\nAfter 18 months\n\n\tRCC\t\nHoefert et al. [58]\tTKI and BPS (case 1)\n\nTKI and BPS (case 2)\n\nTKI and BPS (case 3)\n\n\tAfter 6 months\n\nAfter 19 months\n\nAfter 27 months from TKI inception and after 15 months from BPS inception\n\n\tRCC\t\nBozas et al. [59]\tTKI and BPS\tAfter 5 months from TKI and 4 days after BPS inception\tRCC\t\nKoch et al. [60]\tTKI\tAfter 12 months\tRCC\t\nBrunello et al. [10]\tTKI and BPS\tAfter 4 months from TKI inception and after 17 months from BPS inception\tRCC\t\nEverolimus\tAkkach et al. [61]\tTKI\tAfter 6 months\tKidney transplant\t\nYamamoto et al. [62]\tTKI\tAfter 2 months\tBreast cancer\t\nOmarini et al. [63]\tTKI and BPS\tAfter 19 months from TKI inception\n\nAfter 1 month from BPS inception\n\n\tBreast cancer\t\nGiancola et al. [64]\tTKI and BPS\tAfter 18 months from TKI inception and after 27 months from BPS inception\tRCC\t\nKim et al. [65]\tTKI and BPS\tAfter 3 years from TKI inception and after 6 years of BPS inception\tMTC\t\nCML chronic myelogenous leukemia, GIST gastrointestinal stromal tumors, HCC hepatocellular cancer, MPN myeloproliferative neoplasm, RRC renal cell cancer, TC thyroid cancer\n\n*Osteonecrosis of femoral heads\n\nOur experience with ONJ related to BPS and TKI\n\nA 53-years-old male patient was referred to the Department of Endocrinology, University of Pisa, for a follicular thyroid cancer, with poorly differentiated areas (T3aN0M0). In 1999 he was treated with total thyroidectomy, followed by radioiodine (131I) therapy (130 mCi), without subsequent salivary glands symptoms. A remission of the disease was documented after initial treatment.\n\nSince 2003, a progressive thyroglobulin (Tg) increasing levels were observed without any evidence of structural disease.\n\nIn 2006, a significant increase of serum thyroglobulin values (from 1.1 ng/ml in 2003 to 50 ng/ml in 2006) associated with local relapse of the disease in thyroid bed and lung micrometastases were documented. The structural disease remained stable until January 2010, when a progression of local disease was documented, and the patient underwent a further surgical treatment followed by neck and mediastinal external radiotherapy for a total amount of 60 Gy. Mandibular and maxillary bones were not involved when external beam radiation on the neck was performed.\n\nTen months after the last surgery and 8 months after radiotherapy, a further recurrence of local disease in the neck, a numeric and dimensional increase of the lung micrometastases, and the appearance of an osteolytic bone lesion (4.5 cm) of the right clavicle were documented, and, in November 2010, the patient was enrolled in the study protocol “Bayer 14295 Clinical trial on the advance/metastatic radioiodine-refractory DTC (NCT00984282)”. He was assigned to the placebo arm.\n\nIn May 2012, about 2 years after enrollment, a significant dimensional progression of the right clavicular lesion with pathological fracture occurred and the appearance of an osteolytic lesion of the left iliac bone was documented. According to protocol indications, the patient entered a cross-over phase, starting 800 mg per day of sorafenib. After 3 months of TKI therapy, based on the presence of bone metastases with local pain, intravenous zoledronic acid therapy was associated with sorafenib treatment, preceded by both an accurate clinical and radiological (orthopantomography) dental examination and the cure of the oral cavity.\n\nFor the bone involvement, a local treatment was evaluated and a left iliac lytic lesion percutaneous microwave thermoablation was performed in February 2013. The neoplastic disease remained substantially stable according to the following tbCT scan and to the biochemical examination but, for the appearance of local pain, external radiotherapy was performed on the right clavicular bone lesion in February–March 2013.\n\nIn July 2014, 2 years after its inception, the zoledronic acid therapy was permanently discontinued for a dental infection that was completely cured with antibiotic drugs.\n\nIn December 2016, about four years after the inception of sorafenib, the patient came to our attention complaining bilateral maxillary and mandibular pain with difficulty in feeding. A clinical examination of the oral cavity showed a large gingival lesion with bone exposure in the mandibular body (Fig. 1, panel A), both on the right (Fig. 1, panel B) and on the left (Fig. 1, panel C), and smaller lesions in the maxilla, bilaterally (Fig. 1, panel D). An odontostomatological consultation diagnosed an extensive aseptic bone necrosis with the appearance of radicular residues and consequently, a surgical removal of those radicular parts and a surgical curettage of the jaw alveolar bone bilaterally were performed.\n\nA CT scan of the skull performed 1 month later, showed an inflammatory morphological pattern of the left maxillary bone, that involved soft tissues, with bone erosion, in communication with the oral cavity (Fig. 2). A further radiological evaluation concluded that maxilla and mandibular bone were both compromised and that the alterations observed were compatible with a ONJ. After a multidisciplinary meeting, including a neuroradiologist, an odontologist, and a maxilla-facial surgeon, sorafenib was discontinued and antibiotic therapy was administered to perform a surgical toilette. In March 2017, the patient underwent surgical removal of a tooth and an osteotomy of the necrotic bone, and a further surgical toilette of maxillary necrotic lesions was performed two months later.Fig. 2 CT scan of the skull image showing an inflammatory morphological pattern of the left maxillary bone with bone erosion, in communication with the oral cavity. The inflammatory lesion involved the contiguous soft tissues too\n\nSince the appearance of ONJ sorafenib treatment was discontinued several times to perform surgical toilettes and to let surgical lesions to heal. As per protocol, only when a grade 2 of ONJ adverse event was obtained, sorafenib was started again.\n\nDuring 2018 and 2019 the patient underwent several radiological procedures and odontostomatological consultations that showed a stable alteration of jaws. Regarding thyroid neoplastic disease, in February 2018 patient underwent a thoracotomy to remove a 6th right rib metastatic lesion and, in May 2019, an embolization and cryoablation of a metastatic bone lesion of the left ilio-pubic branch. A further progression of the disease-induced us to definitively stop sorafenib and start another TKI, lenvatinib, but a worsening of clinical condition occurred and the patient died in April 2020.\n\nConclusions\n\nSince, currently, TKI therapy is widely used not only for the treatment of RAI-refractory DTC but for advanced MTC too, and since their association with BPS is frequent when bone metastases are present, endocrinologists/oncologists, dealing with thyroid cancer, should pay attention on this possible side effect due to these drugs, especially when they are used in association.\n\nMetastatic bone disease, as well as in the case we presented, represents a challenging clinical problem in patients with RAI-refractory DTC and metastastic MTC. Since TKIs appear to be less effective in controlling bone metastatic disease in comparison to metastatic disease occurring in other soft tissues (i.e. lungs, liver, and lymph nodes), and a high rate of multiple skeletal-related events following the detection of an initial bone lesion are frequent, according to the current guidelines on DTC management [48], BPS (or denosumab) therapy should be considered in patients with diffuse and/or symptomatic bone metastases from RAI-refractory DTC, either alone or concomitantly with other systemic therapies.\n\nTo significantly reduced the risk of ONJ appearance, preventive measures such as oral examinations with appropriate radiographs, oral hygiene instructions, maintenance of good oral health, completion of necessary dental treatments, should always proposed to patients before initiating not only antiresorptive therapy but also antiangiogenic agents and TKIs. Regular dental examinations during the treatment should also encourage earlier treatment of the non-exposed variant of the traditional ONJ.\n\nUnfortunately, when an ONJ occurred during TKI and BPS treatments, it really worsens the quality of life of cancer patients [19, 49], and we should consider that in the case of ONJ it becomes necessary a TKI discontinuation that could lead to a progression of neoplastic disease. A multidisciplinary approach for this kind of patient could be the best practice to avoid an underestimation of both the ONJ, that can have a variable spectrum of presentation and staging, and of the metastatic disease that becomes a high risk of progression if the antineoplastic drug(s) are discontinued.\n\nAuthor contributions\n\nLL and LA were the subinvestigators in DECISION study and they contributed to preparing the manuscript. LP, DV, ME, BV have been involved in the medical follow-up of the patient and collected all clinical data. MG and MS have been involved in surgical evaluation and treatment of the osteonecrosis of the patient. RE was the principal investigator of the DECISION study and she carefully revised the manuscript.\n\nFunding\n\nOpen access funding provided by Università di Pisa within the CRUI-CARE Agreement. PRIN project 2017YTWKWH was financed by “Ministero dell'Università e della Ricerca Scientifica”.\n\nAvailability of data and materials\n\nNot applicable.\n\nCode availability\n\nNot applicable.\n\nDeclarations\n\nConflicts of interest\n\nLorusso Loredana, Pieruzzi Letizia, Gabriele Mario, Nisi Marco, Viola David, Molinaro Eleonora, Bottici Valeria, and Agate Laura have nothing to disclose and no competing financial interests exist. Elisei Rossella is consultant for Bayer, EISAI, Loxo, Ipsen, Lilly.\n\nEthics approval\n\nNot applicable.\n\nConsent to participate and for publication\n\nThe patient gave his consent to participate and to publish his clinical data.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Marx RE Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic J Oral Maxillofac Surg 2003 61 1115 1117 10.1016/S0278-2391(03)00720-1 12966493\n2. Ruggiero SL Mehrotra B Rosenberg TJ Engroff SL Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases J Oral Maxillofac Surg 2004 62 527 534 10.1016/j.joms.2004.02.004 15122554\n3. Pollock RA Brown TW Rubin DM “Phossy Jaw” and “Bis-phossy Jaw” of the 19th and the 21st centuries: the diuturnity of John Walker and the friction Match Craniomaxillofac Trauma Reconstr 2015 8 262 270 10.1055/s-0035-1558452 27053988\n4. Jacobsen C Zemann W Obwegeser JA Grätz KW Metzler P The phosphorous necrosis of the jaws and what can we learn from the past: a comparison of “phossy” and “bisphossy” jaw Oral Maxillofac Surg 2014 18 31 37 10.1007/s10006-012-0376-z 23271457\n5. Otto S Pautke C Van den Wyngaert T Niepel D Schiødt M Medication-related osteonecrosis of the jaw: prevention, diagnosis and management in patients with cancer and bone metastases Cancer Treat Rev 2018 69 177 187 10.1016/j.ctrv.2018.06.007 30055439\n6. 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Schiodt M Reibel J Oturai P Kofod T Comparison of nonexposed and exposed bisphosphonate-induced osteonecrosis of the jaws: a retrospective analysis from the Copenhagen cohort and a proposal for an updated classification system Oral Surg Oral Med Oral Pathol Oral Radiol 2014 117 204 213 10.1016/j.oooo.2013.10.010 24332520\n28. Bagan JV Hens-Aumente E Leopoldo-Rodado M Poveda-Roda R Bagan L Bisphosphonate-related osteonecrosis of the jaws: study of the staging system in a series of clinical cases Oral Oncol 2012 48 753 757 10.1016/j.oraloncology.2012.02.009 22401869\n29. Devlin H Greenwall-Cohen J Benton J Goodwin TL Littlewood A Horner K Detecting the earliest radiological signs of bisphosphonate-related osteonecrosis Br Dent J 2018 10.1038/sj.bdj.2017.1001 29192692\n30. Taniguchi T Ariji Y Nozawa M Naitoh M Kuroiwa Y Kurita K Ariji E Computed tomographic assessment of early changes of the mandible in bisphosphonate-treated patients Oral Surg Oral Med Oral Pathol Oral Radiol 2016 122 362 372 10.1016/j.oooo.2016.06.002 27544397\n31. Hamada H Matsuo A Koizumi T Satomi T Chikazu D A simple evaluation method for early detection of bisphosphonate-related osteonecrosis of the mandible using computed tomography J Cranio-Maxillofac Surg 2014 42 924 929 10.1016/j.jcms.2014.01.012\n32. Iwata E Akashi M Kishimoto M Kusumoto J Hasegawa T Furudoi S Komori T Meaning and limitation of cortical bone width measurement with DentaScan in medication-related osteonecrosis of the jaws Kobe J Med Sci 2016 62 E114 E119\n33. Dimopoulos MA Kastritis E Bamia C Melakopoulos I Gika D Roussou M Migkou M Eleftherakis-Papaiakovou E Christoulas D Terpos E Reduction of osteonecrosis of the jaw (ONJ) after implementation of preventive measures in patients with multiple myeloma treated with zoledronic acid Ann Oncol 2009 20 117 120 10.1093/annonc/mdn554 18689864\n34. Ripamonti CI Maniezzo M Campa T Fagnoni E Brunelli C Saibene G Bareggi C Ascani L Cislaghi E Decreased occurrence of osteonecrosis of the jaw after implementation of dental preventive measures in solid tumour patients with bone metastases treated with bisphosphonates. The experience of the National Cancer Institute of Milan Ann Oncol 2009 20 137 145 10.1093/annonc/mdn526 18647964\n35. Bonacina R Mariani U Villa F Villa A Preventive strategies and clinical implications for bisphosphonate-related osteonecrosis of the Jaw: a review of 282 patients J Can Dent Assoc 2011 77 b147 22129778\n36. Xing M Recent advances in molecular biology of thyroid cancer and their clinical implications Otolaryngol Clin N Am 2008 41 1135 1146 10.1016/j.otc.2008.07.001\n37. Brose MS Nutting CM Jarzab B Elisei R Siena S Bastholt L De La Fouchardiere C Pacini F Paschke R Shong YK Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial The Lancet 2014 384 319 328 10.1016/S0140-6736(14)60421-9\n38. Schlumberger M Tahara M Wirth LJ Robinson B Brose MS Elisei R Habra MA Newbold K Shah MH Hoff AO Lenvatinib versus placebo in radioiodine-refractory thyroid cancer N Engl J Med 2015 372 621 630 10.1056/nejmoa1406470 25671254\n39. Wells SA Robinson BG Gagel RF Dralle H Fagin JA Santoro M Baudin E Elisei R Jarzab B Vasselli JR Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial J Clin Oncol 2012 30 134 141 10.1200/JCO.2011.35.5040 22025146\n40. Elisei R Schlumberger MJ Müller SP Schöffski P Brose MS Shah MH Licitra L Jarzab B Medvedev V Kreissl MC Cabozantinib in progressive medullary thyroid cancer J Clin Oncol 2013 31 3639 3646 10.1200/JCO.2012.48.4659 24002501\n41. Mauceri R Panzarella V Morreale I Campisi G Medication-related osteonecrosis of the jaw in a cancer patient receiving lenvatinib Int J Oral Maxillofac Surg 2019 48 1530 1532 10.1016/j.ijom.2019.07.010 31378564\n42. Garuti F Camelli V Spinardi L Bucci L Trevisani F Osteonecrosis of the jaw during sorafenib therapy for hepatocellular carcinoma Tumori 2016 102 S69 S70 10.5301/tj.5000504\n43. Guillet M Walter T Scoazec JY Vial T Lombard-Bohas C Dumortier J Sorafenib-induced bilateral osteonecrosis of femoral heads J Clin Oncol 2010 10.1200/JCO.2009.23.4252 19884542\n44. Smidt-Hansen T Folkmar TB Fode K Agerbaek M Donskov F Combination of zoledronic acid and targeted therapy is active but may induce osteonecrosis of the jaw in patients with metastatic renal cell carcinoma J Oral Maxillofac Surg 2013 71 1532 1540 10.1016/j.joms.2013.03.019 23642545\n45. Beuselinck B Wolter P Karadimou A Elaidi R Dumez H Rogiers A Van Cann T Willems L Body JJ Berkers J Concomitant oral tyrosine kinase inhibitors and bisphosphonates in advanced renal cell carcinoma with bone metastases Br J Cancer 2012 107 1665 1671 10.1038/bjc.2012.385 23132391\n46. Marino R Orlandi F Arecco F Gandolfo S Pentenero M Osteonecrosis of the jaw in a patient receiving cabozantinib Aust Dent J 2015 60 528 531 10.1111/adj.12254 25474298\n47. Bennardo F Buffone C Muraca D Antonelli A Giudice A Medication-related osteonecrosis of the jaw with spontaneous hemimaxilla exfoliation: report of a case in metastatic renal cancer patient under multidrug therapy Case Rep Med 2020 10.1155/2020/8093293 33144863\n48. Haugen BR Alexander EK Bible KC Doherty GM Mandel SJ Nikiforov YE Pacini F Randolph GW Sawka AM Schlumberger M 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association Guidelines Task Force on thyroid nodules and differentiated thyroid cancer Thyroid 2016 26 1 133 10.1089/thy.2015.0020 26462967\n49. Capocci M Romeo U Guerra F Mannocci A Tenore G Annibali S Ottolenghi L Medication-related osteonecrosis of the jaws (MRONJ) and quality of life evaluation: a pilot study Clin Ter 2017 168 e253 e257 10.7417/T.2017.2015 28703840\n50. Patel V Sproat C Kwok J Tanna N Axitinib-related osteonecrosis of the jaw Oral Surg Oral Med Oral Pathol Oral Radiol 2017 124 e257 e260 10.1016/j.oooo.2017.08.003 28918879\n51. Okubo-Sato M Yamagata K Fukuzawa S Terada K Uchida F Ishibashi-Kanno N Bukawa H Medication-related osteonecrosis of the jaw spontaneously occurred in a patient with chronic myelogenous leukemia only by imatinib: a report of a rare case Case Reports in Dentistry 2021 10.1155/2021/6621937 33575044\n52. Gupta L Dholam K Janghel Y Gurav SV Osteonecrosis of the jaw associated with imatinib therapy in myeloproliferative neoplasm: a rare case report Oral Surg Oral Med Oral Pathol Oral Radiol 2021 131 e157 e162 10.1016/j.oooo.2020.10.005 33187944\n53. Viviano M Rossi M Cocca S A rare case of osteonecrosis of the jaw related to imatinib J Korean Assoc Oral Maxillofac Surg 2017 43 120 124 10.5125/JKAOMS.2017.43.2.120 28462197\n54. Ashrafi F Derakhshandeh A Movahedian B Moghaddas A Osteonecrosis of the jaws in patient received bisphosphonates and sunitinib separately: a case report J Res Pharm Pract 2017 6 182 10.4103/jrpp.jrpp_17_36 29026845\n55. Agrillo A Siniscalchi EN Facchini A Filiaci F Ungari C Osteonecrosis of the jaws in patients assuming bisphosphonates and sunitinib: two case reports Eur Rev Med Pharmacol Sci 2012 16 952 957 22953645\n56. Fleissig Y Regev E Lehman H Sunitinib related osteonecrosis of jaw: a case report Oral Surg Oral Med Oral Pathol Oral Radiol 2012 10.1016/j.tripleo.2011.06.023 22676833\n57. Nicolatou-Galitis O Migkou M Psyrri A Bamias A Pectasides D Economopoulos T Raber-Durlacher JE Dimitriadis G Dimopoulos MA Gingival bleeding and jaw bone necrosis in patients with metastatic renal cell carcinoma receiving sunitinib: report of 2 cases with clinical implications Oral Surg Oral Med Oral Pathol Oral Radiol 2012 113 234 238 10.1016/j.tripleo.2011.08.024 22669112\n58. Hoefert S Eufinger H Sunitinib may raise the risk of bisphosphonate-related osteonecrosis of the jaw: presentation of three cases Oral Surg Oral Med Oral Pathol Oral Radiol Endodontol 2010 110 463 469 10.1016/j.tripleo.2010.04.049\n59. Bozas G Roy A Ramasamy V Maraveyas A Osteonecrosis of the jaw after a single bisphosphonate infusion in a patient with metastatic renal cancer treated with sunitinib Onkologie 2010 33 321 323 10.1159/000313680 20523097\n60. Koch FP Walter C Hansen T Jäger E Wagner W Osteonecrosis of the jaw related to sunitinib Oral Maxillofac Surg 2011 15 63 66 10.1007/s10006-010-0224-y 20401503\n61. Akkach S Shukla L Morgan D Everolimus-induced osteonecrosis of the jaw in the absence of bisphosphonates: a case report Br J Oral Maxillofac Surg 2019 57 688 690 10.1016/j.bjoms.2019.05.017 31202510\n62. Yamamoto D Tsubota Y Utsunomiya T Sueoka N Ueda A Endo K Yoshikawa K Kon M Osteonecrosis of the jaw associated with everolimus: a case report Mol Clin Oncol 2017 6 255 257 10.3892/mco.2016.1100 28357105\n63. Omarini C Filieri ME Depenni R Grizzi G Cascinu S Piacentini F Osteonecrosis of the jaw in a breast cancer patient treated with everolimus and a single dose of zoledronic acid Breast J 2017 23 610 611 10.1111/tbj.12808 28328105\n64. Giancola F Campisi G Lo-Russo L Muzio LL Di Fede O Osteonecrosis of the jaw related to everolimus and bisphosphonate: a unique case report? Ann Stomatol (Roma) 2013 4 Suppl 2 20\n65. Kim DW Jung YS Park HS Jung HD Osteonecrosis of the jaw related to everolimus: a case report Br J Oral Maxillofac Surg 2013 10.1016/j.bjoms.2013.09.008 24360715\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0391-4097",
"issue": "44(12)",
"journal": "Journal of endocrinological investigation",
"keywords": "Osteonecrosis of the jaw; Sorafenib adverse event; Thyroid cancer; Tyrosine-kinase inhibitors therapy; Zoledronic acid",
"medline_ta": "J Endocrinol Invest",
"mesh_terms": null,
"nlm_unique_id": "7806594",
"other_id": null,
"pages": "2557-2566",
"pmc": null,
"pmid": "34291429",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "33934057;33187944;25414052;24094895;17663640;27079903;30055439;20401503;28918879;28963584;26462967;29026845;19212145;25234529;28703840;15122554;21498483;28462197;31378564;22003964;12966493;33575044;28289268;22401869;22129778;25586958;22025146;18849018;24002501;30153366;24353782;21537047;19884542;24503386;18647964;20692189;20523097;30713280;27053988;28328105;28357105;20464477;27544397;19836866;25282593;18689864;24768112;22676833;25474298;23089584;25671254;22711458;22986334;23271457;23642545;29192692;31202510;24332520;23132391;33144863;19040974;22669112;27956123;22953645;23684411",
"title": "Osteonecrosis of the jaw: a rare but possible side effect in thyroid cancer patients treated with tyrosine-kinase inhibitors and bisphosphonates.",
"title_normalized": "osteonecrosis of the jaw a rare but possible side effect in thyroid cancer patients treated with tyrosine kinase inhibitors and bisphosphonates"
} | [
{
"companynumb": "IT-PFIZER INC-202100963163",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
},
"drugadditional": "4",
... |
{
"abstract": "HSCT has been linked to the development of an assortment of ocular surface complications with the potential to lead to permanent visual impairment if left untreated or if not treated early in the course of disease. Strategies for therapy include maintenance of lubrication and tear preservation, prevention of evaporation, decreasing inflammation, and providing epithelial support. The ultimate aim of treatment is to prevent permanent ocular sequelae through prompt ophthalmology consultation and the use of advanced techniques for ocular surface rehabilitation. We describe several rehabilitation options of ocular surface complications occurring secondarily during the post-HSCT course.",
"affiliations": "Section of Ophthalmology, Department of Surgery, Children's Mercy Hospitals and Clinics, Kansas City, MO, USA.;School of Medicine, University of Missouri - Kansas City, Kansas City, MO, USA.;School of Medicine, University of Missouri - Kansas City, Kansas City, MO, USA.;Section of Hematology/Oncology/BMT, Department of Pediatrics, Children's Mercy Hospitals and Clinics, Kansas City, MO, USA.",
"authors": "Stahl|Erin D|ED|http://orcid.org/0000-0002-3951-1700;Mahomed|Faheem|F|;Hans|Amneet K|AK|;Dalal|Jignesh D|JD|",
"chemical_list": "D000900:Anti-Bacterial Agents; D065346:Lubricant Eye Drops; D013256:Steroids",
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.12678",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "20(3)",
"journal": "Pediatric transplantation",
"keywords": "bone marrow transplantation; complications; graft-vs-host disease; ocular",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D000287:Administration, Topical; D000293:Adolescent; D000650:Amnion; D000755:Anemia, Sickle Cell; D000900:Anti-Bacterial Agents; D002648:Child; D005128:Eye Diseases; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007249:Inflammation; D065346:Lubricant Eye Drops; D008297:Male; D009885:Ophthalmology; D012590:Sclera; D013256:Steroids; D013997:Time Factors; D014180:Transplantation; D019737:Transplants",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "438-42",
"pmc": null,
"pmid": "26869458",
"pubdate": "2016-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Transplant related ocular surface disorders: Advanced techniques for ocular surface rehabilitation after ocular complications secondary to hematopoietic stem cell transplantation.",
"title_normalized": "transplant related ocular surface disorders advanced techniques for ocular surface rehabilitation after ocular complications secondary to hematopoietic stem cell transplantation"
} | [
{
"companynumb": "US-OTSUKA-2016_010785",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
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... |
{
"abstract": "BACKGROUND\nNeurological involvement has been reported in up to 80% of adults with Primary Sjogren's syndrome (pSS) with psychiatric abnormalities including anxiety, depression, and cognitive dysfunction being common. Psychosis due to pSS has been reported in adult patients but has never been previously reported in the adolescent/pediatric literature. Here we describe for the first time four cases of adolescent Sjogren's syndrome that presented with psychotic symptoms. Rituximab treatment was followed by improvement of psychiatric symptoms in all patients.\n\n\nMETHODS\n1: 16 year old female without significant past medical history presented to the emergency department with 4 days of abnormal behavior, tremors, insomnia, polyphagia, polyuria, and suicidal ideation. 2: 16 year old female with a 4 year history of severe anxiety, OCD, and tic disorder treated with fluoxetine with partial benefit presented with an abrupt and severe worsening of anxiety, OCD and new auditory hallucinations. 3: 19 year old female without significant past medical history presented with a 3 day history of progressively altered behavior, incoherent speech, insomnia, headache, and tangential thoughts. 4: 17 year old female without significant past medical history presented with new onset suicidal ideation, paranoia, confusion, and emotional lability.\n\n\nCONCLUSIONS\nPsychosis is more common in autoimmune disease than previously known. To our knowledge, the four teenage women described above are the first reported patients with adolescent pSS manifesting as psychosis. pSS should be considered in the differential diagnosis of young patients with new psychiatric disorders, even in the absence of sicca symptoms. Psychiatric symptoms improved with rituximab infusions in all 4 of our patients, which suggests rituximab may be an effective treatment option that should be considered early after the diagnosis of pSS-associated psychiatric disturbance.",
"affiliations": "Department of Pediatrics, Division of Rheumatology at Rady Children's Hospital, 3020 Childrens Way, San Diego, Ca, 92123, USA. erinkenneysd@gmail.com.;Department of Pediatrics, Division of Neurology at Children's Hospital at Montefiore, 3415 Bainbridge Ave, Bronx, NY, 10467, USA.;Department of Pediatrics, Division of Rheumatology at Children's of Alabama, University of Alabama at Birmingham, 1600 7th Ave S, CPPN, Suite G10, Birmingham, AL, 35233-1711, USA.;Department of Pediatrics, Division of Allergy, Immunology, and Rheumatology at Columbia University Medical Center, 630 W 168th St, New York, NY, 10032, USA.;Department of Pediatrics, Division of Rheumatology at Children's of Alabama, University of Alabama at Birmingham, 1600 7th Ave S, CPPN, Suite G10, Birmingham, AL, 35233-1711, USA.;Department of Pediatrics, Division of Rheumatology at Rady Children's Hospital, 3020 Childrens Way, San Diego, Ca, 92123, USA.",
"authors": "Hammett|Erin K|EK|http://orcid.org/0000-0003-4729-159X;Fernandez-Carbonell|Cristina|C|;Crayne|Courtney|C|;Boneparth|Alexis|A|;Cron|Randy Q|RQ|;Radhakrishna|Suhas M|SM|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D014150:Antipsychotic Agents; D018501:Antirheumatic Agents; D005938:Glucocorticoids; D000069283:Rituximab; C543332:obinutuzumab",
"country": "England",
"delete": false,
"doi": "10.1186/s12969-020-0412-8",
"fulltext": "\n==== Front\nPediatr Rheumatol Online JPediatr Rheumatol Online JPediatric Rheumatology Online Journal1546-0096BioMed Central London 41210.1186/s12969-020-0412-8Case ReportAdolescent Sjogren’s syndrome presenting as psychosis: a case series http://orcid.org/0000-0003-4729-159XHammett Erin K. erinkenneysd@gmail.com 1Fernandez-Carbonell Cristina cfernandezca@northwell.edu 2Crayne Courtney ccrayne@uabmc.edu 3Boneparth Alexis Ab4459@cumc.columbia.edu 4Cron Randy Q. rcron@peds.uab.edu 3Radhakrishna Suhas M. sradh@ucsd.edu 11 0000 0004 0383 2910grid.286440.cDepartment of Pediatrics, Division of Rheumatology at Rady Children’s Hospital, 3020 Childrens Way, San Diego, Ca 92123 USA 2 0000 0004 0566 7955grid.414114.5Department of Pediatrics, Division of Neurology at Children’s Hospital at Montefiore, 3415 Bainbridge Ave, Bronx, NY 10467 USA 3 0000000106344187grid.265892.2Department of Pediatrics, Division of Rheumatology at Children’s of Alabama, University of Alabama at Birmingham, 1600 7th Ave S, CPPN, Suite G10, Birmingham, AL 35233-1711 USA 4 0000 0001 2285 2675grid.239585.0Department of Pediatrics, Division of Allergy, Immunology, and Rheumatology at Columbia University Medical Center, 630 W 168th St, New York, NY 10032 USA 11 2 2020 11 2 2020 2020 18 159 10 2019 3 2 2020 © The Author(s). 2020Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nNeurological involvement has been reported in up to 80% of adults with Primary Sjogren’s syndrome (pSS) with psychiatric abnormalities including anxiety, depression, and cognitive dysfunction being common. Psychosis due to pSS has been reported in adult patients but has never been previously reported in the adolescent/pediatric literature. Here we describe for the first time four cases of adolescent Sjogren’s syndrome that presented with psychotic symptoms. Rituximab treatment was followed by improvement of psychiatric symptoms in all patients.\n\nCase presentation\n1: 16 year old female without significant past medical history presented to the emergency department with 4 days of abnormal behavior, tremors, insomnia, polyphagia, polyuria, and suicidal ideation.\n\n2: 16 year old female with a 4 year history of severe anxiety, OCD, and tic disorder treated with fluoxetine with partial benefit presented with an abrupt and severe worsening of anxiety, OCD and new auditory hallucinations.\n\n3: 19 year old female without significant past medical history presented with a 3 day history of progressively altered behavior, incoherent speech, insomnia, headache, and tangential thoughts.\n\n4: 17 year old female without significant past medical history presented with new onset suicidal ideation, paranoia, confusion, and emotional lability.\n\nConclusion\nPsychosis is more common in autoimmune disease than previously known. To our knowledge, the four teenage women described above are the first reported patients with adolescent pSS manifesting as psychosis. pSS should be considered in the differential diagnosis of young patients with new psychiatric disorders, even in the absence of sicca symptoms. Psychiatric symptoms improved with rituximab infusions in all 4 of our patients, which suggests rituximab may be an effective treatment option that should be considered early after the diagnosis of pSS-associated psychiatric disturbance.\n\nKeywords\nCentral nervous system (CNS) Sjogren’s syndromePediatric Sjogren’s syndromePsychosisissue-copyright-statement© The Author(s) 2020\n==== Body\nIntroduction\nPrimary Sjogren’s syndrome (pSS) is a systemic autoimmune disease typically characterized by plasma-lymphocytic infiltration of the salivary and lacrimal glands. Dry mouth is a common presenting complaint in adults, while parotid swelling may be a more frequently encountered in children [1]. While inflammation is primarily directed toward the exocrine glands, extraglandular manifestations can include arthritis, Raynaud’s phenomenon, purpura, pulmonary disease, renal disease, and neurological involvement. Sjogren’s syndrome can also occur as a secondary condition with underlying systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA). It most often affects middle-aged females with a prevalence of 0.1–3% and incidence of 3.9–5.3 yearly per 100,000 in the adult population [2]. No such epidemiologic data are available for children.\n\nNeurological involvement has been reported in up to 80% of adults with pSS [3, 4] and can preceed the diagnosis in up to 50–80% of the cases [5, 6]. Central nervous system (CNS) manifestations include aphasia, dysarthria, visual loss, aseptic meningitis, transverse myelitis, neuromyelitis optica, and cognitive dysfunction [6]. Psychiatric abnormalities have also been described including depression, anxiety, and cognitive deficits [3]. Psychosis has been reported in adult patients [3, 7–12] with pSS but has never been previously reported in the pediatric literature, although other psychiatric manifestations including major depressive disorder and obsessive compulsive disorder (OCD) have been described in pediatric patients [13].\n\nBrain magnetic resonance imaging (MRI) abnormalities, including non-enhancing T2 hyperintensities in the periventricular and subcortical areas, have been seen in up to 75% of adults with pSS and neuropsychiatric symptoms and 9% of adults with pSS without neuropsychiatric symptoms [14]. Abnormal electroencephalograms (EEG) are found in about 33–48% of patients with CNS pSS [15, 16]. Cerebrospinal fluid (CSF) analysis may be normal or show elevated IgG index [17]. Autopsy and brain biopsy studies in adults have also demonstrated inflammatory changes in pSS patients despite normal brain MRI and cerebral angiogram [18]. Biopsy findings in neurological involvement of Sjogren’s syndrome include small vessel vasculitis of the small cerebral blood vessels and direct inflammatory infiltration of cerebral tissue [15, 19]. There is also evidence for activation of the complement pathway [20]. Patients with anti-Sjogren’s syndrome type A (SSA) antibodies are more likely to have CNS disease than those with anti-Sjogren’s syndrome type B (SSB) [21]. Patients with HLA-DR3/DR4 may have greater risk of CNS disease while HLA-DR1, DR2, and DRw6 may be protective [22].\n\nTreatment for CNS manifestations of Sjogren’s syndrome has been empiric, guided by expert opinion and anecdotal reports. Some experts recommend monthly pulse cyclophosphamide for 6–12 months in patients with progressive nervous system dysfunction [15]. Other immunosuppressive medications used with varying success include azathioprine, methotrexate, and cyclosporine [23]. Rituximab has been used anecdotally in CNS pSS with varying results [24, 25].\n\nHere we describe for the first time four cases of adolescent Sjogren’s syndrome presenting with psychotic symptoms. Rituximab treatment was followed by improvement of psychiatric symptoms in all the patients.\n\nCase presentations\nCase 1\nA 16 year old female without significant past medical history presented to the emergency department (ED) with 4 days of abnormal behavior, tremors, insomnia, polyphagia, polyuria, and suicidal ideation. She reported that she was sexually assaulted and had ingested synthetic cathinones (bath salts). Physical exam was within normal limits (WNL). Laboratory evaluation with complete blood count (CBC), complete metabolic panel (CMP), and thyroid studies were within normal limits. Head computed tomography (CT) showed no acute intracranial abnormality. She was discharged with a diagnosis of drug-induced psychiatric disturbance.\n\nOver the course of the next few months the patient was seen in the ED six further times for suicidal ideation, drug use (methamphetamines and cocaine), and violence toward her family members. She had paranoid delusions that her family was trying to poison her and complained that “someone stole my nose.” She had mood lability and was noted to have abnormal hand gestures. She had cognitive deficits with inability to complete basic reading and writing assignments.\n\nThe patient was admitted to the hospital for further workup of psychosis, rheumatology was consulted for a recently discovered positive antinuclear antibody (ANA) of 1:1280 titer. She denied recent drug use in the last 6 months which her family confirmed. On physical exam she had tenderness to palpation of her parotid glands. Laboratory evaluation was positive for SSA > 8 (nl < 8) iu/ml. All other tests were within normal limits (Table 1): CBC, CMP, erythrocyte sedimentation rate (ESR), C reactive protein (CRP), urine analysis (UA), and urine drug screen were all normal. CSF cells, glucose and protein, C3 Complement (C3), C4 complement (C4) and thyroid stimulating hormone (TSH) were all also WNL. Antibodies to thyroid peroxidase (TPO), ANCA (antineutrophil cytoplasmic antibodies), double stranded deoxyribonucleic acid (dsDNA), ribosomal P, neuronal, N-methyl-D-aspartate receptor (NMDA), Smith, ribonucleoprotein (RNP), Beta 2 glycoprotein/cardiolipin, neuromyelitis optica (NMO)/aquaporin-4 (AQP4), and SSB were negative/WNL. Serum autoimmune encephalopathy panel (performed at Mayo lab) was negative. MRI of the brain showed symmetrical bilateral volume loss of the parietal lobes of uncertain significance. EEG was within normal limits (Table 2).\nTable 1 Presenting Lab Results\n\nInitial Labs\tCase 1\tCase 2\tCase 3\tCase 4\t\nCBC/CMP\tWNL\tWNL\tWNL\tAST 62 U/L, bilirubin 1.11 U/L\t\nSSA\t> 8 iu/mL\t4.8 AI\t4.8 AI\t8 iu/mL\t\nSSB\tNegative\t> 8 AI\t> 8 AI\tNegative\t\nCRP\tWNL\tWNL\t1.1 mg/dL\tWNL\t\nESR\tWNL\t57 mm/hr\t60 mm/hr\tWNL\t\nC3/C4\tWNL\tWNL\tWNL\tWNL/9.6 mg/dL\t\nANA\t1:1280 Speckled\t1:1280 Speckled\t1:160 mixed\t1:640 speckled\t\ndsDNA/Smith/RNP AB\tNegative\tNegative\tNegative\tNegative\t\nRibosomal P/Neuronal/NMDA AB\tNegative\tNegative\tNegative\tNegative\t\nAPS Panel\tNegative\tNegative\tNegative\tNegative\t\nEncephalopathy Panel\tNegative\tNegative\tNegative\tNegative\t\nTSH/TPO\tWNL/Negative\tWNL/Negative\tWNL/Negative\tWNL/Negative\t\nImmunoglobulins\tWNL\tIgG 2116 mg/dL\tWNL\tWNL\t\nRF\tWNL\t58.7 IU/mL\tWNL\tWNL\t\nUA/Utox\tWNL\tWNL\tWNL\tWNL\t\nKey:\n\nCBC complete blood count, CMP complete metabolic panel, AST Aspartate aminotransferase, SSA Sjogren’s syndrome type A, SSB Sjogren’s syndrome type B, CRP C reactive protein, ESR erythrocyte sedimentation rate, C3 C3 Complement, C4 C4 Complement, ANA antinuclear antibody, dsDNA double stranded deoxyribonucleic acid, RNP ribonucleoprotein, AB antibody, NMDA neuronal, N-methyl-D-aspartate receptor, APS antiphospholipid syndrome, TSH thyroid stimulating hormone, TPO thyroid peroxidase, RF rheumatoid factor, UA urinalysis, Utox Urine toxicology\n\n\nTable 2 Disease Summary by Case\n\n\tCase 1\tCase 2\tCase 3\tCase 4\t\nAge\t16\t16\t19\t17\t\nGender\tFemale\tFemale\tFemale\tFemale\t\nInitial Presentation\tInsomnia, polyphagia, polydipsia, SI, abnormal behavior\tAnxiety, OCD, auditory hallucinations\tAbnormal behavior, incoherent speech, insonia, HA, tangential thoughts\tSI, paranoia, confusion, emotional lability, intermittent unresponsiveness, nocturnal enuresis\t\nMRI Brain Findings\tBilateral volume loss of the parietal lobes\tL frontal lobe focus of white matter change\tWNL\tWNL\t\nCSF Findings\tWNL, no pleiocytosis or increased oligoclonal bands\tWNL, no pleiocytosis or increased oligoclonal bands\tWNL, no pleiocytosis or increased oligoclonal bands\tWNL, no pleiocytosis or increased oligoclonal bands\t\nEEG Findings\tWNL\tOccasional delta range slowing in the left fronto-central-temporal region\tWNL\tWNL\t\nInitial Immunosuppresive tx\tRituximab 1000 mg q 2 weeks × 2 and pulse methylprednisolone 1000 mg × 3 days followed by prednisone 60 mg tapered over 24 weeks\tRituximab 1000 mg × 1\tMethylprednisolone 30 mg/kg IV and rituximab 1000 mg q 2 weeks × 2\tMethylprednisolone (8 mg/kg/day IV) followed by oral prednisone (1.3 mg/kg/day) and IVIG 2 g/kg; then rituximab 1000 mg and pulse methylprednisolone; then IV plasmapharesis, rituximab 1000 mg and IV cyclophosphamide 750 mg/m2\t\nTime to Improvement\t2–5 months\t1–5 months\t2 months\t1 week - 7 months\t\nLength of Follow Up Since Initial tx\t18 months\t12 months\t18 months then lost to follow-up\t7 months\t\nTotal # rounds of anti-CD20 tx\t1\t2.5\t2\t2\t\nMaintenance Therapy\tNone\tObinutuzumab q 6 months\tRituximab 1000 mg q2 weeks × 2 every 6 months, mycophenolate mofetil 1500 mg bid\tRituximab 1000 mg q2 weeks × 2 every 6 months, hydroxychloroquine 200 mg daily and prednisone 0.65 mg/kg/day\t\nCurrently Off Antipsychotics?\tYes\tNo\tYes\tYes\t\nKey:\n\nOCD Obsessive compulsive disorder, WNL Within normal limits, Tx Treatment, SI Suicidal Ideation, HA Headache\n\n\n\nA minor salivary gland biopsy showed small foci of lymphoplasmacytic predominantly peri-ductal inflammatory infiltrate with > 50 infiltrates in three foci; giving her a focus score of 3. Schirmer’s test was abnormal at 5 mm bilaterally (normal > 10 mm) (Table 3). She was diagnosed with pSS based on the 2017 American College of Rheumatology (ACR)/European League Against Rheumatism classification criteria (EULAR) [26].\nTable 3 2016 ACR/EULAR Sjogren’s Classification Criteria Met\n\nSjogren’s Criteria\tCase 1\tCase 2\tCase 3\tCase 4\t\nanti-SSa Antibody (3 points)\tY\tY\tY\tY\t\nFocus score >1 (3 points)\tY\tNot performed\tY\tNot performed\t\nOcular Staining Score >5 or VBS >4 (1 point)\tNot performed\tNot performed\tNot performed\tNot performed\t\nSchirmer’s test <5mm/ 5min (1 point)\tY\tNot performed\tY\tNot performed\t\nUnstimulated Salivary Flow Rate <0.1mL/min (1 point)\tNot performed\tNot performed\tNot performed\tNot performed\t\nTotal score (Need 4 of 9)\t7\t3\t7\t3\t\nVBS Van Bijsterveld score, Y Yes\n\n\n\nThe patient was initially treated with olanzapine on an inpatient psychiatry ward. After several months, her recovery was suboptimal and she continued to have severe cognitive deficits with difficulty in comprehension, reasoning, and memory suggesting a diagnosis other than a primary psychiatric disorder. After obtaining consent from her family, immunosuppressive treatment was initiated with 1000 mg rituximab every 2 weeks for two doses in addition to pulse dose methylprednisolone 1000 mg daily for 3 days followed by a prednisone taper over 24 weeks. Since initiation of immunosuppressive therapy the patient has been followed for 18 months and made major cognitive improvements, no longer has psychotic symptoms, and is off psychotropic medication. She has not developed any new symptoms or received further rituximab infusions.\n\nCase 2\nA 16 year old female presented with a 4 year history of severe anxiety, OCD, and tic disorder treated with fluoxetine with partial benefit. Four months prior to evaluation, she developed an abrupt and severe worsening of anxiety, OCD and new auditory hallucinations and was started on aripiprazole which led to a reduction of her auditory hallucinations to approximately once per day. She was able to resume school on a modified schedule. Lab work up was notable for positive ANA 1:1280 (speckled), anti-SSA 4.8 (0.0–0.9) AI and anti-SSB > 8 (0.0–0.9) AI, elevated Immunoglobulin G (IgG)(2116) mg/dL, ESR 57 mm/hr., and positive rheumatoid factor (RF) (58.7 IU/mL). CBC, CMP, TSH and free thyroxine 4 (fT4), thyroid antibodies, UA, CSF analysis (including CSF autoimmune encephalitis antibody panel and oligoclonal bands) were within normal limits (Table 1). MRI brain revealed a single punctate focus of nonspecific white matter signal change in the left frontal lobe, and was otherwise unremarkable (Table 2). Magnetic Resonance spectroscopy brain imaging revealed abnormal brain perfusion with regional cerebral cortical left anterior temporal moderate hypoperfusion and relative minimal hypoperfusion in right thalamus of unclear significance. EEG showed occasional delta range slowing in the left fronto-central-temporal region. The patient did not consent to labial salivary gland biopsy and refused ophthalmology evaluation for Schirmer’s testing.\n\nDespite the absence of sicca symptoms and not fulfilling the 2017 ACR/EULAR diagnostic criteria (Table 3), the patient’s positive serologies and evidence of organic brain disease on MRI spectroscopy and EEG prompted the presumptive diagnosis of neuropsychiatric pSS. The patient was treated with a single dose of rituximab 1000 mg. She then presented with fever, rash and joint pain 10 days after the rituximab infusion. She was found to have platelet count of 124 × 10^3/uL, elevated CRP of 91.4 mg/L, low C4 < 4 mg/dL, C3 of 138 mg/dL, with otherwise unremarkable CBC and CMP. She was diagnosed with rituximab-induced serum sickness reaction and was treated with a 1 week course of prednisolone with resolution of her serum sickness symptoms. Repeat labs showed normal platelet count of 370 and repeat C4 of 11 mg/dL. A lymphocyte panel showed complete B cell depletion with 0% CD19+ cells. Plans for a second dose of rituximab were cancelled.\n\nOne month after treatment with rituximab the patient’s mother reported that the patient’s mood had improved. Five months later, the patient was having less auditory hallucinations, occurring approximately once a month and associated with times of increased stress. She returned to school and extra-curricular activities. She also reported significantly improved sleep quality and mood. She was able to decrease her aripiprazole dose by 50%. The patient and her parents declined treatment with hydroxychloroquine. Six months after her initial rituximab treatment, repopulation of her peripheral CD19+ cell count and previous improvement of psychiatric symptoms with rituximab prompted treatment with obinutuzumab, a humanized anti-CD20 monoclonal antibody that did not confer the same risk of serum-sickness reaction. She tolerated obinutuzumab treatment well. About 5 months after initial treatment with obinutuzumab the patient developed an increase in hallucinations, tics, and anxiety after starting an oral contraceptive (OCP). She was re-treated with obinutuzumab infusion, her OCP was discontinued, and her flare of psychiatric symptoms resolved. She has been followed for 12 months since initiation of immunosuppressive therapy without development of new symptoms. She has not received any further treatment with obinutuzumab or other immunosuppressive therapies.\n\nCase 3\nA 19-year-old female with no significant past medical or psychiatric history presented with a three-day history of progressively altered behavior, incoherent speech, insomnia, headache, and tangential thoughts. In the months preceding initial presentation she was a victim of sexual assault and experienced the death of a close friend. She denied any use of drugs, tobacco or alcohol.\n\nPhysical exam was notable for temperature of 100.7 F. Mental status exam was remarkable for disorganized and repetitive speech, flight of ideas and tangential thoughts. Laboratory tests showed a CRP of 1.1 (0.0–0.8) mg/dL and ESR of 60 (0–20) mm/h. CBC, CMP, UA, CSF cells, glucose and protein, UA, urine toxicology screen, salicylate and acetaminophen level were all normal (Table 1).\n\nSoon after hospital admission, she developed an episode of bilateral hand tremors with upper extremity rigidity, tachycardia and systolic hypertension without fever or elevated inflammatory markers that improved after adding diphenhydramine and lorazepam. A few days later, she had another transient event characterized by posturing, mood lability and generalized tremors. Neurological exam showed generalized hyperreflexia but no focal abnormalities. Due to concern for a primary psychiatric disorder she was discharged to an inpatient psychiatric facility where she received risperidone, benztropine and clonazepam to assist with sleep. She was treated with this regimen for about a month, during this time she developed worsening staring episodes concerning for seizures and was transferred back to the primary hospital for further medical work up that revealed a positive ANA 1:160 mixed pattern, with anti-SSA 4.8 (0.0–0.9) AI and anti-SSB > 8.0 (0.0–0.9) AI. Antibody testing for anti-dsDNA, Smith, ribosomal P, Jo-1, topoisomerase I (SCL-70), centromere, paraneoplastic and autoimmune encephalitis panels (including NMO and NMDA antibodies), and TPO auto-antibodies were negative. UA, C3 and C4 were normal. Blood, urine and CSF cultures showed no growth. Ceruloplasmin, porphyrins, angiotensin converting enzyme, human immunodeficiency virus (HIV) and syphilis testing were negative. An abdominal and pelvic ultrasound (US) were normal. Brain MRI with contrast and brain magnetic resonance angiogram (MRA) were WNL (Table 2). She underwent continuous EEG that showed no evidence of seizure activity. She continued to display disorganized thoughts with fluctuating coherence, persistent delusions, slow psychomotor responses, echolalia, echopraxia and posturing. Symptoms markedly improved after initiation of lorazepam, which prompted a diagnosis of catatonia.\n\nShe was re-started on risperidone and then switched to aripiprazole due to extrapyramidal side effects. She continued to have marked psychiatric symptoms including auditory and olfactory hallucinations, echolalia, paranoia, hyper-religiosity, derailment and thought blocking. Given ongoing symptoms, she was restarted on risperidone along with benztropine and clonazepam.\n\nShe was diagnosed with primary Sjogren’s syndrome based on positive ANA, anti-SSA and anti-SSB titers as well as an abnormal Schirmer’s test and a minor salivary gland biopsy focus score of 1–2 (Table 3). She was started on prednisone 45 mg/day with transient improvement, but developed subsequent worsening of her paranoia with more episodes of staring, intermittent posturing and fluctuating mood after 10 days. Symptoms improved with IV methylprednisolone 30 mg/kg/day for 3 days, restarting aripiprazole and increased lorazepam. IV rituximab was started as a steroid sparing agent. She received the first dose 1.5 months after disease onset. Two months later, her psychotic symptoms and catatonia improved considerably and she was weaned off lorazepam, aripiprazole, and steroids. Her symptoms improved with rituximab infusions 500 mg/m2 (two doses 2 weeks apart) every 4 months, mycophenolate mofetil 1500 mg twice a day, and oral prednisone 2.5 mg/day and she was able to return to nursing school and her extracurricular activities. Neuropsychological assessment 4 months after diagnosis revealed overall low average intellectual ability with weakness in nonverbal reasoning, visuospatial abilities, working memory, processing speed, attention, planning and organization. She received a total of 2 rounds of rituximab and was followed for 18 months after initiation of immunosuppressive medication without development of new symptoms but was subsequently lost to follow up.\n\nCase 4\nA previously healthy 17 year old female presented with new onset suicidal ideation, paranoia, confusion, and emotional lability. She had no auditory or visual hallucinations. Review of systems was otherwise negative. Her mother was noted to have a history of RA.\n\nPhysical exam was notable for flat affect but was otherwise normal. Within the first few days of presentation, her agitation worsened and she became intermittently unresponsive. She also had episodes of nocturnal enuresis. MRI brain with and without contrast was normal (Table 2). EEG was normal. All initial laboratory testing was normal apart from aspartate aminotransferase (AST) 62 (< 26) U/L, bilirubin 1.11 (nl < 0.84) mg/dL, and C4 9.6 (nl > 13) mg/dL. CBC, ESR, CRP, UA, CSF cell counts, glucose, and protein, rapid plasma reagin (RPR) and treponemal Ab, herpes simplex viruses (HSV) polymerase chain reaction (PCR) were normal / negative (Table 1). On day four of admission she received 3 days of pulse methylprednisolone (8 mg/kg/day IV) followed by oral prednisone (1.3 mg/kg/day), and on day 7 received IVIG (2 g/kg, max 100 g) without improvement in her psychotic state.\n\nFollowing empiric treatment, further laboratory testing revealed positive ANA 1:640 in a speckled pattern, Anti-SSA 8 (nl < 1) iu/mL. Other antibody testing for ANCA panel, RF, ribosomal P Ab, Smith, RNP, SSB, anti-Scl70, and anti-dsDNA Ab were negative. She was started on ziprasidone and risperidone. Minor salivary gland biopsy/ keratoconjunctivitis sicca testing was not performed. Given persistent psychosis despite treatment with antipsychotics, positive SSA-antibody, and low C4 without further signs or symptoms of SLE, she was presumptively diagnosed with primary Sjogren’s syndrome (Table 3) and treated with rituximab 1000 mg IV and pulse methylprednisolone for 3 days followed by oral prednisone taper. Her mental status improved and she was discharged home on hydroxychloroquine 200 mg daily and prednisone 0.65 mg/kg/day.\n\nApproximately 12 days after her first rituximab dose, the patient was readmitted for worsening suicidal ideation and new auditory hallucinations. Repeat CMP showed an increase in liver enzymes (AST 49, alanine aminotransferase (ALT) 106 mg/dL). The patient received the second dose of rituximab and one dose of IV cyclophosphamide 750 mg/m2 and was transitioned to oral prednisone. Her mental status improved over a period of weeks to months. She received a second round of rituximab 6 months later. She is currently being treated for depression/anxiety but was able to wean off all antipsychotics, and now has normal cognitive function. She has been followed for 7 months since initiation of immunosuppressive treatment without development of new symptoms.\n\nDiscussion\nPsychosis is defined as a condition that affects the mind where there has been some loss of contact with reality, often with deficits in cognitive processing commonly manifested as hallucinations or delusions [27]. It is separated into primary (idiopathic) and secondary causes due to medical illnesses or substance use [28]. Secondary psychosis is more common in autoimmune disease than previously recognized [29, 30]. It is a common manifestation of neuropsychiatric SLE and has been seen in about 12% of the pediatric neuropsychiatric SLE population [31]. Psychiatric disturbance has also been well documented in various case reports and case series in the adult pSS population [3, 4, 10, 16, 32, 33], including depressive disorder, anxiety disorder and sleep disorder [34]. The reported incidence of psychiatric and/or cognitive impairment in adult pSS patients has been under great debate varying from < 10% in a prospective study of pSS seen in a rheumatology clinic [16] to 80% in a retrospective study [11]. This variability is thought to be due to a lack of definition of CNS manifestations in pSS with inclusion of mild symptoms such as headache and cognitive dysfunction in some studies, use of primary versus secondary Sjogren’s syndrome population and differences in diagnostic criteria used to define Sjogren’s syndrome [35]. Frank psychosis in adult pSS has been seen less commonly and has not yet been documented in the pediatric or adolescent population.\n\nTo our knowledge, the four young women described above are the first reported patients with adolescent pSS manifesting as psychosis. None of the patents presented above had symptoms or lab criteria to suggest a diagnosis of SLE. A history of sexual assault was reported in cases 1 and 3 and drug use was reported in case 1. In both of these cases the psychiatric symptoms were initially attributed to primary psychiatric illness, with the diagnosis of psychosis related to pSS being made only after conventional psychiatric treatment had failed. Although one must consider the possibility that these patient’s psychiatric symptoms were related to substance abuse/traumatic life events, the fact that the patients did not respond typically to anti-psychotic medication and the positive response seen with immunosuppressive medication suggests the psychotic symptoms were indeed related to their confirmed diagnosis of pSS.\n\nIn cases 2 and 4 the diagnosis of pSS was based on the presence of positive anti-SSA serology alone as keratoconjunctivitis sicca testing and minor salivary gland biopsy were not performed; therefore these patients did not satisfy the 2017 ACR-EULAR criteria for pSS [26]. It is important to remember that there are no diagnostic criteria for pSS in the pediatric patient population, and childhood presentations can be quite variable often with extra-glandular manifestations predominating [36]. None of the 4 patients presented above complained of keratoconjunctivitis sicca or xerostomia. It is impossible to exclude the possibility that these patients had primary psychiatric disease and not secondary psychosis related to pSS. However, given the suspicion for organic brain disease in these patients as well as the known association of psychosis with pSS, the risk benefit analysis favored empiric treatment for presumed pSS and all patients showed improvement following treatment with rituximab. Three of the four patients have been weaned off anti-psychotics.\n\nConclusion\nOur case series suggests that psychiatric symptoms, mainly psychosis, can be an initial presentation of pSS in the adolescent population. Thus, pSS should be considered in the differential diagnosis of young patients with new psychiatric disorders, even in the absence of sicca symptoms. Psychiatric symptoms improved with rituximab/anti-CD20 infusions in all 4 of our patients, which suggests that rituximab may be an effective treatment option that should be considered early after the diagnosis of pSS-associated psychiatric disturbance.\n\nAbbreviations\nACRAmerican College of Rheumatology\n\nALTAlanine aminotransferase\n\nANAAntinuclear antibody\n\nANCAAntineutrophil cytoplasmic antibodies\n\nAQP4Aquaporin-4\n\nASTAspartate aminotransferase\n\nC3C3 Complement\n\nC4C4 Complement\n\nCBCComplete blood count\n\nCMPComplete metabolic panel\n\nCNSCentral nervous system\n\nCRPC reactive protein\n\nCSFCerebrospinal fluid\n\nCTComputed tomography\n\ndsDNADouble stranded deoxyribonucleic acid\n\nEDEmergency department\n\nEEGElectroencephalogram\n\nESRErythrocyte sedimentation rate\n\nEULAREuropean League Against Rheumatism classification criteria\n\nfT4Thyroxine 4\n\nHIVHuman immunodeficiency virus\n\nHSVHerpes simplex viruses\n\nIgGImmunoglobulin G\n\nMRAMagnetic resonance angiogram\n\nMRIMagnetic resonance imaging\n\nNMDANeuronal, N-methyl-D-aspartate receptor\n\nNMONeuromyelitis optica\n\nOCDObsessive compulsive disorder\n\nOCPOral contraceptive\n\nPCRPolymerase chain reaction\n\npSSPrimary Sjogren’s syndrome\n\nRARheumatoid arthritis\n\nRFRheumatoid factor\n\nRNPRibonucleoprotein\n\nRPRRapid plasma reagin\n\nSCL-70Topoisomerase I\n\nSLESystemic lupus erythematosus\n\nSSASjogren’s syndrome type A\n\nSSBSjogren’s syndrome type B\n\nTPOThyroid peroxidase\n\nTSHThyroid stimulating hormone\n\nUAUrinalysis\n\nUSUltrasound\n\nWNLWithin normal limits\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable\n\nDeclarations\nAll authors read and approved the final manuscript.\n\nAuthors’ contributions\nAll authors contributed to one case description and the compilation of the final manuscript. All authors read and approved the final manuscript.\n\nFunding\nNot applicable\n\nAvailability of data and materials\nData sharing is not applicable to this article as no datasets were generated or analyzed during the current study.\n\nEthics approval and consent to participate\nNot applicable, Case series was exempt from IRB approval at all institutions.\n\nConsent for publication\nNot applicable\n\nCompeting interests\nAll authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Virdee S Greenan-Barrett J Ciurtin C A systematic review of primary Sjögren's syndrome in male and paediatric populations Clin Rheumatol 2017 36 10 2225 2236 10.1007/s10067-017-3745-z 28735431 \n2. Tucker L. Sjogren’s Syndrome. In: Petty RE, Laxer RM, Lindsley CB, Wedderburn L, editors. Textbook of pediatric rheumatology. 7th ed: Philadelphia: Saunders; 2016. p. 427–35.\n3. Cox PD Hales RE CNS Sjögren's syndrome: an underrecognized and underappreciated neuropsychiatric disorder J Neuropsychiatry Clin Neurosci 1999 11 2 241 247 10.1176/jnp.11.2.241 10333995 \n4. Mauch E Völk C Kratzsch G Krapf H Kornhuber HH Laufen H Neurological and neuropsychiatric dysfunction in primary Sjögren's syndrome Acta Neurol Scand 1994 89 1 31 35 10.1111/j.1600-0404.1994.tb01629.x 8178625 \n5. Delalande S de Seze J Fauchais AL Hachulla E Stojkovic T Ferriby D Neurologic manifestations in primary Sjögren syndrome: a study of 82 patients Medicine (Baltimore) 2004 83 5 280 291 10.1097/01.md.0000141099.53742.16 15342972 \n6. Massara A Bonazza S Castellino G Caniatti L Trotta F Borrelli M Central nervous system involvement in Sjögren's syndrome: unusual, but not unremarkable--clinical, serological characteristics and outcomes in a large cohort of Italian patients Rheumatology (Oxford) 2010 49 8 1540 1549 10.1093/rheumatology/keq111 20444860 \n7. Ampelas JF Wattiaux MJ VanAmarongen AP Troubles psychiatriques du lupus erythmateux dissemine et du syndrome de Gougerot-Sjogren L’ Encephale 2001 27 6 588 599 11865567 \n8. Lin CE One patient with Sjogren's syndrome presenting schizophrenia-like symptoms Neuropsychiatr Dis Treat 2016 12 661 663 10.2147/NDT.S97753 27042076 \n9. Rosado SN Silveira V Reis AI Gordinho A Noronha C Catatonia and psychosis as manifestations of primary Sjögren's syndrome Eur J Case Rep Intern Med 2018 5 6 000855 30756038 \n10. Hietaharju A Yli-Kerttula U Häkkinen V Frey H Nervous system manifestations in Sjögren's syndrome Acta Neurol Scand 1990 81 2 144 152 10.1111/j.1600-0404.1990.tb00951.x 2327235 \n11. Spezialetti R Bluestein HG Peter JB Alexander EL Neuropsychiatric disease in Sjögren's syndrome: anti-ribosomal P and anti-neuronal antibodies Am J Med 1993 95 2 153 160 10.1016/0002-9343(93)90255-N 8356981 \n12. Kang JH Lin HC Comorbidities in patients with primary Sjogren's syndrome: a registry-based case-control study J Rheumatol 2010 37 6 1188 1194 10.3899/jrheum.090942 20360180 \n13. Ong LTC Galambos G Brown DA Primary Sjogren's syndrome associated with treatment-resistant obsessive-compulsive disorder Front Psychiatry 2017 8 124 10.3389/fpsyt.2017.00124 28744230 \n14. Alexander EL Beall SS Gordon B Selnes OA Yannakakis GD Patronas N Magnetic resonance imaging of cerebral lesions in patients with the Sjögren syndrome Ann Intern Med 1988 108 6 815 823 10.7326/0003-4819-108-6-815 3369771 \n15. Alexander EL Neurologic disease in Sjögren's syndrome: mononuclear inflammatory vasculopathy affecting central/peripheral nervous system and muscle. A clinical review and update of immunopathogenesis Rheum Dis Clin N Am 1993 19 4 869 908 \n16. Moll JW Markusse HM Pijnenburg JJ Vecht CJ Henzen-Logmans SC Antineuronal antibodies in patients with neurologic complications of primary Sjögren's syndrome Neurology. 1993 43 12 2574 2581 10.1212/WNL.43.12.2574 8255460 \n17. Alexander EL Lijewski JE Jerdan MS Alexander GE Evidence of an immunopathogenic basis for central nervous system disease in primary Sjögren's syndrome Arthritis Rheum 1986 29 10 1223 1231 10.1002/art.1780291007 2429673 \n18. Alexander E Central nervous system disease in Sjögren's syndrome. New insights into immunopathogenesis Rheum Dis Clin N Am 1992 18 3 637 672 \n19. Ferreiro JE Robalino BD Saldana MJ Primary Sjögren's syndrome with diffuse cerebral vasculitis and lymphocytic interstitial pneumonitis Am J Med 1987 82 6 1227 1232 10.1016/0002-9343(87)90230-0 3605139 \n20. Sanders ME Alexander EL Koski CL Frank MM Joiner KA Detection of activated terminal complement (C5b-9) in cerebrospinal fluid from patients with central nervous system involvement of primary Sjogren's syndrome or systemic lupus erythematosus J Immunol 1987 138 7 2095 2099 3559203 \n21. Alexander EL Ranzenbach MR Kumar AJ Kozachuk WE Rosenbaum AE Patronas N Anti-Ro (SS-A) autoantibodies in central nervous system disease associated with Sjögren's syndrome (CNS-SS): clinical, neuroimaging, and angiographic correlates Neurology. 1994 44 5 899 908 10.1212/WNL.44.5.899 8190294 \n22. Jacob CO Plitt JR Fronek Z HLA class II associated tumor necrosis factor alpha synthesis in central nervous system disease in Sjogren’s syndrome Arthritis Rheum 1992 35 S121 \n23. Vivino FB Carsons SE Foulks G Daniels TE Parke A Brennan MT New treatment guidelines for Sjögren's disease Rheum Dis Clin N Am 2016 42 3 531 551 10.1016/j.rdc.2016.03.010 \n24. Mekinian A Ravaud P Larroche C Hachulla E Gombert B Blanchard-Delaunay C Rituximab in central nervous system manifestations of patients with primary Sjögren's syndrome: results from the AIR registry Clin Exp Rheumatol 2012 30 2 208 212 22341206 \n25. Tokunaga M Saito K Kawabata D Imura Y Fujii T Nakayamada S Efficacy of rituximab (anti-CD20) for refractory systemic lupus erythematosus involving the central nervous system Ann Rheum Dis 2007 66 4 470 475 10.1136/ard.2006.057885 17107983 \n26. Shiboski CH Shiboski SC 2016 American College of Rheumatology/European league against rheumatism classification criteria for primary Sjögren’s syndrome: a consensus and data-driven methodology involving three international patient cohorts Arthritis and Rheumatology 2016 69 1 35 45 10.1002/art.39859 27785888 \n27. Arciniegas DB. Psychosis. Continuum (Minneapolis, Minn). 2015; 21(3 Behavioral neurology and neuropsychiatry): 713–736.\n28. Keshavan MS Kaneko Y Secondary psychoses: an update World Psychiatry 2013 12 1 4 15 10.1002/wps.20001 23471787 \n29. Chen SJ Chao YL Chen CY Chang CM Wu EC Wu CS Prevalence of autoimmune diseases in in-patients with schizophrenia: nationwide population-based study Br J Psychiatry 2012 200 5 374 380 10.1192/bjp.bp.111.092098 22442099 \n30. Eaton WW Byrne M Ewald H Mors O Chen CY Agerbo E Association of schizophrenia and autoimmune diseases: linkage of Danish national registers Am J Psychiatry 2006 163 3 521 528 10.1176/appi.ajp.163.3.521 16513876 \n31. Sibbitt WL Brandt JR Johnson CR Maldonado ME Patel SR Ford CC The incidence and prevalence of neuropsychiatric syndromes in pediatric onset systemic lupus erythematosus J Rheumatol 2002 29 7 1536 1542 12136916 \n32. Pelizza L Bonacini F Ferrari A Psychiatric disorder as clinical presentation of primary Sjögren's syndrome: two case reports Ann General Psychiatry 2010 9 12 10.1186/1744-859X-9-12 \n33. Malinow KL Molina R Gordon B Selnes OA Provost TT Alexander EL Neuropsychiatric dysfunction in primary Sjögren's syndrome Ann Intern Med 1985 103 3 344 350 10.7326/0003-4819-103-3-344 2992332 \n34. Shen CC Yang AC Kuo BI Tsai SJ Risk of psychiatric disorders following primary Sjögren syndrome: a Nationwide population-based retrospective cohort study J Rheumatol 2015 42 7 1203 1208 10.3899/jrheum.141361 25979721 \n35. Soliotis FC Mavragani CP Moutsopoulos HM Central nervous system involvement in Sjogren's syndrome Ann Rheum Dis 2004 63 6 616 620 10.1136/ard.2003.019497 15140765 \n36. Lieberman SM Childhood Sjogren syndrome: insights from adults and animal models Curr Opin Rheumatol 2013 25 5 651 657 10.1097/BOR.0b013e328363ed23 23917159\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1546-0096",
"issue": "18(1)",
"journal": "Pediatric rheumatology online journal",
"keywords": "Central nervous system (CNS) Sjogren’s syndrome; Pediatric Sjogren’s syndrome; Psychosis",
"medline_ta": "Pediatr Rheumatol Online J",
"mesh_terms": "D000293:Adolescent; D061067:Antibodies, Monoclonal, Humanized; D014150:Antipsychotic Agents; D018501:Antirheumatic Agents; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D011618:Psychotic Disorders; D000069283:Rituximab; D012859:Sjogren's Syndrome; D059020:Suicidal Ideation; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101248897",
"other_id": null,
"pages": "15",
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"pmid": "32046763",
"pubdate": "2020-02-11",
"publication_types": "D016428:Journal Article",
"references": "23917159;22341206;15140765;2992332;30756038;20356417;16513876;27042076;23471787;3605139;15342972;20444860;8265827;8356981;22442099;3559203;12136916;28735431;11865567;10333995;3369771;20360180;1496166;2327235;25979721;2429673;26039850;8178625;8255460;17107983;27785888;28744230;8190294;27431353",
"title": "Adolescent Sjogren's syndrome presenting as psychosis: a case series.",
"title_normalized": "adolescent sjogren s syndrome presenting as psychosis a case series"
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"abstract": "Differentiating idiopathic sclerosing orbital inflammation from orbital inflammation secondary to neoplasia may be challenging, as both processes can present similarly. Neoplasms in the orbit may induce inflammation with accompanying fibrosis. Limited sections of histopathological specimens may demonstrate nonspecific inflammation and lead to an inaccurate diagnosis.\nThe authors present a case of infiltrating adenocarcinoma of the orbit with mucinous features which was misdiagnosed as idiopathic sclerosing orbital inflammation due to three separate benign biopsy specimens.\nThe ophthalmologist must remain suspicious of malignancy in cases of suspected idiopathic orbital inflammation with an atypical clinical course, regardless of apparently benign biopsy results.",
"affiliations": "Brooke Army Medical Center, 3351 Roger Brooke Drive, Fort Sam Houston, Texas, USA.;Brooke Army Medical Center, 3351 Roger Brooke Drive, Fort Sam Houston, Texas, USA.;Brooke Army Medical Center, 3351 Roger Brooke Drive, Fort Sam Houston, Texas, USA.;Brooke Army Medical Center, 3351 Roger Brooke Drive, Fort Sam Houston, Texas, USA.;University of Texas Health Science Center at San Antonio, Texas, USA.;Brooke Army Medical Center, 3351 Roger Brooke Drive, Fort Sam Houston, Texas, USA.",
"authors": "Reed|Donovan|D|;Mehta|Aditya|A|;Hayes|Bartlett|B|;Caldwell|Matthew|M|;Scribbick|Frank|F|;Davies|Brett|B|",
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"doi": "10.1016/j.ajoc.2019.100529",
"fulltext": "\n==== Front\nAm J Ophthalmol Case RepAm J Ophthalmol Case RepAmerican Journal of Ophthalmology Case Reports2451-9936Elsevier S2451-9936(18)30456-010.1016/j.ajoc.2019.100529100529Case ReportPrimary adenocarcinoma of the orbit initially diagnosed as idiopathic sclerosing orbital inflammation Reed Donovan donovan.s.reed2.mil@mail.mila∗Mehta Aditya aHayes Bartlett aCaldwell Matthew aScribbick Frank bDavies Brett aa Brooke Army Medical Center, 3351 Roger Brooke Drive, Fort Sam Houston, Texas, USAb University of Texas Health Science Center at San Antonio, Texas, USA∗ Corresponding author. 10710 Cedar Elm Drive, San Antonio, TX, 78230. donovan.s.reed2.mil@mail.mil31 7 2019 12 2019 31 7 2019 16 1005298 10 2018 27 11 2018 29 7 2019 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nDifferentiating idiopathic sclerosing orbital inflammation from orbital inflammation secondary to neoplasia may be challenging, as both processes can present similarly. Neoplasms in the orbit may induce inflammation with accompanying fibrosis. Limited sections of histopathological specimens may demonstrate nonspecific inflammation and lead to an inaccurate diagnosis.\n\nObservations\nThe authors present a case of infiltrating adenocarcinoma of the orbit with mucinous features which was misdiagnosed as idiopathic sclerosing orbital inflammation due to three separate benign biopsy specimens.\n\nConclusions and Importance\nThe ophthalmologist must remain suspicious of malignancy in cases of suspected idiopathic orbital inflammation with an atypical clinical course, regardless of apparently benign biopsy results.\n\nKeywords\nIdiopathic orbital inflammationOrbital adenocarcinomaIdiopathic sclerosing orbital inflammation\n==== Body\n1 Introduction\nIdiopathic orbital inflammation (IOI) is an immune mediated infiltrative condition that has distinct variants, a non-sclerosing and a sclerosing type, which is characterized by a polymorphous lymphoid infiltrate or a predominance of fibrosis, respectively.1,2 The non-sclerosing type is fairly common, representing the majority of orbital inflammatory syndromes.3 The differentiation of idiopathic orbital inflammation and orbital inflammation secondary to neoplasia can be challenging, as both processes may manifest with similar clinical presentations.2\n\n2 Case report\nThe patient discussed is an 86-year-old Hispanic male who presented with complaints of left eye irritation. His past ocular history was significant for a left central retinal vein occlusion, managed over several years with panretinal photocoagulation and multiple anti-VEGF injections. He also had advanced glaucoma with a superotemporal Ahmed valve tube shunt in the left eye, and his left eye was pseudophakic. Additional medical history includes prostate cancer treated with a radical prostatectomy in 1998, coronary artery disease treated with coronary artery bypass grafting in 2002, atrial fibrillation, hypertension, and chronic kidney disease. He has no family history of cancer and his social history is unremarkable. Of note, the collection and evaluation of protected patient health information was HIPAA-complaint.\n\nOn the day of his initial presentation he was scheduled to have an anti-VEGF injection for macular edema for his retinal vein occlusion, but this was deferred because slit lamp examination revealed an elevated inferotemporal subconjunctival mass. The patient denied pain or facial cutaneous sensory changes. An MRI orbit with and without contrast showed soft tissue enhancement in the temporal aspect of the left orbit between the sclera and the lacrimal gland without evidence of bony involvement. A biopsy of the orbital lesion demonstrated chronic inflammation and subepithelial fibrosis but no sign of malignancy. Because of the findings of orbital inflammation without malignant changes, the patient was started on 40mg oral prednisone with a gradual taper.\n\nFour months later he developed a new subconjunctival lesion adjacent to the initial area of concern, but this time it did not resolve with corticosteroids. Another biopsy of the lesion was performed, and was consistent with an admixture of active and chronic inflammation and fibrosis but negative for malignancy. Over the next several months the patient was noted to have a relapsing, remitting course of inflammation and ultimately developed periorbital pain, symblepharon in the area of the biopsies, worsening blepharoptosis, and diplopia from a restrictive strabismus. A more extensive biopsy of the orbital mass was performed which again showed signs of acute and chronic inflammation but no sign of malignancy. After consultation with rheumatology the patient was started on steroid-sparing anti-inflammatory therapy with mycophenolate motefil.\n\nDespite treatment of his inflammation, his pain continued to worsen and vision declined gradually to no light perception, with complete restriction of the left globe but intact facial cutaneous sensation. The patient then developed marked hypotonyand his exam showed the Ahmed valve plate had eroded through the conjunctiva. This was treated by removal of the Ahmed valve and placement of an amniotic membrane graft. On a postoperative fundus exam, the patient was noted to have inferotemporal elevation of the retina and choroid concerning for choroidal effusion from the hypotony which had not been noted on prior fundus exams, but B-scan ultrasound demonstrated indentation of the inferotemporal aspect of the globe secondary to orbital mass effect. A computed tomography scan of the orbits demonstrated marked increase in size of the orbital mass in the temporal orbit involving both intraconal and extraconal spaces but without bony involvement (Fig. 1), and biopsy of the orbital mass was scheduled.Fig. 1 CT orbit without contrast, coronal cut, demonstrating the large orbital mass surrounding and indenting the left globe.\n\nFig. 1\n\nA subtotal exeneration was ultimately performed given the extensive tumor burden noted intraoperatively after the surgical specimens were sent for histopathologic evaluation (Fig. 2). The final pathologic diagnosis was infiltrating adenocarcinoma, not otherwise specified, with some features suggestive of mucoepidermoid carcinoma. The tumor was determined to be fairly well-differentiated and did not appear cytologically aggressive, but with infiltrative growth pattern lining the internal globe suggestive of a high-grade tumor, T4N0M0. The patient was provided the option for additional surgery with or without radiation and chemotherapy, and ultimately decided to undergo adjuvant radiation therapy. The patient has finished adjuvant radiation therapy, and neuroimaging at six months post exenteration showed no signs of recurrence.Fig. 2 A) H&E stain demonstrating cords of epithelial and ductal tissue with fibrotic inflammatory background. B) PAS stain demonstrating pockets of mucinous material. C) Mucicarmine stain, highlighting mucin, which appears pink on a yellow background. D) Pancytokeratin immunostain highlighting surface ectoderm relative to fibrotic background. E) H&E stain of the anterior chamber angle demonstrating epithelial tumor infiltrating the ciliary body and coursing across the anterior surface of the iris and cornea.\n\nFig. 2\n\n3 Discussion\nNeoplasia may induce inflammation with varying clinical presentations to include involvement of the extraocular muscles, lacrimal gland, or sclera. Histopathological specimens may reveal non-specific chronic inflammation, consisting of mature lymphocytes and fibrosis leading to an incorrect diagnosis.1 Additionally, as in the case demonstrated, there exists the possibility initial biopsies performed may not be representative of the main body of the tumor and may be related to prior trauma or surgery. Furthermore, orbital and ocular inflammation may be present irrespective of an underlying malignancy. A review of the literature revealed other cases of malignancies initially diagnosed as idiopathic orbital inflammation to include metastatic breast carcinoma and metastatic orbital carcinoid tumor.4, 5, 6, 7, 8 However, the cases presented were metastatic to the orbit. The authors did not find any other case report of primary adenocarcinoma of the orbit masquerading as idiopathic orbital inflammation.\n\nTypically, idiopathic orbital inflammation presents with abrupt onset of pain and inflammatory signs and responds robustly to administration of systemic corticosteroids.9 The case presented was atypical in that the patient had a painless initial presentation, and his inflammation recurred following administration of corticosteroid therapy. Atypical cases of idiopathic orbital inflammation warrant extensive evaluation for alternative causes. As demonstrated in this case, the clinician must remain vigilant to the possibility of malignancy in cases of suspected idiopathic orbital inflammation, regardless of apparently benign biopsy results. This is particularly true in the presence of worsening clinical signs and symptoms or an atypical initial presentation.\n\nPatient consent\nWritten consent to publish case details was obtained from the patient.\n\nFunding\nNo funding or grant support.\n\nConflicts of interest\nThe following authors have no financial disclosures: DR, AM, BH, MC, FS, BD.\n\nAuthorship\nAll authors attest that they meet the current ICMJE criteria for Authorship.\n\nAppendix A Supplementary data\nThe following is the Supplementary data to this article:Multimedia component 1\nMultimedia component 1 \n\nAcknowledgements\nNone.\n\nAppendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.ajoc.2019.100529.\n==== Refs\nReferences\n1 Heathcote J. Safneck J. Sclerosing Inflammatory pseudotumor of orbit Proceedings of the United States & Canadian Academy of Pathology Annual Meeting; Chicago, Illinois 2002 Feb 25 \n2 Umar R. Deopujari C.E. Shah R. Jumar A. Metastatic adenocarcinoma of bilateral cavernous sinus and optic nerve with unknown primary mimicking orbital pseudotumor Neuro India 57 1 2009 Jan-Feb 82 84 \n3 Ding Z.X. Lip G. Choi V. Idiopathic pseudotumor Colin Ragiol 66 9 2011 Sep 886 892 ePub 2011 May 4 \n4 Toprak H. All. Unusual sclerosing orbital pseudotumour infiltrating orbits and maxillofacial regions J Clin Imaging Sci. 4 2014 30 24991481 \n5 Monson B.K. all. Metastatic mutinous adenocarcinoma of the orbit Orbit 30 1 2011 Jan 18 20 21281073 \n6 Yunj J.J. Unusual presentation of gastric adenocarcinoma metastatic to the orbit Ophthalmol Plast Reconstructive Surg 22 6 2006 Nov-Dec 490 491 \n7 Toller K.K. Gigantelli J.W. Spalding M.J. Bilateral orbital metastases from breast carcinoma. A case of false pseudotumor Ophthalmology 105 10 1998 Oct 1897 1901 9787361 \n8 Knox R.J. Gigantelli J.W. Arthurs B.P. Recurrent orbital inflammation from metastatic orbital carcinoid tumor Ophthalmic Plast Reconstr Surg 17 2 2001 Mar 137 139 11281589 \n9 Ahn Yuen S.J. Rubin P.A.D. Idiopathic orbital inflammation distribution, clinical features, and treatment outcome Arch Ophthalmol 121 2003 491 499 12695246\n\n",
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"issue": "16()",
"journal": "American journal of ophthalmology case reports",
"keywords": "Idiopathic orbital inflammation; Idiopathic sclerosing orbital inflammation; Orbital adenocarcinoma",
"medline_ta": "Am J Ophthalmol Case Rep",
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"nlm_unique_id": "101679941",
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"title": "Primary adenocarcinoma of the orbit initially diagnosed as idiopathic sclerosing orbital inflammation.",
"title_normalized": "primary adenocarcinoma of the orbit initially diagnosed as idiopathic sclerosing orbital inflammation"
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"abstract": "BACKGROUND\nCarbamazepine (CBZ), oxcarbazepine (OXC), and eslicarbazepine (ESL) acetate belong to the dibenzazepine family. In this context, the aim of this literature review is to evaluate the clinical epidemiological profile, pathological mechanisms, and management of CBZ-, OXC-, and ESL-associated movement disorders (MDs).\n\n\nRESULTS\nRelevant reports in 6 databases were identified and assessed by 2 reviewers without language restriction. Reports where the individuals only developed tremor or ataxia after CBZ/OXC/ESL use were not included. A total of 73 reports containing 191 individuals who developed MD associated with CBZ/OXC/ESL were identified. Were found, respectively, the following: 33 patients with myoclonus, 23 with dystonia, 14 with tics, 13 with dyskinesia, 8 with parkinsonism, and 5 with akathisia. In the group not clearly defined, there were 44 with myoclonus, 29 with dyskinesia, 20 with dystonia, 1 with incoordination, and 1 with akathisia. The mean age was 28.53 years. The most frequent sex was male in 52.77% (38/72), and the drug indication was epilepsy in 74.19% (69/93). The mean (SD) CBZ dose when the MD occurred was 692.68 (363.58) mg. The mean time until MD onset was 33.59 days, and the mean recovery period was 8.7 days. The most common form of MD management was drug withdrawal.\n\n\nCONCLUSIONS\nThe number of cases associated with CBZ is higher than those with OXC + ESL. We believe that the study of CBZ contributes not only to the improvement of this drug but also to the knowledge about the drug-induced MD of OXC and ESL. In the literature, the description of the MD onset and recovery has been poorly reported.",
"affiliations": "Medicine Department, Federal University of Santa Maria, Santa Maria, Brazil.",
"authors": "Rissardo|Jamir Pitton|JP|;Caprara|Ana Letícia Fornari|ALF|",
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"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants; D001259:Ataxia; D002220:Carbamazepine; D002648:Child; D002675:Child, Preschool; D003984:Dibenzazepines; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009069:Movement Disorders; D000078330:Oxcarbazepine",
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"title": "Carbamazepine-, Oxcarbazepine-, Eslicarbazepine-Associated Movement Disorder: A Literature Review.",
"title_normalized": "carbamazepine oxcarbazepine eslicarbazepine associated movement disorder a literature review"
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"dru... |
{
"abstract": "A 77-year-old man with inflammatory bowel disease (IBD) and who was treated with anti-tumor necrosis factor (TNF), 6-mercaptopurine and corticosteroids, presented with primary effusion lymphoma-like lymphoma (PEL-like lymphoma) with massive ascites. The patient's clinical course was complicated by acute renal insufficiency and hypotension, which led to death within 2 wk. In general, patients with IBD may have an increased risk for development of lymphoma, which is frequently associated with immunosuppressive and/or anti-TNF antibody therapies. PEL is a rare subset of lymphoma localized to serous body cavities, lacks tumor mass or nodal involvement, and is associated with infection by human herpes virus 8 (HHV-8). Primary neoplastic effusion may also be present in patients with large B-cell lymphoma without evidence of human immunodeficiency virus or HHV-8 infections. This type of lymphoma is classified as PEL-like lymphoma. Both PEL and PEL-like lymphoma types have been reported in patients undergoing immunosuppressive therapy, but to the best of our knowledge, the case described herein represents the first PEL-like lymphoma occurring in a patient with IBD.",
"affiliations": "Elchanan Nussinson, Fahmi Shibli, Azmi Shahbari, Gastroenterology Institute, Emek Medical Center, Afula 18101, Israel.;Elchanan Nussinson, Fahmi Shibli, Azmi Shahbari, Gastroenterology Institute, Emek Medical Center, Afula 18101, Israel.;Elchanan Nussinson, Fahmi Shibli, Azmi Shahbari, Gastroenterology Institute, Emek Medical Center, Afula 18101, Israel.;Elchanan Nussinson, Fahmi Shibli, Azmi Shahbari, Gastroenterology Institute, Emek Medical Center, Afula 18101, Israel.;Elchanan Nussinson, Fahmi Shibli, Azmi Shahbari, Gastroenterology Institute, Emek Medical Center, Afula 18101, Israel.;Elchanan Nussinson, Fahmi Shibli, Azmi Shahbari, Gastroenterology Institute, Emek Medical Center, Afula 18101, Israel.",
"authors": "Nussinson|Elchanan|E|;Shibli|Fahmi|F|;Shahbari|Azmi|A|;Rock|Wasseem|W|;Elias|Mazen|M|;Elmalah|Irit|I|",
"chemical_list": "D001688:Biological Products; D014408:Biomarkers, Tumor; D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v20.i3.857",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-9327",
"issue": "20(3)",
"journal": "World journal of gastroenterology",
"keywords": "Immunosuppressive therapy; Inflammatory bowel disease; Lymphoma; Primary effusion lymphoma; Primary effusion lymphoma-like lymphoma",
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000368:Aged; D001201:Ascites; D001688:Biological Products; D014408:Biomarkers, Tumor; D017809:Fatal Outcome; D006801:Humans; D016867:Immunocompromised Host; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents; D015212:Inflammatory Bowel Diseases; D054685:Lymphoma, Primary Effusion; D008297:Male; D014057:Tomography, X-Ray Computed; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "857-62",
"pmc": null,
"pmid": "24574759",
"pubdate": "2014-01-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20837584;21830262;11241255;22766526;20926881;11677199;22241664;19876384;9850179;19245595;8695812;19837455;9013840;21122554;15621832;19558997;11781282;11736713;18396748;21810684;19075546;17522245;21674712;10986211;15831904;18473348;14692539;21640928;23319997;4052961;23282971;17997602;11007233;22031357;21762120;10910891;12801300;19913208;15551361;16009685;16115121;20927075;19889478;20461118;20428756;17600819;17135726;20150647;21290481;20412066;17142954;10982757",
"title": "Primary effusion lymphoma-like lymphoma in a patient with inflammatory bowel disease.",
"title_normalized": "primary effusion lymphoma like lymphoma in a patient with inflammatory bowel disease"
} | [
{
"companynumb": "PHHY2015IL118443",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "GENTAMICIN"
},
"drugadditional": null,
"dru... |
{
"abstract": "The introduction of BCR-ABL-tyrosine kinase inhibitors (TKI) for treatment of hematologic malignancies has made a significant impact on patient outcome. Contingent upon their targeted and off-target activity, therapy-associated infectious complications may occur. We present a case of cytomegalovirus pneumonitis and a case of adenovirus hemorrhagic cystitis in two patients with Philadelphia chromosome-positive acute lymphoblastic leukemia on BCR-ABL TKI treatment and review the literature to summarize the infectious complications based on clinical data. As life-threatening infections may occur, treating physicians should maintain a heightened awareness in patients treated with BCR-ABL TKIs. Based on the frequent reports of hepatitis B virus (HBV) reactivation under the treatment BCR-ABL TKIs, screening for and prophylactic therapy of chronic HBV infection should be considered. Similarly, patients would benefit from screening for and treatment of latent tuberculosis.",
"affiliations": "Department of Medicine, New York Medical College, Valhalla, NY, USA. Bettina.Knoll@WMCHealth.org.;Department of Medicine, New York Medical College, Valhalla, NY, USA.",
"authors": "Knoll|Bettina M|BM|http://orcid.org/0000-0002-0231-7218;Seiter|K|K|",
"chemical_list": "D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D000069439:Dasatinib",
"country": "Germany",
"delete": false,
"doi": "10.1007/s15010-017-1105-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-8126",
"issue": "46(3)",
"journal": "Infection",
"keywords": "Adenovirus hemorrhagic cystitis; BCR-ABL TKI; Cytomegalovirus pneumonitis; Dasatinib; Infections",
"medline_ta": "Infection",
"mesh_terms": "D000256:Adenoviridae; D000328:Adult; D003556:Cystitis; D003587:Cytomegalovirus; D000069439:Dasatinib; D005260:Female; D016044:Fusion Proteins, bcr-abl; D006509:Hepatitis B; D006801:Humans; D055985:Latent Tuberculosis; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D008403:Mass Screening; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D011014:Pneumonia; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases",
"nlm_unique_id": "0365307",
"other_id": null,
"pages": "409-418",
"pmc": null,
"pmid": "29388066",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "19251803;18194453;22263567;21646774;18619726;20525993;23483799;20143399;20131302;17912440;17541400;21902298;18362995;28419210;20646761;17245498;22160483;24180494;25351958;26432046;14623772;20006827;24982379;15750270;25842192;19204223;26379451;17642017;19669326;26837842;24807266;18413841;23222377;27267844;16321842;19744184;25196702;21713076;24420842;17885950;22211798;27217448;24932855;24944159;12637609;19282833;15572591;8616716;12631595;20430187",
"title": "Infections in patients on BCR-ABL tyrosine kinase inhibitor therapy: cases and review of the literature.",
"title_normalized": "infections in patients on bcr abl tyrosine kinase inhibitor therapy cases and review of the literature"
} | [
{
"companynumb": "US-TEVA-2018-US-918927",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
... |
{
"abstract": "Connubial or consort allergic contact dermatitis occurs when the agent causing the dermatitis has not been used by the patient but by his partner or other cohabitants or proxy. Most cases are due to fragrances, cosmetics or topical nonsteroidal anti-inflammatory agents. We report a case of a connubial dermatitis caused by topical diphenhydramine in a woman who applied the cream on her husband's back.",
"affiliations": "Coimbra University Hospital, Dermatology , Coimbra , Portugal.",
"authors": "Teixeira|Vera|V|;Cabral|Rita|R|;Gonçalo|Margarida|M|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D006634:Histamine H1 Antagonists; D004155:Diphenhydramine",
"country": "England",
"delete": false,
"doi": "10.3109/15569527.2013.812106",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-9527",
"issue": "33(1)",
"journal": "Cutaneous and ocular toxicology",
"keywords": null,
"medline_ta": "Cutan Ocul Toxicol",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D017449:Dermatitis, Allergic Contact; D004155:Diphenhydramine; D005260:Female; D006634:Histamine H1 Antagonists; D006801:Humans; D008875:Middle Aged; D010328:Patch Tests",
"nlm_unique_id": "101266892",
"other_id": null,
"pages": "82-4",
"pmc": null,
"pmid": "23848819",
"pubdate": "2014-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Exuberant connubial allergic contact dermatitis from diphenhydramine.",
"title_normalized": "exuberant connubial allergic contact dermatitis from diphenhydramine"
} | [
{
"companynumb": "PT-BANPHARM-20143224",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DIPHENHYDRAMINE"
},
"drugadditional": null,
... |
{
"abstract": "To examine the efficacy and safety of pegloticase in combination with methotrexate (MTX) in patients with uncontrolled gout in an exploratory, open-label clinical trial (ClinicalTrials.gov: NCT03635957) prior to a randomized, controlled trial.\n\n\n\nA multicenter, open-label efficacy and safety study of pegloticase with MTX co-treatment was conducted in patients with uncontrolled gout. Patients were administered oral MTX (15 mg/week) and folic acid (1 mg/day) 4 weeks prior to and throughout pegloticase treatment. The primary study outcome was the proportion of responders, defined as serum uric acid (sUA) < 6 mg/dL for ≥ 80% of the time during Month 6 (Weeks 20, 22, and 24). All analyses were performed on a modified intent-to-treat population, defined as patients who received ≥ 1 pegloticase infusion.\n\n\n\nSeventeen patients were screened and 14 patients (all men, average age 49.3 ± 8.7 years) were enrolled. On Day 1, mean sUA was 9.2 ± 2.5 mg/dL, and 12 of the 14 patients had visible tophi. At the 6-month timepoint, 11/14 (78.6%, 95% CI 49.2-95.3%) met the responder definition, with 3 patients discontinuing after meeting protocol-defined treatment discontinuation rules (preinfusion sUA values > 6 mg/dL at 2 consecutive scheduled visits). All patients tolerated MTX. No new safety concerns were identified.\n\n\n\nIn this study, an increased proportion of patients maintained therapeutic response at 6 months when treated concomitantly with MTX and pegloticase as compared to the previously reported 42% using pegloticase alone. These results support the need for a randomized study of MTX or placebo with pegloticase to validate these open-label findings.",
"affiliations": "J.K. Botson, MD, RPh, Orthopedic Physicians Alaska, Anchorage, Alaska; jbotson@opaak.com.;J.R. Tesser, MD, R. Bennett, MD, Arizona Arthritis & Rheumatology Associates, P.C., Phoenix, Arizona.;J.R. Tesser, MD, R. Bennett, MD, Arizona Arthritis & Rheumatology Associates, P.C., Phoenix, Arizona.;H.M. Kenney, MD, Arthritis Northwest, PLLC, Spokane, Washington.;P.M. Peloso, MD, MSc, K. Obermeyer, MS, B. LaMoreaux, MD, MS, Horizon Therapeutics, Lake Forest, Illinois.;P.M. Peloso, MD, MSc, K. Obermeyer, MS, B. LaMoreaux, MD, MS, Horizon Therapeutics, Lake Forest, Illinois.;P.M. Peloso, MD, MSc, K. Obermeyer, MS, B. LaMoreaux, MD, MS, Horizon Therapeutics, Lake Forest, Illinois.;M.E. Weinblatt, MD, Brigham and Women's Hospital, Boston, Massachusetts.;J. Peterson, MD, Western Washington Arthritis Clinic, Bothell, Washington, USA.",
"authors": "Botson|John K|JK|;Tesser|John R P|JRP|;Bennett|Ralph|R|;Kenney|Howard M|HM|;Peloso|Paul M|PM|;Obermeyer|Katie|K|;LaMoreaux|Brian|B|;Weinblatt|Michael E|ME|;Peterson|Jeff|J|",
"chemical_list": "D006074:Gout Suppressants; D014527:Uric Acid; D011092:Polyethylene Glycols; D014503:Urate Oxidase; C031545:Pegloticase; D008727:Methotrexate",
"country": "Canada",
"delete": false,
"doi": "10.3899/jrheum.200460",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0315-162X",
"issue": "48(5)",
"journal": "The Journal of rheumatology",
"keywords": "gout; methotrexate; pegloticase; tophi; uricase",
"medline_ta": "J Rheumatol",
"mesh_terms": "D000328:Adult; D006073:Gout; D006074:Gout Suppressants; D006801:Humans; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D011092:Polyethylene Glycols; D016896:Treatment Outcome; D014503:Urate Oxidase; D014527:Uric Acid",
"nlm_unique_id": "7501984",
"other_id": null,
"pages": "767-774",
"pmc": null,
"pmid": "32934137",
"pubdate": "2021-05",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "Pegloticase in Combination With Methotrexate in Patients With Uncontrolled Gout: A Multicenter, Open-label Study (MIRROR).",
"title_normalized": "pegloticase in combination with methotrexate in patients with uncontrolled gout a multicenter open label study mirror"
} | [
{
"companynumb": "US-MYLANLABS-2021M1042452",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "1",
... |
{
"abstract": "High-dose melphalan 200 mg/m(2) (MEL 200) is the standard of care as a conditioning regimen for autologous hematopoietic stem cell transplantation (AHSCT) for multiple myeloma (MM). We compared a novel conditioning combination incorporating busulfan, melphalan, and bortezomib (BUMELVEL) versus standard MEL 200 in newly diagnosed patients undergoing AHSCT for MM. Between July 2009 and May 2012, 43 eligible patients received BUMELVEL conditioning followed by AHSCT. BU was administered i.v. daily for 4 days to achieve a target area under the concentration-time curve total of 20,000 mM·min based on pharmacokinetic analysis after the first dose. MEL 140 mg/m(2) (MEL 140) and VEL 1.6 mg/m(2) were administered i.v. on days -2 and -1, respectively. Outcomes were compared with a contemporaneous North American cohort (n = 162) receiving MEL 200 matched for age, sex, performance status, stage, interval from diagnosis to AHSCT, and disease status before AHSCT. Multivariate analysis of relapse, progression-free survival (PFS), and overall survival (OS) was performed. The median follow-up was 25 months. No transplant-related mortality was observed in the study cohort at 1 year. PFS at 1 year was superior in the BUMELVEL cohort (90%) in comparison with 77% in MEL 200 historical control subjects (P = .02). Cumulative incidence of relapse was lower in the BUMELVEL group versus the MEL 200 group (10% at 1 year versus 21%; P = .047). OS at 1 year was similar between cohorts (93% versus 93%; P = .89). BU can be safely combined with MEL 140 and VEL without an increase in toxicities or transplant-related mortality. We observed a superior PFS in the BUMELVEL cohort without maintenance therapy, warranting further trials.",
"affiliations": "Division of Hematology and Oncology, Department of Medicine, Cardinal Bernardin Cancer Center, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois. Electronic address: trodriguez@lumc.edu.;Department of Medicine and Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, Wisconsin.;Division of Hematology and Oncology, Department of Medicine, Cardinal Bernardin Cancer Center, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois.;Division of Hematology and Oncology, Department of Medicine, Cardinal Bernardin Cancer Center, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois.;Division of Hematology and Oncology, Department of Medicine, Loyola University Medical Center, Maywood, Illinois.;Multiple Myeloma Division, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey; Multiple Myeloma Program, MedStar Georgetown University Hospital, Washington, DC.",
"authors": "Rodriguez|Tulio E|TE|;Hari|Parameswaran|P|;Stiff|Patrick J|PJ|;Smith|Scott E|SE|;Sterrenberg|Danielle|D|;Vesole|David H|DH|",
"chemical_list": "D019653:Myeloablative Agonists; D000069286:Bortezomib; D002066:Busulfan; D008558:Melphalan",
"country": "United States",
"delete": false,
"doi": "10.1016/j.bbmt.2016.03.021",
"fulltext": "\n==== Front\n960062820830Biol Blood Marrow TransplantBiol. Blood Marrow Transplant.Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation1083-87911523-65362716406210.1016/j.bbmt.2016.03.021nihpa817383ArticleBusulfan, Melphalan, and Bortezomib versus High-Dose Melphalan as a Conditioning Regimen for Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma Rodriguez Tulio E. 1*Hari Parameswaran 2Stiff Patrick J. 1Smith Scott E. 1Sterrenberg Danielle 3Vesole David H. 451 Division of Hematology and Oncology, Department of Medicine, Cardinal Bernardin Cancer Center, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois2 Department of Medicine and Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, Wisconsin3 Division of Hematology and Oncology, Department of Medicine, Loyola University Medical Center, Maywood, Illinois4 Multiple Myeloma Division, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey5 Multiple Myeloma Program, MedStar Georgetown University Hospital, Washington, DC* Correspondence and reprint requests: Tulio E. Rodriguez, MD, Cardinal Bernardin Cancer Center, Loyola University Chicago Stritch School of Medicine, 2160 S. First Avenue, Maywood, IL 60153. trodriguez@lumc.edu (T.E. Rodriguez)21 9 2016 07 5 2016 8 2016 24 10 2016 22 8 1391 1396 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).High-dose melphalan 200 mg/m2 (MEL 200) is the standard of care as a conditioning regimen for autologous hematopoietic stem cell transplantation (AHSCT) for multiple myeloma (MM). We compared a novel conditioning combination incorporating busulfan, melphalan, and bortezomib (BUMELVEL) versus standard MEL 200 in newly diagnosed patients undergoing AHSCT for MM. Between July 2009 and May 2012, 43 eligible patients received BUMELVEL conditioning followed by AHSCT. BU was administered i.v. daily for 4 days to achieve a target area under the concentration-time curve total of 20,000 mM·min based on pharmacokinetic analysis after the first dose. MEL 140 mg/m2 (MEL 140) and VEL 1.6 mg/m2 were administered i.v. on days −2 and −1, respectively. Outcomes were compared with a contemporaneous North American cohort (n = 162) receiving MEL 200 matched for age, sex, performance status, stage, interval from diagnosis to AHSCT, and disease status before AHSCT. Multivariate analysis of relapse, progression-free survival (PFS), and overall survival (OS) was performed. The median follow-up was 25 months. No transplant-related mortality was observed in the study cohort at 1 year. PFS at 1 year was superior in the BUMELVEL cohort (90%) in comparison with 77% in MEL 200 historical control subjects (P = .02). Cumulative incidence of relapse was lower in the BUMELVEL group versus the MEL 200 group (10% at 1 year versus 21%; P = .047). OS at 1 year was similar between cohorts (93% versus 93%; P =.89). BU can be safely combined with MEL 140 and VEL without an increase in toxicities or transplant-related mortality. We observed a superior PFS in the BUMELVEL cohort without maintenance therapy, warranting further trials.\n\nStem cell transplantationMultiple myelomaConditioning regimenBusulfanMelphalanBortezomib\n==== Body\nINTRODUCTION\nHigh-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (AHSCT) is an effective therapy for transplant-eligible patients as consolidation after induction therapy in newly diagnosed multiple myeloma (MM). The benefit of AHSCT also extends to patients with relapsed disease who remain transplant eligible. The effectiveness of AHSCT for patients with MM remains relevant despite significant therapeutic advances achieved with the introduction of novel agents such as proteasome inhibitors and immunomodulatory agents. MM remains the most common indication for AHSCT in North America and Europe [1]. Single-agent melphalan, at a dose of 200 mg/m2 (MEL 200), is the international standard for conditioning before AHSCT for MM [2]. Other chemotherapy and chemoradiotherapy regimens have been used in preparation for AHSCT but with no clear superiority over MEL 200 [3]. These other combination regimens are generally associated with increased hematologic and nonhematologic toxicities without improvement in efficacy.\n\nHigh-dose busulfan (BU) and melphalan (MEL) are myeloablative chemotherapeutic agents. Both are effective and well-tolerated agents that have been used for over 20 years in MM and other malignancies as conditioning regimens for AHSCT. The combination of BU and MEL was associated with superior progression-free survival (PFS) compared with MEL 200 in patients who had not achieved European Group for Blood and Marrow Transplantation criteria (CR) before AHSCT [4,5]. Additionally, the combination of bortezomib (VEL) and MEL appears to be synergistic, especially when VEL is administered after MEL 200 [6].\n\nWe prospectively evaluated a conditioning regimen consisting of high-dose i.v. BU and MEL followed by VEL (BUMELVEL) in an open-label, phase I/II fashion aimed at improving PFS after AHSCT for MM patients. A predefined maximum tolerated dose was used in this trial and consisted of BU 130 mg/m2 daily for 4 days and adjusted to achieve a target area under the concentration-time curve (AUC) total of 20,000 µM·min, MEL 140 mg/m2, and VEL 1.6 mg/m2. We then compared the results of patients who received the predefined maximum tolerated dose against a contemporaneous matched cohort of patients with similar characteristics who received single-agent MEL 200.\n\nMETHODS\nBetween July 2009 and May 2012, 43 patients received BUMELVEL conditioning followed by AHSCT in a single-center, open-label phase I/II protocol. Inclusion criteria included adults with MM who had a creatinine of less than 2.5 mg/dL, without active infections or severe obstructive and/or restrictive pulmonary disease determined by pulmonary function testing (ie, DLCO < 50% and/or FEV1 < 50% and/or FVC < 50%) and cardiac ejection fraction greater than 40%. Response criteria were assessed according to the International Myeloma Working Group Uniform Response Criteria [7].\n\nNeutrophil and platelet engraftment were defined as the first of 3 days with a neutrophil count > .5 × 109/L and first date of 3 consecutive laboratory values with an untransfused platelet count ≥ 20 × 109/L. Because BU has been associated with the risk of sinusoidal obstructive syndrome (SOS), we monitored for SOS using the Baltimore diagnostic criteria [8]. It is known that SOS risk is higher when the total BU AUC exceeds 24,000 µM·min [9]. Therefore, BU was administered i.v. daily for a total of 4 days with the first 2 days (days −6 and −5) at fixed dose of 130 mg/m2 over 3 hours and the subsequent 2 doses (days −4 and −3) adjusted to achieve a target AUC total of 20,000 µM·min determined by pharmacokinetic analysis after the first dose of i.v. BU. MEL 140 mg/m2 and VEL 1.6 mg/m2 were administered i.v. on days −2 and −1, respectively.\n\nPatients received prophylaxis for oral mucositis with palifermin: 2 doses of 6.25 mg were administered by i.v. bolus injection for 2 consecutive days before the first BU dose (days −8 and −7), and a third dose of 6.25 mg was administered on day 0 after stem cell infusion. This study was approved by the Loyola University Chicago Stritch School of Medicine Institutional Review Board, and all patients voluntarily signed informed consent.\n\nSTUDY DESIGN\nData from this phase I/II clinical trial in MM patients transplanted at Loyola University Chicago Medical Center using the BUMELVEL conditioning regimen were compared against a matched control cohort of contemporaneous North American MM patients (n = 162) receiving single-agent MEL 200 conditioning. Only patients who received the predefined maximum tolerated dose were included in the comparison analysis. The control subjects were identified from the Center for International Blood and Marrow Transplant Research (CIBMTR) database. The comparison was done on a 1:3 match (Loyola-to-CIBMTR). Control subjects were randomly selected and matched by age, sex, Karnofsky performance status (KPS), disease stage, interval from diagnosis to AHSCT, and disease status before AHSCT. Fifty-four centers, not including the study center, contributed with patients for the control group. Multivariate analysis of relapse, PFS, and overall survival (OS) was performed. Maintenance therapy was not administered to patients or control subjects.\n\nControl Cohort Database\nThe CIBMTR is a research affiliation of the International Bone Marrow Transplant Registry and the National Marrow Donor Program (NMDP) and receives data from over 500 transplantation centers worldwide on allogeneic and autologous hematopoietic stem cell transplantation. Data are submitted to the Statistical Center at the Medical College of Wisconsin in Milwaukee and the NMDP Coordinating Center in Minneapolis, where computerized checks for discrepancies, physicians’ reviews of submitted data, and on-site audits of participating centers ensure data quality. Observational studies conducted by the CIBMTR are performed with approval of the institutional review boards of the NMDP and the Medical College of Wisconsin.\n\nStatistical Analysis\nThe primary endpoint of the study was the 1-year PFS after a myeloablative preparative regimen consisting of i.v. BUMELVEL versus MEL 200. Using a 1:3 match comparison, the study included 43 patients on the BUMELVEL regimen and 162 patients from the CIBMTR database. Descriptive statistics were used to report results including demographics, disease-related factors, transplant-related factors, incidence and severity of mucositis, incidence and severity of SOS, remission rates, and relapse rates. Survival analysis was done using a Cox proportional hazards regression to adjust for differences between the groups. P values were always 2-tailed and considered significant when <.05.\n\nMedians and ranges are listed for continuous variables. The total number of patients and the percentage of each subgroup were calculated for categorical variables. Characteristics of patients in the 2 study cohorts were compared using the Mann-Whitney-Wilcoxon test for continuous variables and chi-square test for discrete variables. For discrete variables with small group size, the Fisher’s exact test was used for comparison. Probability of PFS and OS was calculated using the Kaplan-Meier estimator, with the variance estimated by the Greenwood’s formula. Probabilities of treatment-related mortality (TRM) and relapse were generated using cumulative incidence estimates to accommodate the competing risk event. The point-wise comparison was used to analyze outcomes of 2 study cohorts. All tests were 2-sided with a significant level of .05.\n\nMultivariate analysis of TRM, relapse, PFS, and OS were performed using Cox proportional hazards regression models. The variables considered in the multivariable were preparative regimen, age, gender, KPS, isotype, international stage for MM, Mayo risk stratification at diagnosis, number of prior chemotherapy regimens before transplantation, chemotherapy regimens before transplantation, disease status before transplantation, time from diagnosis to transplantation, and year of transplantation. The assumption of proportional hazards for each factor in the Cox model was tested using time-dependent covariates. A backward stepwise model selection approach was used to identify all significant risk factors. Each step of model building contained the main effect for 2 different regimens. Factors significant at a 5% level were kept in the final model. The potential interactions between main effects and all significant risk factors were tested.\n\nRESULTS\nPatient Characteristics\nBoth cohorts were balanced for age, gender, KPS, MM isotypes, time from diagnosis to transplantation, disease stage, and disease status before transplantation (Table 1). Patient demographics in the BUMELVEL and MEL 200 groups included the following: median age 62 years and 61 years, respectively; KPS ≥ 90% in 74% and 75%, respectively; and chemotherapy-sensitive disease before transplantation in 95% and 91%, respectively. All patients underwent AHSCT within 12 months from diagnosis.\n\nOf note, the MEL 200 control cohort had more standard-risk patients per Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) [10] (78% versus 40% in BUMELVEL, P < .0001) and more patients with only 1 prior line of therapy pre-AHSCT (67% versus 47%, P =.02). Patients in the BUMELVEL group had received induction combination regimens involving VEL, lenalidomide, and dexamethasone (51%); VEL and dexamethasone (35%); or VEL, thalidomide, and dexamethasone (14%) before AHSCT. At the time of transplantation, 3 (7%) and 15 (35%) patients were in CR and very good partial remission (VGPR), respectively. Median follow-up for the BUMELVEL and MEL 200 cohorts were 25 months and 35 months, respectively. Sixty-two percent of the control group received VEL either as a doublet or in combination with thalidomide or lenalidomide. Thirty-six percent received induction therapy with other novel agents consisting of doublets with thalidomide or lenalidomide.\n\nOutcomes\nThe BUMELVEL regimen resulted in an overall response rate of 98%, including at least VGPR in 70% and CR in 42% (Table 2). At 1 year post-AHSCT, 90% of patients on the BUMELVEL cohort remained progression free in comparison with 77% of MEL 200 recipients (P = .02) (Figure 1). OS was similar between both cohorts (93% versus 93% at 1 year; P =.89) (Figure 2). Cumulative incidence of relapse at 1 year was lower in the BUMELVEL group versus MEL 200 (10% versus 21%; P = .047). Neutrophil and platelet engraftment kinetics were similar between both groups (Figures 3 and 4).\n\nIn multivariate analysis, PFS was superior in the BUMELVEL cohort (hazard ratio for relapse/death, 1.87 for MEL 200 cohort; P =.04). BUMELVEL therapy was not associated with any difference in OS or relapse risk at the time of the analysis. Patients who achieved at least a VGPR before AHSCT had a superior PFS post-AHSCT (CR, 1.000 [95% confidence interval {CI}, 1.000 to 1.000]; VGPR, 1.983 [95% CI, .876 to 4.489]; PR, 2.668 [95% CI, 1.260 to 5.652]; and stable disease, 3.468 [95% CI, 1.337 to 8.996]), whereas lower KPS (≤80) and higher international stage were associated with inferior OS (relative risk for OS, 2.283 [95% CI,1.093 to 4.769] for KPS ≤ 80, P =.02; hazard ratio for OS, 3.568 [95% CI, 1.326 to 9.598] for stages II to III, P = .0086).\n\nRegimen-Related Toxicity\nThere was no TRM in the BUMELVEL group and no episodes of SOS disease. There was a small but statistically significant TRM in the MEL cohort (relative risk for TRM, .03 [95% CI, .01 to .06]). The most common grade 3 adverse events (Table 3) included the expected febrile neutropenia, mucositis, and hypophosphatemia. Other adverse events presenting in less than 10% of the patients on the BUMELVEL group were diarrhea, nausea, hypocalcemia, transaminitis, and hyperglycemia. The median hospital stay for the BUMELVEL group was 19 days.\n\nDose Targeting of BU\nThe first 2 daily infusions of BU on the BUMELVEL regimen were given at a fixed dose of 130 mg/m2 over 3 hours from days −6 to −5. This dose has been found to be safe and equivalent to the standard daily dose of 3.2 mg/kg [11]. The third and fourth daily doses of i.v. BU were adjusted to yield a systemic plasma drug exposure, represented by a targeted AUC of 5000 µM·min per dose for a total of 20,000 µM·min. Only 23% of patients had an AUC outside an acceptable range of 5000 µM·min ± 20% (<4000 or >6000 µM·min). Doses were adjusted on days −4 and −3 to achieve the total desired AUC of 20,000 µM·min.\n\nDISCUSSION\nHigh-dose chemotherapy followed by AHSCT is considered a standard approach by the International Myeloma Working Group for transplant-eligible MM patients. The addition of novel agents, like the immunomodulatory drugs thalidomide, lenalidomide, and pomalidomide and the proteasome inhibitors VEL and carfilzomib, in treatment paradigms has led to unprecedented survival improvement in patients with MM [12–14].\n\nIn the context of stem cell transplantation for MM, there is a relationship between the achievement of CR or VGPR and PFS or OS [15]. VEL-based induction regimens result in significant improvements in response, PFS, and OS compared with non-VEL-based induction regimens [16]. In our study 100% of patients in the BUMELVEL cohort received induction with VEL combination regimens before AHSCT versus 62% of patients in the control group. Because control subjects were matched with patients for disease status before transplantation, we believe the lack of VEL in the induction therapy is not impacting the outcomes observed. More patients in the control group were in CR prior to transplantation compared with the BUMELVEL group (20% versus 7%, respectively). The higher CR rate in the control group might be related to a higher representation of standard-risk patients per mSMART and more patients with only 1 prior line of therapy pre-AHSCT in this group.\n\nThe study group was treated before the availability of other proteasome inhibitors. Carfilzomib, which was approved by the US Food and Drug Administration in 2012 for the treatment of patients with MM who have received at least 2 prior therapies, including VEL and an immunomodulatory agent, has shown activity in patients with newly diagnosed as well as relapsed or refractory MM [17]. In a randomized, phase III, open-label, multicenter study for patients with relapsed or refractory MM, carfilzomib with dexamethasone was found to deliver better response and PFS rates when compared with VEL with dexamethasone [18]. These observations suggest that carfilzomib-based regimens could deliver better responses before AHSCT in comparison with VEL-based regimens. Obviously, this will need to be validated in prospective clinical trials while paying special attention to therapeutic index.\n\nDespite achievements of impressive response rates after inductions with novel therapy regimes, AHSCT continues to deliver improvement in PFS and OS as consolidation of these responses [19]. A phase II study of extended treatment with carfilzomib, lenalidomide, and dexamethasone (KRd) plus AHSCT in newly diagnosed MM patients showed that this regimen resulted in higher stringent CR rates than KRd without AHSCT. There was also a higher rate of minimal residual disease negativity in the transplantation group [20]. The improvement in response rate after induction was observed in our analysis where the CR plus VGPR after BUMELVEL followed by AHSCT increased from 42% pre-transplantation to 70% post-AHSCT. Our analysis suggests that the novel preparative regimen BUMELVEL followed by AHSCT is a complementary, nonredundant therapy that can be effectively included in the management of MM supporting the trends in utilization and outcomes of autologous transplantation as a therapy for MM [2].\n\nIn an older study reported by Mansi et al. [21], a 46% response rate was observed after high-dose single-agent oral BU (16 mg/kg) followed by AHSCT in heavily pretreated patients with MM. The absorption of oral BU is unpredictable and may lead to unacceptable nonhematologic toxicity. We used an i.v. BU formulation for our regimen that has been found to deliver effective myeloablation with less nonhematologic toxicity and higher 100-day survival compared with oral BU [22]. Single-agent high-dose MEL 200 has been used almost exclusively as the preferred preparative regimen for MM since a randomized study established the superiority of this regimen over MEL 140 mg/m2 with total body radiation [23].\n\nThere is now evidence of clonal heterogeneity and clonal evolution throughout the natural history of MM [24]. Based on these observations, a response to therapy might represent the suppression of a sensitive clone, whereas resistant clones remain unperturbed and become proportionally more dominant over time, leading to inevitable relapse. This rationale supports the development of preparative regimens combining synergistic agents to achieve deeper responses to circumvent the possibility of heterogeneous resistant clones leading to relapse while maintaining an acceptable therapeutic index. The combination of BU with either MEL or cyclophosphamide has been used for over 20 years as an alternative preparative regimen in MM before AHSCT [25–28].\n\nProteasome inhibitors such as VEL have a consistent anti-tumor activity against chemoresistant and chemosensitive myeloma cells. The sensitivity of chemoresistant myeloma cells to this chemotherapeutic agent is markedly increased (100,000- to 1,000,000-fold) without affecting normal hematopoietic cells [29]. This observation allowed us to deliver this drug 24 hours before the stem cell infusion without potentially affecting engraftment. We did not observe graft failure or delayed engraftment in the BUMELVEL cohort.\n\nIt has been suggested that VEL up-regulates the anti-apoptotic protein MCL-1, and the sequence of administration may be critical to the combination of VEL and MEL 200 [30]. Doses of VEL were escalated from 1.0 mg/m2 up to 1.6 mg/m2. The increase in apoptosis on samples obtained from patients who were treated with MEL followed by VEL was superior to the apoptosis observed with VEL preceding MEL [31]. The combination of MEL and VEL has been found to be effective in the relapse setting as well [32,33].\n\nNishihori et al. [34] completed a phase I/II study of VEL in combination with MEL followed by tandem autologous transplants in primary refractory MM patients. However, with the availability of new potent novel agents, the role of tandem transplantation in patients with MM is in question.\n\nOur novel combination of BUMELVEL delivered an impressive overall response rate of 98%, including at least a VGPR of 70% and a CR rate of 42%. These responses compare favorably with reported responses using single-agent MEL 200 (20% to 40% CR and 40% to 55% CR/VGPR) [15]. The primary endpoint of the study, 1-year PFS, was significantly improved in the BUMELVEL cohort in comparison with single-agent MEL 200 (90% versus 77%, respectively; P =.02). The improvement in PFS was achieved despite a higher proportion of standard-risk patients in the control group in comparison with the BUMELVEL cohort by mSMART criteria and more patients with >1 prior line of therapy pre-AHSCT in the BUMELVEL group. OS was similar between the 2 groups, probably due to the relatively short median duration of follow-up and the multitude of treatment options available in relapsed MM. The main adverse events were manageable and included neutropenic fever, mucositis, and hypophosphatemia. Adverse events did not translate into transplant-related mortality. The incidence of febrile neutropenia (77%) is similar to that reported by Lahuerta using BU and MEL [21]. Among recipients of high-dose chemotherapy in high-risk protocols (eg, BU, cyclophosphamide, etoposide), severe mucositis is reported in excess of 60% to 90% [35]. In our study only 37% and 2% of patients developed grade 3 and grade 4 mucositis, respectively. Thus, collectively, the addition of VEL to BUMEL does not appear to increase adverse events. The lower incidence of adverse events may be due to the use of a targeted dose of BU and the incorporation of palifermin as a mucoprotectant.\n\nEngraftment was prompt and predictable and was not different from historical control subjects with single-agent MEL 200. Moreover, the once-daily dosing of BU allowed us to perform outpatient transplantation using the BUMELVEL regimen.\n\nOur analysis has the limitations of being a case-control retrospective comparison with a registry population. This type of analysis could potentially introduce a selection bias through center effects. However, no center effect has ever been identified in autologous transplant studies for MM in the CIBMTR. The improvement in PFS observed in the BUMELVEL cohort could be related to the targeted BU therapy used in this regimen, the synergism observed in prior studies between MEL and VEL, or both. Randomized prospective clinical trials would probably help in answering these questions.\n\nIn conclusion, pharmacokinetic-directed dosing of BU can be safely combined with MEL 140 mg/m2 and VEL 1.6 mg/m2 (BUMELVEL) without adding nonhematologic toxicity or transplant-related mortality. This novel regimen delivered high response rates and a better PFS compared with MEL 200 and warrants further study in a prospective randomized clinical trial.\n\nFinancial disclosure: This research was supported by Otsuka Pharmaceutical Co, Ltd.\n\nT.E.R. received research funding, consultancy, and honoraria from Otsuka and Takeda and honoraria and consultancy from Celgene and Onyx. P.H. received consultancy, honoraria, and research funding from BMS, Celgene, Onyx, and Takeda; honoraria from Janssen; and honoraria and research funding from Sanofi. P.J.S. received research funding from Amgen, Eisai, Gilead, Plasmacyclics, Incyte, Seattle Genetics, and Fate Therapeutics; consultancy and honoraria from Gilead, Plasmacyclics, Incyte, and Seattle Genetics. S.E.S. received research funding from Seattle Genetics and consultancy and honoraria from Celgene. D.H.V. received honoraria from Millennium, Takeda, and Celgene and research funding and honoraria from Onyx/Amgen.\n\nConflict of interest statement: D.S. reports no conflicts of interest.\n\nFigure 1 PFS in BUMELVEL versus high-dose MEL.\n\nFigure 2 OS in BUMELVEL versus high-dose MEL.\n\nFigure 3 Cumulative incidences of neutrophil engraftment in BUMELVEL versus high-dose MEL.\n\nFigure 4 Cumulative incidences of platelet engraftment in BUMELVEL versus high-dose MEL.\n\nTable 1 Characteristics of Patients Who Underwent Single Autologous Transplant with i.v. BU, MEL Followed by VEL and High-Dose MEL between 2009 and 2012\n\nCharacteristics\tBUMELVEL\tMEL 200\tP\t\nNumber of patients\t43\t162\t\t\nNumber of centers\t1\t54\t\t\nAge at transplant, median\n (range), yr\t62 (46–69)\t61 (41–69)\t\t\n 18–59\t9 (21)\t56 (35)\t.17\t\n 60–64\t17 (40)\t61 (38)\t\t\n 65–70\t17 (40)\t45 (28)\t\t\nGender\t\t\t\t\n Male\t24 (56)\t91 (56)\t.97\t\n Female\t19 (44)\t71 (44)\t\t\nKPS at transplant\t\t\t\t\n ≤80\t11 (26)\t40 (25)\t1\t\n 90–100\t32 (74)\t122 (75)\t\t\nIsotype\t\t\t\t\n IgG\t26 (60)\t100 (62)\t.86\t\n IgA\t8 (19)\t32 (20)\t\t\n Light chain\t7 (16)\t27 (17)\t\t\n IgD\t1 (2)\t1 (<1)\t\t\n Nonsecretory\t1 (2)\t2 (1)\t\t\nInternational stage at transplant\t\t\t\t\n Stage I\t16 (37)\t51 (31)\t.74\t\n Stage II/III\t20 (47)\t79 (53)\t\t\n Unknown\t7 (16)\t25 (15)\t\t\nMayo risk stratification at\n diagnosis (mSMART)\t\t\t\t\n Standard risk\t17 (40)\t127 (78)\t<.0001\t\n High risk\t4 (9)\t18 (11)\t\t\n Unknown\t22 (51)\t17 (10)\t\t\nNumber of chemotherapy sessions\t\t\t\t\n 1\t20 (47)\t108 (67)\t.02\t\n >1\t23 (53)\t54 (33)\t\t\nDisease status before AHSCT\t\t\t\t\n CR\t3 (7)\t33 (20)\t.19\t\n VGPR\t15 (35)\t43 (27)\t\t\n PR\t23 (53)\t72 (44)\t\t\n Stable disease\t1 (2)\t11 (7)\t\t\n Relapse/progression\t1 (2)\t3 (2)\t\t\nMedian follow-up of survivors\n (range), mo\t25 (2–50)\t35 (3–50)\t\t\nValues are number of cases with percents in parentheses, unless otherwise noted.\n\nTable 2 Response Status before and after AHSCT using BUMELVEL Regimen\n\nResponse Status\tPatients before AHSCT\tPatients after AHSCT\t\nCR\t3 (7%)\t18 (42%)\t\nVGPR\t15 (35%)\t12 (28%)\t\nPR\t23 (53%)\t12 (28%)\t\nLess than PR\t2 (4%)\t1 (2%)\t\nTable 3 BUMELVEL Toxicities per National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03\n\nToxicities\tNo. of Cases\t\nGrade 3\t\t\n Febrile neutropenia\t33 (77%)\t\n Mucositis\t16 (37%)\t\n Hypophosphatemia\t8 (19%)\t\n Diarrhea\t4 (9%)\t\n Nausea\t4 (9%)\t\n Hypocalcemia\t3 (7%)\t\n Transaminitis\t3 (7%)\t\n Hyperglycemia\t2 (5%)\t\nGrade 4\t\t\n Hypocalcemia\t2 (5%)\t\n Mucositis\t2 (5%)\t\n Transaminitis\t1 (2%)\n==== Refs\nREFERENCES\n1 Qazilbash MH Giralt SA Appelbaum FR Forman SJ Negrin RS Blume KG Hematopoietic cell transplantation for multiple myeloma Thomas’ hematopoietic cell transplantation 2004 4th West Sussex, UK Blackwell 2295 2307 \n2 Costa LJ Zhang MJ Zhong X Trends in utilization and outcomes of autologous transplantation as early therapy for multiple myeloma Biol Blood Marrow Transplant 2013 19 1615 1624 23939198 \n3 Schallier D Impens N Warson D Additive pulmonary toxicity with melphalan and busulfan therapy Chest 1983 84 492 493 6578007 \n4 Lahuerta JJ Grande C Blade J Myeloablative treatments for multiple myeloma: update of a comparative study of different regimens used in patients from the Spanish registry for transplantation in multiple myeloma Leuk Lymph 2002 43 67 74 \n5 Lahuerta JJ Mateos MV Martínez-Lópezet J Busulfan 12 mg/kg plus melphalan 140 mg/m2 versus melphalan 200 mg/m2 as conditioning regimens for autologous transplantation in newly diagnosed multiple myeloma patients included in the PETHEMA/GEM2000 study Haematologica 2010 95 1913 1920 20663944 \n6 Lonial S Kaufman K Tighiouart M A phase I/II trial combining high dose melphalan and autologous transplant with bortezomib for multiple myeloma: dose and schedule finding study Clin Cancer Res 2010 16 5079 5086 20739431 \n7 Durie BGM Harousseau J-L Miguel JS International uniform response criteria for multiple myeloma Leukemia 2006 20 1467 1473 16855634 \n8 Jones RJ Lee KS Beschorner WE Venoocclusive disease of the liver following bone marrow transplantation Transplantation 1987 44 778 783 3321587 \n9 Dix SP Wingard JR Mullins RE Association of busulfan area under the curve with veno-occlusive disease following BMT Bone Marrow Transplant 1996 17 225 230 8640171 \n10 Kumar SK Mikhael JR Buadi FK Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines Mayo Clin Proc 2009 84 1095 1110 19955246 \n11 de Lima M Couriel D Shahjahan M IV busulfan (Bu) with fludarabine (Flu) or cyclophosphamide (Cy)—comparing ablative preparative regimens for allogeneic transplantation in AML/MDS Blood 2004 104 11 14976060 \n12 Kumar SK Rajkumar SV Dispenzieri A Improved survival in multiple myeloma and the impact of novel therapies Blood 2008 111 2516 2520 17975015 \n13 Kumar SK Dispenzieri A Lacy MQ Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients Leukemia 2014 28 1122 1128 24157580 \n14 Usmani SZ Waheed S Van Rhee F Total therapy 5 (TT5) for newly diagnosed high-risk multiple myeloma (HRMM): comparison with predecessor trials total therapy 3a and 3b (TT3 a/b) J Clin Oncol 2013 31 Suppl 8539 \n15 Harousseau JL Induction therapy in multiple myeloma Hematol Am Soc Hematol Educ Progr 2008 2008 306 312 \n16 Sonneveld P Goldschmidt H Rosiñol L Bortezomib-based versus nonbortezomib-based induction treatment before autologous stem-cell transplantation in patients with previously untreated multiple myeloma: a meta-analysis of phase III randomized, controlled trials J Clin Oncol 2013 31 3279 3287 23897961 \n17 Moreau P Kolb B Attal M Phase 1/2 study of carfilzomib plus melphalan and prednisone in patients aged over 65 years with newly diagnosed multiple myeloma Blood 2015 125 3100 3104 25784682 \n18 Dimopoulos MA Moreau P Palumbo A Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study Lancet Oncol 2016 17 27 38 26671818 \n19 Palumbo A Cavallo F Gay F Autologous transplantation and maintenance therapy in multiple myeloma N Engl J Med 2014 371 895 905 25184862 \n20 Zimmerman TM Griffith KA Jasielec J Phase II MMRC trial of extended treatment with carfilzomib (CFZ), lenalidomide (LEN), and dexamethasone (DEX) plus autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma (NDMM) J Clin Oncol 2015 33 Suppl 8510 \n21 Mansi J da Costa F Viner C High-dose busulfan in patients with myeloma J Clin Oncol 1992 10 1569 1573 1403036 \n22 Kashyap A Wingard J Cagnoni P Intravenous versus oral busulfan as part of a busulfan/cyclophosphamide preparative regimen for allogeneic hematopoietic stem cell transplantation: decreased incidence of hepatic venoocclusive disease (HVOD), HVOD-related mortality, and overall 100-day mortality Biol Blood Marrow Transplant 2002 8 493 500 12374454 \n23 Moreau P Facon T Attal M Comparison of 200 mg/m(2) melphalan and 8 Gy total body irradiation plus 140 mg/m(2) melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myélome 9502 randomized trial Blood 2002 99 731 735 11806971 \n24 Keats JJ Chesi M Egan JB Clonal competition with alternating dominance in multiple myeloma Blood 2012 120 1067 1076 22498740 \n25 Toor AA Ayers J Strupeck J Favourable results with a single autologous stem cell transplant following conditioning with busulphan and cyclophosphamide in patients with multiple myeloma Br J Haematol 2004 124 769 776 15009065 \n26 Cavo M Bandini G Benni M High-dose busulfan and cyclophosphamide are an effective conditioning regimen for allogeneic bone marrow transplantation in chemosensitive multiple myeloma Bone Marrow Transplant 1998 22 27 32 9678792 \n27 Hamon MD Donohue SM Franklin IM Therapeutic progress—review XXVII. High dose chemotherapy in haematological malignancy J Clin Pharm Ther 1987 12 203 211 3305528 \n28 Phillips GL Shepherd JD Barnett MJ Busulfan, cyclophosphamide, and melphalan conditioning for autologous bone marrow transplantation in hematologic malignancy J Clin Oncol 1991 9 1880 1888 1919638 \n29 Ma MH Yang HH Parker K The proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemotherapeutic agents Clin Cancer Res 2003 9 1136 1144 12631619 \n30 Podar K Gouill SL Zhang J A pivotal role for Mcl-1 in bortezomib-induced apoptosis Oncogene 2008 27 721 731 17653083 \n31 Lonial S Kaufman J Tighiouart M A phase I/II trial combining high-dose melphalan and autologous transplant with bortezomib for multiple myeloma: a dose- and schedule-finding study Clin Cancer Res 2010 16 5079 5086 20739431 \n32 Roussel M Moreau P Huynh A Bortezomib and high-dose melphalan as conditioning regimen before autologous stem cell transplantation in patients with de novo multiple myeloma: a phase 2 study of the Intergroupe Francophone du Myelome (IFM) Blood 2010 115 32 37 19884643 \n33 Doo NW Thompson PA Price HM Bortezomib with high dose melphalan conditioning for autologous transplant is safe and effective in patients with heavily pretreated and high risk multiple myeloma Leuk Lymphoma 2013 54 1465 1472 23121086 \n34 Nishihori T Alekshun TJ Shain K Bortezomib salvage followed by a Phase I/II study of bortezomib plus high-dose melphalan and tandem autologous transplantation for patients with primary resistant myeloma Br J Haematol 2012 157 553 563 22449149 \n35 Pico JL Avila-Garavito A Naccache P Mucositis: its occurrence, consequences, and treatment in the oncology setting Oncologist 1998 3 446 451 10388137\n\n",
"fulltext_license": "CC BY-NC-ND",
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"issue": "22(8)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": "Bortezomib; Busulfan; Conditioning regimen; Melphalan; Multiple myeloma; Stem cell transplantation",
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069286:Bortezomib; D002066:Busulfan; D016022:Case-Control Studies; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008558:Melphalan; D008875:Middle Aged; D009101:Multiple Myeloma; D019653:Myeloablative Agonists; D019172:Transplantation Conditioning; D014182:Transplantation, Autologous; D016896:Treatment Outcome",
"nlm_unique_id": "9600628",
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"pages": "1391-1396",
"pmc": null,
"pmid": "27164062",
"pubdate": "2016-08",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "12374454;26671818;20739431;22498740;23897961;10388137;22449149;8640171;1919638;20663944;19884643;6578007;12631619;3305528;19955246;19074101;1403036;17653083;23121086;11908738;25184862;3321587;25784682;23939198;16855634;11806971;15009065;24157580;17975015;9678792",
"title": "Busulfan, Melphalan, and Bortezomib versus High-Dose Melphalan as a Conditioning Regimen for Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma.",
"title_normalized": "busulfan melphalan and bortezomib versus high dose melphalan as a conditioning regimen for autologous hematopoietic stem cell transplantation in multiple myeloma"
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"abstract": "We review the case of a 74-year-old patient with advanced colon cancer who suffered recurrent bouts of hypoglycemia. A state of inappropriate, non-suppressed hyperinsulinism in the presence of severe hypoglycemia was diagnosed. We finally discuss the known mechanisms behind fasting hypoglycemia in patients with advanced cancer, the diagnosis, and possible treatments of this rare paraneoplastic endocrine complication.",
"affiliations": "Medical Oncology Unit, University Hospital La Fe, Avenida Campanar 19-21, Valencia 46009, Spain. rdiazbev@hotmail.com",
"authors": "Díaz|Roberto|R|;Aparicio|Jorge|J|;Mendizábal|Andrea|A|;Faus|Marisa|M|;Fleitas|Tania|T|;Aparisi|Francisco|F|;Martín|Maria|M|",
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"doi": "10.3748/wjg.14.1952",
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"issn_linking": "1007-9327",
"issue": "14(12)",
"journal": "World journal of gastroenterology",
"keywords": null,
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000368:Aged; D003110:Colonic Neoplasms; D015897:Comorbidity; D017809:Fatal Outcome; D006801:Humans; D006946:Hyperinsulinism; D007003:Hypoglycemia; D008297:Male",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "1952-4",
"pmc": null,
"pmid": "18350640",
"pubdate": "2008-03-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10471466;10500928;15575249;7505031;16170199;10500929;2537194;3185662;15497518;10471459;15223980",
"title": "Paraneoplastic hyperinsulinism and secondary hypoglycaemia in a patient with advanced colon cancer: a rare association.",
"title_normalized": "paraneoplastic hyperinsulinism and secondary hypoglycaemia in a patient with advanced colon cancer a rare association"
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"companynumb": "ES-PFIZER INC-2021332012",
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"activesubstancename": "FLUOROURACIL"
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... |
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"abstract": "Direct acting oral anticoagulants (DOACs) have become the mainstay of treatment for patients requiring anticoagulation for atrial arrhythmias and venous thromboembolism (VTE) but safety and efficacy has not been established in lung transplantation. This is a retrospective review of 28 adult lung transplant patients who were prescribed apixaban for stroke prevention in atrial arrhythmias or treatment of VTE between October 15, 2015 and December 31, 2018. The primary outcome was a composite of efficacy and safety measured by recurrence or breakthrough of stroke or thromboembolism and bleeding events. Seven patients were treated for atrial arrhythmias and 21 treated for VTE. Fifteen patients received CYP3A4 or P-gp inhibitors at initiation of anticoagulation, and 4 of these patients received strong CYP3A4 inhibitors. During the follow-up period, one breakthrough DVT and one clinically relevant non-major bleed were observed. These data suggest that apixaban may be safe to use for lung transplant patients, and larger studies are warranted to assess long-term outcomes as well as safety and efficacy of alternative DOACs.",
"affiliations": "Department of Pharmacy, Hennepin County Medical Center, Minneapolis, MN, USA.;Department of Pharmacy, Baylor University Medical Center, Dallas, TX, USA.;Department of Pharmacy, Baylor University Medical Center, Dallas, TX, USA.;Center for Advanced Heart and Lung Disease, Baylor University Medical Center, Dallas, TX, USA.;Center for Advanced Heart and Lung Disease, Baylor University Medical Center, Dallas, TX, USA.;Center for Advanced Heart and Lung Disease, Baylor University Medical Center, Dallas, TX, USA.;Center for Advanced Heart and Lung Disease, Baylor University Medical Center, Dallas, TX, USA.;Department of Pharmacy, Sharp Memorial Hospital, San Diego, CA, USA.",
"authors": "Reininger|Kevin A|KA|;Sam|Teena|T|0000-0002-9780-7227;Patel|Raksha S|RS|;Grazia|Todd J|TJ|;Naik|Chetan A|CA|;Ausloos|Kenneth A|KA|;Rosenblatt|Randall L|RL|;Lam|In Lok L|ILL|",
"chemical_list": "D000925:Anticoagulants; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban",
"country": "Denmark",
"delete": false,
"doi": "10.1111/ctr.14327",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-0063",
"issue": "35(7)",
"journal": "Clinical transplantation",
"keywords": "anticoagulation; apixaban; atrial fibrillation; lung transplantation; stroke; venous thromboembolism",
"medline_ta": "Clin Transplant",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000925:Anticoagulants; D001281:Atrial Fibrillation; D006801:Humans; D016040:Lung Transplantation; D011720:Pyrazoles; D011728:Pyridones; D012189:Retrospective Studies; D020521:Stroke; D054556:Venous Thromboembolism",
"nlm_unique_id": "8710240",
"other_id": null,
"pages": "e14327",
"pmc": null,
"pmid": "33899964",
"pubdate": "2021-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A retrospective analysis of the safety and efficacy of apixaban use after lung transplant.",
"title_normalized": "a retrospective analysis of the safety and efficacy of apixaban use after lung transplant"
} | [
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"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-047335",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "APIXABAN"
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"drugaddit... |
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"abstract": "Breast cancer is the most frequent invasive cancer in women and the second cause of death by cancer in women after lung cancer. It causes metastases especially to bones, liver and lungs. Pancreatic metastases from a primary breast neoplasm are rare and unusual, occurring in less than 3% of the cases. There have been only 28 cases described in the literature. This paper adds one more case to the published literature. We present a case of pancreatic metastasis of the breast in a 64-year-old female and a discussion based on a review of the literature.",
"affiliations": "Mohammed VI University of Health Sciences (UM6SS), Department of Radiotherapy, International University Hospital Sheikh Khalifa, Casablanca, Morocco.;Mohammed VI University of Health Sciences (UM6SS), Department of Radiotherapy, International University Hospital Sheikh Khalifa, Casablanca, Morocco.;Mohammed VI University of Health Sciences (UM6SS), Department of Medical Oncology, International University Hospital Sheikh Khalifa, Casablanca, Morocco.;Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco.;Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco.;Mohammed VI University of Health Sciences (UM6SS), National Reference Laboratory (LNR), Casablanca, Morocco.;Mohammed VI University of Health Sciences (UM6SS), Department of Medical Oncology, International University Hospital Sheikh Khalifa, Casablanca, Morocco.",
"authors": "Kouhen|Fadila|F|;Chihabeddine|Meriem|M|;Squali|Mohammed|M|;Allaoui|Mohammed|M|;Bouzidi|Abderrahmane Al|AA|;Errafiy|Nadia|N|;Ismaili|Nabil|N|",
"chemical_list": null,
"country": "Uganda",
"delete": false,
"doi": "10.11604/pamj.2020.37.260.25228",
"fulltext": "\n==== Front\nPan Afr Med J\nPan Afr Med J\nPAMJ\nThe Pan African Medical Journal\n1937-8688 The African Field Epidemiology Network \n\nPAMJ-37-260\n10.11604/pamj.2020.37.260.25228\nCase Report\nMetastasis to the pancreas: a rare site for secondary malignancy of breast cancer (a case report)\nKouhen Fadila 1& Chihabeddine Meriem 1 Squali Mohammed 2 Allaoui Mohammed 34 Bouzidi Abderrahmane Al 34 Errafiy Nadia 5 Ismaili Nabil 2 1 Mohammed VI University of Health Sciences (UM6SS), Department of Radiotherapy, International University Hospital Sheikh Khalifa, Casablanca, Morocco,\n2 Mohammed VI University of Health Sciences (UM6SS), Department of Medical Oncology, International University Hospital Sheikh Khalifa, Casablanca, Morocco,\n3 Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco,\n4 Department of Pathology, Military Hospital Mohammed V, Rabat, Morocco,\n5 Mohammed VI University of Health Sciences (UM6SS), National Reference Laboratory (LNR), Casablanca, Morocco,\nCorresponding author: Fadila Kouhen, Mohammed VI University of Health Sciences (UM6SS), Department of Radiotherapy, International University Hospital Sheikh Khalifa, Casablanca, Morocco. fadila10m@hotmail.com\n23 11 2020 \n2020 \n37 26027 7 2020 09 11 2020 Copyright: Fadila Kouhen et al.2020The Pan African Medical Journal (ISSN: 1937-8688). This is an Open Access article distributed under the terms of the Creative Commons Attribution International 4.0 License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Breast cancer is the most frequent invasive cancer in women and the second cause of death by cancer in women after lung cancer. It causes metastases especially to bones, liver and lungs. Pancreatic metastases from a primary breast neoplasm are rare and unusual, occurring in less than 3% of the cases. There have been only 28 cases described in the literature. This paper adds one more case to the published literature. We present a case of pancreatic metastasis of the breast in a 64-year-old female and a discussion based on a review of the literature.\n\nBreast cancerpancreatic metastasesprognosiscase report\n==== Body\nIntroduction\nWith two million new cases in 2018, breast cancer is the most frequent invasive cancer in women and the second cause of death by cancer in women after lung cancer [1]. The screening and the treatment improvement decreased the breast cancer mortality, however 20 to 30% of patients develop a distant metastasis [1]. The most common breast cancer metastasis sites are the bones, the lungs, the brain, and the liver. Pancreatic metastases from a primary breast cancer are rare, occurring in less than 3% of the cases [2]. There have been only 28 cases described in the literature. This paper adds one more case to the published literature. We present a case of pancreatic metastasis of the breast in a 64-year-old female and a discussion based on a review of the literature.\n\nPatient and observation\nA 64-year-old post-menopausal female patient, with no significant past medical or family history was admitted to our hospital with the following medical history. Her history dates back 1 year when she detected a lump in her left breast. Five months after, she reported severe lower back pain with jaundice, nausea and loss of nine kilograms in four months. The physical examination showed a retro-nipple mass of 5 cm in diameter in the left breast with frank cutaneous-mucosal jaundice and the abdomen was painful to deep palpation. Neurologic examination revealed no focal deficits. Mammography analysis revealed a retro-nipple lesion of the left breast classified ACR 5. After fine-needle aspiration, invasive lobular breast carcinoma was detected in pathological examination. Immunohistological staining revealed that hormone receptors were positive, with estrogen receptors (ERs) at: 80% and progesterone receptors (PgRs) at 30%. The HER2 score was 1+ and the Ki67 was at 22%. Abdominal computed tomography demonstrated a hyper vascularized, irregular solid lesion of 4.3 cm x 2.7 cm x 7.0 cm in the head of the pancreas with discreet biliary duct dilation. In addition, Bones scintigraphy showed abnormal increased accumulation of radiopharmaceutical along the right humeral head, L4, and femurs\n\nLumbar spine MRI evaluation showed a tumor process involving the vertebral body and the posterior arch of L4. Histopathology by pancreatic endoscopic ultrasound-guided fine needle biopsy confirmed metastatic carcinoma with breast origin. The morphological and immunohistochemical features of pancreatic-metastasis were similar to the primary carcinoma breast (Figure 1, Figure 2, Figure 3). Cancer antigen (CA)-19.9, carcinoembryonic antigen (CEA) and CA-15-3 levels were in the normal range. She underwent percutaneous transhepatic biliary drainage and fluoroscopic guided stenting with a metallic-stent (ELLA stent). The liver-functions normalized gradually and patient´s general-condition also improved.\n\nFigure 1 infiltration by a tumour composed of nests and foci of cells with hyperchromatic nuclei (HE, Gx40)\n\nFigure 2 Ki-67 labelling index is high\n\nFigure 3 estrogen receptor expression by the tumor cells\n\nOur Therapeutic management was started firstly by the placement of a biliary prosthesis, then by analgesic and decompressive conventional radiotherapy at L4 with radiation dose of 30 Gy (3 Gy/fraction). A systemic therapy consisting of letrozole 2.5 mg/day combined with palbociclib 25 mg/day (3 weeks ON and one week OFF) and denosumab at a dose of 120 mg/month was prescribed. The treatment was well tolerated except grade 1 anemia and fatigue. The first assessment three months after starting treatment showed a partial response according to the response evaluation criteria in solid tumors (RECIST) V1.1 criteria. After 22 months of follow-up, the evolution was marked by lesion stability without local and distant disease progression.\n\nDiscussion\nPancreatic metastases from other primary malignancies are uncommon and they don´t exceed 2% of pancreatic cancers [2]. The most common primary cancers with pancreatic metastases are kidney cancer, followed by colorectal cancer, melanoma, breast cancer, lung carcinoma and sarcoma [3]. Breast cancer causes metastases especially to bones, liver and lungs. Pancreatic metastases from a primary breast neoplasm are rare and unusual, occurring in less than 3% of the cases. To our knowledge, 29 cases of pancreatic metastases from breast cancer, including the present case, have been reported at 17 case reports and 6 case series since the first report in 1982 by Azzarelli et al. [4]. Typically, invasive lobular breast carcinoma is the most common type of breast cancer metastasizes to the pancreatic gland [5]. The clinical presentation is similar for both primary and secondary neoplasms. Most patients present with obstructive jaundice caused by compression of the bile duct in the head of the pancreas. The patient can have also epigastric or back pain, and weight loss [6].\n\nIn recent years, diagnostic imaging techniques such as Doppler ultrasound (US), helical computed tomography (CT), enhanced magnetic resonance imaging (MRI), and endoscopic US (EUS) have been developed, elevating the ability to diagnose pancreatic tumors, but it is often difficult to distinguish pancreatic metastasis from a primary pancreatic tumor [7,8]. Our patient had undergone an endoscopic ultrasound with fine needle aspiration which had confirmed a diagnosis of pancreatic metastases of breast cancer. Surgical treatment is indicated when the pancreatic lesion is single and for patients fit to perform a pancreatectomy [9,10]. For our patient, surgery was not indicated due to several metastatic sites.\n\nThe prognosis for patients with pancreatic metastatic disease is usually better than for patients with primary pancreatic tumors. Masetti et al. analyzed the prognostic factors relating to metastatic tumors to the pancreas, and found at univariate survival analysis a 2-years probability of survival of 57.1% in pancreas metastases from breast cancer and a 5-years probability of survival of 34.3% [11]. Palbociclib, highly selective inhibitors of CDK4 and CDK6, serine-threonine kinases that regulate the cell cycle progression, have been approved in recent years for the treatment of endocrine-resistant MBC in combination with endocrine therapy considering their efficacy in prolonging progression-free survival, increasing clinical benefit rate and response rate in different clinical context and treatment lines [12-14]. Our patient remained without disease progression at the time of her last follow-up examination (22 months after diagnosis).\n\nConclusion\nIn summary, this case demonstrates the very rare case of a breast cancer metastasis to the pancreas arising as the first symptom of metastatic breast cancer. Pancreatic metastasis is difficult to diagnose, because its clinical and radiological presentation is similar to that of a primary pancreatic tumor. Thus, the clinician should suspect the possibility of pancreatic metastasis in cases of pancreatic lesions detected in any patient with a prior history of cancer, including breast cancer.\n\nCite this article: Fadila Kouhen et al. Metastasis to the pancreas: a rare site for secondary malignancy of breast cancer (a case report). Pan African Medical Journal. 2020;37(260). 10.11604/pamj.2020.37.260.25228\n\nCompeting interests\nThe authors declare no competing interests.\n\nAuthors' contributions\nAll the authors have read and agreed to the final manuscript.\n==== Refs\n1 Ferlay J Colombet M Soerjomataram I Siegel R Torre L Jemal A global and regional estimates of the incidence and mortality for 38 cancers: GLOBOCAN 2018 2018 Lyon International Agency for Research on Cancer/World Health Organization \n2 Reddy S Wolfgang CL The role of surgery in the management of isolated metastases to the pancreas Lancet Oncol 2009 10 3 287 93 19261257 \n3 Sperti C Moletta L Patanè G Metastatic tumors to the pancreas: the role of surgery World J Gastrointest Oncol 2014 10 15 6 10 381 92 25320654 \n4 Azzarelli A Clemente C Quagliuolo V Baticci F A case of pancreatoduodenectomy as resolutive treatment for a solitary metastasis of breast cancer Tumori 1982 8 68 4 331 5 7147359 \n5 Kliiger J Gorbaty M Metastasis to the pancreas and stomach from a breast cancer primary: a case report J Community Hosp Intern Med Perspect 2017 10 7 4 234 237 29046750 \n6 Apodaca-RuedaI M Chaim FHM Garcia MDS Almeida de Saito HPD Gestic MA Utrini MP et al Solitary pancreatic metastasis from breast cancer: case report and review of literature Sao Paulo Med J 2019 137 2 201 205 29116313 \n7 Molino C Mocerino C Braucci A Riccardi F Trunfio M Carrillo G et al Pancreatic solitary and synchronous metastasis from breast cancer: a case report and systematic review of controversies in diagnosis and treatment World J Surg Oncol 2014 12 2 24387226 \n8 Tsitouridis A Diamantopoulou Michaelides M Arvanity M Papaioannou S Pancreatic metastases: CT and MRI findings Diagn Interv Radiol 2010 3 16 1 45 51 20027546 \n9 Sperti C Moletta L Patanè G Metastatic tumors to the pancreas: the role of surgery World J Gastrointest Oncol 2014 10 15 6 10 381 392 25320654 \n10 Lin Y Wong SI Wang Y Lam C Peng X Periampullary Metastases from Breast cancer: a case report and literature review Hindawi Case Reports in Oncological Medicine. January 2019 2019 1 9 3479568 \n11 Masetti M Zanini N Martuzzi F Fabbri C Mastrangelo L Landolfo G et al Analysis of prognostic factors in metastatic tumors of the pancreas a single-center experience and review of the literature Pancreas 2010 3 39 2 135 43 19820422 \n12 Serra F Lapidari P Quaquarini E Tagliaferri B Sottotetti F Palumbo R Palbociclib in metastatic breast cancer: current evidence and real-life data Drugs Context 2019 7 16 8 212579 31391852 \n13 Finn RS Crown JP Lang I Boer K Bondarenko IM Kulyk SO et al The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen-receptor positive, HER2 negative, advanced breast cancer (PALOMA-1/TRIO18): a randomized phase 2 study Lancet Oncol 2015 1 16 1 25 35 25524798 \n14 Rugo HS Diéras V Gelmon KA Finn RS Slamon DJ Martin M et al Impact of palbociclib plus letrozole on patient-reported health-related quality of life: results from the PALOMA-2 trial Ann Oncol 2018 Apr1 29 4 888 894 29360932\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "37()",
"journal": "The Pan African medical journal",
"keywords": "Breast cancer; case report; pancreatic metastases; prognosis",
"medline_ta": "Pan Afr Med J",
"mesh_terms": "D001943:Breast Neoplasms; D005260:Female; D006801:Humans; D008875:Middle Aged; D010190:Pancreatic Neoplasms",
"nlm_unique_id": "101517926",
"other_id": null,
"pages": "260",
"pmc": null,
"pmid": "33598075",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "20027546;29116313;25320654;7147359;25524798;24387226;29046750;31391852;30729053;29360932;19820422;19261257",
"title": "Metastasis to the pancreas: a rare site for secondary malignancy of breast cancer (a case report).",
"title_normalized": "metastasis to the pancreas a rare site for secondary malignancy of breast cancer a case report"
} | [
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"companynumb": "MA-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-308554",
"fulfillexpeditecriteria": "1",
"occurcountry": "MA",
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"drug": [
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"activesubstancename": "DENOSUMAB"
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"abstract": "Factor V Leiden (G1691A), prothrombin (G20210A) and MTHFR (C677T) gene mutations were investigated in many studies for their association with Deep Venous Thrombosis.\nA North Lebanese family has been examined, from an index case, a 40-year-old woman, who had a history of venous thrombosis with unexplained recurrent miscarriage. The index case was found to be heterozygous for factor V Leiden G1691A, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T gene variants. Her family members were heterozygous for at least two of the three-point mutations, and multiple risk factors associated with thrombophilia were identified.\nOur findings emphasize the need for clarifying the utility and futility of thrombophilia testing in the era of molecular diagnostics.",
"affiliations": "Department of Medical Laboratory Technology, Faculty of Health Sciences, Beirut Arab University, Tripoli, Lebanon.;Department of Medical Laboratory Technology, Faculty of Health Sciences, Beirut Arab University, Tripoli, Lebanon.",
"authors": "Khalife|Sara|S|;Bissar-Tadmouri|Nisrine|N|",
"chemical_list": "C095381:factor V Leiden; D005165:Factor V; D011516:Prothrombin; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2)",
"country": "New Zealand",
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"doi": "10.2147/VHRM.S235784",
"fulltext": "\n==== Front\nVasc Health Risk ManagVasc Health Risk ManagVHRMvhriskmanVascular Health and Risk Management1176-63441178-2048Dove 23578410.2147/VHRM.S235784Original ResearchInherited Thrombophilia in a Lebanese Family of Four Generations: A Case Report of Recurrent Miscarriage Khalife and Bissar-TadmouriKhalife and Bissar-TadmouriKhalife Sara 1Bissar-Tadmouri Nisrine 11 Department of Medical Laboratory Technology, Faculty of Health Sciences, Beirut Arab University, Tripoli, LebanonCorrespondence: Sara Khalife Department of Medical Laboratory Technology, Faculty of Health Sciences, Beirut Arab University, Tripoli, LebanonTel +961 70 557389 Email sara.khalifeh@bau.edu.lb21 1 2020 2020 16 53 56 24 10 2019 08 1 2020 © 2020 Khalife and Bissar-Tadmouri.2020Khalife and Bissar-Tadmouri.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).Introduction\nFactor V Leiden (G1691A), prothrombin (G20210A) and MTHFR (C677T) gene mutations were investigated in many studies for their association with Deep Venous Thrombosis.\n\nCase Presentation\nA North Lebanese family has been examined, from an index case, a 40-year-old woman, who had a history of venous thrombosis with unexplained recurrent miscarriage. The index case was found to be heterozygous for factor V Leiden G1691A, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T gene variants. Her family members were heterozygous for at least two of the three-point mutations, and multiple risk factors associated with thrombophilia were identified.\n\nConclusion\nOur findings emphasize the need for clarifying the utility and futility of thrombophilia testing in the era of molecular diagnostics.\n\nKeywords\nfactor V Leiden G1691AMTHFR C677Tprothrombin G20210Adeep venous thrombosisrecurrent pregnancy lossLebanese family\n==== Body\nIntroduction\nThrombophilia is a hypercoagulable state that predisposes to thrombosis. It is manifested by inappropriate blood clot formation, a multifactorial condition that could arise from genetic, acquired factors or a combination of both.1 Thrombotic events are steadily recognized as an important source of morbidity and mortality. Among the inherited risk factors precipitating venous thromboembolism (VTE), are three main polymorphic biomarkers; prothrombin gene (FII G20210A), Factor V Leiden (FV G1691A) and methylenetetrahydrofolate reductase (MTHFR C677T), although the latter seems to be weakly associated with the condition.1\n\nAn increased risk of thrombosis has been observed in patients with multiple gene defects. Additionally, an increased risk of VTE has been seen in patients with co-occurrence of hereditary thrombophilias and/or prothrombotic polymorphisms.1\n\nDespite the well-established positive correlation between inherited thrombophilia and thrombosis, inherited thrombophilia screening in asymptomatic persons is indicated exclusively for high-risk individuals that need to be promptly identified and tested.2\n\nIn this study we aim to examine the molecular profile of a thrombophilic Lebanese family for three thrombophilic mutations (FII 20210 GA, FV 1691 GA, and MTHFR 677 CT), to gain a better understanding of the relationship between the combinations of mutations and the clinical outcome on family members.\n\nCase Presentation\nThe study was approved by the Institutional Review Board at Beirut Arab University (IRB number: 2019H-0099-HS-R-0368). Written informed consent from patients and parental consent for minors were obtained for the case details to be published.\n\nWe describe a Lebanese family of four generations via patient II-5, a 40-year-old hypertensive woman who has a 5-year-old child and has experienced three consecutive pregnancy losses prior to 20 gestational weeks. She was then taking Oral contraceptive pills containing 3 mg drospirenone and 0.03 mg ethinylestradiol (Bayer HealthCare Pharmaceuticals, Yasmin, Whippany, Germany) for two years before her failed attempts to conceive. The history of our patient revealed one episode of deep venous thrombosis (DVT) at the age of thirty-seven, one year after she started the oral contraception. Her first-degree relatives were asymptomatic to the time of reporting except her brother (II3) who had an ischemic stroke at the age of 44.\n\nThe family comprised of 11 members, age ranging between 1 and 72 years, and the sex ratio was 1.2. Investigated risk factors include Hormonotherapy, underlying diseases, smoking habits, use of oral contraceptives, and family history of thromboembolic diseases (Table 1).Table 1 Clinical Data of Study Participants\n\nPedigree Code\tAge and Gender\tSmoking Habits\tUnderlying Diseases\tPregnancy Loss\tUse of Oral Contraceptives\tThrombotic Episodes\tSurgery, Trauma or Immobilization\t\nI 1\t72 F\tActive\tHypercholesterolemia\t2\tNo\tNo\tNo\t\nII1\t45 F\tActive\tNone\t3\tEthinyl estradiol/drospirenone\tNo\tIVF\t\nII2\t52 M\tActive\tNone\tN/A\tN/A\tNo\tNo\t\nII3\t48 M\tActive\tHypercholesterolemia\tN/A\tN/A\tIschemic Stroke\tMechanical embolectomy\t\nII4\t45 F\tActive\tNone\t0\tNo\tNo\tNo\t\nII5\t40 F\tActive\tHypercholesterolemia\t3\tEthinyl estradiol/drospirenone\tDVT\tNo\t\nII6\t45 M\tActive\tNone\tN/A\tN/A\tNo\tNo\t\nIII1\t20 M\tPassive\tNone\tN/A\tN/A\tNo\tNo\t\nIII2\t23 F\tActive\tNone\t0\tEthinyl estradiol/drospirenone\tNo\tNo\t\nIII3\t5 M\tActive\tNone\tN/A\tN/A\tNo\tNo\t\nIV 1\t1 M\tPassive\tNone\tN/A\tN/A\tNo\tNo\t\nAbbreviations: DVT, Deep Venous Thrombosis; IVF, In-Vitro Fertilization; M, Male; F, Female; N/A, Not Applicable.\n\n\n\n\nThree mL venous blood was collected from each patient in EDTA tubes. Plasma samples were then stored at –20°C until assay. The mutations were detected by ThromboStrip- Opegen (Operon, Zaragoza, Spain) according to the manufacturer’s protocol. The procedure consists of the following steps: DNA extraction, PCR amplification, strip hybridization, strip development, and detection.\n\nOur index patient is a heterozygous carrier of FII G20210A, FV G1691A, and MTHFR C677T variants as shown by genetic analysis. The obtained results brought on the need to test all the patient’s first-degree family members for the same mutations.\n\nEach member of the investigated family has at least two out of the three mutations tested in this study (Figure 1).Figure 1 Pedigree of the investigated family with genotypes for the three selected gene variants. The propositus is indicated by an arrow.\n\n\n\nIn addition, most family members have different combinations of risk factors associated with thrombophilia, mainly hypercholesterolemia, smoking habits and use of oral contraceptives (Table 1).\n\nDiscussion\nIn this family, each investigated member has at least two prothrombotic gene variants out of the three tested, which can be considered as a clinical alarm due to zygosity status combined with the influence of environmental factors. A study on a large cohort of patients with VTE showed that both heterozygous and homozygous FV 1691A (FVL) carriers had a higher prevalence of isolated DVT compared to isolated pulmonary embolism (PE) or combined DVT/PE clinical presentation.3 However, this same study revealed that double heterozygosity was not shown to significantly increase the prevalence of distal DVT or change its clinical presentation as compared to both heterozygous FVL and heterozygous FII 20210A carriers.3 A minor correlation was documented for MTHFR C677T and VTE unless additional risk factors are present.1\n\nAll tested individuals were either active or passive smokers, and 27.3% of the tested family members, including the index patient, were suffering from hypercholesterolemia. It was shown in earlier studies that both smoking and hypercholesterolemia are important risk factors for thrombosis.4,5\n\nThrombophilia has been recognized as a common cause of recurrent pregnancy loss (RPL). A meta-analysis showed an increased risk of VTE in pregnancy with FVL and FII G20210A carrier state.6 Consequently, women with unexplained early RPL should be targeted for FVL and FII G20210A testing, which are considered the most frequently requested genetic thrombophilia investigations.6 However, most experts and evidence-based guidelines argue against such measurements due to a lack of benefits.2\n\nFurthermore, the risk of thrombosis increased significantly in prothrombin G20210A and FV G1691A mutation carriers using combined hormonal contraceptives (CHCs).7,8\n\nAltogether, FV G1691A and FII G20210A testing might identify individuals at risk of recurrent thrombotic episodes for targeted further intervention, but other data do not support this approach.2\n\nIndividual II-1 had recurrent in vitro fertilization failures on the 12th gestational week due to the occurrence of DVT in the fetus. Genetic testing revealed that she is a heterozygous carrier for both MTHFR C677T and FV G1691A mutations. However, the association between these anomalies and the repeated in vitro fertilization failures remains to be discussed as the evidence is inconclusive and not supported by cohort studies. Although, the European Society of Human Reproduction and Embryology and The Society of Obstetricians and Gynecologists of Canada recommend a risk assessment and genetic testing for thrombophilia to women undergoing assisted reproductive technology with ovarian stimulation so prophylaxis can be initiated, in many infertility centers in Lebanon, this is only done after repeated in vitro fertilization failures.\n\nOur index patient had an episode of venous thromboembolism with RPL. Hence, molecular testing to detect genetic polymorphisms that predispose to thrombophilia is to be discussed as it provides information that can guide the therapeutic strategies and improve prognosis. It also allows proposing genetic testing and counseling to relatives to identify individuals at risk, since the natural history of this hereditary disease has an asymptomatic phase, which is sometimes very prolonged.\n\nHowever, much uncertainty exists regarding the importance of genetic testing for thrombophilia, as management strategies are often based on the clinical history of the patient rather than on the underlying genetic anomaly.\n\nNevertheless, a common investigation technique has been adopted for the genetic testing of thrombophilia based on the detection of FV G1691A and FII G20210A mutations.2\n\nConclusion\nTo our knowledge, this is the first study in Lebanon to describe a family with hereditary thrombophilia and examine several risk factors associated with this disease. In addition, we highlight the fact that thrombophilia testing in Lebanon is ordered inappropriately and is not adequately followed up. Education of physicians on the indications and the limitations of genetic tests, as well as genetic counselors are needed to assess each clinical condition and interpret the genetic and environmental risk factors. This will facilitate sound decision making regarding the test, and will help patients cope with the possible psychological distress.\n\nAcknowledgments\nWe would like to thank the participants for their time and efforts in the present study\n\nDisclosure\nThe authors declare no conflicts of interest in this work.\n==== Refs\nReferences\n1. Simone \nB , De Stefano \nV , Leoncini \nE , et al. Risk of venous thromboembolism associated with single and combined effects of factor V Leiden, prothrombin 20210A and methylenetethraydrofolate reductase C677T: a meta-analysis involving over 11,000 cases and 21,000 controls . Eur J Epidemiol . 2013 ;28 (8 ):621 –647 . doi:10.1007/s10654-013-9825-8 23900608 \n2. Favaloro \nEJ . Genetic testing for thrombophilia-related genes: observations of testing patterns for factor V Leiden (G1691A) and prothrombin gene “Mutation” (G20210A) . Semin Thromb Hemost . 2019 ;45 (7 ):730 –742 . doi:10.1055/s-0039-1694772 31398733 \n3. Campello \nE , Spiezia \nL , Dalla Valle \nF , Tormene \nD , Simioni \nP . Factor V Leiden paradox and the occurrence of distal vein thrombosis in a large cohort of thrombotic patients . Thromb Res . 2017 ;156 :20 –22 . doi:10.1016/j.thromres.2017.05.025 28577389 \n4. Nielsen \nVG , Hafner \nDT , Steinbrenner \nEB . Tobacco smoke-induced hypercoagulation in human plasma: role of carbon monoxide . Blood Coagul Fibrinolysis . 2013 ;24 :405 –410 . doi:10.1097/MBC.0b013e32835d5458 23429254 \n5. Chan \nP , Tomlinsoin \nB , Tsai \nCW , Pan \nWH , Lee \nYS . Thrombophilia in patients with hypercholesterolemia . Metabolism . 1996 ;45 :966 –969 .8769353 \n6. Ziakas \nPD , Poulou \nLS , Pavlou \nM , Zintzaras \nE . Thrombophilia and venous thromboembolism in pregnancy: a meta-analysis of genetic risk . Eur J Obstet Gynecol Reprod Biol . 2015 ;191 :106 –111 . doi:10.1016/j.ejogrb.2015.06.005 26115054 \n7. Trenor \nCC , Chung \nRJ , Michleson \nAD , et al. Hormonal contraception and thrombotic risk: a multidisciplinary approach . Pediatrics . 2011 ;127 (2 ):347 –357 . doi:10.1542/peds.2010-2221 21199853 \n8. Momot \nAP , Nikolaeva \nMG , Yasafova \nNN , Zainulina \nMS , Momot \nKA , Taranenko \nIA . Clinical and laboratory manifestations of the prothrombin gene mutation in women of reproductive age . J Blood Med . 2019 ;10 :255 –263 . doi:10.2147/JBM.S212759 31447596\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1176-6344",
"issue": "16()",
"journal": "Vascular health and risk management",
"keywords": "Lebanese family; MTHFR C677T; deep venous thrombosis; factor V Leiden G1691A; prothrombin G20210A; recurrent pregnancy loss",
"medline_ta": "Vasc Health Risk Manag",
"mesh_terms": "D000026:Abortion, Habitual; D020016:Activated Protein C Resistance; D000328:Adult; D001777:Blood Coagulation; D005165:Factor V; D005260:Female; D020022:Genetic Predisposition to Disease; D040941:Heredity; D006801:Humans; D007861:Lebanon; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011247:Pregnancy; D011516:Prothrombin; D012307:Risk Factors; D019851:Thrombophilia; D020246:Venous Thrombosis",
"nlm_unique_id": "101273479",
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"pages": "53-56",
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"references": "8769353;31447596;23900608;23429254;21199853;31398733;28577389;26115054",
"title": "Inherited Thrombophilia in a Lebanese Family of Four Generations: A Case Report of Recurrent Miscarriage.",
"title_normalized": "inherited thrombophilia in a lebanese family of four generations a case report of recurrent miscarriage"
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"abstract": "BACKGROUND\nClopidogrel is a platelet aggregation inhibitor used for the management of cardiovascular disease. While antiplatelet therapy decreases cardiovascular events after successful coronary drug-eluting stenting, it increases the risk of gastrointestinal (GI) bleeding. About 20% of the patients who take clopidogrel exhibit resistance to the drug.\n\n\nMETHODS\nWe report the first case of a small bowel bleeding ulcer in an 86-year-old man with clopidogrel resistance. He had a history of taking clopidogrel due to unstable angina. There was no evidence of bleeding in the stomach, duodenum, or colon through upper and lower GI endoscopies. The abdominal computed tomography showed the extravasation of radiocontrast media at the ileum. Because of unstable vital signs, emergency surgery was performed. Multiple ulcers with inflammation were found in the ileum. The pathologic findings revealed simple inflammation. The VerifyNow P2Y12 test showed clopidogrel resistance. One year after changing to aspirin, capsule endoscopy was performed and the small bowel ulcers were improved.\n\n\nCONCLUSIONS\nSmall bowel ulcers and bleeding due to clopidogrel are not very common, but the prevalence is expected to increase in older age patients with risk factors despite clopidogrel resistance.",
"affiliations": "Division of Gastroenterology, Department of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon-si 24289, South Korea.;Division of Cardiology, Department of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon-si 24289, South Korea. rdr0203@hanmail.net.;Division of Gastroenterology, Department of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon-si 24289, South Korea.;Division of Gastroenterology, Department of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon-si 24289, South Korea.;Division of Cardiology, Department of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon-si 24289, South Korea.;Department of Anatomic Pathology, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon-si 24289, South Korea.;Department of Surgery, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon-si 24289, South Korea.;Department of Hospital Medicine, Kangwon National University Hospital , Chuncheon-si 24289, South Korea.",
"authors": "Lee|Sang Hoon|SH|;Ryu|Dong Ryeol|DR|;Lee|Sung Joon|SJ|;Park|Sung Chul|SC|;Cho|Byung Ryul|BR|;Lee|Seung Koo|SK|;Choi|Sang Ji|SJ|;Cho|Hyun Seok|HS|",
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"doi": "10.12998/wjcc.v9.i15.3689",
"fulltext": "\n==== Front\nWorld J Clin Cases\nWJCC\nWorld Journal of Clinical Cases\n2307-8960\nBaishideng Publishing Group Inc\n\njWJCC.v9.i15.pg3689\n10.12998/wjcc.v9.i15.3689\nCase Report\nSmall bowel ulcer bleeding due to suspected clopidogrel use in a patient with clopidogrel resistance: A case report\nLee SH et al. Clopidogrel resistance presenting with hematochezia\nLee Sang Hoon Division of Gastroenterology, Department of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon-si 24289, South Korea\n\nRyu Dong Ryeol Division of Cardiology, Department of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon-si 24289, South Korea. rdr0203@hanmail.net\n\nLee Sung Joon Division of Gastroenterology, Department of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon-si 24289, South Korea\n\nPark Sung Chul Division of Gastroenterology, Department of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon-si 24289, South Korea\n\nCho Byung Ryul Division of Cardiology, Department of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon-si 24289, South Korea\n\nLee Seung Koo Department of Anatomic Pathology, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon-si 24289, South Korea\n\nChoi Sang Ji Department of Surgery, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon-si 24289, South Korea\n\nCho Hyun Seok Department of Hospital Medicine, Kangwon National University Hospital , Chuncheon-si 24289, South Korea\n\nAuthor contributions: Lee SH and Cho HS was the patient’s doctor; Lee SH performed endoscopy and capsule endoscopy; Choi SJ performed the surgery; Lee SH and Ryu DR reviewed the literature and contributed to manuscript drafting; Park SC, Lee SJ and Cho BR reviewed images and contributed to manuscript drafting; Lee SK performed histological analysis.\n\nCorresponding author: Dong Ryeol Ryu, MD, PhD, Professor, Division of Cardiology, Department of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Baengnyeong-ro 156, Chuncheon-si 24289, South Korea. rdr0203@hanmail.net\n\n26 5 2021\n26 5 2021\n9 15 36893695\n21 12 2020\n10 3 2021\n25 3 2021\n©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.\nBACKGROUND\n\nClopidogrel is a platelet aggregation inhibitor used for the management of cardiovascular disease. While antiplatelet therapy decreases cardiovascular events after successful coronary drug-eluting stenting, it increases the risk of gastrointestinal (GI) bleeding. About 20% of the patients who take clopidogrel exhibit resistance to the drug.\n\nCASE SUMMARY\n\nWe report the first case of a small bowel bleeding ulcer in an 86-year-old man with clopidogrel resistance. He had a history of taking clopidogrel due to unstable angina. There was no evidence of bleeding in the stomach, duodenum, or colon through upper and lower GI endoscopies. The abdominal computed tomography showed the extravasation of radiocontrast media at the ileum. Because of unstable vital signs, emergency surgery was performed. Multiple ulcers with inflammation were found in the ileum. The pathologic findings revealed simple inflammation. The VerifyNow P2Y12 test showed clopidogrel resistance. One year after changing to aspirin, capsule endoscopy was performed and the small bowel ulcers were improved.\n\nCONCLUSION\n\nSmall bowel ulcers and bleeding due to clopidogrel are not very common, but the prevalence is expected to increase in older age patients with risk factors despite clopidogrel resistance.\n\nClopidogrel\nResistance\nSmall bowel\nMultiple ulcers\nHematochezia\nSurgery\nCase report\n==== Body\nCore Tip: Small bowel injury and bleeding are typical side effects of non-steroidal anti-inflammatory drugs and antiplatelet agents like aspirin. However, there are rare previous reports of small bowel injury and bleeding due to clopidogrel and the mechanisms of ulcer formation in patients receiving clopidogrel therapy are unclear. Here, we report the first case of a small bowel bleeding ulcer in an 86-year-old man with clopidogrel resistance.\n\nINTRODUCTION\n\nThe causes of small bowel bleeding vary according to age. Tumors, Meckel’s diverticulum, Dieulafoy’s lesion, and Crohn’s disease are the common causes in young patients (< 40 years), whereas vascular lesions like angiodysplasia and small bowel lesions caused by non-steroidal anti-inflammatory drugs (NSAIDs) and antiplatelet drugs are the major cause of small bowel gastrointestinal (GI) bleeding in elderly patients (> 65 years)[1]. Small bowel injury and bleeding are typical side effects of NSAIDs and antiplatelet agents like aspirin[2]. However, small bowel bleeding caused by clopidogrel is not common. About 20% of the patients exhibit clopidogrel resistance with increased platelet activation and the resistance to this drug is associated with the risk of stent thrombosis[3]. There are no previous reports of small bowel ulcer bleeding suspected to be due to clopidogrel in a patient with clopidogrel resistance.\n\nCASE PRESENTATION\n\nChief complaints\n\nAn 86-year-old male was admitted to our hospital with hematochezia.\n\nHistory of present illness\n\nThe pain started 3 d ago, which was continuous cramping pain aggravated by meal, and severity of pain had increased from numeric rating scale of 3 to 8. The patient denied fevers, diarrhea or jaundice. Upon visit to the emergency room his blood pressure and heart rate were normal, but body temperature was elevated to 38 ºC.\n\nHistory of past illness\n\nHe had a history of taking clopidogrel due to unstable angina, and aspirin or analgesics were not taken. And he had never complained of GI symptoms prior to taking clopidogrel.\n\nPersonal and family history\n\nHe was a nonsmoker, and no notable family history was found.\n\nPhysical examination\n\nPhysical examinations showed pale conjunctiva and his abdomen was soft with mild lower abdominal tenderness. His initial blood pressure was 80/50 mmHg, pulse rate was 102 beats per minute, respiratory rate was 23 breaths per minute, and body temperature was 36.8 °C.\n\nLaboratory examinations\n\nThe baseline laboratory results were as follows: Hemoglobin level, 8.0 g/dL; white blood cell count, 6000/μL; platelet count, 185000/μL; blood urea nitrogen, 25.6 mg/dL; and C-reactive protein, 1.7 mg/dL. The levels of other routine blood chemistry markers were within the reference limits.\n\nImaging examinations\n\nThe levels of other routine blood chemistry markers were within the reference limits. Upper and lower gastrointestinal endoscopy were performed and upper gastrointestinal bleeding was excluded. However, in the lower gastrointestinal endoscopic findings, small bowel bleeding was suspected as the cause of the hematochezia (Figure 1). The abdominal computed tomography showed the extravasation of radiocontrast media at the ileum (Figure 2).\n\nFigure 1 Initial endoscopic findings. A: Lower gastrointestinal endoscopic findings show the possibility of small bowel bleeding; B: No evidence of bleeding was observed in the ascending colon and cecum.\n\nFigure 2 Alternate prism cover test findings. A: Extravasation of contrast media (orange arrow) in the ileum cross-section view; B: Sagittal view.\n\nFINAL DIAGNOSIS\n\nFinal diagnosis was small bowel ulcer bleeding due to clopidogrel resistance.\n\nTREATMENT\n\nBecause of unstable vital signs, emergency surgery was performed. Multiple ulcers with inflammation were found in the ileum (Figure 3). The pathologic findings revealed simple inflammation (Figure 4). VeryfyNow P2Y12 testing was performed to check the clopidogrel response (365PRU), and the results showed clopidogrel resistance.\n\nFigure 3 Excised specimen of the ileum, measuring 50 cm in length with multiple ulcerative lesions (orange arrow).\n\nFigure 4 Histopathologic findings in the ileum. A: Ulcer with inflammatory ulcer debris (orange arrow) [hematoxylin and eosin (H&E) stain, × 40]; B: New vascular proliferation consistent with granulation tissue formation (arrow) (H&E stain, × 200).\n\nOUTCOME AND FOLLOW-UP\n\nThe patient was prescribed aspirin instead of clopidogrel. There were no complaining symptoms. One year after discharge, capsule endoscopy was performed and the small bowel ulcers were improved (Figure 5).\n\nFigure 5 Capsule endoscopic findings one year after surgery. The previous multiple ulcers were not observed.\n\nDISCUSSION\n\nThis is the first report of a small bowel ulcer bleeding, which was suspected to be due to clopidogrel use in a patient with clopidogrel resistance. Clopidogrel, a second-generation oral thienopyridine is most commonly used as dual antiplatelet therapy with aspirin for the treatment of cardiovascular disease[4]. However, despite the use of clopidogrel, a considerable number of patients continue to have cardiovascular events. This phenomenon is called clopidogrel resistance and reflects the failure of the molecule to inhibit the target of its action.\n\nWith respect to clopidogrel resistance, accumulating data from numerous clinical studies underscore the importance of high on-treatment platelet reactivity (HPR) as a prognostic risk factor. There are several methods to evaluate the platelet response to clopidogrel. Ex vivo measurements of ADP-induced platelet aggregation by light transmittance aggregometry is the most commonly used gold standard method[5].\n\nVerifyNow is a simple, rapid, point-of-care test with the advantages of small sample volume, the use of whole blood, and no pipetting. The test is used to assess the effect of clopidogrel resistance on the P2Y12 inhibition of platelet function[6].\n\nWhen HPR was defined as 5 and 20 μmol/L adenosine diphosphate-induced maximal platelet aggregation of ≥ 46% and ≥ 59%, respectively, and P2Y12 reaction units of ≥ 235, HPR determined by light transmittance aggregometry and VeryfiNow P2Y12 were well-matched, and the risk stratification between the two methods showed strong agreement[7].\n\nThe small bowel is a rare site of GI bleeding and a common site of obscure GI bleeding. It became possible to examine the small intestine through as double balloon endoscopy and capsule endoscopy[8,9].According to previous studies, the incidence of small bowel ulcers and bleeding due to NSAIDs was about eight times higher than that of patients who did not take NSAIDs[10]. Low-dose aspirin has been reported to cause small bowel injury and 57.6% of the chronic users had mucosal breaks[11]. The crude risk of GI events in patients taking no antiplatelet therapy was 1.6%. The risk in aspirin users was 4.1%. The risk in clopidogrel users was 6.1%, and the risk in patients on both agents was 6.6%[12]. In a large cohort study, in over 75000 patients who took clopidogrel, the long-term risk of GI events like bleeding, ulcer, and erosion increased from 2% to 6%, comparing never-users with users[13]. However, this study had an observational design and included all GI bleeding. There is no mention of clopidogrel resisitance, so the difference in interstinal ulceration with or without clopidogrel resistance is unknown.\n\nSome studies suggested that phospholipids and mitochondria in the intestinal cells are directly damaged by cyclooxygenase inhibition from NSAIDs. This result induces a decrease in energy synthesis and the generation of free radicals. Then, intercellular junctions are disrupted and intestinal permeability is increased[14]. Another report suggested that the intestinal mucosal barrier is damaged by intraluminal contents such as bile acid, food, bacteria, and enzymes as a result of inflammation that occurs when neutrophils are activated[15]. There are rare previous reports of small bowel injury and bleeding due to clopidogrel and the mechanisms of ulcer formation in patients receiving clopidogrel therapy are unclear.\n\nHowever, it has been hypothesized that an impairment in ulcer healing by adenosine diphosphate (ADP) receptor antagonists may cause gastrointestinal injury[16]. Platelet aggregation may play an important role in ulcer healing through the release of platelet-derived growth factors that promote angiogenesis and ulcer healing. ADP receptor antagonists may impair gastric ulcer healing by suppressing the release of platelet-derived growth factors[17].\n\nTo the best of our knowledge, small bowel ulcer bleeding in patients with clopidogrel resistance has not been reported. Theoretically, clopidogrel cannot cause GI bleeding including small bowel injury in patients with clopidogrel resistance. In this case, there were no specific medications leading to GI bleeding and simple inflammation with no specific disease was found in the histologic examination. Clopidogrel resistance was confirmed by VeryfyNow P2Y12 testing. These results led to the diagnosis of small intestinal ulcers and bleeding associated by clopidogrel. After undergoing an operation and changing clopidogrel to aspirin, the patient's symptoms and blood tests improved, so it could be expected that intestinal bleeding no longer occurred in the patient. However, capsule endoscopy was performed to completely exclude small bowel ulceration, and it was confirmed that small bowel ulceration did not occur. This supports our opinion even though we do not know the exact mechanism of small bowel bleeding in this patient with clopidogrel resistance.\n\nThe mechanisms of clopidogrel resistance are not fully elucidated but there are several opinions on the mechanism for clopidogrel resistance. First opinion includes inappropriate dosing or underdosing of clopidogrel and drug–drug interactions between clopidogrel and other drugs. Second opinion may be hepatic conversion of the active metabolite by cytochrome CYP2C19. Third opinion could include variable intestinal absorption of the prodrug or clearance of the active metabolite. Otherwise, ABC1 activity, increased release of ADP and platelet receptor polymorphisms have been suggested[18]. In this case, these mechanisms might cause inappropriate concentration and action of active metabolite of clopidogrel and lead to ulceration and bleeding of small bowel.\n\nCONCLUSION\n\nIn conclusion, we reported the first case of a small bowel ulcer bleeding, which was suspected to be due to clopidogrel use in a patient with clopidogrel resistance. Small bowel ulcers and bleeding due to clopidogrel are not very common, but the prevalence is expected to increase in older age patients with risk factors despite clopidogrel resistance.\n\nInformed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images.\n\nConflict-of-interest statement: Authors declare no conflict of interest.\n\nCARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).\n\nManuscript source: Unsolicited manuscript\n\nPeer-review started: December 21, 2020\n\nFirst decision: February 25, 2021\n\nArticle in press: March 25, 2021\n\nSpecialty type: Gastroenterology and hepatology\n\nCountry/Territory of origin: South Korea\n\nPeer-review report’s scientific quality classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): 0\n\nGrade C (Good): C\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nP-Reviewer: Zheng YX S-Editor: Zhang H L-Editor: A P-Editor: Li X\n==== Refs\n1 Zhang BL Chen CX Li YM Capsule endoscopy examination identifies different leading causes of obscure gastrointestinal bleeding in patients of different ages Turk J Gastroenterol 2012 23 220 225 22798110\n2 Scarpignato C Bjarnason I Drug-Induced Small Bowel Injury: a Challenging and Often Forgotten Clinical Condition Curr Gastroenterol Rep 2019 21 55 31720893\n3 Breet NJ van Werkum JW Bouman HJ Kelder JC Ruven HJ Bal ET Deneer VH Harmsze AM van der Heyden JA Rensing BJ Suttorp MJ Hackeng CM ten Berg JM Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation JAMA 2010 303 754 762 20179285\n4 Fox KA Mehta SR Peters R Zhao F Lakkis N Gersh BJ Yusuf S Clopidogrel in Unstable angina to prevent Recurrent ischemic Events Trial Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non-ST-elevation acute coronary syndrome: the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) Trial Circulation 2004 110 1202 1208 15313956\n5 Smock KJ Saunders PJ Rodgers GM Johari V Laboratory evaluation of clopidogrel responsiveness by platelet function and genetic methods Am J Hematol 2011 86 1032 1034 21812020\n6 Gasparyan AY Aspirin and clopidogrel resistance: methodological challenges and opportunities Vasc Health Risk Manag 2010 6 109 112 20448796\n7 Jeong YH Bliden KP Antonino MJ Park KS Tantry US Gurbel PA Usefulness of the VerifyNow P2Y12 assay to evaluate the antiplatelet effects of ticagrelor and clopidogrel therapies Am Heart J 2012 164 35 42 22795280\n8 Iwamoto J Mizokami Y Saito Y Shimokobe K Honda A Ikegami T Matsuzaki Y Small-bowel mucosal injuries in low-dose aspirin users with obscure gastrointestinal bleeding World J Gastroenterol 2014 20 13133 13138 25278707\n9 Koffas A Laskaratos FM Epstein O Non-small bowel lesion detection at small bowel capsule endoscopy: A comprehensive literature review World J Clin Cases 2018 6 901 907 30568944\n10 Allison MC Howatson AG Torrance CJ Lee FD Russell RI Gastrointestinal damage associated with the use of nonsteroidal antiinflammatory drugs N Engl J Med 1992 327 749 754 1501650\n11 Ebi M Inoue S Sugiyama T Yamamoto K Adachi K Yoshimine T Yamaguchi Y Tamura Y Izawa S Hijikata Y Funaki Y Ogasawara N Sasaki M Kasugai K A Small Bowel Ulcer due to Clopidogrel with Cytomegalovirus Enteritis Diagnosed by Capsule and Double-Balloon Endoscopy Case Rep Gastroenterol 2018 12 303 310 30022920\n12 Nikolsky E Stone GW Kirtane AJ Dangas GD Lansky AJ McLaurin B Lincoff AM Feit F Moses JW Fahy M Manoukian SV White HD Ohman EM Bertrand ME Cox DA Mehran R Gastrointestinal bleeding in patients with acute coronary syndromes: incidence, predictors, and clinical implications: analysis from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial J Am Coll Cardiol 2009 54 1293 1302 19778672\n13 Grove EL Würtz M Schwarz P Jørgensen NR Vestergaard P Gastrointestinal events with clopidogrel: a nationwide population-based cohort study J Gen Intern Med 2013 28 216 222 22948933\n14 Fortun PJ Hawkey CJ Nonsteroidal antiinflammatory drugs and the small intestine Curr Opin Gastroenterol 2007 23 134 141 17268241\n15 Wallace JL NSAID gastropathy and enteropathy: distinct pathogenesis likely necessitates distinct prevention strategies Br J Pharmacol 2012 165 67 74 21627632\n16 Cryer B Management of patients with high gastrointestinal risk on antiplatelet therapy Gastroenterol Clin North Am 2009 38 289 303 19446259\n17 Ma L Elliott SN Cirino G Buret A Ignarro LJ Wallace JL Platelets modulate gastric ulcer healing: role of endostatin and vascular endothelial growth factor release Proc Natl Acad Sci USA 2001 98 6470 6475 11353854\n18 Angiolillo DJ Fernandez-Ortiz A Bernardo E Alfonso F Macaya C Bass TA Costa MA Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives J Am Coll Cardiol 2007 49 1505 1516 17418288\n\n",
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"issn_linking": "2307-8960",
"issue": "9(15)",
"journal": "World journal of clinical cases",
"keywords": "Case report; Clopidogrel; Hematochezia; Multiple ulcers; Resistance; Small bowel; Surgery",
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"title": "Small bowel ulcer bleeding due to suspected clopidogrel use in a patient with clopidogrel resistance: A case report.",
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"abstract": "Pseudomyxoma peritonei (PMP) is a rare condition characterized by the intraperitoneal accumulation of mucus derived mostly by appendiceal mucinous neoplasm. Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) can offer a favourable overall survival. In this study, we report a single-institute outcomes following CRS and HIPEC in patients with this condition. This is a review of prospectively collected data from 32 patients (11 men and 21 women) affected by PMP of appendiceal origin who underwent CRS and HIPEC from 2008 to 2016 in our Surgical Unit of General and Esophagogastric Surgery. The median age of the patients was 53 years (range 25-77 years). After CRS, all patients underwent HIPEC (mytomicin C 3.3 mg/m2/L and cisplatin 25 mg/m2/L at 41 °C for 60 min) with closed abdomen technique. The median (range) follow-up time for surviving patients was 43 (18-119) months. The median peritoneal cancer index (PCI) was 17. Complete cytoreductive surgery (CC0) was achieved in in 22 patients (69%). The majority of patients (88%) had grade I-II complications, 3 (9%) had grade III complications, and 1 (3%) patient had a grade IV complication. There were no perioperative mortalities. The median hospital stay was 9.5 (range 9-24) days. One year and 5-year overall survival (OS) were 90% and 58%, respectively. Regardless of histotype, disease-free survival was 95% at 1 year and 46% at 5 years. CRS in combination with HIPEC is a feasible treatment strategy and can achieve a satisfactory outcome in patients with PMP of appendiceal origin.",
"affiliations": "General and Upper GI Surgery Division, University of Verona, Piazzale Stefani, 1, 37124, Verona, Italy. dileomd@libero.it.;General and Upper GI Surgery Division, University of Verona, Piazzale Stefani, 1, 37124, Verona, Italy.;General and Upper GI Surgery Division, University of Verona, Piazzale Stefani, 1, 37124, Verona, Italy.;General and Upper GI Surgery Division, University of Verona, Piazzale Stefani, 1, 37124, Verona, Italy.;General and Upper GI Surgery Division, University of Verona, Piazzale Stefani, 1, 37124, Verona, Italy.;General and Upper GI Surgery Division, University of Verona, Piazzale Stefani, 1, 37124, Verona, Italy.",
"authors": "Di Leo|Alberto|A|;Corvasce|Arianna|A|;Weindelmayer|Jacopo|J|;Mason|Elena Jane|EJ|;Casella|Francesco|F|;de Manzoni|Giovanni|G|",
"chemical_list": "D016685:Mitomycin; D002945:Cisplatin",
"country": "Italy",
"delete": false,
"doi": "10.1007/s13304-020-00788-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2038-131X",
"issue": "72(4)",
"journal": "Updates in surgery",
"keywords": "Appendiceal neoplasms; Cytoreductive surgery; HIPEC; Hyperthermic intraperitoneal chemotherapy; PMP; Pseudomyxoma peritonei",
"medline_ta": "Updates Surg",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001063:Appendiceal Neoplasms; D001065:Appendix; D002945:Cisplatin; D003131:Combined Modality Therapy; D065426:Cytoreduction Surgical Procedures; D018572:Disease-Free Survival; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced; D008297:Male; D008875:Middle Aged; D016685:Mitomycin; D010534:Peritoneal Neoplasms; D011553:Pseudomyxoma Peritonei; D015996:Survival Rate; D016896:Treatment Outcome",
"nlm_unique_id": "101539818",
"other_id": null,
"pages": "1207-1212",
"pmc": null,
"pmid": "32410159",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article",
"references": "29412465;16389186;7503361;27065704;25785194;16838392;17197972;19387742;20227231;22614976;28265776;30523470;30456672;27727026",
"title": "Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in pseudomyxoma peritonei of appendiceal origin: result of a single centre study.",
"title_normalized": "cytoreductive surgery crs and hyperthermic intraperitoneal chemotherapy hipec in pseudomyxoma peritonei of appendiceal origin result of a single centre study"
} | [
{
"companynumb": "IT-ACCORD-183186",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "BACKGROUND\nData on the effect of oral bisphosphonates (BPs) on risk of upper gastrointestinal complications (UGIC) are conflicting. We conducted a large population-based study from a network of Italian healthcare utilization databases aimed to assess the UGIC risk associated with use of BPs in the setting of secondary prevention of osteoporotic fractures.\n\n\nMETHODS\nA nested case-control study was carried out within a cohort of 68,970 patients aged 45 years or older, who have been hospitalized for osteoporotic fracture from 2003 until 2005. Cases were the 804 patients who experienced hospitalization for UGIC until 2007. Up to 20 controls were randomly selected for each case. Conditional logistic regression model was used to estimate odds ratio (OR) associated with current and past use of BPs (i.e. for drug dispensation within 30 days and over 31 days prior the outcome onset, respectively) after adjusting for several covariates.\n\n\nRESULTS\nCompared with patients who did not use BPs, current and past users had OR (and 95% confidence interval) of 0.86 (0.60 to 1.22) and 1.07 (0.80 to 1.44) respectively. There was no difference in the ORs estimated according with BPs type (alendronate or risedronate) and regimen (daily or weekly), nor with co-therapies and comorbidities.\n\n\nCONCLUSIONS\nFurther evidence that BPs dispensed for secondary prevention of osteoporotic fractures are not associated with increased risk of severe gastrointestinal complications is supplied from this study. Further research is required to clarify the role BPs and other drugs of co-medication in inducing UGIC.",
"affiliations": "Department of Statistics and Quantitative Methods, Unit of Biostatistics and Epidemiology, University of Milano-Bicocca, Via Bicocca degli Arcimboldi 8, 20126 Milan, Italy. giovanni.corrao@unimib.it.",
"authors": "Ghirardi|Arianna|A|;Scotti|Lorenza|L|;Vedova|Gianluca Della|GD|;D'Oro|Luca Cavalieri|LC|;Lapi|Francesco|F|;Cipriani|Francesco|F|;Caputi|Achille P|AP|;Vaccheri|Alberto|A|;Gregori|Dario|D|;Gesuita|Rosaria|R|;Vestri|Annarita|A|;Staniscia|Tommaso|T|;Mazzaglia|Giampiero|G|;Corrao|Giovanni|G|;|||",
"chemical_list": "D050071:Bone Density Conservation Agents; D002121:Calcium Channel Blockers; D004164:Diphosphonates; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors",
"country": "England",
"delete": false,
"doi": "10.1186/1471-230X-14-5",
"fulltext": "\n==== Front\nBMC GastroenterolBMC GastroenterolBMC Gastroenterology1471-230XBioMed Central 1471-230X-14-52439776910.1186/1471-230X-14-5Research ArticleOral bisphosphonates do not increase the risk of severe upper gastrointestinal complications: a nested case–control study Ghirardi Arianna 1arianna.ghirardi@gmail.comScotti Lorenza 1lorenza.scotti@statistica.unimib.itVedova Gianluca Della 2gianluca.dellavedova@unimib.itD’Oro Luca Cavalieri 3responsabile.uffepi@aslmb.itLapi Francesco 456francesco.lapi@unifi.itCipriani Francesco 4francesco.cipriani@arsanita.toscana.itCaputi Achille P 7caputi@unime.itVaccheri Alberto 8alberto.vaccheri@unibo.itGregori Dario 9dario.gregori@unito.itGesuita Rosaria 10r.gesuita@univpm.itVestri Annarita 11annarita.vestri@uniroma1.itStaniscia Tommaso 12staniscia@unich.itMazzaglia Giampiero 4giampiero.mazzaglia@arsanita.toscana.itCorrao Giovanni 1giovanni.corrao@unimib.iton behalf of the AIFA-BEST Investigators1 Department of Statistics and Quantitative Methods, Unit of Biostatistics and Epidemiology, University of Milano-Bicocca, Via Bicocca degli Arcimboldi 8, 20126 Milan, Italy2 Department of Informatics, Systems and Communications, University of Milano-Bicocca, Milan, Italy3 Operative Unit of Epidemiology, Local Health Unit of Monza and Brianza, Monza, Italy4 Department of Epidemiology, Regional Agency for Healthcare Services of Tuscany, Florence, Italy5 Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy6 Centre for Clinical Epidemiology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada7 Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Messina, Italy8 Regional Centre for Drug Evaluation and Information (CREVIF), Department of Pharmacology, University of Bologna, Bologna, Italy9 Department of Public Health and Microbiology, University of Turin, Turin, Italy10 Center of Epidemiology, Biostatistics, and Medical Information Technology, Polytechnic University of Marche, Ancona, Italy11 Department of Public Health and Infectious Diseases, University “La Sapienza”, Rome, Italy12 Department of Medicine and Aging, University “G. d’Annunzio”, Chieti-Pescara, Italyon behalf of the AIFA-BEST Investigators2014 7 1 2014 14 5 5 8 10 2012 18 12 2013 Copyright © 2014 Ghirardi et al.; licensee BioMed Central Ltd.2014Ghirardi et al.; licensee BioMed Central Ltd.This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nData on the effect of oral bisphosphonates (BPs) on risk of upper gastrointestinal complications (UGIC) are conflicting. We conducted a large population-based study from a network of Italian healthcare utilization databases aimed to assess the UGIC risk associated with use of BPs in the setting of secondary prevention of osteoporotic fractures.\n\nMethods\nA nested case–control study was carried out within a cohort of 68,970 patients aged 45 years or older, who have been hospitalized for osteoporotic fracture from 2003 until 2005. Cases were the 804 patients who experienced hospitalization for UGIC until 2007. Up to 20 controls were randomly selected for each case. Conditional logistic regression model was used to estimate odds ratio (OR) associated with current and past use of BPs (i.e. for drug dispensation within 30 days and over 31 days prior the outcome onset, respectively) after adjusting for several covariates.\n\nResults\nCompared with patients who did not use BPs, current and past users had OR (and 95% confidence interval) of 0.86 (0.60 to 1.22) and 1.07 (0.80 to 1.44) respectively. There was no difference in the ORs estimated according with BPs type (alendronate or risedronate) and regimen (daily or weekly), nor with co-therapies and comorbidities.\n\nConclusions\nFurther evidence that BPs dispensed for secondary prevention of osteoporotic fractures are not associated with increased risk of severe gastrointestinal complications is supplied from this study. Further research is required to clarify the role BPs and other drugs of co-medication in inducing UGIC.\n\nBisphosphonatesDrug safetyHealthcare utilization databaseUpper gastrointestinal complications\n==== Body\nBackground\nOsteoporotic fractures are becoming a major cause of morbidity and mortality worldwide. The lifetime risk of typical osteoporotic fracture (i.e., of the wrist, hip, or vertebra) has been reported to be around 40% [1-3]. Ideally, osteoporosis should be prevented before fragility fractures occur. Nevertheless, an important clinical strategy is to identify patients who have already had a typical osteoporotic fracture and institute treatments aimed at secondary prevention [4-7]. In postmenopausal women, at least 80% to 90% of fractures of the wrist, hip, or vertebra are associated with osteoporosis [8-10] and an osteoporotic patient who experience a fracture has approximately a 20-fold risk of future fracture compared with a patient who has neither osteoporosis nor a history of fracture [2,11].\n\nOral bisphosphonates (BPs), such as alendronate and risedronate, are considered the mainstay therapy for the prevention of osteoporotic fractures. Randomised clinical trials (RCTs) have consistently shown that long-term treatment with these medicaments improves bone mineral density (BMD) and reduces the risk of fracture [12-19]. However, long-term therapy is required to increase and maintain BMD and to keep normal levels of bone resorption [20]. Therefore, therapy must be generally safe, besides being effective, in a long-term fashion.\n\nData from the pivotal RCTs of both alendronate [12-14,19] and risedronate [16-18,20,21] did not found clinical evidence of adverse effects than placebo suggesting that these drugs are well tolerated. However, soon after alendronate release, an unexpected higher number of cases of oesophagitis and oesophageal strictures were encountered when the drug was prescribed to the general population, which resulted in changes to the alendronate label [22,23]. From then on nowadays, inconsistent findings on gastrointestinal (GI) safety of BPs have been reported [24-29]. Two meta-analyses on this topic came to conflicting conclusions [30,31], suggesting that evidence on gastrointestinal safety of these agents are still insufficient.\n\nTo shed further light on the association between use of BPs and the risk of hospitalization for upper gastrointestinal complications (UGIC), we carried out a large nested case–control study in a cohort of patients hospitalized for osteoporotic fracture.\n\nMethods\nData source\nThe data used for the present study were retrieved from the health service databases of all the 13 Italian territorial units participating at the AIFA-BEST (Bisphosphonates Effectiveness-Safety Tradeoff) project. The general aim of this project is to provide an assessment of the benefit-risk profile of BPs use. Further details of the study design and procedure can be found elsewhere [32].\n\nTerritorial units participant to the AIFA-BEST project were four Regions (Abruzzo, Emilia-Romagna, Marche and Toscana) and nine Local Health Authorities (Caserta, Como, Gorizia, Latina, Lodi, Milano, Monza, Sondrio and Varese). A population of about 17 million of beneficiaries of National Health Service (NHS) residents in these territorial units was covered by the corresponding HCU databases, accounting for nearly 30% of the whole Italian population.\n\nItalian population is entirely covered by the NHS that provides universal and free of charge coverage for many healthcares, such as hospitalizations for any causes and several drug therapies (including medicaments for treatment of osteoporosis). This program is administered by an automated system of databases on the use of health services supplied free of charge from NHS and including: (i) an archive of beneficiaries of NHS (practically the whole resident population), inclusive of demographic and administrative data; (ii) details of hospitalizations in private and public hospitals, inclusive of diagnosis at discharge; and (iii) outpatients medicament prescriptions reimbursable from the NHS [according to Italian rules, outpatients medicaments supplied free of charge from NHS may be dispensed only from pharmacies and only by prescription]. With the aim of obtaining the complete history of healthcare utilization of all the NHS beneficiaries, the different pieces of information recorded into these databases can be linked using a unique personal identification code. In order to preserve privacy, we replaced the original identification code with its digest that is the image of the code through a cryptographic hash function -- the Secure Hash Algorithm (SHA-256). Such hash function (i) makes infeasible to obtain the original code from the digest, (ii) is deterministic, i.e. the same digest is always associated to any given individual, and (iii) is collision-resistant, i.e. the probability that two individuals are associated to the same code is insignificant. The specific hash function used (SHA-256) is the industry standard [33] and has been incorporated into the data extraction-transformation-load software produced by the University of Milano-Bicocca.\n\nData were drawn out from databases by means of standardized queries which were defined and tested according to the study protocol. Additional file 1 provides specific diagnostic and therapeutic codes used for our study.\n\nCohort selection\nWe identified patients aged 45 years or older who have been hospitalized for osteoporotic fracture from July 1, 2003 until December 31, 2005 and the date of hospital discharge was designed as that of entry into the cohort. Patients were excluded if, within six months prior the cohort entry date, they had at least one BPs prescription or they have been hospitalized for bone fracture, gastrointestinal adverse events, Paget’s disease, coagulation disorders, alcohol abuse, chronic liver disease or cancer. Patients who were registered into the archive of NHS beneficiaries from less than six months prior the entry into the cohort and those who did not reach at least 60 days of follow-up were also excluded. The remaining patients constituted the study cohort.\n\nEach member of the cohort accumulated person-years of follow-up from the date of entry until the earliest date among those of outcome onset (hospital admission for UGIC) or censoring (death, emigration or 31 December 2007).\n\nSelection of cases and controls\nWe identified patients who during follow-up experienced at least a hospitalization with diagnosis of UGIC including oesophageal/gastrointestinal ulcer, perforation of oesophagus, oesophageal/gastrointestinal haemorrhage (see Additional file 1: Table S1). A patient who experienced at least one of these events was considered as having the outcome. The earliest date of hospital admission recording one of these events was considered as the index date.\n\nUp to twenty controls for each case patient were selected randomly from the cohort to be matched for territorial unit of recruitment, gender, age at cohort entry, date of entry into the cohort and were at risk for the outcome at the time when the matched case had the event. In these conditions each set established from one case and the corresponding matched controls had the same extension of observational period which began at the date of index prescription and stopped at the event date of the index case.\n\nExposure assessment\nDuring the study period two drug types (alendronate and risedronate) either on once-daily (10 mg/day and 5 mg/day, respectively) or once-weekly (70 mg/week and 35 mg/week, respectively) regimens were available for free reimbursement by Italian NHS.\n\nDrug-dispensing history of BPs prescribed to cases and controls during the observational period was assessed from the prescription drug database. Exposure was categorized into mutually exclusive groups of current, past, and no use, taking as reference the index date [27]. A patient was defined current user if at least one prescription of BPs was dispensed within 30 days or less prior the index date. Past users were defined as those who at least one prescription of BPs was dispensed later than 31 days prior the index date. No users were patients who during the entire observational period did not experience BPs dispensation.\n\nCovariates\nFor each case and control the dispensation of some medicaments over the 60-day period prior the index date was investigated. Medicaments included antidepressants, antithrombotic, gastroprotective agents, corticosteroids, statins, calcium channel blockers, other antihypertensive agents and nonsteroidal antiinflammatory agents (NSAIDs) (see Additional file 1: Table S1). In addition, the Charlson comorbidity index score was calculated [34], using the diagnostic information available from inpatient charts in the six months prior the date of entry into the cohort and during the entire period of follow-up. Two categories of the Charlson comorbidity index score were considered, i.e. 0 and 1, respectively denoting absence and presence of at least one comorbidity.\n\nStatistical analyses\nChi-square was used to test differences between cases and controls. A conditional logistic regression model was fitted to estimate the odds ratio (OR), as well as its 95% confidence interval (CI), of UGIC associated with use of BPs (anytime, current or past), taking non-use as reference. Adjustments were made for the above reported covariates. The combined effect of BPs with co-treatments and co-morbidity was estimated by including the corresponding interaction terms in a conditional logistic model. The differential effect of type and regimen of the dispensed BPs was also evaluated by means of stratification analysis.\n\nSensitivity analyses\nThe following sets of sensitivity analyses were performed. First, we verified if our estimates were affected by the adopted criteria for defining UGIC. Data were analysed according to alternative diagnostic criteria, i.e. those recently proposed by Cadarette et al. while investigating oral BPs safety [28], as well as those used by a collaborative project aimed to exploit European healthcare databases for drug safety signal detection, the so called EU-ADR Project [35]. Second, we verified if our estimates were affected by the adopted criteria for defining exposure. With this aim we used time-window lengths of 7, 15 or 45 days prior the index date for defining current use, alternative to 30 days as in the main analysis.\n\nThe SAS statistical package was used for the analyses (SAS, Version 9.1; SAS Institute, Cary, North Carolina, USA). For all hypotheses tested two-tailed p-values less than 0.05 were considered to be significant.\n\nEthical considerations\nThe study protocol was notified to the Italian Medicines Agency (AIFA) and to the local ethics committees of all the territorial units involved in the investigation. There was no legal requirement for ethics committee approval since we used only unidentifiable patient data and did not contact the patients.\n\nResults\nSample selection\nThe distribution of the exclusion criteria is shown in Figure 1. At entry, the 68,970 patients who were included into the cohort had mean age of 76.2 years (SD 12.5 years) and 71% of them were women. During follow-up these patients accumulated 220,135 person-years of observation and generated 804 hospital admissions for UGIC, with an incidence rate of 36.5 cases per 10,000 person-years. The 804 patients who experienced hospitalization for UGIC (case patients) were matched to 12,787 controls.\n\nFigure 1 Study flow diagram. AIFA-BEST Project, Italy, 2003–2007. Flow chart of inclusion and exclusion criteria. BPs: Bisphosphonates.\n\nPatients\nAt the cohort entry, mean age of cases and controls was 79.9 years (SD: 9.9 years), and nearly 72% of them were women (matching variables). As shown in Table 1, there was not statistical evidence that case patients and controls differed for use to BPs during the entire observational period, as well as during current and past periods. Similarly, there was not evidence that cases and controls differ for BPs type and regimen refilled during the current period. Conversely, with the exception of statins and calcium channel blockers, co-treatments with the other considered drugs, as well as the presence of at least one sign of chronic comorbidity, were more frequent among cases than controls.\n\nTable 1 Selected tracts of the 804 cases of upper gastrointestinal complications and 12,787 controls\n\n \tCase patients\tControls\tp-value\n*\n\t\nBPs exposure\n†\n\t \t \t \t\n No use\t709 (88.2%)\t11,345 (88.7%)\t0.6029\t\n Current use\t38 (4.7%)\t643 (5.0%)\t \t\n Past use\t57 (7.1%)\t799 (6.2%)\t \t\n Type prescribed during the current period\t \t \t\n Alendronate\t30 (79.0%)\t412 (64.1%)\t0.0620\t\n Risedronate\t8 (21.0%)\t231 (35.9%)\t \t\n Regimen prescribed during the current period\t \t \t\n Weekly\t37 (97.4%)\t631 (98.1%)\t0.7376\t\n Daily\t1 (2.6%)\t12 (1.9%)\t \t\nUse of other medicaments\n‡\n\t \t \t \t\n Antidepressants\t139 (17.3%)\t1,841 (14.4%)\t0.0242\t\n Antithrombotic\t240 (29.9%)\t3,174 (24.8%)\t0.0014\t\n Gastroprotective agents\t211 (26.2%)\t1,993 (15.6%)\t<0.0001\t\n Corticosteroids\t65 (8.1%)\t533 (4.2%)\t<0.0001\t\n Statins\t41 (5.1%)\t724 (5.7%)\t0.5021\t\n Calcium channel blockers\t105 (13.1%)\t1,548 (12.1%)\t0.4223\t\n Other antihypertensive drugs\t371 (46.1%)\t5,294 (41.4%)\t0.0082\t\n Nonsteroidal antiinflammatory drugs\t170 (21.1%)\t1,529 (12.0%)\t<0.0001\t\nCo-morbidity\n#\n\t \t \t \t\n 0\t629 (78.2%)\t11,531 (90.2%)\t<0.0001\t\n ≥1\t175 (21.8%)\t1,256 (9.8%)\t\nBPs: Bisphosphonates.\n\n†A patient was defined current user if at least one prescription of BPs was refilled within 30 days or less prior the index date. A patient was defined past user if at least one prescription of BPs was refilled later than 31 days prior the index date. No users were patients who during the entire observational period did not experience BPs dispensation.\n\n‡Measured over the 60-day period prior the index date.\n\n#Charlson comorbidity index score measured in the six months prior the entry into the cohort and during the entire observational period.\n\n*According to chi-square test.\n\nUse of bisphosphonates and the risk of upper gastrointestinal complications\nCompared with non users, patients who used BPs anytime during the entire observational period, as well as those who were exposed during current or past period, did not show significant risk excess of UGIC (Figure 2). In addition, there was no evidence that UGIC risk was heterogeneous across the categories of both types and regimens of BPs refilled anytime during the observational period, nor during current and past periods.\n\nFigure 2 Adjusted odds ratios (and 95% confidence intervals) of upper gastrointestinal complications associated with anytime, current and past exposure to bisphosphonates as a whole (all) as well as to type (alendronate and risedronate) and regimen (daily and weekly) of the latest dispensed bisphosphonates. AIFA-BEST Project, Italy, 2003–2007. Odds ratios estimated with conditional logistic regression model. Estimates concerning main analysis (all) were adjusted for use of other medicaments in the 60-day period and for the Charlson index measured before the index date. Estimates concerning subgroup analysis were obtained by including the interaction terms combining the effect of anytime, current or past exposure to BPs together with type and regimen of the dispensed BPs. P-values concern comparison of BPs effect across patient subgroups. BPs: Bisphosphonates.\n\nAs shown in Figure 3, there was not statistical evidence that the UGIC risk associated with current use of BPs was heterogeneous across the categories of patients stratified according with co-treatments and comorbidity. It should be observed, however, that large confidence intervals were obtained for some strata. This was due to the few patients who concomitantly used BPs and other medicaments such as corticosteroids, statins or calcium channel blockers (being the corresponding prevalence 8.6%, 9.3% and 13.3% respectively).\n\nFigure 3 Combined action of current exposure to bisphosphonates, concurrent exposure to other medicaments and categories of Charlson comorbidity index on the risk of upper gastrointestinal complications. AIFA-BEST Project, Italy, 2003–2007. Odds ratios estimated with conditional logistic regression model. Estimates were obtained by including the interaction terms combining the effect of current exposure to BPs together with concurrent use of other medicaments and the categories of the Charlson index. P-values concern comparison of BPs effect across patient subgroups. BPs: Bisphosphonates.\n\nSensitivity analyses\nFigure 4 shows that the adjusted OR did not substantially change by varying criteria for defining diagnosis of UGIC (box A) nor the length of exposure time-window for defining current use of BPs (box B).\n\nFigure 4 Influences of diagnostic criteria for defining upper gastrointestinal complications (panel A), and of the time-window length for defining current use of BPs (panel B) on the observed odds ratio of upper gastrointestinal complications associated with current exposure to bisphosphonates. AIFA-BEST Project, Italy, 2003–2007. Odds ratios estimated with conditional logistic regression model. Estimates were adjusted for use of medicaments in the 60-day period and for the Charlson index measured before the index date. Details for diagnostic criteria are reported in Additional file 1. BPs: Bisphosphonate.\n\nDiscussion\nIn this large nested case–control study we did not found evidence of increased severe UGIC risk associated with current and/or past use of BPs in the setting of secondary prevention of osteoporotic fractures. We also found that the type and regimen of BPs administered, as well as the concurrent use of other drugs known for increasing UGIC, did not modify the gastrointestinal safety of BPs.\n\nComparison with literature\nOur results are consistent with those of two randomized clinical trials (RCTs), FIT (Fracture Intervention Trial) and VERT (Vertebral Efficacy of Risedronate Therapy) trials [16,36], both reporting similar gastrointestinal side-effects profile in patients who received BPs and those on placebo. Similarly to ours, a pooled analysis from 9 RCTs found that the rate of upper GI tract adverse events was similar across risedronate and placebo groups, and that concomitant use of aspirin, NSAIDs, H2-receptor antagonists and/or proton pump inhibitors did not lead to significant between-group differences in the UGIC risk [37].\n\nValidity of our main findings seems to have support by the observed association between use of other medicaments known to cause GI complications and the considered outcome. For example, consistently with literature, we found that, with respect to controls, case patients had higher prevalence in the use of antidepressants, antithrombotic, corticosteroids, some class of antihypertensive agents, and NSAIDs, in the presence of chronic comorbidities [38-45]. Conversely to others, we did not confirm that recent use of calcium-channel blockers and statins increased the risk of UGIC [45,46].\n\nWe found that cases had higher use of gastroprotective drugs than controls. As we cannot suppose that gastroprotective agents cause GI complications, the more likely explanation is that physicians more likely prescribe gastroprotective agents to those patients with a history of GI complications, or to those at whom GI symptoms sudden occurred, i.e. to patients at higher UGIC risk [47].\n\nStrengths and limitations\nSeveral peculiar features of our study deserve to be mentioned. First, the study is based on data from a very large unselected population, which was made possible by the fact that in Italy a cost-free uniformly organized healthcare system involves practically all citizens. By drawing out healthcare utilization data from nearly 30% of the whole Italian population, we were able to build one of the largest observational studies performed on the GI safety of bisphosphonates in the setting of secondary prevention of osteoporotic fractures. Accordingly with the included number of cases and controls, as well as of the observed number of controls who currently used BPs, even small gastrointestinal effects associated with current use of BPs (ORs ≥ 1.5) could have been detected from our study as significant (with p < 0.05 and power of 80%). Our data, furthermore, reflecting routine clinical practice, are unaffected by selective participation and recall bias.\n\nSecond, the drug prescription database provided highly accurate data, because report of prescriptions by the pharmacies is essential for reimbursement and filling of an incorrect report about the dispensed drugs has legal consequences [48]. Third, a number of sensitivity analyses allowed us to verify the robustness of our findings. For example, we found that the criteria employed for UGIC diagnosis, as well as for defining current BPs use, did not substantially affect our estimates. This further strengthens the evidence that the use of BPs unlikely causes serious GI complications.\n\nOur study has a number of potential limitations. First, as outcomes were drawn from hospitalized patients, our data only concern severe GI complications requiring hospitalization. Second, because of privacy regulations, hospital records were not available for analysis so diagnoses cannot be scrutinized and validated. Third, misclassification of BPs exposure might occur because, once the drug is dispensed, it is possible that patients did not assume it. If this happens when GI symptoms occur, a protopathic bias is introduced dragging the investigated association towards that expected under the null hypothesis [49].\n\nFourth, besides the very large sample size, some of our findings are likely to be affected by random uncertainty. For example, during the study period BPs were rarely dispensed once-daily, so the lack of evidence of differential effect of BPs according to the dispensation regimen is particularly weak. Similarly, the lack of evidence of a synergistic effect between BPs and other known GI-harmful drugs might be due to the few number of patients taking co-therapies during the current period.\n\nThe uncommon dispensation of BPs and other medicaments observed in our setting, however, has important clinical implications. For example, patients with more severe form of osteoporosis may need to assume antiinflammatory agents (e.g. NSAIDs or corticosteroids) for the symptomatic relief of pain secondary to this disease. In this way, a high prevalence of patients who concomitantly use BPs and antiinflammatory agents are expected in routine clinical practice. Since BPs co-therapy with NSAIDs has been found to increase the risk of peptic ulcer in rheumatoid arthritis patients with long-term NSAIDs treatment [30], this practice should be avoided, as often occurs in our setting.\n\nFinally, as in all observational studies, there is always some concern for residual confounding due to unmeasured factors. For example, under the assumption that use of BPs increases the UGIC risk, over-the-counter gastroprotective agents might be assumed by some patients once GI symptoms occur. On the other hand, the assumption of over-the-counter antiinflammatory agents might be reduced when GI symptoms occur. Both these sources of selective exposures would drag the investigated association towards that expected under the null hypothesis.\n\nConclusions\nIn summary this study provides further evidence that BPs dispensed for secondary prevention of osteoporotic fractures are not associated with increased risk of severe gastrointestinal complications. Further research is required to clarify the role of co-medication with BPs and other medicaments in inducing upper gastrointestinal complications.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\nAG and LS performed the statistical analyses, GDV was responsible for producing software assuring privacy, AG and GC wrote the paper, GC was responsible for designing the current study, GM was the main investigator of the AIFA-BEST project, LCDO, FL, FC, AC, AV, DG, RG, ARV and TS were the other investigators of the AIFA-BEST; they participated to the project’s design and supplied data. All authors read and approved the final manuscript.\n\nPre-publication history\nThe pre-publication history for this paper can be accessed here:\n\nhttp://www.biomedcentral.com/1471-230X/14/5/prepub\n\nSupplementary Material\nAdditional file 1\nDrugs and diagnoses codes used for the study purpose[28,35].\n\nClick here for file\n\n Acknowledgements\nThis study was almost entirely funded by a research grant from the AIFA - the Italian Medicines Agency – (AIFA grant FARM06R9YY), Rome, Italy. Data analyses were performed at the Unit of Biostatistics and Epidemiology, Dept. of Statistics, University of Milano-Bicocca with grants from the Italian Minister for University and Research (’Fondo d’Ateneo per la Ricerca’ portion, year 2010).\n\nBest investigators\nMazzaglia G, (main investigator): Regional Agency for Healthcare Services of Tuscany, Italy\n\nCipriani F (Head Unit), Lapi F, Sessa E: Regional Agency for Healthcare Services of Tuscany, Italy\n\nCaputi AP (Head Unit), Arcoraci V: Department of Medicine and Pharmacology, University of Messina, Messina, Italy\n\nCorrao G (Head Unit), Ghirardi A, Scotti L, Parodi A, Zambon A: Department of Statistics and quantitative methods, Unit of Biostatistics, epidemiology and public health, University of Milano-Bicocca, Milan, Italy\n\nMontanaro N (Head Unit), Piccinni C, Suzzi C, Puccini A, Vaccheri A: Regional Centre for Drug Evaluation and Information (CREVIF), Department of Pharmacology, University of Bologna, Bologna, Italy.\n\nSturkenboom M (Head Unit): Departments of Epidemiology & Biostatistics and Medical Informatics, Pharmacoepidemiology Unit, Erasmus University Medical Center, The Netherlands\n\nGeppetti P (Head Unit), Sati L, Di Bari M: Center of Pharmacoutilization, Pharmacoepidemiology, Pharmacovigilance and Pharmacoeconomics, University of Florence, Florence, Italy\n\nGregori D (Head Unit), Forlan F: Unit of Biostatistics, Epidemiology and Public Health, Department of Cardiac, Thoracic and Vascular Sciences, University of Padova\n\nCarle F (Head Unit), Gesuita R: Center of Epidemiology, Biostatistics, and Medical Information Technology, Polytechnic University of Marche, Ancona, Italy. Provided data from Marche\n\nStaniscia T (Head Unit), Menna A: Regional Agency of Healthcare services of Abruzzo, L’Aquila, Italy\n\nVestri A (Head Unit): Department of Public Health and Infectious Diseases, University “La Sapienza”, Rome, Italy\n\nValenti M (Head Unit): Department of Clinical Sciences and Applied Biotechnology, University of L’Aquila, L’Aquila, Italy\n==== Refs\nNational Osteoporosis Foundation Physicians’ Guide to Prevention and Treatment of Osteoporosis 1999 Washington, DC: National Osteoporosis Foundation \nScientific Advisory Board, Osteoporosis Society of Canada Clinical practice guidelines for the diagnosis and management of osteoporosis CMAJ 1996 155 1113 1128 8873639 \nKlotzbuecher CM Ross PD Landsman PB Patients with prior fractures have an increased risk of future fractures: a summary of the literature and statistical synthesis J Bone Miner Res 2000 15 721 739 10780864 \nFreedman KB Kaplan FS Bilker WB Treatment of osteoporosis: are physicians missing an opportunity? J Bone Joint Surg Am 2000 82 1063 1070 10954094 \nSiris ES Miller PD Barrett-Connor E Identification and fracture outcomes of undiagnosed low bone mineral density in postmenopausal women JAMA 2001 286 2815 2822 10.1001/jama.286.22.2815 11735756 \nEpstein S Goodman GR Improved strategies for diagnosis and treatment of osteoporosis Menopause 1999 6 242 250 10.1097/00042192-199906030-00011 10486795 \nMcClung MR Therapy for fracture prevention JAMA 1999 282 687 689 10.1001/jama.282.7.687 10517723 \nMelton LJ IIIThamer R Ray NF Fractures attributable to osteoporosis: report from the National Osteoporosis Foundation J Bone Miner Res 1997 12 16 23 10.1359/jbmr.1997.12.1.16 9240721 \nEarnshaw SA Cawte SA Worley A Colles’ fracture of the wrist as an indicator of underlying osteoporosis in post-menopausal women: a prospective study of bone mineral density and bone turnover rate Osteoporos Int 1998 8 53 60 10.1007/s001980050048 9692078 \nSeeley DG Browner WS Nevitt MC Which fractures are associated with low appendicular bone mass in elderly women? Ann Intern Med 1991 115 837 842 10.7326/0003-4819-115-11-837 1952469 \nHajcsar EE Hawker G Bogoch ER Investigation and treatment of osteoporosis in patients with fragility fractures CMAJ 2000 163 819 822 11033708 \nLiberman UA Weiss SR Broll J Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group N Engl J Med 1995 333 1437 1443 10.1056/NEJM199511303332201 7477143 \nBlack DM Cummings SR Karpf DB Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group Lancet 1996 348 1535 1541 10.1016/S0140-6736(96)07088-2 8950879 \nCummings SR Black DM Thompson DE Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial JAMA 1998 280 2077 2082 10.1001/jama.280.24.2077 9875874 \nPols HA Felsenberg D Hanley DA Multinational, placebo-controlled, randomized trial of the effects of alendronate on bone density and fracture risk in postmenopausal women with low bone mass: results of the FOSIT study. Fosamax International Trial Study Group Osteoporos Int 1999 9 461 468 10.1007/PL00004171 10550467 \nHarris ST Watts NB Genant HK Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group JAMA 1999 282 1344 1352 10.1001/jama.282.14.1344 10527181 \nReginster J Minne HW Sorensen OH 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 83 91 10.1007/s001980050010 10663363 \nMcClung MR Geusens P Miller PD Hip Intervention Program Study Group. Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group N Engl J Med 2001 344 333 340 10.1056/NEJM200102013440503 11172164 \nTonino RP Meunier PJ Emkey R Phase III Osteoporosis Treatment Study Group. Skeletal benefits of alendronate: 7-year treatment of postmenopausal osteoporotic women J Clin Endocrinol Metab 2000 85 3109 3115 10999794 \nMortensen L Charles P Bekker PJ Risedronate increases bone mass in an early postmenopausal population: two years of treatment plus one year of follow-up J Clin Endocrinol Metab 1998 83 396 402 9467547 \nWallach S Cohen S Reid DM Effects of risedronate treatment on bone density and vertebral fracture in patients on corticosteroid therapy Calcif Tissue Int 2000 67 277 285 10.1007/s002230001146 11000340 \nGraham DY What the gastroenterologists should know about the gastrointestinal safety profiles of bisphosphonates Dig Dis Sci 2002 47 1665 1678 10.1023/A:1016495221567 12184516 \nDe Groen PC Lubbe DF Hirsch LJ Esophagitis associated with the use of alendronate N Engl J Med 1996 335 1016 1021 10.1056/NEJM199610033351403 8793925 \nVan Staa T Abenhaim L Cooper C Upper gastrointestinal adverse events and cyclical etidronate Am J Med 1997 103 462 467 10.1016/S0002-9343(97)00242-8 9428828 \nDonahue JG Chan KA Andrade SE Gastric and duodenal safety of daily alendronate Arch Intern Med 2002 162 936 942 10.1001/archinte.162.8.936 11966346 \nMiller RG Bolognese M Worley K Incidence of gastrointestinal events among bisphosphonate patients in an observational setting Am J Manag Care 2004 10 S207 S215 \nEtminan M Lévesque L Fitzgerald JM Risk of upper gastrointestinal bleeding with oral bisphosphonates and non steroidal anti-inflammatory drugs: a case–control study Aliment Pharmacol Ther 2009 29 1188 1192 10.1111/j.1365-2036.2009.03989.x 19298582 \nCadarette SM Katz JN Brookhart MA Comparative gastrointestinal safety of weekly oral bisphosphonates Osteoporos Int 2009 20 1735 1747 10.1007/s00198-009-0871-8 19266138 \nMiyake K Kusunoki M Shinji Y Bisphosphonate increases risk of gastroduodenal ulcer in rheumatoid arthritis patients on long-term nonsteroidal antiinflammatory drug therapy J Gastroenterol 2009 44 113 120 10.1007/s00535-008-2278-2 19214672 \nCryer B Bauer DC Oral bisphosphonates and upper gastrointestinal tract problems: what is the evidence? Mayo Clin Proc 2002 77 1031 1043 10.4065/77.10.1031 12374247 \nMacLean C Newberry S Maglione M Systematic review: comparative effectiveness of treatments to prevent fractures in men and women with low bone density or osteoporosis Ann Intern Med 2008 148 197 213 10.7326/0003-4819-148-3-200802050-00198 18087050 \nLapi F Cipriani F Caputi AP on behalf of the Bisphosphonates Efficacy-Safety Tradeoff (BEST) study group Assessing the risk of osteonecrosis of the jaw due to bisphosphonate therapy in the secondary prevention of osteoporotic fractures Osteoporos Int 2013 24 697 705 10.1007/s00198-012-2013-y 22618266 \nFederal Information Processing Standards. Secure Hash Standard (SHS) 2000 PUB 180 184 http://csrc.nist.gov/publications/fips/fips180-4/fips-180-4.pdf \nCharlson ME Charlson RE Peterson JC The Charlson comorbidity index is adapted to predict costs of chronic disease in primary care patients J Clin Epidemiol 2008 61 1234 1240 10.1016/j.jclinepi.2008.01.006 18619805 \nColoma PM Schuemie MJ Trifirò G Combining electronic healthcare databases in Europe to allow for large-scale drug safety monitoring: the EU-ADR Project Pharmacoepidemiol Drug Saf 2011 20 1 11 10.1002/pds.2053 21182150 \nBauer DC Black D Ensrud K Upper gastrointestinal tract safety profile of alendronate: the fracture intervention trial Arch Intern Med 2000 160 517 525 10.1001/archinte.160.4.517 10695692 \nTaggart H Bolognese MA Lindsay R Upper gastrointestinal tract safety of risedronate: a pooled analysis of 9 clinical trials Mayo Clin Proc 2002 77 262 270 10.4065/77.3.262 11888030 \nDalton SO Johansen C Mellemkjaer L Nørgård B Sørensen HT Olsen JH Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal tract bleeding: a population-based cohort study Arch Int Med 2003 163 59 64 10.1001/archinte.163.1.59 12523917 \nZullo A Hassan C Campo SM Morini S Bleeding peptic ulcer in the elderly: risk factors and prevention strategies Drugs Aging 2007 24 815 828 10.2165/00002512-200724100-00003 17896831 \nTata LJ Fortun PJ Hubbard RB Does concurrent prescription of selective serotonin reuptake inhibitors and non- steroidal anti-inflammatory drugs substantially increase the risk of upper gastrointestinal bleeding? Aliment Pharmacol Ther 2005 22 175 181 10.1111/j.1365-2036.2005.02543.x 16091054 \nHernàndez-Diaz S Garcìa Rodriguez LA Association between nonsteroidal anti-inflammatory drugs and upper gastrointestinal tract bleeding/perforation: an overview of epidemiologic studies published in the 1990s Arch Int Med 2000 160 2093 2099 10.1001/archinte.160.14.2093 10904451 \nRamakrishnan K Salinas RC Peptic ulcer disease Am Fam Physician 2007 76 1005 1012 17956071 \nUdd M Miettinen P Palmu A Analysis of the risk factors and their combinations in acute gastroduodenal ulcer bleeding: a case–control study Scand J Gastroenterol 2007 42 1395 1403 10.1080/00365520701478758 17994466 \nGarcía Rodríguez LA Lin KJ Hernández-Díaz S Johansson S Risk of upper gastrointestinal bleeding with low-dose acetylsalicylic acid alone and in combination with clopidogrel and other medications Circulation 2011 123 1108 1115 10.1161/CIRCULATIONAHA.110.973008 21357821 \nSchelleman H Bilker WB Brensinger CM Wan F Yang YX Hennessy S Fibrate/Statin initiation in warfarin users and gastrointestinal bleeding risk Am J Med 2010 123 151 157 10.1016/j.amjmed.2009.07.020 20103024 \nGarcía Rodríguez LA Cattaruzzi C Troncon MG Risk of hospitalization for upper gastrointestinal bleeding associated with ketorolac, other NSAIDs, calcium antagonists and other antihypertensive drugs Arch Int Med 1998 158 33 39 10.1001/archinte.158.1.33 9437376 \nLaporte JR Ibanez L Vidal X Vendrell L Leone R Upper gastrointestinal bleeding associated with the use of NSAIDs: newer versus older agents Drug Saf 2004 27 411 420 10.2165/00002018-200427060-00005 15144234 \nStrom BL Strom BL Overview of automated databases in pharmacoepidemiology Pharmacoepidemiology 2000 3 Chichester, UK: Wiley 219 222 \nTamim H Monfared AA LeLorier J Application of lag-time into exposure definitions to control for protopathic bias Pharmacoepidemiol Drug Saf 2007 16 250 258 10.1002/pds.1360 17245804\n\n",
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"journal": "BMC gastroenterology",
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"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D050071:Bone Density Conservation Agents; D002121:Calcium Channel Blockers; D016022:Case-Control Studies; D015897:Comorbidity; D004164:Diphosphonates; D005260:Female; D005767:Gastrointestinal Diseases; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D015994:Incidence; D007558:Italy; D008297:Male; D008875:Middle Aged; D058866:Osteoporotic Fractures; D012307:Risk Factors; D055502:Secondary Prevention",
"nlm_unique_id": "100968547",
"other_id": null,
"pages": "5",
"pmc": null,
"pmid": "24397769",
"pubdate": "2014-01-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "10999794;9437376;12374247;9692078;10954094;10527181;10517723;15144234;19266138;12184516;21357821;10486795;9428828;11033708;20103024;11735756;18087050;17956071;10780864;10904451;11172164;12523917;7477143;18619805;17896831;11000340;19214672;8793925;16091054;10695692;8950879;17245804;9875874;22618266;19298582;1952469;11966346;8873639;17994466;9240721;10663363;21182150;10550467;9467547;11888030",
"title": "Oral bisphosphonates do not increase the risk of severe upper gastrointestinal complications: a nested case-control study.",
"title_normalized": "oral bisphosphonates do not increase the risk of severe upper gastrointestinal complications a nested case control study"
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"activesubstancename": "ALENDRONATE SODIUM"
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"abstract": "We report the case of an afebrile 59-year-old heart transplant recipient presenting with nausea, vomiting, diarrhea, weight loss, and diffuse lymphadenopathy. Lymph node biopsies revealed non-caseating granulomatous inflammation. Cat-scratch disease was confirmed by serologic studies, Warthin-Starry staining, and polymerase chain reaction testing of lymph node tissue. The patient's symptoms resolved with 3 months of doxycycline. We review clinical presentations of Bartonella henselae infection and review diagnostic approaches for B. henselae in this patient population.",
"affiliations": "Division of Infectious Diseases, Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, MD, USA.;Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, MD, USA.;Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, MD, USA.;Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, MD, USA.;Division of Cardiology, Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, MD, USA.;Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD, USA.;Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD, USA.;Division of Cardiac Surgery, The Johns Hopkins Hospital, Baltimore, MD, USA.;Division of Infectious Diseases, Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, MD, USA.;Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.",
"authors": "Antar|Annukka A R|AAR|;Goyal|Amit|A|;Murphy|Karly|K|;Schimmel|Matthew|M|;Gilotra|Nisha A|NA|;Martin|Isabella|I|;Crane|Genevieve Marie|GM|http://orcid.org/0000-0001-9274-0214;Sciortino|Christopher|C|;Avery|Robin K|RK|;Houston|Brian A|BA|",
"chemical_list": "D000900:Anti-Bacterial Agents; D007166:Immunosuppressive Agents; D004318:Doxycycline",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12678",
"fulltext": null,
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"issn_linking": "1398-2273",
"issue": "19(3)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "Bartonella henselae; gastrointestinal illness; granulomatous inflammation; solid organ transplant",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000900:Anti-Bacterial Agents; D018416:Bartonella henselae; D001706:Biopsy; D001831:Body Temperature; D009202:Cardiomyopathies; D002372:Cat-Scratch Disease; D003967:Diarrhea; D004318:Doxycycline; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D008198:Lymph Nodes; D008297:Male; D008875:Middle Aged; D009325:Nausea; D016133:Polymerase Chain Reaction; D012698:Serologic Tests; D014057:Tomography, X-Ray Computed; D015431:Weight Loss",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28199763",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Disseminated cat-scratch disease presenting as nausea, diarrhea, and weight loss without fever in a heart transplant recipient.",
"title_normalized": "disseminated cat scratch disease presenting as nausea diarrhea and weight loss without fever in a heart transplant recipient"
} | [
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"companynumb": "US-TEVA-2018-US-887723",
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"activesubstance": {
"activesubstancename": "VENLAFAXINE HYDROCHLORIDE"
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"abstract": "Prompt treatment of neuromyelitis optica (NMO) relapses with steroids or plasma exchange (PLEX) often prevents irreversible disability. The objective of this study is to report the use of intravenous immunoglobulins (IVIG) as treatment for acute relapses in NMO. A retrospective review of 10 patients treated with IVIG for acute relapses was conducted. IVIG was used in the majority of cases because of lack of response to steroids with/without PLEX. Improvement was noted in five of 11 (45.5%) events; the remaining had no further worsening. One patient, a 79-year-old woman, had a myocardial infarction seven days after IVIG. IVIG may have a role in treating acute NMO relapses.",
"affiliations": "The Walton Centre NHS Foundation Trust, UK.",
"authors": "Elsone|Liene|L|;Panicker|Jay|J|;Mutch|Kerry|K|;Boggild|Mike|M|;Appleton|Richard|R|;Jacob|Anu|A|",
"chemical_list": "D016756:Immunoglobulins, Intravenous",
"country": "England",
"delete": false,
"doi": "10.1177/1352458513495938",
"fulltext": null,
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"issn_linking": "1352-4585",
"issue": "20(4)",
"journal": "Multiple sclerosis (Houndmills, Basingstoke, England)",
"keywords": "NMO; Neuromyelitis optica; acute treatment; aquaporin 4; intravenous immunoglobulins; relapse",
"medline_ta": "Mult Scler",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D000368:Aged; D002648:Child; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous; D008297:Male; D008875:Middle Aged; D009471:Neuromyelitis Optica; D012189:Retrospective Studies; D055502:Secondary Prevention; D055815:Young Adult",
"nlm_unique_id": "9509185",
"other_id": null,
"pages": "501-4",
"pmc": null,
"pmid": "23986097",
"pubdate": "2014-04",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Role of intravenous immunoglobulin in the treatment of acute relapses of neuromyelitis optica: experience in 10 patients.",
"title_normalized": "role of intravenous immunoglobulin in the treatment of acute relapses of neuromyelitis optica experience in 10 patients"
} | [
{
"companynumb": "GB-OCTA-LIT03816GB",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
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"activesubstancename": "HUMAN IMMUNOGLOBULIN G"
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{
"abstract": "Although benefits of laparoscopic surgery compared with open surgery have been suggested, the long-term survival of patients undergoing laparoscopic surgery for colon cancer requiring Japanese D3 dissection remains unclear. We did a randomised controlled trial to establish non-inferiority of laparoscopic surgery to open surgery.\n\n\n\nWe did an open-label, multi-institutional, randomised, two-arm phase 3 trial in 30 hospitals in Japan. Patients aged 20-75 years who had histologically proven colon cancer; tumours located in the caecum or ascending, sigmoid, or rectosigmoid colon; T3 or deeper lesions without involvement of other organs, node stages N0-2, and metastasis stage M0; and tumour size of 8 cm or smaller were included. Only accredited surgeons did surgery as an operator or instructor. Patients were randomly assigned (1:1) preoperatively to undergo D3 resection either by an open route or a laparoscopic route, via phone call or fax to the Japan Clinical Oncology Group (JCOG) Data Center. Randomisation used a minimisation method with a biased-coin assignment according to tumour location (caecum, ascending vs sigmoid, rectosigmoid) and institution. The primary endpoint was overall survival and was analysed by intention to treat. The non-inferiority margin for the hazard ratio (HR) was set at 1·366. This study is registered with UMIN Clinical Trials Registry, number C000000105, and ClinicalTrials.gov, number NCT00147134.\n\n\n\nBetween Oct 1, 2004, and March 27, 2009, 1057 patients were randomly assigned to either open surgery (n=528) or laparoscopic surgery (n=529). 5-year overall survival was 90·4% (95% CI 87·5-92·6) for open surgery and 91·8% (89·1-93·8) for laparoscopic surgery. Laparoscopic D3 surgery was not non-inferior to open surgery for overall survival (HR 1·06, 90% CI 0·79-1·41; pnon-inferiority=0·073). 65 (13%) patients in the open surgery group and 53 (10%) patients in the laparoscopic surgery group had grade 2-4 adverse events. Grade 2-4 adverse events included diarrhoea (15 [3%] in the open surgery group vs 14 [3%] in the laparoscopic surgery group), paralytic ileus (six [1%] vs nine [2%]), and small intestine bowel obstruction (16 [3%] vs 11 [2%]). Two treatment-related deaths occurred in the open surgery group: one patient died 7 days after surgery (probably due to myocardial infarction), and one patient died from febrile neutropenia, pneumonia, diarrhoea, and gastrointestinal haemorrhage during postoperative chemotherapy.\n\n\n\nLaparoscopic D3 surgery was not non-inferior to open D3 surgery in terms of overall survival for patients with stage II or III colon cancer. However, because overall survival in both groups was similar and better than expected, laparoscopic D3 surgery could be an acceptable treatment option for patients with stage II or III colon cancer.\n\n\n\nNational Cancer Center Research and Development Fund, Grant-in-Aid for Cancer Research, and Health and Labour Sciences Research Grant for Clinical Cancer Research from the Ministry of Health, Labour and Welfare of Japan.",
"affiliations": "Department of Gastroenterological and Pediatric Surgery, Oita University Faculty of Medicine, Oita, Japan.;Department of Gastroenterological and Pediatric Surgery, Oita University Faculty of Medicine, Oita, Japan. Electronic address: inomata@oita-u.ac.jp.;JCOG Data Center, Operations Office, National Cancer Center, Tokyo, Japan.;JCOG Data Center, Operations Office, National Cancer Center, Tokyo, Japan.;Department of Surgery, Kitasato University Hospital, Kanagawa, Japan.;Division of Colorectal Surgery, National Cancer Center Hospital, Tokyo, Japan.;Division of Colorectal Surgery, National Cancer Center Hospital East, Chiba, Japan.;Division of Colon and Rectal Surgery, Shizuoka Cancer Center Hospital, Shizuoka, Japan.;Department of Surgery, Gastroenterological Centre, Yokohama City University, Yokohama, Japan.;Department of Surgery, Jichi Medical University Saitama Medical Center, Saitama, Japan.;Departments of Surgery, Toho University Ohashi Medical Center, Tokyo, Japan.;Department of Surgery, Keio University School of Medicine, Tokyo, Japan.;Department of Gastroenterological and Pediatric Surgery, Oita University Faculty of Medicine, Oita, Japan.;Department of Surgical Oncology, Tokyo Medical and Dental University, Tokyo, Japan.;Department of Surgery, National Hospital Organization, Kyoto Medical Centre, Kyoto, Japan.;Department of Surgery, Kyorin University School of Medicine, Tokyo, Japan.;Department of Gastroenterological Surgery, Osaka City General Hospital, Osaka, Japan.;Department of Surgery, Suita Municipal Hospital, Osaka, Japan.;Department of Gastroenterological and Transplant Surgery, Hiroshima University, Hiroshima, Japan.;Division of Colorectal Surgery, National Cancer Center Hospital, Tokyo, Japan.;Gastrointestinal Oncology Division, National Cancer Center Hospital, Tokyo, Japan.",
"authors": "Kitano|Seigo|S|;Inomata|Masafumi|M|;Mizusawa|Junki|J|;Katayama|Hiroshi|H|;Watanabe|Masahiko|M|;Yamamoto|Seiichiro|S|;Ito|Masaaki|M|;Saito|Shuji|S|;Fujii|Shoichi|S|;Konishi|Fumio|F|;Saida|Yoshihisa|Y|;Hasegawa|Hirotoshi|H|;Akagi|Tomonori|T|;Sugihara|Kenichi|K|;Yamaguchi|Takashi|T|;Masaki|Tadahiko|T|;Fukunaga|Yosuke|Y|;Murata|Kohei|K|;Okajima|Masazumi|M|;Moriya|Yoshihiro|Y|;Shimada|Yasuhiro|Y|",
"chemical_list": null,
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"issue": "2(4)",
"journal": "The lancet. Gastroenterology & hepatology",
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"medline_ta": "Lancet Gastroenterol Hepatol",
"mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D000368:Aged; D003110:Colonic Neoplasms; D004210:Dissection; D000074099:Equivalence Trials as Topic; D005260:Female; D006801:Humans; D057194:Intention to Treat Analysis; D010535:Laparoscopy; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult",
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"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Survival outcomes following laparoscopic versus open D3 dissection for stage II or III colon cancer (JCOG0404): a phase 3, randomised controlled trial.",
"title_normalized": "survival outcomes following laparoscopic versus open d3 dissection for stage ii or iii colon cancer jcog0404 a phase 3 randomised controlled trial"
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"abstract": "The aim of this study was to assess the impact of total intravenous anesthesia (TIVA) on the perioperative inflammatory profile and clinical outcomes of patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC).\n\n\n\nA retrospective review of patients undergoing CRS-HIPEC was performed. Patients receiving a combination of preoperative tramadol extended release (ER), celecoxib, and pregabalin, along with combined intraoperative infusions of propofol, dexmedetomidine, lidocaine, and ketamine were classified as receiving a TIVA regimen (TIVA group). The second group consisted of patients receiving volatile-opioid-based anesthesia (VO group). The neutrophil:leukocyte (NLR) and platelet: leukocyte (PLR) ratios were calculated to evaluate the perioperative inflammatory status of both groups. Length of stay (LOS) and complications of both groups were also evaluated.\n\n\n\nA total of 213 patients were included in the study-139 in the VO group and 74 in the TIVA group. No statistically significant differences were observed between the groups with regard to their postoperative inflammatory profiles, LOS, or complications by organ system; however, the incidence of renal complications was higher in the TIVA group (8.1 vs. 2.2 %) and approached statistical significance (p = 0.068).\n\n\n\nIn this retrospective study of patients undergoing CRS-HIPEC, the combined use of preoperative celecoxib, tramadol ER and pregabalin followed by intraoperative TIVA with infusions of propofol, dexmedetomidine, ketamine, and lidocaine was not associated with a reduction in LOS or complications by organ system. Postoperative NLR and PLR profiles were also not significantly impacted.",
"affiliations": "Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. poagyemang@mdanderson.org.;Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.",
"authors": "Owusu-Agyemang|Pascal|P|;Cata|Juan P|JP|;Fournier|Keith F|KF|;Zavala|Acsa M|AM|;Soliz|Jose|J|;Hernandez|Mike|M|;Hayes-Jordan|Andrea|A|;Gottumukkala|Vijaya|V|",
"chemical_list": "D018686:Anesthetics, Intravenous",
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"journal": "Annals of surgical oncology",
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"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000771:Anesthesia, Intravenous; D018686:Anesthetics, Intravenous; D065426:Cytoreduction Surgical Procedures; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D010976:Platelet Count; D011183:Postoperative Complications; D012189:Retrospective Studies",
"nlm_unique_id": "9420840",
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"pages": "2419-29",
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"pubdate": "2016-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Evaluating the Impact of Total Intravenous Anesthesia on the Clinical Outcomes and Perioperative NLR and PLR Profiles of Patients Undergoing Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy.",
"title_normalized": "evaluating the impact of total intravenous anesthesia on the clinical outcomes and perioperative nlr and plr profiles of patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy"
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"abstract": "In this study, a case with tubercular choroiditis showing severe macular edema and progression of choroidal lesions following initiation of antitubercular treatment is presented and the management of posterior uveitis associated with tuberculosis is evaluated. A 40-year-old female patient was admitted with decreased vision in her right eye and her fundoscopic examination revealed serpiginous choroiditis. It was learned from her medical history that she had taken antitubercular therapy 9 years ago. Mantoux tuberculin skin test showed an area of induration measuring 15 mm and a positive interferon-gamma release assay was documented. Additionally, sequelae lesions due to previous tubercular infection were remarkable on her chest imaging. By excluding other causes of uveitis, the patient was considered presumed ocular tuberculosis and a full standard course of 4-drug antitubercular therapy was initiated. On the seventh day of the treatment existing choroidal lesions showed progression, new foci of choroiditis appeared and severe macular edema occurred. After adding systemic corticosteroid to the treatment, the macular edema resolved and choroidal lesions began to inactivate. In patients with tubercular choroiditis, continued progression may develop after initiation of antitubercular therapy. This paradoxical worsening is thought to be a hyperacute immunologic reaction occurring against antigen load released after antitubercular therapy. This phenomenon may be suppressed by the addition of systemic corticosteroids to the treatment.",
"affiliations": "Çukurova University Faculty of Medicine, Department of Ophthalmology, Adana, Turkey.;Çukurova University Faculty of Medicine, Department of Ophthalmology, Adana, Turkey.;Çukurova University Faculty of Medicine, Department of Ophthalmology, Adana, Turkey.;Çukurova University Faculty of Medicine, Department of Ophthalmology, Adana, Turkey.",
"authors": "Esen|Ebru|E|;Sızmaz|Selçuk|S|;Kunt|Zeynep|Z|;Demircan|Nihal|N|",
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"fulltext": "\n==== Front\nTurk J OphthalmolTurk J OphthalmolTJOTurkish Journal of Ophthalmology2149-86952149-8709Galenos Publishing 10.4274/tjo.948091752Case ReportParadoxical Worsening of Tubercular Serpiginous-Like Choroiditis after Initiation of Antitubercular Therapy Esen Ebru 1*Sızmaz Selçuk 1Kunt Zeynep 1Demircan Nihal 11 \nÇukurova University Faculty of Medicine, Department of Ophthalmology, Adana, Turkey\n* Address for Correspondence: Çukurova University Faculty of Medicine, Department of Ophthalmology, Adana, Turkey GSM: +90 532 781 66 94 E-mail: ebrublg@yahoo.com8 2016 15 8 2016 46 4 186 189 17 9 2014 14 10 2014 ©Turkish Journal of Ophthalmology, Published by Galenos Publishing.2016This 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.In this study, a case with tubercular choroiditis showing severe macular edema and progression of choroidal lesions following initiation of antitubercular treatment is presented and the management of posterior uveitis associated with tuberculosis is evaluated. A 40-year-old female patient was admitted with decreased vision in her right eye and her fundoscopic examination revealed serpiginous choroiditis. It was learned from her medical history that she had taken antitubercular therapy 9 years ago. Mantoux tuberculin skin test showed an area of induration measuring 15 mm and a positive interferon-gamma release assay was documented. Additionally, sequelae lesions due to previous tubercular infection were remarkable on her chest imaging. By excluding other causes of uveitis, the patient was considered presumed ocular tuberculosis and a full standard course of 4-drug antitubercular therapy was initiated. On the seventh day of the treatment existing choroidal lesions showed progression, new foci of choroiditis appeared and severe macular edema occurred. After adding systemic corticosteroid to the treatment, the macular edema resolved and choroidal lesions began to inactivate. In patients with tubercular choroiditis, continued progression may develop after initiation of antitubercular therapy. This paradoxical worsening is thought to be a hyperacute immunologic reaction occurring against antigen load released after antitubercular therapy. This phenomenon may be suppressed by the addition of systemic corticosteroids to the treatment.\n\nTubercular choroiditisantitubercular therapyparadoxical worseningSteroid\n==== Body\nINTRODUCTION\nSerpiginous choroiditis is a rare, idiopathic, chronic inflammatory disease. It is characterized by geographic lesions affecting the choroid and the neighboring retinal pigment epithelium (RPE) and outer retinal layers. There are reports in the literature that patients with tuberculosis (TB) infection exhibit similar choroidal signs and it has been emphasized that the two entities must be evaluated separately. The clinical presentation of patients with definite or presumed ocular TB diagnosis has been termed ‘serpiginous-like choroiditis’.1 Serpiginous choroiditis is believed to be an autoimmune disease and responds well to systemic steroids; in contrast, treating serpiginous-like choroiditis with steroids can lead to serious systemic and local complications if not accompanied by antitubercular therapy (ATT).\n\nIn patients with tuberculous choroiditis, ATT accelerates the healing process and reduces recurrence risk by decreasing the number of bacilli.2 In some patients, the rapid destruction of bacilli that occurs with initiation of ATT may cause existing lesions to worsen and new lesions to form. This paradoxical phenomenon occurs more often during the treatment of systemic TB infections, but has also been reported in a few cases of ocular TB. Here we present a case of TB-related choroiditis that exhibited choroidal lesion progression and severe macular edema following initiation of ATT.\n\nCASE REPORT\nA 40-year-old female patient presented with complaints of vision loss in the right eye beginning 2 months earlier. It was learned that the patient had no known systemic diseases and had received ATT for 6 months 9 years earlier. On ophthalmologic examination, her visual acuity was counting fingers from 2 meters in the right eye and 20/20 in the left eye. Anterior segment examination and intraocular pressure were normal in both eyes. Fundus examination of the right eye revealed multiple round, whitish-yellow, active subretinal lesions and gray sequelae lesions with definite borders and pigment aggregation at the margins. Adjacent to the inactive foci, new foci that tended to converge were noted (Figure 1a). Fundus examination of the left eye was normal. On fundus fluorescein angiography of the right eye, active foci exhibited hypofluorescence in the early arterial phase but were hyperfluorescent in the late venous phase due to leakage. Staining due to pigment epithelium atrophy was observed at the margins of the inactive lesions (Figure 1b). Optical coherence tomography (OCT) revealed hyperreflectivity in the outer retinal layers and choroid as well as intraretinal fluid (Figure 1c).\n\nThe patient’s hemoglobin level was 8.3 g/dL and hematocrit was 25.8%; all other biochemical, serologic and rheumatologic test results were normal (antistreptolysin O, C-reactive protein, and rheumatoid factors were within reference ranges; antinuclear antibody, anti-DNA, and human leukocyte antigen B27 tests were negative; no positive results were returned for cytomegalovirus, toxoplasma, herpes simplex virus, hepatitis B or C, human immunodeficiency virus, Salmonella, Brusella, Lyme disease and syphilis tests). Pathergy test was negative. Chest X-ray and computed tomography (CT) showed calcified hilar lymph nodes on the left and peribronchial nodular lesions of soft tissue density in the anterior and posterior segments of the right upper lobe. Mantoux tuberculin skin test (TST) produced an induration of 15 mm at 72 hours, and QuantiFERON TB-Gold test was positive. Following consultation with the Department of Pulmonary Diseases, the patient was considered consistent with previous pulmonary TB with no active pulmonary infection. Systemic investigation by the Department of Infectious Diseases revealed no signs of active or latent extrapulmonary TB. Treatment for iron deficiency was recommended by the Hematology Department. There was no evidence of rheumatologic or dermatologic disease which could cause uveitis.\n\nDue to the presence of choroiditis, TST ≥15 mm, positive QuantiFERON TB-Gold test, previous TB findings on chest X-ray and CT, and with the exclusion of other causes of uveitis, the patient was presumed intraocular TB and diagnosed with serpiginous-like choroiditis. The patient was started on a 4-drug ATT regimen: isoniazid 300 mg/day, rifampicin 600 mg/day, pyrazinamide 30 mg/kg/day, and ethambutol 25 mg/kg/day.\n\nOn day 7 of treatment the patient’s visual acuity was decreased to counting fingers from 50 cm. Fundus examination revealed progression of the existing lesions, multiple new choroiditis foci, and subretinal fluid leading to serous macular detachment (Figure 2). Oral methylprednisolone (1 mg/kg, 72 mg) was added to the treatment. The subretinal fluid began to regress immediately after the initiation of steroid treatment and had completely resolved 1 week later (Figure 3). After 1 month of treatment, the patient’s visual acuity had increased to 1/10 and a majority of the choroiditis foci were inactive. Extended ATT was planned with 2 months of the 4-drug regimen followed by 10 months of a 2-drug regimen (isoniazid and rifampicin), and reduction of the oral steroid was initiated. After 3 months of treatment, the steroid dose was 24 mg/day. The patient’s visual acuity had increased to 5/10 but new active choroiditis foci were observed. The steroid dose was increased to 54 mg/day and the new foci began to inactivate shortly thereafter. The ATT was continued with the same steroid dose.\n\nAt the patient’s final follow-up examination after 6 months of treatment, his visual acuity was 10/10. Multiple diffuse pigmented inactive lesions were observed in the fundus. OCT revealed disorganization of the RPE and outer retinal layers and disruption of the inner segment/outer segment band due to photoreceptor layer damage (Figure 4).\n\nDISCUSSION\nA definite ocular TB diagnosis is usually not possible because the direct demonstration of TB bacilli in ocular tissues is difficult. Ocular findings alone are not sufficient to diagnose ocular TB due to the many clinical conditions that can simulate it. When other causes of uveitis have been ruled out, a patient with signs of active or latent TB is referred to as presumed ocular TB.3 Especially in endemic areas, patients with findings suggestive of TB uveitis such as granulomatous uveitis, choroiditis, retinal vasculitis, retinal granuloma, and panuveitis should have TB tests included in their systemic evaluation. A TST result of 15 mm or larger is considered positive in vaccinated patients. However, this does not always correspond to a real infection, as the TST can give false positive results, especially in vaccinated individuals. In populations with routine vaccination, the QuantiFERON TB-Gold® (Cellestis Limited, Carnegie, Australia) test may be preferable because it analyzes interferon gamma release and only returns positive results for patients infected with Mycobacterium tuberculosis bacilli.4 Like the TST, however, this test cannot discriminate between active and latent infections. Together with medical history and clinical findings, we also confirmed our patient’s infection with TB bacilli using the QuantiFERON test.\n\nPosterior uveitis is the most common clinical manifestation of ocular TB. One of the clinical findings of this manifestation is serpiginous-like choroiditis, which is believed to result from an immune-mediated hypersensitivity reaction against TB bacilli.2 This reaction can arise against both bacilli found in the ocular tissue and against remote Mycobacterium tuberculosis antigens.5 Treatment response in these patients is relatively slow; it is therefore recommended to start treatment with a 4-drug regimen for 2 months, then continue for 9-12 months with a 2-drug regimen.\n\nWhen ATT begins destroying TB bacilli, the tubercular antigen load increases and this may further exacerbate the reaction. This paradoxical presentation is the ocular form of Jarisch-Herxheimer reaction that emerges in systemic TB infections like TB meningitis, intracranial tuberculoma, pleural effusion and abdominal TB.2 Worsening of clinical findings may be observed in the form of progression of existing lesions and the formation of new lesions. Paradoxical worsening can also occur upon initiation of antibiotic therapy in other ocular infections like syphilis, Lyme’s disease, and leptospirosis. There are other case reports in the literature of ATT inducing clinical exacerbation of ocular TB, similar to our case.2,6,7,8 These patients were managed by adding systemic steroids to treatment, increasing the dose of steroid started with ATT, or adding immunosuppressant therapy. Our patient responded well to a high dose of oral steroid and her inflammation rapidly regressed.\n\nThere is no standard treatment protocol for TB-related posterior uveitis. Although successful outcomes have been reported with the use of ATT alone, the more common approach is to begin systemic steroid with ATT.2,9,10,11 This approach is believed to reduce late stage hypersensitivity-related tissue damage and yield better visual and anatomic improvement. However, it should be noted that steroids can reactivate a latent infection or cause an intraocular infection to spread. Some studies have recommended adding systemic steroids at least 2 weeks after starting ATT.12 Treating TB is a long process which requires patience. Especially for the first 2 months, patients must take quite a few pills each day. For patients who have difficulty complying with treatment, the addition of oral steroids may further reduce their compliance with the ATT. For such patients, it may be prudent to make decisions about steroid therapy based on the patient’s clinical course.\n\nParadoxical worsening may also occur in patients started on both ATT and systemic steroid simultaneously. One reason for this is the very severe inflammation and inadequate suppression. Another reason may be that rifampicin increases steroid metabolism.13 In that case, increasing the steroid dose or adding immunosuppressive therapy may resolve the issue. In our patient, new foci of inflammation developed at the steroid maintenance dose of 24 mg/day and the lesions regressed when the dose was increased.\n\nCONCLUSION\nThe possibility of the paradoxical phenomenon upon ATT initiation should be kept in mind, particularly for patients with TB-related posterior uveitis, and ATT should not be discontinued with the assumption that the treatment is not effective. Systemic steroid therapy may be beneficial to suppress inflammation and control progression.\n\nEthics\nInformed Consent: It was taken.\n\nPeer-review: Externally and internally peer-reviewed.\n\nSurgical and Medical Practices: Ebru Esen, Selçuk Sızmaz, Zeynep Kunt, Nihal Demircan, Concept: Ebru Esen, Selçuk Sızmaz, Zeynep Kunt, Nihal Demircan, Design: Ebru Esen, Selçuk Sızmaz, Zeynep Kunt, Nihal Demircan, Data Collection or Processing: Ebru Esen, Selçuk Sızmaz, Zeynep Kunt, Nihal Demircan, Analysis or Interpretation: Ebru Esen, Selçuk Sızmaz, Zeynep Kunt, Nihal Demircan, Literature Search: Ebru Esen, Selçuk Sızmaz, Zeynep Kunt, Nihal Demircan, Writing: Ebru Esen, Selçuk Sızmaz, Zeynep Kunt, Nihal Demircan.\n\nConflict of Interest: No conflict of interest was declared by the authors.\n\nFinancial Disclosure: The authors declared that this study received no financial support.\n\nFigure 1 The patient’s clinical findings at presentation: a) Fundus photograph of the right eye showing multiple round, whitish-yellow active subretinal lesions at the posterior pole as well as gray, demarcated sequelae lesions with marginal pigment aggregation, inactive foci and convergent newly activated foci; b) Fundus fluorescein angiography of the right eye showing hypofluorescence in the early arterial phase and hyperfluorescence in the late venous phase due to leakage; c) Optical coherence tomography showing subretinal fluid and hyperreflectivity of the outer retinal layers and choroid\nFigure 2 Clinical findings 1 week after initiation of antitubercular therapy: a) Fundus photograph showing progression of existing lesions and multiple new choroiditis foci; b) Optical coherence tomography showing subretinal fluid leading to serous macular detachment\nFigure 3 Clinical findings 1 week after adding oral steroid to the treatment regimen: a) Fundus photograph showing choroiditis foci becoming inactive and serous detachment regressing; b) Optical coherence tomography showing minimal intraretinal fluid and disorganized outer retinal layers\nFigure 4 Clinical findings after 6 months of treatment: a) Fundus photograph showing geographic atrophic lesions in the posterior pole and pigment aggregates in the posterior pole; b) Optical coherence tomography showing disorganization of the retinal pigment epithelium and outer retinal layers and inner segment/outer segment band disruption\n==== Refs\nReferences\n1 Gupta V Gupta A Arora S Bambery P Dogra MR Agarwal A Presumed tubercular serpiginouslike choroiditis: clinical presentations and management Ophthalmology 2003 110 1744 1749 13129872 \n2 Gupta V Bansal R Gupta A Continuous progression of tubercular serpiginous-like choroiditis after initiating antituberculosis treatment Am J Ophthalmol 2011 152 857 863 21794847 \n3 Gupta V Gupta A Rao NA Intraocular tuberculosis--an update Surv Ophthalmol 2007 52 561 587 18029267 \n4 Mackensen F Becker MD Wiehler U Max R Dalpke A Zimmermann S QuantiFERON TB-Gold--a new test strengthening long-suspected tuberculous involvement in serpiginous-like choroiditis Am J Ophthalmol 2008 146 761 766 18718569 \n5 Rao NA Saraswathy S Smith RE Tuberculous uveitis: distribution of Mycobacterium tuberculosis in the retinal pigment epithelium Arch Ophthalmol 2006 124 1777 1779 17159041 \n6 Cheung CM Chee SP Jarisch-Herxheimer reaction: paradoxical worsening of tuberculosis chorioretinitis following initiation of antituberculous therapy Eye (Lond) 2009 23 1472 1473 \n7 Basu S Das T Pitfalls in the management of TB-associated uveitis Eye (Lond) 2010 24 1681 1684 20706283 \n8 Neunhöffer H Gold A Hoerauf H Herbort C Heiligenhaus A Zimmermann O Feltgen N Isolated ocular Jarisch-Herxheimer reaction after initiating tuberculostatic therapy in a child Int Ophthalmol 2014 34 675 677 24022644 \n9 Bansal R Gupta A Gupta V Dogra MR Sharma A Bambery P Tubercular serpiginous-like choroiditis presenting as multifocal serpiginoid choroiditis Ophthalmology 2012 119 2334 2342 22892153 \n10 Vasconcelos- Santos Rao PK Davies JB Sohn EH Rao NA Clinical features of tuberculous serpiginouslike choroiditis in contrast to classic serpiginous choroiditis Arch Ophthalmol 2010 128 853 858 20625045 \n11 Zhang M Zhang J Liu Y Clinical presentations and therapeutic effect of presumed choroidal tuberculosis Retina 2012 32 805 813 21878856 \n12 Mao Y Peng XY You QS Wang H Zhao M Jonas JB Tuberculous uveitis in China Acta Ophthalmol 2014 92 393 397 \n13 McAllister WA Thompson PJ Al-Habet SM Rogers HJ Rifampicin reduces effectiveness and bioavailability of prednisolone Br Med J (Clin Res Ed) 1983 286 923 925\n\n",
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"issue": "46(4)",
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"title": "Paradoxical Worsening of Tubercular Serpiginous-Like Choroiditis after Initiation of Antitubercular Therapy.",
"title_normalized": "paradoxical worsening of tubercular serpiginous like choroiditis after initiation of antitubercular therapy"
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"abstract": "BACKGROUND\nVancomycin is used mostly to overcome infections caused by methicillinresistant microorganisms. There are no well-established administration protocols for neonates and infants, so the leak of a specific administration regime in that population may lead to serum concentrations beyond the specified range.\n\n\nOBJECTIVE\nThis case series evaluated the pharmacokinetics adjustment from a vancomycin therapeutic regimen prescribed to neonates and infants with bacterial infection at a neonatal public hospital intensive- care-unit, with the primary purpose to verify cases of nephrotoxicity.\n\n\nMETHODS\nThree neonates and four infants taking vancomycin therapy, hospitalized in a public hospital from November 2014 to March 2015, were included in the study. Vancomycin serum concentrations were determined by particle-enhanced-turbidimetric inhibition-immunoassay. The vancomycin concentrations were used for dose adjustment by USC*Pack-PC-Collection®, a non-parametric maximization program. The trough serum concentration range of 10 to 20mg.L-1 was considered therapeutic.\n\n\nRESULTS\nThree patients had serum concentration outside the reference-range, one with subtherapeutic, and two with supratherapeutic concentrations. All patients had concomitant use of drugs which interfered with vancomycin distribution and excretion pharmacokinetics parameters, including drugs that may enhance nephrotoxicity. One patient showed signs of acute renal damage, by low vancomycin and creatinine estimated clearances.\n\n\nCONCLUSIONS\nThe pharmacokinetic adjustment has been proven to be a useful and necessary tool to increase therapeutic efficacy and treatment benefits. The standard dose of vancomycin can be used to initiate therapy in neonates and infants admitted to the ICU, but after reaching the drug steady state, the dosing regimen should be individualized and guided by pharmacokinetic parameters.",
"affiliations": "Pharmacy Postgraduate Program, Faculty of Pharmacy, Federal University of Bahia/UFBA, Salvador, Bahia, Brazil.;Clinical Biochemistry Laboratory, Department of Clinical and Toxicological Analysis, Faculty of Pharmacy, Federal University of Bahia/UFBA, Salvador, Bahia, Brazil.;University Center Estácio of Bahia, Bahia, Brazil.;Poison Information Center (Ciave) of Bahia, Salvador, Bahia, Brazil.;Department of Pediatrics, Hospital Roberto Santos, Salvador, Bahia, Brazil.;Pharmacy Postgraduate Program, Faculty of Pharmacy, Federal University of Bahia/UFBA, Salvador, Bahia, Brazil.;Pharmacy Postgraduate Program, Faculty of Pharmacy, Federal University of Bahia/UFBA, Salvador, Bahia, Brazil.;Pharmacy Postgraduate Program, Faculty of Pharmacy, Federal University of Bahia/UFBA, Salvador, Bahia, Brazil.;Pharmacy Postgraduate Program, Faculty of Pharmacy, Federal University of Bahia/UFBA, Salvador, Bahia, Brazil.",
"authors": "Bidu|Nadielle S|NS|;Fernandes|Bruno J D|BJD|;Dias|Eduardo J C|EJC|;Filho|Jucelino N C|JNC|;Bastos|Regina E A|REA|;Godoy|Ana L P C|ALPC|;Azeredo|Francine J|FJ|;Pedreira|Joice N R|JNR|;Couto|Ricardo D|RD|",
"chemical_list": "D000900:Anti-Bacterial Agents; D014640:Vancomycin; D003404:Creatinine",
"country": "Netherlands",
"delete": false,
"doi": "10.2174/1389201020666190319161511",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1389-2010",
"issue": "20(4)",
"journal": "Current pharmaceutical biotechnology",
"keywords": "Vancomycin therapy; drug monitoring; infants; neonates; nephrotoxicity; pharmacokinetics.",
"medline_ta": "Curr Pharm Biotechnol",
"mesh_terms": "D058186:Acute Kidney Injury; D000900:Anti-Bacterial Agents; D001424:Bacterial Infections; D003404:Creatinine; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D012189:Retrospective Studies; D014640:Vancomycin",
"nlm_unique_id": "100960530",
"other_id": null,
"pages": "346-351",
"pmc": null,
"pmid": "30892160",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Vancomycin Therapeutic Regime Adjustment in Newborns and Infants with Bacterial Infection: Case Series.",
"title_normalized": "vancomycin therapeutic regime adjustment in newborns and infants with bacterial infection case series"
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"companynumb": "BR-PENTEC HEALTH-2019PEN00033",
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"actiondrug": "2",
"activesubstance": {
"activesubstancename": "VANCOMYCIN HYDROCHLORIDE"
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"abstract": "Maternal cardiac output and stroke volume increase significantly at the time of cesarean delivery. Parturients with baseline myocardial dysfunction are at increased risk of cardiovascular decompensation in the peripartum period and close hemodynamic monitoring is warranted. We report our use of intraoperative non-invasive cardiac output monitoring during cesarean delivery under epidural anesthesia in a 24-year-old woman with dilated cardiomyopathy secondary to Marfan syndrome, aortic arch, aortic valve and mitral valve replacements and a left ventricular ejection fraction of 37%. Three distinct hemodynamic trends were noted. After achieving adequate surgical anesthesia with 2% lidocaine 20mL, cardiac output and stroke volume rose for approximately 20min from baseline values of 6.3L/min and 69mL, respectively, to 9L/min and 107mL. Values subsequently trended down and remained depressed for nearly 20min following delivery. The lack of immediate post-delivery increases in both cardiac output and stroke volume were attributed to acute blood loss, intravascular volume depletion from fluid restriction, and slow infusion of oxytocin. By the end of surgery, cardiac output and stroke volume ultimately increased by 66% and 84% of baseline values, respectively. Systemic blood pressure, heart rate and cardiac output did not appear to correlate despite the use of phenylephrine to manage hypotension. The patient remained hemodynamically stable with no evidence of acute volume overload.",
"affiliations": "Department of Anesthesiology, New York-Presbyterian/Weill Cornell Medical College, New York, NY, USA. Electronic address: sbeaudr1@jhmi.edu.;Department of Anesthesiology, New York-Presbyterian/Weill Cornell Medical College, New York, NY, USA.;Department of Anesthesiology, New York-Presbyterian/Weill Cornell Medical College, New York, NY, USA.",
"authors": "Beaudry|S|S|;Pick|J|J|;Heerdt|P M|PM|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "0959-289X",
"issue": "25()",
"journal": "International journal of obstetric anesthesia",
"keywords": "Cardiomyopathy; Marfan syndrome; Non-invasive cardiac output monitoring; Oxytocin; Phenylephrine",
"medline_ta": "Int J Obstet Anesth",
"mesh_terms": "D000328:Adult; D000767:Anesthesia, Epidural; D000773:Anesthesia, Obstetrical; D002302:Cardiac Output; D009202:Cardiomyopathies; D002585:Cesarean Section; D005260:Female; D006801:Humans; D008382:Marfan Syndrome; D008991:Monitoring, Physiologic; D011247:Pregnancy",
"nlm_unique_id": "9200430",
"other_id": null,
"pages": "82-5",
"pmc": null,
"pmid": "26718697",
"pubdate": "2016-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Non-invasive cardiac output monitoring for cesarean delivery under epidural anesthesia in a patient with Marfan syndrome and cardiomyopathy.",
"title_normalized": "non invasive cardiac output monitoring for cesarean delivery under epidural anesthesia in a patient with marfan syndrome and cardiomyopathy"
} | [
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"companynumb": "US-PFIZER INC-2016203415",
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"abstract": "BACKGROUND\nPostoperative delirium is a relatively uncommon condition in middle aged patients, but very widespread in patients with psychiatric and neurological diseases undergoing general anesthesia. Few studies are currently available in the literature on the perioperative anesthesiological management of patients suffering from spinocerebellar ataxia.\n\n\nMETHODS\nA 58-year-old Caucasian woman affected by spinocerebellar ataxia type 2 underwent total hip arthroplasty for advanced osteoarthritis. One month later, debridement, antibiotics, and implant retention was performed for periprosthetic hip infection. Both times she underwent general anesthesia and developed an early postoperative delirium treated successfully with chlorpromazine.\n\n\nCONCLUSIONS\nThis case report highlights the need to correctly manage patients at high risk of developing postoperative delirium, especially if suffering from degenerative neurological diseases. On the other hand, further studies will be needed in order to evaluate if spinocerebellar ataxia is an independent risk factor for the development of this acute and transient pathological condition.",
"affiliations": "Department of Anaesthesiology and Intensive Care Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli 1, 00168, Rome, Italy. laura.levantesi@policlinicogemelli.it.;Department of Anaesthesiology and Intensive Care Medicine, Università Cattolica del Sacro Cuore - Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.;Mininvasive and Computer Assisted Orthopaedic Surgery, University of L'Aquila, L'Aquila, Italy.;Department of Orthopaedics, Università Cattolica del Sacro Cuore - Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.",
"authors": "Levantesi|Laura|L|;De Cosmo|Germano|G|;Logroscino|Giandomenico|G|;Saracco|Michela|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s13256-019-2040-9",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 204010.1186/s13256-019-2040-9Case ReportRecurrent postoperative delirium in spinocerebellar ataxia type 2: a case report Levantesi Laura laura.levantesi@policlinicogemelli.it 2De Cosmo Germano germano.decosmo@policlinicogemelli.it 1Logroscino Giandomenico g.logroscino@gmail.com 3Saracco Michela michelasaracco@gmail.com 41 0000 0001 0941 3192grid.8142.fDepartment of Anaesthesiology and Intensive Care Medicine, Università Cattolica del Sacro Cuore - Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy 2 grid.414603.4Department of Anaesthesiology and Intensive Care Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli 1, 00168 Rome, Italy 3 0000 0004 1757 2611grid.158820.6Mininvasive and Computer Assisted Orthopaedic Surgery, University of L’Aquila, L’Aquila, Italy 4 0000 0001 0941 3192grid.8142.fDepartment of Orthopaedics, Università Cattolica del Sacro Cuore - Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy 29 4 2019 29 4 2019 2019 13 1129 9 2018 5 3 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nPostoperative delirium is a relatively uncommon condition in middle aged patients, but very widespread in patients with psychiatric and neurological diseases undergoing general anesthesia. Few studies are currently available in the literature on the perioperative anesthesiological management of patients suffering from spinocerebellar ataxia.\n\nCase presentation\nA 58-year-old Caucasian woman affected by spinocerebellar ataxia type 2 underwent total hip arthroplasty for advanced osteoarthritis. One month later, debridement, antibiotics, and implant retention was performed for periprosthetic hip infection. Both times she underwent general anesthesia and developed an early postoperative delirium treated successfully with chlorpromazine.\n\nConclusions\nThis case report highlights the need to correctly manage patients at high risk of developing postoperative delirium, especially if suffering from degenerative neurological diseases. On the other hand, further studies will be needed in order to evaluate if spinocerebellar ataxia is an independent risk factor for the development of this acute and transient pathological condition.\n\nKeywords\nGeneral anesthesiaDeliriumMental disorderSpinocerebellar ataxiaHip arthroplastyissue-copyright-statement© The Author(s) 2019\n==== Body\nIntroduction\nAtaxia is characterized by a lack of voluntary coordination of muscle movements. There are different types of ataxia according to onset and progress. In addition, the clinical features of most ataxias overlap. Therefore, there is a need to typify the genotype in order to predict the course of the specific disease. Spinocerebellar ataxias (SCAs) are a heterogeneous group of autosomal dominant cerebellar ataxias. SCAs have been classified into 43 subtypes based on the genetic mutations that characterize them. Spinocerebellar ataxia type 2 (SCA2) is the second most common disorder and one of the most severe subtypes, affecting middle aged patients. It is characterized by slowly progressive ataxia and dysarthria associated with nystagmus, slow saccadic eye movements and, in some individuals, ophthalmoparesis or parkinsonism. On the other hand, hypotonia is uncommon. Mutations in the ATXN2 gene cause SCA2. This gene provides instructions for making a protein called ataxin-2. The ATXN2 gene mutation that causes SCA2 involves a DNA segment known as a CAG trinucleotide repeat. Individuals with an abnormally long CAG segment develop this neurological disease [1]. Thus, diagnosis depends on molecular genetic testing. In addition, morphometric magnetic resonance imaging (MRI) shows a severe olivopontocerebellar atrophy pattern and frontal cortex atrophy [2]. Patients with SCA2 are often affected by peripheral neuronopathy with hypo/areflexia, paresthesia, and hypoesthesia. Cognitive performances are characterized by frontal-executive dysfunctions, verbal memory impairments, attentional deficits and, sometimes, dementia. Psychiatric symptoms include depression in 22% of cases and anxiety. People with SCA2 usually survive 10 to 20 years after symptoms appear [3].\n\nIn this case report a patient suffering from SCA2 underwent two different orthopedic surgical procedures under general anesthesia and developed early postoperative delirium (POD). Several reports have been published on the anesthetic management of patients with SCA, but few of these deal with the management of patients affected by the subtype SCA2 and none addresses prevention and management of the POD.\n\nCase presentation\nA 58-year-old Caucasian woman with hip osteoarthritis was examined by an anesthesiologist for a surgical procedure of total hip arthroplasty. She had a history of SCA, which started when she was 55-years old with motor dysfunction. Her clinical condition had slowly worsened with appearance of dysarthria, horizontal saccadic eye movements, and lower extremities hypertonia. An MRI of her brain showed olivopontocerebellar atrophy; a mild motor and sensory ataxic polyneuropathy was highlighted by electromyography. Recent neuropsychological examinations identified a dis-executive deficit. Her family history is negative for SCA and she denied any history of cardiovascular, respiratory, or gastrointestinal diseases. Prior to the diagnosis of SCA, she was in good health and did not regularly take drugs. She denied smoking tobacco or drinking alcohol. At the time of the examination, she was taking benzodiazepines (triazolam 0.25 mg once daily) for anxious depressive syndrome, baclofen 25 mg three times a day for spasticity, and anti-cyclooxygenase type 2 (COX-2) for pain treatment (etoricoxib 60 mg once daily). Preoperative blood tests, electrocardiogram, and thoracic X-ray were negative. On physical examination, it was possible to appreciate that she was tall, 168 cm, and weighed 63 kg. A cardiopulmonary examination was unremarkable. Her vital signs were normal with blood pressure of 135/90 mmHg and heart rate of 90 beats per minute. On neuropsychological examination, she presented a mild reduction in performance on the Rey–Osterrieth Complex Figure Test, a limited ability to inhibit cognitive interference (Stroop Test), inability during the Multiple Features Targets Cancellation task, and a Spatial Span Score lower than normal; these were proofs of her dis-executive deficit. After discussing the case with a neurologist, general anesthesia was planned. In fact, our patient’s anxiety and spasticity would have made regional anesthesia difficult to practice. Preoperatively, no medications were administered. General anesthesia was induced with propofol 2 mg/kg intravenously and fentanyl 2 mcg/kg intravenously. Tracheal intubation was facilitated with rocuronium 0.6 mg/kg intravenously. Anesthesia maintenance was performed with sevoflurane (in an oxygen/air mixture) and fentanyl. The minimum alveolar concentration of sevoflurane was set to achieve a Bi-spectral Index (BIS) value between 40 and 60. Mechanical ventilation was set with a tidal volume of 7 ml/kg, a positive end-expiratory pressure (PEEP) of 5 cmH2O, and an inspiration/expiration rate of 1:2. These parameters remained stable during the surgical procedure. The respiration rate was adjusted to obtain an end-tidal carbon dioxide (etCO2) between 38 and 45 mmHg. The surgery was uneventful with no significant blood loss and no transfusion was needed. The procedure lasted 2 hours. Upon awakening, she appeared calm and parameters were stable. In the post anesthesia care unit (PACU), she was warmed up and oxygen supplementation was administered. Thirty minutes after awakening, she developed an acute hyperactive delirium. She experienced episodes of confusion, logorrhea, and disorientation. She also exhibited reduced awareness of the environment and hallucinations with aggressive behavior. During this episode, her vital signs remained stable and her oxygen saturation was normal. An arterial blood test revealed no hypercapnia or hypoxia or electrolyte disorders. Haloperidol 5 mg was intravenously administered slowly over 5 minutes, but her behavior did not change. To avoid uncontrolled pain, a single shot fascia iliaca block was performed with 25 ml of ropivacaine 0.375% but she continued to have intermittent episodes of delirium. After 10 minutes, chlorpromazine 25 mg was infused intravenously. This drug seemed to have the same efficacy as haloperidol with a subsequent mild sedation. She was transferred to our intensive care unit (ICU) where chlorpromazine 25 mg was given again during the night for another crisis. She was discharged from ICU the next day under normal neurological conditions.\n\nAfter 1 month, she was readmitted for the development of an acute periprosthetic hip infection sustained by Staphylococcus epidermidis and Staphylococcus haemolyticus without signs of systemic sepsis. On examination, her temperature was 36.7°C, blood pressure was 128/95 mmHg, and heart rate was 75 beats per minute. Only the wound swab was positive for infection; hemocultures and urine cultures were negative. Preoperative blood tests showed: hemoglobin 10.4 g/dL; platelets 233 × 109/L; neutrophils 4.26 × 10 9/L; erythrocyte sedimentation rate (ESR) 47 mm/hour, and C-reactive protein (CRP) 27.2 mg/L. Renal and hepatic function indices were within normal limits. Debridement, antibiotics, and implant retention (DAIR) was performed under general anesthesia with the same modalities [4]. During surgery and after taking new periprosthetic tissue for microbiological examination, teicoplanin was administered intravenously at a loading dose of 400 mg. For the second time, our patient developed POD treated with chlorpromazine 25 mg intravenously with immediate sedation. Within 24 hours, the delirium resolved with no consequences. During the following days, 200 mg of teicoplanin was administered daily and 1 gr of cefazolin every 12 hours intravenously until discharge.\n\nOne month after discharge, she returned for follow-up. She was taking her habitual medications and, at the time of the examination, she exhibited no evidence of new disorders or joint infection. She looked well and denied any symptoms of confusion, disorientation, or hallucinations. The hip infection healed without any complication. She was re-evaluated at 3 and 6 months after surgery. Her ESR, CRP, and other biochemical values were within normal limits and her neurological status was stable.\n\nDiscussion\nThere is a large literature on the anesthetic management of patients with SCA but this case report focuses on SCA2 and reports an anesthesia complication, POD, which is uncommon in middle aged people. An age of over 65 years, conventionally, represents a factor that can predispose or precipitate delirium. In general, patients with SCA2 may develop significant complications during and after general anesthesia, such as seizures, cardiomyopathy, and heart blocks. Non-cerebellar manifestations in SCA2 are oculomotor disturbances, signs of corticospinal tract dysfunctions (hyperreflexia and spasticity), and signs of neuronal degeneration, but also peripheral neuronopathy with hypo/areflexia, paresthesia, and hypoesthesia. Some forms of SCA2 present also a parkinsonian phenotype with dystonia, myoclonus, rigidity, and chorea. Common symptoms are also psychiatric disturbances, sleep disorders, and cognitive decline but dementia is rare. Although with less frequency, autonomic dysfunctions may appear, including urogenital, cardiovascular, gastrointestinal, and thermoregulatory disorders. Cardiovascular autonomic dysfunctions with involvement of sympathetic and parasympathetic system may occur in 60% of patients with SCA2 [3]. Patients with spinocerebellar degeneration have been successfully managed under regional and general anesthesia but tremors or rigidity may make performing the procedure difficult. However, autonomic neuropathy makes unpredictable responses after central neuraxial blockade. Moreover, neuropathy may worsen after performing regional anesthesia. On the other hand, general anesthesia exposes the patient to the risk of unpredictable responses to curare derivatives with prolonged paralysis and necessity of mechanical ventilation. However, Schmitt et al. reported the use of rocuronium in two children with Friedreich’s ataxia with no increase in onset and recovery timings [5]. In addition, various atrioventricular blocks have been reported after general anesthesia [6]. Our patient’s clinical conditions made general anesthesia preferable; in fact, no complications occurred during induction and maintenance of general anesthesia, but an early POD occurred. The incidence of POD in non-cardiac surgery is actually between 15 and 54% [7]. This condition seems to be caused by the release of psychoactive inflammatory markers during surgery, such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1 (IL-1) beta, that contribute to delirium through dopamine, gamma-aminobutyric acid (GABA), or cholinergic-mediated pathways. General anesthesia, in addition, exposes the brain to cognitively active drugs.\n\nDiagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for delirium are:A disturbance in attention and awareness.\n\nDevelopment over a short period.\n\nAn additional disturbance in cognition (memory deficit, disorientation).\n\nThe disturbances in Criteria A and C are not explained by pre-existing neurocognitive disorder.\n\nThere is no evidence that the disturbance is a direct physiological consequence of another medical condition, substance intoxication or withdrawal (due to a drug of abuse or to a medication), or exposure to a toxin, or is due to multiple etiologies.\n\n\n\nTherefore, it is important to implement optimal management and prevention strategies. First, the patient’s vital signs should be checked and an arterial blood test should be performed with a complete physical examination in order to exclude hypoxia and hypercarbia, hypoglycemia, and electrolyte disturbances but also stroke, seizures, and central cholinergic syndrome. Following the results of a recent meta-analysis, delirium treatment is multicomponent and antipsychotics are useful in the treatment and prevention of this complication. So, the treatment of delirium is based mainly on the use of typical antipsychotics like haloperidol [8]; however, recent findings suggest that second-generation antipsychotics are suitable for treating delirium and have a better safety profile than haloperidol [9]. In addition, adequate pain control plays a central role in this setting, using epidural analgesia, long-acting morphine and fascia iliaca block. Hydration and early mobilization are also important in preventing recurrence [10].\n\nConclusions\nAccording to the literature, POD is associated with significantly worse outcomes with an increase in adverse events, hospitalization, and mortality [11]. Multidisciplinary prevention programs have been shown to reduce the incidence of delirium among medical and surgical patients by approximately 30% [12]. In conclusion, the best treatment for POD is prevention, which needs recognition and management of risk factors but also close collaboration between surgeons, anesthesiologists, geriatricians, and neurologists in order to reduce the hospitalization. In conclusion, if identifying risk factors is mandatory to prevent this disease, then further studies are needed to evaluate if SCA is an independent risk factor for POD. In fact, it is possible that our patient’s anxious syndrome played a relevant role in the development of this acute neurological disorder.\n\nAbbreviations\nBISBi-spectral Index\n\nCOX-2Cyclooxygenase type 2\n\nCRPC-reactive protein\n\nDAIRDebridement, antibiotics, and implant retention\n\nDSM-5Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition\n\nESRErythrocyte sedimentation rate\n\netCO2End-tidal carbon dioxide\n\nGABAGamma-aminobutyric acid\n\nICUIntensive care unit\n\nIl-1Interleukin-1\n\nIL-6Interleukin-6\n\nMRIMagnetic resonance imaging\n\nPACUPost anesthesia care unit\n\nPEEPPositive end-expiratory pressure\n\nPODPostoperative delirium\n\nSCASpinocerebellar ataxia\n\nSCA2Spinocerebellar ataxia type 2\n\nTNF-alphaTumor necrosis factor-alpha\n\nAcknowledgements\nNot applicable.\n\nFunding\nThe authors declare that there are no conflicts of interest associated with this report.\n\nAvailability of data and materials\nThe dataset supporting the conclusions of this article is included within the article.\n\nAuthors’ contributions\nLL and MS reported the case and wrote the manuscript. GDC and GL helped in drafting the manuscript and participated in revising the manuscript critically. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Ruano L Melo C Silva MC Coutinho P The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies Neuroepidemiology 2014 42 174 183 10.1159/000358801 24603320 \n2. Antenora A Rinaldi C Roca A Pane C Lieto M Saccà F The Multiple Faces of Spinocerebellar Ataxia type 2 Ann Clin Transl Neurol 2017 4 687 695 10.1002/acn3.437 28904990 \n3. Velázquez-Pérez LC Rodríguez-Labrada R Fernandez-Ruiz J Spinocerebellar Ataxia Type 2: Clinicogenetic Aspects, Mechanistic Insights, and Management Approaches Front Neurol 2017 8 472 10.3389/fneur.2017.00472 28955296 \n4. Anemüller R Belden K Brause B Citak M Del Pozo JL Frommelt L Hip and Knee Section, Treatment, Antimicrobials: Proceedings of International Consensus on Orthopedic Infections J Arthroplast 2019 34 S463 S475 10.1016/j.arth.2018.09.032 \n5. Schmitt HJ Wick S Munster T Rocuronium for muscle relaxation in two children with Friedreich’s ataxia Brit J Anaesth 2004 92 592 596 10.1093/bja/aeh106 14977802 \n6. Sugai K Sugai Y Aoki H Matsushima Y Anesthesia for a patient with spinocerebellar degeneration who developed atrioventricular block Masui 1990 39 1397 1401 2255048 \n7. Evered L Silbert B Knopman DS Scott DA DeKosky ST Rasmussen LS Oh ES Crosby G Berger M Eckenhoff RG Nomenclature Consensus Working Group Recommendations for the Nomenclature of Cognitive Change Associated with Anaesthesia and Surgery J Alzheimers Dis 2018 66 1 10 10.3233/JAD-189004 30347621 \n8. Wang W Li HL Wang DX Zhu X Li SL Yao GQ Chen KS Gu XE Zhu SN Haloperidol prophylaxis decreases delirium incidence in elderly patients after noncardiac surgery: a randomized controlled trial Crit Care Med 2012 40 731 739 10.1097/CCM.0b013e3182376e4f 22067628 \n9. Kishi T Hirota T Matsunaga S Iwata N Antipsychotic medications for the treatment of delirium: a systematic review and meta-analysis of randomised controlled trials J Neurol Neurosurg Psychiatry 2016 87 767 774 10.1136/jnnp-2015-311049 26341326 \n10. Zhang H Lu Y Liu M Zou Z Wang L Xu FY Shi XY Strategies for prevention of postoperative delirium: a systematic review and meta-analysis of randomized trials Crit Care 2013 17 R47 10.1186/cc12566 23506796 \n11. Raats JW van Eijsden WA Crolla RM Steyerberg EW van der Laan L Risk Factors and Outcomes for Postoperative Delirium after Major Surgery in Elderly Patients PLoS One 2015 10 e0136071 10.1371/journal.pone.0136071 26291459 \n12. Inouye SK Bogardus ST Baker DI Leo-Summers L Cooney LM The Hospital Elder Life Program: a model of care to prevent cognitive and functional decline in older hospitalized patients J Am Geriatr Soc 2000 48 1697 1706 10.1111/j.1532-5415.2000.tb03885.x 11129764\n\n",
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"issue": "13(1)",
"journal": "Journal of medical case reports",
"keywords": "Delirium; General anesthesia; Hip arthroplasty; Mental disorder; Spinocerebellar ataxia",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000768:Anesthesia, General; D019644:Arthroplasty, Replacement, Hip; D000071257:Emergence Delirium; D005260:Female; D006801:Humans; D008875:Middle Aged; D012086:Reoperation; D020754:Spinocerebellar Ataxias",
"nlm_unique_id": "101293382",
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"pmid": "31030668",
"pubdate": "2019-04-29",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Recurrent postoperative delirium in spinocerebellar ataxia type 2: a case report.",
"title_normalized": "recurrent postoperative delirium in spinocerebellar ataxia type 2 a case report"
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"drugadditional": null,... |
{
"abstract": "OBJECTIVE\nDrug-induced liver injuries (DILI) are overall rare and often associated with use of medications. Medications are also the most common aetiology of Stevens-Johnson syndrome (SJS), but SJS is seldom seen concomitantly with liver injury. Many common drugs can cause either one of these conditions; however, there are no reported cases of concomitant DILI and SJS secondary to fluoxetine.\n\n\nMETHODS\nA 41-year-old female presented with a skin rash and abnormal liver function tests after the recent initiation of fluoxetine. Skin and liver biopsies showed features of SJS and DILI, respectively. Fluoxetine was stopped, following which there was improvement in her liver function tests and skin rash, without progression to fulminant hepatic failure.\n\n\nCONCLUSIONS\nCommonly used and safe pharmaceuticals such as fluoxetine have the potential for serious adverse events affecting the skin and liver.",
"affiliations": "Department of Medicine, Cook County Health and Hospital System, Chicago, Illinois.;Division of Gastroenterology and Hepatology, Department of Medicine, Cook County Health and Hospital System, Chicago, Illinois.;Division of Gastroenterology and Hepatology, Department of Medicine, Cook County Health and Hospital System, Chicago, Illinois.;Division of Gastroenterology and Hepatology, Department of Medicine, Cook County Health and Hospital System, Chicago, Illinois.",
"authors": "Agrawal|Rohit|R|http://orcid.org/0000-0001-7831-1296;Almoghrabi|Anas|A|;Attar|Bashar M|BM|;Gandhi|Seema|S|http://orcid.org/0000-0002-2363-2655",
"chemical_list": "D017367:Serotonin Uptake Inhibitors; D005473:Fluoxetine",
"country": "England",
"delete": false,
"doi": "10.1111/jcpt.12760",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-4727",
"issue": "44(1)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "DILI; Stevens-Johnson syndrome; drug-induced liver injury; fluoxetine",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": "D000328:Adult; D001706:Biopsy; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D005473:Fluoxetine; D006801:Humans; D008111:Liver Function Tests; D017367:Serotonin Uptake Inhibitors; D013262:Stevens-Johnson Syndrome",
"nlm_unique_id": "8704308",
"other_id": null,
"pages": "115-118",
"pmc": null,
"pmid": "30296343",
"pubdate": "2019-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Fluoxetine-induced Stevens-Johnson syndrome and liver injury.",
"title_normalized": "fluoxetine induced stevens johnson syndrome and liver injury"
} | [
{
"companynumb": "US-HERITAGE PHARMACEUTICALS-2018HTG00412",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLUOXETINE HYDROCHLORIDE"
},
"... |
{
"abstract": "OBJECTIVE\nThe study sought to identify the magnitude and characteristic of severe cutaneous adverse reactions (SCAR's) like Steven-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN).\n\n\nMETHODS\nA prospective study was conducted by the Department of Pharmacology in association with Department of Dermatology in SMHS hospital. The study was carried out from June 2013-June 2015 on hospitalized cases of cutaneous adverse drug reaction reporting in hospital. The SCAR's were reported in a structured questionnaire based on adverse drug reaction (ADR) reporting form provided by the Central Drug Standard Control Organization (CDSCO) Ministry of Health and Family welfare, Government of India. The SCAR's were analysed for their characteristics, causality, severity and prognosis. Causality assessment was done by using a validated ADR probability scale of Naranjo as well as WHO Uppsala Monitoring Center (WHO-UMC) system for standardized case causality assessment. The management protocol were analysed for their clinical outcome through a proper follow up period.\n\n\nRESULTS\nA total of 52 hospitalized cases of cutaneous adverse drug reactions were reported during the study period. We identified a total of 15 cases (28%) of SCAR's involving 9(17%) of SJS and 6 (12%) of TEN. SJS was seen in 2(22%) males and 7(78%) females. TEN was seen in all females (100%) and in no male. Drugs implicated in causing these life threatening reactions were identified as anticonvulsant agents like carbamazepine (CBZ), phenytoin (PHT) and Lamotrigine (LTG), oxicam NSAID, Sulfasalazine and levofloxacin. Despite higher reported mortality rates in SJS and TEN all patients survived with 2 patients surviving TEN suffered from long term opthalmological sequelae of the disease.\n\n\nCONCLUSIONS\nPresent study suggest that drug induced cutaneous eruptions are common ranging from common nuisance rashes to rare life threatening diseases like SJS and TEN, SJS/TEN typically occur 1-3 weeks after initiation of therapy. Aromatic AED's, LTG, oxicam NSAID's, sulfasalazine and levofloxacin have a tremendous potential to trigger SCARS's. To ensure safe use of pharmaceutical agents and better treatment outcomes post marketing voluntary reporting of severe rare and unusual reactions remains inevitable.",
"affiliations": "Associate Professor and Head, Department of Pharmacology, Government Medical College (GMC) , Srinagar, India .;Lecturer, Department of Pharmacology, Government Medical College (GMC) , Srinagar, India .;Professor and Head, Department of Dermatology, Government Medical College (GMC) , Srinagar, India .",
"authors": "Farhat|Samina|S|;Banday|Muddasir|M|;Hassan|Iffat|I|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.7860/JCDR/2016/16430.7047",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0973-709X",
"issue": "10(1)",
"journal": "Journal of clinical and diagnostic research : JCDR",
"keywords": "Anticonvulsants; Oxicam NSAIDs; Severe cutaneous adverse reactions (SCAR’s)",
"medline_ta": "J Clin Diagn Res",
"mesh_terms": null,
"nlm_unique_id": "101488993",
"other_id": null,
"pages": "FC01-4",
"pmc": null,
"pmid": "26894082",
"pubdate": "2016-01",
"publication_types": "D016428:Journal Article",
"references": "8736144;8688983;9843104;3632001;17502552;7746067;8823232;9774279;1485042;8435514;23588310;16210071;21917426;2036029;8865797;4078051;7477195;9545161;2404462;2134982;9061826;9407193;2383037;16415921;21428769;7249508;10951229;128641;15897036;17631508;2671067;17533485;18583801;18192896;20456393;9184711;18637831;15262712;154918;1524964;10744287;21149285;7794310",
"title": "Antecedent Drug Exposure Aetiology and Management Protocols in Steven-Johnson Syndrome and Toxic Epidermal Necrolysis, A Hospital Based Prospective Study.",
"title_normalized": "antecedent drug exposure aetiology and management protocols in steven johnson syndrome and toxic epidermal necrolysis a hospital based prospective study"
} | [
{
"companynumb": "IN-LUPIN PHARMACEUTICALS INC.-2016-00514",
"fulfillexpeditecriteria": "2",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LAMOTRIGINE"
},
"drugaddition... |
{
"abstract": "Neurological symptoms such as ptosis may develop due to either chemotherapeutic agents or involvement of the central nervous system (CNS) during hematologic malignancy. It is difficult to make this distinction according to clinical symptoms and magnetic resonance imaging findings. If the neurologic symptoms are increased, it is a warning of CNS involvement. Herein are described the clinical and neuroimaging features of three patients with hematologic malignancy who presented with ptosis.",
"affiliations": "Department of Pediatric Neurology, Osmangazi University Medicine Faculty, Eskisehir, Turkey.",
"authors": "Ekici|Arzu|A|;Yakut|Ayten|A|;Bör|Özcan|Ö|;Yimenicioğlu|Sevgi|S|;Çarman|Kürşat Bora|KB|;Saylısoy|Suzan|S|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "Australia",
"delete": false,
"doi": "10.1111/ped.12238",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1328-8067",
"issue": "56(2)",
"journal": "Pediatrics international : official journal of the Japan Pediatric Society",
"keywords": "central nervous system; chemotherapeutic agent; hematologic malignancy; neurotoxicity; ptosis",
"medline_ta": "Pediatr Int",
"mesh_terms": "D000293:Adolescent; D000970:Antineoplastic Agents; D001763:Blepharoptosis; D002675:Child, Preschool; D005260:Female; D019337:Hematologic Neoplasms; D006801:Humans; D007223:Infant; D008297:Male",
"nlm_unique_id": "100886002",
"other_id": null,
"pages": "264-6",
"pmc": null,
"pmid": "24730629",
"pubdate": "2014-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ptosis during hematologic malignancy in children.",
"title_normalized": "ptosis during hematologic malignancy in children"
} | [
{
"companynumb": "PHHY2015TR090434",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
"... |
{
"abstract": "Atypical hemolytic uremic syndrome (aHUS) treatment consists of eculizumab. Severe acute respiratory syndrome coronavirus 2 causes severe pneumonia and endothelial injury that leads to a prothrombotic state that may be complicated by macrovascular and microvascular thrombosis. Complement activation is thought to contribute to endothelial injury and there are at least seven ongoing clinical trials testing six different anti-complement strategies for coronavirus disease 2019 (COVID-19), including eculizumab. We herein report on a kidney transplant patient with aHUS on chronic eculizumab therapy that developed severe COVID-19 despite eculizumab administration early in the course of the disease. Although eculizumab was unable to prevent the development of severe endothelial cell injury, as assessed by increasing D-dimer levels from 292 to 10 586 ng/mL, the patient eventually recovered following dexamethasone and convalescent plasma administration.",
"affiliations": "Nephrology Service, Hospital Británico de Buenos Aires, Buenos Aires, Argentina.;Nephrology Service, Hospital Británico de Buenos Aires, Buenos Aires, Argentina.;Nephrology Service, Hospital Británico de Buenos Aires, Buenos Aires, Argentina.;Nephrology Service, Hospital Británico de Buenos Aires, Buenos Aires, Argentina.;Nephrology Service, Hospital Británico de Buenos Aires, Buenos Aires, Argentina.",
"authors": "Trimarchi|Hernán|H|0000-0002-6921-4811;Gianserra|Raquel|R|;Lampo|Mauro|M|;Monkowski|Matias|M|;Lodolo|Jimena|J|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/ckj/sfaa166",
"fulltext": "\n==== Front\nClin Kidney J\nClin Kidney J\nckj\nClinical Kidney Journal\n2048-8505\n2048-8513\nOxford University Press\n\n10.1093/ckj/sfaa166\nsfaa166\nEditorial Comments\nAcademicSubjects/MED00340\nEculizumab, SARS-CoV-2 and atypical hemolytic uremic syndrome\nhttp://orcid.org/0000-0002-6921-4811\nTrimarchi Hernán\nGianserra Raquel\nLampo Mauro\nMonkowski Matias\nLodolo Jimena\nNephrology Service, Hospital Británico de Buenos Aires, Buenos Aires, Argentina\nCorrespondence to: Hernán Trimarchi; E-mail: htrimarchi@hotmail.com\n10 2020\n27 9 2020\n27 9 2020\n13 5 739741\n11 7 2020\n© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA.\n2020\nThis 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\nAtypical hemolytic uremic syndrome (aHUS) treatment consists of eculizumab. Severe acute respiratory syndrome coronavirus 2 causes severe pneumonia and endothelial injury that leads to a prothrombotic state that may be complicated by macrovascular and microvascular thrombosis. Complement activation is thought to contribute to endothelial injury and there are at least seven ongoing clinical trials testing six different anti-complement strategies for coronavirus disease 2019 (COVID-19), including eculizumab. We herein report on a kidney transplant patient with aHUS on chronic eculizumab therapy that developed severe COVID-19 despite eculizumab administration early in the course of the disease. Although eculizumab was unable to prevent the development of severe endothelial cell injury, as assessed by increasing D-dimer levels from 292 to 10 586 ng/mL, the patient eventually recovered following dexamethasone and convalescent plasma administration.\n\naHUS\ncomplement\neculizumab\nkidney transplant\nSARS-CoV-2\n==== Body\nBACKGROUND\n\nSince December 2019, the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing coronavirus disease 2019 (COVID-19), has affected >12 377 000 people and killed >557 000 in >150 countries as of 10 July 2020 [1].\n\nThe complement pathway may be activated in COVID-19 through mannose-binding lectin (MBL) binding to viral S glycoprotein and activation of mannose-associated serine protease 2 (MASP2) [2]. Thereafter, MBL–MASP2 complexes activate the lectin pathway and a positive feedback loop, leading to sustained alternative complement pathway amplification, inflammation, endothelial injury and concurrent activation of the coagulation cascade and systemic microangiopathy [2, 3]. Once complement is activated, C5a triggers the inflammatory cascade, contributing to the cytokine storm that is thought to be key to severe COVID-19.\n\nAtypical hemolytic uremic syndrome (aHUS) patients are at potential risk to suffer COVID-19 complications. While eculizumab protects against the viral damage on endothelial cells due to alternative complement activation, it impairs a complete response of this pathway to infections. This situation is complicated in kidney transplant patients, in whom the risk of infections increases if baseline immunosuppression is maintained or the risk of acute allograft rejection increases when immunosuppressants are discontinued or decreased to unlock the immunologic system.\n\nCASE REPORT\n\nA 24-year-old male with a 6-year history of kidney transplant with aHUS (no complement molecule–associated mutation was identified) on eculizumab 900 mg every fortnight, meprednisone 4 mg/day, sodium mycophenolate 720 mg/day and belatacept 500 mg/monthly was admitted due to anosmia and fever (Table 1). A chest cmputed tomography (CT) scan disclosed patchy bilateral pneumonia (Figure 1A). A nasopharyngeal swab polymerase chain reaction revealed SARS-CoV-2. Antibiotic therapy with ceftriaxone–clarithromycin was started, plus intravenous (IV) hydrocortisone 100 twice a day. Mycophenolate was discontinued and the scheduled eculizumab infusion was administered. Microthrombotic biomarkers were absent. One week later he developed respiratory failure, fever and radiological progression of the CT scan infiltrates (Figure 1B), associated with elevated inflammatory biomarkers. In the intensive care unit (ICU), the antibiotic regime was switched to vancomycin and cefepime and hydrocortisone was changed to IV dexamethasone 6 mg/day. A 200-mL convalescent plasma infusion was prescribed. He received oxygen via mask reservoir (5 L/min) and vigil pronation cycles and showed a sustained improvement without the need for mechanical ventilation (Figure 1C). Two weeks after admission, the scheduled eculizumab and belatacept infusions were administered and the patient was discharged.\n\nFIGURE 1: Chest CT scan images. (A) Bilateral and diffuse lower lung with predominant ground-glass opacities and consolidations at admission. (B) Progression of ground-glass opacities and consolidations 1 week after admission. (C) Resolution of bilateral opacities 2 weeks after admission.\n\nTable 1. Laboratory results, clinical course and interventions\n\nVariables\tDay 0\tDay 3\tDay 7\tDay 9\tDay 16\t\nClinical evolution\tAdmission to hospital\t\tAdmission to ICU\t\tRadiological improvement\t\nPharmacologic therapy\tClarithromycin + ceftriaxone\tEcululizumab 900 mg\tVancomycin + cefepime\tDexamethasone, convalescent plasma infusion\tEnd of antibiotics\t\nD-dimer (ng/mL)\t\t292\t\t10586\t454\t\nFibrinogen (mg/dL)\t\t411\t\t494\t227\t\nFerritin (µg/L)\t\t2390\t2223\t\t2287\t\nProcalcitonin (ng/mL)\t\t\t0.26\t15.55\t\t\nHematocrit (%)\t35\t30\t31\t34\t36\t\nPlatelets/µL\t141 000\t132 000\t121 000\t130 000\t208 000\t\nLeukocytes/mm³\t4500\t10 000\t7200\t14 200\t14 100\t\nLymphocytes/mm³\t648\t470\t–\t213\t2044\t\nLDH (U/L)\t\t226\t323\t513\t\t\nHaptoglobin (mg/dL)\t\t197\t\t\t\t\nC3 (mg/dL)\t\t100\t98\t96\t99\t\nC4 (mg/dL)\t\t29\t23\t22\t14\t\nCreatinine (mg/dL)\t3.54\t3.06\t2.79\t2.8\t2.67\t\nPeripheral oxygen saturation (O2IF), n (%)\t98 (0.21)\t98 (0.21)\t97 (0.21)\t98 (0.36)\t96 (0.21)\t\nLDH: lactate dehydrogenase; O2IF: oxygen inspiration fraction.\n\nDISCUSSION\n\nTo our knowledge, this is the first report of a kidney transplant recipient with aHUS on eculizumab therapy who developed SARS-CoV-2 infection. In this novel pandemic, no robust evidence-based approaches are available, thus empirical decisions were made, aimed at maintaining a fine line between patient and graft survival and control of the alternative complement pathway and a potentially fatal infection.\n\nMany factors take place in this particular scene: the immunosuppressed state of a transplant patient, aHUS that predisposes to alternative complement activation and thrombotic microangiopathy and the SARS-CoV-2 capacity to activate the complement system, a procoagulant state with microthrombi generation and systemic inflammation. Graft loss was a concern at admission, but patient death was seriously considered 1 week after admission.\n\nTo avoid aHUS relapse, eculizumab was continued based on a normal biomarkers profile and considerably elevated D-dimer and fibrinogen concentrations, suggesting a procoagulant state and probable microthrombosis, as described in autopsies of subjects with COVID-19 infections [4].\n\nMycophenolate was withheld to improve T-cell response. As in preliminary data, dexamethasone appears to be beneficial in COVID-19 and it replaced hydrocortisone [5]. Finally, 1 U of convalescent plasma was given to passively contribute to the specific immunological response and also as a potential antithrombotic and immunomodulatory tool [6]. The maintenance of a partial immunosuppressant regime may have contributed to limit a systemic cytokine storm. As of 12 July 2020, there were seven ongoing clinical trials exploring six different anti-complement drugs for COVID-19 (Table 2). This is a complex case involving aHUS-associated predisposition to microvascular injury and immune suppression to preserve a kidney graft. However, eculizumab administration, both chronic and early (within 3 days of diagnosis and admission) in the course of COVID-19, was unable to prevent the development of severe pneumonia and severe endothelial cell injury as assessed by a 36-fold increase in D-dimer. Despite the limitations of this complex case, it does not appear to support the efficacy of complement targeting in COVID-19.\n\nTable 2. Ongoing clinical trials targeting complement in COVID-19, according to ClinicalTrials.gov\n\nDrug\tDrug target\tPhase\tNCT number\t\nConestat alfa\tRecombinant C1 esterase inhibitor\t2\tNCT04414631\t\nAMY-101\tC3 inhibitor\t2\tNCT04395456\t\nAPL-9\tC3 inhibitor\t1/2\tNCT04402060\t\nZilucoplan\tC5 inhibitor\t2\tNCT04382755\t\nEculizumab\tAnti-C5 mAb\t2\tNCT04346797\t\nRavulizumab\tAnti-C5 mAb\t4\tNCT04390464\t\nRavulizumab\tAnti-C5 mAb\t3\tNCT04369469\t\nmAb: monoclonal antibody.\n\nPATIENT CONSENT\n\nThe patient gave informed consent to publish this case.\n\nACKNOWLEDGEMENTS\n\nWe thank María Laura Ares for her professional assistance.\n\nCONFLICT OF INTEREST STATEMENT\n\nH.T. was a consultant for Alexion for the drug eculizumab.\n==== Refs\nREFERENCES\n\n1 Zhou P , Yang XL , Wang XG et al A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020; 579 : 270–273 32015507\n2 Magro C , Mulvey JJ , Berlin D et al Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases. Transl Res 2020; 220 : 1–13 32299776\n3 Gao T , Hu M , Zhang X et al Highly pathogenic coronavirus N protein aggravates lung injury by MASP-2-mediated complement over-activation. medRxiv 2020; doi: 10.1101/2020.03.29.20041962\n4 Zhou F , Yu T , Du R et al Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020; 395 : 1054–1062 32171076\n5 Horby P , Lim W , Emberson J et al Effect of dexamethasone in hospitalized patients with COVID-19: Preliminary Report Recovery Collaborative Group. medRxiv 2020; doi: 10.1101/2020.06.22.20137273\n6 Campbell CM , Kahwash R. Will complement inhibition be the new target in treating COVID-19 related systemic thrombosis? Circulation 2020; 141 : 1739–1738 32271624\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2048-8505",
"issue": "13(5)",
"journal": "Clinical kidney journal",
"keywords": "SARS-CoV-2; aHUS; complement; eculizumab; kidney transplant",
"medline_ta": "Clin Kidney J",
"mesh_terms": null,
"nlm_unique_id": "101579321",
"other_id": null,
"pages": "739-741",
"pmc": null,
"pmid": "33117528",
"pubdate": "2020-10",
"publication_types": "D016421:Editorial",
"references": "32015507;32171076;32299776;32271624;32678530",
"title": "Eculizumab, SARS-CoV-2 and atypical hemolytic uremic syndrome.",
"title_normalized": "eculizumab sars cov 2 and atypical hemolytic uremic syndrome"
} | [
{
"companynumb": "AR-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-301855",
"fulfillexpeditecriteria": "1",
"occurcountry": "AR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CLARITHROMYCIN"
},
"... |
{
"abstract": "Surveillance biopsies (SBs) are performed in some pediatric kidney transplant programs, based on data obtained in earlier immunosuppressive eras that the treatment of subclinical acute rejection results in better graft survival. The benefit of SBs for patients on modern immunosuppression regimens is unclear. We have therefore evaluated the clinical utility of SBs in a population of children receiving a kidney transplant.\n\n\n\nWe have performed SBs at 3, 6 and 12 months post-transplantation as standard of care at our institution since 2013 in patients on a regimen of rabbit anti-thymocyte globulin, tacrolimus, mycophenolate and rapid steroid taper (RST; steroids maintained in some exceptions). We reviewed pathology reports of 82 SBs from 34 transplants in 34 children for all abnormal findings and adequacy of specimens. Clinical records were reviewed for changes in management resulting from SB findings and for significant procedure complications.\n\n\n\nOf the 82 biopsies, 41 (50%) had abnormal findings separate from fibrosis, including five Banff Grade I rejections, ten borderline rejections, six calcineurin-inhibitor nephrotoxicity, four BK-virus nephropathy, five recurrent disease and three acute pyelonephritis. Moderate or more fibrosis was present in nine of the 82 (11%) biopsies. Management changes due to SB findings occurred in nine cases (11.0%). The proportion of abnormal findings or management changes did not differ between the RST or steroid-based groups. Patients performing clean intermittent catheterization showed inflammatory changes often read as rejection, but were managed differently. Three biopsies were deemed inadequate. No significant complications occurred.\n\n\n\nA high percentage of the SBs performed under modern immunosuppression showed abnormal findings even when fibrosis was excluded. However, management changes due to the SB findings were less frequent, although they occurred in a clinically meaningful percentage of cases. Complications or inadequate specimens were rare.",
"affiliations": "Division of Pediatric Nephrology, Department of Pediatrics, Washington University School of Medicine in St Louis-St Louis Children's Hospital, Room NWT 10-119, CB 8116, 660 South Euclid Avenue, St Louis, MO, 63110, USA. vikasd@wustl.edu.;Division of Pediatric Nephrology, Department of Pediatrics, Washington University School of Medicine in St Louis-St Louis Children's Hospital, Room NWT 10-119, CB 8116, 660 South Euclid Avenue, St Louis, MO, 63110, USA.;Department of Pathology and Immunology, Washington University School of Medicine in St Louis-St Louis Children's Hospital, St Louis, MO, USA.;Division of Pediatric Nephrology, Department of Pediatrics, Washington University School of Medicine in St Louis-St Louis Children's Hospital, Room NWT 10-119, CB 8116, 660 South Euclid Avenue, St Louis, MO, 63110, USA.;Division of Pediatric Nephrology, Department of Pediatrics, Washington University School of Medicine in St Louis-St Louis Children's Hospital, Room NWT 10-119, CB 8116, 660 South Euclid Avenue, St Louis, MO, 63110, USA.",
"authors": "Dharnidharka|Vikas R|VR|;Vyas|Neil|N|;Gaut|Joseph P|JP|;Walther|Leslie|L|;Hmiel|S Paul|SP|",
"chemical_list": "D000961:Antilymphocyte Serum; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; C512542:thymoglobulin; D009173:Mycophenolic Acid; D016559:Tacrolimus",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00467-017-3864-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0931-041X",
"issue": "33(5)",
"journal": "Pediatric nephrology (Berlin, Germany)",
"keywords": "Acute rejection; BK virus; Kidney; Pediatrics; Surveillance biopsies; Transplant",
"medline_ta": "Pediatr Nephrol",
"mesh_terms": "D000293:Adolescent; D000961:Antilymphocyte Serum; D002648:Child; D002675:Child, Preschool; D005260:Female; D005938:Glucocorticoids; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents; D007668:Kidney; D007674:Kidney Diseases; D016030:Kidney Transplantation; D008297:Male; D009173:Mycophenolic Acid; D012189:Retrospective Studies; D016559:Tacrolimus; D055815:Young Adult",
"nlm_unique_id": "8708728",
"other_id": null,
"pages": "889-895",
"pmc": null,
"pmid": "29260318",
"pubdate": "2018-05",
"publication_types": "D016428:Journal Article",
"references": "9808101;21792611;17699200;20846241;28251702;17300500;17908280;17250556;21161285;12660340;21733554;23414365;27862883;19515080;22694733;10071025;16269047",
"title": "The utility of surveillance biopsies in pediatric kidney transplantation.",
"title_normalized": "the utility of surveillance biopsies in pediatric kidney transplantation"
} | [
{
"companynumb": "PHHY2017US193080",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
"druga... |
{
"abstract": "OBJECTIVE\nDriven by the need of pharmacovigilance centres and companies to routinely collect and review all available data about adverse drug reactions (ADRs) and adverse events of interest, we introduce and validate a computational framework exploiting dominant as well as emerging publicly available data sources for drug safety surveillance.\n\n\nMETHODS\nOur approach relies on appropriate query formulation for data acquisition and subsequent filtering, transformation and joint visualization of the obtained data. We acquired data from the FDA Adverse Event Reporting System (FAERS), PubMed and Twitter. In order to assess the validity and the robustness of the approach, we elaborated on two important case studies, namely, clozapine-induced cardiomyopathy/myocarditis versus haloperidol-induced cardiomyopathy/myocarditis, and apixaban-induced cerebral hemorrhage.\n\n\nRESULTS\nThe analysis of the obtained data provided interesting insights (identification of potential patient and health-care professional experiences regarding ADRs in Twitter, information/arguments against an ADR existence across all sources), while illustrating the benefits (complementing data from multiple sources to strengthen/confirm evidence) and the underlying challenges (selecting search terms, data presentation) of exploiting heterogeneous information sources, thereby advocating the need for the proposed framework.\n\n\nCONCLUSIONS\nThis work contributes in establishing a continuous learning system for drug safety surveillance by exploiting heterogeneous publicly available data sources via appropriate support tools.",
"affiliations": "a Institute of Applied Biosciences , Centre for Research & Technology Hellas , Thermi , Thessaloniki , Greece.;e Centre Reìgional de Pharmacovigilance, Hôpital Européen Georges-Pompidou, AP-HP , F-75015 , Paris , France.;b INSERM, U1142, LIMICS , F-75006 , Paris , France.",
"authors": "Koutkias|Vassilis G|VG|;Lillo-Le Louët|Agnès|A|;Jaulent|Marie-Christine|MC|",
"chemical_list": "D014150:Antipsychotic Agents; D065427:Factor Xa Inhibitors; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban; D003024:Clozapine; D006220:Haloperidol",
"country": "England",
"delete": false,
"doi": "10.1080/14740338.2017.1257604",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1474-0338",
"issue": "16(2)",
"journal": "Expert opinion on drug safety",
"keywords": "Adverse drug events; bibliographic databases; case studies; computational framework; emerging data sources for pharmacovigilance; heterogeneous public data; joint exploitation; social media; spontaneous reporting systems",
"medline_ta": "Expert Opin Drug Saf",
"mesh_terms": "D016907:Adverse Drug Reaction Reporting Systems; D014150:Antipsychotic Agents; D066126:Cardiotoxicity; D002543:Cerebral Hemorrhage; D003024:Clozapine; D064420:Drug-Related Side Effects and Adverse Reactions; D065427:Factor Xa Inhibitors; D006220:Haloperidol; D006801:Humans; D016247:Information Storage and Retrieval; D060735:Pharmacovigilance; D011720:Pyrazoles; D011728:Pyridones",
"nlm_unique_id": "101163027",
"other_id": null,
"pages": "113-124",
"pmc": null,
"pmid": "27813420",
"pubdate": "2017-02",
"publication_types": "D016428:Journal Article; D023361:Validation Study",
"references": null,
"title": "Exploiting heterogeneous publicly available data sources for drug safety surveillance: computational framework and case studies.",
"title_normalized": "exploiting heterogeneous publicly available data sources for drug safety surveillance computational framework and case studies"
} | [
{
"companynumb": "GR-JNJFOC-20170202311",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CLOZAPINE"
},
"drugadditional": null,
"... |
{
"abstract": "Facial emotion processing impairments have been consistently demonstrated among patients with pediatric bipolar disorder (PBD). However, less is known about other domains of nonverbal emotion recognition in this group. Therefore, the aim of the current study was to investigate emotion identification for body postures in addition to facial expressions among PBD patients and matched healthy comparison (HC) subjects.\n\n\n\nYouth with PBD (n = 25) and HC subjects (n = 25), equal on intellectual and demographic variables, completed the body postures and faces subtests of the Diagnostic Analysis of Nonverbal Accuracy-2 scale (DANVA-2) along with diagnostic and clinical assessments.\n\n\n\nCompared to HC, PBD patients made significantly more errors identifying emotion in both body postures and faces. Poorer performance on the faces subtest was associated with more problematic peer functioning. Greater manic symptoms were associated with poorer performance on negative emotional stimuli but not positive.\n\n\n\nIn addition to impairments in facial emotion processing, youth with PBD also show impairments in the ability to correctly identify emotion from body postures. In this group, greater manic symptomatology appears to impair processing for negative facial expressions and body postures, but not positive ones. Interestingly, facial emotion processing impairments appear to be a better indicator of real-world psychosocial difficulties among PBD patients compared to body postures. Psychosocial treatments for youth with PBD should focus on improving the ability to accurately identify and respond to various facial and body postural cues, as well as symptom management and emotion regulation strategies.",
"affiliations": "Department of Psychology, Rochester Institute of Technology , Rochester, NY, USA.;Department of Psychology, Rochester Institute of Technology , Rochester, NY, USA.",
"authors": "Schenkel|Lindsay S|LS|;Towne|Terra L|TL|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/13803395.2020.1799946",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1380-3395",
"issue": "42(7)",
"journal": "Journal of clinical and experimental neuropsychology",
"keywords": "Pediatric bipolar disorder; body postures; emotion processing; face processing; psychosocial functioning",
"medline_ta": "J Clin Exp Neuropsychol",
"mesh_terms": "D000293:Adolescent; D001714:Bipolar Disorder; D002648:Child; D004644:Emotions; D005149:Facial Expression; D000066499:Facial Recognition; D005260:Female; D006801:Humans; D008297:Male; D011187:Posture; D012938:Social Perception",
"nlm_unique_id": "8502170",
"other_id": null,
"pages": "735-746",
"pmc": null,
"pmid": "32787535",
"pubdate": "2020-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Errors in identifying emotion in body postures and facial expressions among pediatric patients with bipolar disorder.",
"title_normalized": "errors in identifying emotion in body postures and facial expressions among pediatric patients with bipolar disorder"
} | [
{
"companynumb": "US-OTSUKA-2021_005956",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "A former 24-week-old premature infant was treated with intravitreal ranibizumab (Lucentis; Genentech, South San Francisco, CA) in one eye and conventional laser in the other eye for aggressive posterior retinopathy of prematurity in both eyes. Fluorescein angiography performed at 149 weeks of age showed persistent avascularity of the temporal peripheral retina in the ranibizumab-treated eye. This case report confirms the need for long-term follow-up of patients treated with ranibizumab monotherapy. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:75-78.].",
"affiliations": null,
"authors": "Day|Shelley|S|;Rainey|Annis M|AM|;Harper|Clio A|CA|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D000069579:Ranibizumab",
"country": "United States",
"delete": false,
"doi": "10.3928/23258160-20161219-11",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2325-8160",
"issue": "48(1)",
"journal": "Ophthalmic surgery, lasers & imaging retina",
"keywords": null,
"medline_ta": "Ophthalmic Surg Lasers Imaging Retina",
"mesh_terms": "D020533:Angiogenesis Inhibitors; D005260:Female; D005451:Fluorescein Angiography; D005500:Follow-Up Studies; D005654:Fundus Oculi; D006801:Humans; D007223:Infant; D007234:Infant, Premature; D058449:Intravitreal Injections; D000069579:Ranibizumab; D012160:Retina; D012171:Retinal Vessels; D012178:Retinopathy of Prematurity; D013997:Time Factors",
"nlm_unique_id": "101599215",
"other_id": null,
"pages": "75-78",
"pmc": null,
"pmid": "28060398",
"pubdate": "2017-01-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Incomplete Retinal Vascularization After Ranibizumab Treatment of Retinopathy of Prematurity.",
"title_normalized": "incomplete retinal vascularization after ranibizumab treatment of retinopathy of prematurity"
} | [
{
"companynumb": "US-ROCHE-1903039",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RANIBIZUMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "The large availability of salicylic acid products makes them an often encountered source of poisoning in the emergency department. Even though in most cases the prognosis is good, with a low incidence of long-term morbidity and mortality, complications do occur, and some of those can be life threatening. We present an unusual case of salicylate intoxication in an adolescent in which several uncommon complications (severe coagulopathy, pulmonary edema, and pancreatitis) conjoined together. We review the literature and discuss the complications pathogenesis and differential diagnosis. We suggest that these potentially life-threatening complications be acknowledged, investigated, and rapidly treated.",
"affiliations": "1Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH; and 2Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH.",
"authors": "Ayalon|Itay|I|;Alder|Matthew Noble|MN|;Langner|Travis Ryan|TR|;Hafberg|Einar Thor|ET|;Miethke|Alexander Gerhard|AG|;Kaplan|Jennifer Melissa|JM|",
"chemical_list": "D000933:Antifibrinolytic Agents; D014812:Vitamin K; D020156:Salicylic Acid",
"country": "United States",
"delete": false,
"doi": "10.1097/MJT.0000000000000385",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-2765",
"issue": "23(6)",
"journal": "American journal of therapeutics",
"keywords": null,
"medline_ta": "Am J Ther",
"mesh_terms": "D000138:Acidosis; D000293:Adolescent; D000472:Alkalosis, Respiratory; D000933:Antifibrinolytic Agents; D053099:Azotemia; D001778:Blood Coagulation Disorders; D005260:Female; D005440:Fluid Therapy; D006801:Humans; D006996:Hypocalcemia; D007010:Hyponatremia; D000860:Hypoxia; D010102:Oxygen Inhalation Therapy; D010195:Pancreatitis; D010949:Plasma; D011654:Pulmonary Edema; D020156:Salicylic Acid; D014812:Vitamin K",
"nlm_unique_id": "9441347",
"other_id": null,
"pages": "e1929-e1932",
"pmc": null,
"pmid": "26938763",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "A Case of Salicylate Intoxication Complicated by Coagulopathy, Pulmonary Edema, and Pancreatitis.",
"title_normalized": "a case of salicylate intoxication complicated by coagulopathy pulmonary edema and pancreatitis"
} | [
{
"companynumb": "US-BAYER-2016-050524",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "The benefits of treating anti-neutrophil cytoplasmic autoantibody-associated vasculitis (AAV) in advancing age remains unclear with most published studies defining elderly as ≥65 years. This study aims to determine outcomes of induction immunosuppression in patients aged ≥75 years.\n\n\n\nA cohort of patients aged ≥75 years with a diagnosis of AAV between 2006 and 2018 was constructed from 2 centres. Follow-up was to 2 years or death. Analysis included multivariable Cox regression to compare mortality and end-stage renal disease (ESRD) based on receipt of induction immunosuppression therapy with either cyclophosphamide or rituximab. A systematic review of outcome studies was subsequently undertaken amongst this patient group through Pubmed, Cochrane and Embase databases from inception until October 16, 2019.\n\n\n\nSixty-seven patients were identified. Mean age was 79 ± 2.9 years and 82% (n = 55) received induction immunosuppression. Following systematic review, 4 studies were eligible for inclusion, yielding a combined total of 290 patients inclusive of our cohort. The aggregated 1-year mortality irrespective of treatment was 31% (95% CI 25-36%). Within our cohort, induction immunosuppression therapy was associated with a significantly lower 2-year mortality risk (hazard ratio [HR] 0.29 [95% CI 0.09-0.93]). The pooled HR by meta-analysis confirmed this with a significant risk reduction for death (HR 0.31 [95% CI 0.16-0.57], I2 = 0%). Treated patients had a lower pooled rate of ESRD, but was not statistically significant (HR 0.71 [95% CI 0.15-3.35]).\n\n\n\nThis meta-analysis suggests that patients ≥75 years with AAV do benefit from induction immunosuppression with a significant survival benefit. Age alone should not be a limiting factor when considering treatment.",
"affiliations": "Renal Medicine, Royal Preston Hospital, Preston, United Kingdom, a.morris@doctors.org.uk.;Renal Medicine, Royal Preston Hospital, Preston, United Kingdom.;Renal Medicine, Royal Preston Hospital, Preston, United Kingdom.;Department of Immunology, Royal Preston Hospital, Preston, United Kingdom.;School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston, United Kingdom.;Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.;Renal Medicine, Royal Preston Hospital, Preston, United Kingdom.",
"authors": "Morris|Adam D|AD|;Elsayed|Mohamed E|ME|;Ponnusamy|Arvind|A|;Rowbottom|Anthony|A|;Martin|Francis|F|;Geetha|Duvuru|D|;Dhaygude|Ajay P|AP|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000506532",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-8095",
"issue": "51(4)",
"journal": "American journal of nephrology",
"keywords": "Anti-neutrophil cytoplasmic autoantibody; Elderly; Immunosuppression; Outcomes; Vasculitis",
"medline_ta": "Am J Nephrol",
"mesh_terms": "D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; D000066491:Clinical Decision-Making; D006801:Humans; D007166:Immunosuppressive Agents; D007676:Kidney Failure, Chronic; D012074:Remission Induction; D018570:Risk Assessment; D016896:Treatment Outcome",
"nlm_unique_id": "8109361",
"other_id": null,
"pages": "327-336",
"pmc": null,
"pmid": "32160625",
"pubdate": "2020",
"publication_types": "D016428:Journal Article; D017418:Meta-Analysis; D000078182:Systematic Review",
"references": null,
"title": "Treatment Outcomes of Anti-Neutrophil Cytoplasmic Autoantibody-Associated Vasculitis in Patients Over Age 75 Years: A Meta-Analysis.",
"title_normalized": "treatment outcomes of anti neutrophil cytoplasmic autoantibody associated vasculitis in patients over age 75 years a meta analysis"
} | [
{
"companynumb": "GB-ROCHE-2605276",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "BACKGROUND\nIn modern surgical era, local haemostatic agents and blood components such as recombinant activated factor VII (rFVIIa) have expanded surgeons' armamentarium in controlling \"surgical\" and \"nonsurgical bleeding\". We report a case of intraoperative thrombosis and cardiac arrest involving use of local haemostatic agent in intraoperative cell salvage and rFVIIa administration in extended right hepatectomy.\n\n\nMETHODS\nA 46-year-old lady underwent extended right hepatectomy using cardiopulmonary bypass (CPB) and autotransfusion with ICS for metastatic gastrointestinal stromal tumour. She became extremely coagulopathic following weaning of CPB despite an array of fluid and blood products replacements. Decision to administer rFVIIa as a measure to arrest bleeding was unsuccessful. Extensive systemic thrombosis occurred which resulted in cardiac arrest and mortality.\n\n\nCONCLUSIONS\nThe thromboembolic event was unclear but likely multifactorial. Two important hypotheses were the administration of rFVIIa and use of local haemostatic agent in ICS.\n\n\nCONCLUSIONS\nReported incidence of thromboembolism with use of rFVIIa in refractory bleeding is variable. More randomised controlled trials are needed to ascertain the efficacy and safety profile of the haemostatic agent. At present, off-label use of rFVIIa should be guided by the risk:benefit profile on a case-to-case basis. The authors also feel strongly against the use of local haemostatic gel in conjunction with ICS due to potential systemic circulation of the thrombin.",
"affiliations": "Department of Surgery, St George Hospital, University of New South Wales, Sydney, New South Wales, Australia. Electronic address: lees.kyang@gmail.com.;Department of Anaesthesia, St George Hospital, Sydney, New South Wales, Australia.;Department of Surgery, St George Hospital, University of New South Wales, Sydney, New South Wales, Australia; College of Medicine, Al-Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia.;Department of Surgery, St George Hospital, University of New South Wales, Sydney, New South Wales, Australia.",
"authors": "Kyang|Lee S|LS|;Howard|Andrew|A|;Alzahrani|Nayef A|NA|;Morris|David L|DL|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ijscr.2019.02.042",
"fulltext": "\n==== Front\nInt J Surg Case RepInt J Surg Case RepInternational Journal of Surgery Case Reports2210-2612Elsevier S2210-2612(19)30106-310.1016/j.ijscr.2019.02.042ArticleCase report: Intraoperative thrombosis cardiac arrest in extended right hepatectomy involving use of local haemostatic agent in intraoperative cell salvage (ICS) and administration of recombinant activated factor VII (rFVIIa) Kyang Lee S. lees.kyang@gmail.coma⁎Howard Andrew bAlzahrani Nayef A. acMorris David L. aa Department of Surgery, St George Hospital, University of New South Wales, Sydney, New South Wales, Australiab Department of Anaesthesia, St George Hospital, Sydney, New South Wales, Australiac College of Medicine, Al-Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia⁎ Corresponding author at: 4a Tulipwood Crescent, Oxley Vale, New South Wales, 2340, Australia. lees.kyang@gmail.com06 3 2019 2019 06 3 2019 57 48 51 20 12 2018 14 2 2019 25 2 2019 Crown Copyright © 2019 Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd.2019This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Highlights\n• Intractable intraoperative haemorrhage is a result of both surgical and coagulopathic (nonsurgical) components.\n\n• There is increasing off-label use of rFVIIa for ceasing refractory bleeding aside from its application in patient with haemophilia.\n\n• rFVIIa use may be associated with increased thromboembolic events according to some literature.\n\n• The use of topical haemostatic agent in conjunction with ICS may potentially lead to systemic clot formation upon re-infusion of the chemical.\n\n• Avoid use of cell saver suction while the surgical field is contaminated with topical clotting factors before irrigation with 0.9% sodium chloride.\n\n\n\nIntroduction\nIn modern surgical era, local haemostatic agents and blood components such as recombinant activated factor VII (rFVIIa) have expanded surgeons’ armamentarium in controlling “surgical” and “nonsurgical bleeding”. We report a case of intraoperative thrombosis and cardiac arrest involving use of local haemostatic agent in intraoperative cell salvage and rFVIIa administration in extended right hepatectomy.\n\nPresentation of case\nA 46-year-old lady underwent extended right hepatectomy using cardiopulmonary bypass (CPB) and autotransfusion with ICS for metastatic gastrointestinal stromal tumour. She became extremely coagulopathic following weaning of CPB despite an array of fluid and blood products replacements. Decision to administer rFVIIa as a measure to arrest bleeding was unsuccessful. Extensive systemic thrombosis occurred which resulted in cardiac arrest and mortality.\n\nDiscussion\nThe thromboembolic event was unclear but likely multifactorial. Two important hypotheses were the administration of rFVIIa and use of local haemostatic agent in ICS.\n\nConclusion\nReported incidence of thromboembolism with use of rFVIIa in refractory bleeding is variable. More randomised controlled trials are needed to ascertain the efficacy and safety profile of the haemostatic agent. At present, off-label use of rFVIIa should be guided by the risk:benefit profile on a case-to-case basis. The authors also feel strongly against the use of local haemostatic gel in conjunction with ICS due to potential systemic circulation of the thrombin.\n\nKeywords\nMortalityRecombinant activated factor VIIIntraoperative cell salvageThrombosisLiver resectionrFVIIa\n==== Body\n1 Background\nIn modern surgical era, local haemostatic agents and blood components such as recombinant activated factor VII (rFVIIa) have expanded surgeons’ armamentarium in controlling “surgical” and “nonsurgical bleeding”. This paper reported a case of intraoperative thrombosis and cardiac arrest involving use of local haemostatic agent in intraoperative cell salvage and rFVIIa administration in extended right hepatectomy. This report was written in accordance with SCARE guideline [1].\n\n2 Case report\nA 46 years old woman was referred to our facility for surgical therapy of an enlarging metastatic gastrointestinal stromal tumour involving the liver. This is on the background of partial gastrectomy for a “benign” tumour in Germany in 1994, which was believed to be the primary. Staging computed tomography scan revealed a grossly enlarged right hepatic lobe secondary to multiple metastases. Two lesions measured 23 cm × 18 cm (oblique axial dimension) and 23 cm × 25 cm × 24 cm (anteroposterior dimension), respectively. The huge tumour led to compression of IVC, right portal and hepatic veins (Fig. 1). The patient’s laboratory studies were within normal except for anaemia (Hb 100). She received neoadjuvant therapy of imatinib, to which the tumour responded with significant size shrinkage.Fig. 1 Pre-operative computed tomography scan of liver showing two huge hypodense masses as labeled 1 and 2.\n\nFig. 1\n\nShe proceeded to undergo an extended right liver resection using cardiopulmonary bypass (CPB) and autotransfusion with intraoperative cell salvage (ICS). Induction of anaesthesia was uncomplicated, followed by placement of lines and a transoesophageal echocardiogram (TOE) probe. On rotational thromboelastometry (ROTEM), maximal clot firmness on FIBTEM was indicative of low fibrinogen (A5 value at 4 mm; A10 value at 4 mm; A20 value at 5 mm). Intraoperatively, a massive tumour of right liver lobe (17 kg) was discovered (Fig. 2). The TOE during early dissection phase was consistent with severe IVC compression and pressure overload on RA/RV suggesting that CPB – instead of veno-venous extracorporeal membrane oxygenation – was necessary to complete the surgery. She was heparinised (20,000 U) to reach activated coagulation time (ACT) of 602 before establishment of CPB. During tumour resection, large volume of fluid and blood products [6 U of packed red blood cells (PRBC), 6 U of fresh frozen plasma (FFP)] was infused to replace intra-abdominal losses. Bleeding from liver edges was controlled adequately with local haemostatic agent (Floseal, Baxter, US). High dose vasopressor support was instituted soon after commencing CPB and early resection – initially with noradrenaline (8 mg/100 ml at 10–50 ml/h) and then vasopressin (2.4 units/h). Eventually, the liver tumour was successfully resected and delivered.Fig. 2 Image showing a grossly enlarged right lobe of liver secondary to metastatic GIST.\n\nFig. 2\n\nThe rates of noradrenaline and vasopressin were running at 50–75 ml/h (16 mg/100 ml) and 6 units/h towards the end of CPB, respectively. Steroids were given and, at this time, there was adequate flow on CPB with no evidence of clot. The patient was then weaned from CBP with good cardiac function. CPB time was 2 h 15 min. A total of 300 mg protamine sulphate was administered for heparin reversal prior to decannulation. Even though her coagulation profile including ACT and ROTEM was acceptable, the haemorrhage was refractory to protamine and blood components. She continued to demand a relatively high dose of vasopressors, although the demand was decreasing over time. Total blood products consumed at that stage were 18 U PRBC, 17 U FFP, 17 U of cryoprecipitate apheresis (equivalent to 34 U of cryoprecipitate derived from whole blood), 3 U pooled platelets and 2500 U prothrombinex. A joint decision among the surgeon, anaesthetist and haematologist was made to administer rFVIIa (90 μ/kg) of rFVIIa (NovoSeven, Novo Nordisk, Denmark) approximately 1-h post-CPB in an attempt to arrest the bleeding. The pH was 6.808 and temperature was 35.3 °C at time of administration.\n\nTen minutes following administration of rFVIIa, the patient became haemodynamically unstable secondary to right ventricular failure and went into cardiac arrest. Intraoperative TOE demonstrated extensive thrombi within the right atrium, right ventricle and bilateral pulmonary arteries (Fig. 3). Heparin was readministered to achieve an ACT of >999 s, CPB was emergently resumed and internal cardiac massage was performed. Right atriotomy and pulmonary atriotomy were attempted successfully to evacuate the aforementioned thrombi. Despite the clearance of right atrium, repeat TOE showed formation of thrombus in left ventricle and aortic arch. There was also noticeable intra-coronary venous thrombosis. The prothrombotic state resulted in eventual propagation of clot into venous drainage line of CPB machine and no flow could be established due to the blocked venous cannulae (SVC and IVC).The treatment was ultimately withdrawn and the patient died soon on the table. Following this event, Therapeutic Goods Aministration (TGA) was notified of the suspected adverse drug reaction.Fig. 3 Intraoperative TOE showing extensive thrombi in a markedly dilated right atrium (RA) and right ventricle (RV).\n\nFig. 3\n\n3 Discussion\nIntractable intraoperative haemorrhage is a result of both surgical and coagulopathic (nonsurgical) components. Advancement in technology has improved control of bleeding during surgery. Surgical bleeding can be reversed with meticulous diathermy haemostasis. In contrast, nonsurgical bleeding can be corrected with appropriate use of intravenous fluid, blood products and haemostatic agents. However, management of coagulopathic haemorrhage is challenging. Dilutional coagulopathy secondary to excessive fluid and blood products replacement has limited the versatility of replacement therapy in the setting of exsanguination [2]. Its interaction with hypothermia and metabolic acidosis may lead to a downward spiral of clotting capability and eventually death [3].\n\nThe need for additional haemostatic agents is apparent with growing interest in the use of rFVIIa. It was initially authorised for administration in patients with haemophilia and alloantibodies to factor VIII and IX. After its success in facilitating haemostasis in a trauma patient less than two decades ago [4], rFVIIa has been increasingly used as an “off-label” rescue treatment in surgery. It aims to rapidly cease refractory bleeding after all conventional approaches have been exhausted [5]. rFVIIa acts pharmacologically via tissue factor-dependent and independent pathway leading to thrombin burst and coagulation [6]. Our patient sustained a rapid blood loss within 30 min (whole blood volume) despite maximal blood products infusion. rFVIIa administration in this setting was conceivable to halt the haemorrhage. Such extreme haemorrhage was likely multifactorial, including haemostatic abnormality secondary to use of anticoagulants and exhaustion of clotting factors and platelets induced by extracorporeal circulation [7].\n\nThe rapid development of systemic clotting in our case was unfortunate. The predicament was unclear; however, we suspect that it is likely contributed by various reasons. First, there is an inherent risk of thromboembolism associated with the unlabelled treatment of rFVIIa in surgery [6]. In CPB, upregulation of TF expression may amplify TF-dependent action of rFVIIa, leading to systemic coagulation [8]. A systematic review of all published and unpublished clinical studies estimated thromboembolic events of 1–2% following administration of rFVIIa in severe bleeding [9]. Meanwhile, some authors reported similar complication at a higher rate (9–11%) [[10], [11], [12]]. These studies, though, could not prove a causal relationship between its use and occurrence of thrombotic events. Risk of thrombosis is also higher in disseminated intravascular coagulation [13], which was present in our case as per baseline ROTEM. Other pertinent thrombogenic factors include pre-existing malignancy and systemic inflammatory response syndrome which led to severe vasoplegia requiring high dose vasopressor.\n\nDue to the extensive clotting, we also speculate that the application of topical haemostatic agent in conjunction with ICS could contribute to this. It is well-established that small strands of the haemostatic gel may pass through 40-μm filters of ICS [14]. It may be aspirated into the collection reservoir, potentially leading to systemic circulation of this chemical and subsequent clot formation upon re-infusion [15]. To prevent this, it is recommended to avoid use of cell saver suction while the surgical field is contaminated with topical clotting factors until they have been washed away with 0.9% sodium chloride [16].\n\n4 Conclusion\nIn summary, this case reports on an intraoperative mortality secondary to systemic thrombosis and cardiac arrest involving the use of local haemostatic agent in ICS and administration of rFVIIa. Current evidence, albeit weak, favour the use of rFVIIa in life-threatening haemorrhage, especially in the setting of CPB [12,17]. More randomised controlled trials are needed to validate the efficacy and safety profile of the haemostatic agent. Nevertheless, it is imperative to consider the risk-benefit profile of rFVIIa due to the thrombogenic potential. In our case, provision of rFVIIa to curtail the vicious cycle of coagulopathy was of patient’s best interest as living through the surgery would greatly improve her survival outcome. The authors also feel strongly against the use of local haemostatic gel in conjunction with ICS due to potential systemic circulation of the thrombin.\n\nConflicts of interest\nNo conflict of interest.\n\nSources of funding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nEthical approval\nNo ethic is required for this research.\n\nConsent\nYes it has been documented in the paper.\n\nAuthor’s contribution\nLSK – main author.\n\nAH and NAA – involved in editing of paper.\n\nDLM – involved in study design and surgery.\n\nRegistration of research studies\nThis is not a first-in-man case report.\n\nGuarantor\nLee S Kyang.\n\nNayef AlZahrani.\n\nDavid L Morris.\n\nProvenance and peer review\nNot commissioned, externally peer reviewed.\n==== Refs\nReferences\n1 Agha R.A. Borrelli M.R. Farwama R. Koshy K. Foowler A. Orgill D.P. For the SCARE Group The SCARE 2018 statement: updating consensus Surgical CAse REport (SCARE) guidelines Int. J. Surg. 60 2018 132 136 30342279 \n2 Martinowitz U. Michaelson M. Guidelines for the use of recombinant activated factor VII (rFVIIa) in uncontrolled bleeding: a report by the Israeli Multidisciplinary rFVIIa Task Force J. Thromb. Haemost. JTH 3 2005 640 648 15842347 \n3 Lynn M. Jeroukhimov I. Klein Y. Martinowitz U. Updates in the management of severe coagulopathy in trauma patients Intensive Care Med. 28 Suppl. 2 2002 S241 7 12404093 \n4 Kenet G. Walden R. Eldad A. Martinowitz U. Treatment of traumatic bleeding with recombinant factor VIIa Lancet (London, England) 354 1999 1879 \n5 von Heymann C. Jonas S. Spies C. Recombinant activated factor VIIa for the treatment of bleeding in major abdominal surgery including vascular and urological surgery: a review and meta-analysis of published data Crit. Care (London, England) 12 2008 R14 \n6 O’Connell K.A. Wood J.J. Wise R.P. Lozier J.N. Braun M.M. Thromboembolic adverse events after use of recombinant human coagulation factor VIIa JAMA 295 2006 293 298 16418464 \n7 Hartmann M. Sucker C. Boehm O. Koch A. Loer S. Zacharowski K. Effects of cardiac surgery on hemostasis Transfus. Med. Rev. 20 2006 230 241 16787830 \n8 Warren O. Mandal K. Hadjianastassiou V. Recombinant activated factor VII in cardiac surgery: a systematic review Ann. Thorac. Surg. 83 2007 707 714 17258029 \n9 Levi M. Peters M. Buller H.R. Efficacy and safety of recombinant factor VIIa for treatment of severe bleeding: a systematic review Crit. Care Med. 33 2005 883 890 15818119 \n10 Bowman L.J. Uber W.E. Stroud M.R. Use of recombinant activated factor VII concentrate to control postoperative hemorrhage in complex cardiovascular surgery Ann. Thorac. Surg. 85 2008 1669 1676 discussion 76-7 18442563 \n11 Thomas G.O. Dutton R.P. Hemlock B. Thromboembolic complications associated with factor VIIa administration J. Trauma 62 2007 564 569 17414329 \n12 Omar H.R. Enten G. Karlnoski R. Ching Y.H. Mangar D. Camporesi E.M. Recombinant activated factor VII significantly reduces transfusion requirements in cardiothoracic surgery Drugs R&D 15 2015 187 194 \n13 Pang G. Donaldson A. Probable right atrial thrombus immediately after recombinant activated factor VII administration Br. J. Anaesth. 99 2007 221 225 17522107 \n14 Spotnitz W.D. Burks S. Hemostats, sealants, and adhesives: components of the surgical toolbox Transfusion 48 2008 1502 1516 18422855 \n15 Kumar S. Goyal K. Dubey S. Bindra A. Kedia S. Anaphylactic reaction after autologous blood transfusion: a case report and review of the literature Asian J. Neurosurg. 10 2015 145 147 \n16 Association of Anaesthetists of Great Britain and Ireland, AAGBI guidelines: cell salvage for peri-operative blood conservation. Edition, cited February 25 February 2018. Available from: https://www.aagbi.org/sites/default/files/CS_2017_for%20member%20consultation.pdf.\n17 Karkouti K. Beattie W.S. Crowther M.A. The role of recombinant factor VIIa in on-pump cardiac surgery: proceedings of the Canadian Consensus Conference Can. J. Anaesth. 54 2007 573 582 17602044\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2210-2612",
"issue": "57()",
"journal": "International journal of surgery case reports",
"keywords": "Intraoperative cell salvage; Liver resection; Mortality; Recombinant activated factor VII; Thrombosis; rFVIIa",
"medline_ta": "Int J Surg Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101529872",
"other_id": null,
"pages": "48-51",
"pmc": null,
"pmid": "30901569",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "17258029;17414329;25972952;30342279;16787830;15818119;12404093;10584732;18442563;15842347;25862216;18422855;17602044;17522107;16418464;18279513",
"title": "Case report: Intraoperative thrombosis cardiac arrest in extended right hepatectomy involving use of local haemostatic agent in intraoperative cell salvage (ICS) and administration of recombinant activated factor VII (rFVIIa).",
"title_normalized": "case report intraoperative thrombosis cardiac arrest in extended right hepatectomy involving use of local haemostatic agent in intraoperative cell salvage ics and administration of recombinant activated factor vii rfviia"
} | [
{
"companynumb": "AU-FRESENIUS KABI-FK201905218",
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"activesubstancename": "COAGULATION FACTOR VIIA RECOMBINANT HUMAN"
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"abstract": "BACKGROUND\nThe recently introduced oral direct anticoagulants (ODAs), presumably safer, and with comparable efficacy to the vitamin K antagonists (VKAs), may reshape the world of anticoagulation medicine. This study aimed to assess the prescription appropriateness of ODAs and VKAs at discharge from hospital.\n\n\nMETHODS\nWe performed a one year retrospective study between August 2012 and July 2013 in the department of internal medicine of a regional hospital (HVs Sion) using Electronic Medical Records. All patients receiving an ODA were included and matched to a patient treated with a VKA. The appropriateness of prescription at discharge was defined by an adequate indication and dosing, the absence of contraindication, a minimal risk of drug-drug interactions and no major bleeding or venous thromboembolism during the hospitalization. The bleeding risk was evaluated with the HAS-BLED score when the indication was atrial fibrillation (AF).\n\n\nRESULTS\nOut of the 44patients included (22 with an ODA and 22 with a VKA), 38 received an appropriate prescription according to all criteria. Two patients had an inadequate dosing. A potential drug-drug interaction was detected in 3patients receiving a VKA and in 1patient receiving an ODA. No major contraindication was found, but a relative contraindication was discussed in 3cases. The majority of patients receiving an ODA for an AF had a minor bleeding risk.\n\n\nCONCLUSIONS\nNo significant difference was ascertained between the two groups regarding the appropriateness of prescription. Our results suggest that ODAs were cautiously used in our setting.",
"affiliations": "Service de pharmacie, institut central (ICHV), hôpital du Valais, avenue du Grand-Champsec 86, 1951 Sion, Suisse.;Service de pharmacie, institut central (ICHV), hôpital du Valais, avenue du Grand-Champsec 86, 1951 Sion, Suisse.;Service de pharmacie, institut central (ICHV), hôpital du Valais, avenue du Grand-Champsec 86, 1951 Sion, Suisse.;Service de médecine interne, hôpital du Valais, avenue du Grand-Champsec 86, 1951 Sion, Suisse.;Service de pharmacie, institut central (ICHV), hôpital du Valais, avenue du Grand-Champsec 86, 1951 Sion, Suisse. Electronic address: lucien.roulet@hopitalvs.ch.",
"authors": "Bochatay|L|L|;Beney|J|J|;Jordan-von Gunten|V|V|;Petignat|P A|PA|;Roulet|L|L|",
"chemical_list": "D000925:Anticoagulants; D014812:Vitamin K; D000069552:Rivaroxaban; D000069604:Dabigatran; D000074:Acenocoumarol; D010644:Phenprocoumon",
"country": "France",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "0248-8663",
"issue": "37(9)",
"journal": "La Revue de medecine interne",
"keywords": "Acenocoumarol; Acénocoumarol; Anticoagulants oraux; Dabigatran; Oral anticoagulants; Rivaroxaban",
"medline_ta": "Rev Med Interne",
"mesh_terms": "D000074:Acenocoumarol; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D001281:Atrial Fibrillation; D017115:Catheter Ablation; D000069604:Dabigatran; D011307:Drug Prescriptions; D005260:Female; D006801:Humans; D007388:Internal Medicine; D008297:Male; D008875:Middle Aged; D010351:Patient Discharge; D010644:Phenprocoumon; D012189:Retrospective Studies; D000069552:Rivaroxaban; D014812:Vitamin K",
"nlm_unique_id": "8101383",
"other_id": null,
"pages": "579-86",
"pmc": null,
"pmid": "26632482",
"pubdate": "2016-09",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Appropriateness of the prescriptions of conventional versus new oral anticoagulants at discharge from a department of internal medicine.",
"title_normalized": "appropriateness of the prescriptions of conventional versus new oral anticoagulants at discharge from a department of internal medicine"
} | [
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"companynumb": "CH-JNJFOC-20160516242",
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"activesubstancename": "RIVAROXABAN"
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"abstract": "The effects of atypical antipsychotic treatment on the brain volume deficits associated with schizophrenia are poorly understood. We assessed the brain volumes of eleven healthy controls and 29 patients with schizophrenia, using magnetic resonance imaging at baseline and at follow-up after two years of treatment with atypical neuroleptics. Two groups of patients were analyzed: treatment-naïve patients (n = 17) and chronic treatment-resistant patients (n = 12). Treatment-naïve patients received risperidone during the follow-up period, whereas chronic patients received clozapine. Gray matter (GM) and white matter (WM) volumes in the frontal, parietal, occipital, and temporal lobes were measured. Contrary to the controls, both groups of patients presented GM increases and WM decreases in the parietal and occipital lobes (p < .005). Frontal GM also increased in the chronic group with clozapine. There was a significant (p < .001) inverse relationship between the baseline volumes (GM deficit/WM excess) and the longitudinal change. These GM and WM changes were not related to changes in weight. Thus, treatment with risperidone and clozapine in schizophrenia may have an effect on gray and white matter volume and needs further exploration.",
"affiliations": "Department of Psychiatry, Hospital Clínico Universitario, P S. Vicente, 58-182. Salamanca 37007, Spain. vmolina@usal.es",
"authors": "Molina|Vicente|V|;Reig|Santiago|S|;Sanz|Javier|J|;Palomo|Tomás|T|;Benito|Carlos|C|;Sánchez|Javier|J|;Sarramea|Fernando|F|;Pascau|Javier|J|;Desco|Manuel|M|",
"chemical_list": "D014150:Antipsychotic Agents; D003024:Clozapine; D018967:Risperidone",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.schres.2005.07.031",
"fulltext": null,
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"issn_linking": "0920-9964",
"issue": "80(1)",
"journal": "Schizophrenia research",
"keywords": null,
"medline_ta": "Schizophr Res",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D001284:Atrophy; D001921:Brain; D002908:Chronic Disease; D003024:Clozapine; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D018967:Risperidone; D012559:Schizophrenia",
"nlm_unique_id": "8804207",
"other_id": null,
"pages": "61-71",
"pmc": null,
"pmid": "16150576",
"pubdate": "2005-12-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Increase in gray matter and decrease in white matter volumes in the cortex during treatment with atypical neuroleptics in schizophrenia.",
"title_normalized": "increase in gray matter and decrease in white matter volumes in the cortex during treatment with atypical neuroleptics in schizophrenia"
} | [
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"companynumb": "ES-JNJFOC-20161208324",
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"actiondrug": "5",
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"activesubstancename": "RISPERIDONE"
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... |
{
"abstract": "To describe and discuss the workup and management of a rare complication of retrobulbar anesthesia, as well as CT and MRI findings of this complication.\nThe patient underwent uncomplicated pars plana vitrectomy with membrane peel for epiretinal membrane removal. Shortly after completion of surgery, the patient noted that he could not see out of his non-operated eye. Visual acuity was bare hand motion, and physical exam revealed a dilated, non-reactive pupil with normal, well-perfused retina. Imaging revealed an air bubble in the optic nerve of the operated eye, suggesting penetration of the optic nerve sheath during retrobulbar block with posterior spread of anesthetic to the contralateral optic nerve.\nAfter imaging ruled out acute intracranial pathology and confirmed the correct diagnosis, the patient was monitored until vision in the non-operated eye returned to baseline. Excellent visual acuity was attained in the operated eye. Central spread of anesthetic after retrobulbar anesthesia is a rare but potentially life-threatening complication that must be promptly diagnosed and addressed.",
"affiliations": "Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, IL, USA.;Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, IL, USA.;The University of Chicago Laboratory Schools, 1362, E. 59th St., Chicago, IL, USA.;Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, IL, USA.;Martel Eye Medical Group, 11216 Trinity River Dr, Rancho Cordova, CA, USA.;Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, IL, USA.",
"authors": "Williams|Blake|B|;Schechet|Sidney A|SA|;Hariprasad|Ishani|I|;Shah|Hassan|H|;Golas|Liliya|L|;Hariprasad|Seenu M|SM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajoc.2019.100487",
"fulltext": "\n==== Front\nAm J Ophthalmol Case RepAm J Ophthalmol Case RepAmerican Journal of Ophthalmology Case Reports2451-9936Elsevier S2451-9936(19)30158-610.1016/j.ajoc.2019.100487100487Case ReportContralateral amaurosis after a retrobulbar block Williams Blake aSchechet Sidney A. aHariprasad Ishani bShah Hassan aGolas Liliya cHariprasad Seenu M. retina@uchicago.edua∗a Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, IL, USAb The University of Chicago Laboratory Schools, 1362, E. 59th St., Chicago, IL, USAc Martel Eye Medical Group, 11216 Trinity River Dr, Rancho Cordova, CA, USA∗ Corresponding author. University of Chicago Medical Center, 5841 S Maryland Avenue, MC 2114, USA. retina@uchicago.edu07 6 2019 9 2019 07 6 2019 15 10048730 3 2019 2 6 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nTo describe and discuss the workup and management of a rare complication of retrobulbar anesthesia, as well as CT and MRI findings of this complication.\n\nObservations\nThe patient underwent uncomplicated pars plana vitrectomy with membrane peel for epiretinal membrane removal. Shortly after completion of surgery, the patient noted that he could not see out of his non-operated eye. Visual acuity was bare hand motion, and physical exam revealed a dilated, non-reactive pupil with normal, well-perfused retina. Imaging revealed an air bubble in the optic nerve of the operated eye, suggesting penetration of the optic nerve sheath during retrobulbar block with posterior spread of anesthetic to the contralateral optic nerve.\n\nConclusions and importance\nAfter imaging ruled out acute intracranial pathology and confirmed the correct diagnosis, the patient was monitored until vision in the non-operated eye returned to baseline. Excellent visual acuity was attained in the operated eye. Central spread of anesthetic after retrobulbar anesthesia is a rare but potentially life-threatening complication that must be promptly diagnosed and addressed.\n\nKeywords\nRetrobulbar blockPars plana vitrectomySurgical complication\n==== Body\n1 Introduction\nRetrobulbar block is an anesthetic technique frequently used prior to ophthalmic surgery as a means of providing ocular anesthesia, akinesia, and post-operative analgesia. Complications from retrobulbar block occur infrequently and range from mild to life-threatening. These complications include retrobulbar hemorrhage, retinal vascular occlusions, optic nerve injury, ocular perforation, subarachnoid infiltration with spread to the central nervous system (CNS), seizures and cardiorespiratory distress. It is essential that the surgeon providing retrobulbar anesthesia be able to promptly recognize and handle complications associated with this procedure.\n\nWe report a case of contralateral amaurosis after retrobulbar block that was performed prior to vitrectomy for epiretinal membrane peel, as well as discuss the differential diagnosis and proposed mechanism.\n\n2 Case report\nA 71-year-old male with a visually significant epiretinal membrane in the left eye underwent 23-gauge pars plana vitrectomy with membrane peeling. He reported a medical history of only hypertension and prostate cancer. He had no other ocular history or previous surgeries.\n\nIn the preoperative area, the patient received three sets of 1% cyclopentolate and 2.5% phenylephrine eye drops to dilate the left eye for surgery. The patient was brought to the operating room and, under monitored anesthesia care with propofol, a left retrobulbar block was performed using a 25-gauge, 1.5 inch Atkinson needle injecting 6 cc of a 1:1 mixture of 0.75% bupivacaine and 2.0% lidocaine. The 25-min surgery went well without complication including normal vital signs throughout. The left surgical eye was patched and when the patient sat up he noticed that he could not see out of his right (non-operative) eye. Visual acuity of the right eye was bare hand motion (baseline pre-operative visual acuity was 20/20), and the right pupil was 7 mm and minimally-reactive. The intraocular pressure was normal and extraocular movements were intact. Indirect ophthalmoscopy of the right eye showed a normal fundus exam with well-perfused retina. One drop of 1% pilocarpine was administered in the right eye and constricted to 1.5 mm, ruling out pharmacologic dilation.\n\nAt this point a hospital code for stroke was called due to the concerning findings. Initial neurologic exam performed by the neurology team was unremarkable, and immediate CT scan of the brain showed no acute intracranial pathology but revealed an air bubble within the left optic nerve sheath (Fig. 1). Subsequent MRI/MRA of the brain and orbits showed no intracranial pathology but revealed abnormal enhancements along the left intra-orbital optic nerve along with confirmation of an air bubble within the optic nerve sheath (Fig. 2). The patient's vision in the right eye slowly returned to baseline, testing 20/20 with a near card 90 minutes after the conclusion of surgery. During the post-operative period, the vision remained normal and both fundus exam and macular optical coherence tomography were unremarkable.Fig. 1 CT scan of the orbits showing an air bubble (white arrow) in the left optic nerve sheath on both coronal (Fig. 1A) and saggital (Fig. 1B) cuts.\n\nFig. 1Fig. 2 Axial T1 view of MRI brain showing an air bubble (white arrow) in the left optic nerve sheath and abnormal enhancement along the left optic nerve (yellow arrows). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)\n\nFig. 2\n\n3 Discussion\nRetrobulbar block is an anesthetic technique frequently used before many ophthalmic surgeries as a means of providing ocular anesthesia, akinesia, and post-operative analgesia. It is known that uncomplicated peribulbar and retrobulbar anesthesia can cause pupillary dilation and a decrease in visual acuity.1 Complications of retrobulbar anesthesia include retrobulbar hemorrhage, retinal vascular occlusions, optic nerve injury, ocular myotoxicity, ocular perforation, subarachnoid infiltration with spread to the CNS, seizures and cardiorespiratory distress.2 Additionally, anesthetic infiltration of the brainstem, the most serious and life-threatening complication of retrobulbar block, can cause confusion, ophthalmoplegia, respiratory depression, apnea, and contralateral amaurosis.3 The first sign of brainstem anesthesia is often a sudden increase in blood pressure or heart rate,4 neither of which occurred during our case.\n\nImmediately after the patient noted vision loss in the contralateral eye, a broad differential diagnosis was quickly considered given the severity of the situation. Considered were occipital lobe stroke, posterior ischemic optic neuropathy (PION), pharmacologic dilation of the non-operative eye, and complication from retrobulbar anesthesia. In order to cause such severe vision loss, bilateral occipital lobe stroke would be necessary. PION was also considered, but there was no significant blood loss during the surgery and normal blood pressure was maintained throughout the case. Pharmacologic dilation of the contralateral eye would not cause such severe vision loss and administration of pilocarpine resulted in constriction of the pupil, ruling out pharmacologic dilation as a confounding variable in this clinical scenario.\n\nThe diagnosis of CNS infiltration of retrobulbar anesthesia was confirmed by CT evidence of an air bubble in the ipsilateral optic nerve (Fig. 1), which showed that the retrobulbar needle had penetrated the optic nerve during administration of anesthetic. We propose that when the anesthetic was injected into the ipsilateral optic nerve sheath, it spread posteriorly to the chiasm and blocked transmission of nerve impulses in the contralateral optic nerve. It has been shown that uncomplicated retrobulbar anesthesia results in a temporary conductivity block in the optic nerve for about 2 hours by comparing visual evoked potential (VEP) before and shortly after administration of the block.5 It is therefore unsurprising that when anesthetic is injected into the optic nerve sheath and has access to the optic chiasm, it may result in a temporary but severe loss of vision with a dilated and minimally reactive pupil in the contralateral eye. In addition, this is the first case we are aware of in which MRI findings have been described after penetration of the optic nerve sheath during retrobulbar block. MRI showed abnormal enhancements along the intraorbital optic nerve, mimicking inflammatory conditions such as perineuritis.\n\nContralateral transient amaurosis is a rare complication of retrobulbar block that has been previously described,4,6, 7, 8 and conduction of the contralateral optic nerve is affected by spread of the anesthetic through the optic nerve sheath to the optic chiasm. Fortunately, in this case central spread of anesthetic beyond the optic chiasm did not occur and no systemic problems occurred. Ophthalmologists that perform retrobulbar blocks should be aware of this possible complication of contralateral amaurosis as well as other potential life-threatening complications.\n\nPatient consent\nVerbal consent for publication was obtained from the patient at his post-operative visit.\n\nAcknowledgements and Disclosures\nNo funding or grant support.\n\nThe following authors have no financial disclosures relevant to this case report: BW, SS, IH, HS, LG, SH.\n\nAll authors attest that they meet the current ICMJE criteria for Authorship.\n==== Refs\nReferences\n1 Talks S.J. Chong N.H.V. Gibson J.M. Francis I.R. Visual acuity and pupillary reactions after peribulbar anesthesia Br J Ophthalmol 78 1994 41 43 8110698 \n2 McGoldrick K.E. Complications of regional anesthesia for ophthalmic surgery Yale J Biol Med 66 1993 443 445 7825345 \n3 Ahn J.C. Stanley J.A. Subarachnoid injection as a complication of retrobulbar anesthesia Am J Ophthalmol 103 2 1987 Feb 15 225 230 3812625 \n4 Jericho B. Ulanski L. Contralateral amaurosis after retrobulbar block for vitrectomy presenting solely with hypertension and tachycardia Internet J Anesthesiol 24 2009 Number 2 \n5 Heuermann T. Anders N. Pham D.T. Wollensak J. The effect of retrobulbar anesthesia on visual evoked responses Klin Monbl Augenheilkd 219 3 2002 Mar 101 108 11987035 \n6 Ghadiali Q. Ghadiali L.K. Schiff W.M. Odel J.G. Contralateral anesthesia in two patients after retrobulbar block Retin Cases Brief Rep 12 2 2018 97 99 Spring 27749747 \n7 Bishara S.A. Estrin I. Rand W.J. Immediate contralateral amaurosis after retrobulbar anesthesia Ann Ophthalmol 22 2 1990 Feb 63 65 2316954 \n8 Friedberg H.L. Kline O.R. Jr. Contralateral amaurosis after retrobulbar injection Am J Ophthalmol 101 6 1986 Jun 15 688 690 3717252\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2451-9936",
"issue": "15()",
"journal": "American journal of ophthalmology case reports",
"keywords": "Pars plana vitrectomy; Retrobulbar block; Surgical complication",
"medline_ta": "Am J Ophthalmol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101679941",
"other_id": null,
"pages": "100487",
"pmc": null,
"pmid": "31211285",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports",
"references": "11987035;2316954;27749747;3717252;3812625;7825345;8110698",
"title": "Contralateral amaurosis after a retrobulbar block.",
"title_normalized": "contralateral amaurosis after a retrobulbar block"
} | [
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"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-19-04184",
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"actiondrug": "6",
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"activesubstancename": "PROPOFOL"
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"drug... |
{
"abstract": "Encorafenib (Braftovi) is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation, in combination with binimetinib (Mektovi). According to the product label of encorafenib, there are no specific treatment recommendations in case of an overdose. We report on a 63-year-old man who ingested a double dose (900 mg) of encorafenib for 16 days. He developed overall minor chronic overdose symptoms such as nausea and vomiting grade 1 and muscle pain. Based on the most occurring adverse events of encorafenib, liver values, kidney function parameters and QTc interval were measured. Kidney function parameters were normal, whereas liver values were slightly increased (grade 1) and QTc slightly prolonged. The plasma concentration 3 h after the last dose was 2110 ng/mL. We describe the course of a case with a chronic overdose during 16 days of the double dose of encorafenib as well as the followed approach, which could be taken into account when observing an encorafenib overdose. Providing information in times of Covid-19 is challenging, but remains necessary for good clinical care.",
"affiliations": "Department of Clinical Pharmacy.;Department of Internal Medicine, Medisch Spectrum Twente, Enschede, the Netherlands.;Department of Internal Medicine, Medisch Spectrum Twente, Enschede, the Netherlands.;Department of Clinical Pharmacy.",
"authors": "Mian|Paola|P|;Meussen|Elvera|E|;Piersma|Djura|D|;Lankheet|Nienke A G|NAG|",
"chemical_list": "D000970:Antineoplastic Agents; D001562:Benzimidazoles; D002219:Carbamates; D013449:Sulfonamides; C581313:binimetinib; C000601108:encorafenib; D048493:Proto-Oncogene Proteins B-raf",
"country": "England",
"delete": false,
"doi": "10.1097/CAD.0000000000001052",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-4973",
"issue": "32(5)",
"journal": "Anti-cancer drugs",
"keywords": null,
"medline_ta": "Anticancer Drugs",
"mesh_terms": "D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D001562:Benzimidazoles; D000086382:COVID-19; D002219:Carbamates; D003140:Communicable Disease Control; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D062787:Drug Overdose; D006801:Humans; D008111:Liver Function Tests; D008133:Long QT Syndrome; D008297:Male; D054539:Medication Therapy Management; D008545:Melanoma; D008875:Middle Aged; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf; D012878:Skin Neoplasms; D013449:Sulfonamides; D014839:Vomiting",
"nlm_unique_id": "9100823",
"other_id": null,
"pages": "589-591",
"pmc": null,
"pmid": "33587356",
"pubdate": "2021-06-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Relatively mild symptoms after chronic overdose with a double-dose encorafenib: a case report.",
"title_normalized": "relatively mild symptoms after chronic overdose with a double dose encorafenib a case report"
} | [
{
"companynumb": "NVSC2021NL043433",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
"drug... |
{
"abstract": "The target brain binding site of levetiracetam (LEV) is synaptic vesicle glycoprotein 2A (SV2A). Up to now, only a homozygous pathogenic SV2A gene mutation was reported in human. We now report a novel heterozygous pathogenic SV2A gene mutation both in a girl and her mother result in epilepsy and poor response to LEV. Furthermore, the girl developed a new seizure type after using LEV. Our report had a clinical relevance that LEV could potentially produce contradictory efficacy in patients with SV2A gene mutation. If patients' seizures became exacerbated while using LEV, SV2A gene testing is recommended.",
"affiliations": "Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China; The Beijing Key Laboratory of Neuromodulation, Beijing 100053, China.;Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China; The Beijing Key Laboratory of Neuromodulation, Beijing 100053, China.;Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China; The Beijing Key Laboratory of Neuromodulation, Beijing 100053, China.;Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China; The Beijing Key Laboratory of Neuromodulation, Beijing 100053, China.;Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China; The Beijing Key Laboratory of Neuromodulation, Beijing 100053, China.;Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China; The Beijing Key Laboratory of Neuromodulation, Beijing 100053, China.;Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China; The Beijing Key Laboratory of Neuromodulation, Beijing 100053, China; Center of Epilepsy, Beijing Institute for Brain Disorder, Beijing 100069, China; Department of Pediatrics, Xuanwu Hospital, Capital Medical University, Beijing 100053, China. Electronic address: wangyuping@xwhosp.org.",
"authors": "Wang|Di|D|;Zhou|Qilin|Q|;Ren|Liankun|L|;Lin|Yicong|Y|;Gao|Lehong|L|;Du|Jialin|J|;Wang|Yuping|Y|",
"chemical_list": "D000927:Anticonvulsants; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; C076414:SV2A protein, human; D000077287:Levetiracetam; D010889:Piracetam",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.clineuro.2019.03.020",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0303-8467",
"issue": "181()",
"journal": "Clinical neurology and neurosurgery",
"keywords": "Levetiracetam; Myoclonus; Novel mutation; SV2A; Spasm",
"medline_ta": "Clin Neurol Neurosurg",
"mesh_terms": "D000927:Anticonvulsants; D001921:Brain; D002675:Child, Preschool; D005260:Female; D006801:Humans; D000077287:Levetiracetam; D008562:Membrane Glycoproteins; D009154:Mutation; D009419:Nerve Tissue Proteins; D010889:Piracetam; D012640:Seizures",
"nlm_unique_id": "7502039",
"other_id": null,
"pages": "64-66",
"pmc": null,
"pmid": "31005049",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Levetiracetam-induced a new seizure type in a girl with a novel SV2A gene mutation.",
"title_normalized": "levetiracetam induced a new seizure type in a girl with a novel sv2a gene mutation"
} | [
{
"companynumb": "CN-FRESENIUS KABI-FK201905513",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nDifferent studies showed correlations between gadolinium-based contrast agent (GBCA) administrations and dentate nucleus (DN) T1-weighted hyperintensity. The clinical impact of gadolinium retention, however, is still largely unknown. The aim of this study was to investigate relations between MRI and clinical disability in relapsing-remitting multiple sclerosis (RR-MS) patients.\n\n\nMETHODS\nIn this retrospective study, clinical data were obtained from 74 RR-MS patients at baseline and after a mean follow-up time of 3.6 years, including the expanded disability status scale (EDSS) score and its change (ΔEDSS). Patients were considered showing clinical worsening if they score a ΔEDSS ≥ 1 (for baseline EDSS ≤ 5.5) or ΔEDSS ≥ 0.5 (for baseline EDSS > 5.5). From the MRI data, the presence of bilateral DN hyperintensity was recorded along with the calculation of longitudinal relaxation rate (R1) maps.\n\n\nRESULTS\nPatients with DN hyperintensity showed similar ΔEDSS change compared to those without visible changes on T1-weighted images (p = 0.32). Similarly, no DN-R1 difference was found comparing stable patients with those showing a significant clinical worsening (p = 0.54). Finally, no significant effect of DN-R1 values explained the variance in ΔEDSS (p = 0.76), thus suggesting their independence from the clinical outcome.\n\n\nCONCLUSIONS\nMS patients with DN hyperintensity show similar EDSS changes compared to subjects without DN high-signal intensity. Furthermore, mean DN-R1 values of patients with significant clinical worsening were comparable to those of stable subjects and were unrelated to clinical disability. Taken together, these findings suggest that gadolinium retention in the brain of MS patients does not affect their clinical worsening, expressed by the EDSS change.",
"affiliations": "Department of Advanced Biomedical Sciences, University of Naples \"Federico II\", Naples, Italy. sirio.cocozza@unina.it.;Department of Advanced Biomedical Sciences, University of Naples \"Federico II\", Naples, Italy.;Department of Neurosciences and Reproductive and Odontostomatological Sciences, University of Naples \"Federico II\", Naples, Italy.;Department of Advanced Biomedical Sciences, University of Naples \"Federico II\", Naples, Italy.;Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.;Department of Advanced Biomedical Sciences, University of Naples \"Federico II\", Naples, Italy.;Department of Advanced Biomedical Sciences, University of Naples \"Federico II\", Naples, Italy.;Department of Advanced Biomedical Sciences, University of Naples \"Federico II\", Naples, Italy.;Department of Neurosciences and Reproductive and Odontostomatological Sciences, University of Naples \"Federico II\", Naples, Italy.;Department of Neurosciences and Reproductive and Odontostomatological Sciences, University of Naples \"Federico II\", Naples, Italy.;Department of Neurosciences and Reproductive and Odontostomatological Sciences, University of Naples \"Federico II\", Naples, Italy.;IRCCS SDN, Naples, Italy.;Department of Neurosciences and Reproductive and Odontostomatological Sciences, University of Naples \"Federico II\", Naples, Italy.;Department of Advanced Biomedical Sciences, University of Naples \"Federico II\", Naples, Italy.;Institute of Biostructure and Bioimaging, National Research Council, Naples, Italy.;Department of Advanced Biomedical Sciences, University of Naples \"Federico II\", Naples, Italy.;Department of Advanced Biomedical Sciences, University of Naples \"Federico II\", Naples, Italy.",
"authors": "Cocozza|Sirio|S|http://orcid.org/0000-0002-0300-5160;Pontillo|Giuseppe|G|;Lanzillo|Roberta|R|;Russo|Camilla|C|;Petracca|Maria|M|;Di Stasi|Martina|M|;Paolella|Chiara|C|;Vola|Elena Augusta|EA|;Criscuolo|Chiara|C|;Moccia|Marcello|M|;Lamberti|Anna|A|;Monti|Serena|S|;Brescia Morra|Vincenzo|V|;Elefante|Andrea|A|;Palma|Giuseppe|G|;Tedeschi|Enrico|E|;Brunetti|Arturo|A|",
"chemical_list": "D003287:Contrast Media; D005682:Gadolinium",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00234-018-02150-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3940",
"issue": "61(2)",
"journal": "Neuroradiology",
"keywords": "EDSS; GBCA accumulation; Gadolinium-based contrast agents; Multiple sclerosis",
"medline_ta": "Neuroradiology",
"mesh_terms": "D000328:Adult; D000368:Aged; D003287:Contrast Media; D004185:Disability Evaluation; D018450:Disease Progression; D005260:Female; D005682:Gadolinium; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting; D012189:Retrospective Studies",
"nlm_unique_id": "1302751",
"other_id": null,
"pages": "155-162",
"pmc": null,
"pmid": "30617409",
"pubdate": "2019-02",
"publication_types": "D016428:Journal Article",
"references": "12482100;16431890;16948524;17113951;17179401;18635615;19938036;19938038;21387374;21882300;22550309;23395575;24475844;24666846;24852287;25742194;25942417;26030293;26079490;26111826;26284778;26345358;26359291;26567968;26863577;26905870;27053146;27211256;27224028;27530966;27548344;27673510;28361260;28495943;28653648;29261786;29786486;29926371;30204075;8827172",
"title": "MRI features suggestive of gadolinium retention do not correlate with Expanded Disability Status Scale worsening in Multiple Sclerosis.",
"title_normalized": "mri features suggestive of gadolinium retention do not correlate with expanded disability status scale worsening in multiple sclerosis"
} | [
{
"companynumb": "IT-BAYER-2019-035507",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "GADOLINIUM"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nIntrathecal baclofen (ITB) is a mainstay of treatment for patients with chronic spasticity. Up to 40% of all patients receiving ITB experience overdose or withdrawal symptoms, which in the most severe cases can lead to multisystem organ failure and death. There is currently no well-established treatment for ITB withdrawal. One previous case report details an intubated pediatric patient who underwent baclofen pump removal in which dexmedetomidine was used in combination with other medications to prevent baclofen withdrawal.\n\n\nMETHODS\nWe report a case of baclofen withdrawal where the decision was made to initiate a dexmedetomidine infusion, with subsequent improvement of the patient's hypertension and tachycardia. At no point during her stay did the patient require intubation for airway protection, and the patient was ultimately discharged to her previous nursing facility on hospital day 9 with no new neurologic deficits. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians should be aware of dexmedetomidine as a promising option for the treatment of ITB withdrawal in the acute setting. Although little evidence is currently present, dexmedetomidine was used successfully in this case, and should be considered as a temporizing treatment for ITB withdrawal. Dexmedetomidine holds promise in the management of ITB withdrawal compared to other previously described treatments, including oral baclofen, cyproheptadine, and dantrolene. In addition, dexmedetomidine has a superior safety profile compared to propofol or large doses of benzodiazepines. Further research will be useful in supporting the use of dexmedetomidine for this purpose.",
"affiliations": "Department of Emergency Medicine, University of Cincinnati, Cincinnati, Ohio.;Department of Anesthesia, University of Cincinnati, Cincinnati, Ohio.;Department of Pharmacy, UC Health University Hospital, Cincinnati, Ohio.;Department of Emergency Medicine, University of Cincinnati, Cincinnati, Ohio.",
"authors": "Gottula|Adam L|AL|;Gorder|Kari L|KL|;Peck|Amanda R|AR|;Renne|B Christian|BC|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jemermed.2019.09.043",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-4679",
"issue": null,
"journal": "The Journal of emergency medicine",
"keywords": "acute; baclofen; benzodiazepine; dexmedetomidine; management; withdrawal",
"medline_ta": "J Emerg Med",
"mesh_terms": null,
"nlm_unique_id": "8412174",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31759793",
"pubdate": "2019-11-20",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Dexmedetomidine for Acute Management of Intrathecal Baclofen Withdrawal.",
"title_normalized": "dexmedetomidine for acute management of intrathecal baclofen withdrawal"
} | [
{
"companynumb": "US-OXFORD PHARMACEUTICALS, LLC-2019OXF00177",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BACLOFEN"
},
"drugadditiona... |
{
"abstract": "Antipsychotics are a known cause of hyperprolactinaemia and can be associated with significant health issues in short term and long term. The effects vary with gender and age of the individual and can contribute towards non-concordance and hence relapse in mental health of our patients. Clinicians need to educate the patients about this significant side effect of not only antipsychotic medications but other medications causing hyperprolactinaemia commonly prescribed in primary care.",
"affiliations": "Consultant Psychiatrist, Department of Psychiatry, Bassetlaw Hospital, Nottinghamshire Healthcare NHS Foundation Trust, Worksop, UK.;Consultant Psychiatrist, Adult Mental Health Inpatient Unit, Rotherham Doncaster and South Humber Mental Health NHS Foundation Trust, Doncaster, UK.;Consultant Psychiatrist, Adult Mental Health Inpatient Unit, Rotherham Doncaster and South Humber Mental Health NHS Foundation Trust, Doncaster, UK.",
"authors": "Mittal|Shweta|S|;Prasad|Suveera|S|;Ghosh|Adwaita|A|",
"chemical_list": "D014150:Antipsychotic Agents",
"country": "England",
"delete": false,
"doi": "10.1136/postgradmedj-2017-135221",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0032-5473",
"issue": "94(1110)",
"journal": "Postgraduate medical journal",
"keywords": "adult psychiatry; psychiatry",
"medline_ta": "Postgrad Med J",
"mesh_terms": "D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents; D019317:Evidence-Based Medicine; D005260:Female; D006801:Humans; D006966:Hyperprolactinemia; D001523:Mental Disorders; D008875:Middle Aged; D017410:Practice Guidelines as Topic; D018570:Risk Assessment; D012307:Risk Factors",
"nlm_unique_id": "0234135",
"other_id": null,
"pages": "226-229",
"pmc": null,
"pmid": "29122927",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Antipsychotic-induced hyperprolactinaemia: case studies and review.",
"title_normalized": "antipsychotic induced hyperprolactinaemia case studies and review"
} | [
{
"companynumb": "GB-OTSUKA-2018_012727",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "We present a case of antigen-negative disseminated histoplasmosis manifesting as an isolated ileal stricture in a patient on chronic infliximab and methotrexate. Diagnosis can be challenging due to imperfect tests, and this condition should remain in the differential, even with negative testing. Mortality of untreated disseminated histoplasmosis can be as high as 80%.",
"affiliations": "Department of Internal Medicine, University of Kansas School of Medicine, Wichita, KS.;Department of Internal Medicine, University of Kansas School of Medicine, Wichita, KS.;Department of Internal Medicine, University of Kansas School of Medicine, Wichita, KS.;Department of Internal Medicine, University of Kansas School of Medicine, Wichita, KS.",
"authors": "Rowe|Kyle M|KM|;Green|Michael|M|;Nehme|Fredy|F|;Tofteland|Nathan|N|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.14309/crj.2017.10",
"fulltext": "\n==== Front\nACG Case Rep JcrjACG Case Reports Journal2326-3253American College of Gastroenterology crj.2017.1010.14309/crj.2017.10Case ReportColonIsolated Ileal Stricture Secondary to Antigen-Negative GI Histoplasmosis in a Patient on Immunosuppressive Therapy Rowe et alGastrointestinal HistoplasmosisRowe Kyle M. MDGreen Michael MDNehme Fredy MDTofteland Nathan MD, FACGDepartment of Internal Medicine, University of Kansas School of Medicine, Wichita, KSCorrespondence: Kyle M. Rowe, University of Kansas School of Medicine, 1010 N Kansas St, Wichita, KS 67214-3199 (krowe2@kumc.edu).2017 18 1 2017 4 e102 8 2016 28 10 2016 Copyright © Rowe et al.2017This is an open-access article. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/We present a case of antigen-negative disseminated histoplasmosis manifesting as an isolated ileal stricture in a patient on chronic infliximab and methotrexate. Diagnosis can be challenging due to imperfect tests, and this condition should remain in the differential, even with negative testing. Mortality of untreated disseminated histoplasmosis can be as high as 80%.\n==== Body\nIntroduction\nGastrointestinal (GI) histoplasmosis is a form of disseminated histoplasmosis. It is a rare and potentially life-threatening infection, most often presenting in immunocompromised hosts in endemic areas. Symptomatology is highly variable and non-specific.1 It rarely has been reported to cause small bowel obstruction, and the majority of these obstructive cases have been reported in patients with acquired immune deficiency syndrome (AIDS).1-5 Diagnosis can be challenging as serum and urine Histoplasma capsulatum antigen testing is not 100% sensitive, and this condition should remain in the differential even with negative testing. GI histoplasmosis has the potential to mimic chronic inflammatory bowel disease, and further immunosuppression without pathologic confirmation is potentially harmful.6 Mortality of untreated disseminated histoplasmosis can be as high as 80%.7\n\nCase Report\nA 73-year-old white woman was referred to our tertiary care gastroenterology service for 7 months of progressive nausea, post-prandial abdominal pain, non-bloody diarrhea, and a 13.5-kg weight loss over the same time period. Her past medical history was significant only for rheumatoid arthritis (RA), for which she was being treated with both subcutaneous methotrexate and infliximab infusions. An initial workup by her primary care physician, including complete metabolic panel, liver function tests, complete blood count, upper endoscopy/colonoscopy, and abdominal computed tomography (CT) scan, was non-revealing. An upper abdominal series with small bowel follow-through showed findings suggestive of ileal stricture without obstruction, and she was referred to our service for small bowel enteroscopy.\n\nThe patient underwent repeat esophagogastroduodenoscopy, which again was non-revealing. On upper balloon enteroscopy, a benign-appearing intrinsic severe stenosis measuring 10 mm in length by 3 mm inner diameter with associated ulcerations was found in the distal ileum (Figure 1). The endoscope was unable traverse the stenosis. Cold forceps biopsies were obtained, and a through-the-scope balloon dilation (8–10 mm) was performed. The scope then was able to pass, and examination of the remaining portions of the ileum had normal appearance.\n\nFigure 1 (A and B) Balloon endoscopy showing intrinsic ileal stricture with ulcerative changes.\n\nMicroscopic examination of the stricture biopsies showed acute ulcerative and granulomatous ileitis with inflammatory granulation tissue positive for plentiful fungal organisms morphologically typical of Histoplasma species (Figure 2). Stains for acid-fast bacilli and cryptococcus were negative. Serum and urine Histoplasma antigens were negative. The patient subsequently failed outpatient oral itraconazole treatment due to progressive nausea, vomiting, and abdominal pain. She was hospitalized for liposomal amphotericin B treatment without therapeutic response. She was taken for partial small bowel resection, where pathology again confirmed diagnosis of histoplasmosis. She recovered well and continued on oral itraconazole for maintenance therapy for several months. Her immunosuppression was held for the duration of treatment, and she has since resumed treatment with certolizumab, an alternative anti-tumor necrosis factor (TNF) agent. As both serum and urine antigens were negative, periodic monitoring will be based on symptoms and fungal blood cultures drawn at 3-month intervals.\n\nFigure 2 Grocott-Gomori's methenamine silver stain from small bowel biopsy demonstrating Histoplasma capsulatum.\n\nDiscussion\nGI histoplasmosis is a rare but reported complication of immunosuppressed states, including patients on TNF inhibitors.8-10 The most common presenting symptoms are fever, hepatosplenomegaly, weight loss, and hematologic findings, with GI symptoms occurring in approximately one-third of patients.1 Diagnosis often is delayed due to non-specific symptoms at presentation. In one institutional review of 111 patients with disseminated histoplasmosis of any nature, only 59% were immunocompromised, highlighting the importance of considering the diagnosis even in immunocompetent hosts.1 Five percent of those patients were reported to be on TNF inhibitors.\n\nDiagnosis hinges largely on serum and urine antigen tests, which are reportedly up to 90% sensitive for the detection of disseminated disease.11 Even in this case, the majority of patients eventually require tissue biopsy for definitive diagnosis and approximately one-third require surgical intervention.1 The use of fungal DNA detection using internal transcribed spacer primer sets has been reported in cases of antigen-negative disease.12 In one pathology series of 52 cases, typical findings on GI specimens included ulcerations, hemorrhagic lesions, and nodules; however, only 6% were reported to have findings of obstructive process.13 Ileocecal fistulizing disease has been reported, as has pseudotumor mimicking malignancy.12,14 Endoscopic findings have the potential to mimic inflammatory bowel disease, and in the case of negative antigen testing, pathologic exclusion of infectious etiology is necessary prior to initiating or increasing immunosuppressive therapy.6\n\nTreatment is based on extended antifungal therapy with oral itraconazole or, in severe cases, amphotericin.15 Surgical resection may be required. Long-term maintenance therapy is required in many cases because recurrence rates are high, especially in those with intrinsic or acquired immunodeficiency. In cases of iatrogenic immunodeficiency, alteration or discontinuation of offending agents should be considered if possible.\n\nThis case illustrates the utility of small bowel enteroscopy in diagnosing suspected strictures found on imaging for which the differential diagnosis remains broad. Tissue diagnosis is required to guide management. Additionally, it is known that balloon dilation of small bowel strictures associated with Crohn’s disease results in statistically significant improvements in surgery-free intervals; however, it is unknown whether there is a similar trend for infectious strictures of this nature.16 In this case, dilation delayed surgery by several months.\n\nBalloon enteroscopy is a useful modality for the diagnosis and treatment of small bowel manifestations of disseminated histoplasmosis. GI histoplasmosis should be considered in both immunocompromised and immunocompetent hosts who have persistent fever, hepatosplenomegaly, GI complaints, and weight loss.1,3,15 Serum and urine antigen detection tests are not 100% sensitive, and further workup should be performed if clinical suspicion remains high, considering the mortality of untreated disseminated histoplasmosis can be as high as 80%. Tissue diagnosis may be required, especially in the case of negative Histoplasma antigen testing.\n\nDisclosures\nAuthor contributions: KM Rowe is the primary author and article guarantor. M. Green and F. Nehme co-wrote the manuscript. N. Tofteland edited the manuscript.\n\nFinancial disclosure: None to report.\n\nInformed consent was obtained for this case report.\n==== Refs\nReferences\n1. Assi MA , Sandid MS , Baddour LM , Roberts GD , Walker RC \nSystemic histoplasmosis: A 15-year retrospective institutional review of 111 patients . Medicine (Baltimore) . 2007 ;\n86 (3 ):162 –9 .17505255 \n2. Escobar B , Maldonado VN , Ansari S , Sarria JC \nAntigen negative gastrointestinal histoplasmosis in an AIDS patient . Am J Case Rep . 2014 ;\n15 :90 –3 .24605181 \n3. Syed U , Ching Companioni RA , Alkhawam H , Walfish A \nAmyloidosis of the gastrointestinal tract and the liver: Clinical context, diagnosis and management . Eur J Gastroenterol Hepatol . 2016 .\n4. Gumbs MA , Girishkumar H , Yousuf A , Levy L , Patel M , Narasimha V \nHistoplasmosis of the small bowel in patients with AIDS . Postgrad Med J . 2000 ;\n76 (896 ):367 –9 .10824055 \n5. Hung CC , Wong JM , Hsueh PR , Hsieh SM , Chen MY \nIntestinal obstruction and peritonitis resulting from gastrointestinal histoplasmosis in an AIDS patient . J Formos Med Assoc . 1998 ;\n97 (8 ):577 -80 .9747071 \n6. Goulet CJ , Moseley RH , Tonnerre C , Sandhu IS , Saint S \nClinical problem-solving. The unturned stone . N Engl J Med . 2005 ;\n352 (5 ):489 –94 .15689588 \n7. Rubin H , Furcolow ML , Yates JL , Brasher CA \nThe course and prognosis of histoplasmosis . Am J Med . 1959 ;\n27 :278 –88 .14439879 \n8. Galandiuk S , Davis BR \nInfliximab-induced disseminated histoplasmosis in a patient with Crohn's disease . Nat Clin Pract Gastroenterol Hepatol . 2008 ;\n5 (5 ):283 –7 .18398409 \n9. Gupta N , Fox CM , Grisolano SW \nDisseminated histoplasmosis with colonic ulcers in a patient receiving infliximab . Gastrointest Endosc . 2009 ;\n70 (3 ):597 –8 .19573865 \n10. Lee JH , Slifman NR , Gershon SK , et al \nLife-threatening histoplasmosis complicating immunotherapy with tumor necrosis factor alpha antagonists infliximab and etanercept . Arthritis Rheum . 2002 ;\n46 (10 ):2565 –70 .12384912 \n11. Wheat LJ , Kohler RB , Tewari RP \nDiagnosis of disseminated histoplasmosis by detection of Histoplasma capsulatum antigen in serum and urine specimens . N Engl J Med . 1986 ;\n314 (2 ):83 –8 .3941695 \n12. Zarrinpar A , Lin GY , Lonergan JT \nA rare cause of an ileocecal fistula in an AIDS patient: Gastrointestinal infection by Histoplasma capsulatum infection identified with internal transcribed spacer primer sets . Gastroenterology . 2013 ;\n144 (4 ):697, 857–58 .23499285 \n13. Lamps LW , Molina CP , West AB , Haggitt RC , Scott MA \nThe pathologic spectrum of gastrointestinal and hepatic histoplasmosis . Am J Clin Pathol . 2000 ;\n113 (1 ):64 –72 .10631859 \n14. Sehgal S , Chawla R , Loomba PS , Mishra B \nGastrointestinal histoplasmosis presenting as colonic pseudotumour . Indian J Med Microbiol . 2008 ;\n26 (2 ):187 –9 .18445963 \n15. Wheat LJ , Azar MM , Bahr NC , Spec A , Relich RF , Hage C \nHistoplasmosis . Infect Dis Clin North Am . 2016 ;\n30 (1 ):207 –27 .26897068 \n16. Sunada K , Shinozaki S , Nagayama M , et al \nLong-term outcomes in patients with small intestinal strictures secondary to Crohn's disease after double-balloon endoscopy-assisted balloon dilation . Inflamm Bowel Dis . 2016 ;\n22 (2 ):380 –6 .26535767\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2326-3253",
"issue": "4()",
"journal": "ACG case reports journal",
"keywords": null,
"medline_ta": "ACG Case Rep J",
"mesh_terms": null,
"nlm_unique_id": "101638398",
"other_id": null,
"pages": "e10",
"pmc": null,
"pmid": "28144615",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "14439879;26535767;19573865;18445963;10824055;26897068;9747071;24605181;10631859;15689588;3941695;23499285;17505255;27362550;12384912;18398409",
"title": "Isolated Ileal Stricture Secondary to Antigen-Negative GI Histoplasmosis in a Patient on Immunosuppressive Therapy.",
"title_normalized": "isolated ileal stricture secondary to antigen negative gi histoplasmosis in a patient on immunosuppressive therapy"
} | [
{
"companynumb": "US-MYLANLABS-2017M1032517",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nPostoperative delirium is associated with opioid use in the elderly and is a common complication of geriatric hip fractures, with reported incidences from 16% to 70%. Intravenous (IV) acetaminophen is a safe and efficacious medication in elderly patients and has been shown to reduce use of opioids after hip fracture. At our institution, IV acetaminophen was implemented for the first 24 hours postoperatively as part of a multimodal pain control regimen for geriatric hip fracture patients.\n\n\nMETHODS\nA retrospective review of 123 hip fragility fracture patients older than 60 years from January 2016 to December 2016 was performed. Delirium was identified using a validated chart-based review tool. The rate of delirium, as well as length of stay, pain scores, opioid administration, need for one-to-one supervision, and readmissions were analyzed.\n\n\nRESULTS\nSixty-five patients (52.8%) received IV acetaminophen during this period. No notable differences were found in baseline characteristics between groups. Ten of 65 patients receiving IV acetaminophen postoperatively experienced delirium compared with 19 of 58 who did not receive the medication (15.4% versus 32.8%, P = 0.024). The IV acetaminophen group also required fewer doses of IV opioids on postoperative day 1 (0.37 versus 1.19 doses, P = 0.008), were less likely to require one-to-one supervision (9.2% versus 24.1%, P = 0.025), and had shorter lengths of hospital stay (6.37 versus 8.47 days, P = 0.037). Readmission rates and discharge dispositions did not vary with significance between the two groups.\n\n\nCONCLUSIONS\nThe inclusion of IV acetaminophen as part of a multimodal pain regimen led to fewer episodes of delirium in this study. The reduced use of opioids immediately after surgery may have been a large factor in this outcome. Lower delirium rates may reduce the utilization of inpatient resources for direct patient supervision and provide for shorter hospital stays.",
"affiliations": "From the Department of Orthopaedic Surgery, University of Pennsylvania (Dr. Connolly, Ms. Kleinman, Dr. Stevenson, and Dr. Mehta), and the Department of Anesthesiology and Critical Care, University of Pennsylvania (Dr. Neuman), Philadelphia, PA.",
"authors": "Connolly|Keith P|KP|;Kleinman|Rachel S|RS|;Stevenson|Kim L|KL|;Neuman|Mark D|MD|;Mehta|Samir N|SN|",
"chemical_list": "D000701:Analgesics, Opioid; D000082:Acetaminophen",
"country": "United States",
"delete": false,
"doi": "10.5435/JAAOS-D-17-00925",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1067-151X",
"issue": "28(8)",
"journal": "The Journal of the American Academy of Orthopaedic Surgeons",
"keywords": null,
"medline_ta": "J Am Acad Orthop Surg",
"mesh_terms": "D000082:Acetaminophen; D000368:Aged; D000369:Aged, 80 and over; D000701:Analgesics, Opioid; D003693:Delirium; D005260:Female; D006620:Hip Fractures; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D010146:Pain; D059408:Pain Management; D011183:Postoperative Complications; D012189:Retrospective Studies",
"nlm_unique_id": "9417468",
"other_id": null,
"pages": "325-331",
"pmc": null,
"pmid": "31393314",
"pubdate": "2020-04-15",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Delirium Reduced With Intravenous Acetaminophen in Geriatric Hip Fracture Patients.",
"title_normalized": "delirium reduced with intravenous acetaminophen in geriatric hip fracture patients"
} | [
{
"companynumb": "US-MALLINCKRODT-T202001818",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": "3",
... |
{
"abstract": "Recurrent medulloblastoma carries a poor prognosis. Long-term survival has been obtained with high-dose chemotherapy with autologous stem cell transplantation and secondary irradiation. A 21-year-old woman with recurrent medulloblastoma after previous chemotherapy and radiotherapy is presented. The patient was treated with high-dose chemotherapy and autologous stem cell transplantation. She developed a severe treatment-related encephalopathy which affected her quality of life and neurocognitive functioning for the rest of her life. Possible causative factors are discussed and central nervous system toxicity by high-dose chemotherapy in brain tumour patients is reviewed. Case reports on severe central nervous system toxicity have been reported, but data from prospective studies on neurocognitive functioning are not available. These data strongly support a systematic long-term follow-up of brain tumour patients treated with high-dose chemotherapy with emphasis on neurocognitive function tests.",
"affiliations": "Department of Haemato-Oncology, Academical Hospital Maastricht, The Netherlands. fboo@sint.azm.nl",
"authors": "van den Berkmortel|F|F|;Gidding|C|C|;De Kanter|M|M|;Punt|C J A|CJ|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "26(1B)",
"journal": "Anticancer research",
"keywords": null,
"medline_ta": "Anticancer Res",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001932:Brain Neoplasms; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008527:Medulloblastoma; D020258:Neurotoxicity Syndromes; D033581:Stem Cell Transplantation; D014182:Transplantation, Autologous",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "729-33",
"pmc": null,
"pmid": "16739345",
"pubdate": "2006",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe encephalopathy after high-dose chemotherapy with autologous stem cell support for brain tumours.",
"title_normalized": "severe encephalopathy after high dose chemotherapy with autologous stem cell support for brain tumours"
} | [
{
"companynumb": "NL-PFIZER INC-13758",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Autoimmune hepatitis is a corticosteroid-responsive liver disease arising consequent to immunogenetic and environmental risk factors. The clinical course reflects relapsing and remitting, hepatocyte targeted immunologic damage, which is countered by reparative responses to cell injury. Appropriate and timely immunosuppressive therapy drives the disease into remission, albeit with inevitable side effects. Many challenges faced in the clinic reflect practice that must capture a heterogeneous disease presentation, course, and treatment response, as well as treatment tolerability. In this Grand Round we appraise the evidence supporting current treatment approaches, address the impact of autoimmune liver disease 'crossover or overlap' presentations, explore important clinical correlates to immune-serological classifiers, and discuss the factors influencing choice of alternative therapy in difficult-to-treat situations.",
"affiliations": "National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre (BRC), Centre for Liver and Gastroenterology Research, University of Birmingham, UK; Liver Unit, University Hospitals Birmingham, Birmingham, UK; Institute of Immunology and Immunotherapy, University of Birmingham, UK.;National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre (BRC), Centre for Liver and Gastroenterology Research, University of Birmingham, UK; Liver Unit, University Hospitals Birmingham, Birmingham, UK; Institute of Immunology and Immunotherapy, University of Birmingham, UK; Dept. of Cellular Pathology, University Hospitals Birmingham, UK.;Institute of Liver Studies, King's College Hospital, London, UK.;Liver Unit, Sheffield Teaching Hospitals Foundation Trust, UK.;National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre (BRC), Centre for Liver and Gastroenterology Research, University of Birmingham, UK; Liver Unit, University Hospitals Birmingham, Birmingham, UK; Institute of Immunology and Immunotherapy, University of Birmingham, UK; Toronto Centre for Liver Disease, University of Toronto and University Health Network, Toronto, Canada. Electronic address: gideon.hirschfield@uhn.ca.",
"authors": "Trivedi|Palak J|PJ|;Hubscher|Stefan G|SG|;Heneghan|Michael|M|;Gleeson|Dermot|D|;Hirschfield|Gideon M|GM|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents; D011239:Prednisolone; D001379:Azathioprine",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jhep.2018.11.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0168-8278",
"issue": "70(4)",
"journal": "Journal of hepatology",
"keywords": "Alternative therapies; Autoimmune hepatitis; Immune-mediated liver injury; Mycophenolate; Primary sclerosing cholangitis; Tacrolimus",
"medline_ta": "J Hepatol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000893:Anti-Inflammatory Agents; D001379:Azathioprine; D000066491:Clinical Decision-Making; D000529:Complementary Therapies; D004361:Drug Tolerance; D005260:Female; D019693:Hepatitis, Autoimmune; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D057285:Precision Medicine; D011239:Prednisolone; D012008:Recurrence; D012307:Risk Factors; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "8503886",
"other_id": null,
"pages": "773-784",
"pmc": null,
"pmid": "30465775",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Grand round: Autoimmune hepatitis.",
"title_normalized": "grand round autoimmune hepatitis"
} | [
{
"companynumb": "GB-ACCORD-102957",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Agents most frequently inducing idiosyncratic drug-induced liver injury (DILI) differ between countries worldwide. Besides, there is no consistent data on the best model predicting mortality or the need for liver transplantation in DILI. We here analysed the DILI cohort of our centre with regard to causative drugs and clinical outcome.\n\n\n\nA retrospective analysis of 157 consecutive severe DILI patients presenting to our tertiary care centre in Hamburg, Germany, from 2008 to 2018, was performed.\n\n\n\nThe most frequent putatively causative drugs were phenprocoumon (n = 21), metamizole (n = 17) and flupirtine (n = 6). The mean values of ALT, bilirubin and Model for End-stage Liver Disease (MELD) score at the time of hospitalisation were 1201 U/L (SD: 1169 U/L), 6.8 mg/dL (SD: 7 mg/dL) and 17 (SD: 8). About 71% of all cases were treated with steroids or steroids combined with n-acetylcysteine. About 12.1% of all DILI cases had a poor outcome (liver transplantation and/or death). At the time of admission, MELD score performed better than Hy's law, the ratio (R) or the new ratio (nR) on their own or combined with bilirubin, regarding sensitivity or specificity for poor outcome. MELD score had a c-statistic of 0.847 (95% CI: 0.731-0.964). Furthermore, the cut-off of 18 MELD points had a sensitivity of 88% and a specificity of 72% for poor outcome.\n\n\n\nPhenprocoumon and metamizole are frequent causative drugs for DILI in Germany. In comparison to other prognostic scores, MELD score ≥18 at the time of admission performed best in our cohort for the prediction of poor outcome in DILI.",
"affiliations": "I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.;I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.;I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.;Department of Pathology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.;Department of Pathology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.;I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.;I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.;I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.;I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.;I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.",
"authors": "Reike-Kunze|Martin|M|0000-0003-0623-1742;Zenouzi|Roman|R|;Hartel|Johannes|J|;Krech|Till|T|;Weidemann|Sören|S|;Sterneck|Martina|M|;Weiler-Normann|Christina|C|;Lohse|Ansgar W|AW|;Schramm|Christoph|C|;Sebode|Marcial|M|0000-0002-5163-6979",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/liv.14985",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1478-3223",
"issue": "41(10)",
"journal": "Liver international : official journal of the International Association for the Study of the Liver",
"keywords": "MELD; acute liver failure; drug-induced liver injury; liver transplantation; outcome",
"medline_ta": "Liver Int",
"mesh_terms": "D056486:Chemical and Drug Induced Liver Injury; D058625:End Stage Liver Disease; D005858:Germany; D006801:Humans; D012189:Retrospective Studies; D012720:Severity of Illness Index; D062606:Tertiary Care Centers",
"nlm_unique_id": "101160857",
"other_id": null,
"pages": "2383-2395",
"pmc": null,
"pmid": "34152686",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Drug-induced liver injury at a tertiary care centre in Germany: Model for end-stage liver disease is the best predictor of outcome.",
"title_normalized": "drug induced liver injury at a tertiary care centre in germany model for end stage liver disease is the best predictor of outcome"
} | [
{
"companynumb": "DE-LUPIN PHARMACEUTICALS INC.-2021-24365",
"fulfillexpeditecriteria": "2",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DICLOFENAC"
},
"drugadditional... |
{
"abstract": "Hypersensitivity reactions caused by carboplatin rarely occur. These reactions can cause lethal complications and make subsequent therapeutic approaches difficult. To date, only a few cases of successful resolution of hypersensitivity by replacement of carboplatin with cisplatin have been reported. We report on a patient with serous papillary extra-ovarian peritoneal carcinoma who developed a hypersensitivity reaction after the 10th weekly administration of carboplatin. Two weeks after reaction, intradermal skin testing with paclitaxel, carboplatin, cisplatin, and mannitol showed intense reaction only to carboplatin. On the basis of these results, the patient was changed to a chemotherapy with cisplatin and paclitaxel. A further eight courses of chemotherapy were administered without evidence of hypersensitivity reactions. Carboplatin seems to be successfully replaceable by cisplatin in case of hypersensitivity reactions.",
"affiliations": "Medical Oncology Unit, University of L'Aquila, Italy.",
"authors": "Porzio|G|G|;Marchetti|P|P|;Paris|I|I|;Narducci|F|F|;Ricevuto|E|E|;Ficorella|C|C|",
"chemical_list": "D000970:Antineoplastic Agents; D016190:Carboplatin; D017239:Paclitaxel; D002945:Cisplatin",
"country": "China",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0392-2936",
"issue": "23(4)",
"journal": "European journal of gynaecological oncology",
"keywords": null,
"medline_ta": "Eur J Gynaecol Oncol",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D018269:Carcinoma, Endometrioid; D002945:Cisplatin; D003937:Diagnosis, Differential; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D017239:Paclitaxel; D010534:Peritoneal Neoplasms; D012882:Skin Tests",
"nlm_unique_id": "8100357",
"other_id": null,
"pages": "335-6",
"pmc": null,
"pmid": "12214738",
"pubdate": "2002",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hypersensitivity reaction to carboplatin: successful resolution by replacement with cisplatin.",
"title_normalized": "hypersensitivity reaction to carboplatin successful resolution by replacement with cisplatin"
} | [
{
"companynumb": "IT-PFIZER INC-2019266368",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nWe present a case of acute rhabdomyolysis in the setting of interferon-β treatment and concomitant pomelo juice ingestion, with concern of possible pharmacological interaction, which has not yet been described in the literature.\n\n\nMETHODS\nA young Caucasian female with multiple sclerosis on chronic therapy with interferon-β presented with acute rhabdomyolysis after mild exercise and concomitant ingestion of pomelo extract. After stopping the suspected drugs, the signs of rhabdomyolysis diminished, the subsequent course was favorable.\n\n\nCONCLUSIONS\nThe most probable cause of rhabdomyolysis in our patient could have been the combination of interferon effect, which down-regulates P450 expression, with inhibition of the P450 activity by furanocoumarin derivatives from pomelo juice. Therefore, patients treated with drugs that have a possible interaction with inhibitors of cytochrome P450 should be warned against pomelo ingestion.
.",
"affiliations": null,
"authors": "Jerman|Alexander|A|;Kovač|Damjan|D|;Večerić-Haler|Željka|Ž|;Hočevar|Alojzija|A|;Ota|Ajda|A|;Banović|Sanela|S|;Lindič|Jelka|J|",
"chemical_list": "D016899:Interferon-beta",
"country": "Germany",
"delete": false,
"doi": "10.5414/CNP88FX08",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-0430",
"issue": "88(13)",
"journal": "Clinical nephrology",
"keywords": null,
"medline_ta": "Clin Nephrol",
"mesh_terms": "D000328:Adult; D002957:Citrus; D005260:Female; D018565:Food-Drug Interactions; D000067030:Fruit and Vegetable Juices; D006801:Humans; D016899:Interferon-beta; D009103:Multiple Sclerosis; D012206:Rhabdomyolysis",
"nlm_unique_id": "0364441",
"other_id": null,
"pages": "32-34",
"pmc": null,
"pmid": "28655386",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Rhabdomyolysis and interferon-β: case report and short review.",
"title_normalized": "rhabdomyolysis and interferon case report and short review"
} | [
{
"companynumb": "SI-EMD SERONO-8172404",
"fulfillexpeditecriteria": "1",
"occurcountry": "SI",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INTERFERON BETA"
},
"drugadditional": "1",
... |
{
"abstract": "Laryngopharyngeal herpes simplex virus infection is rare and presents typically in the supraglottis. Findings on presentation can range from small mucosal lesions to fungating obstructive masses mimicking neoplasm. Laryngopharyngeal herpes is a medically treated disease.\nIdentify potential treatment in cases that are refractory to antiviral medications.\nIndividual case with treatment adapted from other case report.\nWe report a case of bulky, obstructive supraglottic and glottic herpes virus laryngitis that presented with dysphonia, dysphagia, and airway complaints resistant to acyclovir analogues that was treated effectively with intralesional cidofovir injection.\nOur promising initial response suggests a potential novel treatment for this unusual condition.",
"affiliations": "1 Department of Otolaryngology, Walter Reed National Military Medical Center, Bethesda, MD, USA.;2 Departmant of Infectious Disease, Medstar Georgetown University Hospital, Washington, DC, USA.;2 Departmant of Infectious Disease, Medstar Georgetown University Hospital, Washington, DC, USA.;3 Johns Hopkins Otolaryngology-Laryngology Division, Bethesda, MD, USA.",
"authors": "Yang|Charles Q|CQ|https://orcid.org/0000-0001-8673-0327;Mathur|Anisha|A|;Kumar|Princy N|PN|;Dhillon|Vaninder K|VK|",
"chemical_list": "D000998:Antiviral Agents; D000077404:Cidofovir; D000212:Acyclovir",
"country": "United States",
"delete": false,
"doi": "10.1177/0003489418818579",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-4894",
"issue": "128(3)",
"journal": "The Annals of otology, rhinology, and laryngology",
"keywords": "cidofovir; dysphagia; dysphonia; herpes; intralesional; laryngitis; supraglottis",
"medline_ta": "Ann Otol Rhinol Laryngol",
"mesh_terms": "D000212:Acyclovir; D000998:Antiviral Agents; D000077404:Cidofovir; D006561:Herpes Simplex; D006801:Humans; D015552:Injections, Intralesional; D007827:Laryngitis; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "0407300",
"other_id": null,
"pages": "267-270",
"pmc": null,
"pmid": "30556399",
"pubdate": "2019-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intralesional Cidofovir for Treatment of Acyclovir-Resistant Laryngeal Herpes Manifesting as Supraglottic Mass.",
"title_normalized": "intralesional cidofovir for treatment of acyclovir resistant laryngeal herpes manifesting as supraglottic mass"
} | [
{
"companynumb": "US-TEVA-2019-US-1019712",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FOSCARNET"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nVitamin D has been shown to be related to autoimmune diseases, such as multiple sclerosis and psoriasis. Correlations have been reported between vitamin D levels and prevalence and severity of other autoimmune disorders, and also between vitamin D therapy and disease improvement and remission.\n\n\nMETHODS\nThis is a case report of a patient with severe and refractory myasthenia gravis (MG) who followed a \"high-dose vitamin D treatment\", a massive-dose treatment (80,000 to 120,000 IU/day) promoted by a medical center in Brazil (but still not proven), and she had her first complete remission after this type of treatment with increased vitamin D serum levels (400 to 700 ng/mL).\n\n\nCONCLUSIONS\nThis case report may reinforce the reported correlation between vitamin D level and disease severity and introduces a possible new use for vitamin D as a potential target for treating autoimmune diseases. We recommend large, double-blind, placebo-controlled, randomized studies using high-dose vitamin D treatment for refractory autoimmune diseases to reliably assess this pharmacotherapy target for these diseases.",
"affiliations": "Endocrinology Unit, Corpometria, Brasilia, Brazil.",
"authors": "Cadegiani|Flávio Adsuara|FA|",
"chemical_list": "D014815:Vitamins; D014807:Vitamin D",
"country": "United States",
"delete": false,
"doi": "10.12659/ajcr.894849",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1941-5923",
"issue": "17()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008875:Middle Aged; D009157:Myasthenia Gravis; D012074:Remission Induction; D012720:Severity of Illness Index; D014807:Vitamin D; D014815:Vitamins",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "51-4",
"pmc": null,
"pmid": "26822380",
"pubdate": "2016-01-29",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21419266;25669999;24795646;25852682;25590278;25867468;21845364;23999998;24769422;25580272;21664425;23253802;25666936;24895631;22672742",
"title": "Remission of Severe Myasthenia Gravis After Massive-Dose Vitamin D Treatment.",
"title_normalized": "remission of severe myasthenia gravis after massive dose vitamin d treatment"
} | [
{
"companynumb": "BR-VALIDUS PHARMACEUTICALS LLC-BR-2016VAL001579",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PYRIDOSTIGMINE"
},
"dru... |
{
"abstract": "Both carboplatin and vinblastine have demonstrated single-agent activity in children with low-grade gliomas. A phase 1 trial evaluating 2 different schedules of these 2 agents in combination was performed: (1) Schedule A = carboplatin (140 mg/m(2)) weekly × 3 + vinblastine (4.5 or 3.5 mg/m(2)) weekly × 6, every 6 weeks; (2) Schedule B = carboplatin (300, 400, or 500 mg/m(2)) on day 1 + vinblastine (4.0 mg/m(2)) weekly × 3, every 4 weeks. Twenty-six patients, median (range) age 4.4 (0.7-14.8) years, were enrolled. Four of 9 patients enrolled on Schedule A had recurrent grade 4 neutropenia, suggesting that this schedule was not feasible. Seventeen patients were enrolled on Schedule B. At the 500 mg/m(2) carboplatin dose level, 2 of 3 patients developed dose-limiting toxicity (elevated alkaline phosphatase, neutropenia). At the 400 mg/m(2) carboplatin dose level, none of the 6 patients had dose-limiting toxicity. Ten of 16 patients who received treatment on Schedule B completed the prescribed 12 courses. Of the 21 patients evaluable for response, central review confirmed 1 partial response and 6 minor responses. Eleven patients had stable disease (>3 months) and 3 developed progressive disease. Seven of 9 patients with visual pathway tumors and acute visual changes prior to enrollment had documented improvement. The recommended phase 2 dose and schedule is carboplatin, 400 mg/m(2)/dose on day 1, and vinblastine, 4 mg/m(2)/dose, weekly × 3, repeated every 4 weeks. Further study of this regimen in patients with low-grade glioma is warranted.",
"affiliations": "Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA. regina.jakacki@chp.edu",
"authors": "Jakacki|Regina I|RI|;Bouffet|Eric|E|;Adamson|Peter C|PC|;Pollack|Ian F|IF|;Ingle|Ashish M|AM|;Voss|Stephan D|SD|;Blaney|Susan M|SM|",
"chemical_list": "D014747:Vinblastine; D016190:Carboplatin",
"country": "England",
"delete": false,
"doi": "10.1093/neuonc/nor090",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1522-8517",
"issue": "13(8)",
"journal": "Neuro-oncology",
"keywords": null,
"medline_ta": "Neuro Oncol",
"mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D001932:Brain Neoplasms; D016190:Carboplatin; D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D005910:Glioma; D006801:Humans; D007223:Infant; D008297:Male; D020714:Maximum Tolerated Dose; D009367:Neoplasm Staging; D015996:Survival Rate; D016896:Treatment Outcome; D014747:Vinblastine",
"nlm_unique_id": "100887420",
"other_id": null,
"pages": "910-5",
"pmc": null,
"pmid": "21764821",
"pubdate": "2011-08",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "10359145;10590059;10772661;17347491;9126887;11265230;12089224;22393086;10339466;12569610;9195288;17704361;9049885",
"title": "A phase 1 study of vinblastine in combination with carboplatin for children with low-grade gliomas: a Children's Oncology Group phase 1 consortium study.",
"title_normalized": "a phase 1 study of vinblastine in combination with carboplatin for children with low grade gliomas a children s oncology group phase 1 consortium study"
} | [
{
"companynumb": "US-CIPLA LTD.-2016US07977",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VINBLASTINE"
},
"drugadditional": null,
... |
{
"abstract": "The use of naltrexone plus bupropion to treat methamphetamine use disorder has not been well studied.\n\n\n\nWe conducted this multisite, double-blind, two-stage, placebo-controlled trial with the use of a sequential parallel comparison design to evaluate the efficacy and safety of extended-release injectable naltrexone (380 mg every 3 weeks) plus oral extended-release bupropion (450 mg per day) in adults with moderate or severe methamphetamine use disorder. In the first stage of the trial, participants were randomly assigned in a 0.26:0.74 ratio to receive naltrexone-bupropion or matching injectable and oral placebo for 6 weeks. Those in the placebo group who did not have a response in stage 1 underwent rerandomization in stage 2 and were assigned in a 1:1 ratio to receive naltrexone-bupropion or placebo for an additional 6 weeks. Urine samples were obtained from participants twice weekly. The primary outcome was a response, defined as at least three methamphetamine-negative urine samples out of four samples obtained at the end of stage 1 or stage 2, and the weighted average of the responses in the two stages is reported. The treatment effect was defined as the between-group difference in the overall weighted responses.\n\n\n\nA total of 403 participants were enrolled in stage 1, and 225 in stage 2. In the first stage, 18 of 109 participants (16.5%) in the naltrexone-bupropion group and 10 of 294 (3.4%) in the placebo group had a response. In the second stage, 13 of 114 (11.4%) in the naltrexone-bupropion group and 2 of 111 (1.8%) in the placebo group had a response. The weighted average response across the two stages was 13.6% with naltrexone-bupropion and 2.5% with placebo, for an overall treatment effect of 11.1 percentage points (Wald z-test statistic, 4.53; P<0.001). Adverse events with naltrexone-bupropion included gastrointestinal disorders, tremor, malaise, hyperhidrosis, and anorexia. Serious adverse events occurred in 8 of 223 participants (3.6%) who received naltrexone-bupropion during the trial.\n\n\n\nAmong adults with methamphetamine use disorder, the response over a period of 12 weeks among participants who received extended-release injectable naltrexone plus oral extended-release bupropion was low but was higher than that among participants who received placebo. (Funded by the National Institute on Drug Abuse and others; ADAPT-2 ClinicalTrials.gov number, NCT03078075.).",
"affiliations": "From the Peter O'Donnell Jr. Brain Institute at the University of Texas Southwestern Medical Center (M.H.T.) and the University of Texas Southwestern Medical Center (R.W., A.C., T.C., M.K., K.S.-W., S.W.), Dallas, the University of Texas Health Science Center at Houston, Houston (J.S.), and Texas Tech University, Permian Basin, Odessa (A.J.R.); the University of California, Los Angeles, Los Angeles (W.L., S. Shoptaw); the Emmes Company, Rockville (G.S., A.W.), and the National Institute on Drug Abuse Center for the Clinical Trials Network (U.E.G., S. Sparenborg [retired]), Rockville - both in Maryland; the San Francisco Department of Public Health and the University of California, San Francisco, San Francisco (P.C.); CODA, Portland, OR (K.W.); Hennepin Healthcare, University of Minnesota, Minneapolis (G.B.); Medical University of South Carolina, Charleston (S.C.S.); Duke-National University of Singapore, Singapore (A.J.R.); Duke Medical School, Durham, NC (A.J.R.); and Columbia University, New York (E.V.N.).;From the Peter O'Donnell Jr. Brain Institute at the University of Texas Southwestern Medical Center (M.H.T.) and the University of Texas Southwestern Medical Center (R.W., A.C., T.C., M.K., K.S.-W., S.W.), Dallas, the University of Texas Health Science Center at Houston, Houston (J.S.), and Texas Tech University, Permian Basin, Odessa (A.J.R.); the University of California, Los Angeles, Los Angeles (W.L., S. Shoptaw); the Emmes Company, Rockville (G.S., A.W.), and the National Institute on Drug Abuse Center for the Clinical Trials Network (U.E.G., S. Sparenborg [retired]), Rockville - both in Maryland; the San Francisco Department of Public Health and the University of California, San Francisco, San Francisco (P.C.); CODA, Portland, OR (K.W.); Hennepin Healthcare, University of Minnesota, Minneapolis (G.B.); Medical University of South Carolina, Charleston (S.C.S.); Duke-National University of Singapore, Singapore (A.J.R.); Duke Medical School, Durham, NC (A.J.R.); and Columbia University, New York (E.V.N.).;From the Peter O'Donnell Jr. Brain Institute at the University of Texas Southwestern Medical Center (M.H.T.) and the University of Texas Southwestern Medical Center (R.W., A.C., T.C., M.K., K.S.-W., S.W.), Dallas, the University of Texas Health Science Center at Houston, Houston (J.S.), and Texas Tech University, Permian Basin, Odessa (A.J.R.); the University of California, Los Angeles, Los Angeles (W.L., S. Shoptaw); the Emmes Company, Rockville (G.S., A.W.), and the National Institute on Drug Abuse Center for the Clinical Trials Network (U.E.G., S. Sparenborg [retired]), Rockville - both in Maryland; the San Francisco Department of Public Health and the University of California, San Francisco, San Francisco (P.C.); CODA, Portland, OR (K.W.); Hennepin Healthcare, University of Minnesota, Minneapolis (G.B.); Medical University of South Carolina, Charleston (S.C.S.); Duke-National University of Singapore, Singapore (A.J.R.); Duke Medical School, Durham, NC (A.J.R.); and Columbia University, New York (E.V.N.).;From the Peter O'Donnell Jr. Brain Institute at the University of Texas Southwestern Medical Center (M.H.T.) and the University of Texas Southwestern Medical Center (R.W., A.C., T.C., M.K., K.S.-W., S.W.), Dallas, the University of Texas Health Science Center at Houston, Houston (J.S.), and Texas Tech University, Permian Basin, Odessa (A.J.R.); the University of California, Los Angeles, Los Angeles (W.L., S. Shoptaw); the Emmes Company, Rockville (G.S., A.W.), and the National Institute on Drug Abuse Center for the Clinical Trials Network (U.E.G., S. Sparenborg [retired]), Rockville - both in Maryland; the San Francisco Department of Public Health and the University of California, San Francisco, San Francisco (P.C.); CODA, Portland, OR (K.W.); Hennepin Healthcare, University of Minnesota, Minneapolis (G.B.); Medical University of South Carolina, Charleston (S.C.S.); Duke-National University of Singapore, Singapore (A.J.R.); Duke Medical School, Durham, NC (A.J.R.); and Columbia University, New York (E.V.N.).;From the Peter O'Donnell Jr. Brain Institute at the University of Texas Southwestern Medical Center (M.H.T.) and the University of Texas Southwestern Medical Center (R.W., A.C., T.C., M.K., K.S.-W., S.W.), Dallas, the University of Texas Health Science Center at Houston, Houston (J.S.), and Texas Tech University, Permian Basin, Odessa (A.J.R.); the University of California, Los Angeles, Los Angeles (W.L., S. Shoptaw); the Emmes Company, Rockville (G.S., A.W.), and the National Institute on Drug Abuse Center for the Clinical Trials Network (U.E.G., S. Sparenborg [retired]), Rockville - both in Maryland; the San Francisco Department of Public Health and the University of California, San Francisco, San Francisco (P.C.); CODA, Portland, OR (K.W.); Hennepin Healthcare, University of Minnesota, Minneapolis (G.B.); Medical University of South Carolina, Charleston (S.C.S.); Duke-National University of Singapore, Singapore (A.J.R.); Duke Medical School, Durham, NC (A.J.R.); and Columbia University, New York (E.V.N.).;From the Peter O'Donnell Jr. Brain Institute at the University of Texas Southwestern Medical Center (M.H.T.) and the University of Texas Southwestern Medical Center (R.W., A.C., T.C., M.K., K.S.-W., S.W.), Dallas, the University of Texas Health Science Center at Houston, Houston (J.S.), and Texas Tech University, Permian Basin, Odessa (A.J.R.); the University of California, Los Angeles, Los Angeles (W.L., S. Shoptaw); the Emmes Company, Rockville (G.S., A.W.), and the National Institute on Drug Abuse Center for the Clinical Trials Network (U.E.G., S. Sparenborg [retired]), Rockville - both in Maryland; the San Francisco Department of Public Health and the University of California, San Francisco, San Francisco (P.C.); CODA, Portland, OR (K.W.); Hennepin Healthcare, University of Minnesota, Minneapolis (G.B.); Medical University of South Carolina, Charleston (S.C.S.); Duke-National University of Singapore, Singapore (A.J.R.); Duke Medical School, Durham, NC (A.J.R.); and Columbia University, New York (E.V.N.).;From the Peter O'Donnell Jr. Brain Institute at the University of Texas Southwestern Medical Center (M.H.T.) and the University of Texas Southwestern Medical Center (R.W., A.C., T.C., M.K., K.S.-W., S.W.), Dallas, the University of Texas Health Science Center at Houston, Houston (J.S.), and Texas Tech University, Permian Basin, Odessa (A.J.R.); the University of California, Los Angeles, Los Angeles (W.L., S. Shoptaw); the Emmes Company, Rockville (G.S., A.W.), and the National Institute on Drug Abuse Center for the Clinical Trials Network (U.E.G., S. Sparenborg [retired]), Rockville - both in Maryland; the San Francisco Department of Public Health and the University of California, San Francisco, San Francisco (P.C.); CODA, Portland, OR (K.W.); Hennepin Healthcare, University of Minnesota, Minneapolis (G.B.); Medical University of South Carolina, Charleston (S.C.S.); Duke-National University of Singapore, Singapore (A.J.R.); Duke Medical School, Durham, NC (A.J.R.); and Columbia University, New York (E.V.N.).;From the Peter O'Donnell Jr. Brain Institute at the University of Texas Southwestern Medical Center (M.H.T.) and the University of Texas Southwestern Medical Center (R.W., A.C., T.C., M.K., K.S.-W., S.W.), Dallas, the University of Texas Health Science Center at Houston, Houston (J.S.), and Texas Tech University, Permian Basin, Odessa (A.J.R.); the University of California, Los Angeles, Los Angeles (W.L., S. Shoptaw); the Emmes Company, Rockville (G.S., A.W.), and the National Institute on Drug Abuse Center for the Clinical Trials Network (U.E.G., S. Sparenborg [retired]), Rockville - both in Maryland; the San Francisco Department of Public Health and the University of California, San Francisco, San Francisco (P.C.); CODA, Portland, OR (K.W.); Hennepin Healthcare, University of Minnesota, Minneapolis (G.B.); Medical University of South Carolina, Charleston (S.C.S.); Duke-National University of Singapore, Singapore (A.J.R.); Duke Medical School, Durham, NC (A.J.R.); and Columbia University, New York (E.V.N.).;From the Peter O'Donnell Jr. Brain Institute at the University of Texas Southwestern Medical Center (M.H.T.) and the University of Texas Southwestern Medical Center (R.W., A.C., T.C., M.K., K.S.-W., S.W.), Dallas, the University of Texas Health Science Center at Houston, Houston (J.S.), and Texas Tech University, Permian Basin, Odessa (A.J.R.); the University of California, Los Angeles, Los Angeles (W.L., S. Shoptaw); the Emmes Company, Rockville (G.S., A.W.), and the National Institute on Drug Abuse Center for the Clinical Trials Network (U.E.G., S. Sparenborg [retired]), Rockville - both in Maryland; the San Francisco Department of Public Health and the University of California, San Francisco, San Francisco (P.C.); CODA, Portland, OR (K.W.); Hennepin Healthcare, University of Minnesota, Minneapolis (G.B.); Medical University of South Carolina, Charleston (S.C.S.); Duke-National University of Singapore, Singapore (A.J.R.); Duke Medical School, Durham, NC (A.J.R.); and Columbia University, New York (E.V.N.).;From the Peter O'Donnell Jr. Brain Institute at the University of Texas Southwestern Medical Center (M.H.T.) and the University of Texas Southwestern Medical Center (R.W., A.C., T.C., M.K., K.S.-W., S.W.), Dallas, the University of Texas Health Science Center at Houston, Houston (J.S.), and Texas Tech University, Permian Basin, Odessa (A.J.R.); the University of California, Los Angeles, Los Angeles (W.L., S. Shoptaw); the Emmes Company, Rockville (G.S., A.W.), and the National Institute on Drug Abuse Center for the Clinical Trials Network (U.E.G., S. Sparenborg [retired]), Rockville - both in Maryland; the San Francisco Department of Public Health and the University of California, San Francisco, San Francisco (P.C.); CODA, Portland, OR (K.W.); Hennepin Healthcare, University of Minnesota, Minneapolis (G.B.); Medical University of South Carolina, Charleston (S.C.S.); Duke-National University of Singapore, Singapore (A.J.R.); Duke Medical School, Durham, NC (A.J.R.); and Columbia University, New York (E.V.N.).;From the Peter O'Donnell Jr. Brain Institute at the University of Texas Southwestern Medical Center (M.H.T.) and the University of Texas Southwestern Medical Center (R.W., A.C., T.C., M.K., K.S.-W., S.W.), Dallas, the University of Texas Health Science Center at Houston, Houston (J.S.), and Texas Tech University, Permian Basin, Odessa (A.J.R.); the University of California, Los Angeles, Los Angeles (W.L., S. Shoptaw); the Emmes Company, Rockville (G.S., A.W.), and the National Institute on Drug Abuse Center for the Clinical Trials Network (U.E.G., S. Sparenborg [retired]), Rockville - both in Maryland; the San Francisco Department of Public Health and the University of California, San Francisco, San Francisco (P.C.); CODA, Portland, OR (K.W.); Hennepin Healthcare, University of Minnesota, Minneapolis (G.B.); Medical University of South Carolina, Charleston (S.C.S.); Duke-National University of Singapore, Singapore (A.J.R.); Duke Medical School, Durham, NC (A.J.R.); and Columbia University, New York (E.V.N.).;From the Peter O'Donnell Jr. Brain Institute at the University of Texas Southwestern Medical Center (M.H.T.) and the University of Texas Southwestern Medical Center (R.W., A.C., T.C., M.K., K.S.-W., S.W.), Dallas, the University of Texas Health Science Center at Houston, Houston (J.S.), and Texas Tech University, Permian Basin, Odessa (A.J.R.); the University of California, Los Angeles, Los Angeles (W.L., S. Shoptaw); the Emmes Company, Rockville (G.S., A.W.), and the National Institute on Drug Abuse Center for the Clinical Trials Network (U.E.G., S. Sparenborg [retired]), Rockville - both in Maryland; the San Francisco Department of Public Health and the University of California, San Francisco, San Francisco (P.C.); CODA, Portland, OR (K.W.); Hennepin Healthcare, University of Minnesota, Minneapolis (G.B.); Medical University of South Carolina, Charleston (S.C.S.); Duke-National University of Singapore, Singapore (A.J.R.); Duke Medical School, Durham, NC (A.J.R.); and Columbia University, New York (E.V.N.).;From the Peter O'Donnell Jr. Brain Institute at the University of Texas Southwestern Medical Center (M.H.T.) and the University of Texas Southwestern Medical Center (R.W., A.C., T.C., M.K., K.S.-W., S.W.), Dallas, the University of Texas Health Science Center at Houston, Houston (J.S.), and Texas Tech University, Permian Basin, Odessa (A.J.R.); the University of California, Los Angeles, Los Angeles (W.L., S. Shoptaw); the Emmes Company, Rockville (G.S., A.W.), and the National Institute on Drug Abuse Center for the Clinical Trials Network (U.E.G., S. Sparenborg [retired]), Rockville - both in Maryland; the San Francisco Department of Public Health and the University of California, San Francisco, San Francisco (P.C.); CODA, Portland, OR (K.W.); Hennepin Healthcare, University of Minnesota, Minneapolis (G.B.); Medical University of South Carolina, Charleston (S.C.S.); Duke-National University of Singapore, Singapore (A.J.R.); Duke Medical School, Durham, NC (A.J.R.); and Columbia University, New York (E.V.N.).;From the Peter O'Donnell Jr. Brain Institute at the University of Texas Southwestern Medical Center (M.H.T.) and the University of Texas Southwestern Medical Center (R.W., A.C., T.C., M.K., K.S.-W., S.W.), Dallas, the University of Texas Health Science Center at Houston, Houston (J.S.), and Texas Tech University, Permian Basin, Odessa (A.J.R.); the University of California, Los Angeles, Los Angeles (W.L., S. Shoptaw); the Emmes Company, Rockville (G.S., A.W.), and the National Institute on Drug Abuse Center for the Clinical Trials Network (U.E.G., S. Sparenborg [retired]), Rockville - both in Maryland; the San Francisco Department of Public Health and the University of California, San Francisco, San Francisco (P.C.); CODA, Portland, OR (K.W.); Hennepin Healthcare, University of Minnesota, Minneapolis (G.B.); Medical University of South Carolina, Charleston (S.C.S.); Duke-National University of Singapore, Singapore (A.J.R.); Duke Medical School, Durham, NC (A.J.R.); and Columbia University, New York (E.V.N.).;From the Peter O'Donnell Jr. Brain Institute at the University of Texas Southwestern Medical Center (M.H.T.) and the University of Texas Southwestern Medical Center (R.W., A.C., T.C., M.K., K.S.-W., S.W.), Dallas, the University of Texas Health Science Center at Houston, Houston (J.S.), and Texas Tech University, Permian Basin, Odessa (A.J.R.); the University of California, Los Angeles, Los Angeles (W.L., S. Shoptaw); the Emmes Company, Rockville (G.S., A.W.), and the National Institute on Drug Abuse Center for the Clinical Trials Network (U.E.G., S. Sparenborg [retired]), Rockville - both in Maryland; the San Francisco Department of Public Health and the University of California, San Francisco, San Francisco (P.C.); CODA, Portland, OR (K.W.); Hennepin Healthcare, University of Minnesota, Minneapolis (G.B.); Medical University of South Carolina, Charleston (S.C.S.); Duke-National University of Singapore, Singapore (A.J.R.); Duke Medical School, Durham, NC (A.J.R.); and Columbia University, New York (E.V.N.).;From the Peter O'Donnell Jr. Brain Institute at the University of Texas Southwestern Medical Center (M.H.T.) and the University of Texas Southwestern Medical Center (R.W., A.C., T.C., M.K., K.S.-W., S.W.), Dallas, the University of Texas Health Science Center at Houston, Houston (J.S.), and Texas Tech University, Permian Basin, Odessa (A.J.R.); the University of California, Los Angeles, Los Angeles (W.L., S. Shoptaw); the Emmes Company, Rockville (G.S., A.W.), and the National Institute on Drug Abuse Center for the Clinical Trials Network (U.E.G., S. Sparenborg [retired]), Rockville - both in Maryland; the San Francisco Department of Public Health and the University of California, San Francisco, San Francisco (P.C.); CODA, Portland, OR (K.W.); Hennepin Healthcare, University of Minnesota, Minneapolis (G.B.); Medical University of South Carolina, Charleston (S.C.S.); Duke-National University of Singapore, Singapore (A.J.R.); Duke Medical School, Durham, NC (A.J.R.); and Columbia University, New York (E.V.N.).;From the Peter O'Donnell Jr. Brain Institute at the University of Texas Southwestern Medical Center (M.H.T.) and the University of Texas Southwestern Medical Center (R.W., A.C., T.C., M.K., K.S.-W., S.W.), Dallas, the University of Texas Health Science Center at Houston, Houston (J.S.), and Texas Tech University, Permian Basin, Odessa (A.J.R.); the University of California, Los Angeles, Los Angeles (W.L., S. Shoptaw); the Emmes Company, Rockville (G.S., A.W.), and the National Institute on Drug Abuse Center for the Clinical Trials Network (U.E.G., S. Sparenborg [retired]), Rockville - both in Maryland; the San Francisco Department of Public Health and the University of California, San Francisco, San Francisco (P.C.); CODA, Portland, OR (K.W.); Hennepin Healthcare, University of Minnesota, Minneapolis (G.B.); Medical University of South Carolina, Charleston (S.C.S.); Duke-National University of Singapore, Singapore (A.J.R.); Duke Medical School, Durham, NC (A.J.R.); and Columbia University, New York (E.V.N.).;From the Peter O'Donnell Jr. Brain Institute at the University of Texas Southwestern Medical Center (M.H.T.) and the University of Texas Southwestern Medical Center (R.W., A.C., T.C., M.K., K.S.-W., S.W.), Dallas, the University of Texas Health Science Center at Houston, Houston (J.S.), and Texas Tech University, Permian Basin, Odessa (A.J.R.); the University of California, Los Angeles, Los Angeles (W.L., S. Shoptaw); the Emmes Company, Rockville (G.S., A.W.), and the National Institute on Drug Abuse Center for the Clinical Trials Network (U.E.G., S. Sparenborg [retired]), Rockville - both in Maryland; the San Francisco Department of Public Health and the University of California, San Francisco, San Francisco (P.C.); CODA, Portland, OR (K.W.); Hennepin Healthcare, University of Minnesota, Minneapolis (G.B.); Medical University of South Carolina, Charleston (S.C.S.); Duke-National University of Singapore, Singapore (A.J.R.); Duke Medical School, Durham, NC (A.J.R.); and Columbia University, New York (E.V.N.).;From the Peter O'Donnell Jr. Brain Institute at the University of Texas Southwestern Medical Center (M.H.T.) and the University of Texas Southwestern Medical Center (R.W., A.C., T.C., M.K., K.S.-W., S.W.), Dallas, the University of Texas Health Science Center at Houston, Houston (J.S.), and Texas Tech University, Permian Basin, Odessa (A.J.R.); the University of California, Los Angeles, Los Angeles (W.L., S. Shoptaw); the Emmes Company, Rockville (G.S., A.W.), and the National Institute on Drug Abuse Center for the Clinical Trials Network (U.E.G., S. Sparenborg [retired]), Rockville - both in Maryland; the San Francisco Department of Public Health and the University of California, San Francisco, San Francisco (P.C.); CODA, Portland, OR (K.W.); Hennepin Healthcare, University of Minnesota, Minneapolis (G.B.); Medical University of South Carolina, Charleston (S.C.S.); Duke-National University of Singapore, Singapore (A.J.R.); Duke Medical School, Durham, NC (A.J.R.); and Columbia University, New York (E.V.N.).;From the Peter O'Donnell Jr. Brain Institute at the University of Texas Southwestern Medical Center (M.H.T.) and the University of Texas Southwestern Medical Center (R.W., A.C., T.C., M.K., K.S.-W., S.W.), Dallas, the University of Texas Health Science Center at Houston, Houston (J.S.), and Texas Tech University, Permian Basin, Odessa (A.J.R.); the University of California, Los Angeles, Los Angeles (W.L., S. Shoptaw); the Emmes Company, Rockville (G.S., A.W.), and the National Institute on Drug Abuse Center for the Clinical Trials Network (U.E.G., S. Sparenborg [retired]), Rockville - both in Maryland; the San Francisco Department of Public Health and the University of California, San Francisco, San Francisco (P.C.); CODA, Portland, OR (K.W.); Hennepin Healthcare, University of Minnesota, Minneapolis (G.B.); Medical University of South Carolina, Charleston (S.C.S.); Duke-National University of Singapore, Singapore (A.J.R.); Duke Medical School, Durham, NC (A.J.R.); and Columbia University, New York (E.V.N.).",
"authors": "Trivedi|Madhukar H|MH|;Walker|Robrina|R|;Ling|Walter|W|;Dela Cruz|Adriane|A|;Sharma|Gaurav|G|;Carmody|Thomas|T|;Ghitza|Udi E|UE|;Wahle|Aimee|A|;Kim|Mora|M|;Shores-Wilson|Kathy|K|;Sparenborg|Steven|S|;Coffin|Phillip|P|;Schmitz|Joy|J|;Wiest|Katharina|K|;Bart|Gavin|G|;Sonne|Susan C|SC|;Wakhlu|Sidarth|S|;Rush|A John|AJ|;Nunes|Edward V|EV|;Shoptaw|Steven|S|",
"chemical_list": "D003692:Delayed-Action Preparations; D009292:Narcotic Antagonists; D016642:Bupropion; D008694:Methamphetamine; D009271:Naltrexone",
"country": "United States",
"delete": false,
"doi": "10.1056/NEJMoa2020214",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-4793",
"issue": "384(2)",
"journal": "The New England journal of medicine",
"keywords": null,
"medline_ta": "N Engl J Med",
"mesh_terms": "D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D019969:Amphetamine-Related Disorders; D016642:Bupropion; D003692:Delayed-Action Preparations; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007267:Injections; D008297:Male; D055118:Medication Adherence; D008694:Methamphetamine; D008875:Middle Aged; D009271:Naltrexone; D009292:Narcotic Antagonists; D055815:Young Adult",
"nlm_unique_id": "0255562",
"other_id": null,
"pages": "140-153",
"pmc": null,
"pmid": "33497547",
"pubdate": "2021-01-14",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "27379819;32185696;23580868;31328345;25801501;32501207;31671001;21733477;28357460;26886209;12707478;25454409;23355369;25818061;25176528;27411969;17848492;24894963;28379861;23273775;17581531;21540126;28297025;30326396;11556941;27927042;18765480;16319910;27401883",
"title": "Bupropion and Naltrexone in Methamphetamine Use Disorder.",
"title_normalized": "bupropion and naltrexone in methamphetamine use disorder"
} | [
{
"companynumb": "US-GLAXOSMITHKLINE-US2021GSK029718",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BUPROPION HYDROCHLORIDE"
},
"drugadd... |
{
"abstract": "Diabetes mellitus encompasses a group of highly prevalent carbohydrate metabolic disorders with an increasing incidence. Some subtypes are thought to be associated with other immune-mediated diseases. Acquired haemophilia on the other hand is a quite rare autoimmune disease that is thought to be secondary to the emergence of inhibiting anticoagulation factor VIII antibodies (inhibitors) in patients with previously normal haemostatic function. More recently, numerous different diseases have been associated with acquired haemophilia namely immune-mediated diseases, drugs and solid and haematologic neoplasms. The authors report on a case of a patient with new onset acquired haemophilia arising in the setting of diabetic ketoacidosis.",
"affiliations": "Endocrinology, Centro Hospitalar de Lisboa Ocidental-Hospital de Egas Moniz, Lisboa, Portugal.;Immunotherapy, Centro Hospitalar de Lisboa Ocidental - Hospital de Egas Moniz, Lisboa, Portugal.;Immunotherapy, Centro Hospitalar de Lisboa Ocidental - Hospital de Egas Moniz, Lisboa, Portugal.;Endocrinology, Centro Hospitalar de Lisboa Ocidental-Hospital de Egas Moniz, Lisboa, Portugal.",
"authors": "Tavares Bello|Carlos|C|;Vasylenko|Yuliya|Y|;Esteves|José|J|;Vasconcelos|Carlos Augusto|CA|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D007004:Hypoglycemic Agents; D007328:Insulin",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-219807",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "Diabetes; Haematology (incl blood transfusion)",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D016883:Diabetic Ketoacidosis; D005260:Female; D006467:Hemophilia A; D006801:Humans; D007004:Hypoglycemic Agents; D007328:Insulin; D055815:Young Adult",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28438758",
"pubdate": "2017-04-24",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16138334;17124095;18505682;19814739;20204184;21115138;22398803;22551712;23889317;27555625;3135987",
"title": "Diabetes mellitus and acquired haemophilia: new association?",
"title_normalized": "diabetes mellitus and acquired haemophilia new association"
} | [
{
"companynumb": "PT-BAUSCH-BL-2017-018714",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PANTOPRAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "This is the first account of significant aortic injury during diagnostic rigid esophagoscopy in an adult with an esophageal stricture. We describe the resultant hemothorax and hemodynamic collapse and the successful treatment with massive volume resuscitation, vasopressors, and timely surgical intervention including thoracic endovascular aortic repair. We discuss the importance of rapid diagnosis, relevant anatomy, treatment modalities, and communication as cornerstones for learning.",
"affiliations": "From the Department of Anesthesiology, Ronald Reagan UCLA Medical Center, Los Angeles, California.",
"authors": "Hsu|Derek Y|DY|;Gabel|Eilon|E|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000000721",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2575-3126",
"issue": "11(1)",
"journal": "A&A practice",
"keywords": null,
"medline_ta": "A A Pract",
"mesh_terms": "D000369:Aged, 80 and over; D001013:Aorta, Thoracic; D001019:Aortic Rupture; D057510:Endovascular Procedures; D004940:Esophageal Stenosis; D004945:Esophagoscopy; D006801:Humans; D008297:Male; D011183:Postoperative Complications; D015607:Stents",
"nlm_unique_id": "101714112",
"other_id": null,
"pages": "14-15",
"pmc": null,
"pmid": "29634568",
"pubdate": "2018-07-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Rigid Esophagoscopy-Induced Aortic Rupture During Oral Gastric Tube Placement in Patient With Esophageal Stricture: A Case Report.",
"title_normalized": "rigid esophagoscopy induced aortic rupture during oral gastric tube placement in patient with esophageal stricture a case report"
} | [
{
"companynumb": "US-PFIZER INC-2018502933",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EPHEDRINE SULFATE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nPazopanib is one of the recently introduced first-line therapeutic options in the treatment of metastatic renal cell carcinoma (mRCC). There is no published literature from India on the use of pazopanib in mRCC.\n\n\nMETHODS\nWe report the efficacy and toxicity analysis of first-line pazopanib therapy administered for patients with mRCC at our institute. It is a retrospective analysis of a prospectively maintained continuous data.\n\n\nRESULTS\nBetween March 2013 and December 2015, 28 patients have been treated with pazopanib. The median age was 56.5 years with 23 males and five females. Sixty-eight percent patients had clear-cell histology. The most common site of metastasis was lung (75%), followed by bone (36%), liver (25%), and brain (14%) with 43% having more than one metastatic site. Partial response, stable disease, and progression were observed in 3 (11%), 10 (36%), and 4 (14%) cases, respectively, and the response was not evaluable in 11 patients. The median follow-up duration was 11.8 months, and progression-free survival was 5.9 months. Most of the toxicities were Grade I-II except in three patients who experienced Grade III hand-foot syndrome (HFS) and one patient who had Grade III anemia. Common side effects were hypertension, HFS, fatigue, transaminitis, hyperglycemia, dyslipidemia, and proteinuria which were quite manageable. No patient required treatment discontinuation due to toxicity.\n\n\nCONCLUSIONS\nBased on this initial experience at our center, pazopanib seems a feasible first-line treatment for mRCC due to its well-tolerable toxicity profile. However, larger data are required to confirm its efficacy in Indian patients.",
"affiliations": "Department of Medical Oncology, Tata Memorial Centre, Mumbai, Maharashtra, India.;Department of Medical Oncology, Tata Memorial Centre, Mumbai, Maharashtra, India.;Department of Medical Oncology, Tata Memorial Centre, Mumbai, Maharashtra, India.;Department of Medical Oncology, Tata Memorial Centre, Mumbai, Maharashtra, India.;Department of Medical Oncology, Tata Memorial Centre, Mumbai, Maharashtra, India.;Department of Pathology, Tata Memorial Centre, Mumbai, Maharashtra, India.;Department of Radiodiagnosis, Tata Memorial Centre, Mumbai, Maharashtra, India.;Department of Radiodiagnosis, Tata Memorial Centre, Mumbai, Maharashtra, India.;Department of Medical Oncology, Tata Memorial Centre, Mumbai, Maharashtra, India.",
"authors": "Joshi|A|A|;Agarwala|V|V|;Ramaswamy|A|A|;Noronha|V|V|;Patil|V M|VM|;Menon|S|S|;Popat|P|P|;Sable|N|N|;Prabhash|K|K|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib",
"country": "India",
"delete": false,
"doi": "10.4103/0019-509X.204769",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0019-509X",
"issue": "53(4)",
"journal": "Indian journal of cancer",
"keywords": null,
"medline_ta": "Indian J Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D002292:Carcinoma, Renal Cell; D005260:Female; D006801:Humans; D007191:Indazoles; D007680:Kidney Neoplasms; D008297:Male; D008875:Middle Aged; D011743:Pyrimidines; D012189:Retrospective Studies; D013449:Sulfonamides; D016896:Treatment Outcome",
"nlm_unique_id": "0112040",
"other_id": null,
"pages": "575-578",
"pmc": null,
"pmid": "28485355",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Initial experience with first-line pazopanib in the treatment of metastatic renal cell carcinoma: A single institution data.",
"title_normalized": "initial experience with first line pazopanib in the treatment of metastatic renal cell carcinoma a single institution data"
} | [
{
"companynumb": "PHHY2017IN072197",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PAZOPANIB"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "Intravenous administration of acetaminophen is an alternative to the oral and rectal routes, which may be contraindicated in particular clinical settings. This randomized, placebo-controlled study of intravenous acetaminophen (Ofirmev, Mallinckrodt Pharmaceuticals, Bedminster, New Jersey) in neonate and infant patients with acute postoperative pain assessed pharmacokinetics (PK) and safety, in addition to efficacy and pharmacodynamics of repeated doses administered over 24 hours. Neonate and infant patients (<2 years of age) who were undergoing surgery or had experienced a traumatic injury and were expected to need pain management for at least 24 hours were enrolled. Subjects were randomly assigned to receive intravenous acetaminophen low dose, intravenous acetaminophen high dose, or placebo. A population PK model of intravenous acetaminophen was updated by combining 581 samples from the current study of 158 neonate and infant subjects with results from a previously developed model. The individual predicted-versus-observed concentrations plots showed that the structural PK model fit the blood and plasma acetaminophen concentration-versus-time profiles in the active and placebo groups. Terminal elimination half-life was prolonged in neonates and younger infants and in intermediate and older infants similar to values in adults. When compared with placebo, total rescue opioid consumption was similar and significantly fewer intravenous acetaminophen patients prematurely discontinued because of treatment-emergent adverse events (P < .01). For intravenous acetaminophen, neonates receiving 12.5 mg/kg every 6 hours had PK profiles similar to younger, intermediate, and older infants, adolescents, and adults weighing <50 kg receiving 15 mg/kg every 6 hours and adults ≥ 50 kg receiving 1000 mg every 6 hours.",
"affiliations": "Lucile Packard Children's Hospital at Stanford, Stanford, California, USA.;The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.;Duke University Medical Center, Durham, North Carolina, USA.;Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, USA.;Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.;Children's Medical Center of Dallas, Dallas, Texas, USA.;Certara, Princeton, New Jersey, USA.;Certara, Princeton, New Jersey, USA.;Mallinckrodt Pharmaceuticals, Bedminster, New Jersey, USA.;Mallinckrodt Pharmaceuticals, Bedminster, New Jersey, USA.",
"authors": "Hammer|Gregory B|GB|;Maxwell|Lynne G|LG|;Taicher|Brad M|BM|;Visoiu|Mihaela|M|;Cooper|David S|DS|;Szmuk|Peter|P|;Pheng|Leng Hong|LH|;Gosselin|Nathalie H|NH|;Lu|Jia|J|;Devarakonda|Krishna|K|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen",
"country": "England",
"delete": false,
"doi": "10.1002/jcph.1508",
"fulltext": "\n==== Front\nJ Clin PharmacolJ Clin Pharmacol10.1002/(ISSN)1552-4604JCPHJournal of Clinical Pharmacology0091-27001552-4604John Wiley and Sons Inc. Hoboken 10.1002/jcph.1508JCPH1508Continuing Education: Pediatric PharmacologyContinuing Education: Pediatric PharmacologyRandomized Population Pharmacokinetic Analysis and Safety of Intravenous Acetaminophen for Acute Postoperative Pain in Neonates and Infants Hammer et alHammer Gregory B. MD\n1\nham@stanford.edu Maxwell Lynne G. MD\n2\nTaicher Brad M. DO, MBA\n3\nVisoiu Mihaela MD\n4\nCooper David S. MD, MPH\n5\nSzmuk Peter MD\n6\nPheng Leng Hong PhD\n7\nGosselin Nathalie H. PhD\n7\nLu Jia PhD\n8\nDevarakonda Krishna PhD, FCP\n8\n\n1 \nLucile Packard Children's Hospital at Stanford\nStanford\nCalifornia\nUSA\n\n2 \nThe Children's Hospital of Philadelphia\nPhiladelphia\nPennsylvania\nUSA\n\n3 \nDuke University Medical Center\nDurham\nNorth Carolina\nUSA\n\n4 \nChildren's Hospital of Pittsburgh of UPMC\nPittsburgh\nPennsylvania\nUSA\n\n5 \nCincinnati Children's Hospital Medical Center\nCincinnati\nOhio\nUSA\n\n6 \nChildren's Medical Center of Dallas\nDallas\nTexas\nUSA\n\n7 \nCertara\nPrinceton\nNew Jersey\nUSA\n\n8 \nMallinckrodt Pharmaceuticals\nBedminster\nNew Jersey\nUSA\n* Corresponding Author:\nGregory B. Hammer, MD, Stanford University Medical Center, 300 Pasteur Drive, Stanford, CA 94305\nEmail: ham@stanford.edu\n25 8 2019 1 2020 60 1 10.1002/jcph.v60.116 27 26 2 2019 15 7 2019 24 7 2019 © 2019 Mallinckrodt. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical PharmacologyThis 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.Abstract\nIntravenous administration of acetaminophen is an alternative to the oral and rectal routes, which may be contraindicated in particular clinical settings. This randomized, placebo‐controlled study of intravenous acetaminophen (Ofirmev, Mallinckrodt Pharmaceuticals, Bedminster, New Jersey) in neonate and infant patients with acute postoperative pain assessed pharmacokinetics (PK) and safety, in addition to efficacy and pharmacodynamics of repeated doses administered over 24 hours. Neonate and infant patients (<2 years of age) who were undergoing surgery or had experienced a traumatic injury and were expected to need pain management for at least 24 hours were enrolled. Subjects were randomly assigned to receive intravenous acetaminophen low dose, intravenous acetaminophen high dose, or placebo. A population PK model of intravenous acetaminophen was updated by combining 581 samples from the current study of 158 neonate and infant subjects with results from a previously developed model. The individual predicted‐versus‐observed concentrations plots showed that the structural PK model fit the blood and plasma acetaminophen concentration‐versus‐time profiles in the active and placebo groups. Terminal elimination half‐life was prolonged in neonates and younger infants and in intermediate and older infants similar to values in adults. When compared with placebo, total rescue opioid consumption was similar and significantly fewer intravenous acetaminophen patients prematurely discontinued because of treatment‐emergent adverse events (P < .01). For intravenous acetaminophen, neonates receiving 12.5 mg/kg every 6 hours had PK profiles similar to younger, intermediate, and older infants, adolescents, and adults weighing <50 kg receiving 15 mg/kg every 6 hours and adults ≥ 50 kg receiving 1000 mg every 6 hours.\n\nacetaminophenacute postoperative paininfantsneonatesopioidsMallinckrodt Pharmaceuticals, Inc. source-schema-version-number2.0cover-dateJanuary 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.7.5 mode:remove_FC converted:21.01.2020\nhttp://ClinicalTrials.gov Identifier: NCT01635101\n==== Body\nAcetaminophen (known outside the United States by its International Nonproprietary Name, paracetamol) is an analgesic and antipyretic agent used widely in both adult and pediatric populations. Administration of acetaminophen via the oral and rectal routes may be problematic; the former may be contraindicated for patients who are nothing by mouth, and the latter is associated with unpredictable plasma concentrations. In the United States, intravenous acetaminophen (Ofirmev, Mallinckrodt Hospital Products, Inc., Hazelwood, Missouri) is approved for the management of mild to moderate pain in pediatric patients 2 years of age and older (and adults, including those >65 years of age) and for the reduction of fever in pediatric patients and adults.\n\nPrior pharmacokinetic (PK) studies have demonstrated that exposure levels of intravenous acetaminophen in children and adolescents are similar to adults but higher in neonates and infants.1, 2 The study by Zuppa and colleagues included 3 neonates, 25 infants, 25 children, and 22 adolescents, and the study by Palmer and colleagues included 43 neonates and 7 infants. Data from these 2 PK trials were combined for a population PK meta‐analysis, PK modeling, and several dose simulations. This merged data set resulted in 125 neonate and infant subjects with 1260 acetaminophen concentration values for inclusion in the analysis. The developed model was a 2‐compartment structural model with linear elimination and size effect on PK parameters, which fitted the concentration‐time profiles of acetaminophen adequately in the pediatric population from the studies by Zuppa and Palmer.\n\nPrevious models demonstrated that PK parameters in neonates and infants were comparable to adolescent and adult populations after compensating for both significantly decreased clearance and longer terminal elimination half‐life (t1/2). Dosing simulations from PK data in infants and neonates suggested that dose reductions of 33% in infants 1 month to <2 years of age and 50% in neonates up to 28 days, with a minimum dosing interval of 6 hours, will produce a PK exposure similar to that observed in children ≥ 2 years of age.\n\nThe current study sought to update the prior population PK model of intravenous acetaminophen in neonates and infants; in addition, efficacy, pharmacodynamics (PD), and safety were assessed.\n\nMethods\nPrior to initiation of this randomized, placebo‐controlled multicenter study of intravenous acetaminophen for the treatment of acute pain, the protocol was reviewed and approved by each site's institutional review board. A list of the names and locations of all the participating study sites can be found in the online appendix. Neonate and infant patients <2 years of age were eligible to participate if they were scheduled to undergo surgery or had experienced a traumatic injury and were expected to need pain management for at least 24 hours. Each eligible subject's parent or guardian provided written informed consent prior to the subject's participation in the study. Subjects were divided into 4 age groups: neonates (<28 days), younger infants (28 days to <6 months), intermediate‐age infants (6 months to <12 months), and older infants (12 months to <24 months). Neonates were further categorized into extreme preterm neonates (≥28 to <32 weeks’ gestational age), preterm neonates (≥32 to <37 weeks’ gestational age), and full‐term neonates (≥37 weeks to ≤40 weeks’ gestational age).\n\nDuring a 6‐hour preassessment period, all eligible subjects received a protocol‐specified opioid at a bolus dose according to the investigator's clinical discretion and the center's analgesic protocol, if applicable, and then were randomly assigned to 1 of 2 intravenous acetaminophen plus standard‐of‐care (SOC) opioid dosing groups (treatment groups A [low dose] and B [high dose]) or 2 matched placebo plus SOC opioids (control treatment groups C or D) in a 2:2:1:1 ratio. Treatment group A (low dose) received intravenous acetaminophen doses ranging from 7.5 mg/kg for extreme preterm neonates to 12.5 mg/kg for infants. Treatment group B (high dose) received intravenous acetaminophen doses ranging from 10 mg/kg for extreme preterm neonates to 15 mg/kg for infants. Doses of acetaminophen or saline placebo were administered every 6 hours as a continuous intravenous infusion over 15 minutes for 4 doses.\n\nAll treatment groups had access to protocol‐specified opioid rescue medication. After randomization, a certified, dedicated blinded assessor performed a pretreatment pain assessment using the Leuven Neonatal Pain Scale ([LNPS] in neonates and infants <6 months of age) or Face, Legs, Activity, Cry, and Consolability Scale ([FLACC] in infants ≥6 months to <24 months of age). A single dose of standard opioid was given 30 minutes prior to the planned start of study drug (T0). Each subject then received 4 doses of the assigned study drug, 1 dose every 6 hours at T0, T6, T12, and T18, plus SOC opioids for 24 hours, and had protocol‐specified assessments performed.\n\nBlood samples were obtained at T0, T0.5, T2, T7, and T12, and urine samples were collected during the T0‐T6 range and the T18‐T24 range for PK analysis. Pain intensity assessments, LNPS or FLACC, were conducted at T0, T0.5, T1, T2, T3, T4, T6, T12, and T24. Certara USA, Inc. performed population PK and PK‐PD statistical analyses. Study completion assessments were performed 6 hours after the last dose of study drug, which included vital signs, physical examination, liver function tests, global evaluation of satisfaction with study treatment, and adverse event assessment.\n\nThe study's primary end point was total rescue opioid consumption (intravenous morphine equivalent) T0‐T24 in each intravenous acetaminophen group and the combined placebo groups. Total opioid consumption over an 8‐hour prerandomization qualification period initially was used to characterize a subject's consumption as either “low” or “high” based on a threshold hourly average value of 30 µg/kg/h intravenous morphine equivalent (a total of 240 µg/kg over 8 hours). During the study, a change was made to use a shorter time frame of 6 hours (with a total of 210 µg/kg over 6 hours). As a result, stratification by prerandomization opioid consumption was no longer a factor and therefore excluded from the primary and secondary analyses. Secondary PK end points were area under the plasma concentration‐time curve over the 6‐hour dosing interval (AUC0‐6) to the last measurable concentration (AUC0‐t) and extrapolated to infinity (AUC0‐∞), maximum plasma concentration (Cmax), t1/2, and clearance (CL), in addition to population PK and PK‐PD end points. The population PK analysis was performed using a 2‐compartmental model with linear elimination, size effect on PK parameters and sigmoid maturation function on systemic CL. Post hoc PK parameters (AUC, Cmax, Vss, and t1/2) were derived for individual subjects and summarized with descriptive statistics. PK‐PD modeling was performed by including an effect compartment in the structural PK model.\n\nPopulation PK analysis of acetaminophen in plasma was performed using a nonlinear mixed‐effects modeling approach with NONMEM version VI. Data‐set preparation, exploration, and visualization of the data, descriptive statistics, linear regression analysis, and survival PK‐PD analyses were performed using R version 3.2. The programming library Perl‐Speaks‐NONMEM (PsN version 2.3.0) was used to evaluate and validate the model with a visual predictive check.\n\nResults\nThe study was initiated in August 2012 and completed in August 2015, when the last enrolled subject completed the last assessment. A total of 215 subjects were randomized, with 66 in group A (low dose), 72 in group B (high dose), and 77 in group C+D (control group). Disposition of subjects by age category is summarized in Table 1.\n\nTable 1 Subject Disposition by Age Category\n\n\tIntravenous Acetaminophen Groups\tControl Groups\t\n\tGroup A\tGroup B\tGroup A+B\tGroup C\tGroup D\tGroup C+D\tTotal\t\nNumber of subjects randomized, total\t66\t72\t138\t35\t42\t77\t215\t\nNeonates\t15\t13\t28\t9\t8\t17\t45\t\nYounger infant\t17\t23\t40\t8\t10\t18\t58\t\nIntermediate‐age infants\t19\t18\t37\t12\t10\t22\t59\t\nOlder infants\t15\t18\t33\t6\t14\t20\t53\t\nNumber of subjects completed, total (%)\t52 (78.8)\t55 (76.4)\t107 (77.5)\t26 (74.3)\t26 (61.9)\t52 (67.5)\t159 (74.0)\t\nNeonates\t13 (86.7)\t12 (92.3)\t25 (89.3)\t7 (77.8)\t6 (75.0)\t13 (76.5)\t38 (84.4)\t\nYounger infants\t14 (82.4)\t15 (65.2)\t29 (72.5)\t7 (87.5)\t7 (70.0)\t14 (77.8)\t43 (74.1)\t\nIntermediate‐age infants\t13 (68.4)\t14 (77.8)\t27 (73.0)\t6 (50.0)\t3 (30.0)\t13 (59.1)\t40 (67.8)\t\nOlder infants\t12 (80.0)\t14 (77.8)\t26 (78.8)\t6 (100.0)\t6 (42.9)\t12 (60.0)\t38 (71.7)\t\nJohn Wiley & Sons, Ltd.Each participant who received any portion of study medication was included in the safety population (n = 198). The efficacy‐evaluable population (n = 197) included subjects who received a dose of study drug and completed at least 1 assessment and was composed of 38 neonates, 54 younger infants, 55 intermediate‐age infants, and 50 older infants. All patients were classified as surgical patients, and none had a traumatic injury. Demographic and baseline characteristics of subjects in the efficacy‐evaluable population are presented in Table 2.\n\nTable 2 Summary of Demographics and Baseline Characteristics in the Efficacy Population\n\n\tIntravenous Acetaminophen Groups\tControl Groups\t\t\n\tGroup A, n = 61\tGroup B, n = 67\tGroup A+B, n = 128\tGroup C+D, n = 69\tTotal, n = 197\t\nPostnatal age (days)\t\nMean (SD)\t223.1 (175.2)\t245.7 (208.7)\t234.9 (193.0)\t220.4 (175.1)\t229.9 (186.6)\t\nMedian (min, max)\t202.0 (2643)\t187.0 (3725)\t199.0 (2725)\t194.0 (1664)\t195.0 (1725)\t\nAge categories,1 n (%)\t\nNeonates\t13 (21.3)\t12 (17.9)\t25 (19.5)\t13 (18.8)\t38 (19.3)\t\nExtreme preterm\t0\t2 (3.0)\t2 (1.6)\t1 (1.4)\t3 (1.5)\t\nPreterm\t0\t3 (4.5)\t3 (2.3)\t1 (1.4)\t4 (2.0)\t\nFull term\t13 (21.3)\t7 (10.4)\t20 (15.6)\t11 (15.9)\t31 (15.7)\t\nYounger infants\t16 (26.2)\t20 (29.9)\t36 (28.1)\t18 (26.1)\t54 (27.4)\t\nIntermediate age infants\t18 (29.5)\t17 (25.4)\t35 (27.3)\t20 (29.0)\t55 (27.9)\t\nOlder infants\t14 (23.0)\t18 (26.9)\t32 (25.0)\t18 (26.1)\t50 (25.4)\t\nSex, n (%)\t\nMale\t44 (72.1)\t40 (59.7)\t84 (65.6)\t43 (62.3)\t127 (64.5)\t\nFemale\t17 (27.9)\t27 (40.3)\t44 (34.4)\t26 (37.7)\t70 (35.5)\t\nRace, n (%)\t\nWhite\t40 (65.6)\t49 (73.1)\t89 (69.5)\t46 (66.7)\t135 (68.5)\t\nBlack or African American\t12 (19.7)\t9 (13.4)\t21 (16.4)\t9 (13.0)\t30 (15.2)\t\nAmerican Indian or Alaska Native\t1 (1.6)\t0\t1 (0.8)\t0\t1 (0.5)\t\nAsian\t3 (4.9)\t4 (6.0)\t7 (5.5)\t6 (8.7)\t13 (6.6)\t\nOther\t4 (6.6)\t4 (6.0)\t8 (6.3)\t5 (7.2)\t13 (6.6)\t\nMissing\t1 (1.6)\t1 (1.5)\t2 (1.6)\t3 (4.3)\t5 (2.5)\t\nWeight at screening (kg)\t\nMean (SD)\t6.97 (2.79)\t6.96 (3.05)\t6.96 (2.92)\t6.96 (2.69)\t6.96 (2.83)\t\nMedian (min, max)\t6.75 (2.6, 13.7)\t7.00 (1.0, 14.3)\t7.00 (1.0, 14.3)\t7.10 (0.8, 12.0)\t7.00 (0.8, 14.3)\t\nBaseline opioid dose (µg/kg)\t\nMean (SD)\t45.9 (36.08)\t49.7 (36.22)\t47.9 (36.06)\t47.2 (31.85)\t47.6 (34.55)\t\nMedian (min, max)\t48.3 (0, 170.5)\t50.0 (0, 204.8)\t50.0 (0, 204.8)\t50.0 (0, 116.3)\t50.0 (0, 204.8)\t\nkg, kilogram; max, maximum; min, minimum; SD, standard deviation.\n\n1 Subjects were divided into 4 age groups: neonates (<28 days), younger infants (28 days to <6 months), intermediate‐age infants (6 months to <12 months), and older infants (12 months to <24 months). Neonates were further categorized into extreme preterm neonates (≥28 to <32 weeks’ gestational age), preterm neonates (≥32 to <37 weeks’ gestational age), and full‐term neonates (≥37 weeks to ≤40 weeks’ gestational age).\n\nJohn Wiley & Sons, Ltd.Among study participants, 186 subjects provided blood samples for analysis; 27 of these subjects had results below the limits of quantification and were removed from the analysis. One subject was removed because of an unexpectedly high dose reported in the clinical data. As such, 158 subjects remained and were included in the PK analysis. Baseline demographics for these 158 subjects did not show significant deviation from the total study participants.\n\nPopulation PK\nFrom the 581 PK samples, a population PK analysis was done to fit concentration‐time profiles of acetaminophen (Figure 1). Active group (group A+B) showed a biexponential disposition kinetics of acetaminophen. Residual (low) acetaminophen concentrations were observed in the combined placebo group (group C+D).\n\nFigure 1 Population PK concentration‐time profiles for acetaminophen. Lines represent locally weighted scatter smoothing (LOESS).\n\nThe population PK model was updated by combining 581 samples from the current study with the 1260 PK samples from pediatric subjects used in the previously developed intravenous acetaminophen population PK model. Typical values of the final population PK model are presented with the effect of arm (placebo control vs active) on CL and the reestimation of the constant describing age‐related changes in CL (Table 3; Figure 2), along with the typical values derived with the previous model.\n\nTable 3 Typical Acetaminophen Values of Final Population PK Model\n\nParameters\tCurrent Model\tPrevious Model\t\nPopulation model\t\nCL (L/h)\t18.9 × WT700.75\n\t18.4 × WT700.75\n\t\nPlacebo on CL\t\n× 0.524\t\t\nMaturation function\t× 1−0.611×exp(−(PMA−40)×ln(2)32.6∗)\n\t× 1−0.678×exp(−(PMA−40)×ln(2)41.0)\n\t\nVc (L)\t23.0 ×WT70\n\t16.0 ×WT70\n\t\nCLp (L/h)\t47.7 ×WT700.75\n\t97.8 ×WT700.75\n\t\nVp (L)\t45.5 ×WT70\n\t59.5 ×WT70\n\t\nIndividual variability\t\nω2\nCL\n\t0.127\t0.14\t\nω2\nVc\n\t0.993\t0.38\t\nω2\nCLp\n\t\t0.0383\t\nω2\nVp\n\t\t0.0777\t\nResidual variability\t\nLog residual error\t0.221\t\t\nσ2\nprop (%)\t\t27.9\t\nσ2\nadd (mg/L)\t\t168.2\t\nCL, systemic clearance; CLp, intercompartmental clearance; PMA, postmenstrual age; PK, pharmacokinetic; Vc, volume of distribution of the central compartments; Vp, volume of distribution of the peripheral compartment; WT, body weight.\n\nNote: in the current model, the correlation between CL and Vc BSV was 51.4%.\n\n\n*Fixed at previous value derived in.\n\nJohn Wiley & Sons, Ltd.Figure 2 Visual predicted check — final population pk model.\n\nThe final population PK model showed the individual predicted‐versus‐observed concentration plots were in good agreement (Figure 3). The population‐predicted concentrations were clustered around the identity line.\n\nFigure 3 Final population PK model goodness of fit.\n\nThe final population PK model was evaluated with a visual check of predicted concentration. This final model was very robust for predicting acetaminophen in 2 treatment arms (placebo and active). Thus, the model can be used to predict acetaminophen concentration and exposure in patients.\n\nIndividual post hoc acetaminophen PK parameters were derived for the neonate and infant populations, and the precision of the PK parameters was deemed acceptable. Subsequently, a comparability study was conducted between the PK parameter and exposure levels data derived from the neonate and infant populations with similar data gathered from the adult population from a prior study. The results of these 2 sets of data for intravenous acetaminophen and the PK parameters after the first dose of intravenous acetaminophen are shown below (Table 4). Median half‐life of acetaminophen in neonates and younger infants ranged between 3.2–3.4 and 2.7 hours, respectively, which is 1.2‐fold to 1.5‐fold the median in adults (2.33 hours). The median half‐life for intermediate and older infants was similar to that of adults. The median acetaminophen CL adjusted for body weight in neonates (0.19–0.22 L/h/kg) was slightly lower than that observed in adult subjects (0.28 L/h/kg). However, median weight‐adjusted CL in infants (range, 0.30–0.37 L/h/kg) was slightly higher than in adults (0.278 L/h/kg). Median acetaminophen Vss in infant and neonate patients ranged from 0.85 to 0.95 L/kg, which was slightly higher than that observed in adults (0.80 L/kg). Median Cmax values in both neonate dosing cohorts were slightly lower than those observed in infants and adults. The higher dosing cohorts had higher median Cmax for the infant subgroups compared with median values observed in adults (ie, 26.7, 29.1, and 27.9 µg/mL in younger, intermediate, and older infants, respectively, compared with 24.7 µg/mL in adults given 1000 mg every 6 hours). At low‐dose levels, neonates and younger infants showed higher median AUCτ than that observed in intermediate and older infants, with 26% and 28% higher values in neonates and younger infants, respectively, compared with older infants. At higher‐dose levels, median AUCτ values were within 10% of the median observed in adults who received 1000 mg every 6 hours (40.5 µg·h/mL), with the exception of the median in extreme preterm neonates, which was approximately 32% lower. The data for this subgroup should be interpreted with caution given the small sample size of only 2 patients. The majority of subjects included in the new analysis was from 40 to 143 weeks of postmenstrual age (ie, ∼0 to 2 years old), whereas the Palmer study included 50 patients aged from 33.7 to 47.2 weeks of postmenstrual age, and Zuppa data included subjects aged from 41 to 906 weeks of postmenstrual age (∼0 to 17 years old; Figure 4).\n\nTable 4 Model‐Derived PK Parameters of Intravenous Acetaminophen Before and After First Dose\n\n\tPrior to First Dose\tAfter First Dose\t\n\t\t\tCL\tVss\n\t\tLow‐Dose Levels\tHigh‐Dose Levels\t\nSubpopulation\tn\tT1/2β (h)\t(L/h/kg)\t(L/h)\t(L/kg)\t(L)\tn\tCmax (µg/mL)\tAUCτ ug·hr/mL\tCmax (µg/mL)\tAUCτ ug·hr/mL\t\nExtreme preterm neonates\t2\t\n3.26 (0.26)\n\n\n3.26\n\n\n(3.08–3.45)\n\n\n\t\n0.1921 (0.02314)\n\n\n0.192\n\n\n(0.176–0.208)\n\n\n\t\n0.2377 (0.01184)\n\n\n0.238\n\n\n(0.229–0.246)\n\n\n\t\n0.8485 (0.03485)\n\n\n0.848\n\n\n(0.824–0.873)\n\n\n\t\n1.057 (0.1364)\n\n\n1.06\n\n\n(0.960–1.15)\n\n\n\tHigh (10 mg/kg): n = 2\tNA\tNA\t\n20.19 (6.259)\n\n\n21.2\n\n\n(4.37–30.9)\n\n\n\t\n27.70 (8.092)\n\n\n27.2\n\n\n(14.1–46.3)\n\n\n\t\nPreterm neonates\t2\t\n3.23 (0.73)\n\n\n3.23\n\n\n(2.72–3.75)\n\n\n\t\n0.2201 (0.08005)\n\n\n0.220\n\n\n(0.163–0.277)\n\n\n\t\n0.4647 (0.1254)\n\n\n0.465\n\n\n(0.376–0.553)\n\n\n\t\n0.9217 (0.1274)\n\n\n0.922\n\n\n(0.832–1.01)\n\n\n\t\n1.968 (0.07839)\n\n\n1.97\n\n\n(1.91–2.02)\n\n\n\tHigh (12.5 mg/kg): n = 2\tNA\tNA\t\n22.82 (6.629)\n\n\n22.8\n\n\n(18.1–27.5)\n\n\n\t\n43.24 (11.56)\n\n\n43.2\n\n\n(35.1–51.4)\n\n\n\t\nFull‐term neonates\t14\t\n3.92 (2.6)\n\n\n3.38\n\n\n(2.37–14.2)\n\n\n\t\n0.2231 (0.04910)\n\n\n0.217\n\n\n(0.138–0.311)\n\n\n\t\n0.6991 (0.2957)\n\n\n0.673\n\n\n(0.229–1.28)\n\n\n\t\n1.253 (1.281)\n\n\n0.916\n\n\n(0.794–6.36)\n\n\n\t\n4.219 (5.567)\n\n\n2.94\n\n\n(0.960–26.1)\n\n\n\t\nLow (10.0 mg/kg): n = 9\n\n\nHigh (12.5 mg/kg): n = 5\n\n\n\t\n18.13 (4.330)\n\n\n18.3\n\n\n(10.5–25.2)\n\n\n\t\n36.97 (8.325)\n\n\n34.3\n\n\n(28.9–54.6)\n\n\n\t\n19.64 (11.66)\n\n\n22.6\n\n\n(3.52–32.4)\n\n\n\t\n41.77 (22.27)\n\n\n44.6\n\n\n(10.5–69.4)\n\n\n\t\nYounger infants\t34\t\n2.77 (1.2)\n\n\n2.71\n\n\n(1.56–9.06)\n\n\n\t\n0.3140 (0.08617)\n\n\n0.299\n\n\n(0.185–0.522)\n\n\n\t\n1.723 (0.6719)\n\n\n1.58\n\n\n(0.659–3.60)\n\n\n\t\n1.139 (0.7517)\n\n\n0.948\n\n\n(0.758–5.13)\n\n\n\t\n6.13 (4.148)\n\n\n5.65\n\n\n(2.51–27.7)\n\n\n\t\nLow (12.5 mg/kg):\n\n\nn = 15\n\n\nHigh (15.0 mg/kg): n = 19\n\n\n\t\n23.50 (7.144)\n\n\n21.6\n\n\n(11.3–38.6)\n\n\n\t\n37.02 (10.43)\n\n\n34.8\n\n\n(22.2–50.5)\n\n\n\t\n24.69 (9.466)\n\n\n26.7\n\n\n(3.17–44.2)\n\n\n\t\n41.65 (13.82)\n\n\n41.2\n\n\n(13.8–73.9)\n\n\n\t\nIntermediate infants\t31\t\n2.35 (0.6)\n\n\n2.29\n\n\n(1.37–4.11)\n\n\n\t\n0.3568 (0.1109)\n\n\n0.336\n\n\n(0.152–0.633)\n\n\n\t\n3.009 (1.218)\n\n\n2.46\n\n\n(1.20–6.00)\n\n\n\t\n0.9941 (0.2012)\n\n\n0.926\n\n\n(0.833–1.93)\n\n\n\t\n8.339 (2.571)\n\n\n7.50\n\n\n(5.07–16.2)\n\n\n\t\nLow (12.5 mg/kg):\n\n\nn = 14\n\n\nHigh (15.0 mg/kg): n = 17\n\n\n\t\n20.76 (4.343)\n\n\n20.8\n\n\n(8.17–26.2)\n\n\n\t\n30.19 (6.329)\n\n\n30.0\n\n\n(19.2–41.1)\n\n\n\t\n30.01 (9.201)\n\n\n29.1\n\n\n(16.1–53.7)\n\n\n\t\n45.52 (19.81)\n\n\n41.6\n\n\n(23.2–105)\n\n\n\t\nOlder infants\t31\t\n2.21 (0.56)\n\n\n2.15\n\n\n(1.44–4.09)\n\n\n\t\n0.4036 (0.09914)\n\n\n0.368\n\n\n(0.252–0.664)\n\n\n\t\n4.108 (1.140)\n\n\n3.83\n\n\n(2.61–7.78)\n\n\n\t\n1.128 (0.5686)\n\n\n0.952\n\n\n(0.878–3.27)\n\n\n\t\n11.66 (7.020)\n\n\n9.66\n\n\n(7.78–44.9)\n\n\n\t\nLow (12.5 mg/kg):\n\n\nn = 13\n\n\nHigh (15.0 mg/kg): n = 18\n\n\n\t\n20.19 (6.259)\n\n\n21.2\n\n\n(4.37–30.9)\n\n\n\t\n27.70 (8.092)\n\n\n27.2\n\n\n(14.1–46.3)\n\n\n\t\n27.07 (6.838)\n\n\n27.9\n\n\n(5.49–41.4)\n\n\n\t\n38.76 (10.87)\n\n\n38.7\n\n\n(17.1–68.8)\n\n\n\t\nAdults\t34\t\n2.39 (0.57)\n\n\n2.33\n\n\n(1.72–4.50)\n\n\n\t\n0.2678 (0.08236)\n\n\n0.275\n\n\n(0.128–0.598)\n\n\n\t\n20.08 (5.808)\n\n\n20.6\n\n\n(9.24‐33.3)\n\n\n\t\n0.8330 (0.2238)\n\n\n0.798\n\n\n(0.343–1.87)\n\n\n\t\n64.3 (12.55)\n\n\n63.0\n\n\n(28.0–103)\n\n\n\t\nn = 34\n\n\nat 1000 mg every 6 hours\n\n\n\tNA\tNA\t\n28.39 (21.17)\n\n\n24.7\n\n\n(11.8–139)\n\n\n\t\n42.48 (10.65)\n\n\n40.5\n\n\n(25.5–72.4)\n\n\n\t\nAUCτ, area under the concentration‐time curve; CL, systemic clearance; Cmax, maximum concentration; n, number of subjects; NA, not applicable; SD, standard deviation; T1/2β, terminal elimination half‐life; Vss, total volume of distribution in steady state.\n\nMean (SD), median (minimum‐maximum).\n\nJohn Wiley & Sons, Ltd.Figure 4 The relationship between clearance and postmenstrual age: a sigmoidal pattern with a clearance plateau of 18.9 L/h per 70 kg observed in neonates, infants, children, and adolescents.\n\nEfficacy\nTotal rescue opioid consumption was similar in groups A, B, or A+B compared with the combined placebo group (C+D). The primary efficacy result did not demonstrate a statistically significant reduction in the total rescue opioid consumption in each of the individual intravenous acetaminophen groups (A or B) compared with the combined placebo group (C+D). Overall, none of the efficacy end points demonstrated significant differences in pain‐related assessments between the intravenous acetaminophen treatment groups compared with the combined placebo groups.\n\nPK‐PD: Pain Intensity‐by‐Treatment Group\nPK‐PD modeling of pain intensity scores and time after last opioid consumption showed a decrease in pain intensity in both groups 2–3 hours after the first dose of treatment (intravenous acetaminophen or placebo), followed by an increase. The increase in pain intensity scores occurred earlier in the placebo group.\n\nPK‐PD: Survival Analysis on Avoiding Opioid Rescue Medication\nFrom approximately 2 to 20 hours, the percentage of subjects who were not taking rescue medication was higher in the combined intravenous acetaminophen active groups than in the combined placebo groups. Of note, the active group with both low and high prerandomization opioid consumption showed a higher probability of avoiding rescue medication compared with the corresponding placebo group, and the separation between active and placebo groups with high prerandomization opioid consumption was greater (Figure 5). Notably, the probability of avoiding rescue medication was significantly higher in patients with acetaminophen AUC0‐6 values greater than 42.8 µg·h/mL (P < .05).\n\nFigure 5 Probability of avoiding opioid rescue medication versus time — active (intravenous acetaminophen) versus placebo groups by prerandomization opioid level.\n\nPK‐PD: Linear Regression Analysis of AUC and Rescue Opioids\nLinear regression of the relationship between AUCs and rescue opioids on different treatment intervals showed a negative and non–statistically significant relationship for 0–6, 0–12, and 0–18 hours (Figure 6A). Concentrations in the effect compartment (Ceff) were derived with the equilibration half‐life fixed to the value estimated.3 Linear regression of the relationship between Ceff and pain score difference 1 hour postdose showed small negative, non–statistically significant trends for FLACC. In addition, the relationship between total opioid consumption and PK exposure parameters and the correlation between acetaminophen concentration and pain intensity difference 1 hour postdose were performed (Figure 6B).\n\nFigure 6 (A) Relationship between total opioid rescue medication and different treatment intervals (ie, 0–6, 0–12, 0–18, and 0–24 hours) with linear regression results. (B) Relationship between and pain intensity difference 1 hour postdose and concentration of acetaminophen in plasma/blood and effect compartments 1 hour postdose with linear regression results by score scale.\n\nSafety\nPhysical examinations, vital signs, clinical laboratory tests including liver function tests, and treatment‐emergent adverse events (TEAEs) were used to assess safety. No deaths resulting from TEAEs occurred during this study. A total of 3 subjects experienced serious adverse events of whom 2 were treatment emergent: 1 in the combined control treatment group (leukocytosis) and 1 in intravenous acetaminophen treatment group B (apnea). Significantly fewer subjects in group B (32.8%) experienced at least 1 TEAE (P = .010) compared with the combined placebo groups (55.7%). In addition, significantly fewer subjects in groups A and B prematurely discontinued the because of a TEAE when compared with the combined placebo groups (P = 0 and P = .009, respectively). Liver function tests measured through alanine aminotransferase (ALT) and aspartate aminotransferase (AST) enzyme levels showed that no subject in any group had an ALT postbaseline value > 3 × the upper limit of normal (ULN); however, 4 subjects in the combined placebo group and 1 subject each in group A and group B had an AST postbaseline value > 3 × ULN. No subject had a postbaseline ALT or AST value > 5 × ULN.\n\nDiscussion\nWe performed a randomized, placebo‐controlled study of intravenous acetaminophen in neonate and infant patients with acute postoperative pain to assess PK, PD, efficacy, and safety of repeated doses administered over 24 hours. Pharmacokinetic modeling results from this study indicate that acetaminophen PK and exposure levels in neonates receiving intravenous acetaminophen 12.5 mg/kg and in infants receiving 15 mg/kg are comparable to the exposure levels in adults receiving 1000 mg every 6 hours. This served as the basis for revised dosing recommendations for the treatment of fever in neonates (≥32 weeks’ gestational age; no dosing recommendations are provided for neonates <32 weeks’ gestational age) and infants provided in the updated 2017 Ofirmev (acetaminophen) injection prescribing information. For neonates, including premature neonates born ≥32 weeks’ gestational age up to 28 days’ chronological age, the dosing recommendations are 12.5 mg/kg every 6 hours to a maximum daily dose of acetaminophen of 50 mg/kg/day, with a minimum dosing interval of 6 hours. For infants 29 days to 2 years of age, the dosing recommendations are 15 mg/kg every 6 hours to a maximum daily dose of acetaminophen of 60 mg/kg/day, with a minimum dosing interval of 6 hours. Inferences can be made on the findings from this study with healthy adult patients who received a 1000‐mg dose every 6 hours (data not published).\n\nConsistent with the current study, prior PK studies demonstrated exposure of intravenous acetaminophen in children and adolescents was similar to adults, but higher in neonates and infants.1, 2 Population PK modeling of data from these 2 studies — updated to include data from the current study — demonstrated that PK parameters in neonates and infants were comparable to those in older populations by compensating for both significantly decreased CL and longer t1/2.\n\nTo characterize the variation in PK of acetaminophen across the human age span, Wang and colleagues performed a population PK meta‐analysis using data from 8 clinical studies of preterm neonates to adults, with a specific focus on clearance.4 Acetaminophen was administered intravenously in 6 of the studies and PR in 2 of the studies. Concentration‐time data obtained in 220 neonates (postnatal age 1–76 days, gestational age 27–42 weeks), infants (0.11–1.33 years), children (2–7 years), and adults (19–34 years) were analyzed using NONMEM 7.2. In the covariate analysis, linear functions, power functions, and a power function with a body weight‐dependent exponent were tested. A PK model for characterizing changes in acetaminophen PK parameters across the pediatric age range was developed. Clearance was found to change in a nonlinear manner with body weight. Based on the final model, dosing guidelines were proposed from preterm neonates to adolescents, resulting in similar exposure across all age ranges. For individuals from 40 days to 7 years of age with body weight between 7 and 20 kg, the model by Zuppa and colleagues and in the current study estimated slightly greater clearance compared with the estimates by Wang and colleagues.\n\nCook and colleagues sought to develop a population PK model for intravenous acetaminophen in preterm and term neonates and to assess the generalizability of the model by testing its predictive performance in an external data set.5 Nonlinear mixed‐effects models were constructed from acetaminophen concentration‐time data in NONMEM 7.2. Potential covariates included body weight, gestational age, postnatal age, postmenstrual age, sex, race, total bilirubin, and estimated glomerular filtration rate. An external data set was used to test the predictive performance of the model through calculation of bias, precision, and normalized prediction distribution errors. The model‐building data set included 260 observations from 35 neonates with a mean gestational age ± standard deviation (SD) of 33.6 ± 6.6 weeks. A 1‐compartment model with first‐order elimination was used to describe the data. Body weight predicted acetaminophen CL and volume of distribution, which were estimated as 0.35 L/h (5.5% relative standard error; 30.8% coefficient of variation) and 2.46 L (3.5% relative standard error; 14.3% coefficient of variation), respectively, at the mean subject weight of 2.30 kg. An external evaluation was performed on an independent data set that included 436 observations from 60 neonates with a mean gestational age ± SD of 35.6 ± 4.3 weeks, the median prediction error was 10.1% (95% confidence interval [CI], 6.1%–14.3%), and the median absolute prediction error was 25.3% (95%CI, 23.1%–28.1%). The authors concluded that weight predicted intravenous acetaminophen PK in neonates ranging from extreme preterm to full‐term gestational status; external evaluation suggested that these findings should be generalizable to other similar patient populations.\n\nSeveral differences were noted between the study by Cook and colleagues and the current study. Importantly, the dosing regimens were very different in the 2 studies, with Cook and colleagues using higher doses (15 mg/kg versus 10 mg/kg in extreme preterm, preterm, and full‐term infants) and a longer dosing infusion time (30 versus 15 minutes). Also, Cook and colleagues claimed a 1‐compartment model is more accurate than the 2‐compartment model used in the current study, which may be because of the sparseness of the data collected in neonates to evaluate the biphasic elimination. Cook and colleagues only evaluated neonates, and thus for this group they had more subjects and samples and greater ethnic diversity. Although Cook and colleagues showed slightly lower CL than the current study, the U.S. Food and Drug Administration did not express concern regarding the neonate and young infant dosing recommendations proposed and now included in the 2017 Ofirmev (acetaminophen) injection prescribing information, which is consistent with results from our study.\n\nAlthough not demonstrated in the current study, the efficacy of intravenous acetaminophen for postoperative pain management in neonates and infants was shown in 2 prior studies.6, 7 In the study by Allegaert and colleagues, significant improvement in pain score (P < .02) was seen within 30 minutes of administration of intravenous acetaminophen. In the study by Ceelie and colleagues, pediatric patients who received intravenous acetaminophen used significantly less morphine in the first 48 hours postoperatively than those receiving morphine. In the current study, although significant differences were not seen in pain‐related assessments between the intravenous acetaminophen and placebo groups, the subset of patients in the intravenous acetaminophen group with lower prerandomization opioid consumption showed a higher probability of avoiding rescue medication compared with placebo. This result should be interpreted with caution given that during the study the protocol was amended to alter the threshold for prerandomization opioid consumption level (low or high). Subjects previously classified as having either low or high opioid consumption were not reassigned based on the new threshold. On study, all subjects received an opioid dose (full loading dose or lesser amount, based on the subject's pain score) within 30 minutes of the planned first dose of study medication. Further studies are needed to fully characterize the efficacy of intravenous acetaminophen for pain management, including impact on opioid consumption, in this patient population.\n\nConclusion\nIntravenous acetaminophen population PK modeling demonstrated that neonates receiving 12.5 mg/kg every 6 hours show a PK profile similar to younger, intermediate, and older infants, adolescents, and adults weighing <50 kg receiving 15 mg/kg every 6 hours and adults weighing ≥ 50 kg receiving 1000 mg every 6 hours.\n\nConflicts of Interest\nGregory B. Hammer, MD, has no conflicts of interest. Lynne G. Maxwell, MD, received research funding for an intravenous acetaminophen clinical trial (3/2013‐9/2016) from Cadence Pharmaceuticals (acquired by Mallinckrodt). Brad M. Taicher, DO, MBA, has no conflicts of interest. Mihaela Visoiu, MD, is a consultant for Pacira. David S. Cooper, MD, MPH, is on the Mallinckrodt Speakers Bureau. Peter Szmuk, MD, has no conflicts of interest. Jia Lu, PhD, is a former employee of Mallinckrodt. Krishna Devarakonda, PhD, FCP, is a former employee of Mallinckrodt. Leng Hong Pheng, PhD, and Nathalie H. Gosselin, PhD, are associated with Certara.\n\nAcknowledgments\nMichael G. Baker, PhD, and colleagues at Samorn Biosciences, Inc. provided medical writing, proofreading, and editorial support.\n\nFunding\nThis study was funded by Mallinckrodt Pharmaceuticals, Inc.\n\nData Accessibility Statement\nThis trial is registered at https://ClinicalTrials.gov (NCT01635101). The data presented in this article are not publicly available. Requests for additional information should be made to the corresponding author.\n==== Refs\nReferences\n1 \n\nPalmer \nGM \n, \nAtkins \nM \n, \nAnderson \nBJ \n, et al. I.V. Acetaminophen pharmacokinetics in neonates after multiple doses . Br J Anaesth . 2008 ;101 (4 ):523 ‐530 .18628265 \n2 \n\nZuppa \nAF \n, \nHammer \nGB \n, \nBarrett \nJS \n, et al. Safety and population pharmacokinetic analysis of intravenous acetaminophen in neonates, infants, children, and adolescents with pain or fever . J Pediatr Pharmacol Ther . 2011 ;16 (4 ):246 ‐261 .22768009 \n3 \n\nAnderson \nBJ \n, \nWoollard \nGA \n, \nHolford \nNH \n. Acetaminophen analgesia in children: placebo effect and pain resolution after tonsillectomy . Eur J Clin Pharmacol . 2001 ;57 (8 ):559 ‐569 .11758634 \n4 \n\nWang \nC \n, \nAllegaert \nK \n, \nTibboel \nD \n, et al. Population pharmacokinetics of paracetamol across the human age‐range from (pre)term neonates, infants, children to adults . J Clin Pharmacol . 2014 ;54 (6 ):619 ‐629 .24375166 \n5 \n\nCook \nSF \n, \nRoberts \nJK \n, \nSamiee‐Zafarghandy \nS \n, et al. Population pharmacokinetics of intravenous paracetamol (acetaminophen) in preterm and term neonates: model development and external evaluation . Clin Pharmacokinet . 2016 ;55 (1 ):107 ‐119 .26201306 \n6 \n\nAllegaert \nK \n, \nNaulaers \nG \n, \nVanhaesebrouck \nS \n, et al. The paracetamol concentration‐effect relation in neonates . Paediatr Anaesth . 2013 ;23 (1 ):45 ‐50 .23170854 \n7 \n\nCeelie \nI \n, \nde Wildt \nSN \n, \nvan Dijk \nM \n, et al. Effect of intravenous paracetamol on postoperative morphine requirements in neonates and infants undergoing major noncardiac surgery . J Am Med Assoc . 2013 ;309 (2 ):149 ‐154 .\n\n",
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"keywords": "acetaminophen; acute postoperative pain; infants; neonates; opioids",
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"mesh_terms": "D000082:Acetaminophen; D018712:Analgesics, Non-Narcotic; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007262:Infusions, Intravenous; D008297:Male; D059408:Pain Management; D010149:Pain, Postoperative; D016896:Treatment Outcome",
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"title": "Randomized Population Pharmacokinetic Analysis and Safety of Intravenous Acetaminophen for Acute Postoperative Pain in Neonates and Infants.",
"title_normalized": "randomized population pharmacokinetic analysis and safety of intravenous acetaminophen for acute postoperative pain in neonates and infants"
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"abstract": "Polyarteritis nodosa is a systemic necrotizing vasculitis involving medium-sized muscular arteries. Polyneuropathy is the only neurologic manifestation included in the pediatric classification schema. Central nervous system manifestations include infarction, hemorrhage, and encephalitis. We report on a 13-year-old female whose initial presentation of polyarteritis nodosa included hypertension, seizures, and neuroimaging findings of vasogenic edema and posterior reversible encephalopathy syndrome. Posterior reversible encephalopathy syndrome has been reported in association with renal disease, transplantation, autoimmunity, and cytotoxic medications. Posterior reversible encephalopathy syndrome outcomes are usually favorable with supportive care and treatment of the underlying etiology. The patient's neurologic condition improved after treatment of hypertension. Hypertension, posterior reversible encephalopathy syndrome, and abdominal pain led to a diagnostic workup. A systemic vasculitis was confirmed after detection of a perinephric hematoma and intrarenal aneurysms. This is a novel case of posterior reversible encephalopathy syndrome as an initial manifestation of pediatric polyarteritis nodosa.",
"affiliations": "1Baylor College of Medicine and Pediatric Rheumatology Center, Texas Children's Hospital, Houston, TX, USA.",
"authors": "Guirola|Ricardo|R|;Hunter|Jill V|JV|;Perez|Maria|M|;Muscal|Eyal|E|",
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"issue": "29(1)",
"journal": "Journal of child neurology",
"keywords": "polyarteritis nodosa; posterior reversible encephalopathy syndrome; seizures; vasculitis",
"medline_ta": "J Child Neurol",
"mesh_terms": "D000293:Adolescent; D002490:Central Nervous System; D038524:Diffusion Magnetic Resonance Imaging; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D010488:Polyarteritis Nodosa; D054038:Posterior Leukoencephalopathy Syndrome; D015898:Tomography Scanners, X-Ray Computed",
"nlm_unique_id": "8606714",
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"pages": "103-7",
"pmc": null,
"pmid": "23155205",
"pubdate": "2014-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Childhood polyarteritis nodosa presenting with central nervous system manifestations and the posterior reversible encephalopathy syndrome.",
"title_normalized": "childhood polyarteritis nodosa presenting with central nervous system manifestations and the posterior reversible encephalopathy syndrome"
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"companynumb": "US-JNJFOC-20140117275",
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"abstract": "Monoclonal antibodies blocking PD-1 and CTLA-4 immunological checkpoints lead to durable tumor responses in a considerable number of advanced melanoma patients. Besides their anti-neoplastic efficacy, these immune checkpoint inhibitors cause a wide range of immune-related adverse events (irAEs), often enforcing an early discontinuation of therapy. The value of irAEs as a predictive marker for better patient survival is still debated. We report here on a melanoma patient with intramuscular, pulmonary, and bone metastases who developed severe sequential irAEs involving multiple organ systems after single application of a combined immunotherapy with ipilimumab plus nivolumab, followed by a durable complete response despite an early discontinuation of therapy.",
"affiliations": "Department of Dermatology, University of Duisburg-Essen, Essen, Germany.;Department of Dermatology, University of Duisburg-Essen, Essen, Germany.;Department of Diagnostic and Interventional Radiology and Neuroradiology, University of Duisburg-Essen, Essen, Germany.;Department of Dermatology, University of Duisburg-Essen, Essen, Germany.;Department of Dermatology, University of Duisburg-Essen, Essen, Germany.;Department of Endocrinology, Diabetes and Metabolism and Division of Laboratory Research, University of Duisburg-Essen, Essen, Germany.;Department of Dermatology, University of Duisburg-Essen, Essen, Germany.;Department of Dermatology, University of Duisburg-Essen, Essen, Germany.",
"authors": "Matull|Johanna|J|;Livingstone|Elisabeth|E|;Wetter|Axel|A|;Zimmer|Lisa|L|;Zaremba|Anne|A|;Lahner|Harald|H|;Schadendorf|Dirk|D|;Ugurel|Selma|S|",
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"doi": "10.3389/fonc.2020.592609",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X Frontiers Media S.A. \n\n10.3389/fonc.2020.592609\nOncology\nCase Report\nDurable Complete Response in a Melanoma Patient With Unknown Primary, Associated With Sequential and Severe Multi-Organ Toxicity After a Single Dose of CTLA-4 Plus PD-1 Blockade: A Case Report\nMatull Johanna \n1\n\n*\n Livingstone Elisabeth \n1\n Wetter Axel \n2\n Zimmer Lisa \n1\n Zaremba Anne \n1\n Lahner Harald \n3\n Schadendorf Dirk \n1\n Ugurel Selma \n1\n \n1\nDepartment of Dermatology, University of Duisburg-Essen, Essen, Germany\n\n\n2\nDepartment of Diagnostic and Interventional Radiology and Neuroradiology, University of Duisburg-Essen, Essen, Germany\n\n\n3\nDepartment of Endocrinology, Diabetes and Metabolism and Division of Laboratory Research, University of Duisburg-Essen, Essen, Germany\n\nEdited by: Sapna Patel, University of Texas MD Anderson Cancer Center, United States\n\nReviewed by: John August D’Orazio, University of Kentucky, United States; Gagan Chhabra, University of Wisconsin-Madison, United States; Michele Maio, University of Siena, Italy\n\n*Correspondence: Johanna Matull, johanna.matull@uk-essen.de\nThis article was submitted to Skin Cancer, a section of the journal Frontiers in Oncology\n\n\n11 11 2020 \n2020 \n10 59260907 8 2020 16 10 2020 Copyright © 2020 Matull, Livingstone, Wetter, Zimmer, Zaremba, Lahner, Schadendorf and Ugurel2020Matull, Livingstone, Wetter, Zimmer, Zaremba, Lahner, Schadendorf and UgurelThis 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.Monoclonal antibodies blocking PD-1 and CTLA-4 immunological checkpoints lead to durable tumor responses in a considerable number of advanced melanoma patients. Besides their anti-neoplastic efficacy, these immune checkpoint inhibitors cause a wide range of immune-related adverse events (irAEs), often enforcing an early discontinuation of therapy. The value of irAEs as a predictive marker for better patient survival is still debated. We report here on a melanoma patient with intramuscular, pulmonary, and bone metastases who developed severe sequential irAEs involving multiple organ systems after single application of a combined immunotherapy with ipilimumab plus nivolumab, followed by a durable complete response despite an early discontinuation of therapy.\n\ncheckpoint inhibitorsmelanomaimmune-related adverse eventstherapy discontinuationcase report\n==== Body\nIntroduction\nTargeting of immune checkpoints has revolutionized the treatment of metastatic melanoma. Anti-PD-1 monotherapy as well as combined PD-1 and CTLA-4 checkpoint inhibition is approved for metastatic melanoma, and response rates of approximately 40% for anti-PD-1 monotherapy and 60% for the combination with anti-CTLA-4, respectively, have been reported in clinical trials (1). The combination checkpoint inhibition of PD-1 plus CTLA-4 modulates the priming as well as the effector phase of the anti-tumoral immune response (2, 3). However, as a result of this strong immunostimulation, a wide range of immune-related adverse events (irAEs) can be induced by this combination therapy, leading to a frequency of 50 to 60% of severe (grades 3 to 4 according to the CTCAE) treatment-related AEs (4). In clinical trials, anti-PD-1 plus anti-CTLA-4 combination immunotherapy had to be stopped during the induction phase within the first 12 weeks in nearly 40% of cases due to severe adverse events. This early discontinuation, however, was not associated with an inferior outcome (3). Early recognition of irAEs and rapid initiation of appropriate treatment measures are important to prevent life-threatening sequelae or death. We here reported a variety of consecutively occurring severe irAEs involving multiple organ systems after a single dose of combined immunotherapy with ipilimumab and nivolumab in a patient with metastatic melanoma, resulting in treatment discontinuation but also in durable complete response (CR).\n\nCase Presentation\nA 70-year-old male was diagnosed with metastatic melanoma in March 2018 after presenting with a painless subcutaneous swelling of the left scapular region that had increased noticeably in size over the last few months. MRI scans revealed a tumor lesion of 4 cm in diameter within the left deltoid muscle (\nFigure 1A\n). An incisional biopsy confirmed the diagnosis of melanoma. Subsequent CT and FDG-PET scans detected multiple intramuscular, pulmonary, and bone lesions (\nFigure 1C\n). The primary tumor could not be detected even after a thorough physical examination so that the diagnosis of a melanoma of unknown primary was made. Serum LDH and S100B levels were within normal range. Molecular analysis of the tumor tissue biopsy revealed a mutation of the NRAS gene (Q61L); BRAF, KIT, and NF1 genes were wildtype, and the PD-L1 surface expression on tumor cells was negative (0%). After interdisciplinary tumor board discussion, a combined immunotherapy with ipilimumab (3 mg/kg) plus nivolumab (1 mg/kg) Q3W was initiated (for timelines see \nFigure 2\n). As concomitant therapy of bone lesions, the patient received the RANK-L inhibitor denosumab (120 mg Q4W). Sixteen days after the first application of ipilimumab and nivolumab, the patient presented with a sudden onset of severe diarrhea with >10 stools/d, weight loss of 3 kg, exsiccosis, and severe deterioration of his general condition. An immune-related colitis (CTCAE grade 4) was diagnosed, and the patient was hospitalized for intravenous administration of methylprednisolone (2 mg/kg/d) and fluid replacement. After 48 h with no improvement of symptoms, the TNF alpha inhibitor infliximab (5 mg/kg) was added, which led to a complete recovery from diarrhea within 7 days. In addition, a significant elevation of serum amylase and lipase levels (CTCAE grade 4) was noted on the day of admission. One day later, blood tests demonstrated the sudden onset of severe hyperglycemia (glucose 33 mmol/L) and ketoacidosis with inadequately low insulin and c-peptide levels. The patient was diagnosed with an immune-related diabetes mellitus (CTCAE grade 4) and after transferral to the intermediate care unit was carefully substituted intravenously with insulin. Three days later, the patient was switched to subcutaneous insulin application. Four weeks after the first and only application of ipilimumab and nivolumab, the patient developed manifest hyperthyroidism (TSH 0.02 mU/L, normal range 0.3–3.0 mU/L; fT4 37.3 pmol/L, normal range 11.5–22.7 pmol/L) with negative TSH receptor antibodies; \nFigure 3A\n. Ultrasound showed a hypoechoic, heterogeneous, and hypervascular thyroid gland, and Tc99m thyroid scintigraphic scan revealed a slightly elevated uptake in both thyroid lobes corresponding to autoimmune thyroiditis; \nFigures 3B, C\n. The patient was started on thyrostatic therapy with thiamazole 40 mg/d leading to euthyroidism after 8 weeks. Corticosteroids were tapered slowly and the patient was discharged after 5 weeks of hospitalization in a good general condition. Another four weeks after discharge, laboratory tests revealed a rapid and strong increase in serum levels of alanine transaminase (ALT) and aspartate transaminase (AST) CTCAE grade 4. The patient was diagnosed with an immune-related hepatitis; however, a toxic hepatopathy induced by thiamazole could not be ruled out. The patient was again hospitalized, thiamazole was discontinued, and high-dose intravenous methylprednisolone (2 mg/kg/d) was re-initiated. Upon corticosteroids, the liver enzyme levels rapidly normalized, and the patient could be discharged after another 14 days. Three months after the first and only dose of ipilimumab plus nivolumab, CT and MRI scans showed no evidence of disease (\nFigures 1B, D\n), and the patient was classified as a complete responder. At the same time, all therapy-related side effects had completely resolved, all laboratory parameters had returned to normal values, and the patient did not need further substitution therapy of insulin and thyroxin. The latest F18FDG PET/CT was performed on June 18, 2019 without any metabolic abnormality. S100B levels in the peripheral blood were still within normal range (0.05 µg/L) in January 2020. Subsequently, the patient was lost to follow-up.\n\nFigure 1 MRI of the upper left extremity: (A) Strong contrast enhancement of a 4.0 × 2.6 cm metastasis of the left deltoid muscle before initiation of immunotherapy. (B) Complete resolution of the tumor mass at three months after the first and only dose of ipilimumab plus nivolumab. Computed tomography of the chest: (C) Metastasis of the left upper lobe (arrow) before initiation of immunotherapy. (D) Complete resolution of the lung metastasis with residual dystelectasis (arrow) at three months after the first and only dose of ipilimumab plus nivolumab.\n\nFigure 2 Schematic timeline of immune checkpoint inhibition therapy and its immune-related adverse events.\n\nFigure 3 Immune-related thyroiditis. (A) Time course of serum parameters reflecting the thyreoiditis after the application of ipilimumab plus nivolumab on 28.05.2018. Dotted lines represent the timepoint of initiation/discontinuation of thiamazole. TSH, thyroid stimulating hormone; fT4, free thyroxine; LLN, lower limit of normal; ULN, upper limit of normal. (B) Ultrasound showing hypoechoic, heterogeneous and hypervascular thyroid gland. (C) Tc99m scintigraphy showing proportional, slightly elevated tracer uptake (2.6%) throughout the thyroid gland.\n\nDiscussion\nCheckpoint inhibitors such as PD-1 and CTLA-4 antibodies can cause a wide range of irAEs. The types of irAEs and the affected organs are similar for all checkpoint inhibitors, but their frequency and grade of severity are higher for the combination treatment with anti-CTLA-4 plus anti-PD-1 than for the respective monotherapies (5, 6). The randomized phase-3 trial CheckMate-067 showed that hepatitis, colitis, as well as thyroiditis are common side effects of combined checkpoint blockade. Hepatitis and/or elevated liver enzymes were observed in up to one-third of patients treated with ipilimumab plus nivolumab, followed by colitis (13%) and hyperthyroidism (11%) (7). In contrast, immune-related pancreatitis with diabetes mellitus belongs to the rare side effects of checkpoint inhibitor therapy (8, 9). The present case is remarkable for the consecutive occurrence of numerous severe irAEs affecting various organ systems after single administration of ipilimumab plus nivolumab, but also for the complete resolution of all irAEs. irAEs in more than one organ system were reported in 25% of patients treated with nivolumab plus ipilimumab (10); the percentage of patients developing three or more irAEs has not been characterized precisely. In addition, the rapid onset of the individual irAEs observed in our case is unusual. A pooled analysis of patients treated with ipilimumab (10 mg/kg Q3W) showed a characteristic pattern in the timing of the occurrence of distinct irAEs (11). Gastrointestinal irAEs usually arise six to seven weeks after therapy start. In our case, colitis and pancreatitis occurred only three weeks after the first application of immunotherapy. Endocrinal side effects can be expected at approximately nine weeks after treatment start. In our patient, immune-related diabetes was observed at three weeks, and immune-related hyperthyroidism at four weeks after therapy started. It is also remarkable that our patient achieved a deep and durable complete response after only one administration of combined immunotherapy. Repeated imaging only three months after treatment started showed no evidence of disease.\n\nDespite high response rates and durable response—as in the present case—a subset of patients does not respond to immunotherapy or initially respond and finally relapse. Research efforts are underway to identify new agents that could be targeted in combination with immune checkpoint inhibitors to achieve synergistic anti-tumor effects. In the case reported here, the patient received supportive therapies, including infliximab and denosumab, which could have influenced the anti-tumor response. While denosumab with its osteoclastogenetic effect is used to prevent skeletal related events in patients with bone metastases, infliximab is administered for steroid-refractory immune mediated toxicity. There is growing evidence that both infliximab and denosumab can enhance the effectiveness of immunotherapy. In a retrospective observational study combination of denosumab with immune checkpoint inhibition improved overall survival compared with monotherapy in metastatic melanoma patients (12). Likewise, in a case series with 29 melanoma patients, the combination of PD-1 inhibition with denosumab showed a promising efficacy without an increase in toxicity (13). It is assumed that the RANK-RANKL signaling pathway plays a role in tumorigenesis and that denosumab exerts a direct anti-tumor effect by inhibiting this pathway (14). The combination of immunotherapy and Infliximab does not seem to negatively impact anti-tumor efficacy either (15). Rather, preclinical studies have shown that TNF blockade can increase the therapeutic response to anti-PD-1 (16). It is conceivable that both denosumab and infliximab have increased the effectiveness of ipilimumab and nivolumab in our reported case.\n\nDiscontinuation of checkpoint inhibition due to irAE was not associated with a worse treatment outcome in our study. Indeed, there is evidence of a possible association of irAEs with a favorable therapy outcome. In a retrospective analysis, Weber et al. showed that in 576 patients treated with nivolumab monotherapy (excluding those who had progressed prior to week 12), there was no difference in progression-free survival (PFS) between patients without AEs. Similar observations were made for patients with one to two AEs or between those with any-grade AE and all patients (17). In a retrospective analysis of irAEs in patients treated with nivolumab plus peptide vaccine or nivolumab alone, Freeman-Keller et al. noted an overall survival (OS) benefit in patients showing a rash and a vitiligo; no significant survival benefit was seen with other irAEs including endocrinopathies, colitis, and pneumonitis (18). Swami et al. reviewed single institution data of 169 patients treated with anti-PD1-therapy of which 16 discontinued treatment due to irAE and observed a durable clinical benefit in 13 (81.2%) patients (19). Another study by Quach et al. reported cutaneous side effects to be correlated with a favorable response rate and median OS in patients treated with anti-PD-1 therapies. Superior outcomes regarding response rate, PFS, and OS were seen in patients showing a vitiligo and rash as compared to those presenting with pruritus (20). Indini et al. reported an independent association of irAEs with improved PFS and OS on multivariate analysis in patients treated with nivolumab or pembrolizumab (21). Maher et al. observed an association between AEs and tumor response in an examination of seven trials in 1,747 patients with metastatic or locally advanced urothelial cancer treated with anti-program death protein 1 or ligand 1 antibodies. In these analyses a related AESI was reported in 64% of responding patients and in 34% of patients who did not respond to the anti-PD-1/PD-L1 antibody (22). In our patient, the occurrence of multiple and severe irAEs was associated with an extremely favorable therapy outcome of ipilimumab plus nivolumab, reflected by a deep response of CR at three months after therapy onset durably lasting for 19 months.\n\nGiven the methodological limitations of our findings being a case report, the value of irAEs as a predictive marker for better patient survival and response to treatment with immune checkpoint inhibition requires confirmation by further studies on large patient cohorts. In addition, having the patient an unknown primary melanoma, the history of the disease and its clinical progression rate before therapy cannot be evaluated, thus limiting the evaluation of the efficacy of a single course of treatment in reaching a complete response.\n\nData Availability Statement\nThe original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.\n\nEthics Statement\nWritten informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\nAll authors (JM, EL, AW, LZ, AZ, HL, DS, and SU) contributed to data collection, critical revision of the paper, and final approval of the version to be published. JM and SU conceived the work and wrote the paper. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\nJM declares travel support from Bristol Myers Squibb, Novartis and Sun Pharmaceutical Industries. EL declares consulting for Actelion, Bristol-Myers Squibb, MSD, and Novartis; advisory role for Roche, Bristol-Myers Squibb, MSD, and Novartis; honoraria from Amgen, Bristol-Myers Squibb, MSD, Novartis, Janssen, and Medac; travel grants from Medac, Novartis, Bristol-Myers Squibb, Amgen, Pierre Fabre, and Sun Pharma. LZ has served as consultant and/or has received honoraria from Roche, Bristol Myers Squibb, Merck Sharp and Dohme, Novartis, Pierre Fabre, and Sanofi, and received travel support from Bristol Myers Squibb, Merck Sharp and Dohme, Amgen, Pierre Fabre and Novartis. AZ received travel support from Novartis and Bristol-Myers Squibb. DS declares advisory board and speakers honoraria from Roche, Novartis, Bristol-Myers-Squibb, MSD, Merck-Serono, Sanofi, Nektar, Amgen, Hexal, InFlaRx, Array, Pierre Fabre, Immunocore, Philogen Sun Pharma, Regeneron and Ultimovacs as well as grant and travel support from Roche, Novartis, Bristol-Myers-Squibb, MSD, Merck-Serono, and Sanofi. SU declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, and Merck Sharp & Dohme.\n\nThe remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n==== Refs\nReferences\n1 \nLarkin J Chiarion-Sileni V Gonzalez R Grob JJ Cowey CL Lao CD \nCombined nivolumab and ipilimumab or monotherapy in untreated melanoma\n. N Engl J Med (2015 ) 373 :23 –34\n. 10.1056/NEJMoa1504030 \n26027431 \n2 \nKeir ME Butte MJ Freeman GJ Sharpe AH \nPD-1 and its ligands in tolerance and immunity\n. Annu Rev Immunol (2008 ) 26 :677 –704\n. 10.1146/annurev.immunol.26.021607.090331 \n18173375 \n3 \nHodi FS Chesney J Pavlick AC Robert C Grossmann KF McDermott DF \nCombined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial\n. Lancet Oncol (2016 ) 17 (11 ):1558–68. 10.1016/S1470-2045(16)30366-7 \n\n4 \nPalmieri DJ Carlino MS \nImmune checkpoint inhibitor toxicity\n. Curr Oncol Rep (2018 ) 20 :72 . 10.1007/s11912-018-0718-6 \n30066230 \n5 \nWolchok JD Chiarion-Sileni V Gonzalez R Rutkowski P Grob J-J Cowey CL \nOverall survival with combined nivolumab and ipilimumab in advanced melanoma\n. N Engl J Med (2017 ) 377 :1345–56. 10.1056/NEJMoa1709684 \n\n6 \nSchachter J Ribas A Long GV Arance A Grob J-J Mortier L \nPembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006)\n. Lancet (2017 ) 390 (10105 ):1853–62. 10.1016/S0140-6736(17)31601-X \n\n7 \nHodi FS Chiarion-Sileni V Gonzalez R Grob J-J Rutkowski P Cowey CL \nNivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial\n. Lancet Oncol (2018 ) 19 (11 ):1480–92. 10.1016/S1470-2045(18)30700-9 \n\n8 \nShiba M Inaba H Ariyasu H Kawai S Inagaki Y Matsuno S \nFulminant type 1 ciabetes mellitus accompanied by positive conversion of anti-insulin antibody after the administration of anti-CTLA-4 antibody following the discontinuation of anti-PD-1 antibody\n. Intern Med (2018 ) 57 :2029–34. 10.2169/internalmedicine.9518-17 \n\n9 \nAbu-Sbeih H Tang T Lu Y Thirumurthi S Altan M Jazaeri AA \nClinical characteristics and outcomes of immune checkpoint inhibitor-induced pancreatic injury\n. J Immunother Cancer (2019 ) 7 :31 . 10.1186/s40425-019-0502-7 \n30728076 \n10 \nSchadendorf D Hodi FS Robert C Weber JS Margolin K Hamid O \nPooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma\n. J Clin Oncol (2015 ) 33 :1889–94. 10.1200/JCO.2014.56.2736 \n\n11 \nWeber JS Kähler KC Hauschild A \nManagement of immune-related adverse events and kinetics of response with ipilimumab\n. J Clin Oncol (2012 ) 30 :2691–7. 10.1200/JCO.2012.41.6750 \n\n12 \nLiede A Hernandez RK Wade SW Bo R Nussbaum NC Ahern E \nAn observational study of concomitant immunotherapies and denosumab in patients with advanced melanoma or lung cancer\n. Oncoimmunology (2018 ) 7 :e1480301 . 10.1080/2162402X.2018.1480301 \n30524886 \n13 \nAngela Y Haferkamp S Weishaupt C Ugurel S Becker JC Oberndörfer F \nCombination of denosumab and immune checkpoint inhibition: experience in 29 patients with metastatic melanoma and bone metastases\n. Cancer Immunol Immunother (2019 ) 68 :1187–94. 10.1007/s00262-019-02353-5 \n\n14 \nRenema N Navet B Heymann M-F Lezot F Heymann D \nRANK-RANKL signalling in cancer\n. Biosci Rep (2016 ) 36 e00366. 10.1042/BSR20160150 \n\n15 \nBadran YR Cohen JV Brastianos PK Parikh AR Hong TS Dougan M \nConcurrent therapy with immune checkpoint inhibitors and TNFα blockade in patients with gastrointestinal immune-related adverse events\n. J Immunother Cancer (2019 ) 7 :226 . 10.1186/s40425-019-0711-0 \n31439050 \n16 \nBertrand F Montfort A Marcheteau E Imbert C Gilhodes J Filleron T \nTNFα blockade overcomes resistance to anti-PD-1 in experimental melanoma\n. Nat Commun (2017 ) 8 :2256 . 10.1038/s41467-017-02358-7 \n29273790 \n17 \nWeber JS Hodi FS Wolchok JD Topalian SL Schadendorf D Larkin J \nSafety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma\n. J Clin Oncol (2017 ) 35 :785–92. 10.1200/JCO.2015.66.1389 \n\n18 \nFreeman-Keller M Kim Y Cronin H Richards A Gibney G Weber JS \nNivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes\n. Clin Cancer Res (2016 ) 22 :886–94. 10.1158/1078-0432.CCR-15-1136 \n\n19 \nSwami U Monga V Bossler AD Zakharia Y Milhem M \nDurable clinical benefit in patients with advanced cutaneous melanoma after discontinuation of anti-PD-1 therapies due to immune-related adverse events\n. J Oncol (2019 ) 2019 :1856594. 10.1155/2019/1856594 \n31428149 \n20 \nQuach HT Dewan AK Davis EJ Ancell KK Fan R Ye F \nAssociation of anti-programmed cell death 1 cutaneous toxic effects with outcomes in patients with advanced melanoma\n. JAMA Oncol (2019 ) 5 :906–8. 10.1001/jamaoncol.2019.0046 \n\n21 \nIndini A Di Guardo L Cimminiello C Prisciandaro M Randon G de Braud F \nImmune-related adverse events correlate with improved survival in patients undergoing anti-PD1 immunotherapy for metastatic melanoma\n. J Cancer Res Clin Oncol (2019 ) 145 :511–21. 10.1007/s00432-018-2819-x \n\n22 \nMaher VE Fernandes LL Weinstock C Tang S Agarwal S Brave M \nAnalysis of the association between adverse events and outcome in patients receiving a programmed death protein 1 or programmed death ligand 1 antibody\n. J Clin Oncol (2019 ) 37 :2730–7. 10.1200/JCO.19.00318\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2234-943X",
"issue": "10()",
"journal": "Frontiers in oncology",
"keywords": "case report; checkpoint inhibitors; immune-related adverse events; melanoma; therapy discontinuation",
"medline_ta": "Front Oncol",
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"title": "Durable Complete Response in a Melanoma Patient With Unknown Primary, Associated With Sequential and Severe Multi-Organ Toxicity After a Single Dose of CTLA-4 Plus PD-1 Blockade: A Case Report.",
"title_normalized": "durable complete response in a melanoma patient with unknown primary associated with sequential and severe multi organ toxicity after a single dose of ctla 4 plus pd 1 blockade a case report"
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"abstract": "BACKGROUND Hemorrhagic duodenitis is an exceptionally rare adverse event of sodium polystyrene sulfonate (SPS) treatment and is a common manifestation of cytomegalovirus (CMV) reactivation. SPS is known to cause marked inflammation in the lower gastrointestinal tract, including colonic necrosis, whereas involvement of the small bowel is uncommon. Although its effectiveness and safety has been disputed since its introduction, SPS remains widely used due to lack of alternatives. CMV infection and reactivation are well-known complications after solid-organ transplantation, particularly in seronegative recipients receiving organs from seropositive donors, and is associated with significant morbidity and mortality. The lower gastrointestinal tract is more commonly involved, but infections of all parts of the intestine are observed. CASE REPORT Here, we report the case of a 56-year-old man who presented with severe upper-gastrointestinal bleeding. Hemorrhagic duodenitis was initially attributed to the use of SPS, as abundant SPS crystals were detected in the duodenal mucosa but we found only 2 CMV-infected endothelial cells. Two weeks later, gastrointestinal bleeding recurred. However, this time, abundant CMV-infected cells were demonstrated in the duodenal biopsies. CONCLUSIONS Our case report highlights an uncommon adverse event after SPS use with a simultaneous CMV reactivation. The main difficulty was to differentiate between CMV reactivation and CMV as an \"innocent bystander\". This demonstrates the challenge of decision-making in patients with complex underlying diseases.",
"affiliations": "Division of Internal Medicine, University Hospital Basel, University of Basel, Basel, Switzerland.;Department of Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland.;Department of Gastroenterology, University Hospital Basel, Basel, Switzerland.;Department of Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland.;Institute of Pathology, University Hospital Basel, University of Basel, Basel, Switzerland.;Division of Internal Medicine, University Hospital Basel, University of Basel, Basel, Switzerland.;Division of Internal Medicine, University Hospital Basel, University of Basel, Basel, Switzerland.;Division of Internal Medicine, University Hospital Basel, University of Basel, Basel, Switzerland.",
"authors": "Gürtler|Nicolas|N|;Hirt-Minkowski|Patricia|P|;Brunner|Simon S|SS|;König|Katrin|K|;Glatz|Katharina|K|;Reichenstein|David|D|;Bassetti|Stefano|S|;Osthoff|Michael|M|",
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"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 3007268410.12659/AJCR.910655910655ArticlesSodium Polystyrene Sulfonate and Cytomegalovirus-Associated Hemorrhagic Duodenitis: More than Meets the Eye Gürtler Nicolas AEF1Hirt-Minkowski Patricia E2Brunner Simon S. E3König Katrin E2Glatz Katharina DE4Reichenstein David E1Bassetti Stefano E1Osthoff Michael AEF1\n1 Division of Internal Medicine, University Hospital Basel, University of Basel, Basel, Switzerland\n2 Department of Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland\n3 Department of Gastroenterology, University Hospital Basel, Basel, Switzerland\n4 Institute of Pathology, University Hospital Basel, University of Basel, Basel, SwitzerlandAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\nCorresponding Author: Nicolas Gürtler, e-mail: nicolas.guertler@bluewin.ch2018 03 8 2018 19 912 916 17 4 2018 08 5 2018 © Am J Case Rep, 20182018This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 56\n\nFinal Diagnosis: Hemorrhagic duodenitis\n\nSymptoms: Abdominal pain • melena\n\nMedication: —\n\nClinical Procedure: CT scan • gastroscopy • colonoscopy • blood transfusion\n\nSpecialty: General and Internal Medicine\n\nObjective:\nChallenging differential diagnosis\n\nBackground:\nHemorrhagic duodenitis is an exceptionally rare adverse event of sodium polystyrene sulfonate (SPS) treatment and is a common manifestation of cytomegalovirus (CMV) reactivation. SPS is known to cause marked inflammation in the lower gastrointestinal tract, including colonic necrosis, whereas involvement of the small bowel is uncommon. Although its effectiveness and safety has been disputed since its introduction, SPS remains widely used due to lack of alternatives. CMV infection and reactivation are well-known complications after solid-organ transplantation, particularly in seronegative recipients receiving organs from seropositive donors, and is associated with significant morbidity and mortality. The lower gastrointestinal tract is more commonly involved, but infections of all parts of the intestine are observed.\n\nCase Report:\nHere, we report the case of a 56-year-old man who presented with severe upper-gastrointestinal bleeding. Hemorrhagic duodenitis was initially attributed to the use of SPS, as abundant SPS crystals were detected in the duodenal mucosa but we found only 2 CMV-infected endothelial cells. Two weeks later, gastrointestinal bleeding recurred. However, this time, abundant CMV-infected cells were demonstrated in the duodenal biopsies.\n\nConclusions:\nOur case report highlights an uncommon adverse event after SPS use with a simultaneous CMV reactivation. The main difficulty was to differentiate between CMV reactivation and CMV as an “innocent bystander”. This demonstrates the challenge of decision-making in patients with complex underlying diseases.\n\nMeSH Keywords:\nCytomegalovirus InfectionsDuodenitisHyperkalemiaKidney Transplantation\n==== Body\nBackground\nHyperkalemia is commonly observed in renal transplant recipients with several contributing factors, such as treatment with calcineurin inhibitors, trimethoprim, or angiotensin-converting enzyme inhibitors, but treatment options are limited [1,2]. Since 1958, sodium polystyrene sulfonate (SPS) has been widely used for management of acute and chronic hyperkalemia. Initially, it was combined with sorbitol to prevent constipation and fecal impaction. However, an increasing number of case reports showing severe adverse events, such as colonic necrosis, led to the use of SPS without or with only a small amount of sorbitol [3]. Despite (or because of) its long track record for the treatment of hyperkalemia, the pharmacological safety and effectiveness of SPS in reducing serum potassium levels have never been accurately defined. Interestingly, the controversy over the effectiveness of SPS in the management of hyperkalemia is still ongoing, particularly as there are promising new therapies on the horizon, such as patiromer and sodium zirconium sulfonate [4–6].\n\nIn contrast to the abundant case reports documenting severe adverse events in the lower gastrointestinal tract, SPS-related toxicities in the upper-gastrointestinal tract have been rarely described in the literature [7–9].\n\nAfter renal transplantation, reactivation and infection with various pathogens are a major concern of treating physicians. CMV infection/reactivation is associated with significant morbidity and mortality in renal transplant patients [10]; therefore, guidelines recommend CMV serological screening for all organ donors and recipients. If donor and recipient are sero-negative, no prophylaxis is required. In case of a seronegative recipient receiving organs from a seropositive donor and in seropositive recipients, international guidelines recommend anti-viral prophylaxis or preemptive therapy [11]. Antiviral prophylaxis is associated with lower all-cause mortality, particularly in high-risk patients [12].\n\nCMV infection/reactivation often presents with non-specific symptoms, such as fever, night sweats, and fatigue, before symptoms of organ involvement predominate. Apart from antiviral prophylaxis, regular monitoring of the CMV viral load in plasma or whole blood and pre-emptive treatment have become an accepted strategy after solid-organ transplantation in order to avoid a tissue-invasive disease and its consequences. Infection of the gastrointestinal tract is the most common manifestation of CMV disease after kidney transplantation, with the lower gastrointestinal tract affected in the majority of cases [13,14]. A diagnosis of CMV enteritis/colitis may be confirmed with CMV nucleic acid testing of the blood in a patient with signs and symptoms compatible with gastrointestinal CMV disease. Occasionally, histopathological examination of tissue specimens may be required, in particular in patients with unusual signs or a negative CMV nucleic acid test. The presence of cytoplasmic inclusions and nuclear enlargement with eosinophilic nuclear inclusions are classic indicators of tissue-invasive disease. Immunohistochemical tests targeting CMV antigens are applied to increase sensitivity and specificity. Management includes antiviral treatment with ganciclovir or valganciclovir, and reduction of immunosuppressive treatment, if possible.\n\nCase Report\nA 56-year-old male patient presented to the Emergency Department with a 1-day history of sharp lower-abdominal pain and melena. His past medical history included chronic renal failure requiring hemodialysis secondary to type 2 diabetes mellitus and severe arterial hypertension, and dyslipidemia. Three weeks before, he had received a kidney transplant from a deceased child donor and was treated according to our standard immunosuppressive regimen including basiliximab on day 1 and 4, mycophenolate, tacrolimus, and prednisolone. The initial post-transplant course was complicated by a local hematoma that was evacuated, delayed graft function secondary to tubular necrosis, and metabolic acidosis with hyperkalemia that required ongoing treatment with sodium bicarbonate and SPS. Besides immunosuppressive, hypertensive, and diabetic therapy, his discharge medications included acetylsalicylic acid and pantoprazole. As the patient was seropositive and the donor was seronegative for CMV, a strategy of regular monitoring of CMV viral load and preemptive therapy was employed in accordance with national and international guidelines.\n\nOn presentation, the patient was afebrile and blood pressure and heart rate were 107/44 mmHg and 58 bpm, respectively. Physical examination was significant for right lower-quadrant abdominal tenderness. Routine blood tests demonstrated profound anemia (hemoglobin 57 g/l; norm: 140–180), lymphocytopenia (0.22×109/l; norm: 0.9–3.3), hyperglycemia (20.8 mmol/l; norm: 3.8–6.1), hyperkalemia (7.0 mmol/l; norm: 3.6–4.8), and an elevated serum creatinine (249 µmol/l; norm: 49–97). Venous blood gas analysis was significant for metabolic acidosis (pH 7.30; norm: 7.38–7.42, bicarbonate 14.7 mmol/l; norm 21–26). In a non-contrast abdominal CT scan, the distal part of the small bowel and the colon were filled with hyperintense fluid, consistent with gastrointestinal bleeding (Figure 1). The patient immediately received 2 packed red blood cell (PRBC) transfusions (and 4 additional PRBC during the first week of admission) and was transferred to the Intensive Care Unit for monitoring and further treatment. Insulin with glucose was administered and SPS was continued. On the following day, gastroscopy demonstrated severe ulcerative duodenitis with no evidence of active bleeding (Figure 2). Colonoscopy was normal. Histological work-up of gastric and duodenal biopsies revealed a severe erosive duodenitis. Abundant SPS crystals were detectable within the fibrinoleukocytic exudates of the duodenal ulcers and on the surface of the inconspicuous gastric mucosa (Figure 3). In addition, 2 CMV-infected endothelial cells were detected by CMV-immunohistochemistry in the same duodenal biopsies. Given the presence of abundant SPS crystals, the rather small number of detectable CMV-infected cells in the biopsy and the presence of a stable low-level viremia (Figure 4) led to the decision to withhold antiviral treatment. SPS treatment was ceased immediately after the first gastroscopy, and treatment for hyperkalemia was continued with insulin/glucose infusions and inhaled beta-2 agonists [15]. Additionally, treatment with fludrocortisone was initiated due to suspected hyporeninemic hypoaldosteronism [16,17]. Despite immediate cessation of SPS and lack of ongoing melena, the patient’s hemoglobin slowly decreased during the next 2 weeks, at which point he again developed profound melena (Figure 4). Repeat gastroscopy confirmed extensive ulcerative duodenitis as the most likely source of gastrointestinal bleeding, with continuous involvement of the jejunum suspected. In contrast to the first episode, histopathology of duodenal biopsies revealed abundant enlarged endothelial and stromal cells with characteristic intranuclear and cytoplasmic inclusions corresponding to CMV-infected cells. Immunohistochemistry allowed the detection of even more cells, including epithelial cells, containing CMV antigens (Figure 5). At this point, CMV PCR in the peripheral blood was positive with 1585 IU/ml (norm: <137) and peaked in the following days at 14491 IU/ml. After diagnosis of CMV duodenitis, antiviral treatment was initiated with ganciclovir for 5 days and continued with valganciclovir [12]. The CMV viral load became undetectable 22 days after initiating antiviral treatment, and gastrointestinal bleeding ceased. Valganciclovir was continued as secondary prophylaxis. Three months later, renal function had stabilized with creatinine levels of approximately 130 µmol/l (estimated glomerular filtration rate 50 ml/min/1.73 m2), and, importantly, no further complications have occurred.\n\nDiscussion\nIn the present case, detection of SPS crystals in the duodenal mucosa with concomitant inflammation in the setting of severe ulcerative duodenitis was suggestive of SPS-induced gastrointestinal toxicity leading to severe blood loss. The patient received a total of 17 PRBCs over the course of 5 weeks, which underscores the severity of gastrointestinal bleeding in this patient. However, despite absence of overt bleeding, the subsequent clinical course with a slowly decreasing hemoglobin and a second severe bleeding episode 2 weeks later was indicative of an additional pathology, and severe CMV upper-gastrointestinal disease was confirmed on repeat gastroscopy. As there was already weak evidence of CMV infection in the first biopsy, one might argue that SPS was only an “innocent bystander” and disguised the real cause of mucosal inflammation. However, initial biopsies were consistent with SPS-induced inflammation of the duodenum rather than CMV organ disease given the profound ulcerations and profound gastrointestinal bleeding, although we cannot exclude a sampling error. Additionally, major bleeding stopped almost immediately after cessation of SPS, whereas it most likely would have continued if CMV disease was the real culprit causing initial upper-gastrointestinal bleeding. In our opinion, the CMV reactivation was most likely a secondary event in the setting of a severe illness (similar to the observed disease in critically ill patients [18]) and ongoing immunosuppression. Retrospectively, however, immediate initiation of antiviral treatment at the first evidence of CMV-infected cells in the duodenal biopsy in a patient with gastrointestinal bleeding and profound inflammation would have been advisable.\n\nConclusions\nRenal transplant recipients are at increased risk for adverse events in the early post-transplant period, including infections, graft rejection, and medication adverse effects. Adverse events associated with the use of SPS and in the setting of CMV reactivation are well known but may appear in uncommon locations. CMV infection/reactivation should always be considered early as a differential diagnosis among renal transplant recipients presenting with non-specific symptoms. Due to the potential adverse events of SPS, particularly during long-term therapy, alternative treatment options may be considered.\n\nConflict of Interest\n\nNone.\n\nFigure 1. Non-contrast abdominal CT scan demonstrating hyperintense fluid in the ascending colon (asterisk), consistent with gastrointestinal hemorrhage. The small bowel (1) and cecum (2) are also depicted.\n\nFigure 2. Gastroscopy image of the duodenum on the second day of admission, showing severe ulcerative duodenitis without active bleeding.\n\nFigure 3. Biopsy taken from a duodenal ulcer on the occasion of the first gastroscopy, showing polygonal purple SPS crystals (asterisks) embedded within the fibrinoleukocytic exudate. (HE; 100×).\n\nFigure 4. Course of hemoglobin and CMV viral load in the present patient.\n\nFigure 5. Detection of CMV intranuclear inclusions by immunohistochemistry in numerous mesenchymal and epithelial cells in a biopsy taken from a duodenal ulcer on the occasion of the second gastroduodenoscopy. (FLEX Monoclonal Mouse Anti-Cytomegalovirus, Clone CCH2 + DDG9, Dako, Denmark; 200×).\n==== Refs\nReferences:\n1. Palmer BF Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system N Engl J Med 2004 351 6 585 92 15295051 \n2. Evans KJ Greenberg A Hyperkalemia: A review J Intensive Care Med 2005 20 5 272 90 16145218 \n3. McGowan CE Saha S Chu G Intestinal necrosis due to sodium polystyrene sulfonate (Kayexalate) in sorbitol South Med J 2009 102 5 493 97 19373153 \n4. Beccari MV Meaney CJ Clinical utility of patiromer, sodium zirconium cyclosilicate, and sodium polystyrene sulfonate for the treatment of hyperkalemia: An evidence-based review Core Evid 2017 12 11 24 28356904 \n5. Watson M Abbott KC Yuan CM Damned if you do, damned if you don’t: potassium binding resins in hyperkalemia Clin J Am Soc Nephrol 2010 5 10 1723 26 20798253 \n6. Kamel KS Schreiber M Asking the question again: Are cation exchange resins effective for the treatment of hyperkalemia? Nephrol Dial Transplant 2012 27 12 4294 97 22989741 \n7. Harel Z Harel S Shah PS Gastrointestinal adverse events with sodium polystyrene sulfonate (Kayexalate) use: A systematic review Am J Med 2013 126 3 264.e9 24 \n8. Dunlap RH Martinez R Total colectomy for colon perforation after kayexalate administration: A case report and literature review of a rare complication J Surg Case Rep 2016 2016 10 pii: rjw167 \n9. Rashid A Hamilton SR Necrosis of the gastrointestinal tract in uremic patients as a result of sodium polystyrene sulfonate (Kayexalate) in sorbitol: An underrecognized condition Am J Surg Pathol 1997 21 1 60 69 8990142 \n10. Steininger C Clinical relevance of cytomegalovirus infection in patients with disorders of the immune system Clin Microbiol Infect 2007 13 10 953 63 17803749 \n11. Kotton CN Kumar D Caliendo AM The Third International Consensus Guidelines on the management of cytomegalovirus in solid organ transplantation Transplantation 2018 102 6 900 31 29596116 \n12. Hodson EM Jones CA Webster AC Antiviral medications to prevent cytomegalovirus disease and early death in recipients of solid-organ transplants: A systematic review of randomised controlled trials Lancet 2005 365 9477 2105 15 15964447 \n13. Brennan DC Cytomegalovirus in renal transplantation J Am Soc Nephrol 2001 12 4 848 55 11274248 \n14. Arthurs SK Eid AJ Pedersen RA Delayed-onset primary cytomegalovirus disease and the risk of allograft failure and mortality after kidney transplantation Clin Infect Dis 2008 46 6 840 46 18260785 \n15. Nyirenda MJ Tang JI Padfield PL Seckl JR Hyperkalaemia BMJ 2009 339 b4114 19854840 \n16. Imbriano LJ Durham JH Maesaka JK Treating interdialytic hyperkalemia with fludrocortisone Semin Dial 2003 16 1 5 7 12535291 \n17. Singhal PC Desroches L Mattana J Mineralocorticoid therapy lowers serum potassium in patients with end-stage renal disease Am J Nephrol 1993 13 2 138 41 8342580 \n18. Osawa R Singh N Cytomegalovirus infection in critically ill patients: A systematic review Crit Care 2009 13 3 R68 19442306\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "19()",
"journal": "The American journal of case reports",
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"medline_ta": "Am J Case Rep",
"mesh_terms": "D002411:Cation Exchange Resins; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D004382:Duodenitis; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D006947:Hyperkalemia; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011137:Polystyrenes",
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"title": "Sodium Polystyrene Sulfonate and Cytomegalovirus-Associated Hemorrhagic Duodenitis: More than Meets the Eye.",
"title_normalized": "sodium polystyrene sulfonate and cytomegalovirus associated hemorrhagic duodenitis more than meets the eye"
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"abstract": "Autologous stem cell transplantation (ASCT) is still debatable in treatment of patients over 65 years with multiple myeloma (MM). We performed a retrospective analysis of newly diagnosed MM patients who underwent ASCT between January 2010 and July 2016. A non-transplanted group with similar clinical characteristics, aged 65-70 years old, diagnosed and treated in the same timeline was used for comparison. We analyzed a total of 155 patients, 132 of which underwent ASCT (≤ 65 years, n = 103, median 56 years; > 65 years, n = 29, median 67 years) and 23 non-transplanted (median 68 years). Conditioning consisted of melphalan 200 mg/m2 (MEL200) in younger patients and melphalan 140 mg/m2 (MEL140) in half of elderly patients. Stratifying by age, there were no statistically significant differences concerning transplant-related myelotoxicity and non-hematopoietic toxicity; however, elderly patients conditioned with MEL200 had higher needs of transfusional support and more days of intravenous antibiotics. Those patients also had higher needs of transfusional support, higher grade of mucositis (p = 0.028), and more days of intravenous antibiotics (p = 0.019) than the elderly transplanted with MEL140. Global transplant-related mortality was 3.8%. Survival was not influenced by age. Non-transplanted elderly patients had comparable disease features, and induction response was similar in both groups (before ASCT in the transplanted cohort). Survival of transplanted elderly patients was superior to non-transplanted (OS, 59 months vs 30 months, p = 0.037; EFS, 45 months vs 27 months, p = 0.014). Selected elderly patients when transplanted have similar disease response and survival as younger patients. A higher dose of melphalan has more toxicity, but it is globally a well-tolerated procedure.",
"affiliations": "Centro Hospitalar de São João, Porto, Portugal. carolinamarini@gmail.com.;Centro Hospitalar de São João, Porto, Portugal.;Centro Hospitalar de São João, Porto, Portugal.;Centro Hospitalar de São João, Porto, Portugal.;Centro Hospitalar de São João, Porto, Portugal.;Centro Hospitalar de São João, Porto, Portugal.;Centro Hospitalar de São João, Porto, Portugal.",
"authors": "Marini|Carolina|C|http://orcid.org/0000-0002-2452-8032;Maia|Tânia|T|;Bergantim|Rui|R|;Pires|Jorge|J|;Aguiar|Eliana|E|;Guimarães|José Eduardo|JE|;Trigo|Fernanda|F|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-018-3528-x",
"fulltext": "\n==== Front\nAnn HematolAnn. HematolAnnals of Hematology0939-55551432-0584Springer Berlin Heidelberg Berlin/Heidelberg 30368589352810.1007/s00277-018-3528-xOriginal ArticleReal-life data on safety and efficacy of autologous stem cell transplantation in elderly patients with multiple myeloma http://orcid.org/0000-0002-2452-8032Marini Carolina 00351 912 754 834carolinamarini@gmail.com 1Maia Tânia 1Bergantim Rui 12Pires Jorge 1Aguiar Eliana 1Guimarães José Eduardo 12Trigo Fernanda 11 0000 0000 9375 4688grid.414556.7Centro Hospitalar de São João, Porto, Portugal 2 0000 0001 1503 7226grid.5808.5Faculdade de Medicina da Universidade do Porto, Porto, Portugal 27 10 2018 27 10 2018 2019 98 2 369 379 22 2 2018 17 10 2018 © The Author(s) 2018Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Autologous stem cell transplantation (ASCT) is still debatable in treatment of patients over 65 years with multiple myeloma (MM). We performed a retrospective analysis of newly diagnosed MM patients who underwent ASCT between January 2010 and July 2016. A non-transplanted group with similar clinical characteristics, aged 65–70 years old, diagnosed and treated in the same timeline was used for comparison. We analyzed a total of 155 patients, 132 of which underwent ASCT (≤ 65 years, n = 103, median 56 years; > 65 years, n = 29, median 67 years) and 23 non-transplanted (median 68 years). Conditioning consisted of melphalan 200 mg/m2 (MEL200) in younger patients and melphalan 140 mg/m2 (MEL140) in half of elderly patients. Stratifying by age, there were no statistically significant differences concerning transplant-related myelotoxicity and non-hematopoietic toxicity; however, elderly patients conditioned with MEL200 had higher needs of transfusional support and more days of intravenous antibiotics. Those patients also had higher needs of transfusional support, higher grade of mucositis (p = 0.028), and more days of intravenous antibiotics (p = 0.019) than the elderly transplanted with MEL140. Global transplant-related mortality was 3.8%. Survival was not influenced by age. Non-transplanted elderly patients had comparable disease features, and induction response was similar in both groups (before ASCT in the transplanted cohort). Survival of transplanted elderly patients was superior to non-transplanted (OS, 59 months vs 30 months, p = 0.037; EFS, 45 months vs 27 months, p = 0.014). Selected elderly patients when transplanted have similar disease response and survival as younger patients. A higher dose of melphalan has more toxicity, but it is globally a well-tolerated procedure.\n\nKeywords\nMultiple myelomaElderlyAutologous transplantationissue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2019\n==== Body\nIntroduction\nMultiple myeloma (MM) is mainly a disease of the elderly [1, 2]. On the one hand, the lengthening of life expectancy is related to an increase in the incidence of oncological diseases, and on the other hand, the improvement of diagnostic acuity and new therapeutic options on MM has led to a longer survival of elderly patients from median 19 months (in 1973) to 6.1 years (in 2004) [1, 3, 4]. A Mayo Clinic study [2] confirmed a significant increase in cases diagnosed in older age groups when comparing to the 1950s and early 2000s, with the median age at diagnosis of MM increasing from 70 to 74 years, as well as doubling the proportion of newly diagnosed patients aged 80 years or older.\n\nOver the last two decades, there were significant advances in understanding MM disease biology and in development of several new drugs that allowed a paradigm shift from a palliative intent towards the active management of the disease aiming to prolong event-free survival (EFS) and overall survival (OS) [1]. Nowadays, induction followed by autologous stem cell transplantation (ASCT) after high-dose melphalan conditioning continues the standard treatment for MM patients under the age of 65 years [1, 5–7]. Some studies suggest that age at the time of transplant does not have prognostic significance on outcome after ASCT [8, 9], but its safety and efficacy remain uncertain for patients over that age [9–16].\n\nAging determines a progressive deterioration of physiological reserves and endurance that may increase morbidity and mortality, jeopardizing the effectiveness of ASCT as part of treatment options in MM. Despite these concerns, studies show there is a blatant benefit in survival for transplanted elderly patients [14, 17–22], even in analysis adjusted to performance status, comorbidities, and disease stage [20] and after the introduction of novel agents for induction chemotherapy [14, 19, 21]. Therefore, it is imperative to evaluate transplant toxicity in an advanced age. Despite lacking randomized data in the elderly population, recent data reveal that ASCT is becoming more used over 65 years old [12, 19], allowing to determine its efficacy and toxicity in the real-life context for this population.\n\nObjective\nThe main goal of this analysis is the evaluation of ASCT’s toxicity in elderly patients (> 65 years old) when compared to a younger cohort (≤ 65 years old). Secondary endpoints included the efficacy of ASCT and evaluation of OS and progression-free survival (PFS) in the transplanted.\n\nMethods\nPatients and risk stratification\nRetrospective analysis of 132 MM patients consecutively submitted to ASCT between January 2010 and July 2016, at the Department of Hematology of Centro Hospitalar São João (Porto, Portugal). Patients were stratified by age into two groups: group 1, ≤ 65 years old, and group 2, > 65 years old. Data from 65- to 70-year-old patients diagnosed in this same calendar period who were not transplanted were used for comparison (group 3). Exclusion criteria included the following: plasma cell leukemia or amyloidosis at diagnosis, death during induction therapy in patients with indication for ASCT or during the first line of treatment in patients with no indication for ASCT who did not complete all cycles, patients in palliative care. This center also received patients referred for ASCT in whom diagnosis and induction therapy were performed at a different hospital. For risk stratification, we used the International Staging System (ISS) [23], Durie Salmon Staging System (DS) [24], and fluorescence in situ hybridization (FISH) for deletion 17p, deletion 1p, gain of 1q, deletion 13q, deletion 16q, deletion 14q, and translocations t(4;14), t(11;14), and t(14;16). The threshold cytogenetics abnormalities were set at 10%.\n\nTransplant eligibility\nIndication for ASCT followed our center protocol in which eligibility criteria include a performance status (PS) ECOG ≤ 2 and no significant comorbidities, evaluated by echocardiogram, respiratory functional studies, and also daily life performance information reported by patient’s attending physician.\n\nInduction therapy and stem cell mobilization\nPatients received two to seven cycles of induction therapy before stem cell mobilization. Induction therapy was applied according to the local protocol of our center and referring institutions. Peripheral hematopoietic progenitor cells were mobilized with cyclophosphamide (4 g/m2) and granulocyte colony-stimulating factor (G-CSF) 10 mcg/kg twice a day or G-CSF alone if patients had less than complete response or complete response after induction therapy, respectively.\n\nConditioning for transplant\nConditioning regimen consisted of melphalan at high dose 200 mg/m2 (MEL200) or with reduced dose 100 or 140 mg/m2 (rMEL) according to the presence of organ dysfunctions (creatinine clearance ≤ 40 mL/min or subjective evaluation of the patient’s ability to receive high-dose melphalan). Prophylactic care included antiviral and antifungal prophylaxis, thromboprophylaxis before thrombocytopenia, and Caphosol® for mucositis prophylaxis.\n\nAssessment of transplant-related toxicity\nFor transplant safety assessment, data were collected on hematologic toxicity (transfusion needs, time in days until peripheral neutrophil, and platelet count recovery), mucositis (grade, use and duration in days of intravenous morphine), and infection (number of days of fever, antibiotics used, days under antibiotics), days of hospitalization, and need for intensive care during the transplant procedure. Engraftment was defined by absolute neutrophil count (ANC) ≥ 0.5 × 109/L for three consecutive days, and platelet count ≥ 20 × 109/L unsupported by platelet transfusions in the last 7 days. Treatment-related mortality (TRM) was defined as death during the first 100 days after ASCT.\n\nAssessment of complications among elderly patients\nDescription and comparison of complications according to Common Terminology Criteria for Adverse Events (CTCAE) [25] in elderly patients, transplanted or not, in the first 12 months after beginning treatment. Inpatient days due to complications accounted for excess days in treatment-related hospitalizations and complications severe enough to require hospitalization.\n\nAssessment of treatment efficacy and survival\nTreatment response was assessed according to the IMWG guidelines [26]. It was carried out after induction therapy in all groups and 100 days after ASCT in transplanted patients.\n\nEvaluation of overall survival (OS) and event-free survival (EFS) was performed by age and transplant status. EFS was defined as the time from ASCT to relapse/progression or death from the disease. OS was defined as the time from ASCT to death from any cause.\n\nStatistical analysis\nStatistical analysis was performed using SPSS® v.20 [27]. Normal distribution was characterized by skewness and kurtosis for psychometric variables and by Shapiro-Wilk and Kolmogorov-Smirnov tests (p > 0.01). Regarding EFS, we applied nonparametric tests and survival curves according to the Kaplan-Meyer method with the log-rank test to identify differences between groups. For OS, hazard ratio (HR) was calculated according to Cox regression analysis for age and melphalan dose effect. A confidence interval was defined at 95%.\n\nEthics committee analysis\nThis study has been evaluated and approved by our ethics committee, the Ethics Committee for Health of Centro Hospitalar de São João/Faculty of Medicine of Oporto University.\n\nResults\nBaseline clinical and laboratory features\nPatient’s demographics, disease characteristics, and risk stratification by age group are summarized in Table 1. There was a total of 155 MM patients newly diagnosed in the defined period, 103 of which in group 1, 29 in group 2, and 23 in group 3. By Charlson comorbidity index, non-transplanted elderly patients had significantly higher scores ≥ 3 (p = 0.02) when compared to transplanted elderly patients and also higher scores when compared to younger patients (p = 0.013). No statistical difference in disease characteristics or staging (p > 0.05 in all parameters) was found between the three groups.Table 1 Demographics and disease classification at diagnosis\n\n\t≤ 65 years old\tASCT > 65 years old\tNo ASCT ≥ 65 years old\t\nAge at diagnosis, years (median)\t56 (36; 65)\t67 (64; 70)\t68 (65; 70)\t\nAge at transplant, years (median)\t56 (37; 65)\t68 (66; 70)\tNA\t\nGender\t\n Male (n)\t51 (49%)\t21 (72%)\t11 (48%)\t\n Female (n)\t52 (51%)\t8 (28%)\t12 (52%)\t\nPerformance status\t\n ECOG\t\n ≤ 2 (n)\t103 (100%)\t29 (100%)\t19 (82%)\t\n > 2 (n)\t0\t0\t4 (18%)\t\nCharlson score\t\n 1–2 (n)\t86 (83%)\t18 (62%)\t7 (30%)\t\n 3–4 (n)\t16 (16%)\t10 (35%)\t11 (48%)\t\n ≥ 5 (n)\t1 (1%)\t1 (3%)\t5 (22%)\t\nCRAB\t\n Calcium > 2.75 mmol/L (n)\t15 (15%)\t5 (18%)\t3 (13%)\t\n Creatinine > 2 mg/dL (n)\t11 (11%)\t4 (16%)\t10 (43%)\t\n Hemoglobin < 10 g/dL (n)\t38 (37%)\t9 (31%)\t12 (52%)\t\n Bone disease (n)\t74 (71%)\t21 (72%)\t12 (66%)\t\n B2MICRO > 3.5 mg/L (n)\t40 (43%)\t14 (54%)\t14 (88%)\t\nMonoclonal component\t\n IgG (n)\t54 (52%)\t13 (45%)\t11 (48%)\t\n IgA (n)\t19 (18%)\t11 (38%)\t6 (26%) \t\n Light chains only (n)\t18 (17%)\t4 (14%)\t6 (26%)\t\nOther (n)\t12 (13%)\t1 (3%)\t0\t\nStaging ISS\t\n I (n)\t39 (38%)\t7 (24%)\t3 (13%)\t\n II (n)\t32 (31%)\t10 (35%)\t4 (17%)\t\n III (n)\t26 (25%)\t10 (35%)\t13 (56%)\t\n Unknown (n)\t6 (6%)\t2 (6%)\t3 (14%)\t\nCytogenetic risk\t\n Standard (n)\t30 (29%)\t11 (38%)\t4 (17%)\t\n Intermediate (n)\t24 (23%)\t5 (17%)\t10 (43%)\t\n High (n)\t12 (12%)\t2 (7%)\t2 (9%)\t\n Unknown (n)\t37 (36%)\t11 (38%)\t7 (31%)\t\n BM plasma cells (median)\t18 (0; 80)\t10 (0.5; 80)\t15 (1; 86)\t\nCharlson score is calculated at time of diagnosis; CRAB is acronym for calcium, renal, anemia, bone, for clinical classification of MM [28]; BM plasma cells is median percentage of plasma cells in bone marrow at diagnosis, by immunophenotype. Cytogenetic risk is defined by Mayo Stratification of Myeloma and Risk Adapted Therapy consensus guidelines 2013 (mSMART) [29]\n\n\n\nTreatment, response to induction, and mobilization\nRegarding treatment protocol selection (Table 2), there was no statistical difference in choice of novel agents according to age (p = 0.17) or ASCT status (p = 0.58) (Table 1). Concerning treatment response after induction, 73% of younger transplanted patients had at least very good partial response (VGPR) as well as 69% of the elderly transplanted and 65% of the elderly non-transplanted patients (Table 2). Despite these differences, it was not statistically relevant, either in the transplanted group (p = 0.72) or in the non-transplanted group (p = 0.77) when compared to its age-adjusted cohort. Considering transplanted patients, age did not correlate to the selection of mobilization regimen (p = 0.22), to the number of collected PBPCs (p = 0.09), or to the number of apheresis for appropriate collection (p = 0.55).Table 2 Therapy characteristics and response to induction therapy\n\n\t≤ 65 years old\tASCT > 65 years old\tNo ASCT ≥ 65 years old\t\nInduction chemotherapy\t\n Bortezomib-based (n)\t71 (69%)\t22 (76%)\t15 (65%)\t\n IMiD-based (n)\t3 (3%)\t3 (10%)\t4 (17%)\t\n Bortezomib + IMiDs (n)\t27 (26%)\t4 (14%)\t3 (13%)\t\n Neither (n)\t2 (2%)\t0\t1 (5%)\t\nResponse to therapy\t\n CR (n)\t29 (28%)\t7 (24%)\t8 (35%)\t\n VGPR (n)\t46 (45%)\t13 (45%)\t7 (30%)\t\n PR (n)\t27 (26%)\t9 (31%)\t5 (22%)\t\n Refractory/stable (n)\t1 (1%)\t0\t3 (13%)\t\n > 2 lines of treatment for better response (n)\t13 (12%)\t6 (21%)\t3 (13%)\t\n Time to transplant (median months)\t8 (3; 21)\t9 (4; 20)\tNA\t\nMobilization regimen\t\n HD-Cy + GCSF (n)\t78 (76%)\t25 (86%)\tNA\t\n G-CSF only (n)\t25 (24%)\t4 (14%)\tNA\t\n CD34+ collected (median × 106/kg)\t6.5 (2.2; 35)\t5.0 (1.6; 19)\tNA\t\n Number of apheresis ≥ 3\t23 (22%)\t8 (27%)\tNA\t\nIMiDs, immunomodulatory drugs; HD-Cy, high-dose cyclophosphamide; G-CSF, granulocyte colony-stimulating factor\n\n\n\nEngraftment and transplant-related toxicity\nEvaluation of hematologic toxicity according to age subgroups (Table 3) revealed that elderly patients had the same median days of aplasia as the younger cohort. Concerning non-hematopoietic toxicity, there were no significant differences in all parameters, namely infection and mucositis. This was also verified when adjusting to the dose of melphalan.Table 3 Transplant-related toxicity by age, the dose of melphalan and in the elderly group\n\n\t≤ 65 vs > 65\t> 65: rMEL vs MEL200\tMEL200: ≤ 65 vs > 65\t\nMyelotoxicity\t\n Aplasia (median days)\t12 vs 12 (p 0.55)\t12 vs 11 (p 0.025)\t12 vs 11 (p 0.051)\t\n PLT recovery (median days)\t12 vs 12 (p 0.74)\t12 vs 12 (p 0.11)\t12 vs 12 (p 0.43)\t\n PLT support (median units)\t1 vs 2 (p 0.32)\t1 vs 2 (p 0.20)\t1 vs 2 (p 0.06)\t\n RBC support (median units)\t0 vs 0.5 (p 0.32)\t0 vs 1 (p 0.17)\t0 vs 1 (p 0.06)\t\nNon-hematopoietic toxicity—infection\t\n Fever (median days)\t2 vs 2 (p 0.86)\t1 vs 2 (p 0.29)\t2 vs 2 (p 0.30)\t\n CRP (median mg/L)\t147 vs 139 (p 0.71)\t156 vs 129 (p 0.52)\t145 vs 129 (p 0.45)\t\n Antibiotics (median number)\t2 vs 2 (p 0.75)\t1 vs 2 (p 0.17)\t2 vs 2 (p 0.32)\t\n Antibiotics (median days)\t9 vs 7 (p 0.20)\t7 vs 11 (p 0.019)\t9 vs 11 (p 0.21)\t\nNon-hematopoietic toxicity—mucositis\t\n Grade (median)\tIII vs III (p 0.55)\tII vs III (p 0.028)\tIII vs III (p 0.09)\t\n IV morphine (% who need)\t55% vs 41% (p 0.18)\t28% vs 63% (p 0.12)\t56% vs 63% (p 0.75)\t\n IV morphine (median days)\t3 vs 0 (p 0.13)\t0 vs 3 (p 0.08)\t3 vs 3 (p 0.61)\t\n\n\nHowever, when assessed by the dose of melphalan solely in the elderly group, older patients conditioned by MEL200 seem to have fewer days until neutrophil recovery but with a greater need for transfusion support. These patients had more mucositis (grade and need of support) and more days of antibiotics than the ones conditioned by rMEL. Five patients had to be admitted to intensive care unit (3 under 65 years old and 2 over 65 years old), four of them due to septic shock, and one patient for stroke and bronchiolitis obliterans with organizing pneumonitis. The median inpatient days were 21 (range 15 to 91), and there were no differences between groups (p = 0.19). Charlson comorbidity index did not affect transplant-related toxicity, either by age or by the dose of melphalan.\n\nNon-transplanted patients\nEvaluation of complications in transplanted and non-transplanted elderly patients (Table 4) revealed that transplanted patients had more incidence of complications (p = 0.02) and significantly more inpatient days due to these complications (p = 0.04). Infection was the most frequent complication, accounting for 40% in transplanted patients and 48% in non-transplanted patients. Regarding severity, transplanted patients had more grade 3–4 complications (p = 0.043).Table 4 Complications in elderly patients, transplanted or not\n\n\tASCT > 65 years old\tNo ASCT ≥ 65 years old\t\nMedian number of complications in 1 year\t4 (0; 6)\t2 (0; 7)\t\nMedian number of inpatient days due to complications\t8 (0; 50)\t0 (0; 53)\t\nType of complications by number of patients\t\n Neuropathy (n)\t9 (31%)\t5 (22%)\t\n Thrombotic (n)\t2 (7%)\t3 (13%)\t\n Hemorrhagic (n)\t2 (7%)\t1 (4%)\t\n Infection (n)\t28 (96%)\t17 (74%)\t\n Mucositis (n)\t24 (82%)\t0\t\n Others (n)\t5 (17%)\t9 (39%)\t\nGrade of complications by number of events\t\n Number of events (n)\t102\t55\t\n Grade 1–2 (n)\t54 (53%)\t42 (76%)\t\n Grade 3–4 (n)\t48 (47%)\t13 (24%)\t\nIn the type of complications, the category “Others” includes cardiac, hepatic, endocrine, and cutaneous toxicities\n\n\n\nResponse at day 100 and survival\nAfter induction therapy, CR was achieved in 27% of transplanted patients. High-dose chemotherapy and ASCT increased the CR rate to 51%. Response at day 100 post-transplant (Table 5) was significantly better than response after induction therapy (p < 0.01), with no relation to age. Approximately, a quarter of younger patients and a third of elderly patients had improvement in depth of post-transplant response (Graph 1). Autologous transplantation deepened the level of response as highlighted when comparing to age-adjusted non-transplanted patients (p = 0.05).Table 5 Conditioning and outcome after transplant\n\n\t≤ 65 years old\tASCT > 65 years old\tNo ASCT ≥ 65 years old\t\nConditioning\t\n MEL200 (n)\t101 (98%)\t11 (38%)\tNA\t\n MEL140 (n)\t2 (2%)\t15 (52%)\tNA\t\n MEL100 (n)\t0\t3 (10%)\tNA\t\nResponse at day 100\t\n CR (%)\t50 (49%)\t17 (59%)\tNA\t\n VGPR (%)\t39 (38%)\t6 (21%)\tNA\t\n PR (%)\t10 (9%)\t4 (14%)\tNA\t\n Refractory/stable (%)\t1 (1%)\t0\tNA\t\n Death at day 100 (%)\t3 (3%)\t2 (6%)\tNA\t\nMortality (n)\t21 (19%)\t10 (34%)\t13 (56%)\t\n MM progression (n)\t20\t7\t9\t\n Non-MM related (n)\t1\t3\t4\t\nDisease status at last follow-up\t\n CR (n)\t40 (49%)\t13 (68%)\t2 (20%)\t\n VGPR (n)\t23 (28%)\t2 (11%)\t1 (10%)\t\n PR (n)\t5 (6%)\t3 (16%)\t1 (10%)\t\n Refractory/stable (n)\t14 (17%)\t1 (5%)\t6 (60%)\t\nThree patients over 65 years had MEL100 as conditioning regimen: one patient for maintaining renal insufficiency after induction therapy; one patient for reduced number of cells for infusion (1.6 × 106 CD34+ cells/kg); and another patient for subjective evaluation of frailty. Two younger patients had conditioning with MEL140, both for persistent creatinine clearance ≤ 40 mL/min\n\nGraph 1 Deepening of response after transplant according to age. a Transplanted patients ≤ 65 years old; b transplanted elderly patients\n\n\n\nFive patients died during the transplant procedure (n = 3) or the first 100 days after ASCT (n = 2) resulting in a TRM of 3.8%, all deaths related to infectious complications.\n\nData on progression and survival status were collected in September 2016 with a median follow-up of 30 months. Elderly patients had a median EFS of 45 months vs 59 months in younger patient group (p = 0.63), with no difference in OS (HR 1.73, CI 0.81–3.70, p = 0.15) (Graph 2). Elderly patients conditioned with MEL200 had a median EFS of 62 months vs 45 months in elderly patients treated with a reduced dose of melphalan, however with no statistical significance (p = 0.79). There was no effect in OS according to melphalan dose in these patients (HR 0.80, CI 0.22–2.86, p = 0.73) (Graph 3). When comparing elderly transplanted patients to non-transplanted patients, there is an essential difference in survival curves. There is an advantage of the transplanted group on EFS with a median time of 45 months vs 27 months on the non-transplanted group (p = 0.014). This advantage remains significant on OS (Graph 4).Graph 2 OS according to age, median follow-up 30 months. Median 83 months in patients < 65 years old and 59 months in elderly patients (p = 0.15)\n\nGraph 3 OS according to the dose of melphalan in the elderly group, median follow-up 30 months. Median 59 months in patients conditioned with reduced doses of melphalan vs 62 months in patients conditioned with high doses of melphalan (p = 0.73)\n\nGraph 4 OS of elderly patients according to transplant status, median follow-up 30 months. Transplanted group with a median of 59 months vs 30 months in non-transplanted group (p = 0.037)\n\n\n\nDiscussion\nIn our analysis, elderly patients have more toxicity with MEL200 when comparing to reduced doses of melphalan, yet these are manageable complications with the current supportive standard of care. Complications included increased demand for transfusions, support for mucositis, and need for antibiotics for infection control. It is noteworthy that elderly patients treated with MEL200 had less median days of aplasia, which may seem contradictory. Nonetheless, these patients received more supportive measures (higher number of transfused platelet units and erythrocyte concentrates) which may indicate a slower global recuperation. Non-transplanted elderly patients had fewer hospitalizations due to complications, and most of them had low severity, preserving ambulatory management of these patients which is a general aim when handling patients with no curative intent.\n\nThere was no excess transplant-related mortality (TRM) in elderly patients and inpatient days were the same regardless of age despite higher toxicity, reinforcing there was an adequate control of complications. Even though autologous transplantation is a standard of care for multiple myeloma, age still plays an important role when pondering this intensification of treatment as questions are raised on the endurance of elderly patients to receive high-dose chemotherapy. It has been demonstrated in several studies that improvement of supportive care provides adequate control of complications [30], reducing discomfort associated with this procedure and even reducing TRM [12, 31]. Cheikh et al. [31] already hypothesized that improvement in supportive care, particularly the use of G-CSF and prophylactic care after intensive chemotherapy, had a positive effect reducing TRM; likewise, Auner et al. [12] observed a marked decrease in mortality throughout the decade 1991–2001, ≤ 2.4% in all age groups, but considerably higher in older than in younger patients; additionally, in another study, Muchtar et al. [30] showed evidence of decreasing infectious complications, transfusion needs, and inpatient days in this same age group from 1998 to 2015, corroborating the favorable impact of supportive care and emphasizing the absence of a biological reason against age to ASCT eligibility.\n\nIn recent years, not only the feasibility of ASCT in the elderly has been disputed, but also its efficacy. Most studies are retrospective analysis [9, 11, 30, 32]; some are even before the era of novel agents as proteasome inhibitors (PI) and immunomodulatory drugs (IMIDs) [31, 33, 34], and others use matched pair comparison [35]. Notwithstanding its limitations, these studies found similar toxicity, TRM, and non-inferiority in EFS, OS, or disease response to ASCT in elderly patients, even when considering a higher age threshold for older cohorts as 70 years [30, 32]. In prospective studies [13, 33, 36], patients aged over 65 years do not have an inferior outcome when compared to younger cohorts, considering ASCT is a safe and effective treatment for elderly and fit MM patients, either before [33] or in the present era of novel induction agents [36], which highlights the impact on global outcome that ASCT represents as a component on treatment algorithm in this group of patients [33]. Data is more challenging, considering that there are no randomized trials appropriate to conclude about ASCT in this particular population with the availability of newer effective drugs, namely monoclonal antibodies and new-generation PI or IMIDs [10, 37]. In our study, response after transplant, EFS, and OS did not differ according to age in transplanted patients. Elderly patients had the same benefit comparing to younger patients, either in deepening of response after autologous transplantation or in survival as EFS and OS were not significantly shorter. More so, when compared to the non-transplanted age-adjusted cohort, patients who were transplanted had a significant improvement in EFS and OS, despite having similar disease features. Even though our results seem favorable to transplanted elderly patients, this study shares some of the limitations mentioned above, specifically regarding its retrospective nature, non-randomization of patients, and the subjective categorization for transplant eligibility of elderly patients.\n\nAnother matter of discussion, when considering autologous transplantation in elderly patients, is the ideal dose of Melphalan before ASCT. In our analysis, we can see that elderly patients have more toxicity indeed in all parameters with higher doses of melphalan as in previously published data [9, 33]. There is no consensus in the MM community, as some authors defend the use of an intermediate dose of 100 or 140 mg/m2 demonstrating equal efficacy in CR rates, EFS, or OS but with lower toxicity [9, 14, 33, 35, 38] or even lower TRM [39]; other authors are in favor of MEL200 as they did not find any excessive toxicity or worse disease outcomes [11, 32, 40]; and others conclude that reduced doses of melphalan can benefit selected cases, but higher doses are preferred [13, 30]. A recent prospective French study [36] demonstrated that there was no difference in myelotoxicity, infections, TRM, or disease response between MEL200 and MEL140, but it was noticed that patients treated with MEL200 had better EFS rate. In our analysis, even though it was not statistically significant, we also noted a trend to a better EFS rate in MEL200 elderly patients when compared to elderly patients treated with reduced doses of melphalan (62 months vs 45 months). However, once again, this was a retrospective analysis of a small and highly selected group of elderly patients with no standardized approach, which limits its statistical power.\n\nConclusion\nIt is suggested in the several aforementioned studies that age by itself is not a reliable prognostic factor for transplantation eligibility as autologous stem cell transplantation in elderly patients is a well-tolerated procedure with current and proper supportive and prophylactic care, with similar TRM, responses rate, EFS, and OS compared to younger patients. In our study, even after MEL200, elderly patients have clinical benefit with acceptable morbidity presenting similar EFS to the one obtained in younger patients, safeguarding that these are highly selected elderly patients.\n\nTaking into account that optimal management of MM is vital for patient outcome, age should not be considered a major obstacle to transplantation. Eligibility should be based on biological fitness and comorbidities, ideally through geriatric assessment tools and comorbidity scores to avoid subjectivity, which was also an important limitation when analyzing our elderly patients.\n\nOur study reflects real data on managing ASCT in elderly patients, offering them possibility of better results and better survival despite all the limitations we mentioned. From our results and revised published data to date, we may argue that ASCT is an essential step of MM treatment and should be offered as a treatment option regardless of age. However, there is a need to include elderly patients in transplant randomized trials to determine a survival benefit in an era of constant newer and effective drugs available.\n\nAuthor’s contributions\nCM performed data collection, wrote the statistical analysis plan, cleaned and analyzed the data, performed interpretation of data results, and drafted and revised the paper. TM performed data collection, performed interpretation of data results, and drafted and revised the paper. JP, EA, and JEG revised the drafted paper. RB and FT proposed and supervised this study and revised the drafted paper.\n\nCompliance with ethical standards\nThis study has been evaluated and approved by our ethics committee, the Ethics Committee for Health of Centro Hospitalar de São João/Faculty of Medicine of Oporto University.\n\nConflict of interest\nThe authors declare that they have no conflict of interest.\n==== Refs\nReferences\n1. Bergin K McQuilten Z Moore E Wood E Spencer A Myeloma in the real world: what is really happening? Clin Lymphoma Myeloma Leuk 2017 17 3 133 144 10.1016/j.clml.2016.12.002 28153487 \n2. Turesson I Velez R Kristinsson SY Landgren O Patterns of multiple myeloma during the past 5 decades: stable incidence rates for all age groups in the population but rapidly changing age distribution in the clinic Mayo Clin Proc 2010 85 3 225 230 10.4065/mcp.2009.0426 20194150 \n3. Brenner H Gondos A Pulte D Recent major improvement in long-term survival of younger patients with multiple myeloma Blood 2008 111 5 2521 2526 10.1182/blood-2007-08-104984 17901246 \n4. Kristinsson SY Landgren O Dickman PW Derolf AR Björkholm M Patterns of survival in multiple myeloma: a population-based study of patients diagnosed in Sweden from 1973 to 2003 J Clin Oncol 2007 25 15 1993 1999 10.1200/JCO.2006.09.0100 17420512 \n5. Attal M Harousseau JL Stoppa AM Sotto JJ Fuzibet JG Rossi JF Casassus P Maisonneuve H Facon T Ifrah N Payen C Bataille R A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome N Engl J Med 1996 335 2 91 97 10.1056/NEJM199607113350204 8649495 \n6. Barlogie B Jagannath S Desikan KR Mattox S Vesole D Siegel D Tricot G Munshi N Fassas A Singhal S Mehta J Anaissie E Dhodapkar D Naucke S Cromer J Sawyer J Epstein J Spoon D Ayers D Cheson B Crowley J Total therapy with the tandem transplant for newly diagnosed multiple myeloma Blood 1999 93 1 55 65 9864146 \n7. Child JA Morgan GJ Davies FE Owen RG Bell SE Hawkins K Brown J Drayson MT Selby PJ Medical Research Council Adult Leukaemia Working Party High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma N Engl J Med 2003 348 199 1875 1883 10.1056/NEJMoa022340 12736280 \n8. Merz M Neben K Raab MS Sauer S Egerer G Hundemer M Hose D Kunz C Heiß C Ho AD Goldschmidt H Hillengass J Autologous stem cell transplantation for elderly patients with newly diagnosed multiple myeloma in the era of novel agents Ann Oncol 2014 25 1 189 195 10.1093/annonc/mdt509 24356629 \n9. Cohen YC Zuckerman T Yeshurun M Perez G Magen H Henig I Levi I Shargian L Trestman S Rouvio U Naparstek E Ganon-Elazar E Avivi I Ram R Efficacy and safety of autologous hematopoietic cell transplantation in elderly patients with multiple myeloma: a retrospective national multisite cohort study Ann Hematol 2017 96 2 271 278 10.1007/s00277-016-2882-9 28039512 \n10. Facon T Mary JY Hulin C Benboubker L Attal M Pegourie B Renaud M Harousseau JL Guillerm G Chaleteix C Dib M Voillat L Maisonneuve H Troncy J Dorvaux V Monconduit M Martin C Casassus P Jaubert J Jardel H Doyen C Kolb B Anglaret B Grosbois B Yakoub-Agha I Mathiot C Avet-Loiseau H Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomized trial Lancet 2007 370 9594 1209 1218 10.1016/S0140-6736(07)61537-2 17920916 \n11. Siegel DS Desikan KR Mehta J Singhal S Fassas A Munshi N Anaissie E Naucke S Ayers D Spoon D Vesole D Tricot G Barlogie B Age is not a prognostic variable with autotransplants for multiple myeloma Blood 1999 93 1 51 54 9864145 \n12. Auner HW Trends in autologous hematopoietic cell transplantation for multiple myeloma in Europe: increased use and improved outcomes in elderly patients in recent years Bone Marrow Transplant 2015 50 2 209 215 10.1038/bmt.2014.255 25387088 \n13. Sharma M Zhang MJ Zhong X Abidi MH Akpek G Bacher U Callander NS Dispenzieri A Freytes CO Fung HC Gale RP Gasparetto C Gibson J Holmberg LA Kindwall-Keller TL Klumpp TR Krishnan AY Landau HJ Lazarus HM Lonial S Maiolino A Marks DI Mehta P Mikhael JR Nishihori T Olsson R Ramanathan M Roy V Savani BN Schouten HC Scott E Tay J To LB Vesole DH Vogl DT Hari P Older patients with myeloma derive similar benefit from autologous transplantation Biol Blood Marrow Transplant 2014 20 11 1796 1803 10.1016/j.bbmt.2014.07.013 25046833 \n14. Ozaki S Shimizu K Autologous stem cell transplantation in elderly patients with multiple myeloma: past, present, and future Biomed Res Int 2014 2014 1 7 10.1155/2014/394792 \n15. Sanchez L Sylvester M Parrondo R Mariotti V Eloy JA Chang VT In-hospital mortality and post-transplantation complications in elderly multiple myeloma patients undergoing autologous hematopoietic stem cell transplantation: a population-based study Biol Blood Marrow Transplant 2017 23 1203 1207 10.1016/j.bbmt.2017.03.012 28286198 \n16. Dumontet C Ketterer N Espinouse D Neidhardt EM Moullet I Thieblemont C Salles G Coiffier B Reduced progression-free survival in elderly patients receiving intensification with autologous peripheral blood stem cell reinfusion for multiple myeloma Bone Marrow Transplant 1998 21 1037 1041 10.1038/sj.bmt.1701232 9632278 \n17. Merz M Jansen L Castro FA Hillengass J Salwender H Weisel K Scheid C Luttmann S Emrich K Holleczek B Katalinic A Nennecke A Straka C Langer C Engelhardt M Einsele H Kröger N Beelen D Dreger P Brenner H Goldschmidt H GEKID Cancer Survival Working Group and the DRST Survival of elderly patients with multiple myeloma-effect of upfront autologous stem cell transplantation Eur J Cancer 2016 62 1 8 10.1016/j.ejca.2016.04.004 27185572 \n18. Klepin HD Hurd D Autologous transplantation in elderly patients with multiple myeloma: are we asking the right questions? Bone Marrow Transplant 2006 38 585 592 10.1038/sj.bmt.1705486 16953209 \n19. Costa LJ Zhang MJ Zhong X Dispenzieri A Lonial S Krishnan A Freytes C Vesole D Gale RP Anderson K Wirk B Savani BN Waller EK Schouten H Lazarus H Meehan K Sharma M Kamble R Vij R Kumar S Nishihori T Kindwall-Keller T Saber W Hari PN Trends in utilization and outcomes of autologous transplantation as early therapy for multiple myeloma Biol Blood Marrow Transplant 2013 19 11 1615 1624 10.1016/j.bbmt.2013.08.002 23939198 \n20. Wildes TM Finney JD Fiala M Gao F Vij R Stockerl-Goldstein K Carson KR Mikhael J Colditz G High-dose therapy and autologous stem cell transplant in older adults with multiple myeloma Bone Marrow Transplant 2015 50 8 1075 1082 10.1038/bmt.2015.106 25961765 \n21. Ozaki S Harada T Saitoh T Shimazaki C Itagaki M Asaoku H Kuroda Y Chou T Yoshiki Y Suzuki K Murakami H Hayashi K Mina R Palumbo A Shimizu K Japanese Society of Myeloma; European Myeloma Network Survival of multiple myeloma patients aged 65-70 years in the era of novel agents and autologous stem cell transplantation. A multicenter retrospective collaborative study of the Japanese Society of Myeloma and the European Myeloma Network Acta Haematol 2014 132 2 211 219 10.1159/000357394 24662986 \n22. Kumar SK Dispenzieri A Lacy MQ Gertz MA Buadi FK Pandey S Kapoor P Dingli D Hayman SR Leung N Lust J McCurdy A Russell SJ Zeldenrust SR Kyle RA Rajkumar SV Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients Leukemia 2014 28 5 1122 1128 10.1038/leu.2013.313 24157580 \n23. Greipp P International Staging System for multiple myeloma J Clin Oncol 2005 23 3412 3420 10.1200/JCO.2005.04.242 15809451 \n24. Durie BG Salmon SE A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival Cancer 1975 36 3 842 854 10.1002/1097-0142(197509)36:3<842::AID-CNCR2820360303>3.0.CO;2-U 1182674 \n25. National Cancer Institute (2010) Common Terminology Criteria for Adverse Events (CTCAE). Version 4.0. Publication No. 09–5410\n26. Kumar S Paiva B Anderson KC Durie B Landgren O Moreau P Munshi N Lonial S Bladé J Mateos MV Dimopoulos M Kastritis E Boccadoro M Orlowski R Goldschmidt H Spencer A Hou J Chng WJ Usmani SZ Zamagni E Shimizu K Jagannath S Johnsen HE Terpos E Reiman A Kyle RA Sonneveld P Richardson PG McCarthy P Ludwig H Chen W Cavo M Harousseau JL Lentzsch S Hillengass J Palumbo A Orfao A Rajkumar SV Miguel JS Avet-Loiseau H International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma Lancet Oncol 2016 17 8 e328 e346 10.1016/S1470-2045(16)30206-6 27511158 \n27. IBM Corp. Released IBM SPSS Statistics for Windows, Version 20.0 2011 Armonk IBM Corp \n28. Rajkumar S International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma Lancet Oncol 2014 15 e538 e548 10.1016/S1470-2045(14)70442-5 25439696 \n29. Mikhael JR Dingli D Roy V Reeder CB Buadi FK Hayman SR Dispenzieri A Fonseca R Sher T Kyle RA Lin Y Russell SJ Kumar S Bergsagel PL Zeldenrust SR Leung N Drake MT Kapoor P Ansell SM Witzig TE Lust JA Dalton RJ Gertz MA Stewart AK Rajkumar SV Chanan-Khan A Lacy MQ Mayo Clinic Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines 2013 Mayo Clin Proc 2013 88 4 360 376 10.1016/j.mayocp.2013.01.019 23541011 \n30. Muchtar E Dingli D Kumar S Buadi FK Dispenzieri A Hayman SR Wolf RC Gastineau DA Chakraborty R Hogan WJ Leung N Kapoor P Lacy MQ Rajkumar SV Gertz MA Autologous stem cell transplant for multiple myeloma patients 70 years or older Bone Marrow Transplant 2016 51 11 1449 1455 10.1038/bmt.2016.174 27376447 \n31. El Cheikh J Age at transplantation and outcome after autologous stem cell transplantation in elderly patients with multiple myeloma Hematol Oncol Stem Cell Ther 2011 4 1 30 36 10.5144/1658-3876.2011.30 21460604 \n32. Bashir Q Shah N Parmar S Wei W Rondon G Weber DM Wang M Orlowski RZ Thomas SK Shah J Qureshi SR Dinh YT Popat U Anderlini P Hosing C Giralt S Champlin RE Qazilbash MH Feasibility of autologous hematopoietic stem cell transplant in patients aged ≥70 years with multiple myeloma Leuk Lymphoma 2012 53 1 118 122 10.3109/10428194.2011.606942 21780997 \n33. Straka C Liebisch P Salwender H Hennemann B Metzner B Knop S Adler-Reichel S Gerecke C Wandt H Bentz M Bruemmendorf TH Hentrich M Pfreundschuh M Wolf HH Sezer O Bargou R Jung W Trümper L Hertenstein B Heidemann E Bernhard H Lang N Frickhofen N Hebart H Schmidmaier R Sandermann A Dechow T Reichle A Schnabel B Schäfer-Eckart K Langer C Gramatzki M Hinke A Emmerich B Einsele H Autotransplant with and without induction chemotherapy in older multiple myeloma patients: long-term outcome of a randomized trial Haematologica 2016 101 11 1398 1406 10.3324/haematol.2016.151860 27662018 \n34. Sirohi B Powles R Treleaven J Mainwaring P Kulkarni S Pandha H Bhagwati N Horton C Singhal S Mehta J The role of autologous transplantation in patients with multiple myeloma aged 65 years and over Bone Marrow Transplant 2000 25 5 533 539 10.1038/sj.bmt.1702188 10713631 \n35. Kumar SK Dingli D Lacy MQ Dispenzieri A Hayman SR Buadi FK Rajkumar SV Litzow MR Gertz MA Autologous stem cell transplantation in patients of 70 years and older with multiple myeloma: results from a matched pair analysis Am J Hematol 2008 83 8 614 617 10.1002/ajh.21191 18429054 \n36. Garderet L Beohou E Caillot D Stoppa AM Touzeau C Chretien ML Karlin L Moreau P Fontan J Blaise D Polge E Gueye MS Ikhlef S Marjanovic Z Labopin M Mohty M Upfront autologous stem cell transplantation for newly diagnosed elderly multiple myeloma patients: a prospective multicenter study Haematologica 2016 101 11 1390 1397 10.3324/haematol.2016.150334 27612987 \n37. Palumbo A Intermediate-dose melphalan improves survival of myeloma patients aged 50 to 70: results of a randomized controlled trial Blood 2004 104 10 3052 3057 10.1182/blood-2004-02-0408 15265788 \n38. Palumbo A Bringhen S Bertola A Cavallo F Falco P Massaia M Bruno B Rus C Barbui A Caravita T Musto P Pescosta N Rossini F Vignetti M Boccadoro M Multiple myeloma: comparison of two dose-intensive melphalan regimens (100 vs 200 mg/m(2)) Leukemia 2004 18 1 133 138 10.1038/sj.leu.2403196 14586481 \n39. Badros A Barlogie B Siegel E Morris C Desikan R Zangari M Fassas A Anaissie E Munshi N Tricot G Autologous stem cell transplantation in elderly multiple myeloma patients over the age of 70 years Br J Haematol 2001 114 3 600 607 10.1046/j.1365-2141.2001.02976.x 11552985 \n40. Desai A Beitinjaneh A Ramdial J Ali R Lekakis L Pereira D Kimble E Florou V Bravo G Goodman M Byrnes JJ Jimenez AM Saneeymehri S Komanduri KV Safety of high-dose melphalan (200 Mg/M2) as conditioning for autologous stem cell transplantation for myeloma in elderly patients Biol Blood Marrow Transplant 2017 23 S133 S134 10.1016/j.bbmt.2016.12.250\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0939-5555",
"issue": "98(2)",
"journal": "Annals of hematology",
"keywords": "Autologous transplantation; Elderly; Multiple myeloma",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000328:Adult; D000367:Age Factors; D000368:Aged; D000900:Anti-Bacterial Agents; D064592:Autografts; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D052016:Mucositis; D009101:Multiple Myeloma; D012189:Retrospective Studies; D012449:Safety; D015996:Survival Rate",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "369-379",
"pmc": null,
"pmid": "30368589",
"pubdate": "2019-02",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": "10713631;11552985;1182674;12736280;14586481;15265788;15809451;16953209;17420512;17901246;17920916;18429054;20194150;21460604;21780997;23541011;23939198;24157580;24356629;24662986;24719860;25046833;25387088;25439696;25961765;27185572;27376447;27511158;27612987;27662018;28039512;28153487;28286198;8649495;9632278;9864145;9864146",
"title": "Real-life data on safety and efficacy of autologous stem cell transplantation in elderly patients with multiple myeloma.",
"title_normalized": "real life data on safety and efficacy of autologous stem cell transplantation in elderly patients with multiple myeloma"
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"abstract": "The use of non-opioid analgesics following surgery has proven beneficial in managing pain and decreasing adverse outcomes following surgery. Data assessing outcomes related to opioid use is limited in kidney transplant recipients (KTRs). We evaluated the effectiveness of implementing a reduced to no opioid use protocol in KTRs. This retrospective cohort study included adult KTRs between January 2017 and July 2019 with a multimodal analgesic protocol (MAP), focused on limiting opioids, implemented in August 2018. We compared analgesic requirements in morphine milligram equivalents (MME) during transplant admissions between the MAP cohort and traditional cohort. There were 217 KTRs who met the criteria. Inpatient opioid use was significantly reduced in the MAP cohort (16.5 ± 19.2 MME/day vs 24.7 ± 19.7 MME/day; P <.05) with no significant difference in pain scores. No use of opioids within six months of discharge was significantly increased in the MAP cohort (50% vs 7%; P <.001), and there were no reported deaths at six months in either cohort. The use of multimodal analgesia is beneficial in KTRs to provide adequate pain control with limited to no exposure of opioids during admission or at discharge.",
"affiliations": "Department of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, Chapel Hill, NC, USA.;Department of Pharmacy, University of North Carolina Medical Center, Chapel Hill, NC, USA.;Department of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, Chapel Hill, NC, USA.;Department of Surgery, Division Abdominal Transplant Surgery, University of North Carolina Medical Center, Chapel Hill, NC, USA.;Department of Anesthesiology, University of North Carolina Medical Center, Chapel Hill, NC, USA.;Department of Anesthesiology, University of North Carolina Medical Center, Chapel Hill, NC, USA.;Department of Anesthesiology, University of North Carolina Medical Center, Chapel Hill, NC, USA.;Department of Surgery, Division Abdominal Transplant Surgery, University of North Carolina Medical Center, Chapel Hill, NC, USA.",
"authors": "Muir|Michele A|MA|0000-0003-1136-7863;Szempruch|Kristen R|KR|;Dupuis|Robert|R|;Toledo|Alexander H|AH|;Isaak|Robert S|RS|;Arora|Harendra|H|;Prasad|Ravindra|R|;Serrano Rodriguez|Pablo|P|0000-0002-2152-4044",
"chemical_list": "D000700:Analgesics; D000701:Analgesics, Opioid",
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"issue": "35(4)",
"journal": "Clinical transplantation",
"keywords": "patient safety; quality of care/care delivery; transplant pharmacist",
"medline_ta": "Clin Transplant",
"mesh_terms": "D000328:Adult; D000698:Analgesia; D000700:Analgesics; D000701:Analgesics, Opioid; D006801:Humans; D016030:Kidney Transplantation; D010149:Pain, Postoperative; D012189:Retrospective Studies",
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"publication_types": "D016428:Journal Article",
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"title": "Utilizing multimodal analgesia to evaluate postoperative analgesic requirements in kidney transplant recipients.",
"title_normalized": "utilizing multimodal analgesia to evaluate postoperative analgesic requirements in kidney transplant recipients"
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"abstract": "Transgender (TG) persons often receive, or self-treat, with cross-sex hormone (CSH) treatments as part of their treatment plans, with little known about their incidence of breast cancer. This information gap can lead to disparities in the provision of transgender health care. The purpose of the study was to examine the incidence of breast cancer in the largest North American sample of TG patients studied to date to determine their exposure to CSH, incidence of breast cancer, and to compare results with European studies in transsexual populations. We used Veterans Health Administration (VHA) data from 5,135 TG veterans in the United States from 1996 to 2013 to determine the incidence of breast cancer in this population. Chart reviews were completed on all patients who developed breast cancer. Age-standardized incidences of breast cancer from the general population were used for comparison. Person-years of exposure to known CSH treatment were calculated. Ten breast cancer cases were confirmed. Seven were in female-to-male patients, two in male-to-female patients, and one in a natal male with transvestic fetishism. Average age at diagnosis was 63.8 (SD = 8.2). 52 % received >1 dose of CSH treatment from VHA clinicians. All three males presented with late-stage disease were proved fatal. The overall incidence rate was 20.0/100,000 patient-years of VHA treatment (95 % CI 9.6-36.8), irrespective of VA CSH treatment. This rate did not differ from the expected rate in an age-standardized national sample, but exceeded that reported for smaller European studies of transsexual patients that were longer in duration. Although definitive conclusions cannot be made regarding breast cancer incidence in TG veterans who did or did not receive VA CSH due to the sample size and duration of observation, it appears that TG veterans do not display an increase in breast cancer incidence. This is consistent with European studies of longer duration that conclude that CSH treatment in gender dysphoric patients of either birth sex does not result in a greater incidence than the general population.",
"affiliations": "Mountain Home VAMC, Johnson City, TN, USA, george.brown@va.gov.",
"authors": "Brown|George R|GR|;Jones|Kenneth T|KT|",
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"country": "Netherlands",
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"mesh_terms": "D000328:Adult; D000368:Aged; D001943:Breast Neoplasms; D018567:Breast Neoplasms, Male; D005006:Ethnicity; D005260:Female; D012739:Gonadal Steroid Hormones; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D063106:Transgender Persons; D014481:United States",
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"title": "Incidence of breast cancer in a cohort of 5,135 transgender veterans.",
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"abstract": "Asparaginase-associated concurrence of hyperlipidemia, hyperglobulinemia, and thrombocytosis is a rare complication requiring aggressive lipoprotein apheresis, but no one of currently available lipoprotein apheresis methods can simultaneously resolve the 3 abnormalities. Herein, we reported a construction of double-filtration plasmapheresis (DFPP) using a combination of centrifugal/membranous plasma separation techniques to successfully treat a patient with hyperlipidemia, hyperglobulinemia, and thrombocytosis. A male presented with severe hyperlipidemia, hyperglobulinemia, and thrombocytosis during asparaginase treatment for NK/T-cell lymphoblastic lymphoma and was scheduled to receive lipoprotein apheresis. To simultaneously remove lipoproteins, immunoglobulin, and deplete platelets from blood, a centrifuge/membrane hybrid DFPP was constructed as following steps: plasma and part of platelets were separated first from whole blood by centrifugal technique and then divided by a fraction plasma separator into 2 parts: platelets and plasma components with large size, which were discarded; and those containing albumin, which were returned to blood with a supplement of extrinsic albumin solution. DFPP lasted 240 minutes uneventfully, processing 5450-mL plasma. The concentrations of plasma components before DFPP were as follows: triglycerides 38.22 mmol/L, total cholesterols 22.98 mmol/L, immunoglobulin A (IgA) 15.7 g/L, IgG 12.7 g/L, and IgM 14.3 g/L; whereas after treatment were 5.69 mmol/L, 2.38 mmol/L, 2.5 g/L, 7.7 g/L, and 0.4 g/L, respectively. The respective reduction ratio was 85.1%, 89.6%, 83.9%, 39.4%, and 96.9%. Platelet count decreased by 40.4% (from 612 × 10(9)/L to 365 × 10(9)/L). Centrifuge/membrane hybrid DFPP can simultaneously remove lipoproteins, immunoglobulin, and deplete platelets, with a success in treatment of asparaginase treatment-induced hyperlipidemia, hyperglobulinemia, and thrombocytosis, and may be useful for patients requiring DFPP but with particular situations.",
"affiliations": "National Clinical Research Center of Kidney Disease, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.;National Clinical Research Center of Kidney Disease, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.;National Clinical Research Center of Kidney Disease, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.;National Clinical Research Center of Kidney Disease, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.;National Clinical Research Center of Kidney Disease, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China. Electronic address: gong_doctor@126.com.",
"authors": "Wang|Taina|T|;Xu|Bin|B|;Fan|Rong|R|;Liu|Zhihong|Z|;Gong|Dehua|D|",
"chemical_list": "D008567:Membranes, Artificial; D001215:Asparaginase",
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"issue": "10(3)",
"journal": "Journal of clinical lipidology",
"keywords": "Asparaginase; Double filtration plasmapheresis; Hyperglobulinemia; Hyperlipidemia; Thrombocytosis",
"medline_ta": "J Clin Lipidol",
"mesh_terms": "D001215:Asparaginase; D002498:Centrifugation; D020141:Hemostatic Disorders; D006801:Humans; D006949:Hyperlipidemias; D008297:Male; D008567:Membranes, Artificial; D008875:Middle Aged; D010956:Plasmapheresis; D013922:Thrombocytosis; D016896:Treatment Outcome",
"nlm_unique_id": "101300157",
"other_id": null,
"pages": "646-9",
"pmc": null,
"pmid": "27206953",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Asparaginase-associated concurrence of hyperlipidemia, hyperglobulinemia, and thrombocytosis was successfully treated by centrifuge/membrane hybrid double-filtration plasmapheresis.",
"title_normalized": "asparaginase associated concurrence of hyperlipidemia hyperglobulinemia and thrombocytosis was successfully treated by centrifuge membrane hybrid double filtration plasmapheresis"
} | [
{
"companynumb": "CN-FRESENIUS KABI-FK201605113",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PEGASPARGASE"
},
"drugadditional": null,... |
{
"abstract": "BACKGROUND\nThis is a case report describing a reversal of fentanyl overdose with naloxone nasal spray. The patient was not aware that he overdosed on fentanyl being sold as heroin.\n\n\nMETHODS\nThe Veterans Health Administration (VHA) has implemented an initiative to provide education for veterans, their families, friends and significant others about opioid overdose and use of naloxone reversal kits. The Atlanta VA Medical Center adopted this program to reduce the risk of opioid overdose in high risk patients.\n\n\nRESULTS\nOver the past year, we provided educational sessions for 63 veterans and their families. We also prescribed 41 naloxone kits. We have received three reports of opioid overdose reversal with use of naloxone kits prescribed by the Atlanta VA Medical Center.\n\n\nCONCLUSIONS\nThe authors recommend that public health administrators and policy makers advocate for the implementation of these programs to reduce the rising number of overdose death in the United States and worldwide.",
"affiliations": "Atlanta VA Medical Center, Decatur, Georgia.;Atlanta VA Medical Center, Decatur, Georgia.;Atlanta VA Medical Center, Decatur, Georgia.;Atlanta VA Medical Center, Decatur, Georgia.;Atlanta VA Medical Center, Decatur, Georgia.",
"authors": "Fareed|Ayman|A|;Buchanan-Cummings|Ann Marie|AM|;Crampton|Kelli|K|;Grant|Angela|A|;Drexler|Karen|K|",
"chemical_list": "D000069479:Buprenorphine, Naloxone Drug Combination; D013287:Illicit Drugs; D059085:Nasal Sprays; D009270:Naloxone; D003932:Heroin; D005283:Fentanyl",
"country": "England",
"delete": false,
"doi": "10.1111/ajad.12230",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1055-0496",
"issue": "24(5)",
"journal": "The American journal on addictions",
"keywords": null,
"medline_ta": "Am J Addict",
"mesh_terms": "D000069479:Buprenorphine, Naloxone Drug Combination; D062787:Drug Overdose; D005283:Fentanyl; D005392:First Aid; D003932:Heroin; D006556:Heroin Dependence; D006801:Humans; D013287:Illicit Drugs; D008297:Male; D009270:Naloxone; D059085:Nasal Sprays; D012008:Recurrence; D014728:Veterans",
"nlm_unique_id": "9208821",
"other_id": null,
"pages": "388-90",
"pmc": null,
"pmid": "26039379",
"pubdate": "2015-08",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Reversal of overdose on fentanyl being illicitly sold as heroin with naloxone nasal spray: A case report.",
"title_normalized": "reversal of overdose on fentanyl being illicitly sold as heroin with naloxone nasal spray a case report"
} | [
{
"companynumb": "US-ACTAVIS-2016-06500",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": null,
"... |
{
"abstract": "Ensuring reliable gastrointestinal drug absorption of orally administered immunosuppressive medications posttransplant is critical to ensuring graft survival.\n\n\n\nA 66-year-old man of East Asian origin with a previous total gastrectomy was evaluated for living donor kidney transplantation. Pretransplant pharmacokinetic testing was performed to determine the most appropriate posttransplant medication strategy. The Gastrointestinal Quality of Life Index and Gastrointestinal Rating Scale questionnaires were administered to gauge immunosuppressive medication-related side effects in the absence of a stomach.\n\n\n\nThe patient's ability to absorb cyclosporin, tacrolimus (Tac), enteric-coated mycophenolate sodium (EC-MPS) and sirolimus (SRL) in oral dosage forms was well-preserved. Compared to nongastrectomy reference populations, the rate and extent of absorption of SRL and mycophenolic acid from EC-MPS were similar. The absorption of Tac and cyclosporin was greater than expected. Mycophenolate mofetil did not provide mycophenolic acid absorption as well as EC-MPS. The patient had worsened gastrointestinal symptoms with mycophenolate mofetil or EC-MPS in combination with Tac and cyclosporin, but this was not seen with isolated SRL.\n\n\n\nThis case demonstrates that commonly used postkidney transplantation immunosuppressive regimes may be prescribed after total gastrectomy as long as their limitations are noted.",
"affiliations": "1 Renal Transplant Program, St. Michael's Hospital, Toronto, ON, Canada. 2 Department of Pharmacy, St. Michael's Hospital, Toronto, ON, Canada. 3 Department of Pharmacy, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.",
"authors": "Chen|Lucy|L|;Liberatore|Lisa|L|;Chin|Tom|T|;Walker|Scott|S|;Fanous|Helen|H|;Nash|Michelle M|MM|;Rapi|Lindita|L|;Huckle|Jennie|J|;Zaltzman|Jeffrey S|JS|;Prasad|G V Ramesh|GVR|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": "10.1097/TP.0000000000001507",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1337",
"issue": "101(9)",
"journal": "Transplantation",
"keywords": null,
"medline_ta": "Transplantation",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D004359:Drug Therapy, Combination; D005743:Gastrectomy; D065570:Gastric Absorption; D006801:Humans; D007166:Immunosuppressive Agents; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D019520:Living Donors; D008297:Male; D008954:Models, Biological; D018579:Patient Selection; D011788:Quality of Life; D011795:Surveys and Questionnaires; D016896:Treatment Outcome",
"nlm_unique_id": "0132144",
"other_id": null,
"pages": "2213-2217",
"pmc": null,
"pmid": "27748705",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "The Impact of Total Gastrectomy on Pharmacokinetics in Kidney Transplant Immunosuppressive Drug Regimes: A Case Study.",
"title_normalized": "the impact of total gastrectomy on pharmacokinetics in kidney transplant immunosuppressive drug regimes a case study"
} | [
{
"companynumb": "PHHY2016CA153234",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
"drug... |
{
"abstract": "Renal phospholipidosis is a rare cause of proteinuria and kidney dysfunction. We describe a kidney transplant recipient who presented with slowly rising serum creatinine, nephrotic range proteinuria, and lower extremity edema 10 years post transplant. He was diagnosed with renal phospholipidosis on the transplant kidney biopsy. Patient did not have prior history or current symptoms or signs of Fabry disease. Serum α-galactosidase level was normal. The etiology was suspected to be due to chronic use of sertraline, a previously reported cause of drug-induced renal phospholipidosis. Sertraline was discontinued, and proteinuria declined with stabilization of kidney function at 6-months follow-up.",
"affiliations": "John C. McDonald Regional Transplant Center - Willis Knighton Health System.;John C. McDonald Regional Transplant Center - Willis Knighton Health System.;Department of Internal Medicine, Division of Nephrology, Louisiana State University Health Sciences Center (LSUHSC), Shreveport, LA, and.;Department of Internal Medicine, Division of Nephrology, Louisiana State University Health Sciences Center (LSUHSC), Shreveport, LA, and.;Department of General and Interventional Nephrology, Sierra Nevada Nephrology Consultants, Reno, NV, USA.;John C. McDonald Regional Transplant Center - Willis Knighton Health System.",
"authors": "Naseer|Muhammad Saad|MS|;Chand|Raj|R|;Coppola|Stefano|S|;Abreo|Adrian|A|;Sharma|Mukesh|M|;Singh|Neeraj|N|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.5414/CNCS110131",
"fulltext": "\n==== Front\nClin Nephrol Case Stud\nDustri\nClinical Nephrology. Case Studies\n2196-5293 Dustri-Verlag Dr. Karl Feistle \n\n10.5414/CNCS110131\nCase Report\nNephrology\nPost-transplant de-novo renal phospholipidosis in a kidney transplant recipient: Fabry disease or something else? \nNaseer Muhammad Saad 1 Chand Raj 1 Coppola Stefano 2 Abreo Adrian 2 Sharma Mukesh 3 Singh Neeraj 1 1 John C. McDonald Regional Transplant Center – Willis Knighton Health System, \n2 Department of Internal Medicine, Division of Nephrology, Louisiana State University Health Sciences Center (LSUHSC), Shreveport, LA, and \n3 Department of General and Interventional Nephrology, Sierra Nevada Nephrology Consultants, Reno, NV, USA\nCorrespondence to Neeraj Singh, MD Medical Director of Kidney and Kidney-Pancreas Transplant, Associate Professor of Internal Medicine (Gratis), John C. McDonald Regional Transplant Center – Willis Knighton Health System, Shreveport, LA 71103, USA nsingh75@hotmail.com\n2020 \n29 5 2020 \n8 46 48\n13 2 2020 9 4 2020 © Dustri-Verlag Dr. K. Feistle2020 This is an open-access article distributed under the terms of the Creative\nCommons Attribution License, which permits unrestricted use, distribution, and\nreproduction in any medium, provided the original work is properly cited.Renal phospholipidosis is a rare cause of proteinuria and kidney dysfunction. We describe a kidney transplant recipient who presented with slowly rising serum creatinine, nephrotic range proteinuria, and lower extremity edema 10 years post transplant. He was diagnosed with renal phospholipidosis on the transplant kidney biopsy. Patient did not have prior history or current symptoms or signs of Fabry disease. Serum α-galactosidase level was normal. The etiology was suspected to be due to chronic use of sertraline, a previously reported cause of drug-induced renal phospholipidosis. Sertraline was discontinued, and proteinuria declined with stabilization of kidney function at 6-months follow-up. \n\nrenal phospholipidosislamellar inclusionscationic amphiphilic drugsFabry diseasemyelin bodies\n==== Body\nIntroduction \nDrug-induced renal phospholipidosis (DIP) post kidney transplant has not been previously reported. We report a case of sertraline-induced renal phospholipidosis and discuss several other etiologies that may result in renal phospholipidosis mimicking Fabry disease. It is important to recognize DIP, as discontinuation of suspected drug may reverse the pathological process and improve outcomes. \n\nCase description \nA 63-year-old Asian male with prior history of kidney transplant 10 years ago due to end-stage renal disease secondary to hypertension presented with lower extremity edema for 2 weeks. A month post transplant, he had an episode of biopsy-proven rejection but no complications otherwise. His maintenance immunosuppression consisted of mycophenolate mofetil 750 mg oral twice daily, tacrolimus 3 mg oral twice daily, and prednisone 2.5 mg oral once daily. In addition, the patient had been on sertraline 200 mg oral once daily, nifedipine 10 mg oral once daily, and vitamin D3 1,000 U oral once daily. On examination, his vitals were stable, and examination was unremarkable except for 2+ pedal edema. Laboratory data showed a slowly rising serum creatinine over the past 6 months with current value of 2.3 mg/dL (baseline 1.5 – 1.8 mg/dL), a spot urine protein-to-creatinine ratio of 7.6 g/g of creatinine, and tacrolimus level of 4.7 ng/mL. BK virus PCR and donor-specific anti-HLA antibodies were negative. The patient had a spot urine protein-to-creatinine ratio of 0.9 g/g of creatinine 6 months prior. The transplant kidney biopsy showed focal mild interstitial fibrosis with tubular atrophy, glomeruli with lobulation of tufts, large endothelial cells with foamy cytoplasm (Figure 1), glomerular capillary endothelial cells, and mesangial cells containing lamellar and dense cytoplasmic inclusions or myelin bodies (Figure 2). No rejection or viral cytopathic effects, immune complex deposits, or fibrils were identified. The stains for polyomavirus and for C4d were negative. In addition to chronic transplant glomerulopathy, the diagnosis of glomerular phospholipidosis was entertained. The serum α-galactosidase A level was normal, 0.136 U/L (reference range: 0.074 – 0.457). Sertraline was discontinued and patient was switched to bupropion. The proteinuria declined to 2.3 g/g of creatinine with stabilization of serum creatinine at 6-months follow-up visit. \n\nDiscussion \nLysosomes are an important site for the catabolism of phospholipids by different phospholipase enzymes. The inhibition of the activity of phospholipases leads to intracellular accumulation of phospholipids which presents as foamy cytoplasm, evident in Figure 1. On electron microscopy, the development of concentric lamellar bodies, also called myelin or zebra bodies, can be appreciated in detail, which is the ultrastructural hallmark of renal phospholipidosis, as shown in Figure 2. \n\nFabry disease is a well-known cause of renal phospholipidosis and is caused by a genetic deficiency of lysosomal enzyme α-galactosidase A, which results in progressive accumulation of glycosphingolipids within different body cells. Fabry disease is associated with renal and extra-renal manifestations of angiokeratomas, hypohidrosis, hearing loss, corneal opacity, neurological and cardiac involvement. Renal lamellar inclusions in Fabry disease are ultrastructurally similar to those seen in acquired causes of phospholipidosis. The diagnosis of Fabry disease is suggested by typical clinical signs and symptoms and confirmed by low enzyme activity in peripheral blood or in leukocytes, or by genetic mutation analysis. Our patient had no clinical signs and symptoms suggestive of Fabry disease and his serum α-galactosidase A level was normal. Hence, genetic analysis was not ordered. In Fabry patients, recurrence in allograft post kidney transplant from non-Fabry donors is rare and graft survival is not reduced as compared with patients with other causes of end-stage renal disease, but the risk of death post transplant is higher [1]. Niemann-Pick disease, another lipid storage disorder results either due to the deficiency of lysosomal enzyme, acid sphingomyelinase or due to impaired movement of lipids within cells. It primarily affects children, and kidneys are rarely involved [2]. \n\nBesides Fabry and Niemann-Pick disease, renal phospholipidosis has also been reported in silicosis [3] and due to several drugs [4] including amiodarone, chloroquine, aminoglycosides, chlorpromazine, fluoxetine, sertraline, and azithromycin. DIP is a form of acquired lysosomal storage disease. The cationic amphiphilic drugs (CADs) enter the lysosomes and inhibit the activity of phospholipase, leading to intracellular accumulation of phospholipids. Phospholipidosis induction by drugs is dose dependent, and pathological lesions may reverse after drug withdrawal [5]. One of the views is that DIP is an adaptive response to exposure to CADs and is not a toxic response per se. By this theory, drugs are trapped within lysosomes and sequestered from other cellular sites where they may be toxic [4]. Lungs, liver, and other organs may be affected besides kidneys [4]. DIP in the kidneys is rarely reported due to several reasons. The intracellular accumulation of phospholipids is a slow process, and the use of offending drugs may have to continue for several months to years before the lesions become apparent on biopsy. The DIP lesions are focal, and the pathological changes may escape detection due to sampling error on kidney biopsy. Electron microscopy is necessary to detect the hallmark ultrastructural DIP lesions but is not ordered routinely. Furthermore, patients with CKD and proteinuria may have concomitant hypertension and/or diabetes mellitus, and kidney biopsy is not routinely performed in these conditions. \n\nIn summary, DIP is a rare cause of renal dysfunction and nephrotic range proteinuria post kidney transplantation and should be considered in the differential diagnosis in patients presenting with dense cytoplasmic inclusion (myelin) bodies on kidney biopsy after excluding recurrent Fabry disease. \n\nFunding \nNone. \n\nConflict of interest \nNone. \n\nFigure 1 The H & E stain of transplant kidney biopsy done 10 years post transplantation shows enlarged glomerular capillary endothelial cells with foamy cytoplasm (black arrow).\nFigure 2 Electron microscopy of transplant kidney biopsy done 10 years post transplantation shows an endothelial and mesangial cell with numerous lamellar and dense cytoplasmic inclusions (myelin bodies) (black arrow). Glomerular capillary basement membrane is thickened (marked by star), and effacement of podocyte foot processes is present (white arrow).\n==== Refs\nReferences\n1 \nMignani R \nFeriozzi S \nSchaefer RM \nBreunig F \nOliveira JP \nRuggenenti P \nSunder-Plassmann G \nDialysis and transplantation in Fabry disease: indications for enzyme replacement therapy.\n\nClin J Am Soc Nephrol .\n2010 ;\n5 :\n379 –385\n.\n20056752 \n2 \nGrafft CA \nFervenza FC \nSemret MH \nOrloff S \nSethi S \nRenal involvement in Neimann-Pick Disease.\n\nNDT Plus .\n2009 ;\n2 :\n448 –451\n.\n25949377 \n3 \nBanks DE \nMilutinovic J \nDesnick RJ \nGrabowski GA \nLapp NL \nBoehlecke BA \nSilicon nephropathy mimicking Fabry’s disease.\n\nAm J Nephrol .\n1983 ;\n3 :\n279 –284\n.\n6416069 \n4 \nShayman JA \nAbe A \nDrug induced phospholipidosis: an acquired lysosomal storage disorder.\n\nBiochim Biophys Acta .\n2013 ;\n1831 :\n602 –611\n.\n22960355 \n5 \nReasor MJ \nKacew S \nDrug-induced phospholipidosis: are there functional consequences?\n\nExp Biol Med (Maywood) .\n2001 ;\n226 :\n825 –830\n.\n11568304\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2196-5293",
"issue": "8()",
"journal": "Clinical nephrology. Case studies",
"keywords": "Fabry disease; cationic amphiphilic drugs; lamellar inclusions; myelin bodies; renal phospholipidosis",
"medline_ta": "Clin Nephrol Case Stud",
"mesh_terms": null,
"nlm_unique_id": "101638685",
"other_id": null,
"pages": "46-48",
"pmc": null,
"pmid": "32566446",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "20056752;22960355;11568304;6416069;25949377",
"title": "Post-transplant de-novo renal phospholipidosis in a kidney transplant recipient: Fabry disease or something else?",
"title_normalized": "post transplant de novo renal phospholipidosis in a kidney transplant recipient fabry disease or something else"
} | [
{
"companynumb": "US-PFIZER INC-2020242183",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
... |
{
"abstract": "Corticosteroids are commonly used in the treatment of connective tissue diseases such as systemic lupus erythematosus. Although they are usually efficacious, osteoporosis leading to spine compression fractures is not uncommon. In this case report, we describe an elderly patient with systemic lupus erythematosus on long-term corticosteroid therapy who presented with symptoms of acute abdomen with minimal low back symptoms. No intraabdominal process was found by abdominal studies and exploratory laparotomy. Increased lower back symptoms led to further skeletal spine studies, which initially demonstrated a compression fracture at the twelfth thoracic (T12) vertebra. Later, a T8 and a fourth lumbar (L4) compression fracture were also found. Her abdominal and lower back symptoms resolved on conservative therapy. Although the rate of these occurrences are unknown, compression spine fractures should be considered in elderly patients presenting with acute abdomen after being on long-term corticosteroid therapy.",
"affiliations": "Department of Medicine, School of Medicine, East Carolina University, Greenville, NC 27858-4354.",
"authors": "Treadwell|E L|EL|;Cunningham|P R|PR|;Kowalski|H M|HM|;Weaver|M D|MD|",
"chemical_list": "D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0027-9684",
"issue": "82(9)",
"journal": "Journal of the National Medical Association",
"keywords": null,
"medline_ta": "J Natl Med Assoc",
"mesh_terms": "D000368:Aged; D005260:Female; D005598:Fractures, Spontaneous; D006801:Humans; D007415:Intestinal Obstruction; D008159:Lumbar Vertebrae; D008180:Lupus Erythematosus, Systemic; D011241:Prednisone; D016103:Spinal Fractures; D013904:Thoracic Vertebrae; D013997:Time Factors",
"nlm_unique_id": "7503090",
"other_id": null,
"pages": "669-72",
"pmc": null,
"pmid": "2213916",
"pubdate": "1990-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "6996096;3599117;3318847;3279551",
"title": "Thoracolumbar compression fractures presenting with an acute ileus.",
"title_normalized": "thoracolumbar compression fractures presenting with an acute ileus"
} | [
{
"companynumb": "US-ACTAVIS-2016-01108",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nClozapine remains the antipsychotic of choice for refractory schizophrenia. Given the particular side effects of clozapine including neutropenia and myelosuppression, safety and efficacy of add-on chemotherapy for patients who are already under clozapine treatment remain unknown.\n\n\nOBJECTIVE\nWe present evidence from a patient with a diagnosis of refractory schizophrenia on clozapine medication, who required essential chemotherapy for chronic lymphocytic leukemia (CLL). We have also reviewed literature regarding this challenging clinical dilemma.\n\n\nMETHODS\nWe report details about a patient with treatment-resistant schizophrenia who was given chemotherapy (fludarabine, cyclophosphamide and rituximab) for CLL in the course of concomitant treatment with clozapine and granulocyte-colony stimulating factor (G-CSFs). In addition, we have reviewed literature using the PUBMED data base.\n\n\nRESULTS\nCurrent evidence remains insufficient to provide authoritative guide to clinicians regarding the efficacy and safety of the combined use of clozapine and chemotherapy. However, general conclusion from our case and of the published evidence is that a combination of clozapine use and chemotherapeutic agents do not cause additional hematological worsening with no decreasing efficacy concerns raised.\n\n\nCONCLUSIONS\nContinuing with clozapine in the course of chemotherapy may be relatively safer for patients who responded well to clozapine concomitant with G-CSF treatment.",
"affiliations": "Department of Psychiatry, Cerrahpaşa Medical School, University of Istanbul, Turkey.;Department of Psychiatry, Cerrahpaşa Medical School, Istanbul, Turkey, Halaskargazi cad. No:81 Çiçek apt. daire:8,Osmanbey Istanbul/Turkey.;Department of Internal Medicine, Division of Hematology, Istanbul Medical School, University of Istanbul, Turkey.;Department of Psychiatry, Cerrahpaşa Medical School, University of Istanbul, Turkey.",
"authors": "Usta|Nazife Gamze|NG|;Poyraz|Cana Aksoy|CA|;Aktan|Melih|M|;Duran|Alaattin|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/2045125314553610",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2045-1253",
"issue": "4(6)",
"journal": "Therapeutic advances in psychopharmacology",
"keywords": "agranulocytosis; chemotherapy; clozapine; schizophrenia",
"medline_ta": "Ther Adv Psychopharmacol",
"mesh_terms": null,
"nlm_unique_id": "101555693",
"other_id": null,
"pages": "276-81",
"pmc": null,
"pmid": "25489479",
"pubdate": "2014-12",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "11388983;18475227;17847125;22819722;9534838;17728433;2222133;23059755;24247056;12702898;8379568;2664753;11483490;20191292;11146763;10789357;16160616;12004852;18951346;21037135;8837913;14702271;16955993;23338132;7982706;24039428;18606485",
"title": "Clozapine treatment of refractory schizophrenia during essential chemotherapy: a case study and mini review of a clinical dilemma.",
"title_normalized": "clozapine treatment of refractory schizophrenia during essential chemotherapy a case study and mini review of a clinical dilemma"
} | [
{
"companynumb": "PHHY2013TR154944",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": null,
"dru... |
{
"abstract": "Oxalate nephropathy is an uncommon condition that causes acute kidney injury with the potential for progression to end-stage renal disease. Diagnosis is based on the kidney biopsy findings of abundant polarizable calcium oxalate crystals in the epithelium and lumen of renal tubules. We report a case of acute oxalate nephropathy in a 65-year-old woman, temporally associated with the consumption of an oxalate-rich green smoothie juice \"cleanse\" prepared from juicing oxalate-rich green leafy vegetables and fruits. Predisposing factors included a remote history of gastric bypass and recent prolonged antibiotic therapy. She had normal kidney function before using the cleanse and developed acute kidney injury that progressed to end-stage renal disease. Consumption of such juice cleanses increases oxalate absorption, causing hyperoxaluria and acute oxalate nephropathy in patients with predisposing risk factors. Given the increasing popularity of juice cleanses, it is important that both patients and physicians have greater awareness of the potential for acute oxalate nephropathy in susceptible individuals with risk factors such as chronic kidney disease, gastric bypass, and antibiotic use.",
"affiliations": "Division of Nephrology, Nassau University Medical Center, East Meadow, NY. Electronic address: swetha.makkapa@gmail.com.;Department of Pathology, Columbia University, College of Physicians and Surgeons, New York, NY.;Division of Nephrology, Nassau University Medical Center, East Meadow, NY.",
"authors": "Makkapati|Swetha|S|;D'Agati|Vivette D|VD|;Balsam|Leah|L|",
"chemical_list": "D000900:Anti-Bacterial Agents; D010070:Oxalates",
"country": "United States",
"delete": false,
"doi": "10.1053/j.ajkd.2017.08.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0272-6386",
"issue": "71(2)",
"journal": "American journal of kidney diseases : the official journal of the National Kidney Foundation",
"keywords": "Oxalate; Roux-en-Y gastric bypass (RYGB); acute kidney injury (AKI); acute oxalate nephropathy (AON); acute renal failure; crystal; diet; juicing; kidney biopsy; moxifloxacin; spinach; weight-loss",
"medline_ta": "Am J Kidney Dis",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D000900:Anti-Bacterial Agents; D018450:Disease Progression; D005260:Female; D000067030:Fruit and Vegetable Juices; D015390:Gastric Bypass; D006801:Humans; D006959:Hyperoxaluria; D007668:Kidney; D007676:Kidney Failure, Chronic; D010070:Oxalates; D006435:Renal Dialysis; D012307:Risk Factors; D016896:Treatment Outcome",
"nlm_unique_id": "8110075",
"other_id": null,
"pages": "281-286",
"pmc": null,
"pmid": "29203127",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "\"Green Smoothie Cleanse\" Causing Acute Oxalate Nephropathy.",
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"abstract": "OBJECTIVE\nAlthough current guidelines recommend continuing the same antithrombotic strategy regardless of rhythm control after radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF), anticoagulation has a risk of major bleeding. We evaluated the safety of switching warfarin to aspirin in patients with successful AF ablation.\n\n\nMETHODS\nAmong 721 patients who underwent RFCA of AF, 608 patients (age, 57.3±10.9 years; 77.0% male, 75.5% paroxysmal AF) who had no evidence of AF recurrence at 3 months post-RFCA were included. We compared the thromboembolic and hemorrhagic events in patients for whom warfarin was switched to aspirin (ASA group; n=296) and patients who were kept on warfarin therapy (W group; n=312).\n\n\nRESULTS\nThere were no significant differences in CHA₂DS₂-VASc or HAS-BLED scores between the groups. In 30 patients in the ASA group and 37 patients in W group, AF recurred and warfarin was restarted or maintained during the 18.0±12.2 months of follow-up. There were no significant differences in thromboembolic (0.3% vs. 1.0%, p=0.342) and major bleeding incidences (0.7% vs. 0.6%, p=0.958) between ASA and W groups during the follow-up period. In the 259 patients with a CHA₂DS₂-VASc score≥2, there were no significant differences in thromboembolism (0.8% and 2.2%, p=0.380) or major bleeding incidences (0.8% and 1.4%, p=0.640) between ASA and W groups.\n\n\nCONCLUSIONS\nSwitching warfarin to aspirin 3 months after successful RFCA of AF could be as safe and efficacious as long-term anticoagulation even in patients with CHA₂DS₂-VASc score≥2. However, strict rhythm monitoring cannot be overemphasized.",
"affiliations": "Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.;Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.;Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.;Division of Cardiology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Division of Cardiology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.;Division of Cardiology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea. hnpak@yuhs.ac.",
"authors": "Uhm|Jae-Sun|JS|;Won|Hoyoun|H|;Joung|Boyoung|B|;Nam|Gi-Byoung|GB|;Choi|Kee-Joon|KJ|;Lee|Moon-Hyoung|MH|;Kim|You-Ho|YH|;Pak|Hui-Nam|HN|",
"chemical_list": "D000925:Anticoagulants; D014859:Warfarin; D001241:Aspirin",
"country": "Korea (South)",
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"doi": "10.3349/ymj.2014.55.5.1238",
"fulltext": "\n==== Front\nYonsei Med JYonsei Med. JYMJYonsei Medical Journal0513-57961976-2437Yonsei University College of Medicine 2504848010.3349/ymj.2014.55.5.1238Original ArticleCardiac & Cardiovascular SystemsSafety and Efficacy of Switching Anticoagulation to Aspirin Three Months after Successful Radiofrequency Catheter Ablation of Atrial Fibrillation Uhm Jae-Sun 1Won Hoyoun 1Joung Boyoung 1Nam Gi-Byoung 2Choi Kee-Joon 2Lee Moon-Hyoung 1Kim You-Ho 2Pak Hui-Nam 11 Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.2 Division of Cardiology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.Corresponding author: Dr. Hui-Nam Pak, Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea. Tel: 82-2-2228-8459, Fax: 82-2-393-2041, hnpak@yuhs.ac01 9 2014 18 7 2014 55 5 1238 1245 06 8 2013 23 10 2013 22 11 2013 © Copyright: Yonsei University College of Medicine 20142014This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Purpose\nAlthough current guidelines recommend continuing the same antithrombotic strategy regardless of rhythm control after radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF), anticoagulation has a risk of major bleeding. We evaluated the safety of switching warfarin to aspirin in patients with successful AF ablation.\n\nMaterials and Methods\nAmong 721 patients who underwent RFCA of AF, 608 patients (age, 57.3±10.9 years; 77.0% male, 75.5% paroxysmal AF) who had no evidence of AF recurrence at 3 months post-RFCA were included. We compared the thromboembolic and hemorrhagic events in patients for whom warfarin was switched to aspirin (ASA group; n=296) and patients who were kept on warfarin therapy (W group; n=312).\n\nResults\nThere were no significant differences in CHA2DS2-VASc or HAS-BLED scores between the groups. In 30 patients in the ASA group and 37 patients in W group, AF recurred and warfarin was restarted or maintained during the 18.0±12.2 months of follow-up. There were no significant differences in thromboembolic (0.3% vs. 1.0%, p=0.342) and major bleeding incidences (0.7% vs. 0.6%, p=0.958) between ASA and W groups during the follow-up period. In the 259 patients with a CHA2DS2-VASc score ≥2, there were no significant differences in thromboembolism (0.8% and 2.2%, p=0.380) or major bleeding incidences (0.8% and 1.4%, p=0.640) between ASA and W groups.\n\nConclusion\nSwitching warfarin to aspirin 3 months after successful RFCA of AF could be as safe and efficacious as long-term anticoagulation even in patients with CHA2DS2-VASc score ≥2. However, strict rhythm monitoring cannot be overemphasized.\n\nAnticoagulationaspirinatrial fibrillationcatheter ablationMinistry of Health and WelfareA085136National Research Foundation of Korea2010-0010537\n==== Body\nINTRODUCTION\nAtrial fibrillation (AF) is significantly associated with the risk of strokes,1,2 and given this association, antithrombotic therapy is essential in the management of AF. CHADS2 or CHA2DS2-VASc scores have been utilized for risk stratification of ischemic stroke in patients with AF,3,4 and anticoagulation is recommended for the patients with CHADS2 score ≥1 or CHA2DS2-VASc score ≥1.5,6 Radiofrequency catheter ablation (RFCA) has been known to be as effective as or more effective than antiarrhythmic drugs (AAD) at controlling rhythm in AF patients.7,8,9 According to the 2012 HRS/EHRA/ECAS Expert Consensus Statement, AAD-resistant symptomatic paroxysmal AF (PAF) and persistent AF (PeAF) are class I and IIa indications for RFCA, respectively.10 However, the same guidelines recommend that anticoagulation be continued after RFCA of AF based on CHADS2 or CHA2DS2-VASc score.10 Although warfarin is effective for the prevention of stroke in patients with AF, using warfarin is difficult given the various dose-effect relationships as well as potential drug-drug or drug-food interactions. Moreover, warfarin introduces an annual risk of major bleeding of 3.1-3.7%.11,12,13 Of the various bleeding risk stratification schemas, the HAS-BLED score is recommended by the current guidelines for prediction of bleeding risk in patients who take warfarin due to AF,5,14 and special attention should be paid to patients with high HAS-BLED score. Given the risks and benefits of warfarin, controversies remain regarding long-term use of warfarin after successful RFCA of AF. Therefore, we hypothesized that switching warfarin to aspirin (ASA group) may have an equivalent efficacy and safety in the prevention of ischemic stroke, compared with continuous warfarin administration (W group) in patients with no evidence of AF recurrence after RFCA during standard rhythm monitoring.\n\nMATERIALS AND METHODS\nStudy population\nThe study protocol was approved by the Institutional Review Board of Severance Cardiovascular Hospital, Yonsei University Health System and Asan Medical Center, and adhered to the Declaration of Helsinki. This study included 721 patients who were prospectively registered in a database of AF catheter ablation between March 2009 and December 2011 in two centers. Clinical outcomes, thromboembolic events, and hemorrhagic complications were compared between the ASA group and the W group in the registry database. Among these 721 patients, there were 608 patients (age, 57.3±10.9 years; 77.0%, male; 75.5%, PAF; 24.5%, PeAF) who had no evidence of AF recurrence on Holter monitoring 3 months after RFCA in this study. All patients provided written informed consent, and all were AAD-resistant or intolerant patients. The exclusion criteria were as follows: 1) permanent AF refractory to electrical cardioversion; 2) left atrium (LA) size >55 mm as measured by echocardiogram; 3) critical coronary artery stenosis (>75% of luminal diameter); 4) severe rheumatic mitral valvular disease; and 5) prior RFCA of AF. Three-dimensional (3D) spiral computerized tomography (CT) scans (64 Channel, Light Speed Volume CT, Philips, Brilliance 63, the Netherlands) were performed to visually define pulmonary vein (PV) anatomy. The presence of an LA thrombus was excluded by transesophageal echocardiography. All AADs were discontinued for a period corresponding to at least five half-lives. In total, 141 patients (19.6%) were taking amiodarone, which was discontinued for at least four weeks prior to the procedure. Anticoagulation therapy was maintained before RFCA for all patients.\n\nElectrophysiologic mapping and radiofrequency catheter ablation\nIntracardiac electrograms were recorded using the Prucka CardioLab™ electrophysiology system (General Electric Health Care System Inc., Milwaukee, WI, USA) or Workmate\n(St. Jude Medical Inc., Minnetonka, MN, USA). RFCA was performed in all patients using 3D electroanatomical\nmapping (NavX; St. Jude Medical Inc., Minnetonka,\nMN, USA or Carto; Johnson & Johnson Inc., Diamond Bar, CA, USA) merged with 3D spiral CT. We used an open irrigated-tip catheter (Celsius or Thermocool, Johnson & Johnson Inc.; Diamond Bar, CA, USA; irrigation flow rate 20 to 30 mL/min; 25-35 W; 47℃) to deliver radiofrequency\nenergy for ablation (Stockert generator, Biosense Webster Inc.; Diamond Bar, CA, USA). All patients initially underwent circumferential PV isolation (CPVI) and bi-directional\nblock of the cavotricuspid isthmus. For the patients with PAF, we added linear ablations and complex fractionated\natrial electrogram (CFAE) ablation guided by 3D-CFAE-CL map15 in a stepwise approach in patients without AF termination\nduring RFCA. For PeAF, we conducted CPVI, cavotricuspid isthmus block, roof line, posterior inferior line, and anterior line16 as a routine lesion set, and CFAE ablation was added based on the operator's decision. If AF persisted beyond the aforementioned ablation protocols for PAF or PeAF, we stopped the procedure after internal cardioversion. The endpoint of our procedure was no immediate recurrence of AF after cardioversion with isoproterenol infusion (5-20 µg/min). If there were non-PV foci under isoproterenol, we ablated them all. During RFCA, activated clotting time was maintained between 350 to 400 seconds.\n\nPost-RFCA follow-up\nAll patients were followed up at the outpatient clinic after 1, 3, 6, 9, and 12 months post-RFCA and then every 6 months. Electrocardiography (ECG) was performed at every visit and whenever the patients complained of palpitation. A Holter monitoring (24- or 48-hour) and/or an event recorder were performed at 3, 6, 12, 18, and 24 months after RFCA and whenever patients complained of palpitation following the 2012 HRS/EHRA/ECAS Expert Consensus Statement guidelines.10 We defined recurrence of AF as any episode of AF or atrial tachycardia of at least 30 sec in duration.17 If any ECG-documented AF episode occurred within the three-month blanking period during follow-up, patients were then diagnosed as an early recurrence, and any AF recurrence thereafter was diagnosed as clinical recurrence.17 In case of early recurrence and clinical recurrence, AADs were prescribed.\n\nComparisons of ASA switching and continuous warfarin during follow-up\nA total of 608 patients without evidence of AF recurrence on ECG and Holter monitoring at 3 months after RFCA were included in this study. We compared the thromboembolic events and major bleeding complications in 296 patients for whom warfarin was changed to 100 mg of aspirin (ASA group) and 312 patients for whom anticoagulation was maintained (W group) after confirming no recurrence in the 3rd-month post-RFCA Holter monitoring (Fig. 1). The primary endpoints were thromboembolism including ischemic stroke/transient ischemic attack (TIA) and major bleeding after 3 months from RFCA. Stroke was defined as symptomatic ischemic cerebral infarction with apparent brain lesion in imaging studies. TIA was defined as a transient episode of neurologic dysfunction confirmed by a neurologist without brain lesion in imaging studies, with spontaneous symptomatic recovery within 24 hours. Major bleeding events were defined as any type of hemorrhage requiring blood transfusion or intervention, and bleeding with reduction of hemoglobin levels by ≥4.0 g/dL.18 We compared incidences, hazard ratio and event-free survival of thromboembolic events (including stroke, TIA, and other thromboembolism) and major bleeding events between ASA and W groups depending on CHA2DS2-VASc score.\n\nStatistical analyses\nThe results are expressed as mean±standard deviation. The Student's t-test, χ2 test were used for comparison of incidences of primary endpoints between the groups. Univariate and multivariate Cox regression analyses were used for comparison of hazard ratio (HR) between the groups. The assumption was assessed by log-minus-log-survival function and found that the proportion hazards assumption was reasonable. Parameters of a p value ≤0.1 by univariate analysis were included for multivariate analysis. HRs and 95% confidence intervals (CIs) were calculated. The Kaplan-Meier method was used for analyzing event-free survival. A p value <0.05 was considered significant. The data were analyzed using the Statistical Package for the Social Sciences version 20.0 (IBM Inc., Armonk, NY, USA).\n\nRESULTS\nPatient characteristics\nPatient demographic and clinical characteristics in the ASA and W groups at baseline were shown (Table 1). There were no significant differences in clinical profiles, LA size, and left ventricular function. CHADS2, CHA2DS2-VASc, and HAS-BLED scores were not significantly different between two groups. However, past history of stroke/TIA was more frequent in the W group (14.5%) than in the ASA group (7.1%, p=0.006). The time in the therapeutic range of international normalized ratio (INR) for the W group was 44.2% during the follow-up period. In sixty-seven patients (6.1%), AF recurred after 3 months of post-RFCA. After recurrence of AF, warfarin was restarted according to CHA2DS2-VASc score.\n\nHemorrhagic and thromboembolic risks were not different between ASA and W groups\nDuring the 18.0±12.2 months of follow-up, stroke occurred in a patient in the ASA group (0.3%). Stroke and TIA occurred in one and two patients in the W group, respectively (1.0%, p=0.342). All patients who experienced a stroke recovered without sequelae. In all patients with thromboembolic complications, heart rhythm was sinus rhythm at the time of stroke or TIA. Major bleeding events occurred in two patients in ASA and W groups (0.7% and 0.6%, respectively; p=0.958). The detailed information about events in each patient was shown (Table 2). There were no thromboembolic or major bleeding complications in patients with AF recurrence.\n\nIn univariate and multivariate Cox regression analyses, CHA2DS2-VASc score (HR, 3.80; 95% CI, 1.13-12.71; p=0.031) was an independent risk factor for thromboembolic events, and HAS-BLED score (HR, 3.90; 95% CI, 1.13-13.45; p=0.031) was an independent risk factor for major bleeding events (Table 3). By Kaplan-Meier analysis, there were no significant differences of event-free survival from the composite primary endpoint (thromboembolic and major bleeding events) between the groups (p=0.968) (Fig. 2A).\n\nComparisons in patients with CHA2DS2-VASc score ≥2\nAmong the 608 included patients, 259 patients (42.6%) had a CHA2DS2-VASc score ≥2 (ASA group, 121; W group, 138). Table 4 shows comparison of clinical characteristics of the patients with CHA2DS2-VASc score ≥2 in the ASA and W groups. The patients in the W group were younger (62.9±9.0 years vs. 65.5±8.3 years, p=0.019) and more likely to have had a history of stroke/TIA (32.6% vs. 17.3%, p=0.008) than the patients in the ASA group. In patients with CHA2DS2-VASc score ≥2, thromboembolic events occurred in one patient in the ASA group (0.8%) and three patients in the W group (2.2%, p=0.380), respectively during follow-up period. Major bleeding events occurred in one and two patients in the ASA (0.8%) and W groups (1.4%, p=0.640), respectively. By Kaplan-Meier analysis, there were no significant differences of event-free survival from the composite primary endpoint in the patients with CHA2DS2-VASc score ≥2 between the groups (p=0.822) (Fig. 2B).\n\nDISCUSSION\nThis is a retrospective observational study that evaluated the risk and benefit of switching anticoagulation to aspirin after successful RFCA of AF, based on CHADS2, CHA2DS2-VASc, HAS-BLED scores, and recommended a standard rhythm monitoring follow-up strategy. The present study suggested that switching warfarin to aspirin 3 months after RFCA could be as safe and efficacious as continuous anticoagulation even in patients with a CHA2DS2-VASc score ≥2. However, strict and continuous rhythm monitoring and maintenance of optimal INR should be emphasized to achieve these results. We also proved that CHA2DS2-VASc and HAS-BLED scores were very valuable parameters in predicting ischemic stroke and hemorrhagic complications, even after RFCA of AF.\n\nRisk and benefits of anticoagulation in patients with non-valvular AF\nAlthough warfarin can significantly reduce stroke risk by 64% in patients with non-valvular AF,19 it still has an annual 1.6-2.4% risk of stroke or systemic embolism and an annual 3.1-3.4% risk of major hemorrhagic complications.11,12,13 Moreover, the annual risk of fatal hemorrhagic stroke is between 0.7-0.8%.11,12,13 Therefore, the 2010 ESC guidelines recommended caution, regular review, and correction of reversible bleeding risk factors for patients with a HAS-BLED score ≥3.5 In this study, 2 out of 721 patients experienced intracranial and spinal cord hemorrhages during anticoagulation, but they were not included in this analysis because these complications occurred within 3 months after RFCA. Although aspirin has a lower potential risk of major bleeding than warfarin, it reduces ischemic stroke risk by no more than 22% as compared with the 64% risk reduction achieved by anticoagulation.19 Therefore, aspirin can be considered in patients with a very low AF burden and a high HAS-BLED score. However, a previous study reported that the risk of intracranial hemorrhage was similar in patients taking aspirin to those taking warfarin, and that aspirin increases bleeding risk significantly when administered simultaneously with warfarin.20 In a large cohort study from Denmark including over 132000 patients with AF, warfarin was superior for stroke prevention and similar for bleeding risk compared to aspirin.21 Aspirin has rather higher bleeding risk than warfarin in Japan Atrial Fibrillation Stroke Trial (JAST).22 Discrepancies of current study from these two studies were that we included the patients with significantly reduced AF burden by catheter ablation, and those with young and low CHADS2 score. Generally, the risk of bleeding (HAS-BLED score) increases parallel with the risk of stroke (CHADS2 score), such as hypertension, old age, or previous stroke. In spite of ethnical similarity, major bleeding rates were 1.6% in JAST and 0.7% in current study. 2010 EHRA-EAPCI Consensus Documents recommended using warfarin monotherapy in patients with AF and percutaneous coronary intervention who are stable longer than 1 year.23 However, whether warfarin monotherapy is safe enough to prevent an annual 2.8% risk of very late stent thrombosis in patients with drug-eluting stents24 and major hemorrhagic complications remains unclear.\n\nAnticoagulation issue after rhythm control of AF\nThe main reason for continuing oral anticoagulation after successful RFCA is the concern for asymptomatic AF recurrence.10 Previous studies have shown a 0.5 to 7% risk of stroke or thromboembolic events after RFCA of AF,25,26,27 and current guidelines suggest anticoagulation should be maintained even after successful RFCA of AF according to CHADS2 or CHA2DS2-VASc score.10 However, there have been efforts to stop anticoagulation after potentially successful RFCA of AF because of the bleeding risks and inconvenience of warfarin. There have been several studies demonstrating incidence of thromboembolic events decrease after successful RFCA of AF.28,29,30 Oral, et al.25 showed that, among 755 successfully ablated AF patients, discontinuation of anticoagulation therapy was safe in patients younger than 65 years without a history of stroke. Bunch, et al.31 demonstrated the safety of 325 mg aspirin without warfarin in 690 patients with CHADS2 score 0 to 1, and Saad, et al.32 reported that no thromboembolic morbidity without anticoagulation existed in 327 patients with CHADS2 score ≤3. However, in a prior nonrandomized study of 3355 patients who underwent CPVI, suspension of oral anticoagulation therapy after successful RFCA was beneficial in patients at moderate to high risk of thromboembolism.30 Therefore the decision to anticoagulate after successful RFCA should be based on assessment of the risk-benefit ratio, and switching anticoagulation to aspirin can be considered in patients with high risk of hemorrhage and no recurrence of AF. There were two reasons that we grouped the patients based on anticoagulation therapy 3 months after RFCA. First, the current guidelines recommend that warfarin should be continued for 2 months after RFCA. Second, post-procedural 3 months are considered as blanking period and not considered as clinical recurrence.33\n\nHowever, strict rhythm monitoring cannot be overemphasized. In this study, heart rhythm was sinus rhythm at the time of stroke or TIA in patients with thromboembolic complications. We might miss asymptomatic AF recurrence or non-cardioembolic source of stroke in these patients. Careful monitoring for rhythm is important in patients with high CHA2DS2-VASc or high HAS-BLED scores and patients at high risk of AF recurrence, such as those with high LA volume, PeAF, or long ablation time.34 In this study, we suggest that a regular rhythm monitoring strategy based on the current guidelines was acceptable for making a clinical decision of switching warfarin to aspirin. We also implied that CHA2DS2-VASc and HAS-BLED scores were still independent predictors for stroke/TIA and major hemorrhage after successful catheter ablation of AF.\n\nStudy limitations\nThis study was designed as a retrospective observational study, but not as a randomized study. Although CHADS2 and CHA2DS2-VASc scores were not significantly different between two groups, past history of stroke or TIA were higher in W group than in ASA group. It may be because the physicians tended to continue warfarin in patients with a history of stroke or TIA. Although we tried to follow the consensus guidelines for AF rhythm monitoring strictly, all silent recurrence of AF could not be detected on surface ECG or Holter monitoring. The time in therapeutic range was relatively low (44.2%) in the W group compared to previous large scale clinical trials, and it could be one of factors for no significant differences in thromboembolic complication between W group and ASA group. Although recovery of LA contractile function is an important factor for prediction of thromboembolic events, we did not analyze LA contractile function in the current study.\n\nIn conclusion, after successful RFCA of AF, switching warfarin to aspirin 3 months after RFCA could be as safe and efficacious as long-term anticoagulation, even in patients with CHA2DS2-VASc score ≥2. Strict heart rhythm monitoring in the aspirin group and careful INR monitoring in the anticoagulation group are important in patients after RFCA of AF. Future large randomized trials are warranted.\n\nACKNOWLEDGEMENTS\nThis work was supported by a grant (A085136) from the Korea Health 21 R&D Project, Ministry of Health and Welfare, and a grant (2010-0010537) from the Basic Science Research Program of the National Research Foundation of Korea under the Ministry of Education, Science and Technology of the Republic of Korea.\n\nThe authors have no financial conflicts of interest.\n\nFig. 1 Flow diagram and numbers of patients. AF, atrial fibrillation; RFCA, radiofrequency catheter ablation.\n\nFig. 2 Thromboembolic and major bleeding event-free survival by Kaplan-Meier method in all patients (A) and the patients with CHA2DS2-VASc score ≥2 (B) in ASA (solid line) and W (dotted line) groups.\n\nTable 1 Baseline Characteristics of All Patients\n\nLA, left atrium; PAF, paroxysmal atrial fibrillation; TIA, transient ischemic attack.\n\nTable 2 Patients with Primary Endpoints\n\nAF, atrial fibrillation; INR, international normalized ratio; TIA, transient ischemic attack.\n\nTable 3 Clinical Factors Related to Thromboembolic or Major Bleeding Events by Multivariate Cox Regression Analysis\n\nCI, confidence interval; HR, hazard ratio.\n\nTable 4 Baseline Characteristics of Patients with CHA2DS2-VASc Score ≥2\n\nLA, left atrium; PAF, paroxysmal atrial fibrillation; TIA, transient ischemic attack.\n==== Refs\n1 Wyse DG Waldo AL DiMarco JP Domanski MJ Rosenberg Y Schron EB A comparison of rate control and rhythm control in patients with atrial fibrillation N Engl J Med 2002 347 1825 1833 12466506 \n2 Van Gelder IC Hagens VE Bosker HA Kingma JH Kamp O Kingma T A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation N Engl J Med 2002 347 1834 1840 12466507 \n3 Gage BF Waterman AD Shannon W Boechler M Rich MW Radford MJ Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation JAMA 2001 285 2864 2870 11401607 \n4 Lip GY Nieuwlaat R Pisters R Lane DA Crijns HJ Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation Chest 2010 137 263 272 19762550 \n5 European Heart Rhythm Association European Association for Cardio-Thoracic Surgery Camm AJ Kirchhof P Lip GY Schotten U Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC) Eur Heart J 2010 31 2369 2429 20802247 \n6 Lee BH Park JS Park JH Park JS Kwak JJ Hwang ES The effect and safety of the antithrombotic therapies in patients with atrial fibrillation and CHADS score 1 J Cardiovasc Electrophysiol 2010 21 501 507 20021521 \n7 Wazni OM Marrouche NF Martin DO Verma A Bhargava M Saliba W Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: a randomized trial JAMA 2005 293 2634 2640 15928285 \n8 Jaïs P Cauchemez B Macle L Daoud E Khairy P Subbiah R Catheter ablation versus antiarrhythmic drugs for atrial fibrillation: the A4 study Circulation 2008 118 2498 2505 19029470 \n9 Cosedis Nielsen J Johannessen A Raatikainen P Hindricks G Walfridsson H Kongstad O Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation N Engl J Med 2012 367 1587 1595 23094720 \n10 Calkins H Kuck KH Cappato R Brugada J Camm AJ Chen SA 2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design: a report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation. Developed in partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology (ESC) and the European Cardiac Arrhythmia Society (ECAS); and in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), the Asia Pacific Heart Rhythm Society (APHRS), and the Society of Thoracic Surgeons (STS). Endorsed by the governing bodies of the American College of Cardiology Foundation, the American Heart Association, the European Cardiac Arrhythmia Society, the European Heart Rhythm Association, the Society of Thoracic Surgeons, the Asia Pacific Heart Rhythm Society, and the Heart Rhythm Society Heart Rhythm 2012 9 632 696 22386883 \n11 Connolly SJ Ezekowitz MD Yusuf S Eikelboom J Oldgren J Parekh A Dabigatran versus warfarin in patients with atrial fibrillation N Engl J Med 2009 361 1139 1151 19717844 \n12 Patel MR Mahaffey KW Garg J Pan G Singer DE Hacke W Rivaroxaban versus warfarin in nonvalvular atrial fibrillation N Engl J Med 2011 365 883 891 21830957 \n13 Granger CB Alexander JH McMurray JJ Lopes RD Hylek EM Hanna M Apixaban versus warfarin in patients with atrial fibrillation N Engl J Med 2011 365 981 992 21870978 \n14 Pisters R Lane DA Nieuwlaat R de Vos CB Crijns HJ Lip GY A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey Chest 2010 138 1093 1100 20299623 \n15 Verma A Mantovan R Macle L De Martino G Chen J Morillo CA Substrate and Trigger Ablation for Reduction of Atrial Fibrillation (STAR AF): a randomized, multicentre, international trial Eur Heart J 2010 31 1344 1356 20215126 \n16 Pak HN Oh YS Lim HE Kim YH Hwang C Comparison of voltage map-guided left atrial anterior wall ablation versus left lateral mitral isthmus ablation in patients with persistent atrial fibrillation Heart Rhythm 2011 8 199 206 20950713 \n17 European Heart Rhythm Association (EHRA) European Cardiac Arrhythmia Scoiety (ECAS) American College of Cardiology (ACC) American Heart Association (AHA) Society of Thoracic Surgeons (STS) Calkins H HRS/EHRA/ECAS expert Consensus Statement on catheter and surgical ablation of atrial fibrillation: recommendations for personnel, policy, procedures and follow-up. A report of the Heart Rhythm Society (HRS) Task Force on catheter and surgical ablation of atrial fibrillation Heart Rhythm 2007 4 816 861 17556213 \n18 Kastrati A Neumann FJ Mehilli J Byrne RA Iijima R Büttner HJ Bivalirudin versus unfractionated heparin during percutaneous coronary intervention N Engl J Med 2008 359 688 696 18703471 \n19 Hart RG Pearce LA Aguilar MI Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation Ann Intern Med 2007 146 857 867 17577005 \n20 Friberg L Rosenqvist M Lip GY Evaluation of risk stratification schemes for ischaemic stroke and bleeding in 182 678 patients with atrial fibrillation: the Swedish Atrial Fibrillation cohort study Eur Heart J 2012 33 1500 1510 22246443 \n21 Olesen JB Lip GY Lindhardsen J Lane DA Ahlehoff O Hansen ML Risks of thromboembolism and bleeding with thromboprophylaxis in patients with atrial fibrillation: A net clinical benefit analysis using a 'real world' nationwide cohort study Thromb Haemost 2011 106 739 749 21789337 \n22 Sato H Ishikawa K Kitabatake A Ogawa S Maruyama Y Yokota Y Low-dose aspirin for prevention of stroke in low-risk patients with atrial fibrillation: Japan Atrial Fibrillation Stroke Trial Stroke 2006 37 447 451 16385088 \n23 Lip GY Huber K Andreotti F Arnesen H Airaksinen JK Cuisset T Antithrombotic management of atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing coronary stenting: executive summary-a Consensus Document of the European Society of Cardiology Working Group on Thrombosis, endorsed by the European Heart Rhythm Association (EHRA) and the European Association of Percutaneous Cardiovascular Interventions (EAPCI) Eur Heart J 2010 31 1311 1318 20447945 \n24 Spaulding C Daemen J Boersma E Cutlip DE Serruys PW A pooled analysis of data comparing sirolimus-eluting stents with bare-metal stents N Engl J Med 2007 356 989 997 17296825 \n25 Oral H Chugh A Ozaydin M Good E Fortino J Sankaran S Risk of thromboembolic events after percutaneous left atrial radiofrequency ablation of atrial fibrillation Circulation 2006 114 759 765 16908760 \n26 Nademanee K Schwab MC Kosar EM Karwecki M Moran MD Visessook N Clinical outcomes of catheter substrate ablation for high-risk patients with atrial fibrillation J Am Coll Cardiol 2008 51 843 849 18294570 \n27 Cappato R Calkins H Chen SA Davies W Iesaka Y Kalman J Worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation Circulation 2005 111 1100 1105 15723973 \n28 Yagishita A Takahashi Y Takahashi A Fujii A Kusa S Fujino T Incidence of late thromboembolic events after catheter ablation of atrial fibrillation Circ J 2011 75 2343 2349 21778595 \n29 Corrado A Patel D Riedlbauchova L Fahmy TS Themistoclakis S Bonso A Efficacy, safety, and outcome of atrial fibrillation ablation in septuagenarians J Cardiovasc Electrophysiol 2008 19 807 811 18363688 \n30 Themistoclakis S Corrado A Marchlinski FE Jais P Zado E Rossillo A The risk of thromboembolism and need for oral anticoagulation after successful atrial fibrillation ablation J Am Coll Cardiol 2010 55 735 743 20170810 \n31 Bunch TJ Crandall BG Weiss JP May HT Bair TL Osborn JS Warfarin is not needed in low-risk patients following atrial fibrillation ablation procedures J Cardiovasc Electrophysiol 2009 20 988 993 19473299 \n32 Saad EB d'Avila A Costa IP Aryana A Slater C Costa RE Very low risk of thromboembolic events in patients undergoing successful catheter ablation of atrial fibrillation with a CHADS2 score ≤3: a long-term outcome study Circ Arrhythm Electrophysiol 2011 4 615 621 21841192 \n33 Joshi S Choi AD Kamath GS Raiszadeh F Marrero D Badheka A Prevalence, predictors, and prognosis of atrial fibrillation early after pulmonary vein isolation: findings from 3 months of continuous automatic ECG loop recordings J Cardiovasc Electrophysiol 2009 20 1089 1094 19549038 \n34 Shim J Joung B Park JH Uhm JS Lee MH Pak HN Long duration of radiofrequency energy delivery is an independent predictor of clinical recurrence after catheter ablation of atrial fibrillation: over 500 cases experience Int J Cardiol 2013 167 2667 2672 22790188\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0513-5796",
"issue": "55(5)",
"journal": "Yonsei medical journal",
"keywords": "Anticoagulation; aspirin; atrial fibrillation; catheter ablation",
"medline_ta": "Yonsei Med J",
"mesh_terms": "D000368:Aged; D000925:Anticoagulants; D001241:Aspirin; D001281:Atrial Fibrillation; D017115:Catheter Ablation; D005260:Female; D006470:Hemorrhage; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D012189:Retrospective Studies; D018570:Risk Assessment; D013923:Thromboembolism; D016896:Treatment Outcome; D014859:Warfarin",
"nlm_unique_id": "0414003",
"other_id": null,
"pages": "1238-45",
"pmc": null,
"pmid": "25048480",
"pubdate": "2014-09",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": "20215126;17556213;19473299;17577005;18294570;20447945;20950713;22386883;22246443;22790188;19549038;16385088;20021521;19029470;21789337;23094720;18703471;20299623;17296825;15928285;21870978;18363688;12466507;19762550;20802247;21778595;15723973;16908760;21830957;20170810;21841192;12466506;19717844;11401607",
"title": "Safety and efficacy of switching anticoagulation to aspirin three months after successful radiofrequency catheter ablation of atrial fibrillation.",
"title_normalized": "safety and efficacy of switching anticoagulation to aspirin three months after successful radiofrequency catheter ablation of atrial fibrillation"
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"abstract": "Objective Delirium in critically ill patients is considered a risk factor for various long-term consequences. We evaluated delirium and associated long-term outcomes in patients with acute respiratory distress syndrome with non-H1N1 and H1N1- associated severe community-acquired pneumonia (sCAP) who had been recommended to take antiviral drugs associated with delirious symptoms as adverse effects. Methods Of 64 patients, 42 survivors (H1N1, 15; non-H1N1, 27) were analyzed regarding the relationship between medication and the duration of delirium in the intensive care unit. During follow-up (n = 23), we assessed cognitive abilities, post-traumatic stress disorder (PTSD), physical capacity, and health-related quality of life (HRQoL). Results The incidence of delirium was 88%. There was no difference in the incidence and duration of delirium between patients with H1N1 and non-H1N1 infection. The haloperidol and opioid doses were associated with a longer delirium duration. The delirium duration was correlated with reduced cognitive performance in motor skills, memory function, and learning efficiency. Patients with PTSD (16%) had a significantly longer delirium duration and low mental HRQoL. Conclusions H1N1 infection and corresponding antiviral medication had no impact on delirium. The duration of delirium in these patients was associated with impairments in various outcome parameters, illustrating the burden of sCAP.",
"affiliations": "1 Department of Anesthesiology and Operative Intensive Care Medicine, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.;1 Department of Anesthesiology and Operative Intensive Care Medicine, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.;1 Department of Anesthesiology and Operative Intensive Care Medicine, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.;1 Department of Anesthesiology and Operative Intensive Care Medicine, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.;1 Department of Anesthesiology and Operative Intensive Care Medicine, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.;1 Department of Anesthesiology and Operative Intensive Care Medicine, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.;2 SOSTANA GmbH, Berlin, Germany.;3 Department of Anesthesiology and Operative Intensive Care Medicine, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.",
"authors": "Denke|Claudia|C|;Balzer|Felix|F|;Menk|Mario|M|;Szur|Sebastian|S|;Brosinsky|Georg|G|;Tafelski|Sascha|S|;Wernecke|Klaus-Dieter|KD|;Deja|Maria|M|",
"chemical_list": "D000998:Antiviral Agents",
"country": "England",
"delete": false,
"doi": "10.1177/0300060518762040",
"fulltext": "\n==== Front\nJ Int Med ResJ. Int. Med. ResIMRspimrThe Journal of International Medical Research0300-06051473-2300SAGE Publications Sage UK: London, England 2960948910.1177/030006051876204010.1177_0300060518762040Clinical Research ReportsLong-term sequelae of acute respiratory distress syndrome caused by severe community-acquired pneumonia: Delirium-associated cognitive impairment and post-traumatic stress disorder Denke Claudia 1Balzer Felix 1Menk Mario 1Szur Sebastian 1Brosinsky Georg 1Tafelski Sascha 1Wernecke Klaus-Dieter 2Deja Maria 34\n1 Department of Anesthesiology and Operative Intensive Care Medicine, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany\n2 SOSTANA GmbH, Berlin, Germany\n3 Department of Anesthesiology and Operative Intensive Care Medicine, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany\n4 Department of Anesthesiology and Intensive Care, University Medical Center Schleswig-Holstein, Campus Luebeck, Luebeck, GermanyClaudia Denke, Charité Universitätsklinikum Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin, Institute of Health, Department of Anesthesiology and Operative Intensive Care Medicine, Campus Virchow- Klinikum, Augustenburger Platz 1, Berlin 13353, Germany. Email: claudia.denke@charite.de02 4 2018 6 2018 46 6 2265 2283 9 10 2017 15 1 2018 25 1 2018 © The Author(s) 20182018SAGE PublicationsCreative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Objective\nDelirium in critically ill patients is considered a risk factor for various long-term consequences. We evaluated delirium and associated long-term outcomes in patients with acute respiratory distress syndrome with non-H1N1 and H1N1- associated severe community-acquired pneumonia (sCAP) who had been recommended to take antiviral drugs associated with delirious symptoms as adverse effects.\n\nMethods\nOf 64 patients, 42 survivors (H1N1, 15; non-H1N1, 27) were analyzed regarding the relationship between medication and the duration of delirium in the intensive care unit. During follow-up (n = 23), we assessed cognitive abilities, post-traumatic stress disorder (PTSD), physical capacity, and health-related quality of life (HRQoL).\n\nResults\nThe incidence of delirium was 88%. There was no difference in the incidence and duration of delirium between patients with H1N1 and non-H1N1 infection. The haloperidol and opioid doses were associated with a longer delirium duration. The delirium duration was correlated with reduced cognitive performance in motor skills, memory function, and learning efficiency. Patients with PTSD (16%) had a significantly longer delirium duration and low mental HRQoL.\n\nConclusions\nH1N1 infection and corresponding antiviral medication had no impact on delirium. The duration of delirium in these patients was associated with impairments in various outcome parameters, illustrating the burden of sCAP.\n\nCommunity-acquired pneumoniadeliriumlong-term outcomepost-traumatic stress disorderhealth-related quality of lifeanalgesia\n==== Body\nIntroduction\nSevere community-acquired pneumonia (sCAP) is an important cause of intensive care unit (ICU) admission. Diagnosis of sCAP is based on the presence of one of two major criteria (requirement for mechanical ventilation or need for vasopressors) and at least two of nine minor criteria (respiratory rate of ≥30 breaths/min, PaO2/FiO2 ratio of ≤250, multilobar disease, confusion/disorientation, blood urea nitrogen level of ≥20 mg/dL, leukopenia [white blood cell count of <4000 cells/mm³], thrombocytopenia [platelet count of <100 000 cells/mm³], hypothermia [core temperature of <36°C], and hypotension requiring aggressive fluid resuscitation).1,2 sCAP is associated with a risk of acute respiratory distress syndrome (ARDS). ARDS is characterized by bilateral inflammatory pulmonary infiltrates, impaired oxygenation, and acute onset and with an incidence of 13.5 to 58.7 cases per 100,000 person-years, making it a common lung disease requiring intensive care treatment.3–6\n\nRegardless of the cause of ARDS (such as sCAP, nosocomial pneumonia, sepsis, or trauma), patients with ARDS are well known to have a long-term reduction in their health-related quality of life (HRQoL).7,8 Cognitive function, particularly memory performance, concentration, attention, and processing speed, remain affected even years after ARDS onset.9 Therefore, delirium in the ICU has been identified as a predictor of cognitive impairment in patients with ARDS patients.10,11 Delirium is a serious and common complication in up to 80% of patients with severe illness being treated in the ICU and is associated with a prolonged hospital stay and poor long-term outcome.12 However, the long-term outcome of CAP has not been well investigated, especially in patients with CAP in the ICU.13 In a cohort of patients with mild, moderate, and severe CAP, comorbidities other than CAP itself were speculated to have contributed to the observed reduction in HRQoL.14 HRQoL using quality-adjusted life years was recently investigated in elderly patients with and without CAP. The authors observed lower HRQoL in patients with than without CAP as measured with the 36-Item Short Form Health Survey and EQ-5D Index up to 12 months after discharge, and 9.7% of patients with radiologically confirmed CAP were admitted to the ICU.15\n\nFurthermore, in a subgroup of patients with H1N1-associated ARDS, Luyt et al. observed psychological impairment, poorer HRQoL, and symptoms of anxiety, depression, and post-traumatic stress disorder (PTSD).16 Additionally, delirium and delirium-like symptoms have been reported as adverse effects of antiviral drugs such as the neuroaminase inhibitor oseltamivir, which was widely recommended for patients with H1N1 influenza to shorten the disease course.17 Other treatment-related factors that influence the development of delirium are exposure to opioids18,19 and psychoactive medications,20,21 which are administered to 98% of patients in the ICU.22 The pathophysiology of critical illness-associated delirium remains ambiguous and may vary from case to case; thus, the pharmacological approaches and their impact are still unclear. No clear causality between medication and delirium has been identified.\n\nDelirium during treatment in the ICU and its associated risk factors have not been thoroughly investigated in survivors of severe CAP and ARDS. Therefore, in the present study, we focused on the association between medications and delirium in these patients. We examined the incidence and duration of delirium and considered the impact of oseltamivir, opioids, benzodiazepines, propofol, and antipsychotics during treatment of patients with sCAP and ARDS in the ICU. Moreover, we targeted patient-centered long-term outcomes and therefore performed a long-term follow-up of cognitive performance, physical capacity (6-minute walk test [6MWT]), development of PTSD, HRQoL, and the rate of return to work in these patients.\n\nWe hypothesized that oseltamivir used for treatment of H1N1 infection increases the incidence and duration of delirium; that the duration of delirium is associated with the administration of opioids, benzodiazepines, and propofol during ICU treatment; that the decreased cognitive performance and increased incidence of PTSD during follow-up are related to the duration of delirium; and that HRQoL is lower in patients with sCAP than in healthy controls.\n\nThis study was a secondary analysis and follow-up assessment of a dataset used to investigate the clinical courses of H1N1-associated and non-H1N1-associated infection (see Töpfer et al.).23\n\nMaterials and methods\nPatient population\nPatients with CAP and ARDS who were enrolled in a study of H1N1 vs. non-H1N1 infection from January 2009 to December 2010 and discharged alive from the hospital were included in this study and underwent comprehensive follow-up examinations. The follow-up examinations took place from November 2013 to April 2014 at our center 50 ± 6 months after discharge from the ICU. Age-matched healthy controls were also evaluated for cognitive testing using the Wortschatztest [WST] (a vocabulary test), Cambridge Neuropsychological Test Automated Battery (CANTAB), Visual Verbal Learning Test (VVLT), and Stroop Color and Word Test (SCWT).\n\nMethods\nThe study was approved by the ethics committee of the Charité-Universitätsmedizin Berlin (EA1/123/13) and registered in the German Clinical Trails Register (DRKS 00011913). Before follow-up enrollment, written informed consent was obtained from each survivor. The first part of the analysis focused on the clinical and treatment data in relation to the duration of delirium in surviving patients with H1N1 and non-H1N1 infection. The second part of the analysis focused on a follow-up assessment of the survivors with H1N1-infection with respect to their physical and mental health, cognitive performance, HRQoL, and rate of return to work (see Figure 1).\n\nFigure 1. Flowchart of study objective and analytical considerations. sCAP, severe community-acquired pneumonia; ARDS, acute respiratory distress syndrome; ICU, intensive care unit; PTSD, post-traumatic stress disorder; CANTAB, Cambridge Neuropsychological Test Automated Battery; STROOP, Stroop Color and Word Test; HRQoL, health-related quality of life; SF-12, Medical Outcomes Study 12-Item Short Form; VVLT, Visual Verbal Learning Test.\n\nData concerning age, sex, cause of infection (H1N1/non-H1N1), ICU length of stay, duration of mechanical ventilation, daily scores for illness severity and organ dysfunction (Simplified Acute Physiology Score II [SAPS II], Sequential Organ Failure Assessment [SOFA], and Acute Physiology and Chronic Health Evaluation II [APACHE II]), analgosedation, delirium (Richmond Agitation-Sedation Scale [RASS] and Confusion Assessment Method for the ICU [CAM-ICU]), and daily mean and cumulative dose (in mg) of medications were extracted from the patient data management system (PDMS). Psychiatric lifelong and current diagnoses at the time of ICU admission (mood and anxiety disorders) were also extracted from the PDMS.\n\nMedications\nBenzodiazepine doses (diazepam equivalent) were calculated for diazepam, lorazepam, and midazolam. Opioid doses (morphine equivalent) were calculated for sufentanil, piritramide, and morphine. Propofol was mainly used for sedation, and haloperidol was mainly used as an antipsychotic medication for treatment of delirium. The ratio of the duration of haloperidol administration and duration of delirium was calculated to monitor the delirium treatment.\n\nDelirium\nThe RASS was used to measure the patient´s agitation or sedation level.24,25 Daily screening for the presence and severity of delirium was conducted using the CAM-ICU and Delirium Detection Scale by trained nurses during all three shifts every day.26–29 Delirium was determined to be present in patients with a RASS score of +4 to −2, positive CAM-ICU result, and/or Delirium Detection Scale score of >7.\n\nSeveral validated neuropsychological tests were applied to determine the essential aspects of cognitive performance. Intelligence before the onset of ARDS was determined to be the premorbid intelligence.\n\nPremorbid intelligence and cognitive performance\nAssessment of premorbid intelligence level\nThe WST is a vocabulary test that is widely used to estimate the premorbid intelligence level in the German language.30\n\nAssessment of cognitive performance\nThe CANTAB is a computerized system for cognitive testing.31 The correct responses and reaction times were note for each subtest. The Motor Screening Task (MOT) measures speed and accuracy as an index of the subject’s motor skill. Pattern Recognition Memory (PRM) is a test of visual pattern recognition memory with immediate recognition (PRM 1) and 20-minute delayed recognition (PRM 2). Spatial recognition memory (SRM) was tested, and attention was assessed with choice reaction time tasks (CRT).\n\nAssessment of learning efficiency and memory\nThe VVLT is based on Rey’s auditory recall of words and is used to examine learning efficiency and episodic declarative memory.32 A list of 15 words was learned in 3 sequential presentations at a fixed rate, and the patients were asked to recall as many words as possible. They were then asked to perform a fourth recall after a 20-minute delay. The number of errors and correctly recalled words were measured.\n\nAssessment of executive function\nThe SCWT is a measure of executive function and contains three parts that measure selective attention, cognitive inhibition, and cognitive flexibility.33 First, the patients were asked to name a series of color words (“word task”). Second, they were asked to name the color of a bar (“color task”). Finally, they performed a combined “color–word task,” which was used to measure their mental flexibility and ability to inhibit a dominant response. The time and number of errors were recorded for all three parts of the SCWT. An interference measure was calculated according to Valentijn et al.34: Interference = Stroop III − [(Stroop I + Stroop II) / 2].\n\nAssessment of PTSD\nThe German version of the Post-Traumatic Stress Syndrome 14-Questions Inventory (PTSS-14) was used to assess PTSD-related symptoms.35 The Post-traumatic Stress Diagnostic Scale (PDS) established by Foa et al.36 is a screening questionnaire for PTSD according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition. PTSD was diagnosed when both of the following criteria were met: the PTSS-14 score was ≥40 and PTSD was identified using the PDS.\n\nA health status questionnaire was also used to ask patients about any current health problems such as neurological or mental disorders.\n\nAssessment of physical performance\nThe 6MWT is used to assess functional exercise capacity and was performed in accordance with the American Thoracic Society guidelines.37 The reference equations established by Enright and Sherrill38 were used to calculate the predicted 6MWT for each individual: female: (2.11 × height [cm]) − (2.29 × weight [kg]) − (5.78 × age [y]) + 667 and male: (7.57 × height [cm]) − (1.76 × weight [kg]) − (5.02 × age [y]) − 309.\n\nAssessment of HRQoL\nHRQoL was assessed using the Medical Outcomes Study 12-Item Short Form (SF-12) questionnaire, which includes two dimensions of quality of life.39 Six items reflect physical health, and six items reflect mental health. The total score ranges from 0 to 100; higher scores indicate a more favorable quality of life. We matched healthy controls by age and sex from the normal database for the German population.\n\nRate of return to work\nA questionnaire of socioeconomic status was used to ask patients about their employment status at the time of follow-up: work/student; invalidity pension/sick; unemployment; or retirement.\n\nStatistical analysis\nResults are given as median and range or frequency with percentage.\n\nIn the first step of the statistical analysis, clinical and treatment-related variables that had been measured during the ICU stay were analyzed for all surviving patients. To compare patients from independent groups (H1N1 infection vs. non-H1N1 infection and follow-up vs. non-follow-up), the Mann–Whitney U test for nonparametric variables was used because the variables were not normally distributed. The chi-square test was used to compare frequencies between independent groups. Robust regression analysis with backward stepwise feature selection was applied to detect relationships between clinical parameters (length of ICU stay, duration of mechanical ventilation, age, and H1N1 infection) and the duration of delirium (first model) as well as between medications (cumulative dose of benzodiazepines, opioids, haloperidol, and propofol) and the duration of delirium (second model). Clinical and pharmacological factors selected from these two models were combined and included in a third model to estimate their impact on the duration of delirium. These selected clinical and pharmacological factors were found to have a significant association with the duration of delirium.\n\nIn the second step of the statistical analysis, all patients who underwent subsequent measurement of cognitive performance (CANTAB, VVLT, and SCWT), PTSD, HRQoL, and physical capacity (6MWT) were evaluated and compared with the non-followed-up patients and age-matched healthy controls. The Spearman correlation coefficient was applied to estimate relationships between the subdimensions of cognitive performance (visual and verbal memory, attention, executive function, and working speed) and the duration of delirium. A p-value of <0.05 was considered statistically significant. All tests were conducted as an exploratory data analysis. Therefore, no adjustments for multiple testing were made.\n\nAll calculations were performed using Microsoft Excel 2011 Version 14.0 (Microsoft Corp., Redmond, WA, USA), SPSS Version 22 (IBM Corp., Armonk, NY, USA), and R Version 3.0.2 (R Foundation for Statistical Computing, Vienna, Austria).\n\nResults\nPatients\nOf 64 patients with CAP and ARDS enrolled in the previous study of H1N1 vs. non-H1N1 infection from January 2009 to December 2010, 42 patients were discharged alive from the hospital. Of these 42 survivors (H1N1 infection, n = 15; non-H1N1 infection, n = 27), we recruited 23 patients (H1N1 infection, n = 8; non-H1N1 infection, n = 15) for comprehensive follow-up examinations. Nineteen patients were excluded (no address, n = 4; death after ICU discharge, n = 5; impossible to participate because of a severe handicap with the inability to undergo physical and cognitive examination, n = 8; and availability of only the questionnaire results with no physical or cognitive examination, n = 2) (see Figure 2). Twenty age-matched healthy controls were also assessed.\n\nFigure 2. CONSORT diagram of inclusion of patients with H1N1- and non-H1N1-associated ARDS. CONSORT, Consolidated Standards of Reporting Trials; ARDS, acute respiratory distress syndrome; CAP, community-acquired pneumonia.\n\nClinical and pharmacological characteristics in relation to duration of delirium\nThe patients with H1N1 infection and non-H1N1 infection showed no significant differences in sex, age, severity of illness (SAPS II, APACHE II), organ failure (SOFA), ICU length of stay, or duration of mechanical ventilation (see Table 1; see also Töpfer et al.23).\n\nTable 1. Demographic and clinical characteristics of surviving patients with H1N1 and non-H1N1 infection\n\n\tAll patients(n = 42)\tH1N1 infection(n = 15)\tNon-H1N1 infection(n = 27)\tp-value(H1N1 vs. non-H1N1)\t\nMale\t27 (64)\t8 (30)\t19 (70)\t0.325\t\nFemale\t15 (36)\t7 (47)\t8 (53)\t\t\nAge, years\t42 (18–65)\t37 (21–65)\t45 (18–65)\t0.288\t\nAPACHE II score\t18 (6–29)\t16 (6–28)\t20 (11–29)\t0.229\t\nSAPS II score\t37 (19–69)\t36 (19–69)\t38 (20–69)\t0.649\t\nSOFA score\t8 (3–16)\t9 (4–16)\t8 (3–13)\t0.806\t\nTime from discharge to investigation, months\t50 (37–60)\t48 (44–60)\t54 (37–58)\t0.382\t\nICU length of stay, days\t32 (7–360)\t43 (14–161)\t29 (7–360)\t0.090\t\nDuration of mechanical ventilation, days\t22 (1–72)\t24 (1–72)\t20 (2–61)\t0.449\t\nECLA/ECMO\t18 (45)\t6 (43)\t12 (46)\t1.00\t\nDuration of delirium, days\t5 (0–29)\t4 (0–11)\t7 (0–29)\t0.147\t\nIncidence of delirium\t37 (88)\t12 (87)\t25 (93)\t1.00\t\nData are presented as n (%) or median (range).\n\nMann–Whitney U test for comparison between patients with H1N1 infection and non-H1N1 infection. Chi-square test for comparison of frequencies of delirium and H1N1 and non-H1N1 infection. Significance was assumed at a two-tailed p-value of <0.05.\n\nAPACHE II, Acute Physiology and Chronic Health Evaluation II; SAPS II, Simplified Acute Physiology Score II; SOFA, Sequential Organ Failure Assessment; ICU, intensive care unit; ECLA, extracorporeal lung assist; ECMO, extracorporeal membrane oxygenation\n\nDelirium\nThirty-seven patients (88%) developed delirium during their ICU stay. Two patients (5%) were not assessable due to deep sedation. The median duration of delirium was 5 days (range, 0–29 days). However, in all patients, antipsychotic medication was given for twice as long as delirium was detected, and it was given for significantly longer in patients with H1N1 infection than non-H1N1 infection (threefold longer in H1N1 infection vs. twofold longer in non-H1N1 infection, p = 0.019) (see Table 2). Patients with H1N1 infection and non-H1N1 infection received the same high daily dose of benzodiazepines, but those with H1N1 infection received a significantly higher cumulative dose of benzodiazepines (p = 0.001) (see Table 2).\n\nTable 2. Medications\n\nDrug name\tAll patients(n = 42)\tH1N1 infection(n = 15)\tNon-H1N1 infection(n = 27)\tp-value (H1N1 vs. non-H1N1)\t\nBenzodiazepine, mg\t171 (13–348)\t170 (84–348)\t168 (13–306)\t0.989\t\nBenzodiazepine cumulative dose, mg\t1009 (48–10,732)\t3069 (264–10,732)\t720 (48–8370)\t0.001*\t\nPropofol, mg\t1164 (50–3396)\t1172 (50–2698)\t1152 (202–3396)\t0.753\t\nPropofol cumulative dose, mg\t8531 (50–192,442)\t9375 (50–140,286)\t8301 (330–192,442)\t0.862\t\nOpioids, mg\t17 (4–690)\t19 (4–530)\t15 (5–690)\t0.616\t\nOpioids cumulative dose, mg\t46 (4–2063)\t129 (4–647)\t39 (10–2063)\t0.977\t\nHaloperidol, mg\t3 (1–14)\t4 (1–14)\t3 (1–14)\t0.488\t\nHaloperidol cumulative dose, mg\t41 (2–349)\t50 (4–258)\t34 (2–349)\t0.163\t\nDuration of haloperidol to delirium, %\t200 (24–1600)\t342 (173–1600)\t175 (24–800)\t0.019*\t\nData are presented as median (range).\n\nMann–Whitney U test between patients with H1N1 infection and non-H1N1 infection for comparison of daily mean dose and cumulative dose of medication.\n\nSignificance was assumed at a two-tailed p-value of < 0.05. *Significant difference.\n\nAll 15 patients with H1N1 infection received oseltamivir as an antiviral medication for a mean of 8 ± 5 days with a mean daily dose of 245 ± 82 mg and a mean cumulative dose of 1938 ± 1310 mg. There were no differences in the incidence or duration of delirium between patients with H1N1 and non-H1N1 infection (see Table 1). The association between the duration of delirium and drug dose (cumulative dose of opioids, benzodiazepines, haloperidol, and propofol) was analyzed with robust regression. This revealed that a higher cumulative dose of opioids (p = 0.00009) and haloperidol (p = 0.004) as well as a lower dose of propofol (p = 0.026) were significantly predictive of a longer duration of delirium in patients with sCAP with ARDS (see Table 3a). A second robust regression including H1N1 infection, the duration of mechanical ventilation, length of ICU stay, and age was conducted. Neither the H1N1-infection, duration of ICU, mechanical ventilation, nor age showed a significant impact on the duration of delirium (see Table 3b). Finally, in the selected setting (third model), a higher cumulative dose of opioids (p = 0.0051) and haloperidol (p = 0.011) were significantly associated with a longer duration of delirium (see Table 3c).\n\nTable 3a. Robust regression (selected model); multiple R2 = 0.288\n\n\tβ\tSE\tp-value\t\nOpiate cumulative dose\t0.0118\t0.0025\t0.00009*\t\nPropofol cumulative dose\t−0.00008\t0.000035\t0.026*\t\nHaloperidol cumulative dose\t0.0461\t0.0148\t\n0.004*\n\t\nCorrelation between delirium duration (days) and medication (cumulative dose of benzodiazepine, opiate, propofol, and haloperidol (in mg)). *Significant difference.\n\nSE, standard error.\n\nTable 3b. Robust regression (full model); multiple R2 = 0.1667\n\n\tβ\tSE\tp-value\t\nDuration of mechanical ventilation\t0.063\t0.042\t0.148\t\nDuration of ICU stay\t0.065\t0.063\t0.305\t\nH1N1 infection/non-H1N1 infection\t−4.83\t2.503\t0.061\t\nAge\t−0.04\t0.046\t0.575\t\nCorrelation between delirium duration (days) and clinical variables (duration of mechanical ventilation (days), duration of ICU stay (days), age (years), and H1N1 infection (H1N1/non-H1N1)).\n\nICU, intensive care unit; SE, standard error.\n\nTable 3c. Robust regression (selected model); multiple R2 = 0.327\n\n\tβ\tSE\tp-value\t\nH1N1/non-H1N1 infection\t−2.985\t2.086\t0.165\t\nOpiate cumulative dose\t0.00976\t0.00317\t\n0.0051*\n\t\nPropofol cumulative dose\t0.00006\t0.000042\t0.163\t\nHaloperidol cumulative dose\t0.045\t0.0165\t\n0.011*\n\t\nCorrelation between delirium duration (days), opiate (cumulative dose in mg), propofol (cumulative dose in mg), and benzodiazepine (cumulative dose in mg). *Significant difference.\n\nSE, standard error.\n\nLong-term outcomes\nWe compared patients who were followed up (n = 23) and those who were unavailable for follow-up (n = 19) to identify potential confounders for sociodemographic and clinical characteristics between these two groups. Patients who were and were not followed up showed no significant differences in clinical characteristics, incidence of delirium (83% vs. 95%, respectively), or duration of delirium (see Table 4). The proportions of patients with H1N1 infection and non-H1N1 infection were equally distributed between the patients who were and were not followed up. Hence, the patients who were followed up were representative of the entire study population.\n\nTable 4. Demographic and clinical characteristics of followed-up and non-followed-up patients\n\nPatients\tFollowed up (n = 23)\tNot followed up (n = 19)\tp-value\t\nMale\t13 (44)\t14 (74)\t0.337\t\nFemale\t10 (56)\t5 (26)\t\t\nAge, years\t42 (19–65)\t46 (18–60)\t0.807\t\nAPACHE II score\t19 (6–28)\t18 (9–29)\t0.625\t\nSAPS II score\t35 (20–69)\t40 (19–69)\t0.139\t\nSOFA score\t8 (3–16)\t9 (4–13)\t0.304\t\nTime between discharge and investigation, months\t50 (37–60)\t\t\t\nICU length of stay, days\t29 (7–75)\t43 (20–360)\t0.078\t\nDuration of mechanical ventilation, days\t21 (1–68)\t24 (2–72)\t0.334\t\nDelirium\t19 (83)\t18 (95)\t1.00\t\nDuration of delirium, days (n = 38)\t4 (1–29)\t7 (1–29)\t0.051\t\nPost-traumatic stress disorder (n = 25)\t4 (16)\t\t\t\nCause of admission\t\t\t\t\n H1N1 Infection\t8 (35)\t7 (37)\t1.00\t\n non-H1N1 infection\t15 (65)\t12 (63)\t\t\nEmployment status\t\t\t\t\n Work/student\t8 (34)\t\t\t\n Invalidity pension/sick\t4 (17)\t\t\t\n Unemployment\t4 (17)\t\t\t\n Retirement\t5 (22)\t\t\t\nData are presented as n (%) or median (range).\n\nMann–Whitney U test for comparison between followed-up and non-followed-up patients (patients with H1N1 and non-H1N1 infection); Chi-square test for comparison of frequencies of H1N1 and non-H1N1 infection. Significance was assumed at a two-tailed p-value of <0.05.\n\nAPACHE II, Acute Physiology and Chronic Health Evaluation II; SAPS II, Simplified Acute Physiology Score II; SOFA, Sequential Organ Failure Assessment; ICU, intensive care unit\n\nCognitive performance\nThe estimated premorbid intelligence level, measured with the WST-A, was within the normal range (intelligence quotient [IQ], 100 ± 15) in patients who were followed up (IQ, 92 ± 10) and in healthy controls (IQ, 107 ± 12). Psychomotor speed measured by MOT latency and verbal processing speed detected with the SCWT1 were significantly lower in patients than in healthy controls (p = 0.007 and p = 0.010, respectively). Furthermore, the performance of visual short-term memory measured by PRM and verbal short-term memory/working memory measured by VVLT 1 were significantly lower in patients than in healthy controls (p = 0.004 and p = 0.028, respectively) (see Table 5).\n\nTable 5. Comparison of CANTAB between patients and healthy controls (Patients: correlation between delirium duration and CANTAB)\n\n\tPatients(n = 23)\tHealthy controls(n = 20)\tMann–Whitney U test (patients vs. healthy controls)\tCorrelation between delirium duration and CANTAB\t\nCognitive tests\tMedian (range)\tMedian (range)\tp-value\tr\tp-value\t\nMOT mean error, %\t13 (9–18)\t12 (8–20)\t0.147\t−0.10\t0.641\t\nMOT mean latency, ms\t966 (548–1384)\t701 (533–1730)\t0.007*\t0.54\t0.012*\t\nPRM 1 correct, %\t92 (67–100)\t100 (67–100)\t0.004*\t0.08\t0.713\t\nPRM 1 correct latency, ms\t2804 (1283–7702)\t2480 (1238–3203)\t0.140\t0.26\t0.257\t\nSRM mean correct, %\t70 (30–85)\t70 (40–90)\t0.822\t−0.66\t0.001*\t\nSRM mean latency, ms\t2181 (1442–5603)\t2286 (690–3641)\t0.871\t0.18\t0.446\t\nCRT mean correct, %\t100 (98–100)\t100 (98–100)\t0.699\t−0.32\t0.149\t\nCRT mean latency, ms\t388 (282–1043)\t348 (264–572)\t0.147\t0.04\t0.859\t\nPRM 2 mean correct, %\t75 (42–100)\t83 (25–100)\t0.310\t−0.30\t0.180\t\nPRM 2 mean latency, ms\t2316 (1264–10,733)\t2577 (876–3640)\t0.947\t−0.03\t0.883\t\nVVLT 1 correct, n\t7 (3–11)\t8 (5–13)\t0.028*\t−0.49\t0.023*\t\nVVLT 2 correct, n\t10 (5–13)\t11 (5–15)\t0.173\t−0.55\t0.01*\t\nVVLT 3 correct, n\t12 (6–15)\t13 (7–15)\t0.192\t−0.41\t0.065\t\nVVLT 1–3(∑correct − ∑incorrect)\t29 (16–38)\t32 (18–43)\t0.091\t−0.519\t0.016*\t\nVVLT 4 correct, n\t8 (2–13)\t10 (3–15)\t0.203\t−0.37\t0.097\t\nSCWT 1 error, n\t0 (0–1)\t0 (0–0)\t1.0\t\t\t\nSCWT 1 time, s\t21 (13–29)\t16 (12–32)\t0.010*\t0.27\t0.228\t\nSCWT 2 error, n\t0 (0–2)\t0 (0–2)\t0.802\t−0.15\t0.498\t\nSCWT 2 time, s\t25 (17–47)\t23 (16–31)\t0.068\t0.09\t0.689\t\nSCWT 3 error, n\t1 (0–11)\t0 (0–5)\t0.293\t0.13\t0.571\t\nSCWT 3 time, s\t42 (28–102)\t42 (27–80)\t0.273\t0.28\t0.221\t\nSCWT – interference score\t30 (18–78)\t30 (17–64)\t0.394\t0.31\t0.173\t\n*Significant difference.\n\nMann–Whitney U test for comparison of cognitive performance between patients and healthy controls: CANTAB subdimensions, VVLT, and SCWT; For patients: Spearman correlation between delirium duration (days) and subdimensions of cognitive performance. Subdimensions of CANTAB: MOT, PRM 1/PRM 2, SRM, CRT, VVLT, and SCWT (parts 1–3).\n\nCANTAB, Cambridge Neuropsychological Test Automated Battery; SRM, spatial recognition memory; CRT, choice reaction time; VVLT, Visual Verbal Learning Test; SCWT, Stroop Color Word Test; MOT, motor screening; PRM, Pattern Recognition Memory (PRM 1 = immediate, PRM 2 = 20-minute delayed recognition).\n\nA relationship between the duration of delirium and cognitive performance was demonstrated in several subdimensions of cognition. Spearman’s correlation coefficient revealed a significant relationship between the duration of delirium and diminished MOT latency (speed of motor skills) (p = 0.012), spatial recognition memory correct (visual memory performance) (p = 0.001), VVLT 1 correct (p = 0.023), VVLT 2 correct (p = 0.01), and overall performance of ∑VVLT 1–3 correct (learning efficiency and episodic declarative memory) (p = 0.016) (Table 5). There were no group differences in cognitive performance measured with the CANTAB in any subtests, VVLT, or SCWT between patients with H1N1 infection and non-H1N1 infection.\n\nMental impairment\nAccording to the PTSS-14 and PDS results, 16% of patients in the follow-up assessment were diagnosed with PTSD. Patients with PTSD had a significantly longer duration of delirium (median, 7 days; range, 6–8 days) than those without PTSD (median, 2 days; range, 0–29 days) (Z = −2.215, p < 0.027).\n\nAnalysis of the lifelong diagnosis at the time of hospital admission extracted from the PDMS showed that two patients (9%) had previous depression and one patient (4%) had phobia. Neither of these patients showed high PTSD scores. Furthermore, at follow-up, the two patients (9%) who reported depression in the questionnaire of current health status were not in the PTSD group.\n\nHRQoL and physical performance\nThe physical dimension of HRQoL as measured with the SF-12 was significantly lower in patients than in age- and sex-matched healthy controls (p < 0.0001). In a comparison of patients with H1N1 and non-H1N1 infection versus healthy controls, only patients with non-H1N1 infection showed a significantly lower physical dimension than controls (p < 0.0001). The mental dimension was not significantly different between these groups (see Table 6).\n\nTable 6. Health-related quality of life (SF-12) of all patients (H1N1 and non-H1N1) and healthy controls\n\nSF-12\tHealthy controls(n = 20)\tAll patients(n = 23)\tH1N1 infection(n = 8)\tNon-H1N1 infection(n = 15)\tp-value\t\nPhysical dimension\t47 (12–62)\t34 (19–59)\t46 (26–59)\t34 (19–56)\t\n<0.0001\na,b\n\t\nMental dimension\t52 (13–72)\t50 (32–64)\t50 (32–64)\t51 (41–64)\tn.s.\t\nSF-12 scores are presented as median (range). Mann–Whitney U test for comparison among all patients, patients with H1N1 infection, patients with non-H1N1 infection, and healthy controls.\n\naSignificant difference between patients and healthy controls\n\nbSignificant difference between healthy controls and patients with non-H1N1 infection\n\nAdditionally, the 6MWT as a measurement of functional status demonstrated a significantly shorter distance for all patients (median, 425 m; range, 200–570 m) than the inter-individual norms (median, 651 m; range, 303–820 m) (Z = −4.19, p < 0.0001) according to Enright and Sherrill.38 There was no difference in functional capacity between patients with H1N1 infection (median, 458 m; range, 200–570 m) and those with non-H1N1 infection (median, 410 m; range, 200–550 m). None of the patients reported previous impairments in physical abilities. Five patients (22%) had performed sports on a regular basis before hospital admission.\n\nMoreover, patients with PTSD showed a significantly diminished mental dimension of HRQoL (median, 44; range, 32–49) compared with patients without PTSD (median, 52; range, 33–64) (Z = −2.27, p ≤ 0.021) and healthy controls (median, 52; range, 13–72) (Z = −3.23, p < 0.0001).\n\nAt the time of follow-up, 34% of patients were employees or students. However, 17% of patients received an invalidity pension, 17% were unemployed, and 22% were retired (see Table 4).\n\nDiscussion\nIn this study, we assessed the association of PTSD and cognitive performance with the duration of delirium. Moreover, we considered than an increased duration of delirium was influenced by analgosedative medication. However, we found that young survivors of sCAP and ARDS had a relatively high incidence of cognitive dysfunction, reduced functional capacity, and high incidence of PTSD that were associated with diminished HRQoL and a decreased rate of return to work.\n\nBecause the clinical and sociodemographic data were not significantly different between the 23 followed-up patients and 19 non-followed-up patients, we assume that the follow-up results could be transferred to the entire study population.\n\nThe results of this study demonstrated that independent of the primary diagnosis, most of the patients in our sample developed delirium (88%). This incidence is slightly above the normal range12 and might be related to the high severity of illness in our population. Moreover, this investigation focused on comparison of the incidence of delirium between patients with H1N1 and non-H1N1 infection. In contrast to the hypothesis that delirium and delirium-like symptoms are common severe adverse effects of oseltamivir,17 we did not find a higher rate of delirium in the H1N1 group. Other factors suggested to have an important impact on the development of delirium are the ICU environment, treatment procedures, and medications.12,18–21 In the first regression model that considered the selected medication, the propofol dose was negatively associated with the duration of delirium. One meta-analysis revealed evidence of a positive effect of propofol on delirium-associated risk factors such as the duration of mechanical ventilation and length of stay, which might explain the shorter duration of delirium with longer propofol application.40 In a relatively high proportion of patients, mechanical ventilation is only tolerated with concurrent medication. A longer duration of propofol administration is helpful to allow for temporary discontinuation of benzodiazepines (e.g., to increase tube tolerance).41\n\nIn contrast to the literature, our second model showed no association between the duration of delirium and age, length of mechanical ventilation, or length of ICU stay. In the final third regression model, which considered the selected medication and significant clinical parameters, we found that opioids and antipsychotic medications had an increasing impact on the duration of delirium independent of the underlying disease. This is in line with the results reported by Pisani et al.,42 who showed an association of higher opioid doses and haloperidol use with persistent delirium. Both the incidence and severity of delirium appear to be associated with opiates.43\n\nAlthough several studies have identified benzodiazepines as a risk factor for delirium, the effect of these medications remains ambiguous.20,21,42 In our population, we could not prove that the cumulative dose of benzodiazepines had an effect on the duration of delirium. Moreover, a meta-analysis of randomized trials on the effects of benzodiazepine-based versus non-benzodiazepine-based sedation in mechanically ventilated critically ill patients demonstrated a similar prevalence of delirium for both sedation strategies.40 Furthermore, the prevalence of delirium in numerous previous studies and the duration of delirium in the present study might be affected by different moderating variables.\n\nIn the present follow-up study, the prevalence of PTSD was 16%. This confirms previous epidemiological data.44–46 We also proved that patients with PTSD have a significantly longer duration of delirium. The duration of delirium appears to be significantly associated with subsequent PTSD symptoms. This supported previous studies that identified postoperative delirium as a risk factor for acute PTSD.47,48 In their cognitive model, Ehlers and Clark49 postulated that PTSD is characterized by a disturbance of autobiographical memory that manifests as poor elaboration and inadequate integration into autobiographical memories. Delirium is associated with fragmental memories or delusions and therefore seems to affect episodic memory.50 Consequently, delirium might inhibit encoding of factual ICU events und decrease impairment of autobiographic memory, which is associated with PTSD symptoms. In addition, a high level of fear during a traumatic event is a relevant factor in the etiology of PTSD and leads to a fear network according to the model described by Foa et al.51 Acute ICU stress and ICU mood were associated with delirious symptoms such as nightmares, agitation, and hallucination.47\n\nAlthough the evidence regarding the efficacy of haloperidol in the treatment of delirium is controversial, this drug is still widely used.52 Our results suggest that antipsychotic medication during treatment in the ICU prolongs delirium and that delirium-related symptoms presumably trigger future anxiety disorders. Consequently, PTSD affects patients’ mental well-being and mental HRQoL. The hypothesis that patients with H1N1 infection treated with oseltamivir would show a higher risk of PTSD or traumatic memories was not confirmed. Contrary to the preceding results in our study population, none of the patients with PTSD had suffered from previous depression or anxiety disorders according to their lifelong diagnosis at the time of hospital admission extracted from the PDMS. Furthermore, none of these patients reported depression or anxiety disorders in the questionnaire of their current health status at follow-up. This might have been due to the prominent symptoms of PTSD.\n\nIn addition, among survivors of sCAP and ARDS, impairments in objective measurement of exercise capacity (6MWT) corresponded with the patients’ perspective of their limitations in physical functioning as measured by the SF-12. Patients described tiredness and fatigue that significantly affected their activities of daily living.\n\nMoreover, at an average of 4 years after discharge, the patients had various markedly severe cognitive dysfunctions, and our interviews indicated that these dysfunctions might become a future career limitation. The duration of delirium was correlated with diminished cognitive performance, particularly the processing speed of motor skills, which is associated with motor impairments and visuomotor coordination. Disproportionate slowing of the information processing speed is presumably related to cognitive limitations.53 Difficulties in spatial recognition memory as well as short-term or working memory are correlated with the duration of delirium. Because working memory is responsible for planning and carrying out behavior, a decline in working memory leads to difficulties in problem solving and planning. These results confirm previous investigations showing that after hospital discharge, patients experienced a decreased speed of mental performance10,54 and deficits in episodic declarative memory, selective attention, cognitive inhibition, and cognitive flexibility as a function of the duration of delirium. Girard et al.45 discovered cognitive impairments in conjunction with the duration of delirium.\n\nSeveral limitations of our study should be noted. First, the sample size of this study was small and limited by the survival rate and difficulties in participation due to the patients’ existing severe physical impairments. Second, because a main symptom of PTSD is the avoidance of anxiety-inducing or trauma-confronting situations, patients with PTSD avoid frequent re-examination or questioning and therefore also rarely participate in follow-up examinations. Third, because of the weak goodness-of-fit of the regression models, the results must be interpreted cautiously with regard to the influence of the medication on the duration of delirium.\n\nIn summary, in this group of young patients with sCAP, the duration of delirium was associated with long-term mental health and cognitive performance, which in some patients might become a future limitation to career development. Despite the small study group, our findings might be indicative of the disease burden in such patients.55 In addition to medication, nonpharmacological approaches such as nursing, general care provided by medical staff and family caregivers, and a healing environment in the ICU might provide cognitive and emotional support to strengthen any retained adaptive cognitive functioning that the patient possesses.\n\nAbbreviations\nAPACHE II, Acute Physiology and Chronic Health Evaluation II; ARDS, acute respiratory distress syndrome; CAM-ICU, Confusion Assessment Method for the Intensive Care Unit; CANTAB, Cambridge Neuropsychological Test Automated Battery; CAP, community-acquired pneumonia; HRQoL, health-related quality of life; ICU, intensive care unit; IQ, intelligence quotient; MOT, Motor Screening; PDMS, patient data management system; PDS, Post-traumatic Stress Diagnostic Scale; PRM, Pattern Recognition Memory; PRM 1, immediate Pattern Recognition Memory; PRM 2, 20-minute delayed Pattern Recognition Memory; PTSD, post-traumatic stress disorder; PTSS-14, Post-Traumatic Stress Syndrome 14-Questions Inventory; RASS, Richmond Agitation-Sedation Scale; SAPS II, Simplified Acute Physiology Score II; sCAP, severe community-acquired pneumonia; SCWT, Stoop Color Word Test; SF-12, Medical Outcomes Study 12-Item Short Form; SOFA, Sequential Organ Failure Assessment; WST, Wortschatztest (a vocabulary test); VVLT, Visual Verbal Learning Test; 6MWT, 6-Minute Walk Test\n\nDeclaration of conflicting interest\nThe authors declare that there is no conflict of interest.\n\nFunding\nThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\n==== Refs\nReferences\n1 Mandell LA Wunderink RG Anzueto A et al \nInfectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. \nClin Infect Dis \n2007 ; \n44 (Suppl 2 ): S27 –S72 .17278083 \n2 Ewig S Hoffken G Kern WV et al. \n[Management of adult community-acquired pneumonia and prevention - update 2016] . 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[\nCosts of illness and health-related quality of life for community-acquired pneumonia–a systematic review]. \nPneumologie \n2011 ; \n65 : 498 –502 [in German, English Abstract].21512972 \n14 El Moussaoui R Opmeer BC de Borgie CA et al \nLong-term symptom recovery and health-related quality of life in patients with mild-to-moderate-severe community-acquired pneumonia. \nChest \n2006 ; \n130 : 1165 –1172 .17035452 \n15 Mangen MJ Huijts SM Bonten MJ de Wit GA. \nThe impact of community-acquired pneumonia on the health-related quality-of-life in elderly . BMC Infect Dis \n2017 ; \n17 : 208 .28292280 \n16 Luyt CE Combes A Becquemin MH et al \nLong-term outcomes of pandemic 2009 influenza A(H1N1)-associated severe ARDS. \nChest \n2012 ; \n142 : 583 –592 .22948576 \n17 Toovey S Rayner C Prinssen E et al \nAssessment of neuropsychiatric adverse events in influenza patients treated with oseltamivir: a comprehensive review . Drug Saf \n2008 ; \n31 : 1097 –1114 .19026027 \n18 Dubois MJ Bergeron N Dumont M et al \nDelirium in an intensive care unit: a study of risk factors. \nIntensive Care Med \n2001 ; \n27 : 1297 –1304 .11511942 \n19 Marcantonio ER Juarez G Goldman L et al \nThe relationship of postoperative delirium with psychoactive medications. \nJAMA \n1994 ; \n272 : 1518 –1522 .7966844 \n20 Ely EW Siegel MD Inouye SK. \nDelirium in the intensive care unit: an under-recognized syndrome of organ dysfunction. \nSemin Respir Crit Care Med \n2001 ; \n22 : 115 –126 .16088667 \n21 Pandharipande P Cotton BA Shintani A et al \nPrevalence and risk factors for development of delirium in surgical and trauma intensive care unit patients. \nJ Trauma \n2008 ; \n65 : 34 –41 .18580517 \n22 Pandharipande P Ely EW. \nSedative and analgesic medications: risk factors for delirium and sleep disturbances in the critically ill. \nCrit Care Clin \n2006 ;\n22 : 313 –327 , vii.16678002 \n23 Töpfer L Menk M Weber-Carstens S et al \nInfluenza A (H1N1) vs non-H1N1 ARDS: analysis of clinical course. \nJ Crit Care \n2014 ; \n29 : 340 –346 .24508203 \n24 Sessler CN Gosnell MS Grap MJ et al \nThe Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients . 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Anasthesiol Intensivmed Notfallmed Schmerzther \n2010 ; \n45 : 688 –695 [in German, English Abstract].21120766 \n36 Foa EB Cashman L Jaycox L et al \nThe validation of a self-report measure of posttraumatic stress disorder: the posttraumatic diagnostic scale. \nPsychol Assess \n1997 ; \n9 : 445 –451 .\n37 \nATS statement: guidelines for the six-minute walk test . Am J Respir Crit Care Med \n2002 ; \n166 : 111 –117 . DOI: 10.1164/ajrccm.166.1.at110212091180 \n38 Enright PL Sherrill DL. \nReference equations for the six-minute walk in healthy adults. \nAm J Respir Crit Care Med \n1998 ; \n158 : 1384 –1387 .9817683 \n39 Bullinger M. \nGerman translation and psychometric testing of the SF-36 Health Survey: preliminary results from the IQOLA Project. International Quality of Life Assessment. \nSoc Sci Med \n1995 ; \n41 : 1359 –1366 .8560303 \n40 Fraser GL Devlin JW Worby CP et al \nBenzodiazepine versus nonbenzodiazepine-based sedation for mechanically ventilated, critically ill adults: a systematic review and meta-analysis of randomized trials . Crit Care Med \n2013 ; \n41 : S30 –S38 .23989093 \n41 Barr J Fraser GL Puntillo K et al \nClinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. \nCrit Care Med \n2013 ; \n41 : 263 –306 .23269131 \n42 Pisani MA Murphy TE Araujo KL et al \nFactors associated with persistent delirium after intensive care unit admission in an older medical patient population. \nJ Crit Care \n2010 ; \n25 : 540 e1–7.\n43 Granberg Axell AI Malmros CW Bergbom IL et al \nIntensive care unit syndrome/delirium is associated with anemia, drug therapy and duration of ventilation treatment. \nActa Anaesthesiol Scand \n2002 ; \n46 : 726 –731 .12059899 \n44 Jones C Griffiths RD Humphris G Skirrow PM. \nMemory, delusions, and the development of acute posttraumatic stress disorder-related symptoms after intensive care. \nCrit Care Med \n2001 ; \n29 : 573 –580 .11373423 \n45 Girard TD Shintani AK Jackson JC et al \nRisk factors for post-traumatic stress disorder symptoms following critical illness requiring mechanical ventilation: a prospective cohort study . Crit Care \n2007 ; \n11 : R28 .17316452 \n46 Davydow DS Gifford JM Desai SV et al \nPosttraumatic stress disorder in general intensive care unit survivors: a systematic review. \nGen Hosp Psychiatry . 2008 ; \n30 : 421 –434 .18774425 \n47 Wade DM Howell DC Weinman JA et al \nInvestigating risk factors for psychological morbidity three months after intensive care: a prospective cohort study. \nCrit Care . 2012 ; \n16 : R192 .23068129 \n48 Drews T Franck M Radtke FM et al \nPostoperative delirium is an independent risk factor for posttraumatic stress disorder in the elderly patient: a prospective observational study . Eur J Anaesthesiol \n2015 ; \n32 : 147 –151 .24979586 \n49 Ehlers A Clark DM. \nA cognitive model of posttraumatic stress disorder. \nBehav Res Ther \n2000 ; \n38 : 319 –345 .10761279 \n50 Roberts BL Rickard CM Rajbhandari D et al \nFactual memories of ICU: recall at two years post-discharge and comparison with delirium status during ICU admission–a multicentre cohort study. \nJ Clin Nurs \n2007 ; \n16 : 1669 –1677 .17727586 \n51 Foa EB Steketee G Rothbaum BO. \nBehavioural/cognitive conceptualisations of post-traumatic stress disorder . Behav Ther \n1989 ; \n20 : 155 –176 .\n52 Schrijver EJ de Graaf K de Vries OJ et al \nEfficacy and safety of haloperidol for in-hospital delirium prevention and treatment: A systematic review of current evidence. \nEur J Intern Med \n2016 ; \n27 : 14 –23 .26553001 \n53 Salthouse TA. \nThe processing-speed theory of adult age differences in cognition. \nPsychol Rev \n1996 ; \n103 : 403 –428 .8759042 \n54 Hopkins RO Weaver LK Collingridge D et al \nTwo-year cognitive, emotional, and quality-of-life outcomes in acute respiratory distress syndrome. \nAm J Respir Crit Care Med \n2005 ; \n171 : 340 –347 .15542793 \n55 Cassini A Plachouras D Eckmanns T et al \nBurden of six healthcare-associated infections on European population health: estimating incidence-based disability-adjusted life years through a population prevalence-based modelling study. \nPLoS Med \n2016 ; \n13 : e1002150 .27755545\n\n",
"fulltext_license": "CC BY-NC",
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"issue": "46(6)",
"journal": "The Journal of international medical research",
"keywords": "Community-acquired pneumonia; analgesia; delirium; health-related quality of life; long-term outcome; post-traumatic stress disorder",
"medline_ta": "J Int Med Res",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents; D060825:Cognitive Dysfunction; D017714:Community-Acquired Infections; D016638:Critical Illness; D003693:Delirium; D005260:Female; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype; D007251:Influenza, Human; D007362:Intensive Care Units; D008297:Male; D008875:Middle Aged; D011788:Quality of Life; D012128:Respiratory Distress Syndrome; D012307:Risk Factors; D013313:Stress Disorders, Post-Traumatic; D055815:Young Adult",
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"publication_types": "D016428:Journal Article",
"references": "20473145;16088667;26926396;18580517;27755545;20413252;21120766;8759042;23269131;16236739;17727586;12091180;4056765;1574984;22797452;9817683;11373423;12059899;11730446;17042955;18495054;21742223;24979586;11511942;26553001;17278083;15542793;10761279;23068129;8560303;15743277;22948576;16678002;12799407;28292280;19026027;10351930;24508203;19828283;21512972;17316452;7951684;10390379;23989093;12421743;11850334;7966844;22492988;16159057;11445689;18774425;17035452",
"title": "Long-term sequelae of acute respiratory distress syndrome caused by severe community-acquired pneumonia: Delirium-associated cognitive impairment and post-traumatic stress disorder.",
"title_normalized": "long term sequelae of acute respiratory distress syndrome caused by severe community acquired pneumonia delirium associated cognitive impairment and post traumatic stress disorder"
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"abstract": "Low-grade serous ovarian cancer represents a minority of ovarian cancers and has distinctive features from high grade epithelial ovarian cancer. While less aggressive, in advanced stage they can be poorly chemo-responsive and incur a treatment challenge. Next generation sequencing of tumors has allowed for the potential for targeted therapy in cancer treatment, which can allow for avoidance of traditional cytotoxic chemotherapy. We present a case of a 56 year old female with advanced recurrent low grade serous ovarian cancer found to have NRAS mutation who underwent targeted therapy with trametinib with immediate and sustained disease response. We review the response and toxicity experienced by the patient, as well as treatment for her toxicity.",
"affiliations": "Department of Obstetrics & Gynecology and Women's Health, Albert Einstein College of Medicine, Montefiore Medical Center, United States.;Division of Gynecologic Oncology, Department of Obstetrics & Gynecology and Women's Health, Albert Einstein College of Medicine, Montefiore Medical Center, United States.;Division of Gynecologic Oncology, Department of Obstetrics & Gynecology and Women's Health, Albert Einstein College of Medicine, Montefiore Medical Center, United States.",
"authors": "Champer|Miriam|M|;Miller|Devin|D|;Kuo|Dennis Yi-Shin|DY|",
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"doi": "10.1016/j.gore.2019.01.007",
"fulltext": "\n==== Front\nGynecol Oncol RepGynecol Oncol RepGynecologic Oncology Reports2352-5789Elsevier S2352-5789(19)30007-410.1016/j.gore.2019.01.007Case ReportResponse to trametinib in recurrent low-grade serous ovarian cancer with NRAS mutation: A case report Champer Miriam aMiller Devin demiller@montefiore.orgb⁎Kuo Dennis Yi-Shin bca Department of Obstetrics & Gynecology and Women's Health, Albert Einstein College of Medicine, Montefiore Medical Center, United Statesb Division of Gynecologic Oncology, Department of Obstetrics & Gynecology and Women's Health, Albert Einstein College of Medicine, Montefiore Medical Center, United Statesc Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY, United States⁎ Corresponding author at: 1695 Eastchester Road, Suite 601, Bronx, NY 10461. demiller@montefiore.org31 1 2019 5 2019 31 1 2019 28 26 28 16 12 2018 21 1 2019 23 1 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Low-grade serous ovarian cancer represents a minority of ovarian cancers and has distinctive features from high grade epithelial ovarian cancer. While less aggressive, in advanced stage they can be poorly chemo-responsive and incur a treatment challenge. Next generation sequencing of tumors has allowed for the potential for targeted therapy in cancer treatment, which can allow for avoidance of traditional cytotoxic chemotherapy. We present a case of a 56 year old female with advanced recurrent low grade serous ovarian cancer found to have NRAS mutation who underwent targeted therapy with trametinib with immediate and sustained disease response. We review the response and toxicity experienced by the patient, as well as treatment for her toxicity.\n\nHighlights\n• Trametinib was effective in low grade ovarian cancer with NRAS mutation.\n\n• Next generation sequencing of tumors can provide new options.\n\n• Common side effects of trametinib can be managed with dose reduction.\n\n\n\nKeywords\nLow-grade serous ovarian cancerTargeted therapyMEK-inhibitor\n==== Body\n1 Introduction\nLow-grade serous ovarian cancer represents a minority of ovarian cancers. However, it is a distinct entity with unique challenges, and separate treatment guidelines have not yet been developed. Low-grade tumors generally have a better survival rate and are less aggressive than high-grade tumors, but they can result in multiple recurrences and be less responsive to chemotherapeutics (Diaz-Padilla et al., 2012; Plaxe, 2008). Exploring the use of new targeted therapies in these patients could be beneficial toward meeting the treatment challenges of these and other gynecologic cancers.\n\nFoundationOne™ offers next-generation massively parallel DNA sequencing of tumors to provide the opportunity to find unique mutations which may be amenable to treatment with various newer targeted therapies instead of or in addition to traditional cytotoxic chemotherapeutics (Frampton et al., 2013). FoundationOne CDx™ sequencing for solid tumors was approved in November 2017.\n\nWe present a case of a patient with advanced-stage low grade ovarian cancer who recurred after her initial standard treatment regimen. She went on to several different chemotherapies and hormonal therapy. An enlarging perirectal mass was noted while she was on treatment. Next generation sequencing with Foundation medicine allowed us to focus on her treatment to the use of a MEK inhibitor with great response.\n\n2 Case\nThe patient is a 56-year-old para 1 Chinese woman with low grade stage IIIC serous ovarian cancer, who initially underwent debulking surgery consisting of a total abdominal hysterectomy, bilateral salpingo-oophorectomy, pelvic and paraaortic lymph node sampling, omentectomy, and appendectomy. This was followed by three cycles of intravenous/intraperitoneal carboplatinum and paclitaxel which was discontinued due to toxicity, at which point she was transitioned to intravenous carboplatinum and paclitaxel for an additional three cycles. The patient was diagnosed with recurrence via laparoscopic biopsy 3 years later where extensive disease was noted with a vaginal cuff mass, anterior abdominal wall and bowel studding, and nodule near the falciform ligament. The patient then received a course of pegylated doxorubicin and carboplatin. This was complicated by doxorubicin Hand-Foot Syndrome. She was subsequently placed on anastrazole. Hormonal therapy provided her with sustained response. Unfortunately, the patient was again found to have a recurrence in one year later with a rising CA-125 level and growing perirectal mass (Fig. 1).Fig. 1 CT imaging of the pelvis showing a perirectal mass prior to treatment with trametinib.\n\nFig. 1\n\nA tumor specimen from her second surgery was sent for FoundationOne™ testing. This testing revealed NRAS Q61K, DNMT3A R882C, and KMT2C (MLL3) P821L mutations. The NRAS (Neuroblastoma RAS viral oncogene homolog) gene codes for a GTPase that is involved in regulating cell division and has been identified as an oncogene. In ovarian cancer specifically, NRAS mutations have been identified as a distinguishing feature found in low grade serous ovarian cancer such as in this patient, but it was not found in borderline tumors (Emmanuel et al., 2014; Hunter et al., 2015). The NRAS mutation identified in our patient's Foundation report was of particular clinical interest since MEK (mitogen activated protein kinase kinase) inhibitors have been identified as being potentially effective against tumors of this type (Miller et al., 2014).\n\nThe decision was made to attempt treatment with trametinib (Mekinist), which, although not yet approved for treatment of ovarian cancer, has been used to treat several other cancers and has promise to be effective against ovarian cancer with NRAS mutations, such as that found in this patient (Blumenschein Jr et al., 2015; Lugowska et al., 2015). After approval from the manufacturer for compassionate use, the patient started treatment with trametinib 2 mg daily.\n\nApproximately 10 days later, the patient's cancer antigen 125 (CA-125) had decreased from 91.4 U/mL (on 9/28/2017) to 56.7. After three weeks of treatment, however, the patient was admitted for workup of a fever and rash and trametinib was stopped. The rash was described as pruritic, papulopustular over the face, and a pink papular rash over the trunk and extremities. The patient was evaluated by her gynecologic oncologist and consultation from dermatologist. She was treated with doxycycline and steroids. The rash was thought most likely to be an adverse effect of trametinib and less likely a viral exanthem. The patient was noted to have symptomatic relief after initiation of treatment and was discharged on hospital day four.\n\nAfter three weeks without treatment, CA-125 had decreased further to 23.2. The patient was restarted on trametinib at a decreased dose of 1.5 mg, 3 weeks following resolution of the rash. The patient's CA-125 was also found to have normalized at that time. The patient did have a recurrence of the rash, and trametinib was once again stopped after another month on the medication. However, the rash was noted to be much milder than at the time of admission. The patient was instructed to resume taking trametinib at a dose of 1 mg daily, but she did not initially take it because she was concerned about side effects. A CT scan on one month later showed a significant decrease in the size of the patient's perirectal mass from 2.3 cm to 1.1 cm. However, there was also an 8.7 × 5.1 cm new loculated fluid collection noted in the upper abdomen. This collection was sampled and was positive for malignant cells. She agreed to begin trametinib 2 months later, after the resolution of her dermatologic symptoms, at 1 mg daily. A repeat CT scan on 3 months later showed near resolution of the perirectal nodule, and the fluid collection was noted to be stable (Fig. 2). The patient was last seen in the office 2 months later, was doing well, and a plan was made to continue treatment with trametinib. She also continues to follow with dermatology and uses topical treatments for her now mild papulopustular skin lesions.Fig. 2 CT imaging of the pelvis showing near complete resolution of the perirectal mass.\n\nFig. 2\n\n3 Comment\nWe describe the case of a patient with low-grade endometrial cancer that recurred despite initial treatments with surgical cytoreduction and multiple courses of chemotherapeutics. The patient subsequently underwent tumor genetic sequencing and then showed an impressive response to targeted therapy with trametinib. This case report provides further evidence of the potential usefulness of trametinib for patients with low-grade ovarian cancer and the usefulness of tumor sequencing and targeted therapy in general. Other case reports and in vitro studies have shown success in treatment of ovarian cancer with trametinib, some using both trametinib and metformin with synergistic effect for patients with RAS mutations (Mert et al., 2017; Pejovic et al., 2015). A randomized phase II/III clinical trial is currently underway to further study the response to trametinib for patients with recurrent low-grade ovarian cancer (NCT02101788).\n\nAlthough targeted therapies are generally thought of as having less adverse effects than traditional chemotherapies, it is worthwhile to note the significant dermatologic reaction this patient had, which was most likely a side effect of her treatment with trametinib. Known common side effects of trametinib include diarrhea, serous central retinopathy, and rash including the following types dermatologic findings as reported in a phase 1 dose-escalation trial: erythematous rash, follicular rash, generalized rash, macular rash, maculopapular rash, pruritic rash, pustular rash, seborrhoeic dermatitis, and skin exfoliation (Infante et al., 2012). Dermatitis acneiform involving the face and trunk was noted to be among the most common findings, often developing within 4 weeks of treatment as in our patient. Additionally, the dermatologic side effects were noted to be dose-related. For our patient, her dermatologic side effects indeed seemed to subside after a reduction in trametinib dose.\n\nAlthough low-grade serous epithelial ovarian cancer represents less than 10% of all ovarian cancers, it can be a challenging entity to treat. This case shows an excellent response to a MEK-inhibitor for an advanced-stage recurrent low-grade cancer that recurred after traditional chemotherapy. We feel that this case highlights a promising treatment for appropriate low-grade lesions and the effectiveness and rising importance of personalized targeted therapy in medicine.\n\nConflict of interest statement\nThe authors report no conflict of interest relevant to this manuscript\n\nAuthorship contribution statement\nMiriam Champer contributed the majority of original writing to the introduction and case. Devin Miller contributed the majority of the discussion, edits, and figures. Dennis Kuo contributed significantly to the editing and preparation of the manuscript as well as mentor for the paper.\n==== Refs\nReferences\nBlumenschein G.R. Jr. Smit E.F. Planchard D. Kim D.-W. Cadranel J. De Pas T. A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small-cell lung cancer (NSCLC)† Ann. Oncol. 26 5 2015 894 901 May 25722381 \nDiaz-Padilla I. Malpica A.L. Minig L. Chiva L.M. Gershenson D.M. Gonzalez-Martin A. Ovarian low-grade serous carcinoma: a comprehensive update Gynecol. Oncol. 126 2 2012 279 285 Aug 22555104 \nEmmanuel C. Chiew Y.-E. George J. Etemadmoghadam D. Anglesio M.S. Sharma R. Genomic classification of serous ovarian cancer with adjacent borderline differentiates RAS pathway and TP53-mutant tumors and identifies NRAS as an oncogenic driver Clin. Cancer Res. 20 24 2014 6618 6630 Dec 15 25316818 \nFrampton G.M. Fichtenholtz A. Otto G.A. Wang K. Downing S.R. He J. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing Nat. Biotechnol. 31 11 2013 1023 1031 Nov 24142049 \nHunter S.M. Anglesio M.S. Ryland G.L. Sharma R. Chiew Y.-E. Rowley S.M. Molecular profiling of low grade serous ovarian tumours identifies novel candidate driver genes Oncotarget 6 35 2015 37663 37677 Nov 10 26506417 \nInfante J.R. Fecher L.A. Falchook G.S. Nallapareddy S. Gordon M.S. Becerra C. Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial Lancet. Oncol. 13 8 2012 773 781 Aug 22805291 \nLugowska I. Koseła-Paterczyk H. Kozak K. Rutkowski P. Trametinib: a MEK inhibitor for management of metastatic melanoma Onco. Targets. Ther. 8 2015 2251 2259 Aug 25 26347206 \nMert I. Chhina J. Allo G. Dai J. Seward S. Carey M.S. Synergistic effect of MEK inhibitor and metformin combination in low grade serous ovarian cancer Gynecol. Oncol. 146 2 2017 319 326 Aug 28545687 \nMiller C.R. Oliver K.E. Farley J.H. MEK1/2 inhibitors in the treatment of gynecologic malignancies Gynecol. Oncol. 133 1 2014 128 137 Apr 24434059 \nPejovic T. Corless C.L. Taylor M. Allen A.J. Fung A. Beer T.M. Case report significant response to trametinib in a woman with recurrent KRAS-mutated low-grade serous carcinoma of the ovary-a case report Am. J. Clin. Exp. Obstet. Gynecol. 2 3 2015 140 143 \nPlaxe S.C. Epidemiology of low-grade serous ovarian cancer Am. J. Obstet. Gynecol. 198 4 2008 Apr. 459.e1–8; discussion 459.e8–9\n\n",
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"issn_linking": "2352-5789",
"issue": "28()",
"journal": "Gynecologic oncology reports",
"keywords": "Low-grade serous ovarian cancer; MEK-inhibitor; Targeted therapy",
"medline_ta": "Gynecol Oncol Rep",
"mesh_terms": null,
"nlm_unique_id": "101652231",
"other_id": null,
"pages": "26-28",
"pmc": null,
"pmid": "30809568",
"pubdate": "2019-05",
"publication_types": "D002363:Case Reports",
"references": "18395040;22555104;22805291;24142049;24434059;25316818;25722381;26347206;26506417;28545687",
"title": "Response to trametinib in recurrent low-grade serous ovarian cancer with NRAS mutation: A case report.",
"title_normalized": "response to trametinib in recurrent low grade serous ovarian cancer with nras mutation a case report"
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