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"abstract": "Cognitive deficits are known to occur after brain injury, be it perinatal injury, traumatic brain injury (TBI), or any other type of insult to the brain. The problem may be compounded if psychiatric illness is present in addition to the brain injury because the illness itself or the psychotropic medications used in its management may lead to worsening of cognitive functioning. We present the case of a patient who presented to the hospital with symptoms suggestive of mania with psychotic features that had started after a recent TBI, with the brain scan also revealing the presence of a preexisting perinatal birth injury. When the patient recovered from the psychiatric symptoms, he still appeared to have memory problems that improved with the use of add-on memantine, an N-methyl-D-aspartate receptor antagonist. To date, there is some literature supporting the off-label use of memantine as a cognitive enhancer in patients with TBIs and other psychiatric illnesses, such as bipolar disorder.",
"affiliations": null,
"authors": "Das|Aparna|A|;Brasseux|Stephen|S|",
"chemical_list": "D008559:Memantine",
"country": "United States",
"delete": false,
"doi": "10.1097/PRA.0000000000000576",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1527-4160",
"issue": "27(5)",
"journal": "Journal of psychiatric practice",
"keywords": null,
"medline_ta": "J Psychiatr Pract",
"mesh_terms": "D001720:Birth Injuries; D000070642:Brain Injuries, Traumatic; D006801:Humans; D008297:Male; D000087122:Mania; D008559:Memantine; D008569:Memory Disorders",
"nlm_unique_id": "100901141",
"other_id": null,
"pages": "390-394",
"pmc": null,
"pmid": "34529606",
"pubdate": "2021-09-16",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Improvement in Memory Deficits With Memantine in Mania Secondary to Traumatic Brain Injury and Preexisting Perinatal Birth Injury.",
"title_normalized": "improvement in memory deficits with memantine in mania secondary to traumatic brain injury and preexisting perinatal birth injury"
} | [
{
"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2021-26704",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MEMANTINE"
},
"drugadditional"... |
{
"abstract": "Antituberculosis drug-related liver injury (ATLI) is the most prevalent hepatotoxicity in many countries. Whether monitoring liver tests is beneficial to prevent this potentially grave adverse drug reaction (ADR) is open to debate. The Taiwan Drug Relief Foundation (TDRF) was established by the Taiwan Food and Drug Administration to collect severe cases of ADR and carry out drug injury relief tasks. Our intention was to explore the role of monitoring liver tests in the susceptibility and severity of ATLI from the database of this foundation. All cases of suspected ATLI collected by the TDRF from 1999 to 2012 were reviewed. The basic demographic data, clinical course, and laboratory data of these patients were analyzed. A total of 57 cases with severe ATLI were verified and enrolled into this study. There was a high mortality (71.9%) in this cohort. Twenty-four cases (42.1%) were chronic viral hepatitis B carriers, who had higher baseline serum aminotransferase level than noncarriers. The patients without monitoring liver tests had higher peak serum alanine aminotransferase, bilirubin levels, and mortality (adjusted odds ratio, 8.87; 95% confidence interval = 1.32-59.41; p = 0.024) than those with monitoring liver tests. In conclusion, patients with severe ATLI whose records were collected by the TDRF have a high mortality. Patients without follow-up monitoring liver tests had more severe liver injuries and higher mortality than those with monitoring live tests. To alleviate this potentially grave ADR, checking of liver biochemical tests prior to antituberculosis treatment and periodic monitoring of these tests thereafter are highly suggested.",
"affiliations": "Taiwan Drug Relief Foundation, Taipei, Taiwan.;Taiwan Drug Relief Foundation, Taipei, Taiwan.;Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; National Yang-Ming University School of Medicine, Taipei, Taiwan. Electronic address: yshuang@vghtpe.gov.tw.",
"authors": "Chih|Lan-Hui|LH|;On|Angela W F|AWF|;Huang|Yi-Shin|YS|",
"chemical_list": null,
"country": "China (Republic : 1949- )",
"delete": false,
"doi": "10.1016/j.jfda.2013.10.001",
"fulltext": "\n==== Front\nJ Food Drug Anal\nJ Food Drug Anal\nJournal of Food and Drug Analysis\n1021-9498\n2224-6614\nTaiwan Food and Drug Administration\n\n28911426\n10.1016/j.jfda.2013.10.001\njfda-22-03-356\nOriginal Article\nCorrelation of antituberculosis drug-related liver injury and liver function monitoring: A 12-year experience of the Taiwan Drug Relief Foundation\nChih Lan-Hui a\nOn Angela W.F. a\nHuang Yi-Shin bc*\na Taiwan Drug Relief Foundation, Taipei, Taiwan\nb Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan\nc National Yang-Ming University School of Medicine, Taipei, Taiwan\n* Corresponding author. Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei 11217, Taiwan. E-mail address: yshuang@vghtpe.gov.tw (Y.-S. Huang).\n2014\n19 12 2013\n22 3 356362\n22 7 2013\n11 10 2013\n16 10 2013\n© 2014 Taiwan Food and Drug Administration\n2014\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC-BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nAntituberculosis drug-related liver injury (ATLI) is the most prevalent hepatotoxicity in many countries. Whether monitoring liver tests is beneficial to prevent this potentially grave adverse drug reaction (ADR) is open to debate. The Taiwan Drug Relief Foundation (TDRF) was established by the Taiwan Food and Drug Administration to collect severe cases of ADR and carry out drug injury relief tasks. Our intention was to explore the role of monitoring liver tests in the susceptibility and severity of ATLI from the database of this foundation. All cases of suspected ATLI collected by the TDRF from 1999 to 2012 were reviewed. The basic demographic data, clinical course, and laboratory data of these patients were analyzed. A total of 57 cases with severe ATLI were verified and enrolled into this study. There was a high mortality (71.9%) in this cohort. Twenty-four cases (42.1%) were chronic viral hepatitis B carriers, who had higher baseline serum aminotransferase level than noncarriers. The patients without monitoring liver tests had higher peak serum alanine aminotransferase, bilirubin levels, and mortality (adjusted odds ratio, 8.87; 95% confidence interval = 1.32–59.41; p = 0.024) than those with monitoring liver tests. In conclusion, patients with severe ATLI whose records were collected by the TDRF have a high mortality. Patients without follow-up monitoring liver tests had more severe liver injuries and higher mortality than those with monitoring live tests. To alleviate this potentially grave ADR, checking of liver biochemical tests prior to antituberculosis treatment and periodic monitoring of these tests thereafter are highly suggested.\n\nAdverse drug reaction\nAntituberculosis drug\nDrug-induced liver injury\nLiver function test\nTaiwan Food and Drug Administration, Department of Health, TaiwanThis work was supported by the Taiwan Food and Drug Administration, Department of Health, Taiwan.\n==== Body\npmc1. Introduction\n\nDrug-induced liver injury (DILI) is the major cause of acute liver injury in the United States and in many other countries [1,2]. It is also the most common single reason for withdrawing an approved drug in the United States. Many strategies and endeavors have been launched to prevent this inevitable adverse drug reaction (ADR) preclinically and postmarkedly [1]. However, progress in this field seems slow. More efforts should be exerted to mitigate this potentially grave ADR.\n\nTuberculosis (TB) has recently resurged as a hazardous threat to worldwide public health, which is caused by the growing prevalence of drug-resistant mycobacterium TB strains and the increasing number of acquired immunodeficiency syndrome (AIDS) patients [3]. Regimens containing isoniazid, rifampicin, and pyrazinamide are traditionally used as the first line of therapy for TB. However, hepatotoxicity frequently develops in patients receiving these drugs [4–10]. Antituberculosis drug-related liver injury (ATLI) is the most prevalent DILI in Taiwan and many other countries [4–7]. Chronic hepatitis B infection, which was reported to be a risk factor of ATLI, is also endemic in Taiwan. To prevent this DILI, regular monitoring liver tests was suggested by the Center for Disease Control (CDC), Taiwan, for all TB patients [8]. However, this is only recommended to special high-risk groups, such as patients with chronic viral infection, AIDS, and chronic ethanol consumption, as well as pregnant women in the United States [9]. Whether regular monitoring liver tests is beneficial to prevent ATLI is open to debate.\n\nThe Taiwan Drug Relief Foundation (TDRF) has been established by the Taiwan Food and Drug Administration, Department of Health, Taiwan, as a nonprofit organization designated to carry out drug injury relief tasks since 1999 [11]. The premises on which this organization is based are manifold. The core activities of the foundation include issuance of relief payments to the approved claimants, analysis of the causal relationship between injuries and suspected drugs, and research or survey for medication safety-related issues. There have been more than 1,000 applicants for compensation to date. Overall, the top drugs for relief payout in DILI were anti-TB agents [12].\n\nTo our knowledge, no study has been conducted to check on the value of monitoring liver tests in identifying grave DILI induced by anti-TB drugs. In addition, most of the previous studies concerning the risk factors of ATLI are retrospective case-control studies or prospective cohort study based on one or a few hospitals or regions [4–10]. The degree of liver injury in these studies ranged from mild to severe. Most of the patients with mild to moderate ATLI may have an “adaptation” to anti-TB agents, which manifests with normalization of liver tests even with continuation of anti-TB treatment [10]. In contrast, the severe form of ATLI may have ominous outcomes despite discontinuing all drugs for TB [4–10]. Therefore, focusing on the severe form of ATLI is a cost benefit in clinical practice and pharmacovigilance. Based on the applicants’ database of TDRF, we tried to explore the role of monitoring liver tests in the susceptibility and severity of ATLI.\n\n2. Methods\n\nThose who experienced serious ADR resulting in hospitalization, disability, or death can apply to the TDRF for economic relief. The medical records of all applicants to the TDRF were first scrutinized by two experts, and then reviewed by the board committee sponsored by the Department of Health of Taiwan. All applications with suspected ATLI from 1999 to May 2012 were enrolled into this study.\n\nThe inclusion criteria of ATLI were: (1) an increase in serum alanine aminotransferase (ALT) level greater than twice the upper limit of normal value (ULN) during treatment, according to the criteria established by the International Consensus Meeting [13]; (2) a Roussel Uclaf Causality Assessment Method score greater than 5 (when classified as “probable” or “highly probable” drug-induced hepatitis), as derived from the International Consensus Meeting [14].\n\nPatients who had any of the following conditions were excluded from the study: (1) positive serum IgM antibody to hepatitis A virus when ALT or aspartate aminotransferase elevated; (2) other hepatic or systemic diseases that may cause liver dysfunction, such as alcoholic hepatitis, autoimmune hepatitis, primary biliary cirrhosis, Wilson’s disease, hemochromatosis, stones or tumors of liver and biliary tract, shock, hypoxia, heart failure, and respiratory failure; (3) elevation of serum ALT level less than two times the ULN during anti-TB treatment; (4) insufficient data for assessment.\n\nFor evaluating the influence of viral hepatitis infection status to ATLI, hepatitis B and C carriers were enrolled into the analysis. However, the included patients must meet the aforementioned inclusion and exclusion criteria. The definition of hepatitis B and C carriers was positive serum hepatitis B surface antigen or antihepatitis C antibody for more than 6 months.\n\nThe latency of a liver injury was regarded as time of drug administration to first abnormal liver tests. To explore the role of monitoring liver tests, patients were divided into two groups. The first group was the monitoring group, which included the patients who had liver biochemical tests at least two times in the first 2 months of anti-TB treatment, or had liver tests at least twice in the 1st month of treatment, if the ATLI occurred in the 1st month. The second group is the nonmonitoring group, which included those without liver biochemical tests after the anti-TB treatment until the occurrence of overt hepatitis. Those patients who had undergone only one-time liver tests after the anti-TB treatment were enrolled into the nonmonitoring group, because one-time liver tests were deemed not sufficient enough, and checking of liver tests in the 2nd, 4th, and 8th weeks after treatment was recommended by the TB guidelines of the Taiwan CDC [8].\n\nThis study was approved by the Institutional Review Board of Taipei Veterans General Hospital, and is in accordance with the Helsinki Declaration of 1975.\n\nThe Mann–Whitney U test and Fisher’s exact test were used to compare the variables between groups as appropriate. The multivariate logistic regression test was applied to evaluate the risk factor of mortality (SPSS 19.0 for Windows; SPSS Inc., Chicago, IL, USA). A two-tailed p value below 0.05 was considered statistically significant.\n\n3. Results\n\nFrom 1999 to May 2012, there have been 1596 applicants for drug relief in Taiwan. The most frequent ADR was skin disorders, followed by immune system disorders and DILI. Among the 125 cases diagnosed as DILI, the leading culprit drugs were anti-TB agents (57 cases, or 45.6% of all DILI). The clinical characteristics of these 57 patients are shown in Table 1. The male/female ratio of these patients was 3.75 (78.9% vs. 21.1%, Table 2). The patients were relatively old (60.8±16.6 years). Forty-three (75.4%) patients had normal liver biochemical tests prior to the anti-TB treatment. Fifty-two cases (91.2%) had peak serum ALT greater than 5 ULN, and 41 cases (71.9%) died of hepatic failure. In addition, 24 (42.1%) cases had chronic viral hepatitis B infection and three with chronic hepatitis C infection. In hepatitis B virus (HBV) carriers, 12 patients were positive for HBV DNA when ATLI was diagnosed.\n\nHBV carriers had significantly higher baseline ALT levels and longer latency than the noncarriers (p < 0.01, Table 2). However, there was no significant difference in terms of age, sex, peak serum ALT, and bilirubin levels between these two groups. Although HBV carriers had a trend of higher mortality than noncarriers (83.3% vs. 63.6%), the rate did not reach statistical significance.\n\nThe comparison between monitoring liver tests group and nonmonitoring group is shown in Table 3. There was no statistical discrepancy in terms of sex, hepatitis virus B infection status, baseline ALT levels, and latency between the two groups. Of note, the nonmonitoring group had higher serum peak ALT and bilirubin levels, and younger age, compared with those in the monitoring group. After adjusting for possible risk factors, nonmonitoring liver test was the only risk factor of mortality in patients with severe ATLI (odds ratio, 8.87; 95% confidence interval, 1.32–59.41; p = 0.024; Table 4).\n\n4. Discussion\n\nATLI is the most prevalent DILI in many countries [4–10]. It may be serious and may have a fatal outcome. The present national 12 years’ cases analysis in Taiwan revealed that severe ATLI had a very high mortality, and patients without monitoring liver tests had more severe liver injuries and poorer outcomes than those with monitoring liver tests.\n\nPrediction or early detection of the high risk patients with ATLI is always a challenging issue to clinicians, pharmacists, and all healthcare providers. One of the approaches used is the application of pharmacogenetics or pharmacogenomics to correlate the genetic polymorphisms of drug-metabolizing enzymes and ATLI [1,7]. Our previous studies have shown that genetic polymorphisms of N-acetyltransferase 2, cytochrome P450 2E1, glutathione S-transferase M1, and manganese superoxide dismutase (MnSOD, SOD2) may be associated with higher risks of ATLI [15–17]. However, these types of genetic biomarkers warrant further large-scale international studies to validate their real role in the early identification of high-risk groups. Furthermore, these pharmacogenetic assays are still costly and inconvenient for clinical application. We therefore considered that monitoring liver tests may be a simple approach for the early detection and prevention of ATLI.\n\nRegular monitoring liver tests was highly suggested by the Taiwan CDC for all TB patients, which included assaying liver biochemical tests prior to anti-TB treatment and at the 2nd, 4th, and 8th weeks after treatment [8]. Thereafter, the necessity and frequency of monitoring will depend on the status of chronic viral hepatitis infection and clinical condition of the patients. In the United States, monitoring of liver tests is recommended for high-risk groups only, such as patients with chronic viral hepatitis infection, AIDS, and chronic ethanol consumption, and pregnant women [9]. This is attributed to the relatively low incidence of ATLI in the United States, compared with that Taiwan and many other countries. Hepatitis B infection, which is a risk factor for the susceptibility and severity of ATLI in previous reports, is prevalent in Taiwan [4–6]. In the present study, nearly half of the patients were HBV carriers. Thus, the consensus was that patients with chronic viral hepatitis should be followed up with liver tests regularly. However, more than half of our patients were not HBV carriers. Moreover, around 15% patients without hepatitis B or C infection had ATLI in our previous studies [15,16]. Therefore, whether or not the patient is a hepatitis B carrier, the incidence of ATLI is relatively high in Taiwan and many other countries. Because it is difficult to predict who may have grave ATLI, we suggested regular monitoring of liver tests for all patients receiving anti-TB treatment. The present study provides supporting evidence to this recommendation. However, the cost benefit of this approach and the frequency of monitoring liver tests are still debatable. Although further large-scale case-control prospective studies are warranted to elucidate the real role of monitoring, regular assessment of liver tests remains a simple way to ensure the early detection of severe ATLI.\n\nIn this study, hepatitis B carriers had higher baseline ALT than noncarriers (35.8 ± 18.0 U/L vs. 24.8 ± 24.6 U/L, p = 0.001), which concurs with our expectation. Although hepatitis B carriers had higher mortality (83.3% vs. 63.6%), higher mean peak serum ALT (1,458 U/L vs. 1,192 U/L), and peak serum bilirubin (23.8 mg/dL vs. 22.0 mg/dL) than noncarriers, the rates did not reach statistical significance. The first explanation is that all the patients enrolled in this study had severe DILI, and it may be difficult to further detect the subtle differences of severity between hepatitis B carriers and noncarriers. The second possibility is the limited number of cases included in this study. However, it is not easy and rather time-consuming to collect the verified nationwide severe cases with ATLI in 12 years.\n\nAged patients have been reported to be more vulnerable to anti-TB drugs [5,8–10,15,16]. The patients in our study were relatively old (60.8 ± 16.6 years), which is consistent with previous reports [5,15,16]. It is noticeable that the patients with monitoring were older than those without monitoring in this study (71.4 vs. 58.6 years, p = 0.02). It is probable that healthcare providers may pay more attention to the elderly and evaluating their liver tests more frequently.\n\nOnly the severe cases were allowed to apply for drug relief compensation, which explains why this study cohort had a high mortality. The incidence of severe liver injury induced by anti-TB drugs is about 1% in the general population, most of whom may have jaundice [10]. Based on the estimation of Hy’s law [18], at least 10% of the severe cases have a dismal outcome or mortality, which is lower than the 72% mortality noted in this study. We believed that many of the severe cases with DILI were not reported to our foundation, and only those involved in very severe or mortality cases may have been motivated to apply for drug relief. Thus, it should be noted that the enrolled patients in this study only represent the most severe of cases, which comprise our target group as part of our efforts to mitigate mortality.\n\nFurthermore, because of the spontaneous nature of these reports, the data from the TDRF in this study cannot be used as an incidence study. Extrapolating the results in this study to the general population is limited and warrants further justification.\n\nIn conclusion, patients with severe ATLI by TDRF have a high mortality rate. Patients without monitoring liver tests have more severe liver injuries and higher mortality than those with monitoring liver tests. To mitigate this ominous ADR, checking of liver tests prior to anti-TB treatment, and regular monitoring of liver function thereafter are highly recommended.\n\nAcknowledgments\n\nThis work was supported by the Taiwan Food and Drug Administration, Department of Health, Taiwan.\n\nTable 1 Clinical characteristics of patients with severe ATLI.\n\nPatient no.\tAge/sex\tATT combination\tLatency of LFI (wk)\tVirus inf./type\tSerum examination\tLFT before treatment\tLFT after treatment\tJaundice\t\n1a\t71/M\tR/I/P/E\t2\tND\tND\tND\t>5 times\t+\t\n2a\t54/F\tR/I/P/E\t3.8\t+/B\tND\tND\t>5 times\t+\t\n3a\t60/M\tR/I/P\t1.4\t+/B\tHBsAg(+)\tNormal\t>5 times\t+\t\n4a\t59/F\tR/I/P/E\t14.3\t+/B\tHBsAg(+)\tNormal\t>5 times\t+\t\n5a\t55/M\tR/I/P/E\t6\tND\tND\tNormal\t>5 times\t+\t\n6\t68/F\tR/I/P/E\t8\t+/C\tHBsAg(−)\nHCV Ab(+)\tNormal\t>5 times\t+\t\n7a\t41/M\tR/I/P/E\t12\t+/B\tHBsAg(+)\tND\t>5 times\t+\t\n8a,b\t62/M\tR/I/P/E\t20\t+/B\tHBsAg(+)\tND\t>5 times\t+\t\n9\t25/F\tR/I/P/E\t6\t−\tHBsAg(−)\nAnti-HCV(−)\tNormal\t>5 times\t+\t\n10a\t44/M\tR/I/P/E\t3\t−\tHBsAg(−)\nHCV Ab(−)\tNormal\t>5 times\t+\t\n11a\t57/M\tR/I/P/E\t5\t−\tHBsAg(−)\nAnti-HCV(−)\tNormal\t>5 times\t+\t\n12a\t51/F\tR/I/P/E\t22\t−\tHBsAg(−)\nAnti-HCV(−)\tNormal\t>5 times\t+\t\n13\t56/M\tR/I/P/E\t6\t−\tHBsAg(−)\nAnti-HCV(−)\tNormal\t>5 times\t+\t\n14a\t21/M\tR/I/P/E\t5\t−\tHBsAg(−)\nAnti-HCV(−)\tNormal\t>5 times\t+\t\n15\t69/F\tR/I/P/E\t16\t−\tAnti-HBs Ab(+)\nAnti-HBc Ab(+)\tNormal\t>5 times\t+\t\n16a\t82/M\tR/I/P/E\t3\t−\tHBsAg(−)\nAnti-HCV(−)\tNormal\t>2 times and <3 times\t+\t\n17a,b\t71/M\tR/I/P/E\t8\t+/B\tHBeAg(−)\nAnti-HBe(+)\tNormal\t>5 times\t+\t\n18a\t63/F\tR/I/P/E\t6.4\t−\tHBsAg(−)\nHBeAg(−)\nAnti-HCV(−)\tNormal\t>5 times\t+\t\n19a\t76/M\tR/I/P/E\t6.1\t−\tHBsAg(−)\nAnti-HCV(−)\tNormal\t>5 times\t+\t\n20a\t75/M\tR/I/P/E\t3\t−\tHBsAg(−)\nAnti-HCV(−)\tNormal\t>5 times\t+\t\n21b\t55/M\tR/I/P/E\t13\t+/B\tHBsAg(+)\nAnti-HCV(−)\tNormal\t>5 times\t+\t\n22a,b\t57/M\tR/I/P/E\t21.3\t+/B\tHBsAg(+)\nAnti-HBs(−)\nAnti-HBC IgM(−)\t<2 times normal\t>5 times\t+\t\n23a,b\t48/M\tR/I/P/E\t2\t+/B\tHBsAg(+)\nAnti-HCV(−)\tNormal\t>5 times\t+\t\n24a\t76/M\tR/I/P/E\t2\t+/C\tAnti-HCV(+)\t>2 times and <3 times\t>3 times and <5 times\t+\t\n25a\t54/M\tR/I/P/E\t5\t−\tHBsAg(−)\nHCV Ab(−)\tNormal\t>5 times\t+\t\n26a\t65/M\tR/I/P/E\t2\t−\tHBsAg(−)\nHCV Ab(−)\tNormal\t>5 times\t+\t\n27a,b\t52/M\tR/I/P/E\t8\t+/B\tHBsAg(+)\nAnti-HCV(−)\tNormal\t>5 times\t+\t\n28\t34/M\tR/I/P/E\t10\t−\tHBsAg(−)\t<2 times normal\t>5 times\t+\t\n29a,b\t51/M\tR/I/P/E\t10\t+/B\tHBsAg(+)\nAnti-HBc(+)\tNormal\t>5 times\t+\t\n30a\t80/M\tR/I/P/E\t7\t−\tHBsAg(−)\nAnti-HCV(−)\tNormal\t>5 times\t+\t\n31a\t46/M\tR/I/E\t4\t+/B\tHBsAg(+)\tNormal\t>2 times and <3 times\t+\t\n32\t72/M\tR/I/E\t1.2\tND\tND\tNormal\t>5 times\t+\t\n33a\t68/M\tR/I/E\t20\t+/B\tHBsAg(+)\nHBeAg(−)\nAnti-HCV(−)\tNormal\t>5 times\t+\t\n34a,b\t62/M\tR/I/P/E\t16\t+/B\tHBsAg(+)\nHCV-Ab(−)\tNormal\t>5 times\t+\t\n35a\t67/M\tR/I/P/E\t6\t−\tHBsAg(−)\nAnti-HCV(−)\t<2 times normal\t>5 times\t+\t\n36a,b\t79/M\tR/I/P/E\t4\t+/B\tHBsAg(+)\nHBeAg(−)\nHCV Ab(−)\t<2 times normal\t>3 times and <5 times\t+\t\n37a\t53/M\tR/I/P/E\t0.86\t−\tHBsAg(−)\nAnti-HCV(−)\tNormal\t>5 times\t+\t\n38\t61/M\tR/I/P/E\t1.4\t−\tHBsAg(−)\nHCV Ab(−)\tNormal\t>2 times and <3 times\t−\t\n39a,b\t48/M\tR/I/P/E\t13\t+/B\tHBsAg(+)\nAnti-HCV(−)\tNormal\t>5 times\t+\t\n40\t49/M\tR/I/P/E\t25\t+/B\tHBsAg(+)\nAnti-HCV(−)\nHBeAg(−)\tNormal\t>3 times and <5 times\t+\t\n41a\t59/F\tR/I/P/E\t15\t+/B\tHBsAg(+)\nHBeAg(−)\nHBeAb(−)\tNormal\t>5 times\t+\t\n42a,b\t83/M\tR/I/P/E\t10\t+/B\tHBsAg(+)\nHCV-Ab(−)\tNormal\t>5 times\t+\t\n43a,b\t79/M\tR/I/E\t5\t+/B\tHBsAg(+)\nHCV-Ab(−)\tNormal\t>5 times\t+\t\n44a\t79/M\tR/I/P/E\t6\t−\tHBsAg(−)\nAnti-HCV(−)\tNormal\t>5 times\t+\t\n45\t85/M\tR/I/P/E\t4\t−\tHBsAg(−)\nAnti-HCV(−)\tNormal\t>3 times and <5 times\t−\t\n46a\t81/M\tR/I/E\t4\t+/B\tHBsAg(+)\nHCV-Ab(−)\t<2 times normal\t<2 times normal\t+\t\n47\t4/F\tI\t12\t−\tHBsAg(−)\nHCV Ab(−)\tND\t>5 times\t+\t\n48\t74/M\tR/I/P/E\t5\t−\tHBsAg(−)\nAnti-HCV(−)\t<2 times normal\t>5 times\t+\t\n49a\t67/M\tR/I/P/E\t12.4\t+/B\tHBsAg(+)\nHBeAg(−)\t<2 times normal\t>5 times\t+\t\n50\t79/F\tR/I/P\t18.4\t+/B, C\tHBsAg(+)\nAnti-HCV(+)\tND\t>2 times and <3 times\t+\t\n51a\t83/M\tR/I/P/E\t7.3\t−\tHBsAg(−)\nAnti-HCV(−)\tNormal\t>5 times\t+\t\n52a\t50/M\tR/I/P/E\t5\t−\tHBsAg(−)\tNormal\t>5 times\t+\t\n53\t42/F\tR/I/P/E\t5.1\t−\tHBsAg(−)\nAnti-HCV(−)\tNormal\t>5 times\t+\t\n54a\t71/M\tR/I/P/E\t4\t−\tHBsAg(−)\nAnti-HCV(−)\tNormal\t>5 times\t+\t\n55\t52/F\tR/I/P/E\t6.6\t−\tHBsAg(−)\nAnti-HCV(−)\tNormal\t>5 times\t+\t\n56a\t83/M\tR/I/P/E\t1\t−\tHBsAg(−)\nAnti-HCV(−)\tNormal\t>5 times\t+\t\n57\t61/M\tR/I/P/E\t17.6\t+/B\tHBsAg(+)\nHBeAg(−)\tNormal\t>5 times\t+\t\nATLI = antituberculosis drug-related liver injury; ATT = antituberculosis treatment; E = ethambutol; I = isoniazid; LFI = liver function impairment; LFT = liver function test; ND = no available data; P = pyrazinamide; R = rifampicin.\n\na These patients died.\n\nb HBV-DBA viral load: ≥100,000 copies/mL.\n\nTable 2 Characteristics of chronic hepatitis B carriers and noncarriers with severe ATLI.\n\n\tAll patients (n = 57)\tHepatitis B carriers (n = 24)\tNoncarriers (n = 33)\t\nMale/Female\t45/12\t20/4\t25/8\t\nAge (y)a\t60.8 ± 16.6\t62.1 ± 12.1\t59.1 ± 20.5\t\nBaseline ALT (U/L)a\t29.4 ± 22.5\t35.8 ± 18.0\t24.8 ± 24.6†\t\nAfter treatment\t\t\t\t\nLatency (wk)a\t8.2 ± 6.2\t11.4 ± 6.8\t5.8 ± 4.4†\t\nPeak serum ALT (U/L)a\t1304.5 ± 968.3\t1458.8 ± 1188.1\t1192.3 ± 771.6\t\nPeak serum bilirubin (mg/dL)a\t22.8 ± 12.4\t23.8 ± 11.2\t22.0 ± 13.4\t\nMortality\t41 (71.9%)\t20 (83.3%)\t21 (63.6%)\t\n† p < 0.01 as compared with hepatitis B carriers.\n\nALT = alanine aminotransferase; ATLI = antituberculosis drug-related liver injury.\n\na Mean ± standard deviation.\n\nTable 3 Comparison between monitoring group and nonmonitoring group in patients with severe ATLI.\n\n\tMonitoring (n = 10)\tNonmonitoring (n = 47)\tp\t\nMale/female\t7/3\t38/9\t0.445\t\nAge (y)a\t71.4 ± 11.1\t58.6 ± 16.8\t0.020\t\nHepatitis B carrier\t6 (60.0%)\t18 (38.3%)\t0.441\t\nBaseline serum ALT(U/L)a\t34.3 ± 22.1\t28.3 ± 22.8\t0.230\t\nAfter treatment\t\t\t\t\nLatency (wk)a\t9.6 ± 7.4\t7.9 ± 5.9\t0.705\t\nPeak serum ALT (U/L)a\t702.4 ± 614.9\t1432.6 ± 985.8\t0.012\t\nPeak serum bilirubin (mg/dL)a\t15.1 ± 9.4\t24.5 ± 12.4\t0.019\t\nMortality\t5 (50%)\t36 (76.6%)\t0.124\t\nALT = alanine aminotransferase; ATLI = antituberculosis drug-related liver injury.\n\na Mean ± standard deviation.\n\nTable 4 Multivariate analysis of risk factors for mortality in severe ATLI.\n\nRisk factors\tOdds ratio\t95% CI\tp\t\nNonmonitoring\t8.87\t1.32–59.41\t0.024\t\nHepatitis B carrier\t4.13\t0.89–19.10\t0.070\t\nSex\t3.71\t0.77–17.84\t0.102\t\nAge\t1.04\t0.99–1.09\t0.117\t\nATLI = antituberculosis drug-related liver injury; CI = confidence interval.\n\nConflicts of interest\n\nThe authors have no conflicts of interest relevant to the study and content of this manuscript.\n==== Refs\nREFERENCES\n\n1 Corsini A Ganey P Ju C Current challenges and controversies in drug-induced liver injury Drug Saf 2012 35 1099 117 23137150\n2 Chalasani N Fontana RJ Bonkovsky HL Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States Gastroenterology 2008 135 1924 34 18955056\n3 World Health Organization Global Tuberculosis Control WHO report 2010 Geneva, Switzerland Available from: http://whqlibdoc.who.int/publications/2010/9789241500487_eng.pdf accessed 30, 06, 13\n4 Wu JC Lee SD Yeh PF Isoniazid–rifampin-induced hepatitis in hepatitis B carriers Gastroenterology 1990 98 502 4 2295408\n5 Wong WM Wu PC Yuen MF Antituberculosis drug-related liver dysfunction in chronic hepatitis B infection Hepatology 2000 31 201 6 10613746\n6 Hwang SJ Wu JC Lee CN A prospective clinical study of isoniazid–rifampicin–pyrazinamide-induced liver injury in an area endemic for hepatitis J Gastroenterol Hepatol 1997 12 87 91 9076631\n7 Huang YS Genetic polymorphisms of drug-metabolizing enzymes and the susceptibility to antituberculosis drug-induced liver injury Expert Opin Drug Metab Toxicol 2007 3 1 8 17269890\n8 Centers for Disease Control Ministry of Health and Welfare Executive Yuan, Taiwan. Taiwan guidelines for TB diagnosis and treatment 5th ed Available from: http://www.cdc.gov.tw/professional/info.aspx?treeid=beac9c103df952c4&nowtreeid=6744c19c09435458&tid=E36C98D85972C6AA 2013 accessed 04, 10, 13\n9 Saukkonen JJ Cohn DL Jasmer RM An official ATS statement: hepatotoxicity of antituberculosis therapy Am J Respir Crit Care Med 2006 174 935 52 17021358\n10 National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) LiverTox, Clinical and Research information on Drug-Induced Liver Injury Overview—Isoniazid Available from: http://livertox.nlm.nih.gov/Isoniazid.htm accessed 04, 10, 13\n11 On WF Chih LH Liu C A unique drug-injury relief system in Taiwan: comparing drug-injury compensation in different countries J Pharm Health Serv Res 2012 3 3 9\n12 Taiwan Drug Relief Foundation Statistics Available from: http://www.tdrf.org.tw/ch/05knows/kno_07_main.asp?bull_id=4199 2011 accessed 30, 06, 13\n13 Bénichou C Criteria of drug-induced liver disorders: report of an international consensus meeting J Hepatol 1990 11 272 6 2254635\n14 Danan G Benichou C Causality assessment of adverse reactions to drugs – I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries J Clin Epidemiol 1993 46 1323 30 8229110\n15 Huang YS Chern HD Su WJ Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor of antituberculosis drug-induced hepatitis Hepatology 2002 35 883 9 11915035\n16 Huang YS Chern HD Su WJ Cytochrome P450 2E1 genetic polymorphism and the susceptibility to antituberculosis drug-induced hepatitis Hepatology 2003 37 924 30 12668988\n17 Huang YS Su WJ Huang YH Genetic polymorphisms of manganese superoxide dismutase, NAD(P)H: quinone oxidoreductase, glutathione S-transferase M1 and T1, and the susceptibility to drug-induced liver injury J Hepatol 2007 47 128 34 17400324\n18 Bjornsson E Olsson R Outcome and prognostic markers in severe drug-induced liver disease Hepatology 2005 42 481 9 16025496\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": null,
"issue": "22(3)",
"journal": "Journal of food and drug analysis",
"keywords": "Adverse drug reaction; Antituberculosis drug; Drug-induced liver injury; Liver function test",
"medline_ta": "J Food Drug Anal",
"mesh_terms": null,
"nlm_unique_id": "101630927",
"other_id": null,
"pages": "356-362",
"pmc": null,
"pmid": "28911426",
"pubdate": "2014-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Correlation of antituberculosis drug-related liver injury and liver function monitoring: A 12-year experience of the Taiwan Drug Relief Foundation.",
"title_normalized": "correlation of antituberculosis drug related liver injury and liver function monitoring a 12 year experience of the taiwan drug relief foundation"
} | [
{
"companynumb": "PHHY2015TW073726",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RIFAMPIN"
},
"drugadditional": null,
"druga... |
{
"abstract": "Acute promyelocytic leukemia (APL) has become a curable disease by all-trans retinoic acid (ATRA)-based induction therapy followed by two or three courses of consolidation chemotherapy. Currently around 90% of newly diagnosed patients with APL achieve complete remission (CR) and over 70% of patients are curable. To further increase the CR and cure rates, detection and diagnosis of this disease at its early stage is very important, hopefully before the appearance of APL-associated coagulopathy. In induction therapy, concomitant chemotherapy is indispensable, except for patients with low initial leukocyte counts. Prophylactic use of intrathecal methotrexate and cytarabine should be done, particularly for patients with hyperleukocytosis. If patients relapse hematologically or even molecularly, arsenic trioxide will be the treatment of choice under careful electrocardiogram monitoring. Am80, liposomal ATRA, gemtuzumab ozogamicin or ATRA in combination with cytotoxic drugs may be used at this stage or later. Allogeneic SCT will be the treatment of choice after patients of age <50 years have relapsed, provided that they have HLA-identical family donors or DNA-identical unrelated donors.",
"affiliations": "Aichi Cancer Center, Nagoya 464-8681, Japan.",
"authors": "Ohno|R|R|;Asou|N|N|;Ohnishi|K|K|",
"chemical_list": "D000970:Antineoplastic Agents; D014212:Tretinoin",
"country": "England",
"delete": false,
"doi": "10.1038/sj.leu.2403031",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0887-6924",
"issue": "17(8)",
"journal": "Leukemia",
"keywords": null,
"medline_ta": "Leukemia",
"mesh_terms": "D000970:Antineoplastic Agents; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute; D012074:Remission Induction; D023981:Sarcoma, Myeloid; D016896:Treatment Outcome; D014212:Tretinoin",
"nlm_unique_id": "8704895",
"other_id": null,
"pages": "1454-63",
"pmc": null,
"pmid": "12886231",
"pubdate": "2003-08",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Treatment of acute promyelocytic leukemia: strategy toward further increase of cure rate.",
"title_normalized": "treatment of acute promyelocytic leukemia strategy toward further increase of cure rate"
} | [
{
"companynumb": "US-PFIZER INC-2021592615",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FILGRASTIM"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nChronic hepatitis C virus (HCV) infection is highly prevalent among people who inject drugs but is often undiagnosed. The treatment paradigm for HCV patients has been changing since the availability of direct-acting antiviral (DAA) treatment. We aimed to evaluate the change in treatment paradigm of people who previously injected drugs (ex-PWID) in Hong Kong before and after the availability of DAA.\n\n\nMETHODS\nConsecutive ex-PWID referred from various nongovernmental organizations attended education talks at rehabilitation centers and received point-of-care rapid test for HCV antibody (anti-HCV) at the same session. Subjects tested positive for anti-HCV were invited to undergo further assessment. Afterwards, the patients were referred to the regional hospitals for follow-up and/or treatment.\n\n\nRESULTS\nThree hundred sixty-five ex-PWID received HCV rapid test; 268 (73.4%) were found to be anti-HCV positive. Among these 268 HCV-positive ex-PWID, 234 (87.3%) attended the assessment session (mean age 52 years, 90.2% male, 45.5% genotype 1b, 41.1% genotype 6a, and median liver stiffness 5.9 kPa); 187 (69.8%) attended follow-up visits at regional hospitals. Seventy-one patients received antiviral treatment for HCV; 69 first received peginterferon and ribavirin (PegIFN/RBV), whereas 10 patients (eight PegIFN/RBV-treated patients) received DAA treatment. Fifty-two patients achieved sustained virologic response at 12 or 24 weeks. Treatment uptake rates of PegIFN/RBV and DAA treatment in the pre-DAA versus post-DAA era were 22.3% versus 48.5% and 0% versus 15.6%, respectively.\n\n\nCONCLUSIONS\nTargeted screening in ex-PWID is effective in identifying patients with HCV infection in the community. To improve treatment uptake, further improvements in the referral system and treatment regimens are needed.",
"affiliations": "Institute of Digestive Disease, Hong Kong.;Institute of Digestive Disease, Hong Kong.;Department of Medicine, Kwong Wah Hospital, Hong Kong.;Department of Medicine, Queen Elizabeth Hospital, Hong Kong.;Department of Medicine, Queen Mary Hospital, Hong Kong.;Caritas Lok Heep Club, Hong Kong.;Caritas Lok Heep Club, Hong Kong.;Institute of Digestive Disease, Hong Kong.;Institute of Digestive Disease, Hong Kong.",
"authors": "Wong|Grace Lai-Hung|GL|https://orcid.org/0000-0002-2863-9389;Chan|Henry Lik-Yuen|HL|;Loo|Ching-Kong|CK|;Hui|Yee-Tak|YT|;Fung|James Yue-Yan|JY|;Cheung|David|D|;Chung|Cedric|C|;Chim|Angel Mei-Ling|AM|;Wong|Vincent Wai-Sun|VW|https://orcid.org/0000-0003-2215-9410;|||",
"chemical_list": "D000998:Antiviral Agents; D018937:Hepatitis C Antibodies; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C417083:peginterferon alfa-2b; C100416:peginterferon alfa-2a",
"country": "Australia",
"delete": false,
"doi": "10.1111/jgh.14622",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0815-9319",
"issue": "34(9)",
"journal": "Journal of gastroenterology and hepatology",
"keywords": "linkage to care; point-of-care test; screening; unmet need",
"medline_ta": "J Gastroenterol Hepatol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000998:Antiviral Agents; D004359:Drug Therapy, Combination; D055030:Drug Users; D005260:Female; D018937:Hepatitis C Antibodies; D019698:Hepatitis C, Chronic; D006723:Hong Kong; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols; D015995:Prevalence; D015397:Program Evaluation; D011994:Recombinant Proteins; D012254:Ribavirin; D012307:Risk Factors; D015819:Substance Abuse, Intravenous; D000072230:Sustained Virologic Response; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "8607909",
"other_id": null,
"pages": "1641-1647",
"pmc": null,
"pmid": "30707777",
"pubdate": "2019-09",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Change in treatment paradigm in people who previously injected drugs with chronic hepatitis C in the era of direct-acting antiviral therapy.",
"title_normalized": "change in treatment paradigm in people who previously injected drugs with chronic hepatitis c in the era of direct acting antiviral therapy"
} | [
{
"companynumb": "HK-ROCHE-2597612",
"fulfillexpeditecriteria": "1",
"occurcountry": "HK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DASABUVIR"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "OBJECTIVE\nProstaglandin E1 (PGE) has been used to maintain ductus arteriosus patency and unload the suprasystemic right ventricle (RV) in neonates with congenital diaphragmatic hernia (CDH) and severe pulmonary hypertension (PH). Here we evaluate the PH response in neonates with CDH and severe PH treated with PGE.\n\n\nMETHODS\nWe performed a retrospective chart review of CDH infants treated at our center between 2011 and 2016. In a subset, PGE was initiated for echocardiographic evidence of severe PH, metabolic acidosis, or hypoxemia. To assess PH response, we evaluated laboratory data, including B-type natriuretic peptide (BNP) and echocardiograms before and after PGE treatment. Categorical and continuous data were analyzed with Fisher's exact tests and Mann-Whitney t-tests, respectively.\n\n\nRESULTS\nFifty-seven infants were treated with PGE a mean 17 ± 2 days. BNP levels declined after 1.4 ± 0.2 days of treatment and again after 5.2 ± 0.6 days. After 6 ± 0.8 days of treatment, echocardiographic estimates of severe PH by tricuspid regurgitation jet velocity, ductus arteriosus direction, and ventricular septum position also improved significantly. Treatment was not associated with postductal hypoxemia or systemic hypoperfusion.\n\n\nCONCLUSIONS\nIn patients with CDH and severe PH, PGE is well tolerated and associated with improved BNP and echocardiographic indices of PH, suggesting successful unloading of the RV.\n\n\nMETHODS\nTreatment study.\n\n\nMETHODS\nLevel III.",
"affiliations": "The Center for Fetal Diagnosis and Treatment, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.;The Center for Fetal Diagnosis and Treatment, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.;The Center for Fetal Diagnosis and Treatment, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.;The Center for Fetal Diagnosis and Treatment, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.;Department of Pediatrics, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA.;The Center for Fetal Diagnosis and Treatment, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.;The Center for Fetal Diagnosis and Treatment, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.;Department of Pediatrics, Children's Hospital of Philadelphia; Perelman School of Medicine at the University of Pennsylvania.;The Center for Fetal Diagnosis and Treatment, The Children's Hospital of Philadelphia, Philadelphia, PA, USA; Perelman School of Medicine at the University of Pennsylvania.;Department of Pediatrics, Children's Hospital of Philadelphia; Perelman School of Medicine at the University of Pennsylvania.;Department of Pediatrics, Lucille Packard Children's Hospital, Palo Alto, California.;Department of Pediatrics, Children's Hospital of Philadelphia; Perelman School of Medicine at the University of Pennsylvania.;The Center for Fetal Diagnosis and Treatment, The Children's Hospital of Philadelphia, Philadelphia, PA, USA; Perelman School of Medicine at the University of Pennsylvania. Electronic address: Hedrick@email.chop.edu.",
"authors": "Lawrence|Kendall M|KM|;Berger|Kelsey|K|;Herkert|Lisa|L|;Franciscovich|Christine|C|;O'Dea|Carol Lynn H|CLH|;Waqar|Lindsay N|LN|;Partridge|Emily|E|;Hanna|Brian D|BD|;Peranteau|William H|WH|;Avitabile|Catherine M|CM|;Hopper|Rachel K|RK|;Rintoul|Natalie E|NE|;Hedrick|Holly L|HL|",
"chemical_list": "D014665:Vasodilator Agents; D020097:Natriuretic Peptide, Brain; D000527:Alprostadil",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jpedsurg.2018.10.039",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-3468",
"issue": "54(1)",
"journal": "Journal of pediatric surgery",
"keywords": "Congenital diaphragmatic hernia; Prostaglandin E1; Pulmonary hypertension",
"medline_ta": "J Pediatr Surg",
"mesh_terms": "D000527:Alprostadil; D004452:Echocardiography; D005260:Female; D065630:Hernias, Diaphragmatic, Congenital; D006801:Humans; D006976:Hypertension, Pulmonary; D007231:Infant, Newborn; D008297:Male; D020097:Natriuretic Peptide, Brain; D015143:Philadelphia; D012042:Registries; D012189:Retrospective Studies; D016896:Treatment Outcome; D014665:Vasodilator Agents",
"nlm_unique_id": "0052631",
"other_id": null,
"pages": "55-59",
"pmc": null,
"pmid": "30442461",
"pubdate": "2019-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Use of prostaglandin E1 to treat pulmonary hypertension in congenital diaphragmatic hernia.",
"title_normalized": "use of prostaglandin e1 to treat pulmonary hypertension in congenital diaphragmatic hernia"
} | [
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"companynumb": "US-TEVA-2019-US-1013746",
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"occurcountry": "US",
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ALPROSTADIL"
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"drugadditional": null,
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{
"abstract": "Hyperprolactinemia can result from a pituitary tumor or decreased dopamine levels due to compression of the pituitary stalk. Hypothyroidism, renal failure, and drug interaction need to be ruled out as a part of diagnostic evaluation. The prolactin level often indicates the etiology, but drug interaction needs to be ruled out mainly in a patient who is on multiple medications.",
"affiliations": "Department of Pediatrics and Human Development College of Human Medicine Michigan State University East Lansing MI USA.;Department of Pediatrics and Human Development College of Human Medicine Michigan State University East Lansing MI USA.",
"authors": "Nkansah-Amankra|Kwabena|K|;Sudhanthar|Sathyanarayan|S|https://orcid.org/0000-0001-9586-1759",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.2396",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.2396CCR32396Case ReportCase ReportsMedication‐induced obstructive uropathy and hyperprolactinemia in a pediatric patient NKANSAH‐AMANKRA and SUDHANTHARNkansah‐Amankra Kwabena \n1\nnkansaha@msu.edu Sudhanthar Sathyanarayan https://orcid.org/0000-0001-9586-1759\n1\n\n1 \nDepartment of Pediatrics and Human Development\nCollege of Human Medicine\nMichigan State University\nEast Lansing\nMI\nUSA\n* Correspondence\n\nSathyanarayan Sudhanthar, Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, B220 Clinical Center, 788 Service Rd, East Lansing, MI 48824, USA.\n\nEmail: sudhanth@msu.edu\n29 8 2019 10 2019 7 10 10.1002/ccr3.v7.101928 1931 13 5 2019 01 7 2019 27 7 2019 © 2019 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nHyperprolactinemia can result from a pituitary tumor or decreased dopamine levels due to compression of the pituitary stalk. Hypothyroidism, renal failure, and drug interaction need to be ruled out as a part of diagnostic evaluation. The prolactin level often indicates the etiology, but drug interaction needs to be ruled out mainly in a patient who is on multiple medications.\n\nacute medicinenephrologypediatrics and adolescent medicinepharmacologypsychiatry source-schema-version-number2.0component-idccr32396cover-dateOctober 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.7.0 mode:remove_FC converted:11.10.2019\n\n\nNkansah‐Amankra \nK \n, \nSudhanthar \nS \n. Medication‐induced obstructive uropathy and hyperprolactinemia in a pediatric patient . Clin Case Rep . 2019 ;7 :1928 –1931 . 10.1002/ccr3.2396\n==== Body\nLearning points\n\nLiterature suggests hyperprolactinemia >200 ng/mL should raise suspicion about a possible tumor, but it is imperative to rule out drug interactions that may contribute to hyperprolactinemia.\n\nChecking drug interactions should be mandatory in a patient on multiple medications, especially psychotropic drugs, to rule out high prolactin levels.\n\nExposure to radiation and cost associated with imaging can be saved if drug interaction is considered as a primary cause.\n\n\n\n\n\n\n\n1 BACKGROUND\nProlactin, a hormone secreted by the anterior pituitary gland, has wide‐ranging effects on the body.1, 2, 3 Its primary role is in regulating the production of milk in females but has secondary functions, including pancreatic development and immune system and metabolism regulation.1, 2, 4 It is secreted in a pulsatile manner in reaction to activities including eating, mating, ovulation, estrogen treatment, and nursing.1, 3 During pregnancy, high levels of estrogen and progesterone cause a significant increase in circulating levels of prolactin. After childbirth, the sucking of the nipple by the baby prompts an increase in prolactin levels.1, 3 Prolactin levels also vary diurnally as high levels are found during REM sleep and in the early morning.\n\nHyperprolactinemia is defined as levels of prolactin above 18 ng/mL for men and 29 ng/mL for women.1 The etiology of hyperprolactinemia can result from decreased dopamine levels due to compression of the pituitary stalk or a pituitary gland tumor that results in increased secretion of prolactin.2 Drugs that can induce hypersecretion of prolactin include dopamine receptor blockers (risperidone, haloperidol, and metoclopramide), dopamine synthesis inhibitors (alpha‐methyldopa), catecholamine depletors (reserpine), and others. High prolactin levels inhibit gonadotropin‐releasing hormones, decreasing follicle‐stimulating hormone (FSH), and luteinizing hormone (LH) levels.5, 6 As such, patients with hyperprolactinemia present with oligomenorrhea, amenorrhea, or infertility in women and sexual dysfunction, visual problems, and headaches in all hyperprolactinemic patients. Hyperprolactinemia can also result in osteoporosis.2, 6, 7\n\n\nProlactin secretion is regulated by dopamine (a prolactin inhibitory hormone), which binds to D2 receptors on lactotrophs, reducing prolactin secretion from the anterior pituitary gland.8, 9 Thus, substances and conditions that can accentuate or decrease this activity of dopamine will result in hypoprolactinemia and hyperprolactinemia, respectively.9, 10 This paper explores the latter, looking at situations that arise in hyperprolactinemia, specifically drug‐induced hyperprolactinemia, by presenting the case of a 17‐year‐old male on multiple psychotropic medications found to have high prolactin levels.\n\nVery high prolactin levels (>200 ng/mL) are often attributed to pituitary tumors. However, very rarely, they are shown to be due to drug interactions. We present an interesting patient case that of a 17‐year‐old male on Haloperidol, Benzatropine, and Lithium with hyperprolactinemia and obstructive uropathy. The combination of these medications was due to his mental health condition and is managed by a psychiatrist. This patient was diagnosed with levels of prolactin that are rarely seen in drug‐induced hyperprolactinemia. As far as we know, the combination of Lithium, Benzatropine, and Haloperidol has been seldom shown to lead to both hyperprolactinemia and obstructive uropathy.\n\n2 CASE PRESENTATION\nThe patient presented in this report is a 17‐year‐old male with a past medical history of mild cerebral palsy, autism spectrum disorder, and bipolar disorder with aggression, which was being treated with Lithium and Haloperidol for his mental health symptoms over the past 9 months. Over the course of his treatment, he subsequently developed hypothyroidism due to Lithium and was started on Levothyroxine. He was started on Benzatropine as well for prophylaxis against dystonic movement and tremor issues known to be caused by Haloperidol.\n\nDuring his annual well check, he was found to have a suprapubic mass due to the bladder distension and urinary retention. The patient has had a history of urinary retention on and off for a few months. Renal labs and ultrasound of the kidneys and bladder were ordered immediately along with a referral to urology. His initial labs showed that he had developed acute kidney injury (AKI) with high blood urea nitrogen (24 mg/dL) and increasing creatinine (2.4 mg/dL). The AKI was due to the chronic intermittent urinary retention patient had been experiencing for at least the past 4 months. At the urology visit, the plan was made to relieve his obstructive uropathy with intermittent catheterization and to coordinate with his psychiatrist and Primary Care Physician (PCP) to manage his mental health medications.\n\nTwo days after, the urologist saw him, he presented with a febrile illness to the emergency and was admitted to the pediatric Intensive care unit due to his labs, which showed a urinary tract infection, metabolic acidosis, hyponatremia, and toxic levels of Lithium. A prolactin level was also checked since he was on haloperidol and he was found to have galactorrhea on physical exam. His Lithium level (2.2 ng/mL) was in a toxic range, and his prolactin levels were very high, leading to suspicions of a pituitary tumor (267 ng/mL). He was also diagnosed with grade 3 bilateral hydroureteronephrosis with obstructive uropathy as per the ultrasound.\n\nDue to the suspicion of a pituitary tumor, he underwent an MRI imaging of his brain after his creatinine normalized. The MRI showed no abnormality, ruling out a pituitary adenoma. During the subsequent hospital course, Benzatropine, Haloperidol, and Lithium were held until the patient's renal function was normalized. He was later discharged on lower Lithium, Benzatropine, and Haloperidol doses. His prolactin levels were still high at the time of his discharge from the hospital. Urology was consulted in the hospital, and an aggressive bladder program was initiated with close follow‐up planned with his primary care, urologist, and psychiatrist.\n\n2.1 Differential diagnosis\nThe differential diagnoses of hyperprolactinemia clinically depend on the level of prolactin.\n\nLow levels of hyperprolactinemia have found to be due to medications, hypothyroidism, and kidney problems. Clinical judgment, when encountered with higher levels of hyperprolactinemia (>200 ng/mL), calls for ruling out pituitary adenoma. Our patient had many medications that could potentially interact with each other. Due to his initial clinical presentation of cerebral palsy, autism spectrum disorder, and bipolar disorder, this patient was a challenging dilemma in terms of drug prescription. The most likely explanation of the events is that Lithium led to hypothyroidism and hypothyroidism leads to an increase in TRH, which stimulates prolactin release. Our patient was also in combination with Haloperidol and Benzatropine, and the combined anticholinergic effects led to chronic urinary retention, which culminated in AKI, leading to toxic levels of Lithium. Increased Lithium level, in combination with Haloperidol effect on dopamine, is what we suspect led to his hyperprolactinemia.\n\n2.2 Outcome and follow‐up\nThe patient’s prolactin levels normalized over 8 weeks. He continued to be on optimal doses of all three medications and was managed carefully by the psychiatrist. He also underwent a procedure for intermittent suprapubic catheterization, which would address the chronic issue of urinary retention. This is widely believed to be due to the synergistic anticholinergic effects of Haloperidol and Benzatropine, which contributed to obstructive uropathy, causing AKI, which in turn increased Lithium levels in the body, culminating in increased levels of prolactin (Figure 1). Lithium is renally cleared, whereas Haloperidol goes through extensive first‐pass metabolism through the liver. One of the main side effects reported when using Lithium with neuroleptics is there is an increased chance of neurotoxicity in the form of confusion, tremor, extrapyramidal symptoms, neuroleptic malignant syndrome, and QT prolongation.11, 12, 13, 14 One of the possible mechanisms of increased neurotoxicity when using Lithium and the neuroleptic combination is that neuroleptics can increase the intracellular concentration of Lithium.15 Other mechanisms include enhanced dopamine blockade (Risperidone), increased intracellular Lithium levels (Risperidone), and interaction of serotonergic effects of Clozapine with Lithium. This case highlights the importance of monitoring drug dosages, especially when there are multiple drugs involved, as synergistic and antagonistic drug‐drug interactions can be detrimental to the health of the patient.15\n\n\nFigure 1 Demonstration of drug interaction which led to the high prolactin levels in our patient. Combination of Benzatropine and Haloperidol caused obstructive uropathy in this patient, which culminated in AKI, resulting in toxic levels of Lithium causing hyperprolactinemia along with the independent effect of haloperidol\n\n3 DISCUSSION\nCurrent literature shows that anticholinergic and alpha‐adrenergic drugs lead to urinary retention and dopamine antagonists cause hyperprolactinemia. However, the combination of an anticholinergic drug and dopamine antagonist resulting in urinary retention and subsequent hyperprolactinemia, as in this patient case, has not been reported.1, 2\n\n\nHigh prolactin levels associated with antipsychotics are quite common. In a literature review, it was found that 60% of women and 40% of men treated with prolactin‐sparing antipsychotic had a prolactin level above the upper limit of the normal range.16 In a study on the prevalence of hyperprolactinemia in schizophrenic patients, it was found that the mean serum level was 41.5 ng/mL with 69% of the patients having levels above normal.17 Risperidone was found to be especially guilty of increasing prolactin levels, with the prevalence of hyperprolactinemia was 88% among females taking risperidone versus 47.6% of those taking conventional antipsychotic drugs.18 A study that measured prolactin levels and clinically significant sexual dysfunction found that in switching from risperidone to paliperidone palmitate, a fourfold reduction in the measurable parameters was seen.19\n\n\nFurther studies support this claim, as young males treated with risperidone reported diminished sexual function in comparison to those not treated with antipsychotics.20 Haloperidol shows similar effects to risperidone, as one study reported a high of 77 ng/mL in a study population.21 Very high prolactin levels (>200 ng/mL) are often attributed to tumors.2 However, rarely, they are shown to be due to antipsychotics. This is what makes the current case so interesting: that of a 17‐year‐old male on Haloperidol reporting with levels of prolactin that are rarely seen in drug‐induced hyperprolactinemia.\n\nThis case highlights the importance of understanding how drug‐drug interactions can upset the physiological balance in a patient. The patient was on drugs that are rarely used in combination, and their subsequent synergistic effects contributed to his presentation. This drug combination, combined with his unique presentation of obstructive uropathy, leading to hyperprolactinemia offers an insight into understanding dosage prescription and drug‐drug interaction. It is multidisciplinary, tying in multiple disciplines such as physiology, pharmacology, endocrinology, and nephrology.\n\nCONFLICT OF INTEREST\nNone declared.\n\nAUTHOR CONTRIBUTIONS\nAll the authors were involved in patient care when the patient was scheduled for regular follow‐ups. KN wrote the first draft of the manuscript, and SS was involved in the revision of the manuscript and final submission. SS was also involved in getting consent from the family and patient. SS and KN prepared a poster presentation of this case report for the regional medical conferences.\n==== Refs\nREFERENCES\n1 \n\nChoong \nS \n, \nEmberton \nM \n. Acute urinary retention . BJU Int . 2000 ;85 (2 ):186 ‐201 .10671867 \n2 \n\nMolitch \nME \n. Medication‐induced hyperprolactinemia . Mayo Clin Proc . 2005 ;80 (8 ):1050 ‐1057 .16092584 \n3 \n\nSabanegh \nES , Jr\n. Male Infertility: Problems and Solutions . New York :Springer Science & Business Media ; 2010 :83 .\n4 \n\nBolanowski \nM \n, \nZadrozna‐Sliwka \nB \n, \nJawiarczyk \nA \n, \nSyrycka \nJ \n. The influence of other than prolactin hormones on bone mineral density in women with hyperprolactinemia of various origins . Gynecol Endocrinol . 2010 ;26 (8 ):623 ‐627 .20218822 \n5 \n\nMancini \nT \n, \nCasanueva \nFF \n, \nGiustina \nA \n. Hyperprolactinemia, and prolactinomas . Endocrinol Metab Clin North Am . 2008 ;37 (1 ):67 .18226731 \n6 \n\nMelmed \nS \n, \nKleinberg \nD \n. Anterior pituitary. Williams textbook of endocrinology (11 th edn). Philadelphia : Saunders Elsevier ; 185 ‐261 .\n7 \n\nTorre \nDL \n, \nFalorni \nA \n. Pharmacological causes of hyperprolactinemia . Ther Clin Risk Manag . 2007 ;3 (5 ):929 ‐951 .18473017 \n8 \n\nLarsen \nCM \n, \nGrattan \nDR \n. Prolactin, neurogenesis, and maternal behaviors . Brain Behav Immun . 2012 ;26 (2 ):201 ‐209 .21820505 \n9 \n\nBole‐Feysot \nC \n, \nGoffin \nV \n, \nEdery \nM \n, \nBinart \nN \n, \nKelly \nPA \n. Prolactin (PRL) and its receptor: actions, signal transduction pathways, and phenotypes observed in PRL receptor knockout mice\" . Endocr Rev . 1998 ;19 (3 ):225 ‐268 .9626554 \n10 \n\nFitzgerald \nP \n, \nDinan \nTG \n. Prolactin and dopamine: what is the connection? A Review Article . J Psychopharmacol . 2008 ;22 (2 suppl ):12 ‐19 .18477617 \n11 \n\nKeitner \nGI \n, \nRahman \nS \n. Reversible neurotoxicity with combined lithium‐haloperidol administration . J Clin Psychopharmacol . 1984 ;4 (2 ):104 ‐105 .6423702 \n12 \n\nCoffey \nCE \n, \nRoss \nDR \n. Treatment of lithium/neuroleptic neurotoxicity during lithium maintenance . Am J Psychiatry . 1980 ;137 (6 ):736 ‐737 .7377401 \n13 \n\nLee \nSH \n, \nYang \nYY \n. Reversible neurotoxicity induced by a combination of clozapine and lithium: a case report . Zhonghua Yi Xue Za Zhi (Taipei) . 1999 ;62 (3 ):184 ‐187 .10222608 \n14 \n\nBlake \nLM \n, \nMarks \nRC \n, \nLuchins \nDJ \n. Reversible neurologic symptoms with clozapine and lithium . J Clin Psychopharmacol . 1992 ;12 (4 ):297 ‐299 .1527237 \n15 \n\nNetto \nI \n, \nPhutane \nVH \n. Reversible lithium neurotoxicity: review of the literature . Prim Care Companion CNS Disord . 2012 ;1 :14 .\n16 \n\nBesnard \nI \n, et al. Antipsychotic‐drug‐induced hyperprolactinemia: physiopathology, clinical features, and guidance . Encephale . 2014 ;40 (1 ):86 ‐94 .23928066 \n17 \n\nHaddad \nPM \n, \nWieck \nA \n. Antipsychotic‐induced hyperprolactinemia: mechanisms, clinical features, and management . Drugs . 2004 ;64 (20 ):2291 ‐2314 .15456328 \n18 \n\nMontgomery \nJ \n, \nWinterbottom \nE \n, \nJessani \nM \n, et al. Prevalence of hyperprolactinemia in schizophrenia: association with typical and atypical antipsychotic treatment . J Clin Psychiatry . 2004 ;65 (11 ):1491 ‐1498 .15554761 \n19 \n\nKinon \nBJ \n, \nGilmore \nJA \n, \nLiu \nH \n, \nHalbreich \nUM \n. Prevalence of hyperprolactinemia in schizophrenic patients treated with conventional antipsychotic medications or risperidone . Psychoneuroendocrinology . 2003 ;28 (suppl 2 ):55 ‐68 .\n20 \n\nMontalvo \nI \n, \nOrtega \nL \n, \nLópez \nX \n, et al. Changes in prolactin levels and sexual function in young psychotic patients after switching from long‐acting injectable risperidone to paliperidone palmitate . Int Clin Psychopharmacol . 2013 ;28 (1 ):46 ‐49 .23232756 \n21 \n\nRoke \nY \n, \nBuitelaar \nJK \n, \nBoot \nAM \n, \nTenback \nD \n, \nvan Harten \nPN \n. Risk of hyperprolactinemia and sexual side effects in males 10–20 years old diagnosed with autism spectrum disorders or disruptive behavior disorder and treated with risperidone . J Child Adolesc Psychopharmacol . 2012 ;22 (6 ):432 ‐439 .23234586\n\n",
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"issue": "7(10)",
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"keywords": "acute medicine; nephrology; pediatrics and adolescent medicine; pharmacology; psychiatry",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "1928-1931",
"pmc": null,
"pmid": "31624611",
"pubdate": "2019-10",
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"references": "10222608;18473017;1527237;15554761;21820505;16092584;23928066;6423702;9626554;7377401;10671867;23234586;18477617;23232756;12650681;20218822;15456328;22690368;18226731",
"title": "Medication-induced obstructive uropathy and hyperprolactinemia in a pediatric patient.",
"title_normalized": "medication induced obstructive uropathy and hyperprolactinemia in a pediatric patient"
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{
"abstract": "BACKGROUND\nQTc interval prolongation can occur as a result of treatment with both conventional and novel antipsychotic medications and is of clinical concern because of its association with the potentially fatal ventricular arrhythmia, torsade de pointes.\n\n\nMETHODS\nOne case is described in which a patient with schizophrenia, who was being treated for dyslipidemia, developed a prolonged QTc interval while taking quetiapine and lovastatin.\n\n\nRESULTS\nQTc returned to baseline when the lovastatin dose was reduced.\n\n\nCONCLUSIONS\nQTc prolongation associated with antipsychotic medication occurs in a dose-dependent manner. We therefore hypothesize that the addition of lovastatin caused an increase in plasma quetiapine levels through competitive inhibition of the cytochrome P(450) (CYP) isoenzyme 3A4. Our case highlights the potential for a drug interaction between quetiapine and lovastatin leading to QTc prolongation during the management of dysipidemia in patients with schizophrenia.",
"affiliations": "Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles School of Medicine, Los Angeles, California, USA.",
"authors": "Furst|Benjamin A|BA|;Champion|Katherine M|KM|;Pierre|Joseph M|JM|;Wirshing|Donna A|DA|;Wirshing|William C|WC|",
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"mesh_terms": "D000924:Anticholesteremic Agents; D014150:Antipsychotic Agents; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D003987:Dibenzothiazepines; D004562:Electrocardiography; D005260:Female; D006801:Humans; D006949:Hyperlipidemias; D008133:Long QT Syndrome; D008148:Lovastatin; D008875:Middle Aged; D006899:Mixed Function Oxygenases; D000069348:Quetiapine Fumarate; D012559:Schizophrenia; D013997:Time Factors; D014280:Triglycerides",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Possible association of QTc interval prolongation with co-administration of quetiapine and lovastatin.",
"title_normalized": "possible association of qtc interval prolongation with co administration of quetiapine and lovastatin"
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... |
{
"abstract": "BACKGROUND\nThe results of the addition of gemtuzumab ozogamicin, an anti-CD33 antibody conjugate, to the standard treatment for patients with acute myeloid leukaemia in phase 3 trials were contradictory. We investigated whether the addition of low fractionated-dose gemtuzumab ozogamicin to standard front-line chemotherapy would improve the outcome of patients with this leukaemia without causing excessive toxicity.\n\n\nMETHODS\nIn a phase 3, open-label study, undertaken in 26 haematology centres in France, patients aged 50-70 years with previously untreated de novo acute myeloid leukaemia were randomly assigned with a computer-generated sequence in a 1:1 ratio with block sizes of four to standard treatment (control group) with or without five doses of intravenous gemtuzumab ozogamicin (3 mg/m(2) on days 1, 4, and 7 during induction and day 1 of each of the two consolidation chemotherapy courses). The primary endpoint was event-free survival (EFS). Secondary endpoints were relapse-free (RFS), overall survival (OS), and safety. Analysis was by intention to treat. This study is registered with EudraCT, number 2007-002933-36.\n\n\nRESULTS\n280 patients were randomly assigned to the control (n=140) and gemtuzumab ozogamicin groups (n=140), and 139 patients were analysed in each group. Complete response with or without incomplete platelet recovery to induction was 104 (75%) in the control group and 113 (81%) in the gemtuzumab ozogamicin group (odds ratio 1·46, 95% CI 0·20-2·59; p=0·25). At 2 years, EFS was estimated as 17·1% (10·8-27·1) in the control group versus 40·8% (32·8-50·8) in the gemtuzumab ozogamicin group (hazard ratio 0·58, 0·43-0·78; p=0·0003), OS 41·9% (33·1-53·1) versus 53·2% (44·6-63·5), respectively (0·69, 0·49-0·98; p=0·0368), and RFS 22·7% (14·5-35·7) versus 50·3% (41·0-61·6), respectively (0·52, 0·36-0·75; p=0·0003). Haematological toxicity, particularly persistent thrombocytopenia, was more common in the gemtuzumab ozogamicin group than in the control group (22 [16%] vs 4 [3%]; p<0·0001), without an increase in the risk of death from toxicity.\n\n\nCONCLUSIONS\nThe use of fractionated lower doses of gemtuzumab ozogamicin allows the safe delivery of higher cumulative doses and substantially improves outcomes in patients with acute myeloid leukaemia. The findings warrant reassessment of gemtuzumab ozogamicin as front-line therapy for acute myeloid leukaemia.\n\n\nBACKGROUND\nWyeth (Pfizer).",
"affiliations": "Hôpital Mignot, Université Versailles-Saint Quentin, Le Chesnay, France. scastaigne@ch-versailles.fr",
"authors": "Castaigne|Sylvie|S|;Pautas|Cécile|C|;Terré|Christine|C|;Raffoux|Emmanuel|E|;Bordessoule|Dominique|D|;Bastie|Jean-Noel|JN|;Legrand|Ollivier|O|;Thomas|Xavier|X|;Turlure|Pascal|P|;Reman|Oumedaly|O|;de Revel|Thierry|T|;Gastaud|Lauris|L|;de Gunzburg|Noémie|N|;Contentin|Nathalie|N|;Henry|Estelle|E|;Marolleau|Jean-Pierre|JP|;Aljijakli|Ahmad|A|;Rousselot|Philippe|P|;Fenaux|Pierre|P|;Preudhomme|Claude|C|;Chevret|Sylvie|S|;Dombret|Hervé|H|;|||",
"chemical_list": "D000617:Aminoglycosides; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000079982:Gemtuzumab",
"country": "England",
"delete": false,
"doi": "10.1016/S0140-6736(12)60485-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0140-6736",
"issue": "379(9825)",
"journal": "Lancet (London, England)",
"keywords": null,
"medline_ta": "Lancet",
"mesh_terms": "D000368:Aged; D000617:Aminoglycosides; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018572:Disease-Free Survival; D005260:Female; D000079982:Gemtuzumab; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D015996:Survival Rate",
"nlm_unique_id": "2985213R",
"other_id": null,
"pages": "1508-16",
"pmc": null,
"pmid": "22482940",
"pubdate": "2012-04-21",
"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": "Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study.",
"title_normalized": "effect of gemtuzumab ozogamicin on survival of adult patients with de novo acute myeloid leukaemia alfa 0701 a randomised open label phase 3 study"
} | [
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"companynumb": "FR-MYLANLABS-2018M1020043",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GEMTUZUMAB OZOGAMICIN"
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"abstract": "Calcineurin inhibitors (CNI), the cornerstone of immunosuppression after transplantation are implicated in nephrotoxicity and allograft dysfunction. We hypothesized that combined low doses of CNI and Everolimus (EVR) may result in better graft outcomes and greater tolerogenic milieu. Forty adult renal transplant recipients were prospectively randomized to (steroid free) low dose Tacrolimus (TAC) and EVR or standard dose TAC and Mycophenolate (MMF) after Alemtuzumab induction. Baseline characteristics were statistically similar. EVR levels were maintained at 3-8 ng/ml. TAC levels were 4.5±1.9 and 6.4±1.5 ng/ml in the TAC+EVR and TAC+MMF group respectively. Follow up was 14±4 and 17±5 months respectively and included protocol kidney biopsies at 3 and 12 months post-transplantation. Rejection-rate was lower in the TAC+EVR group. However patient and overall graft survival, eGFR and incidence of adverse events were similar. TAC+EVR induced expansion of CD4+CD25hiFoxp3+ regulatory T cells as early as 3 months and expansion of IFN-γ+CD4+CD25hiFoxp3+ regulatory T cells at 12 months post-transplant. Gene expression profile showed a trend toward decreased inflammation, angiogenesis and connective tissue growth in the TAC+EVR Group. Thus, greater tolerogenic mechanisms were found to be operating in patients with low dose TAC+EVR and this might be responsible for the lower rejection-rate than in patients on standard dose TAC+MMF. However, further studies with longer follow up and evaluating impact on T regulatory cells are warranted.",
"affiliations": "Department of Medicine-Nephrology, Northwestern University, Chicago, IL, United States of America.;Department of Surgery, Northwestern University, Chicago, IL, United States of America.;Department of Medicine-Nephrology, Northwestern University, Chicago, IL, United States of America.;Methodist University Transplant Institute; University of Tennessee Health Science Center; Memphis, TN, United States of America.;Methodist University Transplant Institute; University of Tennessee Health Science Center; Memphis, TN, United States of America.;Department of Medicine-Nephrology, Northwestern University, Chicago, IL, United States of America.;Department of Medicine-Nephrology, Northwestern University, Chicago, IL, United States of America.;Comprehensive Transplant Center, Northwestern University, Chicago, IL, United States of America.;Department of Medicine-Nephrology, Northwestern University, Chicago, IL, United States of America.;Department of Surgery, Northwestern University, Chicago, IL, United States of America.;Methodist University Transplant Institute; University of Tennessee Health Science Center; Memphis, TN, United States of America.;Department of Medicine-Nephrology, Northwestern University, Chicago, IL, United States of America.",
"authors": "Traitanon|Opas|O|;Mathew|James M|JM|0000-0002-5667-750X;Shetty|Aneesha|A|;Bontha|Sai Vineela|SV|;Maluf|Daniel G|DG|;El Kassis|Yvonne|Y|;Park|Sook H|SH|;Han|Jing|J|;Ansari|M Javeed|MJ|;Leventhal|Joseph R|JR|;Mas|Valeria|V|;Gallon|Lorenzo|L|",
"chemical_list": "D007166:Immunosuppressive Agents; D000068338:Everolimus; D009173:Mycophenolic Acid; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0216300",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0216300PONE-D-19-01363Research ArticleBiology and Life SciencesCell BiologyCellular TypesAnimal CellsBlood CellsWhite Blood CellsT CellsBiology and Life SciencesCell BiologyCellular TypesAnimal CellsImmune CellsWhite Blood CellsT CellsBiology and Life SciencesImmunologyImmune CellsWhite Blood CellsT CellsMedicine and Health SciencesImmunologyImmune CellsWhite Blood CellsT CellsBiology and life sciencesCell biologyCellular typesAnimal cellsBlood cellsWhite blood cellsT cellsRegulatory T cellsBiology and life sciencesCell biologyCellular typesAnimal cellsImmune cellsWhite blood cellsT cellsRegulatory T cellsBiology and life sciencesImmunologyImmune cellsWhite blood cellsT cellsRegulatory T cellsMedicine and health sciencesImmunologyImmune cellsWhite blood cellsT cellsRegulatory T cellsBiology and Life SciencesGeneticsGene ExpressionMedicine and Health SciencesSurgical and Invasive Medical ProceduresBiopsyMedicine and Health SciencesSurgical and Invasive Medical ProceduresTransplantationOrgan TransplantationRenal TransplantationMedicine and Health SciencesSurgical and Invasive Medical ProceduresUrinary System ProceduresRenal TransplantationBiology and Life SciencesImmunologyImmune ResponseInflammationMedicine and Health SciencesImmunologyImmune ResponseInflammationMedicine and Health SciencesDiagnostic MedicineSigns and SymptomsInflammationMedicine and Health SciencesPathology and Laboratory MedicineSigns and SymptomsInflammationBiology and Life SciencesPhysiologyImmune PhysiologyCytokinesMedicine and Health SciencesPhysiologyImmune PhysiologyCytokinesBiology and Life SciencesImmunologyImmune SystemInnate Immune SystemCytokinesMedicine and Health SciencesImmunologyImmune SystemInnate Immune SystemCytokinesBiology and Life SciencesDevelopmental BiologyMolecular DevelopmentCytokinesBiology and life sciencesCell biologyCellular typesAnimal cellsBlood cellsWhite blood cellsT cellsCytotoxic T cellsBiology and life sciencesCell biologyCellular typesAnimal cellsImmune cellsWhite blood cellsT cellsCytotoxic T cellsBiology and life sciencesImmunologyImmune cellsWhite blood cellsT cellsCytotoxic T cellsMedicine and health sciencesImmunologyImmune cellsWhite blood cellsT cellsCytotoxic T cellsMechanistic analyses in kidney transplant recipients prospectively randomized to two steroid free regimen—Low dose Tacrolimus with Everolimus versus standard dose Tacrolimus with Mycophenolate Mofetil Immunology of TAC-EVR combine in renal transplantsTraitanon Opas Data curationFormal analysisInvestigationMethodologyWriting – original draft12http://orcid.org/0000-0002-5667-750XMathew James M. Formal analysisInvestigationSupervisionWriting – review & editing345*Shetty Aneesha Data curationInvestigationMethodology1Bontha Sai Vineela Data curationFormal analysisInvestigationMethodologyValidationWriting – original draft6Maluf Daniel G. Data curationInvestigationWriting – original draft6El Kassis Yvonne Data curationInvestigation1Park Sook H. Data curationInvestigation1Han Jing Data curationMethodology4Ansari M. Javeed Data curationWriting – review & editing14Leventhal Joseph R. ConceptualizationData curationInvestigationWriting – review & editing34Mas Valeria Data curationInvestigationMethodologySupervisionWriting – review & editing6Gallon Lorenzo ConceptualizationData curationFunding acquisitionInvestigationMethodologyProject administrationSupervisionWriting – review & editing14*1 \nDepartment of Medicine-Nephrology, Northwestern University, Chicago, IL, United States of America2 \nDepartment of Medicine-Nephrology, Thammasart University Hospital, Pathumthani, Thailand3 \nDepartment of Surgery, Northwestern University, Chicago, IL, United States of America4 \nComprehensive Transplant Center, Northwestern University, Chicago, IL, United States of America5 \nDepartment of Microbiology-Immunology, Northwestern University, Chicago, IL, United States of America6 \nMethodist University Transplant Institute; University of Tennessee Health Science Center; Memphis, TN, United States of AmericaCravedi Paolo EditorIcahn School of Medicine at Mount Sinai, UNITED STATESCompeting Interests: The authors have declared that no competing interests exist.\n\n* E-mail: L-gallon@northwestern.edu (LG); James-mathew@northwestern.edu (JMM)28 5 2019 2019 14 5 e021630029 1 2019 17 4 2019 © 2019 Traitanon et al2019Traitanon et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Calcineurin inhibitors (CNI), the cornerstone of immunosuppression after transplantation are implicated in nephrotoxicity and allograft dysfunction. We hypothesized that combined low doses of CNI and Everolimus (EVR) may result in better graft outcomes and greater tolerogenic milieu. Forty adult renal transplant recipients were prospectively randomized to (steroid free) low dose Tacrolimus (TAC) and EVR or standard dose TAC and Mycophenolate (MMF) after Alemtuzumab induction. Baseline characteristics were statistically similar. EVR levels were maintained at 3–8 ng/ml. TAC levels were 4.5±1.9 and 6.4±1.5 ng/ml in the TAC+EVR and TAC+MMF group respectively. Follow up was 14±4 and 17±5 months respectively and included protocol kidney biopsies at 3 and 12 months post-transplantation. Rejection-rate was lower in the TAC+EVR group. However patient and overall graft survival, eGFR and incidence of adverse events were similar. TAC+EVR induced expansion of CD4+CD25hiFoxp3+ regulatory T cells as early as 3 months and expansion of IFN-γ+CD4+CD25hiFoxp3+ regulatory T cells at 12 months post-transplant. Gene expression profile showed a trend toward decreased inflammation, angiogenesis and connective tissue growth in the TAC+EVR Group. Thus, greater tolerogenic mechanisms were found to be operating in patients with low dose TAC+EVR and this might be responsible for the lower rejection-rate than in patients on standard dose TAC+MMF. However, further studies with longer follow up and evaluating impact on T regulatory cells are warranted.\n\nhttp://dx.doi.org/10.13039/100008792Novartis PharmaAgmt 4/16/12Gallon Lorenzo This study was funded in part by Novartis through an investigator initiated grant to LG (Agmt 4/16/12). There was no additional external funding received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. However, the funders approved the publication of the results. Data AvailabilityAll relevant data are within the manuscript and its Supporting Information files.Data Availability\nAll relevant data are within the manuscript and its Supporting Information files.\n==== Body\nIntroduction\nThe advent of calcineurin inhibitor (CNI) based immunosuppression (IS) changed the face of kidney transplantation (KT), dramatically improving short term graft and patient outcomes. However, long term CNI exposure has been associated with poorer graft function, increased risk of cardiovascular events and glucose intolerance [1–3]. Histological features of chronic CNI nephrotoxicity include irreversible and progressive tubular atrophy, interstitial fibrosis, and focal hyalinosis of small renal arteries and arterioles [4]. Additionally, CNIs block IL2 production leading to a negative impact on regulatory T cell (Treg) generation (an important subpopulation of T helper cells that has been associated with positive immunomodulation and donor specific hypo responsiveness). Attempts at complete avoidance of CNIs have been associated with increased cellular rejection [5] while alternative regimens like combination of a full dose CNI with an mTOR inhibitor has been shown to be synergistically nephrotoxic [6].\n\nVarious strategies to minimize CNI exposure and consequently improve graft outcomes have been studied [7]. The A2309 study comparing reduced dose Cyclosporine (CsA) + Everolimus (EVR) with standard dose CsA + Mycophenolate Mofetil (MMF) is one such study, which showed equivalent graft outcomes between the 2 groups and earned Everolimus FDA approval for use in KT [8]. However, previous trials have shown superior graft survival with tacrolimus (TAC) when compared with CsA [9–11] and TAC based regimen is now the standard of care in most institutions.\n\nHerein, we evaluated the combination of low dose TAC+EVR when compared to standard dose TAC+MMF in patients who received T-cell depleting induction therapy followed by steroid free immunosuppression (Fig 1). A detailed longitudinal intragraft gene expression and peripheral blood T cell subset analysis has been done for patients groups receiving TAC+MMF versus those receiving low dose TAC+EVR. We hypothesized that the positive effect of Everolimus on expansion of Tregs combined with low exposure of TAC is sufficient to control allo-reactive T cells translating into better renal allograft outcomes. We observed a greater tolerogenic melieu operating in patients with low dose TAC+EVR and this might be responsible for the lower rejection-rate than in patients on standard dose TAC+MMF.\n\n10.1371/journal.pone.0216300.g001Fig 1 Consort diagram of enrollment.\nPlease see S3 File, Consort Checklist for additional information.\n\nMaterials and methods\nWe conducted a single-center prospective randomized controlled pilot trial (NCT01653847) to study the immune mechanisms operating in adult non-sensitized living donor KT recipients receiving low dose TAC+EVR vs. standard dose TAC+MMF immunosuppressive regimen (Please see S2 File for the Clinical Trial Protocol). Recipients between ages 18–70 were recruited from February 1, 2013 to May 29, 2014 through a Northwestern University Institutional Review Board (IRB) approved protocol after obtaining written informed consent. The randomization was made by a non-study personnel using the online “sealed envelope” randomization service (https://www.sealedenvelope.com/simple-randomiser/v1/). All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. Informed consent was obtained for all subjects. No organs/tissues were procured from prisoners and the organs were procured by Gift of Hope (https://www.giftofhope.org/) and the transplants were performed at the Comprehensive Transplant Center at Northwestern University. Patients with dual organ transplants or a panel reactive antibody (PRA) > 20% were excluded. Additional exclusion criteria included pregnancy, severe hyperlipidemia, history of FSGS and cytopenias. The clinical protocol and patient follow-up was completed on February 7, 2018.\n\nObjectives\nForty patients were randomized 1:1 at the time of transplant to IS with low dose TAC and EVR (n = 20) or standard dose TAC and MMF (n = 20) (Fig 1). We had calculated our sample power for the two interrelated primary endpoints based on our clinical experience to obtain biopsy, cell sub-poulations and genomic data in a small pilot study. Using a two-tailed α of 0.05, the anticipated effect sizes corresponding to the specific aim between the two treatment arms were calculated using a minimum of 80% statistical power and assumed 10% attrition at 12 months. All patients, except a recipient >65 years old, received Alemtuzumab induction as it is standard of care (SOC) at our center. Maintenance IS was steroid free unless indicated by the following medical conditions: acute renal allograft rejection, renal diseases that might require the use of steroids and other systemic diseases such as RA, SLE, or asthma. Everolimus levels were maintained between 3–8 ng/ml. In the standard IS group TAC levels were maintained between 8–10 ng/ml up to 2 months, 6–8 ng/ml from 2–6 months and 4–8 ng/ml after 6 months post-transplant. TAC levels in the low dose group were maintained between 4–7 ng/ml up to 2 months, 3–5 ng/ml from 3–6 months and 2–5 ng/ml after 6 months post-transplant, reflecting a 50% lower dose than the standard IS.\n\nOutcomes\nThe primary endpoints of the study were: 1) to evaluate the impact of the two maintenance immunosuppressive regimens on subpopulation of T cells including regulatory T cells and other T cell subpopulations at different time points post renal transplant, 2) to determine the impact of the two maintenance immunosuppressive regimens on renal allograft function at 12 months post randomization (post-transplant). Secondary endpoints of the study included: 1) to evaluate the impact of the two maintenance immunosuppressive regimens on allograft immunohistopathology and gene expression profiles at 3 and 12 months post-transplant in renal allograft biopsies, 2) to evaluate the impact of the two maintenance immunosuppressive regimens on acute rejection, graft loss and death at 12 months post-transplant.\n\nFollow up\nPatients were followed for 2 years post- transplant. Baseline and follow up clinical data was obtained using the transplant center Electronic Medical Record. In addition to standard of care clinic visits and blood tests, follow up also included protocol kidney biopsies (done at 3 and 12 months post-transplant) and analyses of T cell populations in peripheral blood samples at baseline, 3 and 12 months post-transplant. All allograft biopsies were independently read by our renal pathologist using the Banff classification for renal allograft pathology [12, 13]. Rejection episodes were determined based on pathological evaluation, presence of DSA and clinical judgement. Borderline change was not considered as a Rejection episode for the purposes of this study.\n\nMechanistic data\nSample collection\nBlood samples were obtained from all renal transplant recipients prior to randomization for characterization of the cell subpopulations by flow cytometry. Additional blood samples were collected at 3, 6 and 12 months post-randomization. Peripheral blood mononuclear cells (PBMC) were obtained by Ficoll-Hypaque gradient centrifugation and were stored in liquid nitrogen. Serum was also collected and stored at -80 C. Kidney biopsy samples were collected with standard-of-care samples at the time of transplant, 3 months post-transplant and 12 months post-transplant.\n\nPhenotypic characterization of regulatory T cell subsets\nT cell subpopulations from peripheral blood samples were identified at randomization (baseline, pre-transplant), at 3 months and at 12 months post-transplant by multicolor flow cytometry and were analyzed as described previously[14, 15]. For T cell subtype analysis, the PBMC were stained with CD4-Alexa-PE 700 (Invitrogen, Carlsbad, CA), CD8-APC-Cy7 (BD Biosciences, San Jose, CA), CD28-FITC (eBioscience, San Diego, CA), CD45RA-PE-Cy7 (BD Biosciences, San Jose, CA), CD45RO-PerCP-Cy5.5 (BioLegend, San Diego, CA)\n\nFor intracellular cytokine and transcriptional factor staining, the cryopreserved PBMC were thawed and stimulated with 20ng/ml PMA and 500 ng/ml ionomycin for 6 hours in presence of GolgiStop (BD Biosciences) during the last 4 hours of incubation to prevent cytokine secretion. The stimulated PBMC were then labeled with CD4-v500 (BD Biosciences, San Jose, CA), CD25-Alexa-700 (Biolegend, San Diego, CA), and CD45RO-PerCP Cy5.5 (Biolegend, San Diego, CA). After incubation and washing, the cells were fixed and permeabilized and then incubated with FOXP3-PE (eBioscience, San Diego, CA), RORγt-APC (eBioscience, San Diego, CA), IFN-γ-FITC (BD Biosciences, San Jose, CA), IL-17-PE-Cy7 (BD Biosciences, San Jose, CA). We analyzed the percentage of cells by LSRFortessa flow cytometer (BD Biosciences, San Jose, CA). Regulatory T cells were identified as CD4+CD25hiFoxP3+ cells. A total of 50,000 events were recorded per sample and the data were analyzed by FlowJo software v.10 (Tree Star, Inc. Ashland, OR).\n\nRNA isolation from kidney biopsy samples\nGraft biopsy samples at 3 and 12 months post-randomization were collected in RNAlater reagent (Ambion Inc., Austin, TX) and stored at -80°C until use. Total RNA was isolated using Trizol (Life Technologies, Carlsbad, CA) following the guidelines and recommendations in the Affymetrix GeneChip Expression Analysis Manual (Affymetrix, Santa Clara, CA). RNA quality control was evaluated following previous established parameters for microarray hybridization.[16]\n\nGene expression microarray hybridization and analysis\nTotal RNA were reverse transcribed and used for in vitro transcription to generate labeled cDNA using Affymetrix 3' IVT Express Kit (Santa Clara, CA, USA) following manufacturer protocol and recommendations. Affymetrix HG-U133A v2.0 GeneChip microarrays for gene expression (n = 31) were hybridized and scanned on an Affymetrix GeneChip Scanner 3000 G7. Quality control and normalization were performed as reported previously.[17] Probe sets raw intensities were stored in electronic files (.DAT and .CEL formats) by the GeneChip Operating Software (GCOS). Statistical analyses were performed over all probesets (n = 22,277) on each GeneChip microarray including control probesets to discard significant differences. A two-sample t-test was fit for TAC vs. EVR comparison in the R programming environment.[18] A p-value <0.05 was considered significant for differentially expressed genes. Differential gene expression was illustrated using fold-changes.\n\nInteraction networks, functional analysis, and upstream regulators\nGene ontology analyses were performed using Ingenuity Pathways Analysis (IPA; www.ingenuity.com). Spreadsheet lists containing probeset IDs, Gene IDs, and fold-changes were uploaded to IPA. For these analyses, p-values <0.05 were considered significant. Molecular pathway activity was interpreted using activation z-score (z) generated by IPA. Briefly, z-score estimates the behavior and relationship among several scores to the calculated mean. Zero z-score value indicates similar statistical behavior while positive or negative values indicate shifted trend to activation or inhibition, respectively.\n\nStatistical methods\nAll analyses were conducted on the intent-to treat population. We employed this approach in order to maintain the integrity of randomization, and hence reduce confounding due to non-random loss to follow up. Additionally, intent to treat analysis aligns more with real world practice where the effect of ordering the treatment drug is analyzed as opposed to only the effect of actual drug use. Quantitative data was expressed as mean with standard deviation or median with interquartile range. Qualitative data was expressed in percent frequency. Continuous variables were compared using paired Students T-test while categorical variables were compared using the χ2 or Fischer exact test. Survival curves were plotted using the Kaplan Meier- method and the log-rank test used to compare groups. All significance tests were 2 tailed and a p value <0.05 was considered significant. Statistical analyses were conducted using JMP v. 11.0 (SAS Institute Inc, NC).\n\nResults\nBaseline demographic and clinical characteristics of the 40 study patients are shown in Table 1. The mean age at transplant was 48.3 ± 16 and 48.4 ± 13 years in the TAC+EVR and TAC+MMF group respectively (p = 0.42). Both groups had a higher proportion of males, while the TAC+MMF group had a higher proportion of Caucasian patients. About a third of the patients in each group had pre-emptive transplants i.e. they had never been on dialysis. There was a higher proportion of patients who were diabetic in the TAC+MMF group when compared to the TAC+EVR group. All patients in the TAC+MMF group and all except one patient in the TAC+EVR group received Alemtuzumab induction. Other relevant baseline characteristics including BMI and HLA match were statistically similar.\n\n10.1371/journal.pone.0216300.t001Table 1 Baseline characteristics.\n\tTAC+EVR (%)\tTAC+MMF (%)\t\nN\t20\t20\t\nAge\t48.3 (16)\t48.4(13)\t\nGender (% male)\t13 (65)\t16 (80)\t\nRace (% Caucasian)\t9 (45)\t13 (65)\t\nPre-emptive transplant\t6 (30)\t7 (35)\t\nCause of ESRD\t\t\t\nHypertension\t6 (30)\t5 (25)\t\nPolycystic kidney disease\t3 (15)\t1 (5)\t\nLupus nephritis\t1 (5)\t1 (5)\t\nOther/Unknown\t5 (25)\t5 (25)\t\nDiabetics\t5 (25)\t10 (50)\t\nCoronary artery disease\t2 (10)\t2 (10)\t\nBMI\t24.9 (5)\t28.9(6)\t\nPRA- Class I (Mean ± SD)\t1.4 ± 3.1\t3.3 ± 10.6\t\nPRA- Class II (Mean ± SD)\t2.2 ± 8.3\t3.8 ± 3.1\t\nCrossmatch\tNegative\tNegative\t\nHLA match\t2 (1)\t2.2(1)\t\nAlemtuzumab Induction\t19 (95)\t20 (100)\t\nClinical results\nTable 2shows some of the results. Mean follow up was 14±4 and 17±5 months in the TAC+EVR and TAC+MMF group respectively (p = 0.02). The cumulative mean TAC levels were 4.5 ± 1.9 and 6.4 ± 1.5 ng/ml (p = 0.03) in the TAC+EVR and TAC+MMF group respectively. Graft and patient survival were at 100% in both groups. However none of the patients in the TAC+EVR group had rejection during study follow up, compared with 4 rejection episodes documented in the TAC+MMF group. All rejection episodes, including three antibody-mediated rejection (AMR) and one combined AMR with acute cellular rejection (ACR), were treated with a variable combination of corticosteroids, plasmapheresis, IVIG, Rituximab, Bortezomib and an escalation of immunosuppression. Development of denovo DSA without overt rejection was seen in 1 patient in each group. Similarly, development of proteinuria was seen in 2 patients in each group. A longitudinal anlalysis revealed that rejection rate was lower in the TAC+EVR group compared to the TAC+MMF group (Fig 2). However eGFR remained similar between the two groups at 3,6,12 and 18 months post-transplant (Fig 3). Incidence of adverse events, including opportunistic infections, hyperlipidemia and neutropenia was similar between the two groups (Table 2).\n\n10.1371/journal.pone.0216300.g002Fig 2 Comparison of biopsy proven rejection-rates between study groups.\n10.1371/journal.pone.0216300.g003Fig 3 Comparison of post-transplant estimated GFR between study groups.\n10.1371/journal.pone.0216300.t002Table 2 Clinical results.\nResults\tTAC+EVR\tTAC+MMF\tp value\t\n\tn = 20\tn = 20\t\t\nMean Follow up (months)*\t14 ± 4\t17 ± 5\t0.02*\t\nLost to follow up\t0\t1\t\t\nGraft Survival (percent)\t100\t100\t1.00\t\nTacrolimus level\t4.5 ± 1.9\t6.4 ± 1.5\t0.03\t\nRejection episodes\t0\t4\t0.03*\t\nDevelopment of Denovo DSA without overt rejection\t1\t1\t1.00\t\nProteinuria > 1g/day\t2\t2\t1.00\t\nAdverse Events\t\t\t\t\nHypertriglyceridemia\t3\t1\t0.33\t\nBK nephropathy\t0\t1\t1.00\t\nNeutropenia\t0\t1\t1.00\t\nOther Infections**\t5\t3\t0.44\t\n* Results expressed as mean ± standard deviation. Please see Table A in S4 File for complete information.\n\n** Other infections included bacteremia, clostridium difficile colitis, abdominal abscess and herpes zoster\n\nHistopathological results\nTable 3depicts a comparison of allograft histopathology between the 2 groups seen on 1 year protocol renal allograft biopsies. The presence of features suggestive of CNI nephrotoxicity, including interstitial fibrosis and tubular atrophy (IFTA), isometric vacuolization and arteriolar hyalinosis was similar between the two groups.\n\n10.1371/journal.pone.0216300.t003Table 3 Results– 12 month histopathology data.\nPathology\tTAC+EVR (n = 19)*\tTAC+MMF (n = 16)*\t\nGlomerusclerosis:-Global (GS) and Segmental (SS)\tGS: 8 (42%)\tGS: 5 (33%)\t\nSS: 5 (26%)\tSS: 4 (27%)\t\nAcute glomerulitis (g)\tg1: 0 (0%)\tg1: 2 (13%)\t\ng2: 0 (0%)\tg2: 0 (0%)\t\ng3: 0 (0%)\tg3: 0 (0%)\t\nTubulitis NOT in IFTA (>t)\tt1: 1 (5%)\tt1: 2 (13%)\t\nt2: 2 (11%)\tt2: 1 (6%)\t\nt3: 0 (0%)\tt3: 0 (0%)\t\nAcute Tubular Necrosis (ATN)/Isometric Tubular vacuolization\tMild: 14 (74%)\tMild: 9 (56%)\t\nModerate: 5 (26%)\tModerate: 1 (6%)\t\nSevere: 0 (0%)\tSevere: 0 (0%)\t\nIsometric: 1 (5%)\t\t\nInterstitial Inflammation (i)\ti1: 1 (5%)\ti1: 2 (12%)\t\ni2: 0 (0%)\ti2: 0 (0%)\t\ni3: 0 (0%)\ti3: 0 (0%)\t\nArteriolar Hyalinosis (ah)\tah1: 1 (5%)\tah1: 1 (6%)\t\nah2: 0 (0%)\tah2: 0 (0%)\t\nah3: 0 (0%)\tah3: 0 (0%)\t\nArteriosclerosis (cv)\tcv1: 5 (26%)\tcv1: 4 (25%)\t\ncv2: 1 (5%)\tcv2: 0 (0%)\t\ncv3: 0 (0%)\tcv3: 0 (0%)\t\nPeritubular capillaritis (PTC)\tptc1: 0 (0%)\tptc1: 3 19%)\t\nptc2: 0 (0%)\tptc:2: 2 (13%)\t\nptc3: 0 (0%)\tptc:3: 0 (0%)\t\nInterstitial fibrosis and Tubular atrophy (IFTA)**\tMild: 12 (63%)\tMild: 11 (70%)\t\nModerate: 1 (5%)\tModerate: 1 (6%)\t\nSevere: 0 (0%)\tSevere: 0 (0%)\t\nInflammation associated with IFTA\tMinimal: 4 (21%)\tMinimal: 1 (6%)\t\nMild: 5 (26%)\tMild: 4 (25%)\t\nModerate: 3 (16%)\tModerate: 3(20%)\t\nSevere: 0 (0%)\tSevere: 0 (0%)\t\nTubulitis of intact tubules within/interface (t)\tt1: 4 (21%)\tt1: 3 (20%)\t\nt2: 2 (11%)\tt2: 1 (6%)\t\nt3: 0 (0%)\tt3: 0 (0%)\t\nTransplant glomerulopathy (cg)\tcg1: 0 (0%)\tcg1:0 (0%)\t\ncg2: 0 (0%)\tcg2:0 (0%)\t\ncg3: 0(0%)\tcg3: 0 (0%)\t\nC4d staining on immunofluorescence\tC4d1: 0 (0%)\tC4d1: 0 (0%)\t\nC4d2: 0 (0%)\tC4d2: 0 (0%)\t\nC4d3: 0 (0%)\tC4d3: 4(25%)\t\nOTHER FINDINGS/DIAGNOSIS\tBorderline change:2 (12%)\tBorderline change: 2/15 (13%)\t\nSubcapsular injury: 5 (30%)\tSubcapsular injury: 2/15 (13%)\t\n\tPolyoma Virus: 1/15 (7%)\t\n\tAMR: 4/15 (27%)\t\n* All values expressed as n (%). There was no significant difference between the 2 study groups. All pathological definitions are per Banff criteria. Please see Table B in S4 Data file for complete information.\n\n** IFTA0 and IFTA1 combined in one group.\n\nMechanistic data\nTAC+EVR leads to expansion of regulatory T cells without affecting other T cell subpopulations\nFrequency of CD4 T cells, CD8 T cells, CD4+CD25- T cells, naïve CD4 T cells (CD4+CD45RA+), memory CD4 T cells (CD4+CD45RO+), naïve CD8 T cells (CD8+CD45RA+), memory CD8 T cells (CD8+CD45RO+), and regulatory T cells (CD4+CD25hiFoxp3+) in peripheral blood were analyzed by flow cytometry. Changes in T cells subpopulations and regulatory T cells were compared over time from baseline (pre-transplant) to 3 months and 12 months post-transplant within each group and between TAC+EVR and TAC+MMF groups. The frequencies of CD4 T cells, CD8 T cells, CD4+CD25- T cells, naïve CD4 and CD8, and memory CD4 and CD8 T cells were similar between the two groups [19] However, we observed an increase in frequencies of CD4+CD25hiFoxp3+ regulatory T cells in the TAC+EVR group compared to the TAC+MMF group starting from 3 months post-transplant and the frequencies of CD4+CD25hiFoxp3+ regulatory T cells were significantly higher in the TAC+EVR group at 12 months post-transplant (Fig 4).\n\n10.1371/journal.pone.0216300.g004Fig 4 Percentage of CD4+CD25hiFOXP3+ regulatory T cells in the peripheral blood between study groups.\nFlow cytometric analyses were performed as described in Materials and methods. The number of subjects analyzed at—Baseline: TAC+EVR N = 15,TAC+MMF N = 13; 3 mo: TAC+EVR N = 14,TAC+MMF N = 9; 12 mo: TAC+EVR N = 15,TAC+MMF N = 12. Please see Table C in S5 File for complete information.\n\nCo-expression of IFN-Gamma (IFN-γ) in CD4+CD25hiFoxp3+T cells of recipients receiving TAC+EVR\nWe used intracellular cytokine and transcriptional factor staining to evaluate the CD4+CD25hiFoxp3+ T cells from both TAC+EVR and TAC+MMF group. Intracellular cytokine and transcriptional factor staining for Interferon Gamma (IFN-γ), Interleukin 17 (IL-17) and RAR-related orphan receptor gamma 2 (RORγt) showed no difference at baseline between the two groups. Interestingly, we observed a significant decline in the TAC+MMF group with stable maintenance in TAC+EVR group of percentage IFN-γ positive CD4+CD25hiFoxp3+ T cells at 12 months post-transplant (Fig 5). The frequencies of IL-17 positive CD4+CD25hiFoxp3+ T cells and RORγt positive T cells were similar between the two groups (Fig 5).\n\n10.1371/journal.pone.0216300.g005Fig 5 Intracellular cytokine and transcription factor staining for interferon-γ, interlekin-17 (IL-17) and RAR-related orphan receptor gamma 2 (RORγt) in CD4+CD25hiFOXP3+ regulatory T cells between study groups.\nThe number of subjects analyzed at—Baseline: TAC+EVR N = 15,TAC+MMF N = 13; 3 mo: TAC+EVR N = 14,TAC+MMF N = 9; 12 mo: TAC+EVR N = 15,TAC+MMF N = 12. Please Tables D, E and F in S5 File for complete information.\n\nGene expression results\nA total of 22 patients with longitudinal biopsies at 3- and 12 months post-randomization were available. Of the RNA samples isolated from 44 biopsies, 31 samples (3 mo TAC+EVR n = 7; 12 mo TAC+EVR n = 7; 3 mo TAC+MMF n = 9; 12 mo TAC+MMF n = 8) passed qualility control (QC) conducted at various stages through RNA isolation to gene expression array process and thus were used for the final analysis. Twenty eight of the 31 samples represented paired two-time point biopsy RNA samples from 14 patients (TAC+EVR n = 6; TAC+MMF n = 8) and were used for longitudinal analysis of gene expression. At 3 months post-transplant, there were no differences in the gene expression profiles between TAC+EVR and TAC+MMF groups. However, at 12 months post-transplant a total of 183 probesets were differentially expressed (60% were down regulated and 40% were upregulated in TAC+EVR group) between groups (Fold change cutoff 1.5; p-value cutoff 0.05). Pathway analysis (ingenuity.com) showed that the differentially expressed genes in TAC+EVR group were involved in inhibition of functions like inflammatory response (p-value 5.45E-05; z-score -2.488), growth of connective tissue (p-value 2.68E-04; z-score -2.187), and chemotaxis of lymphatic system cells (p-value 1.29E-04; z-score -2.543), more specifically chemotaxis of T lymphocytes (p = 1.54E-04; z-score -2.366) (Fig 6).\n\n10.1371/journal.pone.0216300.g006Fig 6 Inhibition of major functions.\nFunctions like growth of connective tissue (A), inflammatory response (B), and chemotaxis of T lymphocytes (C) were predicted to be inhibited (blue) and the genes involved were mostly downregulated (green). The legend with the color code for the prediction is shown at the bottom right. Please see Table G in S5 File for complete information.\n\nThe upstream regulator that was most significantly predicted to be inhibited was TGFB1 (p-value 2.02E-08; z-score -2.325); there were others like IL6 (p-value 3.69E-02; z-score -1.919), OSM (p-value 4.65E-04; z-score -2.855) and EDN1 (p-value 1.66E-06; z-score -2.595) (Fig 7). These findings supported a trend of decreased inflammatory response, angiogenesis, and decreased connective tissue growth at 12 months post-transplant in the TAC+EVR group.\n\n10.1371/journal.pone.0216300.g007Fig 7 Predicted upstream regulators.\nBased on the differentially expressed genes, certain functions like inflammatory response, chemotaxis of T lymphocytes, and growth of connective tissue were predicted to be inhibited (blue). IPA analysis predicted that the inhibition of upstream regulators like the cytokine TGFB1, EDN1, IL-6 and OSM would lead to decrease in the functions listed in the third tier of the figure via their effect on the mediator genes that were also seen to be differentially expressed between the two groups. Please see Table H in S5 File for complete information.\n\nA longitudinal analysis of gene expression profile changes in biopsies from TAC+EVR and TAC+MMF groups were also performed. Thus, when compared between 3 months and 12 months post-transplant, TAC+EVR and TAC+MMF groups differentially expressed 189 and 542 probe sets, respectively. This also showed that canonical pathways related to cell proliferation and migration/chemotaxis like renin-angiotensin signaling (Figure A in S1 File), ephrin receptor signaling (Figure B in S1 File), endothelin-1 signaling, PDGF signaling, among others, were more activated in TAC+MMF in comparison to TAC+EVR (Fig 8).\n\n10.1371/journal.pone.0216300.g008Fig 8 Analysis of time dependent changes in gene expression pathways in TAC+EVR and TAC+MMF groups.\nBased on comparison analysis of differentially expressed genes at 12 month in comparison to 3 months post-transplantation on the two studied groups, it was observed that pathways related to cell proliferation, chemotaxis and inflammation were much pronounced in TAC+MMF (grey) in comparison to TAC+EVR (black). Please see Tables J and K in S5 File for complete information.\n\nUsing IPA, T cell related diseases and functions were compared for sequential changes in biopsies from TAC+EVR and TAC+MMF groups. It was observed that though there were common functions between the two groups, functions like chemotaxis of T cells, T cell development, T cell migration were more activated in TAC+MMF. Each group had unique set of genes related to T cell functions implying that these groups started to diverge in terms of their gene expression pattern and thereby T cell functionality (Figure C in S1 File).\n\nDiscussion\nImmunosuppressive protocols in kidney transplantation often utilize a combination of drugs that significantly decrease the rate of acute cellular rejection. Despite advances in surgical and medical care of kidney transplant recipients, long-term graft survival has not yet drastically improved. This is mainly due to the side effects associated with CNI therapy, such as nephrotoxicity as well as increased malignancy and cardiovascular diseases. Consequently, many strategies have been developed to minimize nephrotoxicity while maintaining efficacy of immunosuppression and improve long-term outcomes. Thus, mammalian target of rapamycin (mTOR) inhibitors such as everolimus in combination with low-dose CNI being recognized as an attractive option for providing acceptable rejection rates and better allograft function. De novo treatment with mTOR inhibitors in combination with mycophenolate has been shown to result in higher acute rejection rates [6]. Similarly, early conversion from a CNI to an mTOR inhibitor therapy in selected patients provided only equal or slightly better GFR with some increase in acute rejection rate [7].\n\nFrom our previous report, conversion from TAC to Sirolimus at 12 months post-transplantation is not associated with increased rates of acute rejection and graft loss. Nevertheless, despite CNI elimination, renal allograft function is equally maintained in both groups [20]. We also demonstrated that Sirolimus conversion led to an increase in CD4+CD25hiFoxp3+ regulatory T cells (Treg) overtime after conversion. Despite the expansion of Treg, we found some evidences of chronic immune alterations after sirolimus conversion [21]. There was an increased indirect alloreactive T-cell frequencies measured by IFN-γ ELISPOT. At the molecular level, there was an activation of the antigen presentation, IL-12 signaling, oxidative stress, macrophage-derived production pathways, and increased inflammatory and immune responses. However, data from an in vitro study indicated that combination of an mTOR inhibitor with low dose CNI promotes the differentiation and expansion of donor-specific Tregs without secondary reprogramming to IFN-γFOXP3 and IL-17FOXP3 Treg subsets [22]. Furthermore, mTOR inhibitor was shown to have potent B cell inhibitory effects in-vitro [23] which might help control the humoral immune response to the allograft.\n\nIn contrast to our previous report that demonstrated an unfavorable chronic immune alteration in Sirolimus-treated recipients, we found more encouraging results with Everolimus. Therefore, in this study, we used a combination of low dose TAC+EVR aiming to achieve the immunomodulatory effects of both the mTOR inhibitor and the Calcineurin inhibitor. The study included only living donors so that the complicating effects of cold ischemia time could be avoided. The one-year results are quite promising with lower rejection-rate in the TAC+EVR group. An independent review of biopsies showed that there was a trend towards increased pathological features of immunological activity in the TAC+MMF group compared to the TAC+EVR group, but these features didn’t reach statistical significance when analyzed individually. However, a longer follow up is needed to see if this translates into better long term graft function. As expected, we found an expansion of CD4+CD25hiFoxp3+ regulatory T cell subset in the TAC+EVR group compared to the TAC+MMF group as early as 3 months post-transplant and the expansion continued to persist at 12 months post-transplant. Interestingly, we found a significantly higher percentage of IFN-γ positive CD4+CD25hiFoxp3+ T cells in the TAC+EVR group compared to the TAC+MMF group at 12 months post-transplant. It is increasing being recognized that IFN-gamma plays a major role in both induction and functioning of regulatory T cells [24]. Sawitzki et al. reported that IFN-γ production was important for the regulatory functions of mouse alloantigen-reactive regulatory T cells in vivo [25]. In human, it was observed that kidney transplant recipients with good graft function and a serum creatinine of ≤ 1.8 mg/dl for more than 100 days (mean 5 years) had more CD4+CD25+Foxp3+IFNγ+ T cells in the peripheral blood than recipients with impaired graft function and a serum creatinine of ≥ 2.0 mg/dl [26]. These reports suggest that CD4+CD25+Foxp3+IFNγ+ T cells may be involved in the prevention of acute rejection early in mice and the maintenance of good graft function long-term in the human.\n\nAlthough Everolimus has a similar structure to Sirolimus, the additional hydroxyethyl group at the C(40) of the Everolimus molecule results in different pharmacokinetic and pharmacodynamics properties such as tissue and subcellular distribution, different affinities to active drug transporters and drug-metabolizing enzymes as well as differences in drug-target protein interactions including a much higher potency in terms of interacting with the mTOR complex 2 than Sirolimus [27]. Previous reports in animals comparing both mTOR inhibitors showed that Sirolimus might enhance calcineurin inhibitors nephrotoxicity while Everolimus has less negative effects [28]. Ex vivo study also showed that Everolimus had a more favorable effect on vascular endothelial function than Sirolimus [29] and Everolimus was more effective than Sirolimus in reducing the inflammatory cytokine IL-8 and VEGF release as well as increasing the release of the anti-inflammatory cytokine IL-1RA [30]. Similarly, in the in vitro Treg-MLR assay, EVL was found to be more potent and consistent immunoregulatory agent and less dependent on concentrations than Sirolimus [31]. In this study, the comparison of gene expression profile in kidney tissue between TAC+EVR and TAC+MMF also supported the previous data with the findings of a decreased inflammatory response, angiogenesis, and a decreased connective tissue growth at 12 months post-transplant in the TAC+EVR group.\n\nRecently, a large multi-center prospective study of EVR with reduced CNI exposure demonstrated non-inferiority compared to MMF with standard-exposure of CNI [32]. In contrast to our study, all subjects were on triple immunosuppression including steroids and majority received IL-2R blocker induction. Further, no mechanistic studies were performed. The limitations of our study include a small sample size and only 12 months of follow-up. Despite the short-term follow up, however, we were able to demonstrate promising results in rejection rate and the mechanistic data and gene expression profile favoring the combination of Everolimus with low dose Tacrolimus over the conventional regimen. Longer-term data are needed to confirm these encouraging results. Also for the future, use of single cell mRNA sequencing technique, when it is better developed and validated, may provide more pathological and physiological information affecting the graft.\n\nSupporting information\nS1 File Containing Figure A, Figure B and Figure C.\n(DOCX)\n\nClick here for additional data file.\n\n S2 File Clinical trial protocol.\n(PDF)\n\nClick here for additional data file.\n\n S3 File Consort checklist.\n(DOCX)\n\nClick here for additional data file.\n\n S4 File Table A (clinical data) and Table B (histopathological data).\n(PDF)\n\nClick here for additional data file.\n\n S5 File Tables C, D, E, F, G, H, J and K for Figs 4–8.\n(PDF)\n\nClick here for additional data file.\n\n Abbreviations\nACRAcute cellular rejection\n\nAMRAntibody-mediated rejection\n\nBMIBody mass index\n\nCNICalcineurin inhibitors\n\nCsACyclosporine-A\n\nDSADonor-specific antibodies\n\nELISPOTEnzyme-linked ImmunoSpot\n\nEVREverolimus\n\nFSGSFocal segmental glomerulosclerosis\n\nHLAhuman leukocyte antigen\n\nIFN-γInterferon Gamma\n\nIL-17Interleukin 17\n\nIFTAinterstitial fibrosis and tubular atrophy\n\nIRBInstitutional Review Board\n\nISImmunosuppression, immunosuppressive drugs\n\nKTkidney transplantation\n\nMMFMycophenolate\n\nPBMCPeripheral blood mononuclear cells\n\nPMAPhorbol 12-myristate 13-acetate\n\nRARheumatoid Arthritis\n\nSLESystemic lupus erythematosus\n\nTACTacrolimus\n\nTregsCD4+CD25hiFoxp3+ regulatory T cells\n==== Refs\nReferences\n1 Nankivell BJ , Borrows RJ , Fung CL , O'Connell PJ , Allen RD , Chapman JR . 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J Am Soc Nephrol . 2018 Epub 2018/05/13. 10.1681/asn.2018010009 .29752413\n\n",
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"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D004359:Drug Therapy, Combination; D000068338:Everolimus; D005260:Female; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D016559:Tacrolimus; D066027:Transplant Recipients; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e0216300",
"pmc": null,
"pmid": "31136582",
"pubdate": "2019",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "22052056;24266365;29752413;12392286;22321054;19935373;27639190;27275747;15364885;25912929;24472190;22239125;15943635;24882386;25905982;10213717;25354238;15108252;11888584;19040489;24007570;14668458;15967822;26087255;19218475;16157605;15367210;22282478;23118926;18298587",
"title": "Mechanistic analyses in kidney transplant recipients prospectively randomized to two steroid free regimen-Low dose Tacrolimus with Everolimus versus standard dose Tacrolimus with Mycophenolate Mofetil.",
"title_normalized": "mechanistic analyses in kidney transplant recipients prospectively randomized to two steroid free regimen low dose tacrolimus with everolimus versus standard dose tacrolimus with mycophenolate mofetil"
} | [
{
"companynumb": "US-PBT-000212",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
"drugadmi... |
{
"abstract": "OBJECTIVE\nRound-cell sarcomas lacking specific translocations represent a diagnostic challenge. The aim of this study was to describe seven cases of CIC-DUX4 fusion-positive sarcomas, including the first reported example arising primarily in bone.\n\n\nRESULTS\nPatients ranged in age from 15 years to 44 years (median: 33 years). Six cases arose from the soft tissues, and one from the iliac bone. Morphologically, all cases showed an undifferentiated round-cell population with greater atypia and pleomorphism than Ewing sarcoma. Immunohistochemically, all tumours showed focal and weak positivity for CD99, and five of seven showed nuclear and/or cytoplasmic positivity for Wilms tumour 1. Five patients had lung metastases at presentation. All patients received chemotherapy according to Ewing sarcoma protocols. All but one patient (the one with a bone tumour) died of disease after a mean of 14.5 months from the diagnosis (range: 8-20 months).\n\n\nCONCLUSIONS\nOur series confirms that CIC-DUX4 fusion-positive sarcomas are aggressive tumours with an adverse prognosis, and with clinical, histological and genetic differences from Ewing sarcoma. The best therapeutic approach needs to be investigated.",
"affiliations": "Department of Pathology, Rizzoli Institute, Bologna, Italy.;Department of Pathology, Rizzoli Institute, Bologna, Italy.;Department of Pathology, Rizzoli Institute, Bologna, Italy.;Department of Pathology, Rizzoli Institute, Bologna, Italy.;Department of Oncology, Rizzoli Institute, Bologna, Italy.;Department of Pathology, Treviso Regional Hospital, Treviso, Italy.;Department of Orthopaedic Oncology, Rizzoli Institute, Bologna, Italy.;Department of Pathology, Rizzoli Institute, Bologna, Italy.;Department of Pathology, Rizzoli Institute, Bologna, Italy.;Department of Oncology, Rizzoli Institute, Bologna, Italy.;Department of Pathology, Rizzoli Institute, Bologna, Italy. alberto.righi@ior.it.;Department of Pathology, Rizzoli Institute, Bologna, Italy.",
"authors": "Gambarotti|Marco|M|;Benini|Stefania|S|;Gamberi|Gabriella|G|;Cocchi|Stefania|S|;Palmerini|Emanuela|E|;Sbaraglia|Marta|M|;Donati|Davide|D|;Picci|Piero|P|;Vanel|Daniel|D|;Ferrari|Stefano|S|;Righi|Alberto|A|;Dei Tos|Angelo P|AP|",
"chemical_list": "D014408:Biomarkers, Tumor; C574694:CIC-DUX4 fusion protein, human; D015514:Oncogene Proteins, Fusion",
"country": "England",
"delete": false,
"doi": "10.1111/his.12985",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0309-0167",
"issue": "69(4)",
"journal": "Histopathology",
"keywords": "CIC; DUX4; Ewing sarcoma; round-cell sarcoma",
"medline_ta": "Histopathology",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D014408:Biomarkers, Tumor; D001859:Bone Neoplasms; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D015514:Oncogene Proteins, Fusion; D016133:Polymerase Chain Reaction; D018228:Sarcoma, Small Cell; D012983:Soft Tissue Neoplasms; D055815:Young Adult",
"nlm_unique_id": "7704136",
"other_id": null,
"pages": "624-34",
"pmc": null,
"pmid": "27079694",
"pubdate": "2016-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "CIC-DUX4 fusion-positive round-cell sarcomas of soft tissue and bone: a single-institution morphological and molecular analysis of seven cases.",
"title_normalized": "cic dux4 fusion positive round cell sarcomas of soft tissue and bone a single institution morphological and molecular analysis of seven cases"
} | [
{
"companynumb": "IT-ACCORD-045712",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IFOSFAMIDE"
},
"drugadditional": null,
"drug... |
{
"abstract": "Dalfampridine extended release (DAL) is a broad-spectrum voltage-gated potassium channel blocker that is indicated in multiple sclerosis to improve the nerve conduction of demyelinated axons. Seizures are a known side effect of DAL, which is contraindicated in patients with a history of epilepsy.\n\n\n\nThree cases of multiple sclerosis (MS) with de novo convulsive status epilepticus (CSE) probably related to dalfampridine administration are described.\n\n\n\nNo patients had a history of seizures or renal impairment. Biological tests were normal. A brain magnetic resonance imaging (MRI) showed diffuse cortical and subcortical atrophy without active inflammatory lesions.\n\n\n\nAll three patients presented with CSE that was attributed to DAL and so was discontinued.\n\n\n\nThese case reports illustrate that, aside from seizures, de novo CSE is a potential complication of MS patients treated with DAL.",
"affiliations": "Service de Neurologie, CRCSEP, Hôpital Pasteur 2, Nice, France.;Service de Neurologie, CRCSEP, Hôpital Pasteur 2, Nice, France.;Service de Neurologie, CRCSEP, Hôpital Pasteur 2, Nice, France.;Centre régional de Pharmacovigilance, Hôpital Cimiez, Nice, France.;Service de Neurologie, CRCSEP, Hôpital Pasteur 2, Nice, France.;Service de Neurologie, CRCSEP, Hôpital Pasteur 2, Nice, France.",
"authors": "Panicucci|Emilie|E|;Cohen|Mikael|M|;Bourg|Veronique|V|;Rocher|Fanny|F|;Thomas|Pierre|P|;Lebrun|Christine|C|",
"chemical_list": "D026902:Potassium Channel Blockers; D015761:4-Aminopyridine",
"country": "England",
"delete": false,
"doi": "10.1177/1352458518790379",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1352-4585",
"issue": "25(4)",
"journal": "Multiple sclerosis (Houndmills, Basingstoke, England)",
"keywords": "De novo convulsive status epilepticus; baclofen; dalfampridine; multiple sclerosis",
"medline_ta": "Mult Scler",
"mesh_terms": "D015761:4-Aminopyridine; D000328:Adult; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis; D020529:Multiple Sclerosis, Relapsing-Remitting; D026902:Potassium Channel Blockers; D013226:Status Epilepticus",
"nlm_unique_id": "9509185",
"other_id": null,
"pages": "618-621",
"pmc": null,
"pmid": "30375922",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "De novo convulsive status epilepticus in patients with multiple sclerosis treated with dalfampridine.",
"title_normalized": "de novo convulsive status epilepticus in patients with multiple sclerosis treated with dalfampridine"
} | [
{
"companynumb": "FR-MYLANLABS-2017M1076251",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DALFAMPRIDINE"
},
"drugadditional": "1",
... |
{
"abstract": "Gastrointestinal toxicities of MEK inhibitors in melanoma patients are frequent. In clinical trials, the most common digestive adverse events were nausea, vomiting, and diarrhoea. However, severe toxicities such as colitis and gastrointestinal perforation, some with fatal outcomes, have been reported. These rare but severe adverse events are not well described. We performed a retrospective analysis of all patients with stage IV and unresectable stage III melanoma treated with a MEK inhibitors at Saint-Louis Hospital, Paris, between 1 August 2013 and 15 October 2018. Among 119 patients exposed to MEK inhibitors, 78 were treated with trametinib, 19 with cobimetinib, four with binimetinib, and 18 patients with two different MEK inhibitors at separate times. All grade digestive adverse events were observed in 39 (32.7%) patients. Grade 3 and 4 adverse events occurred in 6 (5%) patients: 2 (1.7%) developed perforations, 3 (2.5%) had colitis and 1 (0.8%) had grade 4 diarrhoea. These adverse events were all reversible following a permanent discontinuation of the MEK inhibitors, or a temporary interruption followed by resumption at a dose lower than conventional posology. There were no fatal outcomes; however one patient had a permanent ileostomy. The mechanism underlying these toxicities is not well known. Clinicians should be aware of such toxicities.",
"affiliations": "APHP, Oncodermatology Unit, Dermatology Department.;APHP, Gastroenterology Department.;APHP, Oncodermatology Unit, Dermatology Department.;APHP, Regional Pharmacovigilance Center, Fernand Widal Hospital.;APHP, Pathology Department, Saint-Louis Hospital.;APHP, Oncodermatology Unit, Dermatology Department.;APHP, Oncodermatology Unit, Dermatology Department.;APHP, Oncodermatology Unit, Dermatology Department.;APHP, Gastroenterology Department.;APHP, Oncodermatology Unit, Dermatology Department.;APHP, Oncodermatology Unit, Dermatology Department.",
"authors": "Mourad|Nadim|N|;Lourenço|Nelson|N|;Delyon|Julie|J|;Eftekhari|Pirayeh|P|;Bertheau|Philippe|P|;Allayous|Clara|C|;Ballon|Alice|A|;Pagès|Cécile|C|;Allez|Matthieu|M|;Lebbé|Céleste|C|;Baroudjian|Barouyr|B|;|||",
"chemical_list": "D000970:Antineoplastic Agents; D001384:Azetidines; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D010880:Piperidines; D011728:Pyridones; D011744:Pyrimidinones; C581313:binimetinib; C560077:trametinib; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; C574276:cobimetinib",
"country": "England",
"delete": false,
"doi": "10.1097/CMR.0000000000000618",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0960-8931",
"issue": "29(5)",
"journal": "Melanoma research",
"keywords": null,
"medline_ta": "Melanoma Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D001384:Azetidines; D001562:Benzimidazoles; D016208:Databases, Factual; D004791:Enzyme Inhibitors; D005260:Female; D041981:Gastrointestinal Tract; D006801:Humans; D048369:MAP Kinase Kinase 1; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D010880:Piperidines; D011728:Pyridones; D011744:Pyrimidinones; D012189:Retrospective Studies; D012878:Skin Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "9109623",
"other_id": null,
"pages": "556-559",
"pmc": null,
"pmid": "31095035",
"pubdate": "2019-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Severe gastrointestinal toxicity of MEK inhibitors.",
"title_normalized": "severe gastrointestinal toxicity of mek inhibitors"
} | [
{
"companynumb": "PHHY2019FR141965",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DABRAFENIB"
},
"drugadditional": "1",
"druga... |
{
"abstract": "To determine the effect of denosumab, which is used in primary osteoporosis (PO), in primary hyperparathyroidism (PHPT)-related osteoporosis.\n\n\n\nRetrospective, longitudinal study.\n\n\n\nOutpatient osteoporosis clinic.\n\n\n\nOlder women with PHPT (78.6 ± 5.5) (n = 25) and PO (78.8 ± 5.2) (n = 25) matched on age, body mass index, familial history of hip fracture, femoral bone mineral density (BMD), and personal history of fragility fractures.\n\n\n\nTwenty-four months of denosumab therapy.\n\n\n\nWe assessed the calcium-phosphorus metabolism parameters; BMD at the lumbar spine (LS), femoral neck (FN), and total hip (TH) using dual X-ray absorptiometry; and morphometric vertebral fractures using radiographs in all subjects at baseline and after 24 months. Changes in BMD and total alkaline phosphatase (ALP) activity were considered significant if they were greater than the least significant change (LS 2.8%, FN 5.9%, TH 4.8%, ALP -22%) and were expressed as percentage difference between end of follow-up and baseline (Δ).\n\n\n\nAfter 24 months, women with PHPT had greater ΔALP (-30.6 ± 11.3), ΔFN (5.6 ± 4.8), and ΔTH (4.8 ± 4.4) than those with PO (ΔALP -21.4 ± 13.1, ΔFN 2.9 ± 4.8, ΔTH 1.2 ± 4.1, P < .05 for all comparisons). A significant increase in BMD was more frequent in women with PHPT (92%) than in those with PO (52%, P < .05) and it was 13.4 times as likely in women with PHPT as in those with PO (P = .02), regardless of possible confounders. Two subjects in each group had an incident fracture.\n\n\n\nDenosumab therapy is effective in older women with PHPT-related osteoporosis.",
"affiliations": "Unit of Endocrinology, Fondazione IRCCS Cà Granda-Ospedale Maggiore Policlinico, Milan, Italy.;Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.;Unit of Endocrinology, Fondazione IRCCS Cà Granda-Ospedale Maggiore Policlinico, Milan, Italy.;Unit of Endocrinology, 'Casa Sollievo della Sofferenza,' IRCCS, San Giovanni Rotondo, Foggia, Italy.;Unit of Endocrinology, 'Casa Sollievo della Sofferenza,' IRCCS, San Giovanni Rotondo, Foggia, Italy.;Unit of Endocrinology, Fondazione IRCCS Cà Granda-Ospedale Maggiore Policlinico, Milan, Italy.;Villa Alba Hospital, Villa Maria Group, Bologna, Italy.;Unit of Endocrinology, Fondazione IRCCS Cà Granda-Ospedale Maggiore Policlinico, Milan, Italy.",
"authors": "Eller-Vainicher|Cristina|C|;Palmieri|Serena|S|;Cairoli|Elisa|E|;Goggi|Giovanni|G|;Scillitani|Alfredo|A|;Arosio|Maura|M|;Falchetti|Alberto|A|;Chiodini|Iacopo|I|0000-0001-7594-3300",
"chemical_list": "D050071:Bone Density Conservation Agents; D000069448:Denosumab",
"country": "United States",
"delete": false,
"doi": "10.1111/jgs.15250",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-8614",
"issue": "66(3)",
"journal": "Journal of the American Geriatrics Society",
"keywords": "bone mineral density; denosumab; fragility fractures; primary hyperparathyroidism",
"medline_ta": "J Am Geriatr Soc",
"mesh_terms": "D000368:Aged; D015519:Bone Density; D050071:Bone Density Conservation Agents; D016723:Bone Remodeling; D000069448:Denosumab; D005260:Female; D006801:Humans; D049950:Hyperparathyroidism, Primary; D008137:Longitudinal Studies; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal; D012189:Retrospective Studies",
"nlm_unique_id": "7503062",
"other_id": null,
"pages": "518-524",
"pmc": null,
"pmid": "29364518",
"pubdate": "2018-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Protective Effect of Denosumab on Bone in Older Women with Primary Hyperparathyroidism.",
"title_normalized": "protective effect of denosumab on bone in older women with primary hyperparathyroidism"
} | [
{
"companynumb": "IT-AMGEN-ITASP2018017809",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DENOSUMAB"
},
"drugadditional": null,
... |
{
"abstract": "There are limited pediatric population pharmacokinetic data for voriconazole dosing, particularly in younger children. In a cohort of 34 patients younger than 3 years receiving voriconazole, the majority (n = 23, 68%) had a low initial serum concentration <1 mg/L. Among 23 children <2 years old, 19 (83%) had an initial trough <1 mg/L. There was large intra- and interindividual variability in trough levels. Dosing also varied from 3.3 to 19.6 mg/kg per dose. Only 2 of 34 patients had a documented adverse drug reaction attributable to voriconazole. More data are needed to establish optimal dosing in very young children.",
"affiliations": "Department of Pharmacy, Infectious Disease Service, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Pharmacy, Infectious Disease Service, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Pediatrics, Infectious Disease Service, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Epidemiology and Biostatistics, Infectious Disease Service, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Infectious Disease Service, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Pharmacy, Infectious Disease Service, Memorial Sloan Kettering Cancer Center, New York, New York.",
"authors": "Yan|Shirley Qiong|SQ|;Seyboth|Brian|B|;Kobos|Rachel|R|;Eaton|Anne|A|;Seo|Susan K|SK|;Cohen|Nina|N|",
"chemical_list": "D000935:Antifungal Agents; D000970:Antineoplastic Agents; D065819:Voriconazole",
"country": "England",
"delete": false,
"doi": "10.1093/jpids/pix022",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2048-7193",
"issue": "7(2)",
"journal": "Journal of the Pediatric Infectious Diseases Society",
"keywords": null,
"medline_ta": "J Pediatric Infect Dis Soc",
"mesh_terms": "D000935:Antifungal Agents; D000970:Antineoplastic Agents; D002675:Child, Preschool; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016867:Immunocompromised Host; D015470:Leukemia, Myeloid, Acute; D008297:Male; D009181:Mycoses; D009190:Myelodysplastic Syndromes; D012189:Retrospective Studies; D065819:Voriconazole",
"nlm_unique_id": "101586049",
"other_id": null,
"pages": "169-171",
"pmc": null,
"pmid": "28407118",
"pubdate": "2018-05-15",
"publication_types": "D016428:Journal Article",
"references": "21258094;18462102;25371690;22430956;18171251;25451051;16207133;19223632;13679531",
"title": "Voriconazole Dosing in Children Younger Than 3 Years Undergoing Cancer Chemotherapy or Hematopoietic Stem Cell Transplantation.",
"title_normalized": "voriconazole dosing in children younger than 3 years undergoing cancer chemotherapy or hematopoietic stem cell transplantation"
} | [
{
"companynumb": "US-TEVA-2019-US-1046733",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "VORICONAZOLE"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nIn a recent randomized controlled trial our group has demonstrated in 102 patients that late post-conditioning with sevoflurane performed in the intensive care unit after surgery involving extracorporeal circulation reduced damage to cardiomyocytes exposed to ischemia reperfusion injury. On the first post-operative day the sevoflurane patients presented with lower troponin T values when compared with those undergoing propofol sedation. In order to assess possible clinical relevant long-term implications in patients enrolled in this study, we performed the current retrospective analysis focusing on cardiac and non-cardiac events during the first 6 months after surgery.\n\n\nMETHODS\nAll patients who had successfully completed the late post-conditioning trial were included into this follow-up. Our primary and secondary endpoints were the proportion of patients experiencing cardiac and non-cardiac events, respectively. Additionally, we were interested in assessing therapeutic interventions such as initiation or change of drug therapy, interventional treatment or surgery.\n\n\nRESULTS\nOf 102 patients analyzed in the primary study 94 could be included in this follow-up. In the sevoflurane group (with 41 patients) 16 (39%) experienced one or several cardiac events within 6 months after cardiac surgery, in the propofol group (with 53 patients) 19 (36%, p=0.75). Four patients (9%) with sevoflurane vs. 7 (13%) with propofol sedation had non-cardiac events (p=0.61). While a similar percentage of patients suffered from cardiac and/or non-cardiac events, only 12 patients in the sevoflurane group compared to 20 propofol patients needed a therapeutic intervention (OR: 0.24, 95% CI: 0.04-1.43, p=0.12). A similar result was found for hospital admissions: 2 patients in the sevoflurane group had to be re-admitted to the hospital compared to 8 in the propofol group (OR 0.23, 95% CI: 0.04-1.29, p=0.10).\n\n\nCONCLUSIONS\nSevoflurane does not seem to provide protection with regard to the occurrence of cardiac and non-cardiac events in the 6-month period following cardiac surgery with the use of extracorporeal circulation. However, there was a clear trend towards fewer interventions (less need for treatment, fewer hospital admissions) associated with sevoflurane post-conditioning in patients experiencing any event. Such results might encourage launching large multicenter post-conditioning trials with clinical outcome defined as primary endpoint.",
"affiliations": "Institute of Anesthesiology, University Hospital Zurich, Raemistrasse 100, Zurich, 8091, Switzerland.;Institute of Anesthesiology, University Hospital Zurich, Raemistrasse 100, Zurich, 8091, Switzerland; Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Winterthurerstrasse 190, Zurich 8057, Switzerland; Department of Anesthesiology, University of Illinois College of Medicine at Chicago, 1740 West Taylor Street, Suite 3200 West, Chicago, IL, 60612, United States of America.;Institute of Anesthesiology, University Hospital Zurich, Raemistrasse 100, Zurich, 8091, Switzerland.;Antropological Institute and Museum, University of Zurich, Winterthurerstrasse 190, Zurich, 8057, Switzerland.;Department of Anesthesia & Intensive Care Medicine, Cantonal Hospital of Muensterlingen, Campus 1, Muensterlingen, 8596, Switzerland.;Institute of Anesthesiology, University Hospital Zurich, Raemistrasse 100, Zurich, 8091, Switzerland; Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Winterthurerstrasse 190, Zurich 8057, Switzerland.",
"authors": "Bonvini|John M|JM|;Beck-Schimmer|Beatrice|B|;Kuhn|Sonja J|SJ|;Graber|Sereina M|SM|;Neff|Thomas A|TA|;Schläpfer|Martin|M|",
"chemical_list": "D018685:Anesthetics, Inhalation; D008738:Methyl Ethers; D010975:Platelet Aggregation Inhibitors; D000077149:Sevoflurane",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0132165",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 2619613310.1371/journal.pone.0132165PONE-D-15-06051Research ArticleLate Post-Conditioning with Sevoflurane after Cardiac Surgery - Are Surrogate Markers Associated with Clinical Outcome? Late Post-Conditioning after Cardiac Surgery - A Six Month Follow UpBonvini John M. \n1\nBeck-Schimmer Beatrice \n1\n\n2\n\n3\n*Kuhn Sonja J. \n1\nGraber Sereina M. \n4\nNeff Thomas A. \n5\nSchläpfer Martin \n1\n\n2\n\n1 \nInstitute of Anesthesiology, University Hospital Zurich, Raemistrasse 100, Zurich, 8091, Switzerland\n\n2 \nInstitute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Winterthurerstrasse 190, Zurich 8057, Switzerland\n\n3 \nDepartment of Anesthesiology, University of Illinois College of Medicine at Chicago, 1740 West Taylor Street, Suite 3200 West, Chicago, IL, 60612, United States of America\n\n4 \nAntropological Institute and Museum, University of Zurich, Winterthurerstrasse 190, Zurich, 8057, Switzerland\n\n5 \nDepartment of Anesthesia & Intensive Care Medicine, Cantonal Hospital of Muensterlingen, Campus 1, Muensterlingen, 8596, Switzerland\nGuo Yiru Editor\nUniversity of Louisville, UNITED STATES\nCompeting Interests: BBS has received honoraria from Baxter and Abbott in the past; these were not related to the current study. This does not affect the authors' adherence to the PLOS ONE policies on sharing data and materials. JMB, SJK, SMG, TAN and MS declare no conflicts of interests.\n\nConceived and designed the experiments: BBS MS. Performed the experiments: SJK. Analyzed the data: BBS MS SMG SJK. Wrote the paper: BBS MS JMB SJK SMG TAN.\n\n* E-mail: beatrice.beckschimmer@uzh.ch21 7 2015 2015 10 7 e013216510 2 2015 10 6 2015 © 2015 Bonvini et al2015Bonvini et alThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.Introduction\nIn a recent randomized controlled trial our group has demonstrated in 102 patients that late post-conditioning with sevoflurane performed in the intensive care unit after surgery involving extracorporeal circulation reduced damage to cardiomyocytes exposed to ischemia reperfusion injury. On the first post-operative day the sevoflurane patients presented with lower troponin T values when compared with those undergoing propofol sedation. In order to assess possible clinical relevant long-term implications in patients enrolled in this study, we performed the current retrospective analysis focusing on cardiac and non-cardiac events during the first 6 months after surgery.\n\nMethods\nAll patients who had successfully completed the late post-conditioning trial were included into this follow-up. Our primary and secondary endpoints were the proportion of patients experiencing cardiac and non-cardiac events, respectively. Additionally, we were interested in assessing therapeutic interventions such as initiation or change of drug therapy, interventional treatment or surgery.\n\nResults\nOf 102 patients analyzed in the primary study 94 could be included in this follow-up. In the sevoflurane group (with 41 patients) 16 (39%) experienced one or several cardiac events within 6 months after cardiac surgery, in the propofol group (with 53 patients) 19 (36%, p=0.75). Four patients (9%) with sevoflurane vs. 7 (13%) with propofol sedation had non-cardiac events (p=0.61). While a similar percentage of patients suffered from cardiac and/or non-cardiac events, only 12 patients in the sevoflurane group compared to 20 propofol patients needed a therapeutic intervention (OR: 0.24, 95% CI: 0.04-1.43, p=0.12). A similar result was found for hospital admissions: 2 patients in the sevoflurane group had to be re-admitted to the hospital compared to 8 in the propofol group (OR 0.23, 95% CI: 0.04-1.29, p=0.10).\n\nConclusions\nSevoflurane does not seem to provide protection with regard to the occurrence of cardiac and non-cardiac events in the 6-month period following cardiac surgery with the use of extracorporeal circulation. However, there was a clear trend towards fewer interventions (less need for treatment, fewer hospital admissions) associated with sevoflurane post-conditioning in patients experiencing any event. Such results might encourage launching large multicenter post-conditioning trials with clinical outcome defined as primary endpoint.\n\nThe authors have no support or funding to report. Data AvailabilityAll relevant data are within the paper and its Supporting Information files.Data Availability\nAll relevant data are within the paper and its Supporting Information files.\n==== Body\nIntroduction\nStrategies to minimize ischemia—reperfusion injury have been a topic of discussion over decades [1]. Conditioning of the ischemic organ can occur at different time points in relation to the ischemic insult: before the onset of ischemia (pre-conditioning) [2, 3], after the onset of ischemia (post-conditioning) [4] or throughout the ischemic event (per-conditioning) [5, 6]. The nature of the intervention can be mechanical (several brief periods of ischemia followed by reperfusion and re-oxygenation), or pharmacological. Both mechanisms seem to share common pathways and different mediators play a role at cellular and subcellular level, primarily providing mitochondrial protection from the ischemic insult [7, 8].\n\nModern volatile anesthetics such as sevoflurane or desflurane have proven efficient in reducing ischemia reperfusion injury in various settings (pharmacological conditioning). In liver surgery both pre- and post-conditioning strategies lead to a significant reduction of hepatocellular injury as well as perioperative complications [9, 10]. In heart surgery procedures involving extracorporeal circulation (ECC), exposing myocardial tissue to ischemia-reperfusion induces cardiomyocyte damage, possibly leading to perioperative infarction, increasing morbidity and mortality for up to three years [11, 12]. In this setting the use of volatile anesthetics leads to reduced myocardial tissue damage, a reduction of myocardial infarction and overall mortality [8, 13–15].\n\nIn a recent randomized controlled trial (RCT) our group has demonstrated that patients could benefit from exposure to volatile anesthetics after heart surgery as late as upon arrival in the intensive care unit (ICU, late post-conditioning) [16]. In that study 117 patients scheduled for elective cardiac surgery requiring the use of ECC at the University Hospital Zurich, Switzerland, were sedated with target-controlled propofol infusion during the surgical procedure. After arrival at the ICU, sedation was continued for at least 4 hours either with propofol or, defined as the alternative intervention, with sevoflurane. Late post-conditioning with sevoflurane proved to be superior to propofol, reducing myocardial injury measured by the specific surrogate biochemical marker troponin T at post-operative day 1.\n\nFor sevoflurane pre-conditioning, an early (first 23h after pre-conditioning) and a late (12-96h after pre-conditioning) window have been described before, with the latter protecting patients undergoing coronary artery bypass grafting from late cardiac events [11]. In analogy to this study of Garcia et al. [11] and in order to assess possible clinically relevant long-term implications of late sevoflurane post-conditioning in patients enrolled in our primary study, we decided to perform a retrospective analysis, in which we focused on cardiac as well as on non-cardiac events and their diagnostic and/or therapeutic consequences over a period of 6 months following the surgical procedure. We hypothesized that sevoflurane patients might have a better outcome.\n\nMaterials and Methods\nThe RCT “Late pharmacologic conditioning with volatile anesthetics after cardiac surgery” was published in Critical Care in October 2012 [16]. This study was approved by the local ethics committee (Kantonale Ethikkommission, Zurich, Switzerland, trial number StV 5–2007) and was registered in ClinicalTrials.gov (NCT00924222).\n\nIn the RCT, conducted between October 2007 and September 2009 at the University Hospital Zurich, Switzerland, 102 patients undergoing cardiopulmonary bypass for aortic or mitral valve surgery with or without coronary bypass grafting were included. Potential short-term benefits of late post-conditioning for ≥4h upon arrival at the ICU comparing propofol and sevoflurane sedation were evaluated. Patients had to be between 18 and 90 years old. Exclusion criteria were poor cardiac baseline function, significant coronary impairment, emergency procedures, previous cardiac surgery, chronic pulmonary disease, renal dysfunction, insulin-dependent diabetes mellitus, pregnancy, and current steroid treatment. Randomization took place by a computer. Both, the surgeon and the anesthesiologist in the operating theatre were blinded to the intervention group. The primary endpoint of this study was cardiac injury on postoperative day 1 (POD1), measured by cardiac injury markers. Secondary endpoints included oxygenation index after 4 hours of sedation, incidence of postoperative pulmonary complications, and the need for antiemetic drugs.\n\nThe main finding was a decreased troponin T level on POD1 in patients sedated with sevoflurane in comparison to patients sedated with propofol.\n\nEvaluation of the 6-month follow-up\nThis retrospective study was approved by the ethical committee of the canton of Zurich, Switzerland (KEK-ZH No. 2014–0040, April 22nd, 2014) and was registered at clinicaltrials.gov (NCT02378168).\n\nAll patients who had successfully completed the late post-conditioning trial [16] were included into this retrospective follow-up analysis. We obtained written and informed consent of all patients for the first study. No consent had been withdrawn either before or after publication of the first trial. According to the ethical committee, no new consent had to be obtained. Patient data were anonymized prior to further analysis.\n\nThe time frame of our retrospective analysis was limited to 6 months after surgery. Data were retrieved primarily from the internal hospital database. In addition, secondary care units and family doctors were contacted by sending them a concise questionnaire. To assure data completeness these institutions were, when necessary, contacted by phone by one of our consultant anesthesiologist between May 2014 and August 2014. Researchers gathering data were blinded for the study group of the patients.\n\nThe primary endpoint was the proportion of patients with cardiac events (dysrhythmias, congestive heart failure, and cardiac ischemic event). We also assessed re-admission to the hospital and therapeutic interventions such as introduction or modification of specific drug regimen, interventional treatments such as cardioversion or catheter based treatments (e.g. thermal ablation of atrial flutter, percutaneous coronary intervention), as well as conventional surgery (e.g. coronary artery bypass grafting, Maze procedure, Batista procedure).\n\nThe proportion of patients experiencing non-cardiac events was defined as the secondary endpoint. We focused on acute or chronic pulmonary embolism, bleeding events, infections, cerebral events, and acute as well as chronic kidney failure, defined as glomerular filtration rate below 60 ml/min. In line with the primary endpoints we assessed the necessity for re-admission to the hospital, for drug or interventional treatment (e.g. cerebral angiography with thrombectomy or intra-arterial lysis, dialysis), and the need for surgery (e.g. surgical hemostasis, surgical abscess evacuation, and kidney transplantation).\n\nIf any question (primary or secondary endpoints) was answered affirmatively, family doctors were asked to provide detailed information about the event, indicating how exactly patients had to be treated for the event and whether they had to be re-admitted to the hospital. Details about the patient included into this study are found in S1 Dataset.\n\nStatistical analysis of the anonymized data was performed using Programm R (R Development Core Team, R Foundation for Statistical Computing, Vienna, Austria) and GraphPad Prism 6 (GraphPad Software Inc, La Jolla, CA). Logistic regression models with propofol as reference group were chosen. Odds ratio (OR), 95% confidence interval (95% CI), and p-values were computed. Patient characteristics were evaluated by Mann-Whitney and Fisher’s exact tests. For bootstrapping we used an ordinary nonparametric approach based on 10,000 replications. A p-value of <0.05 was considered significant.\n\nPower estimation\nThe maximal number of patients available for this study was given by the primary randomized controlled trial, in which 102 patients were included. A power calculation based on a Chi-Square test with a power of 90%, an estimated effect size of 10%, and an alpha-error of 0.05 would result in a total sample size of 964 individuals. The power issue is discussed in detail in the discussion section.\n\nResults\nPatient enrollment\nOf the 102 patients analyzed in the trial of Steurer et al. [16], 94 could be included in this follow-up study. For 6 patients there were no data in the hospital database available, nor could the family doctor be contacted. One patient had left the country after hospitalization, while another had died during his rehabilitation period. Unfortunately, no information was available about the circumstances of this death. Therefore, this patient was listed under ‘characteristics’ (n = 95, Table 1), but due to missing information not taken into account for the detailed analysis of adverse events during the follow-up period (n = 94) (Fig 1).\n\n10.1371/journal.pone.0132165.t001Table 1 Demographic and surgical characteristics.\n\tsevoflurane\tpropofol\tp-value\t\n\tn = 42\tn = 53\t\t\nAge (years), median (25%-75% percentile)\t66 (54–73)\t67 (54–75)\t0.65\t\nMale subjects, n (%)\t27 (64)\t39 (74)\t0.37\t\nAortic valve surgery, n (%)\t35 (83)\t42 (79)\t0.79\t\nIsolated mitral valve surgery, n (%)\t6 (14)\t11 (21)\t0.59\t\nConcurrent aortocoronary bypass surgery, n (%)\t13 (31)\t17 (32)\t1.00\t\n10.1371/journal.pone.0132165.g001Fig 1 Included patients.\nFlow chart of the patients included into the late post-conditioning study and patients that could be enrolled to the six-month follow-up study after late cardiac surgery.\n\nData from 60% (56 out of 94) of the patients could be gathered from our hospital information system and were compared to the data provided from family doctors. While 89% (41/46) of the data were complete in the sevoflurane group, the according number was 95% (53/56) in the propofol group.\n\nDemographic and surgical characteristics\nPatient characteristics were similar in the sevoflurane and the propofol group as expected in an RCT. Median age after 6-month follow-up was 66 (25%-75% percentile: 54–73) years\n\nin the sevoflurane and 67 (25%-75% percentile: 54–75) years in the propofol group. The sevoflurane group consisted of 27 (64%) male subjects, the propofol group of 39 (74%) (Table 1).\n\nOf the 94 patients analyzed, 77 patients (82%) underwent aortic valve surgery, 35 (45%) in the sevoflurane group and 42 (55%) in the propofol group. Concurrent aortocoronary bypass was similar in both groups: sevoflurane 13 (31%) and propofol 17 (32%). Isolated mitral valve surgery was performed in 17 patients (18%), 6 (14%) in the sevoflurane group and 11 (21%) in the propofol group.\n\nPatients with cardiac events\nIn the sevoflurane group (n = 41) 16 patients (39%), in the propofol group (n = 53) 19 (36%) suffered from one or several cardiac events during the first 6 months after cardiac surgery. Table 2 gives an overview of patients with reported events and the corresponding therapies initiated. Of the 16 sevoflurane patients 4 patients experienced two events, of the 19 propofol patients 5 patients had two and one patient three cardiac events.\n\n10.1371/journal.pone.0132165.t002Table 2 Patients with cardiac events: type of event, therapies initiated and need for hospitalization.\n\tsevoflurane\tpropofol\tOR\t95% CI\tp-value\t\ntotal number of patients (% of all patients)\t16 (39)\t19 (36)\t1.15\t0.49\t2.66\t0.75\t\npatients with dysrhythmias (%)\t13 (32)\t12 (23)\t1.59\t0.63\t3.98\t0.33\t\ndrug or interventional treatment, n\t11\t13\t\t\t\t\t\nsurgery, n\t1\t1\t\t\t\t\t\nadmission to hospital, n\t2\t3\t\t\t\t\t\npatients with congestive heart failure (%)\t7 (17)\t13 (25)\t0.63\t0.23\t1.77\t0.38\t\ndrug or interventional treatment, n\t7\t13\t\t\t\t\t\nsurgery, n\t0\t1\t\t\t\t\t\nadmission to hospital, n\t0\t1\t\t\t\t\t\npatients with cardiac ischemia (%)\t0 (0)\t1 (2)\t0.00\t0.00\tinf.\t1.00\t\ndrug or interventional treatment, n\t0\t1\t\t\t\t\t\nsurgery, n\t0\t0\t\t\t\t\t\nadmission to hospital, n\t0\t0\t\t\t\t\t\nOR: odds ratio\n\nCI: confidence interval\n\ninf.: infinite.\n\nThe chance for a patient to have a cardiac event was similar in both groups (overall OR: 1.15; 95% CI: 0.49–2.66, p = 0.75, Table 2). The most common cardiac event was dysrhythmia, with an OR of 1.59 to occur in the sevoflurane group (95% CI: 0.63–3.98, p = 0.33, Table 2), followed by congestive heart failure. Also here, no statistical significance could be reached comparing the two patient groups. Of note is that chances were smaller to experience congestive heart failure in the sevoflurane compared to the propofol group (OR: 0.63, 95% CI: 0.23–1.77, p = 0.38, Table 2).\n\nFor dysrhythmias, being the most common cardiac complication, the rate for intervention and surgery was similar in both groups: Nine of 13 patients in the sevoflurane group vs. 11 of 12 propofol patients had to undergo drug treatment for dysrhythmias (OR: 0.21, 95% CI: 0.02–2.17, p = 0.19, Table 2).\n\nCongestive heart failure was diagnosed in 7 patients in the sevoflurane group and 13 in the propofol group (OR: 0.63, 95% CI: 0.23–1.77, p = 0.38, Table 2). All these patients underwent drug and/or interventional treatment.\n\nOne patient in the propofol group suffered from cardiac ischemia and had to undergo interventional treatment (Table 2).\n\nPatients with non-cardiac events\nNon-cardiac events (pulmonary embolism, bleeding, infections, cerebral events, acute and chronic kidney failure) were reported in 4 (9%) patients with sevoflurane vs. 7 (13%) with propofol sedation. The OR for a patient in the sevoflurane group suffering from a non-cardiac complication was 0.71 without reaching statistical significance (95% CI: 0.19–2.61, p = 0.61, Table 3, Fig 2). All 4 sevoflurane patients had only one event, whereas in the propofol group 2 patients had 2 events.\n\n10.1371/journal.pone.0132165.t003Table 3 Patients with non-cardiac events: type of event, therapies initiated and need for hospitalization.\n\tsevoflurane\tpropofol\tOR\t95% CI\tp-value\t\ntotal number of patients (% of all patients)\t4 (9)\t7 (13)\t0.71\t0.19\t2.61\t0.61\t\npulmonary embolism, n (%)\t0 (0)\t1 (2)\t0.00\t0.00\tinf.\t1.00\t\ndrug or interventional treatment, n\t0\t1\t\t\t\t\t\nsurgery, n\t0\t0\t\t\t\t\t\nadmission to hospital, n\t0\t1\t\t\t\t\t\nbleeding, n (%)\t0 (0)\t2 (4)\t0.00\t0.00\tinf.\t1.00\t\ndrug or interventional treatment, n\t0\t1\t\t\t\t\t\nsurgery, n\t0\t1\t\t\t\t\t\nadmission to hospital, n\t0\t2\t\t\t\t\t\ninfection, n (%)\t3 (8)\t2 (4)\t2.01\t0.32\t12.65\t0.46\t\ndrug or interventional treatment, n\t1\t0\t\t\t\t\t\nsurgery, n\t0\t1\t\t\t\t\t\nadmission to hospital, n\t0\t2\t\t\t\t\t\ncerebral events, n (%)\t1 (3)\t0 (0)\t>100\t0.00\tinf.\t1.00\t\ndrug or interventional treatment, n\t1\t0\t\t\t\t\t\nsurgery, n\t0\t0\t\t\t\t\t\nadmission to hospital, n\t0\t0\t\t\t\t\t\nchronic kidney failure, n (%)\t0 (0)\t4 (8)\t0.00\t0.00\tinf.\t1.00\t\ndrug or interventional treatment, n\t0\t1\t\t\t\t\t\nsurgery, n\t0\t0\t\t\t\t\t\nadmission to hospital, n\t0\t2\t\t\t\t\t\nOR: odds ratio\n\nCI: confidence interval\n\ninf.: infinite.\n\n10.1371/journal.pone.0132165.g002Fig 2 Type of sedation and odds ratio for adverse events.\nOdds ratios and 95% confidence intervals of patients with overall adverse events, with cardiac and non-cardiac events, with need for drug, interventional or surgical treatment and need for admission to the hospital. Patients with propofol sedation in the ICU were taken as the reference group.\n\nThree patients in the sevoflurane group experienced an infection, one of them needing an intervention. In addition, a cerebral event was reported in one patient. In the propofol group 2 patients were diagnosed with pulmonary embolism, 2 had bleeding events, 2 were identified with infections and 4 with chronic kidney failure (Table 3). None of these differences were significant.\n\nCombination of patients experiencing cardiac and non-cardiac events\nOf the 94 patients analyzed, a similar number of patients in the sevoflurane (17 patients, 41%) and in the propofol group (22 patients, 42%) suffered from one or several adverse events (cardiac and/or non-cardiac) with an OR of 1.00 (95% CI: 0.44–2.28, p = 1.00, Fig 2, Table 4). As some patients have experienced a cardiac as well as a non-cardiac event the total number of patients in the according group (sevoflurane n = 17, propofol n = 22) is smaller than the sum of the patients with cardiac (sevoflurane n = 16, propofol n = 19) and non-cardiac events (sevoflurane n = 4, propofol n = 7). Six patients in the sevoflurane group and 7 patients in the propofol group were reported with two or more events.\n\n10.1371/journal.pone.0132165.t004Table 4 Patients with cardiac and/ or non-cardiac events, need for treatment and need for hospitalization.\n\tsevoflurane\tpropofol\tOR\t95% CI\tp-value\t\ntotal number of patients (% of patients with events)\t17 (44)\t22 (56)\t1.00\t0.44\t2.28\t1.00\t\ndrug, interventional treatment or surgery, n (%)\t12 (31)\t20 (51)\t0.24\t0.04\t1.43\t0.12\t\nadmission to hospital, n (%)\t2 (5)\t8 (21)\t0.23\t0.04\t1.29\t0.10\t\nOR: odds ratio\n\nCI: confidence interval.\n\nInterestingly, despite a similar number of patients with adverse events, only 12 patients (31% of the patients with an adverse event) in the sevoflurane group compared to 20 (51%) in the propofol group needed a drug, an interventional treatment, and/or surgery (OR: 0.24, 95% CI: 0.04–1.43, p = 0.12, Fig 2, Table 4). Bootstrapping based on 10,000 replications did lead to similar results (median OR: 0.22, 95% CI: 0.00–4.00). A similar picture was observed for hospital admissions: 2 sevoflurane patients (5% of the patients with ≥1 event) as compared to 8 propofol patients (21% of the patients with ≥1 event) had to be re-admitted to the hospital (OR 0.23, 95% CI: 0.04–1.29, p = 0.10, Fig 2, Table 4). Also for this data the odds ratio could be confirmed by bootstrapping (median OR: 0.21, 95% CI: 0.00–2.21).\n\nDiscussion\nIn a recent randomized controlled trial from our group [16], immediate cardioprotective effects of late anesthetic post-conditioning with sevoflurane after aortic and mitral valve replacement in combination with CABG or ascending aorta surgery have been reported. The current follow-up study has investigated the potential impact of sevoflurane exposure on a 6-month long-term outcome with regard to cardiac and non-cardiac complications. While no statistical significance was reached, the results clearly point towards a possible beneficial effect of sevoflurane post-conditioning. Data from this follow-up study suggest a 4 times lower risk for the need for medical treatment (12 vs. 20 patients; OR 0.240; 95% CI 0.040–1.43; p = 0.118) and need for hospital admission (2 vs. 8 patients; OR 0.233, 95% CI: 0.042–1.293; p = 0.095, Table 4) in the sevoflurane as compared to the propofol group when experiencing a cardiac and/or non-cardiac event. The observed differences in the need for medical treatment could be regarded as composite endpoint for future studies. In order to address the problem of a potential bias and model assumption violations bootstrap analyses were performed, which could further underline a certain robustness of the data. Even bootstrap results support the 6-months follow-up data, this procedure of course does not overcome the problem of a potential lack of power.\n\nAn estimated 4% of the worldwide population undergoes major surgery requiring regional or general anesthesia each year [17]. Overall, the incidence of postoperative complications and death is low. However, sub-groups of high-risk patients (e.g. advanced age, co-morbid disease, major, and urgent surgery) are associated with increased risk for complications. Given the substantial costs associated with major postoperative complications, reducing morbidity by innovative therapies may be essential to economize health care resources, to reduce overall cost of care, and to improve quality of care.\n\nIt is well known from extensive clinical [11, 14, 15, 18–23] and experimental work [8, 24–29] that halogenated anesthetics may exert many non-anesthetic properties such as inducing an endogenous adaptive response of cells against ischemia-reperfusion injury [30, 31]. Protection is thereby mediated by adenosine receptor stimulation with subsequent activation of protein kinase C, increased production of nitric oxide, and free oxygen [32].\n\nIn non heart beating surgery, myocardial ischemia and reperfusion is an inherent and inevitable part of the surgical procedure itself. Strategies capable of limiting the ischemic trauma of cardiomyocytes and thus improving cardiac recovery are therefore of pivotal interest. Conservation of postoperative cardiac function was first described in 1999 in a small clinical study that used a pre-conditioning protocol with isoflurane before cross-clamping of the aorta [18]. A meta-analysis from Landoni and co-workers in 2007 suggested that sevoflurane and desflurane are equally effective in reducing the incidence of myocardial infarction and postoperative mortality after cardiac surgery [13].\n\nBeyond well-described immediate protective effects of volatile anesthetics on specific and organ dependent biomarkers in various clinical and experimental settings, it is of major interest whether these results could be translated from the level of surrogate markers to clinical outcome after cardiac surgery. Some studies have already shown certain benefits of volatile anesthetics on clinical parameters such as duration of mechanical ventilation, length of ICU as well as hospital stay [15, 23, 33, 34]. Both, reduction of ventilator time as well as length of stay are considered relevant in terms of patient recovery and cost. A recent randomized controlled trial from our group [10] clearly demonstrated that pharmacological post-conditioning with sevoflurane in patients undergoing liver resection not only significantly reduced peak levels of aspartate transaminase (AST), a valuable biomarker for liver injury, it also had a significant impact on the occurrence of postoperative complications, determined by a the well-established Clavien-Dindo scoring system [35].\n\nImmediate cardioprotective effects of late anesthetic post-conditioning with sevoflurane after aortic and mitral valve replacement in combination with coronary artery bypass surgery (CABG) or ascending aorta surgery revealed a benefit for the sevoflurane group, reflected in a lower cardiac damage, measured by the surrogate marker troponin T, on POD 1 [16] whereas this follow-up study has investigated the potential impact of sevoflurane exposure on a 6-month long-term outcome with regard to clinical cardiac and non-cardiac complications. In the primary trial baseline characteristics of the two groups were similar [16] as expected with an RCT design minimizing therefore the possibility of unbalanced group bias on the troponin T differences.\n\nThe relevance of troponin T on long-term outcome after cardiac surgery is not quite clear. Brown and colleagues could not associate troponin T levels after on- and off-pump coronary artery bypass with a prognostic value [36]. However recent studies and meta-analyses did associate high troponin T levels with poor long-term outcome after vascular surgery [37], after percutaneous coronary interventions [38], and after cardiac transplantation [39].\n\nThe lack of significance in this study may be explained by the fact that the initial sample size calculation was performed for the primary study and was targeting the acute cardiac injury markers troponin, creatine kinase and myoglobin. In contrast to the primary study, the endpoints of the actual follow-up study were designed to detect differences in pure clinical endpoints: the appearance of cardiac and non-cardiac events with diagnostic and/or therapeutic consequences including hospital re-admission within a 6-month follow-up period after surgery. Hence, the follow-up study is likely to be underpowered for these respective endpoints. If we would calculate the sample size of the groups based on the endpoints we focused on in this follow-up study we would have needed 7302 patients in our analysis to detect a difference in postoperative cardiac events. To detect differences in the need for medical treatment (drug therapy, interventional treatment or surgery) already 1036 patients would have been sufficient, and for detecting a difference in hospital admission rates significance would have been reached with a total of 160 patients. The above mentioned power calculations are based on a Chi-square test with a power of 80%, an alpha-error of 0.05 and using the results of our follow-up study for the proportions.\n\nSeveral limitations of the study have to be acknowledged. First, the post-conditioning phase was relatively short with 4 hours only. Second, the applied dose of sevoflurane reflecting an age-adjusted 0.5 minimum alveolar concentration (MAC) was rather low when compared to anesthetic concentrations during surgery. Higher concentrations of volatile anesthetics and prolonged exposure might have exerted more pronounced organ-protection and turned the results into significance.\n\nIn addition, propofol may also be able to offer protective effects, especially via ATP sensitive potassium channels [40]. It appears to act synergistic with volatile anesthetic conditioning [41]. When addressing potential effects of propofol a word of caution should be warranted as it is clinically available as emulsified solution of drug and additives. The presence of ethylenediaminetetraacetic acid (EDTA) is particularly relevant since EDTA itself offers anti-inflammatory properties by destabilizing bacterial walls [42]. Therefore it might be difficult to separate effects of the drug from those of the additives.\n\nThe major strength of this study is its data quality. Even though data collection was done in a retrospective manner, data robustness is very high since the follow-up was based on a randomized controlled trial. In addition, a carefully developed and standardized questionnaire was used for data retrieval. The return rate of 93% of questionnaires was exceptionally high. Another remarkable aspect of our study is the exclusive use of clinical follow-up parameters, which might be more relevant than studying biochemical surrogate markers of uncertain clinical significance.\n\nDespite the lacking significance of our data, promising trends are reported, which might translate in reduced postoperative adverse events and reduced treatment cost. This emphasizes the importance of collecting clinical outcome data on this important topic in the future. Larger randomized trials will add more value to the current body of evidence and are highly likely to reveal an improved clinical outcome by exposure to volatile anesthetics.\n\nConclusions\nWe document a similar percentage of cardiac as well as of non-cardiac events in patients exposed to sevoflurane as compared to propofol in a post-conditioning manner. Despite not reaching statistical significance, we observed less severe complications in the sevoflurane group (less need for treatment, fewer hospital readmissions). Statistical significance might not have been reached because the original study was powered for biochemical surrogate markers and not for clinical outcomes.\n\nSupporting Information\nS1 Dataset Dataset of the patients included into the study.\n(XLSX)\n\nClick here for additional data file.\n==== Refs\nReferences\n1 \nMaroko PR , Kjekshus JK , Sobel BE , Watanabe T , Covell JW , Ross J Jr, et al\nFactors influencing infarct size following experimental coronary artery occlusions . Circulation . 1971 ;43 (1 ):67 –82 . .5540853 \n2 \nMurry CE , Jennings RB , Reimer KA . Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium . Circulation . 1986 ;74 (5 ):1124 –36 . .3769170 \n3 \nMurry CE , Richard VJ , Reimer KA , Jennings RB . Ischemic preconditioning slows energy metabolism and delays ultrastructural damage during a sustained ischemic episode . Circulation research . 1990 ;66 (4 ):913 –31 . .2317895 \n4 \nZhao ZQ , Corvera JS , Halkos ME , Kerendi F , Wang NP , Guyton RA , et al\nInhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning . American journal of physiology Heart and circulatory physiology . 2003 ;285 (2 ):H579 –88 . 10.1152/ajpheart.01064.2002 \n.12860564 \n5 \nBotker HE , Kharbanda R , Schmidt MR , Bottcher M , Kaltoft AK , Terkelsen CJ , et al\nRemote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial . Lancet . 2010 ;375 (9716 ):727 –34 . 10.1016/S0140-6736(09)62001-8 \n.20189026 \n6 \nSchmidt MR , Smerup M , Konstantinov IE , Shimizu M , Li J , Cheung M , et al\nIntermittent peripheral tissue ischemia during coronary ischemia reduces myocardial infarction through a KATP-dependent mechanism: first demonstration of remote ischemic perconditioning . American journal of physiology Heart and circulatory physiology . 2007 ;292 (4 ):H1883 –90 . 10.1152/ajpheart.00617.2006 \n.17172279 \n7 \nHausenloy DJ , Ong SB , Yellon DM . The mitochondrial permeability transition pore as a target for preconditioning and postconditioning . Basic research in cardiology . 2009 ;104 (2 ):189 –202 . 10.1007/s00395-009-0010-x \n.19242644 \n8 \nZaugg M , Lucchinetti E , Spahn DR , Pasch T , Schaub MC . Volatile anesthetics mimic cardiac preconditioning by priming the activation of mitochondrial K(ATP) channels via multiple signaling pathways . Anesthesiology . 2002 ;97 (1 ):4 –14 . .12131097 \n9 \nBeck-Schimmer B , Breitenstein S , Urech S , De Conno E , Wittlinger M , Puhan M , et al\nA randomized controlled trial on pharmacological preconditioning in liver surgery using a volatile anesthetic . Ann Surg . 2008 ;248 (6 ):909 –18 . 10.1097/SLA.0b013e31818f3dda \n.19092335 \n10 \nBeck-Schimmer B , Breitenstein S , Bonvini JM , Lesurtel M , Ganter M , Weber A , et al\nProtection of pharmacological postconditioning in liver surgery: results of a prospective randomized controlled trial . Ann Surg . 2012 ;256 (5 ):837 –44 ; discission 44–5. Epub 2012/10/26. 10.1097/SLA.0b013e318272df7c \n.23095629 \n11 \nGarcia C , Julier K , Bestmann L , Zollinger A , von Segesser LK , Pasch T , et al\nPreconditioning with sevoflurane decreases PECAM-1 expression and improves one-year cardiovascular outcome in coronary artery bypass graft surgery . British journal of anaesthesia . 2005 ;94 (2 ):159 –65 . 10.1093/bja/aei026 \n.15556966 \n12 \nRiedel BJ , Grattan A , Martin CB , Gal J , Shaw AD , Royston D . Long-term outcome of patients with perioperative myocardial infarction as diagnosed by troponin I after routine surgical coronary artery revascularization . Journal of cardiothoracic and vascular anesthesia . 2006 ;20 (6 ):781 –7 . 10.1053/j.jvca.2006.01.015 \n.17138080 \n13 \nLandoni G , Biondi-Zoccai GG , Zangrillo A , Bignami E , D'Avolio S , Marchetti C , et al\nDesflurane and sevoflurane in cardiac surgery: a meta-analysis of randomized clinical trials . Journal of cardiothoracic and vascular anesthesia . 2007 ;21 (4 ):502 –11 . Epub 2007/08/07. S1053-0770(07)00043-2 [pii] 10.1053/j.jvca.2007.02.013 \n.17678775 \n14 \nDe Hert SG , Van der Linden PJ , Cromheecke S , Meeus R , Nelis A , Van Reeth V , et al\nCardioprotective properties of sevoflurane in patients undergoing coronary surgery with cardiopulmonary bypass are related to the modalities of its administration . Anesthesiology . 2004 ;101 (2 ):299 –310 . Epub 2004/07/28. .15277911 \n15 \nGuarracino F , Landoni G , Tritapepe L , Pompei F , Leoni A , Aletti G , et al\nMyocardial damage prevented by volatile anesthetics: a multicenter randomized controlled study . Journal of cardiothoracic and vascular anesthesia . 2006 ;20 (4 ):477 –83 . 10.1053/j.jvca.2006.05.012 \n.16884976 \n16 \nSteurer MP , Steurer MA , Baulig W , Piegeler T , Schlapfer M , Spahn DR , et al\nLate pharmacologic conditioning with volatile anesthetics after cardiac surgery . Critical care (London, England) . 2012 ;16 (5 ):R191 Epub 2012/10/16. 10.1186/cc11676 \n23062276 \n17 \nWeiser TG , Regenbogen SE , Thompson KD , Haynes AB , Lipsitz SR , Berry WR , et al\nAn estimation of the global volume of surgery: a modelling strategy based on available data . Lancet . 2008 ;372 (9633 ):139 –44 . 10.1016/S0140-6736(08)60878-8 \n.18582931 \n18 \nBelhomme D , Peynet J , Louzy M , Launay JM , Kitakaze M , Menasche P . Evidence for preconditioning by isoflurane in coronary artery bypass graft surgery . Circulation . 1999 ;100 (19 Suppl ):II340 –4 . .10567326 \n19 \nCromheecke S , Pepermans V , Hendrickx E , Lorsomradee S , Ten Broecke PW , Stockman BA , et al\nCardioprotective properties of sevoflurane in patients undergoing aortic valve replacement with cardiopulmonary bypass . Anesthesia and analgesia . 2006 ;103 (2 ):289 –96 , table of contents. 10.1213/01.ane.0000226097.22384.f4 \n.16861404 \n20 \nDe Hert S , Vlasselaers D , Barbe R , Ory JP , Dekegel D , Donnadonni R , et al\nA comparison of volatile and non volatile agents for cardioprotection during on-pump coronary surgery . Anaesthesia . 2009 ;64 (9 ):953 –60 . 10.1111/j.1365-2044.2009.06008.x \n.19686479 \n21 \nDe Hert SG , ten Broecke PW , Mertens E , Van Sommeren EW , De Blier IG , Stockman BA , et al\nSevoflurane but not propofol preserves myocardial function in coronary surgery patients . Anesthesiology . 2002 ;97 (1 ):42 –9 . .12131102 \n22 \nHellstrom J , Owall A , Bergstrom J , Sackey PV . Cardiac outcome after sevoflurane versus propofol sedation following coronary bypass surgery: a pilot study . Acta anaesthesiologica Scandinavica . 2011 ;55 (4 ):460 –7 . 10.1111/j.1399-6576.2011.02405.x \n.21342154 \n23 \nTritapepe L , Landoni G , Guarracino F , Pompei F , Crivellari M , Maselli D , et al\nCardiac protection by volatile anaesthetics: a multicentre randomized controlled study in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass . European journal of anaesthesiology . 2007 ;24 (4 ):323 –31 . 10.1017/S0265021506001931 \n.17156509 \n24 \nDai AL , Fan LH , Zhang FJ , Yang MJ , Yu J , Wang JK , et al\nEffects of sevoflurane preconditioning and postconditioning on rat myocardial stunning in ischemic reperfusion injury . Journal of Zhejiang University Science B . 2010 ;11 (4 ):267 –74 . 10.1631/jzus.B0900390 \n20349523 \n25 \nFang NX , Yao YT , Shi CX , Li LH . Attenuation of ischemia-reperfusion injury by sevoflurane postconditioning involves protein kinase B and glycogen synthase kinase 3 beta activation in isolated rat hearts . Molecular biology reports . 2010 ;37 (8 ):3763 –9 . 10.1007/s11033-010-0030-5 \n.20217242 \n26 \nKnapp J , Bergmann G , Bruckner T , Russ N , Bottiger BW , Popp E . Pre- and postconditioning effect of Sevoflurane on myocardial dysfunction after cardiopulmonary resuscitation in rats . Resuscitation . 2013 ;84 (10 ):1450 –5 . 10.1016/j.resuscitation.2013.04.012 \n.23707567 \n27 \nLou PH , Zhang L , Lucchinetti E , Heck M , Affolter A , Gandhi M , et al\nInfarct-remodelled hearts with limited oxidative capacity boost fatty acid oxidation after conditioning against ischaemia/reperfusion injury . Cardiovascular research . 2013 ;97 (2 ):251 –61 . 10.1093/cvr/cvs323 \n.23097573 \n28 \nPravdic D , Mio Y , Sedlic F , Pratt PF , Warltier DC , Bosnjak ZJ , et al\nIsoflurane protects cardiomyocytes and mitochondria by immediate and cytosol-independent action at reperfusion . British journal of pharmacology . 2010 ;160 (2 ):220 –32 . 10.1111/j.1476-5381.2010.00698.x \n20423337 \n29 \nXiao YY , Chang YT , Ran K , Liu JP . Delayed preconditioning by sevoflurane elicits changes in the mitochondrial proteome in ischemia-reperfused rat hearts . Anesthesia and analgesia . 2011 ;113 (2 ):224 –32 . 10.1213/ANE.0b013e3182239b71 \n.21659557 \n30 \nHausenloy DJ , Yellon DM . Preconditioning and postconditioning: underlying mechanisms and clinical application . Atherosclerosis . 2009 ;204 (2 ):334 –41 . 10.1016/j.atherosclerosis.2008.10.029 \n.19081095 \n31 \nSanada S , Komuro I , Kitakaze M . Pathophysiology of myocardial reperfusion injury: preconditioning, postconditioning, and translational aspects of protective measures . American journal of physiology Heart and circulatory physiology . 2011 ;301 (5 ):H1723 –41 . 10.1152/ajpheart.00553.2011 \n.21856909 \n32 \nZaugg M , Lucchinetti E , Uecker M , Pasch T , Schaub MC . Anaesthetics and cardiac preconditioning. Part I. Signalling and cytoprotective mechanisms . British journal of anaesthesia . 2003 ;91 (4 ):551 –65 . .14504159 \n33 \nMeiser A , Sirtl C , Bellgardt M , Lohmann S , Garthoff A , Kaiser J , et al\nDesflurane compared with propofol for postoperative sedation in the intensive care unit . British journal of anaesthesia . 2003 ;90 (3 ):273 –80 . .12594136 \n34 \nRohm KD , Wolf MW , Schollhorn T , Schellhaass A , Boldt J , Piper SN . Short-term sevoflurane sedation using the Anaesthetic Conserving Device after cardiothoracic surgery . Intensive care medicine . 2008 ;34 (9 ):1683 –9 . 10.1007/s00134-008-1157-x \n.18500419 \n35 \nDindo D , Demartines N , Clavien PA . Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey . Ann Surg . 2004 ;240 (2 ):205 –13 . 15273542 \n36 \nBrown JR , Hernandez F Jr., Klemperer JD , Clough RA , DiPierro FV , Hofmaster PA , et al\nLong-term survival and cardiac troponin T elevation in on- and off-pump coronary artery bypass surgery . The heart surgery forum . 2008 ;11 (3 ):E163 –8 . 10.1532/HSF98.20081017 \n.18583287 \n37 \nWinkel TA , Schouten O , Hoeks SE , Voute MT , Chonchol M , Goei D , et al\nPrognosis of vascular surgery patients using a quantitative assessment of troponin T release: is the crystal ball still clear? \nEuropean journal of vascular and endovascular surgery: the official journal of the European Society for Vascular Surgery . 2010 ;40 (6 ):739 –46 . 10.1016/j.ejvs.2010.08.012 \n.20884259 \n38 \nFeldman DN , Kim L , Rene AG , Minutello RM , Bergman G , Wong SC . Prognostic value of cardiac troponin-I or troponin-T elevation following nonemergent percutaneous coronary intervention: a meta-analysis . Catheterization and cardiovascular interventions: official journal of the Society for Cardiac Angiography & Interventions . 2011 ;77 (7 ):1020 –30 . 10.1002/ccd.22962 \n.21574239 \n39 \nErbel C , Taskin R , Doesch A , Dengler TJ , Wangler S , Akhavanpoor M , et al\nHigh-sensitive Troponin T measurements early after heart transplantation predict short- and long-term survival . Transplant international: official journal of the European Society for Organ Transplantation . 2013 ;26 (3 ):267 –72 . 10.1111/tri.12024 \n.23252662 \n40 \nLiu Q , Yao JY , Qian C , Chen R , Li XY , Liu SW , et al\nEffects of propofol on ischemia-induced ventricular arrhythmias and mitochondrial ATP-sensitive potassium channels . Acta pharmacologica Sinica . 2012 ;33 (12 ):1495 –501 . 10.1038/aps.2012.86 \n22983391 \n41 \nHuang Z , Zhong X , Irwin MG , Ji S , Wong GT , Liu Y , et al\nSynergy of isoflurane preconditioning and propofol postconditioning reduces myocardial reperfusion injury in patients . Clinical science . 2011 ;121 (2 ):57 –69 . 10.1042/CS20100435 \n.21291422 \n42 \nHaitsma JJ , Lachmann B , Papadakos PJ . Additives in intravenous anesthesia modulate pulmonary inflammation in a model of LPS-induced respiratory distress . Acta anaesthesiologica Scandinavica . 2009 ;53 (2 ):176 –82 . 10.1111/j.1399-6576.2008.01844.x \n.19175577\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "10(7)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D000368:Aged; D018685:Anesthetics, Inhalation; D006348:Cardiac Surgical Procedures; D005260:Female; D005500:Follow-Up Studies; D006331:Heart Diseases; D006801:Humans; D008297:Male; D008738:Methyl Ethers; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors; D012189:Retrospective Studies; D000077149:Sevoflurane; D016896:Treatment Outcome",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e0132165",
"pmc": null,
"pmid": "26196133",
"pubdate": "2015",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": "10567326;23062276;12131102;12594136;12860564;14504159;15273542;15277911;5540853;3769170;2317895;15556966;16861404;16884976;17138080;17156509;17172279;17678775;18583287;18582931;18500419;19092335;19175577;19242644;19081095;19686479;20189026;20349523;21291422;21574239;21659557;21856909;23095629;22983391;23097573;23252662;23707567;12131097;20423337;20217242;20884259;21342154",
"title": "Late Post-Conditioning with Sevoflurane after Cardiac Surgery--Are Surrogate Markers Associated with Clinical Outcome?",
"title_normalized": "late post conditioning with sevoflurane after cardiac surgery are surrogate markers associated with clinical outcome"
} | [
{
"companynumb": "CH-BAXTER-2015BAX050081",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SEVOFLURANE"
},
"drugadditional": null,
... |
{
"abstract": "A fatal case of multidrug poisoning by tramadol and nicotine is reported. Tramadol is a centrally acting analgesic used in the treatment of moderate to severe acute or chronic pain. Nicotine, a lipid-soluble alkaloid, is one of the most readily available drugs in modern society. A 46-year-old man was found dead in his bed, and a suicide note was discovered near the body. He had 25 transdermal nicotine patches attached to his thorax and abdomen. Two half emptied bottles were found on the bedside table; the toxicological examination revealed that they contained tobacco and nicotine as well as other drugs such as diphenhydramine. At autopsy, areas of fresh and old myocardial infarction as well as diffuse pulmonary congestion and edema were present. The tramadol concentration was 6.6 microg/mL in femoral venous blood, while levels of nicotine and its primary metabolite cotinine were determined to be 0.6 and 2.0 microg/mL in femoral venous blood. Based on these results, we determined the cause of death to be cardiorespiratory failure induced by the additive effects of tramadol and nicotine shortly after consumption.",
"affiliations": "Institute of Legal Medicine and Forensic Sciences, University Medical Centre Charité, University of Berlin, Berlin, Germany. bisola@tin.it",
"authors": "Solarino|Biagio|B|;Riesselmann|Benno|B|;Buschmann|Claas T|CT|;Tsokos|Michael|M|",
"chemical_list": "D000701:Analgesics, Opioid; D005731:Ganglionic Stimulants; D014147:Tramadol; D009538:Nicotine; D003367:Cotinine",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.forsciint.2009.09.019",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "194(1-3)",
"journal": "Forensic science international",
"keywords": null,
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D000279:Administration, Cutaneous; D000701:Analgesics, Opioid; D001929:Brain Edema; D003367:Cotinine; D053593:Forensic Toxicology; D005731:Ganglionic Stimulants; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium; D009538:Nicotine; D011654:Pulmonary Edema; D013405:Suicide; D014147:Tramadol",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "e17-9",
"pmc": null,
"pmid": "19850423",
"pubdate": "2010-01-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Multidrug poisoning involving nicotine and tramadol.",
"title_normalized": "multidrug poisoning involving nicotine and tramadol"
} | [
{
"companynumb": "DE-GLAXOSMITHKLINE-DE2017GSK013568",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRAMADOL"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nFebrile infection-related epilepsy syndrome (FIRES) is a syndrome of new-onset status epilepticus preceded by fever and highly refractory to treatment, thus resulting in high mortality and severe neurologic morbidity in surviving patients. Anakinra is an IL-1 receptor antagonist that has previously demonstrated efficacy in treating children with FIRES.\n\n\nMETHODS\nA 21-year-old previously healthy woman presented with new-onset superrefractory status epilepticus following a febrile illness. This was subsequently diagnosed as FIRES after an extensive evaluation failed to identify an alternative etiology. The patient's seizures were refractory to numerous antiepileptic drugs and immunomodulatory therapy. She was maintained under pharmacologic sedation for 31 days.\nAnakinra was initiated on day 32 of her hospital stay, with swift and complete remission of her status epilepticus. Seizures ceased within 24 hours. The patient remains in remission with minimal side effects from the medication and no known long-term morbidity.\n\n\nCONCLUSIONS\nHere we report what we believe is the second case of super-refractory status epilepticus due to FIRES responding to anakinra, and the first such case in an adult patient. Anakinra was well tolerated with few side effects. Our results are further evidence for the autoinflammatory nature of FIRES and support the use of anakinra early in the treatment to prevent long-term sequelae.",
"affiliations": "University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.;University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.;University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.;University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.;University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.;University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.;University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.;University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, hsu@neurology.wisc.edu.;Mayo Clinic, Rochester, Minnesota.",
"authors": "Westbrook|Cecilia|C|;Subramaniam|Thanujaa|T|;Seagren|Ryan M|RM|;Tarula|Erick|E|;Co|Dominic|D|;Furstenberg-Knauff|Meghan|M|;Wallace|Adam|A|;Hsu|David|D|;Payne|Eric|E|",
"chemical_list": "D053590:Interleukin 1 Receptor Antagonist Protein",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1098-1861",
"issue": "118(3)",
"journal": "WMJ : official publication of the State Medical Society of Wisconsin",
"keywords": null,
"medline_ta": "WMJ",
"mesh_terms": "D000073376:Epileptic Syndromes; D005260:Female; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D003294:Seizures, Febrile; D055815:Young Adult",
"nlm_unique_id": "9716054",
"other_id": null,
"pages": "135-139",
"pmc": null,
"pmid": "31682750",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports",
"references": "27894452;25398790;26010959;27890484;29247995;22878274;29476535;21883180;21967356;27770579;22473710;29426321;27065452",
"title": "Febrile Infection-Related Epilepsy Syndrome Treated Successfully With Anakinra in a 21-Year-Old Woman.",
"title_normalized": "febrile infection related epilepsy syndrome treated successfully with anakinra in a 21 year old woman"
} | [
{
"companynumb": "US-PFIZER INC-2019514728",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "3",
... |
{
"abstract": "Background: Cardiac metastasis may be encountered more frequently than primary cardiac tumors. They are discovered at autopsies with an incidence between 1.5 - 20%. The primary tumors that generate cardiac metastasis are malignant melanomas, lymphoma, the lungs, the breast, the esophagus. The organ most affected is the pericardium (62-81%). In 90% of cases from a clinical point of view, they are generally silent. In the case of patients diagnosed with breast cancer and who have undergone radiotherapy, differential diagnosis with fibrosis post radiotherapy interferes. The treatment is palliative and should be administered according to the primary location of the tumor and the patient's performance status. Case presentation: We are presenting the case of a 73-year-old diagnosed and treated for a breast neoplasm in the left breast in 2006. After a period of time of 9 years, the patient presents secondary sternal bone determination, radio-treated and for which she once again goes under hormonal therapy. In 2018, patient performed an imaging evaluation that revealed lung metastases. At the moment of stage review, performed in 2020, secondary epicardial determinations are noted. We present the case, the therapeutic management, diagnostic procedures and treatment and also, we discuss the data from literature. Conclusion: Cardiac metastases are rare and and in most cases are silent. The incidence has changed due to treatment options and imaging investigations. Stereotactic body radiation therapy can be considereda a therapeutic option in the cases with good performance status and with oligometastatic disease.",
"affiliations": null,
"authors": "Rebegea|Laura|L|;Ilie|Ana Maria|AM|;Paslaru|Ana Maria|AM|;Firescu|Dorel|D|;Serban|Cristina|C|;Voinescu|Carina|C|;Sapira|Violeta|V|;Stoleriu|Gabriela|G|;Lungu|Mihaela|M|;Zgura|Anca|A|;Anghel|Rodica|R|",
"chemical_list": null,
"country": "Romania",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1221-9118",
"issue": "116(5)",
"journal": "Chirurgia (Bucharest, Romania : 1990)",
"keywords": "breasttumor; chemotherapy; epicardialmetastases; radiotherapy; surgery",
"medline_ta": "Chirurgia (Bucur)",
"mesh_terms": "D000368:Aged; D001943:Breast Neoplasms; D005260:Female; D006338:Heart Neoplasms; D006801:Humans; D008175:Lung Neoplasms; D012878:Skin Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "9213031",
"other_id": null,
"pages": "627-633",
"pmc": null,
"pmid": "34749859",
"pubdate": "2021-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Management of Epicardial Metastasis in Breast Cancer.",
"title_normalized": "management of epicardial metastasis in breast cancer"
} | [
{
"companynumb": "RO-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-319104",
"fulfillexpeditecriteria": "1",
"occurcountry": "RO",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"dr... |
{
"abstract": "Wohlfahrtiimonas chitiniclastica has been associated with open wound infections, cellulitis, osteomyelitis, and bacteremia.\nWe report the case of a 41 year old woman with history of congenital myelomeningocele, paraplegia and extensive decubitus ulcers that developed W. chitiniclastica bacteremia secondary to an infected ulcer.\nW. chitiniclastica is an emerging human pathogen that can be readily identified by MALDI-TOF or sequencing.",
"affiliations": "Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.;Department of Internal Medicine, Division of Infectious Diseases, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.;Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.;Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.",
"authors": "Chavez|Jesus A|JA|;Alexander|Andrew J|AJ|;Balada-Llasat|Joan M|JM|;Pancholi|Preeti|P|",
"chemical_list": null,
"country": "England",
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"doi": "10.1099/jmmcr.0.005134",
"fulltext": "\n==== Front\nJMM Case RepJMM Case RepJMMCRJMM Case Reports2053-3721Microbiology Society jmmcr00513410.1099/jmmcr.0.005134Case ReportBlood/Heart and LymphaticsA case of Wohlfahrtiimonas chitiniclastica bacteremia in continental United States http://jmmcr.microbiologyresearch.orgChavez Jesus A. 1Alexander Andrew J. 2Balada-Llasat Joan M. 1Pancholi Preeti 1*1 Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA2 Department of Internal Medicine, Division of Infectious Diseases, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA*Correspondence: Preeti Pancholi, Preeti.Pancholi@osumc.edu12 2017 21 12 2017 21 12 2017 4 12 e00513405 10 2017 08 12 2017 2017 @ The authors2017This is an open access article under the terms of the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.Introduction\nWohlfahrtiimonas chitiniclastica has been associated with open wound infections, cellulitis, osteomyelitis, and bacteremia.\n\nCase presentation\nWe report the case of a 41 year old woman with history of congenital myelomeningocele, paraplegia and extensive decubitus ulcers that developed W. chitiniclastica bacteremia secondary to an infected ulcer.\n\nConclusion\nW. chitiniclastica is an emerging human pathogen that can be readily identified by MALDI-TOF or sequencing.\n\nWohlfahrtiimonas chitiniclasticainfectionbacteremiaMALDI-TOF MSulcerosteomyelitisantibioticssusceptibilityOpenAccessEmbargo0\n==== Body\nIntroduction\nThe first description of Wohlfahrtiimonas chitiniclastica was made in 2008 by Tóth et al. and the name of the bacteria is related to the first described vector, a species of obligate parasitic flies known as Wohlfahrtia magnifica [1]. It is known to be transmitted by other fly species, including Chrysomya megacephala, Lucilia sericata and Musca domestica, when larvae are deposited in open wounds [2]. W. chitiniclastica is a strictly aerobic, non-motile, non-spore forming, Gram-negative rod that grows best between 28 and 37 ˚C. It is catalase- and oxidase-positive, but urease-, indole- and H2S-negative [1]. A strong chitinase activity has been described as an important characteristic [1, 3]. It has been reported to be misidentified by the VITEK 2 system, but successfully confirmed by matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) and 16S rRNA gene sequencing [2, 4]. A total of twelve cases of human infection have been described in the literature worldwide [2] and, even though it has been mostly associated with parasitic flies, the bacteria have also been isolated in chicken meat [5] and arsenic-affected soils in Bangladesh [6]. The majority of the reports have been from areas with relatively warm climates, but there is a recent case report from an area of northern temperate climate [3, 7]. Here we present the first, to our knowledge, well documented case of bacteremia and the second case of human infection in the continental USA.\n\nCase report\nA 41-year-old female presented to the emergency department with a one-week history of abdominal pain, worsening back pain and constipation. Past medical history included congenital lumbar myelomeningocele causing paraplegia status post spinal fixation, extensive sacral decubitus ulcers, obesity, severe lower extremity lymphedema, Arnold Chiari malformation type II with remote ventriculoperitoneal shunt placement and neurogenic bladder with chronic indwelling Foley catheter. She complained of vomiting and fatigue but denied fevers and chills. Her Foley catheter was changed two days prior to admission. Upon physical examination, she was found to have a foul smelling stage IV right ischial decubitus ulcer, bilateral leg lymphedema with multiple skin excoriations and poor dentition. The patient was unable to recall how long she had the wounds. The wounds had worsened over time due to inadequate wound care and the inability to shower at home due to body habitus and paraplegia. Additional exposure history included living with a dog and cigarette smoking. She denied intravenous (IV) drug use.\n\nLaboratory data was consistent with an elevated white blood cell count (WBC) of 42.60 K µl−1, hyperkalemia, hyponatremia and pyuria with acute kidney injury. Computed tomography of the abdomen and pelvis was concerning for osteomyelitis of the right ischium with adjacent abscess. The patient was diagnosed with sepsis, blood cultures were obtained and she was treated with empiric IV vancomycin and cefepime. An unsuccessful attempt to place an intraosseous catheter was performed. Blood culture became positive after 17 h of incubation and a Gram stain of the blood culture revealed Gram-negative bacilli (Fig. 1). The sample was inoculated to sheep blood, chocolate and MacConkey media (Becton, Dickinson and Company) and cultured aerobically at 37 ˚C for 24 h, growing W. chitiniclastica (Fig. 2). Proteus mirabilis was also isolated from the culture after 48 h. The organisms were identified accurately by MALDI-TOF MS (RUO version 3.1, Bruker Daltonics) with a score of >2.0. Extraction was not required. A culture sent from the ischial wound grew W. chitiniclastica, Myroides injenensis and Enterococcus faecalis aerobically, and Bacteroides ovatus/Bacteroides xylanisolvens anaerobically. Susceptibilities were determined using the MicroScan WalkAway (Beckman Coulter). The interpretation of antibiotic susceptibility was based on the minimal inhibitory concentration breakpoints (µg ml−1) for other non-Enterobacteriaceae described in the M100 Performance Standards for Antimicrobial Susceptibility Testing, CLSI, 27th edition January 2017. Appropriate quality controls (Escherichia coli ATCC 35218, Klebsiella pneumoniae ATCC 700603 and Pseudomonas aeruginosa ATCC 27853) were utilized for the interpretation of susceptibility results. The W. chitiniclastica isolate was susceptible to all antibiotics tested (Table 1).\n\nFig. 1. Gram-negative rod from positive blood culture on microscopic examination (1000×).\n\nFig. 2. Colonies growing on sheep blood agar revealing a characteristic mucoid morphology.\n\nTable 1. Antimicrobial susceptibility testing of W. chitiniclastica\nAntibiotic\tMIC (µg ml−1)\tSusceptible=S\t\nAmikacin\t≤16\tS\t\nCefepime\t≤4\tS\t\nCeftazidime\t≤1\tS\t\nCiprofloxacin\t≤1\tS\t\nGentamicin\t≤4\tS\t\nLevofloxacin\t≤2\tS\t\nPiperacillin–tazobactam\t≤16\tS\t\nTobramycin\t≤4\tS\t\nTrimethoprim–sulfamethoxazole\t≤2/38\tS\t\nThe patient remained afebrile throughout her admission and WBC improved with antibiotics. On hospital day 6 she was taken to the operating room for wound debridement, but no additional cultures were obtained. Given her improvement on hospital day 15 she was discharged to a skilled nursing facility on IV vancomycin and cefepime via a peripherally inserted central catheter, and oral metronidazole for a planned 6 week course.\n\nFive days after discharge she developed altered mental status and became hypotensive. She was admitted to the ICU and required vasopressor support. She was treated with IV vancomycin and meropenem. A stool PCR was positive for Clostridium difficile so IV metronidazole and oral vancomycin were added. She developed worsening metabolic acidosis, requiring continuous renal replacement therapy, and acute encephalopathy, necessitating intubation for airway protection. Despite aggressive treatment she continued to decline and on hospital day three, her family decided to transition her to comfort care and she expired shortly thereafter. Blood cultures from the second admission were initially negative, but a line culture was positive for Candida albicans shortly after she expired.\n\nDiscussion\nWe present the fifth case of W. chitiniclastica bacteremia worldwide [2, 3, 7–9], the first bacteremia case and second of human infection in the continental USA. The first reported case involved an open leg wound [4]. Other cases in the USA have been described, including a zoonotic case of bacterial septicemia in Michigan in 2014 [10], and two elderly patients infected in Hawaii [11], one of whom was bacteremic. To the best of our knowledge, a total of 12 cases of human disease [2–4, 7–9, 12] and three zoonotic cases [10, 13, 14] have been reported in the literature. Misidentification as Acinetobacter iwoffii, Comamonas testosteroni or Rhizobium radiobacter has been reported in previous cases using the Vitek 2 system [2, 4, 7]. When our isolate was tested with the MicroScan WalkAway, the system was unable to identify the organism since low probability scores for Moxarella/Psychrobacter spp., Vibrio spp., Pasteurella/Actinobacillus spp. and Pseudomonas spp. were generated (data not shown). Neither of the systems (Vitek and Microscan) includes these organisms in their database. MALDI-TOF MS and 16S rRNA sequencing have proven to be good identification methods for W. chitiniclastica [2, 7, 8, 11, 15], in fact, the W. chitiniclastica strain SH04 genome is available [16].\n\nThe geographic distribution of W. chitiniclastica is variable, but most cases have been described in Europe [2–4, 7–9, 11, 12], however, epidemiological studies are required to better understand its geographic distribution and host-associated risk factors. To date, all reported cases of human infections are related to poor hygienic conditions and/or chronic open skin wounds with multiple comorbidities. Several cases have been associated with maggots. Our patient did not have any evidence of larvae or maggots but did have chronic wounds with very poor wound care and hygiene. Continuous exposure of the open wound to the environment might have facilitated transmission through exposure to Musca domestica or other fly species. Nevertheless, this cannot be proven with certainty since the patient denied any other risk factors, including recent travel history, and maggots were not identified by physical exam or autopsy. The vast majority of infections are polymicrobial, including our case, in which Proteus mirabilis bacteremia was also identified, albeit 24 h after W. chitiniclastica was isolated, thus we consider W. chitiniclastica to be the primary pathogen. The organism has been shown to be susceptible to the majority of the antimicrobials available, with β-lactams being the most commonly used treatment. Intrinsic fosfomycin resistance has been reported [2, 5].\n\nIn conclusion, W. chitiniclastica is an emerging human pathogen, sometimes associated with flies and maggots, which often causes infection of chronic wounds especially in the setting of poor hygienic conditions. Both MALDI-TOF MS and 16S rRNA sequencing are able to identify this organism reliably.\n\nFunding information\nThe authors received no specific grant from any funding agency.\n\nAcknowledgements\nJ. A. C.: Data Collection, main writer, editing and submitting. A. J. A.: Diagnosis, data collection and editing. J. M. B.-L.: Diagnosis, data collection and editing. P. P.: Diagnosis, data collection, senior author and editing.\n\nConflicts of interest\nThe authors declare that there are no conflicts of interest.\n\nEthical statement\nOur study consists of observations only and no intervention/change to patient care was made. Appropriate consent forms were obtained for this case report according to the institution's requirements.\n==== Refs\nReferences\n1 Tóth EM Schumann P Borsodi AK Kéki Z Kovács AL Wohlfahrtiimonas chitiniclastica gen. nov., sp. nov., a new gammaproteobacterium isolated from Wohlfahrtia magnifica (Diptera: Sarcophagidae) Int J Syst Evol Microbiol 2008 58 976 981 10.1099/ijs.0.65324-0 18398205 \n2 Schröttner P Rudolph WW Damme U Lotz C Jacobs E Wohlfahrtiimonas chitiniclastica : current insights into an emerging human pathogen Epidemiol Infect 2017 145 1292 1303 10.1017/S0950268816003411 28162132 \n3 Rebaudet S Genot S Renvoise A Fournier PE Stein A Wohlfahrtiimonas chitiniclastica bacteremia in homeless woman Emerg Infect Dis 2009 15 985 987 10.3201/eid1506.080232 19523315 \n4 de Dios A Jacob S Tayal A Fisher MA Dingle TC First report of Wohlfahrtiimonas chitiniclastica isolation from a patient with cellulitis in the United States J Clin Microbiol 2015 53 3942 3944 10.1128/JCM.01534-15 26378273 \n5 Matos J Queiroga AP de Oliveira Pedroza Bindi dos Reis CC Ribeiro RL Teixeira LM First report of the emerging zoonotic agent Wohlfahrtiimonas chitiniclastica isolated from a retail frozen chicken in Rio de Janeiro, Brazil Antonie Van Leeuwenhoek 2016 109 729 734 10.1007/s10482-016-0673-x 26961699 \n6 Sanyal SK Mou TJ Chakrabarty RP Hoque S Hossain MA Diversity of arsenite oxidase gene and arsenotrophic bacteria in arsenic affected Bangladesh soils AMB Express 2016 6 21 10.1186/s13568-016-0193-0 26980601 \n7 Kõljalg S Telling K Huik K Murruste M Saarevet V First report of Wohlfahrtiimonas chitiniclastica from soft tissue and bone infection at an unusually high northern latitude Folia Microbiol 2015 60 155 158 10.1007/s12223-014-0355-x 25300355 \n8 Almuzara MN Palombarani S Tuduri A Figueroa S Gianecini A First case of fulminant sepsis due to Wohlfahrtiimonas chitiniclastica J Clin Microbiol 2011 49 2333 2335 10.1128/JCM.00001-11 21471333 \n9 Campisi L Mahobia N Clayton JJ Wohlfahrtiimonas chitiniclastica bacteremia associated with Myiasis, United Kingdom Emerg Infect Dis 2015 21 1068 1069 10.3201/eid2106.140007 25989017 \n10 Thaiwong T Kettler NM Lim A Dirkse H Kiupel M First report of emerging zoonotic pathogen Wohlfahrtiimonas chitiniclastica in the United States J Clin Microbiol 2014 52 2245 2247 10.1128/JCM.00382-14 24671785 \n11 Nogi M Bankowski MJ Pien FD Wohlfahrtiimonas chitiniclastica Infections in 2 elderly patients, Hawaii Emerg Infect Dis 2016 22 567 568 10.3201/eid2203.151701 26889722 \n12 Suryalatha K John J Thomas S Wohlfahrtiimonas chitiniclastica -associated osteomyelitis: a rare case report Future Microbiol 2015 10 1107 1109 10.2217/fmb.15.44 26119949 \n13 Josue DD Eva S Isabel VA Lucas D Marisa A Endocarditis associated with Wohlfahrtiimonas chitiniclastica in a short-beaked common dolphin (Delphinus delphis ) J Wildl Dis 2015 51 283 286 10.7589/2014-03-072 25375942 \n14 Qi J Gao Y Wang GS Li LB Li LL Identification of Wohlfahrtiimonas chitiniclastica isolated from an infected cow with hoof fetlow, China Infect Genet Evol 2016 41 174 176 10.1016/j.meegid.2016.04.008 27079266 \n15 Schröttner P Gunzer F Schüppel J Rudolph WW Identification of rare bacterial pathogens by 16S rRNA gene sequencing and MALDI-TOF MS J Vis Exp 2016 113 e53176 10.3791/53176 27500532 \n16 Cao XM Chen T Xu LZ Yao LS Qi J Complete genome sequence of Wohlfahrtiimonas chitiniclastica strain SH04, isolated from Chrysomya megacephala collected from Pudong International Airport in China Genome Announc 2013 1 e00119-13 10.1128/genomeA.00119-13 23405300\n\n",
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"abstract": "This study aims to evaluate the efficacy and safety of repeated treatments with low-dose rituximab for relapsing mixed cryoglobulinemia vasculitis. Thirty-seven patients with mixed cryoglobulinemia vasculitis refractory to standard of care treatment, 34 of which were HCV-positive, were treated with rituximab at the reduced dosage of 250 mg/m2 given twice 1 week apart per cycle. Thirty patients (81%) achieved a clinical response; 5 of them remain in remission, 3 were lost to follow-up or died, and 22 relapsed after a mean of 15.7 months. Eleven relapsers were retreated with one (6 patients), 2 (3 patients), or 3 (2 patients) additional rituximab cycles given at each relapse. Clinical and laboratory efficacy and side effects of long-term treatment were evaluated. Clinical response to retreatment was 91% (10/11) at the first relapse, 80% (4/5) at the second relapse, and 100% (2/2) at the third relapse. The mean (±SD) time to relapse was 17.1 ± 14.1 months in 30 patients who were treated with only one cycle (from first cycle to the first relapse) and 45.7 ± 30.6 months (from first cycle to the last observed relapse) in 11 patients treated with 2 or more cycles (p = 0.0037). Severe adverse reactions occurred in 3 patients, in 2 of whom at the first cycle. Our results suggest that repeated treatment of relapsing mixed cryoglobulinemia with a low-dose rituximab regimen is efficacious, safe, and cost-effective for the long-term management of this disorder.",
"affiliations": "Department of Clinical Medicine, Sapienza University of Rome, Viale dell'Università 37, 00185, Rome, Italy.;Department of Clinical Medicine, Sapienza University of Rome, Viale dell'Università 37, 00185, Rome, Italy.;Department of Clinical Medicine, Sapienza University of Rome, Viale dell'Università 37, 00185, Rome, Italy.;Department of Clinical Medicine, Sapienza University of Rome, Viale dell'Università 37, 00185, Rome, Italy.;Department of Clinical Medicine, Sapienza University of Rome, Viale dell'Università 37, 00185, Rome, Italy.;Department of Infectious Diseases, Sapienza University of Rome, Rome, Italy.;Department of Clinical Medicine, Sapienza University of Rome, Viale dell'Università 37, 00185, Rome, Italy.;Department of Clinical Medicine, Sapienza University of Rome, Viale dell'Università 37, 00185, Rome, Italy.;Department of Clinical Medicine, Sapienza University of Rome, Viale dell'Università 37, 00185, Rome, Italy. marcella.visentini@uniroma1.it.",
"authors": "Colantuono|Stefania|S|;Mitrevski|Milica|M|;Yang|Baoran|B|;Tola|Julia|J|;Carlesimo|Maurizio|M|;De Sanctis|Giuseppe M|GM|;Fiorilli|Massimo|M|;Casato|Milvia|M|;Visentini|Marcella|M|",
"chemical_list": "D007155:Immunologic Factors; D000069283:Rituximab",
"country": "Germany",
"delete": false,
"doi": "10.1007/s10067-017-3552-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0770-3198",
"issue": "36(3)",
"journal": "Clinical rheumatology",
"keywords": "Low-dose; Mixed cryoglobulinemia; Retreatment; Rituximab",
"medline_ta": "Clin Rheumatol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003449:Cryoglobulinemia; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007155:Immunologic Factors; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D019233:Retreatment; D000069283:Rituximab; D016896:Treatment Outcome; D014657:Vasculitis",
"nlm_unique_id": "8211469",
"other_id": null,
"pages": "617-623",
"pmc": null,
"pmid": "28111716",
"pubdate": "2017-03",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": "27483451;27161362;25837517;26031898;17060540;26255249;11470986;24024840;25431357;21053035;20740617;24424176;27605512;17314160;11825916;21821153;10524695;25687730;24418300;26276965;22474249;24418294;22147444;21570494;21239761;21303705;22147661;27640316;25815218;25030430",
"title": "Efficacy and safety of long-term treatment with low-dose rituximab for relapsing mixed cryoglobulinemia vasculitis.",
"title_normalized": "efficacy and safety of long term treatment with low dose rituximab for relapsing mixed cryoglobulinemia vasculitis"
} | [
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"companynumb": "IT-ROCHE-1889203",
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"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
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{
"abstract": "Neonatal sepsis is a significant cause of morbidity and mortality among term and preterm infants. Ampicillin and gentamicin are standard empiric therapy for early onset sepsis. Four cases of neonatal sepsis secondary to Escherichia coli (E. coli) found to be gentamicin resistant occurred within a five week period in one neonatal intensive care unit (NICU). To determine whether these cases could be tied to a single vector of transmission, and to more broadly evaluate the incidence of gentamicin resistant strains of E. coli in the neonatal population at our institution compared to other centers, we reviewed the charts of the four neonates (Infants A through D) and their mothers. The E. coli isolates were sent for Pulse Field Gel Electrophoresis (PFGE) to evaluate for genetic similarity between strains. We also reviewed all positive E. coli cultures from one NICU over a two year period. Infants A and B had genetically indistinguishable strains which matched that of urine and placental cultures of Infant B's mother. Infant C had a genetically distinct organism. Infant D, the identical twin of Infant C, did not have typing performed. Review of all cultures positive for E. coli at our institution showed a 12.9 percent incidence of gentamicin-resistance. A review of other studies showed that rates of resistance vary considerably by institution. We conclude that gentamicin-resistant E. coli is a relatively uncommon cause of neonatal sepsis, but should remain a consideration in patients who deteriorate despite initiation of empiric antibiotics.",
"affiliations": "University of Michigan, Ann Arbor, MI, USA.",
"authors": "Hasvold|J|J|;Bradford|L|L|;Nelson|C|C|;Harrison|C|C|;Attar|M|M|;Stillwell|T|T|",
"chemical_list": "D000900:Anti-Bacterial Agents; D005839:Gentamicins",
"country": "Netherlands",
"delete": false,
"doi": "10.3233/NPM-1365512",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-4429",
"issue": "6(2)",
"journal": "Journal of neonatal-perinatal medicine",
"keywords": "Neonatal sepsis; antibiotic resistance",
"medline_ta": "J Neonatal Perinatal Med",
"mesh_terms": "D000900:Anti-Bacterial Agents; D004200:Diseases in Twins; D024881:Drug Resistance, Bacterial; D004927:Escherichia coli Infections; D005260:Female; D005839:Gentamicins; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D007235:Infant, Premature, Diseases; D018445:Infectious Disease Transmission, Vertical; D008297:Male; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D018805:Sepsis",
"nlm_unique_id": "101468335",
"other_id": null,
"pages": "173-7",
"pmc": null,
"pmid": "24246520",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Gentamicin resistance among Escherichia coli strains isolated in neonatal sepsis.",
"title_normalized": "gentamicin resistance among escherichia coli strains isolated in neonatal sepsis"
} | [
{
"companynumb": "US-ACTAVIS-2014-16834",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
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"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "This study was purposed to investigate the therapeutic efficacy of haploidentical allogeneic hemopoietic stem cell transplantation (allo-HSCT) for severe aplastic anemia (SAA), and evaluate the safety of this treatment by retrospective analysis. A total of 21 patients with SAA (13 cases of SAA-I, 8 cases of SAA-II) were treated with haploidentical allo-HSCT. Donors were the relatives of the patients (12 were the parents, 9 were the siblings). The conditioning regimen contained cyclophosphamide, fludarabine and antithymocyte globulin. Methylaminopterin, mycophenolate mofetil and cyclosporin A were used for preventing graft versus host disease (GVHD). The chimerism rate was monitored periodically after successful graft. The long survival rate, incidence and severity of complication, such as GVHD, infection, and so on were analyzed. The results showed that 15 out of 21 patients were survived for 16 (3-46) months, survival rate was 71.4%. Graft tailure happened in one case who died of mycetes septicemia at 43 days after allo-HSCT. Two patients died of pulmonary infection at 6 days and 10 days respectively after transplantation. Rejection happened in one case at 3 months who died of pulmonary infection at 17 days after the second transplantation with the same donor. Two patients died of IV grade intestinal GVHD at 35 days and 52 days. GVHD occurred in 14 of 21 patients, the accumulative incidence was 66.7%, 5 cases of them were severe. It is concluded that the therapeutic efficacy of haploidentical allo-HSCT is effective for SAA and with slighter complications.",
"affiliations": "Department of Hematology, General Hospitol of Beijing Military Command, Chinese PLA, Beijing 100700, China.;Department of Hematology, General Hospitol of Beijing Military Command, Chinese PLA, Beijing 100700, China.;Department of Hematology, General Hospitol of Beijing Military Command, Chinese PLA, Beijing 100700, China.;Department of Hematology, General Hospitol of Beijing Military Command, Chinese PLA, Beijing 100700, China.;Department of Hematology, General Hospitol of Beijing Military Command, Chinese PLA, Beijing 100700, China.;Department of Hematology, General Hospitol of Beijing Military Command, Chinese PLA, Beijing 100700, China. E-mail: chenhui-ren@medmail.com.cn.",
"authors": "Zhang|Yuan|Y|;Liu|Xiao-Dong|XD|;He|Xue-Peng|XP|;Lou|Jing-Xin|JX|;Guo|Zhi|Z|;Chen|Hui-Ren|HR|",
"chemical_list": "D000961:Antilymphocyte Serum; D016572:Cyclosporine; D014740:Vidarabine; C024352:fludarabine",
"country": "China",
"delete": false,
"doi": "10.7534/j.issn.1009-2137.2014.05.033",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1009-2137",
"issue": "22(5)",
"journal": "Zhongguo shi yan xue ye xue za zhi",
"keywords": null,
"medline_ta": "Zhongguo Shi Yan Xue Ye Xue Za Zhi",
"mesh_terms": "D000293:Adolescent; D064591:Allografts; D000741:Anemia, Aplastic; D000961:Antilymphocyte Serum; D016572:Cyclosporine; D006086:Graft vs Host Disease; D006238:Haploidy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D012189:Retrospective Studies; D035781:Siblings; D015996:Survival Rate; D014019:Tissue Donors; D019172:Transplantation Conditioning; D014740:Vidarabine",
"nlm_unique_id": "101084424",
"other_id": null,
"pages": "1354-8",
"pmc": null,
"pmid": "25338588",
"pubdate": "2014-10",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Retrospective analysis of therapeutic efficacy of haploidentical allogeneic hematopoietic stem cell transplantation for severe aplastic anemia.",
"title_normalized": "retrospective analysis of therapeutic efficacy of haploidentical allogeneic hematopoietic stem cell transplantation for severe aplastic anemia"
} | [
{
"companynumb": "CN-ALKEM-000987",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": null,
"drugadditional": null,
"drugadministrationroute": "042",
"drugauthorization... |
{
"abstract": "We report an Epstein-Barr virus (EBV)-associated pulmonary posttransplant smooth muscle tumor arising in the left lung of a 71-year-old bilateral lung transplant recipient nearly 3 years after transplantation, treated with thoracoscopic wedge resection. Four previous smooth muscle tumors have been reported following lung transplantation. To our knowledge, this is the first reported case of an EBV-positive posttransplant smooth muscle tumor within the transplanted lung. We describe the clinical, pathologic, and histologic diagnosis of this uncommon tumor.",
"affiliations": "Saint Louis University School of Medicine, St. Louis, Missouri.;Section of General Thoracic Surgery, Emory University School of Medicine, Atlanta, Georgia.;Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia.;Division of Pulmonary, Allergy, and Critical Care Medicine, Emory University School of Medicine, Atlanta, Georgia.;Section of General Thoracic Surgery, Emory University School of Medicine, Atlanta, Georgia. Electronic address: sforce@emory.edu.",
"authors": "Brescia|Alexander A|AA|;Khullar|Onkar V|OV|;Gal|Anthony A|AA|;Neujahr|David|D|;Force|Seth D|SD|",
"chemical_list": "D000914:Antibodies, Viral",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-4975",
"issue": "99(6)",
"journal": "The Annals of thoracic surgery",
"keywords": null,
"medline_ta": "Ann Thorac Surg",
"mesh_terms": "D000368:Aged; D000914:Antibodies, Viral; D003937:Diagnosis, Differential; D020031:Epstein-Barr Virus Infections; D004854:Herpesvirus 4, Human; D006801:Humans; D008175:Lung Neoplasms; D016040:Lung Transplantation; D008297:Male; D011013:Pneumonectomy; D049268:Positron-Emission Tomography; D018235:Smooth Muscle Tumor; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "15030100R",
"other_id": null,
"pages": "e145-6",
"pmc": null,
"pmid": "26046906",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Epstein-Barr Virus-Associated Pulmonary Smooth Muscle Tumor After Lung Transplantation.",
"title_normalized": "epstein barr virus associated pulmonary smooth muscle tumor after lung transplantation"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-19-49297",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"dr... |
{
"abstract": "Delayed leukoencephalopathy (DL) is a rare entity associated with cerebral hypoxia and heroin consumption. We describe the clinical course of three cases of DL due to non-heroin drug use.\nWe describe the cases of three DL patients admitted to our hospital in 2012.\nThese cases contribute to the aetiological spectrum of DL since multifactorial causes could account for the clinical symptoms.\nSubstances toxic to the CNS can damage the CNS directly (direct toxicity) or by depressing the respiratory centre (cerebral hypoxia).As clinical manifestations can appear after a time lag, we recommend a period of initial monitoring.Histological and radiological findings can contribute to better understanding of the pathophysiological mechanisms and causes involved.",
"affiliations": "Internal Medicine Department, University Hospital 12 de Octubre, Madrid, Spain.;Internal Medicine Department, University Hospital 12 de Octubre, Madrid, Spain.;Internal Medicine Department, University Hospital 12 de Octubre, Madrid, Spain.;Neurology Department, University Hospital 12 de Octubre, Madrid, Spain.;Internal Medicine Department, University Hospital 12 de Octubre, Madrid, Spain.",
"authors": "Torralba-Morón|Ángel|Á|;Ortiz-Imedio|Juan|J|;Morales-Conejo|Montserrat|M|;Ruiz-Morales|Juan|J|;Guerra-Vales|Juan-Manuel|JM|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.12890/2016_000511",
"fulltext": "\n==== Front\nEur J Case Rep Intern MedEur J Case Rep Intern MedEuropean Journal of Case Reports in Internal Medicine2284-2594SMC Media Srl 10.12890/2016_000511511-1-3277-1-10-20161130ArticlesDelayed Leukoencephalopathy: Three Case Reports and a Literature Review Torralba-Morón Ángel 1Ortiz-Imedio Juan 1Morales-Conejo Montserrat 1Ruiz-Morales Juan 2Guerra-Vales Juan-Manuel 1\n1 Internal Medicine Department, University Hospital 12 de Octubre, Madrid, Spain\n2 Neurology Department, University Hospital 12 de Octubre, Madrid, Spain2017 27 3 2017 4 2 00051103 10 2016 08 11 2016 © EFIM 20162016This article is licensed under a Commons Attribution Non-Commercial 4.0 LicenseBackground\nDelayed leukoencephalopathy (DL) is a rare entity associated with cerebral hypoxia and heroin consumption. We describe the clinical course of three cases of DL due to non-heroin drug use.\n\nMaterial and methods\nWe describe the cases of three DL patients admitted to our hospital in 2012.\n\nDiscussion\nThese cases contribute to the aetiological spectrum of DL since multifactorial causes could account for the clinical symptoms.\n\nLEARNING POINTS\nSubstances toxic to the CNS can damage the CNS directly (direct toxicity) or by depressing the respiratory centre (cerebral hypoxia).\n\nAs clinical manifestations can appear after a time lag, we recommend a period of initial monitoring.\n\nHistological and radiological findings can contribute to better understanding of the pathophysiological mechanisms and causes involved.\n\ndelayed leukoencephalopathyglobus pallidusmethadone\n==== Body\nBACKGROUND\nDelayed leukoencephalopathy (DL) is caused by structural injury to the white matter of the central nervous system (CNS), with a characteristic two-phase clinical course: recovery from an episode of low level of awareness, caused by acute or chronic neurological damage, is followed by neuropsychiatric symptoms which include cognitive and level of consciousness disorders, behavioural disorders and dysautonomy. The disorder is associated with parkinsonism when grey matter basal nuclei are involved[1].\n\nThe condition was initially called delayed post-hypoxic leukoencephalopathy (DPHL) and correlated with causes of cerebral hypoxia, such as CO poisoning or respiratory depression due to asphyxia, constriction, drugs, etc.[2,3]. In DL, the grey matter basal nuclei are damaged by hypoxia[1], the posterior fossa structures are not affected, and there is increased permeability of the blood–brain barrier[4]. There is severe diffuse demyelination, but the subcortical U-fibres are not damaged, and neither spongiosis nor vacuolation occur[3]. The disease usually has a good prognosis.\n\nLeukoencephalopathy following heroin pyrolysate inhalation predominantly affects the cerebellum and brainstem. The condition presents with two gradual clinical phases, without an intervening recovery period. During the initial stage the disease causes cerebellar ataxia, hyperactive deep tendon reflexes, hypertonic hemiplegia or tetraplegia, choreoathetoid movements and pseudobulbar reflexes. In the terminal stage, which does not always develop, it causes central pyrexia, spasms, hypotonic paresis, areflexia and akinetic mutism. Specific histological findings include spongiform degeneration of the CNS white matter with vacuoles and cavities, foci of necrosis in the spongiform white matter and multivacuolar degeneration of the oligodendroglia and axons, all of which affect the hemispheres, cerebellum, brainstem and spinal cord[5].\n\nIsolated cases with a similar neurological picture, attributable to consumption of methadone and other toxic substances (benzodiazepines, neuroleptics, barbiturates, etc.), demonstrating a low level of consciousness and possible associated hypoxia, have been reported[2].\n\nWe present the case reports below to increase knowledge of the aetiological spectrum of DL syndromes. A review of the literature on the subject is also provided.\n\nCASE REPORT\nCase 1 was a 42-year-old male polydrug user (but no heroin use for over 5 years). After a methadone, alprazolam and alcohol overdose, he experienced an episode of low level of consciousness, respiratory depression and fever without clinical focus. Initial neuroimaging revealed non-specific findings.\n\nThe patient’s consciousness level initially recovered but suddenly worsened 13 days later. During the following weeks, he remained febrile, with spontaneous resolution, and with fluctuating consciousness, which gradually improved. He had widespread myoclonus. Cranial MRI (Fig. 1) revealed bilateral, symmetrical and diffuse involvement of the cerebral white matter, as well as bilateral globus pallidus injury. EEG revealed diffuse slowing of background neuronal activity. The patient remained stable. Lack of attention and dysexecutive and amnestic abnormalities persisted at discharge.\n\nCase 2 was a 43-year-old man living with HIV treated with emtricitabine/tenofovir and lopinavir/ritonavir, HCV genotype 3 chronic liver disease and drug abuse (no heroin use for over 5 years). He was admitted after a methadone overdose with a low level of consciousness and a bradypnoea episode. This was associated with tachycardia and sweating, as well as fever without clinical focus, which resolved spontaneously. An initial cranial CT scan revealed decreased image density in both globus pallidi.\n\nDuring the first few days, the patient recovered awareness and made spontaneous voluntary movements. He reacted by opening his eyes when spoken to and answered with basic words. However, drowsiness, slow thinking and occasional agitation remained.\n\nDuring the following days, the low level of awareness, sweating, tachypnoea and fever reappeared. Associated infection was not observed. A chest angio-CT ruled out pulmonary embolism. The patient did not speak, and presented spastic rigidity and an extensor motor response to pain. Neuroimaging revealed bilateral, symmetrical and diffuse involvement of the cerebral white matter, with clinical progression of the lesions in both globus pallidi (Fig. 2). EEG revealed diffuse slowing of background neuronal activity. A cerebrospinal fluid study was normal.\n\nThe patient gradually deteriorated without recovering consciousness. Tachypnoea, fever and sweating remained. He died 40 days after the onset of symptoms.\n\nCase 3 was a 52-year-old male polydrug user (no heroin use for over 5 years), living with HIV treated with emtricitabine/tenofovir and lopinavir/ritonavir and chronic liver disease secondary to HBV/HDV coinfection. He was admitted for abnormal behaviour, disorientation, inattention and low level of consciousness after intoxication with venlafaxine and alprazolam. There were no findings on initial cranial CT.\n\nOver the following days, the patient regained consciousness and stayed alert, inattentive and with hyperreflexia. Brain MRI revealed homogeneous, bilateral and symmetrical changesin the intensity of the cerebral white matter (Fig. 3). EEG showed slow background baseline activity. There were no abnormalities in the cerebrospinal fluid study.\n\nThe patient gradually showed a better level of consciousness, maintained a coherent conversation and obeyed simple commands. He achieved independent gait. At discharge, he remained disoriented, with disturbed immediate memory and motor apraxia.\n\nDISCUSSION\nIn all three cases reported, the patient underwent an episode of low level of consciousness, followed by initial improvement and then further development of leukoencephalopathy symptoms. This biphasic clinical course indicates all three patients had DL. Motor symptoms may follow globus pallidus injury, but were not present in case 3. Damage to the cerebral grey matter suggests cerebral hypoxia, which is a rare finding in the pure toxic leukoencephalopathies[4].\n\nThese patients had not used heroin for at least 5 years and no cerebellar involvement was shown by the neuroimaging tests. Two of the three patients also experienced a recovery period between the two clinical phases of the disease, but this temporary recovery was not seen in the leukoencephalopathy caused by heroin inhalation[5].\n\nThe time lag between the two clinical phases of the disease could be due to oligodendrocyte injury, which prevents replacement of myelin in the CNS and causes late onset demyelination[3].\n\nThese case reports contribute to the possible aetiology of this rare disease, since the drugs involved can cause both direct brain toxicity and cerebral hypoxia through depression of the respiratory centre. The mentioned drugs should be included in the differential diagnosis of DL. Their mechanisms of action can cause both DPHL and delayed toxic leukoencephalopathy. It is also thought that both conditions can sometimes co-exist.\n\nConflicts of Interests: The Authors declare that there are no competing interests.\n\nFigure 1 Cranial MRI. (A) Hypointense lesions in both globus pallidi (arrows). (B) Bilateral symmetrical hyperintense white matter lesions (arrows)\n\nFigure 2 (A, B) Cranial CT showing hyperintense lesions in globus pallidi (arrows) and a hypointense white matter lesion (arrowhead). (C) Cranial MRI showing hypointense lesions in globus pallidi, with peripheral hyperintense (arrow) and diffuse, bilateral and symmetrical hyperintense white matter lesions (arrowhead)\n\nFigure 3 Cranial MRI showing (A) confluent, homogeneous, bilateral and symmetrical changes in the white matter (arrows) and (B) no involvement of the grey matter basal nuclei.\n==== Refs\nREFERENCES\n1 Filley C Kleinschmidt-DeMasters BK Toxic leukoencephalopathy N Engl J Med 2001 345 425 432 11496854 \n2 Carroll I Heritier AC Dirren E Burkhard PR Horvath J Delayed leukoencephalopathy after alprazolam and methadone overdose: a case report and review of the literature Clin Neurol Neurosurg 2012 114 816 819 22341930 \n3 Shprecher D Mehta L The syndrome of delayed post-hypoxic leukoencephalopathy NeuroRehabilitation 2010 26 65 72 20166270 \n4 Cerase A Leonini S Bellini M Chianese G Venturi C Methadone-induced toxic leukoencephalopathy: diagnosis and follow-up by magnetic resonance imaging including diffusion-weighted imaging and apparent diffusion coefficient maps J Neuroimaging 2011 21 283 286 20977538 \n5 Wolters EC van Wijngaarden GK Stam FC Rengelink H Lousberg RJ Schipper ME Leucoencephalopathy after inhaling heroin pyrolysate Lancet 1982 2 1233 1237 6128545\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2284-2594",
"issue": "4(2)",
"journal": "European journal of case reports in internal medicine",
"keywords": "delayed leukoencephalopathy; globus pallidus; methadone",
"medline_ta": "Eur J Case Rep Intern Med",
"mesh_terms": null,
"nlm_unique_id": "101648453",
"other_id": null,
"pages": "000511",
"pmc": null,
"pmid": "30755921",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": "11496854;20166270;20977538;22341930;6128545",
"title": "Delayed Leukoencephalopathy: Three Case Reports and a Literature Review.",
"title_normalized": "delayed leukoencephalopathy three case reports and a literature review"
} | [
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"companynumb": "ES-TEVA-777319ROM",
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"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
},
"drugadditional": null,
... |
{
"abstract": "Mirtazapine is a commonly prescribed antidepressant with sedative properties. We report a case of nocturnal involuntary limb movements developing in an opioid-dependent young man after starting mirtazapine. The involuntary repetitive bilateral leg movements during initial phase of sleep began when mirtazapine was initiated. They continued for 4 days till mirtazapine was stopped and did not recur subsequently. The role of mirtazapine should be considered when a patient on this drug complains of leg movement during early phase of sleep.",
"affiliations": "Drug De-addiction & Treatment Centre, Department of Psychiatry, Postgraduate Institute of Medical Education & Research, Chandigarh 160012, India.",
"authors": "Mattoo|Surendra K|SK|;Mahajan|Sudhir|S|;Sarkar|Siddharth|S|;Nebhinani|Naresh|N|",
"chemical_list": "D000929:Antidepressive Agents, Tricyclic; D008803:Mianserin; D000078785:Mirtazapine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-8343",
"issue": "35(5)",
"journal": "General hospital psychiatry",
"keywords": "Antidepressive agents; Mirtazapine; Nocturnal myoclonus; Sleep disorders",
"medline_ta": "Gen Hosp Psychiatry",
"mesh_terms": "D000328:Adult; D000929:Antidepressive Agents, Tricyclic; D006801:Humans; D008297:Male; D008803:Mianserin; D000078785:Mirtazapine; D020189:Nocturnal Myoclonus Syndrome; D009293:Opioid-Related Disorders",
"nlm_unique_id": "7905527",
"other_id": null,
"pages": "576.e7-8",
"pmc": null,
"pmid": "23273829",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "PLMD-like nocturnal movements with mirtazapine.",
"title_normalized": "plmd like nocturnal movements with mirtazapine"
} | [
{
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"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MIRTAZAPINE"
},
"drugadditional": null,
"dru... |
{
"abstract": "A case of severe hypokalaemia and hyperglycaemia in connection with indapamide treatment is reported. Indapamide affects plasma potassium and also blood glucose. The significance of regular control of these parameters during treatment is emphasized.",
"affiliations": "Bispebjerg Hospital, København, medicinsk afdeling C.",
"authors": "Thomsen|J F|JF|;Feldt-Rasmussen|B F|BF|",
"chemical_list": "D007190:Indapamide",
"country": "Denmark",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-5782",
"issue": "153(25)",
"journal": "Ugeskrift for laeger",
"keywords": null,
"medline_ta": "Ugeskr Laeger",
"mesh_terms": "D006801:Humans; D007003:Hypoglycemia; D007008:Hypokalemia; D007190:Indapamide; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "0141730",
"other_id": null,
"pages": "1804",
"pmc": null,
"pmid": "1853463",
"pubdate": "1991-06-17",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Severe hypokalemia and hyperglycemia developed during indapamide therapy.",
"title_normalized": "severe hypokalemia and hyperglycemia developed during indapamide therapy"
} | [
{
"companynumb": "DK-SA-2019SA323686",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INDAPAMIDE"
},
"drugadditional": "1",
"dru... |
{
"abstract": "Donepezil is a commonly prescribed cholinesterase inhibitor in Alzheimer's dementia. We present a case of probable donepezil-induced generalised myoclonus causing total inability to mobilise in a 93-year-old woman.",
"affiliations": "Older People's Unit, Royal United Hospitals Bath NHS Foundation Trust, Combe Park, Bath, UK.;Older People's Unit, Royal United Hospitals Bath NHS Foundation Trust, Combe Park, Bath, UK.;Older People's Unit, Royal United Hospitals Bath NHS Foundation Trust, Combe Park, Bath, UK.",
"authors": "Whateley|Jennifer M|JM|;Huffman|Alice J|AJ|;Henderson|Emily J|EJ|",
"chemical_list": "D002800:Cholinesterase Inhibitors; D000077265:Donepezil",
"country": "England",
"delete": false,
"doi": "10.1093/ageing/afy093",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-0729",
"issue": "47(6)",
"journal": "Age and ageing",
"keywords": null,
"medline_ta": "Age Ageing",
"mesh_terms": "D000369:Aged, 80 and over; D000544:Alzheimer Disease; D002800:Cholinesterase Inhibitors; D000077265:Donepezil; D005260:Female; D006801:Humans; D051346:Mobility Limitation; D009207:Myoclonus; D012307:Risk Factors",
"nlm_unique_id": "0375655",
"other_id": null,
"pages": "907-908",
"pmc": null,
"pmid": "29939205",
"pubdate": "2018-11-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute inability to mobilise resulting from probable donepezil-induced myoclonus.",
"title_normalized": "acute inability to mobilise resulting from probable donepezil induced myoclonus"
} | [
{
"companynumb": "GB-UNICHEM PHARMACEUTICALS (USA) INC-UCM201811-000312",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DONEPEZIL"
},
"dr... |
{
"abstract": "OBJECTIVE\nThe aim of the present study was to evaluate a single center experience with hepatic arterial infusion (HAI) in patients with hepatocellular carcinoma.\n\n\nMETHODS\nA retrospective analysis of 20 patients treated for hepatocellular carcinoma between 1994 and 2007.\n\n\nRESULTS\nMost patients were treated with an HAI of doxorubicin and cisplatin combined with 5-fluorouracil and folinic acid. The response was not evaluable in the majority of patients, predominantly because of associated surgical procedure or because only one cycle of HAI was administered. The median progression-free survival was 7.7 months. The median survival of all patients was 12.2 months (5-year survival 5%). Serious adverse events were observed in 5 patients, and one patient died of liver failure in association with the administration of HAI.\n\n\nCONCLUSIONS\nThe data show the limited efficacy of HAI in patients with hepatocellular carcinoma.",
"affiliations": "Department of Oncology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic.",
"authors": "Melichar|Bohuslav|B|;Dvorak|Josef|J|;Ferko|Alexander|A|;Kamaradova|Katerina|K|;Krajina|Antonin|A|",
"chemical_list": "D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D014803:Vitamin B Complex; D002945:Cisplatin; D002955:Leucovorin; D005472:Fluorouracil",
"country": "Czech Republic",
"delete": false,
"doi": "10.5507/bp.2014.054",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1213-8118",
"issue": "159(1)",
"journal": "Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia",
"keywords": null,
"medline_ta": "Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D006528:Carcinoma, Hepatocellular; D002945:Cisplatin; D018153:Czech Republic; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D005472:Fluorouracil; D005500:Follow-Up Studies; D006499:Hepatic Artery; D006801:Humans; D007166:Immunosuppressive Agents; D007261:Infusions, Intra-Arterial; D002955:Leucovorin; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D011247:Pregnancy; D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome; D014803:Vitamin B Complex",
"nlm_unique_id": "101140142",
"other_id": null,
"pages": "139-44",
"pmc": null,
"pmid": "25482737",
"pubdate": "2015-03",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Hepatic arterial infusion in hepatocellular carcinoma: a single center experience.",
"title_normalized": "hepatic arterial infusion in hepatocellular carcinoma a single center experience"
} | [
{
"companynumb": "CZ-MYLANLABS-2016M1057506",
"fulfillexpeditecriteria": "1",
"occurcountry": "CZ",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nA 13-month-old child was treated for choroid plexus carcinoma with partial embolisation, complete surgical excision and chemotherapy. The patient's course was complicated by the presence of chronic bilateral subdural collections.\n\n\nMETHODS\nFour months from completing treatment, the child presented with an empyema in the subdural space caused by Streptococcus pneumoniae subtype 6A.\n\n\nCONCLUSIONS\nThe case highlights a number of questions about pneumococcal immunisation after standard chemotherapy. Evidence-based guidelines are required urgently to direct best practice.",
"affiliations": "Department of Haematology/Oncology, Great Ormond Street Hospital, London WC1N 3JH, UK.",
"authors": "Jorgensen|Mette|M|;Bate|Jessica|J|;Gatscher|Sylvia|S|;Chisholm|Julia C|JC|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00520-009-0804-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0941-4355",
"issue": "18(5)",
"journal": "Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer",
"keywords": null,
"medline_ta": "Support Care Cancer",
"mesh_terms": "D016545:Choroid Plexus Neoplasms; D013354:Empyema, Subdural; D006801:Humans; D007114:Immunization; D007223:Infant; D011008:Pneumococcal Infections; D012703:Serotyping; D013296:Streptococcus pneumoniae",
"nlm_unique_id": "9302957",
"other_id": null,
"pages": "647-50",
"pmc": null,
"pmid": "20076974",
"pubdate": "2010-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12023167;19764991;17278052;19368505;10749457;17488489;12876171;11920317;17090650;11972532;11840082;15680158;11194790;18595971;7559916",
"title": "Invasive pneumococcal disease following treatment for choroid plexus carcinoma.",
"title_normalized": "invasive pneumococcal disease following treatment for choroid plexus carcinoma"
} | [
{
"companynumb": "GB-PFIZER INC-675080",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VINCRISTINE SULFATE"
},
"drugadditional": null,
... |
{
"abstract": "Methotrexate is a dihydrofolate reductase inhibitor with application both as a chemotherapeutic agent and as a disease-modifying antirheumatic drug. Although its ability to inhibit cellular proliferation is a desired effect in its role as an antineoplastic agent, this property may also hinder normal physiologic regeneration of the nasal epithelium. This effect may predispose patients to septal cartilage ischemia, necrosis and, eventually, perforation. We report 2 cases of septal perforations in the setting of prolonged methotrexate use and present a literature review. Patient 1 is an 8-year-old boy with juvenile rheumatoid arthritis managed with weekly methotrexate who developed a 4-mm septal perforation with an unremarkable biopsy. This was closed with a mucosal advancement flap without incident. Patient 2 is an 11-year-old boy with non-Hodgkin lymphoma treated with methotrexate. His examination was significant for a large perforation of the dorsocaudal septum. A biopsy was negative for malignancy in this patient. Repair has been deferred-initially for chemotherapy and currently for treatment relapse. We hypothesize that prolonged use of methotrexate alters the balance between physiologic desquamation and epithelial regeneration. This imbalance may promote septal ischemia and predispose patients to the development of septal perforations.",
"affiliations": "Ear, Nose & Throat Center, Altru Health System, Grand Forks, ND 58201, USA. slee@altru.org",
"authors": "Lee|Scott L|SL|;Neskey|David|D|;Mouzakes|Jason|J|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D018501:Antirheumatic Agents; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0145-5613",
"issue": "88(8)",
"journal": "Ear, nose, & throat journal",
"keywords": null,
"medline_ta": "Ear Nose Throat J",
"mesh_terms": "D000964:Antimetabolites, Antineoplastic; D018501:Antirheumatic Agents; D001171:Arthritis, Juvenile; D002356:Cartilage; D002648:Child; D004198:Disease Susceptibility; D006801:Humans; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008727:Methotrexate; D009300:Nasal Septum; D009667:Nose Deformities, Acquired; D012225:Rhinoplasty",
"nlm_unique_id": "7701817",
"other_id": null,
"pages": "E12-4",
"pmc": null,
"pmid": "19688702",
"pubdate": "2009-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Potential predisposition for nasal septal perforation with methotrexate use: report of 2 cases and literature review.",
"title_normalized": "potential predisposition for nasal septal perforation with methotrexate use report of 2 cases and literature review"
} | [
{
"companynumb": "US-HOSPIRA-414699",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "Acute pneumatosis cystoides intestinalis (PCI) has been described after bone marrow transplantation (BMT). Several case series have demonstrated successful conservative treatment of PCI in children. We present a child with Fanconi anaemia, who developed severe graft versus host disease of the gastrointestinal tract, skin and liver after BMT and an acute, severe form of PCI. Our case report illustrates the complexity of diagnostic and therapeutic procedures in PCI in immunocompromised children.",
"affiliations": "Department of Pediatric Surgery, University Children's Hospital Basel, Basel, Switzerland.;Department of Pediatric Surgery, University Children's Hospital Basel, Basel, Switzerland.",
"authors": "Schuster|Blanca|B|;Mayr|Johannes|J|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-219310",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "GI bleeding; gastrointestinal surgery; haematology (incl blood transfusion); paediatric surgery; radiology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000293:Adolescent; D001284:Atrophy; D016026:Bone Marrow Transplantation; D003082:Colectomy; D003106:Colon; D003937:Diagnosis, Differential; D006086:Graft vs Host Disease; D006801:Humans; D008297:Male; D011006:Pneumatosis Cystoides Intestinalis; D011183:Postoperative Complications; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28630222",
"pubdate": "2017-06-19",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12511155;17038525;18424288;19541582;21721114;2375647;23946603;25076294;7572888;9630323;9645580",
"title": "Acute pneumatosis cystoides intestinalis with atrophic desmosis of the colon in a child.",
"title_normalized": "acute pneumatosis cystoides intestinalis with atrophic desmosis of the colon in a child"
} | [
{
"companynumb": "CH-EDENBRIDGE PHARMACEUTICALS, LLC-CH-2017EDE000154",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
... |
{
"abstract": "HIV positive patients on ritonavir-containing antiretroviral therapy (ART) can develop iatrogenic Cushing syndrome (IACS) and adrenal insufficiency as a result of drug-drug interactions with inhaled or intranasal glucocorticoid therapy. Reports related to epidural triamcinolone injections are relatively uncommon but increasingly reported. We describe a 48-year-old woman with immunologically and virologically well-controlled HIV on ritonavir-based ART, who developed headache, dizziness, and candida and herpes simplex virus (HSV) ulcerative esophagitis 7 days after receiving an epidural triamcinolone injection for cervical radicular pain. Iatrogenic Cushing syndrome and relative adrenal insufficiency were suspected and proven. The patient's ART was changed to a non-HIV protease inhibitor- (PI-) containing program, her symptoms improved, and she did not require hydrocortisone replacement. In this paper, we review the literature on IACS and relative secondary adrenal insufficiency from epidural triamcinolone injections in HIV patients on ritonavir-containing ART regimens. A high index of clinical suspicion is needed for diagnosis. Prevention of drug-drug interactions by taking a thorough medication history for patients on ritonavir-containing ART regimens before prescribing any form of corticosteroid is crucial and effective and sustained interdisciplinary communication in the care of such patients.",
"affiliations": "Division of Infectious Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.;Ambulatory Care Pharmacy Services, Indiana University Health LifeCare Clinic, Indianapolis, IN 46202, USA.;Division of Pain Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.;Division of Infectious Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.",
"authors": "Sadarangani|Sapna|S|0000-0002-8781-0713;Berg|Melody L|ML|;Mauck|William|W|0000-0003-0704-181X;Rizza|Stacey|S|0000-0002-2854-2915",
"chemical_list": null,
"country": "Egypt",
"delete": false,
"doi": "10.1155/2014/849432",
"fulltext": "\n==== Front\nInterdiscip Perspect Infect DisInterdiscip Perspect Infect DisIPIDInterdisciplinary Perspectives on Infectious Diseases1687-708X1687-7098Hindawi Publishing Corporation 10.1155/2014/849432Review ArticleIatrogenic Cushing Syndrome Secondary to Ritonavir-Epidural Triamcinolone Interaction: An Illustrative Case and Review http://orcid.org/0000-0002-8781-0713Sadarangani Sapna \n1\n*Berg Melody L. \n2\nhttp://orcid.org/0000-0003-0704-181XMauck William \n3\nhttp://orcid.org/0000-0002-2854-2915Rizza Stacey \n1\n1Division of Infectious Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA2Ambulatory Care Pharmacy Services, Indiana University Health LifeCare Clinic, Indianapolis, IN 46202, USA3Division of Pain Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA*Sapna Sadarangani: sadarangani.sapna@mayo.eduAcademic Editor: Sandro Cinti\n\n2014 7 5 2014 2014 84943231 12 2013 17 4 2014 18 4 2014 Copyright © 2014 Sapna Sadarangani et al.2014This 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.HIV positive patients on ritonavir-containing antiretroviral therapy (ART) can develop iatrogenic Cushing syndrome (IACS) and adrenal insufficiency as a result of drug-drug interactions with inhaled or intranasal glucocorticoid therapy. Reports related to epidural triamcinolone injections are relatively uncommon but increasingly reported. We describe a 48-year-old woman with immunologically and virologically well-controlled HIV on ritonavir-based ART, who developed headache, dizziness, and candida and herpes simplex virus (HSV) ulcerative esophagitis 7 days after receiving an epidural triamcinolone injection for cervical radicular pain. Iatrogenic Cushing syndrome and relative adrenal insufficiency were suspected and proven. The patient's ART was changed to a non-HIV protease inhibitor- (PI-) containing program, her symptoms improved, and she did not require hydrocortisone replacement. In this paper, we review the literature on IACS and relative secondary adrenal insufficiency from epidural triamcinolone injections in HIV patients on ritonavir-containing ART regimens. A high index of clinical suspicion is needed for diagnosis. Prevention of drug-drug interactions by taking a thorough medication history for patients on ritonavir-containing ART regimens before prescribing any form of corticosteroid is crucial and effective and sustained interdisciplinary communication in the care of such patients.\n==== Body\n1. Case\n\nA 48-year-old HIV positive Caucasian woman, immunologically and virologically well controlled on a ritonavir-boosted protease inhibitor- (PI-) based antiretroviral therapy (ART) regimen, developed iatrogenic Cushing syndrome (IACS) and relative secondary adrenal insufficiency (SAI) following an epidural triamcinolone injection for cervical radicular pain.\n\nThe patient was diagnosed with HIV in 2008, which was acquired after a sexual assault. Her HIV viral load was 6400 copies/mL at time of diagnosis and CD4 T-cell count was 1125/μL (31%) with a nadir CD4 T-cell count of 524/μL in September 2010. Pretreatment HIV genotyping showed wildtype virus.\n\nScreening for coinfections and sexually transmitted infections, including hepatitis C and syphilis, was negative. The HSV serum IgG was positive.\n\nThe patient had a nine-year history of chronic pain involving her right neck, suboccipital head, shoulder, low back, and lateral hip that had predated her HIV diagnosis. She had been followed by a pain medicine clinic and had received epidural and trochanteric bursa injections periodically for cervical radiculitis and trochanteric bursitis. She also had a history of tobacco use (30 pack years), remote history of illicit drug abuse with last use of IV cocaine in 1983. She had used alcohol heavily in the past but not within the last 10 years. Her psychiatric history included that of anxiety and depression/dysthymic disorder for which she was on low dose fluoxetine. Surgical history only included hysterectomy.\n\nThe patient had been followed clinically in the HIV clinic and had been in good health with CD4 T-cell count above 500. She was then randomized to be enrolled in the treatment arm of the (START) study—Strategic Timing of Antiretroviral Treatment. After enrollment, she was initiated on ART consisting of tenofovir-emtricitabine 300 mg/200 mg tablet daily, atazanavir 300 mg daily, and ritonavir 100 mg daily in June 2012. CD4 T-cell count was 596 and viral load was 39,500 copies/mL prior to therapy. She tolerated the antiretroviral regimen well; however, she developed a diffuse rash involving her trunk, arms, and thighs ten days after starting the ART program. She was evaluated by dermatology and her physicians in the HIV clinic, and the rash was not felt to be drug related. The rash eventually disappeared with no specific therapy and her HIV regimen was continued unchanged with no return of the rash.\n\nThe patient had been receiving cervical epidural triamcinolone injections for a year without incident prior to initiating ritonavir. For the six months prior to initiating ritonavir, the patient received two cervical epidural steroid injections and two trochanteric bursa injections with total dose of 60 mg triamcinolone and 6 mg dexamethasone. The last dose was 4 weeks prior to ritonavir initiation. Ten weeks after initiating ritonavir-based ART, the patient received a 40 mg triamcinolone epidural injection at C7-T1 and a 20 mg triamcinolone injection into the right trochanteric bursa to address her chronic neck and leg pain.\n\nSeven days after the injection, she developed symptoms of headache, change in taste, and dizziness. She was advised to closely observe her symptoms and report any changes. Nine days later, she developed significant esophageal reflux symptoms despite having no prior history of gastroesophageal reflux disease. She was seen at her primary care internal medicine clinic and advised symptomatic therapy with an over-the-counter antacid.\n\nDue to continued worsening of her symptoms, specifically worse epigastric pain, nausea, and esophageal reflux symptoms, the patient presented to the emergency department (ED) 5 days after developing esophageal reflux symptoms. Diagnostic workup included basic labs: white cell count of 12.2 × 109/L with a normal differential (absolute lymphocyte count of 2150), hemoglobin 13.5 g/dL, platelets 263 × 109/L, sodium 136 mmol/L, potassium 3.8 mmol/L, random glucose of 92 mg/dL, AST 22 U/L, bilirubin 2.6 (direct of 0.3) mg/dL, Cr 0.7 mg/dL, and lipase 30 U/L. An ultrasound of her hepatobiliary tree was normal. She was discharged from the ED with famotidine and aluminum/magnesium hydroxide suspension and advised to follow up with her primary care provider the following day.\n\nAt the follow-up visit at the primary care internal medicine clinic, an esophagogastroduodenoscopy (EGD) was arranged which revealed significant findings of scattered irregular ulcers 5–10 mm in size, from distal to mid esophagus which were biopsied. The proximal esophagus had scattered diffuse white exudates consistent with candida esophagitis. Ulceration covered 75% of the circumference of the gastroesophageal junction (5-6 mm). The biopsy findings from ulcerated mid and distal esophagus showed hyperplastic squamous esophageal mucosa and gastroesophageal junction-type mucosa with focal active chronic inflammation. The immunohistochemical staining of the mucosal tissue was positive for herpes simplex virus and negative for cytomegalovirus.\n\nFour weeks following the epidural steroid injection and one week following the onset of esophageal reflux symptoms, the patient complained of “facial swelling” and insomnia. She had also gained 5 lbs and noted mood changes in the form of increased anxiety.\n\nShe was started on oral omeprazole and fluconazole therapy for 14 days for esophagitis. Due to ongoing esophageal symptoms, when HSV immunostain from EGD returned positive, a course of oral valacyclovir 1000 mg three times daily for 2 weeks was initiated. The patient's CD4 T-cell count at that time was 745 (25%) and serum HIV RNA viral load was detected but not quantifiable.\n\nThe patient's constellation of symptoms and normal CD4 T-cell count raised suspicion for IACS from interaction between triamcinolone injection and oral ritonavir therapy which would account for her relative immunodeficiency state despite an adequate CD4 T-cell number. A random morning serum cortisol was 3 mcg/dL (range 7–25 mcg/dL), and for an early morning specimen this signifies a lower serum cortisol value than physiologically expected. Table 1 shows her ACTH (adrenocorticotropic hormone) stimulation test, also known as cosyntropin stimulation test and other relevant labs regarding her adrenal axis [1]. Her urine synthetic glucocorticoid screen detected significant triamcinolone 0.61 mcg/dL 4 weeks after her injection.\n\nThe patient began to complain of orthostatic dizziness particularly in the mornings; her orthostatic blood pressure and pulse rate (albeit in afternoon) were normal. She remained euglycemic throughout this time. Follow-up ACTH stimulation test showed an intact response.\n\nFollowing completion of valacyclovir and fluconazole treatment courses, the patient's esophageal symptoms improved by 80% but did not completely resolve. A decision was made to increase the omeprazole dose and due to continued risk of medication interactions, the antiretroviral therapy program was changed to a non-PI based regimen, tenofovir-emtricitabine, and raltegravir.\n\nSynthetic glucocorticoid screen did not show detectable triamcinolone levels, and a follow-up 24-hour urine cortisol was measured as 12 mcg/24-hour period 3 weeks following change in the ART program.\n\nThe score on the Drug Interaction Probability Scale assessing possible interaction between triamcinolone and ritonavir was 8, translating to a probable interaction [2]. No points were given for rechallenge of the drug (triamcinolone), and the dose also was not increased in this case as this was a one-time occurrence.\n\nThe patient's clinical course slowly improved and returned to baseline approximately 3 months after the triamcinolone injection, without requiring hydrocortisone replacement. She was advised not to have any further epidural triamcinolone injections without proper approval by her HIV specialist or endocrinologist.\n\n2. Review of Other Cases\nOur patient had significant morbidity as a result of HIV protease inhibitor and glucocorticoid interactions. We have reviewed the literature and report all available published experience of the interaction between ritonavir and triamcinolone resulting in IACS and secondary adrenal insufficiency.\n\nRitonavir, a potent inhibitor of the cytochrome P450 (CYP) 3 A4 isoenzyme, is used to increase therapeutic levels of other PIs (e.g., lopinavir, atazanavir, darunavir), thereby allowing for lower or less frequent dosing of the active PI. However, this portends numerous drug interactions with medications from various other classes including HMG Co-A reductase inhibitors, phosphodiesterase inhibitors, antiarrhythmics, and corticosteroids [3].\n\nThere have been numerous case reports on interaction of inhaled or intranasal fluticasone with ritonavir resulting in IACS and secondary adrenal insufficiency. There have been fewer but increasing number of recent case reports on the interaction between triamcinolone given as an epidural injection and ritonavir.\n\nFoisy et al. published a review of 25 cases (15 adult and 10 pediatric) of adrenal suppression and Cushing's syndrome as result of an interaction between ritonavir and inhaled fluticasone [4]. The mean inhaled fluticasone dose was 992 mcg/day (range 500–2000 mcg/day) in adult patients and 455 mcg/day (range 200–1000 mcg/day) in pediatric patients. The majority of cases occurred with high doses of fluticasone and therefore the authors recommended great caution in giving inhaled fluticasone higher than 400 mcg/day in children and higher than 1000 mcg/day in adults on ritonavir based antiretroviral based programs.\n\nThere are fewer case reports on IACS and secondary adrenal insufficiency in context of triamcinolone and ritonavir. Table 2 summarizes these cases [5–15]. Most patients presented with both IACS and SAI. More severe manifestations occurred in some patients including hyperglycemic hyperosmolar state [7], as well as avascular necrosis of the hip [8]. One patient had a rather delayed diagnosis with the fat distribution changes thought of as due to lipodystrophy [11]. The lowest dose of triamcinolone administered was a one-time 40 mg injection, and the highest was cumulative dose of 240 mg of triamcinolone given as 3 injections of 80 mg dose each. Seven of these cases needed hydrocortisone replacement. Four of these cases had received 80 mg or higher dose of triamcinolone, and the other three had received a single time 40 mg triamcinolone dose.\n\n2.1. Clinical Presentation\nThe clinical manifestations of IACS as a result of ritonavir use vary greatly. The symptoms may be as subtle as change in weight distribution/weight gain that may be mistaken for lipodystrophy and the diagnosis may therefore be delayed potentially for months [11]. The more severe presentations reported include hypertension, glucose intolerance to the point of hyperglycemic hyperosmotic state, metabolic syndrome, and avascular necrosis resulting in significant morbidity [5–15]. Other severe presentations reported include steroid induced myopathy and herpes zoster reactivation due to secondary immune deficiency [14]. Our patient had a dramatic change in weight distribution and a relative immune deficiency state from prolonged systemic steroid exposure resulting in severe esophagitis (with candida and HSV esophagitis). Ramanathan et al. also described a patient who presented with symptoms of similar severity, although our patient had more severe esophagitis [6].\n\nThe presentation of relative secondary adrenal insufficiency may also be variable, ranging from fatigue to overt dizziness and hypotension. A high index of suspicion should be used for any of these symptoms in a patient on ritonavir and receiving any source of corticosteroids and taking a thorough drug history is crucial.\n\n2.2. Diagnosis\nWhen there is a clinical suspicion of HIV PI and glucocorticoid interactions, a patient's adrenal axis needs to be assessed in a systematic manner. An early morning random cortisol level should be obtained as well as an ACTH level. An ACTH stimulation test can be used to confirm adrenal axis suppression from exogenous steroids. A synthetic glucocorticoid screen is also beneficial in demonstrating the source of exogenous excess steroids. These may need to be repeated at more than one time point depending on patient's clinical course, especially if changes to the antiretroviral therapy regimen are made and/or symptoms are not improving with time as expected.\n\n2.3. Management\nMost patients in the literature had spontaneous recovery of symptoms and recovery of adrenal axis in a matter of months, ranging from 2 to 8 months depending on severity of the initial presentation and dose of triamcinolone used once the HIV PI or the glucocorticoid is stopped. Some patients required hydrocortisone replacement during the recovery phase. The need for hydrocortisone replacement appears to depend on the degree of suppression of the hypothalamus-pituitary-adrenal (HPA) axis (based on cosyntropin stimulation test) and is temporary until the HPA axis recovers. Ramanathan et al. showed the elimination half-life of triamcinolone acetonide was prolonged as much as 170-fold when coadministered with ritonavir [6]. Recommended steroid replacement is at a low physiological dose of 10–20 mg a day of hydrocortisone.\n\nThe first step, however, is to remove the source of exogenous corticosteroids and/or the ritonavir causing the medication interaction.\n\nWhen possible, replacing the ritonavir-boosted PI regimen with another antiretroviral agent with no CYP3A4 inhibition such as a non-nucleoside transcriptase inhibitor, chemokine receptor 5 (CCR5 receptor) antagonist, or an integrase inhibitor (specifically raltegravir or dolutegravir), should be considered, as we did with our patient. However, choices may be limited in highly ART treatment experienced patients. In addition, it is not yet known whether cobicistat, currently used to boost elvitegravir concentrations via CYP3A inhibition mechanism, may also have a similar interaction and therefore would not be a good substitution for ritonavir-based regimen with respect to this particular drug-drug interaction.\n\nEnteral or parenteral exogenous corticosteroids may be prescribed for various pain conditions across every subspecialty. The management of acute or chronic pain requires patient education as well as coordination of care with those prescribing ritonavir and those who may be offering exogenous corticosteroids. The literature describing the specific ritonavir and triamcinolone interaction is limited and not widely appreciated, but not unique to other corticosteroids. Alternative pain management options should be explored when a patient is on a boosted PI regimen.\n\n3. Background/Discussion of Mechanism\nCytochrome P450 is a major pathway for drug metabolism via the liver. It is largely responsible for transferring lipid-soluble agents, through a process of oxidation, hydrolysis, or reduction, to water-soluble agents that are easier for the body to eliminate. Ritonavir is known to be a potent inhibitor of a particular isoenzyme of this metabolism pathway, CYP3A4 [16]. CYP3A4 is involved in the metabolism of over half of all commonly used medications [17]. In fact, it is because of its effect of inhibition of CYP3A4 that ritonavir continues to be included as an essential component of many antiretroviral regimens. All of the PIs used for treatment of HIV undergo metabolism, to some degree, by CYP3A4 and, therefore, use of these medications with ritonavir results in increased concentrations and prolonged half-life of the active PIs. This allows for reduced pill burden or decreased dosing frequency which may help improve adherence [18].\n\nAlthough drug interactions with ritonavir and PIs are beneficial, the potent inhibition of CYP3A4 by ritonavir can have detrimental effects on other medications, particularly if the interaction potential goes unrecognized. In the case of our patient, an unrecognized interaction between ritonavir and a corticosteroid, triamcinolone, resulted in adrenal suppression. Glucocorticoids, including triamcinolone, undergo metabolism via CYP3A4 [19].\n\nTherefore, use of ritonavir with glucocorticoids can result in increased exposure to the glucocorticoid and increased potential for side effects including HPA axis suppression, osteoporosis, and osteonecrosis.\n\nGlucocorticoids differ with regards to potency and elimination half-life [19–25]. As mentioned previously, all undergo some degree of metabolism via the CYP3A4 enzyme. Hydrocortisone, methylprednisolone, and triamcinolone are the three corticosteroids used most commonly for injection. Triamcinolone and methylprednisolone have lower potency than hydrocortisone and longer half-life. All three agents have similar half-lives. The impact of these parameters on pharmacodynamics effect of these corticosteroids in the body following epidural injection is not clearly established. Systemic absorption of intra-articular injections has been shown to be dependent on the corticosteroid used, type of preparation, dose, number of injections given, and location of injection [26]. Triamcinolone has been shown to be absorbed into soft tissues from intra-articular and periarticular injections for 2-3 weeks [27]. There have been reported cases of Cushing syndrome in patients following triamcinolone injections using doses of 40 mg triamcinolone for pain, in the absence of other drugs that may cause drug-drug interactions thereby exponentially increasing systemic steroid levels [28].\n\n4. Conclusion\nThe above case illustrates the importance of being cognizant of drug-drug interactions for HIV patients who are on ritonavir-containing regimens. This is particularly important in situations when the medication interactions may not have been well described or medications are administered in nontraditional methods, such as via inhalation or neuraxial injections.\n\nIn this particular case, the corticosteroid was documented through a separate surgical electronic record compared to other prescribed office based medications including this patient's ART. Also, at that time, this drug-drug interaction between triamcinolone and ritonavir was not as well described and did not appear in drug-interaction databases. Taking a thorough medical and medication (including over-the-counter medications) at each visit with HIV patients is imperative, as well as being vigilant in instances involving chronic pain conditions treated with injectable steroids for potential drug-drug interactions. This drug-drug interaction will not necessarily be readily recognized by the proceduralist administering injectable corticosteroids thus necessitating good communication between providers.\n\nA similar concern for glucocorticoid-ART interaction is also present with cobicistat containing ART regimens although there is more evidence in the literature for ritonavir containing ART regimens.\n\nOngoing education of pharmacists, providers involved in care of these patients with emphasis on counselling and interdisciplinary communication between various HIV caregivers, and other specialists as well as patients themselves is important in prevention of such drug-drug interactions and morbidity. A high index of clinical suspicion is needed.\n\nFurthermore, use of a universal medication ordering system would help identify such drug interactions, even when the medications were ordered in completely different departments, and prevent these potential complications.\n\nIf IACS and secondary relative adrenal insufficiency are suspected, as in this illustrative case, prompt assessment of steroid axis is key, as well as consideration of changing ART regimen, when possible, and a multidisciplinary knowledgeable approach to chronic pain for patients on boosted-PI regimens.\n\nAcknowledgment\nThe authors would like to thank Dr. Paul Carpenter, M.D., Endocrinology, Mayo Clinic Rochester, MN, USA.\n\nConflict of Interests\nThe authors declare that they have no conflict of interests regarding the publication of this paper.\n\nAuthors' Contribution\nAll the authors had access to patient's information and data and contributed in drafting and editing the paper.\n\nTable 1 Assessment of the patient's adrenal axis at various time points following triamcinolone injection.\n\n \t Four weeks and 2 days after injection\tFive weeks and 3 days after injection\tNine weeks and 2 days after injection\tFourteen weeks after injection and about 3 weeks after change in ART regimen\t\nCortisol 0 min \n(mcg/dL)\t—\t3.4\t4.3\t—\t\nCortisol 15 min following administration of cosyntropin) \n(mcg/dL)\t—\t8.0\t—\t—\t\nCortisol 30 min following administration of cosyntropin \n(mcg/dL)\t—\t13\t21\t—\t\nCortisol 45 min following administration of cosyntropin \n(mcg/dL)\t—\t14\t—\t—\t\nCortisol 60 min following administration of cosyntropin \n(mcg/dL)\t—\t—\t26\t—\t\nUrine synthetic glucocorticoid screen\tTriamcinolone 0.61 mcg/dL (range <0.10)\t—\tNegative \t—\t\n24 h urine cortisol \t—\t—\t—\t12 mcg/24 hours (range 3.5–45)\t\nThe criterion for expected serum cortisol on the standard high dose ACTH stimulation test is a minimum value 18 to 20 mcg/dL before or after ACTH injection [1].\n\nTable 2 Summary of other cases.\n\nReference/author journal\tCase\tHAART regimen\tInjection (TCA)\tClinical presentation\tHydrocortisone replacement\tTime to recovery\t\n\nYombi et al. \nClin Rheumatol 2008 [5]\t54 yo woman\t3TC/DDI/lopinavir-ritonavir\t40 mg (knee)\tIACS \nHypertension \nSAI\t20 mg daily\t8 months\t\n56 yo man\tD4T/AZT/indinavir-ritonavir\t40 mg (cervical)\tIACS \nSAI\t10 mg daily\t4 months\t\n49 yo woman\t3TC/DDI/lopinavir-ritonavir\t40 mg (shoulder)\tIACS \nSAI\tNone\t5 months\t\n\n\n\t\nRamanathan et al. [6] \nCID 2008\t35 yo man\tTenofovir-emtricitabine/lopinavir-ritonavir\t60 mg and then 80 mg (L spine)\tIACS \nHypertension \nEsophageal reflux\t—\t4 months\t\n\n\n\t\nDanaher et al. [7] \nOrthopedics 2009\t44 yo man\tRitonavir based regimen\t80 mg (hip)\tHHS-ICU admission \nIACS \nSAI\tUnknown\tUnknown\t\n\n\n\t\n\nDort et al. [8] \nAIDS Research and Therapy 2009\t41 yo man\tTenofovir-emtricitabine, atazanavir-ritonavir\t80 mg twice (epidural)\tIACS \nHypertension \nAVN hip (at 11 months)\tNone\t6 months\t\n42 yo woman\tTenofovir-emtricitabine, atazanavir-ritonavir\t40 mg (shoulder)\tIACS\t30 mg daily (short)\t2 months\t\n\n\n\t\nLevine et al. [9] \nJ Am Acad Dermatol 2011\t41 yo woman\tLamivudine, tenofovir, atazanavir-ritonavir\t60 mg IM (topical steroid unresponsive nonspecific dermatitis)\tIACS \nSAI\tNone\t6 months\t\n\n\n\t\nAlbert et al. [10] \nAm J Med Sciences 2012\t58 yo woman\tTenofovir-emtricitabine, fosamprenavir-ritonavir\tEpidural dose is not mentioned\tIACS \nSAI\tNone\t2 months\t\n\n\n\t\n\nGrierson and Harrast [11] \nAm Acad PMR 2012\t47 yo woman\tTenofovir-emtricitabine, atazanavir-ritonavir\t80 mg 3 occasions (epidural L spine)\t“Lipodystrophy” \nDM \nMetabolic syndrome \nIACS \nSAI\t20 mg daily (extended taper)\t“Several months” \t\n\n\n\t\n\nFessler et al. [12] \nPain Physician 2012 \t42 yo man\tTenofovir-emtricitabine, atazanavir-ritonavir\t80 mg (lumbar epidural)\tHypertension\nAcne (on back)\tNone\t3 months\t\n47 yo woman\tAbacavir, lamivudine, darunavir-ritonavir → changed to abacavir, lamivudine, unboosted fosamprenavir upon dx\t80 mg 2 occasions (lumbar epidural)\nAlso used inhaled fluticasone/salmeterol inhaler for asthma for 5 days\tWeight gain \nEmotional lability \nIACS \nHypertension \nOral candidiasis\tNone\t10 weeks (improved)\t\n\n\n\t\n\nMaviki et al. [13] \nSkeletal Radiology 2013\t39 yo woman\tTenofovir-emtricitabine, darunavir-ritonavir\t40 mg 2 occasions (right L5 nerve root)\tIACS \nOral candidiasis \nSAI\tHydrocortisone “maintenance”\t8 months\t\n47 yo man\tTenofovir-emtricitabine, lopinavir-ritonavir\t80 mg (subacromial, subdeltoid bursa)\tIACS \nHyperglycemia \nWeight gain \nSAI\tHydrocortisone “maintenance”\t6 months\t\n\n\n\t\nSchwarze-Zander et al. [14] \nInfection\n2013\t35 yo woman\tTenofovir-emtricitabine, saquinavir-ritonavir → changed to tenofovir-emtricitabine with raltegravir\t6 times 20 mg weekly (L5-S1 periradicular)\tIACS\nHypokalemia \nSAI\nSteroid-induced myopathy \nAcute herpes zoster (4 week later)\tHydrocortisone 15 mg/daily-tapered at 8 months \nComment: also needed potassium replacement for hypokalemia\t8 months\t\n\n\n\t\nHall et al. [15] \nInt J STD AIDS\n2013\t53 yo woman\tDarunavir-ritonavir \nRaltegravir\t40 mg (left shoulder)\tHyperglycemia (worse than usual for her controlled DM)\nHypertension (worse than prior)\nIACS\nAnxiety\tNone \nComment: needed initiation of insulin for DM previously controlled by metformin\t3 months\t\n\n\n\t\n\nSadarangani et al.\t48 yo woman\tTenofovir-emtricitabine, atazanavir-ritonavir → changed to tenofovir-emtricitabine with raltegravir\t40 mg triamcinolone epidural injection and 20 mg triamcinolone injection into right trochanteric bursa\tSevere esophagitis (erosive, as well as candida and HSV esophagitis)\nIACS \nRelative SAI\nMood changes-anxiety \nWeight gain\tNone\nComment: needed course of fluconazole and valacyclovir as well as extended course therapy with proton pump inhibitor for esophagitis\t3-4 months\t\nHHS: hyperglycemic hyperosmolar state, \n\n3TC: lamivudine, \n\nDDI: didanosine, \n\nD4T: stavudine, \n\nAZT: zidovudine, and \n\nAVN: avascular necrosis.\n==== Refs\n1 May ME Carey RM Rapid adrenocorticotropic hormone test in practice. Retrospective review The American Journal of Medicine 1985 79 6 679 684 2-s2.0-0022343747 3000177 \n2 Horn JR Hansten PD Chan L-N Proposal for a new tool to evaluate drug interaction cases Annals of Pharmacotherapy 2007 41 4 674 680 2-s2.0-34247231457 17389673 \n3 Hull MW Montaner JSG Ritonavir-boosted protease inhibitors in HIV therapy Annals of Medicine 2011 43 5 375 388 2-s2.0-79959359682 21501034 \n4 Foisy MM Yakiwchuk EMK Chiu I Singh AE Adrenal suppression and Cushing’s syndrome secondary to an interaction between ritonavir and fluticasone: a review of the literature HIV Medicine 2008 9 6 389 396 2-s2.0-47649110602 18459946 \n5 Yombi JC Maiter D Belkhir L Nzeusseu A Vandercam B Iatrogenic Cushing’s syndrome and secondary adrenal insufficiency after a single intra-articular administration of triamcinolone acetonide in HIV-infected patients treated with ritonavir Clinical Rheumatology 2008 27 supplement 2 S79 S82 2-s2.0-56349159494 18827959 \n6 Ramanathan R Pau AK Busse KH Iatrogenic cushing syndrome after epidural triamcinolone injections in an HIV type 1-infected patient receiving therapy with ritonavir-lopinavir Clinical Infectious Diseases 2008 47 12 e97 e98 2-s2.0-56749153964 18991509 \n7 Danaher PJ Salsbury TL Delmar JA Metabolic derangement after injection of triamcinolone into the hip of an HIV-infected patient receiving ritonavir Orthopedics 2009 32 6 p. 450 2-s2.0-70349183887 \n8 Dort K Padia S Wispelwey B Moore CC Adrenal suppression due to an interaction between ritonavir and injected triamcinolone: a case report AIDS Research and Therapy 2009 6 8, article 10 2-s2.0-67649958515 \n9 Levine D Ananthakrishnan S Garg A Iatrogenic Cushing syndrome after a single intramuscular corticosteroid injection and concomitant protease inhibitor therapy Journal of the American Academy of Dermatology 2011 65 4 877 878 2-s2.0-80052809209 21920248 \n10 Albert NE Kazi S Santaro J Dougherty R Ritonavir and epidural triamcinolone as a cause of iatrogenic Cushing’s syndrome The American Journal of the Medical Sciences 2012 344 1 72 74 22543594 \n11 Grierson MJ Harrast MA Iatrogenic Cushing syndrome after epidural steroid injections for lumbar radiculopathy in an HIV-infected patient treated with ritonavir: a case report highlighting drug interactions for spine interventionalists PM and R 2012 4 3 234 237 2-s2.0-84858720336 22443962 \n12 Fessler D Beach J Keel J Stead W Iatrogenic Hypercortisolism Complicating triamcinolone acetonide injections in patients with HIV on ritonavir-boosted protease inhibitors Pain Physician 2012 15 489 493 23159966 \n13 Maviki M Cowley P Marmery H Injecting epidural nand intra-articular triamcinolone in HIV-positive patients on ritonavir: beware of iatrogenic Cushing’s syndrome Skeletal Radiology 2013 42 2 313 315 23151875 \n14 Schwarze-Zander C Klingmüller D Klumper J Strassbag P Rockstroh JK Triamcinolone and ritonavir leading to drug-induced Cushing syndrome and adrenal suppression: description of a new case and review of the literature Infection 2013 41 6 1183 1187 23873267 \n15 Hall JJ Hughes CA Foisy MM Houston S Shafran S Iatrogenic Cushing syndrome after intra-articular triamcinolone in a patient receiving ritonavir-boosted darunavir International Journal of STD & AIDS 2013 24 9 748 752 23970582 \n16 Product Information: NORVIR(R) Oral Capsules, Ritonavir Oral Capsules 2012 North Chicago, Ill, USA Abbott Laboratories \n17 Danielson PB The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in humans Current Drug Metabolism 2002 3 6 561 597 2-s2.0-0036890399 12369887 \n18 DHHS Antiretroviral Guidelines for Adults and Adolescents, http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf \n19 Schimmer BP Funder JW Bruton L ACTH, adrenal steroids, and pharmacology of the adrenal cortex Goodman & Gilman’s The Pharmacologic Basis of Therapeutics 2011 12th edition \n20 Dexamethasone DRUGDEX System. Version 5.1 Greenwood Village, Colo, USA Thomson Healthcare \n21 Hydrocortisone DRUGDEX System. Version 5.1 Greenwood Village, Colo, USA Thomson Healthcare \n22 Prednisone DRUGDEX System. Version 5.1 Greenwood Village, Colo, USA Thomson Healthcare \n23 Prednisolone DRUGDEX System. Version 5.1 Greenwood Village, Colo, USA Thomson Healthcare \n24 Methylprednisolone DRUGDEX System. Version 5.1 Greenwood Village, Colo, USA Thomson Healthcare \n25 Derendorf H Mollmann H Gruner A Haack D Gyselby G Pharmacokinetics and pharmacodynamics of glucocorticoid suspensions after intra-articular administration Clinical Pharmacology and Therapeutics 1986 39 3 313 317 2-s2.0-0022623170 3948470 \n26 Habib GS Systemic effects of intra-articular corticosteroids Clinical Rheumatology 2009 28 7 749 756 2-s2.0-67349178456 19252817 \n27 Triamcinolone DRUGDEX System. Version 5.1 Greenwood Village, Colo, USA Thomson Healthcare \n28 Jansen TLTA Van Roon EN Four cases of a secondary Cushingoid state following local triamcinolone acetonide (Kenacort) injection Netherlands Journal of Medicine 2002 60 3 151 153 2-s2.0-0036527586 12164373\n\n",
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"title": "Iatrogenic cushing syndrome secondary to ritonavir-epidural triamcinolone interaction: an illustrative case and review.",
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"abstract": "A 74-year-old male with lung squamous cell carcinoma who was treated with the anti PD-1 antibody nivolumab developed frequent diarrhea four months after initiating treatment. However, his condition did not improve despite prednisolone at 20mg. Endoscopic examination revealed loss of vascular pattern, erosions, and mucosal friability, resembling ulcerative colitis. Colonoscopy revealed punch-out ulcers in the affected mucosa. Therefore, he was definitively diagnosed with severe colitis caused by immune checkpoint inhibitor treatment and cytomegalovirus colitis. Nivolumab was discontinued, and he was treated with 60mg prednisolone and ganciclovir. Although his colitis improved, he developed pneumonia and died thereafter. This case highlights adverse events that are associated with immune checkpoint inhibitors which should be treated properly.",
"affiliations": "Department of Gastroenterology, Mitoyo General Hospital.;Department of Gastroenterology, Mitoyo General Hospital.;Department of Gastroenterology, Mitoyo General Hospital.;Department of Gastroenterology, Mitoyo General Hospital.;Department of Gastroenterology, Mitoyo General Hospital.;Department of Gastroenterology, Mitoyo General Hospital.;Department of Gastroenterology, Mitoyo General Hospital.;Department of Gastroenterology, Mitoyo General Hospital.;Department of Gastroenterology, Mitoyo General Hospital.;Department of Gastroenterology, Mitoyo General Hospital.",
"authors": "Kanamori|Hiroki|H|;Yasuhara|Hisae|H|;Mashima|Souichiro|S|;Suto|Kozue|K|;Yamauchi|Kenji|K|;Akita|Mitsuhiro|M|;Jinno|Hideki|H|;Hata|Hidenori|H|;Nakatsu|Morihito|M|;Ando|Masaharu|M|",
"chemical_list": "D000077594:Nivolumab",
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"journal": "Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology",
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"medline_ta": "Nihon Shokakibyo Gakkai Zasshi",
"mesh_terms": "D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung; D003093:Colitis, Ulcerative; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D000077594:Nivolumab",
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"title": "A case of severe colitis caused by immune checkpoint inhibitor.",
"title_normalized": "a case of severe colitis caused by immune checkpoint inhibitor"
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"abstract": "Gestational pemphigoid, a rare autoimmune skin disease typically occurring during pregnancy, is caused by autoantibodies against collagen XVII. Clinically it is characterised by severe itching followed by erythematous and bullous lesions of the skin. Topical or oral glucocorticoids usually relieve symptoms, but in more severe cases systemic immunosuppressive treatments are needed. Data on immunosuppressive medication controlling gestational pemphigoid are sparse. We report 3 intractable cases of gestational pemphigoid treated with cyclosporine.",
"affiliations": "Deparment of Dermatology, Medical Research Center, University of Oulu, Oulu University Hospital, P.B. 20, 90029 OYS, FIN-90220 Oulu, Finland. laura.huilaja@oulu.fi.",
"authors": "Huilaja|Laura|L|;Mäkikallio|Kaarin|K|;Hannula-Jouppi|Katariina|K|;Väkevä|Liisa|L|;Höök-Nikanne|Johanna|J|;Tasanen|Kaisa|K|",
"chemical_list": "D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D016572:Cyclosporine",
"country": "Sweden",
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"issue": "95(5)",
"journal": "Acta dermato-venereologica",
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"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D016572:Cyclosporine; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005387:Finland; D005865:Gestational Age; D005938:Glucocorticoids; D006801:Humans; D007166:Immunosuppressive Agents; D006559:Pemphigoid Gestationis; D011247:Pregnancy; D011256:Pregnancy Outcome; D035583:Rare Diseases; D018570:Risk Assessment; D012494:Sampling Studies; D012720:Severity of Illness Index; D016896:Treatment Outcome",
"nlm_unique_id": "0370310",
"other_id": null,
"pages": "593-5",
"pmc": null,
"pmid": "25519774",
"pubdate": "2015-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Cyclosporine treatment in severe gestational pemphigoid.",
"title_normalized": "cyclosporine treatment in severe gestational pemphigoid"
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"activesubstancename": "HYDROXYZINE\\HYDROXYZINE HYDROCHLORIDE"
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"abstract": "Bacillus cereus can cause serious infections in immunosuppressed patients. This population may be susceptible to B. cereus pneumonia, bacteremia, cellulitis, and rarely cerebral abscess. Here we report an 8-year-old boy undergoing induction therapy for acute lymphoblastic leukemia who developed multifocal B. cereus cerebral abscesses, highlighting the propensity for B. cereus to develop cerebral abscesses. A review of the literature over the past 25 years identified another 11 cases (3 children and 8 adults) of B. cereus cerebral abscess in patients undergoing cancer therapy. B. cereus cerebral abscesses were associated with a high mortality rate (42%) and significant morbidity. Notably, B. cereus bacteremia with concomitant cerebral abscess was associated with induction chemotherapy for acute leukemia in both children and adults (10 of 12 case reports). Our case report and review of the literature highlights the propensity for B. cereus to develop cerebral abscess(es). Therefore, early consideration for neuroimaging should be given for any neutropenic cancer patient identified with B. cereus bacteremia, in particular those with acute leukemia during induction therapy.",
"affiliations": "*Department of Hematology and Oncology, Princess Margaret Hospital for Children †School of Pediatrics and Child Health University of Western Australia ‡PathWest §Department of Pediatric and Adolescent Medicine, Princess Margaret Hospital ∥Telethon Institute for Child Health Research, Centre for Child Health Research, Perth, WA, Australia.",
"authors": "Hansford|Jordan R|JR|;Phillips|Marianne|M|;Cole|Catherine|C|;Francis|Joshua|J|;Blyth|Christopher C|CC|;Gottardo|Nicholas G|NG|",
"chemical_list": "D000900:Anti-Bacterial Agents; D011092:Polyethylene Glycols; D014750:Vincristine; C042705:pegaspargase; D003907:Dexamethasone; D001215:Asparaginase",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0b013e31828e5455",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "36(3)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000900:Anti-Bacterial Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D001215:Asparaginase; D001409:Bacillus cereus; D016470:Bacteremia; D001922:Brain Abscess; D002648:Child; D003907:Dexamethasone; D016908:Gram-Positive Bacterial Infections; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D009894:Opportunistic Infections; D011092:Polyethylene Glycols; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011379:Prognosis; D012074:Remission Induction; D014750:Vincristine",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e197-201",
"pmc": null,
"pmid": "23619116",
"pubdate": "2014-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bacillus cereus bacteremia and multiple brain abscesses during acute lymphoblastic leukemia induction therapy.",
"title_normalized": "bacillus cereus bacteremia and multiple brain abscesses during acute lymphoblastic leukemia induction therapy"
} | [
{
"companynumb": "AU-ROXANE LABORATORIES, INC.-2014-RO-01784RO",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEGASPARGASE"
},
"drugaddi... |
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"abstract": "Live attenuated varicella vaccine is recommended for healthy individuals who are susceptible to varicella. Although the vaccine is safe, effective, and used worldwide, serious adverse events have been reported, mainly in immunocompromised patients who subsequently recovered. Here, we describe the fatality of an immunocompromised patient who received the varicella vaccine. His medical history provides a cautionary lens through which to view the decision of when vaccination is appropriate. A middle-aged man with non-Hodgkin lymphoma received chemotherapy and a stem cell transplant. He was vaccinated 4 years post-transplantation, despite diagnosis of a new low-grade lymphoma confined to the lymph nodes. Within 3 months of vaccination, he developed recurrent rashes with fever, malaise, weakness, hepatitis, weight loss, and renal failure. The syndrome was eventually determined to be associated with persistent disseminated zoster caused by the vaccine virus. This case illustrates a circumstance when a live viral vaccine should not be used.",
"affiliations": "Department of Medicine, Oregon Health Science University, Portland.;Department of Medicine, Oregon Health Science University, Portland Portland Veterans Affairs Medical Center, Oregon.;Department of Pathology and Cell Biology.;Department of Pathology and Cell Biology.;Department of Pathology and Cell Biology.;Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, New York.;Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, New York.;Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, New York.",
"authors": "Bhalla|Preeti|P|;Forrest|Graeme N|GN|;Gershon|Michael|M|;Zhou|Yan|Y|;Chen|Jason|J|;LaRussa|Philip|P|;Steinberg|Sharon|S|;Gershon|Anne A|AA|",
"chemical_list": "D019433:Chickenpox Vaccine",
"country": "United States",
"delete": false,
"doi": "10.1093/cid/ciu970",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-4838",
"issue": "60(7)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": "granulomas; vOka; vaccine; varicella; zoster",
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D019433:Chickenpox Vaccine; D017809:Fatal Outcome; D006566:Herpesviridae Infections; D014645:Herpesvirus 3, Human; D006801:Humans; D016867:Immunocompromised Host; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008875:Middle Aged; D033581:Stem Cell Transplantation",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "1068-74",
"pmc": null,
"pmid": "25452596",
"pubdate": "2015-04-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "11475151;11115716;11910864;14513412;4139526;3948560;2845831;3054418;1346169;7864296;8728043;8731677;9395360;9536241;10508017;16279222;16440810;16503895;17088366;17416267;16798784;17974726;18419392;19747629;21143835;21539861;22043019;22378912;23044970;23074321;24092852;24092643;24421306;24418481;23982221;24965252;11483849;10959752;10970349",
"title": "Disseminated, persistent, and fatal infection due to the vaccine strain of varicella-zoster virus in an adult following stem cell transplantation.",
"title_normalized": "disseminated persistent and fatal infection due to the vaccine strain of varicella zoster virus in an adult following stem cell transplantation"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2015US-97976",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VALACYCLOVIR HYDROCHLORIDE"
},... |
{
"abstract": "The purpose of our study was to test the efficacy and toxicity of everolimus plus exemestane therapy for breast cancer. Between 2014 and 2015, 20 patients diagnosed with breast carcinoma were selected for this retrospective study. Patients received everolimus plus exemestane. As a result, 4 patients showed a partial response to treatment and the median PFS was 2.5 months (range, 1-9). The most common adverse events (AEs) associated with combination therapy were stomatitis, rash, dysgeusia, and non-infectious lung disease. The AEs reported were mostly grade 1 and 2, and manageable with appropriate intervention. Therefore, everolimus plus exemestane therapy for breast cancer seems to be effective and generally tolerable.",
"affiliations": "Dept. of Surgery, Kansai Medical University.",
"authors": "Yamamoto|Daigo|D|;Tsubota|Yu|Y|;Sueoka|Noriko|N|;Yamamoto|Chizuko|C|;Kon|Masanori|M|",
"chemical_list": "D000730:Androstadienes; D000068338:Everolimus; C056516:exemestane",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "42(10)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000730:Androstadienes; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D000068338:Everolimus; D005260:Female; D006801:Humans; D008875:Middle Aged; D017698:Postmenopause; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1319-21",
"pmc": null,
"pmid": "26489585",
"pubdate": "2015-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Everolimus plus Exemestane in Postmenopausal Metastatic Breast Cancer Patients.",
"title_normalized": "everolimus plus exemestane in postmenopausal metastatic breast cancer patients"
} | [
{
"companynumb": "JP-PFIZER INC-2016245803",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "EVEROLIMUS"
},
"drugadditional": null,
... |
{
"abstract": "Cefepime is a fourth-generation cephalosporin widely used to treat gram-positive and gram-negative infections. Its half-life is approximately two hours in patients with normal renal function and may increase to 13.5 hours in patients with acutely or chronically impaired renal function. Although dosage adjustment is recommended for patients with renal insufficiency to prevent drug accumulation, toxicity has been reported in patients even with normal renal function. One underreported complication of cefepime toxicity is cefepime-induced encephalopathy (CIE). While the pathophysiology is unclear, treatment involves early discontinuation of this antibiotic to decrease morbidity and mortality. We report five cases of cefepime-induced encephalopathy occurring within one year at a single institution.",
"affiliations": "Student, Medical College of Wisconsin, Wauwatosa, USA.;Student, Medical College of Wisconsin, Wauwatosa, USA.;Medicine, Medical College of Wisconsin, Milwaukee, USA.;Medicine, Medical College of Wisconsin, Brookfield, USA.",
"authors": "Schlidt|Kevin|K|;Kadlec|Andrew|A|;Bhandari|Sanjay|S|;Jha|Pinky|P|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.3666",
"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.3666Internal MedicineMedical EducationInfectious DiseaseCefepime-induced Neurotoxicity: Five Cases Reported in a Single Institution Muacevic Alexander Adler John R Schlidt Kevin 1Kadlec Andrew 1Bhandari Sanjay 2Jha Pinky 3\n1 \nStudent, Medical College of Wisconsin, Wauwatosa, USA \n2 \nMedicine, Medical College of Wisconsin, Milwaukee, USA \n3 \nMedicine, Medical College of Wisconsin, Brookfield, USA \nKevin Schlidt kschlidt@mcw.edu30 11 2018 11 2018 10 11 e366611 10 2018 30 11 2018 Copyright © 2018, Schlidt et al.2018Schlidt et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/15463-cefepime-induced-neurotoxicity-five-cases-reported-in-a-single-institutionCefepime is a fourth-generation cephalosporin widely used to treat gram-positive and gram-negative infections. Its half-life is approximately two hours in patients with normal renal function and may increase to 13.5 hours in patients with acutely or chronically impaired renal function. Although dosage adjustment is recommended for patients with renal insufficiency to prevent drug accumulation, toxicity has been reported in patients even with normal renal function. One underreported complication of cefepime toxicity is cefepime-induced encephalopathy (CIE). While the pathophysiology is unclear, treatment involves early discontinuation of this antibiotic to decrease morbidity and mortality. We report five cases of cefepime-induced encephalopathy occurring within one year at a single institution.\n\ncefepimeencephalopathyneurotoxicityrenal failureThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nCefepime, a fourth-generation cephalosporin, has an antibacterial spectrum that covers aerobic gram-positive and gram-negative bacteria, including pseudomonas [1-2]. It is recommended for a wide array of infections including hospital-acquired pneumonia, febrile neutropenia, skin/soft tissue infections, and intra-abdominal infections [1-3]. Like other cephalosporins, cefepime is primarily excreted unchanged in the urine; the half-life is two hours with normal renal function, but can increase up to 13.5 hours in the presence of impaired renal function. To avoid adverse drug events, dosage adjustments are recommended in the setting of renal insufficiency [4]. In 2002, the Food and Drug Administration (FDA) adjusted the labeling to account for an increased risk of seizures, encephalopathy, and myoclonus, particularly in the setting of renal impairment [3]. These adverse events were mainly seen in patients 65 years old or greater with renal dysfunction but without proper dose adjustments, with an incidence of 56%. Improved and early recognition may help to decrease morbidity and mortality, and generate a more accurate estimate of true incidence. The current case-series includes five cases of cefepime-induced encephalopathy (CIE) diagnosed within one year at a single tertiary-care academic center, with a resolution of symptoms following discontinuation of cefepime.\n\nCase presentation\nCase 1\n\nA 63-year-old man with a history of type 2 diabetes mellitus complicated by a prior stroke, chronic foot ulcers, and end-stage-renal disease (ESRD) on hemodialysis presented with a fever and increased drainage from a right foot ulcer. A computed tomography (CT) scan of his foot showed cortical destruction and sclerosis consistent with osteomyelitis. The patient underwent a toe amputation and a six-week course of intravenous (IV) cefepime 1g every 24 hours and vancomycin 1,750mg with hemodialysis three days a week. Three days after starting cefepime, the patient became confused during hemodialysis and had difficulty grasping objects with his right hand. The head CT was negative for acute intracranial pathology and his laboratory tests were unremarkable. Brain magnetic resonance imaging (MRI), lumbar puncture, and electroencephalogram (EEG) did not reveal the cause of his encephalopathy. Despite the cessation of all sedating and psychotropic medications, the mental status failed to improve. Review of the patient’s medical records showed that he had received cefepime, with dosing unadjusted for his impaired renal function, for two days following his procedure. Cefepime was promptly discontinued which corresponded to the 12th day of hospitalization. He was then started on ertapenem. His mental status returned to baseline two days later without any neurological sequelae. He continued to be on ertapenem along with vancomycin without manifesting any further encephalopathy during the remaining part of his hospital course.\n\nCase 2\n\nA 65-year-old female with a past medical history of lupus, hypertension, ESRD on dialysis, and recent left lower extremity graft repair presented to the hospital with complaints of fever, pain, and redness around her graft site. Upon admission, she was febrile and tachycardic with a white blood cell count of 30,000/cubic millimeter. Physical examination revealed erythema and tenderness around her left lower extremity graft site. Transplant surgery was consulted for debridement of her infected graft site, and she was started on IV vancomycin and cefepime 2g every 24 hours. On the second day of hospitalization, she underwent surgery but experienced right arm weakness, left eye deviation, and aphasia postoperatively. The patient was transferred to the neuro ICU where she required intubation for airway protection. The CT angiogram and brain MRI were both negative, and the electroencephalogram (EEG) showed diffuse triphasic waves and severe generalized slowing. Given the unremarkable workup, the infectious disease service recommended holding cefepime, which resulted in an improvement of mental status two days after stopping the drug. The patient was extubated and transferred to the medicine floor in stable condition.\n\nCase 3\n\nA 70-year-old African-American female with a past medical history significant for non-ischemic cardiomyopathy, pulmonary hypertension, chronic kidney disease (CKD) stage III, and ankle fracture status post open reduction and internal fixation complicated by a wound infection, presented to our hospital with word-finding difficulty. Three weeks prior, the patient was hospitalized for a wound infection of her surgical site with wound cultures positive for pseudomonas and enterococcus. She subsequently underwent surgical debridement, incision and drainage, and was started on IV piperacillin/tazobactam 4.6g every six hours. She was later discharged to a subacute rehabilitation on IV vancomycin 1,250mg every 24 hours and cefepime IV 2g every 12 hours. At the rehabilitation facility, the patient’s daughter noted that the patient’s cognitive ability had continued to deteriorate since discharge from the hospital. The patient now had word-finding difficulty prompting an emergency department (ED) evaluation for a stroke. The vitals in the ED were within normal limits and the physical exam only remarkable for asterixis. Complete blood count showed anemia and mild leukocytosis and basal metabolic panel was remarkable for a blood urea nitrogen of 38mg/dL (ref range: 7-20mg/dL), bicarbonate of 19mEq/L (ref range: 23-29mEq/L), and a creatinine of 4.66mg/dL (ref range: 0.8-1.4mg/dL). CT, chest x-ray, ultrasound, and MRI did not identify any acute processes contributing to her presentation. An EEG suggested moderate diffuse cerebral dysfunction (encephalopathy) with possible structural or physiologic disturbances in the left hemisphere. Due to the high dose of antibiotic in the setting of chronic renal disease, there was a high suspicion for cefepime-induced neurotoxicity. Infectious disease switched the antibiotic regimen to IV meropenem 1g every 24 hours, and the patient experienced a drastic improvement in mentation. The patient was subsequently discharged back to subacute rehabilitation to finish her antibiotic course for wound infection.\n\nCase 4\n\nA 63-year-old Caucasian woman with a past medical history of type 2 diabetes, neurogenic bladder, and a recent diagnosis of bilateral hydronephrosis was re-admitted due to worsening weakness and confusion. Two weeks prior to her re-admission, she had presented to an outside hospital for abdominal cramping and was found to have an obstructive urinary tract infectioin (UTI) with growth of candida glabrata on urinalysis. Urology was consulted for her complicated pyelonephritis with hydronephrosis, ultimately leading to bilateral stent placement. At this time, she had a creatinine of 1.2mg/dL. The patient was then discharged on fluconazole 200mg every 12 hours and cefepime 2g every 12 hours empirically for two weeks. One week later, she had complaints of weakness, difficultly ambulating, and confusion. At baseline, the patient was functional and alert and oriented to time, place, and person. However, upon admission, she was confused and oriented to only name and place but could not recall the name of the hospital. Vitals were unremarkable except for mild tachycardia (110/minute). Physical examination was significant for suprapubic region tenderness upon palpation. The repeat urinalysis was positive with culture growing candida glabrata. Head CT and other laboratory results were unremarkable. She was started on IV hydration and continued on cefepime and fluconazole. Urology performed a CT cystogram, which showed findings consistent with a combination of cystitis and partial disruption of the bladder dome, and the patient was subsequently continued on her Foley catheter that was started during the admission. Antibiotics were discontinued after the patient completed the two-week course. Within 24 hours of cessation of the antibiotics, the patient’s mental status improved. Due to persistent suprapubic pain along with re-growth of candida in the urine culture, the patient was restarted on fluconazole, which was subsequently changed to amphotericin deoxycholate for seven days based on sensitivities and infectious disease’s recommendations. The patient’s mental status returned to baseline during hospitalization in parallel with an improvement in her creatinine and discontinuation of cefepime, and the patient was discharged to a subacute rehabilitation facility.\n\nCase 5\n\nA 60-year-old male with a past medical history of asthma, spastic paraplegia, hypertension, hyperlipidemia, peptic ulcer disease, and tibial osteomyelitis post-infected hardware removal was admitted for altered mental status. He was admitted to the orthopedic service for infected hardware removal one month prior to the current admission. He was subsequently started on IV cefepime 2g every eight hours for tibial osteomyelitis and then discharged to a skilled nursing facility for six weeks. Approximately 17 days later, the staff at the nursing facility reported that the patient was delirious, slurring his speech, and pulling out his peripherally inserted central catheter (PICC) line in the night. He was then hospitalized at an outside facility for four days where he had an extensive workup, including a CT head, MRI head, and EEG without any conclusive etiology for his altered mental status. The EEG showed generalized slowing and evidence of metabolic encephalopathy and he was discharged. He returned to an outside emergency department three days later for persistent neurological symptoms, where he was found to have acute kidney injury. Following administration of IV fluids, he was discharged to his skilled nursing facility. His mental status did not improve. After consultation with the infectious disease team, the patient was admitted to our hospital for further workup. Upon admission, his vitals were unremarkable and physical examination showed confusion and disorientation without any other focal neurological deficits. Laboratory results were unremarkable except for an elevated creatinine of 1.8mg/dL (baseline 1-1.2mg/dL) indicative of unresolved acute kidney injury. Cefepime was discontinued, and the patient’s mental status and speech improved over the next 72 hours. Nephrology was consulted. After extensive workup, acute kidney injury was presumed to be secondary to cefepime toxicity with a component of acute tubular necrosis given the hyaline and granular casts seen on urinalysis. The patient was later discharged back to the facility where he had no further episodes of confusion or altered mental status.\n\nDiscussion\nThe five patients discussed here demonstrated a consistent presentation of an acute change in mental status while receiving cefepime, a thorough but quite unremarkable neurological workup, and improvement in symptoms upon cessation of cefepime. Cases one, two, and three had underlying renal disease, while cases four and five had a normal baseline renal function prior to the initiation of cefepime. Cefepime-induced encephalopathy is a rare and under-reported diagnosis.\n\nCefepime is a parenteral fourth-generation antibiotic widely used to treat infections. Compared to third-generation cephalosporins such as ceftazidime, cefepime use is associated with a lower incidence of anaphylaxis, seizures, neutropenia, and bleeding episodes [5]. The exact incidence of cefepime-induced encephalopathy is unknown, as it is likely under-recognized and under-reported. At our institution, there were five cases in a single year. Because cefepime is primarily (85%) excreted by the kidneys, drug accumulation can occur in patients with impaired renal function. While cefepime-induced neurotoxicity, presenting as encephalopathy, myoclonus, seizures, non-convulsive status epilepticus, and mortality, is more common if renal dysfunction is present, it can also occur with normal renal function [4]. Predisposing factors for neurotoxicity include a high cefepime dose (>4g/day), reduced renal drug clearance, increased unbound antibiotic levels, and increased drug cerebral penetration [2]. In patients with renal disease, the maintenance dose should be reduced, and the patient closely monitored for neurotoxicity. Symptoms usually present between one and ten days after administration of cefepime and resolve within two to seven days following discontinuation. If unrecognized, cefepime-induced encephalopathy can have severe, sometimes fatal outcomes [4]. The exact mechanism of the neurotoxicity is unknown, although some studies have suggested that beta-lactam antibiotics competitively inhibit gamma-amino butyric acid (GABA)-induced chloride currents via direct binding and subsequently inhibit the inhibitory response, which causes depolarization of the postsynaptic membrane potential and contributes to neurological symptoms, including seizure [2].\n\nA study by Jallon et al. in 2000 reported 19 cases of encephalopathy over a three year period associated with cefepime usage [6]. The patients’ ages ranged from 57 to 91 years and all had underlying renal insufficiency. Each case presented with confusion and EEGs displaying diffuse, rhythmic triphasic sharp waves. Following discontinuation of cefepime, clinical symptoms resolved. Another study in 2005 examined three cases with cephalosporin-induced non-convulsive status epilepticus in the setting of underlying renal insufficiency, with each case presenting altered mental status associated with epileptiform activity of continuous or almost continuous rhythmic generalized bi-triphasic sharp waves on electroencephalography [7].\n\nGarces et al. conducted a prospective cohort study that followed 498 patients using cefepime between February 2005 through February 2006 [8]. When cefepime was suspected as the probable cause of encephalopathy with all other metabolic problems ruled out, EEGs were performed to assist in the diagnosis, with the first performed during cefepime use and another performed at least 48 hours following drug discontinuation and/or clinical improvement [9]. Five patients in the study were diagnosed with cefepime-induced encephalopathy, indicating a cumulative incidence of approximately 1% (0.01). In this cohort, 111 patients had a mean glomerular filtration rate (GFR) <60 ml/min; mean GFR in patients with encephalopathy (n=5) was 17.20ml/min + 10.75ml/min and, in patients without encephalopathy (n=106), mean GFR was 32.59ml/min + 14.89ml/min. This study suggested that the development of cefepime-induced encephalopathy may be related to the severity of impairment in glomerular function [8], which was consistent with the findings from our institution. Three out of five of our patients had underlying renal disease, and the other two cases presenting with CIE had concurrent acute kidney injury.\n\nPayne et al. performed a systematic review which included 135 cases of CIE [8]. The cohort median age was 69 years old. Majority of the patients presented with renal dysfunction (80%) and required intensive care (81%). All patients exhibited altered mental status, with other symptoms including reduced consciousness (47%), myoclonus (42%), and confusion (42%). Ninety-eight of the 135 patients (73% of the cohort) had EEGs with abnormalities, including triphasic waves (40%), focal sharp waves (39%), non-convulsive epilepticus (25%), and myoclonic status epilepticus (7%). Per drug dosing guidelines, it was determined that 48% of patients were overdosed with 26 experiencing neurotoxicity despite appropriate dosing. The mean cefepime serum and CSF concentrations were 56mg/L (n=21) and 13mg/L (n=4), respectively. Symptoms improved in 89% of patients, with 87% surviving. Symptoms began, on average, four days following drug initiation and resolution occurred, on average, two days following discontinuation of cefepime, antiepileptic administration or hemodialysis interventions, consistent with the time-to-onset and time-to-resolution observed in the above cases [10].\n\nThree meta-analyses measured the all-cause mortality of cefepime with conflicting results [10]. The first study in 2006 with 33 trials evaluated antibiotic treatment for neutropenic fever, finding a higher all-cause mortality after 30 days with cefepime when compared to other beta-lactam antibiotics (RR 1.04, 95% CI 1.24-3.07) [3, 11]. Yahav et al. in 2007 performed a meta-analysis with 57 randomized trials comparing cefepime with other beta-lactam alternatives and found a higher all-cause mortality as well. This study suggested that the causes may be from unrecognized adverse effects such as encephalopathy [2-3]. In contrast, in 2008, the FDA performed a meta-analysis with 88 clinical trials including the trials from Yahav et al. and reported no significant difference in observed mortality [3, 12].\n\nCefepime has been shown to have significant adverse effects, even with renal dose adjustments. In 2013, Fugate et al. evaluated 100 patients for neurotoxicity in the ICU setting and found 15 patients who likely had cefepime encephalopathy and 7 patients who definitely had cefepime encephalopathy [13-14]. This study found that four of the patients had cefepime doses adjusted for renal function, but still experienced adverse effects [2], suggesting neurotoxic effects despite normal renal function. In 2005, a case with a 79-year-old female with normal function became actively confused while being treated with cefepime for a pseudomonal urinary tract infection [14]. Her EEG showed generalized sharp and slow wave discharges. The patient’s mental status did not change with treatment with lorazepam and valproic acid but returned back to baseline over three days once cefepime was discontinued [15]. Another case report in 2005 discussed cefepime and cefixime-induced encephalopathy in a patient with normal renal function whose acute delirium resolved following discontinuation of the cephalosporins on two separate occasions [2, 16]. A study in 2011 showed epileptiform discharges in 14 of 1120 patients receiving cefepime, most of whom had normal renal function [2, 17]. A recent case report by Andrew Meiller et al. reported an additional case of cefepime-induced encephalopathy in a patient with normal renal function; a 75-year-old male being treated with cefepime for pneumonia developed altered mental status that improved three days following discontinuation of cefepime with no other explanation, despite an extensive workup [2].\n\nOur study found cefepime-induced neurotoxicity in the setting of acute or chronic renal dysfunction. As with other studies, other causes of encephalopathy were first ruled out, including infectious, metabolic, and neurologic etiologies. Like other studies, the EEG had diffuse slowing with triphasic waves [2]. However, only two of the five EEGs were positive for the characteristic EEG changes normally associated with CIE. While EEGs may be beneficial to order to better determine the etiology of the affected mental function, the absence of the characteristic cefepime-induced EEG findings does not appear to rule out the possibility of CIE.\n\nThe cases presented here further illustrate how cefepime-induced encephalopathy is a diagnosis of exclusion, requiring an extensive workup and early recognition. Notably, despite an incidence of approximately 3% in other studies [18], we identified five cases in a single year at a single institution, suggesting that the true incidence is likely much higher than previous estimates. The discrepancy likely results from lack of awareness of this drug-related adverse effect and thus underdiagnosis. Therefore, we suggest that clinicians should increasingly consider the diagnosis of CIE in cefepime-treated patients presenting with altered mental status who present with a generally unremarkable workup for common causes of acute neurological changes, along with suggestive EEG findings.\n\nConclusions\nCefepime-induced neurotoxicity is a challenging diagnosis. Clinicians should maintain a high index of suspicion of drug-induced encephalopathy in all patients presenting with altered mental status during the course of cefepime treatment, especially in the absence of other identifiable sources. Further research is needed to identify the mechanism of cefepime-induced encephalopathy, additional risk factors, and true incidence. While there are relatively few cases of cefepime-induced neurotoxicity reported, the presence of five known cases at our institution within a one-year timespan suggests that this condition is likely vastly under-reported and under-diagnosed.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n\nWe would like to thank Dr. Jennifer Good, Dr. Lara Voight, Dr. Sushma Raju, Dr. Hari Poudel, Dr. Sarvpreet Ahluwalia and Dr. Bader Hasan for their contributions, both clinically and academically, with respect to this project.\n==== Refs\nReferences\n1 Evaluating outcomes of alternative dosing strategies for cefepime: a qualitative systematic review Ann Pharmacother Burgess SV Mabasa VH Chow I Ensom MH 311 322 49 2015 https://www.ncbi.nlm.nih.gov/pubmed/25575975 25575975 \n2 Cefepime-induced encephalopathy with normal renal function Oxf Med Case Reports Meillier A Rahimian D 118 120 6 2016 https://doi.org/10.1093/omcr/omw042 \n3 Newer beta-lactam antibiotics: doripenem, ceftobiprole, ceftaroline and cefepime Med Clin North Am Bazan J Martin S Kaye K 983 996 23 2009 \n4 Cefepime-induced neurotoxicity Cent Nerv Syst Agents Med Chem Augusto Bragatti J 229 233 8 2008 \n5 FDA drug safety communication: cefepime and risk of seizure in patients not receiving dosage adjustments for kidney impairment 2016 http://www.fda.gov/drugs/drugsafety/ucm309661.htm \n6 Neurotoxicity induced by beta-lactam antibiotics: from bench to bedside Eur J Clin Microbiol Infect Dis Chow KM Hui AC Szeto CC Eur J 649 653 24 2005 16261307 \n7 Severe but reversible encephalopathy associated with cefepime Neurophysiol Clin Jallon P Fankhauser L Du Pasquier R Coeytaux A Picard F Hefft S 383 386 30 2000 https://www.ncbi.nlm.nih.gov/pubmed/11191931 11191931 \n8 Renal failure is a risk factor for cefepime-induced encephalopathy J Nephrol Garces E Andrade de Anzambuja M da Silva D Bragatti JA Jacoby T Saldanha Thomé F 526 534 21 2008 https://www.ncbi.nlm.nih.gov/pubmed/18651542 18651542 \n9 Cephalosporin-induced nonconvulsive status epilepticus: clinical and electroencephalographic features Epilepsia Fernandez-Torre J Martinez-Martinez M Gonzalez-Rato J 1550 1552 46 2005 16146453 \n10 Cefepime-induced neurotoxicity: a systemic review Crit. Care Payne LE Gagnon DJ Riker RR 276 21 2017 https://www.ncbi.nlm.nih.gov/pubmed/29137682 29137682 \n11 Empirical antibiotic monotherapy for febrile neutropenia: a systematic review and meta-analysis of randomized controlled trials J Antimicrob Chemother Paul M Yahav D Fraser A Leibovici L 176 189 57 2006 16344285 \n12 Efficacy and safety of cefepime: a systematic review and meta-analysis Lancet Infect Dis Yahav D Paul M Fraser A Sarid N Leibovici L 338 348 7 2007 17448937 \n13 Information for healthcare professionals: cefepime (marketed at maxipime) 2 2016 2013 https://www.fda.gov/Drugs/DrugSafety/ucm198675.htm \n14 Cefepime neurotoxicity in the intensive care unit: a cause of severe, underappreciated encephalopathy Crit Care Fugate J Kalimullah E Hocker S 0 17 2013 https://ccforum.biomedcentral.com/articles/10.1186/cc13094 \n15 Nonconvulsive status epilepticus due to cefepime in a patient with normal renal function Epilepsy Behav Maganti R Jolin D Rishi D Biswas A 312 314 8 2006 16278098 \n16 Cefepime- and cefixime-induced encephalopathy in a patient with normal renal function Neurology Capparelli F Diaz M Hlavnika A 1840 65 2005 \n17 Continuous epileptiform discharges in patients treated with cefepime or meropenem Arch Neurol Naeije G Lorent S Vincent J Legros B 1303 1307 68 2011 https://jamanetwork.com/journals/jamaneurology/fullarticle/1107889 21987544 \n18 Cefepime-induced encephalopathy with triphasic waves in three Asian patients Ann Acad Med Singapore De Silva D Pan A Lim S 450 451 36 2007 http://www.annals.edu.sg/pdf/36VolNo6Jun2007/V36N6p450.pdf 17597975\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "10(11)",
"journal": "Cureus",
"keywords": "cefepime; encephalopathy; neurotoxicity; renal failure",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e3666",
"pmc": null,
"pmid": "30740285",
"pubdate": "2018-11-30",
"publication_types": "D002363:Case Reports",
"references": "11191931;16146453;16261307;16278098;16344285;16344542;17448937;17597975;18651542;19909894;21987544;24200036;25575975;27274853;29137682",
"title": "Cefepime-induced Neurotoxicity: Five Cases Reported in a Single Institution.",
"title_normalized": "cefepime induced neurotoxicity five cases reported in a single institution"
} | [
{
"companynumb": "US-PFIZER INC-2019071181",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CEFEPIME HYDROCHLORIDE"
},
"drugadditional": "... |
{
"abstract": "Nocardiosis is a rare bacterial infection occurring mainly in patients with deficient cell-mediated immunity. Although disseminated nocardiosis after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a rare complication, it is associated with high mortality. Moreover, after allo-HSCT, nocardiosis may be mistaken for other bacterial or fungal infections because clinical and radiographic findings of pulmonary, cerebral, and cutaneous nocardiosis lesions are non-specific. Here, we report a case of disseminated nocardiosis (caused by Nocardia abscessus) with skin, pulmonary, liver, lymph node, and multiple brain abscesses in a patient after allo-HSCT. The patient initially responded clinically and radiographically to imipenem/cilastin and trimethoprim-sulfamethoxazole therapy. Clinicians should be aware of the possibility of nocardiosis in allo-HSCT recipients who are treated with multiple immunosuppressive agents to control chronic graft-versus-host disease. Accurate diagnosis and identification of disseminated nocardiosis is important to ensure administration of the correct antibiotic regimen.",
"affiliations": "Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.;Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.;Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.;Department of Clinical Laboratory, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.;Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.;Department of Dermatology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokya, Japan.;Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.",
"authors": "Hino|Yutaro|Y|;Doki|Noriko|N|;Senoo|Yasushi|Y|;Sekiya|Noritaka|N|;Kurosawa|Shuhei|S|;Tsuboi|Satoshi|S|;Ohashi|Kazuteru|K|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12617",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "18(6)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "allogeneic stem cell transplant; chronic graft-versus-host disease; disseminated nocardiosis",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000900:Anti-Bacterial Agents; D019072:Antibiotic Prophylaxis; D000970:Antineoplastic Agents; D016026:Bone Marrow Transplantation; D001922:Brain Abscess; D018893:Bronchoalveolar Lavage; D001992:Bronchoalveolar Lavage Fluid; D001999:Bronchoscopy; D003092:Colitis; D003587:Cytomegalovirus; D005260:Female; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D015470:Leukemia, Myeloid, Acute; D008099:Liver; D008168:Lung; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D009615:Nocardia; D009617:Nocardia Infections; D012867:Skin; D014057:Tomography, X-Ray Computed; D014184:Transplantation, Homologous; D061349:Unrelated Donors",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "942-945",
"pmc": null,
"pmid": "27696601",
"pubdate": "2016-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Disseminated nocardiosis after unrelated bone marrow transplantation.",
"title_normalized": "disseminated nocardiosis after unrelated bone marrow transplantation"
} | [
{
"companynumb": "JP-BAUSCH-BL-2017-006696",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "Multiple myeloma (MM) almost invariably progresses through novel therapies. Patients with quad-refractory MM (refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide) and penta-refractory MM (additional refractoriness to daratumumab) have few treatment options. Two chemotherapy regimens, bendamustine/prednisone (BP) and dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP), are often used in quad- and penta-refractory MM, but there are limited data on outcomes in this heavily pre-treated population. We conducted a single-center retrospective study to identify all patients who received DCEP and/or BP for quad- or penta-refractory MM. Disease response and refractoriness were defined by International Myeloma Working Group criteria. The primary endpoint was overall response rate (ORR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), and duration of response (DOR). We identified 27 patients who received BP for quad- or penta-refractory MM. The median number of prior lines of therapy was 6. The ORR for BP was 26%. The median PFS for BP was 1.4 months (95% CI 1.1-1.6) and median OS was 8.7 months (95% CI 2.3-15.0). Patients treated with cyclophosphamide had less response to BP. Thirty-one patients received DCEP for quad-refractory or penta-refractory MM. The median number of prior treatment regimens was 8. The ORR to DCEP was 35%. The median PFS was 2.7 months (95% CI 1.5-3.8) and median OS was 6.2 months (95% CI 4.4-7.8). DCEP and BP retain efficacy in quad- and penta-refractory MM. Our analysis supports prospective study of these regimens, possibly in combination or in comparison with other agents in this area of unmet need.",
"affiliations": "Division of Oncology, Department of Medicine, Washington University School of Medicine, 660 S Euclid Ave, Box 8056, St. Louis, MO, 63110, USA. goldsm.s@wustl.edu.;Division of Oncology, Department of Medicine, Washington University School of Medicine, 660 S Euclid Ave, Box 8056, St. Louis, MO, 63110, USA.;Division of Oncology, Department of Medicine, Washington University School of Medicine, 660 S Euclid Ave, Box 8056, St. Louis, MO, 63110, USA.;Division of Oncology, Department of Medicine, Washington University School of Medicine, 660 S Euclid Ave, Box 8056, St. Louis, MO, 63110, USA.;Division of Oncology, Department of Medicine, Washington University School of Medicine, 660 S Euclid Ave, Box 8056, St. Louis, MO, 63110, USA.;Division of Oncology, Department of Medicine, Washington University School of Medicine, 660 S Euclid Ave, Box 8056, St. Louis, MO, 63110, USA.;Division of Oncology, Department of Medicine, Washington University School of Medicine, 660 S Euclid Ave, Box 8056, St. Louis, MO, 63110, USA.;Division of Oncology, Department of Medicine, Washington University School of Medicine, 660 S Euclid Ave, Box 8056, St. Louis, MO, 63110, USA.",
"authors": "Goldsmith|Scott R|SR|http://orcid.org/0000-0001-9216-2418;Fiala|Mark A|MA|;Wang|Brandon|B|;Schroeder|Mark A|MA|;Wildes|Tanya M|TM|;Ghobadi|Armin|A|;Stockerl-Goldstein|Keith|K|;Vij|Ravi|R|",
"chemical_list": "D005047:Etoposide; D003907:Dexamethasone; D003520:Cyclophosphamide; D000069461:Bendamustine Hydrochloride; D011239:Prednisolone; D002945:Cisplatin",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-020-03970-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "99(5)",
"journal": "Annals of hematology",
"keywords": "Bendamustine; DCEP; Penta-refractory multiple myeloma; Quad-refractory multiple myeloma; Salvage therapy",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069461:Bendamustine Hydrochloride; D002945:Cisplatin; D003520:Cyclophosphamide; D003907:Dexamethasone; D018572:Disease-Free Survival; D005047:Etoposide; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D011239:Prednisolone; D012189:Retrospective Studies; D016879:Salvage Therapy; D015996:Survival Rate",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "1041-1048",
"pmc": null,
"pmid": "32130471",
"pubdate": "2020-05",
"publication_types": "D016428:Journal Article",
"references": "26883334;30523328;26282654;29654271;29344579;25838345;27002115;22422823;28895206;27033237;25482145;28637662;26308596;27557302;27705267;22498740;29257139;30858549;29381435;28025583;30572922;19996200;16402269;20159666;26085055;16154860;29616871;26149422;3710442;24240976;27722131;26156122;31042825",
"title": "DCEP and bendamustine/prednisone as salvage therapy for quad- and penta-refractory multiple myeloma.",
"title_normalized": "dcep and bendamustine prednisone as salvage therapy for quad and penta refractory multiple myeloma"
} | [
{
"companynumb": "US-AMGEN-USASP2020040130",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARFILZOMIB"
},
"drugadditional": "3",
... |
{
"abstract": "An 81-year-old man was diagnosed with Goodpasture syndrome (GS) because he met the criteria of positive anti-GBM antibodies, rapid progressive glomerulonephritis and pulmonary hemorrhage. After starting plasmapheresis and steroid pulse therapy, he experienced tarry stool and contrast-enhanced CT revealed an aneurysmal finding in the jejunum. Paroral enteroscopy showed a jejunal Dieulafoy's lesion (DL) with gush-out hemorrhage. Hemostasis was successfully achieved by hemoclipping, and he then experienced no re-bleeding events. GS can present as a jejunal DL, and contrast-enhanced CT is useful for investigating the etiology and site of small intestinal bleeding, which can lead to smooth, effective endoscopic hemostasis.",
"affiliations": "Department of Gastroenterology, Kyoto Okamoto Memorial Hospital, 100 Nishinokuchi, Sayama, Kumiyama-cho, Kuze-gun, Kyoto, 613-0034, Japan. hkawabata@okamoto-hp.or.jp.;Department of Gastroenterology, Kyoto Okamoto Memorial Hospital, 100 Nishinokuchi, Sayama, Kumiyama-cho, Kuze-gun, Kyoto, 613-0034, Japan.;Department of Gastroenterology, Kyoto Okamoto Memorial Hospital, 100 Nishinokuchi, Sayama, Kumiyama-cho, Kuze-gun, Kyoto, 613-0034, Japan.;Department of Gastroenterology, Kyoto Okamoto Memorial Hospital, 100 Nishinokuchi, Sayama, Kumiyama-cho, Kuze-gun, Kyoto, 613-0034, Japan.;Department of Gastroenterology, Kyoto Okamoto Memorial Hospital, 100 Nishinokuchi, Sayama, Kumiyama-cho, Kuze-gun, Kyoto, 613-0034, Japan.;Department of Gastroenterology, Kyoto Okamoto Memorial Hospital, 100 Nishinokuchi, Sayama, Kumiyama-cho, Kuze-gun, Kyoto, 613-0034, Japan.;Department of Gastroenterology, Kyoto Okamoto Memorial Hospital, 100 Nishinokuchi, Sayama, Kumiyama-cho, Kuze-gun, Kyoto, 613-0034, Japan.;Department of Gastroenterology, Kyoto Okamoto Memorial Hospital, 100 Nishinokuchi, Sayama, Kumiyama-cho, Kuze-gun, Kyoto, 613-0034, Japan.;Department of Gastroenterology, Kyoto Okamoto Memorial Hospital, 100 Nishinokuchi, Sayama, Kumiyama-cho, Kuze-gun, Kyoto, 613-0034, Japan.;Department of Gastroenterology, Kyoto Okamoto Memorial Hospital, 100 Nishinokuchi, Sayama, Kumiyama-cho, Kuze-gun, Kyoto, 613-0034, Japan.;Department of Nephrology, Kyoto Okamoto Memorial Hospital, Kyoto, Japan.;Department of Nephrology, Kyoto Okamoto Memorial Hospital, Kyoto, Japan.",
"authors": "Kawabata|Hideaki|H|http://orcid.org/0000-0002-7162-705X;Kawakatsu|Yukino|Y|;Sone|Daiki|D|;Yamaguchi|Katsutoshi|K|;Inoue|Naonori|N|;Ueda|Yuki|Y|;Okazaki|Yuji|Y|;Hitomi|Misuzu|M|;Miyata|Masatoshi|M|;Motoi|Shigehiro|S|;Nishimura|Masayasu|M|;Shikano|Tsutomu|T|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s12328-019-01078-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1865-7265",
"issue": "13(3)",
"journal": "Clinical journal of gastroenterology",
"keywords": "Bleeding; Dieulafoy’s lesion; Enteroscopy; Goodpasture syndrome; Small intestine",
"medline_ta": "Clin J Gastroenterol",
"mesh_terms": "D000369:Aged, 80 and over; D019867:Anti-Glomerular Basement Membrane Disease; D016099:Endoscopy, Gastrointestinal; D006471:Gastrointestinal Hemorrhage; D006489:Hemostatic Techniques; D006801:Humans; D007579:Jejunal Diseases; D008297:Male; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101477246",
"other_id": null,
"pages": "382-385",
"pmc": null,
"pmid": "31786734",
"pubdate": "2020-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A rare case of Goodpasture syndrome concomitant with bleeding jejunal Dieulafoy's lesion.",
"title_normalized": "a rare case of goodpasture syndrome concomitant with bleeding jejunal dieulafoy s lesion"
} | [
{
"companynumb": "JP-MYLANLABS-2020M1060917",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": "3",
... |
{
"abstract": "Calcineurin-inhibitor induced pain syndrome (CIPS) is a condition characterized by lower extremity pain in patients receiving tacrolimus or cyclosporine therapy following organ transplantation. Through two cases, we demonstrate key imaging findings in CIPS with bone scintigraphy and magnetic resonance imaging (MRI), which are those of increased scintigraphic activity and marrow edema in the lower extremities, respectively. CIPS is an important condition that has characteristic imaging findings, but is unfortunately underappreciated in the radiology literature. To our knowledge, this is the first article in the radiology literature presenting two cases of CIPS, as well as the first to present both scintigraphic and MRI findings in this condition.",
"affiliations": "Department of Radiology, University of California San Diego Medical Center, 200 West Arbor, Drive, Mail Code #8756, San Diego, CA 92103, USA. Electronic address: Yatin.chadha@nygh.on.ca.;Department of Radiology, Scripps Green Hospital, 10666 N Torrey Pines Rd, La Jolla, CA 92307, USA. Electronic address: brahme.sevil@scrippshealth.org.;Department of Radiology, University of California San Diego Medical Center, 408 Dickinson, Street, Mail Code #8226, San Diego, CA 92103, USA.;Department of Radiology, University of California San Diego Medical Center, 408 Dickinson, Street, Mail Code #8226, San Diego, CA 92103, USA; Radiology Service, VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA.",
"authors": "Chadha|Yatin|Y|;Brahme|Sevil K|SK|;Huang|Brady K|BK|;Chang|Eric Y|EY|",
"chemical_list": "D065095:Calcineurin Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clinimag.2018.10.022",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0899-7071",
"issue": "53()",
"journal": "Clinical imaging",
"keywords": "CIPS; Calcineurin-inhibitor induced pain syndrome; MRI; Magnetic resonance imaging; Post-transplant pain syndrome; Scintigraphy",
"medline_ta": "Clin Imaging",
"mesh_terms": "D000328:Adult; D065095:Calcineurin Inhibitors; D005260:Female; D006801:Humans; D016030:Kidney Transplantation; D035002:Lower Extremity; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010146:Pain; D011877:Radionuclide Imaging; D013577:Syndrome",
"nlm_unique_id": "8911831",
"other_id": null,
"pages": "174-178",
"pmc": null,
"pmid": "30415182",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Calcineurin-inhibitor induced pain syndrome - Magnetic resonance imaging and scintigraphic findings illustrated through two cases.",
"title_normalized": "calcineurin inhibitor induced pain syndrome magnetic resonance imaging and scintigraphic findings illustrated through two cases"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2018SP009837",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional"... |
{
"abstract": "The regimen of concurrent administration of trastuzumab and anthracyclines in the adjuvant treatment of breast cancer has never been evaluated prospectively for fear of cardiac toxicity.\nPatients with HER2-positive operable breast cancer were randomised to receive adjuvant treatment with concurrent or sequential administration of trastuzumab and anthracyclines. Cardiac monitoring was scheduled at baseline and every 3 months after the first dose of trastuzumab. The primary study endpoint was cardiac safety. Secondary endpoints were disease-free and overall survival.\nFrom 2011 to 2014, 201 participants were enrolled and randomised. The median follow-up time was 42 months. Nineteen patients (19.4%) in the concurrent group and 22 patients (22.4%) in the sequential group met the criteria for cardiac events with non-significant difference (P=0.598). There was no difference in the mean LVEF between the two groups at the baseline and at 3, 6, 9, 12, and 24 months after the first dose of trastuzumab. No case of congestive heart failure or cardiac death occurred. The differences between the efficacies of the two regimens, defined by disease-free or overall survival, were not significant.\nConcurrent administration of trastuzumab and anthracyclines is a safe adjuvant regimen and it provides evidence for further clinical trials.",
"affiliations": "Department of Breast Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, 1 Shuaifuyuan, Dongcheng District, Beijing 100730, China.;Department of Breast Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, 1 Shuaifuyuan, Dongcheng District, Beijing 100730, China.;Department of Breast Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, 1 Shuaifuyuan, Dongcheng District, Beijing 100730, China.;Department of Breast Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, 1 Shuaifuyuan, Dongcheng District, Beijing 100730, China.;Department of Breast Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, 1 Shuaifuyuan, Dongcheng District, Beijing 100730, China.;Department of Breast Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, 1 Shuaifuyuan, Dongcheng District, Beijing 100730, China.",
"authors": "Shen|Songjie|S|;Xu|Ying|Y|;Zhou|Yidong|Y|;Mao|Feng|F|;Guan|Jinghong|J|;Sun|Qiang|Q|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.18632/oncotarget.21579",
"fulltext": "\n==== Front\nOncotargetOncotargetOncotargetImpactJOncotarget1949-2553Impact Journals LLC 2157910.18632/oncotarget.21579Research PaperConcurrent administration of trastuzumab and anthracyclines as adjuvant regimen for HER2-positive breast cancer: a randomised controlled trial Shen Songjie 1Xu Ying 1Zhou Yidong 1Mao Feng 1Guan Jinghong 1Sun Qiang 11 Department of Breast Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, 1 Shuaifuyuan, Dongcheng District, Beijing 100730, ChinaCorrespondence to:Qiang Sun,sunqiangpumc@sina.com3 11 2017 6 10 2017 8 54 92778 92787 22 6 2017 28 8 2017 Copyright: © 2017 Shen et al.2017This article is distributed under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.Background\nThe regimen of concurrent administration of trastuzumab and anthracyclines in the adjuvant treatment of breast cancer has never been evaluated prospectively for fear of cardiac toxicity.\n\nMethods\nPatients with HER2-positive operable breast cancer were randomised to receive adjuvant treatment with concurrent or sequential administration of trastuzumab and anthracyclines. Cardiac monitoring was scheduled at baseline and every 3 months after the first dose of trastuzumab. The primary study endpoint was cardiac safety. Secondary endpoints were disease-free and overall survival.\n\nResults\nFrom 2011 to 2014, 201 participants were enrolled and randomised. The median follow-up time was 42 months. Nineteen patients (19.4%) in the concurrent group and 22 patients (22.4%) in the sequential group met the criteria for cardiac events with non-significant difference (P=0.598). There was no difference in the mean LVEF between the two groups at the baseline and at 3, 6, 9, 12, and 24 months after the first dose of trastuzumab. No case of congestive heart failure or cardiac death occurred. The differences between the efficacies of the two regimens, defined by disease-free or overall survival, were not significant.\n\nConclusions\nConcurrent administration of trastuzumab and anthracyclines is a safe adjuvant regimen and it provides evidence for further clinical trials.\n\nbreast canceradjuvant therapytrastuzumabanthracyclinecardiac safety\n==== Body\nINTRODUCTION\nThe human epidermal growth factor receptor 2 (HER2) is overexpressed in approximately 15%–25% of invasive breast cancers, and is associated with a high risk of disease recurrence and reduced survival [1–3]. Trastuzumab, a monoclonal antibody directed against HER2, has been shown to improve disease-free survival (DFS) and overall survival (OS) in HER2-positive breast cancer patients [1–3]. Moreover, many clinical trials have also indicated that patients with HER2-positive breast cancer might derive preferential benefit from anthracyclines [4–6].\n\nHowever, cardiac dysfunction is the most concerning toxicity associated with these regimens, especially when trastuzumab is given concurrently with anthracyclines. In a pivotal trial in the metastatic setting, the concurrent administration of trastuzumab and anthracyclines was reported to result in unacceptably high rates of cardiac dysfunction (27%), although the highest survival benefit was also observed in this treatment [7]. However, in the neoadjuvant therapy, trastuzumab administered concurrently with anthracyclines has shown exceedingly low cardiotoxicity [8–11], and expectedly high rates of pathological complete response (pCR) and prolonged survival [8–10].\n\nAlthough the findings of the North Central Cancer Treatment Group N9831 trial indicated an increase in disease-free survival with concurrent trastuzumab and paclitaxel compared to sequential regimen in the adjuvant treatment of breast cancer [12], only the sequential regiment of trastuzumab and anthracyclines administration was evaluated in prospective clinical trials. To date, the safety and efficacy of trastuzumab administered concurrently with anthracyclines has never been evaluated prospectively in the adjuvant treatment. Concurrent administration of trastuzumab and anthracyclines was not recommended in the adjuvant therapy of breast cancer in all the guidelines, including the latest version of the National Comprehensive Cancer Network (NCCN) guidelines of breast cancer (version 2.2016) and the American Society of Clinical Oncology (ASCO) guideline adaptation of the Cancer Care Ontario clinical practice guideline [13], because fear of cardiac toxicity. Thus, we conducted the present prospective, randomised, and controlled trial to assess the cardiac safety, as well as the therapeutic efficacy, of the concurrent administration of trastuzumab and anthracyclines in the adjuvant treatment of HER2-positive early breast cancer.\n\nRESULTS\nPatient characteristics\nA total of 201 patients were enrolled (101 in the concurrent group and 100 in the sequential group) in the investigation from August 10, 2011 to March 1, 2014 (Figure 1). The last follow-up date was August 1, 2016, and the median follow-up time was 42 months (range: 19–62 months). Three of these patients in the concurrent group and two participants in the sequential group withdrew consent before starting treatment. Therefore, 196 participants (98 in the concurrent group and 98 in the sequential group) were eligible for final analysis. Table 1 showed the baseline characteristics for the concurrent and sequential groups. Characteristics were well balanced between the two treatment groups.\n\nFigure 1 CONSORT diagram\nHER2, human epidermal growth factor receptor.\n\nTable 1 Demographic and baseline characteristics\nVariable, N (%)\tConcurrent group(n=98)\tSequential group(n=98)\tP-value\t\nAge(years)\t\t\t\t\n Mean±SD\t48.0±9.0\t48.7±9.5\t0.628\t\n Median (range)\t49.5 (25∼67)\t50.0 (28∼66)\t\t\n Age Group\t\t\t0.986\t\n ≤35\t10\t10\t\t\n 36∼55\t64\t63\t\t\n >55\t24\t25\t\t\nBSA, m2\t1.73\t1.74\t\t\n Mean±SD\t1.72±0.12\t1.74±0.11\t0.499\t\n Median (range)\t1.71 (1.43∼2.01)\t1.72 (1.45∼2.06)\t\t\nHistory of hypertension\t14\t12\t0.674\t\nTumor size (cm)\t\t\t0.907\t\n ≤2.0\t48\t51\t\t\n 2.1∼5.0\t45\t42\t\t\n >5.0\t5\t5\t\t\nGrade\t\t\t0.827\t\n G1\t5\t4\t\t\n G2\t44\t48\t\t\n G3\t49\t46\t\t\nER positive\t47\t52\t0.475\t\nPR positive\t39\t42\t0.663\t\np53 positive\t56\t63\t0.306\t\nKi-67 high(≥14%)\t81\t76\t0.371\t\nLymph nodes\t\t\t0.867\t\n 0\t38\t37\t\t\n 1∼3\t25\t28\t\t\n 4∼9\t13\t15\t\t\n >9\t22\t18\t\t\nAJCC stage\t\t\t0.839\t\n I\t24\t23\t\t\n II\t38\t42\t\t\n III\t36\t33\t\t\nChemotherapy Regimen\t\t\t0.539\t\n Anthracyclines, no taxanes\t33\t29\t\t\n Anthracyclines plus taxanes\t65\t69\t0.059\t\n Concurrent\t37\t28\t\t\n Sequential\t28\t41\t\t\nCumulative anthracyclines dose (mg/m2)\t361.2\t359.1\t0.869\t\nRadiotherapy\t43\t48\t0.474\t\n Left-sided tumor\t24\t23\t\t\nEndocrine Therapy\t51\t55\t0.566\t\nSD, standard deviation; BSA, body surface area; ER, estrogen receptor; PR, progesterone receptor.\n\nCardiac safety and other safety\nThe cardiac safety events were graded according to the NCI-CTC, version 2.0. Trastuzumab and anthracyclines was well tolerated in both the concurrent group and the sequential group. There was no patient documented congestive heart failure or cardiac death. The primary cardiac safety event in both treatment groups was an asymptomatic decrease in the left ventricular ejection fraction. Nineteen patients (19.4%, 95% CI 12.4-28.9) in the concurrent group and 22 patients (22.4%, 95% CI 14.9-32.2) in the sequential group met the criteria for cardiac events (odds ratio 0.831, 95% CI 0.417-1.656, P = 0.598, Table 2). No difference between the two groups was found in the mean LVEF determined at baseline, every 3 months during trastuzumab administration, and at 24 months after the first dose of trastuzumab (Figure 2). In the concurrent group, more than 10% but less than 20% reduction in LVEF (NCI-CTC Grade 1) was detected in 17 patients (17.3%, 95% CI 10.7-26.6), whereas a reduction higher than 20% in LVEF or a decline below 50% (NCI-CTC Grade 2) was established in two patients (2.0%, 95% CI 0.3-7.9). On the other hand, in the sequential group, 21 patients (21.4%, 95% CI 14.0-31.1) exhibited a Grade 1 LVEF reduction, and 1 patient (1.0%, 95% CI 0.1-6.4) manifested a Grade 2 reduction. Trastuzumab was temporarily withheld in two participants in the concurrent group and one patient in the sequential group with Grade 2 LVEF reduction. The LVEF values of these three patients recovered in four weeks, and trastuzumab administration was continued. Trastuzumab was permanently discontinued in one patient in the concurrent group after the application of 14 doses because of hearing loss.\n\nTable 2 Cardiac events during treatment and follow-up\n\tConcurrent group(N=98)\tSequential group(N=98)\tP-value\t\nLVEF reduction\t19 (19.4)\t22 (22.4)\t0.598\t\n NCI-CTC grade 1 †\t17 (17.3)\t21 (21.4)\t\t\n NCI-CTC grade 2 ‡\t2 (2.0)\t1 (1.0)\t\t\n NCI-CTC grade 3 *\t0\t0\t\t\n NCI-CTC grade 4⁑\t0\t0\t\t\nCardiac death\t0\t0\t\t\nLVEF, left ventricular ejection fraction; NCI-CTC, National Cancer Institute common toxicity criteria.\n\nData are n (%). †Asymptomatic reduction of 10% or more, but less than 20% of baseline. ‡Asymptomatic reduction to lower limit of normal or 20% or more of baseline. *Congestive heart failure, responsive to treatment. ⁑Refractory or poorly controlled heart failure due to drop in ejection fraction. Lower limit of normal:EF value = 50%.\n\nFigure 2 Mean left ventricular ejection fraction (LVEF) measurements during treatment and follow-up\nVertical bars represent standard deviation.\n\nDisease-free survival and overall survival\nFifteen recurrent events were observed in the concurrent group and 16 events in the sequential group (Table 3 and Figure 3). The percentages of patients alive and disease-free at five years were 84.5% in the concurrent group and 79.4% in the sequential group (hazard ratio, 0.956; 95% CI 0.471–1.939; P = 0.901). There was no significant difference between the rates of DFS in the two groups.\n\nTable 3 First disease-free survival events by trial arms\n\tConcurrent group(N=98)\tSequential group(N=98)\t\nLocoregional recurrence\t4\t3\t\n Chest wall\t1\t0\t\n Lymph nodes\t3\t3\t\nDistant metastasis\t12\t13\t\n Bone\t4\t7\t\n Brain\t4\t1\t\n Liver\t1\t3\t\n Lung\t3\t2\t\nTotal DFS events\t15*\t16\t\n* One case presented with both bone and lymph nodes involvement as first manifestation of recurrence.\n\nFigure 3 Kaplan-Meier estimates of disease-free survival (A) and overall survival (B).\n\nThere were 14 deaths occurred during follow-up, eight in the concurrent group and six in the sequential group. The Kaplan-Meier estimates of the OS at five years was 91.2% in the concurrent group and 92.4% in the sequential group (hazard ratio, 1.443; 95% CI 0.500–4.167; P = 0.495; Figure 3). The difference was also non-significant.\n\nDISCUSSION\nTo our knowledge, this is the first randomised and controlled trial that demonstrated the safety of the concurrent use of trastuzumab and anthracyclines in the adjuvant treatment of early breast cancer. With a median follow-up time of 42 months, 19.4% of the patients in the concurrent group and 22.4% in the sequential group met the criteria for cardiac events. There was no patient documented congestive heart failure or cardiac death. No significant difference was found in cardiac safety event rates between the two groups (P = 0.598). A slight decline in the mean LVEF values was observed during the administration of trastuzumab; however, they recovered in both groups within one year.\n\nAlthough the concurrent use of trastuzumab and anthracyclines caused unacceptably high rates of cardiac dysfunction in the metastatic setting [7], this regimen was proven fairly safe in the neoadjuvant setting [8, 9]. No prospective randomised trial to investigate the cardiac safety of the concurrent regimen of trastuzumab and anthracyclines in the adjuvant treatment of early breast cancer has been reported before. Only one Japanese study by Watanabe and colleagues [14, 15] retrospectively reviewed the cardiac tolerability of the concurrent administration of trastuzumab and anthracyclines. In that analysis, 49 patients with HER2-positive breast cancer received paclitaxel (P) followed by epirubicin, fluorouracil, and cyclophosphamide (FEC) and concurrent trastuzumab (Trastuzumab Group). The LVEF values of the patients in the Trastuzumab Group was assessed regularly for more than one year and compared with those of HER2-negative breast cancer patients who received P followed by FEC (Standard Group). Twelve patients (24.9%) in the Trastuzumab Group had a LVEF reduction of more than 10%, compared to 22.2% in the Standard Group [14, 15]. There was no significant difference in LVEF reduction between the two groups (P = 0.386) [14, 15]. The cardiac event rate of this retrospective study was similar to that of our trial, which supported our conclusion regarding the cardiac safety of the concurrent administration of trastuzumab and anthracyclines.\n\nNevertheless, it is unclear whether there is anthracycline-trastuzumab interaction contributing to cardiotoxicity, although some possible mechanisms have been proposed [16, 17]. It is currently considered that anthracyclines cause type I cardiac damage, which is dose-related and associated with identifiable ultrastructural abnormalities, and begins from the initial administration of the drug [18]. While trastuzumab-related cardiotoxicity is classified as Type II, which is highly reversible, non-dose-dependent, and unassociated with ultrastructural changes [18]. Since the cardiac toxicity caused by anthracyclines persists during the sequential use of trastuzumab, we propose that the timing of trastuzumab administration is not related to the severity of cardiotoxicity. The high rate of cardiac failure in the metastatic setting might not be caused by the concurrent regimen of trastuzumab and anthracyclines, but by the high cumulative dose of anthracyclines and poor baseline cardiac conditions of the metastatic patients. Therefore, there suggested a high possibility the cardiotoxicity rate would not change even trastuzumab was given sequentially in that trial. The absence of observations of a high rate of cardiotoxicity in all other related trials also provides evidence in support of our interpretation.\n\nApart from the well-tolerated concurrent administration of trastuzumab and anthracyclines in the adjuvant treatment of breast cancer, there are at least two other reasons to prefer this regimen.\n\nFirstly, the required treatment duration is the shortest of all regimens containing both trastuzumab and anthracyclines, and all phases of this regimen can be completed within 12 months. This will shorten the duration of treatment by 3–6 months, and reduce considerably hospitalization times and costs.\n\nSecondly, the genes encoding topoisomerase II alpha and HER2, the targets for anthracyclines and trastuzumab, respectively, are frequently co-amplified in breast cancers [19]. Pre-clinical studies showed there were additive and/or synergistic therapeutic effects between anthracyclines and trastuzumab [20]. The findings of some trials also suggested that the HER2 status was a predictor of responsiveness to adjuvant anthracyclines administration, and patients with HER2-positive breast tumor might derive preferential benefit from the administration of anthracyclines [4–6]. The concurrent administration of trastuzumab and anthracyclines in neoadjuvant trials has resulted in high rates of pCR and prolonged survival [8–10].\n\nOne limitation of our trial is the relatively small number of patients to show the secondary endpoint of survival benefits. However, the safety issue has priority over the effect, and for more than a decade, cardiac safety has been the obstacle that prevented clinical researchers from investigating the effect of the concurrent administration of trastuzumab and anthracyclines in the adjuvant treatment of breast cancer. The present trial has provided the first evidence of cardiac safety, but larger trials are warranted to confirm the effect.\n\nConcurrent administration of trastuzumab and anthracyclines is a safe adjuvant regimen with a low frequency of cardiac dysfunction, although careful cardiac monitoring is needed. Due to the limitation of the relatively small sample size and short follow-up time, further multicenter clinical trials are required to determine the cardiac safety of the concurrent regimen and whether it improves the survival of patients.\n\nMATERIALS AND METHODS\nStudy design\nThe present study was a prospective, randomised, and controlled trial in patients with newly diagnosed early breast cancer from Peking Union Medical College Hospital (PUMCH). At the time of registration, the patients with histopathologically confirmed Her2-positive early breast cancer had undergone definitive surgery and planned to receive anthracycline-based adjuvant chemotherapy and trastuzumab treatment. The primary study endpoint was cardiac safety, including symptoms, electrocardiogram, and LVEF changes. Secondary endpoints involved DFS and OS. DFS was defined as the interval from randomization to: local, regional, or distant recurrence; second primary cancer; contralateral breast cancer; or death from any cause, whichever came first. OS was defined as the time from random assignment to death from any cause.\n\nThe study was approved by the Institutional Review Board of PUMCH. All patients provided written informed consent. The study was conducted in accordance with the Declaration of Helsinki.\n\nThis study was registered at the ClinicalTrials.gov (Identifier: NCT01413828).\n\nEligibility criteria\nEligibility requirements included primary operable node-positive or high-risk node-negative invasive breast cancer. All tumors had to be removed by definitive surgery within 60 days of trial registration, and neoadjuvant treatments were not permitted.\n\nAll the patients had HER2-positive breast cancer, which was defined as immunohistochemistry (IHC) score of 3+ (Herceptest, Dako, Denmark) or gene amplified by fluorescence in situ hybridization (FISH, Pathvysion HER2 test, Abbott-Vysis, USA) according to the PUMCH laboratory. Participants were excluded if they had locally advanced or metastatic breast cancer, bilateral breast cancer, previous or concurrent any other malignant disease, previous administration of anthracyclines and/or trastuzumab for any disease.\n\nOnly adult female patients with adequate hepatic, renal, and bone marrow functions were included as participants in the investigation. An additional requirement for enrollment included having a LVEF value of 55% or higher measured by echocardiography. Patients were ineligible if they had a history of documented congestive heart failure, angina pectoris, unstable arrhythmias, coronary artery disease with previous myocardial infarction, clinically significant valvular disease, and uncontrolled hypertension.\n\nRandomisation and masking\nEligible participants were randomly assigned, in a 1:1 ratio, to receive adjuvant therapy with trastuzumab administered concurrently with anthracyclines (concurrent group) or sequentially to anthracyclines (sequential group). The chemotherapy regimen and radiation therapy was chosen before randomisation. Randomisation was done by a computer-generated randomization sequence, using a permuted-block randomisation method with a block size of four.\n\nTreatment regimens\nEligible participants were randomised after definitive surgery to receive concurrent or sequential administration of trastuzumab and anthracyclines. The regimens of chemotherapy consisting of at least four cycles of anthracycline-based treatment were chosen at the discretion of their physician based on the National Comprehensive Cancer Network guidelines before randomisation. If anthracyclines were given alone or followed by taxanes, the starting doses of doxorubicin and epirubicin were 60 mg/m2 and 90–100 mg/m2, respectively. Alternatively, if anthracyclines were administered concurrently with taxanes, doses of 50 mg/m2 of doxorubicin and 75 mg/m2 of epirubicin were employed. In all cases, the maximum cumulative allowable doses were 360 mg/m2 of doxorubicin and 600 mg/m2 of epirubicin. The anthracyclines were given every two or three weeks.\n\nTrastuzumab was administered intravenously, beginning with a loading dose of 8 mg/kg of body weight, and followed by maintenance doses of 6 mg/kg given every three weeks for one year. If the treatment of trastuzumab was delayed by more than one week, the administration was restarted with the initial dose of 8 mg/kg, followed by the usual maintenance dose (6 mg/kg every three weeks).\n\nRadiation therapy was required after completion of chemotherapy to patients who underwent breast-conserving surgery or mastectomy with at least four positive nodes. Patients with hormone receptor-positive disease were given adjuvant endocrine therapy after chemotherapy unless contraindicated. Trastuzumab treatment was continued during radiotherapy and/or endocrine therapy. No cardioprotective drugs (dexrazoxane, angiotensin-converting enzyme inhibitors, beta blockers, et al.) were permitted to use prophylactically.\n\nCardiac safety\nIn addition to monitoring general safety, an intense cardiac monitoring was also scheduled. Cardiac events were graded according to the National Cancer Institute Common Toxicity Criteria, version 2.0 (NCI-CTC, version 2.0). Cardiac monitoring in the concurrent group and the sequential group included history-taking, a 12-lead electrocardiogram, and an assessment of LVEF by echocardiography at baseline and at 3, 6, 9, 12, and 24 months after the first dose of trastuzumab. Thereafter, history-taking and physical examination were scheduled every 6 months until the end of the study. Additional scans could be performed at the investigator's discretion. Cardiac safety was monitored by independent cardiologists.\n\nIf the absolute value of LVEF declined by 20% or more from baseline or below 50%, trastuzumab was temporarily discontinued for four weeks during which the LVEF value was reassessed. The administration of trastuzumab was permanently discontinued in case that LVEF values remained below these levels or the participant experienced symptomatic cardiac failure.\n\nStatistical design and analysis\nIn the present trial, the primary end point was cardiac safety, defined as the incidence of an asymptomatic LVEF reduction of 10% absolutely or more from baseline, or below 50%, or symptomatic heart failure. To calculate the sample size, we had to assume the rate of cardiac safety events in each of the two groups, whose values can vary due to the different definitions and populations used in each specific trial. We adopted the rate of cardiac dysfunction of the Breast Cancer International Research Group 006 trial, in which 18.6% of participants in the sequential group had a LVEF reduction of more than 10% [3]. According to a trial in the metastatic setting, in which prohibition of the concurrent administration of trastuzumab and anthracyclines in clinical practice was recommended, the rate of heart failure in the concurrent group was increased to 27% [7]. Thus, we can infer a much higher rate of asymptomatic LVEF reduction of the concurrent administration of trastuzumab and anthracyclines since asymptomatic LVEF reduction is much more common than heart failure. In our investigation, if we were to assume rates of cardiac events in the sequential group and the concurrent group of 19% and 32%, respectively, 176 participants would have been needed to achieve a two-sided statistical significance of 5% with 80% power.\n\nCategorical data were compared using the two-tailed chi-square test. When the expected counts were low, we employed the Fisher's exact test. Quantitative data were compared by Student's t-test. The DFS and OS were estimated using the Kaplan-Meier method. Two-sided log-rank test for time-to event endpoints were used. Differences were considered significant at P < 0.05.\n\nWe thank all the patients who have participated in our trial, and the medical teams for their cooperation.\n\nAuthor contributions\n\nAll authors have reviewed the data interpretation, prepared the report, and approved the final version of the submitted manuscript. QS and SS participated in the study design. YX was involved in statistical planning and data analysis.\n\nCONFLICTS OF INTEREST\n\nThe authors declare that they have no conflicts of interest.\n\nFUNDING\n\nThis work was supported by the Beijing Natural Science Foundation (7172168), Beijing Municipal Science and Technology Key Development Program (D090507043409009) and the Twelfth Five-year Key Programs for Science and Technology Development of China (2014BAI08B03).\n==== Refs\nREFERENCES\n1 Gianni L Dafni U Gelber RD Azambuja E Muehlbauer S Goldhirsch A Untch M Smith I Baselga J Jackisch C Cameron D Mano M Pedrini JL Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial Lancet Oncol 2011 12 236 44 https://doi.org/10.1016/S1470-2045(11)70033-X 21354370 \n2 Perez EA Romond EH Suman VJ Jeong JH Davidson NE Geyer CE Jr Martino S Mamounas EP Kaufman PA Wolmark N Four-year follow-up of trastuzumab plus adjuvant 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Holloway JN Hurria A King TA Lyman GH Partridge AH Telli ML Trudeau ME Wolff AC Selection of optimal adjuvant chemotherapy regimens for human epidermal growth factor receptor 2 (HER2) -negative and adjuvant targeted therapy for HER2-positive breast cancers: An American Society of Clinical Oncology Guideline Adaptation of the Cancer Care Ontario Clinical Practice Guideline J Clin Oncol 2016 34 2416 27 https://doi.org/10.1200/JCO.2016.67.0182 27091714 \n14 Watanabe N Otsuka S Sasaki Y Shimojima R Wani Y Uchino K Cardiac tolerability of concurrent administration of trastuzumab and anthracycline-based regimen as adjuvant chemotherapy for breast cancer Breast Care (Basel) 2014 9 46 51 https://doi.org/10.1159/000358754 24803887 \n15 Watanabe N Otsuka S Sasaki Y Yuasa T Shimada K Retrospective analysis of cardiac tolerability of concurrent administration of trastuzumab and anthracycline-based regimen for breast cancer, to address one-year-term issues in LVEF Breast Dis 2015 35 253 61 https://doi.org/10.3233/BD-150418 26518668 \n16 Romond EH Jeong JH Rastogi P Swain SM Geyer CE Jr Ewer MS Rathi V Fehrenbacher L Brufsky A Azar CA Flynn PJ Zapas JL Polikoff J Seven-year follow-up assessment of cardiac function in NSABP B-31, a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel (ACP) with ACP plus trastuzumab as adjuvant therapy for patients with node-positive, human epidermal growth factor receptor 2-positive breast cancer J Clin Oncol 2012 30 3792 9 https://doi.org/10.1200/JCO.2011.40.0010 22987084 \n17 Ewer MS The anthracycline-trastuzumab interaction: up-regulated binding may provide vital mechanistic insight Eur J Cancer 2007 43 2024 5 https://doi.org/10.1016/j.ejca.2007.07.008 17719769 \n18 Ewer MS Lippman SM Type II chemotherapy-related cardiac dysfunction: time to recognize a new entity J Clin Oncol 2005 23 2900 2 https://doi.org/23/13/2900 15860848 \n19 Jarvinen TA Tanner M Rantanen V Barlund M Borg A Grenman S Isola J Amplification and deletion of topoisomerase IIalpha associate with ErbB-2 amplification and affect sensitivity to topoisomerase II inhibitor doxorubicin in breast cancer Am J Pathol 2000 156 839 47 10702400 \n20 Pegram M Hsu S Lewis G Pietras R Beryt M Sliwkowski M Coombs D Baly D Kabbinavar F Slamon D Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers Oncogene 1999 18 2241 51 https://doi.org/10.1038/sj.onc.1202526 10327070\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1949-2553",
"issue": "8(54)",
"journal": "Oncotarget",
"keywords": "adjuvant therapy; anthracycline; breast cancer; cardiac safety; trastuzumab",
"medline_ta": "Oncotarget",
"mesh_terms": null,
"nlm_unique_id": "101532965",
"other_id": null,
"pages": "92778-92787",
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"pmid": "29190955",
"pubdate": "2017-11-03",
"publication_types": "D016428:Journal Article",
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"title": "Concurrent administration of trastuzumab and anthracyclines as adjuvant regimen for HER2-positive breast cancer: a randomised controlled trial.",
"title_normalized": "concurrent administration of trastuzumab and anthracyclines as adjuvant regimen for her2 positive breast cancer a randomised controlled trial"
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"companynumb": "CN-MYLANLABS-2017M1077900",
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"abstract": "BACKGROUND\nAmong patients with steroid-refractory ulcerative colitis (UC) in whom a first rescue therapy has failed, a second line salvage treatment can be considered to avoid colectomy.\n\n\nOBJECTIVE\nTo evaluate the efficacy and safety of second or third line rescue therapy over a one-year period.\n\n\nMETHODS\nResponse to single or sequential rescue treatments with infliximab (5mg/kg intravenously (iv) at week 0, 2, 6 and then every 8weeks), ciclosporin (iv 2mg/kg/daily and then oral 5mg/kg/daily) or tacrolimus (0.05mg/kg divided in 2 doses) in steroid-refractory moderate to severe UC patients from 7 Swiss and 1 Serbian tertiary IBD centers was retrospectively studied. The primary endpoint was the one year colectomy rate.\n\n\nRESULTS\n60% of patients responded to the first rescue therapy, 10% went to colectomy and 30% non-responders were switched to a 2(nd) line rescue treatment. 66% of patients responded to the 2(nd) line treatment whereas 34% failed, of which 15% went to colectomy and 19% received a 3(rd) line rescue treatment. Among those, 50% patients went to colectomy. Overall colectomy rate of the whole cohort was 18%. Steroid-free remission rate was 39%. The adverse event rates were 33%, 37.5% and 30% for the first, second and third line treatment respectively.\n\n\nCONCLUSIONS\nOur data show that medical intervention even with 2(nd) and 3(rd) rescue treatments decreased colectomy frequency within one year of follow up. A longer follow-up will be necessary to investigate whether sequential therapy will only postpone colectomy and what percentage of patients will remain in long-term remission.",
"affiliations": "Department of Gastroenterology, Spital Tiefenau, Tiefenaustrasse 112, 3004 Bern, Switzerland; Division of Clinical Pharmacology and Toxicology, University Hospital Zürich, Zürich, Switzerland. Electronic address: marijana.n.protic@gmail.com.;Department of Gastroenterology, Spital Tiefenau, Tiefenaustrasse 112, 3004 Bern, Switzerland; Department of Gastroenterology, Inselspital, University Hospital Bern, Switzerland. Electronic address: Frank.Seibold@spitalnetzbern.ch.;Department of Gastroenterology and Hepatology, University Hospital Lausanne, Lausanne, Switzerland. Electronic address: alain.schoepfer@chuv.ch.;Department of Statistics, Faculty of Organizational Sciences, Belgrade, Serbia. Electronic address: zoran@fon.rs.;Department of Gastroenterology, Inselspital, University Hospital Bern, Switzerland. Electronic address: pascal.juillerat@insel.ch.;Department of Gastroenterology, University Hospital Zvezdara, Belgrade, Serbia. Electronic address: 8411112@telenormail.rs.;Division of Clinical Pharmacology and Toxicology, University Hospital Zürich, Zürich, Switzerland. Electronic address: jessica.mwinyi@usz.ch.;Department of Gastroenterology, Hospital Neuchâtel, Neuchâtel, Switzerland. Electronic address: christian.mottet@h-ne.ch.;Department of Gastroenterology, University Hospital Zvezdara, Belgrade, Serbia. Electronic address: ibd@eunet.rs.;Department of Gastroenterology, University Hospital Basel, Basel, Switzerland. Electronic address: beglinger@tmr.ch.;Department of Gastroenterology and Hepatology, Stadtspital Triemli, Zürich, Switzerland. Electronic address: stephan.vavricka@triemli.stzh.ch.;Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland. Electronic address: gerhard.rogler@usz.ch.;Department of Gastroenterology, See Spital, Horgen, Switzerland. Electronic address: pascal.frei@see-spital.ch.",
"authors": "Protic|Marijana|M|;Seibold|Frank|F|;Schoepfer|Alain|A|;Radojicic|Zoran|Z|;Juillerat|Pascal|P|;Bojic|Daniela|D|;Mwinyi|Jessica|J|;Mottet|Christian|C|;Jojic|Njegica|N|;Beglinger|Christoph|C|;Vavricka|Stephan|S|;Rogler|Gerhard|G|;Frei|Pascal|P|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D013256:Steroids; D016572:Cyclosporine; D000069285:Infliximab; D016559:Tacrolimus",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1873-9946",
"issue": "8(11)",
"journal": "Journal of Crohn's & colitis",
"keywords": "Ciclosporin; Inflammatory bowel disease; Infliximab; Tacrolimus; Ulcerative colitis",
"medline_ta": "J Crohns Colitis",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D003082:Colectomy; D003093:Colitis, Ulcerative; D016572:Cyclosporine; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D019233:Retreatment; D012189:Retrospective Studies; D016879:Salvage Therapy; D012720:Severity of Illness Index; D013256:Steroids; D016559:Tacrolimus; D017211:Treatment Failure; D055815:Young Adult",
"nlm_unique_id": "101318676",
"other_id": null,
"pages": "1427-37",
"pmc": null,
"pmid": "24908178",
"pubdate": "2014-11",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "The effectiveness and safety of rescue treatments in 108 patients with steroid-refractory ulcerative colitis with sequential rescue therapies in a subgroup of patients.",
"title_normalized": "the effectiveness and safety of rescue treatments in 108 patients with steroid refractory ulcerative colitis with sequential rescue therapies in a subgroup of patients"
} | [
{
"companynumb": "CH-JNJFOC-20141211462",
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"abstract": "Follicular dendritic cell sarcoma (FDCS) is a rare sarcoma, which commonly presents as a slow-growing, painless mass. There are only a few hundred reported FDCS cases, and the role for adjuvant chemo- or radiation therapy has not been established. Choosing an appropriate therapy in disseminated disease can therefore be challenging. A 26-year-old patient with FDCS was admitted with dyspnea, fever, and night sweats. He was found to have a large right hemothorax with compressive atelectasis on initial imaging. CT of the chest revealed multiple bilateral lung and pleural nodules with associated bilateral hilar adenopathy, a hypodense mass within the right hemithorax, and necrotic right external iliac and inguinal nodes. Inguinal node biopsy diagnosed FDCS. The patient was initially treated with cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy. Gemcitabine/Taxotere was given as second-line therapy and pembrolizumab as third-line therapy, with continued disease progression after 2 cycles of both regimens. The patient was switched to fourth-line therapy with pazopanib and had a partial response for 9 months. This case illustrates a successful FDCS treatment with pazopanib. Due to the rarity of FDCS, where large studies comparing treatment approaches are not available, recommendations for optimal treatment are not well defined. This case is in support of growing evidence suggesting that FDCS responds to systemic therapies that are used for soft tissue sarcoma, such as pazopanib.",
"affiliations": "Department of Internal Medicine, Reading Hospital, Tower Health, West Reading, Pennsylvania, USA.;Department of Internal Medicine, Reading Hospital, Tower Health, West Reading, Pennsylvania, USA.;Department of Hematology/Oncology, Reading Hospital, Tower Health, West Reading, Pennsylvania, USA.",
"authors": "Shah|Pooja|P|;Shah|Smit|S|;Agostino|Nicole|N|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000509771",
"fulltext": "\n==== Front\nCase Rep Oncol\nCase Rep Oncol\nCRO\nCase Reports in Oncology\n1662-6575 S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com \n\n10.1159/000509771\ncro-0013-1131\nCase Report\nDisease Response to Pazopanib in Follicular Dendritic Cell Sarcoma\nShah Pooja a* Shah Smit a Agostino Nicole b aDepartment of Internal Medicine, Reading Hospital, Tower Health, West Reading, Pennsylvania, USA\nbDepartment of Hematology/Oncology, Reading Hospital, Tower Health, West Reading, Pennsylvania, USA\n*Pooja Shah, Tower Health - Reading Hospital, Internal Medicine, 420 S 5th Street, West Reading PA 19611 (USA), pooja.shah@towerhealth.org\nSep-Dec 2020 \n21 9 2020 \n21 9 2020 \n13 3 1131 1135\n27 6 2020 28 6 2020 2020 Copyright © 2020 by S. Karger AG, Basel2020This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Follicular dendritic cell sarcoma (FDCS) is a rare sarcoma, which commonly presents as a slow-growing, painless mass. There are only a few hundred reported FDCS cases, and the role for adjuvant chemo- or radiation therapy has not been established. Choosing an appropriate therapy in disseminated disease can therefore be challenging. A 26-year-old patient with FDCS was admitted with dyspnea, fever, and night sweats. He was found to have a large right hemothorax with compressive atelectasis on initial imaging. CT of the chest revealed multiple bilateral lung and pleural nodules with associated bilateral hilar adenopathy, a hypodense mass within the right hemithorax, and necrotic right external iliac and inguinal nodes. Inguinal node biopsy diagnosed FDCS. The patient was initially treated with cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy. Gemcitabine/Taxotere was given as second-line therapy and pembrolizumab as third-line therapy, with continued disease progression after 2 cycles of both regimens. The patient was switched to fourth-line therapy with pazopanib and had a partial response for 9 months. This case illustrates a successful FDCS treatment with pazopanib. Due to the rarity of FDCS, where large studies comparing treatment approaches are not available, recommendations for optimal treatment are not well defined. This case is in support of growing evidence suggesting that FDCS responds to systemic therapies that are used for soft tissue sarcoma, such as pazopanib.\n\nKeywords\nFollicular dendritic cell sarcomaPazopanibKinase inhibitorsPembrolizumab\n==== Body\nIntroduction\nFollicular dendritic cell sarcoma (FDCS) is an uncommon sarcoma which most commonly presents as a slow-growing, painless mass. FDCS may easily be confused with other solid tumors. This rare sarcoma was first described by Monda's group in 1986 and is now recognized to be a low-grade sarcoma of mesenchymal dendritic cell origin. FDCS originates in antigen-presenting cells of the B-cell follicles of lymph nodes. Dendritic cells play a crucial role in the immune system, contributing to both phagocytosis and antigen processing and presentation to B and T cells [1]. FDCS has been found to have an immunophenotype distinct from other malignant histiocytic tumors. FDCS is associated with widespread chromosomal instability, dysregulation of cell cycle progression, nuclear factor-κB activation, mitogen-activated protein kinase activation, and immune evasion. The mitotic index of FDCS is usually low (0–10), and the Ki-67 is most often less than 25%. FDCS characteristically has a significant infiltrate of B and T cells, including T lymphocytes that express terminal deoxytransferase. The diagnosis of FDCS is based on tissue pathology and presence of immunohistologic markers of dendritic cells (i.e., CD21, CD23, CD35, serglycin, and follicular dendritic cell-secreted protein). FDCS has histologic features of a low-grade sarcoma, with spindle-shaped cells that contain weakly eosinophilic cytoplasm seen in a storiform or whorled pattern [2]. There have only been a few hundred reported cases of FDCS, and most cases seen have presented with localized disease. However, extranodal sites such as tonsils, lung, liver, or spleen have been described. Males and females are affected equally, and the mean age of incidence is in the fifth decade of life, although reported cases have ranged from 9 to 82 years of age [3]. Unfavorable prognostic factors include large tumors (>6 cm), significant cellular atypia, coagulative necrosis seen on pathologic slides, intra-abdominal location, and high mitotic rate (>5 mitoses in 10 high-power field) [4].\n\nCase Presentation\nWe report a 26-year-old patient with FDCS. The patient was admitted in September of 2018 with dyspnea, fever, and night sweats and was found to have a large right hemothorax with compressive atelectasis on initial imaging. CT chest revealed multiple bilateral lung and pleural nodules with associated bilateral hilar adenopathy, a thick-walled septated centrally hypodense mass within the right hemithorax, and necrotic right external iliac and inguinal nodes. Initial biopsy at our institution was negative for malignancy. Second pathology opinion at tertiary care center diagnosed FDCS. One month later, the patient was admitted for recurrent malignant right pleural effusion and underwent a VATS procedure. The VATS procedure demonstrated significant tumor infiltration and ingrowth within the entire pleural cavity. The patient was initially treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy. After 2 cycles, CT scan showed disease progression. Next generation sequencing did not show any actionable targets. Microsatellite instability was stable, and tumor mutation burden remained low. PD-L1 was negative 2+, 1%. Gemcitabine and Taxotere chemotherapy were given as second-line treatment. After 2 cycles, he once again had disease progression in all anatomic areas. Most concerning was a lytic lesion in the right femur that was a risk for pathologic fracture. He was initiated on radiation therapy to the right femur and pembrolizumab simultaneously. After 2 cycles of pembrolizumab, he had disease progression in all areas of disease except the radiation field (Fig. 1). The patient was switched to fourth-line therapy with pazopanib 800 mg daily. After 1 month of pazopanib, he had significant symptomatic improvement in his cough. He had improved exercise tolerance and decreased oxygen requirements. After 2 months of pazopanib, the patient experienced at 50–75% partial disease response (Fig. 2). A partial response was sustained for 9 months before disease progression occurred in the lungs. After pazopanib, the patient received sunitinib, ifosfamide/carboplatin/etoposide chemotherapy and cabozantinib with short interval progression on all therapies. At the time of this reporting, hospice discussions are taking place.\n\nDiscussion\nDue to the rarity of FDCS, large studies comparing treatment approaches are not available, and thus recommendations for optimal treatment are not well defined. The primary treatment of localized FDCS is surgical resection. A role for adjuvant therapy has not been established for either radiation therapy or chemotherapy [5]. FDCS usually has an indolent course, but 50% of patients develop local recurrence. An aggressive course is possible as well, with metastases to the lung, liver, and lymph nodes. Growing evidence suggests that FDCS responds to systemic therapies that are used for soft tissue sarcoma.\n\nLymphoma regimens such as CHOP and ABVD have been used to treat FDCS with variable outcomes. Other lymphoma-based regimens such as ifosfamide, carboplatin, and etoposide (ICE) have also been employed in cases of FDCS with outcomes similar to CHOP [6]. A case review of 50 cases by Wang et al. [7] showed no recurrence of disease in 80% patients in which CHOP therapy was used after excision of the sarcoma.\n\nSarcoma-based regimens such as gemcitabine and Taxotere as well as Adriamycin, ifosfamide, and mesna have also been used with success in FDCS. There have been several case reports of FDCS that show that therapy with gemcitabine in combination with a taxane (paclitaxel or docetaxel) have been successful [6]. A study of 46 patients with FDCS in which different chemotherapy agents were used, gemcitabine and Taxotere combination therapy showed the best outcomes. Among patients who received gemcitabine and Taxotere with/without other modalities, 42% (5/12) were complete responders, 41% were partial responders (5/12), and 2 patients were non-responders. In the 10 responders, 6 patients had surgery prior to chemotherapy, 3 had radiotherapy, and 1 had chemotherapy alone [8].\n\nA second study of 66 patients with FDCS who were treated with chemotherapy (gemcitabine and a taxane, CHOP-based, or ifosfamide-based) in non-resectable disease, showed an overall response rate of 80% (including complete response and partial response) in gemcitabine + taxane therapy, 100% partial response with ifosfamide-based therapy, and 50% partial response in CHOP-based therapy. The median duration of response with gemcitabine and docetaxel in particular was 13.4 months [9]. This study agreed with other cases that showed favorable outcomes with the combination of gemcitabine and docetaxel. Common factors in the patients who did not respond were bulky and/or intra-abdominal disease, as seen in our patient.\n\nPembrolizumab is a highly selective anti-programmed cell death-1 humanized monoclonal antibody which inhibits programmed cell death-1 (PD-1) activity by binding to the PD-1 receptor on T cells. Anti-PD-1 antibodies (including pembrolizumab) reverse T-cell suppression and induce antitumor responses [10]. In patients with undifferentiated pleomorphic sarcoma, pembrolizumab showed encouraging activity. In a phase 2, two-cohort, single-arm, open-label study, patients with soft tissue sarcoma or bone sarcoma were enrolled. Out of the 40 patients enrolled, 7 (18%) had an objective response including 4 (40%) of 10 patients with undifferentiated pleomorphic sarcoma and 2 (20%) of 10 patients with liposarcoma (LPS). PD-L1 expression was not assessed in this study [11].\n\nPazopanib is a tyrosine kinase inhibitor that inhibits angiogenesis by inhibiting various cell surface receptors. It has been approved to treat renal cell carcinomas and soft tissue sarcomas, especially in patients who have advanced soft tissue sarcomas (aSTS) and have received prior chemotherapy. Several studies have shown pazopanib to be effective in treating aSTS. In a landmark phase 3 randomized study, the PALETTE trial, pazopanib was compared with placebo in patients with aSTS whose disease had progressed during or following prior chemotherapy. Longer median progression-free survival (mPFS) of 4.6 months (pazopanib) versus 1.6 months (placebo) was observed. The overall response rate was low at 6% for pazopanib versus 0% for placebo [12]. Another prospective single-arm phase 2 study showed further evidence of efficacy of pazopanib in LPS, leiomyosarcomas, synovial sarcomas, and an “other” group of less common sarcomas. Unfortunately, FDCS was not in this less common group. This multicenter study treated patients with intermediate or high-grade LPS with pazopanib and reported an mPFS of 4.4 months and an overall survival of 12.6 months [13]. These findings were consistent with the data for other STS subtypes that were studied in the PALETTE trial. There are ongoing studies to find predictive biomarkers for use in selecting patients with aSTS for pazopanib, but there is no clinically validated data at present. This unfortunately limits the clinical effectiveness and cost-effectiveness of the therapy [14].\n\nIn conclusion, there are several therapies that have been proven to be efficacious in treating aSTS. Because of the rarity of FDCS, however, there are still no treatment guidelines, and the data from therapies for aSTS must be extrapolated when treating FDCS. In the case presented above, chemotherapy-based treatments were initially given with progression of disease. Pazopanib, shown in several studies to have significant efficacy in advanced and aggressive soft tissue sarcomas, yielded significant regression of the tumor along with clinical improvement after just a few weeks of therapy. At the time of this writing, the patient had completed 9 months of therapy with pazopanib before showing progression on imaging studies. He was treated with sunitinib, ICE chemotherapy, and cabozantinib, unfortunately showing progression through all therapies. Hospice discussions are ongoing.\n\nStatement of Ethics\nThe subject of the above case report has given their express permission in the form of written informed consent to publish their case, including publication of images.\n\nConflict of Interest Statement\nThe authors have no conflicts of interest to declare.\n\nFunding Sources\nNo funding sources were used in this case report.\n\nAuthor Contributions\nPooja Shah − written contribution. Smit Shah − written contribution. Nicole Agostino − access to case file, treatment modalities, written contribution.\n\nFig. 1 CT chest with contrast status after pembrolizumab (03/2019), continued disease progression.\n\nFig. 2 CT chest with contrast status after 2 months of pazopanib (05/2019), significant disease regression.\n==== Refs\nReferences\n1 Perez-Ordonez B Erlandson RA Rosai J Follicular dendritic cell tumor: report of 13 additional cases of a distinctive entity Am J Surg Pathol 1996 20 (8) 944 55 8712294 \n2 Wang RF Han W Qi L Shan LH Wang ZC Wang LF Extranodal follicular dendritic cell sarcoma: A clinicopathological report of four cases and a literature review Oncol Lett 2015 9 (1) 391 8 25435998 \n3 Shahryari J Ohgami RS Follicular dendritic cell sarcoma Atlas Genet Cytogenet Oncol Hematol 2017 21 (9) 324 6 \n4 Dalia S Shao H Sagatys E Cualing H Sokol L Dendritic cell and histiocytic neoplasms: biology, diagnosis, and treatment Cancer Control 2014 21 (4) 290 300 25310210 \n5 Miyoshi R Sonobe M Miyamoto E Date H Completely resected follicular dendritic cell sarcoma of the posterior mediastinum: report of a case Surg Case Rep 2016 2 (1) 28 27001632 \n6 Jain P Milgrom SA Patel KP Nastoupil L Fayad L Wang M Characteristics, management, and outcomes of patients with follicular dendritic cell sarcoma Br J Haematol 2017 8 178 (3) 403 12 28382648 \n7 Wang H Su Z Hu Z Wen J Liu B Follicular dendritic cell sarcoma: a report of six cases and a review of the Chinese literature Diagn Pathol 2010 5 (1) 67 6 20937101 \n8 Jain P Patel KP Futreal A Gumbs C Hu S Bueso Ramos C Clinico-pathological characteristics, treatments and outcomes of patients with dendritic cell sarcoma (DS) Blood. 2015 126 (23) 2700 \n9 Conry RM Response of follicular dendritic cell sarcoma to gemcitabine and docetaxel: report of two cases and literature review Clin Sarcoma Res 2014 Jun 28 4 6 25009738 \n10 Robert C Ribas A Wolchok JD Hodi FS Hamid O Kefford R Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial Lancet 2014 384 (9948) 1109 17 25034862 \n11 Tawbi HA Burgess M Bolejack V Van Tine BA Schuetze SM Hu J Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial Lancet Oncol 2017 11 18 (11) 1493 501 28988646 \n12 Cesne AL Bauer S Demetri GD Han G Dezzani L Ahmad Q Safety and efficacy of Pazopanib in advanced soft tissue sarcoma: PALETTE (EORTC 62072) subgroup analyses BMC Cancer 2019 Aug 13 19 (1) 794 31409302 \n13 Sleijfer S Ray-Coquard I Papai Z Le Cesne A Scurr M Schöffski P Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European organisation for research and treatment of cancer-soft tissue and bone sarcoma group (EORTC study 62043) J Clin Oncol 2009 Jul 1 27 (19) 3126 32 19451427 \n14 Lee ATJ Jones RL Huang PH Pazopanib in advanced soft tissue sarcomas Signal Transduct Target Ther 2019 May 17 4 16 31123606\n\n",
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"issn_linking": "1662-6575",
"issue": "13(3)",
"journal": "Case reports in oncology",
"keywords": "Follicular dendritic cell sarcoma; Kinase inhibitors; Pazopanib; Pembrolizumab",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
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"other_id": null,
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"title": "Disease Response to Pazopanib in Follicular Dendritic Cell Sarcoma.",
"title_normalized": "disease response to pazopanib in follicular dendritic cell sarcoma"
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... |
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"abstract": "OBJECTIVE\nNeuromyelitis optica (NMO) is characterized by disabling relapses of optic neuritis and myelitis and the presence of aquaporin 4 antibodies (AQP4-abs). Interleukin 6, which is significantly elevated in serum and cerebrospinal fluid of patients with NMO, induces AQP4-ab production by plasmablasts and represents a novel therapeutic target.\n\n\nOBJECTIVE\nTo evaluate the long-term safety and efficacy of tocilizumab, a humanized antibody targeting the interleukin 6 receptor, in NMO and NMO spectrum disorder.\n\n\nMETHODS\nRetrospective observational study with 10 to 51 months of follow-up between December 2010 and February 2015, in neurology departments at tertiary referral centers. Participants were 8 female patients of white race/ethnicity with highly active AQP4-ab-seropositive NMO (n = 6) and NMO spectrum disorder (n = 2) whose disease had been resistant to previous medications, including B-cell depletion, and who switched to tocilizumab (6-8 mg/kg of body weight per dose).\n\n\nMETHODS\nAnnualized relapse rate, Expanded Disability Status Scale score, spinal cord and brain magnetic resonance imaging, AQP4-ab titers, pain levels (numerical rating scale), and adverse effects.\n\n\nRESULTS\nPatients were followed up for a mean (SD) of 30.9 (15.9) months after switching to tocilizumab. Two of eight patients received add-on therapy with monthly corticosteroid pulses (temporary) or azathioprine, respectively. During tocilizumab treatment, the median annualized relapse rate significantly decreased from 4.0 (interquartile range, 3.0-5.0) in the year before tocilizumab therapy to 0.4 (interquartile range, 0.0-0.8) (P = .008), and the median Expanded Disability Status Scale score significantly decreased from 7.3 (interquartile range, 5.4-8.4) to 5.5 (interquartile range, 2.6-6.5) (P = .03). Active magnetic resonance imaging lesions were seen in 6 of 8 patients at tocilizumab initiation and in 1 of 8 patients at the last magnetic resonance imaging. Three patients remained relapse free during tocilizumab treatment. In 5 patients, a total of 8 relapses occurred, 4 within the first 2½ months of therapy. Five attacks were associated with delayed tocilizumab administration (≥40 days), and 6 attacks were associated with reduced tocilizumab dosage (6 vs 8 mg/kg). The AQP4-ab titers (P = .02) and pain levels (P = .02) dropped significantly during tocilizumab treatment. Adverse effects included moderate cholesterol elevation in 6 of 8 patients, infections in 4 of 8 patients, and deep venous thrombosis and neutropenia in one patient each.\n\n\nCONCLUSIONS\nProlonged tocilizumab therapy may be safe and effective from early treatment phases onward for otherwise therapy-resistant highly active NMO and NMO spectrum disorder. Relapse patterns indicate that adherence to a regular therapeutic regimen with monthly infusions of tocilizumab (8 mg/kg) may increase efficacy.",
"affiliations": "Department of Neurology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.;Department of Neurology, St Josef Hospital, Ruhr University Bochum, Bochum, Germany.;Department of Neurology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.;Deutschen Klinik für Diagnostik Helios Klinik Wiesbaden, Wiesbaden, Germany.;Deutschen Klinik für Diagnostik Helios Klinik Wiesbaden, Wiesbaden, Germany.;Department of Neurology, Clinic Osnabrück, Osnabrück, Germany.;Department of Neurology, St Josef Hospital, Ruhr University Bochum, Bochum, Germany.;Department of Neurology, St Josef Hospital, Ruhr University Bochum, Bochum, Germany.;Department of Neurology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.;Department of Neurology, St Josef Hospital, Ruhr University Bochum, Bochum, Germany.;Department of Neurology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.;Department of Neurology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.;Department of Neurology, St Josef Hospital, Ruhr University Bochum, Bochum, Germany.;Department of Neurology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.;Department of Neurology, St Josef Hospital, Ruhr University Bochum, Bochum, Germany.",
"authors": "Ringelstein|Marius|M|;Ayzenberg|Ilya|I|;Harmel|Jens|J|;Lauenstein|Ann-Sophie|AS|;Lensch|Eckart|E|;Stögbauer|Florian|F|;Hellwig|Kerstin|K|;Ellrichmann|Gisa|G|;Stettner|Mark|M|;Chan|Andrew|A|;Hartung|Hans-Peter|HP|;Kieseier|Bernd|B|;Gold|Ralf|R|;Aktas|Orhan|O|;Kleiter|Ingo|I|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D019947:Receptors, Interleukin-6; C502936:tocilizumab",
"country": "United States",
"delete": false,
"doi": "10.1001/jamaneurol.2015.0533",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2168-6149",
"issue": "72(7)",
"journal": "JAMA neurology",
"keywords": null,
"medline_ta": "JAMA Neurol",
"mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008875:Middle Aged; D009471:Neuromyelitis Optica; D019947:Receptors, Interleukin-6; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "101589536",
"other_id": null,
"pages": "756-63",
"pmc": null,
"pmid": "25985228",
"pubdate": "2015-07",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Long-term Therapy With Interleukin 6 Receptor Blockade in Highly Active Neuromyelitis Optica Spectrum Disorder.",
"title_normalized": "long term therapy with interleukin 6 receptor blockade in highly active neuromyelitis optica spectrum disorder"
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"companynumb": "DE-MYLANLABS-2019M1028266",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "TOCILIZUMAB"
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"abstract": "Klebsiella pneumoniae (K. pneumoniae, KP) are divided into two types: classic K. pneumoniae (cKP) and hypervirulent K. pneumoniae (hvKP). hvKP causes liver abscess and metastatic infection. Here, we report one case with pyogenic liver abscess (PLA) and endogenous endophthalmitis (EE) due to a relatively rarely reported serotype of K. pneumoniae in China.\nAn 80-year old man presented with nausea, vomiting, and epigastric discomfort for 2 weeks.\nPLA was identified by CT scan and abdominal ultrasound. Urgent ophthalmologic consultation was performed. B-scan ocular ultrasound was done and he was diagnosed as EE.\nAntibiotic treatment, intravitreal injection of eyes and eye drops were given. Percutaneous needle aspiration, evisceration, and drainage of the right eye were performed.\nCultures of the blood, the aspirated pus from the liver abscess, and the contents of the eyeball all yielded K. pneumoniae with a positive string test. The capsular serotype was K64. According to the existence of multiple virulence genes and the severe invasive clinical manifestation, this strain is regarded as a hvKp strain. Multilocus sequence typing (MLST) revealed the sequence type (ST) of this strain was K64-ST1764. Antimicrobial resistance genes, bla NDM-1 and bla KPC-2, were not detected in the genome. The patient lost his eyesight but his symptoms subsided. During 15 months follow-up, the result was satisfactory.\nHere, we report one case with PLA due to a relatively rarely reported serotype of K. pneumoniae in China. This K64 K. pneumoniae strain is confirmed as hvKp by multiple methods. It is noteworthy that the sequence type is K64-ST1764 instead of the commonest ST11. Moreover, this strain is not considered a K. pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp) or a carbapenem-resistant K. pneumoniae (CRKP) as it is usually. Further follow-up and research are required to investigate this strain.",
"affiliations": "Department of Gastroenterology, The Affiliated Wuxi Second People's Hospital of Nanjing Medical University, Wuxi, People's Republic of China.;Department of Clinical Laboratory, The Affiliated Wuxi Second People's Hospital of Nanjing Medical University, Wuxi, People's Republic of China.;Department of Gastroenterology, The Affiliated Wuxi Second People's Hospital of Nanjing Medical University, Wuxi, People's Republic of China.;Department of Gastroenterology, The Affiliated Wuxi Second People's Hospital of Nanjing Medical University, Wuxi, People's Republic of China.;Department of Gastroenterology, The Affiliated Wuxi Second People's Hospital of Nanjing Medical University, Wuxi, People's Republic of China.;Department of Gastroenterology, The Affiliated Wuxi Second People's Hospital of Nanjing Medical University, Wuxi, People's Republic of China.",
"authors": "Zhao|Bo|B|;Hu|Renjing|R|0000-0001-6631-1643;Gong|Lei|L|;Wang|Xiaoyun|X|;Zhu|Yingwei|Y|;Wu|Gaojue|G|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/IDR.S289088",
"fulltext": "\n==== Front\nInfect Drug Resist\nInfect Drug Resist\nidr\nidr\nInfection and Drug Resistance\n1178-6973 Dove \n\n289088\n10.2147/IDR.S289088\nCase Report\nPyogenic Liver Abscess and Endogenous Endophthalmitis Due to K64-ST1764 Hypervirulent Klebsiella pneumoniae: A Case Report\nZhao et alZhao et alZhao Bo 1* http://orcid.org/0000-0001-6631-1643Hu Renjing 2* Gong Lei 1 Wang Xiaoyun 1 Zhu Yingwei 1 Wu Gaojue 1 1 Department of Gastroenterology, The Affiliated Wuxi Second People’s Hospital of Nanjing Medical University, Wuxi, People’s Republic of China\n2 Department of Clinical Laboratory, The Affiliated Wuxi Second People’s Hospital of Nanjing Medical University, Wuxi, People’s Republic of China\nCorrespondence: Xiaoyun Wang Department of Gastroenterology, The Affiliated Wuxi Second People’s Hospital of Nanjing Medical University, Wuxi, People’s Republic of ChinaTel +86 15061857125Fax +86 510 685662052 Email xiaoyunwang68@aliyun.com* These authors contributed equally to this work\n\n\n12 1 2021 \n2021 \n14 71 77\n28 10 2020 09 12 2020 © 2021 Zhao et al.2021Zhao et al.This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Rationale\nKlebsiella pneumoniae (K. pneumoniae, KP) are divided into two types: classic K. pneumoniae (cKP) and hypervirulent K. pneumoniae (hvKP). hvKP causes liver abscess and metastatic infection. Here, we report one case with pyogenic liver abscess (PLA) and endogenous endophthalmitis (EE) due to a relatively rarely reported serotype of K. pneumoniae in China.\n\nPatient Concerns\nAn 80-year old man presented with nausea, vomiting, and epigastric discomfort for 2 weeks.\n\nDiagnoses\nPLA was identified by CT scan and abdominal ultrasound. Urgent ophthalmologic consultation was performed. B-scan ocular ultrasound was done and he was diagnosed as EE.\n\nInterventions\nAntibiotic treatment, intravitreal injection of eyes and eye drops were given. Percutaneous needle aspiration, evisceration, and drainage of the right eye were performed.\n\nOutcomes\nCultures of the blood, the aspirated pus from the liver abscess, and the contents of the eyeball all yielded K. pneumoniae with a positive string test. The capsular serotype was K64. According to the existence of multiple virulence genes and the severe invasive clinical manifestation, this strain is regarded as a hvKp strain. Multilocus sequence typing (MLST) revealed the sequence type (ST) of this strain was K64-ST1764. Antimicrobial resistance genes, blaNDM-1 and blaKPC-2, were not detected in the genome. The patient lost his eyesight but his symptoms subsided. During 15 months follow-up, the result was satisfactory.\n\nLessons\nHere, we report one case with PLA due to a relatively rarely reported serotype of K. pneumoniae in China. This K64 K. pneumoniae strain is confirmed as hvKp by multiple methods. It is noteworthy that the sequence type is K64-ST1764 instead of the commonest ST11. Moreover, this strain is not considered a K. pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp) or a carbapenem-resistant K. pneumoniae (CRKP) as it is usually. Further follow-up and research are required to investigate this strain.\n\nKeywords\ncase reporthypervirulent Klebsiella pneumoniaepyogenic liver abscessantibiotic resistanceultrasonography guided puncture aspirationthe National Natural Science Foundation of ChinaFoundation for Key Medical Talents in Jiangsu ProvinceSix Talent Peaks Project of Jiangsu ProvinceSix One Top-notch Talent Project of Jiangsu ProvinceThis work was supported by the National Natural Science Foundation of China No.81500467, Foundation for Key Medical Talents in Jiangsu Province No.QNRC2016151, Six Talent Peaks Project of Jiangsu Province No.WSN-220, Six One Top-notch Talent Project of Jiangsu Province No.LGY201701. The funders had no role in the study design, conduct, analysis, interpretation of study results, decision to publish, or preparation of the manuscript. No additional external funding was received for this study.\n==== Body\nIntroduction\nPLA is a potentially life-threatening disease which is mainly caused by bacteria. Along with the increasing prevalence of hvKp, PLA due to K. pneumoniae has been steadily increasing. K. pneumoniae are divided into two types: cKP and hvKP.1 Ckp is an opportunistic pathogen which mainly infects immunodeficient patients or the immunocompromised population. HvKP can infect young healthy people without underlying diseases.2 Increased virulence of hvkp is related to its hypermucoviscous phenotype and stronger ability of iron acquisition.3,4 HvKP often causes primary liver abscess and metastatic infections like endophthalmitis, meningitis, and so on.5 HvKP infections are more common in the Asian Pacific but now are occurring globally.\n\nHere we report one case who presented in China with PLA and EE due to a relatively rarely reported serotype of hvKP. Different from previous reports, the ST of this strain was K64-ST1764 instead of the commonest ST11. It is especially noteworthy that antimicrobial susceptibility testing showed that this strain was sensitive to all antibiotics, which means it is not a KPC-Kp or a CRKP.\n\nCase Presentation\nAn 80-year old Chinese male patient presented to the emergency department with nausea, vomiting, and epigastric discomfort for 2 weeks without treatment. This patient had a history of Type II diabetes mellitus, hypertension, and coronary heart disease. There was no relevant family history or history of genetic disease. Laboratory investigations revealed a white cell count 14.42×109 cells/L (normal range=3.5–9.5×109 cells/L), 85% neutrophils (normal range=40–75%), aspartate transaminase (AST) 109 U/L (normal range<50 U/L), lactate dehydrogenase (LDH) 349 U/L (normal range=109–245 U/L), random blood glucose 19.96 mmol/L (normal range=3.8–6.2 mmol/L), blood urea 11.3 mmol/L (normal range=2.1–8.6 mmol/L), creatinine 141.7 µmol/L (normal range=35.2–97.5 μmol/L). Severe infection and ketoacidosis were suspected so emergency doctors gave him antibiotics (imipenem combined with ornidazole), rabeprazole, antiemetic drug, and fluid infusion, but his condition worsened. Fever appeared and the highest armpit temperature was 39°C.\n\nHe was admitted to the Department of Gastroenterology for further treatment. Laboratory investigations revealed C-reactive protein 439.43 mg/L (normal range<10 mg/L), serum sodium (Na) 133.9 mmol/L (normal range=136–145 mmol/L), serum potassium (K) 3.71 mmol/L (normal range=3.5–5.3 mmol/L), total bilirubin 21 μmol/L (normal range=3.4–20.6 μmol/L), and alanine aminotransferase (ALT) 88.6 U/L (normal range<50 U/L). Physical examination revealed mild epigastric tenderness. A right lobe liver abscess was identified on CT scan (Figure 1). Abdominal ultrasound showed a right lobe liver abscess (mixed echoes) with the size of 3.5×2.7 cm in the right liver lobe (Figure 2).Figure 1 Abdominal CT scan showed a right lobe liver abscess (rounded, low density areas).\n\nFigure 2 Abdominal ultrasound showed a right lobe liver abscess (mixed echoes, with a size of 3.5cm×2.7 cm).\n\n\n\nThe patient was treated by anti-infection treatment (biapenem and morinidazole by intravenous injection), liver protection (polyene phosphatidylcholine), decreasing blood sugar, controlling blood pressure, and fluid infusion. Ultrasonography guided puncture aspiration for hepatic abscess was proposed but he refused. Both his white cell count and C-reactive protein were dropped after treatment but he was still feverish. Bacteria culturing and antimicrobial susceptibility testing were performed by using the VITEK-II Compact automated microbiological system and confirmed by using the broth microdilution method. Blood cultures, from both aerobic and anaerobic bottles, showed K. pneumoniae which was sensitive to all antibiotics.\n\nThe vision of this patient became blurred so urgent ophthalmologic consultation was performed. A B-scan ocular ultrasound was done and he was diagnosed as EE with bad prognosis. Intravitreal injection (vancomycin and cefoperazone) of eyes and eye drops were given. Finally, after obtaining the patient’s consent, ultrasonography guided puncture aspiration was performed, which resulted in lowering the temperature and improving the inflammatory marker levels. Liver aspirate culture was also positive for K. pneumoniae and sensitive to all antibiotics (Table 1). The patient’s eyes were swollen and empyema and the light perception of both eyes was basically lost. The ophthalmologist performed evisceration and drainage of the right eye, as well as repeated intravitreal injection of the left eye. Abdominal ultrasonography was performed 6 days after the first therapeutic puncture. The abscess cavity decreased conspicuously and the second percutaneous needle aspiration was given. After treatment, the patient’s eye swelling and the empyema was significantly improved and he became afebrile. He was given ceftriaxon 2 g by intravenous injection once a day for 4 weeks. Repeated blood cultures were negative and ultrosound reexamination showed the abscess cavity had disappeared. He was discharged and referred to the gastroenterology clinic for follow-up. During 15 months follow-up, the result was satisfactory.Table 1 Antimicrobial Susceptibility Testing Results for K. Pneumoniae Isolate, Using Reference Broth Microdilution According to Clinical and Laboratory Standards Institute (CLSI) Guidelines\n\nAntimicrobial Agent\tMinimum Inhibitory Concentration (µg/mL)\tInterpretation*\t\nAmikacin\t≤2\tS\t\nAmpicillin\t>32\tS\t\nAztreonam\t≤1\tS\t\nCeftriaxone\t≤1\tS\t\nCeftazidime\t≤1\tS\t\nCefepime\t≤1\tS\t\nCiprofloxacin\t≤0.25\tS\t\nGentamicin\t≤1\tS\t\nImipenem\t≤1\tS\t\nLevofloxacin\t≤0.25\tS\t\nErtapenem\t≤0.5\tS\t\nPiperacillin-Tazobactam\t≤4\tS\t\nTigecycline\t0.5\tS\t\nNotes: *Interpretative criteria were applied according to CLSI document M100 (Performance Standards for Antimicrobial Susceptibility Testing. 28th ed. 2018) except for tigecycline where criteria established by the US Food and Drug Administration were used.\n\nAbbreviations: R, resistant; S, susceptible.\n\n\n\n\nIsolates were retested by 16S rRNA gene sequences as previously reported6 and K. pneumoniae was identified and reconfirmed.\n\nString test was performed as previously reported.2 The colony was grown at 37°C overnight on a sheep blood agar plate and then stretched by a bacteriology inoculation loop. A positive result is defined as the formation of a string >5 mm in length. Cultures of the blood, the aspirated pus from the liver abscess, and the contents of the eyeball all yielded K. pneumoniae with a positive string test (Figure 3).Figure 3 All cultures yielded K. pneumoniae with a positive string test (>5mm in string length).\n\n\n\nCapsular serotype of each isolate was performed by polymerase chain reaction (PCR) as previously reported.7 PCR analysis indicated that the capsular serotype of the isolated K. pneumoniae was K64, which was validated by wzi sequencing as described.8\n\nMLST was performed by PCR amplification as previously reported9 and this strain belongs to ST1764.\n\nMultiple biomarkers, including peg-344 (+), iroB (+), iucA (+), prmpA (+), prmpA2 (+), crmpA (-), ureA (+), uge (+), wabG (+), allS (+), mrkD (+), and fimH (+) were detected by PCR as described10 and multiple virulence genes were found in all the above isolates.\n\nScreening for carbapenemase genes was performed by PCR as described11 and blaNDM-1 and blaKPC-2 were not found in this K64 strain.\n\nWe evaluated the virulence of this K. pneumoniae strain in a Galleria mellonella infection model.12 We infected the Galleria mellonella larvae with different concentrations (102~108 colony-forming units/mL) of K. pneumoniae and recorded the survival rate (Figure 4). This strain showed a strong concentration-dependent lethality to the larvae.Figure 4 Survival curves for Galleria mellonella larvae inoculated with different concentrations (102~108 colony-forming units/mL) of the K. pneumoniae strain.\n\n\n\nDiscussion and Conclusions\nThe first clinical report about hvKp was in Taiwan in 1986.13 Although it is more common in the Asia-Pacific region, infections due to hvKp have gradually become global.14,15 Because hvKP was considered to have a hypermucoviscosity phenotype, the string test has been used to defining hvKP.3 However, more and more studies have shown that hypermucoviscosity is not pathognomonic for hvKp since this phenotype also can be observed in cKp strains.16 Recently, several virulence genes, like iuc, peg-344, rmpA, and rmpA2, have been shown to most accurately predict hvKp strains.16\n\nSince the 1980s, PLA due to K. pneumoniae has been steadily increasing. Especially in the Asia-Pacific region, hvKP has already become the predominant pathogen of PLA.17–19 Furthermore, these infections are occurring globally. A study in China has reported that among all PLA cases, K pneumonia was the most common pathogen and a higher incidence of diabetes mellitus was shown in patients with K. pneumoniae-induced PLA.20 Another study has reported that most of the liver abscesses were caused by K. pneumoniae and mostly occurred in patients with diabetes mellitus.21 The major clinical features of KP-PLA are fever, nausea, vomiting, abdominal discomfort, and laboratory inspection shows elevated white blood cell count and liver dysfunction. In this patient, all the above features can be found.\n\nThere are mainly three treatment methods: appropriate early antibiotic treatment, ultrasonography guided puncture aspiration or draining treatment, and open surgical drainage or surgical resection of the liver abscesses. We initially treated the patient with carbapenems and Morinidazole. After the condition stabilized, the antibiotics were changed to ceftriaxone for another 4 weeks. Some studies have suggested that the majority of PLA cases require drainage.22 A report showed that antimicrobial therapy alone was effective for small abscesses, while percutaneous needle aspiration or draining should be chosen for larger abscesses.23 A study reported that liver abscesses due to K. pneumoniae that were >5 cm were likely to have a delayed response to therapy.24 In the present study, the liver abscess was <5 cm (35×27 mm) and this hvKP strain was sensitive to all antibiotics. Even so, early antimicrobial therapy alone was ineffective. Once aspiration was performed, clinical improvement was observed. This suggested that, even for small abscesses, puncture or drainage should be performed as early as possible when the effect of drug therapy is unsatisfactory.\n\nIn recent years, the incidence of EE has gradually increased. Gram-positive bacteria and fungal organisms account for the majority of the cases in the developed world, whereas gram-negative organisms like K. pneumoniae are more common in the Asia-Pacific region.25 Now it has become a frequent complication: approximately 5% of individuals with hvKp bacteremia ultimately develop EE.26\n\nEE is a common metastatic complication of K. pneumoniae liver abscess.27 Diabetes mellitus was considered to be a significant risk factor. The prognosis of EE is generally poor even with prompt diagnosis and aggressive treatment given. The final visual outcome was only light perception or worse in 89% of patients with EE associated with K. pneumoniae-induced PLA.27 Diabetes mellitus and poor initial visual acuity were associated with poor visual outcome.28 Reports showed that the main prognostic factor in Klebsiella EE is the presence of hypopyon which can be found in our patient.29 This patient lost his eyesight.\n\nIt has long been recognized that almost all patients with severe infection with liver abscess and extrahepatic infections are infected exclusively with K. pneumoniae serotypes K1 or K2.2 However, it is clear now that non-K1/K2 hvKp strains can express virulence genes and are capable of causing liver abscess and metastatic spread.16,30 The serotype of the isolated K. pneumoniae strain in our patient was K64, a relatively rarely reported serotype. This serotype has always been considered a cKP. But it is recently recognized that K64 is predicted to be observed for hvKp strains.31,32 Recent research finds that some cKp strains can acquire the hvKp virulence plasmid and evolve into hvKp strains.12,32 Our K64 K. pneumoniae strain showed strong virulence in the Galleria mellonella infection model. According to positive string test, the existence of multiple virulence genes, the strong lethality to the larvae and the severe invasive clinical manifestation of its infection, we can regard this K64 strain as a hvKp strain. Compared to the classification based on string test alone, our method is more reasonable.\n\nIn particular, ST was determined by MLST and the result was K64-ST1764 instead of the commonest ST11, which was considered to be predominant in Extended-Spectrum β-lactamases (ESBL)-producing strains and was prevalent in CRKP strains.33,34 However, previous reports showed that ST11 was predominant in K64 capsular type, hence K64 was considered as a prevalent type of CRKP.35–38 Furthermore, blaNDM-1 and blaKPC-2, two important carbapenemase genes, were not found in this K64 strain and antimicrobial susceptibility testing showed that it was sensitive to all antibiotics. Contrary to previous studies,31,32,36,39 these findings indicated that this K64 strain is not a KPC-Kp or a CRKP strain.\n\nIn conclusion, here we report one patient with PLA and EE due to a relatively rarely reported serotype of K. pneumoniae: K64. As the existence of multiple virulence genes, the strong lethality to the larvae and the severe invasive clinical manifestation and positive string test, this K64 K. pneumoniae can be regarded as a hvKp strain. Different from previous reports, the ST of this strain was K64-ST1764 instead of the commonest ST11. It is not a KPC-Kp or a CRKP, either. Further follow-up and research are required to investigate this strain.\n\nAcknowledgments\nThe key discipline of Wuxi No.ZDXK002 Workstation of academician Fan Daiming No.CYR1705\n\nAbbreviations\nCRKP, carbapenem-resistant K. pneumoniae; cKP, classic K. pneumoniae; ESBL, extended-spectrum β-lactamases; hvKP, hypervirulent K. pneumoniae; KPC-Kp, K. pneumoniae carbapenemase (KPC)-producing ; MLST, multilocus sequence typing; PLA, pyogenic liver abscess; ST, sequence type.\n\nData Sharing Statement\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nEthics Approval\nThis case report was approved by the ethics committee of The Affiliated Wuxi Second People’s Hospital of Nanjing Medical University.\n\nConsent for Publication\nWritten informed consent for publication of his clinical details and clinical images was obtained from the patient.\n\nAuthor Contributions\nBo Zhao and Renjing Hu have contributed equally to this work and they are co-first authors. Conceived the study: Xiaoyun Wang, Bo Zhao; Acquired data, analyzed data: Bo Zhao, Renjing Hu; Performed the microbiological analysis: Renjing Hu; Wrote the manuscript: Bo Zhao; Contributed reagents/materials/analysis tools: Lei Gong, Xiaoyun Wang; and Revised the manuscript: Xiaoyun Wang, Yingwei Zhu, Gaojue Wu.\n\nAll authors made substantial contributions to the conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.\n\nDisclosure\nThe authors declare that they have no conflicts of interest to this work.\n==== Refs\nReferences\n1. Shon \nAS , Bajwa \nRP , Russo \nTA . Hypervirulent (hypermucoviscous) Klebsiella pneumoniae: a new and dangerous breed\n. Virulence . 2013 ;4 (2 ):107 –118\n. doi:10.4161/viru.22718 23302790 \n2. Siu \nLK , Yeh \nK-M , Lin \nJ-C , Fung \nC-P , Chang \nF-Y . Klebsiella pneumoniae liver abscess: a new invasive syndrome\n. Lancet Infect Dis . 2012 ;12 (11 ):881 –887\n. doi:10.1016/S1473-3099(12)70205-0 23099082 \n3. Fang \nCT , Chuang \nYP , Shun \nCT , Chang \nSC , Wang \nJT . A novel virulence gene in Klebsiella pneumoniae strains causing primary liver abscess and septic metastatic complications\n. J Exp Med . 2004 ;199 (5 ):697 –705\n. doi:10.1084/jem.20030857 14993253 \n4. Huang \nYH , Chou \nSH , Liang \nSW , et al. Emergence of an XDR and carbapenemase-producing hypervirulent Klebsiella pneumoniae strain in Taiwan\n. J Antimicrob Chemother . 2018 ;73 (8 ):2039 –2046\n. doi:10.1093/jac/dky164 29800340 \n5. Shon \nAS , Russo \nTA . Hypervirulent Klebsiella pneumoniae: the next superbug?\n\nFuture Microbiol . 2012 ;7 (6 ):669 –671\n. doi:10.2217/fmb.12.43 22702521 \n6. He \nY , Guo \nX , Xiang \nS , et al. Comparative analyses of phenotypic methods and 16S rRNA, khe, rpoB genes sequencing for identification of clinical isolates of Klebsiella pneumoniae\n. Antonie Van Leeuwenhoek . 2016 ;109 (7 ):1029 –1040\n. doi:10.1007/s10482-016-0702-9 27147066 \n7. Turton \nJ , Perry \nC , Elgohari \nS , Hampton \nC . PCR characterization and typing of Klebsiella pneumoniae using capsular type-specific, variable number tandem repeat and virulence gene targets\n. J Med Microbiol . 2010 ;59 :541 –547\n. doi:10.1099/jmm.0.015198-0 20110386 \n8. Brisse \nS , Passet \nV , Haugaard \nA , et al. wzi Gene sequencing, a rapid method for determination of capsular type for Klebsiella strains\n. J Clin Microbiol . 2013 ;51 (12 ):4073 –4078\n. doi:10.1128/JCM.01924-13 24088853 \n9. Diancourt \nL , Passet \nV , Verhoef \nJ , Grimont \nP , Brisse \nS . Multilocus sequence typing of Klebsiella pneumoniae nosocomial isolates\n. 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Arch Intern Med . 1986 ;146 (10 ):1913 –1916\n. doi:10.1001/archinte.1986.00360220057011 3532983 \n14. Rossi \nB , Gasperini \nML , Leflon-Guibout \nV , et al. Hypervirulent klebsiella pneumoniae in cryptogenic liver abscesses, Paris, France\n. Emerg Infect Dis . 2018 ;24 (2 ):221 –229\n. doi:10.3201/eid2402.170957 29350134 \n15. Fazili \nT , Sharngoe \nC , Endy \nT , Kiska \nD , Javaid \nW , Polhemus \nM . Klebsiella pneumoniae liver abscess: an emerging disease\n. Am J Med Sci . 2016 ;351 (3 ):297 –304\n. doi:10.1016/j.amjms.2015.12.018 26992260 \n16. Russo \nTA , Olson \nR , Fang \nCT , et al. Identification of biomarkers for differentiation of hypervirulent klebsiella pneumoniae from classical K. pneumoniae\n. J Clin Microbiol . 2018 ;56 :9 . doi:10.1128/JCM.00776-18 \n17. Cheng \nDL , Liu \nYC , Yen \nMY , Liu \nCY , Shi \nFW , Wang \nLS . Causal bacteria of pyogenic liver abscess\n. Taiwan Yi Xue Hui Za Zhi . 1989 ;88 (10 ):1008 –1011\n.2699489 \n18. Chang \nFY , Chou \nMY , Fan \nRL , Shaio \nMF . A clinical study of Klebsiella liver abscess\n. Taiwan Yi Xue Hui Za Zhi . 1988 ;87 (3 ):282 –287\n.3397725 \n19. Lee \nTY , Wan \nYL , Tsai \nCC . Gas-containing liver abscess: radiological findings and clinical significance\n. Abdom Imaging . 1994 ;19 (1 ):47 –52\n. doi:10.1007/BF02165861 8161903 \n20. Kong \nH , Yu \nF , Zhang \nW , Li \nX . Clinical and microbiological characteristics of pyogenic liver abscess in a tertiary hospital in East China\n. Medicine . 2017 ;96 (37 ):e8050 . doi:10.1097/MD.0000000000008050 28906397 \n21. Wang \nWJ , Tao \nZ , Wu \nHL . Etiology and clinical manifestations of bacterial liver abscess: A study of 102 cases\n. Medicine . 2018 ;97 (38 ):e12326 . doi:10.1097/MD.0000000000012326 30235686 \n22. Waghmare \nM , Shah \nH , Tiwari \nC , Khedkar \nK , Gandhi \nS . Management of liver abscess in children: our experience\n. Euroasian J Hepatogastroenterol . 2017 ;7 (1 ):23 –26\n. doi:10.5005/jp-journals-10018-1206 29201767 \n23. Cheema \nHA , Saeed \nA . Etiology, presentation and management of liver abscesses at the children’ s hospital lahore\n. Annals King Edward Medical University . 2008 ;14 (4 ):148 .\n24. Chan \nDS , Archuleta \nS , Llorin \nRM , Lye \nDC , Fisher \nD . Standardized outpatient management of Klebsiella pneumoniae liver abscesses\n. Int J Infect Dis . 2013 ;17 (3 ):e185 –188\n. doi:10.1016/j.ijid.2012.10.002 23154175 \n25. Sadiq \nMA , Hassan \nM , Agarwal \nA , et al. Endogenous endophthalmitis: diagnosis, management, and prognosis\n. J Ophthalmic Inflamm Infect . 2015 ;5 (1 ):32 . doi:10.1186/s12348-015-0063-y 26525563 \n26. Lee \nHC , Chuang \nYC , Yu \nWL , et al. Clinical implications of hypermucoviscosity phenotype in Klebsiella pneumoniae isolates: association with invasive syndrome in patients with community-acquired bacteraemia\n. J Intern Med . 2006 ;259 (6 ):606 –614\n. doi:10.1111/j.1365-2796.2006.01641.x 16704562 \n27. Yang \nCS , Tsai \nHY , Sung \nCS , Lin \nKH , Lee \nFL , Hsu \nWM . Endogenous Klebsiella endophthalmitis associated with pyogenic liver abscess\n. Ophthalmology . 2007 ;114 (5 ):876 –880\n. doi:10.1016/j.ophtha.2006.12.035 17467526 \n28. Sheu \nSJ , Kung \nYH , Wu \nTT , Chang \nFP , Horng \nYH . Risk factors for endogenous endophthalmitis secondary to klebsiella pneumoniae liver abscess: 20-year experience in Southern Taiwan\n. Retina . 2011 ;31 (10 ):2026 –2031\n. doi:10.1097/IAE.0b013e31820d3f9e 21499189 \n29. Ang \nM , Jap \nA , Chee \nSP . Prognostic factors and outcomes in endogenous Klebsiella pneumoniae endophthalmitis\n. Am J Ophthalmol . 2011 ;151 (2 ):338 –344.e332\n. doi:10.1016/j.ajo.2010.08.036 21168820 \n30. Gu \nDX , Huang \nYL , Ma \nJH , et al. Detection of colistin resistance gene mcr-1 in hypervirulent klebsiella pneumoniae and escherichia coli isolates from an infant with diarrhea in China\n. Antimicrob Agents Chemother . 2016 ;60 (8 ):5099 –5100\n. doi:10.1128/AAC.00476-16 27270278 \n31. Liu \nY , Liu \nPP , Wang \nLH , Wei \nDD , Wan \nLG , Zhang \nW . Capsular polysaccharide types and virulence-related traits of epidemic kpc-producing klebsiella pneumoniae isolates in a Chinese University Hospital\n. Microb Drug Resist . 2017 ;23 (7 ):901 –907\n. doi:10.1089/mdr.2016.0222 28437231 \n32. Yu \nF , Lv \nJ , Niu \nS , et al. In vitro activity of ceftazidime-avibactam against carbapenem-resistant and hypervirulent klebsiella pneumoniae isolates\n. Antimicrob Agents Chemother . 2018 ;62 :8 . doi:10.1128/AAC.01031-18 \n33. Rhee \nJY , Park \nYK , Shin \nJY , et al. KPC-producing extreme drug-resistant Klebsiella pneumoniae isolate from a patient with diabetes mellitus and chronic renal failure on hemodialysis in South Korea\n. Antimicrob Agents Chemother . 2010 ;54 (5 ):2278 –2279\n. doi:10.1128/AAC.00011-10 20211897 \n34. Lee \nMY , Ko \nKS , Kang \nCI , Chung \nDR , Peck \nKR , Song \nJH . High prevalence of CTX-M-15-producing Klebsiella pneumoniae isolates in Asian countries: diverse clones and clonal dissemination\n. Int J Antimicrob Agents . 2011 ;38 (2 ):160 –163\n. doi:10.1016/j.ijantimicag.2011.03.020 21605960 \n35. Pan \nYJ , Lin \nTL , Lin \nYT , et al. Identification of capsular types in carbapenem-resistant Klebsiella pneumoniae strains by wzc sequencing and implications for capsule depolymerase treatment\n. Antimicrob Agents Chemother . 2015 ;59 (2 ):1038 –1047\n. doi:10.1128/AAC.03560-14 25451047 \n36. Lu \nMC , Tang \nHL , Chiou \nCS , Wang \nYC , Chiang \nMK , Lai \nYC . Clonal dissemination of carbapenemase-producing Klebsiella pneumoniae: two distinct sub-lineages of Sequence Type 11 carrying blaKPC-2 and blaOXA-48\n. Int J Antimicrob Agents . 2018 ;52 (5 ):658 –662\n. doi:10.1016/j.ijantimicag.2018.04.023 29753130 \n37. Cheng \nYH , Lin \nTL , Pan \nYJ , Wang \nYP , Lin \nYT , Wang \nJT . Colistin resistance mechanisms in Klebsiella pneumoniae strains from Taiwan\n. Antimicrob Agents Chemother . 2015 ;59 (5 ):2909 –2913\n. doi:10.1128/AAC.04763-14 25691646 \n38. Yu \nF , Lv \nJ , Niu \nS , et al. Multiplex pcr analysis for rapid detection of klebsiella pneumoniae carbapenem-resistant (Sequence Type 258 [ST258] and ST11) and Hypervirulent (ST23, ST65, ST86, and ST375) Strains\n. J Clin Microbiol . 2018 ;56 :9 .\n39. Dong \nN , Zhang \nR , Liu \nL , et al. Genome analysis of clinical multilocus sequence Type 11 Klebsiella pneumoniae from China\n. Microb Genom . 2018 .\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1178-6973",
"issue": "14()",
"journal": "Infection and drug resistance",
"keywords": "antibiotic resistance; case report; hypervirulent Klebsiella pneumoniae; pyogenic liver abscess; ultrasonography guided puncture aspiration",
"medline_ta": "Infect Drug Resist",
"mesh_terms": null,
"nlm_unique_id": "101550216",
"other_id": null,
"pages": "71-77",
"pmc": null,
"pmid": "33469321",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "22702521;29800340;2699489;27270278;23099082;21499189;21168820;16081970;27147066;23154175;17467526;16704562;24088853;25451047;29424684;26992260;3397725;21605960;21398074;20110386;28437231;25691646;28906397;8161903;14993253;29350134;29891605;29925644;28864030;29925642;30235686;20211897;29201767;26525563;23302790;29753130;3532983;26753990",
"title": "Pyogenic Liver Abscess and Endogenous Endophthalmitis Due to K64-ST1764 Hypervirulent Klebsiella pneumoniae: A Case Report.",
"title_normalized": "pyogenic liver abscess and endogenous endophthalmitis due to k64 st1764 hypervirulent klebsiella pneumoniae a case report"
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"abstract": "Autoimmune hemolytic anemia (AIHA) may occur after any type of allogeneic hematopoietic stem cell transplantation (HCT), even ABO-matched transplantation. It tends to be refractory to standard corticosteroid treatment and requires multiple transfusions. Though, there is no consensus regarding the optimal treatment for post-transplant severe AIHA. We present a pediatric patient with refractory AIHA after umbilical cord blood transplantation. She developed severe AIHA at 3months after transplantation and was unresponsive to multiple treatment modalities, including corticosteroids, intravenous immunoglobulin, plasma exchange and rituximab, resulting in persistent transfusion dependency. Sirolimus, a mammalian target of rapamycin inhibitor, was started on day 67 after the onset of AIHA, and this patient was successfully rescued without any complications. Sirolimus induces apoptosis in autoreactive lymphocytes, increases regulatory T cells and has been reported to have a positive effect on AIHA following solid organ transplantation (SOT). We reviewed the literature regarding post-transplant AIHA in the PubMed database and evaluated the treatment outcome of sirolimus in AIHA after SOT.",
"affiliations": "Department of Pediatrics, Haeundae-Paik Hospital, Inje University College of Medicine, Busan, Korea. Electronic address: jeonga95@paik.ac.kr.;Department of Pediatrics, Haeundae-Paik Hospital, Inje University College of Medicine, Busan, Korea.;Department of Pediatrics, Haeundae-Paik Hospital, Inje University College of Medicine, Busan, Korea.;Department of Pediatrics, Haeundae-Paik Hospital, Inje University College of Medicine, Busan, Korea.;Department of Diagnostic Laboratory Medicine, Haeundae-Paik Hospital, Inje University College of Medicine, Busan, Korea.;Department of Diagnostic Laboratory Medicine, Haeundae-Paik Hospital, Inje University College of Medicine, Busan, Korea.",
"authors": "Park|Jeong A|JA|;Lee|Hyun-Hee|HH|;Kwon|Hyun-Seop|HS|;Baik|Chung-Ryul|CR|;Song|Sae-Am|SA|;Lee|Jung Nye|JN|",
"chemical_list": "D020123:Sirolimus",
"country": "United States",
"delete": false,
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"issn_linking": "0887-7963",
"issue": "30(1)",
"journal": "Transfusion medicine reviews",
"keywords": "Autoimmune hemolytic anemia; Hematopoietic stem cell transplantation; Regulatory T cells; Rituximab; Sirolimus; Solid organ transplantation",
"medline_ta": "Transfus Med Rev",
"mesh_terms": "D000744:Anemia, Hemolytic, Autoimmune; D004351:Drug Resistance; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D020123:Sirolimus; D014184:Transplantation, Homologous",
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"title": "Sirolimus for Refractory Autoimmune Hemolytic Anemia after Allogeneic Hematopoietic Stem Cell Transplantation: A Case Report and Literature Review of the Treatment of Post-Transplant Autoimmune Hemolytic Anemia.",
"title_normalized": "sirolimus for refractory autoimmune hemolytic anemia after allogeneic hematopoietic stem cell transplantation a case report and literature review of the treatment of post transplant autoimmune hemolytic anemia"
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"abstract": "Sildenafil, a phosphodiesterase-5 inhibitor, is a controversial treatment option for pulmonary arterial hypertension (PAH), a significant complication of bronchopulmonary dysplasia (BPD). The objective of this study was to evaluate the use of sildenafil in infants with PAH secondary to BPD. This was a retrospective review of medical records of all premature infants with PAH associated with BPD treated with sildenafil between January 2009 and May 2013 in a level 3 neonatal intensive care unit. The primary outcomes were clinical response (20 % decreases in respiratory support score or oxygen requirements) and echocardiographic response (20 % decrease in tricuspid regurgitation gradient or change of at least 1° of septal flattening). Twenty-three infants were included in the study. Significant echocardiographic and clinical responses were, respectively, observed in 71 and 35 % of cases. Most clinical responses were observed in the first 48 h of treatment, and the median time to an echocardiographic response was of 19 days. The median dose of sildenafil used was 4.4 mg/kg/day, with a median time to reach the maximum dose of 9 days. Transient hypotension was the primary reported side effect, and it was observed in 44 % of our study population. Sildenafil treatment in patients with PAH secondary to BPD was associated with an echocardiographic improvement in the majority of patients, whereas clinical improvement was observed in a minority of patients. Many infants presented with transient hypotension during the course of the treatment. Further prospective studies are required to better assess safety and efficacy of this treatment in this population.",
"affiliations": "Department of Pediatrics, CHU Sainte-Justine, 3175 chemin de la Cote-Sainte-Catherine, Montreal, QC, H3T 1C5, Canada, mntrottierboucher@gmail.com.",
"authors": "Trottier-Boucher|M N|MN|;Lapointe|A|A|;Malo|J|J|;Fournier|A|A|;Raboisson|M J|MJ|;Martin|B|B|;Moussa|A|A|",
"chemical_list": "D058986:Phosphodiesterase 5 Inhibitors; D000068677:Sildenafil Citrate; D010100:Oxygen",
"country": "United States",
"delete": false,
"doi": "10.1007/s00246-015-1154-0",
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"issn_linking": "0172-0643",
"issue": "36(6)",
"journal": "Pediatric cardiology",
"keywords": null,
"medline_ta": "Pediatr Cardiol",
"mesh_terms": "D001997:Bronchopulmonary Dysplasia; D004305:Dose-Response Relationship, Drug; D004452:Echocardiography; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary; D007022:Hypotension; D007223:Infant; D007231:Infant, Newborn; D015931:Intensive Care, Neonatal; D008297:Male; D010100:Oxygen; D058986:Phosphodiesterase 5 Inhibitors; D056152:Respiratory Rate; D012189:Retrospective Studies; D000068677:Sildenafil Citrate; D016896:Treatment Outcome; D014262:Tricuspid Valve Insufficiency",
"nlm_unique_id": "8003849",
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"title": "Sildenafil for the Treatment of Pulmonary Arterial Hypertension in Infants with Bronchopulmonary Dysplasia.",
"title_normalized": "sildenafil for the treatment of pulmonary arterial hypertension in infants with bronchopulmonary dysplasia"
} | [
{
"companynumb": "CA-PFIZER INC-2015243002",
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"patient": {
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{
"actiondrug": "1",
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"activesubstancename": "SILDENAFIL CITRATE"
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{
"abstract": "An 8-year-old boy with a bone marrow relapse of T cell acute lymphoblastic leukemia underwent stem-cell transplantation from a human leukocyte antigen (HLA)-haploidentical mother. Five months later, he relapsed with central nervous system (CNS) involvement. Systemic chemotherapy and repeated intrathecal chemotherapy induced consciousness disturbances and frequent arrhythmia, prompting us to discontinue the chemotherapy. He had already received an 18-Gy prophylactic cranial irradiation, an 8-Gy total body irradiation, and a 15-Gy local irradiation for pituitary gland involvement. We therefore performed five intrathecal donor lymphocyte infusions (IDLIs) in escalating doses from 1 × 10(4) up to 1 × 10(6) cells/kg. All IDLIs were safe without infusion reactions or graft-versus-host disease. After the second and later IDLIs, donor mononuclear cells were continuously detected in cerebrospinal fluid; however, he did not achieve donor-dominant chimerism. Based on our case and four cases reported in the literature, the efficacy of IDLI therapy is limited for CNS relapse of hematological malignancies. However, we suggest that IDLI remains a feasible and safe option, as no GVHD or other adverse effects occurred, even in the HLA-haploidentical setting. We will make further efforts to increase the efficacy.",
"affiliations": "Department of Pediatrics, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, 390-8621, Japan.;Department of Pediatrics, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, 390-8621, Japan. yxnakaza@shinshu-u.ac.jp.;Department of Pediatrics, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, 390-8621, Japan.;Department of Pediatrics, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, 390-8621, Japan.;Department of Pediatrics, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, 390-8621, Japan.;Department of Pediatrics, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, 390-8621, Japan.;Division of Blood Transfusion, Shinshu University Hospital, Matsumoto, Japan.;Department of Pediatrics, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, 390-8621, Japan.",
"authors": "Yanagisawa|Ryu|R|;Nakazawa|Yozo|Y|;Sakashita|Kazuo|K|;Saito|Shoji|S|;Tanaka|Miyuki|M|;Shiohara|Masaaki|M|;Shimodaira|Shigetaka|S|;Koike|Kenichi|K|",
"chemical_list": "D006680:HLA Antigens",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-015-1902-1",
"fulltext": null,
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"issn_linking": "0925-5710",
"issue": "103(1)",
"journal": "International journal of hematology",
"keywords": "Acute lymphoblastic leukemia; CNS relapse; Donor lymphocyte infusion; Stem cell transplantation",
"medline_ta": "Int J Hematol",
"mesh_terms": "D064591:Allografts; D001853:Bone Marrow; D016543:Central Nervous System Neoplasms; D002648:Child; D005260:Female; D006680:HLA Antigens; D018380:Hematopoietic Stem Cell Transplantation; D006648:Histocompatibility; D006801:Humans; D007278:Injections, Spinal; D017710:Lymphocyte Transfusion; D008297:Male; D009364:Neoplasm Recurrence, Local; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; D014019:Tissue Donors",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "107-11",
"pmc": null,
"pmid": "26586462",
"pubdate": "2016-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "6181221;18822104;25373730;23347901;26056165;17339194;7951116;17124053;17042768;25132538;1608676;21924223;24311149;21318573;19207225;25510272;18804039",
"title": "Intrathecal donor lymphocyte infusion for isolated leukemia relapse in the central nervous system following allogeneic stem cell transplantation: a case report and literature review.",
"title_normalized": "intrathecal donor lymphocyte infusion for isolated leukemia relapse in the central nervous system following allogeneic stem cell transplantation a case report and literature review"
} | [
{
"companynumb": "JP-MYLANLABS-2016M1009360",
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{
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"activesubstance": {
"activesubstancename": "PREDNISOLONE"
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"drugadditional": null,
... |
{
"abstract": "Benign gastrobronchial fistula (GBF) is a rare but potentially life-threatening complication of oesophagectomy for malignancy. We present a case of GBF post Ivor-Lewis surgery manifesting as pulmonary sepsis and type II respiratory failure. Clues to the diagnosis were persistent hypercapnia despite high minute ventilation, aspiration of gastric content through the endotracheal tube and accumulation of air in the nasogastric drainage bag. Flexible bronchoscopy confirmed the diagnosis. Surgical exploration identified necrosis of the proximal stomach as causative factor. Despite reconstruction of the oesophagogastric anastomosis and interposition of an intercostal muscle flap, the patient developed a new episode of type II respiratory failure. Bronchoscopy revealed in situ recurrence of the fistula. Patency of the fistula was proven through application of methylene blue with subsequent gastroscopy. A conservative, symptom-based, management was conducted. The patient died 6 hours later.",
"affiliations": "Faculty of Medicine and Health Sciences, Ghent University, Gent, Belgium.;Intensive Care Department, Universitair Ziekenhuis Gent, Gent, Belgium.;Intensive Care Department, Universitair Ziekenhuis Gent, Gent, Belgium.;Intensive Care Department, Universitair Ziekenhuis Gent, Gent, Belgium.",
"authors": "Favere|Kasper|K|;Vanderbiest|Klaas|K|;Bresseleers|Jan|J|;Depuydt|Pieter|P|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-228537",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(9)",
"journal": "BMJ case reports",
"keywords": "adult intensive care; air leaks; gastrointestinal surgery; oesophageal cancer; oesophagus",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D001983:Bronchial Fistula; D004938:Esophageal Neoplasms; D016629:Esophagectomy; D017809:Fatal Outcome; D005260:Female; D005747:Gastric Fistula; D006801:Humans; D012131:Respiratory Insufficiency",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31488439",
"pubdate": "2019-09-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24580929;24109590;26903338;2676399;17382232;26520033;16901364;21684205;18586574;26254683;9529504;14421290;17720434;24449022;3178358;11269372;25722285;21643779;25364580;15729244;12928968;18696169;20030856;20494070;11981718;30089078;17982541;19319386;25266029;15019679;16963694;7944726;18651196;11869338;14752456;19943963;17669975;25607756;25982608;17611917;22854632;15989688;25526402",
"title": "Benign gastrobronchial fistula following oesophagectomy in a patient presenting with respiratory failure.",
"title_normalized": "benign gastrobronchial fistula following oesophagectomy in a patient presenting with respiratory failure"
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"abstract": "Recurrent anogenital herpes simplex virus infections are common in patients with human immunodeficiency virus (HIV), of whom approximately 5% develop resistance to acyclovir. We present a case of a 49-year-old man with HIV who had an 8-year history of recurrent left inguinal herpes simplex virus type 2 ulcerations. He initially responded to oral acyclovir, but developed resistance to acyclovir and eventually foscarnet. The lesion progressed to a large hypertrophic mass that required surgical excision, which led to resolution without recurrences. Our case highlights the importance of surgical excision as a treatment option in refractory herpes simplex virus anogenital infections.",
"affiliations": "Division of Infectious Diseases, Vanderbilt University Medical Center, A2200 MCN 1161 21st Avenue South Nashville, Nashville, TN, 37232-2605, USA. folasade.a.arinze@vanderbilt.edu.;Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.;Division of Infectious Diseases, Vanderbilt University Medical Center, A2200 MCN 1161 21st Avenue South Nashville, Nashville, TN, 37232-2605, USA.",
"authors": "Arinze|Folasade|F|;Shaver|Aaron|A|;Raffanti|Stephen|S|",
"chemical_list": "D000998:Antiviral Agents; D017245:Foscarnet; D000212:Acyclovir",
"country": "Germany",
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"doi": "10.1007/s15010-017-1027-y",
"fulltext": null,
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"issn_linking": "0300-8126",
"issue": "45(5)",
"journal": "Infection",
"keywords": "HSV-1; HSV-2; Herpes simplex infection; Hypertrophic HSV herpes simplex vegetans; Recurrent herpes simplex infection",
"medline_ta": "Infection",
"mesh_terms": "D000212:Acyclovir; D000998:Antiviral Agents; D024882:Drug Resistance, Viral; D017245:Foscarnet; D015658:HIV Infections; D006558:Herpes Genitalis; D018258:Herpesvirus 2, Human; D006801:Humans; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "0365307",
"other_id": null,
"pages": "705-707",
"pmc": null,
"pmid": "28508238",
"pubdate": "2017-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23864092;9366853;2828440;16327322;20157021;16804851;12523920;22210631;82035;8232486;18297220;19858782",
"title": "Surgical excision for recurrent herpes simplex virus 2 (HSV-2) anogenital infection in a patient with human immunodeficiency virus (HIV).",
"title_normalized": "surgical excision for recurrent herpes simplex virus 2 hsv 2 anogenital infection in a patient with human immunodeficiency virus hiv"
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"abstract": "BACKGROUND\nRecently, immunosuppressant-associated malignant lymphoma (ML) cases have been increasing along with the development of several effective immunosuppressant drugs for rheumatoid arthritis (RA). Among methotrexate (MTX)-associated lymphoproliferative disorders, primary hepatic lymphoma (PHL) in patients with RA following surgical resection has not been reported previously.\n\n\nMETHODS\nA 65-year-old woman who is a hepatitis B virus carrier with a history of RA was admitted. MTX was introduced seven years prior as an RA treatment. Her laboratory data showed no elevation of several tumor markers, and liver function test results were normal. On contrasted computed tomography (CT) scanning, a slightly enhanced tumor was detected at the early phase, and tumor staining was sustained at the delayed phase. Further, subsegmentectomy of the S6 was performed. The pathological diagnosis was diffuse large B-cell lymphoma. However, positron emission tomography-CT and bone marrow aspiration sample showed no resident sign of ML.\n\n\nCONCLUSIONS\nDiagnosis of PHL before surgery is difficult. If the mass lesion was solitary and had a certain degree of size, then resection could be performed for its treatment and diagnosis. The treatment for ML requires a diagnosis of the subtypes to select a therapeutic agent and determine the prognosis. Once a precise preoperative diagnosis was made, withdrawing MTX could be the first treatment in case of MTX-related ML.\n\n\nCONCLUSIONS\nLong-term usage of immunosuppressant drugs could cause proliferative ML. Considering the increasing occurrence of MTX-related ML, withdrawing MTX should be considered, especially in patients with long-term immunosuppressant usage for RA.",
"affiliations": "Department of Surgery, Onomichi General Hospital, Onomichi, Hiroshima, Japan.;Department of Surgery, Onomichi General Hospital, Onomichi, Hiroshima, Japan. Electronic address: t.abe.hiroshima@gmail.com.;Department of Surgery, Onomichi General Hospital, Onomichi, Hiroshima, Japan; Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Japan.;Department of Gastroenterology,Onomichi General Hospital, Onomichi, Hiroshima, Japan.;Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Japan.;Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Japan.;Kawasaki Medical School Hospital, Kurashiki, Okayama, Japan.;Department of Surgery, Onomichi General Hospital, Onomichi, Hiroshima, Japan.;Department of Surgery, Onomichi General Hospital, Onomichi, Hiroshima, Japan; Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Japan.",
"authors": "Takei|Daisuke|D|;Abe|Tomoyuki|T|;Amano|Hironobu|H|;Hirano|Naomichi|N|;Kobayashi|Tsuyoshi|T|;Ohdan|Hideki|H|;Kondo|Toshinori|T|;Nakahara|Masahiro|M|;Noriyuki|Toshio|T|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ijscr.2016.12.012",
"fulltext": "\n==== Front\nInt J Surg Case RepInt J Surg Case RepInternational Journal of Surgery Case Reports2210-2612Elsevier S2210-2612(16)30550-810.1016/j.ijscr.2016.12.012Case ReportMethotrexate-associated primary hepatic malignant lymphoma following hepatectomy: A case report Takei Daisuke aAbe Tomoyuki t.abe.hiroshima@gmail.coma⁎Amano Hironobu abHirano Naomichi cKobayashi Tsuyoshi bOhdan Hideki bKondo Toshinori dNakahara Masahiro aNoriyuki Toshio aba Department of Surgery, Onomichi General Hospital, Onomichi, Hiroshima, Japanb Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Japanc Department of Gastroenterology,Onomichi General Hospital, Onomichi, Hiroshima, Japand Kawasaki Medical School Hospital, Kurashiki, Okayama, Japan⁎ Corresponding author at: Department of Surgery, Onomichi General Hospital, 1-10-23 Hirahara, Onomichi, Hiroshima 722-850, Japan.Department of SurgeryOnomichi General HospitalOnomichiHiroshimaJapan t.abe.hiroshima@gmail.com21 12 2016 2017 21 12 2016 31 5 9 28 11 2016 13 12 2016 © 2016 The Author(s)2016This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• Primary hepatic lymphoma is difficult to diagnose preoperatively.\n\n• MTX use encouraged MTX-related ML.\n\n• In MTX-related MLs, withdrawing MTX had a therapeutic effect.\n\n\n\nIntroduction\nRecently, immunosuppressant-associated malignant lymphoma (ML) cases have been increasing along with the development of several effective immunosuppressant drugs for rheumatoid arthritis (RA). Among methotrexate (MTX)-associated lymphoproliferative disorders, primary hepatic lymphoma (PHL) in patients with RA following surgical resection has not been reported previously.\n\nPresentation of case\nA 65-year-old woman who is a hepatitis B virus carrier with a history of RA was admitted. MTX was introduced seven years prior as an RA treatment. Her laboratory data showed no elevation of several tumor markers, and liver function test results were normal. On contrasted computed tomography (CT) scanning, a slightly enhanced tumor was detected at the early phase, and tumor staining was sustained at the delayed phase. Further, subsegmentectomy of the S6 was performed. The pathological diagnosis was diffuse large B-cell lymphoma. However, positron emission tomography-CT and bone marrow aspiration sample showed no resident sign of ML.\n\nDiscussion\nDiagnosis of PHL before surgery is difficult. If the mass lesion was solitary and had a certain degree of size, then resection could be performed for its treatment and diagnosis. The treatment for ML requires a diagnosis of the subtypes to select a therapeutic agent and determine the prognosis. Once a precise preoperative diagnosis was made, withdrawing MTX could be the first treatment in case of MTX-related ML.\n\nConclusion\nLong-term usage of immunosuppressant drugs could cause proliferative ML. Considering the increasing occurrence of MTX-related ML, withdrawing MTX should be considered, especially in patients with long-term immunosuppressant usage for RA.\n\nKeywords\nDiffuse large B cell lymphomaPrimary hepatic malignant lymphomaMethotrexate\n==== Body\n1 Introduction\nPrimary hepatic lymphoma (PHL) is a rare disease among hepatic malignancies. The incidence of PHL was reported to be less than 1% among extranodular lymphoma cases [1]. Recently, along with the introduction of methotrexate (MTX) usage for rheumatoid arthritis (RA) treatment, MTX-related malignant lymphoma cases have been increasing [2]. RA patients are susceptible to develop malignant lymphoma (ML). Moreover, these immunosuppressant drugs for RA override the occurrence of malignant diseases.\n\nIt is hypothesized that occult Epstein-Barr virus (EBV) infection relapse, which was activated by long-term usage of MTX, could cause PHL. Thus, long-term low dose usage of MTX is the risk factor for MTX-associated lymphoproliferative disorders (MTX-LPDs) [3]. Preoperative diagnosis of PHL was difficult due to the lack of characteristic radiological findings and its low incidence among liver malignancies. On computed tomography (CTs), low-density mass lesions are revealed, while on contrasted CT, tumors showed ischemic patterns. Further, T1- and T2-weighted magnetic resonance images (MRI) revealed low intense and high intense areas, respectively. However, these findings were not specific [4], [5]. Portal or hepatic veins extended through a hepatic lesion without evidence of appreciable mass effect, occlusion, or displacement of the vessels. These findings were also not specific, but can be used as a basis for suspicion [6].\n\nAlthough increasing numbers of MTX-ML cases have been reported, the condition remains rare. This is the first case of solitary PHL without distant metastasis that developed during MTX treatment for RA. Our case demonstrated an MTX-associated PHL following curative resection supported with review of literatures.\n\n2 Presentation of case\nA 65-year-old woman was admitted for the treatment of her liver tumor in April 2015. Her height and weight were 146 cm and 48 kg, respectively. She is a hepatitis B virus carrier and has a history of RA. MTX was introduced seven years prior for RA treatment. Her laboratory data showed no elevation of several tumor markers. Both her physical examination and liver function test results were normal. On abdominal echo, a low echoic tumor was detected at segment 6 (S6), with a size of 16 × 29 mm. On contrasted CT, the tumor was slightly enhanced at the early phase, and tumor staining was sustained at the delayed phase (Fig. 1a–d). MRI showed that the tumor was weakly enhanced at the early phase, and revealed hypo intense areas at both late and hepatobiliary phases (Fig. 2a–d). The differential diagnoses include well-differentiated hepatocellular carcinoma, intrahepatic cholangiocarcinoma, metastatic liver tumor, and PHL. Subsegmentectomy of the S6 was performed with an operative time of 252 min and intraoperative bleeding amount of 240 mL. The specimen shows that the tumor was a whitish solid with an irregular margin (Fig. 3). The final pathological diagnosis was MTX-associated PHL. On immunohistochemical analysis, CD20, CD30, and CD79a were positive, but CD10 and CD15 were negative (Fig. 4). EBER (EBV-encoded small RNA) was also positive. These findings were consistent with non-Hodgkin’s lymphoma (NHL), diffuse large B cell lymphoma (DLBCL), and other iatrogenic immunodeficiency-associated lymphoproliferative disorders (LPDs) according to the WHO 2008 classification of lymphoid tissue. However, positron emission tomography (PET)-CT and bone marrow aspiration sample did not indicate any sign of ML.\n\nThe patient was discharged in our department without any complication, and was transferred to the hematology department of Kawasaki University. Additionally, bone marrow aspiration was performed, but residual tumor cells were not detected. She survived with no recurrence for one year even without any additional chemotherapy. MTX withdrawal was effective for the recurrence of ML afterwards.\n\n3 Discussion\nMTX-associated PHL following curative hepatectomy was demonstrated. To date, only a few reports of MTX associated with PHL were seen [1], [2], [7] (Table 1). In all cases, the pathological diagnosis was DLBCL. Diagnosis was performed with biopsy in all three cases, and the treatment was chemotherapy: either R-CHOP (rituximab, cyclophosphamide, hydroxyldaunorubicin, oncovin, prednisone) or R-THP-COP (rituximab, 4′-O-tetrahydropyranyl adriamycin, cyclophosphamide, oncovin, prednisone). In the present case, surgery was performed as both a therapeutic and diagnostic procedure, and follow-up was done after MTX discontinuation without chemotherapy.\n\nIn 1991, the association between lymphoma and MTX therapy in patients with RA was first reported by Ellman et al. [8]. Patients with RA have various immunologic abnormalities, including T-cell dysfunction and B-cell activation associated with autoantigen stimulation [9]. The high inflammatory activity in these patients associated with RA, immunosuppressive agents including MTX used for treatment, or EBV infection/reactivation. In Japan, 95% of adults with latent infection of B-cells throughout their life were infected with EBV. In addition to EBV infection, immunologic abnormality and gene alteration in the infection cells encourage carcinogenic occurrences. In our case, EBV was positive and relapsed due to MTX usage, which was considered as a reason for the occurrence of PHL.\n\nRA patients have a modestly increased risk of developing LPDs independent of immunosuppressive therapy for the disease. In RA treatment, the most popular immunosuppressive agent is MTX. MTX is usually used for several malignant diseases such as lymphoblastoma, trophoblastic disease, and leukemia. In one study on 29 RA patients with MTX-LPD, the median durations of RA and MTX treatment were reported to be 96 and 56 months, respectively, with a median cumulative dose of 864 mg [10]. In the present case, the duration of MTX treatment was 84 months, and the total dose of MTX was over 25,550 mg. This suggests that the immunosuppressive state induced by MTX may have played a major role in the development of PHL in the current patient.\n\nPrevious reports have indicated that EBV may be related to the development of MTX-LPD [11], [12]. Forty-six percent of MTX-LPD patients exhibited EBV-positive findings in the nuclei of the atypical cells of lymphoma [13]. Cell cycle dysregulation and latent EBV infection have been reported to be important factors for the development of LPD in autoimmune disease patients with an immunosuppressed condition due to treatment with MTX [14]. Further, EBV may be associated with spontaneous regression following the withdrawal of MTX in MTX-LPD patients. Salloum et al. reported that EBV was detected in eight out of ten patients who responded to the withdrawal of MTX, whereas only one of six EBV-negative patients responded to MTX withdrawal [15]. Therefore, the presence of EBV may be a predictive factor for the efficacy of MTX withdrawal.\n\nTreatment option of PHL include surgery, chemotherapy, radiation, or carrying out combinations of these modalities [16]. However, the optimal treatment is not established due to the heterogeneous occurrence patterns in patients. Chemotherapy with CHOP (cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone)-based regimens is generally the gold standard [16], [17]. The role of surgery is not fully clarified, but there are reports that liver resection followed by adjuvant chemotherapy and/or radiation results in better prognosis [16], [18]. However, approximately 55% of MTX-LPD patients have been reported to improve following the withdrawal of MTX, without additional antitumor therapy [15].\n\nDiagnosis has been difficult using the preoperative imaging tests, but malignant tumor was suspected from the size observed. We considered that curative resection was possible for a solitary lesion. Therefore, we performed surgery for its diagnosis and treatment. The pathological diagnosis was ML. Generally, it is better to take adjuvant chemotherapy. However, in the MTX-related ML, withdrawing MTX could be an effective therapy. In our case, we suspected MTX-related ML since the medical history of the patient reveals she was taking MTX. After the diagnosis of ML with surgery, we opted to withdraw MTX without adjuvant chemotherapy for the reason mentioned above.\n\nPrecise diagnosis played an important role in selecting the appropriate treatment. Therefore, it is important to consider MTX-related ML in patients with a history of MTX usage.\n\n4 Conclusion\nThe frequency of MTX-associated PHL is rare, and the lack of characteristic findings makes it difficult to make a precise diagnosis. Long-term MTX use encouraged MTX-related ML, and withdrawing MTX alone could have a therapeutic effect. Therefore, it is important to monitor for PHL occurrence in patients treated with MTX on a long-term basis.\n\nConflicts of interest\nNone of the authors have any commercial or financial involvement in connection with this study that represents or appears to represent any conflicts of interest.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nEthical approval\nThis research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nAuthor contribution\nAll authors in this manuscript contributed to the interpretation of data, and drafting and writing of this manuscript. Daisuke Takei is first author of this paper. Tomoyuki Abe is corresponding author of this paper. Daisuke Takei, Tomoyuki Abe and Hironobu Amano conceived and designed the study and drafted the manuscript. Naomichi Hirano first diagnosed the hepatic tumor and introduced the patient to our department of surgery. Daisuke Takei, Tomoyuki Abe, Hironobu Amano, Masahiro Nakahara and Toshio Noriyuki were engaged in patient’s care in our hospital including surgery. Toshinori Kondo performed the postoperative treatment strategy. Tsuyoshi Kobayashi and Hideki Ohdan contributed to study concept, and review of the final manuscript and submission of the paper. All the authors read and approved the final manuscript.\n\nGuarantor\nTomoyuki Abe.\n\nAcknowledgments\nNone.\n\nFig. 1 An abdominal contrast-enhanced computed tomography (CT) scan showed a solitary mass in the liver (a). The size was 16 × 29 mm. In the arterial phase (b), the tumor was slightly enhanced. In the portal and delayed phase (c, d), the tumor staining was sustained.\n\nFig. 1Fig. 2 Magnetic resonance imaging (MRI) showed a solitary mass in the liver. (a) The tumor was weakly enhanced in the early phase. (b) In the late and hepatobiliary phase (c, d), the tumor gradually revealed as a hypo intense area.\n\nFig. 2Fig. 3 The specimen shows that the tumor was a whitish solid with an irregular margin.\n\nFig. 3Fig. 4 Immunohistochemistry demonstrated that the tumor was positive for CD20, CD30, and CD79a, but negative for CD10 and CD15.\n\nFig. 4Table 1 Detailed clinicopathological findings and prognosis in four patients with MTX-associated PHL.\n\nTable 1Year\tAuthor\tSex\tTreatment\tDiagnosis\tPathology\tNumber of tumors\tImmunohistochemistry\tPrognosis\t\n2015\tK. Miyagawa\tF\tR-CHOP\tUS-guided\naspiration biopsy\tDLBCL\tMultiple\tCD10+, CD79a+, CD20+\nCD5-, EBER-\tAlive\t\n2014\tG. Tatsumi\tF\tR-THP-COP\tUS-guided fine-needle biopsy\tDLBCL\tMultiple\tCD10-, CD20+, CD5-\nEBER+\tAlive\t\n2015\tA. Kawahara\tM\tR-CHOP\tPercutaneous\ntumor biopsy\tDLBCL\tMultiple\tCD10+, CD79a+, CD20+\nbcl-2-, CD3-, EBER-\tAlive\t\n2016\tOur case\tF\tMTX withdrawal\tSurgery\tDLBCL\tSingle\tCD10-, CD15-, CD20+\nCD30+, CD79a+, EBER+\tAlive\t\nAbbreviations: bcl, B cell lymphoma; DLBCL, diffuse large B cell lymphoma; EBER, EBV-encoded small RNA; F, female; M, male; R-CHOP, rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone.\n==== Refs\nReferences\n1 Tatsumi G. Ukyo N. Hirata H. Tsudo M. Primary hepatic lymphoma in a patient with rheumatoid arthritis treated with methotrexate Case Rep. Hematol. 2014 2014 460574 25610674 \n2 Miyagawa K. Shibata M. Noguchi H. Hayashi T. Oe S. Hiura M. Methotrexate-related primary hepatic lymphoma in a patient with rheumatoid arthritis Intern. Med. 54 2015 401 405 25748956 \n3 Feng W.H. Cohen J.I. Fischer S. Li L. Sneller M. Goldbach-Mansky R. Reactivation of latent Epstein-Barr virus by methotrexate: a potential contributor to methotrexate-associated lymphomas J. Natl. Cancer Inst. 96 2004 1691 1702 15547182 \n4 Maher M.M. McDermott S.R. Fenlon H.M. Conroy D. O’Keane J.C. Carney D.N. Imaging of primary non-Hodgkin’s lymphoma of the liver Clin. Radiol. 56 2001 295 301 11286581 \n5 Lee W.K. Lau E.W. Duddalwar V.A. Stanley A.J. Ho Y.Y. Abdominal manifestations of extranodal lymphoma: spectrum of imaging findings AJR Am. J. Roentgenol. 191 2008 198 206 18562746 \n6 Apicella P.L. Mirowitz S.A. Weinreb J.C. Extension of vessels through hepatic neoplasms: MR and CT findings Radiology 191 1994 135 136 8134559 \n7 Kawahara A. Tsukada J. Yamaguchi T. Katsuragi T. Higashi T. Reversible methotrexate-associated lymphoma of the liver in rheumatoid arthritis: a unique case of primary hepatic lymphoma Biomark. Res. 3 2015 10 25964853 \n8 Ellman M.H. Hurwitz H. Thomas C. Kozloff M. Lymphoma developing in a patient with rheumatoid arthritis taking low dose weekly methotrexate J. Rheumatol. 18 1991 1741 1743 1787499 \n9 Kudoh M. Harada H. Matsumoto K. Sato Y. Omura K. Ishii Y. Methotrexate-associated lymphoproliferative disorder arising in the retromolar triangle and lung of a patient with rheumatoid arthritis Oral Surg. Oral Med. Oral Pathol. Oral Radiol. 118 2014 e105 10 24811204 \n10 Niitsu N. Okamoto M. Nakamine H. Hirano M. Clinicopathologic correlations of diffuse large B-cell lymphoma in rheumatoid arthritis patients treated with methotrexate Cancer Sci. 101 2010 1309 1313 20210795 \n11 Baecklund E. Askling J. Rosenquist R. Ekbom A. Klareskog L. Rheumatoid arthritis and malignant lymphomas Curr. Opin. Rheumatol. 16 2004 254 261 15103253 \n12 Kamel O.W. van de Rijn M. Weiss L.M. Del Zoppo G.J. Hench P.K. Robbins B.A. Brief report: reversible lymphomas associated with Epstein-Barr virus occurring during methotrexate therapy for rheumatoid arthritis and dermatomyositis N. Engl. J. Med. 328 1993 1317 1321 8385742 \n13 Sibilia J. Liote F. Mariette X. Lymphoproliferative disorders in rheumatoid arthritis patients on low-dose methotrexate Rev. Rhum. Engl. Ed. 65 1998 267 273 9599795 \n14 Menke D.M. Griesser H. Moder K.G. Tefferi A. Luthra H.S. Cohen M.D. Lymphomas in patients with connective tissue disease. Comparison of p53 protein expression and latent EBV infection in patients immunosuppressed and not immunosuppressed with methotrexate Am. J. Clin. Pathol. 113 2000 212 218 10664623 \n15 Salloum E. Cooper D.L. Howe G. Lacy J. Tallini G. Crouch J. Spontaneous regression of lymphoproliferative disorders in patients treated with methotrexate for rheumatoid arthritis and other rheumatic diseases J. Clin. Oncol. 14 1996 1943 1949 8656264 \n16 Noronha V. Shafi N.Q. Obando J.A. Kummar S. Primary non-Hodgkin’s lymphoma of the liver Crit. Rev. Oncol. Hematol. 53 2005 199 207 15718146 \n17 Page R.D. Romaguera J.E. Osborne B. Medeiros L.J. Rodriguez J. North L. Primary hepatic lymphoma: favorable outcome after combination chemotherapy Cancer 92 2001 2023 2029 11596015 \n18 Zentar A. Tarchouli M. Elkaoui H. Belhamidi M.S. Ratbi M.B. Bouchentouf S.M. Primary hepatic lymphoma J. Gastrointest. Cancer 45 2014 380 382 23686662\n\n",
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"issue": "31()",
"journal": "International journal of surgery case reports",
"keywords": "Diffuse large B cell lymphoma; Methotrexate; Primary hepatic malignant lymphoma",
"medline_ta": "Int J Surg Case Rep",
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"nlm_unique_id": "101529872",
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"title": "Methotrexate-associated primary hepatic malignant lymphoma following hepatectomy: A case report.",
"title_normalized": "methotrexate associated primary hepatic malignant lymphoma following hepatectomy a case report"
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"abstract": "We herein report a rare case that describes and visualizes nocardiosis in a patient with diabetes. The patient presented with recurring fever, gout, leg pain, frailty and muscular pain through nine months, before a core needle biopsi, from an abscess in the abdominal musculature, revealed Nocardia Paucivorans. A PET-CT-scan showed multiple muscular FDG-positive sites. Furthermore, he experienced serious side effects to Sulfametoxazole and Trimethoprim, the antibiotic of choice for this type of infection. He was then switched to Moxifloxacin and Ampicillin. Nocardia often presents as opportunistic infections, typically in patients with severe immunodeficiencies, such as HIV, use of high-dose corticosteroids, hematologic malignancies or immunosuppression following organ transplantation. This case illustrates how a patient with only relative immunodeficiency gets rare nocardiosis. Our sparse knowledge on clinical presentation is based on case-reports and treatment is empirical. Hence, a better understanding of the clinical presentation and treatment is important. Especially given the prospect, that the health care system faces a greater load of patients with diabetes and other immunodeficiencies in the future.",
"affiliations": "Department of Internal Medicine, Holstebro Regional Hospital, Hospital Unit West, Holstebro, Denmark.;Department of Internal Medicine, Holstebro Regional Hospital, Hospital Unit West, Holstebro, Denmark.;Department of Nuclear Medicine & PET- Centre, Herning Regional Hospital, Hospital Unit West, Herning, Denmark.;Department of Internal Medicine, Holstebro Regional Hospital, Hospital Unit West, Holstebro, Denmark.",
"authors": "Norup Thomsen|Cecilie|C|;Sperling|Søren|S|;Fledelius|Joan|J|;Gjørup|Pia Holland|PH|",
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"doi": "10.1080/20018525.2021.1882030",
"fulltext": "\n==== Front\nEur Clin Respir J\nEur Clin Respir J\nEuropean Clinical Respiratory Journal\n2001-8525\nTaylor & Francis\n\n33708362\n10.1080/20018525.2021.1882030\n1882030\nVersion of Record\nCase Report\nCase Report\nRare nocardiosis in danish patient with diabetes\nC. NORUP THOMSEN ET AL.\nEUROPEAN CLINICAL RESPIRATORY JOURNAL\nNorup Thomsen Cecilie a\nSperling Søren a\nFledelius Joan b\nGjørup Pia Holland a\na Department of Internal Medicine, Holstebro Regional Hospital, Hospital Unit West , Holstebro, Denmark\nb Department of Nuclear Medicine & PET- Centre, Herning Regional Hospital, Hospital Unit West , Herning, Denmark\nCONTACT Cecilie Norup Thomsen sille.noth@gmail.com Department of Internal Medicine, Holstebro Regional Hospital, Hospital Unit West , Holstebro, Denmark\n24 2 2021\n2021\n24 2 2021\n8 1 1882030Integra21 12 2021\nIntegra21 12 2021\n02 11 2020\n22 1 2021\n© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.\n2021\nThe Author(s)\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 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.\n\nABSTRACT\n\nWe herein report a rare case that describes and visualizes nocardiosis in a patient with diabetes. The patient presented with recurring fever, gout, leg pain, frailty and muscular pain through nine months, before a core needle biopsi, from an abscess in the abdominal musculature, revealed Nocardia Paucivorans. A PET-CT-scan showed multiple muscular FDG-positive sites. Furthermore, he experienced serious side effects to Sulfametoxazole and Trimethoprim, the antibiotic of choice for this type of infection. He was then switched to Moxifloxacin and Ampicillin. Nocardia often presents as opportunistic infections, typically in patients with severe immunodeficiencies, such as HIV, use of high-dose corticosteroids, hematologic malignancies or immunosuppression following organ transplantation. This case illustrates how a patient with only relative immunodeficiency gets rare nocardiosis. Our sparse knowledge on clinical presentation is based on case-reports and treatment is empirical. Hence, a better understanding of the clinical presentation and treatment is important. Especially given the prospect, that the health care system faces a greater load of patients with diabetes and other immunodeficiencies in the future.\n\nKEYWORDS\n\nDiabetes\nnocardiosis\nopportunistic infection\n==== Body\npmcIntroduction\n\nThis case report describes and visualizes infection with Actinomyces Naeslundii (AN) and Nocardia Paucivorans (NP), causing lung infection and multiple muscular abscesses, respectively.\n\nCase-report\n\nA 78 year old male, with a medical history of hypertension, atrial fibrillation, arthritis urica, insulin-dependent type-2-diabetes complicated by diabetic nephropathy and former cancer prostate, for which he had undergone treatment, was initially admitted in September 2018. He presented a history, over the past six months, of recurring fever, gout, leg pain, frailty, alongside muscular pain from right humeral, and abdominal musculature.\n\nThe initial diagnostic CT-imaging showed a pulmonary infiltrate. The patient responded clinically and biochemically on antibiotic treatment, however, a 6 week control scan showed progression of the infiltrate. Hence, the patient underwent additional diagnosing with PET-CT, bronchoscopy, and core needle biopsy (CNB). PET-CT showed multiple muscular abscesses (Figure 1). AN was found in fluid from bronchoalveolar lavage and CNB from the lung did not confirm malignity. Only CNB from the abdominal musculature was positive for bacterial growth, namely NP. The patient was HIV negative and had normal levels of immunoglobulins.Figure 1. First PET-CT scan, November 2018\n\nDuring medical examinations, the patient was treated with Piperacillin/Tazobactam and Metronidazole. After discovering NP, antibiotic treatment was adjusted to Sulfametoxazole and Trimethoprim (STM). However, three weeks later, the patient was submitted with bradycardia, acute kidney failure and myelosuppression, most likely side effects to STM. After normalization of bone marrow function, the antibiotic strategy was changed to Amoxicillin and Moxifloxacin. Regular PET-CT and blood sampling over additionally nine months showed sporadic and slowly regression of the abscesses. A year after first submitted the patient was without any muscular complaints. This lead to pause of antibiotics, which two months later, resulted in progression of the original lung foci. BAL was now positive for Actinomycis Odontolyticus (AO), which in writing, is treated with high doses of penicillin.\n\nDiscussion\n\nThis patient was infected with both AN and NP. Pulmonary infection with AN is likely due to aspiration of infected oral material, given this agent’s natural presence in the mucosal barrier of the oral cavity. It is likely that the AO infection of the lung was acquired through the first bronchoscopy. Conversely, Nocardia normally thrives in organic matter, and human infections are acquired by either inhalation or skin laceration [1]. We suspect the latter to have been the way of contamination, since Nocardia was found in the abdominal rectus musculature, suggesting, that the patient has used a contaminated needle during insulin administration.\n\nBoth AN and NP are capable of hematogen spread and can present with abscesses and fever. The presence of NP could only be identified in the abdominal abscess, so whether we have to do with disseminated NP or AN infection in this case, is difficult to say. PET-CT scans show a relatively quick pulmonary response to antibiotic treatment, compared to a generally more vague response in the muscular foci (Figures 1–3). These circumstances lead us to suspect disseminated NP infection. However, we cannot exclude that AN has been the cause of fever for this patient in some cases.Figure 2. PET-CT, March 2019. Note the quick pulmonary response, against the more vague muscular response\n\nFigure 3. PET-CT, Juni 2019. Muscular foci are clearly in regression\n\nMalignancy is a relevant differential diagnosis to infections with low pathogenic microorganism such as fungi, mycobacteria or, as in this case, actinomycetales. Clinically it can be hard to distinguish between them. The brief clinically and biochemically response to antibiotics in this case, together with PET-CT scans, supports the infection suspicion. If the physician suspects infection with the above-mentioned pathogens, the microbiological department must be notified, since these pathogens need either special media, circumstances (temperature, pH etc.) or longer time for growth.\n\nNocardia often presents as opportunistic infections, typically in patients with severe immunodeficiencies, such as HIV, use of high-dose corticosteroids, hematologic malignancies or immunosuppression following organ transplantation. But infections in immunocompetent patients and lung colonization in patients with COPD have been described [2,3]. The comorbidities of this patient are causing a relative immunodeficiency making him vulnerable to be infected with both AN and NP. Especially his diabetes must be considered a lead actor in this vulnerability, given that diabetes impairs the cellular immune system, which is vital for successful clearance of Nocardia infections [4].\n\nRegarding prognosis, a review from 2020 presents, that for pleuropulmonary Nocardia infection approximately 80% are cured and only 3% with disseminated nocardiosis are cured [5].\n\nThis case illustrates how a patient with a common diagnosis such as diabetes gets infected with two opportunistic bacteria. Especially NP is rare. In addition, he did not tolerate first-line antibiotics for this type of infection. Our sparse knowledge on clinical presentation is based on case-reports and treatment is empirical. Hence, a better understanding of the clinical presentation is important, especially given the prospect, that the health care system faces a greater load of patients with diabetes and other immunodeficiencies in the future.\n\nCecilie Norup Thomsen, MD. Is a physician at the Department of Internal Medicine and Respiratory Diseases, at Holstebro Hospital, Hospital Unit West, Denmark.\n\nSøren Sperling, MD. Is a physician, taking his rehsidency in Internal Medicine and Respiratory Diseases at Department of Internal Medicine, Holstebro Hospital, Hospital Unit West, Denmark and Department of Respiratory Diseases Aarhus University Hospital, Denmark.\n\nJoan Fedelius, MD, PhD. Is a senior doctor with specialty in Radiology, working at the Department of Nuclearmedicine, Herning, Hospital Unit West.\n\nPia Holland Gjørup, MD, PhD. Is a senior doctor with specialty in Internal Medicine and Respiratory Diseases, working at the Department of Internal Medicine, Holstebro, Hospital Unit West, Denmark\n\nDisclosure statement\n\nThe authors report no conflict of interest.\n==== Refs\nReferences\n\n[1] Warren NG. Actinomycosis, nocardiosis and actinomycetoma. Dermatol Clin. 1996 Jan 1;14:85–95 .\n[2] Gray TJ, Serisier DJ. Nocardia paucivorans – a cause of disseminated Nocardiosis. J Infect. 2007 Feb 1;54 (2 ):e95–5.16808975\n[3] Aliaga L, Fatoul G, Guirao E, et al. Nocardia paucivorans brain abscess. Clinical and microbiological characteristics. IDCases. 2018 Jul;4 (13 ):e00422.\n[4] Lin YJ, Yang KY, Ho JT. Nocardial brain abscess. J Clin Neurosci. 2010;17 :250–253.20005722\n[5] Rathish B, Zito PM Nocardia. StatPearls Publishing; 2020 Sep 29.\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2001-8525",
"issue": "8(1)",
"journal": "European clinical respiratory journal",
"keywords": "Diabetes; nocardiosis; opportunistic infection",
"medline_ta": "Eur Clin Respir J",
"mesh_terms": null,
"nlm_unique_id": "101662134",
"other_id": null,
"pages": "1882030",
"pmc": null,
"pmid": "33708362",
"pubdate": "2021-02-24",
"publication_types": "D002363:Case Reports",
"references": "16808975;20005722;30101067;8821161",
"title": "Rare nocardiosis in danish patient with diabetes.",
"title_normalized": "rare nocardiosis in danish patient with diabetes"
} | [
{
"companynumb": "DK-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-288977",
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"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
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"abstract": "Transient global amnesia (TGA) is a syndrome featuring acute anterograde amnesia as the most striking clinical symptom. Its etiology is still a matter of debate. Most neurological guidelines allow the diagnosis on the basis of clinical criteria only; a more extensive evaluation is recommended only for patients with \"red flags\" like severe headache, nausea or vomiting, or metabolic abnormalities. The aim of our study was to assess the frequency of a severe underlying disease or alternative diagnoses (mimics) in patients fulfilling the clinical criteria.\n\n\n\nWe evaluated the medical records and the imaging data of an unselected consecutive cohort of patients with suspected TGA over a 7-year period. All patients were hospitalized and received a neurological workup including brain imaging, color-coded duplex sonography of the brain supplying arteries, electroencephalography, and laboratory studies of blood and (in selected cases) cerebrospinal fluid.\n\n\n\n163 patients with 166 episodes of suspected TGA were hospitalized (3 patients twice). After the workup, the diagnosis of TGA was confirmed in 148/166 (89.2%) episodes (\"simple TGA\"). Eighteen patients (10.8%) either had an alternative diagnosis or a severe comorbidity that was assumed to have had an impact on the occurrence of the amnestic episode (\"complicated TGA/mimic\"). The most important differential diagnosis was stroke (11 patients, 6.6% of all TGA suspects and 61.1% of the complicated TGA/mimic group). Other mimics were transient epileptic amnesia (2 patients) and steroid-induced delirium (1 patient). Important comorbidities that had not been obvious at the time of presentation were severe sleep apnea (2 patients), triptan overuse (1 patient), and an involuntary amlodipine intoxication during TGA.\n\n\n\nAs approximately every tenth patient with suspected TGA either had an alternative diagnosis or a severe comorbidity, which had not been obvious at the time of admission, we consider in-patient treatment of all suspected TGA cases as appropriate, preferably in the setting of a stroke unit, as ischemic stroke was the by far most important diagnosis mimicking TGA.",
"affiliations": "Department of Neurology/Stroke Unit, Katholisches Klinikum Koblenz-Montabaur, Koblenz, Germany, Ralph-Werner@t-online.de.;Department of Neurology/Stroke Unit, Katholisches Klinikum Koblenz-Montabaur, Koblenz, Germany.",
"authors": "Werner|Ralph|R|;Woehrle|Johannes C|JC|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000512602",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1015-9770",
"issue": "50(2)",
"journal": "Cerebrovascular diseases (Basel, Switzerland)",
"keywords": "Clinical neurology; Emergency neurology; Transient global amnesia",
"medline_ta": "Cerebrovasc Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020236:Amnesia, Transient Global; D015897:Comorbidity; D003937:Diagnosis, Differential; D005260:Female; D005858:Germany; D006801:Humans; D008297:Male; D008570:Memory, Short-Term; D008875:Middle Aged; D059906:Neuroimaging; D009460:Neurologic Examination; D011237:Predictive Value of Tests; D015995:Prevalence; D011379:Prognosis; D018570:Risk Assessment; D012307:Risk Factors; D020521:Stroke; D013997:Time Factors",
"nlm_unique_id": "9100851",
"other_id": null,
"pages": "171-177",
"pmc": null,
"pmid": "33412553",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Prevalence of Mimics and Severe Comorbidity in Patients with Clinically Suspected Transient Global Amnesia.",
"title_normalized": "prevalence of mimics and severe comorbidity in patients with clinically suspected transient global amnesia"
} | [
{
"companynumb": "DE-TEVA-2021-DE-1936365",
"fulfillexpeditecriteria": "1",
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"activesubstance": {
"activesubstancename": "AMLODIPINE BESYLATE"
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{
"abstract": "Platinum-based chemotherapy plus cetuximab represents the first-line treatment for recurrent or metastatic squamous cell carcinoma of the head and neck. The most common adverse events associated with cetuximab are infusion reactions and skin reactions, and a risk of venous thromboembolic events has also recently been reported in association with cetuximab. It is well known that thrombosis is a common complication of malignancy, and represents the second most frequent cause of mortality in cancer patients. The present study reports the case of a 79-year-old man who presented with lung and liver metastases from tongue squamous cell carcinoma, for which platinum-based chemotherapy plus cetuximab was administered. After 1 cycle, the patient showed rapid growth of a left ventricular (LV) thrombus, despite ongoing antiplatelet therapy for an old myocardial infarction. Anticoagulant therapy was administered to treat the LV thrombus, which resolved within 1 week. To the best of our knowledge, this represents the first reported case of rapidly occurring LV thrombus associated with platinum-based chemotherapy plus cetuximab. Platinum-based chemotherapy plus cetuximab may be associated with a higher risk of embolic thrombus.",
"affiliations": "Department of Oral and Maxillofacial Reconstructive Surgery, Okayama University Hospital, Okayama, Okayama 700-8558, Japan.;Department of Oral and Maxillofacial Reconstructive Surgery, Okayama University Hospital, Okayama, Okayama 700-8558, Japan.;Department of Dentistry, Oral and Maxillofacial Surgery, Osaka Police Hospital, Osaka, Osaka 543-0035, Japan.;Department of Oral and Maxillofacial Reconstructive Surgery, Okayama University Hospital, Okayama, Okayama 700-8558, Japan.;Department of Oral and Maxillofacial Reconstructive Surgery, Okayama University Hospital, Okayama, Okayama 700-8558, Japan.;Department of Oral and Maxillofacial Reconstructive Surgery, Okayama University Hospital, Okayama, Okayama 700-8558, Japan.;Department of Oral and Maxillofacial Reconstructive Surgery, Okayama University Hospital, Okayama, Okayama 700-8558, Japan.",
"authors": "Ikeda|Atsushi|A|;Yamachika|Eiki|E|;Mizutani|Masahide|M|;Matsubara|Masakazu|M|;Moritani|Norifumi|N|;Nakatsuji|Kazuki|K|;Iida|Seiji|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3892/mco.2017.1393",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2049-9450",
"issue": "7(5)",
"journal": "Molecular and clinical oncology",
"keywords": "cetuximab; head and neck; left ventricular thrombus; squamous cell carcinoma",
"medline_ta": "Mol Clin Oncol",
"mesh_terms": null,
"nlm_unique_id": "101613422",
"other_id": null,
"pages": "833-836",
"pmc": null,
"pmid": "29181174",
"pubdate": "2017-11",
"publication_types": "D016428:Journal Article",
"references": "19726226;12407439;8726168;19068274;21810688;7242633;25889614;8285811;24023347;17922809;22241897;6478564;10737280;18784101;10783046",
"title": "Rapid occurrence of left ventricular thrombus associated with platinum-based chemotherapy plus cetuximab for the treatment of metastatic squamous cell carcinoma of the head and neck: A case report.",
"title_normalized": "rapid occurrence of left ventricular thrombus associated with platinum based chemotherapy plus cetuximab for the treatment of metastatic squamous cell carcinoma of the head and neck a case report"
} | [
{
"companynumb": "JP-PFIZER INC-2017438841",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
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... |
{
"abstract": "OBJECTIVE\nTo investigate characteristics of hepatitis B virus (HBV) implicated in HBV reactivation in patients with hematological malignancies receiving immunosuppressive therapy.\n\n\nMETHODS\nSerum samples were collected from 53 patients with hematological malignancies negative for hepatitis B surface antigen (HBsAg) before the start of and throughout the chemotherapy course. HBV reactivation was diagnosed when the HBsAg status changed from negative to positive after the initiation of chemotherapy and/or when HBV DNA was detected by real-time detection polymerase chain reaction (RTD-PCR). For detecting the serological markers of HBV infection, HBsAg as well as antibodies to the core antigen (anti-HBc) and to the surface antigen were measured in the sera by CEIA. Nucleic acids were extracted from sera, and HBV DNA sequences spanning the S gene were amplified by RTD-PCR. The extracted DNA was further subjected to PCR to amplify the complete genome as well as the specific genomic sequences bearing the enhancer II/core promoter/pre-core/core regions (nt 1628-2364). Amplicons were sequenced directly.\n\n\nRESULTS\nThirty-five (66%) of the 53 HBsAg-negative patients were found to be negative serologically for anti-HBc, and the remaining 18 (34%) patients were positive for anti-HBc. Five of the 53 (9.4%) patients with hematologic malignancies experienced HBV reactivation. Genotype D1 was detected in all five patients. Four types of mutant strains were detected in the S gene product of HBV strains and were isolated from 3 patients with HBV reactivation: T/S120, L143, and I126. HBV DNA was detected in the pretreatment HBsAg-negative samples in one of the five patients with HBV reactivation. In this patient, sequences encompassing the HBV full genome obtained from sera before the start of chemotherapy and at the time of de novo HBV hepatitis were detected and it showed 100% homology. Furthermore, in the phylogenetic tree, the sequences were clustered together, thereby indicating that this patient developed reactivation from an occult HBV infection.\n\n\nCONCLUSIONS\nPast infection with HBV is a risk factor for HBV reactivation in Egypt. Mandatory anti-HBc screening prior to chemotherapy in patients with hematological malignancies is recommended.",
"affiliations": "Abeer Elkady, Shuko Murakami, Sayuki Iijima, Yasuhito Tanaka, Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.",
"authors": "Elkady|Abeer|A|;Aboulfotuh|Sahar|S|;Ali|Elsayed Mostafa|EM|;Sayed|Douaa|D|;Abdel-Aziz|Nashwa M|NM|;Ali|Amany M|AM|;Murakami|Shuko|S|;Iijima|Sayuki|S|;Tanaka|Yasuhito|Y|",
"chemical_list": "D000970:Antineoplastic Agents; D015415:Biomarkers; D004279:DNA, Viral; D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens; D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v19.i37.6214",
"fulltext": null,
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"issn_linking": "1007-9327",
"issue": "19(37)",
"journal": "World journal of gastroenterology",
"keywords": "Hepatitis B surface antigen; Hepatitis B virus; Occult infection; Reactivation",
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D015415:Biomarkers; D002648:Child; D002675:Child, Preschool; D004279:DNA, Viral; D004534:Egypt; D005260:Female; D005838:Genotype; D019337:Hematologic Neoplasms; D006509:Hepatitis B; D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens; D006515:Hepatitis B virus; D006801:Humans; D007166:Immunosuppressive Agents; D015994:Incidence; D008297:Male; D010802:Phylogeny; D012307:Risk Factors; D016896:Treatment Outcome; D014775:Virus Activation; D055815:Young Adult",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "6214-20",
"pmc": null,
"pmid": "24115819",
"pubdate": "2013-10-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "15990987;21528070;17112622;17255759;14671065;10914949;16923112;7715341;20597091;19842236;12081601;22677988;19041311;17877727;9392700;21472119;17368969;18551607;18847320;8410512;12021331;21264861;16409685;22232374;16831590;15914368;16006001",
"title": "Incidence and characteristics of HBV reactivation in hematological malignant patients in south Egypt.",
"title_normalized": "incidence and characteristics of hbv reactivation in hematological malignant patients in south egypt"
} | [
{
"companynumb": "JP-PFIZER INC-2021492287",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE SODIUM"
},
"drugadditional": "3",... |
{
"abstract": "Background: Disordered metabolism of bone and minerals is a problem frequently encountered in patients with chronic kidney disease. Early biochemical changes include altered calcium and phosphate balance, while advanced disease produces reduced bone strength and extraskeletal calcification. The syndrome describing this constellation of findings is termed chronic kidney disease mineral and bone disorder. Case Report: This report details a rare and extreme manifestation of chronic kidney disease mineral and bone disorder in a patient on long-term hemodialysis for end-stage renal failure. Progressive abnormalities of the thoracic skeleton were ultimately severe enough to produce restrictive lung physiology and symptomatic respiratory failure. Conclusion: Cases of chronic kidney disease mineral and bone disorder with pronounced clinical sequelae occur uncommonly in contemporary practice because of early detection and effective therapies. To our knowledge, this report is the first case in the literature of severe thoracic involvement manifesting as respiratory failure.",
"affiliations": "Department of Nephrology, Gold Coast University Hospital, Gold Coast, Queensland, Australia.;Department of Nephrology, Townsville Hospital, Townsville, Queensland, Australia.",
"authors": "Yaxley|Julian|J|;Scott|Tahira|T|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.31486/toj.18.0177",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1524-5012",
"issue": "19(3)",
"journal": "The Ochsner journal",
"keywords": "Bone remodeling; hyperparathyroidism; kidney failure–chronic; osteodystrophy; respiratory insufficiency",
"medline_ta": "Ochsner J",
"mesh_terms": null,
"nlm_unique_id": "101125795",
"other_id": null,
"pages": "282-285",
"pmc": null,
"pmid": "31528143",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "12081600;16775593;17251386;21389978;29702682;8460225;9166570",
"title": "Respiratory Failure: A Rare Complication of Chronic Kidney Disease Mineral and Bone Disorder.",
"title_normalized": "respiratory failure a rare complication of chronic kidney disease mineral and bone disorder"
} | [
{
"companynumb": "AU-ALKEM LABORATORIES LIMITED-AU-ALKEM-2019-08727",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AMLODIPINE BESYLATE"
},
... |
{
"abstract": "Multidrug-resistant tuberculosis (MDR-TB) is of low proportion in comparison to the total number of TB patients, however, due to the necessity of a complex medication with potentially severe and life threatening adverse reactions, long term sequelae, and unfavorable outcome special attention is essential. We report the case of a 30-year-old geriatric nurse with a history of chronic cough and hereditary alpha-1-anti-trypsin deficiency (AATD), who suffered from MDR-TB and experienced a number of severe adverse reactions.",
"affiliations": "Universitätsspital Basel, Bereich für Pneumologie, Basel, Schweiz.;Robert-Koch-Klinik, Klinikum Sankt Georg, Leipzig, Deutschland.;Robert-Koch-Klinik, Klinikum Sankt Georg, Leipzig, Deutschland.;Praxis für Pneumologie/Allergologie, Leipzig, Deutschland.;Praxis für Neurologie, Leipzig, Deutschland.;Pneumologisches Facharztzentrum, Teuchern, Deutschland.;Praxis für Pneumologie/Allergologie, Leipzig, Deutschland.",
"authors": "Hoheisel|Andreas|A|;Vogt|Geert|G|;Nagel|Stephan|S|;Bonitz|Andreas|A|;Müller|Christian|C|;Köhnlein|Thomas|T|;Hoheisel|Gerhard|G|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1055/a-1493-1206",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0934-8387",
"issue": "75(12)",
"journal": "Pneumologie (Stuttgart, Germany)",
"keywords": null,
"medline_ta": "Pneumologie",
"mesh_terms": null,
"nlm_unique_id": "8906641",
"other_id": null,
"pages": "971-980",
"pmc": null,
"pmid": "34233361",
"pubdate": "2021-12",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "MDR tuberculosis, Alpha-1-anti-trypsin Deficiency, Cough in a Geriatric Nurse.",
"title_normalized": "mdr tuberculosis alpha 1 anti trypsin deficiency cough in a geriatric nurse"
} | [
{
"companynumb": "DE-HQ-000173",
"fulfillexpeditecriteria": "1",
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LINEZOLID"
},
"drugadditional": "1",
"drugadmini... |
{
"abstract": "Psychotropic medications may cause many ocular adverse effects including toxic optic neuropathy. We present a unique case of a 44-year-old woman using duloxetine who presented with unilateral visual loss due to retrobulbar neuritis. Physicians and patients should be alerted to this potential side effect. To the best of our knowledge, this is the first case of developing retrobulbar neuritis related to duloxetine usage.",
"affiliations": "a Department of Ophthalmology , Diskapi Yildirim Beyazit Training and Research Hospital , Ankara , Turkey.;a Department of Ophthalmology , Diskapi Yildirim Beyazit Training and Research Hospital , Ankara , Turkey.;a Department of Ophthalmology , Diskapi Yildirim Beyazit Training and Research Hospital , Ankara , Turkey.;a Department of Ophthalmology , Diskapi Yildirim Beyazit Training and Research Hospital , Ankara , Turkey.",
"authors": "Bicer|Tolga|T|;Kosker|Mustafa|M|;Celikay|Osman|O|;Gurdal|Canan|C|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D000928:Antidepressive Agents; D000068736:Duloxetine Hydrochloride; D011241:Prednisone; D008775:Methylprednisolone",
"country": "England",
"delete": false,
"doi": "10.3109/15569527.2015.1076435",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-9527",
"issue": "35(3)",
"journal": "Cutaneous and ocular toxicology",
"keywords": "Cymbalta; duloxetine; eye; optic neuritis; selective serotonin reuptake inhibitors; toxic optic neuropathy",
"medline_ta": "Cutan Ocul Toxicol",
"mesh_terms": "D000328:Adult; D000893:Anti-Inflammatory Agents; D000928:Antidepressive Agents; D003865:Depressive Disorder, Major; D000068736:Duloxetine Hydrochloride; D005074:Evoked Potentials, Visual; D005123:Eye; D005260:Female; D006801:Humans; D008775:Methylprednisolone; D009902:Optic Neuritis; D011241:Prednisone; D014792:Visual Acuity; D014794:Visual Fields",
"nlm_unique_id": "101266892",
"other_id": null,
"pages": "251-3",
"pmc": null,
"pmid": "26362493",
"pubdate": "2016-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of retrobulbar optic neuritis caused by duloxetine.",
"title_normalized": "a case of retrobulbar optic neuritis caused by duloxetine"
} | [
{
"companynumb": "TR-SUN PHARMACEUTICAL INDUSTRIES LTD-2016RR-122378",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DULOXETINE HYDROCHLORIDE"
},
... |
{
"abstract": "Intra-arterial chemotherapy (IAC) for retinoblastoma has been documented as causing visual loss and ocular motility problems. A lack of safety data has precluded its acceptance in all centres.\n\n\n\nRetrospective cohort study of patients with retinoblastoma from 2013 to 2015 who had a healthy foveola and relapsed following systemic chemotherapy. All required IAC. The correlation of complications with doses of melphalan +/- topotecan used and putative catheterisation complications was assessed. Ocular complications were determined using vision, macular (including pattern visual evoked potentials (PVEPs)), retinal electroretinograms (ERGs) and ocular motility functions. Efficacy (tumour control) was also assessed.\n\n\n\nAll eyes had age appropriate doses of melphalan with five having additional doses of topotecan. Severe physiological reactions requiring adrenaline were seen in six patients during the catheterisation procedure. Difficulty was documented in accessing the ophthalmic artery in 7/27 catheterisations. The median/mean number of courses of chemotherapy was three. No child had severe visual loss as assessed by age appropriate tests (median follow-up 20.9 months, range 3.7-35.2 months). One child had nasal choroidal ischaemia and a sixth nerve palsy. Post-IAC PVEPs were performed in eight and reported as normal. All post-IAC ERGs were normal apart from one (total dose 20 mg melphalan 0.8 mg topotecan). Tumour control was achieved in six of nine cases.\n\n\n\nThe proportion of visual and ocular motility complications may be reduced by providing age-adjusted doses of melphalan. Dose rather than complications from catheterisation is the most important risk factor for ocular injury.",
"affiliations": "Department of Ophthalmology, Barts Health NHS Trust, London, UK.;Retinoblastoma Unit, Barts Health NHS Trust, London, UK.;Great Ormond Street Hospital For Children NHS Trust, London, UK.;Great Ormond Street Hospital For Children NHS Trust, London, UK.;Great Ormond Street Hospital For Children NHS Trust, London, UK.;Department of Radiology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.;Clinical and Academic Department of Ophthalmology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.;Clinical and Academic Department of Ophthalmology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.;Retinoblastoma Unit, Barts Health NHS Trust, London, UK.",
"authors": "Reddy|M Ashwin|MA|;Naeem|Zishan|Z|;Duncan|Catriona|C|;Robertson|Fergus|F|;Herod|Jane|J|;Rennie|Adam|A|;Liasis|Alki|A|;Thompson|Dorothy Ann|DA|;Sagoo|Mandeep|M|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "England",
"delete": false,
"doi": "10.1136/bjophthalmol-2017-310294",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1161",
"issue": "101(12)",
"journal": "The British journal of ophthalmology",
"keywords": "Child health (paediatrics); Electrophysiology; Neoplasia; Retina; Vision",
"medline_ta": "Br J Ophthalmol",
"mesh_terms": "D000970:Antineoplastic Agents; D004596:Electroretinography; D005074:Evoked Potentials, Visual; D005260:Female; D005451:Fluorescein Angiography; D005500:Follow-Up Studies; D005654:Fundus Oculi; D006801:Humans; D007223:Infant; D007261:Infusions, Intra-Arterial; D008297:Male; D009880:Ophthalmic Artery; D012160:Retina; D019572:Retinal Neoplasms; D012175:Retinoblastoma; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D014786:Vision Disorders; D014792:Visual Acuity",
"nlm_unique_id": "0421041",
"other_id": null,
"pages": "1704-1708",
"pmc": null,
"pmid": "28432112",
"pubdate": "2017-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Reduction of severe visual loss and complications following intra-arterial chemotherapy (IAC) for refractory retinoblastoma.",
"title_normalized": "reduction of severe visual loss and complications following intra arterial chemotherapy iac for refractory retinoblastoma"
} | [
{
"companynumb": "GB-ACCORD-051202",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TOPOTECAN HYDROCHLORIDE"
},
"drugadditional": "3",
... |
{
"abstract": "A 63-year-old Caucasian taxi driver presented with a 3-week history of malaise, night sweats, 7 kg weight loss, generalized arthralgia, and persistent mid-lower abdominal pain. Blood inflammatory markers were raised, and a computed tomography scan demonstrated an irregular degeneration of the infrarenal aorta, with a differential diagnosis including aortic infection. An urgent type IV thoracoabdominal aneurysm repair was performed with a rifampicin-soaked aortic tube graft during an open procedure. No organisms were grown from multiple peripheral blood cultures or culture of the affected aorta. However, subsequent 16S ribosomal polymerase chain reaction analysis of the resected aorta identified Capnocytophaga canimorsus as the causative organism-a commensal that lives in the mouth of dogs and cats. The patient subsequently gave a history of multiple bites from his pet dog over recent months-the likely source of infection. He was treated with 8 weeks of intravenous antibiotics before switching to oral antibiotics for an additional 6 weeks.",
"affiliations": "Department of Infection, Guy's and St Thomas' NHS Foundation Trust, London, UK. Electronic address: john.evans@gstt.nhs.uk.;Department of Vascular Surgery, Guy's and St Thomas' NHS Foundation Trust, London, UK.;Department of Infection, Guy's and St Thomas' NHS Foundation Trust, London, UK.;Department of Infection, Guy's and St Thomas' NHS Foundation Trust, London, UK.;Department of Vascular Surgery, Guy's and St Thomas' NHS Foundation Trust, London, UK.;Department of Vascular Surgery, Guy's and St Thomas' NHS Foundation Trust, London, UK.",
"authors": "Evans|Terry J|TJ|;Lyons|Oliver T|OT|;Brown|Aisling|A|;Price|Nicholas|N|;Bell|Rachel E|RE|;Sallam|Morad|M|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0890-5096",
"issue": "32()",
"journal": "Annals of vascular surgery",
"keywords": null,
"medline_ta": "Ann Vasc Surg",
"mesh_terms": "D000785:Aneurysm, Infected; D000818:Animals; D000900:Anti-Bacterial Agents; D017545:Aortic Aneurysm, Thoracic; D001027:Aortography; D001733:Bites and Stings; D019917:Blood Vessel Prosthesis Implantation; D002206:Capnocytophaga; D000072226:Computed Tomography Angiography; D004285:Dogs; D016905:Gram-Negative Bacterial Infections; D006801:Humans; D008297:Male; D008875:Middle Aged; D000072078:Positron Emission Tomography Computed Tomography; D021521:Ribotyping; D016896:Treatment Outcome",
"nlm_unique_id": "8703941",
"other_id": null,
"pages": "130.e5-7",
"pmc": null,
"pmid": "26802291",
"pubdate": "2016-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Mycotic Aneurysm following a Dog Bite: The Value of the Clinical History and Molecular Diagnostics.",
"title_normalized": "mycotic aneurysm following a dog bite the value of the clinical history and molecular diagnostics"
} | [
{
"companynumb": "GB-LUPIN PHARMACEUTICALS INC.-2016-02127",
"fulfillexpeditecriteria": "2",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN"
},
"drugadditi... |
{
"abstract": "BACKGROUND\nPrimary choriocarcinoma of the colon is an extremely rare neoplasm which has a poor prognosis. Only 18 cases have been previously reported in English medical literature. Here we present a case of primary rectal choriocarcinoma with a good response to chemotherapy and review the literature on this uncommon tumor.\n\n\nMETHODS\nA 36-year-old woman presented with abdominal pain and vaginal bleeding. Abdominal magnetic resonance imaging revealed 6.9 × 5.3 × 6.4 cm hypervascular mass posterior to uterus very close to rectum. Beta-human chorionic gonadotropin (β-hCG) level was markedly elevated. Low anterior resection of the rectum with lymph node dissection and total abdominal hysterectomy with bilateral salpingo-oophorectomy were performed. Pathologic diagnosis was reported as colonic choriocarcinoma with a focal component of adenocarcinoma. Post-operative magnetic resonance imaging detected multiple metastatic lesions throughout the liver. The patient was treated with systemic chemotherapy using bleomycin, etoposide and cisplatin (BEP protocol). After three cycles, β-hCG level decreased to normal and magnetic resonance imaging showed regression of liver metastasis. However, the patient died of respiratory failure due to bleomycin toxicity and pneumonia accompanied by rapid disease progression.\n\n\nCONCLUSIONS\nThis is an extremely rare case of primary rectal choriocarcinoma. Due to poor prognosis of the disease, it seems very important to start prompt treatment to improve patient's survival.",
"affiliations": "Division of Medical Oncology, Department of Internal Medicine, Marmara University School of Medicine, Istanbul, Turkey.;Division of Medical Oncology, Department of Internal Medicine, Marmara University School of Medicine, Istanbul, Turkey.;Division of Medical Oncology, Department of Internal Medicine, Marmara University School of Medicine, Istanbul, Turkey.;Division of Medical Oncology, Department of Internal Medicine, Marmara University School of Medicine, Istanbul, Turkey.;Division of Medical Oncology, Department of Internal Medicine, Marmara University School of Medicine, Istanbul, Turkey.;Division of Medical Oncology, Department of Internal Medicine, Marmara University School of Medicine, Istanbul, Turkey.;Department of General Surgery, Marmara University School of Medicine, Istanbul, Turkey.;Department of Radiology, Marmara University School of Medicine, Istanbul, Turkey.;Department of Pathology, Marmara University School of Medicine, Istanbul, Turkey.;Division of Medical Oncology, Department of Internal Medicine, Marmara University School of Medicine, Istanbul, Turkey.;Division of Medical Oncology, Department of Internal Medicine, Marmara University School of Medicine, Istanbul, Turkey.;Division of Medical Oncology, Department of Internal Medicine, Marmara University School of Medicine, Istanbul, Turkey.;Division of Medical Oncology, Department of Internal Medicine, Marmara University School of Medicine, Istanbul, Turkey.",
"authors": "Telli|Tugba A|TA|https://orcid.org/0000-0001-6535-6030;Demircan|Nazim C|NC|https://orcid.org/0000-0001-6630-5278;Alan|Ozkan|O|https://orcid.org/0000-0002-6635-2012;Tuylu|Tugba B|TB|;Arikan|Rukiye|R|;Ercelep|Ozlem|O|;Atıcı|Ali E|AE|;Ergelen|Rabia|R|;Seven|Ipek E|IE|;Babacan|Nalan A|NA|;Kaya|Serap|S|;Dane|Faysal|F|;Fulden Yumuk|Perran|P|",
"chemical_list": "D001761:Bleomycin; D005047:Etoposide; D002945:Cisplatin",
"country": "England",
"delete": false,
"doi": "10.1177/1078155219875510",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "26(4)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Choriocarcinoma; chemotherapy; colorectal",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001761:Bleomycin; D031954:Choriocarcinoma, Non-gestational; D002945:Cisplatin; D005047:Etoposide; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D012004:Rectal Neoplasms; D012007:Rectum",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "989-994",
"pmc": null,
"pmid": "31547751",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "A rare case of primary rectal choriocarcinoma and review of the literature.",
"title_normalized": "a rare case of primary rectal choriocarcinoma and review of the literature"
} | [
{
"companynumb": "TR-MEITHEAL PHARMACEUTICALS-2020MHL00024",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional... |
{
"abstract": "The clinical benefit of adjuvant intravenous immunoglobulin (IVIG) therapy is controversial in immunocompromised patients with severe varicella. A twenty-one-year-old woman who had received a kidney transplant one year earlier presented with fever and generalized rash for 5 days. Initial immunoglobulin M (IgM) and IgG for varicella zoster virus (VZV) were negative; however, the patient was diagnosed with varicella with fulminant hepatitis because VZV-specific PCR from skin vesicles and blood was positive. The patient received intravenous acyclovir and 5-day IVIG. The decline of plasma viral load was steeper (beta coefficient -0.446) during IVIG therapy than after the therapy (beta coefficient -0.123) (P = 0.04), while VZV glycoprotein IgG titers and VZV-specific T cell responses were not detected during the 5-day IVIG therapy. The patient improved without any complications. This case provides an experimental evidence that adjuvant IVIG can significantly reduce viral load in immunocompromised patients with severe varicella.",
"affiliations": "Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea.;Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. kimsunghanmd@hotmail.com.",
"authors": "Hsing|Li Chang|LC|https://orcid.org/0000-0002-2328-7580;Kim|Ji Yeun|JY|;Kwon|Ji Soo|JS|;Shin|Eui Cheol|EC|;Kim|Sung Han|SH|https://orcid.org/0000-0002-6596-8253",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.3947/ic.2019.51.3.310",
"fulltext": "\n==== Front\nInfect ChemotherInfect ChemotherICInfection & Chemotherapy2093-23402092-6448The Korean Society of Infectious Diseases and Korean Society for Chemotherapy 3158386510.3947/ic.2019.51.3.310Case ReportSuccessful Treatment of Fulminant Hepatitis due to Varicella Zoster Virus using Immunoglobulin in a Kidney Transplant Patient https://orcid.org/0000-0002-2328-7580Hsing Li-Chang 1*Kim Ji Yeun 1*Kwon Ji-Soo 12Shin Eui-Cheol 2https://orcid.org/0000-0002-6596-8253Kim Sung-Han 11 Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.2 Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea.Corresponding Author: Sung-Han Kim, MD, PhD. Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea. Tel: +82-2-3010-3305, Fax: +82-2-3010-6970, kimsunghanmd@hotmail.com*Li-Chang Hsing and Ji Yeun Kim contributed equally to this study.\n\n9 2019 29 11 2018 51 3 310 314 16 2 2017 30 6 2017 Copyright © 2019 by The Korean Society of Infectious Diseases and Korean Society for Chemotherapy2019The Korean Society of Infectious Diseases and Korean Society for ChemotherapyThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.The clinical benefit of adjuvant intravenous immunoglobulin (IVIG) therapy is controversial in immunocompromised patients with severe varicella. A twenty-one-year-old woman who had received a kidney transplant one year earlier presented with fever and generalized rash for 5 days. Initial immunoglobulin M (IgM) and IgG for varicella zoster virus (VZV) were negative; however, the patient was diagnosed with varicella with fulminant hepatitis because VZV-specific PCR from skin vesicles and blood was positive. The patient received intravenous acyclovir and 5-day IVIG. The decline of plasma viral load was steeper (beta coefficient −0.446) during IVIG therapy than after the therapy (beta coefficient −0.123) (P = 0.04), while VZV glycoprotein IgG titers and VZV-specific T cell responses were not detected during the 5-day IVIG therapy. The patient improved without any complications. This case provides an experimental evidence that adjuvant IVIG can significantly reduce viral load in immunocompromised patients with severe varicella.\n\nVaricella zoster virusFatal hepatitisIntravenous immunoglobulinMinistry of Health and Welfarehttp://doi.org/10.13039/501100003625HI15C1763\n==== Body\nIntroduction\nVaricella Zoster Virus (VZV) infection is usually a self-limited disease in immunocompetent patients; however, it could be fatal for immunocompromised patients; such as organ transplantation recipients [1]. Theoretically, intravenous immunoglobulin (IVIG) could suppress viremia by preventing invasion of VZV into target cells [23]. However, there are few reports on whether IVIG is beneficial in immunocompromised patients with severe varicella [34]. Here, we describe a case of a young adult kidney transplant recipient who had severe varicella with fulminant hepatitis and was successfully treated by intravenous acyclovir (ACV) with adjuvant IVIG. We present the details of viral kinetics in the plasma and of humoral and cell-mediated immune responses from this case.\n\nCase report\nA 21-year-old woman who had received a living-related kidney transplant 1 year earlier presented with fever and generalized rash for 5 days. She had a generalized multistage blister-like rash (Supplemental Fig. 1). She was admitted to another hospital and was diagnosed with chickenpox. She received ACV 10 mg/kg IV every 12 hours for 2 days according to her estimated glomerular filtration rate of 38 ml/min/1.73m2. However, the fulminant hepatitis progressed and she was referred to our hospital for an emergency liver transplantation. Her immunosuppressive regimen consisted of tacrolimus 2 mg twice a day, mycophenolate mofetil 1 g twice a day, and prednisone 7.5 mg once daily. Her antimicrobial prophylaxis consisted of trimethoprim/sulfamethoxazole. She had no past history of chickenpox, and had received varicella vaccine at 12 months of age. She did not drink alcohol, and there was no history of taking herbal medicine. Initial blood examination revealed a white blood cell count of 22.8×103/mm3, hemoglobin 13.3 g/dL, platelet count 53×103/mm3, prothrombin time (PT) 17.8 sec, serum creatinine 1.65 mg/dL, alanine aminotransferase (ALT) 2,016 IU/L, aspartate aminotransferase (AST) 4,434 IU/L, albumin 4.1 g/dL, blood urea nitrogen (BUN) 20 mg/dL, total bilirubin 0.4 mg/dL, lactate dehydrogenase (LD) 6,484 IU/L, and creatine kinase (CK) 117 IU/L. Serum examination for hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), and cytomegalovirus(CMV) were negative, and additional workup including autoimmune and Wilson's disease was unremarkable. Initial IgM and IgG for VZV were negative on hospital day (HD 1), but VZV-specific PCR from skin vesicles and blood was positive on HD 7. Thus, the patient was diagnosed with varicella with fulminant hepatitis. The patient received empirical antibiotics including meropenem 1 g IV every 12 hours from HD 1 to HD 6, teicoplanin 400 mg IV every 72 hours from HD 1 to HD 3, ACV 10 mg/kg IV every 12 hours according to her estimated glomerular filtration rate of 38 ml/min/1.73m2 from HD 1 to HD 15. Because the initial trough levels of tacrolimus was 13.7 ng/mL, the tacrolimus dose was decreased to 1 mg twice a day with a target trough concentration range of 6-8 ng/mL; prednisone dose was decreased to 5 mg once daily, and mycophenolate mofetil was discontinued. On HD 2, her ALT and AST rapidly increased to 7,638 IU/L and 3,034 IU/L, respectively, and PT increased to 25.8 sec. Adjuvant IVIG 500 mg/kg/day was administered from HD 2 to 7. The decreasing slope (beta coefficient −0.446) of blood viral load was steeper during the IVIG therapy than after the therapy(beta coefficient −0.123) (P = 0.04, Fig. 1A), and VZV glycoprotein IgG titer and VZV-specific T cell response were not detectible during the 5-day IVIG therapy (Fig. 1B and 1C). On HD 7, her AST and ALT decreased to 265 IU/L and 435 IU/L, respectively, and PT decreased to 16.2 sec; however, platelet count decreased to 6x103/mm3 and serum creatinine increased to 2.49 mg/dL. Her general condition and laboratory findings improved and she was discharged without any complication on HD 14.\n\nFigure 1 (A) Detailed kinetic data on varicella-zoster virus (VZV) DNA loads in plasma and saliva, and alanine aminotransferase, according to days after symptom onset in a 21-year-old woman with fulminant varicella hepatitis. The decline in viral copies in plasma (pupple line) and saliva (orange line), and alanine aminotransferase (sky blue line) are shown. The duration of antimicrobial therapy and intravenous immunoglobulin(IVIG) is shown by the yellow bars. The dashed line represents the day of hospitalization. (B) Changes of VZV glycoprotein IgG titer and (C) VZV lysate-specific T cell response as a function of hospital day. (PBMCs: peripheral blood mononuclear cells).\n1. Varicella zoster viral load\nTo quantify the viral load, patient's plasma and saliva were collected. Saliva samples of one mL or more were collected using Omnigene-Oral kit (DNA GenotekInc., Ottawa, Ontario, Canada) at any time of day, but at least one hour after a meal. The saliva samples were vigorously shaken for at least 10 seconds and incubated in a water bath at 50 °C for 1 hour. DNA was extracted from plasma and saliva samples using a Qia-Amp DNA mini kit (Qiagen Inc., Chatsworth, CA, USA), and VZV was quantified with a VZV real-time PCR kit (GeneProof, Brno, Czech Republic) using a LightCycler 480 System (Roche, Basel, Switzerland). VZV DNA copy number was determined by comparing the cycle threshold (Ct) value of test samples with the Ct value of the reference VZV DNA provided with the PCR kit. The limit of quantitative PCR detection was 1 copy of VZV DNA per PCR reaction or 10 copies per mL of plasma or saliva.\n\n2. VZV-specific T cell response and antibody response\nPeripheral blood mononuclear cells (PBMCs) were isolated from whole blood samples using lymphocyte separation medium (Corning Inc., New York, NY, USA) and cryopreserved. Cryopreserved PBMCs were quickly thawed at 37°C, washed twice with RPMI-1640 medium with 10% heat-inactivated fetal bovine serum, and resuspended at 2 × 106 cells/mL. Samples of 100 μL of PBMCs were seeded onto 96-well plates coated with anti-human interferon gamma antibody (Thermo Fisher Scientific, Waltham, MA, USA, 2 µg/mL) and stimulated with a VZV lysate (VZ-10 strain, Microbix Biosystems Inc. Toronto, Ontario, Canada). Phytohemagglutinin (Sigma Aldrich, St. Louis, MO, USA; 50 ng/mL) was used as a positive control. Spots were counted and analyzed with an automated enzyme-linked ImmunoSpot plate reader (ImmunoSpot analyzer, Cellular Technology Limited, Shaker Heights, Cleveland, OH, USA). The resulting spot numbers were expressed as mean numbers of spot-forming units per 106 cells in duplicate assays. The titers of anti-VZV glycoprotein IgG in plasma samples from the patient were measured with a commercial VZV glycoprotein ELISA kit (Binding Site Group Ltd, Edgbaston, Birmingham, UK).\n\n3. Statistical Analysis\nThe patient's plasma viral loads (varicella copies/mL) were plotted on a logarithmic scale against time (in days) and fitted by linear regression. We evaluated the slope changes between before and after IVIG administration, which was assessed by adding the interaction effect to linear regression. Statistical significance was defined at P <0.05.\n\nDiscussion\nEarly ACV therapy has been known to prevent dissemination of VZV and ameliorate the disease course [56]. However, in some disseminated VZV infection, ACV may not be sufficient for controlling VZV infection in immunocompromised patients [78]. In the present case, fulminant hepatitis due to VZV progressed despite 2-day ACV therapy, at which point the patient was referred to our hospital. We administered adjuvant IVIG with intravenous ACV therapy, and her condition gradually improved. After infusion of IVIG for 5 days, serum creatinine increased. Considering the cause of elevated serum creatinine, IVIG might not be excluded. The use of IVIG must be carried out with care because renal toxicity following IVIG infusion is not uncommon. Also, infusion of IVIG may lead to several complications such as anaphylaxis, central nerve system complications, thromboembolism, hemolysis, and neutropenia [9]. A previous study showed that current IVIG preparations have high levels of VZV-specific IgG despite waning immunity to VZV in the general population due to the lack of circulating virus [10]. However, there are few data on whether IVIG can suppress viremia by neutralizing VZV. Despite continuous ACV infusion, the slope of blood viral load was steeper during the 5-day IVIG infusion than that after the infusion. Furthermore, we clearly showed that VZV-specific T cell and antibody responses were not mounted up to the end of the IVIG infusion (Fig. 1B and 1C), which means that the patient's own immune response was not yet able to control the disseminated VZV during the IVIG therapy. Previous studies have shown that VZV-specific IgG antibody is detected in most patients within the first 4 days after the onset of rash [11]. In addition, viral load in peripheral blood in patients with varicella rapidly decline 1 week after the onset of symptom [12]. We assume that the immunocompromised status may have contributed to the delayed antibody response and viral clearance in this patient. We believe that this case provides important experimental evidence that adjuvant IVIG can significantly reduce viral load kinetics in immunocompromised patients with severe varicella.\n\nFunding: This study was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant no. HI15C1763).\n\nConflict of Interest: No conflicts of interest.\n\nAuthor Contributions:\nConceptualization: LCH, ECS, SHK.\n\nData curation: LCH, JYK, JSK.\n\nFormal analysis: LCH, ECS, SHK.\n\nFunding acquisition: SHK.\n\nInvestigation: LCH, SHK.\n\nMethodology: JYK, JSK.\n\nSupervision: SHK.\n\nValidation: SHK.\n\nWriting - original draft: LCH, JYK.\n\nWriting - review & editing: LCH, SHK.\n\n\n\n\nSUPPLEMENTARY MATERIAL\nSupplemental Figure 1\nPhotographs of (A) vesicular eruption on the trunk of the patient, and (B) close-up view of a vesicle on the trunk.\n==== Refs\n1 Fehr T Bossart W Wahl C Binswanger U Disseminated varicella infection in adult renal allograft recipients: four cases and a review of the literature Transplantation 2002 73 608 611 11889440 \n2 Errasti P Alvarez ML Gomez G Lavilla FJ Garcia N Ballester B García I Purroy A Chickenpox in four adult renal transplant recipients Transplant Proc 1999 31 2341 2342 10500608 \n3 Kim JH Kwon DH Bae EY Han SB Lee JW Chung NG Jeong DC Cho B Kang JH Kim HK Use of intravenous immunoglobulin in a disseminated varicella infection in an immunocompromised child Korean J Pediatr 2014 57 370 373 25210525 \n4 Han SB Seo YE Kim SK Lee JW Lee DG Chung NG Cho B Kang JH Kim HK Jung ES Varicella with rapidly progressive hepatitis presenting with multiple hepatic nodules in a child with acute leukemia J Infect Chemother 2016 22 822 825 27496601 \n5 Gnann JW Jr Barton NH Whitley RJ Acyclovir: mechanism of action, pharmacokinetics, safety and clinical applications Pharmacotherapy 1983 3 275 283 6359082 \n6 Nyerges G Meszner Z Gyarmati E Kerpel-Fronius S Acyclovir prevents dissemination of varicella in immunocompromised children J Infect Dis 1988 157 309 313 2826611 \n7 Bensousan TA Moal MC Vincent F Nousbaum JB Bourbigot B Fulminant hepatitis revealing primary varicella in a renal graft recipient Transplant Proc 1995 27 2512 7652908 \n8 Patti ME Selvaggi KJ Kroboth FJ Varicella hepatitis in the immunocompromised adult: a case report and review of the literature Am J Med 1990 88 77 80 2403757 \n9 Stiehm ER Adverse effects of human immunoglobulin therapy Transfus Med Rev 2013 27 171 178 23835249 \n10 Maranich AM Rajnik M Varicella-specific immunoglobulin G titers in commercial intravenous immunoglobulin preparations Pediatrics 2009 124 e484 8 19706589 \n11 Baba K Yabuuchi H Takahashi M Gershon AA Ogra PL Seroepidemiologic behavior of varicella zoster virus infection in a semiclosed community after introduction of VZV vaccine J Pediatr 1984 105 712 716 6094778 \n12 Kimura H Kido S Ozaki T Tanaka N Ito Y Williams RK Morishima T Comparison of quantitations of viral load in varicella and zoster J Clin Microbiol 2000 38 2447 2449 10835029\n\n",
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"title": "Successful Treatment of Fulminant Hepatitis due to Varicella Zoster Virus using Immunoglobulin in a Kidney Transplant Patient.",
"title_normalized": "successful treatment of fulminant hepatitis due to varicella zoster virus using immunoglobulin in a kidney transplant patient"
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"affiliations": "Department of Neurosciences B.B. Brodie, Headache Center, University of Cagliari, Italy.",
"authors": "Del Zompo|M|M|;Lai|M|M|;Loi|V|V|;Pisano|M R|MR|",
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"abstract": "We report a rare case that was initially diagnosed as an inflammatory lesion and ultimately confirmed as primary central nervous system lymphoma (PCNSL) in an immunocompetent patient who was not treated with corticosteroid prior to the initial biopsy. A 70-year-old female patient presented with numbness in the left side of face, arm, and leg. Brain magnetic resonance imaging (MRI) revealed a lesion with intense gadolinium (Gd)-enhancement in the ventral portion of the midbrain. A stereotactic biopsy demonstrated mixed T-cell and B-cell infiltrating inflammatory lesions without demyelination. Three months after postoperative treatment with steroid, the lesion markedly decreased on follow-up MRI. Twenty-six months after the initial attack, she complained of dysarthria and urinary incontinence. Repetitive MRI showed a lesion with homogeneous enhancement, extensively involving the bilateral cerebral hemisphere, corpus callosum, and the right middle cerebellar peduncle. The confirmed diagnosis was diffuse large B-cell lymphoma on the second biopsy. Despite our best efforts, she died 38 months after disease onset. Based on review of the literature and our case, preceding inflammatory lesions are not always demyelinating and T-cell dominant inflammatory lesions. When the initial biopsy reveals an inflammatory lesion in an old-aged patient, the clinician should keep in mind the development of PCNSL and perform close clinical and radiological observations for a timely diagnosis.",
"affiliations": "Department of Neurosurgery, Chonnam National University Research Institute of Medical Science, Chonnam National University Hwasun Hospital and Medical School, Jeollanam-do 58128, Korea.;Department of Radiology, Chonnam National University Research Institute of Medical Science, Chonnam National University Hwasun Hospital and Medical School, Jeollanam-do 58128, Korea.;Department of Neurosurgery, Chonnam National University Research Institute of Medical Science, Chonnam National University Hwasun Hospital and Medical School, Jeollanam-do 58128, Korea.;Department of Neurosurgery, Chonnam National University Research Institute of Medical Science, Chonnam National University Hwasun Hospital and Medical School, Jeollanam-do 58128, Korea.;Department of Pathology, Chonnam National University Research Institute of Medical Science, Chonnam National University Hwasun Hospital and Medical School, Jeollanam-do 58128, Korea.;Department of Neurosurgery, Chonnam National University Research Institute of Medical Science, Chonnam National University Hwasun Hospital and Medical School, Jeollanam-do 58128, Korea.",
"authors": "Kim|Yeong Jin|YJ|;Kim|Seul Kee|SK|;Jung|Tae-Young|TY|;Kim|In-Young|IY|;Lee|Kyung-Hwa|KH|;Moon|Kyung-Sub|KS|0000-0002-1129-1064",
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"fulltext": "\n==== Front\nBrain Sci\nBrain Sci\nbrainsci\nBrain Sciences\n2076-3425\nMDPI\n\n33557224\n10.3390/brainsci11020191\nbrainsci-11-00191\nCase Report\nInflammatory Brain Lesions as Omen of Primary Central Nervous System Lymphoma: A Case Report and Literature Review\nKim Yeong Jin 1\nKim Seul Kee 2\nJung Tae-Young 1\nKim In-Young 1\nLee Kyung-Hwa 3*\nhttps://orcid.org/0000-0002-1129-1064\nMoon Kyung-Sub 1*\nBrahmajothi Mulugu V. Academic Editor\n1 Department of Neurosurgery, Chonnam National University Research Institute of Medical Science, Chonnam National University Hwasun Hospital and Medical School, Hwasun 58128, Korea; mbdosa88@naver.com (Y.J.K.); jung-ty@jnu.ac.kr (T.-Y.J.); kiy87@hanmail.net (I.-Y.K.)\n2 Department of Radiology, Chonnam National University Research Institute of Medical Science, Chonnam National University Hwasun Hospital and Medical School, Hwasun 58128, Korea; kimsk.rad@gmail.com\n3 Department of Pathology, Chonnam National University Research Institute of Medical Science, Chonnam National University Hwasun Hospital and Medical School, Hwasun 58128, Korea\n* Correspondence: mdkaylee@jnu.ac.kr (K.-H.L.); moonks@chonnam.ac.kr (K.-S.M.); Tel.: +82-61-379-7050 (K.-H.L.); +82-61-379-7666 (K.-S.M.)\n04 2 2021\n2 2021\n11 2 19131 12 2020\n02 2 2021\n© 2021 by the authors.\n2021\nLicensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).\nWe report a rare case that was initially diagnosed as an inflammatory lesion and ultimately confirmed as primary central nervous system lymphoma (PCNSL) in an immunocompetent patient who was not treated with corticosteroid prior to the initial biopsy. A 70-year-old female patient presented with numbness in the left side of face, arm, and leg. Brain magnetic resonance imaging (MRI) revealed a lesion with intense gadolinium (Gd)-enhancement in the ventral portion of the midbrain. A stereotactic biopsy demonstrated mixed T-cell and B-cell infiltrating inflammatory lesions without demyelination. Three months after postoperative treatment with steroid, the lesion markedly decreased on follow-up MRI. Twenty-six months after the initial attack, she complained of dysarthria and urinary incontinence. Repetitive MRI showed a lesion with homogeneous enhancement, extensively involving the bilateral cerebral hemisphere, corpus callosum, and the right middle cerebellar peduncle. The confirmed diagnosis was diffuse large B-cell lymphoma on the second biopsy. Despite our best efforts, she died 38 months after disease onset. Based on review of the literature and our case, preceding inflammatory lesions are not always demyelinating and T-cell dominant inflammatory lesions. When the initial biopsy reveals an inflammatory lesion in an old-aged patient, the clinician should keep in mind the development of PCNSL and perform close clinical and radiological observations for a timely diagnosis.\n\nprimary central nervous system lymphoma\ntumor regression\ndiagnosis\ninflammation\ntumefactive lesion\n==== Body\n1. Introduction\n\nPrimary central nervous system lymphoma (PCNSL) is a rare brain tumor, accounting for 3% of all brain tumors and 6% of all extra-nodal lymphomas [1]. In recent decades, the incidence of PCNSL has increased in patients aged > 65 years. PCNSL can develop in patients of any age, with the highest incidence rate in the fifth to seventh decade. Although PCNSL is more common in immunosuppressed patients, its incidence has also increased in immunocompetent individuals [2]. The pathogenesis of PCNSL in immunocompetent individual is still poorly understood. There are a few case studies demonstrating inflammatory brain lesions preceding the development of PCNSL. In previous reports, preceding inflammatory lesions, also called “sentinel lesions”, are described as demyelinating, T-cell dominant inflammatory lesions, and PCNSL can develop in chronological order in different locations [3,4,5]. The relationship between preceding inflammatory lesions and pathogenesis of PCNSL has not yet been revealed. Elucidating this relationship may be helpful to understand the development of PCNSL in immunocompetent patients.\n\nMedian survival of patients has improved since the introduction of methotrexate-based chemotherapy for PCNSL treatment [6]. Therefore, timely diagnosis and treatment are important to improve the prognosis of patients with PCNSL [1]. Herein, we report a rare case of PCNSL with a preceding inflammatory lesion in an immunocompetent patient who was not treated with a corticosteroid prior to initial biopsy.\n\n2. Case Presentation\n\nA 70-year-old woman without previous medical history presented with a one-week history of numbness in the left side of face, arm, and leg. A neurologic examination revealed no additional neurologic sign except above-mentioned symptoms. There were no abnormal laboratory findings from blood samples. Brain MRI showed a contrast-enhancing lesion in the ventral portion of the right midbrain with perilesional edema (Figure 1A–C).\n\nWith suspect of glioma or lymphoma, Leksell frame-based stereotactic biopsy was performed without cerebrospinal fluid (CSF) examination. Biopsy of the lesion showed lymphocytic infiltration composed of mixed CD3+ T-cells and CD20+ B-cells with low Ki-67 index in the perivascular space and glial stroma. Demyelinating features such as foamy macrophages engulfing myelin debris were not detected (Figure 2). Descriptive diagnosis was made as an inflammatory lesion with dense lymphocytic infiltration.\n\nBrain computed tomography (CT) and MRI were performed after the biopsy procedure. Proper specimens were sampled with minimal hemorrhage (Figure 1D). After careful consideration, the patient was treated with intravenous methylprednisolone 160 mg daily for 5 days, leading to subsidence of symptoms gradually. Subsequently, daily doses of 10 mg oral prednisolone were introduced for remaining mild symptoms. Three months after the initial brain MRI, there was nearly complete resolution of the lesion. Brain MRI was performed at 6-month interval and did not reveal specific pathologic findings. Twenty-six months after the initial attack, she suddenly developed urinary incontinence, quadriparesis, and mental deepening. Brain MRI showed homogenously enhancing lesions in both cerebral hemispheres and a curvilinear enhancing lesion involving the middle cerebellar peduncle, distant from the initial lesion (Figure 3A–C).\n\nNeuro-navigation guided burr hole biopsy targeting the right frontal lobe revealed diffuse large B-cell lymphoma (Figure 4). A subsequent systemic evaluation provided no evidence of a systemic lymphoma. She was treated with methotrexate chemotherapy and cytarabine chemotherapy due to methotrexate-induced diabetic insipidus. This treatment provided clinical improvement and nearly complete remission of the lesions on subsequent brain MRI (Figure 3D). Thirty-five months after the initial attack, she suddenly developed right hemiparesis and cognitive impairment. Brain MRI showed homogenously enhancing lesions in the left basal ganglia and pons along the corticospinal tract. She refused further treatment and died at 38 months after the disease onset.\n\n3. Discussion\n\nWe present a patient with a steroid-unaffected inflammatory brain lesion preceding PCNSL. This rare clinical presentation implies that tumefactive inflammatory brain lesions, not only demyelinating lesions, could be omen of PCNSL development and that close clinical observation is mandatory for such patients. PCNSL can be associated with preceding inflammatory lesions as summarized in a few case reports [3,7]. In rare cases, preceding inflammatory lesions resolved spontaneously or through steroid treatment, ultimately resulting in PCNSL development.\n\nIt is difficult to distinguish imaging features of space-occupying inflammatory lesions and brain tumors like PCNSL and glioma from the beginning. Although several imaging studies have been performed, they have not clearly contributed to differential diagnosis. MRI features such as T1 hypo-intensity, T2 hyper-intensity, and contrast enhancing are common to that disease. With the metabolic data from positron emission tomography (PET), advanced MRI techniques (diffusion, spectroscopy, or perfusion) may be useful for differential diagnosis and disease monitoring [8,9]. After all, histological confirmation is required for final diagnosis as done in our case. Unlike other brain tumors, resection of PCNSL is not recommended. Infiltrative spreading and the deep seated location impede tumor removal. Chemotherapy-sensitive, radiotherapy-sensitive, and corticosteroid-responsive features of PCNSL make aggressive surgical resection meaningless. Stereotactic biopsy or other less invasive technique is recommended when CSF examination and eye examination are unable to reach a diagnosis [6]. In the present case, MR images suggested brain tumors like glioma or PCNSL in the deep seated midbrain. We inevitably performed Leksell frame-based stereotactic biopsy.\n\nMost previous studies have reported that preceding inflammatory lesions were histopathologically characterized by a predominance of T cell infiltration with few B cell and demyelination [4,10]. Demyelination is inconclusive, but a characteristic feature to help narrow diagnosis candidates, including infectious, metabolic, toxic and autoimmune etiology [11]. Especially in patients treated with inappropriate steroid treatment before pathologic confirmation, incomplete demyelination with extensive inflammation at the initial biopsy can raise the possibility of PCNSL in recurred brain lesions [11]. Unlike previous studies, our case did not show demyelinating features like foamy macrophages engulfing myelin debris. In addition, mixed T- and B- lymphocytes infiltrated in the perivascular space and glial stroma. Not only our case, but also a few previous case studies have reported minimal inflammation and a mixture of T- and B-cells without demyelination [3,12]. Thus, T-cell dominant lymphocytic infiltration and demyelinating features are not mandatory characteristics of heralding inflammatory lesions.\n\nThere may be questions about the accuracy of the biopsy result. Corticosteroid treatment before initial biopsy can mask clinical symptoms, imaging appearance, and even histological findings of PCNSL. Corticosteroids have a cytolytic effect on lymphoma cells, making them disappear and causing inaccurate diagnosis [13]. As we thought of PCNSL as a disease candidate, corticosteroid treatment was not applied before the initial biopsy in the present case. The stereotactic biopsy target site might obscure histopathological diagnosis. The specimen acquired by stereotactic biopsy could be an appropriate target tissue or an uncertain surrounding tissue. Even with appropriately targeted tissues, indefinite diagnosis can be made because of heterogenous pathology of PCNSL [13]. In our case, brain CT and MRI performed after stereotactic biopsy supported that the lesion was sampled properly with minimal hemorrhage.\n\nThe interval between preceding inflammatory lesions and following PCNSL ranged from 6 months to 4 years [7]. The preceding inflammatory lesions can disappear spontaneously or by corticosteroid treatment without showing clues of PCNSL. Some reports have proposed clinical criteria to raise suspicion for preceding inflammatory lesions and PCNSL. However, there are many exceptions [10]. The present case had descriptive diagnosis as an inflammatory lesion with dense lymphocytic infiltration based on predominant lymphocytic population composed of mixed T- and B- cells with low Ki-67 labeling index in the perivascular space and glial stroma without mitoses, necrosis, or microvascular proliferation. Her initial symptoms and imaging features disappeared after two months of low dose corticosteroid treatment. After that, the patient was free of symptoms and the inflammatory lesion resolved completely for 23 months. At that time, we could not think that PCNSL would awfully develop because her symptoms were mild and the lesion responded well to corticosteroid for a long time. Twenty-five months after the initial histopathological diagnosis, her newly emerging symptoms suddenly exacerbated within three days. Repetitive biopsy from another site confirmed diffuse large B cell lymphoma, different from previous findings. Furthermore, we ruled out the possibility of Epstein-Barr virus-positive PCNSL due to high dose steroid treatment by negative result of in situ hybridization for Epstein-Barr virus encoded RNA performed on the second biopsy.\n\nPCNSL might emerge unexpectedly due to abnormal lymphocyte proliferation after independent preceding inflammatory lesions. It can be triggered by preceding inflammatory lesions in pro-inflammatory patients [4]. PCNSL associated with chronic inflammation has also been reported in immunocompetent patients [14]. On the other hand, preceding inflammatory lesions may be the first immunological defense against emerging PCNSL, causing diagnostic difficulty [5]. Similar cases have been reported repeatedly, but the pathogenetic association between preceding inflammatory lesion and PCNSL is yet mere hypothetical, and further studies on the underlying mechanism are needed. Although the underlying mechanism is unknown, inflammatory response plays an important role in developing PCNSL. Histopathological features as in the present case may be helpful for understanding the pathogenesis of PCNSL in immunocompetent patients. To find common features to give clues, we searched previous studies in English literature that reported biopsy-proven preceding inflammatory lesions and following PCNSL in immunocompetent and corticosteroid-untreated patients before initial biopsy [3,4,5,15,16,17] (Table 1). Combining six cases from the literature and our case, we found that patient’s age was the most noticeable factor. PCNSL in immunocompetent patients usually developed between the age of 55–70 years, while inflammatory demyelinating disease without following PCNSL was present in young adulthood [18]. Similar to PCNSL, preceding inflammatory lesions in the reported cases developed between the age of 44–70 years. Other clinical characteristics were not unified. In brain imaging, either space-occupying lesions or not-occupying lesions such as chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) could be preceding inflammatory lesions [17]. In microscopic findings, inflammatory lesions could be preceding lesions regardless of demyelination or T-cell dominant infiltration. Even steroid responsiveness was variable among previous reports. Collectively, inflammatory brain lesions in aged patients should be suspected as preceding lesions of PCNSL.\n\nAnderson et al. have named inflammatory demyelinating brain lesions preceding PCNSL as “sentinel lesions” [3]. After that, reported studies have used “sentinel lesions” to describe inflammatory brain lesions preceding PCNSL. However, the term of “sentinel lesions” is not suitable to describe chronologically related diseases. The relationship between “sentinel lesions” and PCNSL resembles transient ischemic attack and ischemic stroke rather than sentinel lymph node and breast cancer. Thus, we propose that inflammatory brain lesions preceding PCNSL should be termed as “omen” or “prodromal lesion” of PCNSL.\n\n4. Conclusions\n\nIn conclusion, preceding inflammatory lesions are not always demyelinating lesions or T-cell dominant inflammatory lesions. Inflammatory brain lesions in old-aged patients have a possibility to be an “omen” or “prodromal lesion” of PCNSL. Thus, clinicians must carry out close clinical and radiological observations to reach a timely diagnosis. It is important not to hesitate repetitive biopsy for suspicious lesions.\n\nAcknowledgments\n\nThe English in this document has been checked by at least two professional editors, both native speakers of English.\n\nAuthor Contributions\n\nK.-H.L. and K.-S.M. designed this study. K.-H.L. carried out the pathological studies. Y.J.K. and K.-S.M. drafted the manuscript. S.K.K. and I.-Y.K. carried out the acquisition of radiologic data. Y.J.K., T.-Y.J. and K.-S.M. carried out the interpretation of clinical data. T.-Y.J. and I.-Y.K. revised the manuscript for critical points. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Minist (2018R1A5A2024181 for K.-H.L. and 2020R1C1C1007832 for K.-S.M.) and the Chonnam National University Hospital Biomedical Research Institute (BCRI20051 for K.-H.L.). There was no role of the funding bodies in the design of the study, in collection, analysis, and interpretation of data or in writing the manuscript.\n\nInstitutional Review Board Statement\n\nEthic review and approval were waived for this study, due to the fact that this is a single case repot.\n\nInformed Consent Statement\n\nWritten informed consent has been obtained from the patient(s) to publish this paper.\n\nData Availability Statement\n\nNot applicable.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nFigure 1 MRI of a preceding inflammatory lesion. T2-weighted (A) and T1-weighted MRI with gadolinium (B,C) showing an enhancing lesion in the ventral portion of the right midbrain with perilesional edema. Follow-up T1-weighted MRI with gadolinium (D) after steroid therapy demonstrating the proper location of biopsy (white arrow).\n\nFigure 2 Pathological images of the preceding inflammatory lesion. Histopathological examination of the specimen (A,B) showing dense mononuclear cell infiltration in the perivascular space and glial stroma without necrosis, mitosis, or microvascular proliferation (hematoxylin and eosin staining, 100×, 400×). Immunohistochemical staining showing mixed CD3+ (C) and CD20+ (D) lymphocytic population with a low Ki-67 index (E) (200×).\n\nFigure 3 MRI of primary central nervous system lymphoma (PCNSL) following the preceding inflammatory lesion. T1-weighted MRI with gadolinium (A–C) showing homogeneously enhancing lesions in the bilateral cerebral hemisphere and corpus callosum with punctate enhancing lesions in the right middle cerebellar peduncle. Follow-up T1-weighted MRI with gadolinium (D) demonstrating complete resolution of the lesions after chemotherapy therapy.\n\nFigure 4 Pathological images of PCNSL. Histopathological examination of the specimen (A) showing atypical, large, and irregular cells with vesicular nuclei and prominent nucleoli (hematoxylin and eosin staining, 200×). The majority of tumor cells were negative for CD3 (B) but positive for CD20 (C) with a high Ki-67 index (D) (200×).\n\nbrainsci-11-00191-t001_Table 1 Table 1 Summary of PCNSL with preceding inflammatory lesions in immunocompetent and corticosteroid-untreated patients before initial biopsy.\n\nCase No */Ref.\tAge/Sex\tFirst Lesions\tInterval #\n(mos)\tRelapsed Lesions\t\nSymptom\tMRI\tPathology\tTx\tSymptom\tMRI\tPathology\tTx\tPx !\t\n1/[15]\t56/F\tFatigue\tSmall multifocal T2-hyperintense lesion\tDemyelination with lymphocyte infiltration, reactive astrocytosis\tCorticosteroid\t5\tDementia\nQuadriplegia\tWidespread T2-hyperintense white matter lesion\tPCNSL (B-cell) with severe T-cell in filtration\tNone\n(autopsy)\t13 mos survival\t\n2/[3]\t49/F\tAtaxia\nDeafness\tEnhancing lesion\tNormal tissue with minimal inflammation\tCorticosteroid\t11\tConfusion\nDysarthria\tEnhancing lesion\tPCNSL (B-cell)\tUnknown\tUnknown\t\n3/[4]\t59/F\tFacial paralysis\nHemihypesthesia\tT2-hyperintense, mild enhancing lesion\tT-cell dominant inflammatory lesion with partial demyelination\tCorticosteroid\t28\tDysmetria\nAtaxia\tEnhancing lesions\tPCNSL (B-cell)\tMTX-chemotherapy;\nStem cell apheresis;\nWBRT\t34 mos survival\t\n4/[17]\t58/M\tAtaxia\nDiplopia\tPunctate, curvilinear enhancing lesions\tT-cell dominant inflammatory lesion without demyelination\tCorticosteroid\n& Azathioprine\t14\tAtaxia\nDiplopia\tPunctate, curvilinear\nenhancing lesions\tPCNSL (B-cell)\tNone\t37 mos survival\t\n5/[16]\t70/M\tDementia\nHemiparesis\tHomogenous and ring enhancing lesions\tDemyelinating changes with reactive astrocytes\tCorticosteroid\t3\tDementia\nHemiparesis\tHomogenous enhancing lesion\tPCNSL (B-cell)\tWBRT\t8 mos survival\t\n6/[5]\t44/F\tHand numbness\nAtaxia\nVertigo\tIrregular enhancing lesion\tBoth myelin and axonal loss with focal demyelination\tCorticosteroid\n& MTX\t10\tDementia\nSeizure\nMental change\tEnhancing lesions\tPCNSL (B-cell)\tNone\n(autopsy)\t10 mos survival\t\n7 (current case)\t70/F\tFacial numbness\nHemiparesthesia\tHomogenous\nenhancing lesion\tInflammatory lesion with mixed T/B-cell infiltration\nwithout demyelination\tCorticosteroid\t26\tQuadriparesis\nMental change\tHomogenous enhancing lesions\tPCNSL (B-cell)\tMTX-chemotherapy\t38 mos survival\t\n*: in the order of publication date, #: Interval: from 1st biopsy to 2nd biopsy, !: survival duration from initial diagnosis; MRI; magnetic resonance imaging, Tx; treatment, Px; prognosis, PCNSL; primary central nervous system lymphoma, MTX; methotrexate, WBRT; whole brain radiation treatment, mos; months, F; female, M; male.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Schlegel U. Primary CNS lymphoma Ther. Adv. Neurol. Disord. 2009 2 93 104 10.1177/1756285608101222 21180644\n2. Shiels M.S. Pfeiffer R.M. Besson C. Clarke C.A. Morton L.M. Nogueira L. Pawlish K. Yanik E.L. Suneja G. Engels E.A. Trends in primary central nervous system lymphoma incidence and survival in the U.S Br. J. Haematol. 2016 174 417 424 10.1111/bjh.14073 27018254\n3. Alderson L. Fetell M.R. Sisti M. Hochberg F. Cohen M. Louis D.N. Sentinel lesions of primary CNS lymphoma J. Neurol. Neurosurg. Psychiatry 1996 60 102 105 10.1136/jnnp.60.1.102 8558135\n4. Husseini L. Saleh A. Reifenberger G. Hartung H.P. Kieseier B.C. Inflammatory demyelinating brain lesions heralding primary CNS lymphoma Can. J. Neurol. Sci. 2012 39 6 10 10.1017/S0317167100012610 22384490\n5. Lu J.Q. O’Kelly C. Girgis S. Emery D. Power C. Blevins G. Neuroinflammation preceding and accompanying primary central nervous system lymphoma: Case study and literature review World Neurosurg. 2016 88 692.e1 692.e8 10.1016/j.wneu.2015.11.099 26724610\n6. Grommes C. DeAngelis L.M. Primary CNS lymphoma J. Clin. Oncol. 2017 35 2410 2418 10.1200/JCO.2017.72.7602 28640701\n7. Ng S. Butzkueven H. Kalnins R. Rowe C. Prolonged interval between sentinel pseudotumoral demyelination and development of primary CNS lymphoma J. Clin. Neurosci. 2007 14 1126 1129 10.1016/j.jocn.2006.05.003 17890092\n8. Kuhlmann T. Schröter A. Dechent P. Weber F. Rustenbeck H.H. Füzesi L. Brück W. Ehrenreich H. Frahm J. Diagnosis of a multifocal B cell lymphoma with preceding demyelinating central nervous system lesions by single voxel proton MR spectroscopy J. Neurol. Neurosurg. Psychiatry 2001 70 259 262 10.1136/jnnp.70.2.259 11160483\n9. Chiavazza C. Pellerino A. Ferrio F. Cistaro A. Soffietti R. Ruda R. Primary CNS lymphomas: Challenges in diagnosis and monitoring BioMed Res. Int. 2018 21 3606970 10.1155/2018/3606970 30035121\n10. Kvarta M.D. Sharma D. Castellani R.J. Morales R.E. Reich S.G. Kimball A.S. Shin R.K. Demyelination as a harbinger of lymphoma: A case report and review of primary central nervous system lymphoma preceded by multifocal sentinel demyelination BMC Neurol. 2016 16 72 10.1186/s12883-016-0596-1 27206499\n11. Barrantes-Freer A. Engel A.S. Rodríguez-Villagra O.A. Winkler A. Bergmann M. Mawrin C. Kuempfel T. Pellkofer H. Metz I. Bleckmann A. Diagnostic red flags: Steroid-treated malignant CNS lymphoma mimicking autoimmune inflammatory demyelination Brain Pathol. 2018 28 225 233 10.1111/bpa.12496 28213912\n12. Nagano M. Ayaki T. Koita N. Kitano T. Nishikori M. Goda N. Minamiguchi S. Ikeda A. Takaori-Kondo A. Takahashi R. Recurrent epstein-barr virus-positive (EBV+) primary central nervous system lymphoma (PCNSL) in a patient with clinical features of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) Intern. Med. 2019 58 849 854 10.2169/internalmedicine.1246-18 30880301\n13. Giannini C. Dogan A. Salomão D.R. CNS lymphoma: A practical diagnostic approach J. Neuropathol. Exp. Neurol. 2014 73 478 494 10.1097/NEN.0000000000000076 24806301\n14. Sugita Y. Masuoka J. Kameda K. Takahashi K. Kimura Y. Higaki K. Furuta T. Ohshima K. Primary central nervous system lymphomas associated with chronic inflammation: Diagnostic pitfalls of central nervous system lymphomas Brain Tumor Pathol. 2020 37 127 135 10.1007/s10014-020-00373-z 32627089\n15. Kuroda Y. Kawasaki T. Haraoka S. Fujiyama F. Kakigi R. Abe M. Tabuchi K. Kuroiwa T. Kishikawa T. Sugihara H. Autopsy report of primary CNS B-cell lymphoma indistinguishable from multiple sclerosis: Diagnosis with the immunoglobulin gene rearrangements analysis J. Neurol. Sci. 1992 111 173 179 10.1016/0022-510X(92)90065-S 1431983\n16. Yamamoto J. Shimajiri S. Nakano Y. Nishizawa S. Primary central nervous system lymphoma with preceding spontaneous pseudotumoral demyelination in an immunocompetent adult patient: A case report and literature review Oncol. Lett. 2014 7 1835 1838 10.3892/ol.2014.2033 24932243\n17. Taieb G. Uro-Coste E. Clanet M. Lassmann H. Benouaich-Amiel A. Laurent C. Delisle M.B. Labauge P. Brassat D. A central nervous system B-cell lymphoma arising two years after initial diagnosis of CLIPPERS J. Neurol. Sci. 2014 344 224 246 10.1016/j.jns.2014.06.015 24990651\n18. Lister A. Abrey L.E. Sandlund J.T. Central nervous system lymphoma Hematol. ASH Educ. Program 2002 283 296 10.1182/asheducation-2002.1.283 12446428\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2076-3425",
"issue": "11(2)",
"journal": "Brain sciences",
"keywords": "diagnosis; inflammation; primary central nervous system lymphoma; tumefactive lesion; tumor regression",
"medline_ta": "Brain Sci",
"mesh_terms": null,
"nlm_unique_id": "101598646",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33557224",
"pubdate": "2021-02-04",
"publication_types": "D002363:Case Reports",
"references": "24990651;24806301;28213912;12446428;27018254;27206499;17890092;30880301;1431983;24932243;30035121;26724610;21180644;11160483;8558135;22384490;28640701;32627089",
"title": "Inflammatory Brain Lesions as Omen of Primary Central Nervous System Lymphoma: A Case Report and Literature Review.",
"title_normalized": "inflammatory brain lesions as omen of primary central nervous system lymphoma a case report and literature review"
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"abstract": "OBJECTIVE\nTo evaluate effects of G-CSF on a cancelled ART cycle due to thin endometrium.\n\n\nMETHODS\nIn a nonrandomized clinical trial from January 2011 to January 2013 in two tertiary university based hospitals fifteen patients undergoing embryo transfer and with the history of cycle cancellation due to thin endometrium were studied. Intrauterine infusion of G-CSF was done on the day of oocyte pick-up or 5 days before embryo transfer. The primary outcome to be measured was an endometrium thickened to at least 6 mm and the secondary outcome was clinical pregnancy rate and consequently take-home baby. All previous cycles were considered as control for each patient.\n\n\nRESULTS\nThe G-CSF was infused at the day of oocyte retrieval or 5 days before embryo transfer. The endometrial thickness reached from 3.593±0.251 mm to 7.120 ± 0.84 mm. The mean age, gravidity, parity, and FSH were 35.13± 9.531 years, 3, 1 and 32.78 ± 31.10 mIU/ml, respectively. The clinical pregnancy rate was 20%, and there was one missed abortion, a mother death at 34 weeks, and a preterm labor at 30 weeks due to PROM.\n\n\nCONCLUSIONS\nG-CSF may increase endometrial thickness in the small group of patients who had no choice except cycle cancellation or surrogacy.",
"affiliations": "Reproductive Health Research Center, Tehran University of Medical Sciences, Tehran, Iran.;Department of Reproductive Endocrinology, Women's Hospital, Tehran University of Medical Sciences, Tehran, Iran.;Department of Reproductive Biology, Women's Hospital, Tehran University of Medical Sciences, Tehran, Iran.;Department of Public Health, School of Public Health, Zanjan University of Medical Sciences, Zanjan, Iran.;Reproductive Health Research Center, Tehran University of Medical Sciences, Tehran, Iran.;Reproductive Health Research Center, Tehran University of Medical Sciences, Tehran, Iran.",
"authors": "Tehraninejad|Ensieh|E|;Davari Tanha|Fateme|F|;Asadi|Ebrahim|E|;Kamali|Koorosh|K|;Aziminikoo|Elham|E|;Rezayof|Elahe|E|",
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"fulltext": "\n==== Front\nJ Family Reprod HealthJ Family Reprod HealthJFRHJournal of Family & Reproductive Health1735-89491735-9392Tehran University of Medical Sciences Tehran, Iran JFRH-9-107Original ArticleG-CSF Intrauterine for Thin Endometrium, and Pregnancy Outcome Tehraninejad Ensieh M.D.1Davari Tanha Fateme M.D.2Asadi Ebrahim M.Sc.3Kamali Koorosh M.D.- MPH- Ph.D.4Aziminikoo Elham M.D.1Rezayof Elahe B.Sc.11 Reproductive Health Research Center, Tehran University of Medical Sciences, Tehran, Iran2 Department of Reproductive Endocrinology, Women’s Hospital, Tehran University of Medical Sciences, Tehran, Iran3 Department of Reproductive Biology, Women’s Hospital, Tehran University of Medical Sciences, Tehran, Iran4 Department of Public Health, School of Public Health, Zanjan University of Medical Sciences, Zanjan, IranCorrespondence: Fateme Davari Tanha, Women’s Hospital, Villa Street, 15978, Tehran, Iranfatedavari@yahoo.com9 2015 9 3 107 112 12 2014 5 2015 5 2015 Copyright © Vali-e-Asr Reproductive Health Research Center, Tehran University of Medical SciencesThis is an Open Access article distributed under the terms of the Creative Commons Attribution License, (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nObjective: To evaluate effects of G-CSF on a cancelled ART cycle due to thin endometrium. \n\n\nMaterials and methods: In a nonrandomized clinical trial from January 2011 to January 2013 in two tertiary university based hospitals fifteen patients undergoing embryo transfer and with the history of cycle cancellation due to thin endometrium were studied. Intrauterine infusion of G-CSF was done on the day of oocyte pick-up or 5 days before embryo transfer. The primary outcome to be measured was an endometrium thickened to at least 6 mm and the secondary outcome was clinical pregnancy rate and consequently take-home baby. All previous cycles were considered as control for each patient.\n\n\nResults: The G-CSF was infused at the day of oocyte retrieval or 5 days before embryo transfer. The endometrial thickness reached from 3.593±0.251 mm to 7.120 ± 0.84 mm. The mean age, gravidity, parity, and FSH were 35.13± 9.531 years, 3, 1 and 32.78 ± 31.10 mIU/ml, respectively. The clinical pregnancy rate was 20%, and there was one missed abortion, a mother death at 34 weeks, and a preterm labor at 30 weeks due to PROM.\n\n\nConclusion: G-CSF may increase endometrial thickness in the small group of patients who had no choice except cycle cancellation or surrogacy.\n\nKey Words\nART cyclethin endometriumG-CSF\n==== Body\nIntroduction\nDuring implantation, blastocyst attach to endometrium in secretory phase (1). The relationship between the developing embryo and maternal tissue plays an important role in Successful implantation (2). Studies show that positional injury in endometrium can increase the rate of implantation and pregnancy due to enormous release of growth factors and cytokines from the site of injury (3, 4). G-CSF plays an important role in human reproductive achievement. It is believed that G-CSF has important function in follicular maturation, ovulation, implantation and pregnancy after conception, uterine epithelial cell G-CSF expression remains high for the first few days then due to inhibitory effect of progesterone its levels declines around the time of embryo implantation. In addition, G-CSF concentration in endometrial co-culture correlated with pregnancy luck (5).\n\nThe level of G-CSF in serum and follicular fluid is a prophesier for the success of human IVF (6). The normal thickness of endometrium is 7 to 14 mm in the secretory phase (7, 8) and it is a prominent factor for successful pregnancy in IVF cycles (9, 10). \n\nStudies show that pregnancy will not happen if endometrium thickness is less than 6mm (11, 12).\n\nFurthermore, thin endometrium causes higher risk of miscarriage (13). One obvious potential explanation for the effects of G-CSF deficiency on pregnancy outcome is a role in targeting leukocytes required for establishing or maintaining pregnancy. Traditional treatment such as low dose aspirin, vaginal sildenafil, pentoxifylline, tocopherol, and estrogen administration are widely inefficient (14- 16). Only 0.6%-0.8% patients do not reach to the minimum thickness of the endometrium (17). Moreover, clinician suggest that the IVF cycle should be canceled and all the embryos should be cryopreservated, however, in future cycles there is merely a probability of reaching to the sufficient endometrium thickness. In the other way, clinician would transfer the embryo even though; the chance of pregnancy might decrease. In the present survey, we describe the impact of G-CSF infusion on unresponsive thin endometrium and ART outcome.\n\nMaterials and methods\nThis study was approved by the ethical committee of deputy research of Tehran University of Medical Sciences and was registered in (Iranian registry for clinical trial) IRCT by number: IRCT201012272576N4 and informed consent had been obtained from all patients.\n\nFifteen infertile women have been included. The inclusion criteria were history of IVF cycle cancellation due to thin endometrium. The age of patients ranged from 22 to 45 years old and their characteristics are summarized in the table-1. They were selected from the patients who referred to our clinic for ART cycle from June 2011 to September 2012. Their ART cycle had been canceled due to thin endometrial thickness (ET < 6mm) whereas routine treatments are administrated such as estradiol 2mg twice daily orally, 1mg three times daily per vagina and sildenafil citrate vaginal suppositories, 25 mg four times daily.\n\nAt first, ovaries were stimulated with a standard protocol (GnRH Agonist /GONAL-f ®, Merck Serono, Germany) or GnRH Antagonist /GONAL-f). When at least two follicles achieved 18mm diameter, Human chorionic gonadotropin (Ovitrelle 250 micrograms/0.5 ml, Merck Serono, Germany) was administered for ovulation triggering. Transvaginal oocyte retrieval was performed at 36 hrs after injection of hCG. The oocytes were fertilized by intra cytoplasmic sperm injection (ICSI) method. The thickness of endometrium was evaluated on the day of oocyte retrieval and a syringe which containing (300mcg/1ml) G-CSF (NeupogenTM , Filgastrim, Amgen Inc., Thousand Oaks, Canada) Was infused slowly in the uterine cavity and after 5 days endometrial thickness was evaluated again.\n\nTo judge implantation, the levels of serum β-hCG were measured 16 days after embryo transfer. The clinical pregnancy was confirmed by ultrasound observation of pregnancy sac. Ultrasound assessment was used for measuring thickness of the endometrium before and after G-CSF infusion. All scans were done by one operator, with a Siemens elegra and a 6.5 MHz transvaginal probe. Endometrial thickness was measured in the sagital plane. It was described as the minimal distance from the outer edge of endometrial myometrial interface to the outer edge in the widest part of the endometrium. All of these patients had at least one cycle which was cancelled because of thin endometrium and that cycle was considered as control cycle for each patient, which means that every patient was her own control in prior cycle.The paired t-test was used to evaluate the change in the thickness of endometrium before and after G-CSF infusion and the Mann-Whitney u-test was employed to compared the differences between thickness of endometrium and other individuality of patients who became pregnant or not. The statistical analysis was done using SPSS version 16, the significance was defined as p ≤ 0.05.\n\nResults\nFifteen patients undergoing intrauterine G-CSF infusion before embryo transfer who had thin endometrium regardless of treatment with oral and vaginal esteradiol and sildnafil. Demographic characteristic of patients are presented in table-1.\n\nAll patients had thin endometrium (mean = 3.6 ± 0.98) at the time of infusion, after intrauterine infusion of G-CSF mean of endometrial thickness was 7.12 ± 0.84 (p value < 0.001). \n\nTable 1 Demographic characteristics of patients (n= 15)\n\nAge (year) (mean ± SD)\t35.13 ± 9.531\t\nParity (mean)\t1\t\nGravidity (mean)\t3\t\nFailed prior IVF cycles (n) (mean ± SD) \t1.2 ± 0.532\t\nFSH on cycle day 3 (mIU/ml) (mean ± SD)\t32.78 ± 31.10\t\nCause of infertility\t\t\nDiminished ovarian reserve [n (%)]\t7 (46.6%)\t\nMale factor [n (%)]\t2 (13.3%)\t\nUterine factor [n (%)]\t4 (26.7%)\t\nPCO [n (%)]\t2 (13.3%)\t\nDuration of infertility (year) (mean ± SD)\t11.20 ± 7.73\t\nTwo patients had history of tubercoulosis endometritis which had been received standard treatment for tuberculosis and after medical treatment hysteroscopy and adheisolysis was done. They had very resistant thin endometrium (3mm) who had 2 times cycle cancellation. After G-CSF infusion endometrial thickness (ET) was 5mm and they referred for surrogacy.\n\nFour other patients had infertility due to uterine factor and adheisionolysis was done with hysteroscopy before ICSI cycles, all these four had increased endometrial thickness after intranuterine infusion of G-CSF, but just one of them got pregnant.\n\nWe transferred 2-3 good quality embryos for 13 patients except two who had endometrial thickness less than 6 mm, with history of endometrial tuberculosis. The clinical pregnancy rate was 20%.\n\n\nTable 2 presents endometrial thickness in patients before and after treatment with G-CSF. \n\nThere was significant difference between endometrial thickness at the time of G-CSF infusion versus day of embryo transfer in cycle leading to pregnancy (p = 0.002) and those not resulting in pregnancy (p = 0.04).\n\n\nTable 3 demonstrates outcome in women who conceived, there were three pregnancies. The first patient got pregnant and pregnancy continued until 34 weeks, which mother had died due to gas (CO) toxicities in her home.\n\nThe second patient got pregnant but at 12 weeks, pregnancy was terminated due to missed abortion.\n\nThe third patient who got pregnant terminated with cesarean delivery at 30 weeks due to premature rupture of membrane and the neonatal weight was 1800 gr.\n\n\nTable 4 shows comparison between endometrial thickness at past cancelled cycle at the day of OPU and at the cancellation day, however the mean of endometrial thickness difference was statistically significant, because the final thickness was 5.18±0.41 the cycles were cancelled. \n\nThe Δ difference between endometrial thickness before and after intrauterine infusion of G-CSF was 3.53 ± 0.88. Also the Δ difference between past cycle and GCSF cycle was 1.36 ± 1.1, p value = 0.001.\n\nDiscussion\nIn this study, we found that granulocyte- colony stimulating factor may improve endometrial thickness from 3.3 to 6.1mm. Furthermore, it seems that this effect was associated with a higher potential of pregnancy.\n\nTable 2 Endometrial thickness in patients before and after treatment with G-CSF (n = 15)\n\n\t\t\nConceived\n\n\n(n = 3)\n\t\nNot conceived\n\n\n(n = 12)\n\t\nEndometrial thickness at day of GCSF infusion (mean ± SD)\t3.6mm ± 0.98\t3.6mm ± 1.5\t3.4mm ± 0.87\t\nEndometrial thickness at day of embryo transfer (mean ± SD)\t7.120mm ± 0.84\t7.5mm ± 1.4\t7.mm ± 0.71\t\nΔ endometrial thickness (mean± SD)\t3.53mm ± 0.88\t4.2mm ± 1.3a\t3.6mm ± 0.72b\t\na Wilcoxon test p value = 0.109; \n\nb Wilcoxon test p value = 0.002\n\nTable 3 Patients’ outcome in case of pregnancy\n\n\nPatient \n\t\nage\n\t\nOutcome\n\t\nDiagnosis\n\t\nTimes of cycle \n\n\ncancellation due to thin \n\n\nendometrium\n\t\nDay of \n\n\nGCSF \n\n\ninfusion\n\t\nEndometrium \n\n\nbefore/after \n\n\n(mm)\n\t\n1\t36\tMother died at 3th trimester a\tUterine factor\t1\tOPU\t3\t7.6\t\n2\t30\tMissed abortion\tPOF\t1\tOPU\t5\t7.9\t\n3\t45\tPreterm labor 30w\tOld age\t1\t5 days before ET\t4\t8.1\t\na due to CO toxicity\n\nTable 4 Endometrial thickness in previous cancelled cycles and current cycle (G-CSF cycle)\n\n\t\nOPU day\n\t\ncancellation \n\n\nday\n\t\nDifference\n\n\n(mean ± SD)\n\t\nEmbryo \n\n\ntransfer (n)\n\t\nClinical \n\n\npregnancy \n\n\n[n (%)]\n\t\nNumber of cancelled \n\n\npatients [n (%)]\n\t\nPrevious cycle \t3.01± 0.5\t5.18 ± 0.41\t2.17 ± 0.74\t0\t0 (0%)\t15 (100%)\t\nCurrent cycle \t3.6 ± 0.98\t7.120 ± 0.84\t3.53 ± 0.88a\t13\t3 (20%)\t2 (13.3%)\t\na p value = 0.001\n\nActually, G-CSF may increase the thickness of endometrium in the patient with extremely thin endometrium when other methods to improve endometrial thickness are widely inadequate. Another treatments such as low dose aspirin and vaginal sildenafil increase blood supply of uterine rather than expand the thickness of endometrium (14, 15). Alternative treatment like tocopherol and pentoxifylline increase endometrial thickness and pregnancy outcome but length of treatment period ought to be 6-9 months (16). In our study, we used G-CSF in patients who have thin endometrium in order to avoid canceling their ART cycle. In fact, increasing the pregnancy success was not our study’s aim although; our data show that the chance of pregnancy may increase because of improving endometrial thickness after administering of G-CSF. In addition, other studies suggested that granulocyte- colony stimulating factor increase implantation rate in human and animal model (18, 19) and G-CSF receptors that are found in the trophoblast and decidua are necessary for implantation (20, 21).The effect of G-CSF and their receptors in implantation may play an important role in increasing the rate of pregnancy. Another author have reported that Patients with a good response to ovarian stimulating protocol (rFSH) demonstrated high level of G-CSF in serum and follicular fluid compared with patients who had low response to ovarian stimulating with rFSH. In addition, the pregnancy rate of the first group was 33.5% whereas pregnancy did not occur in the second group (6). Also others show that G-CSF is a member of implantation window as a result of its concentration at the time of implantation (6). These reports are similar to our findings and support them in association with improving endometrial thickness and increasing the possibility of success in ART cycle. Esteradiol and sildnafile induce averagely 3.01 mm increment in the endometrial thickness, although the final endometrial thickness was < 6.5 mm and all cycle had to be cancelled. But G-CSF increases the endometrial thickness averagely 4.106mm and in comparison to esteradiol and sildnafil alone it increases 1.36mm more thickening, so the final endometrial thickness was more suitable (7.12 ± 0.218) for embryo transfer. \n\nIt seems that G-CSF may have a role for increasing thickness in association with esteradiol and sildnafil and it may be a useful option in thin endometrium refractory to the other treatments.\n\nHowever others report that in 3 cases G-CSF couldn’t improve thin endometrium to a more fertile level and all failed to conceive in G-CSF cycle but one of them conceived on another cycle without G-CSF and surprisingly with endometrial thickness 4mm (22), the sample size is lower than current study.\n\nIn two another study there was remarkable results (23, 24) ,in first study four case with refractory thin endometrium had intrauterine infusion of G-CSF and all four cases had found endometrial thickness suitable for embryo transfer, one twin pregnancy and two singleton and one intramural ectopic pregnancy which had terminated, but the results of two other was reported as ongoing pregnancy at the time of article publication, in current study there were three pregnancy that just one of them results in take home baby and unfortunately one pregnant mother died at third trimester and one of them had missed abortion at first trimester, and current study is unique because followed the pregnant women until end of pregnancy, however the results are not as remarkable as the first study by Gleicher, still the result are noticeable, and the sample size was more (23).\n\nIn the second study by Gleicher in 21 patients with thin endometrium the ongoing clinical pregnancy rate was 19.1%, like the present study, but our study reports the results at the end of study (24). \n\nThe limitation of current study is the small sample size, and nonrandomized method, due to limited number of patients. We suggest a randomized clinical trial with greater sample size for evaluating the effect of G-CSF on thin endometrium.\n\nConclusion\nInfusion of G-CSF in endometrial cavity is a safe and probably effective method to increasing endometrial thickness for patients with thin and unresponsive endometrium.\n\nAcknowledgments\nThis work was a research project which was supported by research deputy of Tehran University of Medical Sciences.\n==== Refs\nReferences\n1 Senturk LM Erel CT Thin endometrium in assisted reproductive technology Curr Opin Obstet Gynecol 2008 20 221 8 18460935 \n2 Loke YW King A Burrows TD Decidua in human implantation Hum Reprod 1995 10 Suppl 2 14 21 8745297 \n3 Zhou L Li R Wang R Huang HX Zhong K Local injury to the endometrium in controlled ovarian hyperstimulation cycles improves implantation rates Fertil Steril 2008 89 1166 76 17681303 \n4 Barash A Dekel N Fieldust S Segal I Schechtman E Granot I Local injury to the endometrium doubles the incidence of successful pregnancies in patients undergoing in vitro fertilization Fertil Steril 2003 79 1317 22 12798877 \n5 Spandorfer SD Barmat LI Liu HC Mele C Veeck L Rosenwaks Z Granulocyte macrophage-colony stimulating factor production by autologous endometrial co-culture is associated with outcome for in vitro fertilization patients with a history of multiple implantation failures Am J Reprod Immunol 1998 40 377 81 9870083 \n6 Salmassi A Schmutzler AG Schaefer S Koch K Hedderich J Jonat W Is granulocyte colony-stimulating factor level predictive for human IVF outcome? Hum Reprodx 2005 20 2434 40 \n7 Bakos O Lundkvist O Bergh T Transvaginal sonographic evaluation of endometrial growth and texture in spontaneous ovulatory cycles--a descriptive study Hum Reprod 1993 8 799 806 8345066 \n8 Grow DR Iromloo K Oral contraceptives maintain a very thin endometrium before operative hysteroscopy Fertil Steril 2006 85 204 7 16412754 \n9 Zhang X Chen CH Confino E Barnes R Milad M Kazer RR Increased endometrial thickness is associated with improved treatment outcome for selected patients undergoing in vitro fertilization-embryo transfer Fertil Steril 2005 83 336 40 15705371 \n10 Esmailzadeh S Faramarzi M Endometrial thickness and pregnancy outcome after intrauterine insemination Fertil Steril 2007 88 432 7 17434500 \n11 Shapiro H Cowell C Casper RF The use of vaginal ultrasound for monitoring endometrial preparation in a donor oocyte program Fertil Steril 1993 59 1055 8 8486173 \n12 Sundström P Establishment of a successful pregnancy following in-vitro fertilization with an endometrial thickness of no more than 4 mm Hum Reprod 1998 13 1550 2 9688390 \n13 Ohno Y Fujimoto Y Endometrial oestrogen and progesterone receptors and their relationship to sonographic appearance of the endometrium Hum Reprod Update 1998 4 560 4 10027609 \n14 Weckstein LN Jacobson A Galen D Hampton K Hammel J Low-dose aspirin for oocyte donation recipients with a thin endometrium: prospective, randomized study Fertil Steril 1997 68 927 30 9389827 \n15 Sher G Fisch JD Effect of vaginal sildenafil on the outcome of in vitro fertilization (IVF) after multiple IVF failures attributed to poor endometrial development Fertil Steril 2002 78 1073 6 12413996 \n16 Lédée-Bataille N Olivennes F Lefaix JL Chaouat G Frydman R Delanian S Combined treatment by pentoxifylline and tocopherol for recipient women with a thin endometrium enrolled in an oocyte donation programme Hum Reprod 2002 17 1249 53 11980747 \n17 Al-Ghamdi A Coskun S Al-Hassan S Al-Rejjal R Awartani K The correlation between endometrial thickness and outcome of in vitro fertilization and embryo transfer (IVF-ET) outcome Reprod Biol Endocrinol 2008 6 37 18764940 \n18 Würfel W Approaches to a better implantation J Ass Reprod Genet 2000 17 473 \n19 Loureiro B Bonilla L Block J Fear JM Bonilla AQ Hansen PJ Colony-stimulating factor 2 (CSF-2) improves development and posttransfer survival of bovine embryos produced in vitro Endocrinology 2009 150 5046 54 19797121 \n20 Miyama M Umesaki N Kawabata M Identification of the granulocyte colony-stimulating factor (G-CSF) producing cell population in human decidua and its biological action on trophoblast cell Osaka City Med J 1998 44 85 96 9834621 \n21 Uzumaki H Okabe T Sasaki N Hagiwara K Takaku F Tobita M Identification and characterization of receptors for granulocyte colony-stimulating factor on human placenta and trophoblastic cells Proc Natl Acad Sci U S A 1989 86 9323 6 2480598 \n22 Check JH Choe JK Cohen R Summers-Chase D Failure to Increase the Thickness of Thin Endometria with Intrauterine Infusion of Gamma Colony Stimulation Factor (G-CSF) Fertility and Sterility 2013 99 S22 \n23 Gleicher N Vidali A Barad DH Successful treatment of unresponsive thin endometrium Fertil Steril 2011 95 2123 21324451 \n24 Gleicher N Kim A Michaeli T Lee HJ Shohat-Tal A Lazzaroni E A pilot cohort study of granulocyte colony-stimulating factor in the treatment of unresponsive thin endometrium resistant to standard therapies Hum Reprod 2013 28 172 7 23081869\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1735-9392",
"issue": "9(3)",
"journal": "Journal of family & reproductive health",
"keywords": "ART cycle; G-CSF; thin endometrium",
"medline_ta": "J Family Reprod Health",
"mesh_terms": null,
"nlm_unique_id": "101496684",
"other_id": null,
"pages": "107-12",
"pmc": null,
"pmid": "26622308",
"pubdate": "2015-09",
"publication_types": "D016428:Journal Article",
"references": "10027609;11980747;12413996;12798877;15705371;15890733;16412754;17434500;17681303;18460935;18764940;19797121;21324451;23081869;2480598;27328485;8345066;8486173;8745297;9389827;9688390;9834621;9870083",
"title": "G-CSF Intrauterine for Thin Endometrium, and Pregnancy Outcome.",
"title_normalized": "g csf intrauterine for thin endometrium and pregnancy outcome"
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"abstract": "Fanconi anemia, complementation group D1 with bi-allelic FANCD1 (BRCA2) mutations, is a very rare genetic disorder characterized by early onset of childhood malignancies, including acute leukemia, brain cancer and nephroblastoma. Here, we present a case report of a family with 3 affected children in terms of treatment outcome, toxicity and characterization of the malignancies using comprehensive cytogenetic analysis. The first child was diagnosed with T-cell acute lymphoblastic leukemia when he was 11 months old. During chemotherapy, he suffered from repeated pancytopenia, sepsis and severe vincristine polyneuropathy, and 18 months after primary diagnosis, he succumbed to secondary acute monocytic leukemia. The second child was diagnosed with stage 2 triphasic nephroblastoma (Wilms tumor), when he was 3 years and 11 months old. During chemotherapy, he suffered from vincristine polyneuropathy. Currently, he is in complete remission, 29 months following the initial diagnosis. The third child was diagnosed with medulloblastoma with classical histology, when she was 4 years and 5 months old. After the first cycle of chemotherapy, she suffered from prolonged pancytopenia, sepsis and severe skin and mucosal toxicity. Six weeks after primary diagnosis, a first relapse in the posterior fossa was diagnosed, and at 7 and half months after primary diagnosis, a second relapse was diagnosed that led to the patient's death. Our case report underscores tumor heterogeneity, treatment toxicity and poor outcome in Fanconi anemia patients of complementation group D1.",
"affiliations": "Department of Pediatric Hematology and Oncology, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic. Electronic address: karel.svojgr@fnmotol.cz.;Department of Pediatric Hematology and Oncology, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.;Department of Biology and Medical Genetics, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.;Department of Pediatric Hematology and Oncology, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.;Department of Pediatric Hematology and Oncology, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.;Center of Oncocytogenetics, General Teaching Hospital, Prague, Czech Republic.;Department of Pediatric Hematology and Oncology, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.;Department of Pediatric Hematology and Oncology, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.;Department of Radiology, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.;Department of Biology and Medical Genetics, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.;Department of Epidemiology and Cancer Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.;Czech Gene Bank, Prague, Czech Republic.;Department of Pediatric Surgery, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.;Department of Neurosurgery, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.;Department of Pathology and Molecular Medicine, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.;Department of Pediatric Hematology and Oncology, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.",
"authors": "Svojgr|Karel|K|;Sumerauer|David|D|;Puchmajerova|Alena|A|;Vicha|Ales|A|;Hrusak|Ondrej|O|;Michalova|Kyra|K|;Malis|Josef|J|;Smisek|Petr|P|;Kyncl|Martin|M|;Novotna|Drahuse|D|;Machackova|Eva|E|;Jencik|Jan|J|;Pycha|Karel|K|;Vaculik|Miroslav|M|;Kodet|Roman|R|;Stary|Jan|J|",
"chemical_list": "D024682:BRCA2 Protein",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1769-7212",
"issue": "59(3)",
"journal": "European journal of medical genetics",
"keywords": "BRCA2; FANCD1; Fanconi anemia; Leukemia; Medulloblastoma; Wilms tumor",
"medline_ta": "Eur J Med Genet",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D024682:BRCA2 Protein; D002675:Child, Preschool; D005190:Family; D005199:Fanconi Anemia; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D017404:In Situ Hybridization, Fluorescence; D019656:Loss of Heterozygosity; D008279:Magnetic Resonance Imaging; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide",
"nlm_unique_id": "101247089",
"other_id": null,
"pages": "152-7",
"pmc": null,
"pmid": "26657402",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Fanconi anemia with biallelic FANCD1/BRCA2 mutations - Case report of a family with three affected children.",
"title_normalized": "fanconi anemia with biallelic fancd1 brca2 mutations case report of a family with three affected children"
} | [
{
"companynumb": "CZ-WATSON-2016-07185",
"fulfillexpeditecriteria": "1",
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"activesubstance": {
"activesubstancename": "METHOTREXATE SODIUM"
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{
"abstract": "Of 476 patients with multiple myeloma treated during a 9-year period, 11 developed acute myelogenous leukemia or sideroblastic anemia. In all, the myeloma was in remission from chemotherapy with melphalan-prednisone combinations that had been continued for a median duration of 3 years. The incidence of acute leukemia or sideroblastic anemia was about 100 times higher than found in normal individuals of the same age. In all patients studied, major cytogenetic abnormalities were present, with hypodiploidy and evidence of chromosomal damage being noted most frequently. The frequency and nature of the chromosome changes were attributed to effects resulting from the prolonged drug therapy. These findings supported the long-term follow-up of selected patients with myeloma without any chemotherapy when marked degrees of remission followed the initial treatment courses.",
"affiliations": null,
"authors": "Gonzalez|F|F|;Trujillo|J M|JM|;Alexanian|R|R|",
"chemical_list": "D008558:Melphalan; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.7326/0003-4819-86-4-440",
"fulltext": null,
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"issn_linking": "0003-4819",
"issue": "86(4)",
"journal": "Annals of internal medicine",
"keywords": null,
"medline_ta": "Ann Intern Med",
"mesh_terms": "D000368:Aged; D002875:Chromosomes; D004171:Diploidy; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008134:Long-Term Care; D008297:Male; D008558:Melphalan; D008875:Middle Aged; D009101:Multiple Myeloma; D011241:Prednisone; D012075:Remission, Spontaneous",
"nlm_unique_id": "0372351",
"other_id": null,
"pages": "440-3",
"pmc": null,
"pmid": "403840",
"pubdate": "1977-04",
"publication_types": "D016428:Journal Article; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Acute leukemia in multiple myeloma.",
"title_normalized": "acute leukemia in multiple myeloma"
} | [
{
"companynumb": "US-APOPHARMA USA, INC.-2017AP012246",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "PREDNISONE"
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{
"abstract": "The ever-changing landscape of dieting and its correlation with health outcomes have continued to evolve with time. New diets appear and disappear just as quickly as they gain notoriety. This is a rare case of a 67-year-old female with a history of type II diabetes who presented with generalized weakness, nausea, and vomiting, and was found to have severe anion gap metabolic acidosis. In an effort to lose weight, she was combining a ketogenic diet with prolonged fasting and exogenous ketone supplement use that she purchased online. The patient reported drinking an exogenous ketone ester supplement that contained 30 g of D-beta hydroxybutyrate (BHB) per serving, three times per day. This case is unique in that the patient was initially thought to be in diabetic ketoacidosis upon arrival, but after further investigation into her initial labs, medication, and social history, the underlying factor for hospitalization became evident; that is, a combination of a ketogenic diet with prolonged fasting and exogenous BHB-induced ketoacidosis in the setting of type II diabetes. Thus, this case highlights the importance of thorough history taking, the dangers of over-the-counter supplement consumption, and the risks consumers inherit with trend dieting.",
"affiliations": "Internal Medicine, University of Central Florida College of Medicine, Graduate Medical Education/North Florida Regional Medical Center, Internal Medicine Residency Program, Gainesville, USA.;Internal Medicine, University of Central Florida College of Medicine, Graduate Medical Education/North Florida Regional Medical Center, Internal Medicine Residency Program, Gainesville, USA.;Internal Medicine, University of Central Florida College of Medicine, Graduate Medical Education/North Florida Regional Medical Center, Internal Medicine Residency Program, Gainesville, USA.;Internal Medicine - Critical Care, University of Central Florida College of Medicine, Graduate Medical Education/North Florida Regional Medical Center, Internal Medicine Residency Program, Gainesville, USA.",
"authors": "Malhi|Manjot S|MS|;Duerson|Frank|F|;Salabei|Joshua K|JK|;Okonoboh|Peters|P|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.15778",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.15778\nEndocrinology/Diabetes/Metabolism\nInternal Medicine\nOther\nStarvation Ketoacidosis Induced by Ketogenic Diet and Consumption of Ketone Supplement\nMuacevic Alexander\nAdler John R\nMalhi Manjot S 1\nDuerson Frank 1\nSalabei Joshua K 1\nOkonoboh Peters 2\n1 Internal Medicine, University of Central Florida College of Medicine, Graduate Medical Education/North Florida Regional Medical Center, Internal Medicine Residency Program, Gainesville, USA\n2 Internal Medicine - Critical Care, University of Central Florida College of Medicine, Graduate Medical Education/North Florida Regional Medical Center, Internal Medicine Residency Program, Gainesville, USA\nManjot S. Malhi manjot.malhi@hcahealthcare.com\n20 6 2021\n6 2021\n13 6 e1577820 6 2021\nCopyright © 2021, Malhi et al.\n2021\nMalhi et al.\nhttps://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/60142-starvation-ketoacidosis-induced-by-ketogenic-diet-and-consumption-of-ketone-supplement\nThe ever-changing landscape of dieting and its correlation with health outcomes have continued to evolve with time. New diets appear and disappear just as quickly as they gain notoriety. This is a rare case of a 67-year-old female with a history of type II diabetes who presented with generalized weakness, nausea, and vomiting, and was found to have severe anion gap metabolic acidosis. In an effort to lose weight, she was combining a ketogenic diet with prolonged fasting and exogenous ketone supplement use that she purchased online. The patient reported drinking an exogenous ketone ester supplement that contained 30 g of D-beta hydroxybutyrate (BHB) per serving, three times per day. This case is unique in that the patient was initially thought to be in diabetic ketoacidosis upon arrival, but after further investigation into her initial labs, medication, and social history, the underlying factor for hospitalization became evident; that is, a combination of a ketogenic diet with prolonged fasting and exogenous BHB-induced ketoacidosis in the setting of type II diabetes. Thus, this case highlights the importance of thorough history taking, the dangers of over-the-counter supplement consumption, and the risks consumers inherit with trend dieting.\n\nketo diet\nstarvation ketoacidosis\nstarvation ketosis\nchronic kidney disease (ckd)\ndiabetes\nmetformin\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\n\nAlthough traditionally used to treat epilepsy and other neurological conditions over the past decades, the ketogenic diet has gained popularity for its weight-reducing effects [1,2]. The basic foundation of this diet is to eliminate nearly all carbohydrate intake, reduce protein-sourced calories, and consume 70% or more of one’s daily caloric intake from fats. Thus, the ketogenic diet ultimately causes a state of insulin deficiency which allows for the production of ketones in the liver by a process called ketogenesis [3]. One of the main benefits of ketones is their ability to act as an alternative energy source to glucose. Blood ketone levels above 0.5 mM indicate a state of ketosis [4].\n\nUnder certain circumstances, a ketogenic diet coupled with a prolonged fasting state and ingestion of exogenous ketones can quickly induce a state of ketoacidosis. When this occurs, the patient’s serum bicarbonate levels decrease along with the pH leading to metabolic acidosis [5-7]. Although ketoacidosis is commonly associated with diabetes, there are other causes of ketoacidosis including, but not limited to, the use of sodium-glucose co-transporter 2 (SGLT2) inhibitors, alcohol, and starvation.\n\nCase presentation\n\nWe present the case of a 67-year-old female with a history significant for type II diabetes mellitus and obesity (body mass index of 43) who had been trying to lose weight with a combination of intermittent fasting and consumption of exogenous ketone supplements purchased online. Three months prior to hospitalization, the patient began a ketogenic diet that entailed intermittent fasting, whereby she would fast for upwards of 40 hours at a time with only drinking water and ingesting keto supplements; she reported drinking the ketone ester supplement three times a day on an empty stomach. The patient stated she had lost over 25 pounds since the beginning of her diet. After one of her fasting cycles, she ate half an avocado, some shrimp, and drank a ketone ester drink. Shortly after, the patient began feeling dizzy and started to vomit and ultimately presented to the hospital with severe fatigue, lower abdominal pain, nausea, and vomiting. She last took metformin (she was on a 750 mg twice daily home dose) on the morning of her presentation to the hospital and admitted to taking exogenous ketone supplements containing 30 g of beta-hydroxybutyrate (BHB) three times a day.\n\nOn evaluation, she was hemodynamically stable with baseline normal mental function but appeared dehydrated. Assessment of vitals showed the patient was tachycardic with a pulse rate of 120 beats per minute and borderline tachypnea with a respiratory rate of 20 breaths per minute. Her electrocardiogram did not show any arrhythmias or concerning changes in ST segments. On examination, she had dry mucous membranes and diffuse lower abdominal pain to palpation without guarding or rebound tenderness. Laboratory evaluation was notable for a white blood cell count of 30,100/mm3 (normal range: 4,500-11,000/mm3), creatinine 1.47 mg/dL (0.60-1.30 mg/dL), blood urea nitrogen 32 mg/dL (7-18 mg/dL), glucose 176 mg/dL (74-106 mg/dL), serum bicarbonate 8 mEq/L (21-32 mEq/L), anion gap 27.7 mEq/L (3-15 mEq/L), and a serum lactic acid of 2.9 mmol/L (0.4-2.0 mmol/L). The patient also had a moderately positive serum qualitative acetone level, plasma osmolality 312 mOsm/kg (275-301 mOsm/Kg), sodium 136 mEq/L (136-145 moml/L), and HbA1C of 8.4% (<5.7%). A urinalysis showed elevated urine ketones and was negative for glucose. Her pH from a venous blood gas analysis on admission was 6.81.\n\nDifferential diagnoses of diabetic ketoacidosis, alcoholic ketoacidosis, lactic acidosis, and salicylate toxicity were investigated. Serum and urine drug screens were negative for ethanol, acetaminophen, and salicylates. The patient was started on intravenous fluids with dextrose 5%-0.9% normal saline, sliding scale insulin, and 50 meq sodium bicarbonate 8.4%. After two days in the intensive care unit, the patient clinically felt much better. Her anion gap closed and her pH on a venous blood gas analysis was 7.38. The patient was transferred to the floors and was discharged the following day.\n\nDiscussion\n\nKetosis is a metabolic state characterized by elevated levels of ketone bodies in the blood or urine. Ketone bodies, that is, acetoacetate, 3-BHB, and acetone are the predominant ones produced during ketogenesis. Ketogenesis occurs in the liver initiated in a hypoinsulinemic state. Low insulin levels due to either absolute or relative hypoglycemia as in a fasted state activate hormone-sensitive lipase that causes lipolysis releasing fatty acids that are transported to the liver ultimately producing ketone bodies [5,8].\n\nThe goal of ketosis in conditions such as fasting and ketogenic diets where the carbohydrate intake is severely limited is to provide an alternative source of energy other than glucose. Studies have shown that the ketogenic diet, which is designed as a low-carbohydrate and high-fat diet can induce ketosis and help in weight loss [3]. It has also been successfully used in effectively reducing seizures in pediatric epilepsy [9]. However, increased ketogenesis may have a negative effect on diabetic patients. Diabetic patients are prone to elevated levels of blood ketones because of low basal insulin levels/reduced responsiveness to insulin as insulin is needed to adequately reclear ketones [10,11]. Ketones are organic acids that are ionized at physiological pH; the hydrogen ions thus released bind to bicarbonate causing a drastic drop in serum bicarbonate. As the ketones in the blood increase, and as bicarbonate stores are depleted, metabolic acidosis with a corresponding drop in blood pH ensues, that is, ketoacidosis [5].\n\nOur patient almost entirely excluded carbohydrates from her diet while consuming exogenous ketone esters containing 30 g of D-BHB per serving three times per day. Exogenous D-BHB is directly absorbed into the circulation and quickly increases blood ketone concentrations to 2.8 ± 0.2 mM with just one ketone ester drink, as shown in a study where 15 participants consumed a ketone ester drink which contained up to 24 g of BHB resulting in a decrease of blood pH from 7.41 to 7.31 following one ketone ester drink. In addition, serum bicarbonate was reduced from 23.6 ± 0.7 to 17.0 ± 0.8 mM [4]. Of note, circulating ketone body levels, which in normal individuals are generally <0.5 mM, can reach up to 6-7.5 mM during prolonged fasting and up to 25 mM in cases of severe insulin deficiency [11].\n\nThe differential diagnoses including diabetic ketoacidosis, alcoholic ketoacidosis, lactic acidosis, and salicylate toxicity were considered. Given the patient’s normal salicylate and ethanol levels, these etiologies were ruled out. The patient did not have chronic kidney disease, making lactic acidosis secondary to metformin use less likely. Moreover, serum ketones were elevated further, suggesting an alternative cause of acidosis. Therefore, our differential was narrowed down to ketoacidosis caused either by diabetes or consumption of ketones/fasting. Although our patient did have type II diabetes mellitus, her random blood sugar was 176 mg/dL not suggestive of overt diabetic ketoacidosis. In addition, she was not taking any antidiabetic medication of the SGLT2 inhibitor class known to cause euglycemic ketoacidosis. Thus, her ketoacidosis was most likely due to prolonged fasting plus ingestion of exogenous ketone supplements. That notwithstanding, it is plausible that metformin use contributed to her acidosis given that she presented with acute kidney injury and had continued to take her prescribed dose of metformin.\n\nConclusions\n\nHere, we presented a case of ketoacidosis induced by keto dieting and consumption of ketone supplements. Although some studies have shown significant weight reduction with the implementation of a ketogenic diet, the adverse consequences of such dieting must be highlighted. As shown in this case, especially in at-risk patient populations such as those with diabetes and/or CKD, the use of exogenous ketone supplements, not often regulated to the same extent as Food and Drug Administration-approved medications, must be cautioned. Our patient was thus counseled on the dangers of taking these weight loss supplements that are unregulated. She was further counseled to follow up with her primary care provider for further education on other safer means to achieve weight loss.\n\nHuman Ethics\n\nThis work was supported by HCA Healthcare and/or an HCA Healthcare-affiliated entity. The views expressed in this publication represent those of the author(s) and do not necessarily represent the official views of HCA Healthcare or any of its affiliated entities.\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 The effect of a ketogenic diet versus a high-carbohydrate, low-fat diet on sleep, cognition, thyroid function, and cardiovascular health independent of weight loss: study protocol for a randomized controlled trial Trials Iacovides S Meiring RM 62 19 2018 29361967\n2 Neuroprotective and disease-modifying effects of the ketogenic diet Behav Pharmacol Gasior M Rogawski MA Hartman AL 431 439 17 2006 16940764\n3 Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics Cell Metab Puchalska P Crawford PA 262 284 25 2017 28178565\n4 Metabolism of exogenous D-beta-hydroxybutyrate, an energy substrate avidly consumed by the heart and kidney Front Nutr Cuenoud B Hartweg M Godin JP 13 7 2020 32140471\n5 Hyperketonemia and ketosis increase the risk of complications in type 1 diabetes Free Radic Biol Med Kanikarla-Marie P Jain SK 268 277 95 2016 27036365\n6 On the metabolism of exogenous ketones in humans Front Physiol Stubbs BJ Cox PJ Evans RD 848 8 2017 29163194\n7 Postmortem biochemistry in suspected starvation-induced ketoacidosis J Forensic Leg Med Palmiere C Tettamanti C Augsburger M Burkhardt S Sabatasso S Lardi C Werner D 51 55 42 2016 27239954\n8 Pathways and control of ketone body metabolism: on the fringe of lipid biochemistry Prostaglandins Leukot Essent Fatty Acids Fukao T Lopaschuk GD Mitchell GA 243 251 70 2004 14769483\n9 Efficacy of the Atkins diet as therapy for intractable epilepsy Neurology Kossoff EH Krauss GL McGrogan JR Freeman JM 1789 1791 61 2003 14694049\n10 Ketone body kinetics in humans: the effects of insulin-dependent diabetes, obesity, and starvation J Lipid Res Hall SE Wastney ME Bolton TM Braaten JT Berman M 1184 1194 25 1984 https://www.jlr.org/article/S0022-2275(20)34462-X/pdf 6440941\n11 Effect of diabetes mellitus and insulin on the turnover and metabolic response to ketones in man Diabetes Sherwin RS Hendler RG Felig P 776 784 25 1976 955305\n\n",
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"abstract": "Benefits of serial electrocardiographic (ECG) monitoring to detect QT prolongation in patients with hematological malignancies remain unclear. This retrospective, single-center, study evaluated 316 adult acute leukemia and high-risk MDS patients who received 11,775 patient-days of voriconazole prophylaxis during induction chemotherapy. Of these, 37 patients (16.2%) experienced QTc prolongation. Medications associated with QTc prolongation included furosemide, haloperidol, metronidazole, mirtazapine, prochlorperazine, and venlafaxine. Hypokalemia and hypomagnesemia were also significantly associated with QTc prolongation (HR 3.15; p = .003 and HR 6.47, p = .007, respectively). Management modifications due to QTc prolongation included discontinuation of QT prolonging medications (n = 25), more aggressive electrolyte repletion (n = 5), and enhanced ECG monitoring (n = 3). One patient with multiple QT prolonging factors experienced possible Torsades de Pointes. Overall mortality was 15% with no cardiac-related deaths. Serial ECG monitoring during induction chemotherapy can be tailored proportionally to QT-prolonging risk factors. Management should include aggressive electrolyte repletion and avoidance of concurrent QT prolonging medications.",
"affiliations": "Department of Pharmacy, Mayo Clinic, Rochester, MN, USA.;Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.;Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.;Department of Pharmacy, Mayo Clinic, Rochester, MN, USA.;Department of Pharmacy, Mayo Clinic, Rochester, MN, USA.;Department of Pharmacy, Mayo Clinic, Rochester, MN, USA.;Division of Infectious Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.;Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.;Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.;Division of Heart Rhythm Services, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.",
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"abstract": "BACKGROUND\nMedullary ischemia secondary to surgical procedures of the infrarenal aorta is an infrequent and mostly devastating complication of this procedure, and its nonspecific clinical presentation makes it difficult to promptly diagnose. Prevention measures for this complication are not yet clear; therefore, the need for anticoagulant and/or antiplatelet therapy is discussed.\n\n\nMETHODS\nThis paper reports a case of a 69-year-old Hispanic man presenting with sudden pain and signs of ischemia on his left lower extremity 8 weeks after endovascular repair with endoprosthesis of an infrarenal aorta and left iliac aneurysm. The patient was admitted to the emergency room, where an extensive arterial thrombosis compromising the right iliac and femoral arteries was diagnosed. Dual anticoagulation and antiplatelet therapies were initiated, and therapeutic ranges were achieved. Nonetheless, the patient presented medullary ischemia by microembolization diagnosed by contrast-enhanced magnetic resonance imaging, with unsatisfactory evolution of an intracranial hemorrhagic event without documented excessive anticoagulation. The patient developed permanent pure motor deficit of his lower extremities, absence of sphincter control, and mild cognitive impairment.\n\n\nCONCLUSIONS\nThis is a complex and extremely rare case. It is important to continue with clinical investigations that give more clarity about the onset of anticoagulation, antiplatelet therapy, and management of dual schemes to decrease the risk of complications in this type of surgical procedure.",
"affiliations": "Clínica Universidad de la Sábana, Chía, Colombia. erikaperi@unisabana.edu.co.;Clínica Universidad de la Sábana, Chía, Colombia.;Clínica Universidad de la Sábana, Chía, Colombia.;Clínica Universidad de la Sábana, Chía, Colombia.;Clínica Universidad de la Sábana, Chía, Colombia.",
"authors": "Pérez-Riveros|Erika D|ED|;Cardona-Montes|Cesar A|CA|;Zapata-Álvarez|Carlos A|CA|;Sotelo-Hernández|Wendy L|WL|;Bastidas-Goyes|Alirio R|AR|",
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"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 216810.1186/s13256-019-2168-7Case ReportMedullary ischemia after endovascular procedure of infrarenal aorta in a patient with dual anticoagulant and antiplatelet therapy: a case report Pérez-Riveros Erika D. erikaperi@unisabana.edu.coerikadayana22@gmail.com Cardona-Montes Cesar A. cesar.cardona@outlook.comcesarcamo@unisabana.edu.co Zapata-Álvarez Carlos A. carlosandresmed22@gmail.comcarlos.zapata@uam.edu.co Sotelo-Hernández Wendy L. wenlore1905@gmail.comwendysohe@unisabana.edu.co Bastidas-Goyes Alirio R. aliriorodrigo@yahoo.comalirio.bastidas@unisabana.edu.co 0000 0001 2111 4451grid.412166.6Clínica Universidad de la Sábana, Chía, Colombia 5 8 2019 5 8 2019 2019 13 2428 10 2018 19 6 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\nMedullary ischemia secondary to surgical procedures of the infrarenal aorta is an infrequent and mostly devastating complication of this procedure, and its nonspecific clinical presentation makes it difficult to promptly diagnose. Prevention measures for this complication are not yet clear; therefore, the need for anticoagulant and/or antiplatelet therapy is discussed.\n\nCase presentation\nThis paper reports a case of a 69-year-old Hispanic man presenting with sudden pain and signs of ischemia on his left lower extremity 8 weeks after endovascular repair with endoprosthesis of an infrarenal aorta and left iliac aneurysm. The patient was admitted to the emergency room, where an extensive arterial thrombosis compromising the right iliac and femoral arteries was diagnosed. Dual anticoagulation and antiplatelet therapies were initiated, and therapeutic ranges were achieved. Nonetheless, the patient presented medullary ischemia by microembolization diagnosed by contrast-enhanced magnetic resonance imaging, with unsatisfactory evolution of an intracranial hemorrhagic event without documented excessive anticoagulation. The patient developed permanent pure motor deficit of his lower extremities, absence of sphincter control, and mild cognitive impairment.\n\nConclusions\nThis is a complex and extremely rare case. It is important to continue with clinical investigations that give more clarity about the onset of anticoagulation, antiplatelet therapy, and management of dual schemes to decrease the risk of complications in this type of surgical procedure.\n\nKeywords\nSpinal cord ischemiaBlood vessel prosthesisPlatelet aggregation inhibitorsAnticoagulantsissue-copyright-statement© The Author(s) 2019\n==== Body\nIntroduction\nMedullary ischemia secondary to surgical procedures of the infrarenal aorta has been reported in the literature as an infrequent complication; however, when present, it can be catastrophic [1]. The diagnosis of this complication is mostly clinical and achieved with the aid of imaging [2]. In several reviews in the literature, it is considered that this event may be preventable with adequate postoperative care; however, the need for anticoagulant and/or antiplatelet therapy is discussed in several clinical studies [3]. Despite not having a clear indication, it is thought that in certain patients it is necessary to consider prescribing at least one antiplatelet medication in order to reduce prothrombotic risks [4]. This paper reports the case of a 69-year-old man who underwent an endovascular repair of an infrarenal aorta and left iliac aneurysm, and even after receiving anticoagulant and antiplatelet therapy, both within therapeutic ranges, he had multiple thromboembolic, ischemic, and hemorrhagic complications 8 weeks after his surgery, with permanent sequelae.\n\nCase presentation\nThe patient was a 69-year-old Hispanic man with no family history of cardiovascular or hematological diseases. He was a heavy smoker with a history of 15 pack-years. He was retired and not an alcoholic. He had a history of arterial hypertension, revascularized ischemic heart disease, and aortic valve replacement 10 years earlier, in addition to five coronary stents, chronic peripheral arterial disease of the lower limbs, and an aneurysm of the infrarenal aorta and left primitive iliac artery (Fig. 1a, b). He underwent endovascular surgery with an Endurant II stent (Medtronic, Minneapolis, MN, USA) and a successful right hypogastric artery embolization (Fig. 2a–d). There were no complications in the postoperative period; he received ambulatory anticoagulant therapy with low-molecular-weight heparin and subsequent change to warfarin, but with little adherence to the initial treatment. In addition, he received atorvastatin 40 mg daily, acetaminophen 1 g every 8 hours, clonidine 150 mg every 8 hours, losartan 50 mg every 12 hours, nimodipine 60 mg every 4 hours, phenytoin 300 mg/night, and bisacodyl 10 mg daily. He did not receive any antibiotics before the surgery; after the surgery, he received norfloxacin 400 mg every 12 hours for 7 days to treat a urinary tract infection.Fig. 1 a Abdominal computed tomographic (CT) scan in transverse section prior to endovascular surgery. An infrarenal aortic aneurysm is observed. b CT angiography showing infrarenal aortic aneurysm\n\nFig. 2 a Abdominal computed tomography transverse section after endovascular surgery. Endovascular prosthesis implantation is observed. b Aneurysmal stent implantation is observed. c Coronal section with implantation of prosthesis. d Sagittal section with implant of prosthesis. The prosthesis is marked with white arrows\n\n\n\nTwo months after surgery, he was admitted to the emergency room with blood pressure of 97/52 mmHg, heart rate 79 beats/minute, respiratory rate 20 breaths/minute, and temperature of 36 °C. He presented with sudden pain in his lower left limb with signs of ischemia (absence of popliteal and pedis pulses, paleness and coldness of the extremity, motor and sensitivity loss), a partially normal neurological examination regarding orientation, with compromise of superficial and deep sensitivity of the lower limbs. He had laboratory test results of white blood cell count of 15,2 x10^3/uL, neutrophils 82%, lymphocytes 17%, hemoglobin 15.2 g/dL, hematocrit 44.5%, platelets 154 x10^3/uL, blood urea nitrogen 14.3 mg/dL, creatinine 0.87 mg/dL, and initial international normalized ratio (INR) in subtherapeutic range (INR 1.05–1.95). He was diagnosed with an exacerbation of his chronic peripheral arterial disease with an arterial duplex of his lower limbs, showing moderate atheromatous process of lower limb arteries, with acute left femoral popliteal artery occlusion from its origin extending to the anterior and posterior tibial arteries and pedis artery. The patient was initiated on intravenous unfractionated heparin (UFH) and dual antiplatelet therapy achieving anticoagulation goals with subsequent gradual improvement of limb ischemia. After 48 hours of observation, he had a sudden pain in his lumbar region associated with absence of sphincter control and loss of strength of his lower limbs with a Medical Research Council scale score of 0/5 (complete paralysis). Contrast-enhanced magnetic resonance imaging (MRI) was performed, which revealed extensive dorsal myelopathy from T3–T4 to T11–T12 (Fig. 3a–d) of compressive and/or ischemic nature, and extensive spinal cord infarction was determined. Twenty-four hours later, despite the established antihypertensive treatment, he presented with a hypertensive emergency with acute target organ damage. Anti-ischemic management was initiated, and it was decided to stop heparin due to possible excessive anticoagulation. During the evolution of this presentation, he had headaches; hence, cerebral computed tomographic angiography was performed, which showed supra- and infratentorial intraparenchymal hemorrhage and thalamic hematoma. An intensive care unit stay as well as rehabilitation for the subsequent management of his symptoms and stabilization of comorbidities was required.Fig. 3 a Magnetic resonance imaging (MRI) T2-weighted transverse section. A hyperintensity zone is observed showing spinal infarction at the T10 level. b MRI T1-weighted hypointensity showing spinal cord infarction. c MRI T2-weighted sagittal section showing extension of the medullary infarction with hyperintensity zone. d MRI T1-weighted image showing extension of the medullary infarction with hypointensity zone. The area of infarction is indicated by the white arrow\n\n\n\nAfter commonly agreeing with the family, he was discharged for home healthcare planning. When discharged, the patient’s pure motor deficit in his lower extremities persisted, along with absence of sphincter control and presence of mild cognitive impairment, specifically in memory. Seven months after outpatient treatment, with progressive worsening of complications of his disease with depression, recurrent infections, and skin ulcers, the patient died.\n\nDiscussion\nA 69-year-old man with multiple comorbidities had an infrarenal aortic aneurysm treated with endovascular surgery and hypogastric artery embolization without complications. He received anticoagulant therapy with little adherence to the treatment. Two months after surgery, he was admitted to the emergency room with an exacerbation of his chronic peripheral arterial disease. Treatment with intravenous UFH and dual antiplatelet therapy achieved anticoagulation goals. However, 48 hours later, he was diagnosed with an extensive dorsal myelopathy of compressive and ischemic nature, as well as an extensive spinal cord infarction, despite the management with dual anticoagulation and antiplatelet therapy, making this case report an important contribution to the medical literature. There is no specific data for patients who undergo this type of endovascular correction; therefore, it is necessary to continue with clinical investigations that provide more clarity about the onset of anticoagulation, antiplatelet management of dual schemes with the purpose of decreasing the risk of complications.\n\nThe endovascular treatment for an aortic aneurysm, both thoracic and abdominal, has increased due to the multiple benefits it offers, being a minimally invasive technique that does not require general anesthesia. The costs associated with the intervention are minor, and the intervention can be performed by different specialties such as endovascular surgery or interventional radiology [1]. However, some reports indicate concern with the high probability of generating embolization at any level secondary to the endovascular approach compared with open surgery [5].\n\nMedullary ischemia after a surgical intervention in the infrarenal aorta, according to some cohorts, has an extremely low reported incidence, up to 0.21% [3]; however, in other reports, it has reached 13.8%, increasing if the patient presents with risk factors such as hypotension during surgery [6, 7], history of repair with a previous endoprosthesis, size of the aneurysm, and surgical technique [8]; using minimally invasive strategies such as the use of catheters and other artifacts can have prothrombotic effects [5]. It is believed that neurological damage after an aortic intervention is secondary to hypoxic damage of the spinal cord and the generation of free radicals in addition to reperfusion edema [9].\n\nThe clinical presentation of this complication is unspecific. It has been described that patients arrive with symptoms that suggest abdominal disease because many cases start with abdominal pain associated with nausea, vomiting, and low back pain, which confuses the clinical presentation with a wide range of diagnostic possibilities of abdominal origin [10, 11]. Subsequently, the neurological compromise is generated; however, the onset of this compromise is variable [12]. In one case, it was reported that complete paraplegia was established within the first 18 hours of admission to the emergency room [13], and other clinical cases report that the appearance of this complication was later, between 2 and 10 months after the intervention [14, 15].\n\nThe diagnosis of this complication is confirmed by imaging, with MRI being the best tool available with a very high specificity [2]; however, not all cases present a visible alteration on the MRI scan, and it should be suspected on the basis of the patient’s clinical presentation [15]. The diagnosis of spinal cord ischemia in a patient undergoing abdominal aneurysm repair with stent placement is an interesting clinical challenge. In our patient’s case, he was not in therapeutic anticoagulation ranges at admission, and despite initiating anticoagulant and antiplatelet treatment obtaining early therapeutic goal values, he finally presented with the ischemic event at the spinal level associated with a hemorrhagic cerebrovascular event.\n\nConclusion\nSeveral ideal conditions to minimize the risk of complications in patients undergoing this type of procedure have been proposed in the literature; nevertheless, there is no clarity on the need or indications for the use of anticoagulant or antiplatelet therapies with good clinical evidence in this type of patient. However, it is considered that patients should receive treatment with at least one antiplatelet medication after surgery to reduce potential risks associated with it. In this regard, the most frequently used antiplatelet agents, aspirin and clopidogrel, have been discussed because both have shown considerable effects in the reduction of ischemic events [4]. However, there is no specific data for patients who have undergone this type of endovascular correction; therefore, it is necessary to continue with clinical investigations that give more clarity about the onset of anticoagulation and antiplatelet management in dual schemes with the purpose of decreasing the risk of complications.\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\nAuthors’ contributions\nEP conceived of the case report; acquired, analyzed, and interpreted data; and wrote the case report. CC acquired, analyzed, and interpreted data and wrote the case report. CZ acquired, analyzed, and interpreted data. WS acquired, analyzed, and interpreted data. AB critically revised the manuscript. All authors read and approved the final manuscript.\n\nFunding\nIn relation to this article, the authors did not participate in any open calls or receive any financial support from their educational institution or from any other entity during the development of the study. Therefore, they did not receive any research funding, nor are they currently receiving any research funding; thus, there are no competing interests.\n\nAvailability of data and materials\nData sharing is not applicable to this article, because no datasets were generated or analyzed during the current study.\n\nEthics approval and consent to participate\nApproval by the ethics committee was not necessary, because diagnostic procedures and treatments were performed according to standard clinical care [16]. The patient signed an institutional informed consent for receiving treatments.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images [17]. 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==== Refs\nReferences\n1. Maldonado TS Rockman CB Riles E Douglas D Adelman MA Jacobowitz GR Riles TS Ischemic complications after endovascular abdominal aortic aneurysm repair J Vasc Surg 2004 40 4 703 710 10.1016/j.jvs.2004.07.032 15472598 \n2. Defraigne JO Otto B Sakalihasan N Limet R Spinal ischaemia after surgery for abdominal infrarenal aortic aneurysm: diagnosis with nuclear magnetic resonance Acta Chir Belg 1997 97 5 250 256 9394968 \n3. Buth J Harris PL Hobo R van Eps R Cuypers P Duijm L Tielbeek X Neurologic complications associated with endovascular repair of thoracic aortic pathology: incidence and risk factors. A study from the European Collaborators on Stent/Graft Techniques for Aortic Aneurysm Repair (EUROSTAR) Registry J Vasc Surg 2007 46 6 1103 1111 10.1016/j.jvs.2007.08.020 18154984 \n4. Saratzis A Saratzis N Melas N Kiskinis D Pharmacotherapy before and after endovascular repair of abdominal aortic aneurysms Curr Vasc Pharmacol 2008 6 4 240 249 10.2174/157016108785909689 18855712 \n5. Rockman CB Riles TS Landis R Lower extremity paraparesis or paraplegia subsequent to endovascular management of abdominal aortic aneurysms J Vasc Surg 2001 33 1 178 180 10.1067/mva.2001.111801 11137940 \n6. Amato ACM Stolf NAG Amato ACM Stolf NAG Anatomia da circulação medular J Vasc Brasileiro 2015 14 3 248 252 10.1590/1677-5449.0004 \n7. Wikinski JA, Salgueiro C. The artery of Adamkiewicz and its role in medullar irrigation [in Spanish]. Rev Arg Anest. 2003;61(3):170–81. https://www.anestesia.org.ar/search/articulos_completos/1/1/625/c.pdf\n8. Chiesa R Melissano G Marrocco-Trischitta MM Civilini E Setacci F Spinal cord ischemia after elective stent-graft repair of the thoracic aorta J Vasc Surg 2005 42 1 11 17 10.1016/j.jvs.2005.04.016 16012446 \n9. Oudega M Molecular and cellular mechanisms underlying the role of blood vessels in spinal cord injury and repair Cell Tissue Res 2012 349 1 269 288 10.1007/s00441-012-1440-6 22592628 \n10. Rodríguez-Baeza A Muset-Lara A Rodríguez-Pazos M Domenech-Mateu JM Anterior spinal arteries: origin and distribution in man Acta Anat 1989 136 3 217 221 10.1159/000146889 2603634 \n11. Melissano G Bertoglio L Rinaldi E Leopardi M Chiesa R An anatomical review of spinal cord blood supply J Cardiovasc Surg 2015 56 5 699 706 25881616 \n12. Riess KP Gundersen SB Ziegelbein KJ Delayed neurologic deficit after infrarenal endovascular aortic aneurysm repair Am Surg 2007 73 4 385 387 17439034 \n13. Cho JS Rhee RY Makaroun MS Delayed paraplegia 10 months after endovascular repair of thoracic aortic aneurysm J Vasc Surg 2008 47 3 625 628 10.1016/j.jvs.2007.09.042 18295114 \n14. Reid JA Mole DJ Johnston LC Lee B Delayed paraplegia after endovascular repair of abdominal aortic aneurysm J Vasc Surg 2003 37 6 1322 1323 10.1016/S0741-5214(02)75447-5 12764283 \n15. Goldstein LJ Rezayat C Shrikhande GV Bush HL Delayed permanent paraplegia after endovascular repair of abdominal aortic aneurysm J Vasc Surg 2010 51 3 725 728 10.1016/j.jvs.2009.09.023 20206815 \n16. Ministerio de Salud. Resolución número 8430 de 1993: Por la cual se establecen las normas científicas, técnicas y administrativas para la investigación en salud. https://www.minsalud.gov.co/sites/rid/Lists/BibliotecaDigital/RIDE/DE/DIJ/RESOLUCION-8430-DE-1993.PDF. Accessed 29 Sept 2017.\n17. 2019 Asociación Médica Mundial. Declaración de Helsinki de la AMM - Principios Éticos para las Investigaciones Médicas en Seres Humanos. AMM; 2015.\n\n",
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"abstract": "BACKGROUND\nThe incidence of tuberculosis (TB) in end-stage renal disease is significantly higher than that in the general population. Among those with kidney dysfunction, anti-TB treatment is associated with increased side effects, but the effect on healthcare utilization is unknown. Methods/Aim: To assess patient-reported symptoms, adverse effects and describe changes in healthcare utilization patterns during treatment for TB, we conducted a case series (n = 12) of patients receiving maintenance hemodialysis (HD) from Mayo Clinic Dialysis Services and concurrent drug therapy for TB from January 2002 through May 2014. Healthcare utilization (hospitalizations and emergency department (ED) visits independent of hospital admission) was compared before and during treatment.\n\n\nRESULTS\nPatients were treated for latent (n = 7) or active (n = 5) TB. The majority of patients with latent disease were treated with isoniazid (n = 5, 71%), while active-disease patients received a 4-drug regimen. Adverse effects were reported in 83% of patients. Compared to measurements prior to drug initiation, serum albumin and dialysis weights were similar at 3 months. Commonly reported anti-TB drug toxicities were described. More than half (58%) of the patients were hospitalized at least once. No ED or hospital admissions occurred in the period prior to drug therapy, but healthcare utilization increased during treatment in the latent disease group (hospitalization rate per person-month: pre 0 vs. post 1).\n\n\nCONCLUSIONS\nAmong HD patients, anti-TB therapy is associated with frequently reported symptoms and increased healthcare utilization. Among this subset, patients receiving treatment for latent disease may be those with greatest increase in healthcare use. Careful monitoring and early complication detection may help optimize medication adherence and minimize hospitalizations.",
"affiliations": "Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, Minn., USA.",
"authors": "Hamadah|Abdurrahman M|AM|;Beaulieu|Lynn M|LM|;Wilson|John W|JW|;Aksamit|Timothy R|TR|;Gregoire|James R|JR|;Williams|Amy W|AW|;Dillon|John J|JJ|;Albright|Robert C|RC|;Onuigbo|Macaulay|M|;Iyer|Venkateshwaran K|VK|;Hickson|LaTonya J|LJ|",
"chemical_list": "D000995:Antitubercular Agents; D007538:Isoniazid",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000444148",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1660-8151",
"issue": "132(3)",
"journal": "Nephron",
"keywords": null,
"medline_ta": "Nephron",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000995:Antitubercular Agents; D015331:Cohort Studies; D004632:Emergency Medical Services; D005260:Female; D006760:Hospitalization; D006801:Humans; D007538:Isoniazid; D007676:Kidney Failure, Chronic; D055985:Latent Tuberculosis; D008297:Male; D008875:Middle Aged; D010342:Patient Acceptance of Health Care; D006435:Renal Dialysis; D016896:Treatment Outcome; D014376:Tuberculosis; D055815:Young Adult",
"nlm_unique_id": "0331777",
"other_id": null,
"pages": "198-206",
"pmc": null,
"pmid": "26859893",
"pubdate": "2016",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "17014512;26017823;22916137;25500361;21454737;14974751;12212979;12836625;10881762;23580807;8053617;21488766;8321366;23848358;15139473;20955284;24049269;15311732;16382216;20413440;12904741;12535299;23492998;26614191;22216316;19895701;16968724;23303634",
"title": "Tolerability and Healthcare Utilization in Maintenance Hemodialysis Patients Undergoing Treatment for Tuberculosis-Related Conditions.",
"title_normalized": "tolerability and healthcare utilization in maintenance hemodialysis patients undergoing treatment for tuberculosis related conditions"
} | [
{
"companynumb": "US-TEVA-665355USA",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ISONIAZID"
},
"drugadditional": null,
"drug... |
{
"abstract": "The prognosis for disease relapse after first hematopoietic cell transplantation (HCT1) is poor. Here, we present a retrospective multicenter study to evaluate the clinical outcome and the prognostic factors for second hematopoietic cell transplantation (HCT2). The cohort in this study comprised 60 patients diagnosed with acute leukemia, who underwent HCT2 due to hematological relapse after HCT1. The overall survival (OS) at two years, non-relapse mortality (NRM), and relapse mortality (RM) were 30.3%, 40.9%, and 28.8%, respectively. Multivariate analysis for OS identified the use of a donor other than matched-related (MR) donor (hazard ratios [HR] = 4.10, 95% confidence intervals [CI]: 1.72-9.74, p = .001) and high disease status (HR = 2.90, 95% CI: 1.28-6.56, p = .011) as the adverse risk factors for HCT2. On analyzing the combination of factors during HCT1 and HCT2, MR donor, reduced intensity conditioning regimen, and standard status were found to be significant as favorable prognostic factors for OS. Therefore, evaluating these prognostic factors would be helpful in taking decisions regarding post-relapse management.",
"affiliations": "a Department of Hematology and Clinical Immunology , Yokohama City University, Graduate School of Medicine , Yokohama , Japan.;c Yokohama City University Medical Center , Yokohama , Japan.;b Department of Hematology , Kanagawa Cancer Center , Yokohama , Japan.;c Yokohama City University Medical Center , Yokohama , Japan.;c Yokohama City University Medical Center , Yokohama , Japan.;c Yokohama City University Medical Center , Yokohama , Japan.;b Department of Hematology , Kanagawa Cancer Center , Yokohama , Japan.;a Department of Hematology and Clinical Immunology , Yokohama City University, Graduate School of Medicine , Yokohama , Japan.;c Yokohama City University Medical Center , Yokohama , Japan.;a Department of Hematology and Clinical Immunology , Yokohama City University, Graduate School of Medicine , Yokohama , Japan.;d Department of Hematology , Shizuoka Red Cross Hospital , Shizuoka , Japan.;c Yokohama City University Medical Center , Yokohama , Japan.;b Department of Hematology , Kanagawa Cancer Center , Yokohama , Japan.;a Department of Hematology and Clinical Immunology , Yokohama City University, Graduate School of Medicine , Yokohama , Japan.",
"authors": "Tachibana|Takayoshi|T|;Matsumoto|Kenji|K|;Tanaka|Masatsugu|M|;Hagihara|Maki|M|;Motohashi|Kenji|K|;Yamamoto|Wataru|W|;Ogusa|Eriko|E|;Koyama|Satoshi|S|;Numata|Ayumi|A|;Tomita|Naoto|N|;Taguchi|Jun|J|;Fujisawa|Shin|S|;Kanamori|Heiwa|H|;Nakajima|Hideaki|H|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1080/10428194.2016.1243678",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "58(6)",
"journal": "Leukemia & lymphoma",
"keywords": "Second donor; acute leukemia; hematologic relapse",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D005260:Female; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007938:Leukemia; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012008:Recurrence; D019233:Retreatment; D012189:Retrospective Studies; D016019:Survival Analysis; D014019:Tissue Donors; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "1403-1411",
"pmc": null,
"pmid": "27739916",
"pubdate": "2017-06",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Outcome and prognostic factors among patients who underwent a second transplantation for disease relapse post the first allogeneic cell transplantation.",
"title_normalized": "outcome and prognostic factors among patients who underwent a second transplantation for disease relapse post the first allogeneic cell transplantation"
} | [
{
"companynumb": "JP-ADIENNEP-2017AD000070",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "A 67-year-old man diagnosed with clinical Stage Ⅳ gastric cancer was administered nivolumab as fourth-line chemotherapy. After 9 courses, he was emergently admitted with complaints of low blood pressure and general malaise. On the fourth hospital day, he had high-grade fever and elevated serum C-reactive protein. Computed tomography showed a moderate amount of pericardial effusion. He was administered 1.7 mg/kg of methylprednisolone and improved rapidly. A hormonal blood examination showed his adrenal gland disorder. This is the first case in our country of pericardial effusion as an immune-reactive adverse event, which is not well known in Japan.",
"affiliations": "Dept. of Resident, Osaka Red Cross Hospital.",
"authors": "Shiraishi|Kei|K|;Tokoro|Yukinari|Y|;Kanai|Yugo|Y|;Hayashi|Fujio|F|;Marusawa|Hiroyuki|H|;Kanaya|Seiichiro|S|;Tsumura|Takehiko|T|",
"chemical_list": "D000077594:Nivolumab",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "47(8)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D006801:Humans; D007564:Japan; D008297:Male; D000077594:Nivolumab; D010490:Pericardial Effusion; D013274:Stomach Neoplasms; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1237-1240",
"pmc": null,
"pmid": "32829363",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Gastric Cancer with Pericardial Effusion as an Immune-Reactive Adverse Events.",
"title_normalized": "a case of gastric cancer with pericardial effusion as an immune reactive adverse events"
} | [
{
"companynumb": "JP-BRISTOL-MYERS SQUIBB COMPANY-BMS-2019-019044",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE"
... |
{
"abstract": "OBJECTIVE\nTo describe the evolution of adverse drug reactions (ADRs) spontaneously reporting in the Emilia-Romagna region (ERR) in the period 2001 - 2010 through qualitative and quantitative indicators following local educational and editorial initiatives.\n\n\nMETHODS\nData of regional spontaneous reporting from 1 January 2001 to 31 December 2010 were obtained from the Pharmacovigilance National Network of the Italian Medicines Agency. Drugs were classified according to the Anatomical Therapeutic Chemical classification. ADRs were coded using the Medical Dictionary for Regulatory Activities Terminology.\n\n\nRESULTS\nThe overall contribution of the ERR was 9.7% of the total national number of reports (9631 out of 99,319) with a rate of 8 reports per 100 physicians and 230 per million inhabitants. Reports concerned more females and more patients aged 0 - 2 and 60 - 80 years. Differences between the individual local health authorities were identified in rate of ADR reporting. Hospital doctors were the main source of reports followed by general physicians. Out of 2555 serious reports, 124 cases were lethal (4.9% of serious ADRs and 1.3% of all regional reports).\n\n\nCONCLUSIONS\nThe results represent a useful trend analysis of the post-marketing surveillance and suggest that, although the pharmacovigilance system has succeeded in reaching a stable and lasting flow of information in ERR, there is considerable place for improvement.",
"affiliations": "University of Bologna, Department of Medical and Surgical Sciences, Unit of Pharmacology , Via Irnerio 48, 40126 Bologna , Italy +39 0512091779 ; +39 0512091780 ; domenico.motola@unibo.it.",
"authors": "Motola|Domenico|D|;Melis|Mauro|M|;Lo Bianco|Salvatore|S|;Buccellato|Elena|E|;Biagi|Chiara|C|;Vaccheri|Alberto|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1517/14740338.2014.916687",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1474-0338",
"issue": "13(7)",
"journal": "Expert opinion on drug safety",
"keywords": "adverse drug reaction; drug safety; pharmacovigilance; spontaneous reporting",
"medline_ta": "Expert Opin Drug Saf",
"mesh_terms": "D016907:Adverse Drug Reaction Reporting Systems; D000368:Aged; D000369:Aged, 80 and over; D002675:Child, Preschool; D016208:Databases, Factual; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007558:Italy; D008297:Male; D008875:Middle Aged; D060735:Pharmacovigilance",
"nlm_unique_id": "101163027",
"other_id": null,
"pages": "867-73",
"pmc": null,
"pmid": "24809453",
"pubdate": "2014-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Ten years of pharmacovigilance in Italy: the experience of Emilia-Romagna region in the monitoring of drug's safety profile.",
"title_normalized": "ten years of pharmacovigilance in italy the experience of emilia romagna region in the monitoring of drug s safety profile"
} | [
{
"companynumb": "IT-JNJFOC-20140705673",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVOFLOXACIN"
},
"drugadditional": null,
... |
{
"abstract": "Renal transplant recipients are highly susceptible to infections caused by uncommon pathogens because of their immunocompromised state. We report a case of disseminated Mycobacterium genavense infection in a patient with a combined renal and cardiac transplant. Diagnosing M. genavense infections remains a challenge because of the absence of specific clinical symptoms in combination with the difficulties of culturing the organism using standard mycobacterial culture procedures. This clinical case demonstrates the importance of molecular techniques as part of the initial work-up in order to rapidly establish the diagnosis.",
"affiliations": "Department of Nephrology, University Hospitals Leuven, Leuven, Belgium.;Department of General Internal Medicine, University Hospitals Leuven, Leuven, Belgium.;Department of Laboratory Medicine, University Hospitals Leuven, Leuven, Belgium.;Department of Pathology, University Hospitals Leuven, Leuven, Belgium.;Department of Nuclear Medicine, University Hospitals Leuven, Leuven, Belgium.;Department of Cardiology, University Hospitals Leuven, Leuven, Belgium.;Department of Nephrology, AZ Groeninge, Kortrijk, Belgium.;Department of Nephrology, University Hospitals Leuven, Leuven, Belgium.;Department of Nephrology, University Hospitals Leuven, Leuven, Belgium.",
"authors": "Ombelet|S|S|;Van Wijngaerden|E|E|;Lagrou|K|K|;Tousseyn|T|T|;Gheysens|O|O|;Droogne|W|W|;Doubel|P|P|;Kuypers|D|D|;Claes|K J|KJ|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12493",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "18(1)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "Mycobacterium genavense; outcome; renal transplantation",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D016027:Heart Transplantation; D006801:Humans; D016867:Immunocompromised Host; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009165:Mycobacterium Infections, Nontuberculous; D009170:Nontuberculous Mycobacteria",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "125-31",
"pmc": null,
"pmid": "26688125",
"pubdate": "2016-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Mycobacterium genavense infection in a solid organ recipient: a diagnostic and therapeutic challenge.",
"title_normalized": "mycobacterium genavense infection in a solid organ recipient a diagnostic and therapeutic challenge"
} | [
{
"companynumb": "PHHY2016BE015678",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Levonorgestrel emergency contraception (LNG-EC) tends to make uterus unfavorable for implantation but does not prevent embryo implantation. Emergency contraceptives pills should be used with caution among lactating women who at the same time should be monitored closely for ectopic pregnancy.",
"affiliations": "Research Unit Department of Medical Education College of Medicine King Saud bin Abdulaziz University for Health Sciences Riyadh Saudi Arabia.;King Abdullah International Medical Research Center Riyadh Saudi Arabia.;King Abdullah International Medical Research Center Riyadh Saudi Arabia.;Department of Medicine Khyber Teaching Hospital MTI Peshawar Pakistan.;Department of Medicine Lady Reading Hospital MTI Peshawar Pakistan.",
"authors": "Masud|Nazish|N|https://orcid.org/0000-0003-2366-9770;AlShaibi|Saleh|S|;AlBassri|Tala|T|;Khan|Saad|S|;Khan|Fahad|F|https://orcid.org/0000-0002-6145-0406",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.3849",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904\nJohn Wiley and Sons Inc. Hoboken\n\n10.1002/ccr3.3849\nCCR33849\nCase Report\nCase Reports\nCase of rupture ectopic pregnancy with emergency contraception levonorgestrel 0.075 mg in a lactating woman\nMASUD et al.\nMasud Nazish https://orcid.org/0000-0003-2366-9770\n1 2\nAlShaibi Saleh 2 3\nAlBassri Tala 2 3\nKhan Saad 4\nKhan Fahad https://orcid.org/0000-0002-6145-0406\n5 fahad7300@gmail.com\n\n1 Research Unit Department of Medical Education College of Medicine King Saud bin Abdulaziz University for Health Sciences Riyadh Saudi Arabia\n2 King Abdullah International Medical Research Center Riyadh Saudi Arabia\n3 College of Medicine King Saud bin Abdulaziz University for Health Sciences Riyadh Saudi Arabia\n4 Department of Medicine Khyber Teaching Hospital MTI Peshawar Pakistan\n5 Department of Medicine Lady Reading Hospital MTI Peshawar Pakistan\n* Correspondence\nFahad Khan, Post Graduate Resident, Department of medicine, Lady Reading hospital, MTI, Peshawar, Khyber Pakhtunkhwa, Pakistan.\nEmail: fahad7300@gmail.com\n\n18 2 2021\n3 2021\n9 3 10.1002/ccr3.v9.3 16051609\n05 12 2020\n19 3 2020\n05 1 2021\n© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.\nThis is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.\n\nAbstract\n\nLevonorgestrel emergency contraception (LNG‐EC) tends to make uterus unfavorable for implantation but does not prevent embryo implantation. Emergency contraceptives pills should be used with caution among lactating women who at the same time should be monitored closely for ectopic pregnancy.\n\nLevonorgestrel emergency contraception (LNG‐EC) tends to make uterus unfavorable for implantation but does not prevent embryo implantation. Emergency contraceptives pills should be used with caution among lactating women who at the same time should be monitored closely for ectopic pregnancy.\n\ncontraceptives\nectopic\nlactation\nLNG‐EC\npregnancy\nsource-schema-version-number2.0\ncover-dateMarch 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.0 mode:remove_FC converted:21.03.2021\nMasud N , AlShaibi S , AlBassri T , Khan S , Khan F . Case of rupture ectopic pregnancy with emergency contraception levonorgestrel 0.075 mg in a lactating woman. Clin Case Rep. 2021;9 :1605–1609. 10.1002/ccr3.3849\n==== Body\n1 INTRODUCTION\n\nEctopic pregnancy (EP) is defined as extrauterine ovum implantation. After fertilization, the embryo must reach the uterus after travelling through the fallopian tube. In most cases, EP occurs in the fallopian tubes and rarely in the cervix, intramural, ovaries, or abdominal region. 1 There are even reports of coexistent EP and intrauterine pregnancy. 2 Regardless of the implantation site, EP is a life‐threatening condition that accounts for 10% of early pregnancy‐related mortality. 3 The exact etiology of the disease remains unknown, but the main reason is the abnormal tubal motility and changes in the microenvironment leading to arrest of the embryo in the fallopian tube and early implantation. 3 Studies have shown that there are few main factors that increase the risk of EP. The most common risk factors that are associated with EP are previous EP, 4 uterine/Fallopian tube instrumentation or procedures, 5 pelvic inflammatory disease, 2 and use of intrauterine contraceptive devices. 6\n\nFor over 20 years, emergency contraception methods have been widely used to prevent undesired pregnancy after unprotected coitus. 7 The most commonly used emergency contraception is Levonorgestrel emergency contraction (LNG‐EC; 0.075 mg; two tablets, stat dose), which is a synthetic progesterone derivative. Various clinical trials have shown its efficacy and safety over a long period. 8 The mechanism of action includes inhibition of ovulation and making the uterus unfavorable for implantation. To avoiding conception, it has to be taken within 72 hours of coitus. It works better if taken 2‐3 days before the luteal surge in the cycle. However, using Levonorgestrel before or after the ovulation period has an unclear effect, and it also increases the risk of EP. Noe et al reported 100% prevention of clinical pregnancy when LNG‐EC was used in the preovulation period, while LNG‐EC was less effective in preventing pregnancy and did not prevent implantation when taken on the day of ovulation or after the ovulation period. 9 Not much information is available about the safety of emergency contraception pill (ECP) use among breastfeeding women. Here, we report the case of a patient with a ruptured EP following LNG‐EC administration in a lactating mother.\n\n2 PATIENT INFORMATION\n\nA 39‐year‐old woman with a high education level, who was married for 12 years, and gravida 7, para 3, abortion 3 presented to the emergency department with severe abdominal pain. She was lactating for the previous 14 months. Frequency of lactation was four to six times a day, and the maximum duration between feeds was 3 hours. Her social history was negative for smoking, alcoholism, or drug abuse. The patient was seen in March 2019.\n\n2.1 Main concerns and symptoms\n\nThe main symptoms were acute onset severe pain in the right lower quadrant that was associated with nausea, cold sweats, and feeling dizzy. The patient had intermittent pain in the right lower abdomen for the past week, for which she was taking acetaminophen tablets, and the pain resolved with rest and medication. The patient was not sure if she was pregnant on presentation to the emergency department. She had an episode of vaginal bleeding with pain 3 days before the current episode. She soaked one normal pad and bleeding was more like normal menstrual bleeding, and no clots or heavy bleeding was reported. The patient thought that it was dysmenorrhea related to a normal menstrual cycle, so she ignored the pain and bleeding and did not seek any medical advice for her complaints. She also assumed that she was not pregnant because she had taken LNG‐EC (0.75 mg, two tablets, stat dose) 18 hours after unprotected coitus. She took the ECP around 20 days before the current presentation.\n\n2.2 Past medical and obstetric history\n\nThe patient had no surgical or medical history of any chronic illness. She had a bad obstetric history with severe postpartum hemorrhage after spontaneous vaginal delivery during her first childbirth. In the second childbirth, the patient had a history of antepartum hemorrhage, and induced labor ended with vaginal delivery. This was followed by three consecutive abortions all within 35‐40 days of conception with levels of β‐human chorionic gonadotropin (HCG) not exceeding 300‐400 mIU/mL. Her treating doctors indicated that this was a chemical pregnancy because no intervention was needed, and the patient recovered with conservative management. The last childbirth was an uncomplicated full‐term vaginal delivery at 40 weeks. The patient had no history of EP, and no history of irregular cycles, with the duration of menstrual cycles ranging from 24 to 27 days and bleeding for up to a maximum of 6 days. After the last childbirth, she had lactational amenorrhea for 8 months followed by a normal cycle until the current episode of EP. She was not sure of the exact date of her last menstrual period (LMP) at the time of presentation to the hospital. In the patient record, β‐HCG at 25 days before this event was available, and this test was completed before performing an X‐ray of the lower limbs. Thus, the current EP was not more than 25 days. Patient was not using any regular contraceptive method.\n\n2.3 Clinical findings\n\nThe patient presented to the emergency room and was admitted for further investigation because her urine dipstick test was positive for pregnancy. According to the facility's protocol, a urine dipstick test is performed during vital sign assessment for each childbearing married woman who is unsure of pregnancy. Therefore, the patient was admitted with a working diagnosis of unexplained pain and pregnancy. On examination, the patient was well oriented, and her vital signs were stable. The palpation test was positive for guarding and rebound tenderness. Pressure in the left lower quadrant caused pain in the right lower quadrant. The rest of the abdominal and pelvic exam was unremarkable. There was no per vaginal bleeding or spotting at the time of presentation. The patient's pregnancy status was confirmed using a serum β‐HCG test, which showed an elevated β‐HCG level of 40,000 mIU/mL.\n\n2.4 Diagnostic assessment\n\nFor the initial assessment, all the routine investigations were performed including complete blood chemistry (CBC) tests and routine urine examination to rule out urinary tract infection or appendicitis. Renal and liver function tests were also performed. Initial transabdominal ultrasound was performed and showed empty uterine cavity with right sided undifferentiated mass. Investigation of an ovarian cyst on abdominal ultrasound was later confirmed to be a corpus luteal cyst of pregnancy. The diagnosis of an EP was confirmed using transvaginal ultrasound, which showed an anteverted uterus with an empty cavity. The patient had a history of mild bicornuate uterus, which was observed as a slight dimple in the middle of the fundus, but no complete septation was noted. Both ovaries had several small follicles and one clear cyst (corpus luteal cyst of pregnancy), and positive blood flow was observed. There was a small amount of free fluid in the pouch of Douglas. There was a heterogeneous mass at the right adnexa lateral and anterior to the right ovary, which measured 3.7 × 2.6 × 2.3 cm. A hypoechoic structure was seen within the mass, but no obvious fetal pole was observed. All the blood chemistry tests including the CBC tests, renal function test, coagulation profile, liver profile, and serum electrolytes were performed, and the results were unremarkable.\n\nAfter the diagnosis of an EP was confirmed, the initial management plan was to discharge the patient home on medical treatment with methotrexate and follow‐up on the β‐HCG levels. After 9 hours in the ER, the patient's blood pressure was consistently slightly low and based on the high levels of β‐HCG above 40 000 units mIU/mL and no visible fetal parts that were detected on the ultrasound, the management plan was switched to laparoscopic removal of the EP. After the patient was prepared for surgery and general anesthesia, it was discovered that the EP had ruptured and the patient had internal bleeding. Almost 850 mL of blood was drained though the suction from the pelvic cavity. The bleeding site was the right tube, which was secured, followed by a right salpingectomy and removal of the EP. The right ovary was preserved and hemostasis was secured. The pregnancy was confirmed on the histopathology report, and it showed decidual and chorionic villi. The site of rupture was 1.5 cm from the fimbriated end and 6 cm from the stapled end. No fetal parts were identified on biopsy. The patient was stable after surgery, and she was given supportive postsurgical treatment and discharged in stable condition. A follow‐up appointment was made to discuss long‐term alternative contraceptive methods.\n\n3 DISCUSSION\n\nWe present the case of a multigravida lactating woman with a ruptured EP. The unique features in the case were the presence of high β‐HCG levels of 40,000 mIU/mL, no identifiable fetal parts, and a history of taking ECP. In cases of normal pregnancy with β‐HCG levels > 10,000 mIU/mL, there is usually a gestational sac and an embryo is clearly visible. 10 The high β‐HCG level in early pregnancy is associated in the literature with multiple gestations, abnormal pregnancy such as hydatidiform mole, and chromosomal abnormalities. However, no specific abnormality could be confirmed at any stage during the surgery or the histology examination in our patient.\n\nThe patient conceived irrespective of use of LNG‐EC and ended up with an EP. There are two common oral regimens that are used for emergency contraception: the Yuzpe regimen and Levonorgestrel only pills. 11 The Yuzpe regimen is a method that uses a combination of 0.1 mg of ethinyl estradiol and 0.5 mg of Levonorgestrel at 12‐hour intervals while the other includes only Levonorgestrel. 12 Both regimens are effective if taken within 72 hours after unprotected sexual intercourse. Trials have also shown that ECP can be effective even up to 120 hours after the first dose. However, the efficacy is lower compared to the 72‐hour timeframe. In our case, the patient took the Levonorgestrel within 18 hours. The chances of conception were very low, but our patient still conceived, which is contrary to what is reported in the literature. 11 One possible explanation could be that the patient took the medication on or during the postovulatory period. The literature shows that ECP, if taken during the postovulatory period, its less effective for preventing pregnancy. 9\n\nThe exact mechanism of EP remains unknown, but numerous risk factors have been proposed that increase the likelihood of EP. Some of the most common risk factors that have been reported are adnexal or pelvic surgery, previous cesarean section, pelvic infections, and previous EP. 13 None of the commonly reported risk factors were present in our patient. ECP works in numerous ways to prevent pregnancy. According to Croxatto et al, the processes that are affected by ECP are sperm survival and transfer, ovulation, fertilization, embryo tubal transfer, and implantation, and thus, the theory of defective tubal mortality resulting in implantation in the tube during embryo transfer cannot be overlooked. 14 In our patient, there was no other mechanism that could have hindered tubal motility, as would be expected in the case of a previous surgery or pelvic infection. The patient had no previous history that had a connection to the occurrence of EP. The literature shows that ECP should be taken 2‐3 days before the luteal surge for its maximum effectiveness. 15 Our patient was most likely to have taken the medication at time of ovulation. This may be the reason for the EP because if ECP is taken before ovulation, then pregnancy is not possible because it prohibits ovulation.\n\nThe use of contraception methods postpartum helps to improve the health of both the mother and her offspring. Longer birth intervals prevent dangerous complications such as death, anemia, and third‐trimester bleeding, and they help women to avoid psychological and financial issues after delivery. 16 However, in lactating women, the choices of contraception methods are limited. Because most hormonal contraception affects the quality and quantity of milk, progesterone only pills and an intrauterine contraceptive device (IUCD) are the most effective methods that are used in the first 6 month postpartum. 17 In our case, the patient had a history of uterine abnormalities, and the use of IUCD was contraindicated for her. More research is needed to test the efficacy of IUCDs among women with uterine abnormalities.\n\nAlthough the safety of ECP has been well studied and established to help in preventing unwanted pregnancies, cases have still been reported with EP linked to its use. Since 2002, several cases of EP after the use of ECPs were reported. However, some evidence suggests that the rate of EP following the use of LNG‐EC is not greater than that in the general population. 18 There is a dearth of knowledge about the safety of ECP among lactating women, and future research is needed to bridge this gap and establish the cause‐and‐effect relationship between ECP use and EP.\n\nThis study has some limitations. This is a single case report and causality cannot be directly linked to the use of ECP that was taken to prevent pregnancy based on this case. Additionally, there is little information in the context of lactating women. The manufacturers of the medications and the prescribing information that comes with the dispensed pack also do not indicate that breastfeeding is a contraindication to the use of ECP. This limits the generalizability of the claim from this report, but in situations of unprotected sex, the most suitable approach toward prevention of unwanted pregnancy is administration of ECP. However, contraception strategies among lactating women must be improved to avoid the need for ECP.\n\n4 CONCLUSIONS\n\nWe report the case of a patient who used ECP but who did not have any identifiable risks for EP. This case report cannot establish an association between the use of ECP and the occurrence of EP. However, based on the existing literature and the lack of clear guidelines for administration of ECP to lactating women, we recommend that ECP should be used with caution among such women. Additionally, the patients need to be strictly monitored for any symptoms of genital bleeding, abdominal pain, or a positive pregnancy test to rule out EP so that similar consequences such as those that are described in this case report can be avoided.\n\nCONFLICT OF INTEREST\n\nNone declared.\n\nAUTHOR CONTRIBUTIONS\n\nNM: contributed as a senior member to conception, drafting manuscript and technical revision of the manuscript for purpose of publication. SS: contributed to data extraction, writing the first draft also provided support in literature review. TB, SK, and FK: contributed equally to writing the first draft also provided support in literature review. All authors have read and approved the final version of the article for submission.\n\nINFORMED CONSENT\n\nInformed consent for the publication was obtained from the patient.\n\nACKNOWLEDGMENTS\n\nNo relevant acknowledgements.\n\nDATA AVAILABILITY STATEMENT\n\nData sharing is not applicable to this article as no new data were created or analyzed in this study.\n==== Refs\nREFERENCES\n\n1 Tahmina S , Daniel M , Solomon P . Clinical analysis of ectopic pregnancies in a tertiary care centre in southern India: a six‐year retrospective study. J Clin Diagn Res. 2016;10 (10 ):qc13‐qc16.\n2 Anderson J , Patterson C , Riley A . Heterotopic interstitial pregnancy: A case report. Case Rep Women's Health. 2018;17 :8‐10.29594007\n3 Abdulaziz A‐T . Trends in ectopic pregnancies in eastern saudi arabia. ISRN Obstet Gynecol. 2013;2013 :975251.23533797\n4 Pisarska MD , Carson SA , Buster JE . Ectopic pregnancy. Lancet. 1998;351 :1115‐1120.9660597\n5 Marchbanks PA , Annegers JF , Coulam CB , Strathy JH , Kurland LT . Risk factors for ectopic pregnancy: a population‐based study. JAMA. 1988;259 :1823‐1827.3343790\n6 Xiong X , Beukens P , Wollast E . IUD use and the risk of ectopic pregnancy: a meta‐analysis of case‐control studies. Contraception. 1995;52 :23‐34.8521711\n7 Ghosh B , Dadhwal V , Deka D , Ramesan CK , Mittal S . Ectopic pregnancy following levonorgestrel emergency contraception: a case report. Contraception. 2009;79 (2 ):155‐157.19135575\n8 Hamoda H , Ashok PW , Stalder C , Flett GM , Kennedy E , Templeton A . A randomized trial of mifepristone (10 mg) and levonorgestrel for emergency contraception. Obstet Gynecol. 2004;104 (6 ):1307‐1313.15572495\n9 Noé G , Croxatto HB , Salvatierra AM , et al. Contraceptive efficacy of emergency contraception with levonorgestrel given before or after ovulation. Contraception. 2011;84 (5 ):486‐492.22018122\n10 Connolly A , Ryan DH , Stuebe AM , Wolfe HM . Reevaluation of discriminatory and threshold levels for serum β‐hCG in early pregnancy. Obstet Gynecol. 2013;121 (1 ):65‐70.23262929\n11 Allen RH , Goldberg AB . Emergency contraception: a clinical review. Clin Obstet Gynecol. 2007;50 (4 ):927‐936.17982335\n12 Leung VW , Soon JA , Lynd LD , Marra CA , Levine M . Population‐based evaluation of the effectiveness of two regimens for emergency contraception. Int J Gynaecol Obstet. 2016;133 (3 ):342‐346.26969148\n13 Lozeau AM , Potter B . Diagnosis and management of ectopic pregnancy. Am Family Phys. 2005;72 (9 ):1707‐1714.\n14 Croxatto HB , Devoto L , Durand M , et al. Mechanism of action of hormonal preparations used for emergency contraception: a review of the literature. Contraception. 2001;63 :111‐121.11368982\n15 Sarkar NN . The emergency contraceptive drug, levonorgestrel: a review of post‐coital oral and peri‐coital vaginal administration for prevention of pregnancy. J Obstet Gynaecol. 2011;31 (8 ):703‐707.22085058\n16 Truitt ST , Fraser AB , Grimes DA , Gallo MF , Schulz KF . Hormonal contraception during lactation. systematic review of randomized controlled trials. Contraception. 2003;68 (4 ):233‐238.14572885\n17 Kelsey JJ . Hormonal contraception and lactation. J Hum Lactat. 1996;12 (4 ):315‐318.\n18 Cleland K , Raymond E , Trussell J , Cheng L , Zhu H . Ectopic pregnancy and emergency contraceptive pills: a systematic review. Obstet Gynecol. 2010;115 (6 ):1263‐1266.20502299\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2050-0904",
"issue": "9(3)",
"journal": "Clinical case reports",
"keywords": "LNG‐EC; contraceptives; ectopic; lactation; pregnancy",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "1605-1609",
"pmc": null,
"pmid": "33768899",
"pubdate": "2021-03",
"publication_types": "D002363:Case Reports",
"references": "22085058;20502299;29594007;26969148;3343790;23533797;15572495;17982335;16300032;9025449;9660597;8521711;23262929;22018122;11368982;14572885;27891402;19135575",
"title": "Case of rupture ectopic pregnancy with emergency contraception levonorgestrel 0.075 mg in a lactating woman.",
"title_normalized": "case of rupture ectopic pregnancy with emergency contraception levonorgestrel 0 075 mg in a lactating woman"
} | [
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"companynumb": "SA-ALVOGEN-2021-ALVOGEN-116856",
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"occurcountry": "SA",
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"activesubstancename": "LEVONORGESTREL"
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{
"abstract": "BACKGROUND\nElectric left atrial appendage (LAA) isolation (LAAI) may occur during catheter ablation of atrial tachyarrhythmias. Data regarding the risk of thromboembolic events and stroke after LAAI are sparse. This study evaluated the incidence of LAA thrombus formation and thromboembolic events after LAAI.\n\n\nRESULTS\nFifty patients had LAAI (age=71 years; female=56%; CHA2DS2-VASc score before ablation =3 [2;3]). LAAI patients were compared with matched patients with comparable baseline characteristics who underwent atrial fibrillation ablation without LAAI (n=50). Ablation strategies in the LAAI group included pulmonary vein isolation in 50 (100%), left atrial isthmus line in 47 (94%), anterior line in 45 (90%), complex atrial fractionated potentials in 24 (48%), and roofline in 14 (28%) patients. Transesophageal echocardiography was performed during follow-up in 47/50 (94%) patients in the LAAI group and in all patients of the control group. Oral anticoagulation (OAC) independent of CHA2DS2-VASc score was strongly recommended in all patients. During a median follow-up of 6.5 (4-12) months, stroke occurred in 2 patients on OAC and transient ischemic attack in one without OAC in the LAAI group. In the remaining 47 patients, LAA thrombus was identified on transesophageal echocardiography in 10 (21%) patients (OAC=9; no OAC=1). In the control group, no LAA thrombus was detected and no stroke occurred (P<0.001). Stable sinus rhythm was maintained in 32 patients (64%) of the LAAI group after a median follow-up of 6.5 months (4-12), including 17/32 patients on antiarrhythmic drugs.\n\n\nCONCLUSIONS\nAfter LAAI, an unexpectedly high incidence of LAA thrombus formation and stroke was observed despite OAC therapy.",
"affiliations": "From the Department of Cardiology, Asklepios Klinik St Georg (A.R., R.R.T., T.L., T.F., C.-H.H., A.A., A.M., S.M., E.W., H.M., K.-H.K., F.O.) and Asklepios proresearch, Hamburg, Germany (P.W.). arillig5@yahoo.de.;From the Department of Cardiology, Asklepios Klinik St Georg (A.R., R.R.T., T.L., T.F., C.-H.H., A.A., A.M., S.M., E.W., H.M., K.-H.K., F.O.) and Asklepios proresearch, Hamburg, Germany (P.W.).;From the Department of Cardiology, Asklepios Klinik St Georg (A.R., R.R.T., T.L., T.F., C.-H.H., A.A., A.M., S.M., E.W., H.M., K.-H.K., F.O.) and Asklepios proresearch, Hamburg, Germany (P.W.).;From the Department of Cardiology, Asklepios Klinik St Georg (A.R., R.R.T., T.L., T.F., C.-H.H., A.A., A.M., S.M., E.W., H.M., K.-H.K., F.O.) and Asklepios proresearch, Hamburg, Germany (P.W.).;From the Department of Cardiology, Asklepios Klinik St Georg (A.R., R.R.T., T.L., T.F., C.-H.H., A.A., A.M., S.M., E.W., H.M., K.-H.K., F.O.) and Asklepios proresearch, Hamburg, Germany (P.W.).;From the Department of Cardiology, Asklepios Klinik St Georg (A.R., R.R.T., T.L., T.F., C.-H.H., A.A., A.M., S.M., E.W., H.M., K.-H.K., F.O.) and Asklepios proresearch, Hamburg, Germany (P.W.).;From the Department of Cardiology, Asklepios Klinik St Georg (A.R., R.R.T., T.L., T.F., C.-H.H., A.A., A.M., S.M., E.W., H.M., K.-H.K., F.O.) and Asklepios proresearch, Hamburg, Germany (P.W.).;From the Department of Cardiology, Asklepios Klinik St Georg (A.R., R.R.T., T.L., T.F., C.-H.H., A.A., A.M., S.M., E.W., H.M., K.-H.K., F.O.) and Asklepios proresearch, Hamburg, Germany (P.W.).;From the Department of Cardiology, Asklepios Klinik St Georg (A.R., R.R.T., T.L., T.F., C.-H.H., A.A., A.M., S.M., E.W., H.M., K.-H.K., F.O.) and Asklepios proresearch, Hamburg, Germany (P.W.).;From the Department of Cardiology, Asklepios Klinik St Georg (A.R., R.R.T., T.L., T.F., C.-H.H., A.A., A.M., S.M., E.W., H.M., K.-H.K., F.O.) and Asklepios proresearch, Hamburg, Germany (P.W.).;From the Department of Cardiology, Asklepios Klinik St Georg (A.R., R.R.T., T.L., T.F., C.-H.H., A.A., A.M., S.M., E.W., H.M., K.-H.K., F.O.) and Asklepios proresearch, Hamburg, Germany (P.W.).;From the Department of Cardiology, Asklepios Klinik St Georg (A.R., R.R.T., T.L., T.F., C.-H.H., A.A., A.M., S.M., E.W., H.M., K.-H.K., F.O.) and Asklepios proresearch, Hamburg, Germany (P.W.).;From the Department of Cardiology, Asklepios Klinik St Georg (A.R., R.R.T., T.L., T.F., C.-H.H., A.A., A.M., S.M., E.W., H.M., K.-H.K., F.O.) and Asklepios proresearch, Hamburg, Germany (P.W.).",
"authors": "Rillig|Andreas|A|;Tilz|Roland R|RR|;Lin|Tina|T|;Fink|Thomas|T|;Heeger|Christian-H|CH|;Arya|Anita|A|;Metzner|Andreas|A|;Mathew|Shibu|S|;Wissner|Erik|E|;Makimoto|Hisaki|H|;Wohlmuth|Peter|P|;Kuck|Karl-Heinz|KH|;Ouyang|Feifan|F|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1161/CIRCEP.115.003461",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1941-3084",
"issue": "9(5)",
"journal": "Circulation. Arrhythmia and electrophysiology",
"keywords": "appendage isolation; atrial fibrillation; catheter ablation; left atrial appendage; stroke; thrombus",
"medline_ta": "Circ Arrhythm Electrophysiol",
"mesh_terms": "D000368:Aged; D020517:Atrial Appendage; D001281:Atrial Fibrillation; D017115:Catheter Ablation; D017548:Echocardiography, Transesophageal; D005260:Female; D005858:Germany; D006331:Heart Diseases; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D018570:Risk Assessment; D020521:Stroke; D013927:Thrombosis",
"nlm_unique_id": "101474365",
"other_id": null,
"pages": "e003461",
"pmc": null,
"pmid": "27153877",
"pubdate": "2016-05",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Unexpectedly High Incidence of Stroke and Left Atrial Appendage Thrombus Formation After Electrical Isolation of the Left Atrial Appendage for the Treatment of Atrial Tachyarrhythmias.",
"title_normalized": "unexpectedly high incidence of stroke and left atrial appendage thrombus formation after electrical isolation of the left atrial appendage for the treatment of atrial tachyarrhythmias"
} | [
{
"companynumb": "DE-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2016-BI-37825BI",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "Acute promyelocytic leukemia (APL) is a curable leukemia with > 90% survival in clinical trials. Population-based studies from Sweden and US SEER data have shown long-term survival rates of 62% and 65.7%, with the lower rate being from a higher percentage of early deaths.\n\n\n\nIn this prospective, multicenter trial, we developed a simplified algorithm that focused on prevention and early treatment of the three main causes of death: bleeding, differentiation syndrome, and infection. All patients with a diagnosis of APL were included. The initial 6 months were spent educating oncologists about early deaths in APL. At the time of suspicion of an APL, an expert was contacted. The algorithm was made available followed by discussion of the treatment plan. Communication between expert and treating physician was frequent in the first 2 weeks, during which time most deaths take place.\n\n\n\nBetween September 2013 and April 2016, 120 patients enrolled in the study from 32 hospitals. The median age was 52.5 years, with 39% > 60 years and 25% with an age-adjusted Charlson comorbidity index > 4. Sixty-three percent of patients were managed at community centers. Two patients did not meet the criteria for analysis, and of 118 evaluable patients, 10 died, with an early mortality rate of 8.5%. With a median follow-up of 27.3 months, the overall survival was 84.5%.\n\n\n\nInduction mortality can be decreased and population-wide survival improved in APL with the use of standardized treatment guidelines. Support from experts who have more experience with induction therapy is crucial and helps to improve the outcomes.",
"affiliations": "Division of Hematology and Oncology, Georgia Cancer Center at Augusta University, Augusta, GA.;Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA.;Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA.;Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA.;Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA.;Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA.;Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA.;Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute of Emory University, Atlanta, GA.;Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA.;Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA.;Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA.;Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA.;Division of Hematology and Oncology, Georgia Cancer Center at Augusta University, Augusta, GA.;Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA.;Phoebe Putney Cancer Center, Albany, GA.;South Carolina Oncology Associates, Columbia, SC.;Gibbs Cancer Center & Research Institute, Spartanburg, SC.;Department of Hematologic Oncology and Blood Disorders, The Levine Cancer Institute of Atrium Health, Charlotte, NC.;Department of Hematologic Oncology and Blood Disorders, The Levine Cancer Institute of Atrium Health, Charlotte, NC.;Division of Hematology and Oncology, Georgia Cancer Center at Augusta University, Augusta, GA.;Blood & Marrow Transplant, Cellular Immunotherapy & Acute Leukemia Program at Northside Hospital and Blood and Marrow Transplant Group of Georgia, Atlanta, GA.;Hollings Cancer Institute at Medical University of South Carolina, Charleston, SC.;Division of Hematology and Oncology, Georgia Cancer Center at Augusta University, Augusta, GA.",
"authors": "Jillella|Anand P|AP|;Arellano|Martha L|ML|;Gaddh|Manila|M|;Langston|Amy A|AA|0000-0003-0649-1915;Heffner|Leonard T|LT|;Winton|Elliott F|EF|;McLemore|Morgan L|ML|;Zhang|Chao|C|0000-0002-9066-8658;Caprara|Catherine R|CR|;Simon|Kathryn S|KS|;Bolds|Sheldon L|SL|;DeBragga|Stephanie|S|;Karkhanis|Prachi|P|;Krishnamurthy|Shruthi H|SH|;Tongol|Jose|J|;El Geneidy|Mohamed M|MM|;Pati|Asim|A|;Gerber|Jonathan M|JM|;Grunwald|Michael R|MR|;Cortes|Jorge|J|0000-0002-8636-1071;Bashey|Asad|A|;Stuart|Robert K|RK|;Kota|Vamsi K|VK|0000-0002-5290-9289",
"chemical_list": null,
"country": "United States",
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"doi": "10.1200/OP.20.00395",
"fulltext": "\n==== Front\nJCO Oncol Pract\nJCO Oncol Pract\nop\nop\nOP\nJCO Oncology Practice\n2688-1527\n2688-1535\nWolters Kluwer Health\n\n33125295\nOP.20.00395\n10.1200/OP.20.00395\nORIGINAL CONTRIBUTIONS\nCare Delivery\nComanagement Strategy Between Academic Institutions and Community Practices to Reduce Induction Mortality in Acute Promyelocytic Leukemia\nReducing Early Deaths in Acute Promyelocytic Leukemia\nJillella Anand P. MD 1\nArellano Martha L. MD 2\nGaddh Manila MD 2\nhttps://orcid.org/0000-0003-0649-1915\nLangston Amy A. MD 2\nHeffner Leonard T. MD 2\nWinton Elliott F. MD 2\nMcLemore Morgan L. MD 2\nhttps://orcid.org/0000-0002-9066-8658\nZhang Chao PhD 3\nCaprara Catherine R. MSN, BSN 2\nSimon Kathryn S. PA-C 2\nBolds Sheldon L. MS 2\nDeBragga Stephanie MS, PA-C 2\nKarkhanis Prachi BDS, MPH 1\nKrishnamurthy Shruthi H. MD 2\nTongol Jose MD 4\nEl Geneidy Mohamed M. MD, MBChB 5\nPati Asim MD 6\nGerber Jonathan M. MD 7\nGrunwald Michael R. MD 7\nhttps://orcid.org/0000-0002-8636-1071\nCortes Jorge MD 1\nBashey Asad MD, PhD 8\nStuart Robert K. MD 9\nhttps://orcid.org/0000-0002-5290-9289\nKota Vamsi K. MD 1\n1 Division of Hematology and Oncology, Georgia Cancer Center at Augusta University, Augusta, GA\n2 Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA\n3 Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute of Emory University, Atlanta, GA\n4 Phoebe Putney Cancer Center, Albany, GA\n5 South Carolina Oncology Associates, Columbia, SC\n6 Gibbs Cancer Center & Research Institute, Spartanburg, SC\n7 Department of Hematologic Oncology and Blood Disorders, The Levine Cancer Institute of Atrium Health, Charlotte, NC\n8 Blood & Marrow Transplant, Cellular Immunotherapy & Acute Leukemia Program at Northside Hospital and Blood and Marrow Transplant Group of Georgia, Atlanta, GA\n9 Hollings Cancer Institute at Medical University of South Carolina, Charleston, SC\nAnand P. Jillella, MD, Georgia Cancer Center at Augusta University, BAA 5409, 1120 15th St, Augusta, GA 30912; e-mail: ajillella@augusta.edu.\n4 2021\n30 10 2020\n17 4 e497e505\n© 2020 by American Society of Clinical Oncology\n2020\nAmerican Society of Clinical Oncology\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ Creative Commons Attribution Non-Commercial No Derivatives 4.0 License: https://creativecommons.org/licenses/by-nc-nd/4.0/\n\nPURPOSE:\n\nAcute promyelocytic leukemia (APL) is a curable leukemia with > 90% survival in clinical trials. Population-based studies from Sweden and US SEER data have shown long-term survival rates of 62% and 65.7%, with the lower rate being from a higher percentage of early deaths.\n\nMETHODS:\n\nIn this prospective, multicenter trial, we developed a simplified algorithm that focused on prevention and early treatment of the three main causes of death: bleeding, differentiation syndrome, and infection. All patients with a diagnosis of APL were included. The initial 6 months were spent educating oncologists about early deaths in APL. At the time of suspicion of an APL, an expert was contacted. The algorithm was made available followed by discussion of the treatment plan. Communication between expert and treating physician was frequent in the first 2 weeks, during which time most deaths take place.\n\nRESULTS:\n\nBetween September 2013 and April 2016, 120 patients enrolled in the study from 32 hospitals. The median age was 52.5 years, with 39% > 60 years and 25% with an age-adjusted Charlson comorbidity index > 4. Sixty-three percent of patients were managed at community centers. Two patients did not meet the criteria for analysis, and of 118 evaluable patients, 10 died, with an early mortality rate of 8.5%. With a median follow-up of 27.3 months, the overall survival was 84.5%.\n\nCONCLUSION:\n\nInduction mortality can be decreased and population-wide survival improved in APL with the use of standardized treatment guidelines. Support from experts who have more experience with induction therapy is crucial and helps to improve the outcomes.\n\nSJS Exportv1\nSTATUSONLINE-ONLY\n==== Body\npmcINTRODUCTION\n\nLarge multicenter trials in the United States and around the world using combinations of anthracyclines, arsenic trioxide (ATO), and all-trans retinoic acid (ATRA) have reported cure rates for patients with acute promyelocytic leukemia (APL) > 85%.1-6 Early deaths during induction in clinical trials have been reported to occur in 5%-10% of patients. Contrary to this excellent outcome in trials, reports from single institutions, pooled data from multiple institutions, and large population-based registries have reported induction mortality rates (ie, during the first 30 days after the start of therapy) of 17.3%-40%.7-14 In this study, we report the implementation of a standardized treatment algorithm for standard treatment in a network of leukemia treatment centers and comanagement by community oncologists and APL experts.\n\nMETHODS\n\nTrial Design\n\nThis study was designed to comanage patients with APL at their local/regional practices between the community oncologists and an APL expert in an academic institution. Patients age > 18 years with a confirmed diagnosis of APL and receiving standard therapy were eligible; there were no exclusion criteria. Confirmation of promyelocytic leukemia/retinoic acid receptor-α by fluorescence in situ hybridization was required before enrolling the patient. Patients were consented to collect treatment data, which were stored at Emory University. At the lead sites, an institutional review board (IRB)–approved consent was used, and at community sites, an Emory IRB-approved consent was signed after discussing the study over the phone. Patients diagnosed at the community centers were treated at their local hospitals; no patient was transferred to an academic center. Patients managed at the larger academic centers did not initiate therapy before transfer (Fig 1).\n\nFIG 1. CONSORT diagram showing 120 patients accrued from 32 hospitals. APL, acute promyelocytic leukemia.\n\nStudy Treatments and Supportive Care\n\nThe available guidelines15 for the management of APL and its complications were simplified into a two-page treatment algorithm. Emphasis was on prevention and early identification of disease complications and APL-directed therapy. Standard-of-care APL therapy was recommended but not directed by the study. Adherence to standard APL therapy as recommended by established guidelines was encouraged, with modifications allowed to account for age or comorbid conditions at the discretion of the treating physician in consultation with the APL expert. Suggested regimens were ATRA and ATO for non–high-risk patients and ATRA and idarubicin for high-risk patients.15 After five instances of early death occurred in elderly patients who had received ATRA 45 mg/m2 and developed severe differentiation syndrome (DS), it was recommended that all patients > 60 years of age and/or with significant comorbidities receive dose-reduced ATRA at 25 mg/m2,16 with ATO added after 10-14 days of therapy.\n\nPrednisone at 0.5 mg/kg was recommended at diagnosis in non–high-risk patients, and dexamethasone at 10 mg twice a day was started in high-risk patients per previously published protocols.17 At the first sign of DS, the corticosteroid dose was increased, and ATRA, ATO, or both were held. Hyperleukocytosis was managed with hydroxyurea and rarely with chemotherapy per published studies.6 Patients were weighed at admission on a standing bedside scale, and aggressive diuresis was used to maintain patients at baseline weight. (Treatment guidelines are provided in the Data Supplement, online only.)\n\nNetwork\n\nThe trial included a 6-month period of education of health care providers in Georgia and South Carolina to increase awareness of causes of early death in APL and the strategies being implemented to reduce mortality by a collaborative approach. Because of increased referrals from other neighboring states (predominantly Florida and North Carolina) after growing awareness of the trial, the trial was expanded to these regions. This involved sending e-mail communications and physically visiting and presenting the strategy in 15 community centers. Four large leukemia centers were identified as lead sites, and experts from the four expert sites were engaged in identifying and establishing communication with leukemia treatment centers in the four states. Cell phone numbers of APL experts were made available 24/7 during the entire study period for all necessary communications. Patients with APL who presented to the lead centers were managed with supervision by an APL expert at the site or with discussions among APL experts. Patients who presented to community leukemia centers were enrolled if an APL expert was contacted at the time of diagnosis. After the initial contact, the patient’s presentation and comorbid conditions were discussed by the treating physician with A.P.J., V.K.K., or both. Patient progress was discussed by phone, e-mail, or text messaging on a daily basis in the first 2 weeks and then every 2-3 days until discharge. In all patients, a consolidation plan and follow-up plan were also recommended at the time of completion of the induction period.\n\nStatistical Methods\n\nWe defined early death as mortality from the time of diagnosis until the end of induction. Deaths after 30 days as a result of complications from induction were also included as early deaths for the purpose of this analysis. We estimated that a sample size of 120 patients would have 98% power to detect a difference of 15% at the end of 30 days with an α of 0.05 compared with a control group identified through the SEER database. This control group consisted of patients from the SEER database in the 3 years from 2010 to 2012. Secondary end points were survival at 1 year and relapse rates at 12 months.\n\nStatistical analysis was conducted using SAS 9.4 software (SAS Institute, Cary, NC). Descriptive statistics for each variable were reported. For numeric covariates, the mean and standard deviation were calculated and presented. Frequency and percentage were shown for categorical variables. The univariable association of each covariate on overall survival (OS) was assessed using the Cox proportional hazards regression model. A multivariable Cox model was fit by a backward variable selection method with an α = 0.20 removal criterion. OS was represented in a Kaplan-Meier plot.\n\nRESULTS\n\nPatient and Hospital Characteristics\n\nBetween September 2013 and April 2016, 120 patients were enrolled. Two patients were excluded from the analysis: one because of refusal of transfusion support for religious reasons and a second enrolled 12 days after initiation of therapy and already with multiorgan failure at the time expert consultation was requested. This analysis includes all 118 eligible patients. Median age was 52.5 years (range, 21-84 years); 46 patients (39%) were ≥ 60 years. Sixty-eight patients (57%) were female, 23 (19.5%) were high risk,18 and 25% had an age-adjusted Charlson comorbidity index of > 4.19 Patient characteristics are listed in Table 1. Patients were treated at 32 hospitals; 16 hospitals treated only one patient during the observation period, five hospitals managed two patients, four hospitals managed three patients, and two hospitals managed four patients. The remaining five hospitals managed five, six, 10, 12, and 39 patients. Overall, 73 patients (62%) were treated in community centers and 45 (38%) in academic centers.\n\nTABLE 1. Patient Characteristics\n\nInduction Therapy and Supportive Care\n\nATRA was initiated at the time of suspicion of APL in 100% of patients. Of the 23 high-risk patients, four received ATRA alone as induction therapy. ATRA was initiated at 45 mg/m2 in two patients: one diagnosed with postmyocardial infarction with an ejection fraction of 20% and the other on the day of admission with a non–ST-elevation myocardial infarction. Cytarabine was used for reducing leukocytosis. The patients underwent consolidation therapy with ATRA/ATO postinduction and were in molecular remission at 19 and 32 months. In two patients who were > 70 years of age and had multiple comorbid conditions, ATRA was initiated at 25 mg/m2 and continued throughout their hospital stay at the same dose. Both these patients died as a result of complications from multiorgan failure and DS on days 16 and 18, respectively. In five high-risk patients, ATRA/ATO was initiated for induction in place of chemotherapy because of age or comorbid conditions precluding the use of chemotherapy (n = 4) or patient preference (n = 1). All five patients achieved hematological remission. One of these five patients (age 77 years) died as a result of recurrence of ovarian cancer 9 months after diagnosis of APL. The other four were in molecular remission at 19, 29, 38, and 40 months from diagnosis. In the remaining 14 patients, ATRA/idarubicin was the induction regimen. Two of them died during induction (days 5 and 6), both as a result of disease-related coagulopathy. Overall, 19 (82.6%) of the 23 high-risk patients achieved complete hematological remission after induction, with an induction mortality rate of 17.4%.\n\nIn the 95 non–high-risk patients, two received ATRA/chemotherapy per physician preference. One patient died on day 24 as a result of gram-negative sepsis and the other achieved complete hematological remission. In eight patients, ATRA was used as a single agent because of age and/or multiple comorbidities. One of them (age 32 years) presented with intracranial bleed and despite aggressive supportive measures, died on day 6 after initiating ATRA. Among the other seven patients receiving single-agent ATRA, one died on day 19 as a result of DS, and the other six are in molecular remission after dose-reduced ATRA/ATO consolidation. The other 85 patients received induction with ATRA/ATO. This included three patients who were pregnant with 10, 16, and 32 weeks gestation at the time of diagnosis. Two patients in their first trimester opted for termination and initiated therapy with dose-reduced ATRA at 25 mg/m2 to correct the coagulopathy, and ATO was added post-termination. The patient in her third trimester started ATRA alone but required a caesarean section for toxemia of pregnancy and then received ATO postsurgery. At 18 months of follow-up, the baby is in good health. All three patients achieved complete hematological remission after induction and molecular remission after ATRA/ATO consolidation. Thus, of the 95 low-risk patients, 89 (93.6%) achieved remission after induction, with an induction mortality rate of 6.4%. Despite adherence to transfusion guidelines, the targets could not be achieved in a few patients, especially during the initial period, because of florid coagulopathy, but there were no early deaths as a result of inadequate transfusion support.\n\nEarly Deaths\n\nTen patients (six non–high risk and four high risk) died, for an early death rate of 8.5%. Median age in the patients with early death was 67 years (range, 21-84 years). The cause of death was DS in five, coagulopathy in three, DS and infection in one, and infection in one. The median time to death in these 10 patients was 17 days (range, 1-36 days). In the three patients with early death as a result of coagulopathy, two (ages 32 and 40 years) died as a result of intracranial bleeding on days 1 and 6. One patient (age 21 years) presented with brain infarcts and died on day 5. All patients who died as a result of DS and/or infection were older, with a median age of 67 years (range, 61-84 years). Two patients (ages 76 and 72 years) died as a result of gram-negative sepsis (one also had DS) on days 16 and 24.\n\nConsolidation Therapy\n\nAt the end of induction therapy, recommendations were given to the treating physicians on the best choice of consolidation therapy. Patients were managed per published regimens.1,6\n\nRelapse and Late Deaths\n\nOf the 108 patients who achieved a remission, seven (6.4%) experienced a relapsed (three of whom were high risk). The three high-risk patients experienced relapse at 12, 29, and 32 months while on maintenance therapy per established protocol1 at the time of relapse. Two of them died at the time of relapse, one as a result of intracranial bleed on day 4 of re-induction and the other after refusal of therapy. The patient who experienced relapse at 32 months underwent re-induction followed by an autologous hematopoietic stem-cell transplantation (HSCT) but had a molecular relapse 4 months after HSCT. ATO was given for disease control followed by a haploidentical HSCT, and the patient was in remission at 4 months after HSCT.\n\nThree of the four non–high-risk patients who experienced relapse received inadequate consolidation with ATO because of social issues and nonadherence to therapy. All four patients received re-induction therapy with ATRA/ATO/chemotherapy and achieved a second remission. Two underwent autologous HSCT and are in remission at 6 and 7 months after transplantation. The other two patients refused HSCT and are in remission after consolidation with ATRA/ATO 4 and 30 months after achieving remission. The causes of late deaths were APL relapse (n = 2), relapse of ovarian cancer (n = 1), relapsed bladder cancer (n = 1), and complications from preexisting chronic medical problems and unrelated to APL or therapy (n = 4).\n\nSurvival\n\nThe 1-year survival probability for the entire cohort was 87.3%. After 18 months from last patient first visit and a median follow-up of 27.3 months, the OS rate was 84.5%, with an early death rate of 8.5% (Fig 2). In addition to the risk classification at diagnosis (by WBC count), age-adjusted comorbidity index and the presence of moderate to severe DS during induction were statistically significant independent predictors of OS on multivariable analysis (Table 2).\n\nFIG 2. Kaplan-Meier graph of overall survival (OS), with 118 patients included in the survival analysis. The 1-month mortality rate was 7.6%. There were eight late deaths as a result of relapse (n = 2), ovarian cancer (n = 1), relapsed bladder cancer (n = 1), and other chronic medical conditions (n = 4). Data in parentheses are the rate (CI, %).\n\nTABLE 2. Univariable and Multivariable Analyses\n\nOutcomes in Community Versus Academic Centers\n\nSeventy-three patients (61.8%) were managed at the community centers. Patients were registered under an academic center if they were transferred for management at the time of diagnosis. The median age (52 v 52.5 years) and comorbidity index (3 v 3) were similar at the academic and community centers, respectively. There was no difference in induction mortality, irrespective of where the patient was managed. Of the 73 managed at community centers, there were six deaths (three in low-risk patients and three in high-risk patients), with an induction mortality rate of 8.2%. This was similar to the 8.8% (four of 45 patients, with one high-risk patient) mortality rate seen in the academic centers. Similarly, there was no difference in survival at 1 year depending on location of therapy.\n\nDISCUSSION\n\nOur study shows that a high proportion of patients with APL are managed in the community similar to what is observed with other cancers. Recent population-based studies have shown that outcomes in acute myeloid leukemia were worse when managed in community centers compared with academic centers.20 In this study, we show that it is possible to improve 1-year survival in patients treated in community clinics when comanaged by an APL expert and the local treating physician. The outcomes in 29 community centers were similar to the three academic centers both at the end of induction (early death rate, 8.2% v 8.8%, respectively) and at 1 year. Overall, the 1-year survival rate in this study of 87.3% is superior to the US SEER data that showed a relative survival rate of 70.7%.8 The overall long-term survival of 84.5% with a median follow-up of 27.3 months is higher than what is seen in published population-based studies.8,9,12\n\nAPL is an uncommon disease, with approximately 3,000 cases diagnosed annually in the United States.21 The high incidence of complications, such as bleeding, thrombosis, and DS, has resulted in a recommendation that patients with APL should be referred to specialized centers. During the course of this study, 16 hospitals managed only one patient each over 3 years. Published data suggest that most large cancer centers may only see three to four patients per year.22,23 The Swedish and Canadian registry data showed that the outcomes were superior in academic centers.11,24 With our approach, using a simple algorithm along with frequent expert advice, revealed an excellent outcome overall and with no difference between community centers and academic institutions. The early death rate was similar at 8.8% in academic institutions and 8.2% in nonacademic community centers.\n\nElderly patients and patients with comorbidities are generally excluded from clinical trials. These patients have a significantly higher risk and early mortality than those eligible for clinical trials. In a review of patients not enrolled in trials from Germany, the early death rate in noneligible patients was 48%.14 Similarly, population-based data have shown that older age is a high-risk factor.7,9,18 These patients frequently have to be managed differently because this is a vulnerable population. The superiority of ATO-containing regimens over chemotherapy6 offers the chance of cure if early death can be reduced in most patients, including those ineligible for chemotherapy and who are elderly. In our study, there was no age- or comorbidity-based exclusion criteria. In fact, while the median age of patients in most clinical trials is in the low- to mid-40s,1,6 the median age in our study was 52.5 years, which is similar to the Swedish registry data (54 years). Forty-six patients (39%) were > 60 years of age with a median age-adjusted Charlson comorbidity index19 score of 5 in this group. There were 24 patients age > 70 years, including six who were age ≥ 80 years.\n\nOur study does have limitations. Our comparator arm being SEER is a limitation. Our study primary end point was to compare our outcomes to SEER data. The data from SEER cover only 27% of the US population. In addition, patient and treatment data are not clearly available. Despite these issues, we wanted to include all patients who we were called about and attempted to improve outcomes in this heterogeneous group. SEER data provided us the only source of outcomes in such a heterogeneous group of patients. We did exclude two patients in our analysis: one for not being involved in the care from the diagnosis and the other who refused treatment for religious reasons. Even with including these two patients, our results are comparable to that of selected populations of clinical trials, which was our main aim of the study. Another major limitation is the lack of data on the total number of patients diagnosed with APL in the same hospitals during the study period. The majority of the patients enrolled came from Georgia and South Carolina. SEER data themselves are not accurate, and review of SEER data in the same years actually shows that the total number of patients with APL diagnosed was less than what we enrolled. Our accrual did go up in the last part of the study as many referring physicians called us with patients. This also means that we were not called for patients with APL in the earlier part of the trial.\n\nOur algorithm by itself would not be expected to completely eliminate early deaths. Consultation with an APL expert is equally important. Accrual was lower in the first year, but with increased awareness, recruitment improved (two or fewer patients v four patients per month in the first 6 months v last 6 months). This suggests that ongoing communication and education were essential. The significance of networking and its effects on improving APL outcomes was shown by Rego et al25 in Latin America. Across six countries, patients were enrolled up to age 75 years and treated with a standard protocol, with weekly discussion by a centralized group of experts. The early death rate of 32% was decreased to 15% with this approach.\n\nIn the present era of targeted therapies in the management of diseases, a decentralized approach might offer better care over a large area and reduce disparities on the basis of geographical location. A similar approach showed remarkable improvements in the management of hepatitis C by primary care physicians under guidance from experts at the University of New Mexico.26 In our opinion, a similar approach to comanaging patients will be valuable in many other oncological conditions. Multiple targeted therapies have been approved in the past decade for various oncology indications, each with peculiar adverse effects. We are exploring the same concept in myeloma and chronic myeloid leukemia.\n\nIn summary, we show that a simplified algorithm and partnership between experts and treating community oncologists can significantly decrease early death as a result of APL in both academic and community centers. Our model is presently being implemented as an ECOG-ACRIN study (ClinicalTrials.gov identifier: NCT03253848) across the country. This model also paves the way for use in other conditions where education and academic-community partnerships could lead to better care for patients, even outside a clinical trial.\n\nPRIOR PRESENTATION\n\nSUPPORT\n\nCLINICAL TRIAL INFORMATION\n\nAUTHOR CONTRIBUTIONS\n\nConception and design: Anand P. Jillella, Martha L. Arellano, Amy A. Langston, Morgan L. McLemore, Chao Zhang, Asad Bashey, Robert K. Stuart, Vamsi K. Kota\n\nAdministrative support: Prachi Karkhanis, Shruthi H. Krishnamurthy, Sheldon L. Bolds\n\nProvision of study material or patients: Anand P. Jillella, Martha L. Arellano, Manila Gaddh, Amy A. Langston, Leonard T. Heffner, Elliott F. Winton, Morgan L. McLemore, Chao Zhang, Jose Tongol, Mohamed M. El Geneidy, Asim Pati, Jonathan M. Gerber,Michael R. Grunwald, Jorge Cortes, Asad Bashey, Robert K. Stuart, Vamsi K. Kota\n\nCollection and assembly of data: Manila Gaddh, Sheldon L. Bolds, Stephanie DeBragga, Prachi Karkhanis, Shruthi H. Krishnamurthy, Jose Tongol, Vamsi K. Kota\n\nData analysis and interpretation: Anand P. Jillella, Martha L. Arellano, Manila Gaddh, Amy A. Langston, Morgan L. McLemore, Chao Zhang, Kathryn S. Simon, Sheldon L. Bolds, Prachi Karkhanis, Jose Tongol, Jonathan M. Gerber, Michael R. Grunwald, Jorge Cortes, Asad Bashey, Robert K. Stuart\n\nManuscript writing: All authors\n\nFinal approval of manuscript: All authors\n\nAccountable for all aspects of the work: All authors\n\nAUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST\n\nComanagement Strategy Between Academic Institutions and Community Practices to Reduce Induction Mortality in Acute Promyelocytic Leukemia\n\nThe following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.\n\nOpen Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).\n\nPresented at the 62nd American Society of Hematology Annual Meeting, December 5-8, 2020.\n\nSupported in part by a grant from the Leukemia and Lymphoma Society.\n\nNCT02309333\n\nConflicts of Interest Statement: Accepted on September 22, 2020.\n\nMartha L. Arellano\n\nConsulting or Advisory Role: Gilead Sciences\n\nResearch Funding: Cephalon (Inst)\n\nManila Gaddh\n\nConsulting or Advisory Role: Agios, Pfizer\n\nResearch Funding: MedImmune (Inst), Apellis Pharmaceuticals (Inst), Celgene (Inst), Janssen Pharmaceuticals (Inst), Daiichi Sankyo (Inst)\n\nTravel, Accommodations, Expenses: Agios, Pfizer\n\nAmy A. Langston\n\nResearch Funding: Chimerix (Inst), Astellas Pharma (Inst), Incyte (Inst), Takeda Pharmaceuticals (Inst), Jazz Pharmaceuticals (Inst), Kadmon (Inst), Novartis (Inst)\n\nLeonard T. Heffner\n\nSpeakers’ Bureau: Kite Pharma\n\nResearch Funding: Pharmacyclics (Inst), Genentech (Inst), Kite Pharma (Inst), ADC Therapeutics (Inst), Astex Pharmaceuticals (Inst)\n\nElliott F. Winton\n\nResearch Funding: Incyte, Sierra Oncology, Samus Therapeutics, Blueprint Medicines\n\nAsim Pati\n\nHonoraria: Aptitude Health, ITA Group, AstraZeneca, Bristol Myers Squibb, BeiGene\n\nMichael R. Grunwald\n\nStock and Other Ownership Interests: Medtronic\n\nHonoraria: OncLive, Med Learning Group, Physicians’ Education Resource\n\nConsulting or Advisory Role: Incyte, Cardinal Health, Pfizer, Agios, AbbVie, Trovagene, Daiichi Sankyo, Bristol-Myers Squibb, Premier, Astellas Pharma\n\nResearch Funding: Janssen Pharmaceuticals (Inst), FORMA Therapeutics (Inst), Incyte (Inst), Genentech (Inst), Roche (Inst)\n\nTravel, Accommodations, Expenses: Amgen, Incyte\n\nJonathan M. Gerber\n\nPatents, Royalties, Other Intellectual Property: US Patent No. 9,012,215, US Patent No. 10,222,376\n\nJorge Cortes\n\nConsulting or Advisory Role: Bristol Myers Squibb, BioLineRx, Novartis, Pfizer, Amphivena Therapeutics, Daiichi Sankyo, Bio-Path Holdings, Astellas Pharma, Takeda Pharmaceuticals, Jazz Pharmaceuticals\n\nResearch Funding: Bristol Myers Squibb (Inst), Novartis (Inst), Pfizer (Inst), Astellas Pharma (Inst), Immunogen (Inst), Sun Pharma (Inst), Takeda Pharmaceuticals (Inst), Merus (Inst), Daiichi Sankyo (Inst), Tolero Pharmaceuticals (Inst), Trovagene (Inst), Jazz Pharmaceuticals (Inst)\n\nRobert K. Stuart\n\nConsulting or Advisory Role: Ono Pharmaceutical\n\nResearch Funding: Ono Pharmaceutical, Agios, Astellas Pharma\n\nVamsi K. Kota\n\nConsulting or Advisory Role: Pfizer, Novartis, AbbVie\n\nNo other potential conflicts of interest were reported.\n\nMartha L. Arellano\n\nConsulting or Advisory Role: Gilead Sciences\n\nResearch Funding: Cephalon (Inst)\n\nManila Gaddh\n\nConsulting or Advisory Role: Agios, Pfizer\n\nResearch Funding: MedImmune (Inst), Apellis Pharmaceuticals (Inst), Celgene (Inst), Janssen Pharmaceuticals (Inst), Daiichi Sankyo (Inst)\n\nTravel, Accommodations, Expenses: Agios, Pfizer\n\nAmy A. Langston\n\nResearch Funding: Chimerix (Inst), Astellas Pharma (Inst), Incyte (Inst), Takeda Pharmaceuticals (Inst), Jazz Pharmaceuticals (Inst), Kadmon (Inst), Novartis (Inst)\n\nLeonard T. Heffner\n\nSpeakers’ Bureau: Kite Pharma\n\nResearch Funding: Pharmacyclics (Inst), Genentech (Inst), Kite Pharma (Inst), ADC Therapeutics (Inst), Astex Pharmaceuticals (Inst)\n\nElliott F. Winton\n\nResearch Funding: Incyte, Sierra Oncology, Samus Therapeutics, Blueprint Medicines\n\nAsim Pati\n\nHonoraria: Aptitude Health, ITA Group, AstraZeneca, Bristol Myers Squibb, BeiGene\n\nMichael R. Grunwald\n\nStock and Other Ownership Interests: Medtronic\n\nHonoraria: OncLive, Med Learning Group, Physicians’ Education Resource\n\nConsulting or Advisory Role: Incyte, Cardinal Health, Pfizer, Agios, AbbVie, Trovagene, Daiichi Sankyo, Bristol-Myers Squibb, Premier, Astellas Pharma\n\nResearch Funding: Janssen Pharmaceuticals (Inst), FORMA Therapeutics (Inst), Incyte (Inst), Genentech (Inst), Roche (Inst)\n\nTravel, Accommodations, Expenses: Amgen, Incyte\n\nJonathan M. Gerber\n\nPatents, Royalties, Other Intellectual Property: US Patent No. 9,012,215, US Patent No. 10,222,376\n\nJorge Cortes\n\nConsulting or Advisory Role: Bristol Myers Squibb, BioLineRx, Novartis, Pfizer, Amphivena Therapeutics, Daiichi Sankyo, Bio-Path Holdings, Astellas Pharma, Takeda Pharmaceuticals, Jazz Pharmaceuticals\n\nResearch Funding: Bristol Myers Squibb (Inst), Novartis (Inst), Pfizer (Inst), Astellas Pharma (Inst), Immunogen (Inst), Sun Pharma (Inst), Takeda Pharmaceuticals (Inst), Merus (Inst), Daiichi Sankyo (Inst), Tolero Pharmaceuticals (Inst), Trovagene (Inst), Jazz Pharmaceuticals (Inst)\n\nRobert K. Stuart\n\nConsulting or Advisory Role: Ono Pharmaceutical\n\nResearch Funding: Ono Pharmaceutical, Agios, Astellas Pharma\n\nVamsi K. Kota\n\nConsulting or Advisory Role: Pfizer, Novartis, AbbVie\n\nNo other potential conflicts of interest were reported.\n==== Refs\nREFERENCES\n\n1. 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Cancer 118 :5811-5818, 2012 22707337\n10. Serefhanoglu S Buyukasik Y Goker H , et al : Clinical features and outcomes of 49 Turkish patients with acute promyelocytic leukemia who received ATRA and anthracyclines (PETHEMA protocol) therapy. Leuk Res 34 :e317-e319, 2010 20696473\n11. Lehmann S Ravn A Carlsson L , et al : Continuing high early death rate in acute promyelocytic leukemia: A population-based report from the Swedish Adult Acute Leukemia Registry. Leukemia 25 :1128-1134, 2011 21502956\n12. Jácomo RH Melo RA Souto FR , et al : Clinical features and outcomes of 134 Brazilians with acute promyelocytic leukemia who received ATRA and anthracyclines. Haematologica 92 :1431-1432, 2007 18024380\n13. Jillella AP, Sadek I, Morrison D, et al: A simple but effective model to decrease early deaths in acute promyelocytic leukemia (APL). J Clin Oncol 30, 2012 (suppl; abstr 6573)\n14. Lengfelder E Hanfstein B Haferlach C , et al : Outcome of elderly patients with acute promyelocytic leukemia: Results of the German Acute Myeloid Leukemia Cooperative Group. Ann Hematol 92 :41-52, 2013 23090499\n15. Sanz MA Fenaux P Tallman MS , et al : Management of acute promyelocytic leukemia: Updated recommendations from an expert panel of the European LeukemiaNet. Blood 133 :1630-1643, 2019 30803991\n16. Castaigne S Lefebvre P Chomienne C , et al : Effectiveness and pharmacokinetics of low-dose all-trans retinoic acid (25 mg/m2) in acute promyelocytic leukemia. Blood 82 :3560-3563, 1993 8260694\n17. Lo-Coco F Avvisati G Vignetti M , et al : Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: Results of the AIDA-2000 trial of the GIMEMA Group. Blood 116 :3171-3179, 2010 20644121\n18. Powell BL Moser B Stock W , et al : Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood 116 :3751-3757, 2010 20705755\n19. Charlson M Szatrowski TP Peterson J , et al : Validation of a combined comorbidity index. J Clin Epidemiol 47 :1245-1251, 1994 7722560\n20. Bhatt VR Shostrom V Giri S , et al : Early mortality and overall survival of acute myeloid leukemia based on facility type. Am J Hematol 92 :764-771, 2017 28437868\n21. Yamamoto JF Goodman MT : Patterns of leukemia incidence in the United States by subtype and demographic characteristics, 1997-2002. Cancer Causes Control 19 :379-390, 2008 18064533\n22. Elliott MA Letendre L Tefferi A , et al : Therapy-related acute promyelocytic leukemia: Observations relating to APL pathogenesis and therapy. Eur J Haematol 88 :237-243, 2012 22023492\n23. Altman JK Rademaker A Cull E , et al : Administration of ATRA to newly diagnosed patients with acute promyelocytic leukemia is delayed contributing to early hemorrhagic death. Leuk Res 37 :1004-1009, 2013 23768930\n24. Paulson K Serebrin A Lambert P , et al : Acute promyelocytic leukaemia is characterized by stable incidence and improved survival that is restricted to patients managed in leukaemia referral centres: A pan-Canadian epidemiological study. Br J Haematol 166 :660-666, 2014 24780059\n25. Rego EM Kim HT Ruiz-Argüelles GJ , et al : Improving acute promyelocytic leukemia (APL) outcome in developing countries through networking, results of the International Consortium on APL. Blood 121 :1935-1943, 2013 23319575\n26. Arora S Thornton K Murata G , et al : Outcomes of treatment for hepatitis C virus infection by primary care providers. N Engl J Med 364 :2199-2207, 2011 21631316\n\n",
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"title": "Comanagement Strategy Between Academic Institutions and Community Practices to Reduce Induction Mortality in Acute Promyelocytic Leukemia.",
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"abstract": "A 24-yr-old woman was found dead in her home from apparent propofol \"toxicity.\" Her blood level of propofol was 4.3 microg/mL. She had no history of drug abuse and no evidence of such behavior at autopsy. The medical examiner and police investigators felt that she died from probable homicide. Attention was focused on a male registered nurse acquaintance, who had acquired propofol and other drugs in the course of his regular duties in a surgical intensive care unit. This is the first reported case of murder with propofol.",
"affiliations": "Department of Anesthesiology, University of Florida College of Medicine, Box 100254 JHMHSC, Gainesville, FL 32610-0254, USA. RKirby@anest.ufl.edu",
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"title": "Death from propofol: accident, suicide, or murder?",
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"abstract": "We describe a 7-year-old child with multisystemic inflammatory syndrome that was temporarily associated with the novel coronavirus disease which evolved into serious illness, with coronary aneurysm, using human immunoglobulin and acetylsalicylic acid, in which clinical manifestations including hepatitis, convulsions, and coma were aggravated with Reye's syndrome. To date, there has been no report of the association of multisystemic inflammatory syndrome that is temporarily associated with the novel coronavirus disease and Reye's syndrome.",
"affiliations": "Department of Microbial Biology, Ceuma University, São Luis, Brazil.;Department of Microbial Biology, Ceuma University, São Luis, Brazil.;Intermediate Care Unit, Dr. Odorico de Amaral Matos Children's Hospital, São Luis, Brazil.;Intermediate Care Unit, Dr. Odorico de Amaral Matos Children's Hospital, São Luis, Brazil.",
"authors": "Pessoa|Fabrício Silva|FS|;Lacerda|Eliza Maria da Costa Brito|EMDCB|;Gonçalves|Valdênia Costa|VC|;Tanaka|Barbara Neiva|BN|",
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"fulltext": "\n==== Front\nFront Pediatr\nFront Pediatr\nFront. Pediatr.\nFrontiers in Pediatrics\n2296-2360\nFrontiers Media S.A.\n\n10.3389/fped.2021.650697\nPediatrics\nCase Report\nCase Report: MIS-C Temporarily Associated With COVID-19 Complicated by Reye's Syndrome\nPessoa Fabrício Silva 1234*\n\nLacerda Eliza Maria da Costa Brito 1\n\nGonçalves Valdênia Costa 23\nTanaka Barbara Neiva 23\n1Department of Microbial Biology, Ceuma University, São Luis, Brazil\n2Intermediate Care Unit, Dr. Odorico de Amaral Matos Children's Hospital, São Luis, Brazil\n3Pediatric Intensive Care Unit, Dr. Carlos Macieira High Complexity Hospital, São Luis, Brazil\n4Pediatric Infectious Diseases Department, Federal University of Maranhão Hospital (UFMA) University Hospital, São Luis, Brazil\nEdited by: Kyung-Yil Lee, Catholic University of Korea, South Korea\n\nReviewed by: Jagadeesh Bayry, Institut National de la Santé et de la Recherche Médicale (INSERM), France; Ilaria Maccora, University of Florence, Italy\n\n*Correspondence: Fabrício Silva Pessoa fabriciosilvapessoa@hotmail.com\nThis article was submitted to Pediatric Immunology, a section of the journal Frontiers in Pediatrics\n\n16 4 2021\n2021\n16 4 2021\n9 65069709 1 2021\n15 3 2021\nCopyright © 2021 Pessoa, Lacerda, Gonçalves and Tanaka.\n2021\nPessoa, Lacerda, Gonçalves and Tanaka\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nWe describe a 7-year-old child with multisystemic inflammatory syndrome that was temporarily associated with the novel coronavirus disease which evolved into serious illness, with coronary aneurysm, using human immunoglobulin and acetylsalicylic acid, in which clinical manifestations including hepatitis, convulsions, and coma were aggravated with Reye's syndrome. To date, there has been no report of the association of multisystemic inflammatory syndrome that is temporarily associated with the novel coronavirus disease and Reye's syndrome.\n\nCOVID-19\nmultisystem inflammatory syndrome in children\nReye syndrome\nCOVID-19 pandemic\nSARS-CoV-2 (COVID-19)\n==== Body\nIntroduction\n\nMultisystemic inflammatory syndrome in children (MIS-C) that is temporarily associated with the novel coronavirus disease 2019 (COVID-19) has been recently described as an inflammatory complication after exposure to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with the possibility of serious and lethal complications, including coronary aneurysm (1). Reye's syndrome is a rare complication due to the use of aspirin, with onset following recovery from a viral disease (2).\n\nThis article describes the complete clinical course and follow-up data of a 7-year-old child treated at a pediatric intensive care unit (PICU) with severe MIS-C with coronary aneurysm, who was treated with human intravenous immunoglobulin (IVIG) and acetylsalicylic acid (ASA). The patient subsequently developed Reye's syndrome with life-threatening clinical presentations, including hepatitis, seizures, and coma. To our knowledge, there has been no reported association between MIS-C and Reye's syndrome.\n\nCase Report\n\nA 7-year-old boy from the countryside of the state of Maranhão, northeastern Brazil, was admitted to the PICU having had fever for 6 days, headache, vomiting, maculopapular rash, severe abdominal pain, conjunctival hyperemia, photophobia, raspberry tongue, hyperemia with lip desquamation, right cervical lymphadenomegaly, and edema. In addition, he experienced mild tachypnea without respiratory symptoms when breathing normal room air (Figure 1).\n\nFigure 1 (A) Presence of bilateral, nonexudative conjunctival hyperemia. (B) Maculopapular lesions in the palmoplantar region. (C) Presence of mucosal changes with peeling lip and raspberry tongue.\n\nOn admission, the patient underwent a fluorescence immunoassay for SARS-CoV-2 to test for the presence of reagent immunoglobulin G (IgG) antibodies, with titers >30.0 AU/mL (normal, <1.4 AU/mL) and antibodies nonreactive to immunoglobulin M (IgM), with a titer of 0.1 AU (normal, <1.1 AU). The mother reported that the child had flu-like symptoms 1 month before admission.\n\nLaboratory tests indicated inflammatory responses (Table 1). His C-reactive protein measured 96 mg/dL, blood count showed lymphopenia, anemia, and thrombocytopenia; hypoalbuminemia (2.3 g/dL); hypertriglyceridemia (262 mg/dL); and increased levels of transaminases, ferritin (1,812 ng/mL), d-dimer (8,500 ng/mL), and troponin (0.26 ng/mL). The patient's blood type was O positive. Serology tests for dengue IgG and IgM and anti-HIV were nonreactive. Serology tests for toxoplasmosis, cytomegalovirus, Epstein–Barr virus, herpes simplex 1 and 2, and rubella were all negative. Blood culture for aerobic and anaerobic microbes using selective media showed no bacterial growth. Urine culture also revealed no bacterial growth.\n\nTable 1 Clinical laboratory results during the current hospitalization.\n\nHospitalization day\t11/06\t12/06\t13/06\t14/06\t17/06\t27/06\t29/06\t30/06\tRange & Units\t\nHemoglobin (g/dL)\t9.6\t7.6\t11.7\t11.9\t12.0\t12.6\t12.2\t11.5\t11.5–15.5\t\nHematocrit (%)\t30.3\t23.5\t35.6\t35.9\t36.5\t37.6\t36.1\t34.2\t35–45\t\nWBC (× 109/L)\t20.0\t7.47\t13.13\t11.4\t10.31\t4.03\t8.62\t8.29\t3.20–10.0\t\nNEU (× 109/L)\t18.0\t5.7\t11.3\t9.12\t6.59\t1.49\t4.12\t3.72\t3.0–7.0\t\nLYM (× 109/L)\t0.86\t0.93\t1.37\t1.69\t2.29\t2.10\t3.53\t3.20\t1.5–4.0\t\nPLT (× 109/L)\t74\t64\t155\t246\t530\t239\t173\t162\t150–450\t\nC-reactive protein (mg/dL)\t18.3\t10.5\t7.4\t4.0\t1.5\t2.43\t4.18\t4.13\t<1.0\t\nALT (U/L)\t74.1\t41.9\t47\t–\t31\t–\t479.5\t459.9\t10–40\t\nAST (U/L)\t190\t53.1\t43\t–\t34\t–\t1.117\t1.073\t10–40\t\nLDH (U/L)\t325\t–\t–\t–\t230\t–\t–\t–\t100–190\t\nBUN (mg/dL)\t76\t25.1\t23.8\t23.7\t30.0\t–\t21.6\t19.1\t16–40\t\nSCR (mg/dL)\t0.9\t0.3\t0.28\t0.26\t0.38\t–\t0.47\t0.47\t0.6–1.1\t\nD-Dimer (ng/mL)\t8.500\t–\t–\t4.780\t1.331\t–\t30.970\t–\t<500\t\nCreatine phosphokinase (U/L)\t81\t–\t\t\t19\t–\t199\t283\t32–190\t\nCK-MB (U/L)\t–\t–\t–\t–\t–\t–\t–\t1.83\t<5\t\nTroponin (ng/mL)\t0.26\t–\t–\t0.07\t0.04\t–\t6.5\t5.5\t<0.04\t\nFerritin (ng/mL)\t1.385\t–\t–\t385.6\t321.9\t–\t16.500\t–\t30–300\t\nBNP (pg/mL)\t1.812\t–\t–\t–\t\t–\t42.4\t–\t0–70\t\nTriglycerides (mg/dL)\t262\t–\t–\t–\t159\t–\t158\t176\t<160\t\nAlbumin (g/dL)\t2.3\t3.6\t\t\t3.7\t–\t3.8\t3.5\t3.5–5.5\t\nMyglobin (ng/mL)\t–\t–\t–\t–\t–\t–\t34\t–\t<110\t\nFibrinogen (mg/dL)\t–\t–\t–\t–\t–\t–\t–\t130.4\t200–400\t\nAmmonia (150 μmol/L)\t–\t–\t–\t–\t–\t–\t150\t–\t10–80\t\n\nReal-time polymerase chain reaction (PCR) of the nasopharyngeal swab for influenza A, influenza B, and respiratory syncytial virus revealed that these viruses as undetectable. PCR of nasopharyngeal and rectal samples showed SAR2-CoV-2 as undetectable. The patient had normal C3, C4, and CH50 serum complement levels. Other test results included negative direct Coombs, normal reticulocytes, and a normal simple urine test. The chest computed tomography (CT) scan showed moderate bilateral pleural effusion associated with fissure thickening on the right, interlobular septa thickening, mild infectious/inflammatory opacity, and mild pericardial effusion. The abdominal CT scan showed diffuse subcutaneous tissue edema and large amounts of free fluids in the abdominal and pelvic cavities. The transthoracic echocardiogram showed aneurysmal dilation of the right coronary and left main coronary arteries (Figure 2).\n\nFigure 2 (A) Pretreatment echocardiographic images of the left main coronary artery measuring 3.762 mm (Z score +3.22). (B) Pretreatment echocardiographic images of the proximal right coronary measuring 3.38 mm (Z score +2.86). (C) Posttreatment echocardiographic images of the left main coronary artery measuring 3.28 mm (Z score +2.04). (D) Posttreatment echocardiographic images of the right proximal coronary artery measuring 2.87 mm (Z score +1.66).\n\nThe patient received intensive support and was treated with antimicrobials (ceftriaxone, oxacillin, and azithromycin) and received intravenous human albumin. In addition, MIS-C was treated with a single IVIG dose of 2 g/kg by continuous infusion over 10 h, with the aim of promoting anti-inflammatory and immunomodulatory action and ASA, initially at the oral anti-inflammatory dose of 80 mg/kg per day (6/6 h) until the child became afebrile after 48 h and the oral maintenance dose was reduced to 5 mg/kg per day, single oral dose, as an antiplatelet agent, indicated by the presence of coronary dilations.\n\nTwo weeks after IVIG and ASA administration, while still hospitalized, the patient experienced a seizure crisis. His consciousness level lowered, and coma eventuated. He was intubated and managed with neuroprotective and anticonvulsant measures. The patient also had increased liver enzymes. Laboratory tests showed significant liver function damage (Table 1) and an ammonia level of 150 μmol/L. Cerebrospinal fluid (CSF) was collected with a cell count of 6/mm3, normal protein (33.9 mg/dL), and normal glucose (66.32 mg/dL). Other results included negative CSF Gram stain bacterioscopy and liquor culture without growth. Latex agglutination reactions were performed with specific antibodies for groups A, B, C, Y, and W-135 Neisseria meningitidis, Streptococcus pneumoniae, and type B Haemophilus influenzae, and these were all undetectable. Electroencephalogram showed no epileptiform activity. Blood was detected in the feces and fecal leukocytes. Skull CT demonstrated no abnormal changes.\n\nInitially, the diagnosis of sepsis of hospital origin was considered, with meropenem and teicoplanin being prescribed. The patient received blood components, including red blood cells, fresh plasma, and vitamin K for severe coagulation disorders. In addition, he was administered sodium bicarbonate for metabolic acidosis, and ventilation control was provided. It was also necessary to administer vasoactive amines.\n\nAt that time, the patient was still using ASA; after clinical and laboratory investigation of the patient, the diagnosis of Reye's syndrome was given, as ASA is associated with such a syndrome, with the switch from ASA to clopidogrel, in one initial dose of 1 mg/kg per day, in order to maintain the antiplatelet activity.\n\nThe patient showed signs of improvement clinically. His liver enzymes decreased, and neurological condition improved. He was extubated and discharged from hospital after 2 weeks and followed up as an outpatient. A control echocardiogram was done and showed no coronary aneurysmal dilation (Figure 2).\n\nDiscussion\n\nThis case report described a 7-year-old child with MIS-C, treated with IVIG and ASA, who subsequently developed Reye's syndrome with neurological and hepatic deteriorations, without other justified causes. The case presented a rare complication that was severe and potentially lethal, with critical progression and difficult management, but, ultimately, a satisfactory outcome.\n\nInfections with SARS-CoV-2 in children are generally mild, but there may be complications associated with an inflammatory disorder, which can lead to serious illnesses and long-term side effects, referred to here as MIS-C. Most cases of MIS-C associated with COVID-19 are treated following the standard protocols for Kawasaki disease (3). Dufort et al. highlight that the incidence of MIS-C was 2 per 100,000 in people younger than 21 years (4).\n\nMIS-C is a severe condition similar to Kawasaki disease, based on six main diagnostic elements: pediatric age, persistent fever, presence of laboratory markers of inflammation, signs or symptoms of organ dysfunctions, absence of an alternative diagnosis, and history of COVID-19 infection or exposure with possible cardiac and neurological presentations (5, 6). Several societies and organizations, such as the World Health Organization and the Centers for Disease Control and Prevention (CDC), have defined the diagnostic criteria of MIS-C (1). This case had a presentation that matched the diagnostic criteria of MIS-C, as the patient had fever for 6 days; headache; vomiting; maculopapular rash; severe abdominal pain; nonpurulent conjunctival hyperemia; photophobia; mucocutaneous inflammation signs (raspberry tongue, hyperemia with epithelial desquamation of the lips); presence of laboratory inflammatory markers, including erythrocyte sedimentation rate, C-reactive protein, D-dimer, and ferritin; right cervical lymphadenomegaly; and cardiac changes, as well as previous exposure to SARS-CoV-2 as confirmed by serology, and no other justified cause.\n\nThere are similarities between MIS-C and atypical Kawasaki disease; however, we observed some differences that can help to differentiate both situations. In this case, MIS-C generally presents in a higher incidence of gastrointestinal diseases, in children of older ages and with greater cardiac involvement (7). Despite the differential diagnoses between MIS-C and atypical Kawasaki disease being very close, the differences point to MIS-C, marked by the previous exposure to SARV-Cov-2, as a 7-year-old child, with gastrointestinal manifestations, represented by abdominal pain and, in addition, cardiac manifestations with coronary dilation, evidencing the importance of always performing this differential diagnosis in the management of these cases.\n\nThe presence of coronary aneurysm is a serious complication, well-described in Kawasaki disease, and present in MIC-S. Coronary aneurysm may progress to thrombosis, infarction, and cardiac arrhythmias that may persist for life and even lead to death. The timely treatment with IVIG until the 10th day of the disease reduced the possibilities of these complications (5, 8). The child described in this case report had MIC-S with cardiac changes as confirmed by echocardiography and was treated using IVIG and ASA.\n\nReye's syndrome begins within days of recovery from a viral disease wherein aspirin was administered. Reye's syndrome usually presents with an acute noninflammatory encephalopathy with fatty liver failure. It is a rare and potentially fatal pediatric disease. Affected children present with vomiting and mental confusion, rapid progression to coma, and death. Diagnosis of Reye's syndrome is based on clinical signs and laboratory tests (8).\n\nReye's syndrome is a known complication reported during the administration of ASA in children after a viral infection. Possible explanations for the pathophysiology of Reye's syndrome should be made. This syndrome is associated with a generalized disturbance in mitochondrial metabolism, resulting in metabolic failure in the liver and other tissues. Hypothetically, we can define that there are genetic factors, which can be modified by exogenous agents (in this case, ASA) and stimulated by a response to previous viral infection (9). In the case reported here, we describe a child who had a COVID-19 infection and subsequently progressed with MIC-S, presenting a cardiac complication (coronary aneurysm), with IVIG and ASA being administered and later progressing with liver failure and neurological condition, receiving the diagnosis of Reye's syndrome.\n\nThe CDC defined the diagnostic criteria for Reye's syndrome with three items: (1) acute noninflammatory encephalopathy (documented by changed consciousness); (2) CSF containing ≤ 8 leukocytes/mm (or a histological sample showing cerebral edema without perivascular or meningeal inflammation); and (3) liver disease (confirmed via liver biopsy/autopsy or a 3-fold or higher increase in serum glutamic-oxaloacetic transaminase, serum glutamic–pyruvic transaminase, and serum ammonia). In addition, Reye's syndrome is diagnosed when there are no other reasonable explanations for the brain and liver abnormalities (8).\n\nThis case report described a child with MIC-S, who underwent IVIG and ASA treatment and deteriorated after 1 week of treatment, with an altered level of consciousness, seizures, normal CSF, laboratory-proven hepatic changes, and no explanations to justify the brain and liver changes.\n\nAn important point that should be highlighted in the case was the prescription of ASA for the child because of the need to reduce coronary complications and thrombotic events. Ahmed et al. reported that up to 16.8% of all MIC-S cases reported the use of ASA (5).\n\nBianconi et al. described the use of ASA in COVID-19 and the possible complications from its anti-inflammatory and antithrombotic effects. The authors concluded that although the possibility of significant complications was rare, severe liver and brain injuries in children may result (i.e., Reye's syndrome) (10).\n\nOne of the important strategies used to ensure antithrombotic benefits and improve the clinical course of Reye's syndrome (given the need to maintain an antiplatelet agent and reduce the risk of complications) was to replace ASA with clopidogrel. Eleftheriou et al. reported that clopidogrel is an alternative antiplatelet agent that can be used in Kawasaki disease and therefore may be useful for MIC-S (11).\n\nThe literature highlights that the anatomopathological criterion for Reye's syndrome, with liver biopsy, may be useful, but the risk of complications, such as bleeding, is increased (12). In this reported case, hepatic changes were verified by tests that showed an increase in liver enzymes and ammonia.\n\nThe child underwent treatment with intensive support, initially for MIC-S and, subsequently, for Reye's syndrome. The patient progressed satisfactorily and demonstrated good clinical and laboratory results, reversed hepatic and neurological dysfunctions, and complete regression of the coronary aneurysm as confirmed during his outpatient follow-up.\n\nRecent articles show that SARS-CoV-2 infection can complicate the onset of several autoimmune and autoinflammatory diseases, including MIS-C and Guillain-Barré syndrome, that need fundamental immunological therapies, such as immunoglobulin (13–16).\n\nMIC-S is an inflammatory disease arising after exposure to SARS-CoV-2, may progress to systemic and vascular changes, and is potentially lethal. This description of a case of MIC-S, complicated by Reye's syndrome, resulted in a good clinical response after management and is unprecedented in the literature. Reye's syndrome should be considered in all pediatric cases of MIC-S treated with ASA.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by the Research Ethics Committee of Universidade Ceuma (CEP) in compliance with the requirements of Resolution 466/2012 of the National Health Council that guides research involving human beings, directly or indirectly. The project was approved with CEP Opinion N°. 4,315,245. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. Written informed consent was obtained from the minor(s)' legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nFP, VG, BT, and EL conceptualized and designed the study, coordinated and supervised data collection, and drafted and critically reviewed the manuscript for important intellectual content. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nThe authors would like to thank the research group at Department of Microbial Biology, CEUMA University and the support of the Support Foundation for Research and Scientific and Technological Development of Maranhão - FAPEMA for the support and contribution.\n\nAbbreviations\n\nMIS-C Multisystemic inflammatory syndrome\n\nCOVID-19 Novel coronavirus disease\n\nSARS-CoV-2 Severe acute respiratory syndrome coronavirus 2\n\nPICU Pediatric intensive care unit\n\nIVIG Human immunoglobulins\n\nASA Acetylsalicylic acid.\n==== Refs\nReferences\n\n1. García-Salido A Antón J Martínez-Pajares JD Garcia GG Gómez B Tagarro A . (2021). Documento español de consenso sobre diagnóstico, estabilización y tratamiento del síndrome inflamatorio multisistémico pediátrico vinculado a SARS-CoV-2 (SIM-PedS). Anales Pediatría 94:116.e1–116.e11. 10.1016/j.anpedi.2020.09.005\n2. Chapman J Arnold JK . Reye syndrome. in: StatPearls. Treasure Island, FL: StatPearls Publishing (2020).\n3. Jiang L Tang K Levin M Irfan O Morris SK Wilson K . COVID-19 and multisystem inflammatory syndrome in children and adolescents. Lancet Infect Dis. 20 , e276–e288. 10.1016/S1473-3099(20)30651-4 32818434\n4. Dufort EM Koumans EH Chow EJ Rosenthal EM Muse A Rowlands J . Multisystem inflammatory syndrome in children in New York State. New Engl J Med. (2020) 383 :347–58. 10.1056/NEJMoa2021756 32598830\n5. Ahmed M Advani S Moreira A Zoretic S Martinez J Chorath K . Multisystem inflammatory syndrome in children: a systematic review. EClinicalMedicine. (2020) 26 :100527. 10.1016/j.eclinm.2020.100527 32923992\n6. De Paulis M Oliveira DB Vieira RP Pinto IC Machado RR Cavalcanti MP . Multisystem inflammatory syndrome associated with COVID-19 with neurologic manifestations in a child: a brief report. Pediatr Infect Dis J. (2020) 39 :e321–4. 10.1097/INF.0000000000002834 32932334\n7. Belay E Cheung E Oster M Tremoulet A . Clinical management of multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-19) (2020).\n8. Castro PAD Urbano LMF Costa IMC . Doença de Kawasaki. Anais Bras Dermatol. (2009) 84 :317–29. 10.1590/S0365-05962009000400002\n9. Schrör K . Aspirin and Reye syndrome: a review of the evidence. Paediatr Drugs. (2007) 9 :195–204. 10.2165/00148581-200709030-00008 17523700\n10. Bianconi V Violi F Fallarino F Pignatelli P Sahebkar A Pirro M . Is acetylsalicylic acid a safe and potentially useful choice for adult patients with COVID-19? Drugs. (2020) 80 :1383–96. 10.1007/s40265-020-01365-1 32705604\n11. Eleftheriou D Levin M Shingadia D Tulloh R Klein NJ Brogan PA . Management of Kawasaki disease. Arch Dis Child. (2014) 99 :74–83. 10.1136/archdischild-2012-302841 24162006\n12. Sousa AC Pires S Jacinto M Abreu TT . Biopsia Hepática Percutânea: segurança e utilidade em 137 procedimentos consecutivos. Med Interna. (2016) 23 :11–5.\n13. Cao W Liu X Bai T Fan H Hong K Song H . High-dose intravenous immunoglobulin as a therapeutic option for deteriorating patients with coronavirus disease 2019. In: Open Forum Infectious Diseases. Vol. 7. Wuhan: Oxford University Press (2020). p. ofaa102\n14. Galeotti C Bayry J. Autoimmune and inflammatory diseases following COVID-19. Nat Rev Rheumatol. (2020) 16 :413–4. 10.1038/s41584-020-0448-7 32499548\n15. Toscano G Palmerini F Ravaglia S Ruiz L Invernizzi P Cuzzoni MG . Guillain-Barré Syndrome Associated with SARS-CoV-2. N Engl J Med. (2020) 382 :2574–6. 10.1056/NEJMc2009191 32302082\n16. Galeotti C Kaveri SV Bayry J . Intravenous immunoglobulin immunotherapy for coronavirus disease-19 (COVID-19). Clin Transl Immunology. (2020) 9 :e1198. 10.1002/cti2.1198 33088506\n\n",
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"journal": "Frontiers in pediatrics",
"keywords": "COVID-19; COVID-19 pandemic; Reye syndrome; SARS-CoV-2 (COVID-19); multisystem inflammatory syndrome in children",
"medline_ta": "Front Pediatr",
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"pubdate": "2021",
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"title": "Case Report: MIS-C Temporarily Associated With COVID-19 Complicated by Reye's Syndrome.",
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"abstract": "Giant cell myocarditis, characterized by infiltration of multinucleated giant cells in the myocardium, is a rare type of myocarditis. It often progresses rapidly into fulminant heart failure and indicates a poor prognosis. When a patient with giant cell myocarditis develops into severe myocarditis presenting with a cardiogenic shock, we should use a percutaneous cardiopulmonary support (PCPS), which could occur complications. We experienced a patient with giant cell myocarditis, who developed left ventricular thrombus formations during the circulation support therapy with PCPS for cardiogenic shock.\nA 60-year-old man who developed a cardiogenic shock was transferred to our hospital. After the admission, inotropic agents were increased and an intra-aortic balloon pumping was started. But these therapies did not improve his hemodynamic status. He was placed PCPS. Then, he underwent endomyocardial biopsy and was diagnosed with giant cell myocarditis. On the next morning, he developed complete atrioventricular block, and subsequently, thrombus formations occurred in his left ventricular outlet tract and Valsalva sinus despite an anticoagulant therapy. Thereafter, we intensified the anticoagulant therapy to prevent further thrombus formation, but he developed an intracranial hemorrhage. He did not recover from heart failure and died 16 days after the admission.\nWe present a patient with giant cell myocarditis who developed widespread thrombosis in the left ventricle during the circulatory support with PCPS, despite anticoagulant therapy. In this case, decreased left myocardial contractility caused by giant cell myocarditis and increased left ventricular afterload by the retrograde perfusion from the PCPS induced the thrombotic tendency and congestion in the left ventricle. In addition, he developed complete atrioventricular block, which reduced the left ventricular ejection and enhanced the thrombus formation. Because patients with giant cell myocarditis have a low probability of spontaneous recovery, heart transplantation or ventricular assist device implantation may be required for circulatory support. We should establish mechanical circulatory support rapidly to improve the prognosis of patients with giant cell myocarditis. Moreover, a ventricular assist device, which can prevent both ventricular congestion and retrograde blood flow, might be suitable to prevent complications as this case.",
"affiliations": "Department of Anesthesiology, Tohoku University Hospital, 1-1 Seiryomachi, Aoba-ku, Sendai, 980-8574 Japan.;Division of Surgical Center and Supply, Sterilization, Tohoku University Hospital, 1-1 Seiryomachi, Aoba-ku, Sendai, 980-8574 Japan.;Department of Anesthesiology, Tohoku University Hospital, 1-1 Seiryomachi, Aoba-ku, Sendai, 980-8574 Japan.;Department of Anesthesiology, Tohoku University Hospital, 1-1 Seiryomachi, Aoba-ku, Sendai, 980-8574 Japan.;Department of Anesthesiology, Tohoku University Hospital, 1-1 Seiryomachi, Aoba-ku, Sendai, 980-8574 Japan.;Anesthesiology and Perioperative Medicine, Tohoku University School of Medicine, 2-1 Seiryomachi, Aoba-ku, Sendai, 980-8575 Japan.",
"authors": "Takei|Yusuke|Y|0000-0001-7044-4537;Ejima|Yutaka|Y|;Toyama|Hiroaki|H|;Takei|Kana|K|;Ota|Takahisa|T|;Yamauchi|Masanori|M|",
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"fulltext": "\n==== Front\nJA Clin RepJA Clin RepJa Clinical Reports2363-9024Springer Berlin Heidelberg Berlin/Heidelberg 6710.1186/s40981-016-0067-0Case ReportA case of a giant cell myocarditis that developed massive left ventricular thrombus during percutaneous cardiopulmonary support http://orcid.org/0000-0001-7044-4537Takei Yusuke +81-22-717-7321y-takei@xf7.so-net.ne.jp 1Ejima Yutaka y-ejima@umin.net 2Toyama Hiroaki h-toyama@umin.ac.jp 1Takei Kana bloominice@gmail.com 1Ota Takahisa taketaketakemorimorimori@yahoo.co.jp 1Yamauchi Masanori yamauchi@med.tohoku.ac.jp 31 Department of Anesthesiology, Tohoku University Hospital, 1-1 Seiryomachi, Aoba-ku, Sendai, 980-8574 Japan 2 Division of Surgical Center and Supply, Sterilization, Tohoku University Hospital, 1-1 Seiryomachi, Aoba-ku, Sendai, 980-8574 Japan 3 Anesthesiology and Perioperative Medicine, Tohoku University School of Medicine, 2-1 Seiryomachi, Aoba-ku, Sendai, 980-8575 Japan 29 11 2016 29 11 2016 2016 2 1 413 8 2016 18 11 2016 © The Author(s) 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Background\nGiant cell myocarditis, characterized by infiltration of multinucleated giant cells in the myocardium, is a rare type of myocarditis. It often progresses rapidly into fulminant heart failure and indicates a poor prognosis. When a patient with giant cell myocarditis develops into severe myocarditis presenting with a cardiogenic shock, we should use a percutaneous cardiopulmonary support (PCPS), which could occur complications. We experienced a patient with giant cell myocarditis, who developed left ventricular thrombus formations during the circulation support therapy with PCPS for cardiogenic shock.\n\nCase presentation\nA 60-year-old man who developed a cardiogenic shock was transferred to our hospital. After the admission, inotropic agents were increased and an intra-aortic balloon pumping was started. But these therapies did not improve his hemodynamic status. He was placed PCPS. Then, he underwent endomyocardial biopsy and was diagnosed with giant cell myocarditis. On the next morning, he developed complete atrioventricular block, and subsequently, thrombus formations occurred in his left ventricular outlet tract and Valsalva sinus despite an anticoagulant therapy. Thereafter, we intensified the anticoagulant therapy to prevent further thrombus formation, but he developed an intracranial hemorrhage. He did not recover from heart failure and died 16 days after the admission.\n\nConclusions\nWe present a patient with giant cell myocarditis who developed widespread thrombosis in the left ventricle during the circulatory support with PCPS, despite anticoagulant therapy. In this case, decreased left myocardial contractility caused by giant cell myocarditis and increased left ventricular afterload by the retrograde perfusion from the PCPS induced the thrombotic tendency and congestion in the left ventricle. In addition, he developed complete atrioventricular block, which reduced the left ventricular ejection and enhanced the thrombus formation. Because patients with giant cell myocarditis have a low probability of spontaneous recovery, heart transplantation or ventricular assist device implantation may be required for circulatory support. We should establish mechanical circulatory support rapidly to improve the prognosis of patients with giant cell myocarditis. Moreover, a ventricular assist device, which can prevent both ventricular congestion and retrograde blood flow, might be suitable to prevent complications as this case.\n\nKeywords\nGiant cell myocarditisVentricular thrombusPercutaneous cardiopulmonary support systemissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nGiant cell myocarditis, characterized by infiltration of multinucleated giant cells in the myocardium, is a rare type of myocarditis. Fulminant myocarditis can occur during its clinical course. When it occurs, prognosis is extremely poor due to acute heart failure [1–4]. Herein, we report a patient with giant cell myocarditis who developed massive left ventricular thrombus during the circulatory support with percutaneous cardiopulmonary support (PCPS) for the treatment of progressive heart failure.\n\nCase presentation\nA 60-year-old man noted cold-like symptoms. After a month, he was visited to a local hospital and was suspected with myocarditis because his blood examination showed high inflammatory reactions and his echocardiogram showed severe cardiac dysfunction. He was started on intravenous continuous infusions of dobutamine (5 μg/kg/min) and dopamine (5 μg/kg/min) and transferred to our hospital. Upon admission to the intensive care unit, his consciousness, heart rate, blood pressure, arterial oxygen saturation level (5 L/min of supplemental oxygen via facemask), and body temperature were clear, 105 bpm, 105/66 mmHg, 100%, and 38.2 °C, respectively. His chest radiograph and chest computed tomography showed pulmonary congestion and bilateral pleural effusion without cardiomegaly, and the electrocardiogram showed low voltage of R-wave and intraventricular conduction disturbance in all leads (Fig. 1). His laboratory examination showed inflammatory reaction, elevated levels of cardiac enzyme, and serum brain natriuretic peptide but almost normal range of coagulation (Table 1). His transthoracic echocardiogram showed a significant decrease in the myocardial contractility of the both ventricles but did not show the enlargement of both ventricles and a thrombus formation in all ventricles. Right cardiac catheterization, under the continuous infusions of dopamine (5 μg/kg/min) and dobutamine (5 μg/kg/min), showed that cardiac output (CO), pulmonary arterial pressure (PAP), pulmonary arterial wedge pressure, and mixed venous oxygenation saturation (SvO2) were 3.60 L/min, 37/18(26) mmHg, 26 mmHg, and 40%, respectively, which indicated cardiogenic shock and post-capillary pulmonary hypertension (Table 2). Coronary angiography showed no abnormal findings. Because he was diagnosed with myocarditis and refractory to inotropic agents, he was inserted with intra-aortic balloon pumping (IABP). Despite 6 h of IABP support, his hemodynamic status progressively deteriorated; hence, we decided to start the mechanical ventilation and mechanical circulatory support by a PCPS on him. We administered 1 mg of midazolam, 0.2 mg of fentanyl, and 50 mg of rocuronium, performed endotracheal intubation, and started the airway pressure release ventilation with fraction of inspired oxygen (FIO2) of 0.6, the high continuous airway pressure (CPAP) of 20 cmH2O, duration of high CPAP of 9.5 s, low CPAP of 0 cmH2O, and duration of low CPAP of 0.5 s in order to avoid the lung collapse. In this setting, his minute ventilation volume was 2.4 L (approximately 400 mL of tidal volume and 6/min of respiratory rate). After the initiation of the mechanical ventilation, his arterial blood gas analysis from the right radial artery showed a pH of 7.499, arterial oxygen tension (PaO2) of 153 mmHg, and arterial carbon dioxide (CO2) tension (PaCO2) of 34.8 mmHg. And we started continuous infusion of propofol (1–2.5 mg/kg/h) and fentanyl (40 μg/h) for sedation. Then, we administered heparin (7000 IU) as an intravenous bolus, and his activated clotting time (ACT) was prolonged to 198 s. We placed a venous cannula into the right atrium via the common right femoral vein and an arterial cannula into the left femoral artery and started the PCPS.Fig. 1 The 12-lead electrocardiogram of the patient upon admission to the intensive care unit. Sinus rhythm, low-voltage R-wave, and intraventricular conduction disturbance in all leads were seen\n\n\nTable 1 The blood examination on admission and 1 and 10 days after the admission\n\n\tAdmission\t1 day after the admission (after PCPS placement)\t10 days after the admission (after intensive anticoagulant therapy)\t\nWhite blood cell counts (/μL)\t9200\t9100\t12,400\t\nHemoglobin (g/dL)\t10.2\t10.6\t10.7\t\nPlatelet counts (×104/μL)\t38.2\t29.3\t27.6\t\nTotal bilirubin (mg/dL)\t0.8\t0.7\t1.5\t\nAspartate transaminase (IU/L)\t401\t431\t194\t\nAlanine aminotransferase (IU/L)\t403\t367\t236\t\nLactate dehydrogenase (IU/L)\t1081\t926\t932\t\nBlood urea nitrogen (mg/dL)\t18\t17\t15\t\nCreatinine (mg/dL)\t1.18\t1.01\t0.94\t\nC-reactive protein (mg/dL)\t13.2\t10.9\t17.1\t\nCreatine kinase (IU/L)\t1194\t776\t871\t\nCreatine kinase-MB (IU/L)\t32\t32\t39\t\nTroponin T (ng/dL)\t5.19\t–\t–\t\nBrain natriuretic peptide (pg/mL)\t3035\t2266\t–\t\nLactate (mmol/L)\t1.20\t1.12\t0.97\t\nBE (mmol/L)\t−0.2\t−0.1\t−1.3\t\nInternational normalized ratio of prothrombin time\t1.14\t1.16\t1.21\t\nActivated partial thromboplastin time (s)\t30.0\t38.7\t118.9\t\nActivated clotting time (s)\t140\t198\t273\t\nAlmost the normal ranges of coagulation test were found on admission. The marked prolonged activated partial thromboplastin time and activated clotting time were found after the intensive anticoagulation therapy for the intraventricular thrombus\n\n\nTable 2 Hemodynamic status of the patient on admission, before and after the initiation of PCPS, after the onset of complete atrioventricular block, and after ventricular pacing\n\n\tAdmission\tBefore initiation of PCPS\tInitiation of PCPS\tOnset of complete AVB\tAfter ventricular pacing\t\nRespiratory support\tFace mask, 5 L/min of oxygen\tFace mask, 6 L/min of oxygen\tAPRV, FIO2 = 0.6, P\nhigh = 20 cm H2O, T\nhigh = 9.5 s, P\nlow = 0 cm H2O, T\nlow = 0.5 s\tSame as on the left\tAPRV, FIO2 = 0.6, P\nhigh = 15 cm H2O, T\nhigh = 5.5 s, P\nlow = 0 cm H2O, T\nlow = 0.5 s\t\npH\t7.531\t7.532\t7.449\t7.272\t7.554\t\nSaO2 (%)\t95.1\t97.0\t98.5\t95.7\t98.5\t\nPaO2 (mmHg)\t75.4\t97.0\t153.0\t100.8\t158.0\t\nPaCO2 (mmHg)\t25.5\t28.1\t34.8\t62.5\t27.3\t\nEtCO2 (mmHg)\t–\t–\t21\t41\t17\t\nBE (mmol/L)\t−0.2\t1.7\t−0.1\t0.3\t1.9\t\nLac (mmol/L)\t1.2\t1.3\t1.12\t1.03\t1.28\t\nABP (mmHg)\t110/55\t112/42\t97/41\t70/40\t136/37\t\nPAP (mmHg)\t37/18 (26)\t28/11\t19/10\t60/20\t18/13\t\nPAWP (mmHg)\t25\t–\t12\t30\t–\t\nRAP (mmHg)\t18\t18\t12\t18\t8\t\nCO (L/min)\t3.60\t3.80\t2.3\t<<1.0\t1.3\t\nOutput of PCPS (L/min)\t–\t–\t3.0\t3.0\t3.5\t\nThe sum of PCPS blood flow and his own cardiac output (L/min)\t3.60\t3.80\t5.3\t3.0\t4.8\t\nTotal gas flow of oxygenator (L/min)\t–\t–\t1.0\t1.0\t4.0\t\nSvO2 (%)\t40\t39.7\t66\t55\t69\t\nThe cardiogenic shock was improved by the PCPS support. After the onset of complete AV block, significant decrease of CO, pulmonary congestion, and increased PaCO2 were observed\n\n\nPCPS percutaneous cardiopulmonary support, AVB atrioventricular block, APRV airway pressure release ventilation, F\nI\nO\n2 fraction of inspired oxygen, P\nhigh high continuous positive airway pressure, T\nhigh duration of P\nhigh, P\nlow low continuous positive airway pressure, T\nlow duration of P\nlow, EtCO\n2 end-tidal carbon dioxide tension, PaCO\n2 arterial carbon dioxide tension, ABP arterial blood pressure, PAP pulmonary artery pressure, PAWP pulmonary artery wedge pressure, RAP right atrial pressure, CO cardiac output, SvO\n2 mixed venous oxygenation saturation\n\n\n\n\nAt the initiation of PCPS, the target value of PCPS blood flow was set at 3.0 L/min (rotation speed of 3000 rpm), and the FIO2 and total gas flow of the membrane oxygenator were set at 0.6 and 1 L/min, respectively.\n\nAnd the intravenous continuous infusion of heparin (10,000 IU/day) was started in order to maintain his ACT within the range of 150 to 200 s. After the PCPS blood flow reached to 3.0 L/min, the SvO2 increased to 66% and the total blood flow, which was the sum of PCPS blood flow and his own cardiac output, increased from 3.0 to 5.3 L/min (Table 2).\n\nSubsequently, we performed endomyocardial biopsy (EMB) followed by rapid microscopic examination, which showed the characteristic infiltration of multinucleated giant cells in the myocardium. He was eventually diagnosed with giant cell myocarditis (Fig. 2).Fig. 2 Microscopic examination from the endomyocardial biopsy of the right ventricle. Characteristic infiltrations of multinucleated giant cells in the myocardium (open circle) were seen\n\n\n\n\nOn the next morning, he developed complete atrioventricular block (Fig. 3), subsequent decreased blood pressure from 100/50 to 70/40 mmHg, and increased pulmonary arterial pressure from 35/15 to 60/20 mmHg. In addition, sudden elevation of PaCO2 from 31 to 62.5 mmHg was also observed despite the preservation of both the steady PCPS output and the mechanical ventilation setting (Fig. 4 and Table 2). Hence, we performed transesophageal echocardiography (TEE), which indicated widespread thrombus formations and marked congestion in his left ventricular outlet tract and Valsalva sinus and closure of the aortic valve; however, there is no thrombus in his right ventricle (Fig. 5). Then, we checked ACT, which was 168 s, and performed an additional test for heparin-induced thrombocytopenia (HIT) antibody, which we learned of the negative result later.Fig. 3 Electrocardiogram strips on the next morning. Complete atrioventricular block was seen\n\n\nFig. 4 The change in the hemodynamic status around the onset of the atrioventricular block. HR heart rate, ABP arterial blood pressure, PAP pulmonary artery pressure, P\nE\ntCO\n2 end-tidal carbon dioxide tension, PaCO\n2 arterial carbon dioxide tension, SvO\n2 mixed venous oxygenation saturation, PCPS percutaneous cardiopulmonary support, CO cardiac output. ① The onset of the complete atrioventricular block. ② The start of the ventricular pacing. After the onset of the complete atrioventricular block, the decrease of BP and the increase of PAP and PaCO2 continued until the point when the blood flow and the gas flow of the PCPS were augmented. The hemodynamics of the patient improved along with the recovery of the ventricular contraction by the ventricular pacing\n\n\nFig. 5 Transesophageal echocardiography (TEE) after the onset of atrioventricular block. a Mid-esophageal 4-chamber (ME 4ch) view showed thrombus formations and congestion in the left ventricle. b Mid-esophageal aortic valve short-axis (ME AV SAX) view showed thrombus formations in the Valsalva sinus and aortic valve closure. c Mid-esophageal long-axis (ME AV LAX) view showed thrombus formations in the left ventricular tract and the Valsalva sinus\n\n\n\n\nWe increased the PCPS blood flow up to 3.5 L/min and total gas flow up to 4.0 L/min, which lead to success of CO2 excretion, but his hemodynamic status remained unstable. After that, we started temporary cardiac pacing to treat complete atrioventricular block, which restored his left ventricular contractility, opened the aortic valve, and subsequently washed out the thrombus.\n\nThereafter, for the purpose of preventing further thrombus formation, anticoagulant therapy was intensified (20,000 IU/day of heparin) to maintain ACT within the range of 200 to 240 s. Ten days after the admission, his ACT was markedly prolonged up to 273 s (Table 2) and he presented with an anisocoria. Therefore, we performed a computed tomography (CT) scan of the brain, which revealed the intracranial hemorrhage. He did not recover from the heart failure and died 16 days after the admission.\n\nDiscussion\nGiant cell myocarditis is characterized by infiltration of multinucleated giant cells in the myocardium and distinguished from cardiac sarcoidosis by the absence of non-caseous necrosis. Cardiac sarcoidosis is generally associated with extracardiac lesions and progresses slowly, whereas giant cell myocarditis develops and progresses to heart failure rapidly, which results in poor prognosis [1–3]. An accurate data about the morbidity of giant cell myocarditis has not been shown because the pathological diagnosis of the disease is difficult. However, approximately 100 cases were reported despite the rarity of this myocarditis type [4]. Mechanical circulatory support, such as IABP and/or PCPS as well as inotropes, is required for the treatment of acute giant cell myocarditis because the disease often progresses to fulminant myocarditis. Some reports showed the efficacy of immunosuppressive therapy for giant cell myocarditis, which suggested a relationship between giant cell myocarditis and autoimmune reaction [5–7]. In addition, a multicenter study of immunosuppressive therapy for giant cell myocarditis showed the prolonged median transplant-free survival from 3 to 12.3 months [1]. However, some studies also showed that few patients recovered from heart failure and weaned from mechanical circulatory support [7–9]. The patients of that study eventually required heart transplantation or circulatory support, such as ventricular assist device (VAD) for destination therapy. In Japan, VAD is a practical option for the rescue treatment of chronic giant cell myocarditis because only 40 heart transplantations are performed per year, and the mean waiting period for transplantation is 636 days. We need to transfer the patients to the hospital capable for left VAD (LVAD) surgery, which is limited in Japan, if needed for LVAD placement.\n\nWe could not save this patient because of the disease progression and the complications, including the thrombosis due to the congestion of the left ventricle and intracranial hemorrhage due to the intensive anticoagulant therapy to prevent thrombosis.\n\nMyocarditis alone rarely accompanies ventricular thrombosis unlike dilated cardiomyopathy. Left ventricular distension strongly contributes to intraventricular thrombosis. Therefore, the cornerstone in prevention of intraventricular thrombosis is systemic anticoagulant therapy and prevention of left ventricular distension. In this case, thrombotic tendency was induced by the left ventricular congestion due to decreased left myocardial contractility. Regardless of promoting the left ventricular ejection by inotropic agents and IABP, adequate cardiac output was not obtained, which resulted in the placement of PCPS. However, peripheral PCPS perfused the aortic root retrogradely, which caused the increase of left ventricular afterload, the subsequent distension of the left ventricle, and the further increase of thrombotic tendency and congestion at the left ventricular outlet tract. Approximately 15% of patients with giant cell myocarditis are associated with atrioventricular block [1, 4]. In this case, the complete atrioventricular block induced a critical decrease of the left ventricular ejection, which resulted in the further left ventricle distension, which might trigger the thrombosis (Fig. 6).Fig. 6 The mechanism of thrombus formation in this case. PCPS percutaneous cardiopulmonary support, AV-block atrioventricular block, BP systemic blood pressure, PAP pulmonary artery pressure, PaCO\n2 arterial carbon dioxide tension. Giant cell myocarditis induced the left ventricular distension and subsequent thrombus formation tendency. The retrograde perfusion by the PCPS and the complete atrioventricular block further enhanced thrombus formation tendency. As a result, widespread thrombi were formed in the left ventricular tract and the Valsalva sinus\n\n\n\n\nBefore the onset of the atrioventricular block, the patient had 2.3 L/min of the pulmonary circulation with 2.4 L/min of minute volume of ventilation and 3.0 L/min of the PCPS blood flow with 1 L/min of gas flow of the artificial lung. In this condition, the main pathway of his CO2 elimination was thought to be the pulmonary circulation. After the onset of the atrioventricular block, the pulmonary circulation decreased to far less than 1.0 L/min because of the loss of the cardiac output while 3.0 L/min of the PCPS blood flow was maintained. Hence, the total lung blood flow decreased to approximately 3.0 L/min, and the artificial lung ought to excrete almost whole CO2. However, the gas flow of the artificial lung remained 1.0 L/min, which might be too little to excrete sufficient amount of the CO2. Thereafter, the PaCO2 of the patient rose from 34.8 to 62.5 mmHg.\n\nTo our knowledge, no guideline is available for treatment of intraventricular thrombosis in PCPS patients. The treatment choices are thrombectomy and intensive anticoagulant therapy [10–12]. Because of the unstable circulatory status of the patient, intensive systemic anticoagulant therapy and temporary cardiac pacing, which could recover the ventricular contractility and ejection, were the possible choices. Therefore, we started temporary cardiac pacing, which recovered the left ventricular contractility, opened the aortic valve, and washed out the thrombi. Additionally, the efficacy of local thrombolysis in intraventricular thrombosis was recently reported. This technique might be effective in this case [13].\n\nThe washed out thrombi formed at the onset of the complete atrioventricular block could cause cerebral infarctions, and the intensified coagulation therapy might deteriorate the cerebral infarctions into the intracranial hemorrhage. At the onset of complete atrioventricular block, we did not perform a CT scan of the brain or awaken him from the deep sedation due to his unstable circulatory status. But 10 days after the admission, we performed a CT scan of the brain at the risk of circulatory failure because the patient presented with an anisocoria. However, we could not identify the true pathogenesis of the intracranial hemorrhage.\n\nDifferent types of myocarditis show different clinical courses and prognoses and require different treatments. Therefore, EMB, identifying the histological type of myocarditis, should be performed as the patient’s condition permits. In this case, multidrug immunosuppressive therapy was started after the histological diagnosis of giant cell myocarditis. However, as previously described, heart transplantation or VAD may be required for a definitive therapy within months or years. LVAD, withdrawing the blood from the left ventricular apex and returning the blood to the ascending aorta, can establish physiological perfusion and reduce left ventricular volume, whereas peripheral PCPS perfuses aorta retrogradely, increases left ventricular afterload, and might induce left ventricular distension. In addition, LVAD can cause less bleeding complications than PCPS because LVAD requires weaker anticoagulation than PCPS [14]. If we could place an LVAD on the patient at the diagnosis of giant cell myocarditis, complications such as thrombosis and bleeding might be prevented, which might result in smooth bridge to heart transplantation. To improve the prognosis of myocarditis, full knowledge of the clinical course of myocarditis, precise diagnosis, transfer to an advanced medical center where LVAD placement can be performed and rapid establishment of adequate mechanical circulatory support should be required.\n\nConclusions\nWe present a patient with giant cell myocarditis who developed widespread thrombosis in the left ventricle during PCPS support. Retrograde perfusion by PCPS and complete atrioventricular block promoted left ventricular distension, reduced left ventricular ejection, and caused widespread thrombosis. In the circulation management of patients with giant cell myocarditis, we should rapidly establish physiological mechanical circulatory support.\n\nAbbreviations\nACTActivated clotting time\n\nCOCardiac output\n\nCO2Carbon dioxide\n\nCPAPContinuous positive airway pressure\n\nCTComputed tomography\n\nEMBEndomyocardial biopsy\n\nFIO2Fraction of inspired oxygen\n\nHITHeparin-induced thrombocytopenia\n\nIABPIntra-aortic balloon pumping\n\nLVADLeft ventricular assist device\n\nPaCO2Arterial carbon dioxide tension\n\nPaO2Arterial oxygen tension\n\nPAPPulmonary arterial pressure\n\nPCPSPercutaneous cardiopulmonary support\n\nSvO2Mixed venous oxygenation saturation\n\nTEETransesophageal echocardiography\n\nVADVentricular assist device\n\nAuthors’ contributions\nYT, KT, and TO were anesthesiologists attending to the intensive care. YT drafted the manuscript. YE, HT, and MY supervised the treatment and helped to draft the manuscript. All authors read and approved the final manuscript.\n\nAuthors’ information\nYT, KT, and TO are M.D. and Stuff Anesthesiologists of the Department of Anesthesiology, Tohoku University Hospital. HT is M.D., PhD., and a Lecturer of the Department of Anesthesiology, Tohoku University Hospital. YE is M.D., PhD., and the Associate Director of the Department of Surgical Center and Supply, Sterilization, Tohoku University Hospital. MY is M.D., PhD., and a Professor of Anesthesiology and Perioperative Medicine, Tohoku University School of Medicine.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nWritten informed consent was obtained from the patient’s family 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==== Refs\nReferences\n1. Cooper LT Jr Berry GJ Shabetai R Idiopathic giant-cell myocarditis—natural history and treatment. Multicenter Giant Cell Myocarditis Study Group Investigators N Engl J Med 1997 336 1860 6 10.1056/NEJM199706263362603 9197214 \n2. Shirani J Freant LJ Roberts WC Gross and semiquantitative histologic findings in mononuclear cell myocarditis causing sudden death, and implication for endomyocardial biopsy Am J Cardiol 1993 72 952 7 10.1016/0002-9149(93)91113-V 8213554 \n3. Blauwet LA Cooper LT Idiopathic giant cell myocarditis and cardiac sarcoidosis Heart Fail Rev 2013 18 733 46 10.1007/s10741-012-9358-3 23111533 \n4. Cooper LT Giant cell and granulomatous myocarditis Heart Fail Clin 2005 1 431 7 10.1016/j.hfc.2005.06.004 17386865 \n5. Menghini VV Savecenko V Olson LJ Tazelaar HD Dec GW Kao A Cooper LT Jr Combined immunosuppression for the treatment of idiopathic giant cell myocarditis Mayo Clin Proc 1999 74 122 6 10.4065/74.12.1221 \n6. Levy NT Olson LJ Wayand C Brack A Tazelaar HD Edwards WD Hammill SC Histologic and cytokine response to immunosuppression in giant-cell myocarditis Ann Intern Med 1998 128 648 50 10.7326/0003-4819-128-8-199804150-00007 9537938 \n7. Steinhaus D Gelfand E Vanderlaan PA Kociol RD Recovery of giant-cell myocarditis using combined cytolytic immunosuppression and mechanical circulatory support J Heart Lung Transplant 2014 33 769 71 10.1016/j.healun.2014.02.018 24656644 \n8. Ankersmit HJ Ullrich R Moser B Hoetzenecker K Hacker S German P Krenn C Horvat R Grimm M Wolner E Zuckermann A Recovery from giant cell myocarditis with ECMO support and utilisation of polyclonal antihymocyte globulin: a case report Thorc cardiovasc Surg 2006 54 278 280 10.1055/s-2006-923803 \n9. Marelli D Kermani R Bresson J Fishbein MC Hamilton M Moriguchi J Fonarow GC Cohen B Kobashigawa J Laks H Support with the BVS 5000 assist device during treatment of acute giant-cell myocarditis Tex Heart Inst J 2003 30 50 6 12638672 \n10. Kuhl T Wendt S Langebartels G Kröner A Wahlers T Recurrent left atrial and left ventricular thrombosis due to heparin-induced thrombocytopenia: case report and short review Thorac Cardiovasc Surg 2013 61 537 40 10.1055/s-0032-1328930 23424064 \n11. Moubarak G Weiss N Leprince P Luyt CE Massive intraventricular thrombus complicating extracorporeal membrane oxygenation support Can J Cardiol 2008 24 e1 10.1016/S0828-282X(08)70555-5 18209764 \n12. Ramjee V Shreenivas S Rame JE Kirkpatrick JN Jagasia D Complete spontaneous left heart and aortic thrombosis on extracorporeal membrane oxygenation support Echocardiography 2013 30 E342 3 10.1111/echo.12323 23889597 \n13. Sangalli F Greco G Galbiati L Formica F Calcinati S Avalli L Regional thrombolysis with tenecteplase during extracorporeal membrane oxygenation: a new approach for left ventricular thrombosis J Card Surg 2015 30 541 3 10.1111/jocs.12556 25940057 \n14. Menon AK, Götzenrich A, Sassmannshausen H, Haushofer M, Autschbach R, Spillner JW. Low stroke rate and few thrombo-embolic events after HeartMate II implantation under mild anticoagulation. Eur J Cardiothorac Surg. 2012;42(2):319–23.\n\n",
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"keywords": "Giant cell myocarditis; Percutaneous cardiopulmonary support system; Ventricular thrombus",
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"title": "A case of a giant cell myocarditis that developed massive left ventricular thrombus during percutaneous cardiopulmonary support.",
"title_normalized": "a case of a giant cell myocarditis that developed massive left ventricular thrombus during percutaneous cardiopulmonary support"
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"abstract": "An analysis of the clinical outcomes in 66 patients with hairy cell leukemia treated with pentostatin under the Special Exception mechanism of the Division of Cancer Treatment, National Cancer Institute, between 1983 and 1987 has revealed a favorable balance of risk and benefit. Hematologic parameters and performance status were improved in most patients treated outside the clinical trials mechanism. The treating physicians considered 37 patients (56%) to be complete responders and 15 patients (23%) to be partial responders. Four patients (6%) died while receiving pentostatin. Life-threatening leukopenia (wbc count, less than 1,000/mm3) was reported in 24% of patients, and severe or life-threatening infection occurred in 11%. The experience gained with these patients supplements the information presently being collected from the controlled clinical trials and supports the development of a group C treatment protocol.",
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"title": "Pentostatin in hairy cell leukemia: treatment by the special exception mechanism.",
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"abstract": "Colonic vascular lesion secondary to verapamil overdose is mediated by free radicals, forming vascular microtrombos and endotoxin generation, being a difficult diagnosis.\nA 27-year-old female is admitted with an acute abdomen of 4 days after an event referred for a suicidal attempt due to an overdose of verapamil, operating surgically where there is a right transmural colon necrosis, performing a right hemicolectomy with terminal ileostomy.\nRecognize and properly treat an acute abdomen, not always reach an adequate diagnosis, so a thorough history could conclude.",
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"authors": "Aburto-Fernández|Ma Del Carmen|MDC|;Araujo-López|Adán|A|;García-Godoy|Irwin U|IU|;Alvarado-González|Antonio|A|;Gutiérrez-Samperio|José L|JL|;de Orendáin|Alfonso Álvarez-Manila|AÁ|;Ocio|Mario A Romero|MAR|;Arteaga-Villalba|Luis R|LR|;Herrera-Díaz|Arturo|A|;Jiménez-Ríos|Christian O|CO|;Lerma-Alvarado|Ricardo M|RM|",
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"keywords": "Abdomen agudo; Acute abdomen; Colonic vascularity; Vascularidad colónica; Verapamil; Verapamilo",
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"title": "Secondary colonic necrosis. Case report.",
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"abstract": "A 24-year-old man with acute lymphoblasticleukemia underwent allogeneicperipheral blood stem cell transplantation (allo-PBSCT)from a human leukocyte antigen-matched sibling after myeloablative conditioning, with a regimen including total body irradiation(TBI)(12 Gy/6 fractions), 6 years ago. The patient developed extensive chronic graft-versus-host disease(cGVHD)of the skin, mouth, liver, and gut four months after allo-PBSCT. Treatment with cyclosporine and prednisolone was necessary to control the cGVHD. Six years after allo-PBSCT, the patient experienced odynophagia and was diagnosed with cervical esophageal squamous cell carcinoma(cT1bN1M0, cStage II B). Because we considered laryngeal preservation, risk of anastomotic leakage, and infection related to the operation, the patient was planned to receive chemoradio- therapy with 5-fluorouracil and cisplatin. Regarding irradiation, the patient received radiotherapy(50.4 Gy/28 fractions)for a primary tumor and lymph node without an elective nodal area. The patient achieved complete response and remained disease- free without any treatment-related complications for 3 years.",
"affiliations": "Division of Radiation Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital.",
"authors": "Kawamoto|Terufumi|T|;Nihei|Keiji|K|;Doki|Noriko|N|;Najima|Yuho|Y|;Kaito|Satoshi|S|;Karasawa|Katsuyuki|K|",
"chemical_list": "D002945:Cisplatin; D005472:Fluorouracil",
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"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D059248:Chemoradiotherapy; D002945:Cisplatin; D004938:Esophageal Neoplasms; D000077277:Esophageal Squamous Cell Carcinoma; D005472:Fluorouracil; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D014916:Whole-Body Irradiation; D055815:Young Adult",
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"title": "Definitive Radiotherapy for Esophageal Squamous Cell Carcinoma after Allogeneic Hematopoietic Stem Cell Transplantation with Conditioning of Total Body Irradiation.",
"title_normalized": "definitive radiotherapy for esophageal squamous cell carcinoma after allogeneic hematopoietic stem cell transplantation with conditioning of total body irradiation"
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"abstract": "A 67-year-old female with rheumatoid arthritis and asthma-chronic obstructive pulmonary disease overlap syndrome was admitted for drug-induced hypersensitivity syndrome (DIHS) caused by salazosulfapyridine. Human herpes virus 6 (HHV-6) variant B was strongly positive on peripheral blood. Multiple cavities with ground grass opacities rapidly emerged predominantly in the upper and middle lobes. She was diagnosed with invasive pulmonary aspergillosis (IPA), and was treated successfully with antifungal agents. Therapeutic systemic corticosteroids, emphysematous change in the lungs, and the worsening of the patient's general condition due to DIHS were considered major contributing factor leading to IPA. HHV-6 reactivation could have an effect on clinical course of IPA. Cavities with halo sign would provide an early clue to IPA in non-neutropenic and immunosuppressive patients.",
"affiliations": "Department of Respiratory Medicine, Center for Respiratory Diseases, JCHO Hokkaido Hospital, Japan.;Department of Respiratory Medicine, Center for Respiratory Diseases, JCHO Hokkaido Hospital, Japan.;Department of Connective Tissue Disease, JCHO Hokkaido Hospital, Japan.;Department of Respiratory Medicine, Center for Respiratory Diseases, JCHO Hokkaido Hospital, Japan.;Department of Respiratory Medicine, Center for Respiratory Diseases, JCHO Hokkaido Hospital, Japan.",
"authors": "Ikari|Tomoo|T|;Nagai|Katsura|K|;Ohe|Masashi|M|;Harada|Toshiyuki|T|;Akiyama|Yasushi|Y|",
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"fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(17)30046-110.1016/j.rmcr.2017.04.017Case ReportMultiple cavities with halo sign in a case of invasive pulmonary aspergillosis during therapy for drug-induced hypersensitivity syndrome Ikari Tomoo aNagai Katsura katnagai@kme.biglobe.ne.jpa∗Ohe Masashi bHarada Toshiyuki aAkiyama Yasushi aa Department of Respiratory Medicine, Center for Respiratory Diseases, JCHO Hokkaido Hospital, Japanb Department of Connective Tissue Disease, JCHO Hokkaido Hospital, Japan∗ Corresponding author. Japan Community Health Care Organization (JCHO), Hokkaido Hospital, 1-8, Nakanoshima, Toyohira-ku, Sapporo, 062-8618 Hokkaido, Japan.Japan Community Health Care Organization (JCHO)Hokkaido Hospital1-8, NakanoshimaToyohira-kuSapporoHokkaido062-8618Japan katnagai@kme.biglobe.ne.jp19 4 2017 2017 19 4 2017 21 124 128 13 2 2017 10 4 2017 18 4 2017 © 2017 The Authors2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).A 67-year-old female with rheumatoid arthritis and asthma-chronic obstructive pulmonary disease overlap syndrome was admitted for drug-induced hypersensitivity syndrome (DIHS) caused by salazosulfapyridine. Human herpes virus 6 (HHV-6) variant B was strongly positive on peripheral blood. Multiple cavities with ground grass opacities rapidly emerged predominantly in the upper and middle lobes. She was diagnosed with invasive pulmonary aspergillosis (IPA), and was treated successfully with antifungal agents. Therapeutic systemic corticosteroids, emphysematous change in the lungs, and the worsening of the patient's general condition due to DIHS were considered major contributing factor leading to IPA. HHV-6 reactivation could have an effect on clinical course of IPA. Cavities with halo sign would provide an early clue to IPA in non-neutropenic and immunosuppressive patients.\n\nKeywords\nInvasive pulmonary aspergillosisDrug-induced hypersensitivity syndromeHuman herpes virus 6 (HHV-6)Chronic obstructive pulmonary disease (COPD)Halo signAbbreviation\nBAL, bronchoalveolar lavageBG, 1,3-β-glucanCMV, cytomegalovirusCOPD, chronic obstructive pulmonary diseaseCT, computed tomographyDIHS, drug-induced hypersensitivity syndromeDRESS, drug reaction with eosinophilia and systemic syndromeGGO, ground grass opacityGM, galactomannan antigenemiaHHV-6, Human herpes virus 6IPA, invasive pulmonary aspergillosisLAA, low attenuation areaMCFG, micafunginVRCZ, voriconazole\n==== Body\n1 Introduction\nInvasive pulmonary aspergillosis (IPA) predominantly affects severely immunocompromised patients, particularly those with prolonged neutropenia or organ transplantation [1]. IPA is increasingly being recognized as an emerging disease in non-neutropenic patients such as COPD, connective tissue diseases requiring corticosteroid therapy [2].\n\nDrug-induced hypersensitivity syndrome (DIHS) or drug reaction with eosinophilia and systemic syndrome (DRESS) presents clinically as an extensive mucocutaneous rash, accompanied by fever, lymphadenopathy, hepatitis, hematologic abnormalities with eosinophilia and atypical lymphocytes, and may involve other organs with resultant damage in several systems [3]. An immune response against the drug with secondary viral reactivation related to a cytokine storm, and early viral reactivation responsible for most of the manifestations of DIHS [4]. It has a relapsing-remitting course despite withdrawal of causative drugs. Herpes viruses such as HHV-6/HHV-7, Epstein-Barr virus and cytomegalovirus can be reactivated during the course of DRESS/DIHS [3]. The treatment of DIHS was based on systemic glucocorticoids.\n\nThis patient has a lot of risk factors in non-neutropenic IPA including asthma-chronic obstructive pulmonary disease overlap syndrome, systemic corticosteroids use, and duration of antibiotic treatment longer than 10 days. In addition to these factors, HHV-6 reactivation may have some effect on the clinical course of IPA. This case showed unique imaging findings on computed tomography (CT) scan at the early phase of IPA.\n\n2 Case report\nA 67-year-old woman admitted for a febrile skin rash that progressed erythroderma for a week. One month earlier, she had diagnosed with rheumatoid arthritis and received anti-rheumatic drugs for predonisolone:PSL 5 mg/day, salazosulfapyridine:SASP 0.5 g/day. She is well controlled asthmatic patient with inhaled fluticasone furoate 200 μg/vilanterol 25 μg. Her past medical history included chronic obstructive pulmonary disease (COPD). She was an ex-smoker (40 pack years of smoking).\n\nThe physical findings on admission consisted of erythroderma, erosion of the lips, persistent high fever, superficial lymphadenopathy at neck, purpura over the extremities, and hypovolemic shock. Laboratory tests showed neutrophilic leukocytosis with mild eosinophilia (WBC: 13130/μl, neu: 75%, and eos: 13%), (AST: 16 IU/L, ALT: 20 IU/L, LDH 359 IU/L, total bilirubin:0.4 mg/dL, C-reactive protein 10.7 mg/dL, BUN 41.6 mg/dl and serum creatinine 1.29 mg/dl, RA 17 U/ml, anti-SS-A/Ro Ab 46.2 U/ml). Blood cultures resulted normal. The aspergillus galactomannan antigenemia (GM) and anti-Aspergillus IgG antibodies were negative, but Aspergillus precipitationg antibody was positive on admission. The level of 1,3-β-glucan (BG) was within normal limits as 5.0 pg/ml. A chest X-ray showed infiltration in middle lesions of both lungs (Fig. 1a). A chest CT scan showed low attenuation area (LAA) throughout in upper lobe and small thin–walled cavities surrounded by GGO (Fig. 1b). Pulmonary function test performed on day 47 showed an obstructive pattern with no reversibility: FEV1/FVC 63.8%, pre bronchodilator FEV1 1.55L (89.1%), post bronchodilator FEV1 1.58L (+1.9%).Fig. 1 a: A chest X-ray showed infiltration in middle and lower lesions of both lungs on admission. b: Chest CT images showed low attenuation area (LAA) throughout in upper lobe and small thin–walled cavities surrounded by GGO on admission.\n\nFig. 1\n\nThe course of treatment was shown in Fig. 2. SASP was discontinued on admission, an antibiotic treatment and an increase in corticosteroid dose by 5 mg–25 mg/day showed a small effect on erythroderma and erosion of the lips. The temperature has gone down to normal. Skin biopsy revealed that the superficial infiltration of inflammatory cells at junction of the epidermis and dermis, perivascular inflammation. Nine days after admission, her clinical condition (erythroderma, erosion of the lips, and high fever) exacerbated again. The IgG titer against human herpes virus-6 (HHV-6) increased from × 80 to × 160. The PCR test for HHV-6 variant B was strongly positive on peripheral blood (8000 copies/ml). DIHS was diagnosed based on the presence of a skin rash developing more than 3 weeks after SASP initiation, clinical symptoms persisting more than 2 weeks after stopping SASP, fever >38 °C, leukocytosis, kidney dysfunction, lymphadenopathy, HHV-6 reactivation [4]. High dose methylprednisolone (500 mg/day) was administrated on day 11–13. However, multiple cavities rapidly emerged predominantly in the upper and middle lobes on day 12 (Fig. 3a and b), when positive conversion of GM test was identified. Because she refused to undergo bronchoscopic examination at first, micafungin (MCFG) 150 mg/day was administrated for clinically diagnosed invasive pulmonary aspergillosis. PCR tests were positive for cytomegalovirus (CMV) and negative for the Epstein-Barr virus on day 21, however they were both negative on admission. Treatment of Ganciclovir 500 mg/day was started on day 26 for two weeks. Multiple cavities persisted despite antifungal treatment, she decided to have bronchoscopic examination on 26 days after admission. The culture of bronchoalveolar lavage (BAL) fluid performed at left B3 was positive for Aspergillus fumigatus. The total cell count in BAL fluids was significantly increased (78 × 104/ml) and the inflammatory cell profile showed the increased percentage of neutrophils (macrophages 31%, neutrophils 65%, lymphocytes 4%, eosinophils 0%). Transbronchial lung biopsy specimen obtained from left B3 showed inflammatory cell infiltration, necrotic tissue destruction and bleeding, but acid first bacilli and fungus were undetected. A dose of 200 mg voriconazole (VRCZ) (400 mg for starting dose) was concurrently administrated on day 29. Severe cough disappeared and cavity walls became thinner afterward. She left the hospital on day 52. Multiple cavities disappeared on CT scan one year after discharge from the hospital (Fig. 4).Fig. 2 The course of the hospitalized. High dose methylprednisolone (500 mg/day) was administrated on day 11–13, and gradual decrease after day 14. After treatment, HHV-6 DNA decreased but CMV-antigen increased on day 26. PSL: predonisolone, mPSL: methylprednisolone, AZM:azithromycin, MEPM: meropenem, MCFG: micafungin, VRCZ: voriconazole, GCV: ganciclovir, HHV-6: Human herpes virus 6, CMV: cytomegalovirus.\n\nFig. 2Fig. 3 a: A chest X-ray showed the cavity in the left lung on day 12. b: Chest CT images showed multiple cavities rapidly emerged predominantly in the upper and middle lobes on day 12.\n\nFig. 3Fig. 4 Chest CT images showed multiple nodules without cavities one year after discharge from the hospital.\n\nFig. 4\n\n3 Discussion\nIt has been reported that IPA may be identified by chest CT at an early stage of disease.\n\nThe lesion of CT images as having a ‘halo sign’ (i.e., GGO surrounding a nodule or mass), ‘hypodense sign’ (i.e., hypodensity or low attenuation within the mass or nodule), or cavitation were commonly observed in IPA [5]. The halo sign has been pathophysiologically characterized as a discrete nodule of angioinvasive aspergillosis with infarction and coagulative necrosis surrounded by alveolar hemorrhage. This sign is seen only in the first 10 days of angioinvasion [6]. Typical chest CT scan findings include multiple nodules and the halo sign is seen in neutropenic patients with IPA early in the course of infection. Halo sign can be also seen in Bronchiolitis Obliterans with Organizing Pneumonia, granulomatosis with polyangiitis, metastatic angiosarcoma and focal lung injury. In this case, pathological findings consistent with the halo sign of IPA. However, the diagnosis of IPA in non-neutropenic critically ill patients as well as in the COPD patients is usually difficult because signs and symptoms are non-specific [7]. A halo sign on a CT scan has been reported to be the first reliable sign of infection, with a high specificity but a low sensitivity [8], [9]. A lower sensitivity (5–24%) of the halo sign and the air crescent sign in non-neutropenic patients has been reported in the literature [9], [10], [11] as well as COPD [2], [12], [13]. The radiological abnormalities of IPA in COPD patients based on CT scan were cavity lesions in 20% and solitary or multiple nodules in 6% [14]. In non-neutropenic patients, the histologic pattern is characterized by central liquefaction necrosis and prominent neutrophilic infiltration. Both the crescent sign and cavitation are the result of WBC recovery with release of proteases that lead to resorption of necrotic tissue at the periphery of lesions [15]. Therefore, the finding of a halo sign at baseline was strongly associated with improved responses to treatment and better survival [16].\n\nThis case was finally diagnosed with “probable invasive aspergillosis” according to the presence of a positive culture for Aspergillus species from lower respiratory tract sample together with one major criterion on CT scan [17], [18]. Steroids are believed to play a role in the emergence of IPA in COPD patients. The accumulated doses of corticosteroids (>700 mg) received during the 3 months prior to admission significantly increased the risk of IPA in COPD patients [2]. In a separate report, a total daily dose ≥20 mg prednisone more than 3 weeks or equivalent dose met the criteria for defining cases of IPA in COPD patients [19]. This patient received 5mg daily PSL for a month prior to admission. Aspergillus species might be colonized in the lungs.\n\nDIHS is some of the most life-threatening severe cutaneous adverse reactions [4], [20]. The demonstration of HHV reactivation may be a useful marker for the diagnosis of DIHS, and has been added to the DIHS-scoring criteria in Japan [21]. The incidence of viral reactivation was significantly higher after treatment with systemic steroids [22]. HHV-6 is considered to be an immunomodulatory virus that may facilitate superinfections with fungal or other opportunistic infections [23]. Flamand reported that Infection of T cells by HHV-6 results in immune suppression characterized by a downregulation of IL-2 mRNA and protein synthesis accompanied by diminished cellular proliferation [24]. HHV-6 has been associated with various indirect effects, including a high rate of cytomegalovirus (CMV) disease, opportunistic infection such as invasive fungal disease [23], [25], [26]. HHV-6 reactivated during the course of DIHS may promote IPA as well as the use of systemic steroids in this case. IPA manifests within 10–14 days of the trigger of immunosuppression. In addition to these risk factors, there is an evidence that CMV infection in these patients increases the risk of IPA [27]. The hazard ratio for IPA in the setting of CMV disease increases 13.3-fold [28].\n\nTaken together, in this case, GGO surrounding a cavity on a CT scan may be considered as a feature of IPA in patients with immunosuppression caused by systemic steroids and DIHS at early stage.\n\nThe sensitivity of GM was 87.5% for cases of proven and probable IPA in intensive care unit [29] or 42.4% for probable IPA in patients with COPD [2]. GM test results were positive at the time that the greatest pathological change was revealed by CT scan [30]. In this case, positive conversion of GM test was on day 12 when the multiple cavities rapidly emerged in the lungs.\n\nAlthough micafungin showed a trend towards a decreased incidence of Aspergillus infection, VRCZ is recommended for the primary treatment of invasive aspergillosis in most patients [31]. After diagnosis with IPA, the patients are successfully treated with VRCZ in this case. Clinicians should consider the possibility of IPA in cases of immunosuppressive clinical condition and find early signs on CT scan with cavities surrounded by GGO in addition to the existing typical signs before getting positive results of GM tests or fungal culture.\n\nThe authors state that they have no Conflicts of Interest (COI).\n\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n==== Refs\nReferences\n1 Turc J. Lamblin A. Vitry T. Clinical diagnosis of invasive pulmonary aspergillosis in a non-neutropenic critically ill patient Respir. Care 59 9 2014 e137 e139 24327748 \n2 Guinea J. Torres-Narbona M. Gijon P. Pulmonary aspergillosis in patients with chronic obstructive pulmonary disease: incidence, risk factors, and outcome Clin. Microbiol. Infect. Off. Publ. Eur. Soc. Clin. Microbiol. Infect. Dis. 16 7 2010 870 877 [published Online First: 2009/11/13] \n3 Criado P.R. Avancini J. Santi C.G. Drug reaction with eosinophilia and systemic symptoms (DRESS): a complex interaction of drugs, viruses and the immune system Israel Med. Assoc. J. IMAJ 14 9 2012 577 582 [published Online First: 2012/10/30] \n4 Descamps V. Ranger-Rogez S. DRESS syndrome Jt. Bone, Spine Rev. Rhum. 81 1 2014 15 21 [published Online First: 2013/07/03] \n5 Milito M.A. Kontoyiannis D.P. Lewis R.E. Influence of host immunosuppression on CT findings in invasive pulmonary aspergillosis Med. Mycol. 48 6 2010 817 823 [published Online First: 2010/01/30] 20109093 \n6 Prasad A. Agarwal K. Deepak D. Pulmonary aspergillosis: what CT can offer before it is too late! J. Clinical Diagn. Res. JCDR 10 4 2016 Te01 Te05 [published Online First: 2016/05/18] \n7 Bassetti M. Righi E. De Pascale G. How to manage aspergillosis in non-neutropenic intensive care unit patients Crit. Care London, Engl. 18 4 2014 458 [published Online First: 2014/08/30] \n8 Maertens J. Van Eldere J. Verhaegen J. Use of circulating galactomannan screening for early diagnosis of invasive aspergillosis in allogeneic stem cell transplant recipients J. Infect. Dis. 186 9 2002 1297 1306 12402199 \n9 Meersseman W. Vandecasteele S.J. Wilmer A. Invasive aspergillosis in critically ill patients without malignancy Am. J. Respir. Crit. Care Med. 170 6 2004 621 625 [published Online First: 2004/07/02] 15229094 \n10 Trof R.J. Beishuizen A. Debets-Ossenkopp Y.J. Management of invasive pulmonary aspergillosis in non-neutropenic critically ill patients Intensive Care Med. 33 10 2007 1694 1703 [published Online First: 2007/07/25] 17646966 \n11 Barberan J. Sanz F. Hernandez J.L. Clinical features of invasive pulmonary aspergillosis vs. colonization in COPD patients distributed by gold stage J. Infect. 65 5 2012 447 452 [published Online First: 2012/08/07] 22863904 \n12 Huang L. He H. Ding Y. Values of radiological examinations for the diagnosis and prognosis of invasive bronchial-pulmonary aspergillosis in critically ill patients with chronic obstructive pulmonary diseases Clin. Respir. J. 2016 [published Online First: 2016/09/11] \n13 He H. Ding L. Li F. Clinical features of invasive bronchial-pulmonary aspergillosis in critically ill patients with chronic obstructive respiratory diseases: a prospective study Crit. Care London, Engl. 15 1 2011 R5 [published Online First: 2011/01/08] \n14 Samarakoon P. Soubani A. Invasive pulmonary aspergillosis in patients with COPD: a report of five cases and systematic review of the literature Chron. Respir. Dis. 5 1 2008 19 27 [published Online First: 2008/02/28] 18303098 \n15 Brodoefel H. Vogel M. Hebart H. Long-term CT follow-up in 40 non-HIV immunocompromised patients with invasive pulmonary aspergillosis: kinetics of CT morphology and correlation with clinical findings and outcome AJR Am. J. Roentgenol. 187 2 2006 404 413 [published Online First: 2006/07/25] 16861545 \n16 Greene R.E. Schlamm H.T. Oestmann J.W. Imaging findings in acute invasive pulmonary aspergillosis: clinical significance of the halo sign Clin. Infect. Dis. 44 3 2007 373 379 [published Online First: 2007/01/06] 17205443 \n17 De Pauw B. Walsh T.J. Donnelly J.P. Revised definitions of invasive fungal disease from the European organization for research and treatment of cancer/invasive fungal infections cooperative group and the national institute of allergy and infectious diseases mycoses study group (EORTC/MSG) consensus group Clin. Infect. Dis. 46 12 2008 1813 1821 18462102 \n18 Ascioglu S. Rex J.H. de Pauw B. Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus Clin. Infect. Dis. 34 1 2002 7 14 11731939 \n19 Garnacho-Montero J. Amaya-Villar R. Ortiz-Leyba C. Isolation of Aspergillus spp. from the respiratory tract in critically ill patients: risk factors, clinical presentation and outcome Crit. Care London, Engl. 9 3 2005 R191 R199 [published Online First: 2005/07/01] \n20 Schrijvers R. Gilissen L. Chiriac A.M. Pathogenesis and diagnosis of delayed-type drug hypersensitivity reactions, from bedside to bench and back Clin. Transl. Allergy 5 2015 31 [published Online First: 2015/09/05] 26339470 \n21 Shiohara T. Inaoka M. Kano Y. Drug-induced hypersensitivity syndrome (DIHS): a reaction induced by a complex interplay among herpesviruses and antiviral and antidrug immune responses Allergol. Int. 55 1 2006 1 8 [published Online First: 2006/11/01] 17075280 \n22 Funck-Brentano E. Duong T.A. Bouvresse S. Therapeutic management of DRESS: a retrospective study of 38 cases J. Am. Acad. Dermatol. 72 2 2015 246 252 [published Online First: 2015/01/17] 25592341 \n23 Lautenschlager I. Razonable R.R. Human herpesvirus-6 infections in kidney, liver, lung, and heart transplantation: review Transpl. Int. 25 5 2012 493 502 [published Online First: 2012/02/24] 22356254 \n24 Flamand L. Gosselin J. Stefanescu I. Immunosuppressive effect of human herpesvirus 6 on T-cell functions: suppression of interleukin-2 synthesis and cell proliferation Blood 85 5 1995 1263 1271 [published Online First: 1995/03/01] 7858257 \n25 Rogers J. Rohal S. Carrigan D.R. Human herpesvirus-6 in liver transplant recipients: role in pathogenesis of fungal infections, neurologic complications, and outcome Transplantation 69 12 2000 2566 2573 [published Online First: 2000/07/26] 10910278 \n26 Singh N. Carrigan D.R. Gayowski T. Human herpesvirus-6 infection in liver transplant recipients: documentation of pathogenicity Transplantation 64 5 1997 674 678 [published Online First: 1997/10/06] 9311701 \n27 Marr K.A. Carter R.A. Boeckh M. Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors Blood 100 13 2002 4358 4366 [published Online First: 2002/10/24] 12393425 \n28 Fukuda T. Boeckh M. Carter R.A. Risks and outcomes of invasive fungal infections in recipients of allogeneic hematopoietic stem cell transplants after nonmyeloablative conditioning Blood 102 3 2003 827 833 [published Online First: 2003/04/12] 12689933 \n29 Cornillet A. Camus C. Nimubona S. Comparison of epidemiological, clinical, and biological features of invasive aspergillosis in neutropenic and nonneutropenic patients: a 6-year survey Clin. Infect. Dis. 43 5 2006 577 584 [published Online First: 2006/08/04] 16886149 \n30 Weisser M. Rausch C. Droll A. Galactomannan does not precede major signs on a pulmonary computerized tomographic scan suggestive of invasive aspergillosis in patients with hematological malignancies Clin. Infect. Dis. 41 8 2005 1143 1149 [published Online First: 2005/09/16] 16163633 \n31 Walsh T.J. Anaissie E.J. Denning D.W. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America Clin. Infect. Dis. 46 3 2008 327 360 18177225\n\n",
"fulltext_license": "CC BY-NC-ND",
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"issue": "21()",
"journal": "Respiratory medicine case reports",
"keywords": "BAL, bronchoalveolar lavage; BG, 1,3-β-glucan; CMV, cytomegalovirus; COPD, chronic obstructive pulmonary disease; CT, computed tomography; Chronic obstructive pulmonary disease (COPD); DIHS, drug-induced hypersensitivity syndrome; DRESS, drug reaction with eosinophilia and systemic syndrome; Drug-induced hypersensitivity syndrome; GGO, ground grass opacity; GM, galactomannan antigenemia; HHV-6, Human herpes virus 6; Halo sign; Human herpes virus 6 (HHV-6); IPA, invasive pulmonary aspergillosis; Invasive pulmonary aspergillosis; LAA, low attenuation area; MCFG, micafungin; VRCZ, voriconazole",
"medline_ta": "Respir Med Case Rep",
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"pages": "124-128",
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"pmid": "28480161",
"pubdate": "2017",
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"references": "20109093;18462102;21211008;18177225;22356254;24327748;10910278;23101424;18303098;16886149;7858257;27614086;9311701;12689933;17205443;17646966;23816504;19906275;17075280;11731939;22863904;12402199;27190919;12393425;16163633;26339470;15229094;25167934;25592341;16861545;15987390",
"title": "Multiple cavities with halo sign in a case of invasive pulmonary aspergillosis during therapy for drug-induced hypersensitivity syndrome.",
"title_normalized": "multiple cavities with halo sign in a case of invasive pulmonary aspergillosis during therapy for drug induced hypersensitivity syndrome"
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"abstract": "BACKGROUND\nSymptomatic primary Epstein-Barr virus infection is a usually self-limiting illness in adolescents. We present a case of an adolescent who had been receiving azathioprine for inflammatory bowel disease for four years and developed a life-threatening primary Epstein-Barr virus infection successfully treated with rituximab.\n\n\nMETHODS\nAn 11-year-old girl presented with chronic, bloody diarrhea. Endoscopic biopsies confirmed a diagnosis of chronic ulcerative colitis with features of Crohn's disease. Azathioprine was initiated after one year due to active colitis. She responded well and remission was achieved. At the age of 16 years she developed a life-threatening Epstein-Barr virus infection including severe multiple organ failure and was critically ill for 4 weeks in the intensive care unit. Natural killer cells were virtually absent in the lymphocyte subset analysis. Azathioprine was stopped on admission. She was initially treated with corticosteroids, acyclovir and intravenous immunoglobulin. Approximately 30 days after admission, she developed signs of severe hepatitis and pneumonitis and received weekly rituximab infusions for 8 weeks. Primary immunodeficiency was excluded by whole exome sequencing in two independent laboratories. Persistent viremia stopped when the natural killer cell count started to rise, approximately 90 days after the cessation of azathioprine.\n\n\nCONCLUSIONS\nWe found 17 comparable cases in the literature. None of the previous cases reported in the literature, who had been treated with azathioprine and developed either a severe or a fatal Epstein-Barr virus infection, underwent full genetic and prospective immunological workup to rule out known primary immunodeficiencies. Recently, azathioprine has been shown to cause rather specific immunosuppression, resulting in natural killer cell depletion. Our case demonstrates that slow recovery from azathioprine-induced natural killer cell depletion, 3 months after the stopping of azathioprine, coincided with the clearance of viremia and clinical recovery. Finally, our choice of treating the patient with rituximab, as previously used for patients with a severe immunosuppression and Epstein-Barr virus viremia, appeared to be successful in this case. We suggest testing for Epstein-Barr virus serology before starting azathioprine and measuring natural killer cell counts during the treatment to identify patients at risk of developing an unusually severe primary Epstein-Barr virus infection.",
"affiliations": "Department of Children and Adolescents, Oulu University Hospital, P.O. Box 23, FIN-90029 OYS, Oulu, Finland. minna.honkila@oulu.fi.;Department of Children and Adolescents, Oulu University Hospital, P.O. Box 23, FIN-90029 OYS, Oulu, Finland.;Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Helsinki University Hospital, Helsinki, Finland.;PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu, Oulu, Finland.;Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.;Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.;Department of Children and Adolescents, Oulu University Hospital, P.O. Box 23, FIN-90029 OYS, Oulu, Finland.;Department of Children and Adolescents, Oulu University Hospital, P.O. Box 23, FIN-90029 OYS, Oulu, Finland.;Department of Children and Adolescents, Oulu University Hospital, P.O. Box 23, FIN-90029 OYS, Oulu, Finland.",
"authors": "Honkila|Minna|M|http://orcid.org/0000-0002-8288-9442;Niinimäki|Riitta|R|;Taskinen|Mervi|M|;Kuismin|Outi|O|;Kettunen|Kaisa|K|;Saarela|Janna|J|;Turunen|Sami|S|;Renko|Marjo|M|;Tapiainen|Terhi|T|",
"chemical_list": "D007166:Immunosuppressive Agents; D000069283:Rituximab; D001379:Azathioprine",
"country": "England",
"delete": false,
"doi": "10.1186/s12879-019-4022-3",
"fulltext": "\n==== Front\nBMC Infect DisBMC Infect. DisBMC Infectious Diseases1471-2334BioMed Central London 402210.1186/s12879-019-4022-3Case ReportA nearly fatal primary Epstein-Barr virus infection associated with low NK-cell counts in a patient receiving azathioprine: a case report and review of literature http://orcid.org/0000-0002-8288-9442Honkila Minna +358-8-315 5863minna.honkila@oulu.fi 12Niinimäki Riitta riitta.niinimaki@ppshp.fi 12Taskinen Mervi mervi.taskinen@hus.fi 3Kuismin Outi outi.kuismin@ppshp.fi 24Kettunen Kaisa kaisa.kettunen@helsinki.fi 5Saarela Janna janna.saarela@fimm.fi 5Turunen Sami sami.turunen@ppshp.fi 1Renko Marjo marjo.renko@uef.fi 12Tapiainen Terhi terhi.tapiainen@oulu.fi 121 0000 0004 4685 4917grid.412326.0Department of Children and Adolescents, Oulu University Hospital, P.O. Box 23, FIN-90029 OYS, Oulu, Finland 2 0000 0001 0941 4873grid.10858.34PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu, Oulu, Finland 3 0000 0000 9950 5666grid.15485.3dDivision of Pediatric Hematology, Oncology and Stem Cell Transplantation, Helsinki University Hospital, Helsinki, Finland 4 0000 0004 4685 4917grid.412326.0Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland 5 0000 0004 0410 2071grid.7737.4Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland 10 5 2019 10 5 2019 2019 19 4047 2 2019 25 4 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\nSymptomatic primary Epstein-Barr virus infection is a usually self-limiting illness in adolescents. We present a case of an adolescent who had been receiving azathioprine for inflammatory bowel disease for four years and developed a life-threatening primary Epstein-Barr virus infection successfully treated with rituximab.\n\nCase presentation\nAn 11-year-old girl presented with chronic, bloody diarrhea. Endoscopic biopsies confirmed a diagnosis of chronic ulcerative colitis with features of Crohn’s disease. Azathioprine was initiated after one year due to active colitis. She responded well and remission was achieved. At the age of 16 years she developed a life-threatening Epstein-Barr virus infection including severe multiple organ failure and was critically ill for 4 weeks in the intensive care unit. Natural killer cells were virtually absent in the lymphocyte subset analysis. Azathioprine was stopped on admission. She was initially treated with corticosteroids, acyclovir and intravenous immunoglobulin. Approximately 30 days after admission, she developed signs of severe hepatitis and pneumonitis and received weekly rituximab infusions for 8 weeks. Primary immunodeficiency was excluded by whole exome sequencing in two independent laboratories. Persistent viremia stopped when the natural killer cell count started to rise, approximately 90 days after the cessation of azathioprine.\n\nConclusions\nWe found 17 comparable cases in the literature. None of the previous cases reported in the literature, who had been treated with azathioprine and developed either a severe or a fatal Epstein-Barr virus infection, underwent full genetic and prospective immunological workup to rule out known primary immunodeficiencies. Recently, azathioprine has been shown to cause rather specific immunosuppression, resulting in natural killer cell depletion. Our case demonstrates that slow recovery from azathioprine-induced natural killer cell depletion, 3 months after the stopping of azathioprine, coincided with the clearance of viremia and clinical recovery. Finally, our choice of treating the patient with rituximab, as previously used for patients with a severe immunosuppression and Epstein-Barr virus viremia, appeared to be successful in this case. We suggest testing for Epstein-Barr virus serology before starting azathioprine and measuring natural killer cell counts during the treatment to identify patients at risk of developing an unusually severe primary Epstein-Barr virus infection.\n\nKeywords\nEpstein-Barr virus infectionsAzathioprineKiller cells, naturalWhole exome sequencingRituximabissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nSymptomatic primary Epstein-Barr virus (EBV) infection is a usually self-limiting illness presenting with fever, lymphadenitis, tonsillitis, hepatitis, and splenomegaly in adolescents and young adults. The duration of EBV viremia during primary EBV infection is rather short, while the median half-time for viral elimination is three days [1]. It is well known that after organ or allogenic hematopoietic stem cell transplantation (HSCT), or in patients with primary immunodeficiency, EBV primary infection or reactivation can cause uncontrolled and severe infection and lymphoproliferation. We present a case of an adolescent who had been receiving azathioprine for inflammatory bowel disease for four years who developed a life-threatening EBV infection. In addition, we performed a systematic review of the literature on azathioprine and EBV infection.\n\nCase presentation\nMethods\nWe first followed our patient up closely during severe EBV infection using repeated flow cytometry measurements to detect all lymphocyte subpopulations, including natural killer (NK) cell counts. The EBV viral load was measured using a quantitative nucleic acid amplification test (Fig. 1). Immunoglobulin (Ig) M antibodies against viral capsid antigen (VCA) and IgG antibodies to EBV nuclear antigen (EBNA) were measured. Whole exome sequencing (WES) was performed in two independent laboratories, the Institute for Molecular Medicine, Helsinki, Finland, as previously described [2], and Centogene, Germany (www.centogene.com), in order to detect any known primary immunodeficiency. Both the patient and her mother gave their written informed consent to the publication of this case history. We then performed a systematic literature search via PubMed in December 2016 using the terms “Epstein-Barr virus” and “azathioprine”. A total 154 possible papers were identified for review, of which 13 were retrieved for detailed examination.Fig. 1 Epstein-Barr viremia and NK-cell counts after admission in a critically ill adolescent with a primary EBV infection and previously treated with azathioprine for inflammatory bowel disease. Azathioprine was stopped on day 1. NK-cell counts started to rise after 90 days and were normal after 120 days, coinciding with clearance of the viremia. During the course of illness, CD8+ T-cell counts were 1131 (220–1129 × 106/L) on day 32, 2535 on day 70, 2487 on day 93 and 2537 on day 106\n\n\n\nThe patient\nAn 11-year-old girl presented with chronic, bloody diarrhea. Endoscopic biopsies confirmed a diagnosis of chronic ulcerative colitis with features of Crohn’s disease. She was treated first with prednisolone and mesalazine, but azathioprine, 75 mg/day (2.5 mg/kg), was started after one year on account of continued active colitis. She responded well to this and remission was achieved. At the age of 16 years she was admitted to hospital on account of a high fever and poor general condition. Azathioprine was stopped on account of acute infection, as three-lineage cytopenia was detected on admission: her white blood cell count was 2.5 (4.5–11 × 109/L), platelets 38 (200–450 × 109/L) and hemoglobin 89 g/L (117–155 g/L). Splenomegaly, acute cardiac failure and acute hepatic failure, with 15% necrosis in a biopsy, were observed in the next few days. Symptoms of encephalitis were present, but a brain MRI was normal. Viral genome examinations by EBV polymerase chain reaction revealed > 350,000 copies/mL in plasma on admission and > 1 million copies/mL after 4 days of treatment (Fig. 1). A high viral load of > 8 million copies/mL was also detected in the liver biopsy specimen. Tests for IgM antibodies to VCA were positive on admission, whereas IgG antibodies to EBNA were negative, indicating acute EBV infection. She was treated once with rituximab and then with corticosteroids, acyclovir and intravenous immunoglobulin. She developed severe multiple organ failure, including cardiac, hepatic and respiratory failure, and was critically ill for 4 weeks in the intensive care unit. After this treatment in the intensive care unit, approximately 30 days after admission, the viral load started to increase again and she developed signs of severe hepatitis and pneumonitis, so that regular weekly rituximab infusions were given for a total of 8 weeks. Very low NK-cells were noted and the persistent viremia (detection level 300 copies/mL) stopped when the NK-cell count started to rise, approximately 90 days after the cessation of azathioprine (Fig. 1). During the course of illness, CD8+ T-cell counts were 1131 (220–1129 × 106/L) on day 32, 2535 on day 70, 2487 on day 93 and 2537 on day 106. Due to the prolongation of viremia and hepatitis despite the discontinuation of azathioprine, WES was performed. This did not reveal any known primary immunodeficiency, but the patient was found to be carrying two rare heterozygous variants of the TLR3 and OAS1 genes, in which variants have previously shown to be associated with susceptibility to viral infections. TPMT genotype leading to low enzyme activity was excluded in this case after the patient’s recovery. A high total IgG level (> 15 g/L) persisted for 6 months after clearance of the viremia, and the low CD19-cell count attributable to the rituximab treatment started to rise 6 months after cessation of the infusions. At the last follow-up visit, she was asymptomatic and healthy and had successfully returned to her studies 6 months after the onset of the EBV infection. She was still in remission with respect to her inflammatory bowel disease without any medication.\n\nSystematic review of the literature\nExamination of the 13 relevant publications yielded a total of 17 corresponding cases, mainly of adolescents or young adults with Crohn’s disease or ulcerative colitis who had been treated with azathioprine and developed either severe or fatal EBV infections, or EBV-driven hemophagocytic lymphohistiocytosis or some other lymphoproliferative disorder, excluding lymphomas [3–15]. Four patients had died [4, 7, 10, 14]. High EBV viremia (> 100,000 copies/mL) was documented in five patients [3, 7, 10–12]. NK-cell counts had been made in two out of the 17 patients and either a low count or low NK-cell cytotoxicity had been noted during the acute phase of the illness in both patient cases [3, 13]. CD8+ T-cell counts of the patients were not reported in the literature. Three patients had been successfully treated with repeated rituximab infusions [3, 8, 11]. Most patients had received corticosteroids and also acyclovir or ganciclovir. X-linked lymphoproliferative disease (XLP) was excluded in two male patients by genetic testing [7, 10].\n\nDiscussion and conclusions\nAzathioprine is widely used for the treatment of Crohn’s disease and ulcerative colitis. Our case and systematic literature search confirm that a primary EBV infection can be extremely severe or even fatal for EBV-negative adolescents or young adults receiving azathioprine.\n\nAzathioprine has recently been shown to cause rather specific immunosuppression, resulting in NK-cell [16, 17], but not T-cell depletion [17]. Moreover, early-differentiated NK-cells seem to be critical in the immune control of primary EBV infection as this subset of NK-cells expands and restricts lytic EBV infection that is poorly controlled in infectious mononucleosis [18, 19]. We repeatedly monitored our patient’s lymphocyte subpopulation count using flow cytometry and noted an almost total loss of the NK-cell population, whereas the number of CD8+ T-cells were within the normal range. We were thus able to draw a clear time series showing that the clearance of EBV viremia coincided with the normalization of NK-cell counts three to four months after ceasing to administer azathioprine. This supports the idea that azathioprine caused a severe secondary immunodeficiency and a lack of NK-cells, resulting in an uncontrolled EBV infection and hyperinflammation, since NK-cells play a role in down-regulating inflammatory responses [20]. Thus the phenotype observed in our patient mimics the known pathomechanism of congenital hemophagocytic lymphohistiocytosis, which is a hyperinflammatory condition explained by low cytotoxic functioning of the NK-cells or T-cells on account of genetic defects [20]. The risk of hemophagocytic lymphohistiocytosis in children with Crohn’s disease, often treated with thiopurines, has been estimated to be 100-fold in a population-based patient series of 5 cases with HLH and inflammatory bowel disease [4]. The risk of lymphoproliferative disorders, including lymphomas, has been reported in a large cohort of inflammatory bowel disease patients to be five-fold in those patients receiving thiopurines [21]. Our findings offer a possible explanation for this observed epidemiological risk.\n\nCorticosteroids and acyclovir are recommended for the treatment of severe EBV infection. After an organ or HSCT EBV is known to cause a lymphoproliferative disorder which can be treated with rituximab, an anti-CD20 monoclonal antibody, in order to reduce B-cells and stop viremia, since B-cells are the main replication site of Epstein-Barr viruses during infection. In patients with XLP, a primary immunodeficiency leading to uncontrolled EBV infection, severe EBV infection has recently been treated with rituximab before HSCT. We chose to treat our patient with corticosteroids, acyclovir and one dose of rituximab at the onset of the disease. However, as the EBV viral load started to increase again after 1 month despite corticosteroid and acyclovir therapy and she simultaneously developed new signs of severe pneumonitis and hepatitis, we decided to administer rituximab weekly until viremia had been arrested, three months after admission. Donor-derived EBV-specific cytotoxic T-cells are a novel experimental treatment for uncontrolled EBV infections in patients with primary or secondary immunodeficiency [22], and we consequently considered treating our patient with EBV-specific cytotoxic T-cells before she started to respond well to rituximab treatment.\n\nThe previous cases reported in the literature had not undergone thorough WES to rule out undiagnosed known primary immunodeficiencies, and even though XLP was not a diagnostic alternative for a female patient, defects in the ITK, STK4, TNFRSF7 and CORO1A genes, for instance, can lead to a life-threatening EBV infection. If a primary immunodeficiency had been diagnosed, the patient could have been considered for treatment with EBV-specific cytotoxic T-cells as a bridge before HSCT. Rapid WES is thus a very useful diagnostic tool in cases of unusually severe EBV infection, in order to exclude primary immunodeficiencies, as these need to be treated with a prompt HSCT.\n\nOur clinical case demonstrates that azathioprine-induced NK-cell depletion could be the reason for a severe, life-threatening primary EBV infection in this context. Achieving immune reconstitution may take several months after the cessation of azathioprine medication. All infectious disease specialists treating adolescents and young adult patients who have been receiving azathioprine should be aware of the risk. Testing for EBV serology before starting azathioprine could help to identify EBV-seronegative adolescents and young adults who might have a high risk of developing an unusually severe primary infection.\n\nAbbreviations\nEBVEpstein-Barr virus\n\nEBNAEpstein-Barr virus nuclear antigen\n\nHSCTHematopoietic stem cell transplantation\n\nIgImmunoglobulin\n\nNKNatural killer\n\nVCAViral capsid antigen\n\nWESWhole exome sequencing\n\nAcknowledgements\nNot applicable.\n\nFunding\nThis case report received no funding.\n\nAvailability of data and materials\nAll data generated or analyzed during this study are included in this article.\n\nAuthors’ contributions\nMH, RN, ST, MR and TT participated in the clinical care of the patient. MT, OK, KK and JS advised and supervised the laboratory testing, interpretation and reporting. MH and RN collaborated in the writing of the case report, which was critically reviewed and edited by TT. All authors approved the final manuscript as submitted.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nBoth the patient and her legal guardian gave their written consent to the publication of this case history.\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. Balfour HH Jr Holman CJ Hokanson KM A prospective clinical study of Epstein-Barr virus and host interactions during acute infectious mononucleosis J Infect Dis 2005 192 1505 1512 10.1086/491740 16206064 \n2. Sulonen AM Ellonen P Almusa H Comparison of solution-based exome capture methods for next generation sequencing Genome Biol 2011 12 R94 10.1186/gb-2011-12-9-r94 21955854 \n3. Fitzgerald MP Armstrong L Hague R Russell RK A case of EBV driven haemophagocytic lymphohistiocytosis complicating a teenage Crohn's disease patient on azathioprine, successfully treated with rituximab J Crohns Colitis 2013 7 314 317 10.1016/j.crohns.2012.05.002 22640698 \n4. Biank VF Sheth MK Talano J Association of Crohn's disease, thiopurines, and primary epstein-barr virus infection with hemophagocytic lymphohistiocytosis J Pediatr 2011 159 808 812 10.1016/j.jpeds.2011.04.045 21722918 \n5. Gidrewicz D Lehman D Rabizadeh S Majlessipour F Dubinsky M Primary EBV infection resulting in lymphoproliferative disease in a teenager with Crohn disease J Pediatr Gastroenterol Nutr 2011 52 103 105 10.1097/MPG.0b013e3181e80410 20890216 \n6. Angelucci E Cesarini M Caturelli E Vernia P EBV hepatitis in a young Crohn's disease patient on prolonged remission with azathioprine Inflamm Bowel Dis 2011 17 E1 10.1002/ibd.21278 20848464 \n7. Ross S Rajwal SK Sugarman I Epstein-Barr virus-associated lymphoproliferative disorder in Crohn disease treated with azathioprine J Pediatr Gastroenterol Nutr 2010 51 229 231 10.1097/MPG.0b013e3181d893c6 20512052 \n8. Courby S Fabre B Salameire D Multifocal polyclonal Epstein-Barr virus-associated B-cell lymphoproliferative disorder secondary to azathioprine therapy successfully treated with rituximab Leuk Lymphoma 2010 51 174 177 10.3109/10428190903402029 20001240 \n9. Moreira T Lago P Salgado M Pimentel R Epstein-Barr virus and parvovirus B19 coinfection in a Crohn's disease patient under azathioprine Inflamm Bowel Dis 2010 16 905 906 10.1002/ibd.21104 19760779 \n10. N'guyen Y Andreoletti L Patey M Fatal Epstein-Barr virus primo infection in a 25-year-old man treated with azathioprine for Crohn's disease J Clin Microbiol 2009 47 1252 1254 10.1128/JCM.02052-08 19193838 \n11. Serrate C Silva-Moreno M Dartigues P Epstein-Barr virus-associated lymphoproliferation awareness in hemophagocytic syndrome complicating thiopurine treatment for Crohn's disease Inflamm Bowel Dis 2009 15 1449 1451 10.1002/ibd.20823 19177429 \n12. Hagel S Bruns T Kantowski M Fix P Seidel T Stallmach A Cholestatic hepatitis, acute acalculous cholecystitis, and hemolytic anemia: primary Epstein-Barr virus infection under azathioprine Inflamm Bowel Dis 2009 15 1613 1616 10.1002/ibd.20856 19137606 \n13. Francolla KA Altman A Sylvester FA Hemophagocytic syndrome in an adolescent with Crohn disease receiving azathioprine and infliximab J Pediatr Gastroenterol Nutr 2008 47 193 195 10.1097/MPG.0b013e31816a30b9 18664872 \n14. Posthuma EF Westendorp RG Van der Sluys Veer A Kluin-Nelemans JC Kluin PM Lamers CB Fatal infectious mononucleosis: a severe complication in the treatment of Crohn's disease with azathioprine Gut. 1995 36 311 313 10.1136/gut.36.2.311 7883236 \n15. Larvol L Soule JC Le TA Reversible lymphoma in the setting of azathioprine therapy for Crohn's disease N Engl J Med 1994 331 883 884 10.1056/NEJM199409293311321 \n16. Bouma G Baggen JM van Bodegraven AA Thiopurine treatment in patients with Crohn's disease leads to a selective reduction of an effector cytotoxic gene expression signature revealed by whole-genome expression profiling Mol Immunol 2013 54 472 481 10.1016/j.molimm.2013.01.015 23454163 \n17. Lord JD Shows DM Thiopurine use associated with reduced B and natural killer cells in inflammatory bowel disease World J Gastroenterol 2017 23 3240 3251 10.3748/wjg.v23.i18.3240 28566883 \n18. Azzi T Lünemann A Murer A Role for early-differentiated natural killer cells in infectious mononucleosis Blood. 2014 124 2533 2543 10.1182/blood-2014-01-553024 25205117 \n19. Chijioke O Müller A Feederle R Human natural killer cells prevent infectious mononucleosis features by targeting lytic Epstein-Barr virus infection Cell Rep 2013 5 1489 1498 10.1016/j.celrep.2013.11.041 24360958 \n20. Janka GE Lehmberg K Hemophagocytic syndromes--an update Blood Rev 2014 28 135 142 10.1016/j.blre.2014.03.002 24792320 \n21. Beaugerie L Brousse N Bouvier AM Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study Lancet. 2009 374 1617 1625 10.1016/S0140-6736(09)61302-7 19837455 \n22. Bollard CM Heslop HE T cells for viral infections after allogeneic hematopoietic stem cell transplant Blood. 2016 127 3331 3340 10.1182/blood-2016-01-628982 27207801\n\n",
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"keywords": "Azathioprine; Epstein-Barr virus infections; Killer cells, natural; Rituximab; Whole exome sequencing",
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"mesh_terms": "D001379:Azathioprine; D001706:Biopsy; D002648:Child; D020031:Epstein-Barr Virus Infections; D005260:Female; D004854:Herpesvirus 4, Human; D006801:Humans; D007166:Immunosuppressive Agents; D015212:Inflammatory Bowel Diseases; D007694:Killer Cells, Natural; D018655:Lymphocyte Count; D011446:Prospective Studies; D000069283:Rituximab; D016896:Treatment Outcome",
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"title": "A nearly fatal primary Epstein-Barr virus infection associated with low NK-cell counts in a patient receiving azathioprine: a case report and review of literature.",
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"abstract": "Surgical stress, corticosteroids, and mycophenolate may contribute to gastrointestinal ulcers/bleeding after kidney transplantation. Prophylactic acid suppression with H2RAs or PPIs is often utilized after transplantation, although unclear if truly indicated after early corticosteroid withdrawal (CSWD). PPIs have been associated with increased risks of Clostridium difficile infection (CDI), pneumonia, and acute rejection. This retrospective cohort study investigated benefits and risks of prolonged PPI use following kidney transplantation and included 286 kidney recipients undergoing CSWD within five d of transplant who were maintained on tacrolimus and mycophenolate mofetil/sodium. Patients on PPI before transplant, H2RA before/after transplant, and/or those with pre-transplant GI complications were excluded. A total of 171 patients received PPI>30 d, mean duration 287 ± 120 d (PPI group); 115 patients were not maintained on acid suppression (No-PPI group). GI ulceration and bleeding events were rare in PPI group (1.2% and 2.3%, respectively) and not observed in No-PPI group (p = NS). The incidence of infectious or hematological complications was not significantly different between groups. The PPI group experienced more biopsy-proven acute rejection (9.4% vs. 2.6%, p = 0.03). No direct benefit was observed with PPI in reducing the incidence of GI ulcers and bleeding events in kidney transplant recipients undergoing early CSWD. Further studies are needed to investigate the association of PPI and acute rejection.",
"affiliations": "Department of Pharmacy, New York-Presbyterian Hospital, Weill Cornell Medical Center, New York, NY, USA.;Division of Nephrology, Department of Medicine, New York-Presbyterian Hospital, Weill Cornell Medical Center, New York, NY, USA.;Division of Transplantation Surgery, Department of Surgery, New York-Presbyterian Hospital, Weill Cornell Medical Center, New York, NY, USA.;Department of Pharmacy, New York-Presbyterian Hospital, Weill Cornell Medical Center, New York, NY, USA.;Division of Transplantation Surgery, Department of Surgery, New York-Presbyterian Hospital, Weill Cornell Medical Center, New York, NY, USA.;Department of Pharmacy, New York-Presbyterian Hospital, Weill Cornell Medical Center, New York, NY, USA.",
"authors": "Courson|Alesa Y|AY|http://orcid.org/0000-0001-5722-9859;Lee|John R|JR|;Aull|Meredith J|MJ|;Lee|Jennifer H|JH|;Kapur|Sandip|S|;McDermott|Jennifer K|JK|",
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"mesh_terms": "D000293:Adolescent; D000305:Adrenal Cortex Hormones; D000328:Adult; D005260:Female; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D054328:Proton Pump Inhibitors; D012189:Retrospective Studies; D066027:Transplant Recipients; D028761:Withholding Treatment; D055815:Young Adult",
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"title": "Routine prophylaxis with proton pump inhibitors and post-transplant complications in kidney transplant recipients undergoing early corticosteroid withdrawal.",
"title_normalized": "routine prophylaxis with proton pump inhibitors and post transplant complications in kidney transplant recipients undergoing early corticosteroid withdrawal"
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"abstract": "Carbonic anhydrase inhibitors, such as acetazolamide, are widely used in the treatment of open-angle glaucoma. Severe metabolic acidosis is a rare complication of acetazolamide use, and life-threatening acidosis occurs most commonly in elderly patients, in patients with advanced renal failure, and in patients with diabetes. We describe an unusual case of an elderly patient with diabetic nephropathy and chronic renal failure who presented to the emergency department with severe metabolic acidosis and coma after exposure to high doses of acetazolamide in the postoperative period of ophthalmic surgery. As symptoms of acetazolamide intoxication and uremia are similar, high suspicion is required to detect excessive plasma drug concentrations and intoxication in patients presenting with concomitant uremia. Clinical symptoms are potentially reversible with prompt diagnosis and treatment, including supportive treatment, bicarbonate therapy, and renal replacement therapy. Hemodialysis is particularly helpful in the management of acetazolamide overdose as the medication is dialyzable.",
"affiliations": "School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.;School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.;Intensive Care Unit, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil.;Department of Neurology, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil.;Intensive Care Unit, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil.;Intensive Care Unit, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil.",
"authors": "Kerber|Juliana Maria|JM|https://orcid.org/0000-0003-2943-4489;de Mello|Juliana Dias|JD|;Moura|Karolinny Borinelli de Aquino|KBA|;da Silva|Gustavo Cardoso|GC|;Wawrzeniak|Iuri Christmann|IC|https://orcid.org/0000-0001-8320-0822;Rech|Tatiana Helena|TH|https://orcid.org/0000-0001-9582-2821",
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"fulltext": "\n==== Front\nCase Rep Crit CareCase Rep Crit CareCRICCCase Reports in Critical Care2090-64202090-6439Hindawi 10.1155/2020/3764972Case ReportAcetazolamide Intoxication in an Elderly Patient with Diabetes and Chronic Renal Failure after Cataract Surgery https://orcid.org/0000-0003-2943-4489Kerber Juliana Maria \n1\nde Mello Juliana Dias \n1\nMoura Karolinny Borinelli de Aquino \n2\nda Silva Gustavo Cardoso \n3\nhttps://orcid.org/0000-0001-8320-0822Wawrzeniak Iuri Christmann \n2\nhttps://orcid.org/0000-0001-9582-2821Rech Tatiana Helena threch@hcpa.edu.br\n2\n\n4\n\n1School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil\n2Intensive Care Unit, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil\n3Department of Neurology, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil\n4Graduate Program in Medical Sciences: Endocrinology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, BrazilAcademic Editor: Kenneth S. Waxman\n\n2020 31 1 2020 2020 376497219 7 2019 18 10 2019 13 11 2019 Copyright © 2020 Juliana Maria Kerber et al.2020This 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.Carbonic anhydrase inhibitors, such as acetazolamide, are widely used in the treatment of open-angle glaucoma. Severe metabolic acidosis is a rare complication of acetazolamide use, and life-threatening acidosis occurs most commonly in elderly patients, in patients with advanced renal failure, and in patients with diabetes. We describe an unusual case of an elderly patient with diabetic nephropathy and chronic renal failure who presented to the emergency department with severe metabolic acidosis and coma after exposure to high doses of acetazolamide in the postoperative period of ophthalmic surgery. As symptoms of acetazolamide intoxication and uremia are similar, high suspicion is required to detect excessive plasma drug concentrations and intoxication in patients presenting with concomitant uremia. Clinical symptoms are potentially reversible with prompt diagnosis and treatment, including supportive treatment, bicarbonate therapy, and renal replacement therapy. Hemodialysis is particularly helpful in the management of acetazolamide overdose as the medication is dialyzable.\n==== Body\n1. Background\nAcetazolamide is a carbonic anhydrase inhibitor that acts by inhibiting the reversible reaction of hydration of carbon dioxide and dehydration of carbonic acid. This medication decreases the production of aqueous humor within the eye, reducing intraocular pressure [1]. In the kidney, it stimulates the formation of bicarbonate-rich urine in the renal proximal tubular epithelium, producing a diuretic effect and metabolic acidosis [2]. In the central nervous system, it retards abnormal excessive discharge of neurons and lowers intracranial pressure, been widely used for this purpose. This mechanism of action is based on the reduction of cerebrospinal fluid (CSF) secretion by the choroid plexus, where acetazolamide affects both ion transport and protein expression [3]. Therefore, acetazolamide is commonly used to treat elevated intraocular pressure, fluid retention, and epilepsy, as well as other rare diseases such as high altitude sickness, hypokalemic periodic paralysis, hydrocephalus, and Meniere's disease [4].\n\nSerious side effects are rare, but acetazolamide may induce adverse reactions in several organs and systems. In the central nervous system, it causes drowsiness, depression, malaise, fatigue, and paresthesia, while in the kidney, it causes polyuria, metabolic acidosis, and electrolyte imbalance [2, 5]. Advanced renal dysfunction is the most important contraindication to its use, as acetazolamide is eliminated from the body exclusively by the kidneys and its use can induce bicarbonaturia and normal anion gap hyperchloremic metabolic acidosis. Other contraindications include hypersensitivity to the medication, hepatic dysfunction, hypokalemia or hyponatremia, concomitant use of high-dose aspirin, adrenal insufficiency, and hyperchloremic metabolic acidosis [1].\n\nSevere metabolic acidosis is a rare complication, but life-threatening acidosis may occur particularly in elderly patients, in patients with advanced renal failure, in patients with diabetes, and in the presence of concomitant use of nephrotoxic agents. These situations should be seen as risk factors for prescribing acetazolamide.\n\nAltered mental status is common in elderly patients, but the differential diagnosis is not always straightforward because several diseases are possible and may occur concomitantly with polypharmacy [6]. We present here the case of an elderly patient with coma and severe metabolic acidosis with risk factors for acetazolamide intoxication.\n\n2. Case Report\nA 70-year-old woman with a history of systemic arterial hypertension and type 2 diabetes was admitted to the emergency department with inappetence, altered mental status, hyperreflexia, and myoclonus lasting for 2 weeks. Despite the diabetic retinopathy and nephropathy with advanced renal failure, the patient had been in her usual state until 3 weeks before admission, when she underwent cataract surgery in the right eye at a private clinic, with no intraoperative complications. In the postoperative period, she was maintained on acetazolamide 500 mg 4 times a day for 5 days, and then the dosage was reduced to 250 mg 4 times a day because of incipient neurologic symptoms. Acetazolamide was prescribed for a total of 20 days.\n\nOn examination at the emergency department, the temperature was 34.6°C, heart rate 112 beats per minute, blood pressure 98/61 mmHg, respiratory rate 28 breaths per minute, oxygen saturation 95% while breathing room air, and capillary blood glucose 161 mg/dL. Findings from the physical examination were normal, and her pupils were medium sized and reactive to light, with no focal neurologic deficits or signs of meningeal irritation. The urinary output at admission was 2.0 mL/kg/h. Her condition deteriorated with respiratory insufficiency due to a declining mental status, requiring intubation and mechanical ventilation.\n\nTogether with the neurologic signs and symptoms, she presented with severe metabolic acidosis. Arterial blood gas analysis obtained during mechanical ventilation with FiO2 0.21 revealed the following values: pH 7.23; PaCO2 26 mmHg; bicarbonate 11 mmol/L; base excess 15 mmol/L; PaO2 118 mmHg; SaO2 96%; anion gap 18 mEq/L; and lactate 0.5 mmol/L. Diagnostic workup did not suggest the presence of an infectious process: C-reactive protein 0.3 mg/L and leukocytes 11.5 × 103/μL. The chest X-ray was normal. A computed tomography scan of the brain was obtained, revealing small old ischemic defects, with no acute abnormal findings. Cerebrospinal fluid analysis revealed clear fluid, with an opening pressure of 20 mmHg, glucose 107 mg/dL, protein 86 mg/dL, and lactate 1 mmol/L.\n\nEight hours after emergency department admission, the patient was transferred to the intensive care unit (ICU) due to coma and worsening renal function, with a serum creatinine of 4.8 mg/dL (more than twice as much as the value before surgery), urea 275 mg/dL, bicarbonate 11 mEq/L, chloride 106 mEq/L, phosphate 4.3 mg/dL, and anion gap 18.5 mEq/L. The results of blood tests for sodium, potassium, magnesium, calcium, and phosphate were normal (Table 1). Urinary density and sediment were also normal, as were the ultrasound images of the urinary tract. The patient underwent an electroencephalogram, notable for a severe diffuse metabolic encephalopathy, without epileptiform paroxysms. In addition, aggressive intravenous fluids were administered to treat hypovolemic shock, and sodium bicarbonate was infused to reverse severe metabolic acidosis (250 mEq of sodium bicarbonate over 24 hours).\n\nRenal replacement therapy was prescribed because severe metabolic acidosis was resistant to sodium bicarbonate infusion and as the patient remained in coma, probably secondary to uremia exacerbated by the use of acetazolamide. After 2 sessions of intermittent hemodialysis, her neurologic status progressively improved and she was successfully extubated after 3 days in the ICU. On hospital day 6, she was discharged home with a normal neurologic examination and without the need for renal replacement therapy, as serum creatinine levels and urine output returned to baseline.\n\n3. Discussion\nWe described here a case of severe acetazolamide intoxication in an elderly patient with diabetic nephropathy and chronic renal failure. Because acetazolamide is eliminated solely by the kidneys, it accumulates in patients with renal impairment [5, 7]. Altered mental status, ranging from fatigue to deep coma, occurs as a result of the direct effects of acetazolamide on the central nervous system, but hyperammonemia may also contribute to neurologic symptoms during acetazolamide intoxication [8]. Moreover, due to the similarity of symptoms of acetazolamide toxicity and hyperammonemia, drug toxicity may go unnoticed in patients who subsequently develop renal dysfunction and uremia. Unfortunately, ammonia levels and toxicological screen tests were not measured in our patient. However, a classic feature of acetazolamide intoxication, in contrast to uremic symptoms, is the rapid recovery and resolution of the symptoms soon after the start of renal replacement therapy, as the medication is easily dialyzable [4, 9]. This was precisely the clinical course presented by our patient, with rapid clinical and neurologic improvement after only 2 hemodialysis sessions.\n\nThe usual dose of acetazolamide in patients with glaucoma ranges from 250 to 1000 mg per day [1]. Our patient received a dose of up to 2000 mg per day in the first 5 days of treatment, which can be interpreted as overdose. Furthermore, some important remarks can be made based on the treatment of this patient: the off-label use of acetazolamide in cataract surgery; the prescription of the medication to a patient with renal dysfunction; and the iatrogenic use of the medication at higher than recommended doses. In addition, advanced age and diabetes are risk factors for acetazolamide toxicity. Taken together, all these clinical features have evolved with the development of acute neurologic impairment and worsening chronic renal disease leading to the severe metabolic acidosis presented by the patient.\n\nThe mechanism involved in acetazolamide intoxication is the inhibition of carbonic anhydrase in the renal proximal tubular epithelium, leading to bicarbonate-rich urine and hyperchloremic metabolic acidosis. This mechanism appears to be more pronounced in elderly patients with diabetes or with renal failure [2, 10]. Serum levels of acetazolamide were not measured in our patient, because acetazolamide levels are not commonly measured in clinical settings, which is a limitation of this report. However, the patient's laboratory workup revealed increased acid production, with markedly increased anion gap in the absence of other sources of plasma acidification, such as lactate or ketones. This fact, together with her clinical history of medication overdose, strongly suggests hyperchloremic metabolic acidosis caused by acetazolamide intoxication in combination with high anion gap acidosis due to tubular abnormalities associated with chronic renal failure secondary to diabetic nephropathy. Despite its high intraerythrocytic distribution and plasma binding properties (about 94%), acetazolamide can be effectively removed by dialysis, especially if renal impairment coexists. It is estimated that the rate of acetazolamide clearance in hemodialysis is about 150 mg in 4 hours and the acetazolamide-to-urea nitrogen excretion ratio is 0.16, which allows the prediction of the acetazolamide dialysance in several dialyzing conditions [4]. As expected, the drug was rapidly eliminated in our patient, with rapid and full neurologic recovery.\n\n4. Conclusion\nAltered mental status is common in elderly patients presenting to the emergency department. However, differential diagnosis is often difficult. The present case provides a rare report of acetazolamide overdose, an uncommon entity that requires high suspicion because of the similarity of symptoms with those of more frequent causes of metabolic encephalopathy. Elderly patients, patients with diabetes, and patients with chronic kidney disease are at the highest risk of acetazolamide intoxication. The deleterious neurologic effects are caused by the direct action of the drug on the central nervous system, together with hyperammonemia and severe metabolic acidosis, since acetazolamide leads to renal excretion of bicarbonate. Renal replacement therapy is recommended early, especially when renal failure is present, leading to rapid resolution of symptoms.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nTable 1 Laboratory values at baseline (before surgery) and at ICU admission.\n\nVariable\tBaseline\tICU admission\tNormal range\t\nSodium (mmol/L)\t137\t137\t135–145\t\nPotassium (mmol/L)\t4.9\t5.1\t3.5–5.5\t\nCalcium (mg/dL)\t9.4\t8.3\t8.5–10.2\t\nChloride (mEq/L)\t—\t106\t98–107\t\nPhosphate (mg/dL)\t4.2\t4.3\t2.5–4.5\t\nCreatinine (mg/dL)\t2.1\t4.8\t0.5–1.1\t\nUrea (mg/mL)\t111\t275\t16–48\t\npH\t—\t7.23\t7.35–7.45\t\nBicarbonate (mmol/L)\t—\t10.9\t22–26\t\nTotal CO2 (mmol/L)\t—\t11.8\t23–27\t\nAnion gap (mEq/L)\t—\t18.5\t10–20\n==== Refs\n1 van Berkel M. A. Elefritz J. L. Evaluating off-label uses of acetazolamide American Journal of Health-System Pharmacy 2017 75 8 524 531 10.2146/ajhp170279 2-s2.0-85045315063 \n2 Heller I. Halevy J. Cohen S. Significant metabolic acidosis induced by acetazolamide: not a rare complication Archives of Internal Medicine 1985 145 10 1815 1817 10.1001/archinte.1985.00360100075012 2-s2.0-0022406782 4037942 \n3 Uldall M. Botfield H. Jansen-Olesen I. Sinclair A. Jensen R. Acetazolamide lowers intracranial pressure and modulates the cerebrospinal fluid secretion pathway in healthy rats Neuroscience Letters 2017 645 33 39 10.1016/j.neulet.2017.02.032 2-s2.0-85014403923 28219789 \n4 Vaziri N. D. Saiki J. Barton C. H. Rajudin M. Ness R. L. Hemodialyzability of acetazolamide Southern Medical Journal 1980 73 4 422 423 10.1097/00007611-198004000-00006 2-s2.0-0019278872 7367929 \n5 Yano I. Takayama A. Takano M. Pharmacokinetics and pharmacodynamics of acetazolamide in patients with transient intraocular pressure elevation European Journal of Clinical Pharmacology 1998 54 1 63 68 10.1007/s002280050422 2-s2.0-0031970406 9591933 \n6 Smith A. T. Han J. H. Altered mental status in the emergency department Seminars in Neurology 2019 39 01 005 019 10.1055/s-0038-1677035 2-s2.0-85061391511 \n7 Schwenk M. H. Blaustein D. A. Wagner J. D. The pharmacokinetics of acetazolamide during CAPD Advances in Peritoneal Dialysis 1994 10 44 46 7999862 \n8 Kim J.-M. Ryu W.-S. Hwang Y.-H. Kim J. S. Aggravation of ataxia due to acetazolamide induced hyperammonaemia in episodic ataxia Journal of Neurology, Neurosurgery & Psychiatry 2006 78 7 771 772 10.1136/jnnp.2006.105353 2-s2.0-34347223630 \n9 Schwenk M. H. Peter W. L. Meese M. G. Acetazolamide toxicity and pharmacokinetics in patients receiving hemodialysis Pharmacotherapy 1995 15 4 522 527 7479208 \n10 Elinav E. Ackerman Z. Gottehrer N. P. Recurrent life-threatening acidosis induced by acetazolamide in a patient with diabetic type IV renal tubular acidosis Annals of Emergency Medicine 2002 40 20 259 260 10.1067/mem.2002.126373 2-s2.0-0036315321 12140510\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6420",
"issue": "2020()",
"journal": "Case reports in critical care",
"keywords": null,
"medline_ta": "Case Rep Crit Care",
"mesh_terms": null,
"nlm_unique_id": "101598416",
"other_id": null,
"pages": "3764972",
"pmc": null,
"pmid": "32082641",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "9591933;30743288;7999862;7479208;7367929;29626002;28219789;12140510;17575025;4037942",
"title": "Acetazolamide Intoxication in an Elderly Patient with Diabetes and Chronic Renal Failure after Cataract Surgery.",
"title_normalized": "acetazolamide intoxication in an elderly patient with diabetes and chronic renal failure after cataract surgery"
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"companynumb": "BR-ACCORD-174694",
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"activesubstancename": "ACETAZOLAMIDE"
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"abstract": "Selective androgenic receptor modulators (SARMs) have not been approved by the U.S. Food and Drug Administration but they are heavily promoted as alternatives to androgenic anabolic steroids. We present two cases of liver injury associated with SARMs.",
"affiliations": "Canberra Hospital Garran ACT Australia.;Canberra Hospital Garran ACT Australia.;Canberra Hospital Garran ACT Australia.",
"authors": "Flores|Joan Ericka|JE|;Chitturi|Shivakumar|S|;Walker|Sarah|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/hep4.1456",
"fulltext": "\n==== Front\nHepatol Commun\nHepatol Commun\n10.1002/(ISSN)2471-254X\nHEP4\nHepatology Communications\n2471-254X John Wiley and Sons Inc. Hoboken \n\n10.1002/hep4.1456\nHEP41456\nOriginal Article\nOriginal Articles\nDrug‐Induced Liver Injury by Selective Androgenic Receptor Modulators\nFlores, Chitturi, WalkerFlores Joan Ericka \n1\nericka.flores@act.gov.au Chitturi Shivakumar \n1\n\n2\n Walker Sarah \n1\n \n1 \nCanberra Hospital\nGarran\nACT\nAustralia\n\n\n2 \nAustralian National University\nActon\nACT\nAustralia\n\n* Address Correspondence and Reprint Requests to:\n\nJoan Ericka Flores, M.B.B.S.\n\nCanberra Hospital\n\nYamba Drive\n\nGarran, 2605 ACT, Australia\n\nE‐mail: ericka.flores@act.gov.au\n\nTel.: +61‐2‐5124‐0000\n\n03 1 2020 \n3 2020 \n4 3 10.1002/hep4.v4.3450 452\n04 9 2019 16 11 2019 © 2020 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Selective androgenic receptor modulators (SARMs) have not been approved by the U.S. Food and Drug Administration but they are heavily promoted as alternatives to androgenic anabolic steroids. We present two cases of liver injury associated with SARMs.\n\n source-schema-version-number2.0cover-dateMarch 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.7.6.1 mode:remove_FC converted:02.03.2020Potential conflict of interest: Nothing to report.\n==== Body\nAbbreviations\nAASandrogenic anabolic steroid\n\nALPalkaline phosphatase\n\nALTalanine aminotransferase\n\nASTaspartate aminotransferase\n\nGGTgamma‐glutamyl transpeptidase\n\nSARMselective adrenergic receptor modulator\n\nTraditional androgenic anabolic steroids (AASs), like testosterone, have positive anabolic (bone, muscle) actions, but androgenic (virilization, acne) effects limit their use. Selective androgenic receptor modulators (SARMs), such as Ligandrol, enobosarm, and RAD‐140, bind androgen receptors with tissue‐selective activity that promotes anabolic actions without significant androgenic effects. Although not U.S. Food and Drug Administration approved, they are heavily promoted as AAS alternatives and are being trialed in aging and muscle‐wasting disorders. Unlike AASs, which have well‐recognized hepatotoxic potential, only limited human hepatic safety data are available for SARMs.1, 2, 3, 4\n\n\nPatients and Methods\nCase 1\nA previously healthy 24‐year‐old man presented with a 5‐week history of jaundice, anorexia, nausea, lethargy, and weight loss of 5 kg. He had used a gym supplement (LGD‐4033 LIGANDROL capsules) for 9 weeks, and his symptoms developed a week after its cessation. He had a history of binge drinking once a month. He was not on any regular medications and gave no previous history of liver disease.\n\nExamination revealed normal vital signs, jaundice, and mild hepatomegaly, without peripheral stigmata of chronic liver disease. His liver tests showed the following: bilirubin, 116 μmol/L (reference, <30); alanine aminotransferase (ALT), 273 U/L (reference, <45); aspartate aminotransferase (AST), 111 U/L (reference, <45); alkaline phosphatase (ALP), 289 U/L (reference, <100); gamma‐glutamyl transpeptidase (GGT), 62 U/L (reference <110); platelets, 387 × 109/L (reference, 150‐450); international normalized ratio (INR), 1.0; globulin, 34 g/L; creatinine, 114 (reference, <110 μmol/L); eosinophil count, 0.21 × 109/L (reference, 0.00‐0.70); and R ratio of 8.22 (indicating hepatocellular liver injury). Viral, autoimmune and metabolic liver diseases, and biliary obstruction were excluded by blood tests and liver ultrasonography.\n\nThe subject’s bilirubin peaked at 116 μmol/L after 2 weeks, but his liver tests and creatinine normalized over 4 months (Table 1). Rechallenge was not performed.\n\nTable 1 Trend of Available Liver Tests Related to Nonsteroidal SARM Use for Case 1\n\nCase 1\t\nTimeline\tALT, U/L (<40)\tAST, U/L (<40)\tALP, U/L (30‐110)\tBilirubin, μmol/L (2‐20)\tComment\t\nBaseline\t29\t—\t111\t4\t4 years prior\t\n−6 weeks\t\t\t\t\tSARM use ceased after 9 weeks of use\t\n−2 weeks\t589\t175\t197\t68\tSymptoms present for 3 weeks when seen by primary care physician\t\n−1 week\t273\t111\t289\t116\tReferred to hepatologist\t\nInitial review by hepatologist\t160\t76\t272\t92\t\t\n2 weeks\t334\t155\t266\t46\t\t\n4 weeks\t178\t—\t182\t23\t\t\n8 weeks\t79\t—\t134\t18\t\t\n8 months\t20\t—\t96\t13\t\t\nJohn Wiley & Sons, LtdCase 2\nA 49‐year‐old man presented with jaundice and itching of 5 weeks duration. His only regular medication was an antidepressant (venlafaxine) for 11 months. Four months prior to presentation, he reported using a SARM (RAD‐140) for 4 weeks and intermittent use thereafter. Investigations showed the following: bilirubin, 291 umol/L; ALT, 54 U/L; AST, 59 U/L; ALP, 327 U/L; GGT, 60 U/L; albumin, 40 g/L; globulin, 28 g/L; creatinine, 120 μmol/L (peaking at 132 μmol/L); INR, 1.2; platelets, 347 × 109/L; and R ratio of 5.0 (indicating mixed hepatocellular–cholestatic liver injury). Alcohol consumption was insignificant. Appropriate blood tests and liver imaging excluded other liver diseases and biliary obstruction. Liver histology showed moderate cholestasis with ductopenia and minimal fibrosis and inflammation, consistent with drug‐induced liver injury. Venlafaxine was ceased, and he was treated with ursodiol and cholestyramine. His bilirubin peaked at 346 μmol/L but gradually improved over 2 months; all his liver tests and creatinine were completely normal when rechecked 12 months after his initial presentation (Table 2). Rechallenge was not performed.\n\nTable 2 Trend of Available Liver Tests Related to Nonsteroidal SARM Use for Case 2\n\nCase 2\t\nTime line\tALT, U/L (<40)\tAST, U/L (<40)\tALP, U/L (30‐110)\tBilirubin, μmol/L (2‐20)\tComment\t\nBaseline\t24\t21\t57\t10\t8 months prior\t\n−2 weeks\t200\t111\t111\t80\tOrdered by primary care physician for pruritus; referred to hepatologist; SARM use had ceased after intermittent use for months\t\nInitial review by hepatologist\t54\t63\t327\t291\t\t\n2 weeks\t51\t—\t299\t321\t\t\n3 weeks\t44\t61\t286\t346\t\t\n4 weeks\t60\t65\t262\t187\t\t\n8 weeks\t172\t123\t121\t32\t\t\n12 months\t27\t—\t59\t7\t\t\nJohn Wiley & Sons, LtdResults\nIn both cases, the supplements were sent for toxicologic analysis and were screened by ultra‐high performance liquid chromatography/photodiode array and gas chromatography–mass spectrometry. The presence of SARM in both cases (Ligandrol in case 1 and RAD‐140 in case 2) was confirmed, and no other contaminants were identified.\n\nDiscussion\nTo our knowledge, these individuals represent the first cases of significant liver injury with SARM. Mild, transient, self‐limiting increases in aminotransferases were reported in clinical trials,1, 2, 3, 4 but discontinuation due to raised ALT was rare (one case), and serious liver injury was not documented. Causality assessment scores (Roussel Uclaf Causality Assessment Method) for cases 1 and 2 were 7 and 6 points (probable), respectively.5 The Drug Induced Liver Injury Network (DILIN) causality score was 2 (probable) for both cases, and the DILIN severity score was 2 (moderate liver injury, case 1) and 3 (moderate to severe liver injury, case 2).6 In both cases, the presence of SARM in the supplements was confirmed and other contaminants (especially AASs) were excluded. In the first case, alcohol was a potential confounding factor, but the pattern of liver tests (ALT>AST, normal GGT) was inconsistent with alcoholic hepatitis. In the second case, it is possible that venlafaxine may have contributed; however, he had been taking this for nearly a year, whereas venlafaxine hepatotoxicity is usually seen within 1 to 3 months (https://livertox.nih.gov).\n\nThe liver injury in both cases is within the described spectrum of liver injury associated with AASs. While case 2 showed the more well‐known cholestatic injury profile, the hepatocellular presentation of case 1 is also well described. These off‐target effects question the so‐called tissue selectivity of SARMs, which has been their main selling point.\n\nWhether these cases represent the “tip of the iceberg” remains to be seen, but given the increasing popularity of SARM use, greater vigilance and reporting of potential cases is required.\n==== Refs\nReferences\n1 \n\nBhattacharya \nI \n, \nTarabar \nS \n, \nLiang \nY \n, \nPradhan \nV \n, \nOwens \nJ \n, \nOemar \nB \n. Safety, pharmacokinetic, and pharmacodynamic evaluation after single and multiple ascending doses of a novel selective androgen receptor modulator in healthy subjects\n. Clin Ther \n2016 ;38 :1401 ‐1416\n.27085586 \n2 \n\nBasaria \nS \n, \nCollins \nL \n, \nDillon \nEL \n, \nOrwoll \nK \n, \nStorer \nTW \n, \nMiciek \nR \n, et al. The safety, pharmacokinetics, and effects of LGD‐4033, a novel nonsteroidal oral, selective androgen receptor modulator, in healthy young men\n. J Gerontol A Biol Sci Med Sci \n2013 ;68 :87 ‐95\n.22459616 \n3 \n\nDalton \nJT \n, \nBarnette \nKG \n, \nBohl \nCE \n, \nHancock \nML \n, \nRodriguez \nD \n, \nDodson \nST \n, et al. The selective androgen receptor modulator GTx‐024 (enobosarm) improves lean body mass and physical function in healthy elderly men and postmenopausal women: results of a double‐blind, placebo‐controlled phase II trial\n. J Cachexia Sarcopenia Muscle \n2011 ;2 :153 ‐161\n.22031847 \n4 \n\nDobs \nA \n, \nBoccia \nR \n, \nCroot \nC \n, \nGabrail \nN \n, \nDalton \nJ \n, \nHancock \nM \n, et al. Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double‐blind, randomised controlled phase 2 trial\n. Lancet Oncol \n2013 ;14 :335 ‐345\n.23499390 \n5 \n\nChalasani \nNP \n, \nHayashi \nPH \n, \nBonkovsky \nHL \n, \nNavarro \nVJ \n, \nLee \nWM \n, \nFontana \nRJ \n; Practice Parameters Committee of the American College of Gastroenterology \n. ACG clinical guideline: the diagnosis and management of idiosyncratic drug‐induced liver injury\n. Am J Gastroenterol \n2014 ;109 :950 ‐966\n.24935270 \n6 \n\nRegev \nA \n, \nSeeff \nLB \n, \nMerz \nM \n, \nOrmarsdottir \nS \n, \nAithal \nGP \n, \nGallivan \nJ \n, et al. Causality assessment for suspected DILI during clinical phases of drug development\n. Drug Saf \n2014 ;37 (Suppl. 1 ): S47 ‐S56\n.25352327\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2471-254X",
"issue": "4(3)",
"journal": "Hepatology communications",
"keywords": null,
"medline_ta": "Hepatol Commun",
"mesh_terms": null,
"nlm_unique_id": "101695860",
"other_id": null,
"pages": "450-452",
"pmc": null,
"pmid": "32140660",
"pubdate": "2020-03",
"publication_types": "D016428:Journal Article",
"references": "25352327;22459616;23499390;24935270;22031847;27085586",
"title": "Drug-Induced Liver Injury by Selective Androgenic Receptor Modulators.",
"title_normalized": "drug induced liver injury by selective androgenic receptor modulators"
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{
"companynumb": "AU-MYLANLABS-2019M1097422",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VENLAFAXINE HYDROCHLORIDE"
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"abstract": "The issue of vancomycin-induced acute kidney injury (AKI) has resurged with the use of intravenous vancomycin as a first-line antibiotic, often for prolonged periods of time for the management of serious methicillin-resistant Staphylococcus aureus infections, and with a higher recommended trough level (15-20 μg/mL). We have observed 3 patients on intravenous vancomycin who developed very high trough levels (>40 μg/mL) and severe (stage 3) AKI. Those 3 patients underwent kidney biopsy for unresolving AKI, which revealed findings compatible with acute tubular necrosis. The first patient initially developed asymptomatic acute interstitial nephritis because of a concomitant antibiotic that caused worsening of kidney function, and the dose of vancomycin was not properly adjusted while staying at the nursing home. The second was an emaciated patient (BMI, 14) whose serum creatinine level was a deceptive marker of kidney function for the proper dosing of vancomycin, resulting in a toxic level. The third patient developed vancomycin-related AKI on an initially high therapeutic level, which then contributed to further rising in vancomycin level and subsequently causing severe AKI. One patient required hemodialysis, but all 3 patients ultimately recovered their kidney function significantly. A regular monitoring (preferably twice weekly) of serum creatinine and vancomycin trough level is advisable to minimize vancomycin-associated AKI, primarily acute tubular necrosis, for patients requiring prolonged administration of vancomycin (>2 weeks) on the currently recommended higher therapeutic trough levels (>15 μg/mL).",
"affiliations": "Nephrology Division, Montefiore Medical Center-Wakefield Campus, New York, NY.",
"authors": "Katikaneni|Madhavi|M|;Lwin|Lin|L|;Villanueva|Hugo|H|;Yoo|Jinil|J|",
"chemical_list": "D000900:Anti-Bacterial Agents; D014640:Vancomycin; D003404:Creatinine",
"country": "United States",
"delete": false,
"doi": "10.1097/MJT.0000000000000287",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-2765",
"issue": "23(4)",
"journal": "American journal of therapeutics",
"keywords": null,
"medline_ta": "Am J Ther",
"mesh_terms": "D058186:Acute Kidney Injury; D000900:Anti-Bacterial Agents; D003404:Creatinine; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D007683:Kidney Tubular Necrosis, Acute; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus; D008875:Middle Aged; D009395:Nephritis, Interstitial; D013203:Staphylococcal Infections; D014640:Vancomycin",
"nlm_unique_id": "9441347",
"other_id": null,
"pages": "e1064-7",
"pmc": null,
"pmid": "26035034",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute Kidney Injury Associated With Vancomycin When Laxity Leads to Injury and Findings on Kidney Biopsy.",
"title_normalized": "acute kidney injury associated with vancomycin when laxity leads to injury and findings on kidney biopsy"
} | [
{
"companynumb": "PHHY2016US111701",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
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"drugadditional": "1",
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{
"abstract": "BACKGROUND\nThe concept of precision medicine in cancer includes individual molecular studies to predict clinical outcomes. In the present N = 1 case we retrospectively have analysed lymphoma tissue by exome sequencing and global gene expression in a patient with unexpected long-term remission following relaps. The goals were to phenotype the diagnostic and relapsed lymphoma tissue and evaluate its pattern. Furthermore, to identify mutations available for targeted therapy and expression of genes to predict specific drug effects by resistance gene signatures (REGS) for R-CHOP as described at http://www.hemaclass.org. We expected that such a study could generate therapeutic information and a frame for future individual evaluation of molecular resistance detected at clinical relapse.\n\n\nMETHODS\nThe patient was diagnosed with a transformed high-grade non-Hodgkin lymphoma stage III and treated with conventional R-CHOP [rituximab (R), cyclophosphamide (C), doxorubicin (H), vincristine (O) and prednisone (P)]. Unfortunately, she suffered from severe toxicity but recovered during the following 6 months' remission until biopsy-verified relapse. The patient refused second-line combination chemotherapy, but accepted 3 months' palliation with R and chlorambucil. Unexpectedly, she obtained continuous complete remission and is at present >9 years after primary diagnosis. Molecular studies and data evaluation by principal component analysis, mutation screening and copy number variations of the primary and relapsed tumor, identified a pattern of branched lymphoma evolution, most likely diverging from an in situ follicular lymphoma. Accordingly, the primary diagnosed transformed lymphoma was classified as a diffuse large B cell lymphoma (DLBCL) of the GCB/centrocytic subtype by \"cell of origin BAGS\" assignment and R sensitive and C, H, O and P resistant by \"drug specific REGS\" assignment. The relapsed DLBCL was classified as NC/memory subtype and R, C, H sensitive but O and P resistant.\n\n\nCONCLUSIONS\nThorough analysis of the tumor DNA and RNA documented a branched evolution of the two clinical diagnosed tFL, most likely transformed from an unknown in situ lymphoma. Classification of the malignant tissue for drug-specific resistance did not explain the unexpected long-term remission and potential cure. However, it is tempting to consider the anti-CD20 immunotherapy as the curative intervention in the two independent tumors of this case.",
"affiliations": "Department of Hematology, Aalborg University Hospital, Aalborg, Denmark ; Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark.;Department of Hematology, Aalborg University Hospital, Aalborg, Denmark ; Department of Clinical Medicine, Aalborg University, Sdr. Skovvej 15, 9000 Aalborg, Denmark.;Department of Hematology, Aalborg University Hospital, Aalborg, Denmark ; Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark ; Department of Clinical Medicine, Aalborg University, Sdr. Skovvej 15, 9000 Aalborg, Denmark.;Department of Hematology, Aalborg University Hospital, Aalborg, Denmark ; Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark.;Department of Hematology, Aalborg University Hospital, Aalborg, Denmark.;Department of Hematology, Aalborg University Hospital, Aalborg, Denmark.;Department of Hematology, Aalborg University Hospital, Aalborg, Denmark.;Department of Hematology, Aalborg University Hospital, Aalborg, Denmark ; Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark.;Department of Hematology, Aalborg University Hospital, Aalborg, Denmark ; Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark.;Department of Hematology, Aalborg University Hospital, Aalborg, Denmark ; Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark ; Department of Clinical Medicine, Aalborg University, Sdr. Skovvej 15, 9000 Aalborg, Denmark.;Department of Hematology, Aalborg University Hospital, Aalborg, Denmark ; Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark.;Department of Hematology, Aalborg University Hospital, Aalborg, Denmark.;Department of Hematology, Aalborg University Hospital, Aalborg, Denmark ; Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark ; Department of Clinical Medicine, Aalborg University, Sdr. Skovvej 15, 9000 Aalborg, Denmark.;Department of Hematology, Aalborg University Hospital, Aalborg, Denmark ; Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark ; Department of Clinical Medicine, Aalborg University, Sdr. Skovvej 15, 9000 Aalborg, Denmark.;Department of Hematology, Aalborg University Hospital, Aalborg, Denmark ; Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark ; Department of Clinical Medicine, Aalborg University, Sdr. Skovvej 15, 9000 Aalborg, Denmark.",
"authors": "Bødker|Julie Støve|JS|;Severinsen|Marianne Tang|MT|;El-Galaly|Tarec Christoffer|TC|;Brøndum|Rasmus Froberg|RF|;Laursen|Maria Bach|MB|;Falgreen|Steffen|S|;Nyegaard|Mette|M|;Schmitz|Alexander|A|;Jakobsen|Lasse Hjort|LH|;Schönherz|Anna Amanda|AA|;Due|Hanne|H|;Reinholdt|Linn|L|;Bøgsted|Martin|M|;Dybkær|Karen|K|;Johnsen|Hans Erik|HE|",
"chemical_list": null,
"country": "England",
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"doi": "10.1186/s40164-016-0063-0",
"fulltext": "\n==== Front\nExp Hematol OncolExp Hematol OncolExperimental Hematology & Oncology2162-3619BioMed Central London 6310.1186/s40164-016-0063-0Case ReportMolecular classification of tissue from a transformed non-Hogkin’s lymphoma case with unexpected long-time remission Bødker Julie Støve j.boedker@rn.dk 12Severinsen Marianne Tang m.severinsen@rn.dk 13El-Galaly Tarec Christoffer tceg@rn.dk 123Brøndum Rasmus Froberg rfb@rn.dk 12Laursen Maria Bach maria.bach.laursen@clin.au.dk 1Falgreen Steffen falgreen@me.com 1Nyegaard Mette nyegaard@hum-gen.au.dk 1Schmitz Alexander alex.schmitz@rn.dk 12Jakobsen Lasse Hjort lasse.j@rn.dk 12Schönherz Anna Amanda a.schonherz@rn.dk 123Due Hanne hanne.rasmussen@rn.dk 12Reinholdt Linn linn.reinholdt@rn.dk 1Bøgsted Martin martin.boegsted@rn.dk 123Dybkær Karen k.dybkaer@rn.dk 123Johnsen Hans Erik haej@dcm.aau.dkhaej@rn.dk 1231 Department of Hematology, Aalborg University Hospital, Aalborg, Denmark 2 Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark 3 Department of Clinical Medicine, Aalborg University, Sdr. Skovvej 15, 9000 Aalborg, Denmark 11 1 2017 11 1 2017 2017 6 33 11 2016 31 12 2016 © The Author(s) 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nThe concept of precision medicine in cancer includes individual molecular studies to predict clinical outcomes. In the present N = 1 case we retrospectively have analysed lymphoma tissue by exome sequencing and global gene expression in a patient with unexpected long-term remission following relaps. The goals were to phenotype the diagnostic and relapsed lymphoma tissue and evaluate its pattern. Furthermore, to identify mutations available for targeted therapy and expression of genes to predict specific drug effects by resistance gene signatures (REGS) for R-CHOP as described at http://www.hemaclass.org. We expected that such a study could generate therapeutic information and a frame for future individual evaluation of molecular resistance detected at clinical relapse.\n\nCase presentation\nThe patient was diagnosed with a transformed high-grade non-Hodgkin lymphoma stage III and treated with conventional R-CHOP [rituximab (R), cyclophosphamide (C), doxorubicin (H), vincristine (O) and prednisone (P)]. Unfortunately, she suffered from severe toxicity but recovered during the following 6 months’ remission until biopsy-verified relapse. The patient refused second-line combination chemotherapy, but accepted 3 months’ palliation with R and chlorambucil. Unexpectedly, she obtained continuous complete remission and is at present >9 years after primary diagnosis. Molecular studies and data evaluation by principal component analysis, mutation screening and copy number variations of the primary and relapsed tumor, identified a pattern of branched lymphoma evolution, most likely diverging from an in situ follicular lymphoma. Accordingly, the primary diagnosed transformed lymphoma was classified as a diffuse large B cell lymphoma (DLBCL) of the GCB/centrocytic subtype by “cell of origin BAGS” assignment and R sensitive and C, H, O and P resistant by “drug specific REGS” assignment. The relapsed DLBCL was classified as NC/memory subtype and R, C, H sensitive but O and P resistant.\n\nConclusions\nThorough analysis of the tumor DNA and RNA documented a branched evolution of the two clinical diagnosed tFL, most likely transformed from an unknown in situ lymphoma. Classification of the malignant tissue for drug-specific resistance did not explain the unexpected long-term remission and potential cure. However, it is tempting to consider the anti-CD20 immunotherapy as the curative intervention in the two independent tumors of this case.\n\nElectronic supplementary material\nThe online version of this article (doi:10.1186/s40164-016-0063-0) contains supplementary material, which is available to authorized users.\n\nKeywords\nTransformed lymphomaLong-time remissionMolecular classificationRituximab palliationDrug resistance predictionissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nFollicular lymphoma (FL) is a low-grade non-Hodgkin’s type lymphoma with a median survival of 8–10 years [1, 2]. It can evolve into the more aggressive histology of transformed FL (tFL) [3], resembling diffuse large B-cell lymphoma (DLBCL), but share a distinct gene expression profile and immunophenotype with the primary FL [4–8]. This transformation occurs by the expansion of one or more subclones with loss of the follicular growth pattern resulting in a rapidly progressive clinical course refractory to treatment and with inferior prognosis. To distinguish between progression and transformation of FL a biopsy for histological examination is needed in case of symptoms and CT verified tumor progression. The histological verified presence of both follicular and diffuse architecture in the initial diagnostic biopsy represents a finding that implies early transformation of FL [2, 3]. The survival post-transformation ranges between median 7–20 months [9, 10].\n\nSimilar to progression, the transformation is a clonal evolution from an ancestral clone that initially arises from a common normal cell of origin (COO) through linear or branched outgrowth of an existing subclone, deregulated by random genetic or epigenetic hits.\n\nOur knowledge of genetic aberrations in FL has dramatically increased over the last few years, and recent comprehensive studies by exome sequencing has identified the mutational landscape and the genetic changes that contribute to the step wise tumor progression, including transformation to DLBCL [4–8, 11–18].\n\nHere we report a unique, biopsy and histology verified case of primary tFL with relapse and long-term remission following palliation therapy. As molecular studies of such unexpected outcome may be informative, we decided to study the two malignant tissue biopsies and a germ line DNA sample to thorough analysis with the aim to identify differences in an attempt to understand and explain the clinical outcome.\n\nThe case will also illustrate the molecular technologies, knowledge and competences that are increasingly available to challenge the “one size fits all” approach to early clinical phase I–II drug trials in relapsed patients and replace this with a predictive strategy. We envisage that therapies will be stratified to reflect disease heterogeneity, in a departure from the current use of non-precise chemotherapeutic agents and allow for the development of new taxonomy and companion diagnostics—a clear need in future clinical care.\n\nCase presentation\nEarly August, 2007, a previously healthy 74 year-old woman was referred to the Department of Hematology at Aalborg University Hospital with a 3-month history of weight loss (5%) and abdominal pain. A computed tomography (CT) was performed as part of the initial diagnostic work-up and revealed a bulky retroperitoneal tumor measuring 13.5 × 12 × 7.5 cm. Pathologically enlarged lymph nodes were also detected in all supra- and infra-diaphragmatic stations and the spleen was enlarged (Additional file 1: Figure S1A, July, 2007). Furthermore, she had bilateral hydronephrosis.\n\nA tumor biopsy from an axillary lymph node was performed. Morphological examinations revealed a picture typical for diffuse large B-cell lymphoma (DLBCL), but with nodular areas consistent with an underlying follicular lymphoma. The cells were monoclonal IgM+, kappa+, CD20+, CD19+, CD10+, CD38+, CD79A+, BCL2+ and BCL6+, CD30− with a high Ki67-estimated sproliferation rate. On the basis of these findings a diagnosis of DLBCL transformed from follicular lymphoma was made. The routine bone marrow biopsy and aspiration was clear for signs of lymphoma infiltration. The disease was categorized as stage III according to the Ann Arbor classification based on the extensive nodal involvement on both sides of the diaphragm.\n\nA combined modality treatment with six cycles of R-CHOP (Rituximab, cyclophosphamide, doxorubicin (hydroxydaunomycin), vincristine (oncovin) and prednisolon) followed by consolidating radiotherapy against the abdominal bulk tumor was planned. Unfortunately, her treatment was complicated by severe infectious episodes including septicemia. After the final R-CHOP cycle, she had lost an additional 10 kg and was in a clinical poor performance status. An 18F-FDG positron emission tomography/CT (PET/CT) performed at this point showed a residual PET-negative tumor mass surrounding the aorta (Additional file 1: Figure S1B, January, 2008). As a result of her poor condition she entered post-therapy follow-up without receiving the planned radiotherapy.\n\nA routine PET/CT study performed after three months of follow-up confirmed continues remission (Additional file 1: Figure S1C, March, 2008). However, a routine PET/CT study performed 6 months into the follow-up period revealed clear progression of the retroperitoneal tumor in terms of increased size and FDG-uptake (SUVmax 11.2) (Additional file 1: Figure S1D, July, 2008). A tumor biopsy directed from an enlarged cervical lymph node revealed a morphological and immunohistochemical picture similar to that seen in the primary diagnostic biopsy (see above)—thus being consistent with relapse of DLBCL transformed from a follicular component.\n\nIn light of the severe complications during the primary R-CHOP therapy, she declined intensive chemotherapy and specifically asked for a palliative approach. She therefore received four doses of rituximab given every 3 weeks combined with continues oral chlorambucil (Leukeran®) at a dose of 4 mg per day as maintenance. Chlorambucil was stopped after 6 month due to side effects. At this point she was unwilling to accept any further lymphoma directed therapies or investigations but accepted clinical follow up including a PET/CT scan documenting remission.\n\nSurprisingly, she slowly recovered and regained weight over the following months and a control PET/CT showed remission (Additional file 1: Figure S1E, July, 2010). At the last follow-up visit August 2016, 9 years after the initial diagnosis, she was still in good health without lymphoma-related symptoms or findings.\n\nMethod section\nThe aim, design and setting of the study\nBased on the unexpected long-term remission of a tFL patient on palliative therapy for her first relapse, we obtained informed consent to perform a thorough molecular analysis on her primary and relapsed tumor. The idea was to explore den molecular background in her tumor samples in search for an explanation for her cure following palliation with rituximab (Mabthera®) and chlorambucil (Leukeran®).\n\nAdditional malignant tissue were available and included, from NHL patients at time of diagnosis before treatment and diagnosis were evaluated according to the Revised European-American Lymphoma Classification [1] and confirmed by two expert hematopathologists at Aalborg University Hospital. Included were patients who had tissue stored in the “Diagnostic Biobank, Department of Hematology, Aalborg” and clinical data, staging, therapy and outcome registered in the National Clinical Quality Database for lymphoma, as approved by the local ethical committee (RetroGene, N-20140099).\n\nGene expression profiling (GEP)\nRNA from 50 lymphoma samples FL (n = 7), tFL (n = 2; the case) and DLBCL (n = 41) was purified, labeled and hybridized to Affymetrix GeneChip Human Genome U133 Plus 2.0 Arrays and.CEL files generated as described [18] and presented in Additional file 2: Table S1. All were diagnostic samples taken before initiation of treatment. The relapse tFL sample (H385) being the exception, as the patients received R-CHOP treatment for her primary tumor (H302).\n\nResistance gene signatures (REGS) for drug response\nThe effect of the drugs cyclophosphamide (C), doxorubicin (H), vincristine (O) and rituximab (R) on viable proliferating B-cell lines was measured by an in vitro drug screen strategy as recently described by our group [19–24]. Sensitivity or resistance towards individual drugs can be predicted by the REGS assignment of probability, which ranges from zero to one, respectively. A website (http://www.hemaClass.org) [25] has been generated to grant access to the classification and prediction tools to all researchers by easy upload of .CEL-file data. The.CEL files from the patient case tumors were analyzed and as build-in reference, our collection of lymphoma samples (RetroGene) performed at our laboratory was chosen in the RMA pre-processing normalization step. We chose the following classification systems: BAGS, R, C, H, O, P and R-CHOP, with the following ranges of non classified/intermediate groups: 0.1–0.9; 0.38–0.54; 0.33–0.55; 0.14–0.9; 0.46–0.62; 0.09–0.93, respectively. The results are downloaded and displayed in Table 3.\n\nDNA purification\nDNA from the patient’s two tumor samples was purified as described [26]. The patient’s saliva sample was collected using the Oragene DNA Self-Collection Kit (OG-500) and the DNA purified from non-involved mucosa cells using the Oragene DNA purifier (OG-L2P) following manufactures instructions in protocol PD-PR-006 Issue 3.2 (DNA Genotek Inc, Ottawa, Ontario, Canada).\n\nGlobal copy number variation (CNV)\nThe purified DNA was labeled and hybridized to Affymetrix SNP6 arrays as described [26]. The .CEL files, generated through AGCC after scanning the arrays, were imported to Partek Genomics Suite Software v. 6.6 (6.14.0828) using interrogating probes only with a pre-background adjustment for GC content and probe sequence. Probe sets wire summarized using allele specific summarization, and normalized against the human Hapmap genome. Amplification and deletions were detected through genomic copy number segmentation using standard settings, in brief: minimum 10 genomic markers, a P value threshold of 0.001, and a signal to noise ratio of 0.3. The diploid copy number range was set to 1.7–2.3.\n\nExome sequencing and analysis\nFrom the patient’s saliva, primary and relapse tumor samples, standard sequence libraries for studies of point mutations were created from 100 ng of DNA from each sample, following exome capture using the Agilent SureSelect Human All Exon 50 Mb system (Agilent Technologies). Sequencing was performed on a HighSeq 2000 (Illumina, Hinxton, UK) using 76-bp paired-end reads, as described [27, 28].\n\nRaw reads from the sequencer were processed following the Genome Analysis Toolkit (GATK) best practice guidelines [29, 30]. Reads were aligned to the grch37 assembly of the human genome with BWA v0.7.12 [31]. Aligned reads were sorted, converted to BAM format and had PCR duplicates marked using Picard v2.0.1 (http://broadinstitute.github.io/picard/). Sequence realignment around INDELs and adjustment of quality scores was done using GATK v.3.5.0 [32]. Discovery of somatic variants in both primary and relapse tumors was performed using MuTect2 [33] incorporating information from dbSNP v138 [34] and COSMICv75 [35]. Somatic variants that passed quality filters were annotated using Oncotator v.1.8.0.0 [36] and finally PHIAL v1.0 [37] was used to score and rank somatic mutations according to clinical relevance and to identify potential targeted therapy for the analyzed patient.\n\nDatasets\nThe micro array data are deposited at Gene Expression Omnibus in project GSE86622, see Additional file 2: Table S1. The exome sequencing data from the tFL patient samples: non-involved mucosa cells, the lymphoma diagnostic sample and the sample following clinical relaps, are available through the European Genome Phenomena Archive at the European Bioinformatics Institute under accession number EGAD00001002707.\n\nStatistical analysis\nAll statistical analyses were performed using R (The R Development Core Team, 2013) version 3.0.1 [38–41].\n\nResults\nIn the present N = 1 case we have analysed the diagnostic and relapsed lymphoma tissue DNA and RNA by exome sequencing and microarray expression respectively. The primary goal was to phenotype the lymphoma tissues and evaluates its evolution pattern. The secondary goals were in a therapeutic context to identify specific mutations available for targeted therapy and expression of genes to predict specific drug effects of R-CHOP. It is expected that we could generate information useful in this specific and unexpected case.\n\nPrincipal component analysis of DLBCL, FL and the case samples\nThe gene expression profiles of the primary and relapse samples from our patient case were analyzed together with 7 FL and 41 DLBCL cases from our clinic in a principal component analysis (PCA) with the results as illustrated in Fig. 1. The cases formed two distinct groups, where the diagnostic and relapse tFL samples were different, in close proximity to the FL and DLBCL groups, respectively.Fig. 1 Principal component analysis (PCA) of the tFL case compared to FL and DLBCL samples. A principal component (PC) analysis on GEP from 7 FL, 41 DLBCL samples and the patient’s primary and relapse tumors was performed. All probe sets for all samples were included in the PC analysis. a The two diagnostic entities, FL and DLBCL, segregated into distinct clusters in the PC analysis, with the primary and relapse tumor samples located at the edges of the FL and DLBCL groups, respectively. b The proportion of variance in the 10 first PC’s are displayed\n\n\n\n\nMutation identification by exome sequencing of the case samples\nWe performed exome sequencing on the primary and the relapse tumor and identified somatic changes in 687 SNPs and INDELs compared to the constitutional DNA obtained from the patient’s saliva. The primary (H302) and relapse (H385) tumors contained 329 and 358 somatic tumor specific changes, respectively, with an overlap of 127, as shown in Table 1. A thorough review of clinically relevant mutated genes, two (EZH2 and DNMT3A) were unique for the primary tumor and two were unique for the relapse tumor (FBXW7 and FIP1L1). Three of the genes were found in both tumors (NOTCH2, TP53 and EP300), however, NOTCH2 were present at different allelic fractions in the two tumors (Table 2). Of the 37 recurrent gene mutations described by Pasqualucci [8] we recognized mutations in BCL2, HIST1H1E, EP300, TP53 and STAT6 in both tumors, EZH2 in the primary and KDM6B in the relapsed tissue. Overall, the mutation pattern recognized suggests a branched evolution from an unknown common mutated ancestor through the independent acquisition of distinct genetic lesions.Table 1 Classification of variants in primary and relapsed tumor\n\nVariant\tPrimary\tRelapse\tShared\t\n3’UTR\t4\t10\t4\t\n5’Flank\t1\t1\t0\t\n5’UTR\t2\t2\t1\t\nFrame_Shift_Del\t0\t3\t0\t\nFrame_Shift_Ins\t2\t1\t0\t\nIGR\t48\t42\t12\t\nIn_Frame_Del\t0\t3\t0\t\nIntron\t109\t124\t42\t\nlincRNA\t4\t8\t2\t\nMissense_Mutation\t110\t94\t46\t\nNonsense_Mutation\t3\t6\t2\t\nRNA\t18\t20\t8\t\nSilent\t23\t37\t7\t\nSplice_Site\t5\t7\t3\t\nTotal\t329\t358\t127\t\n\nTable 2 Clinically relevant variants detected by PHIAL\n\n\tCoverage\tAllelic fraction\t\nGene\tVariant\tPrimary\tRelapse\tPrimary\tRelapse\t\nTP53\tMissense_Mutation\t35\t37\t0.66\t0.62\t\nNOTCH2\tNonsense_Mutation\t24\t26\t0.58\t0.27\t\nEP300\tMissense_Mutation\t55\t63\t0.31\t0.33\t\nDNMT3A\tSplice_Site\t52\tNA\t0.08\tNA\t\nEZH2\tMissense_Mutation\t37\tNA\t0.3\tNA\t\nFBWX7\tMissense_Mutation\tNA\t64\tNA\t0.38\t\nFIP1L1\tSplice_Site\tNA\t59\tNA\t0.37\t\n\n\n\nThis was also visualized by global SNP6-microarray analysis for copy number variations (CNV) above 100 kb as illustrated in Fig. 2. The diagnostic and relapse samples had various chromosomal regions with identical CNV, illustrated for chromosomes 1, 6, 9, 16, 17 and X. However, many CNVs were unique to the primary tumor—see chromosomes 3, 4, 7, 10, 17 and X, or unique to the relapsed tissue seen in chromosomes 2, 3, 4, 5, 7, 8, 10, 11, 12, 16, 18, 19.Fig. 2 Copy number analysis of diagnostic and relapsed tFL tissue. Copy number variations above 100 kb in all chromosomes are displayed for the saliva sample, the primary and the relapse tumors from the tFL patient case. The image was generated through Partek™ Genomics Suite Software\n\n\n\n\nIn summary, the diagnostic and relapsed tFL harbor unique mutations and CNVs documenting that the tumors have a common genetic background and the tFL case is a consequence of branched and not direct linear clonal selection and evolution.\n\nEstimation of drug sensitivity for the case samples\nThe primary and relapse samples were assigned a cell of origin (COO) subtype as described [18] resistance estimate for R-CHOP by REGS [19–21] classifiers following assignment in http://www.hemaClass.org [25]. This tool provides an easy interface for one-by-one microarray based classification based on our preclinical models for BAGS and REGS. By individual REGS assignment, the primary tumor was predicted to be resistant to the drugs C, H, O and P, but sensitive towards R. In contrast, the relapse tumor had changed drug sensitivity for the alkylating agents C but still resistant towards O and P as well as the very high sensitive towards R, as shown in Table 3.Table 3 Probability of resistance and predicted R-class from http://www.Hemaclass.org\n\n\nPredicted classification\tPrimary tumor (H302)\tRelapse tumor (H385)\t\nProbability of BAGS\t0.595\t0.363\t\nBAGS class\tCentrocyte\tMemory\t\nProbability of ABC\t1.19E + 09\t1.09E − 01\t\nABC-GCB-NC class\tGCB\tNC\t\nProbability of R\t0.034\t0.049\t\nR class\tSensitive\tSensitive\t\nProbability of C\t0.662\t0.225\t\nC class\tResistant\tSensitive\t\nProbability of H\t0.963\t0.041\t\nH class\tResistant\tSensitive\t\nProbability of O\t0.750\t0.639\t\nO class\tResistant\tResistant\t\nProbability of Dex\t0.023\t0.037\t\nDex class\tResistant\tResistant\t\nProbability combined\t0.993\t0.022\t\nCombined class\tResistant\tSensitive\t\nThe probability of resistance towards cyclophosphamide (C), doxorubicin, (H), vincristine (O), and rituximab (R) determined by applying the REGS classification (Dybkaer et al. [18] and Laursen et al. [19] in preparation) onto .CEL files from Affymetrix U133plus2.0 arrays of the indicated samples through http://www.hemaclass.org. A probability close to 1 predicts resistance, whereas a value close to 0, predicts sensitivity to the indicated drug\n\n\nNC not classified\n\n\n\n\nIn summary, the gene signature based subtyping of the two tFL tissue support that they were different although with important overlaps. From a functional perspective both tissues are R sensitive, indicating that the patient was cured by the targeted anti-CD20 therapy.\n\nDiscussion\n“N of 1” case studies require prospective collection of individual tissue into biobanks and storage of molecular data from standardized tissue analysis. Here we describe a unique patient who was “cured” for tFL and we present data that identify the differential pattern of genetic evolution and furthermore classify the lymphomas by resistance estimates for the specific drugs in question.\n\nThe tFL presented in this case was advanced stage at diagnosis and a poor outcome was expected [9]. Even if such cases are rare, we believe that the knowledge from our work will be useful if we can collect and assemble such data across several cases [42]. In the era of precision medicine, the design of various types of medical “data commons” may allow us to compare individual cases. It is our hope that other research groups will perform similar extensive molecular analysis of tFL cases with long-term remission in order to improve understanding of pathogenesis and individual treatment response.\n\nDocumentation of lymphoma evolution\nSequencing the malignant genome has opened new knowledge to the complexity of malignant lymphoma cell genetics, selection and Darwinian evolution [43, 44]. Multiple studies have analysed paired biopsies from indolent follicular lymphoma and its transformation for differential genetic aberrations associated to the clinical progression. A common finding is the premalignant IGH-BCL2 hybrid transcript expression and several key genetic events that seem to drive the process of progression [5, 6, 8]. In parallel, comparative analysis can also identify the genotypic background and, as in our case, document patterns of branched or linear lymphoma evolution. From published data, we have a long list of recurrent driver mutations from functional screening that illustrates the complexity and how heterogeneous the tFL genomes actually are.\n\nIn the present case, recurrent somatic mutations of BCL2, NOTCH2, TP53 and EP300 were identified in the primary and relapsed tumor, which indicates a common progenitor cell, most likely a transformation from an unknown in situ or premalignant follicular lymphoma [45, 46]. The branched evolution was supported by the presence of gene mutations unique to the primary tFL tumour, e.g. the recurrent genes, EZH2 and DNMT3A that were mutated in 30 and 8% of the reads, but not mutated in the reads from the relapse tFL tumour. On the contrary the relapsed tumor had several specific mutations e.g. in FBXW7 and FIP1L1.\n\nIn summary, the data (Figs. 1, 2 and Tables 1, 2) confirms that each of the individual tFL in our patient case has unique genomic profiling. The precision medicine concept argues that genetic heterogeneity is a key-factor for therapeutic failure. This limitation is broadly recognized and represents a considerable challenge, technically and bioinformatically. Understanding the genetic diversity and how it changes in response to interventions, will require deep sequencing and analysis of the genomes of highly selected single cells [47, 48].\n\nImpact of gene signature classification of COO and drug resistance\nDespite the enormous resources spent on developing molecular based cancer classification systems, most of these are still not available in clinical practice. To allow implementation and fast validation of our recent findings in DLBCL [18–21], we have developed an easily accessible web application that permits other users to assign ABC/GCB, B-cell associated gene signature (BAGS) as well as drug specific resistance gene signature (REGS) on their own datasets. The website called hemaClass.org [25] is a new prospect for easy individual subtyping of malignant B cell diseases; in particular for DLBCL and myeloma.\n\nIn summary, the primary diagnosed tFL was classified as a diffuse large B cell lymphoma (DLBCL) of the GCB/centrocytic subtype by “cell of origin BAGS” assignment and R-CHOP resistant by “drug specific REGS” assignment. The relapsed DLBCL was classified as NC/memory subtype and R-CHOP sensitive in support of the branched evolution. Monitoring such functional variations following treatment may identify the mechanisms of molecular drug resistance resulting in clinical relapse.\n\nLimitations of the study\nThis case study may be important for future diagnostic phenotyping and implementation of individual targeted drug or specific predictive therapy, however it involves a range of clinical, biological, and statistical limitations to be considered.\n\n\nFirst, we cannot trust the conventional classification of poor prognosis associated with tFL, to make a clinical decision at the individual level. However, we expected this to be fulfilled by molecular profiling of drug specific sensitivity and resistance and mutations status for targeted therapy by designer drugs [49]. However, this strategy needs to be prospective validated by selected clinical end point, like level of remission, event free or overall survival. Such studies are ongoing, also in our center including all relapsed patients with haematological malignancies, to be used in the future evidence based strategy for individualized targeted and predicted therapy [49–53].\n\n\nSecond, the tissues analyzed are obtained from the biopsy of a single tumor focus, knowing that an entirely different profile might be seen from the biopsy of an adjacent lesion. The identification of the mutations within sub-clones is lost when DNA is extracted from the total cell population. This is most important if patient-and drug-specific genomic profiles are used for selecting therapeutic targets. This limitation represents a considerable challenge, technically and bioinformatically and will require deep sequencing and analysis of the genomes of single cells sorted by multiparametric flow cytometry.\n\n\nThird, this case study has described a frame for future individual evaluation of clinical resistance detected at relapse. However, the individual REGS assignments given in Table 3 showed that the two tFL biopsies are R sensitive and indicate a clinical response to targeted anti-CD20 therapy for both tissues. However, we did not have a drug specific REGS predictor for the alkylating drug Chlorambucil, but the shift in sensitivity for the alkylating drug C may illustrate a potential sensitivity also to Chlorambucil therapy and a clinical impact in combination with R [54, 55]. Ongoing preclinical drug screens do include clinical available drugs and clinical relevant combinations.\n\n\nFourth, it has to be stressed that the clinical impact of REGS assignment is documented by retrospective analysis of thousands of patient sample data from several international clinical drug trials [20–23]. Therefore, we need to await ongoing prospective implementation trials validating the clinical impact of REGS assignment in clinical resistant haematological malignancies, before introducing our “second generation” companion diagnostics for malignant B cell diseases. However, the present case illustrates our research strategy for implementation of individualized care focused on patients with relapse or progression. The specific challenges in this area are the unexplained molecular drug resistance and the undocumented use of drug combinations transferred from the “one size fits all” approach. Key to address this challenge is an understanding of the molecular/genetic profiles of each tumour such that we can tailor therapy appropriately, generate improved and evidence based clinical outcomes, and make the most efficient use of healthcare resources. Predictive companion diagnostics will identify multidrug resistant patients that will be extensively characterized and screened for specific pathway and/or mutations, attempting to validate target therapy by small and limited number of patients [56].\n\nConclusions\nThe present case of primary tFL was treated with conventional R-CHOP and suffered from severe side effects but obtained a 6 months remission. However, she relapsed after 6 months and accepted palliation with rituximab and chlorambucil for 6 months. Unexpectedly, she obtained a continuous complete remission, at present >9 years after primary diagnosis.\n\nThe retrospective analysis of the tumor tissue, documented the following key points:Genomic sequencing, CNV and gene expression defined a branched evolution of the two independent lymphomas, most likely transformed from an unknown lymphoma in situ.\n\nClassification for drug specific sensitivity and resistance propose the targeted anti-CD20 antibody therapy with the curative potential in the present case.\n\n\n\n\nTogether this case foresees a paradigm shift in the clinical treatment culture for relapsed patients with haematological malignancies—toward “personalised medicine” and “precision medicine” that need individual molecular work out [49–53].\n\nAdditional files\n\n\nAdditional file 1. Diagnostic image examinations of the patient case. A) The computed tomography (CT) from the primary lymphoma diagnosis showed retroperitoneal bulk tumor and bilateral hydronephrosis (July 2007). B) A PET/CT was performed after six cycles of R-CHOP and identified a large abdominal residual tumor without FDG (January 2008). C) A routine scan was performed after three months of follow-up and confirmed continues remission (March 2008). D) A control scan was performed six months after therapy showing FDG accumulation in the retroperitoneal residual tumor as well as a palpable cervical tumor (July 2008). After four cycles of rituximab and continues chlorambucil treatment (total 6 months) a status scan was performed and showed a marked reduction of FDG-uptake in the abdominal bulk tumor (November 2008 - data not shown), and repeated as illustrated in E) consistent with continuous complete remission (July 2010) according to the revised response criteria for malignant lymphoma. The superficial process at abdomen in E) was a benign lipoma.\n\n\n\nAdditional file 2. Micro array data files. The Affymetrix .CEL files were deposited at the GEO website under GSE86622. In total, U133 plus 2.0 arrays were performed on 41 DLBCL, 2 tFL and 7 FL patient samples and 3 SNP6.0 arrays were performed on the saliva, primary and relapse tumors on the patient case. Clinical data are registered in the National Clinical Quality Database for Malignant Lymphoma (http://www.lymphoma.dk).\n\n\n\n\nAbbreviations\nCcyclophosphamide\n\nHdoxorubicin\n\nOvincristine\n\nPprednisolon\n\nRrituximab\n\nBAGSB cell associated gene signature\n\nREGSdrug resistence gene signature\n\nDLBCLdiffuse large B-cell lymphoma\n\ntFLtransformed follicular lymphoma\n\nFLfollicular lymphoma\n\nSNPsingle-nucleotide polymorphism\n\nINDELinsertion or the deletion of bases in the DNA\n\nCNVcopy number variation\n\nCOOcell of origin\n\nNHLnon Hodgkin lymphoma\n\nAuthors’ contributions\nMTS and HEJ were responsible for the conception of the study, interpretation and the primary writing of the manuscript together with JSB; MTS and TCE collected the clinical data and contributed to the execution of the study; KD, MN, MB and JSB designed the molecular analysis and data review; MB, SF, AS, LHJ, AAS, HDR and LR were responsible for statistical analysis and its review. JSB and HEJ finalized the manuscript. All authors meet the Vancouver definition of authorship. All authors read and approved the final manuscript.\n\nAcknowledgements\nExom sequencing was performed by and bioinformatic assistance was introduced by Christopher Wardell and Brian Walker from the Haemato-Oncology Research Unit, Division of Molecular Pathology, Institute of Cancer Research, London, United Kingdom. Routine diagnostics by PET/CT was performed by Victor Iyer (vvi@rn.dk) the Department of Nuclear Medicine, and hematopathology evaluation of tissues by Preben Johansen (pj@rn.dk), Hematopathology Aalborg University Hospital. Technicians Ann-Maria Jensen, Louise Hvilshøj Madsen, Helle Høholt, and bioengineer Anette Mai Tramm participated in different aspects of the laboratory work and are acknowledged for their professionalism.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAvailability of data and materials\nThe micro array data are deposited at Gene Expression Omnibus in the following projects GSE56313 [18], GSE37977 [26] and GSE86613, see Additional file 2: Table S1. The exome sequencing data from the tFL patient samples: non-involved mucosa cells, the lymphoma diagnostic sample and the sample following clinical relaps, are available through the European Genome Phenomena Archive at the European Bioinformatics Institute under accession number GSE86621.\n\nConsent for publication\nConsent to publicize this article was obtained from the tFL patient presented in this case report.\n\nEthics approval and consent to participate\nLymphoma tissue from the patients (tFL, FL and DLBCL-diagnoses) was collected and handled in accordance with the research protocols “CHEPRETRO/RetroGene” approved by the local ethics committee (Chepretro N-20100059 RetroGen, N-20140099). Tissue was from time of diagnosis and/or relapse before treatment and histological diagnosis was evaluated according to the Revised European-American Lymphoma Classification. Included were patients who had tissue stored in the “Diagnostic Biobank, Department of Hematology, Aalborg University Hospital” and clinical data, staging, therapy and outcome registered in the National Clinical Quality Database for lymphoma. A saliva sample was collected from the tFL patient case, following informed consent, in accordance with the research protocol “MSCNET” accepted by the local ethical committee (N-20080062MCH).\n\nFunding\nSupport was provided by research funding from the EU 6th FP to MSCNET (LSHC-CT-2006-037602), the Danish Cancer Society, the Danish Research Agency to CHEPRE (#2101-07-0007) and the KE Jensen Foundation (2006–2010) to HEJ and KD.\n==== Refs\nReferences\n1. Swerdlow SH Campo E Harris NL WHO classification of tumours of haematopoietic and lymphoid tissues 2008 Geneva World Health Organization \n2. Kridel R Sehn LH Gascoyne RD Pathogenesis of follicular lymphoma J Clin Invest. 2012 122 10 3424 3431 10.1172/JCI63186 23023713 \n3. Montoto S Davies AJ Matthews J Risk and clinical implications of transformation of follicular lymphoma to diffuse large B-cell lymphoma J Clin Oncol 2007 25 2426 2433 10.1200/JCO.2006.09.3260 17485708 \n4. Bouska A McKeithan TW Deffenbacher KE Genome-wide copy-number analyses reveal genomic abnormalities involved in transformation of follicular lymphoma Blood 2014 123 11 1681 1690 10.1182/blood-2013-05-500595 24037725 \n5. Lossos IS Alizadeh AA Diehn M Transformation of follicular lymphoma to diffuse large-cell lymphoma: alternative patterns with increased or decreased expression of c-myc and its regulated genes Proc Natl Acad Sci USA 2002 99 8886 8891 10.1073/pnas.132253599 12077300 \n6. Martinez-Climent JA Alizadeh AA Segraves R Transformation of follicular lymphoma to diffuse large cell lymphoma is associated with a heterogeneous set of DNAcopy number and gene expression alterations Blood 2003 101 3109 3117 10.1182/blood-2002-07-2119 12406872 \n7. Green MR Gentles AJ Nair RV Hierarchy in somatic mutations arising during genomic evolution and progression of follicular lymphoma Blood 2013 121 9 1604 1611 10.1182/blood-2012-09-457283 23297126 \n8. Pasqualucci L Khiabanian H Fangazio M Genetics of follicular lymphoma transformation Cell Rep. 2014 6 1 130 140 10.1016/j.celrep.2013.12.027 24388756 \n9. Al-Tourah AJ Gill KK Chhanabhai M Population-based analysis of incidence and outcome of transformed non-Hodgkin’s lymphoma J Clin Oncol 2008 26 32 5165 5169 10.1200/JCO.2008.16.0283 18838711 \n10. Bastion Y Sebban C Berger F Incidence, predictive factors, and outcome of lymphoma transformation in follicular lymphoma patients J Clin Oncol 1997 15 4 1587 1594 9193357 \n11. Morin RD Johnson NA Severson TM Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin Nat Genet 2010 42 2 181 185 10.1038/ng.518 20081860 \n12. Bödör C Grossmann V Popov N EZH2 mutations are frequent and represent an early event in follicular lymphoma Blood 2013 122 18 3165 3168 10.1182/blood-2013-04-496893 24052547 \n13. Mamessier E, Song JY, Eberle FC, et al. Early lesions of follicular lymphoma: a genetic perspective. Haematologica. 2013.\n14. Leich E Zamo A Horn H Haralambieva E MicroRNA profiles of t(14;18)-negative follicular lymphoma support a late germinal center B-cell phenotype Blood 2011 118 20 5550 5558 10.1182/blood-2011-06-361972 21960592 \n15. Carlotti E Wrench D Matthews J Transformation of follicular lymphoma to diffuse large B-cell lymphoma may occur by divergent evolution from a common progenitor cell or by direct evolution from the follicular lymphoma clone Blood 2009 113 15 3553 3557 10.1182/blood-2008-08-174839 19202129 \n16. Kluin PM Origin and migration of follicular lymphoma cells Haematologica 2013 98 9 1331 1333 10.3324/haematol.2013.091546 24006404 \n17. Irish JM Myklebust JH Alizadeh AA B-cell signaling networks reveal a negative prognostic human lymphoma cell subset that emerges during tumor progression Proc Natl Acad Sci USA. 2010 107 29 12747 12754 10.1073/pnas.1002057107 20543139 \n18. Dybkær K Bøgsted M Falgreen S Diffuse large B-cell lymphoma classification system that associates normal B-cell subset phenotypes with prognosis J Clin Oncol 2015 33 12 1379 1388 10.1200/JCO.2014.57.7080 25800755 \n19. Laursen MB Falgreen S Bødker JS Human B-cell cancer cell lines as a preclinical model for studies of drug effect in diffuse large B-cell lymphoma and multiple myeloma Exp Hematol 2014 42 11 927 938 10.1016/j.exphem.2014.07.263 25072621 \n20. Falgreen S Laursen MB Bødker JS Exposure time independent summary statistics for assessment of drug dependent cell line growth inhibition BMC Bioinform 2014 15 168 10.1186/1471-2105-15-168 \n21. Falgreen S Dybkær K Young KH Predicting response to multidrug regimens in cancer patients using cell line experiments and regularised regression models BMC Cancer 2015 8 15 235 10.1186/s12885-015-1237-6 \n22. Boegsted M Holst JM Fogd K Generation of a predictive melphalan resistance index by drug screen of B-cell cancer cell lines PLoS ONE 2011 6 e19322 10.1371/journal.pone.0019322 21559449 \n23. Bøgsted M Bilgrau AE Wardell CP Proof of the concept to use a malignant B cell line drug screen strategy for identification and weight of melphalan resistance genes in multiple myeloma PLoS ONE 2013 8 e83252 10.1371/journal.pone.0083252 24376673 \n24. Reinholdt L Laursen MB Schmitz A Bødker JS Jakobsen LH Bøgsted M Johnsen HE Dybkær K The CXCR4 antagonist plerixafor enhances the effect of rituximab in diffuse large B-cell lymphoma cell lines Biomark Res. 2016 14 4 12 10.1186/s40364-016-0067-2 \n25. Falgreen S Ellern Bilgrau A Brøndum RF hemaClass.org: online one-by-one microarray normalization and classification of hematological cancers for precision medicine PLoS ONE. 2016 11 10 e0163711 10.1371/journal.pone.0163711 27701436 \n26. Bødker JS Gyrup C Johansen P Performance comparison of affymetrix SNP6.0 and cytogenetic 2.7M whole-genome microarrays in complex cancer samples Cytogenet Genome Res. 2013 139 2 80 87 10.1159/000345125 23182917 \n27. Kozarewa I Rosa-Rosa JM Wardell CP A modified method for whole exome resequencing from minimal amounts of starting DNA PLoS ONE 2012 7 e32617 10.1371/journal.pone.0032617 22403682 \n28. Walker BA Wardell CP Murison A APOBEC family mutational signatures are associated with poor prognosis translocations in multiple myeloma Nat Commun. 2015 23 6 6997 10.1038/ncomms7997 \n29. Auwera GA, Carneiro MO, Hartl C, et al. From FastQ data to high confidence varant calls: the genonme analysis toolkit best practices pipeline. 2014.\n30. DePristo MA Banks E Poplin R A framework for variation discovery and genotyping using next-generation DNA sequencing data Nat Genet 2011 43 5 491 498 10.1038/ng.806 21478889 \n31. Li H Durbin R Fast and accurate short read alignment with Burrows-Wheeler transform Bioinformatics 2009 25 14 1754 1760 10.1093/bioinformatics/btp324 19451168 \n32. McKenna A Hanna M Banks E The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data Genome Res 2010 20 9 1297 1303 10.1101/gr.107524.110 20644199 \n33. Cibulskis K Lawrence MS Carter SL Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples Nat Biotechnol 2013 31 3 213 219 10.1038/nbt.2514 23396013 \n34. Sherry ST, Ward MH, Kholodov M, et al. DbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 2001;29(1):308–11. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=29783&tool=pmcentrez&rendertype=abstract.\n35. Futreal PA Coin L Marshall M A census of human cancer genes Nat Rev Cancer. 2004 4 3 177 183 10.1038/nrc1299 14993899 \n36. Ramos AH Lichtenstein L Gupta M Oncotator: cancer variant annotation tool Hum Mutat 2015 36 4 E2423 E2429 10.1002/humu.22771 25703262 \n37. Van Allen EM Wagle N Stojanov P Whole-exome sequencing and clinical interpretation of formalin-fixed, paraffin-embedded tumor samples to guide precision cancer medicine Nat Med 2014 20 6 682 688 10.1038/nm.3559 24836576 \n38. The R Development Core Team (2010) R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing. http://cran.r-projet.org/doc/manuals/refman.pdf.\n39. Rossini AJ, Lumley T, Leisch F. On the edge: statistics & computing. 2012.\n40. Irizarry RA Hobbs B Collin F Exploration, normalization, and summaries of high density oligonucleotide array probe level data Biostatistics 2003 4 249 264 10.1093/biostatistics/4.2.249 12925520 \n41. Friedman J Hastie T Tibshirani R Regularization paths for generalized linear models via coordinate descent J Stat Softw 2010 33 1 22 10.18637/jss.v033.i01 20808728 \n42. Brannon AR Sawyers CL “N of 1” case reports in the era of whole-genome sequencing J Clin Invest. 2013 123 11 4568 4570 10.1172/JCI70935 24135144 \n43. Greaves M Maley CC Clonal evolution in cancer Nature 2012 481 7381 306 313 10.1038/nature10762 22258609 \n44. Greaves M Evolutionary determinants of cancer Cancer Discov. 2015 5 8 806 820 10.1158/2159-8290.CD-15-0439 26193902 \n45. Morita K Nakamine H Nakai T A retrospective study of patients with follicular lymphoma (FL): identification of in situ FL or FL-like B cells of uncertain significance in lymph nodes resected at the time of previous surgery for carcinomas J Clin Pathol 2015 68 7 541 546 10.1136/jclinpath-2015-202933 25862812 \n46. Ganapathi KA Pittaluga S Odejide OO Early lymphoid lesions: conceptual, diagnostic and clinical challenges Haematologica 2014 99 9 1421 1432 10.3324/haematol.2014.107938 25176983 \n47. Aparicio S Caldas C The implications of clonal genome evolution for cancer medicine N Engl J Med 2013 368 9 842 851 10.1056/NEJMra1204892 23445095 \n48. Johnsen HE Bøgsted M Schmitz A The myeloma stem cell concept, revisited: from phenomenology to operational terms Haematologica. 2016 101 12 1451 1459 10.3324/haematol.2015.138826 27903712 \n49. Collins FS Varmus H A new initiative on precision medicine N Engl J Med 2015 372 9 793 795 10.1056/NEJMp1500523 25635347 \n50. Toward precision medicine: building a knowledge network for biomedical research and a new taxonomy of disease. Committee on a framework for development a new taxonomy of disease; National Research Council; 2001. http://www8.nationalacademies.org/onpinews/newsitem.aspx?RecordID=13284.\n51. Lander ES Cutting the Gordian Helix—regulating genomic testing in the era of precision medicine N Engl J Med. 2015 372 1185 1186 10.1056/NEJMp1501964 25689017 \n52. Gutman S Kessler LG The US Food and Drug Administration perspective on cancer biomarker development Nat Rev Cancer 2006 6 7 565 571 10.1038/nrc1911 16794639 \n53. Fridlyand J Simon RM Walrath JC Considerations for the successful co-development of targeted cancer therapies and companion diagnostics Nat Rev Drug Discov. 2013 12 10 743 755 10.1038/nrd4101 24008432 \n54. Martinelli G Montoro J Vanazzi A Chlorambucil-rituximab as first-line therapy in patients affected by follicular non-Hodgkin’s lymphoma: a retrospective single-centre study Hematol Oncol 2015 33 4 129 135 10.1002/hon.2154 25047267 \n55. Rigacci L Nassi L Puccioni M Rituximab and chlorambucil as first-line treatment for low-grade ocular adnexal lymphomas Ann Hematol 2007 86 8 565 568 10.1007/s00277-007-0301-y 17483948 \n56. Tannock IF Hickman JA Limits to personalized cancer medicine N Engl J Med 2016 375 13 1289 1294 10.1056/NEJMsb1607705 27682039\n\n",
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"journal": "Experimental hematology & oncology",
"keywords": "Drug resistance prediction; Long-time remission; Molecular classification; Rituximab palliation; Transformed lymphoma",
"medline_ta": "Exp Hematol Oncol",
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"other_id": null,
"pages": "3",
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"pmid": "28097046",
"pubdate": "2017",
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"title": "Molecular classification of tissue from a transformed non-Hogkin's lymphoma case with unexpected long-time remission.",
"title_normalized": "molecular classification of tissue from a transformed non hogkin s lymphoma case with unexpected long time remission"
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"abstract": "This report preliminarily evaluates the efficacy and safety of cladribine, cytarabine, mitoxantrone, and granulocyte colony-stimulating factor (CLAG-M) as bridging therapy to myeloablative allogeneic hematopoietic cell transplantation (allo-HCT) in the treatment of patients with refractory or relapsed acute myeloid leukemia. Five patients with high-risk refractory or relapsed acute myeloid leukemia received the CLAG-M regimen and subsequent bridging to myeloablative allo-HCT between December 2014 and August 2015 in our hospital. The CLAG-M regimen consisted of cladribine 5 mg/m2 on days 1-5, cytarabine 2 g/m2 on days 1-5, granulocyte-colony stimulating factor 300 μg on days 0-5, and mitoxantrone 10 mg on days 1-5. At 3-8 days after CLAG-M, patients accepted myeloablative allo-HCTs. One patient (20%) died before stem cell infusion from treatment toxicity. Four patients (80%) underwent allo-HCT from matched sibling or haploidentical donors and all achieved complete remission. The median follow-up was 25 months (range, 22-31). Three patients (60%) survived, and 1 patient (20%) died owing to relapse 22 months after transplantation. Two patients (40%) among survivors achieved 2-year disease-free survival. The other survivor, who had survived for 31 months, experienced isolated central nervous system relapse 4 months after transplantation, but was cured by intrathecal injecting and cranial radiotherapy. CLAG-M bridging to myeloablative allo-HCT might be a well-tolerated and highly effective salvage regimen in patients with poor risk refractory or relapsed acute myeloid leukemia.",
"affiliations": "Department of Hematology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.;Department of Hematology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.;Department of Hematology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.;Department of Hematology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.;Department of Blood Transfusion, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.;Department of Hematology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. Electronic address: lixudong_sys@163.com.",
"authors": "Zhang|J|J|;Sun|Y|Y|;Zhang|X|X|;Long|B|B|;Lu|Y|Y|;Li|X|X|",
"chemical_list": "D003561:Cytarabine; D016179:Granulocyte Colony-Stimulating Factor; D017338:Cladribine; D008942:Mitoxantrone",
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"issue": "50(1)",
"journal": "Transplantation proceedings",
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"mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D017338:Cladribine; D003131:Combined Modality Therapy; D003561:Cytarabine; D018572:Disease-Free Survival; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008942:Mitoxantrone; D009364:Neoplasm Recurrence, Local; D012074:Remission Induction; D016879:Salvage Therapy; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "246-249",
"pmc": null,
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"pubdate": "2018",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": null,
"title": "Treatment of High-Risk Acute Myeloid Leukemia With Cladribine, Cytarabine, Mitoxantrone, and Granulocyte Colony-Stimulating Factor Then Subsequent Bridging to Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation: A Case Series.",
"title_normalized": "treatment of high risk acute myeloid leukemia with cladribine cytarabine mitoxantrone and granulocyte colony stimulating factor then subsequent bridging to myeloablative allogeneic hematopoietic stem cell transplantation a case series"
} | [
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"companynumb": "CN-PFIZER INC-2018070692",
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"abstract": "OBJECTIVE\nWe used a clinically oriented phenotype-first approach to identify patients with VEXAS syndrome from a single-center cohort of Italian patients with vasculitis.\n\n\nMETHODS\nThe clinical records of 147 consecutive male patients followed in our vasculitis clinic from 2013 to date were retrospectively reviewed. All patients with a diagnosis of vasculitis and inflammatory manifestations resistant to treatment, persistently elevated inflammatory markers, and hematologic abnormalities were identified. Bone marrow aspirates were reviewed for the presence of vacuoles. Sequencing of UBA1 was performed using genomic DNA from peripheral blood leukocytes or bone marrow tissue.\n\n\nRESULTS\n7 patients with vasculitis and concomitant features of VEXAS syndrome were identified. A final diagnosis of VEXAS syndrome was made in 3 of the 5 patients who underwent sequencing of UBA1 (for 1 patient it was a post-mortem diagnosis). All 3 patients had evidence of the characteristic vacuoles at bone marrow aspirate, and all 3 patients met the definite WHO criteria for myelodysplastic syndrome. Cytogenetic analysis showed a normal karyotype in all 3 patients. We report the first case of VEXAS syndrome associated with ANCA-associated vasculitis.\n\n\nCONCLUSIONS\nOur data emphasize the need to consider VEXAS syndrome when evaluating patients with many different forms of systemic vasculitis. The novel association between VEXAS syndrome and ANCA associated vasculitis needs further investigations.",
"affiliations": "Rheumatology Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy.;Rheumatology Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy.;Rheumatology Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy.;Molecular Biology Laboratory, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy.;Molecular Biology Laboratory, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy.;Clinical Chemistry and Endocrinology Laboratory, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy.;Clinical Chemistry and Endocrinology Laboratory, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy.;Clinical Chemistry and Endocrinology Laboratory, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy.;Rheumatology Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy.;National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.;National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.;National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.;Rheumatology Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy.;Rheumatology Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy.;Rheumatology Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy.",
"authors": "Muratore|Francesco|F|;Marvisi|Chiara|C|;Castrignanò|Paola|P|;Nicoli|Davide|D|;Farnetti|Enrico|E|;Bonanno|Orsola|O|;Longo|Rosina|R|;Zaldini|Piera|P|;Galli|Elena|E|;Balanda|Nicholas|N|;Beck|David B|DB|;Grayson|Peter C|PC|https://orcid.org/0000-0002-8269-9438;Pipitone|Nicolò|N|;Boiardi|Luigi|L|;Salvarani|Carlo|C|https://orcid.org/0000-0003-3708-3148",
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"doi": "10.1002/art.41992",
"fulltext": "\n==== Front\nArthritis Rheumatol\nArthritis Rheumatol\n10.1002/(ISSN)2326-5205\nART\nArthritis & Rheumatology (Hoboken, N.j.)\n2326-5191\n2326-5205\nWiley Periodicals, Inc. Boston, USA\n\n34611997\n10.1002/art.41992\nART41992\nBrief Report\nVasculitis\nBrief Report\nVEXAS Syndrome: A Case Series From a Single‐Center Cohort of Italian Patients With Vasculitis\nVEXAS SYNDROME IN VASCULITIS\nMURATORE ET AL\nMuratore Francesco 1\nMarvisi Chiara 2\nCastrignanò Paola 2\nNicoli Davide 1\nFarnetti Enrico 1\nBonanno Orsola 1\nLongo Rosina 1\nZaldini Piera 1\nGalli Elena 2\nBalanda Nicholas 3\nBeck David B. 3\nGrayson Peter C. https://orcid.org/0000-0002-8269-9438\n4\nPipitone Nicolò 1\nBoiardi Luigi 1\nSalvarani Carlo https://orcid.org/0000-0003-3708-3148\n2 Salvarani.carlo@ausl.re.it\n\n1 Azienda Unità Sanitaria Locale‐IRCCS di Reggio Emilia Reggio Emilia Italy\n2 Azienda Unità Sanitaria Locale‐IRCCS di Reggio Emilia, Reggio Emilia, Italy, and Università di Modena e Reggio Emilia Modena Italy\n3 National Human Genome Research Institute NIH Bethesda Maryland\n4 National Institute of Arthritis and Musculoskeletal and Skin Diseases NIH Bethesda Maryland\n* Address correspondence to Carlo Salvarani, MD, Department of Rheumatology, Azienda Unità Sanitaria Locale‐IRCCS di Reggio Emilia, Viale Risorgimento 80, 42123 Reggio Emilia, Italy. Email: Salvarani.carlo@ausl.re.it.\n\n03 3 2022\n4 2022\n74 4 10.1002/art.v74.4 665670\n19 8 2021\n03 6 2021\n01 10 2021\n© 2021 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.\n\nObjective\n\nTo identify patients with VEXAS syndrome (vacuoles, E1 enzyme, X‐linked, autoinflammatory, somatic syndrome) from a single‐center cohort of Italian patients with vasculitis, using a clinically oriented phenotype‐first approach.\n\nMethods\n\nWe retrospectively reviewed the clinical records of 147 consecutive male patients followed up in our vasculitis clinic from 2013 to date. All patients with a diagnosis of vasculitis and treatment‐resistant manifestations of inflammation, persistently elevated inflammation markers, and hematologic abnormalities were identified. Bone marrow aspirates were examined for the presence of vacuoles. Sequencing of ubiquitin‐activating enzyme E1 (UBA‐1) was performed using genomic DNA from peripheral blood leukocytes or bone marrow tissue.\n\nResults\n\nSeven patients with vasculitis and concomitant features of VEXAS syndrome were identified. A final diagnosis of VEXAS syndrome was made in 3 of the 5 patients who underwent sequencing of UBA‐1 (diagnosis was made postmortem for 1 patient). In all 3 patients, examination of the bone marrow aspirate revealed vacuoles characteristic of VEXAS syndrome, and all 3 patients met the definitive World Health Organization criteria for myelodysplastic syndrome. Cytogenetic analysis showed normal karyotypes in all 3 patients.\n\nConclusion\n\nTo our knowledge, this is the first report of VEXAS syndrome associated with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis. Our data emphasize the need to consider VEXAS syndrome when evaluating patients with various forms of systemic vasculitis. The novel association between VEXAS syndrome and ANCA‐associated vasculitis reported herein warrants further investigation.\n\nsource-schema-version-number2.0\ncover-dateApril 2022\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.2.0 mode:remove_FC converted:07.10.2022\nDrs. Muratore and Marvisi contributed equally to this work.\n\nAuthor disclosures are available at https://onlinelibrary.wiley.com/action/downloadSupplement?doi=10.1002%2Fart.41992&file=art41992‐sup‐0001‐Disclosureform.pdf.\n==== Body\npmcINTRODUCTION\n\nUsing a genotype‐first approach, researchers recently identified somatic mutations affecting methionine 41 in the X‐linked gene UBA1, which encodes ubiquitylation initiating E1 enzyme, in men with late‐onset, treatment‐refractory inflammatory syndrome and hematologic abnormalities. Clinical findings included recurrent fever, skin involvement, pulmonary infiltrate, ear and nose chondritis, venous thromboembolism, hematologic abnormalities, and bone marrow vacuoles. Most of the patients in this population met the diagnostic criteria for various inflammatory syndromes and/or hematologic conditions, including relapsing polychondritis, myelodysplastic syndrome (MDS), polyarteritis nodosa, and giant cell arteritis. This disorder was named VEXAS syndrome (vacuoles, E1 enzyme, X‐linked, autoinflammatory, somatic syndrome) (1). Since the initial description of the syndrome, pathogenic UBA‐1 variants have been identified in 2 cohorts of patients with relapsing polychondritis (7.6% and 69% of cases, respectively) (2, 3). The aim of the present study was to use a clinically oriented, phenotype‐first approach to identify patients with VEXAS syndrome in a single‐center cohort of Italian patients with vasculitis.\n\nPATIENTS AND METHODS\n\nStudy subjects\n\nTo identify patients with suspected/confirmed vasculitis and clinical features of VEXAS syndrome, the clinical records of all consecutive male patients followed up in our vasculitis clinic from 2013 to date were retrospectively reviewed. The vasculitis clinic is part of the division of rheumatology at the Hospital of Reggio Emilia, which is a large tertiary care referral center for Italian patients with vasculitides.\n\nPatients satisfying all the following criteria were included in the study: 1) recurrent fever and at least 1 of the following: skin involvement, pulmonary infiltrate, ear or nose chondritis, or venous thromboembolism; 2) a C‐reactive protein (CRP) level of >20 mg/liter and at least 1 of the following: macrocytic anemia (hemoglobin value <12 gm/dl and mean corpuscular volume [MCV] >100 fl), thrombocytopenia (platelet count <130.000/mm3), neutropenia (neutrophil count <1.500/mm3), or a hematologic diagnosis of myelodysplastic syndrome (MDS); and 3) failure to respond to at least 1 synthetic or biologic disease‐modifying antirheumatic drug (DMARD) and ongoing need for glucocorticoid therapy. Bone marrow aspirates from all patients included in the study were reviewed for the presence of the characteristic vacuoles restricted to myeloid and erythroid precursor cells (1). Sequencing of UBA1 was performed using genomic DNA from peripheral blood leukocytes or bone marrow tissue.\n\nEthics considerations\n\nThe study was approved by the Reggio Emilia Provincial Ethics Committee. Written informed consent was obtained from all patients or their legal guardians.\n\nGenetic screening\n\nGenomic DNA was obtained from peripheral whole blood and formalin‐fixed paraffin‐embedded slides from bone marrow biopsies according to the standard procedures of the Maxwell 16 DNA extraction kit (Promega). We designed a new primer pair using Primer3Plus software to amplify a 251‐bp region of UBA1 exon 3 containing a mutation at p.Met41* (5′‐TGGGTGGGAAAGTCTTTTGT‐3′ [forward] and 5′‐CTGCCAGGTTAGGGGGTACT‐3′ [reverse]). Sequencing was performed on an Applied Biosystems 3500 Dx Series DNA analyzer using an ABI Prism BigDye Terminator v3.1 kit.\n\nTo verify our findings, additional whole blood and bone marrow samples from the patients were sent to the National Human Genome Research Institute laboratory at the National Institutes of Health. All UBA1 mutations we found were confirmed.\n\nIn 1 individual (patient 2) who was not shown to have a UBA1 mutation by Sanger sequencing, exome sequencing was performed to an average coverage of 100× (1). DNA raw reads were aligned to the human genome reference GRCh38 using BWA‐MEM2 (4). Somatic variant calling was performed on aligned reads using the Genome Analysis Toolkit Mutect2 (5). Germline variant assessment in UBA1 was performed using the Integrative Genomics Viewer.\n\nRESULTS\n\nDuring the study period, 147 male patients were followed up in our vasculitis clinic. Of the 147 patients, 142 received the following diagnoses: large vessel vasculitis (55 patients), antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (36 patients), Behçet's syndrome (30 patients), primary central nervous system vasculitis (7 patients), cryoglobulinemic vasculitis (5 patients), polyarteritis nodosa (4 patients), IgA vasculitis (3 patients), and relapsing polychondritis (2 patients). Five additional patients referred for suspected vasculitis (3 for suspected Behçet's syndrome and 2 for suspected polyarteritis nodosa) received a final diagnosis of undifferentiated inflammatory syndrome with vasculitis features (6) when a vasculitis diagnosis could not be confirmed.\n\nSeven of the 147 patients satisfied the inclusion criteria and were included in the study. Demographic and clinical characteristics of these patients are reported in Table 1. Patient 1 died before VEXAS syndrome had been described, and no bone marrow tissue or peripheral blood samples were available for genetic screening. Bone marrow aspirates from patient 2 did not show evidence of vacuolization, and genetic screening, both by Sanger and exome sequencing, did not reveal the previously reported pathogenic UBA1 variant (2) or any candidate disease‐causing variants. Examination of bone marrow aspirates from both patient 3 and patient 4 revealed evidence of vacuolization restricted to myeloid and erythroid precursor cells. Genetic screening by Sanger sequencing did not reveal the previously reported pathogenic UBA1 variants in patient 3, and exome sequencing was not performed in this patient because there was not enough DNA available. Genetic screening was not performed in patient 4 because samples of bone marrow tissue or peripheral blood were not available. Mosaicism in other tissues was not investigated for patients 3 and 4. Finally, examination of bone marrow aspirates and genetic screening revealed vacuolization and UBA1 somatic mutations in patients 5, 6, and 7. These patients received a final diagnosis of VEXAS syndrome (the diagnosis of patient 5 was made postmortem).\n\nTable 1 Demographic and clinical characteristics of the identified patients*\n\n\tPatient\t\nCharacteristic\t1\t2\t3\t4\t5\t6\t7\t\nAge at onset, years\t76\t46\t53\t72\t67\t72\t64\t\nDeath (age at death, years)\t+ (79)\t–\t+ (59)\t+ (74)\t+ (75)\t–\t–\t\nUBA1 mutation\tNT\t–\t–\tNT\tc.122 T>C, p.Met41Thr\tc.121 A>G, p.Met41Val\tc.122 T>C, p.Met41Thr\t\nKey features\t\t\t\t\t\t\t\t\nFever\t+\t+\t+\t+\t+\t+\t+\t\nSkin involvement\t+\t–\t+\t+\t+\t–\t+\t\nPulmonary infiltrates\t–\t+\t+\t+\t+\t+\t+\t\nEar/nose chondritis\t–\t–\t–\t–\t–\t–\t+\t\nDVT\t+\t+\t–\t+\t+\t–\t+\t\nBone marrow vacuoles\tNT\t–\t+\t+\t+\t+\t+\t\nMacrocytic anemia\t+\t–\t+\t+\t+\t+\t+\t\nOther\tLobular panniculitis, testicular pain\tGenital aphthosis\t\tTesticular pain\tArthritis, testicular pain\t\tArthritis\t\nLaboratory findings\t\t\t\t\t\t\t\t\nCRP, mg/liter\t180\t41\t153\t120\t180\t250\t140\t\nESR, mm/hour\t83\t63\t50\t133\t112\t137\t78\t\nTreatment\t\t\t\t\t\t\t\t\nsDMARDs\tAZA\tAZA, CYC\tMTX, AZA\tAZA\tAZA\tCYC, MMF\tMTX, AZA\t\nb/tsDMARDs\tADA, IFX, ANK\tIFX\tRTX\n\n\t–\tANK, RTX\tRTX\tupadacitinib\n\n\t\nGCs\t+\t+\t+\n\n\t+\t+\t+\t+\n\n\t\nClinical diagnosis\t\t\t\t\t\t\t\t\nBehçet's syndrome\t–\t+\t–\t–\t–\t–\t–\t\nRP\t–\t–\t–\t–\t–\t–\t+\t\nLCV\t–\t–\t–\t+\t–\t–\t–\t\nAAV\t–\t–\t–\t–\t–\t+\t–\t\nUIS\t+\t–\t+\t–\t+\t–\t–\t\nMDS\t–\t–\t+\t+\t+\t+\t+\t\n* NT = not tested; DVT = deep venous thrombosis; CRP = C‐reactive protein; ESR = erythrocyte sedimentation rate; sDMARDs = synthetic disease‐modifying antirheumatic drugs; AZA = azathioprine; CYC = cyclophosphamide; MTX = methotrexate; MMF = mycophenolate mofetil; b/tsDMARDs = biologic/targeted synthetic disease‐modifying antirheumatic drugs; ADA = adalimumab; IFX = infliximab; ANK = anakinra; RTX = rituximab; GCs = glucocorticoids; RP = relapsing polychondritis; LCV = leukocytoclastic vasculitis; AAV = antineutrophil cytoplasmic antibody–associated vasculitis; UIS = undifferentiated inflammatory syndrome with vasculitis features; MDS = myelodysplastic syndrome.\n\nCase series\n\nPatient 5\n\nPatient 5, a 71‐year‐old man, was admitted to our vasculitis clinic with relapsing superficial and deep venous thrombosis, arthritis of the wrists, recurrent fever, weight loss, dyspnea, skin lesions, and testicular pain. These symptoms had begun 2 years prior and responded to high doses of glucocorticoids, but recurred each time the prednisone dosage was reduced to <15 mg/day. Laboratory tests revealed increased levels of acute‐phase reactants and macrocytic anemia (Table 1). Skin lesions on the lower leg and upper thigh of both legs were found to be erythematous purpuric, slightly infiltrated macules. Skin biopsy showed mild lymphocytic and granulocytic infiltration of the upper dermis without vasculitis. Computed tomography (CT) scan of the chest revealed diffuse bilateral opacities in the lungs. Bronchoalveolar lavage fluid cultures were negative. Examination of bone marrow aspirate revealed findings consistent with MDS with multilineage dysplasia. An initial diagnosis of undifferentiated inflammatory syndrome with vasculitis features was made, and treatment with prednisone (50 mg/day) and azathioprine (2 mg/kg/day) was started.\n\nAfter 1 year, anakinra at 100 mg/day was added to the patient's treatment regimen due to the recurrence of inflammatory symptoms with prednisone dosages of <25 mg/day. Treatment with anakinra was stopped after a few injections because the patient experienced a severe cutaneous reaction. A course of 2 gm of rituximab (2 doses of 1 gm given 2 weeks apart) was subsequently started with no clinical response; thus, high doses of glucocorticoids were maintained. The patient died in 2019 at the age of 74 years as a result of pulmonary complications. After the description of VEXAS syndrome in 2020 (1), reexamination of the bone marrow aspirate revealed numerous vacuoles in the myeloid and erythroid precursor cells, and DNA sequencing using bone marrow tissue revealed a pathogenic UBA1 somatic mutation.\n\nPatient 6\n\nPatient 6, a 75‐year‐old man with a diagnosis of microscopic polyangiitis (MPA), was referred to our vasculitis clinic with persistent fever, weight loss, and dyspnea. MPA had been diagnosed 3 years prior based on renal biopsy showing necrotizing and crescentic glomerulonephritis, the presence of myeloperoxidase‐ANCAs (MPO‐ANCAs) (28 units/ml [normal range <3.5]), chest CT scan showing diffuse ground‐glass opacities, and systemic symptoms. At the onset of symptoms, laboratory evaluations revealed rapidly progressive renal failure, increased levels of acute‐phase reactants, and macrocytic anemia (Table 1). Examination of bone marrow aspirate revealed MDS with single‐lineage dysplasia. The patient was started on prednisone (1 mg/kg/day) and oral cyclophosphamide (1.5 mg/kg/day). After 3 months, MPO‐ANCAs disappeared, treatment with cyclophosphamide was stopped, and the prednisone dosage was tapered to a maintenance regimen of 5 mg/day.\n\nTwo years later, when the patient first presented to us, he was still taking prednisone 5 mg daily and he reported recurrence of fever, weight loss and dyspnea in the last 3 months. Laboratory tests showed increased levels of acute‐phase reactants and pancytopenia and results of ANCA testing remained negative. An extensive evaluation excluded infections. Examination of a second bone marrow aspirate revealed findings consistent with MDS with multilineage dysplasia with ring sideroblasts. The prednisone dosage was increased to 1 mg/kg/day and a course of rituximab (2 doses of 1 gm given 2 weeks apart) was given because an MPA flare was suspected. Systemic symptoms recurred at each reduction of the prednisone dosage to <25 mg/day. The patient remained ANCA negative.\n\nAfter 9 months, the patient was started on mycophenolate mofetil (2 gm/day) and intravenous immunoglobulin (0.4 gm/kg/day for 5 consecutive days every 4 weeks). Six months later, he developed fever and dyspnea became more severe. Chest CT scan showed worsened ground‐glass opacities and pleural effusion. Intravenous cyclophosphamide was started (7.5 mg/kg) according to the European Vasculitis Study Group protocol, without clinical response. The patient remained dependent on high‐dose glucocorticoids (25 mg/day of prednisone). After the description of VEXAS syndrome in 2020 (1), the 2 bone marrow aspirates from the patient were reviewed and both revealed numerous vacuoles in the myeloid and erythroid precursor cells. DNA sequencing using the last bone marrow aspirate showed a pathogenic mutation in the UBA1 region and confirmed the diagnosis of VEXAS syndrome.\n\nPatient 7\n\nPatient 7, a 66‐year‐old man, was referred to our vasculitis clinic in 2019 with fever, deep venous thrombosis, arthritis of the wrists, dyspnea, painful migratory subcutaneous nodules, skin lesions, and recurrent episodes of ear and nose chondritis. These symptoms had begun 2 years prior and responded to high doses of glucocorticoids, but recurred each time the prednisone dosage was reduced to <15 mg/day. Laboratory tests revealed increased levels of acute‐phase reactants and macrocytic anemia (Table 1). Examination of bone marrow aspirate revealed features suggestive of MDS with multilineage dysplasia. Skin lesions on the upper thighs were found to be erythematous purpuric, slightly infiltrated macules. A diagnosis of relapsing polychondritis was made, and the patient was started on prednisone (0.5 mg/kg/day) and methotrexate (15 mg/week). The patient's systemic and cutaneous manifestations recurred each time the prednisone dosage was reduced to <15 mg/day. A skin biopsy showed lymphocytic and granulocytic infiltration of small vessels with fibrinoid necrosis. CT scan of the chest revealed diffuse pulmonary infiltrates. Treatment with methotrexate was stopped and the patient was started on azathioprine (2 mg/kg/day).\n\nIn December 2020, a few months after azathioprine treatment was begun, he was admitted to our rheumatology department with swelling of the neck, periorbital edema, diffuse cutaneous nodules, and fever. Examination of bone marrow aspirate revealed vacuoles in the erythroid and myeloid precursors and findings consistent with MDS with multilineage dysplasia (Figures 1A and B). DNA sequencing of the peripheral blood showed a pathogenic mutation in the UBA1 region and confirmed the diagnosis of VEXAS syndrome. The patient was started on upadacitinb (15 mg/day) and prednisone (50 mg/day). The prednisone dosage was progressively reduced, and in June 2021 the patient had a flare of nasal chondritis while being treated with upadacitinb 15 mg/day and prednisone 10 mg/day. Prednisone was increased to 25 mg/day and symptoms resolved rapidly. At the patient's last follow‐up (July 2021), his disease was in remission with upadacitinib 15 mg/day and prednisone 12.5 mg/day. The CRP level was 18 mg/liter, the hemoglobin level was 12.2 gm/dl (MCV 113 fl), and the ferritin level was 361 ng/ml.\n\nFigure 1 A, Bone marrow aspirate from patient 7, showing evidence of dysplasia and cytoplasmic vacuolization of the erythroid and myeloid precursor cells. B, Higher‐magnification view of the bone marrow aspirate from patient 7, showing dysplasia (neutrophils with pseudo Pelger‐Huët anomaly) and cytoplasmic vacuolization of the erythroid precursor cells (blue arrows) and myeloid precursor cells (red arrow). Stained with May‐Grünwald‐Giemsa stain; original magnification × 400 in A; × 1,000 in B.\n\nDISCUSSION\n\nUsing a clinically oriented phenotype‐first approach, we identified 7 patients with vasculitis and concomitant treatment‐resistant systemic manifestations and hematologic abnormalities consistent with MDS. A final diagnosis of VEXAS syndrome was made in 60% of patients (3 of 5) who underwent sequencing of UBA1. In all 3 patients, examination of bone marrow aspirate revealed evidence of the characteristic vacuoles. The 2 patients who were not shown by genetic sequencing to have previously reported pathogenic UBA1 variants were younger than the patients with a UBA1 mutation, and only 1 patient (patient 3) had evidence of vacuoles indicative of VEXAS syndrome upon examination of bone marrow aspirate.\n\nSomatic mutations in UBA1 outside of codon 41 have recently been reported as a cause of VEXAS syndrome, but we could not test for these mutations in patient 3 because there was not enough DNA available to perform exome sequencing (7, 8, 9); therefore, the diagnosis of VEXAS syndrome cannot be completely ruled out. Examination of bone marrow tissue from another patient (patient 4) also showed the presence of vacuoles characteristic of VEXAS syndrome, but a DNA sample was unavailable, so the presence of pathogenic UBA1 variants could not be determined. Our data confirmed that, in the right clinical setting, the presence of vacuoles in bone marrow aspirate is quite specific for VEXAS syndrome. Genetic sequencing for somatic UBA1 mutations should be performed in all patients with treatment‐resistant inflammatory syndrome, hematologic abnormalities, and evidence of vacuoles.\n\nIn the present study, definitive World Health Organization criteria for MDS were met by all 5 patients with evidence of vacuoles and by all 3 patients with a final diagnosis of VEXAS syndrome, and MDS diagnosis was confirmed by an expert hemopathologist (10). Investigations for mosaicism in other tissues were not performed in the 2 patients with MDS without VEXAS syndrome. Cytogenetic analysis showed normal karyotypes in all 5 patients. The higher proportion of MDS among patients in the present study compared with the original series described by Beck et al (6 of 25 patients [24%]) (1) may denote the progressive nature of hematologic abnormalities that can evolve into overt hematologic malignancy. Early detection of UBA1 mutations may therefore identify patients with rheumatic diseases who may benefit from increased hematologic surveillance (2).\n\nOur study confirms that patients with VEXAS syndrome were resistant to multiple DMARDs, and high‐dose glucocorticoids were the only treatment that ameliorated severe inflammatory symptoms in the patients studied. Nevertheless, most of the patients died of disease‐related causes or complications related to treatment. Transcriptome analysis of the peripheral blood and analysis of cytokines in the serum of patients with VEXAS syndrome showed highly activated inflammatory signatures in multiple pathways, including tumor necrosis factor, interleukin‐6, and interferon‐γ (1). Components of the JAK/STAT pathway have been shown to be mutated or up‐regulated in several hematologic malignancies, and JAK inhibitors have been approved for use in the treatment of some blood disorders (8). JAK inhibitors target multiple inflammatory cytokines simultaneously, and thus in complex inflammatory states such as VEXAS, JAK inhibitors may be more effective than inhibitors of a single cytokine. We therefore decided to treat patient 7 with the selective JAK1 inhibitor upadacitinib. The drug showed a steroid‐sparing effect and a good safety profile. Further studies evaluating the efficacy and safety of JAK inhibitors in the treatment of patients with VEXAS syndrome are needed.\n\nBecause VEXAS syndrome is a newly identified genetic disease, knowledge of the complete clinical spectrum of the disease is continuously expanding. To our knowledge, patient 6 in our study represents the first reported case of VEXAS syndrome associated with ANCA‐associated vasculitis. Patient 6 had concomitant manifestations of rapidly progressive renal failure, pulmonary involvement, inflammatory manifestations, anti–MPO‐ANCA positivity, and myelodysplastic features. A diagnosis of MPA and MDS was made. Despite an initial period of remission, the patient developed inflammatory manifestations resistant to multiple immunosuppressants and requiring high doses of glucocorticoids. Reexamination of the 2 bone marrow aspirates (the first aspiration performed when the MPA diagnosis was made and the second 3 years later when systemic manifestations recurred) revealed numerous vacuoles in the myeloid and erythroid precursor cells. The pathogenic UBA1 somatic mutation was found using a DNA sample from the second bone marrow aspirate. Unfortunately, the first bone marrow aspirate was unavailable for testing UBA1 mutations.\n\nTaken together, these findings support the hypothesis of a connection between ANCA‐associated vasculitis and VEXAS syndrome, and in our patient a unique evolving condition cannot be excluded, particularly since necrotizing and crescentic glomerulonephritis has not been described in VEXAS syndrome. The link between these 2 conditions may be related to proinflammatory neutrophil activation with dysregulated neutrophil extracellular trap (NET) formation. Increasing research evidence suggests that dysregulated NET formation is central to ANCA‐associated vasculitis pathogenesis (11), and functional studies of neutrophils obtained from patients with VEXAS syndrome have recently shown enhanced spontaneous NET formation, findings that confirm that proinflammatory neutrophil activation is also dysregulated in VEXAS syndrome (1).\n\nThe main limitation of this study is its retrospective nature. There may have been some selection bias related to the inclusion criteria we used. First, because more than half of the reported patients with VEXAS syndrome do not meet criteria for MDS (12), we could have excluded some patients who did not have significant hematologic abnormalities. Furthermore, since all patients were identified within a vasculitis clinic, there was likely selection bias toward identification of VEXAS syndrome patients with severe inflammatory disease.\n\nIn conclusion, our findings emphasize the need to consider VEXAS syndrome when evaluating patients with many different forms of systemic vasculitis. The novel association between VEXAS syndrome and ANCA‐associated vasculitis warrants further investigation.\n\nAUTHOR CONTRIBUTIONS\n\nAll authors contributed to drafting or critically revising the article for intellectual content and approved the final version of the article. Dr. Salvarani had full access to all of the data in the study and takes responsibility for the integrity of the data analysis.\n\nStudy conception and design\n\nMuratore, Marvisi, Beck, Grayson, Pipitone, Salvarani.\n\nAcquisition of data\n\nMuratore, Marvisi, Castrignanò, Nicoli, Farnetti, Bonanno, Longo, Galli, Boiardi.\n\nAnalysis and interpretation of data\n\nMuratore, Marvisi, Nicoli, Farnetti, Bonanno, Longo, Zaldini, Balanda, Beck, Grayson, Pipitone, Salvarani.\n\nSupporting information\n\nDisclosureform\n\nClick here for additional data file.\n\nACKNOWLEDGMENTS\n\nOpen Access Funding provided by Universita degli Studi di Modena e Reggio Emilia within the CRUI‐CARE Agreement.\n==== Refs\nREFERENCES\n\n1 Beck DB , Ferrada MA , Sikora KA , Ombrello AK , Collins JC , Pei W , et al. Somatic mutations in UBA1 and severe adult‐onset autoinflammatory disease. N Engl J Med 2020;383 :2628–38.33108101\n2 Ferrada MA , Sikora KA , Luo Y , Wells KV , Patel B , Groarke EM , et al. Somatic mutations in UBA1 define a distinct subset of relapsing polychondritis patients with VEXAS. Arthritis Rheumatol 2021;73 :1886–95.33779074\n3 Tsuchida N , Kunishita Y , Uchiyama Y , Kirino Y , Enaka M , Yamaguchi Y , et al. Pathogenic UBA1 variants associated with VEXAS syndrome in Japanese patients with relapsing polychondritis. Ann Rheum Dis 2021 doi: 10.1136/annrheumdis-2021-220089. E‐pub ahead of print.\n4 Md V , Misra S , Li H , Aluru S . Efficient architecture‐aware acceleration of BWA‐MEM for multicore systems. Proc‐2019 IEEE 33rd Int Parallel Distrib Process Symp IPDPS 2019 2019:314–24.\n5 Cibulskis K , Lawrence MS , Carter SL , Sivachenko A , Jaffe D , Sougnez C , et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat Biotechnol 2013;31 :213–9.23396013\n6 Lamprecht P , Pipitone N , Gross WL . Unclassified vasculitis [review]. Clin Exp Rheumatol 2011;29 Suppl 64 :S81–5.\n7 Poulter JA , Collins JC , Cargo C , de Tute RM , Evans P , Cardona DO , et al. Novel somatic mutations in UBA1 as a cause of VEXAS syndrome. Blood 2021;137 :3676–81.33690815\n8 Oganesyan A , Jachiet V , Chasset F , Hirsch P , Hage‐Sleiman M , Fabiani B , et al. VEXAS syndrome: still expanding the clinical phenotype. Rheumatology (Oxford) 2021;60 :e321–3.33693570\n9 Bourbon E , Heiblig M , Gerfaud‐Valentin M , Barba T , Durel CA , Lega JC , et al. Therapeutic options in Vexas syndrome: insights from a retrospective series. Blood 2021;137 :3682–4.33619558\n10 Arber DA , Orazi A , Hasserjian R , Thiele J , Borowitz MJ , Le Beau MM , et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016;127 :2391–405.27069254\n11 Nakazawa D , Masuda S , Tomaru U , Ishizu A . Pathogenesis and therapeutic interventions for ANCA‐associated vasculitis [review]. Nat Rev Rheumatol 2019;15 :91–101.30542206\n12 Obiorah IE , Beck DB , Wang W , Ombrello A , Ferrada MA , Wu Z , et al. Myelodysplasia and bone marrow manifestations of somatic UBA1 mutated autoinflammatory disease. Blood 2020;136 :20–1.\n\n",
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"issue": null,
"journal": "Arthritis & rheumatology (Hoboken, N.J.)",
"keywords": "ANCA; VEXAS syndrome; autoinflammatory syndrome; myelodysplastic syndrome; vasculitis",
"medline_ta": "Arthritis Rheumatol",
"mesh_terms": null,
"nlm_unique_id": "101623795",
"other_id": null,
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"pmid": "34611997",
"pubdate": "2021-10-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "VEXAS syndrome: a case series from a single-center cohort of Italian patients with vasculitis.",
"title_normalized": "vexas syndrome a case series from a single center cohort of italian patients with vasculitis"
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{
"abstract": "Mucosal angioedema of the face, lips, tongue, and throat is a well-recognized adverse reaction to angiotensin-converting enzyme (ACE) inhibitors that is experienced by a minority of patients. Rarely, this angioedema can involve the small bowel, and patients commonly present with abdominal pain and small bowel obstruction. Due to the increasing number of patients being treated for hypertension, clinicians should consider the diagnosis of small bowel angioedema secondary to ACE inhibitor use in all patients with this presentation who are using this class of medications.",
"affiliations": "At the time this article was written, Megan Melendez was a student in the PA program at Marietta (Ohio) College. She now practices at Catawba Radiology in Hickory, N.C. John M. Grosel is a radiologist at Riverside Radiology and Interventional Associates, Inc., based in Columbus, Ohio, and a McCoy professor in the PA program at Marietta College. The authors have disclosed no potential conflicts of interest, financial or otherwise.",
"authors": "Melendez|Megan|M|;Grosel|John M|JM|",
"chemical_list": "D000806:Angiotensin-Converting Enzyme Inhibitors; D004338:Drug Combinations; C091365:hydrochlorothiazide, lisinopril drug combination; D006852:Hydrochlorothiazide; D017706:Lisinopril",
"country": "United States",
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"doi": "10.1097/01.JAA.0000668864.61980.c0",
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"issn_linking": "0893-7400",
"issue": "33(8)",
"journal": "JAAPA : official journal of the American Academy of Physician Assistants",
"keywords": null,
"medline_ta": "JAAPA",
"mesh_terms": "D000799:Angioedema; D000806:Angiotensin-Converting Enzyme Inhibitors; D001772:Blood Cell Count; D004338:Drug Combinations; D057915:Drug Substitution; D006801:Humans; D006852:Hydrochlorothiazide; D007415:Intestinal Obstruction; D007421:Intestine, Small; D017706:Lisinopril; D008297:Male; D008875:Middle Aged; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "9513102",
"other_id": null,
"pages": "28-31",
"pmc": null,
"pmid": "32740111",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "ACE inhibitor-induced angioedema causing small bowel obstruction.",
"title_normalized": "ace inhibitor induced angioedema causing small bowel obstruction"
} | [
{
"companynumb": "US-MYLANLABS-2021M1015652",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"activesubstance": {
"activesubstancename": "LISINOPRIL"
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