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"abstract": "BACKGROUND\nHeritable thrombophilias are assumed important etiologies for recurrent pregnancy loss. Unlike in the Caucasian populations, protein S and protein C deficiencies, instead of Factor V Lieden and Prothrombin mutations, are relatively common in the Han Chinese population. In this study we aimed to investigate the therapeutic effect of low molecular weight heparin upon women with recurrent pregnancy loss and documented protein S deficiency.\n\n\nMETHODS\nDuring 2011-2016, 68 women with recurrent pregnancy loss (RPL) and protein S deficiency (both the free antigen and function of protein S were reduced) were initially enrolled. All the women must have experienced at least three recurrent miscarriages. After excluding those carrying balanced translocation, medical condition such as diabetes mellitus, chronic hypertension, and autoimmune disorders (including systemic lupus erythematosus and anti-phospholipid syndrome), coexisting thrombophilias other than persistent protein S deficiency (including transient low protein S level, protein C deficiency, and antithrombin III), only 51 women with RPL and sole protein S deficiency were enrolled. Initially they were prescribed low dose Aspirin (ASA: 100 mg/day) and unfortunately there were still 39 women ended up again with early pregnancy loss (12 livebirths were achieved though). Low-molecular-weight-heparin (LMWH) was given for the 39 women in a dose of 1 mg/Kg every 12 h from the day when the next clinical pregnancy was confirmed to the timing at least 24 h before delivery. The perinatal outcomes were assessed.\n\n\nRESULTS\nOf 50 treatment subjects performed for the 39 women (i.e. 11 women enrolled twice for two pregnancies), 46 singletons and one twin achieved livebirths. The successful live-birth rate in the whole series was 94 % (47/50). Nineteen livebirths delivered vaginally whereas 28 delivered by cesarean section. The cesarean delivery rate is thus 59.57 %. Emergent deliveries occurred in 3 but no postpartum hemorrhage had been noted.\n\n\nCONCLUSIONS\nOur pilot study in Taiwan, an East Asian population, indicated anti-coagulation therapy is of benefit to women with recurrent pregnancy loss who had documented sole protein S deficiency.\n\n\nBACKGROUND\nISRCTN64574169. Retrospectively registered 29 Jun 2016.",
"affiliations": "Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan.;Department of Obstetrics and Gynecology, Changhua Christian Hospital, Changhua, Taiwan.;Department of Obstetrics and Gynecology, Chang-Gung Memorial Hospital Linkou Medical Center and Chang-Gung University, Taoyuan, Taiwan.;Department of Genomic Medicine, Changhua Christian Hospital, 500 Changhua, Taiwan.;Department of Obstetrics and Gynecology, Puli Christian Hospital, Nantou, Taiwan.;Department of Obstetrics and Gynecology, Taipei Chang-Gung Memorial Hospital, Taipei, Taiwan.;Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan.;Department of Genomic Medicine, Changhua Christian Hospital, 500 Changhua, Taiwan.;Department of Obstetrics and Gynecology, Changhua Christian Hospital, Changhua, Taiwan.",
"authors": "Shen|Ming-Ching|MC|;Wu|Wan-Ju|WJ|;Cheng|Po-Jen|PJ|;Ma|Gwo-Chin|GC|;Li|Wen-Chu|WC|;Liou|Jui-Der|JD|;Chang|Cheng-Shyong|CS|;Lin|Wen-Hsiang|WH|;Chen|Ming|M|0000-0001-5076-2917",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12959-016-0118-9",
"fulltext": "\n==== Front\nThromb JThromb JThrombosis Journal1477-9560BioMed Central London 11810.1186/s12959-016-0118-9ResearchLow-molecular-weight-heparin can benefit women with recurrent pregnancy loss and sole protein S deficiency: a historical control cohort study from Taiwan Shen Ming-Ching 111710@cch.org.tw 1Wu Wan-Ju crystalwu835@gmail.com 23Cheng Po-Jen pjcheng@cgmh.org.tw 4Ma Gwo-Chin 128729@cch.org.tw 3Li Wen-Chu m84243@gmail.com 5Liou Jui-Der liou88@ms13.hinet.net 6Chang Cheng-Shyong 15120@cch.org.tw 1Lin Wen-Hsiang 397620cch@gmail.com 3http://orcid.org/0000-0001-5076-2917Chen Ming +886-4-7238595mchen_cch@yahoo.commingchenmd@gmail.com 23781 Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan 2 Department of Obstetrics and Gynecology, Changhua Christian Hospital, Changhua, Taiwan 3 Department of Genomic Medicine, Changhua Christian Hospital, 500 Changhua, Taiwan 4 Department of Obstetrics and Gynecology, Chang-Gung Memorial Hospital Linkou Medical Center and Chang-Gung University, Taoyuan, Taiwan 5 Department of Obstetrics and Gynecology, Puli Christian Hospital, Nantou, Taiwan 6 Department of Obstetrics and Gynecology, Taipei Chang-Gung Memorial Hospital, Taipei, Taiwan 7 Department of Obstetrics and Gynecology, and Department of Medical Genetics, College of Medicine, and Hospital, National Taiwan University, Taipei, Taiwan 8 Department of Life Science, Tunghai University, Taichung, Taiwan 28 10 2016 28 10 2016 2016 14 4423 4 2016 22 10 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. 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\nHeritable thrombophilias are assumed important etiologies for recurrent pregnancy loss. Unlike in the Caucasian populations, protein S and protein C deficiencies, instead of Factor V Lieden and Prothrombin mutations, are relatively common in the Han Chinese population. In this study we aimed to investigate the therapeutic effect of low molecular weight heparin upon women with recurrent pregnancy loss and documented protein S deficiency.\n\nMethods\nDuring 2011–2016, 68 women with recurrent pregnancy loss (RPL) and protein S deficiency (both the free antigen and function of protein S were reduced) were initially enrolled. All the women must have experienced at least three recurrent miscarriages. After excluding those carrying balanced translocation, medical condition such as diabetes mellitus, chronic hypertension, and autoimmune disorders (including systemic lupus erythematosus and anti-phospholipid syndrome), coexisting thrombophilias other than persistent protein S deficiency (including transient low protein S level, protein C deficiency, and antithrombin III), only 51 women with RPL and sole protein S deficiency were enrolled. Initially they were prescribed low dose Aspirin (ASA: 100 mg/day) and unfortunately there were still 39 women ended up again with early pregnancy loss (12 livebirths were achieved though). Low-molecular-weight-heparin (LMWH) was given for the 39 women in a dose of 1 mg/Kg every 12 h from the day when the next clinical pregnancy was confirmed to the timing at least 24 h before delivery. The perinatal outcomes were assessed.\n\nResults\nOf 50 treatment subjects performed for the 39 women (i.e. 11 women enrolled twice for two pregnancies), 46 singletons and one twin achieved livebirths. The successful live-birth rate in the whole series was 94 % (47/50). Nineteen livebirths delivered vaginally whereas 28 delivered by cesarean section. The cesarean delivery rate is thus 59.57 %. Emergent deliveries occurred in 3 but no postpartum hemorrhage had been noted.\n\nConclusions\nOur pilot study in Taiwan, an East Asian population, indicated anti-coagulation therapy is of benefit to women with recurrent pregnancy loss who had documented sole protein S deficiency.\n\nTrial registration\n\nISRCTN64574169. Retrospectively registered 29 Jun 2016.\n\nElectronic supplementary material\nThe online version of this article (doi:10.1186/s12959-016-0118-9) contains supplementary material, which is available to authorized users.\n\nKeywords\nAnticoagulationProtein S deficiencyThrombophiliaRecurrent miscarriagesLow-molecular-weight-heparinChanghua Christian Hospital105-CCH-PRJ-004Chen Ming issue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nHabitual abortion (defined as at least three recurrent miscarriages), namely recurrent pregnancy loss (RPL), is a condition caused by heterogeneous etiologies such as hormonal (luteal defect), chromosomal (carriers of balanced translocation), structural (Mullerian anomalies such as didelphys, bicornuate, or septate uterus), immunological (anti-phospholipid antibody or aberrations involving nature killer cells), and thrombophilia [1, 2]. Among them, heritable thrombophilias are treatable theoretically despite most published studies, including some but very limited well-conducted randomized trials, in the literature did not observe an apparent benefit by using anticoagulants to enhance the livebirth rate in women with RPL [3–9].\n\nHeritable thrombophilias ever reported with clinical significance include protein S deficiency, protein C deficiency, anti-thrombin III deficiency, Factor V Leiden mutation, and prothrombin mutation, however, there are ethnic differences: The most common heritable thrombophilias in the Caucasian populations are Factor V Leiden mutation and prothrombin mutation whereas in Taiwan, protein S, protein C, and antithrombin III deficiencies are the most common [10–14]. Despite most published reports in the literature failed to observe a beneficial effect of anti-coagulants to enhance the livebirth rates in women with RPL, it may be inappropriate to extrapolate those results, mainly based on other ethnic groups, into an East Asian population (Taiwan is a multi-ethnic group country with a predominance of Han Chinese). According to our previous studies, the most common heritable thrombophilias in the thromboembolic patients in Taiwan are protein S and protein C deficiencies [13, 14]. Meanwhile, the selection criteria and treatment protocol varied across different studies and thus we should be cautious when reading reviews based upon meta-analysis [3–5, 15].\n\nWe are keen to explore if there is any role of using anticoagulants in this group of patients in Taiwan. In order to better define the enrollment criteria, those with other confounding factors such as anti-phospholipid antibody syndrome, underlying medical conditions including autoimmune diseases, diabetes mellitus, chronic hypertension, and previous history of thromboembolism are excluded. Only nulliparous women with protein S deficiency and suffered from RPL are enrolled in this pilot study. We intended to include women with in whom protein S deficiency is the only attributable etiology, and from another point of view, to include women with protein S deficiency who were otherwise healthy (that is, without previous thromboembolic events) until adult life except suffering from RPL. In addition, in order to simplify and better understand the actual effect of anti-coagulants in the enrolled cases, we only included those receiving low-molecular-weight-heparin as the sole therapy. The livebirth rate is the primary outcome we aimed to observe in this historical cohort. Attributable causes of the failed cases, if any, will be assessed by examinations including fetal/placental pathology, immunological and genetic investigations.\n\nMethods\nPatient enrollment\nDuring 2011–2016, women suffered from at least three recurrent miscarriages who came to our clinic received a series of investigation including karyotyping, thrombophilia profile (antithrombin III, protein C, Protein S levels), and immune profile (lupus anti-coagulant to explore if she has anti-phospholipid antibody syndrome). Only those women with sole protein S deficiency, and naturally conceived, were enrolled. They were prescribed low dose Aspirin (ASA, 100 mg per day) when another new pregnancy was achieved and in those ended up again with early pregnancy loss (less than 12 complete weeks of gestation), these patients were enrolled in this cohort and would be given daily anti-coagulant treatment in the injection starting from when next pregnancy is established. It is noteworthy that since the level of protein S may decrease physiologically during pregnancy due to the estrogen effect, only those with persistent low protein S level in the non-gestational period (we enrolled only those with low levels in both protein S function and free protein S antigen (Ag)), were included. Assays adopted for protein S measurement used the functional assay by clotting based kits (the reference ranges: protein S function 63.5~149 %; free protein S antigen: 54.7~123.7 %) according to the method reported by Moraes and colleagues in 2000 [16]. Women with other heritable thromobophilias (Protein C and antithrombin III deficiency), immune problems (such as systemic lupus erythematosus, anti-phospholipid antibody syndrome), other pre-conceptional underlying medical conditions (such as diabetes mellitus and chronic hypertension), or carrying balanced translocation, were excluded. The institutional review board (IRB) of Changhua Christian Hospital had approved the study (CCH-IRB-151209).\n\nClinical management protocol\nLow-molecular-weight-heparin (enoxaparin) was given in a dose of 1 mg/Kg every 12 h from the day being enrolled to the timing a few days (at least 24 h) before delivery. Standard antenatal care was unaffected otherwise and the perinatal outcome was assessed. The patients received both the antenatal care from two of the coauthors (M Chen, an obstetrician who specializes in high-risk pregnancy, and MC Shen, a hematologist who specializes in thrombosis and hemostasis). In order to avoid the risk of postpartum hemorrhage due to emergent deliveries, which often occurs unexpectedly, the patients were either arranged for induction of labor if she chose to deliver vaginally, or scheduled cesarean section if there are obstetric indications or by their autonomous choice to choose elective cesareans. The anticoagulants were ought to be stopped at least 24 h before delivery in the ideal situation. The risk of postpartum hemorrhage as well as other side effects that may occur because of this treatment protocol were discussed and explained in great details to these patients and the informed consents were obtained. The blood coagulation profiles such as prothrombin time (PT), activated partial thromboplastin time (aPTT), or other assays to assess the status of the molecules involving the coagulation cascade were not regularly monitored. The livebirth rate is the primary outcome indicator. Secondary outcome indicators are also recorded for the obstetric complications such as premature births, low birth weight, and pre-eclampsia. The whole investigation period reported in this historical control cohort study ended at 22, May, 2016.\n\nResults\nA total of 68 patients with at least three recurrent miscarriages and having protein S deficiency (both the free antigen and the function of protein S) went to our clinics. In these 68 patients, 17 of them were further filtered out because these patients were found with heritable thromobophilias other than protein S deficiency (protein C deficiency (n = 1), antithrombin III (n = 1), immune problems (e.g., systemic lupus erythematosus (n = 2), anti-phospholipid antibody syndrome (n = 1)), or with other underlying medical conditions (e.g., diabetes mellitus (n = 1) and chronic hypertension (n = 1)), or carrying balanced translocation (n = 1). Another 9 women who only had transient low level of protein S during pregnancy were also excluded. Therefore, 51 women entered the cohort initially (12 of them enjoyed livebirths simply by being given low dose Aspirin in a dose with 100 mg per day). Of the remaining 39 women, 11 had two pregnancies being enrolled. Consequently, 50 treatment subjects were performed for the 39 women and 47 livebirths were achieved (Fig. 1). Only 3 pregnancies failed, two of which were later proved to be an aneuploidy pregnancy (trisomy 22 and monosomy X respectively) and one was ectopic pregnancy ended with tubal abortion. Of the 11 women with two pregnancies enrolled, 10 had successful two livebirths and one had one livebirth with one abortion due to trisomy 22. In 47 successful livebirths, 48 live babies were born (because there were one twin pregnancy), 19 of them delivered vaginally (40.43 %), and 28 of them delivered by cesarean section (59.57 %). Notably only 4 of the cesarean group demanded elective cesarean section due to the concern about the risk of natural births, and all the remaining 24 out of the 28 women in the cesarean group had obstetric indications. The indications include previous uterine surgery (n = 5, two are both repeated sections and entered the group twice and the first cesareans were elective), placenta previa (n = 2), prolonged labor (n = 2), fetal malpresentation (n = 6, one case is twin pregnancy with one fetal malpresentation), non-reassuring fetal heart rate tracings (n = 8), and severe pre-eclampsia (n = 1). All the successful live babies were born after gestational age (GA) 28 weeks (Table 1), with the patient numbers (percentage) delivered at GA 36 weeks or greater, between GA 32 and 35+6 weeks, between GA 28 and 31+6 weeks and less than 28 weeks were 33 (70.21 %), 12 (25.23 %), 2 (4.26 %), and 0 (0 %). The distribution of the percentiles (calculated by Hadlock chart) regarding birth body weights of these babies was 27.08 % (n = 13, < 10th percentile, “small for gestational age (SGA)” by definition), 41.67 % (n = 20, 10th–25th percentile), 22.92 % (n = 11, 25th–50th percentile), and 8.33 % (n = 4, > 50th percentile) (Table 2). Nine of the babies born with SGA were in the cesarean section group (exactly those whose indications for cesareans were non-reassuring fetal heart rate tracings (n = 8) and severe-preeclampsia (n = 1)). Only 3 of the entire cohort delivered emergently (two vaginal births and one cesarean birth) and no postpartum hemorrhage occurred. Pathological examination of the placentae belonging to the SGA babies all showed gross hypoplasia and histological vascular lesions.Fig. 1 Patient summary and treatment flowchart\n\n\nTable 1 Summary of the gestational age (GA) at delivery and mode of delivery of the 47 livebirths\n\n\t% (= n/47)\t\nGA at delivery\t\n ≥ 36 weeks\t70.2 (33/47)\t\n 32–35+6 weeks\t25.23 (12/47)\t\n 28–31+6 weeks\t4.26 (2/47)\t\n < 28 weeks\t0 (0/47)\t\nMode of delivery\t\n Normal spontaneous delivery\t40.43 (19/47)\t\n Cesarean section\t59.57 (28/47)\t\n\nTable 2 Percentile distributions of the birth body weight of the 48 live-birth babies\n\nPercentile of birth body weight (Hadlock)\t% (= n/48)\t\nSGA (<10th percentile)\t27.08 (13/48)\t\n10th–25th percentile\t41.67 (20/48)\t\n25th–50th percentile\t22.92 (11/48)\t\n>50th percentile\t8.33 (4/48)\t\n\nSGA small for gestational age\n\n\n\n\nIn summary, the rate of successful livebirth was thus 94 % (47/50). If by comparing to their historical cohort (the livebirth rate before being enrolled into the treatment group is theoretically zero) themselves, the benefit to this group of patients is clear (p = 0 by Fisher’s exact test).\n\nDiscussion\nRecurrent pregnancy loss (RPL), or recurrent miscarriages, is a serious problem in women’s health. It affects 1–2 % of women of reproductive age if 3 or more first trimester pregnancy losses (less than 12 complete gestational weeks) and 5 % of women of reproductive age if 2 or more first trimester pregnancy losses (less than 12 complete gestational weeks) [7]. The causes of RPL are varying and complicated. Etiologies that had been reported included structural (e.g., mullerian anomalies), hormonal (e.g., luteal defect), chromosomal (e.g., balanced translocation carriers), immune-related (e.g., anti-phospholipid antibody syndrome), thrombophilias (e.g., factor V Lieden mutations and prothrombin mutations in the caucasian populations), and others. Strategies to combat these putative causative factors were therefore developed, with varying efficacies [17, 18]. For example, some advocated anti-coagulation therapy (such as aspirin or low-molecular-weight-heparin) is effective in improving the pregnancy outcome in women suffered from anti-phospholipid antibody syndrome and RPL but the results were inconsistent among different trials [6, 19–21]. Most of the recently conducted randomized trials failed to show significant benefit of anti-coagulation therapy (either aspirin or low molecular weight heparin alone or if both were combined) to improve the livebirth rates in women with RPL [6, 7, 15]. However, these well-conducted trials actually did not well characterize the underlying possible causative factors in their study subjects, the subgroups due to different etiologies were pooled and no specific analyses were conducted separately on each subgroup.\n\nThere are at least three randomized trials conducted in earlier times dealing with women with RPL and a concomitant heritable thrombophilia and the results were varying. In 2004, the French group published their result of the randomized trial to compare low-molecular-weight heparin (LMWH) versus aspirin (ASA) and reported that LMWH was superior to ASA regarding the livebirth rates. In 2008, the Jordan group reported a similar beneficial effect of anticoagulant therapy (LMWH versus placebo, please refer to Qubian et al., 2008 [22]). However, the Canadian group reported there seemed no benefit to the livebirth rates when comparing LMWH plus ASA and ASA alone in 2009 (the HepASA Trial, please refer to Laskin et al., 2009 [23]). Tan and colleagues therefore conducted a meta-analysis and concluded that no obvious benefit can be attributed to the anti-coagulation therapy regarding the improvement of livebirth rates in women with RPL and a heritable thrombophilia [5]. However, the mixture of those three randomized trials is too arbitrary to exclude the possibility of real benefit in this group of women since the three randomized trails had different inclusion criteria and even different therapeutic regimens.\n\nIt is noteworthy that there are some recently well-conducted randomized trials being published and all of these trials failed to demonstrate the benefit of anticoagulant therapy in women with RPL (but not aiming solely at women with heritable thrombophilias). The Netherland study published in NEJM 2010 did included some women with heritable thrombophilas (even included protein S deficiency) but the authors also admitted the study lacked the power to study the effect in the subgroups of the study population [6]. The Scottish Pregnancy Intervention study (SPIN) also included some women with heritable thrombophilia but admitted their result did not exclude the possible benefit in women with a particular thrombophilia disorder as well [7]. A recent multi-center with minimized randomization scheme conduced in Germany and Austria actually excluded the women with constitutional thrombophilia disorders and therefore the trial result is of no reference value to our study [15].\n\nIn our study, it is obvious LMWH is beneficial to the livebirth rate in women suffered from RPL with documented sole protein S deficiency (94 versus 0 % by historical control). Particularly, 2 of the 11 women treated twice had initially decided not being enrolled into the treatment group receiving anticoagulants after one successful birth and got pregnant again and both of them suffered from spontaneous abortion (the karyotyping results of the abortion were both normal), and thereby they entered the study for the second time when again getting pregnant and successful livebirths ensued. Such experience strengthened the justification of this study. However, it seems LMWH was unable to prevent other obstetric complications such as placental insufficiency and therefore intrauterine growth restriction (IUGR) are common in our cohort. Among 48 live born babies, Nearly 70 % of them were born with birth weight less than 25th percentile (68.75 %; n = 33), and the percentage of small for gestational age (SGA) was 27.08 % (n = 13). Among the babies born with SGA, five infants were born before 36 weeks of GA, including one case of severe pre-eclampsia, one case of oligohydroamnios, and all of them demonstrated non-reassuring fetal heart rate tracings during intrapartum. The result was compatible with the prior reports [24], showed a link between thrombophilias and fetal growth restriction (odds ratio (OR) 10.2; 95 % confidence interval (CI) 1.1–91.0) by meta-analysis. However, available evidences in the literature do not support the prophylactic use of anticoagulants can prevent obstetric complications, including preeclampsia, fetal growth restriction, or abruption in women with any form of inherited thrombophilias [25], despite it may of be benefit in women with recurrent implantation failures when receiving in vitro fertilization [26]. It is still under debate if thrombophilias truly associated, or simply it is only by chance a coincidence, with the placental insufficiency [27]. Further investigations and surveys were required to establish causality. Hence, in addition to anti-coagulation therapy, frequent fetal surveillance is necessary for pregnant women with thrombophilia to prevent adverse neonatal outcomes. The American Congress of Obstetricians and Gynecologists (ACOG) did not suggest special management in thrombophilia patients in the absence of obstetric complications such as preeclampsia, abruption or IUGR. Weekly fetal assessment with non-stress test beginning at ≥36 weeks of gestation and delivery at 39 weeks of gestation is still the recommended standard of care when managing these patients [28].\n\nWe admit the evidence level of historical control is much lower than prospective randomized control trials. Many inherent defects underlying the historical control study hampered its use. The most frequently cited defects of this historical control conducted by patients as their own controls included different diagnostic criteria, differences in the concomitant standard of care, and missing records across different times along the time period (especially if the time spans very long such as 10 or 20 years). However, the credibility of historical control study may be better if there is a large treatment effect, or it is very difficult to bias outcome assessment, or it follows the pair availability design (proposed by Baker and Lindeman in 1994) [29–32].\n\nConclusion\nIn this study, a strikingly high 94 % successful livebirth rate, straight-forward outcome indicators (livebirth rate and pregnancy complications), and the short time period (within 5 years), all indicated that our result is of better power, despite the limitations of historical control discussed above, to convince us that such intervention did benefit this group of patients in Taiwan. Our study clearly demonstrated a potential benefit of daily anti-coagulation therapy in women suffered from RPL and had documented sole protein S deficiency. Future prospective randomized studies are needed to further prove its efficacy.\n\nAdditional file\n\nAdditional file 1: Table S1. Details of the 47 livebirths (resulting in 48 live-birth babies from 46 singletons and 1 twin pregnancy) from 37 patients prescribed low molecular weight heparin low molecular weight heparin. (XLSX 15 kb)\n\n\n\n\nAbbreviations\nACOGThe American Congress of Obstetricians and Gynecologists\n\nASAAspirin\n\nCIConfidence interval\n\nGAGestational age\n\nIUGRIntrauterine growth restriction\n\nLMWHLow-molecular-weight heparin\n\nOROdds ratio\n\nRPLRecurrent pregnancy loss\n\nSGASmall for gestational age\n\nAcknowledgements\nThe expenses of the medical care of the patients, however, were compensated and supported by the National Health Insurance System of Taiwan.\n\nFunding\nThis study received a research fund from Changhua Christian Hospital (grant number: 105-CCH-PRJ-004) to M. Chen.\n\nAvailability of data and supporting materials\nDetails of the treatment outcome were summarized in Additional file 1: Table S1.\n\nAuthors’ contributions\nMCS, WJW, GCM, WHL, and MC wrote the paper. MCS, PJC, WCL, JDL, CSC, and MC conceived the idea and designed the study. MCS, WJW, and MC recruited the patients and analyzed the results. All authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nNot applicable.\n\nEthics approval and consent to participate\nThis study is a retrospective cohort study. The institutional review board (IRB) of Changhua Christian Hospital had approved the study (CCH-IRB-151209).\n==== Refs\nReferences\n1. Saravelos SH Regan L Unexplained recurrent pregnancy loss Obstet Gynecol Clin North Am 2014 41 1 157 166 10.1016/j.ogc.2013.10.008 24491990 \n2. 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Schleussner E Kamin G Seliger G Rogenhofer N Ebner S Toth B Schenk M Henes M Bohlmann MK Fischer T Brosteanu O Bauersachs R Petroff D ETHIG II group Low-molecular-weight heparin for women with unexplained recurrent pregnancy loss: a multicenter trial with a minimization randomization scheme Ann Intern Med 2015 162 9 601 609 10.7326/M14-2062 25938990 \n16. Moraes C Lofthouse E Eikelboom J Thom J Baker R Detection of protein S deficiency: a new functional assay compared to an antigenic technique Pathology 2000 32 2 94 97 10.1080/003130200104303 10840827 \n17. Regan L Rai R Epidemiology and the medical causes of miscarriage Baillieres Best Pract Res Clin Obstet Gynaecol 2000 14 839 854 10.1053/beog.2000.0123 11023804 \n18. Kutteh WH Novel strategies for the management of recurrent pregnancy loss Semin Reprod Med 2015 33 3 161 168 10.1055/s-0035-1552586 26036897 \n19. Empson M Lassere M Craig J Scott J Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant Cochrane Database Syst Rev 2005 2 CD002859 \n20. Farquharson RG Quenby S Greaves M Antiphospholipid syndrome in preg- nancy: a randomized, controlled trial of treatment Obstet Gynecol 2002 100 408 413 12220757 \n21. Rai R Cohen H Dave M Regan L Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies) BMJ 1997 314 253 257 10.1136/bmj.314.7076.253 9022487 \n22. Qublan H Amarin Z Dabbas M Farraj AE Beni-Merei Z Al-Akash H Bdoor AN Nawasreh M Malkawi S Diab F Al-Ahmad N Balawneh M Abu-Salim A Low-molecular-weight heparin in the treatment of recurrent IVF-ET failure and thrombophilia: a prospective randomized placebo-controlled trial Hum Fertil (Camb) 2008 11 4 246 253 10.1080/14647270801995431 19085261 \n23. Laskin CA Spitzer KA Clark CA Crowther MR Ginsberg JS Hawker GA Kingdom JC Barrett J Gent M Low molecular weight heparin and aspirin for recurrent pregnancy loss: results from the randomized, controlled HepASA Trial J Rheumatol 2009 36 2 279 287 10.3899/jrheum.080763 19208560 \n24. Alfirevic Z Roberts D Martlew V How strong is the association between maternal thrombophilia and adverse pregnancy outcome? A systematic review Eur J Obstet Gynecol Reprod Biol 2002 101 1 6 10.1016/S0301-2115(01)00496-1 11803092 \n25. Bates SM Greer IA Middeldorp S Veenstra DL Prabulos AM Vandvik PO American College of Chest Physicians VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines Chest 2012 141 2 Suppl e691S 10.1378/chest.11-2300 22315276 \n26. Potdar N Gelbaya TA Konje JC Nardo LG Adjunct low-molecular-weight heparin to improve live birth rate after recurrent implantation failure: a systematic review and meta-analysis Hum Reprod Update 2013 19 6 674 684 10.1093/humupd/dmt032 23912476 \n27. Rodger MA Paidas M McLintock C Middeldorp S Kahn S Martinelli I Hague W Rosene Montella K Greer I Inherited thrombophilia and pregnancy complications revisited Obstet Gynecol 2008 112 2 Pt 1 320 324 10.1097/AOG.0b013e31817e8acc 18669729 \n28. ACOG Practice Bulletin No. 111 Inherited thrombophilias in pregnancy Obstet Gynecol 2010 115 4 877 887 10.1097/AOG.0b013e3181d9d82d 20308860 \n29. Walton MK Powers JH 3rd Hobart J Patrick D Marquis P Vamvakas S Isaac M Molsen E Cano S Burke LB International Society for Pharmacoeconomics and Outcomes Research Task Force for Clinical Outcomes Assessment: Clinical Outcome Assessments: Conceptual Foundation-Report of the ISPOR Clinical Outcomes Assessment–Emerging Good Practices for Outcomes Research Task Force Value Health 2015 18 6 741 752 10.1016/j.jval.2015.08.006 26409600 \n30. Castillo RC Scharfstein DO MacKenzie EJ Observational studies in the era of randomized trials: finding the balance J Bone Joint Surg Am 2012 94 Supp 1 112 117 10.2106/JBJS.L.00242 22810460 \n31. Baker SG Lindeman KS The pair availability design: a proposal for evaluating epidural analgesia during labor Stat Med 1994 13 2269 2278 10.1002/sim.4780132108 7846425 \n32. Baker SG Lindeman KS Rethinking historical controls Biostatistics 2001 2 4 383 396 10.1093/biostatistics/2.4.383 12933631\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1477-9560",
"issue": "14()",
"journal": "Thrombosis journal",
"keywords": "Anticoagulation; Low-molecular-weight-heparin; Protein S deficiency; Recurrent miscarriages; Thrombophilia",
"medline_ta": "Thromb J",
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"nlm_unique_id": "101170542",
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"title": "Low-molecular-weight-heparin can benefit women with recurrent pregnancy loss and sole protein S deficiency: a historical control cohort study from Taiwan.",
"title_normalized": "low molecular weight heparin can benefit women with recurrent pregnancy loss and sole protein s deficiency a historical control cohort study from taiwan"
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"companynumb": "TW-SA-2016SA204950",
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"abstract": "The objectives of a phase 1/2 trial of pomalidomide with dexamethasone for the treatment of light chain (AL) amyloidosis were to determine the safety, tolerability, maximum tolerated dose (MTD), recommended phase 2 dose, and hematologic and clinical response. A 3+3 dose-escalation phase (15 patients) was followed by an expansion cohort (12 patients) enrolled at the MTD. Pomalidomide was administered at 2 and 3 mg on days 1 to 28 (cohorts 1 and 2) and 4 mg on days 1 to 21 (cohort 3) every 28 days, with weekly dexamethasone at a dose of 20 mg. Twenty-seven patients with previously treated AL were enrolled, 15 during dose escalation (6 at 2 mg, 3 at 3 mg, and 6 at 4 mg) and 12 during dose expansion (all at 4 mg). One patient experienced dose-limiting toxicity at 4 mg; the MTD was determined as 4 mg. The most common grade ≥3 drug-related adverse events included myelosuppression and fatigue. Overall, hematologic response (HR) was 50% in 24 evaluable patients. The median time to best HR was 3 cycles, and median duration of HR was 15 months. Median overall survival has not yet been reached, with a median follow-up of 17.1 months and median event-free survival of 17.8 months. This trial was registered at www.clinicaltrials.gov as #NCT01570387.",
"affiliations": "Section of Hematology and Oncology, Department of Medicine, and Amyloidosis Center, Boston University School of Medicine and Boston Medical Center, Boston, MA.;Section of Hematology and Oncology, Department of Medicine, and Amyloidosis Center, Boston University School of Medicine and Boston Medical Center, Boston, MA.;Section of Hematology and Oncology, Department of Medicine, and Amyloidosis Center, Boston University School of Medicine and Boston Medical Center, Boston, MA.;Section of Hematology and Oncology, Department of Medicine, and Amyloidosis Center, Boston University School of Medicine and Boston Medical Center, Boston, MA.;Section of Hematology and Oncology, Department of Medicine, and Amyloidosis Center, Boston University School of Medicine and Boston Medical Center, Boston, MA.;Section of Hematology and Oncology, Department of Medicine, and Amyloidosis Center, Boston University School of Medicine and Boston Medical Center, Boston, MA.",
"authors": "Sanchorawala|Vaishali|V|0000-0002-6307-2445;Shelton|Anthony C|AC|;Lo|Stephen|S|;Varga|Cindy|C|;Sloan|J Mark|JM|0000-0001-7069-4528;Seldin|David C|DC|",
"chemical_list": "D013792:Thalidomide; D003907:Dexamethasone; C467566:pomalidomide",
"country": "United States",
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"doi": "10.1182/blood-2016-04-710822",
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"issn_linking": "0006-4971",
"issue": "128(8)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D000328:Adult; D000368:Aged; D000686:Amyloidosis; D003907:Dexamethasone; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D016019:Survival Analysis; D013792:Thalidomide; D016896:Treatment Outcome",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "1059-62",
"pmc": null,
"pmid": "27381904",
"pubdate": "2016-08-25",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Pomalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 1 and 2 trial.",
"title_normalized": "pomalidomide and dexamethasone in the treatment of al amyloidosis results of a phase 1 and 2 trial"
} | [
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"companynumb": "US-CELGENEUS-USA-2016091469",
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"abstract": "Metastatic, persistent, or recurrent epithelial ovarian cancer (MPR-EOC) remains a significant threat to patient mortality despite advances in novel targeted agents. Radiation therapy (RT) is often used as a palliative option. We report outcomes of a large series of MPR-EOC patients treated with modern palliative RT (PRT) in an era of novel systemic therapies.\nA retrospective review was conducted of women treated with PRT for MPR-EOC between 2007 and 2019 at an academic institution. Clinical response rates were recorded at <1 month, 1 to 3 months, and >3 months. Radiographic responses were categorized by RECIST 1.1 criteria. Overall response rate (ORR) was the sum of complete and partial response. Linear regression analyses of baseline characteristics were conducted for statistical testing.\nEighty-six patients with PMR-OC received 120 courses of palliative RT. Median follow-up was 8.6 months. Median age was 61 (range, 22-82). Thirty-six percent of women received central nervous system (CNS)-directed RT. In addition, 43% received targeted therapies before RT. Clinical ORR within 1 month and at last follow-up for non-CNS lesions was 79% and 61% (69% and 88% for CNS lesions, respectively). High-grade serous lesions were more likely to have clinical response (P = .04). Biologically effective doses (BED) >39 Gy were associated with improved clinical response in CNS lesions (P = .049). Bony sites were associated with worse clinical (P = .004) response in non-CNS lesions compared with soft tissue or nodal sites. Acute or late grade 3+ toxicities with bevacizumab were low (8.7%/4.3%).\nPRT offers excellent rates of response for symptomatic patients with MPR-EOC within 1 month of treatment, with durable responses beyond 3 months. High-grade serous lesions were associated with improved response in all patients. Higher BED and soft tissue or nodal sites were associated with improved response in CNS and non-CNS patients, respectively. Acute or late toxicities with bevacizumab and PRT were low. Prospective investigation is warranted to determine the optimal PRT regimen.",
"affiliations": "Department of Radiation Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.;Albany Medical College, Albany, New York.;Department of Radiation Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Gynecologic Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Gynecologic Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Radiation Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Radiation Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.",
"authors": "Butala|Anish A|AA|;Patel|Roshal R|RR|;Manjunath|Shwetha|S|;Latif|Nawar A|NA|;Haggerty|Ashley F|AF|;Jones|Joshua A|JA|;Taunk|Neil K|NK|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.adro.2020.11.009",
"fulltext": "\n==== Front\nAdv Radiat Oncol\nAdv Radiat Oncol\nAdvances in Radiation Oncology\n2452-1094 Elsevier \n\nS2452-1094(20)30354-7\n10.1016/j.adro.2020.11.009\n100624\nScientific Article\nPalliative Radiation Therapy for Metastatic, Persistent, or Recurrent Epithelial Ovarian Cancer: Efficacy in the Era of Modern Technology and Targeted Agents\nButala Anish A. MDa1 Patel Roshal R. BAb1 Manjunath Shwetha MDa Latif Nawar A. MD, MPH, MSCEc Haggerty Ashley F. MD, MSCEc Jones Joshua A. MD, FAAHPMa Taunk Neil K. MD, MSCTStaunk@pennmedicine.upenn.edua∗ a Department of Radiation Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania\nb Albany Medical College, Albany, New York\nc Department of Gynecologic Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania\n∗ Corresponding author: Neil K. Taunk, MD, MSCTS taunk@pennmedicine.upenn.edu1 A.A.B. and R.R.P. contributed equally to this article.\n\n\n25 11 2020 \nJan-Feb 2021 \n25 11 2020 \n6 1 1006248 4 2020 10 8 2020 11 11 2020 © 2020 The Author(s)2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nMetastatic, persistent, or recurrent epithelial ovarian cancer (MPR-EOC) remains a significant threat to patient mortality despite advances in novel targeted agents. Radiation therapy (RT) is often used as a palliative option. We report outcomes of a large series of MPR-EOC patients treated with modern palliative RT (PRT) in an era of novel systemic therapies.\n\nMethods and Materials\nA retrospective review was conducted of women treated with PRT for MPR-EOC between 2007 and 2019 at an academic institution. Clinical response rates were recorded at <1 month, 1 to 3 months, and >3 months. Radiographic responses were categorized by RECIST 1.1 criteria. Overall response rate (ORR) was the sum of complete and partial response. Linear regression analyses of baseline characteristics were conducted for statistical testing.\n\nResults\nEighty-six patients with PMR-OC received 120 courses of palliative RT. Median follow-up was 8.6 months. Median age was 61 (range, 22-82). Thirty-six percent of women received central nervous system (CNS)-directed RT. In addition, 43% received targeted therapies before RT. Clinical ORR within 1 month and at last follow-up for non-CNS lesions was 79% and 61% (69% and 88% for CNS lesions, respectively). High-grade serous lesions were more likely to have clinical response (P = .04). Biologically effective doses (BED) >39 Gy were associated with improved clinical response in CNS lesions (P = .049). Bony sites were associated with worse clinical (P = .004) response in non-CNS lesions compared with soft tissue or nodal sites. Acute or late grade 3+ toxicities with bevacizumab were low (8.7%/4.3%).\n\nConclusions\nPRT offers excellent rates of response for symptomatic patients with MPR-EOC within 1 month of treatment, with durable responses beyond 3 months. High-grade serous lesions were associated with improved response in all patients. Higher BED and soft tissue or nodal sites were associated with improved response in CNS and non-CNS patients, respectively. Acute or late toxicities with bevacizumab and PRT were low. Prospective investigation is warranted to determine the optimal PRT regimen.\n==== Body\nIntroduction\nOvarian cancer (OC) is a highly aggressive gynecologic malignancy, with the majority of patients presenting with advanced disease at diagnosis. The general treatment paradigm for advanced OC is maximal cytoreductive surgery with platinum-based chemotherapy.1 Recent literature has also reported a progression-free survival benefit with maintenance inhibition of poly (adenosine diphosphate-ribose) polymerase (PARP) in women with partial or complete response to platinum-based regimens.2,3\n\nWhole abdominal radiation therapy was historically indicated as adjuvant therapy to address microscopic residual disease.4 However, due to its considerable toxicity and the development of platinum-based chemotherapy, whole abdominal radiation therapy is no longer included in primary OC treatment paradigms.1\n\nDespite advances in cytoreductive strategies and front-line systemic therapy, >70% of women relapse within 3 years of diagnosis.5 As such, many patients with OC benefit from palliative care referrals to assist with symptom management, goals of care discussions, and complex medical decision making at the end of life.\n\nThere is a growing body of evidence to support the incorporation of palliative services in cancer care. In 2010, a seminal randomized trial6 reported early palliative care among patients with metastatic non-small cell lung cancer significantly improved quality of life, led to less aggressive care at the end of life, and resulted in longer overall survival. Furthermore, both the American Society of Clinical Oncology and the Society of Gynecologic Oncology have published official practice guidelines recommending the routine and early integration of palliative services.7,8\n\nRadiation therapy (RT) is often used as an effective therapeutic option in the palliation of patients with metastatic, persistent, or recurrent epithelial OC (MPR-EOC) as a means for symptomatic relief and local control. This includes oligometastatic disease or symptomatic disease causing pain, bowel or ureteral obstruction, or bleeding. Despite their rarity in OC (2% incidence9), brain metastases can also cause significant morbidity and can be treated with palliative RT to reduce the risk of progression and neurocognitive deficits.10,11\n\nAs patient survival improves with modern systemic agents, there is a growing need to understand the efficacy of palliative RT regimens for MPR-EOC in the same era. Although radiation therapy has traditionally been delivered for symptomatic control in MPR-EOC, the recognition of the biologically distinct (and potentially curable) oligometastatic state12,13 is expanding the scope of RT indications. Data from phase 2 trials in other malignancies evaluating the effect of locally directed therapy to oligometastatic lesions has demonstrated improvements in overall survival.14,15\n\nWe therefore conducted, a large contemporary retrospective analysis of palliative RT in MPR-EOC. This patient cohort is highly relevant to modern practice given the number of patients who received novel systemic agents, the prominent usage of advanced RT technology, and the representation of patients with BMs from OC (an area with limited data but increasing prevalence in practice). The analysis will report the outcomes and durability of palliative RT in MPR-EOC and delineate factors predictive of response in the modern era.\n\nMethods and Materials\nWe conducted a retrospective chart review of women treated with palliative radiation therapy for metastatic ovarian cancer from 2007 through 2019 at [University of Pennsylvania] and affiliate sites. Institutional review board approval was obtained before conducting this review. Patients were included in this analysis if they were treated for palliative intent, including treatment of oligometastatic disease. All patients had MPR-EOC ovarian cancer and received anywhere from one to 5 courses of radiation treatment.\n\nGiven the poor prognosis of patients with metastatic ovarian cancer, clinical and radiographic response rates were categorized in intervals of <1 month, 1 to 3 months, and >3 months after the end of radiation treatment to indicate acute and durable responses. Clinical responses were categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Pain scores were classified using the Bone Metastases Consensus Working Party guidelines16 (indeterminate responses, which are neither PR nor PD per BMWCP guidelines, were classified as SD to maintain consistency with other clinical response categorizations). Radiographic responses were categorized as CR, PR, SD, or PD based on the RECIST 1.1 criteria.17 Overall response rate (ORR) was the sum of CR and PR in a given patient. Given the large subset of patients with brain metastases (BMs), courses were stratified by central nervous system (CNS) and non-CNS anatomic locations. Acute (during RT and within 3 months of completion) and late (>3 months after completion of RT) toxicities were recorded with concurrent and prior bevacizumab using Common Terminology Criteria for Adverse Events version 5.018 classification.\n\nRates of response (CR or PR at any point) were compared with demographic and treatment characteristics. χ2 (n ≥ 20) or Fisher exact (n < 20) tests were used for such comparison with variables for race, histology, platinum chemotherapy, or targeted therapy before RT, RT technology, RT location, and biologically effective dose (BED) >39. Binary logistic regression analyses were used for comparison with continuous variables (age and BED). Covariates with P < .1 were included in multiple logistic regression modeling to assess for independent effect. Additionally, χ2 analyses were used to compare rates of radiographic response between patients treated for clinical symptoms and asymptomatic progression. Statistical analysis was conducted using IBM SPSS Statistics, version 26 (IBM Corporation, Armonk, NY).\n\nResults\nWe identified 86 patients with PMR-OC that received 120 combined courses of palliative radiation treatment. Median follow-up was 8.6 months (range, 0.5-119 months). Excluding 10 patients (15 courses) with no evaluable clinical or radiographic follow-up, 51 patients (58 courses) were treated to non-CNS locations and 18 patients (25 courses) were treated to CNS locations; 7 patients (22 courses) received palliative RT to both CNS (13 courses) and non-CNS (9 courses) locations.\n\nTable 1 describes baseline patient characteristics and details related to patient treatments. The median age of patients in this cohort was 61, with a range of 22 to 82. Patients were most commonly white (83%) and black (8%). Tumor histologies were primarily high-grade serous (HGS, 59%), although adenocarcinoma (undifferentiated or unspecified), low-grade serous, clear cell, endometrioid, and carcinosarcoma were also observed.Table 1 Patient characteristics and treatment details\n\nNo. of courses\t105\t\nNo. of patients\t76\t\nMedian age\t61\t\nEthnicity\t\t\n White\t82.9% (63/76)\t\n Black\t9.2% (7/76)\t\n Asian\t3.9% (3/76)\t\n Hispanic\t2.6% (2/76)\t\n Unknown\t1.3% (1/76)\t\nHistology\t\t\n High-grade serous\t59.2% (45/76)\t\n Adenocarcinoma, other\t13.2% (10/76)\t\n Low grade serous\t9.2% (7/76)\t\n Clear cell\t5.3% (4/76)\t\n Other\t7.9% (6/76)\t\n Endometrioid\t3.9% (3/76)\t\n Carcinosarcoma\t1.3% (1/76)\t\nAnatomic site\t\t\n Soft tissue/organ\t35.2% (37/105)\t\n Lymph node\t21.0% (22/105)\t\n Bone\t11.4% (12/105)\t\n CNS\t36.2% (38/105)\t\nIndications\t\t\n Clinical symptoms\t59.0% (62/105)\t\n Progressive/metastatic\t33.3% (35/105)\t\n Postoperative\t7.6% (8/105)\t\nSystemic therapy before RT\t\t\n Platinum chemotherapy\t27.6% (29/105)\t\n Nonplatinum chemotherapy\t61.9% (65/105)\t\n Targeted therapy\t42.9% (45/105)\t\n None/other\t1.0% (1/105)\t\nTechnique\t\t\n 2D/3D CRT\t53.3% (56/105)\t\n SRS\t21.9% (23/105)\t\n VMAT/IMRT\t16.2% (17/105)\t\n SBRT\t4.8% (5/105)\t\n Proton\t3.8% (4/105)\t\nNon-SRS dose\t14-63 Gy in 4-35 fractions\t\nSBRT dose\t24-50 Gy in 3-5 fractions\t\nSRS dose\t15-25 Gy in 1-5 fractions\t\nAbbreviations: 2D = 2-dimensional; 3D CRT = 3-dimensional conformal radiation therapy; CNS = central nervous system; IMRT = intensity modulated radiation therapy; RT = radiation therapy; SBRT = stereotactic body radiation therapy; SRS = stereotactic radiosurgery; VMAT = volumetric modulated arc therapy.\n\n\n\nNon-CNS treatment locations included tumors in soft tissue or organs (35%), lymph nodes (21%), and bone (11%); 4 patients were treated simultaneously to adjacent soft tissue and lymph nodes. Treatment for CNS metastases comprised the remaining 36% of patients.\n\nMost patients were treated for clinical symptoms (59%). Pain and bleeding were the most common clinical indications. Others included neurologic deficits, spinal cord compression, airway compression, and bowel obstruction. A large cohort of patients were treated for asymptomatic progressive or metastatic disease (33%) with a small cohort treated adjuvantly after surgery (eg, metastasectomy or palliative debulking; 7.6%).\n\nAlmost all patients (90%) received chemotherapy immediately before radiation therapy. The most common systemic therapy regimens were platinum-based (ie, carboplatin) followed by taxanes and doxorubicin. Many patients (43%) also received treatment with targeted therapy agents before radiation treatment. Bevacizumab was the most commonly used targeted therapy agent (20%), although patients also received PARP inhibitors (9%) and immune checkpoint inhibitors (5%).\n\nA wide range of palliative radiation regimens were delivered across several modalities. Nonstereotactic treatment regimens to both CNS and non-CNS locations ranged from 14 Gy in 4 fractions to 63 Gy in 35 fractions. Common palliative doses were 30 Gy in 10 fractions (14%), 20 Gy in 5 fractions (8.6%), and 35 Gy in 14 fractions (7.6%). Nonstereotactic modalities included 2-dimensional or 3-dimensional (53%), intensity modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (16%), and proton therapy (3.8%). Stereotactic body radiation therapy (SBRT) was less commonly used (4.8%) with treatment regimen ranging from 24 Gy in 3 fractions to 50 Gy in 5 fractions. Lastly, patients with BMs commonly received stereotactic radiosurgery (SRS, 22% of all courses) with doses ranging from 15 Gy in 1 fraction to 25 Gy in 5 fractions. Nearly half of the patients who underwent SRS received 21 Gy in 1 fraction.\n\nAcross the entire cohort, the clinical ORR was 76% within the first month after treatment and 67% at least 3 months after treatment (Table 2). Radiographic ORR between patients treated for clinical symptoms (symptomatic) and asymptomatic progression (asymptomatic) were 48% and 59%, respectively. Although patients treated for asymptomatic progression had higher rates of response, no significant differences were observed between the 2 cohorts (P = .23).Table 2 Response rates (all lesions)\n\n\t<1 mo\t1-3 mo\t>3 mo\t\nClinical response\t\t\t\t\nCR\t32.8% (19/58)\t45.0% (18/40)\t48.4% (15/31)\t\nPR\t43.1% (25/58)\t35.0% (14/40)\t19.4% (6/31)\t\nSD\t12.1% (7/58)\t2.5% (1/40)\t0.0% (0/31)\t\nPD\t12.1% (7/58)\t17.5% (7/40)\t32.3% (10/31)\t\nORR\t75.9% (44/58)\t80.0% (32/40)\t67.7% (21/31)\t\nRadiographic response: symptomatic patients\t\t\nCR\t15.2% (5/33)\t16.7% (5/30)\t25.9% (7/27)\t\nPR\t24.2% (8/33)\t30.0% (9/30)\t22.2% (6/27)\t\nSD\t51.5% (17/33)\t43.3% (13/30)\t40.7% (11/27)\t\nPD\t9.1% (3/33)\t10.% (3/30)\t11.1% (3/27)\t\nORR\t39.4% (13/33)\t46.7% (14/30)\t48.1% (13/27)\t\nRadiographic response: asymptomatic patients\t\t\t\nCR\t39.4% (13/33)\t47.1% (16/34)\t53.1% (17/32)\t\nPR\t9.1% (3/33)\t8.8% (3/34)\t6.3% (2/32)\t\nSD\t45.5% (15/33)\t41.2% (14/34)\t34.4% (11/32)\t\nPD\t6.1% (2/33)\t2.9% (1/34)\t6.3% (2/32)\t\nORR\t48.5% (16/33)\t55.9% (19/34)\t59.4% (19/32)\t\nAbbreviations: CR = complete response; ORR = overall response rate; PD = progressive disease; PR = partial response; SD = stable disease.\n\nExcludes patients treated with postoperative palliative radiation.\n\nDenominator reflects evaluable patients.\n\n\n\nOf patients treated to non-CNS locations, the clinical and radiographic ORR within the first month after treatment were 79% and 33%, respectively (Table 3). Clinical ORR at last follow-up (at least 3 months after treatment) was 61%. Notably, of the patients with a CR (38.1%) within the first month, only 2 went on to have PD at last follow-up (4 were lost to follow-up), indicating durable response to treatment. All but one patient treated for malignancy-related vaginal bleeding (13/14) had a clinical response within 1 month, of which only one patient had recurrence of bleeding at last follow-up. Seventy percent of patients treated for pain (n = 27) had a clinical response within 1 month, of which only 3 patients demonstrated worsening pain at last follow-up. Radiographically, ORR improved to 38% for symptomatic patients and 47% for asymptomatic patients at last follow-up, with no significant differences in response rates between the 2 groups (P = .44). All lesions that responded within 1 month of radiation treatment maintained response through last follow-up. Furthermore, only 3 of 22 lesions that were initially SD, progressed over time (1 treated for clinical symptoms, 2 treated for asymptomatic progression).Table 3 Response rates (non-CNS lesions)\n\n\t<1 mo\t1-3 mo\t>3 mo\t\nClinical response\t\t\t\t\nCR\t38.1% (16/42)\t44.8% (13/29)\t43.5% (10/23)\t\nPR\t40.5% (17/42)\t31.0% (9/29)\t17.4% (4/23)\t\nSD\t14.3% (6/42)\t3.4% (1/29)\t0.0% (0/23)\t\nPD\t7.1% (3/42)\t20.7% (6/29)\t39.1% (9/23)\t\nORR\t78.6% (33/42)\t75.9% (22/29)\t60.9% (14/23)\t\nRadiographic response: symptomatic patients\t\t\nCR\t9.5% (2/21)\t10.5% (2/19)\t18.8% (3/16)\t\nPR\t23.8% (5/21)\t26.3% (5/19)\t18.8% (3/16)\t\nSD\t52.4% (11/21)\t52.6% (10/19)\t50.0% (8/16)\t\nPD\t14.3% (3/21)\t10.5% (2/19)\t12.5% (2/16)\t\nORR\t33.3% (7/21)\t36.8% (7/19)\t37.5% (6/16)\t\nRadiographic response: asymptomatic patients\t\t\t\nCR\t21.1% (4/19)\t31.6% (6/19)\t41.2% (7/17)\t\nPR\t10.5% (2/19)\t10.5% (2/19)\t5.9% (1/17)\t\nSD\t57.9% (11/19)\t52.6% (10/19)\t41.2% (7/17)\t\nPD\t10.5% (2/19)\t5.3% (1/19)\t11.8% (2/17)\t\nORR\t31.6% (6/19)\t42.1% (8/19)\t47.1% (8/17)\t\nAbbreviations: CNS = central nervous system; CR = complete response; ORR = overall response rate; PD = progressive disease; PR = partial response; SD = stable disease.\n\nExcludes patients treated with postoperative palliative radiation.\n\nDenominator reflects evaluable patients.\n\n\n\nOf patients treated to CNS locations, the clinical and radiographic ORR within the first month after treatment were 72% and 62%, respectively (Table 4). No patients with a demonstrated clinical or radiographic response within the first month went on to have documented progressive symptoms or imaging at last follow-up (although 2 patients died and 4 were lost to follow-up). Although clinical responses stayed constant over time, radiographic responses tended to improve, especially in patients treated for clinical symptoms. There was no difference in rates of radiographic responses between CNS patients treated for clinical symptoms and those treated for asymptomatic progression (P = .41). All patients receiving SRS responded or had SD at 1 month; only one patient had locally progressive symptoms and disease at last follow-up. Three of the 4 patients with progressive symptoms within the first month were those who received whole brain radiation therapy with more extensive CNS disease before treatment.Table 4 Response rates (CNS lesions)\n\n\t<1 mo\t1-3 mo\t>3 mo\t\nClinical response\t\t\t\t\nCR\t18.8% (3/16)\t45.5% (5/11)\t62.5% (5/8)\t\nPR\t50.0% (8/16)\t45.5% (5/11)\t25.0% (2/8)\t\nSD\t6.3% (1/16)\t0.0% (0/11)\t0.0% (0/8)\t\nPD\t25.0% (4/16)\t9.1% (1/11)\t12.5% (1/8)\t\nORR\t68.8% (11/16)\t90.9% (10/11)\t87.5% (7/8)\t\nRadiographic response: symptomatic patients\t\t\t\nCR\t25.0% (3/12)\t27.3% (3/11)\t36.4% (4/11)\t\nPR\t25.0% (3/12)\t36.4% (4/11)\t27.3% (3/11)\t\nSD\t50.% (6/12)\t27.3% (3/11)\t27.3% (3/11)\t\nPD\t0.0% (0/12)\t9.1% (1/11)\t9.1% (1/11)\t\nORR\t50.0% (6/12)\t63.6% (7/11)\t63.6% (7/11)\t\nRadiographic response: asymptomatic patients\t\t\t\nCR\t64.3% (9/14)\t66.7% (10/15)\t66.7% (10/15)\t\nPR\t7.1% (1/14)\t6.7% (1/15)\t6.7% (1/15)\t\nSD\t28.6% (4/14)\t26.7% (4/15)\t26.7% (4/15)\t\nPD\t0.0% (0/14)\t0.0% (0/15)\t0.0% (0/15)\t\nORR\t71.4% (10/14)\t73.3% (11/15)\t73.3% (11/15)\t\nAbbreviations: CNS = central nervous system; CR = complete response; PD = progressive disease; PR = partial response; ORR = overall response rate; SD = stable disease.\n\nExcludes patients treated with postoperative palliative radiation.\n\nDenominator reflects evaluable patients.\n\n\n\nPatients in both CNS and non-CNS cohorts tended to have clinical responses early on, with sustained response at last follow-up. Furthermore, if a patient were to have a clinical CR, it most often occurred within the first month. Only 4 patients demonstrated a CR after the first month, and all of these patients had a PR initially; no patients with initially stable disease went on to have a CR. Most patients with radiographic SD at initial follow-up maintained SD over time. The initial responses of patients developing progressive symptoms after 3-month follow-up varied considerably: CR (2), PR (3), SD (2), and PD (3). No patients who progressed within the first month of follow-up went on to have any response.\n\nEight patients were treated with postoperative RT after surgical resection in the brain (6), mediastinal lymph node (1), and inguinal lymph node (1). Three patients with evaluable clinical symptoms before and after surgery-RT all demonstrated diminished (PR) or complete (CR) resolution of symptoms within 1 month after RT. Of the 6 patients with radiographic follow-up, one recurred 9 months after treatment; the rest maintained stable disease (ie, no recurrence) through last follow-up.\n\nAcute and late grade 3 or higher (G3 +) toxicities with bevacizumab were low (8.7% and 4.3%, respectively). CNS and mediastinal locations were the only treatment sites in which G3 + toxicity occurred. CNS toxicity (acute G3 fatigue, late G3 radiation necrosis, and late G4 optic neuritis) was identified in a single patient who received craniospinal irradiation with prior Gamma Knife irradiation. A second patient treated to the mediastinum had acute but not chronic grade 3 esophagitis. Notably, no acute or late G3 + toxicity was seen in patients treated to the abdomen or pelvis (the most common treatment location; Table 5).Table 5 Observed toxicities in patients treated with bevacizumab before or concurrent with radiation therapy, by treatment course\n\n\tNone\tGrade 1-2\tGrade 3\tGrade 4\t\nAcute\t\t\t\t\t\n Non-CNS (17)\t6\tAnorexia (1),\ndepression (1),\ndermatitis (1),\nfatigue (5),\nGI (6), GU (1),\nodynophagia (1),\npneumonitis (1),\nvaginal hemorrhage (1)\tDermatitis (1),\nesophagitis (1)\t-\t\n CNS (6)\t4\tGI (1)\tFatigue (1)\t-\t\nLate\t\t\t\t\t\n Non-CNS (9)\t8\tGI (1)\t-\t-\t\n CNS (5)\t3\tIntracranial hemorrhage (1)\tRadionecrosis (1)\tOptic neuropathy (1)\t\nAbbreviations: CNS = central nervous system; GI = gastrointestinal; GU = genitourinary.\n\nToxicities defined according to the Common Terminology Criteria for Adverse Events, version 5.0.\n\nNumbers indicate number of treatment courses; more than one toxicity may be attributed to a single treatment course. Late toxicity data unavailable for 9 treatment courses (all due to patient death).\n\nLate grade 3 and 4 toxicities occurred in the same patient.\n\n\n\nAn exploratory analysis examining patient demographics and treatment characteristics was performed to identify predictors of clinical or radiographic response. In all patients (CNS and non-CNS sites), HGS histology was associated with clinical responses (88% vs 64%, P = .04). In patients with CNS lesions, BED >39 Gy was associated with clinical response (P = .049). In non-CNS locations, bony site was associated with worse clinical (44% vs 89%, P = .004) response compared with soft tissue/nodal (STN) sites. Lastly, we compared BED regimens ≤39 Gy versus >39 Gy (assuming an alpha/beta ratio of 10,19,20 the BED of 30 Gy in 10 fractions is 39 Gy) in non-CNS locations and found no differences in clinical (P = .10) or radiographic response rates (P = .47). We otherwise compared the most common regimens of 20 Gy in 5 fractions and 30 Gy in 10 fractions and found no significant differences in clinical (P = .60) or radiographic responses (P = .29; Table E1).2\n\nDiscussion\nWe report the outcomes of a large modern cohort of women with PMR-OC who received palliative radiation therapy in an era of novel systemic agents. In a population with poor prognosis, palliative radiation therapy resulted in excellent clinical and radiographic response rates (Table 2) within 1 month of treatment, with many responses durable beyond 3 months. Brain metastases, a rare site of anatomic spread, were also well represented in this cohort (36%, 38 courses) and responded favorably to palliative intracranial radiation therapy (Table 3). Exploratory analyses demonstrated an association between HGS histology and improved clinical response in all patients, BED >39 Gy and improved clinical response in BMs, and STN sites with improved clinical response in non-CNS sites. Our analysis is unique in its (1) large sample size compared with prior reports with significant number of BMs, (2) high proportion of patients treated with modern RT techniques, (3) inclusion of patients treated with novel systemic agents (ie, PARP inhibitors, bevacizumab, and immunotherapy), and (4) dedicated toxicity analysis of RT with concurrent or prior bevacizumab, an area of increasing clinical significance in MPR-EOC with a dearth of robust data.\n\nOur high clinical response rates (79% ORR within 1 month) are similar to other reports, including literature from prior decades demonstrating durable pain relief and bleeding control from locally directed palliative RT in 80% of OC patients.20, 21, 22 More recently, Bansal and colleagues also found pain control rates of 88.2% and vaginal bleeding control rates of 100% in 23 heavily pretreated women who received palliative pelvic RT.23 Investigators from Brigham and Women’s Hospital also recently published rates and predictors of response to palliative RT for recurrent OC from 2003 to 201424 and demonstrated high rates of response for pain and bleeding (87% and 93%, respectively).\n\nIdentified predictors of response, including HGS histology and STN sites of disease are also compatible with prior investigations. In the above Brigham and Women’s Hospital study, patients treated at nonbony sites had higher response rates than those with bony sites of disease (96% vs 75%, respectively). Furthermore, patients with clear cell histology had the lowest response rates (60%), compared with others like serous histology (82%).\n\nThe sizable nature of our cohort allowed for a temporal analysis of index lesion response rates. Patients in both CNS and non-CNS cohorts tended to have clinical responses early on, with some benefitting from sustained response at last follow-up. Lesions with clinical CR often occurred within the first month. Furthermore, no patients who progressed in the index lesion within the first month of follow-up went on to have any response, suggesting that initial response is of paramount importance. Patients who had progressive symptoms after 3 months had variable initial responses, suggesting progressive disease is still expected no matter what the initial response may be.\n\nRegarding dose response, higher BED was associated with clinical response in brain metastases. This is a result of ablative SRS technology that radiobiologically induces high rates of cell kill compared with those of conventional palliative techniques or doses. Advanced stereotactic techniques permit the delivery of otherwise unsafe high dose-per-fraction regimens due to their sharp dose gradients that allow for normal tissue sparing. In non-CNS locations, however, regimens with BED >39 Gy (ie, greater than 30 Gy in 10 fractions) were no different than lower BED regimens, suggesting dose escalation may not increase the efficacy of palliative RT. Use of higher BED regimens in such (predominantly abdominopelvic) locations is typically limited by larger fields due to tumor size and organ motion. Dose-limiting toxicities from nearby organs at risk such as the stomach, bowel, kidneys, and bladder also constrain prescriptions.\n\nNotably, 47% of all courses were delivered with advanced radiation therapy techniques (SRS, SBRT, IMRT/volumetric-modulated arc therapy, proton therapy). This is in keeping with the increasing number of patients referred for ablative or definitive therapy to oligometastatic or oligoprogressive disease or previously irradiated lesions requiring retreatment. In such scenarios, advanced techniques allow practitioners to deliver higher dose per fraction while sparing normal organs and tissue of radiation, or even reirradiation, toxicity. In fact, recently published reports have evaluated the roles of advanced RT in OC. For example, definitive involved-field RT using IMRT has demonstrated promising rates of local control (LC) and disease-free survival with low toxicity.25,26 Two recent retrospective studies also explored SBRT in oligometastatic OC. Lazzari et al reported the treatment of 82 patients with a median dose of 24 Gy in 3 fractions and demonstrated the safety of SBRT along with an increase in systemic therapy-free survival with reasonable LC27 (more than one-third of patients were disease-free at 1 year). Similarly, Macchia et al reported SBRT in MPR-EOC was well tolerated and afforded higher LC in patients receiving a total dose >25 Gy.28\n\nForty-three percent of patients received targeted therapy immediately before RT in this cohort. This is in keeping with the litany of recent publications studying the use of novel systemic agents (PARP inhibitors,29, 30, 31 bevacizumab,32 nivolumab33) in the setting of MPR-EOC. The response rates described thus reflect the potential outcomes of palliative RT in conjunction with advanced systemic therapies, a scenario that will be increasingly encountered by practitioners. Furthermore, given the sizeable population that received prior or concurrent bevacizumab, a dedicated subgroup analysis was conducted and demonstrated low acute and late grade 3 or higher (G3 +) toxicities (8.7% and 4.3%, respectively) with RT. Although G3 + toxicities occurred in patients treated to CNS and mediastinal locations, it is unclear if this was in relation to prior bevacizumab or reflected the increased risk toxicity with prior RT (Gamma Knife in the CNS patient treated with craniospinal irradiation) or unfavorable tumor location (in the mediastinal patient experiencing esophagitis after receiving 59.4 Gy). No acute or late G3 + toxicity was seen in patients treated to the abdomen or pelvis (the most common treatment location), suggesting that this may be a reasonable treatment option in symptomatic patients.\n\nLimitations\nThe study is limited primarily by its retrospective nature which lends itself to both selection and sample bias. For example, patient performance status and prior lines of therapy (including prior radiation) may effect physician choice of RT technique, dose, and fractionation. Furthermore, lesions necessitating reirradiation demonstrate inherent radioresistance and may negatively affect response rates. Moreover, although the study population is sizeable, it is heterogenous with respect to treatment sites and prior lines of therapy. As such appropriate interpretation required subdivision of data (ie, CNS vs non-CNS, symptomatic vs asymptomatic indication), which led to more descriptive findings. Finally, the variety of systemic therapies used negatively affect our ability to make conclusions regarding the efficacy of RT with respect to individual agents.\n\nFuture directions\nAs the role for palliative radiation therapy expands in the context of the oligometastatic paradigm, nuanced decision-making must be taken to deliver the most efficacious treatment although promoting cost-effective care. As such, prospective evaluation is warranted to determine the optimal dose, timing, and fractionation of RT as it relates to systemic agents and surgery. The high response rates demonstrated in this cohort may warrant prospective investigation of RT as a standard component therapy in MPR-EOC, either before systemic agents as a cytoreductive strategy or after as consolidation therapy.\n\nConclusions\nWe performed a large retrospective cohort analysis of women with MPR-EOC receiving palliative RT in the era of modern technology and systemic agents. Our large population of patients with BMs adds relevant data to the limited body of existing literature and can be used as a practical reference when counseling women. Patients demonstrated favorable clinical and radiographic response rates within 1 month, with >60% experiencing durable clinical responses beyond 3 months. HGS histology was associated with improved clinical response in all patients. BED >39 Gy was associated with improved response in brain metastases. Bony sites were associated with worse response compared with STN sites in non-CNS locations. Acute and late grade 3 or higher toxicities were low with prior bevacizumab, and none of these occurred in patients treated to abdominopelvic locations.\n\nAlthough MPR-EOC is associated with limited prognosis, our data demonstrate that responses to palliative RT can be durable and meaningful. As such, without a conclusive effect on survival, it would be reasonable to consider treatment of such disease after taking into consideration patient symptom severity, goals of care, prognosis, performance status, and extracranial disease burden for BM.\n\nSupplementary Materials\nTables E1 and E2\n \n\nSources of support: The authors received no specific funding for this work.\n\nDisclosures: The authors of this manuscript have no conflicts of interest to report.\n\nResearch data are stored in an institutional repository and will be shared upon request.\n\nSupplementary material for this article can be found at https://doi.org/10.1016/j.adro.2020.11.009.\n==== Refs\nReferences\n1 NCCN Clinical Practice Guidelines in Oncology: Ovarian Cancer. Version 1.2020 2020 National Comprehensive Cancer Network Plymouth Meeting, PA \n2 Gonzalez-Martin A. Pothuri B. Vergote I. Niraparib in patients with newly diagnosed advanced ovarian cancer N Engl J Med 381 2019 2391 2402 31562799 \n3 Moore K. Colombo N. Scambia G. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer N Engl J Med 379 2018 2495 2505 30345884 \n4 Fields E.C. McGuire W.P. Lin L. Temkin S.M. Radiation treatment in women with ovarian cancer: Past, present, and future Front Oncol 7 2017 177 28871275 \n5 Ledermann J.A. Raja F.A. Fotopoulou C. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol 24 Suppl 6 2013 vi24 vi32 24078660 \n6 Temel J.S. Greer J.A. Muzikansky A. Early palliative care for patients with metastatic non-small-cell lung cancer N Engl J Med 363 2010 733 742 20818875 \n7 Landrum L.M. Blank S. Chen L.M. Comprehensive care in gynecologic oncology: The importance of palliative care Gynecol Oncol 137 2015 193 202 25749723 \n8 Ferrell B.R. Temel J.S. Temin S. Integration of palliative care into standard oncology care: American Society of Clinical Oncology Clinical Practice Guideline Update J Clin Oncol 35 2017 96 112 28034065 \n9 Pietzner K. Oskay-Oezcelik G. El Khalfaoui K. Boehmer D. Lichtenegger W. Sehouli J. Brain metastases from epithelial ovarian cancer: Overview and optimal management Anticancer Res 29 2009 2793 2798 19596963 \n10 Yamamoto M. Serizawa T. Shuto T. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): A multi-institutional prospective observational study Lancet Oncol 15 2014 387 395 24621620 \n11 NCCN Practice Guidelines in Oncology: Central Nervous System Cancers. Version 3.2019 2019 National Comprehensive Cancer Network Plymouth Meeting, PA \n12 Hellman S. Weichselbaum R.R. Oligometastases J Clin Oncol 13 1995 8 10 7799047 \n13 Lancia A. Ingrosso G. Carosi A. Oligometastatic cancer: Stereotactic ablative radiotherapy for patients affected by isolated body metastasis Acta Oncol 56 2017 1621 1625 28820285 \n14 Gomez D.R. Tang C. Zhang J. Local consolidative therapy vs maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer: Long-term results of a multi-institutional, phase II, randomized study J Clin Oncol 37 2019 1558 1565 31067138 \n15 Palma D.A. Olson R. Harrow S. Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): A randomised, phase 2, open-label trial Lancet 393 2019 2051 2058 30982687 \n16 Chow E. Wu J.S. Hoskin P. Coia L.R. Bentzen S.M. Blitzer P.H. International consensus on palliative radiotherapy endpoints for future clinical trials in bone metastases Radiother Oncol 64 2002 275 280 12242115 \n17 Schwartz L.H. Seymour L. Litiere S. RECIST 1.1: Standardisation and disease-specific adaptations: Perspectives from the RECIST Working Group Eur J Cancer 62 2016 138 145 27237360 \n18 Cancer Therapy Evaluation Program Available at: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE _v5_Quick_Re ference_8.5x11.pdf \n19 Choi N. Chang J.H. Kim S. Kim H.J. Radiation for persistent or recurrent epithelial ovarian cancer: A need for reassessment Radiat Oncol J 35 2017 144 152 28712280 \n20 Corn B.W. Lanciano R.M. Boente M. Hunter W.M. Ladazack J. Ozols R.F. Recurrent ovarian cancer. Effective radiotherapeutic palliation after chemotherapy failure Cancer 74 1994 2979 2983 7525039 \n21 Tinger A. Waldron T. Peluso N. Effective palliative radiation therapy in advanced and recurrent ovarian carcinoma Int J Radiat Oncol Biol Phys 51 2001 1256 1263 11728685 \n22 Choan E. Quon M. Gallant V. Samant R. Effective palliative radiotherapy for symptomatic recurrent or residual ovarian cancer Gynecol Oncol 102 2006 204 209 16427685 \n23 Bansal A. Rai B. Kumar S. Suri V. Ghoshal S. Fractionated palliative pelvic radiotherapy as an effective modality in the management of recurrent/refractory epithelial ovarian cancers: An institutional experience J Obstet Gynaecol India 67 2017 126 132 28405120 \n24 Jiang G. Balboni T. Taylor A. Liu J. Lee L.J. Palliative radiation therapy for recurrent ovarian cancer: Efficacy and predictors of clinical response Int J Gynecol Cancer 28 2018 43 50 29040187 \n25 Chang J.S. Kim S.W. Kim Y.J. Involved-field radiation therapy for recurrent ovarian cancer: Results of a multi-institutional prospective phase II trial Gynecol Oncol 151 2018 39 45 30146110 \n26 Chundury A. Apicelli A. DeWees T. Intensity modulated radiation therapy for recurrent ovarian cancer refractory to chemotherapy Gynecol Oncol 141 2016 134 139 26876923 \n27 Lazzari R. Ronchi S. Gandini S. Stereotactic body radiation therapy for oligometastatic ovarian cancer: A step toward a drug holiday Int J Radiat Oncol Biol Phys 101 2018 650 660 29893277 \n28 Macchia G. Lazzari R. Colombo N. A large, multicenter, retrospective study on efficacy and safety of stereotactic body radiotherapy (SBRT) in Oligometastatic Ovarian Cancer (MITO RT1 Study): A collaboration of MITO, AIRO GYN, and MaNGO groups Oncologist 25 2020 e311 e320 32043791 \n29 Buechel M. Herzog T.J. Westin S.N. Coleman R.L. Monk B.J. Moore K.N. Treatment of patients with recurrent epithelial ovarian cancer for whom platinum is still an option Ann Oncol 30 2019 721 732 30887020 \n30 Pujade-Lauraine E. Ledermann J.A. Selle F. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): A double-blind, randomised, placebo-controlled, phase 3 trial Lancet Oncol 18 2017 1274 1284 28754483 \n31 Penson R.T. Valencia R.V. Cibula D. 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"issn_linking": "2452-1094",
"issue": "6(1)",
"journal": "Advances in radiation oncology",
"keywords": null,
"medline_ta": "Adv Radiat Oncol",
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"nlm_unique_id": "101677247",
"other_id": null,
"pages": "100624",
"pmc": null,
"pmid": "33665491",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": "7525039;7799047;32043791;28034065;24621620;29040187;30146110;25749723;24078660;28754483;31067138;31562799;27237360;28712280;16427685;31600397;29893277;12242115;19596963;26876923;28820285;28438473;20818875;30345884;30982687;28871275;32073956;11728685;30887020;28405120",
"title": "Palliative Radiation Therapy for Metastatic, Persistent, or Recurrent Epithelial Ovarian Cancer: Efficacy in the Era of Modern Technology and Targeted Agents.",
"title_normalized": "palliative radiation therapy for metastatic persistent or recurrent epithelial ovarian cancer efficacy in the era of modern technology and targeted agents"
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"abstract": "Background: There is a lack of information about the course of coronavirus disease 2019 (COVID-19) in patients with severe asthma who were treated with biologics. Some reports indicated that treatment with benralizumab, dupilumab, and omalizumab in patients with severe asthma was not associated with significant adverse effects during COVID-19. Methods: Asthma itself or the biologic agents used to treat asthma can have a positive effect on the course of COVID-19. There seem not to be any cases that specifically reported the use of mepolizumab in a patient who was infected with COVID. Results: We reported of a 55-year-old woman with a diagnosis of severe asthma for; 3 years and who was being treated with mepolizumab, with no evidence of loss of asthma control, at the time of contracting COVID-19 and who had been followed up in the allergy clinic. In addition, there are no data on mepolizumab therapy in patients with elevated liver enzyme levels. Conclusion: With this case, we also reported that no adverse effects were observed during mepolizumab treatment in a patient with elevated liver enzyme levels.",
"affiliations": null,
"authors": "Aksu|Kurtuluş|K|;Yesilkaya|Selma|S|;Topel|Musa|M|;Turkyilmaz|Suleyman|S|;Ercelebi|Dilek Cuhadar|DC|;Oncul|Ali|A|;Kalkan|Ilkay Koca|IK|;Ates|Hale|H|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C434107:mepolizumab",
"country": "United States",
"delete": false,
"doi": "10.2500/aap.2021.42.200125",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1088-5412",
"issue": "42(2)",
"journal": "Allergy and asthma proceedings",
"keywords": null,
"medline_ta": "Allergy Asthma Proc",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D001249:Asthma; D000086382:COVID-19; D005260:Female; D006801:Humans; D008875:Middle Aged",
"nlm_unique_id": "9603640",
"other_id": null,
"pages": "e55-e57",
"pmc": null,
"pmid": "33536114",
"pubdate": "2021-03-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "32767400;32544254;32294485;32895599;32553608;32620309;32251625;32417136;32605700;32797762",
"title": "COVID-19 in a patient with severe asthma using mepolizumab.",
"title_normalized": "covid 19 in a patient with severe asthma using mepolizumab"
} | [
{
"companynumb": "TR-ORGANON-O2105TUR000276",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "MONTELUKAST SODIUM"
},
"drugadditional": null... |
{
"abstract": "BACKGROUND\nAn increasing number of anticancer drugs have been reported to cause pneumonitis. Chemotherapy-induced pneumonitis may cause severe morbidity and event death. As there has been a lack of effective treatment, new treatment strategies are needed. A previous case report has indicated that imatinib may be useful.\n\n\nMETHODS\nThe SWENOTECA experience of four cases with severe life-threatening chemotherapy-induced pneumonitis treated with imatinib is presented.\n\n\nRESULTS\nAll four patients responded to treatment with imatinib.\n\n\nCONCLUSIONS\nImatinib appears to be an effective treatment of severe chemotherapy-induced pneumonitis in germ cell cancer patients.",
"affiliations": "a Faculty of Medicine , University of Oslo , Oslo , Norway.;b Department of Oncology-Pathology , Karolinska University Hospital and Karolinska Institutet , Stockholm , Sweden.;b Department of Oncology-Pathology , Karolinska University Hospital and Karolinska Institutet , Stockholm , Sweden.;c Institute of Clinical Medicine - Oncology , University of Tromsø and University Hospital of North Norway , Tromsø , Norway.;d The Cancer Clinic , St. Olavs Hospital , Trondheim , Norway.;e Department of Oncology , University Hospital of Oslo , Oslo , Norway.",
"authors": "Langberg|Marie K|MK|;Berglund-Nord|Carina|C|;Cohn-Cedermark|Gabriella|G|;Haugnes|Hege S|HS|;Tandstad|Torgrim|T|;Langberg|Carl W|CW|",
"chemical_list": "D000970:Antineoplastic Agents; D000068877:Imatinib Mesylate",
"country": "England",
"delete": false,
"doi": "10.1080/0284186X.2018.1479072",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0284-186X",
"issue": "57(10)",
"journal": "Acta oncologica (Stockholm, Sweden)",
"keywords": null,
"medline_ta": "Acta Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D011014:Pneumonia",
"nlm_unique_id": "8709065",
"other_id": null,
"pages": "1401-1406",
"pmc": null,
"pmid": "29869895",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Imatinib may reduce chemotherapy-induced pneumonitis. A report on four cases from the SWENOTECA.",
"title_normalized": "imatinib may reduce chemotherapy induced pneumonitis a report on four cases from the swenoteca"
} | [
{
"companynumb": "NO-HQ SPECIALTY-NO-2018INT000239",
"fulfillexpeditecriteria": "1",
"occurcountry": "NO",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe number of elderly patients with diffuse large B-cell lymphoma (DLBCL) in our aging society continues to rise, although the optimal management of very elderly patients with DLBCL is unknown.\n\n\nMETHODS\nThis study evaluated 207 patients who were 80 years old or older at the diagnosis of DLBCL from 2002 to 2014 at The University of Texas MD Anderson Cancer Center. Analyzed features included clinical characteristics, treatment outcomes, and tolerability of therapy. Cox proportional hazards models examined relations between the treatment regimen and survival.\n\n\nRESULTS\nThe median age was 83 years (range, 80-96 years). Fifty-four percent of the patients had intermediate- to high-risk or high-risk International Prognostic Index scores. Fifteen percent had scores of 4 or higher on the Charlson Comorbidity Index (CCI). The initial therapies included rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; 70%); rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (R-EPOCH; 6%); and non-anthracycline-based therapies, including rituximab, cyclophosphamide, etoposide, vincristine, and prednisone (R-CEOP) and rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP; 10%). With a median follow-up of 38.1 months, the 3-year failure-free survival (FFS) and overall survival (OS) rates were 55% and 54%, respectively. Eighty-eight patients experienced relapse during the follow-up, but only 3 patients (3.4%) experienced relapse beyond 3 years. Patients who received R-CHOP or R-EPOCH had significantly longer FFS than those who received R-CEOP or R-CVP, with 3-year FFS rates of 63% for R-CHOP, 74% for R-EPOCH, and 23% for R-CEOP and R-CVP. Male sex, a monocyte count ≥ 500 × 107 /L, and a CCI score ≥ 4 were significantly associated with inferior OS. Extranodal disease (≥2) and a higher CCI score were associated with a high risk of treatment-related mortality.\n\n\nCONCLUSIONS\nWith anthracycline-based regimens such as R-CHOP and R-EPOCH, very elderly patients with DLBCL had superior outcomes similar to those achieved for younger patients with DLBCL. Cancer 2016;122:3145-51. © 2016 American Cancer Society.",
"affiliations": "Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas. lnastoupil@mdanderson.org.",
"authors": "Chihara|Dai|D|;Westin|Jason R|JR|;Oki|Yasuhiro|Y|;Ahmed|Mohamed A|MA|;Do|Bryan|B|;Fayad|Luis E|LE|;Hagemeister|Fredrick B|FB|;Romaguera|Jorge E|JE|;Fanale|Michelle A|MA|;Lee|Hun J|HJ|;Turturro|Francesco|F|;Samaniego|Felipe|F|;Neelapu|Sattva S|SS|;Rodriguez|M Alma|MA|;Fowler|Nathan H|NH|;Wang|Michael|M|;Davis|Richard E|RE|;Nastoupil|Loretta J|LJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/cncr.30173",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0008-543X",
"issue": "122(20)",
"journal": "Cancer",
"keywords": "comorbidity; diffuse large B-cell lymphoma; elderly; etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH)",
"medline_ta": "Cancer",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D009367:Neoplasm Staging; D011379:Prognosis; D015996:Survival Rate",
"nlm_unique_id": "0374236",
"other_id": null,
"pages": "3145-3151",
"pmc": null,
"pmid": "27351173",
"pubdate": "2016-10-15",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Management strategies and outcomes for very elderly patients with diffuse large B-cell lymphoma.",
"title_normalized": "management strategies and outcomes for very elderly patients with diffuse large b cell lymphoma"
} | [
{
"companynumb": "US-JNJFOC-20161011095",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "The treatment of malignancy in cancer predisposition syndromes that also confer exquisite sensitivity to standard chemotherapy and radiation regimens remains a challenge. Bloom syndrome is one such disorder that is caused by a defect in DNA repair, predisposing to the development of early-onset age-related medical conditions and malignancies. We report on two patients with Bloom syndrome who responded well to chemotherapy despite significant alterations to standard protocols necessitated by hypersensitivity. Both patients experienced severe toxicities and exacerbation of endocrine comorbidities during chemotherapy. A multidisciplinary team of oncologists and endocrinologists is best suited to care for this patient population.",
"affiliations": "Division of Pediatric Hematology/Oncology, Department of Pediatrics, Cohen Children's Medical Center, Zucker School of Medicine at Hofstra/Northwell, New Hyde Park, New York.;Division of Endocrinology, Department of Medicine, Long Island Jewish Medical Center, Zucker School of Medicine at Hofstra/Northwell, New Hyde Park, New York.;Department of Pediatrics, Cohen Children's Medical Center, New Hyde Park, New York.;Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York.;Division of Endocrinology, Department of Medicine, Long Island Jewish Medical Center, Zucker School of Medicine at Hofstra/Northwell, New Hyde Park, New York.",
"authors": "Fein Levy|Carolyn|C|0000-0002-9285-2248;Presswala|Lubaina S|LS|;Slomovic|Alana|A|;Stiefel|Jessica|J|;Schulman-Rosenbaum|Rifka|R|",
"chemical_list": "D000970:Antineoplastic Agents; C097151:Bloom syndrome protein; D053484:RecQ Helicases",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.28815",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "68(2)",
"journal": "Pediatric blood & cancer",
"keywords": "Bloom syndrome; endocrinopathies; malignancy; treatment-related toxicity",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000970:Antineoplastic Agents; D001816:Bloom Syndrome; D004260:DNA Repair; D004700:Endocrine System Diseases; D005260:Female; D006801:Humans; D008297:Male; D009369:Neoplasms; D053484:RecQ Helicases; D055815:Young Adult",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e28815",
"pmc": null,
"pmid": "33226170",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Multidisciplinary management of endocrinopathies and treatment-related toxicities in patients with Bloom syndrome and cancer.",
"title_normalized": "multidisciplinary management of endocrinopathies and treatment related toxicities in patients with bloom syndrome and cancer"
} | [
{
"companynumb": "US-PFIZER INC-2021078325",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROCORTISONE SODIUM SUCCINATE"
},
"drugaddit... |
{
"abstract": "Duloxetine is a second-generation selective serotonin and norepinephrine reuptake inhibitor used primarily for the treatment of depression. Relatively few fatalities have been reported in association with its use. Similarly, there are no known reports that provide a comprehensive analysis of blood, fluid and tissue samples in an overdose setting. Herein we present a fatal case of duloxetine toxicity with both the highest reported post-mortem blood concentration and a comprehensive toxicological analysis of duloxetine in femoral blood, vitreous humor, liver tissue, urine and gastric contents. In doing so, we hope to provide data that can assist both toxicologists and forensic pathologists with assessing duloxetine toxicity in the future.",
"affiliations": "Medical Examiner's Office, Onondaga County Health Department, Syracuse, NY, USA kellyscanlon@ongov.net.;Medical Examiner's Office, Onondaga County Health Department, Syracuse, NY, USA.;NMS Labs, Willow Grove, PA, USA.;Medical Examiner's Office, Onondaga County Health Department, Syracuse, NY, USA.",
"authors": "Scanlon|Kelly Ann|KA|;Stoppacher|Robert|R|;Blum|Lee M|LM|;Starkey|Samantha J|SJ|",
"chemical_list": "D017367:Serotonin Uptake Inhibitors; D000639:Amitriptyline; C004704:cyclobenzaprine; D004155:Diphenhydramine; D000068736:Duloxetine Hydrochloride",
"country": "England",
"delete": false,
"doi": "10.1093/jat/bkv134",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0146-4760",
"issue": "40(2)",
"journal": "Journal of analytical toxicology",
"keywords": null,
"medline_ta": "J Anal Toxicol",
"mesh_terms": "D000368:Aged; D000437:Alcoholism; D000639:Amitriptyline; D003863:Depression; D004155:Diphenhydramine; D062787:Drug Overdose; D000068736:Duloxetine Hydrochloride; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D017367:Serotonin Uptake Inhibitors",
"nlm_unique_id": "7705085",
"other_id": null,
"pages": "167-70",
"pmc": null,
"pmid": "26662354",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Comprehensive Duloxetine Analysis in a Fatal Overdose.",
"title_normalized": "comprehensive duloxetine analysis in a fatal overdose"
} | [
{
"companynumb": "US-TEVA-651945USA",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DIPHENHYDRAMINE"
},
"drugadditional": null,
... |
{
"abstract": "High anion gap metabolic acidosis in adults is a severe metabolic disorder for which the primary organic acid usually is apparent by clinical history and standard laboratory testing. We report a case of recurrent high anion gap metabolic acidosis in a 48-year-old man who initially presented with anorexia and malaise. Physical examination was unrevealing. Arterial pH was 6.98, P co 2 was 5 mm Hg, and chemistry tests showed a bicarbonate level of 3 mEq/L (3 mmol/L), anion gap of 32 mEq/L (32 mmol/L), and a negative toxicology screen result, except for an acetaminophen (paracetamol) level of 7.5 mug/mL. Metabolic acidosis resolved with administration of intravenous fluids. Subsequently, he experienced 5 more episodes of high anion gap metabolic acidosis during an 8-month span. Methanol, ethylene glycol, acetone, ethanol, d -lactate, and hippuric acid screens were negative. Lactate levels were modestly elevated, and acetaminophen levels were elevated for 5 of 6 admissions. These episodes defied explanation until 3 urinary organic acid screens, obtained on separate admissions, showed striking elevations of 5-oxoproline levels. Inborn errors of metabolism in the gamma-glutamyl cycle causing recurrent 5-oxoprolinuria and high anion gap metabolic acidosis are rare, but well described in children. Recently, there have been several reports of apparent acquired 5-oxoprolinuria and high anion gap metabolic acidosis in adults in association with acetaminophen use. Acetaminophen may, in susceptible individuals, disrupt regulation of the gamma-glutamyl cycle and result in excessive 5-oxoproline production. Suspicion for 5-oxoproline-associated high anion gap metabolic acidosis should be entertained when the cause of high anion gap metabolic acidosis remains poorly defined, the anion gap cannot be explained reasonably by measured organic acids, and there is concomitant acetaminophen use.",
"affiliations": "Hospital of St Raphael.",
"authors": "Tailor|Prayus|P|;Raman|Tuhina|T|;Garganta|Cheryl L|CL|;Njalsson|Runa|R|;Carlsson|Katarina|K|;Ristoff|Ellinor|E|;Carey|Hugh B|HB|",
"chemical_list": "D001639:Bicarbonates; D000082:Acetaminophen; D005981:Glutathione Synthase; D011761:Pyrrolidonecarboxylic Acid",
"country": "United States",
"delete": false,
"doi": "10.1053/j.ajkd.2005.03.021",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0272-6386",
"issue": "46(1)",
"journal": "American journal of kidney diseases : the official journal of the National Kidney Foundation",
"keywords": null,
"medline_ta": "Am J Kidney Dis",
"mesh_terms": "D000082:Acetaminophen; D000136:Acid-Base Equilibrium; D000138:Acidosis; D000592:Amino Acid Metabolism, Inborn Errors; D000855:Anorexia; D001639:Bicarbonates; D004417:Dyspnea; D005221:Fatigue; D005981:Glutathione Synthase; D006801:Humans; D008297:Male; D008875:Middle Aged; D011761:Pyrrolidonecarboxylic Acid; D016482:Urinalysis",
"nlm_unique_id": "8110075",
"other_id": null,
"pages": "e4-10",
"pmc": null,
"pmid": "15983950",
"pubdate": "2005-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Recurrent high anion gap metabolic acidosis secondary to 5-oxoproline (pyroglutamic acid).",
"title_normalized": "recurrent high anion gap metabolic acidosis secondary to 5 oxoproline pyroglutamic acid"
} | [
{
"companynumb": "US-RANBAXY-2014US-91555",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "Scopulariopsis/Microascus isolates cause infections with high mortality in lung transplant recipients. Treatment is challenging due to antimicrobial resistance. We describe two cases of Scopulariopsis/Microascus tracheobronchitis in lung transplant recipients successfully treated with nebulized micafungin. This antifungal was well tolerated and achieved high concentrations in epithelial lining fluid up to 14 h after nebulization without significant plasma concentrations. Nebulized micafungin may be a safe and effective option for the treatment of fungal tracheobronchitis.",
"affiliations": "Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.;Lung Transplant Unit, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.;Microbiology Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.;Pharmacy Department, Hospital del Mar, Universitat Autònoma de Barcelona, Barcelona, Spain.;Pharmacy Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.;Thoracic Surgery Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.;Critical Care Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.;Pharmacy Department, Hospital del Mar, Universitat Autònoma de Barcelona, Barcelona, Spain.;Lung Transplant Unit, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.;Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.",
"authors": "Los-Arcos|Ibai|I|0000-0001-8835-2702;Berastegui|Cristina|C|;Martín-Gómez|María Teresa|MT|;Grau|Santiago|S|;Campany-Herrero|David|D|;Deu|María|M|;Sacanell|Judith|J|;Campillo|Nuria|N|;Bravo|Carles|C|;Len|Oscar|O|0000-0002-1819-3141",
"chemical_list": "D000935:Antifungal Agents; D000077551:Micafungin",
"country": "United States",
"delete": false,
"doi": "10.1128/AAC.02174-20",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0066-4804",
"issue": "65(6)",
"journal": "Antimicrobial agents and chemotherapy",
"keywords": "echinocandin; fungal infections; inhaled antibiotics; lung transplantation; stenting",
"medline_ta": "Antimicrob Agents Chemother",
"mesh_terms": "D000935:Antifungal Agents; D006801:Humans; D008168:Lung; D000077551:Micafungin; D009181:Mycoses; D060645:Scopulariopsis; D066027:Transplant Recipients",
"nlm_unique_id": "0315061",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33722884",
"pubdate": "2021-05-18",
"publication_types": "D016428:Journal Article",
"references": "25376207;24726020;28257903;24548001;30801642;29120502;31329937;25583727;21419994;26180134;21182358;20439610;18828858;26100698;26678668;31481441;31166635;28199491;31469629;25902706;26014943",
"title": "Nebulized Micafungin Treatment for Scopulariopsis/Microascus Tracheobronchitis in Lung Transplant Recipients.",
"title_normalized": "nebulized micafungin treatment for scopulariopsis microascus tracheobronchitis in lung transplant recipients"
} | [
{
"companynumb": "ES-FRESENIUS KABI-FK202111279",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MICAFUNGIN"
},
"drugadditional": "1",
... |
{
"abstract": "Since fall 2019, SARS-CoV-2 spread world-wide, causing a major pandemic with estimated ~ 220 million subjects affected as of September 2021. Severe COVID-19 is associated with multiple organ failure, particularly of lung and kidney, but also grave neuropsychiatric manifestations. Overall mortality reaches > 2%. Vaccine development has thrived in thus far unreached dimensions and will be one prerequisite to terminate the pandemic. Despite intensive research, however, few treatment options for modifying COVID-19 course/outcome have emerged since the pandemic outbreak. Additionally, the substantial threat of serious downstream sequelae, called 'long COVID' and 'neuroCOVID', becomes increasingly evident. Among candidates that were suggested but did not yet receive appropriate funding for clinical trials is recombinant human erythropoietin. Based on accumulating experimental and clinical evidence, erythropoietin is expected to (1) improve respiration/organ function, (2) counteract overshooting inflammation, (3) act sustainably neuroprotective/neuroregenerative. Recent counterintuitive findings of decreased serum erythropoietin levels in severe COVID-19 not only support a relative deficiency of erythropoietin in this condition, which can be therapeutically addressed, but also made us coin the term 'hypoxia paradox'. As we review here, this paradox is likely due to uncoupling of physiological hypoxia signaling circuits, mediated by detrimental gene products of SARS-CoV-2 or unfavorable host responses, including microRNAs or dysfunctional mitochondria. Substitution of erythropoietin might overcome this 'hypoxia paradox' caused by deranged signaling and improve survival/functional status of COVID-19 patients and their long-term outcome. As supporting hints, embedded in this review, we present 4 male patients with severe COVID-19 and unfavorable prognosis, including predicted high lethality, who all profoundly improved upon treatment which included erythropoietin analogues.\n\n\n\nSubstitution of EPO may-among other beneficial EPO effects in severe COVID-19-circumvent downstream consequences of the 'hypoxia paradox'. A double-blind, placebo-controlled, randomized clinical trial for proof-of-concept is warranted.",
"affiliations": "Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Hermann-Rein-Str.3, 37075, Göttingen, Germany.;Department of Nephrology and Rheumatology, University Medical Center, Göttingen, Germany.;Hospital Clinic, Institute of Neuroscience, IDIBAPS, CIBERSAM, Barcelona, Spain.;Johann Friedrich Blumenbach Institute of Zoology & Anthropology, University of Göttingen, Göttingen, Germany.;Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Hermann-Rein-Str.3, 37075, Göttingen, Germany.;Hospital Clinic, Institute of Neuroscience, IDIBAPS, CIBERSAM, Barcelona, Spain.;Department of Neurology, Hannover Medical School, Hannover, Germany.;Psychiatric Centre Copenhagen, University Hospital, Rigshospitalet, Copenhagen, Denmark.;Department of Anaesthesiology, University Medical Center Göttingen, Göttingen, Germany.;Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Hermann-Rein-Str.3, 37075, Göttingen, Germany. ehrenreich@em.mpg.de.",
"authors": "Begemann|Martin|M|0000-0003-0493-7370;Gross|Oliver|O|0000-0002-8390-8852;Wincewicz|Dominik|D|0000-0002-0747-6306;Hardeland|Rüdiger|R|0000-0003-0178-6378;Daguano Gastaldi|Vinicius|V|0000-0002-6249-6035;Vieta|Eduard|E|0000-0002-0548-0053;Weissenborn|Karin|K|0000-0002-1157-8938;Miskowiak|Kamilla W|KW|0000-0003-2572-1384;Moerer|Onnen|O|0000-0002-4210-388X;Ehrenreich|Hannelore|H|0000-0001-8371-5711",
"chemical_list": "C554270:EPO protein, human; D011994:Recombinant Proteins; D004921:Erythropoietin",
"country": "England",
"delete": false,
"doi": "10.1186/s10020-021-00381-5",
"fulltext": "\n==== Front\nMol Med\nMol Med\nMolecular Medicine\n1076-1551\n1528-3658\nBioMed Central London\n\n381\n10.1186/s10020-021-00381-5\nReview\nAddressing the ‘hypoxia paradox’ in severe COVID-19: literature review and report of four cases treated with erythropoietin analogues\nhttps://orcid.org/0000-0003-0493-7370\nBegemann Martin 12\nhttps://orcid.org/0000-0002-8390-8852\nGross Oliver 3\nhttps://orcid.org/0000-0002-0747-6306\nWincewicz Dominik 4\nhttps://orcid.org/0000-0003-0178-6378\nHardeland Rüdiger 5\nhttps://orcid.org/0000-0002-6249-6035\nDaguano Gastaldi Vinicius 1\nhttps://orcid.org/0000-0002-0548-0053\nVieta Eduard 4\nhttps://orcid.org/0000-0002-1157-8938\nWeissenborn Karin 6\nhttps://orcid.org/0000-0003-2572-1384\nMiskowiak Kamilla W. 7\nhttps://orcid.org/0000-0002-4210-388X\nMoerer Onnen 8\nhttps://orcid.org/0000-0001-8371-5711\nEhrenreich Hannelore ehrenreich@em.mpg.de\n\n1\n1 grid.419522.9 0000 0001 0668 6902 Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Hermann-Rein-Str.3, 37075 Göttingen, Germany\n2 grid.411984.1 0000 0001 0482 5331 Department of Psychiatry and Psychotherapy, University Medical Center, Göttingen, Germany\n3 grid.411984.1 0000 0001 0482 5331 Department of Nephrology and Rheumatology, University Medical Center, Göttingen, Germany\n4 grid.10403.36 Hospital Clinic, Institute of Neuroscience, IDIBAPS, CIBERSAM, Barcelona, Spain\n5 grid.7450.6 0000 0001 2364 4210 Johann Friedrich Blumenbach Institute of Zoology & Anthropology, University of Göttingen, Göttingen, Germany\n6 grid.10423.34 0000 0000 9529 9877 Department of Neurology, Hannover Medical School, Hannover, Germany\n7 grid.475435.4 Psychiatric Centre Copenhagen, University Hospital, Rigshospitalet, Copenhagen, Denmark\n8 grid.411984.1 0000 0001 0482 5331 Department of Anaesthesiology, University Medical Center Göttingen, Göttingen, Germany\n26 9 2021\n26 9 2021\n2021\n27 12027 7 2021\n13 9 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.\nBackground\n\nSince fall 2019, SARS-CoV-2 spread world-wide, causing a major pandemic with estimated ~ 220 million subjects affected as of September 2021. Severe COVID-19 is associated with multiple organ failure, particularly of lung and kidney, but also grave neuropsychiatric manifestations. Overall mortality reaches > 2%. Vaccine development has thrived in thus far unreached dimensions and will be one prerequisite to terminate the pandemic. Despite intensive research, however, few treatment options for modifying COVID-19 course/outcome have emerged since the pandemic outbreak. Additionally, the substantial threat of serious downstream sequelae, called ‘long COVID’ and ‘neuroCOVID’, becomes increasingly evident.\n\nMain body of the abstract\n\nAmong candidates that were suggested but did not yet receive appropriate funding for clinical trials is recombinant human erythropoietin. Based on accumulating experimental and clinical evidence, erythropoietin is expected to (1) improve respiration/organ function, (2) counteract overshooting inflammation, (3) act sustainably neuroprotective/neuroregenerative. Recent counterintuitive findings of decreased serum erythropoietin levels in severe COVID-19 not only support a relative deficiency of erythropoietin in this condition, which can be therapeutically addressed, but also made us coin the term ‘hypoxia paradox’. As we review here, this paradox is likely due to uncoupling of physiological hypoxia signaling circuits, mediated by detrimental gene products of SARS-CoV-2 or unfavorable host responses, including microRNAs or dysfunctional mitochondria. Substitution of erythropoietin might overcome this ‘hypoxia paradox’ caused by deranged signaling and improve survival/functional status of COVID-19 patients and their long-term outcome. As supporting hints, embedded in this review, we present 4 male patients with severe COVID-19 and unfavorable prognosis, including predicted high lethality, who all profoundly improved upon treatment which included erythropoietin analogues.\n\nShort conclusion\n\nSubstitution of EPO may—among other beneficial EPO effects in severe COVID-19—circumvent downstream consequences of the ‘hypoxia paradox’. A double-blind, placebo-controlled, randomized clinical trial for proof-of-concept is warranted.\n\nKeywords\n\nRecombinant human EPO\nDarbepoetin\nNeuroprotection\nTreatment\nSignaling\nCritical care\nOutcome\ndfgTRR 274/1 2020 - 408885537 Ehrenreich Hannelore http://dx.doi.org/10.13039/501100003554 lundbeckfonden R215-2015-4121 Miskowiak Kamilla W. http://dx.doi.org/10.13039/501100004189 max-planck-gesellschaft Max Planck Institute of Experimental Medicine (2)Open Access funding enabled and organized by Projekt DEAL.\n\nissue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\nSince December 2019, a pandemic, COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Lu et al. 2020; Zhou et al. 2020; Zhu et al. 2020), approached 220 million confirmed cases and led to the death of ~ 4.5 million people worldwide, as of September 2021. Despite considerable success in developing vaccines (Haas et al. 2021; Sahin et al. 2021), COVID-19 keeps progressing around the globe with very limited advancement in the development of drugs for COVID-19 treatment (Batista et al. 2021; Kim et al. 2020; Kluge et al. 2021; WHO Solidarity Trial Consortium 2021; World Health Organization 2021a, b).\n\nSARS-CoV-2 is a beta-coronavirus that infects cells via the angiotensin-converting enzyme 2 (ACE2) receptor. Multitropic by nature, it can in severe cases cause multi-organ failure, in particular of lung, heart, and kidney (Puelles et al. 2020). SARS-CoV-2 is often associated with a so-called cytokine storm (Fajgenbaum and June 2020; Mehta et al. 2020; Moore and June 2020), a hypercoagulable state (Bilaloglu et al. 2020; Klok et al. 2020; Levi et al. 2020), and induction of pronounced autoimmune reactions (Dotan et al. 2021; Halpert and Shoenfeld 2020; Wang et al. 2021). Via the olfactory mucosa, it penetrates to the central nervous system along the olfactory tract, appears to follow neuroanatomical structures, and affects predominantly the brainstem, including primary respiratory and cardiovascular control centers in the medulla oblongata (Matschke et al. 2020; Meinhardt et al. 2021). SARS-CoV-2 targets the blood–brain-barrier (BBB), affects endothelial cells (Buzhdygan et al. 2020; Rhea et al. 2021), and can lead to microvascular injury in the brain and spreading neuroinflammation of COVID-19 patients (Lee et al. 2021). Neurological manifestations or complications of COVID-19 disturb central and peripheral nervous system functions and structures, and have been shown in essentially all age groups (Kihira et al. 2020; LaRovere et al. 2021; Mao et al. 2020; Oxley et al. 2020; Paterson et al. 2020; Solomon 2021).\n\nPersistent symptoms after recovery from the acute infection, referred to as post-acute or long COVID, as well as damage to the nervous system, inducing neuropsychiatric downstream syndromes, called neuroCOVID, may lead to significant long-term disability after survival of the acute phase (Al-Ramadan et al. 2021; Boldrini et al. 2021; Carfi et al. 2020; Davis et al. 2021; Huang et al. 2021; Iqbal et al. 2021; Nalbandian et al. 2021; Solomon et al. 2020; Sudre et al. 2021; Taquet et al. 2021; Townsend et al. 2020). Across brain cell types, COVID-19 perturbations overlap with those in chronic brain disorders and reside in genetic variants associated with cognition, schizophrenia, and depression (Yang et al. 2021). Due to the recognized neuroprotective, procognitive and neuroregenerative capacities of erythropoietin (EPO) in exactly these conditions, this very recent report strongly supports its application for preventing neuroCOVID, as outlined below. In general, host genetic factors influence the severity of the COVID-19 course (Kuo et al. 2020; Severe Covid-19 GWAS Group 2020). Among the risk genes is for instance the APOE4 allele that affects BBB integrity (Hammer et al. 2014; Kuo et al. 2020; Masoli et al. 2021; Montagne et al. 2020).\n\nDespite intensive research within the last year, only few treatments for COVID-19 are currently available (Kim et al. 2020; Kluge et al. 2021; WHO Solidarity Trial Consortium 2021), and to date, no effective measures are known to improve conditions of long COVID or neuroCOVID (Llach and Vieta 2021). This scarcity of options for the management of COVID-19 and the emergence of ‘immune escape’ against established vaccines plus ‘breakthrough infections’ (Birhane et al. 2021; Edara et al. 2021; Garcia-Beltran et al. 2021; Li et al. 2021; Plante et al. 2021; Prevost and Finzi 2021; Thorne et al. 2021; Wall et al. 2021; Zhou et al. 2021), reducing the hope of a speedy termination of the pandemic, call for new strategies to treat COVID-19. Based on the known neuroprotective and anti-inflammatory features of EPO, and its proven efficacy and excellent tolerability in different neuropsychiatric conditions (Ehrenreich et al. 2020; Miskowiak et al. 2021; Sargin et al. 2010; Sirén et al. 2009), we proposed the use of recombinant human (rh) EPO for the treatment of severely affected COVID-19 patients. The sketched double-blind, placebo-controlled, randomized clinical trial (Ehrenreich et al. 2020), has not yet received appropriate funding. However, our proposal is now strongly reinforced by further post-mortem data on COVID-19 (Yang et al. 2021). Here we present four cases of severe COVID-19 and unfavorable prognosis, that received EPO analogues. These were the only cases we became aware of except for a published case report (Hadadi et al. 2020). We report the disease course of these male patients upon treatment and discuss possible mechanisms contributing to their beneficial outcome.\n\nCases\n\nThe 4 patients (individual synopses presented in Table 1) were all men in the range of 58 to 80 years, who presented with dyspnea, malaise, and other nonspecific signs of viral infection, and were confirmed by nasopharyngeal swab and PCR to be positive for SARS-CoV-2. All patients progressed swiftly to respiratory failure, were critically ill, hospitalized and treated in intensive care units (ICUs) for variable length of time. The duration of severe hypoxia, requiring oxygen supplementation, amounted to only 3 days in case 1—under the immediately started rhEPO application as compassionate use approach, in absence of any approved treatment for severe COVID-19. This unusually fast improvement may at least hypothetically be attributable to EPO. The underlying beneficial effects likely go beyond erythropoiesis and include counteraction of the complex pathophysiology of COVID-19 as delineated in the present paper and previous reviews on EPO in COVID-19 (Ehrenreich et al. 2020; Sahebnasagh et al. 2020). The 3 other patients (cases 2–4) developed severe acute respiratory distress syndrome (ARDS), clinically reflected by the need for invasive ventilatory settings, and additional prone positioning. Acute renal injury and cardio-circulatory deterioration were swiftly prominent in these patients and led to an instant treatment with EPO analogues. Cases 2 and 4 needed renal replacement therapy. Cases 2–4 were on anticoagulation treatment as is the standard for COVID-19 in German intensive care units, at least the low molecular weight heparin for prophylaxis of venous thrombosis. All 4 patients of our case report series were anemic, additionally underlining their severe disease state (Taneri et al. 2020). None of them received blood transfusions. The iron status of all remained within the normal range or close to normal (transferrin saturation 12–31%; normal range 16–45%). Other laboratory values, as much as available for all four cases, were further consistent with a severe course of COVID-19 with hypoxia and highly elevated inflammatory markers in the sense of a cytokine storm (Table 1). All 4 patients received injections of rhEPO analogues, according to conventional dosing for anemia treatment in nephrology (around 2000–4000 IU per injection), and recovered either during hospitalization (Case 1; the least severe of our cases) or during rehabilitation care (Cases 2–4).Table 1 Synopsis of 4 male COVID-19 patients treated with EPO analogues\n\n\tCase 1\tCase 2\tCase 3\tCase 4\t\nAge (years)\t68\t59\t80\t58\t\nGender\tMale\tMale\tMale\tMale\t\nTime/place of SARS-CoV-2 contact\tMarch 2020, Poland\tMarch 2020, Austria\tFebruary 2021, Germany\tFebruary 2021, Germany\t\nPremedical history\tChronic kidney disease (stage 2)\n\nArterial hypertension\n\n\tIntermittent atrial fibrillation\n\nArterial hypertension\n\nPast heavy smoker\n\n\tChronic kidney disease (stage 2)\n\nChronic obstructive pulmonary disease\n\nArterial hypertension\n\nPulmonary embolism 2016\n\nPast heavy smoker\n\n\tArterial hypertension\n\nAdipositas\n\nMetabolic syndrome\n\n\t\nPresenting symptoms\tCough, dyspnea, fever\tUnspecific malaise, dyspnea\tUnspecific malaise, dry cough, headache, diarrhea\tUnspecific malaise, dyspnea, diarrhea\t\nCourse, complications and treatment\tProgression to respiratory failure with hypoxemia and normocapnia\n\nTransfer to ICU with nasal O2 insufflation\n\nDelivery of oxygen through face mask (initial flow 6 L/min, finally reduced to 4 L/min to target SPO2 of 90–92%\n\nSupportive treatment only\n\n\tProgression to respiratory failure\n\nTransfer to ICU with ARDS (mechanical ventilation for 24 days; intermittent prone position; max FiO2 100%, max inspiratory pressure 30 cmH2O, max PEEP 14 cmH2O)\n\nAKI with renal replacement therapy for 42 days\n\nCritical care/treatment with:\n\n• Anticoagulation with heparin/argatroban\n\n•Prednisolon pulse therapy\n\n• Toculizumab infusion\n\n• Antiviral therapy: Lopinavir/Ri-tonavir for 2 weeks at start of hospital stay, hydrochloroquine\n\nCritical illness polyneuropathy\n\n\tProgression to respiratory failure\n\nTransfer to ICU with ARDS\n\n(high-flow oxygen therapy HFNC and intermittent non-invasive mechanical ventilation for 21 days, intermittent prone position; max FiO2 85%, max. pressure support 6 cmH2O, max PEEP 8 cmH2O)\n\nAKI without need for renal replacement therapy (minimal eGFR 28 ml/min)\n\nCritical care/treatment with:\n\n• Anticoagulation with heparin\n\n• Prednisolon pulse therapy\n\n• Antiviral therapy: none\n\nCritical illness polyneuropathy\n\n\tProgression to respiratory failure\n\nTransfer to ICU with ARDS (mechanical ventilation for 17 days, intermittent prone position; max FiO2 100%, max inspiratory pressure 26 cmH2O, max PEEP 12 cmH2O)\n\nAKI with renal replacement therapy for 6 days\n\nCritical care/treatment with:\n\n• Anticoagulation: heparin\n\n• Prednisolon pulse therapy\n\n• Antiviral therapy: Camostat for 10 days\n\nCritical illness polyneuropathy\n\n\t\nEPO analogue Treatment (started within the first 2 days of ICU admission)\tRecombinant human EPO (Epoetin beta, NeoRecormon- Roche 20 IU/kg body weight, every 12 h; 5 infusions)\tDarbepoetin alfa (40 µg sc. once weekly, Aranesp-Amgen) for 5 weeks\tDarbepoietin alfa (40 µg sc. once weekly, Aranesp-Amgen)—for 4 weeks\tDarbepoietin alfa (40 µg sc. once weekly, Aranesp -Amgen) for 3 weeks\t\nEPO equivalent dose in total\t100 µg (10,000 IU)\t200 µg (20,000 IU)\t160 µg (16,000 IU)\t120 µg (12,000 IU)\t\nOutcome\tDischarge from ICU after 72 h; patient remained hospitalized for additional 3 weeks\n\nRespiratory: complete recovery\n\n\tDischarge after 8 weeks ICU stay, rehabilitation care 3 weeks\n\nRespiratory: complete recovery\n\nRenal: complete recovery\n\nNeurological: complete recovery\n\n\tDischarge after 44 days with 22 days ICU stay\n\nRespiratory: recovery\n\nRenal: recovery\n\nNeurological: partial recovery, remaining general weakness\n\n\tDischarge after 31 days with 19 days ICU stay\n\nRespiratory: complete recovery\n\nRenal: complete recovery\n\nNeurological: complete recovery\n\n\t\nLaboratory parameters (inflammation markers)\tCRP max. 79.9 mg/l\n\n(normal < 5.0 mg/l)\n\n\tCRP max. 119.6 mg/l\n\n(normal < 5.0 mg/l)\n\nIL-6: 259–775 pg/ml\n\n(normal < 7.0 pg/ml)\n\ns-Interleukin 2 R (IU/ml):\n\n3359–6189 (normal range 223–710);\n\nd-Dimers: max. 7.11 mg/l (normal < 0.5 mg/l)\n\nFibrinogen: max. 936 mg/dl (normal range 200–393 mg/dl)\n\n\tCRP max. 210.0 mg/l\n\n(normal < 5.0 mg/l)\n\nIL-6: 68 pg/ml\n\n(normal < 7.0 pg/ml)\n\ns-Interleukin 2 R: N/A\n\nd-Dimers: max. 6.64 mg/l (normal < 0.5 mg/l)\n\nFibrinogen: max. 927 mg/dl (normal range 200–393 mg/dl)\n\n\tCRP max. 119.9 mg/l\n\n(normal < 5.0 mg/l)\n\nIL-6: 18 pg/ml\n\n(normal < 7.0 pg/ml)\n\ns-Interleukin 2 R (IU/ml):\n\n3002–3038 (normal range 223–710)\n\nd-Dimers: max. 17.42 mg/l (normal < 0.5 mg/l)\n\nFibrinogen: max. 661 mg/dl (normal range 200–393 mg/dl)\n\n\t\nLaboratory parameters\n\nHematocrit (Hct)\n\nHemoglobin (Hb)\n\n\tPrior to EPO:\n\nHb 9.6 g/dl; Hct 28.4%\n\nDischarge from ICU (EPO subsequently stopped):\n\nHb 10.1 g/dl; Hct 29.9%\n\n\tPrior to EPO:\n\nHb 8.1 g/dl; Hct 22.7%\n\nDischarge from ICU (with EPO):\n\nHb 8.7 g/dl; Hct 26.0%\n\nEPO discontinued at:\n\nHb11g/dl; Hct 35%\n\n\tPrior to EPO:\n\nHb 7.9 g/dl; Hct 23.1%\n\nDischarge from ICU (with EPO):\n\nHb 8.1 g/dl; Hct 24.9%\n\nEPO discontinued at:\n\nHb > 11 g/dl; Hct ca. 35%\n\n\tPrior to EPO:\n\nHb 9.5 g/dl; Hct 27.9%,\n\nDischarge from ICU (with EPO):\n\nHb 11.7 g/dl; Hct 34.5%\n\nEPO discontinued at:\n\nHb 12 g/dl\n\n\t\nBold indicates common symptoms/measurements shared between the cases\n\nAKI acute kidney injury, ARDS acute respiratory distress syndrome, HFNC high flow nasal canula, ICU intensive care unit, max maximal, N/A not available\n\nDiscussion\n\nWe recently advocated the use of rhEPO for supportive treatment of severe COVID-19, provided a comprehensive review backing this idea, and published the design of a clinical trial (Ehrenreich et al. 2020). So far, we did not succeed in obtaining the necessary funding for a clinical study. Since rhEPO has been approved for decades as well-tolerated and safe anemia drug, funding agencies send applicants for clinical rhEPO projects to industry or at least request industry to take a share in the costs of a clinical trial. Upon patent expiration in 2008, however, industry faces competition for the highly lucrative anemia market by biosimilar producers and fears off-label use and emergence of new side effects, thus unfortunately does not welcome clinical research on further rhEPO indications. Hence, at this point, we can only present as further supporting hints for our concept, 4 male patients with severe COVID-19 who were treated with EPO analogues. These were the only COVID-19 cases who received EPO analogues we became aware of and had access to. In all cases, EPO was well tolerated and associated with remarkable recovery despite severe COVID-19 with multiple critical complications, including respiratory and renal failure, documented cytokine storm, and critical illness polyneuropathy. Additional factors in our cases, known to be associated with unfavorable prognosis in hospitalized patients, were older age, male gender, and their comorbidities (Becher and Frerichs 2020).\n\nWe had originally considered for our small case series a ‘center control group’, however, had to surrender this plan because in our hospital, sufficient numbers of adequate male patients with comparable age and disease severity would not have been available for a convincing ‘twin-matching’ (which would require at least 1:3 or 1:4, i.e. N = 12–16 suitable ‘statistical twins’). Instead, and also to avoid an impression of ‘cherry picking’ controls post-hoc, we cite outcomes of highly representative German surveys, e.g. on 10,021 patients with COVID-19 admitted to 920 German hospitals (Karagiannidis et al. 2020). In-hospital mortality in mechanically ventilated patients requiring dialysis was here 73% (342 of 469). In the respective observational time period of our cases, the mortality of mechanically ventilated COVID-19 patients in ICUs in Germany remained at 50% across age groups even with introduction of additional therapeutic measures like early corticosteroids/dexamethasone or IL-6 blockade (Karagiannidis et al. 2021; Kluge et al. 2021; Wilkinson 2020). Clinical course and laboratory values in cases 2–4 showed dramatic increases in IL-6, often as part of the cytokine storm and predictor of poor survival (Chang et al. 2021; Chen et al. 2020; Mehta et al. 2020; Moore and June 2020; Tan et al. 2020; Webb et al. 2020).\n\nIn striking contrast to the very poor prognosis is the outcome with full recovery of all patients. The here presented four cases are consistent with a prior case report of an 80 year-old man with multiple medical comorbidities who recovered completely after EPO treatment (Hadadi et al. 2020). The total EPO equivalent dose that this case and our 4 patients received, ranged between 10,000 and 20,000 IU (100–200 µg) over 1–5 weeks, corresponding to the conventional dosing for anemia treatment in nephrology (around 2000–4000 IU per injection). These doses are low as compared to those needed for improving cognition and motor performance in neuropsychiatric indications like multiple sclerosis, schizophrenia or affective disorders (Ehrenreich et al. 2007a, b; Miskowiak et al. 2014a, b) or for reducing progressive brain matter loss in these conditions (Miskowiak et al. 2015; Wüstenberg et al. 2011). Although the presence of a slightly compromised BBB in some patients suffering from these neuropsychiatric diseases is well established and allows a higher quantity of EPO to reach the brain (Ehrenreich et al. 2004), it is unlikely equivalent to the massive BBB breakdown expected in severe COVID-19 with the typical cytokine storm. This may explain why in COVID-19 comparably low doses seem sufficient also for improving neurological sequelae which was not the case in e.g. multiple sclerosis (Ehrenreich et al. 2007a). Nevertheless, in a potential clinical trial, investigating EPO treatment for improving outcome of severe COVID-19 patients (Ehrenreich et al. 2020), and particularly for preventing neuroCOVID and long COVID (Llach and Vieta 2021), at least 10× higher doses may have to be tested—perhaps as parallel study arm—to disclose the optimal amount required for these conditions.\n\nSafety issues\n\nOverall, in critically ill patients, EPO is safe and probably efficient, as summarized in recent meta-analyses (Litton et al. 2019; Mesgarpour et al. 2017). Nevertheless, employing EPO in severe COVID-19 for improving acute and downstream outcome (long COVID), requires watchful and comprehensive safety management as much as in all other EPO indications and, in particular, when using high doses of EPO to obtain sufficient levels also in brain (Bartels et al. 2008). Careful observation and follow-up at all times is mandatory, including clinical examination (blood pressure monitoring etc.) as well as routine laboratory screening (hematocrit, hemoglobin, thrombocyte counts etc.) during the period of EPO application to prevent augmentation of prothrombotic constellations in addition to the known hypercoagulable state in COVID-19 (Bilaloglu et al. 2020; Klok et al. 2020; Levi et al. 2020). Hematocrit/hemoglobin have to stay within clearly defined limits. Although the necessity of blood lettings in COVID-19 is expectedly extremely low due to the here reviewed reduced production of and/or response to EPO, in the unlikely situation of hematocrit increase towards the upper limit, blood letting should be initiated. Along the same lines, no iron substitution is allowed in this indication at any time, as it could possibly induce undesired ‘side effects’ in non-anemic COVID-19 patients. Iron substitution, as performed in studies targeting pure anemia, acts pro-inflammatory and may push hematopoiesis, even though expectedly weaker in the inflammatory environment of COVID-19. The fact that EPO treatment leads to temporary shifts in iron stores, and upon longterm application causes a picture similar to that of true iron deficiency, as reported in chronic progressive multiple sclerosis (Ehrenreich et al. 2007a), might even provide additional benefit for COVID-19 patients, adding to the panel of protective effects of this growth factor. Notably, also iron chelators have been proposed for treatment of COVID-19 (Carota et al. 2021).\n\nHypothetical explanations of the ‘hypoxia paradox’\n\nSurprisingly, recent reports showed decreased serum EPO levels in patients with severe COVID-19 (Viruez-Soto et al. 2021; Yagci et al. 2021). In the context of hypoxia, as experienced in this condition, we would rather have expected increased levels of EPO as a hypoxia-inducible growth factor (Brines and Cerami 2005; Jelkmann 1992; Krantz 1991). This phenomenon, which we coined ‘hypoxia paradox’, likely contributes to unfavorable outcomes in COVID-19. Along these lines of thought, people living at high-altitude have elevated levels of serum EPO and are therefore believed to be better protected from a severe course of COVID-19 (Arias-Reyes et al. 2020, 2021; Beall 2007; Jaramillo et al. 2021; Soliz et al. 2020; Viruez-Soto et al. 2021; Zubieta-Calleja et al. 2020). In our patients, serum EPO levels were not available, as EPO determinations are not part of any clinical laboratory routine, but an assumption of diminished levels would perfectly fit with their documented anemia prior to EPO treatment (Table 1). Interestingly, a recent systematic review and meta-analysis also reported that severe COVID-19 cases had lower hemoglobin levels compared to moderate cases (Taneri et al. 2020). However, even if baseline serum EPO concentrations in our patients had been normal, not lowered (which we do not know), this would not abrogate potential beneficial effects of exogenous rhEPO administration.\n\nThe apparent ‘hypoxia paradox’ indicates dysfunctional signaling of the hypoxia circuitry required for the induction of EPO. The molecular mechanisms behind this ‘hypoxia paradox’ are still widely unknown. Several hypotheses that will have to be experimentally addressed in the future are listed here and sketched in Fig. 1:Fig. 1 Suppression of EPO expression as a consequence of SARS-CoV2 infection and the rationale for rhEPO supplementation. Putative action of viral nonstructural proteins (NSP) and viral proteases on host protein biosynthesis and stability of host proteins (see text for references and details). Failure of EPO response to hypoxia may result in anemia and enhanced tissue/brain/neural injury. External EPO or EPO biosimilars are expected to combat anemia, reconstitute neuroprotection and tissue protection and mediate beneficial immune modulation. PAMP (pathogen-associated molecular pattern) and DAMP (damage-associated molecular pattern) recognition can induce primary and secondary cytokine storms, respectively. EPO suppression by TNFα and by TNFα/NF-κB-mediated induction of miR-122 has been demonstrated under various inflammatory conditions (Cluzeau et al. 2017; Rivkin et al. 2016). Anti-inflammatory actions, vascular protection and beneficial effects of EPO on respiratory functions have been reviewed in detail earlier (Ehrenreich et al. 2020)\n\nMitochondrial dysfunction: SARS-CoV-2 obviously hijacks host mitochondria in COVID-19 pathogenesis (Singh et al. 2020). By SARS-CoV-2 protein interaction map (Gordon et al. 2020) or by combining an RNA-centric approach and functional CRISPR screens, physical and functional connection between SARS-CoV-2 and mitochondria has been demonstrated, highlighting this organelle as a general platform for antiviral activity (Flynn et al. 2021). Moreover, altered expression of mitochondrial genes has been demonstrated by scRNAseq in a primate model of Corona infection (Speranza et al. 2021), and SARS-CoV-2 downregulated nuclear-encoded mitochondrial genes related to cellular respiration and complex I (Miller et al. 2021). Mitochondrial dysfunction has further been reported in the context of metabolic programs that define dysfunctional immune responses in severe COVID-19 (Thompson et al. 2021).\n\nHypoxia signaling via HIF-1α and dioxygenase enzymes, prolyl hydroxylases 1,2,3 (PHD1,2,3), requires intact mitochondria. In COVID-19 sepsis, mitochondria become dysfunctional through a disturbed HIF-1α/sirtuin pathway (Shenoy 2020). Mitochondrial function and HIF are intimately interconnected to regulate each other (Tormos and Chandel 2010), and their impairment may well contribute to uncoupling of the hypoxia pathway. Tissue proteomic studies in turn showed the induction of hypoxia pathways in different organs of patients who deceased from COVID-19, but did not list EPO (Nie et al. 2021). This is perhaps less surprising, considering that due to its very low expression, mRNA of EPO regularly escapes single cell mRNA-seq analysis, a known dropout effect of this methodology. We note that EPO is an extremely potent hypoxia-inducible factor, locally effective in auto-paracrine fashion at femtomol concentrations (Butt et al. 2021; Wakhloo et al. 2020). In the situation of COVID-19, however, the low expression is likely further inhibited as a result of the uncoupled hypoxia pathway.\n\nInflammation and biosynthesis of EPO: Inflammatory processes induce the expression of microRNA122 that targets an evolutionary well-preserved seed site in the 3ʹUTR of EPO leading to reduced biosynthesis of EPO in the kidney (Rivkin et al. 2016). Moreover, proinflammatory proteins S100A9 and TNFα suppress EPO expression e.g. in myelodysplastic syndrome (Cluzeau et al. 2017). EPO biosynthesis might be further inhibited by viral gene products like NSP1 (nonstructural protein 1) which suppresses production of a whole array of host proteins (Yuan et al. 2020). This could also occur via derangement of host signaling circuitries as shown for structural proteins of SARS-CoV-2 (Jakhmola et al. 2021).\n\nProteolysis and degradation of EPO: The viral serine proteases such as NSP3 and/or NSP5 (Dai et al. 2020; Osipiuk et al. 2021; Zhang et al. 2020) might target EPO as well and lead to its proteolysis. Interestingly, recently identified inhibitors against the SARS-CoV-2 encoded main protease have been suggested as a treatment option for COVID-19 (Günther et al. 2021). In addition, host proteases that are induced in severe COVID-19 might proteolyse EPO.\n\nEPO efficiency: In addition to its reduced production or enhanced degradation, leading to low circulating levels, the efficiency of EPO is likely reduced upon inflammation, as long known for its hematopoietic effects. This relative hyporesponsiveness of the haematopoietic system to EPO in systemic inflammatory conditions has been explained by altered cytokine patterns that modulate the bone marrow response to EPO (Kwack and Balakrishnan 2006). This may be partially overcome by higher doses and does not necessarily reflect on extrahematopoietic effectiveness of EPO (Ehrenreich et al. 2007a).\n\nConclusions\n\nSubstitution of EPO appears as a rational strategy (Fig. 1) to circumvent downstream consequences of the ‘hypoxia paradox’, including dysfunctional synthesis or accelerated inactivation of endogenous EPO, in addition to the likely beneficial pharmacological profile of EPO applications pointed out earlier (Ehrenreich et al. 2020; Leventhal et al. 2020; Sahebnasagh et al. 2020). The obvious limitation of the present work is that case reports can only serve as first hints and ultimately require rigorous confirmation in a clinically controlled setting. An appropriate double-blind, placebo-controlled, randomized clinical trial is prerequisite for claiming any beneficial effects of rhEPO or biosimilars for the treatment of severely affected COVID-19 patients as well as for preventing COVID-19 downstream sequelae, long COVID and neuroCOVID.\n\nAcknowledgements\n\nSee funding. Otherwise not applicable.\n\nAuthors’ contributions\n\nConcept, design and drafting of the article: HE, MB, OG. Literature search, comments, and interpretation: MB, HE, RH, together with OG, DW, VDG, EV, KW, KWM, OM. Contribution and follow-up of cases: OG, DW, OM. All authors read and approved the final manuscript.\n\nFunding\n\nOpen Access funding enabled and organized by Projekt DEAL. This work was supported by the Max Planck Society, the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) TRR 274/1 2020 - 408885537. KWM holds a 5-year Lundbeck Foundation Fellowship (Grant no. R215-2015-4121).\n\nAvailability of supporting data\n\nNot applicable.\n\nDeclarations\n\nEthical approval and consent to participate\n\nNot applicable.\n\nConsent for publication\n\nAll authors read and approved the final version of the manuscript. Otherwise consent not applicable.\n\nCompeting interests\n\nAuthors report no conflict of interest related to this article.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nMartin Begemann and Oliver Gross—shared first authorship\n==== Refs\nReferences\n\nAl-Ramadan A Rabab'h O Shah J Gharaibeh A Acute and post-acute neurological complications of COVID-19 Neurol Int 2021 13 102 119 10.3390/neurolint13010010 33803475\nArias-Reyes C Zubieta-Deurioste N Poma-Machicao L Aliaga-Raduan F Carvajal-Rodriguez F Dutschmann M Does the pathogenesis of SARS-CoV-2 virus decrease at high-altitude? 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Mol Psychiatry. 2011;16:26–36, 21. 10.1038/mp.2010.51\nYagci S Serin E Acicbe O Zeren MI Odabasi MS The relationship between serum erythropoietin, hepcidin, and haptoglobin levels with disease severity and other biochemical values in patients with COVID-19 Int J Lab Hematol 2021 10.1111/ijlh.13479 33554466\nYang AC Kern F Losada PM Agam MR Maat CA Schmartz GP Dysregulation of brain and choroid plexus cell types in severe COVID-19 Nature 2021 10.1038/s41586-021-03710-0 34552241\nYuan S Peng L Park JJ Hu Y Devarkar SC Dong MB Nonstructural protein 1 of SARS-CoV-2 is a potent pathogenicity factor redirecting host protein synthesis machinery toward viral RNA Mol Cell 2020 80 1055 1066.e1056 10.1016/j.molcel.2020.10.034 33188728\nZhang L Lin D Sun X Curth U Drosten C Sauerhering L Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved alpha-ketoamide inhibitors Science 2020 368 409 412 10.1126/science.abb3405 32198291\nZhou P Yang XL Wang XG Hu B Zhang L Zhang W A pneumonia outbreak associated with a new coronavirus of probable bat origin Nature 2020 579 270 273 10.1038/s41586-020-2012-7 32015507\nZhou D Dejnirattisai W Supasa P Liu C Mentzer AJ Ginn HM Evidence of escape of SARS-CoV-2 variant B.1.351 from natural and vaccine-induced sera Cell 2021 184 2348 2361.e2346 10.1016/j.cell.2021.02.037 33730597\nZhu N Zhang D Wang W Li X Yang B Song J A novel coronavirus from patients with pneumonia in China, 2019 N Engl J Med 2020 382 727 733 10.1056/NEJMoa2001017 31978945\nZubieta-Calleja G Zubieta-Deurioste N Venkatesh T Das KK Soliz J COVID-19 and pneumolysis simulating extreme high-altitude exposure with altered oxygen transport physiology; multiple diseases, and scarce need of ventilators: andean Condor's-eye-view Rev Recent Clin Trials 2020 15 347 359 10.2174/1574887115666200925141108 32981508\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1076-1551",
"issue": "27(1)",
"journal": "Molecular medicine (Cambridge, Mass.)",
"keywords": "Critical care; Darbepoetin; Neuroprotection; Outcome; Recombinant human EPO; Signaling; Treatment",
"medline_ta": "Mol Med",
"mesh_terms": "D000086382:COVID-19; D004921:Erythropoietin; D006801:Humans; D000860:Hypoxia; D008168:Lung; D058873:Pandemics; D011994:Recombinant Proteins; D000086402:SARS-CoV-2",
"nlm_unique_id": "9501023",
"other_id": null,
"pages": "120",
"pmc": null,
"pmid": "34565332",
"pubdate": "2021-09-26",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": "32345591;25099079;17033631;33175121;33666649;34308300;32816244;32321856;32767095;32015507;32270515;33554466;34010947;33743211;33264556;34090624;32402155;32007145;21619868;33015645;33743213;33531113;32558485;28983059;32333993;33531496;33836148;27477940;33130000;33684356;32376954;33166287;32152318;33692530;34087493;19110203;34070628;17728357;32637987;33053430;31978945;33997827;33691089;23999527;28841235;1557429;32705305;33778179;33503446;33610751;33431511;32838352;33428867;32303591;33564132;32522574;16551293;33264547;33420163;33769431;32863034;34043615;32702090;33798491;21180577;32534130;20479759;33257876;31297547;32546125;32644129;32981508;32451547;17644049;33730597;33554186;33414554;34036253;32198291;33031735;33705702;33992951;25641635;33823427;33378608;15928718;33803475;32735840;32530583;33188728;32291094;1991159;33571301;33780470;32407672;24322509;34036254;32192578;33328624;33811162;32510973;33753937;33964222;32353859;14581931;20158574;34153974;32343504;32275288;34044428;32735842;33789086",
"title": "Addressing the 'hypoxia paradox' in severe COVID-19: literature review and report of four cases treated with erythropoietin analogues.",
"title_normalized": "addressing the hypoxia paradox in severe covid 19 literature review and report of four cases treated with erythropoietin analogues"
} | [
{
"companynumb": "DE-LUPIN PHARMACEUTICALS INC.-2021-25399",
"fulfillexpeditecriteria": "2",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
"drugad... |
{
"abstract": "The aim of the present study was to assist rheumatologists in differentiating hypophosphatemic osteomalacia (HO) from mimic rheumatology diseases. Clinical data was obtained from 9 patients with acquired HO, initially misdiagnosed as mimic rheumatologic diseases. The data were retrospectively analyzed and a literature review was performed. The etiology of the cases was as follows: Adefovir dipivoxil-induced Fanconi syndrome was present in 6 of the cases, 2 were tumors and 1 case was chronic nephropathy. The chief complaint was thoracic or back pain and arthralgia, followed by progressive muscle weakness and dramatic movement limitation. All patients were transferred to 3-6 hospitals for extended periods due to misdiagnosis with conditions such as ankylosing spondylitis, chronic arthritis, lumbar disc disease, osteoporosis and somatoform disorder. Hypophosphatemia was observed in the patients and bone scans revealed diffusely decreased tracer uptake, with multiple hot spots of fractured sites and involved joints. Furthermore, patients' bone density was markedly low compared with the normal range for their age and sex. In the present study, 6 of the patients recovered when adefovir dipivoxil was stopped. In 1 case, hypophosphatemia was ameliorated following tumor resection. The remaining patients, 1 with sub-skull tumor and 1 with chronic kidney disease, had poor prognoses due to incurable diseases. In conclusion, diagnosing HO is challenging for rheumatologists and physicians. Basic examinations of electrolyte balance and bone mineral density should be performed, as should tumor screening and a careful collection of patient medical history and drugs in young patients with unexplained thoracic or back pain and muscle weakness. Removing any secondary etiology, such as drugs may dramatically improve the patients clinical manifestations and result in an improved prognosis.",
"affiliations": "Department of Rheumatology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, P.R. China.;Department of Nuclear Medicine, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, P.R. China.;Department of Pathology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, P.R. China.;Department of Pathology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, P.R. China.;Department of Rheumatology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, P.R. China.;Department of Rheumatology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, P.R. China.;Department of Rheumatology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, P.R. China.",
"authors": "Li|Ling|L|;Wang|Shu-Xia|SX|;Wu|Hong-Mei|HM|;Luo|Dong-Lan|DL|;Dong|Guang-Fu|GF|;Feng|Yuan|Y|;Zhang|Xiao|X|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.3892/etm.2018.6106",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1792-0981",
"issue": "15(6)",
"journal": "Experimental and therapeutic medicine",
"keywords": "adefovir dipivoxil; ankylosing spondylitis; hypophosphatemia; osteomalacia; tumor",
"medline_ta": "Exp Ther Med",
"mesh_terms": null,
"nlm_unique_id": "101531947",
"other_id": null,
"pages": "5389-5393",
"pmc": null,
"pmid": "29904418",
"pubdate": "2018-06",
"publication_types": "D016428:Journal Article",
"references": "19669798;25653092;16160135;27247753;15327411;23098847;24999675;22532501;10342386;22126791;12711740;26783348;26634142;19339725;22167381;22736784;6418367;17673594;22506503;21714795;27085966;26110001",
"title": "Acquired hypophosphatemic osteomalacia is easily misdiagnosed or neglected by rheumatologists: A report of 9 cases.",
"title_normalized": "acquired hypophosphatemic osteomalacia is easily misdiagnosed or neglected by rheumatologists a report of 9 cases"
} | [
{
"companynumb": "CN-GILEAD-2018-0339772",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ADEFOVIR DIPIVOXIL"
},
"drugadditional": "1",
... |
{
"abstract": "Zolpidem is an imidazopyridine agent indicated for the short-term treatment of insomnia. Sleepwalking is a rare side effect of zolpidem. A review of the literature produced only 2 cases. We report a case of a male rehabilitation inpatient in his mid fifties with a history of alcoholism and traumatic brain injury who had undergone a right hip hemiarthroplasty. He had no history of somnambulism or insomnia but walked in his sleep on 2 nonconsecutive nights after taking zolpidem. He had exhibited no such behavior before taking zolpidem, on the intervening night that was he was not given medication, and after the medication was discontinued. We conclude that zolpidem can cause sleepwalking, and patients who have suffered a brain injury may be more susceptible to this side effect. Here we describe the clinical presentation and review the relevant literature on zolpidem and sleepwalking.",
"affiliations": "Department of Neurology and Rehabilitation, University of Illinois, Chicago, IL, USA. wyangem@yahoo.com",
"authors": "Yang|Weibin|W|;Dollear|Mary|M|;Muthukrishnan|Sri Ranjini|SR|",
"chemical_list": "D006993:Hypnotics and Sedatives; D011725:Pyridines; D000077334:Zolpidem",
"country": "United States",
"delete": false,
"doi": "10.1016/j.apmr.2004.11.022",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-9993",
"issue": "86(6)",
"journal": "Archives of physical medicine and rehabilitation",
"keywords": null,
"medline_ta": "Arch Phys Med Rehabil",
"mesh_terms": "D006801:Humans; D006993:Hypnotics and Sedatives; D008297:Male; D008875:Middle Aged; D011725:Pyridines; D007319:Sleep Initiation and Maintenance Disorders; D013009:Somnambulism; D000077334:Zolpidem",
"nlm_unique_id": "2985158R",
"other_id": null,
"pages": "1265-6",
"pmc": null,
"pmid": "15954071",
"pubdate": "2005-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "One rare side effect of zolpidem--sleepwalking: a case report.",
"title_normalized": "one rare side effect of zolpidem sleepwalking a case report"
} | [
{
"companynumb": "US-VIVIMED-2018SP004023",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ZOLPIDEM\\ZOLPIDEM TARTRATE"
},
"drugadditiona... |
{
"abstract": "While the fundamental principles of epistaxis management have not changed over the decades, the methods by which tamponade is achieved have been evolving. Inflatable nasal tampons are being used and seen with increasing frequency in our ENT clinic. They are usually placed by emergency department personnel, who then refer patients to our clinic for removal. The classically described complications of nasal packs are induction of the nasopulmonary reflex, toxic shock syndrome, and discomfort. In this article, we describe a case of pneumocephalus following placement of an inflatable nasal tampon. To the best of our knowledge, this is the first report of pneumocephalus after placement of an inflatable nasal tampon.",
"affiliations": "Department of Otolaryngology/Head and Neck Surgery, University of North Carolina Memorial Hospitals, 170 Manning Dr., Ground Floor, Physician Office Building, CB #7070, Chapel Hill, NC 27599, USA. kimplead@med.unc.edu.",
"authors": "Kimple|Adam J|AJ|;Ferguson|Michael O|MO|",
"chemical_list": "D000925:Anticoagulants; D014859:Warfarin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0145-5613",
"issue": "95(4-5)",
"journal": "Ear, nose, & throat journal",
"keywords": null,
"medline_ta": "Ear Nose Throat J",
"mesh_terms": "D000328:Adult; D000755:Anemia, Sickle Cell; D000925:Anticoagulants; D004844:Epistaxis; D005260:Female; D006801:Humans; D011007:Pneumocephalus; D013630:Tampons, Surgical; D014057:Tomography, X-Ray Computed; D020246:Venous Thrombosis; D014859:Warfarin",
"nlm_unique_id": "7701817",
"other_id": null,
"pages": "172-4",
"pmc": null,
"pmid": "27140017",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pneumocephalus after insertion of an inflatable nasal tampon for the management of epistaxis.",
"title_normalized": "pneumocephalus after insertion of an inflatable nasal tampon for the management of epistaxis"
} | [
{
"companynumb": "US-ZYDUS-015691",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": "1",
"drugadmi... |
{
"abstract": "A 42 year-old male with premature atherosclerosis, severe dyslipidemia and resistance to treatment with high dose statin and a recommended dose of a PCSK9 inhibitor, was found to have a duplication of the PCSK9 gene. However, the clinical phenotype, which included a more than 15-fold elevation in circulating PCSK9, was unexpected given that he had one additional gene copy.\n\n\n\nHere we have carried out whole genome sequencing and transcriptional reporter assays to investigate the molecular mechanism leading to this unusual FH phenotype.\n\n\n\nThe PCSK9 duplication was found to contain the full coding sequence but with an 829 bp shorter 3'-untranslated region (UTR) sequence. All possible rearrangements include a head-to-head fusion between a completely duplicated PCSK9 and a chromosomal region, normally situated ~80 kb away, that includes HNF4 and USF1 binding sites that could promote transcription of the PCSK9 gene. Transcriptional reporter assays demonstrated that a construct harboring the HNF4 binding site significantly increased the promoter activity by 2.5-fold with a smaller effect noted for a USF1 construct.\n\n\n\nHere we describe, in a patient with resistant hypercholesterolemia, a novel PCSK9 gene rearrangement that enables upregulation of PCSK9 expression by allowing proximity to an active enhancer binding to HNF4A.",
"affiliations": "Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Canada.;Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Canada.;Robarts Research Institute, London, ON, Canada.;Lipoprotein Receptor Biology Laboratory, University of Ottawa Heart Institute, Ottawa, Canada.;Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Canada. Electronic address: rmcpherson@ottawaheart.ca.",
"authors": "Lau|Paulina|P|;Soubeyrand|Sébastien|S|;Hegele|Robert A|RA|;Lagace|Thomas A|TA|;McPherson|Ruth|R|",
"chemical_list": "C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.atherosclerosis.2020.05.013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-9150",
"issue": "304()",
"journal": "Atherosclerosis",
"keywords": "CNV; HNF4; Hypercholesterolemia; PCSK9; Statin-resistance",
"medline_ta": "Atherosclerosis",
"mesh_terms": "D000328:Adult; D056915:DNA Copy Number Variations; D051557:Hepatocyte Nuclear Factor 4; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006937:Hypercholesterolemia; D008297:Male; D000071449:Proprotein Convertase 9",
"nlm_unique_id": "0242543",
"other_id": null,
"pages": "39-43",
"pmc": null,
"pmid": "32585424",
"pubdate": "2020-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Molecular mechanism linking a novel PCSK9 copy number variant to severe hypercholesterolemia.",
"title_normalized": "molecular mechanism linking a novel pcsk9 copy number variant to severe hypercholesterolemia"
} | [
{
"companynumb": "CA-AMGEN-CANSP2020113585",
"fulfillexpeditecriteria": "2",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "EZETIMIBE"
},
"drugadditional": null,
... |
{
"abstract": "Inflammatory and subcutaneous nodules can arise in treated and untreated cases of Whipple disease (WD). The inflammatory immune reconstitution syndrome describes paradoxical clinical inflammatory worsening of a preexisting condition because of a return of immune function. Clinicopathologic examination of 4 patients with WD who presented with erythema nodosum leprosum (ENL)-like lesions and the findings of a systematic review of this phenomenon revealed that ENL-like lesions occurred in predominantly middle-aged male patients who suffered from WD, mostly on the legs. Patients showed a nonvasculitic, mostly septal panniculits with neutrophils, macrophages, and lymphocytes. Numerous bacteria-laden periodic acid-Schiff + macrophages and free bacilli were detected in the dermis, as well as subcutaneous septae and adipose lobules. These lesions occurred in both untreated and treated patients as part of inflammatory immune reconstitution syndrome. In conclusion, ENL-like lesions represent a characteristic histopathologic pattern associated with WD, which can occur in different contexts whenever there is a change in the immunological status of the patient. This change can be triggered by antimicrobial treatment, immunomodulatory and immunosuppressant therapy, or occur spontaneously, rarely.",
"affiliations": "*Dermatopathology Duisburg, Duisburg, Germany; †Department of Pathology, APHP Cochin Hospital, University Paris-Descartes, Paris, France; ‡Department of Dermatology, Saint Pierre-Brugmann and Children's University Hospitals, UniversiteLibre de Bruxelles, Brussels, Belgium; and §Divisions of Dermatopathology and Dermatology, Department of Pathology, Albany Medical College, Albany, NY.",
"authors": "Liersch|Julia|J|;Carlotti|Agnès|A|;Theunis|Anne|A|;Leonard|Alexandra|A|;Barrett|Mary|M|;Carlson|John Andrew|JA|;Schaller|Jörg|J|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": "10.1097/DAD.0000000000000641",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0193-1091",
"issue": "39(4)",
"journal": "The American Journal of dermatopathology",
"keywords": null,
"medline_ta": "Am J Dermatopathol",
"mesh_terms": "D004893:Erythema Nodosum; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D008061:Whipple Disease",
"nlm_unique_id": "7911005",
"other_id": null,
"pages": "259-266",
"pmc": null,
"pmid": "28098596",
"pubdate": "2017-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review; D000078182:Systematic Review",
"references": null,
"title": "Erythema Nodosum Leprosum-Like Lesions Are a Histopathologic Pattern in Whipple's Disease and a Sign of the Immune Reconstitution Inflammatory Syndrome: A Case Series and Review of the Literature.",
"title_normalized": "erythema nodosum leprosum like lesions are a histopathologic pattern in whipple s disease and a sign of the immune reconstitution inflammatory syndrome a case series and review of the literature"
} | [
{
"companynumb": "DE-PFIZER INC-2018347340",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE SODIUM"
},
"drugadditional": "3",... |
{
"abstract": "Pituitary carcinoma (PC) is an aggressive neuroendocrine tumor diagnosed when a pituitary adenoma (PA) becomes metastatic. PCs are typically resistant to therapy and develop multiple recurrences despite surgery, radiotherapy and chemotherapy. Recently, treatment with temozolomide (TMZ) has shown promising results, although the lack of prospective trials limits assessment of benefit.\nWe describe a single-center multidisciplinary experience in managing PC patients over a 22-year period and review previously published PC series.\nSeventeen patients were identified. Median age at PC diagnosis was 44 years (range 16-82 years), and the median time from PA to PC transformation was 5 years (range 1-29 years). Median follow-up time was 28 months. Most PCs were hormone-positive (n = 12): ACTH (n = 5), PRL (n = 4), LH/FSH (n = 2) and GH (n = 1). All patients underwent at least one resection and at least one course of radiation after PC diagnosis. Immunohistochemistry showed high Ki-67 labeling index (>3%) in 10/15 cases. Eight patients (47%) had only central nervous system (CNS) metastases; six (35%) had combined CNS and systemic metastases. The most commonly used chemotherapy was TMZ, and TMZ-based therapy was associated with the longest PFS in 12 (71%) cases, as well as the longest period from PC diagnosis to first progression (median 30 months). The 2, 3 and 5-year survival rate of the entire cohort was 71, 59 and 35%, respectively. All patients surviving >5 years had been treated with TMZ-based therapy.\nPC management benefits from multidisciplinary care and multimodality therapy. TMZ-based regimens were associated with high survival rates and long disease control.",
"affiliations": "Department of Neurology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.;Department of Neuro-Oncology, MD Anderson Cancer Center, Houston, Texas, USA.;Department of Neuro-Oncology, MD Anderson Cancer Center, Houston, Texas, USA.;Department of Endocrinology, MD Anderson Cancer Center, Houston, Texas, USA.;Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA.;Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA.;Department of Radiology, MD Anderson Cancer Center, Houston, Texas, USA.;Department of Pathology, MD Anderson Cancer Center, Houston, Texas, USA.;Department of Neurosurgery, MD Anderson Cancer Center, Houston, Texas, USA.",
"authors": "Santos-Pinheiro|Fernando|F|;Penas-Prado|Marta|M|;Kamiya-Matsuoka|Carlos|C|;Waguespack|Steven G|SG|;Mahajan|Anita|A|;Brown|Paul D|PD|;Shah|Komal B|KB|;Fuller|Gregory N|GN|;McCutcheon|Ian E|IE|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0804-4643",
"issue": "181(4)",
"journal": "European journal of endocrinology",
"keywords": null,
"medline_ta": "Eur J Endocrinol",
"mesh_terms": "D000236:Adenoma; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D010911:Pituitary Neoplasms; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9423848",
"other_id": null,
"pages": "397-407",
"pmc": null,
"pmid": "31349217",
"pubdate": "2019-10",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Treatment and long-term outcomes in pituitary carcinoma: a cohort study.",
"title_normalized": "treatment and long term outcomes in pituitary carcinoma a cohort study"
} | [
{
"companynumb": "US-009507513-1909USA005176",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TEMOZOLOMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Chronic radiation proctopathy is a frequent complication after both pelvic external radiation therapy and brachytherapy and most commonly presents as rectal bleeding. Deep rectal ulcers and fistulae are much rarer and more clinically challenging consequences. We present the case of a 72-year-old male with a history of prostate adenocarcinoma treated with brachytherapy, who was referred to our institution due to a deep painful rectal ulcer refractory to medical treatment. The ulcer presented shortly after a haemorrhoid elastic band ligation and progressed to rectourethral fistulisation despite both faecal and urinary diversion. Our case demonstrates the importance of favouring a conservative approach when dealing with an irradiated rectum.",
"affiliations": "Serviço de Gastroenterologia, Instituto Português de Oncologia Francisco Gentil, Porto, Portugal.;Serviço de Gastroenterologia, Instituto Português de Oncologia Francisco Gentil, Porto, Portugal.;Serviço de Gastroenterologia, Instituto Português de Oncologia Francisco Gentil, Porto, Portugal.",
"authors": "Pita|Inês|I|;Bastos|Pedro|P|;Dinis-Ribeiro|Mário|M|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000477769",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2387-1954",
"issue": "25(1)",
"journal": "GE Portuguese journal of gastroenterology",
"keywords": "Brachytherapy; Radiation proctitis; Rectal fistulae; Rectal ulcer",
"medline_ta": "GE Port J Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "101685861",
"other_id": null,
"pages": "42-46",
"pmc": null,
"pmid": "29457050",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article",
"references": "15690650;1670631;25572299;27111831;22558821;27123955;26034407;26198994;26778712;15879789;26981189;25516492;21763213;18342453;11488787;10962052;7713792;11066049;19248043;10425416",
"title": "Pelvic Catastrophe after Elastic Band Ligation in an Irradiated Rectum.",
"title_normalized": "pelvic catastrophe after elastic band ligation in an irradiated rectum"
} | [
{
"companynumb": "PT-MYLANLABS-2019M1020457",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
"drugadditional": "... |
{
"abstract": "BACKGROUND\nAnaphylactoid syndrome of pregnancy (ASP) is a rare but extremely serious complication, with an estimated incidence in North America of 1 in 15 200 deliveries. Despite its rarity, ASP is responsible for approximately 10% of all childbirth-associated deaths in the United States. At present, there is no validated biomarker or specific set of risk factors sufficiently predictive of ASP risk to incorporate into clinical practice. Toward the goal of developing a methodology predictive of an impending ASP event for use by obstetricians, anesthesiologists, and other practitioners participating in infant deliveries, physicians encountering an ASP event have been encouraged to report the occurrence of a case and its biologically plausible risk factors.\n\n\nMETHODS\nHerein, we report on 2 patients who presented with a presumptive diagnosis of ASP to the delivery unit of a community hospital. Patient One was a 21-year-old, obese (5'11\" tall, 250 lbs., BMI 34.9) white female, 1 pregnancy, no live births (G1P0), estimated gestational age (EGA) 40.2 weeks. Patient Two was a 29-year-old, obese (5'7\" tall, 307 lbs., BMI 48.1) Hispanic female, second pregnancy, with 1 previous live birth via C-section (G2P1-0-0-1). Her pregnancy was at gestational age 38 weeks plus 2 days.\n\n\nCONCLUSIONS\nPatient One had 2 possible risk factors: administration of Pitocin to induce labor and post-coital spotting from recent intercourse. Patient Two suffered premature rupture of the placental membranes. Both Patient One and Patient Two had very high body mass indices (BMIs), at the 97th and 99th percentiles, respectively. In the relatively few cases of anaphylactoid syndrome of pregnancy described to date, this is the first report of a possible association with high BMI.",
"affiliations": "Nurse Anesthesia Program, Florida State University, Panama, FL, USA.;Nurse Anesthesia Program, Florida State University, Panama, FL, USA.;Nurse Anesthesia Program, Florida State University, Panama, FL, USA.",
"authors": "Kradel|Brian K|BK|;Hinson|Scarlett B|SB|;Smith|Carr J|CJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12659/ajcr.897984",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1941-5923",
"issue": "17()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D002585:Cesarean Section; D004619:Embolism, Amniotic Fluid; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D009765:Obesity; D011247:Pregnancy; D035583:Rare Diseases",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "444-7",
"pmc": null,
"pmid": "27363628",
"pubdate": "2016-07-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19049991;24804725;26197375;371460;15841940;11725740;23522720;24804724;24804723;2195407;7557636;26273468;7726251;16202747;26314236;19172292;25697667;8828446;19879393;26013425;1568317;24804727;17112682;24804728;9692424;3777058",
"title": "Two Obese Patients with Presumptive Diagnosis of Anaphylactoid Syndrome of Pregnancy Presenting at a Community Hospital.",
"title_normalized": "two obese patients with presumptive diagnosis of anaphylactoid syndrome of pregnancy presenting at a community hospital"
} | [
{
"companynumb": "US-PFIZER INC-2016440011",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LABETALOL HYDROCHLORIDE"
},
"drugadditional": ... |
{
"abstract": "Alpha glucosidase inhibitors have been shown to be associated with pneumatosis intestinalis (PI) in recent reports. We herein report the case of a 73-year old man who received treatment with an alpha glucosidase inhibitor (acarbose) and presented with acute abdomen. A computed tomography scan demonstrated PI in addition to intrahepatic portal air and pneumoperitoneum. During exploratory laparotomy, we found no evidence of hollow organ perforation or bowel necrosis. The patient recovered after conservative treatment with cessation of the alpha glucosidase inhibitor. This is the first report to describe the combination of PI with portal venous gas and pneumoperitoneum caused by an alpha-glucosidase inhibitor.",
"affiliations": "Department of General Surgery, Hadassah-Hebrew University Medical Center, Israel.",
"authors": "Rottenstreich|Amihai|A|;Agmon|Yahel|Y|;Elazary|Ram|R|",
"chemical_list": "D065089:Glycoside Hydrolase Inhibitors; D020909:Acarbose",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.54.4255",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0918-2918",
"issue": "54(14)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D020909:Acarbose; D000368:Aged; D065089:Glycoside Hydrolase Inhibitors; D006801:Humans; D007813:Laparotomy; D008297:Male; D011006:Pneumatosis Cystoides Intestinalis; D011027:Pneumoperitoneum; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1733-6",
"pmc": null,
"pmid": "26179526",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Rare Case of Benign Pneumatosis Intestinalis with Portal Venous Gas and Pneumoperitoneum Induced by Acarbose.",
"title_normalized": "a rare case of benign pneumatosis intestinalis with portal venous gas and pneumoperitoneum induced by acarbose"
} | [
{
"companynumb": "IL-ROXANE LABORATORIES, INC.-2015-RO-01519RO",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ACARBOSE"
},
"drugaddition... |
{
"abstract": "OBJECTIVE\nTo compare the visual and anatomic outcomes of macular edema secondary to retinal vein occlusion after switching from bevacizumab to ranibizumab, aflibercept, or dexamethasone implant.\n\n\nMETHODS\nFifteen eyes were switched to ranibizumab, 12 to aflibercept, and 10 to dexamethasone. At 3, 6, 9, and 12 months, the outcome measures were visual acuity (VA) and central macular thickness (CMT).\n\n\nRESULTS\nOne year after the switch, CMT decreased from 430.11 ± 91.21 to 291.86 ± 43.87 μm (p < 0.001). VA increased in 59.5% of the eyes. No difference between the groups was found in those outcomes at 1 year, but the number of injections varied: 3.30 ± 0.95 for dexamethasone, 6.50 ± 2.11 for aflibercept, and 8.27 ± 2.37 for ranibizumab (p < 0.001).\n\n\nCONCLUSIONS\nMost of the eyes that failed initial bevacizumab therapy benefit from switching to another modality. The number of required injections during the first year after the switch varies.",
"affiliations": "Department of Ophthalmology, Shaare Zedek Medical Center, Jerusalem, Israel.",
"authors": "Hanhart|Joel|J|;Rozenman|Yaacov|Y|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D005938:Glucocorticoids; D011993:Recombinant Fusion Proteins; C533178:aflibercept; D000068258:Bevacizumab; D003907:Dexamethasone; D040262:Receptors, Vascular Endothelial Growth Factor; D000069579:Ranibizumab",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000473864",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0030-3755",
"issue": "238(1-2)",
"journal": "Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde",
"keywords": "Aflibercept; Anti-VEGF; Bevacizumab; Intravitreal dexamethasone implant; Ranibizumab; Retinal vein occlusion; Treatment switch",
"medline_ta": "Ophthalmologica",
"mesh_terms": "D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab; D003907:Dexamethasone; D004305:Dose-Response Relationship, Drug; D057915:Drug Substitution; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D058449:Intravitreal Injections; D008266:Macula Lutea; D008269:Macular Edema; D008297:Male; D008875:Middle Aged; D000069579:Ranibizumab; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins; D012170:Retinal Vein Occlusion; D012189:Retrospective Studies; D041623:Tomography, Optical Coherence; D017211:Treatment Failure; D014792:Visual Acuity",
"nlm_unique_id": "0054655",
"other_id": null,
"pages": "110-118",
"pmc": null,
"pmid": "28535531",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Comparison of Intravitreal Ranibizumab, Aflibercept, and Dexamethasone Implant after Bevacizumab Failure in Macular Edema Secondary to Retinal Vascular Occlusions.",
"title_normalized": "comparison of intravitreal ranibizumab aflibercept and dexamethasone implant after bevacizumab failure in macular edema secondary to retinal vascular occlusions"
} | [
{
"companynumb": "IL-ALLERGAN-1722792US",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "Triazole antifungals are useful in the treatment of Aspergillus disease and these drugs have side effects which clinicians should be aware of. Posaconazole is an orally administered second-generation triazole antifungal agent which inhibits lanosterol 14-alpha-demethylase, an enzyme that converts lanosterol to ergosterol, a vital component of the fungal cell membrane. Posaconazole has a favorable side effect profile, is safe and well tolerated when compared to the earlier generation of triazole antifungals. Common side effects of posaconazole include gastrointestinal, hepatobiliary, neurological, and skin and subcutaneous disorders. Renal disorders are classed as an uncommon side effect of posaconazole, occurring in ∼0.1-1% of patients. We describe 2 episodes of acute kidney injury (AKI) in a Caucasian whose Aspergillus lung disease was being treated with posaconazole. Regular monitoring of renal function may be necessary for patients on posaconazole to facilitate early identification of acute kidney injury which is reversible.",
"affiliations": "a University of Calabar , Calabar , Cross River State , Nigeria.;b The National Aspergillosis Centre, 2nd Floor Education and Research Centre , Manchester University NHS Foundation Trust , Manchester , UK.;b The National Aspergillosis Centre, 2nd Floor Education and Research Centre , Manchester University NHS Foundation Trust , Manchester , UK.;b The National Aspergillosis Centre, 2nd Floor Education and Research Centre , Manchester University NHS Foundation Trust , Manchester , UK.",
"authors": "Otu|Akaninyene|A|;Bongomin|Felix|F|;Kosmidis|Chris|C|;Denning|David W|DW|",
"chemical_list": "D000935:Antifungal Agents; D014230:Triazoles; C101425:posaconazole",
"country": "England",
"delete": false,
"doi": "10.1080/1120009X.2018.1522472",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1120-009X",
"issue": "30(6-8)",
"journal": "Journal of chemotherapy (Florence, Italy)",
"keywords": "Acute kidney injury; Aspergillus; Posaconazole; Therapeutic drug monitoring; Triazole",
"medline_ta": "J Chemother",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D000935:Antifungal Agents; D001228:Aspergillosis; D001230:Aspergillus; D006801:Humans; D008297:Male; D014230:Triazoles",
"nlm_unique_id": "8907348",
"other_id": null,
"pages": "380-383",
"pmc": null,
"pmid": "30663547",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute kidney injury: an unusual complication of posaconazole use.",
"title_normalized": "acute kidney injury an unusual complication of posaconazole use"
} | [
{
"companynumb": "GB-ASTELLAS-2019US005130",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ISAVUCONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "Human herpesvirus 6 (HHV-6) is one of the life-threatening infectious complications with significant morbidity and mortality following hematopoietic stem cell transplantation (HSCT). Clinically, the diagnosis of HHV-6 encephalitis can be challenging due to a lack of specific symptoms and definitive diagnostic tests. We report a pediatric HSCT recipient who developed late-onset HHV-6 encephalitis without typical radiographic findings. The routine viral infection monitoring protocol contributed to the prompt diagnosis of HHV-6 encephalitis and early therapeutic intervention. The patient was treated successfully without any neurological complications attributable to HHV-6 encephalitis. HHV-6 encephalitis should remain in the differential diagnosis as an important but treatable disease, even for several months after HSCT and even without radiographic findings. Whenever HHV-6 encephalitis is suspected, antivirals should be initiated promptly to prevent its complications.",
"affiliations": "Center for Postgraduate Education and Training, National Center for Child Health and Development, Tokyo, Japan.;Department of Advanced Medicine for Viral Infections, Tokyo, Japan. yamada-mas@ncchd.go.jp.;Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.;Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.;Division of Gastroenterology, National Center for Child Health and Development, Tokyo, Japan.;Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.;Center for Postgraduate Education and Training, National Center for Child Health and Development, Tokyo, Japan.;Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.;Department of Advanced Medicine for Viral Infections, Tokyo, Japan.;Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.",
"authors": "Sakamoto|Atsushi|A|http://orcid.org/0000-0002-2222-5425;Yamada|Masaki|M|;Tsujimoto|Shin-Ichi|SI|;Osumi|Tomoo|T|;Arai|Katsuhiro|K|;Tomizawa|Daisuke|D|;Ishiguro|Akira|A|;Matsumoto|Kimikazu|K|;Imadome|Ken-Ichi|KI|;Kato|Motohiro|M|",
"chemical_list": "D000998:Antiviral Agents",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-020-02905-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "112(5)",
"journal": "International journal of hematology",
"keywords": "Hematopoietic stem cell transplantation; Human herpesvirus 6; Post-transplant encephalitis; Viral load",
"medline_ta": "Int J Hematol",
"mesh_terms": "D000998:Antiviral Agents; D002648:Child; D002675:Child, Preschool; D003937:Diagnosis, Differential; D003955:Diagnostic Tests, Routine; D042241:Early Diagnosis; D018792:Encephalitis, Viral; D018380:Hematopoietic Stem Cell Transplantation; D015654:Herpesvirus 6, Human; D006801:Humans; D008297:Male; D011183:Postoperative Complications; D019349:Roseolovirus Infections; D014184:Transplantation, Homologous",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "751-754",
"pmc": null,
"pmid": "32529583",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of human herpesvirus 6 encephalitis following pediatric hematopoietic stem cell transplantation: early diagnosis and treatment matters.",
"title_normalized": "a case of human herpesvirus 6 encephalitis following pediatric hematopoietic stem cell transplantation early diagnosis and treatment matters"
} | [
{
"companynumb": "JP-TEVA-2020-JP-1863077",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "We report the case of a 70-year-old Japanese male diagnosed with advanced lung adenocarcinoma harboring the echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion gene. As soon as crizotinib was administered, tumor shrank immediately. On Day 25, he developed interstitial lung disease. Bronchoalveolar lavage fluid analysis demonstrated elevated lymphocytes fractionation. A drug lymphocyte stimulating test for crizotinib with the bronchoalveolar lavage lymphocytes was negative. Crizotinib administration was discontinued, but a life-threatening flare of tumor growth occurred. Since there was no alternative treatment for the lung cancer, we restarted crizotinib in combination with prednisolone. The patient experienced neither disease progression nor recurrence of interstitial lung disease at 6 months. In cases in which no alternate treatment is known, crizotinib retreatment combined with steroid therapy after crizotinib-induced interstitial lung disease could be considered after a careful consideration of the potential risks and benefits.",
"affiliations": "Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan mt0318@med.kobe-u.ac.jp.;Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.;Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.;Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.;Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.;Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.;Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.;Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.",
"authors": "Tachihara|Motoko|M|;Kobayashi|Kazuyuki|K|;Ishikawa|Yumiko|Y|;Hori|Suya|S|;Tamura|Daisuke|D|;Otera|Hiroshi|H|;Funada|Yasuhiro|Y|;Nishimura|Yoshihiro|Y|",
"chemical_list": "D018931:Antineoplastic Agents, Hormonal; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; D011239:Prednisolone",
"country": "England",
"delete": false,
"doi": "10.1093/jjco/hyu074",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0368-2811",
"issue": "44(8)",
"journal": "Japanese journal of clinical oncology",
"keywords": "EML4-ALK; bronchoalveolar lavage (BAL); crizotinib; drug lymphocyte stimulating test (DLST); interstitial lung disease",
"medline_ta": "Jpn J Clin Oncol",
"mesh_terms": "D000368:Aged; D018931:Antineoplastic Agents, Hormonal; D001992:Bronchoalveolar Lavage Fluid; D001999:Bronchoscopy; D002289:Carcinoma, Non-Small-Cell Lung; D000077547:Crizotinib; D004359:Drug Therapy, Combination; D006801:Humans; D017563:Lung Diseases, Interstitial; D008175:Lung Neoplasms; D008214:Lymphocytes; D008297:Male; D011239:Prednisolone; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "0313225",
"other_id": null,
"pages": "762-4",
"pmc": null,
"pmid": "24872405",
"pubdate": "2014-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful crizotinib rechallenge after crizotinib-induced interstitial lung disease.",
"title_normalized": "successful crizotinib rechallenge after crizotinib induced interstitial lung disease"
} | [
{
"companynumb": "JP-PFIZER INC-2014232187",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BUDESONIDE\\FORMOTEROL FUMARATE DIHYDRATE"
},
... |
{
"abstract": "Rhodococcus species are environmental organisms that predominantly cause opportunistic infections in immunocompromised hosts. Rhodococcus equi is the most common species associated with human infections, but there are uncommon but increasing number of cases of infections caused by non-equi Rhodococcus species. We report a case of Rhodococcus globerulus bacteremia in an allogeneic hematopoietic stem cell transplant recipient, who presented with subacute systemic illness accompanied by severe hepatitis. In the context of this case, we review the literature on Rhodococcus species infections in transplant recipients.",
"affiliations": "Division of Infectious Diseases and the William J von Liebig Transplant Center, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.",
"authors": "Ramanan|P|P|;Deziel|P J|PJ|;Razonable|R R|RR|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12220",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "16(3)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "Rhodococcus; Rhodococcus globerulus; allogeneic stem cell transplant; bacteremia; bone marrow transplant",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000193:Actinomycetales Infections; D000368:Aged; D000900:Anti-Bacterial Agents; D016470:Bacteremia; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D012240:Rhodococcus; D014184:Transplantation, Homologous",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "484-9",
"pmc": null,
"pmid": "24797154",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Rhodococcus globerulus bacteremia in an allogeneic hematopoietic stem cell transplant recipient: report of the first transplant case and review of the literature.",
"title_normalized": "rhodococcus globerulus bacteremia in an allogeneic hematopoietic stem cell transplant recipient report of the first transplant case and review of the literature"
} | [
{
"companynumb": "US-BAYER-2015-426926",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": null,
"drugadditional": null,
"drugadministrationroute": "048",
"drugauthoriz... |
{
"abstract": "BACKGROUND\nTamoxifen citrate is an anti-estrogen agent used in the treatment of breast carcinoma. Crystalline maculopathy is a rare complication of tamoxifen therapy. The clinical picture resembles that of idiopathic macular telangiectasia (IMT) Type 2, which is a more common clinical entity.\n\n\nOBJECTIVE\nTo report a case of crystalline maculopathy secondary to tamoxifen and highlight the importance of the medical history and investigations in differentiating it from IMT Type 2.\n\n\nMETHODS\nA diabetic female with a past history of breast carcinoma treated with tamoxifen came to the hospital for a routine eye check-up. Crystalline deposits were seen in the parafoveal region in both the eyes.The spectral domain optical coherence tomography (SD-OCT) showed foveal cysts in the inner retinal layer and fundus autofluorescence (FAF) and fundus fluorescein angiography (FFA) were within normal limits.\n\n\nCONCLUSIONS\nWhile tamoxifen maculopathy is reversible on stopping the therapy, IMT needs a long-term follow-up to monitor the potential risk of loss of vision due to choroidal neovascularization, hence necessitating the distinction between these two different clinical entities.",
"affiliations": "Aravind Eye Hospital and Postgraduate Institute of Ophthalmology, Pondicherry, 605007 India.",
"authors": "Rijal|Roshija Khanal|RK|;Nakhwa|Chinmay|C|;Sindal|Manavi D|MD|",
"chemical_list": "D004965:Estrogen Antagonists; D013629:Tamoxifen",
"country": "Nepal",
"delete": false,
"doi": "10.3126/nepjoph.v6i2.11713",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2072-6805",
"issue": "6(2)",
"journal": "Nepalese journal of ophthalmology : a biannual peer-reviewed academic journal of the Nepal Ophthalmic Society : NEPJOPH",
"keywords": null,
"medline_ta": "Nepal J Ophthalmol",
"mesh_terms": "D000328:Adult; D004965:Estrogen Antagonists; D005260:Female; D005451:Fluorescein Angiography; D005654:Fundus Oculi; D006801:Humans; D008266:Macula Lutea; D012164:Retinal Diseases; D013629:Tamoxifen; D013684:Telangiectasis; D041623:Tomography, Optical Coherence; D014792:Visual Acuity",
"nlm_unique_id": "101505288",
"other_id": null,
"pages": "227-9",
"pmc": null,
"pmid": "25680254",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Crystalline deposits in the macula - tamoxifen maculopathy or macular telangiectasia?",
"title_normalized": "crystalline deposits in the macula tamoxifen maculopathy or macular telangiectasia"
} | [
{
"companynumb": "IN-WATSON-2015-20652",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TAMOXIFEN"
},
"drugadditional": null,
"... |
{
"abstract": "The anti-IgE Omalizumab may be helpful to treat clopidogrel hypersensitivity without stopping thienopyridine administration in patients requirining continuous antiplatellet therapy after coronary stent placement.",
"affiliations": "Department of Emergency and Organ Transplantation, School of Allergology and Clinical Immunology, University of Bari Aldo Moro, Bari, Italy.;Department of Emergency and Organ Transplantation, School of Allergology and Clinical Immunology, University of Bari Aldo Moro, Bari, Italy.;Cardiology Department, University of Pavia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.;Section of Allergy and Clinical Immunology, Unit of Internal Medicine-\"F. Miulli\" Hospital, Acquaviva Delle Fonti, Bari, Italy.;Department of Emergency and Organ Transplantation, School of Allergology and Clinical Immunology, University of Bari Aldo Moro, Bari, Italy.;Department of Biomedical Science and Human Oncology, Dermatological Clinic, University of Bari, 70124 Bari, Italy.;Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine, University of Bari \"Aldo Moro\" Medical School, Bari, Italy.;Department of Cardiology, University of Patras Medical School, Patras, Greece.",
"authors": "Calogiuri|Gianfranco|G|;Nettis|Eustachio|E|;Mandurino-Mirizzi|Alessandro|A|;Di Leo|Elisabetta|E|;Macchia|Luigi|L|;Foti|Caterina|C|;Vacca|Angelo|A|;Kounis|Nicholas G|NG|",
"chemical_list": "D018926:Anti-Allergic Agents; D010975:Platelet Aggregation Inhibitors; D000069444:Omalizumab; D000077144:Clopidogrel; D001241:Aspirin",
"country": "United Arab Emirates",
"delete": false,
"doi": "10.2174/1871523018666190522105055",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1871-5230",
"issue": "19(3)",
"journal": "Anti-inflammatory & anti-allergy agents in medicinal chemistry",
"keywords": "Clopidogrel; omalizumab; prasugrel; thienopyridines; ticagrelor; urticaria.",
"medline_ta": "Antiinflamm Antiallergy Agents Med Chem",
"mesh_terms": "D000368:Aged; D018926:Anti-Allergic Agents; D001241:Aspirin; D000077144:Clopidogrel; D003324:Coronary Artery Disease; D023903:Coronary Restenosis; D004342:Drug Hypersensitivity; D004359:Drug Therapy, Combination; D054855:Drug-Eluting Stents; D005260:Female; D006801:Humans; D000069444:Omalizumab; D062645:Percutaneous Coronary Intervention; D010975:Platelet Aggregation Inhibitors; D016896:Treatment Outcome; D014581:Urticaria",
"nlm_unique_id": "101462262",
"other_id": null,
"pages": "335-339",
"pmc": null,
"pmid": "31113348",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Omalizumab for the Treatment of Persistent Drug Induced Urticaria Elicited by Thienopyridines: A Case Report.",
"title_normalized": "omalizumab for the treatment of persistent drug induced urticaria elicited by thienopyridines a case report"
} | [
{
"companynumb": "IT-ACCORD-135435",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
},
"drugadditional": "3",
"druga... |
{
"abstract": "The primary treatment for head and neck adenoid cystic carcinoma (ACC) is surgery. Infrequently, however, ACC's propensity for perineural and base of skull invasion can preclude definitive surgical management. We present our experience with proton radiation therapy (RT) and concurrent platinum-based chemotherapy.\n\n\n\nNine patients with unresectable node-negative, nonmetastatic head and neck ACC received definitive proton RT and concurrent cisplatin. Outcomes and toxicities were recorded. A systematic review of the literature was performed.\n\n\n\nMedian follow-up was 27 months (range, 9.2-48.3 months). Four patients achieved complete response at the primary site, and an additional 4 patients achieved stabilization of local disease. Only 1 patient developed local disease progression. Four patients had 5 acute grade 3 (G3) toxicities, and 1 patient developed a chronic G4 optic nerve disorder.\n\n\n\nOur preliminary results suggest proton RT and concurrent chemotherapy is a definitive treatment option for select patients with head and neck ACC. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1472-E1480, 2016.",
"affiliations": "Department of Radiation Oncology, Kaiser Permanente Medical Center, Los Angeles, California.;Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.",
"authors": "Bhattasali|Onita|O|;Holliday|Emma|E|;Kies|Merrill S|MS|;Hanna|Ehab Y|EY|;Garden|Adam S|AS|;Rosenthal|David I|DI|;Morrison|William H|WH|;Gunn|G Brandon|GB|;Fuller|C David|CD|;Zhu|X Ronald|XR|;Frank|Steven J|SJ|",
"chemical_list": "D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": "10.1002/hed.24262",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1043-3074",
"issue": "38 Suppl 1()",
"journal": "Head & neck",
"keywords": "adenoid cystic; chemotherapy; head and neck neoplasms; proton radiotherapy",
"medline_ta": "Head Neck",
"mesh_terms": "D000328:Adult; D000368:Aged; D003528:Carcinoma, Adenoid Cystic; D059248:Chemoradiotherapy; D002945:Cisplatin; D005260:Female; D006258:Head and Neck Neoplasms; D006801:Humans; D008297:Male; D008875:Middle Aged; D061766:Proton Therapy; D011879:Radiotherapy Dosage; D016896:Treatment Outcome",
"nlm_unique_id": "8902541",
"other_id": null,
"pages": "E1472-80",
"pmc": null,
"pmid": "26561041",
"pubdate": "2016-04",
"publication_types": "D016428:Journal Article; D016454:Review; D000078182:Systematic Review",
"references": null,
"title": "Definitive proton radiation therapy and concurrent cisplatin for unresectable head and neck adenoid cystic carcinoma: A series of 9 cases and a critical review of the literature.",
"title_normalized": "definitive proton radiation therapy and concurrent cisplatin for unresectable head and neck adenoid cystic carcinoma a series of 9 cases and a critical review of the literature"
} | [
{
"companynumb": "US-ACCORD-035863",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
"druga... |
{
"abstract": "Contrast-induced encephalopathy (CIE) is a rare complication that presents with transient neurologic deficits and is caused by neurotoxicity of intravascular contrast media. The prognosis can be extremely favorable even in comatose patients. We reported a 76-year-old woman admitted for scheduled coronary angiography. The total amount of Optiray contrast media used was 150 mL. Immediately after the procedure, the patient developed consciousness disturbance, global aphasia, cortical blindness and right-sided weakness. CIE was diagnosed by computed tomography and subsequent magnetic resonance imaging. The patient recovered completely within 48 hours without any neurological deficits.\n\n\nBACKGROUND\nAngioplasty; Contrast-induced encephalopathy; Percutaneous coronary intervention.",
"affiliations": "Division of Cardiology, Departments of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.;Division of Cardiology, Departments of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.;Division of Cardiology, Departments of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.;Division of Cardiology, Departments of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.;Division of Cardiology, Departments of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.",
"authors": "Liao|Min-Tsun|MT|;Lin|Tin-Tse|TT|;Lin|Lian-Yu|LY|;Hwang|Juey-Jen|JJ|;Tseng|Chuen-Den|CD|",
"chemical_list": null,
"country": "China (Republic : 1949- )",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1011-6842",
"issue": "29(3)",
"journal": "Acta Cardiologica Sinica",
"keywords": null,
"medline_ta": "Acta Cardiol Sin",
"mesh_terms": null,
"nlm_unique_id": "101687085",
"other_id": null,
"pages": "277-80",
"pmc": null,
"pmid": "27122717",
"pubdate": "2013-05",
"publication_types": "D002363:Case Reports",
"references": "9222178;6712182;17943057;10227646;21861745;5534969;8448799;21927883;21861746;8793235",
"title": "Contrast-Induced Encephalopathy after Percutaneous Coronary Intervention.",
"title_normalized": "contrast induced encephalopathy after percutaneous coronary intervention"
} | [
{
"companynumb": "TW-MALLINCKRODT-T201601666",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nConcomitant treatment with radiation therapy and cisplatin (CDDP) remains the gold standard for bladder preservation in the treatment of muscle-invasive bladder cancer (MIBC). We present the long-term results of a phase 1 clinical trial to assess the association of twice-weekly gemcitabine with CDDP and radiation therapy in this setting.\n\n\nMETHODS\nPatients with pT2-pT4N0M0 MIBC without hydronephrosis or diffuse carcinoma in situ were enrolled in this study. After maximal transurethral resection of the bladder tumor, patients received concomitant radiation therapy (63 Gy in 1.8 fractions) and chemotherapy (CDDP 20 mg/m²/day over 4 days every 21 days and gemcitabine twice a week). The starting dose of gemcitabine was 15 mg/m² with dose escalation to 20, 25, and 30 mg/m². The primary endpoint was the maximum tolerated dose (MTD). Secondary endpoints included toxicity and tumor control.\n\n\nRESULTS\nFourteen patients were enrolled. Dose-limiting toxicity occurred in 2 patients treated with 30 mg/m² gemcitabine (grade 4 thrombocytopenia and severe impairment of World Health Organization performance status, respectively). Nine patients received the complete chemoradiation therapy protocol. The recommended dose of gemcitabine was 25 mg/m². The median follow-up time was 53 months, and the overall and disease-specific 5-year survival rates were 62% and 77%, respectively. Among the patients who received the complete treatment, bladder-intact survival was 76% at 5 years, and the median overall survival was 69.6 months.\n\n\nCONCLUSIONS\nThis regimen was well tolerated. The gemcitabine MTD was 25 mg/m². Bladder preservation and disease control were promising. A multicenter phase 2 randomized trial is ongoing.",
"affiliations": "Department of Radiation Oncology and Radiophysics Unit, Montpellier Cancer Institute (ICM), Montpellier, France; INSERM, U896, IRCM, Montpellier, France. Electronic address: david.azria@icm.unicancer.fr.;Department of Radiation Oncology and Radiophysics Unit, Montpellier Cancer Institute (ICM), Montpellier, France.;Department of Urology, Clinique Beausoleil, Montpellier, France.;Biostatistics Unit, Montpellier Cancer Institute, Montpellier, France.;Department of Urology, Montpellier University Hospital, Montpellier, France.;Department of Radiation Oncology and Radiophysics Unit, Montpellier Cancer Institute (ICM), Montpellier, France.;Department of Medical Oncology, AP-HP Saint-Louis, Paris, France.;Department of Medical Oncology, AP-HP Saint-Louis, Paris, France.",
"authors": "Azria|David|D|;Riou|Olivier|O|;Rebillard|Xavier|X|;Thezenas|Simon|S|;Thuret|Rodolphe|R|;Fenoglietto|Pascal|P|;Pouessel|Damien|D|;Culine|Stephane|S|",
"chemical_list": "D003841:Deoxycytidine; C056507:gemcitabine; D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0360-3016",
"issue": "88(4)",
"journal": "International journal of radiation oncology, biology, physics",
"keywords": null,
"medline_ta": "Int J Radiat Oncol Biol Phys",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D059248:Chemoradiotherapy; D002945:Cisplatin; D003841:Deoxycytidine; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D059351:Organ Sparing Treatments; D015996:Survival Rate; D001743:Urinary Bladder; D001749:Urinary Bladder Neoplasms",
"nlm_unique_id": "7603616",
"other_id": null,
"pages": "853-9",
"pmc": null,
"pmid": "24368064",
"pubdate": "2014-03-15",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article",
"references": null,
"title": "Combined chemoradiation therapy with twice-weekly gemcitabine and cisplatin for organ preservation in muscle-invasive bladder cancer: long-term results of a phase 1 trial.",
"title_normalized": "combined chemoradiation therapy with twice weekly gemcitabine and cisplatin for organ preservation in muscle invasive bladder cancer long term results of a phase 1 trial"
} | [
{
"companynumb": "FR-CIPLA LTD.-2013FR00947",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
"d... |
{
"abstract": "Primary neuroendocrine tumors of the thymus are extremely rare. In patients with advanced disease, tumor growth control, and sometimes also syndrome control are the main goals of systemic therapy. Unfortunately, no standard therapies are available in clinical practice; therefore, clinical studies are strongly recommended. Axitinib (AXI) is a tyrosine kinase inhibitor, currently under investigation in an international phase II/III trial including thymic neuroendocrine tumors. Over the past 5 months, the entire world has been facing a devastating medical emergency brought about by a pandemic due to a novel coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which emerged in Wuhan, China, in late 2019. Since then, health professionals have been expending all their efforts on trying to provide the best available treatments for patients involved. Patients with cancer, especially those with thoracic involvement, are at higher risk of coronavirus disease 19 (COVID-19) and its complications because of their immunosuppressive status caused by the cancer and the anticancer therapies. As it remains unclear how to optimally manage such patients, we wished to report our experience with a patient with a metastatic neuroendocrine tumor of the thymus infected with SARS-CoV-2 in the hope that it may provide some insights and reflections on the management of cancer patients during this challenging time in our history.",
"affiliations": "Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO), IRCCS, Via Ripamonti 435, 20141, Milan, Italy.;Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO), IRCCS, Via Ripamonti 435, 20141, Milan, Italy.;Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO), IRCCS, Via Ripamonti 435, 20141, Milan, Italy.;Division of Radiology, European Institute of Oncology (IEO), IRCCS, Via Ripamonti 435, 20141, Milan, Italy.;Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO), IRCCS, Via Ripamonti 435, 20141, Milan, Italy.;Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO), IRCCS, Via Ripamonti 435, 20141, Milan, Italy.;Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO), IRCCS, Via Ripamonti 435, 20141, Milan, Italy.;Medical Oncology Department, Hospital Universitario Doce de Octubre, Imas12, UCM, Madrid, Spain.;Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO), IRCCS, Via Ripamonti 435, 20141, Milan, Italy. nicola.fazio@ieo.it.",
"authors": "Spada|F|F|;Pellicori|S|S|;Zampino|G|G|;Funicelli|L|L|;Gervaso|L|L|;Laffi|A|A|;Rubino|M|M|;Garcia-Carbonero|R|R|;Fazio|N|N|http://orcid.org/0000-0001-6869-0704",
"chemical_list": "D006886:Hydroxychloroquine; D017963:Azithromycin; D000077784:Axitinib; D011505:Protein-Tyrosine Kinases",
"country": "United States",
"delete": false,
"doi": "10.1007/s12020-020-02419-w",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1355-008X",
"issue": "70(1)",
"journal": "Endocrine",
"keywords": "COVID-19; NET; Neuroendocrine tumors; Thymus",
"medline_ta": "Endocrine",
"mesh_terms": "D000368:Aged; D000077784:Axitinib; D017963:Azithromycin; D000073640:Betacoronavirus; D000086382:COVID-19; D002276:Carcinoid Tumor; D015897:Comorbidity; D018352:Coronavirus Infections; D006801:Humans; D006886:Hydroxychloroquine; D007558:Italy; D008297:Male; D018358:Neuroendocrine Tumors; D058873:Pandemics; D011024:Pneumonia, Viral; D011505:Protein-Tyrosine Kinases; D016032:Randomized Controlled Trials as Topic; D000086402:SARS-CoV-2; D013953:Thymus Neoplasms; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "9434444",
"other_id": null,
"pages": "6-10",
"pmc": null,
"pmid": "32681385",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24764238;26291008;32066541;32192578;32147577;31794273;24206640;32073213",
"title": "SARS-CoV-2-related pneumonia can be successfully managed in patients with metastatic neuroendocrine tumors: a critical point of view.",
"title_normalized": "sars cov 2 related pneumonia can be successfully managed in patients with metastatic neuroendocrine tumors a critical point of view"
} | [
{
"companynumb": "IT-MYLANLABS-2020M1098744",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AZITHROMYCIN ANHYDROUS"
},
"drugadditional": ... |
{
"abstract": "The administration of target inhibitors is paramount to grant the longest survival in patients with ALK-positive non-small cell lung cancer (NSCLC). The eventual resistance to tyrosine kinase inhibitors (TKI) is monitored clinically and radiologically for prompt molecule shift to further generation TKI, if available. However, the early radiological detection of progression pattern (e.g. nodule onset) should be regarded with caution because overlaps exist with non-tumor cell proliferation and/or accumulation. Here we report the case of a stage IV ALK-rearranged NSCLC patient exposed to serial crizotinib, brigatinib, ceritinib, and lorlatinib (this latter brought to complete brain and leptomeningeal disease response), in a period of more than five years. During lorlatinib, the appearance of solid pulmonary nodules was obviously interpreted as disease progression. However, surgical biopsies of the pulmonary nodules revealed features of sarcoid-like granulomatous lymphadenitis, namely without tumor cell. This invasive approach, besides documenting for the first time a sarcoid-like reaction to ALK inhibitors, allowed to revert the radiological diagnosis and maintain lorlatinib, for the best patient outcome. The pragmatic relevance of these findings suggests a careful attitude towards the interpretation of radiologic patterns of disease progression in patients under TKI.",
"affiliations": "Medical Oncology Unit, University Hospital of Parma, Via Gramsci, 14, 43126, Parma, Italy. francescofacchinetti2@gmail.com.;Pathology Section, University Hospital of Parma, Parma, Italy.;Thoracic Surgery, University Hospital of Parma, Parma, Italy.;Section of Radiology, Unit of Surgical Sciences, Department of Medicine and Surgery (DiMeC), University of Parma, Parma, Italy.;Pathology Section, University Hospital of Parma, Parma, Italy.;Thoracic Surgery, University Hospital of Parma, Parma, Italy.;Pulmonology and Thoracic Endoscopy Unit, University Hospital of Parma, Parma, Italy.;Medical Oncology Unit, University Hospital of Parma, Via Gramsci, 14, 43126, Parma, Italy.;Medical Oncology Unit, University Hospital of Parma, Via Gramsci, 14, 43126, Parma, Italy.",
"authors": "Facchinetti|Francesco|F|;Gnetti|Letizia|L|;Balestra|Valeria|V|;Silva|Mario|M|;Silini|Enrico Maria|EM|;Ventura|Luigi|L|;Majori|Maria|M|;Bordi|Paola|P|;Tiseo|Marcello|M|",
"chemical_list": "D000631:Aminopyridines; D007769:Lactams; D047029:Lactams, Macrocyclic; D011720:Pyrazoles; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; C000590786:lorlatinib",
"country": "United States",
"delete": false,
"doi": "10.1007/s10637-018-0652-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-6997",
"issue": "37(2)",
"journal": "Investigational new drugs",
"keywords": "ALK inhibitors; Lorlatinib; Non-small cell lung cancer; Progression-mimicking reaction; Sarcoid-like reaction; Sarcoidosis",
"medline_ta": "Invest New Drugs",
"mesh_terms": "D000328:Adult; D000631:Aminopyridines; D000077548:Anaplastic Lymphoma Kinase; D002289:Carcinoma, Non-Small-Cell Lung; D003937:Diagnosis, Differential; D018450:Disease Progression; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D007769:Lactams; D047029:Lactams, Macrocyclic; D008175:Lung Neoplasms; D011379:Prognosis; D011720:Pyrazoles; D012507:Sarcoidosis",
"nlm_unique_id": "8309330",
"other_id": null,
"pages": "360-363",
"pmc": null,
"pmid": "30066208",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "26452227;29174221;29650534;28475456;29763666;29074098;26698910;29768119",
"title": "Sarcoid-like reaction mimicking disease progression in an ALK-positive lung cancer patient receiving lorlatinib.",
"title_normalized": "sarcoid like reaction mimicking disease progression in an alk positive lung cancer patient receiving lorlatinib"
} | [
{
"companynumb": "IT-TAKEDA-2018TUS025000",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BRIGATINIB"
},
"drugadditional": null,
... |
{
"abstract": "We report a renal allograft transplant recipient with esophageal tuberculosis (TB) coinfected with herpes simplex virus (HSV) and Candida. The patient presented with oropharyngeal candidiasis and was started on fluconazole. Upper gastrointestinal endoscopy showed whitish patches with mucosal ulcers in the esophagus. Histopathological examination confirmed TB and HSV infection. The patient recovered after antiviral, antifungal, and anti-tubercular therapy with reduction in immunosuppression. In a TB-endemic zone, TB can coexist with opportunistic infections in an immunocompromised host.",
"affiliations": "Department of Renal Transplant Surgery, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.;Department of Renal Transplant Surgery, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.;Department of Gastroenterology, PGIMER, Chandigarh, India.;Department of Histopathology, PGIMER, Chandigarh, India.;Department of Renal Transplant Surgery, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.;Department of Renal Transplant Surgery, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.;Department of Renal Transplant Surgery, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.",
"authors": "Kumar|Sunil|S|;Minz|Mukut|M|;Sinha|Saroj K|SK|;Vaiphei|Kim|K|;Sharma|Ashish|A|;Singh|Sarbpreet|S|;Kenwar|Deepesh B|DB|",
"chemical_list": "D000935:Antifungal Agents; D000995:Antitubercular Agents; D000998:Antiviral Agents; D015725:Fluconazole",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12640",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "19(1)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "\nCandida albicans\n; esophageal tuberculosis; herpes simplex virus; infectious esophagitis; renal transplantation",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000935:Antifungal Agents; D000995:Antitubercular Agents; D000998:Antiviral Agents; D002180:Candidiasis, Oral; D003680:Deglutition Disorders; D016099:Endoscopy, Gastrointestinal; D000071041:Esophageal Mucosa; D004941:Esophagitis; D015725:Fluconazole; D006561:Herpes Simplex; D006606:Hiccup; D006801:Humans; D016867:Immunocompromised Host; D007150:Immunohistochemistry; D007165:Immunosuppression Therapy; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009894:Opportunistic Infections; D018139:Simplexvirus; D066027:Transplant Recipients; D014184:Transplantation, Homologous; D014385:Tuberculosis, Gastrointestinal; D014839:Vomiting",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "27885762",
"pubdate": "2017-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Esophageal tuberculosis with coexisting opportunistic infections in a renal allograft transplant recipient.",
"title_normalized": "esophageal tuberculosis with coexisting opportunistic infections in a renal allograft transplant recipient"
} | [
{
"companynumb": "IN-BAUSCH-BL-2017-006449",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
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"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "1",
... |
{
"abstract": "Our patient was severely injured, and had a prolonged period of hypotension. After operation she received moderate doses of cefazolin, intravenously, in the face of acute renal failure. Seizures associated with a serum cefazolin level of 455 mg/ml were observed. Although a cause and effect relationship between high cefazolin levels and neurotoxicity cannot be proven conclusively, the implication of this relationship exists. The clinician should be aware of the potential neurotoxicity of this commonly used drug. The importance of adjusting the dose in patients with renal failure is re-emphasized.",
"affiliations": null,
"authors": "Yost|R L|RL|;Lee|J D|JD|;O'Leary|J P|JP|",
"chemical_list": "D002511:Cephalosporins; D002437:Cefazolin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-1348",
"issue": "43(6)",
"journal": "The American surgeon",
"keywords": null,
"medline_ta": "Am Surg",
"mesh_terms": "D058186:Acute Kidney Injury; D002437:Cefazolin; D002511:Cephalosporins; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D007263:Infusions, Parenteral; D007677:Kidney Function Tests; D008875:Middle Aged; D011183:Postoperative Complications; D012640:Seizures; D013530:Surgical Wound Infection; D014949:Wounds, Nonpenetrating",
"nlm_unique_id": "0370522",
"other_id": null,
"pages": "417-20",
"pmc": null,
"pmid": "869336",
"pubdate": "1977-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Convulsions associated with sodium cefazolin: a case report.",
"title_normalized": "convulsions associated with sodium cefazolin a case report"
} | [
{
"companynumb": "US-PFIZER INC-2017542120",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SODIUM BICARBONATE"
},
"drugadditional": null... |
{
"abstract": "There is a well-known association between vitamin K deficiency and haemorrhagic events including gastrointestinal bleeding. There is also a well-known association between both poor dietary intake of vitamin K and chronic antibiotic use and the development of vitamin K deficiency. Although the medical literature notes that cephalosporin antibiotics have a propensity to cause vitamin K deficiency due to the molecular structure of the medications and their ability to suppress the synthesis of clotting factors, there are other antibiotics that have also been implicated in the development of vitamin K deficiency. There are very few reports of trimethoprim/sulfamethoxazole causing vitamin K deficiency and further leading to bleeding episodes. We present such a case and discuss the risk factors leading to such complications.",
"affiliations": "Department of Internal Medicine, University of Arizona Medical Center-University Campus, Tucson, Arizona, USA.;Department of Internal Medicine, University of Arizona Medical Center-University Campus, Tucson, Arizona, USA.;Department of Internal Medicine, University of Arizona Medical Center-University Campus, Tucson, Arizona, USA.;Department of Internal Medicine, University of Arizona Medical Center-University Campus, Tucson, Arizona, USA.",
"authors": "Fotouhie|Azadeh|A|;Desai|Hem|H|;Parsa|Nour Alhoda|NA|;King|Skye|S|",
"chemical_list": "D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2016()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D006471:Gastrointestinal Hemorrhage; D006801:Humans; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D014813:Vitamin K Deficiency; D006475:Vitamin K Deficiency Bleeding",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "27268289",
"pubdate": "2016-06-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "26495183;4750303;6047959;25849657;24231121;3191733;7022156;2267487;6470528",
"title": "Gastrointestinal bleeding secondary to trimethoprim-sulfamethoxazole-induced vitamin K deficiency.",
"title_normalized": "gastrointestinal bleeding secondary to trimethoprim sulfamethoxazole induced vitamin k deficiency"
} | [
{
"companynumb": "US-NOVEL LABORATORIES, INC-2016-03233",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
... |
{
"abstract": "Deferasirox is a standard treatment for chronic transfusional iron overload. Adverse effects of deferasirox have been reported in large prospective studies. We report two cases of monozygotic twins manifesting with proximal muscular atrophy and weakness under deferasirox. Discontinuation of deferasirox resulted in symptom improvement and ultimately in complete remission five months after successful haematopoietic stem cell transplantation. Broad diagnostic work-up could not bring evidence of another aetiology of muscular weakness. Iron overload or beta thalassemia itself as a cause is considered unlikely in our patients because the chronological coincidence of muscular symptoms was contra-directional to serum ferritin levels and significant clinical improvement was observed promptly after cessation of deferasirox even before transplantation. These observations suggest that the development of muscular weakness in patients on deferasirox should be recognised as a possible adverse effect of the drug.",
"affiliations": "Department of Pediatric Neurology and Developmental Medicine, Dr. v. Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany. Electronic address: katharina.vill@med.uni-muenchen.de.;Department of Pediatric Neurology and Developmental Medicine, Dr. v. Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany.;Department of Pediatric Radiology, Dr. v. Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany.;Department of Pediatric Neurology and Developmental Medicine, Dr. v. Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany.;Department of Pediatric Neurology and Developmental Medicine, Dr. v. Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany.;Department of Pediatric Hematology and Oncology, Dr. v. Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany.;Department of Pediatric Hematology and Oncology, Dr. v. Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany.",
"authors": "Vill|K|K|;Müller-Felber|W|W|;Teusch|V|V|;Blaschek|A|A|;Gerstl|L|L|;Huetker|S|S|;Albert|M H|MH|",
"chemical_list": "D001565:Benzoates; D007502:Iron Chelating Agents; D014230:Triazoles; D007501:Iron; D000077588:Deferasirox",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0960-8966",
"issue": "26(4-5)",
"journal": "Neuromuscular disorders : NMD",
"keywords": "Adverse effects; Beta-thalassemia major; Deferasirox; Iron chelation therapy; Muscular weakness",
"medline_ta": "Neuromuscul Disord",
"mesh_terms": "D001565:Benzoates; D015913:Chelation Therapy; D002648:Child; D002675:Child, Preschool; D000077588:Deferasirox; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007501:Iron; D007502:Iron Chelating Agents; D018908:Muscle Weakness; D009133:Muscular Atrophy; D014184:Transplantation, Homologous; D014230:Triazoles; D014430:Twins, Monozygotic; D017086:beta-Thalassemia",
"nlm_unique_id": "9111470",
"other_id": null,
"pages": "322-5",
"pmc": null,
"pmid": "27068298",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Proximal muscular atrophy and weakness: An unusual adverse effect of deferasirox iron chelation therapy.",
"title_normalized": "proximal muscular atrophy and weakness an unusual adverse effect of deferasirox iron chelation therapy"
} | [
{
"companynumb": "PHHY2016DE060776",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DEFERASIROX"
},
"drugadditional": null,
"dru... |
{
"abstract": "Biological agents are widely used in the treatment of autoimmune rheumatic disorders. We report on serious adverse events during treatment with anti-tumor necrosis factor antibody in two of our patients with juvenile idiopathic arthritis. One patient was treated with a biological agent due to juvenile idiopathic arthritis complicated by uveitis, developing miliary tuberculosis during treatment. After treatment with antituberculotics, she recovered completely. Her underlying disease is currently in remission. Another patient was treated for juvenile spondyloarthritis and developed an inflammatory process of the central nervous system with serious neurological deficits. He was treated with high-dose corticosteroids, followed by slowly tapering doses of corticosteroids. His neurological deficits improved, but are still present. Similar cases have been described previously, but there are no recommendations how to treat arthritis afterwards in such patients. We would like to emphasize the need of developing guidelines for further treatment of arthritis after the occurrence of serious adverse effects during treatment with biological agents.",
"affiliations": "1Department of Pediatrics, Split University Hospital Centre, University of Split School of Medicine, Split, Croatia; 2Department of Pediatrics, Division of Pediatric Rheumatology and Immunology, Zagreb University Hospital Centre, University of Zagreb School of Medicine, Zagreb, Croatia.;1Department of Pediatrics, Split University Hospital Centre, University of Split School of Medicine, Split, Croatia; 2Department of Pediatrics, Division of Pediatric Rheumatology and Immunology, Zagreb University Hospital Centre, University of Zagreb School of Medicine, Zagreb, Croatia.;1Department of Pediatrics, Split University Hospital Centre, University of Split School of Medicine, Split, Croatia; 2Department of Pediatrics, Division of Pediatric Rheumatology and Immunology, Zagreb University Hospital Centre, University of Zagreb School of Medicine, Zagreb, Croatia.;1Department of Pediatrics, Split University Hospital Centre, University of Split School of Medicine, Split, Croatia; 2Department of Pediatrics, Division of Pediatric Rheumatology and Immunology, Zagreb University Hospital Centre, University of Zagreb School of Medicine, Zagreb, Croatia.;1Department of Pediatrics, Split University Hospital Centre, University of Split School of Medicine, Split, Croatia; 2Department of Pediatrics, Division of Pediatric Rheumatology and Immunology, Zagreb University Hospital Centre, University of Zagreb School of Medicine, Zagreb, Croatia.;1Department of Pediatrics, Split University Hospital Centre, University of Split School of Medicine, Split, Croatia; 2Department of Pediatrics, Division of Pediatric Rheumatology and Immunology, Zagreb University Hospital Centre, University of Zagreb School of Medicine, Zagreb, Croatia.",
"authors": "Sršen|Saša|S|;Marušić|Eugenija|E|;Metličić|Vitomir|V|;Stričević|Luka|L|;Frković|Marijan|M|;Jelušić|Marija|M|",
"chemical_list": "D000079424:Tumor Necrosis Factor Inhibitors; D014409:Tumor Necrosis Factor-alpha; D000068879:Adalimumab",
"country": "Croatia",
"delete": false,
"doi": "10.20471/acc.2020.59.01.20",
"fulltext": "\n==== Front\nActa Clin Croat\nActa Clin Croat\nACC\nActa Clinica Croatica\n0353-9466 1333-9451 Sestre Milosrdnice University Hospital and Institute of Clinical Medical Research, Vinogradska cesta c. 29 Zagreb \n\nacc-59-161\n10.20471/acc.2020.59.01.20\nCase Reports\nHOW TO TREAT PATIENTS AFTER SERIOUS ADVERSE EFFECTS CAUSED BY TNF INHIBITORS?\nSršen Saša 1 Marušić Eugenija 1 Metličić Vitomir 1 Stričević Luka 1 Frković Marijan 2 Jelušić Marija 2 1Department of Pediatrics, Split University Hospital Centre, University of Split School of Medicine, Split, Croatia; 2Department of Pediatrics, Division of Pediatric Rheumatology and Immunology, Zagreb University Hospital Centre, University of Zagreb School of Medicine, Zagreb, Croatia\nCorrespondence to: Prof. Marija Jelušić, MD, PhD, Department of Pediatrics, Division of Rheumatology and Immunology, Referral Centre for Pediatric and Adolescent Rheumatology, University of Zagreb School of Medicine, Zagreb University Hospital Centre, Kišpatićeva 12, HR-10000 Zagreb, Croatia, E-mail: marija.jelusic@mef.hr\n3 2020 \n3 2020 \n59 1 161 165\n07 7 2016 30 12 2016 2020Sestre Milosrdnice University HospitalThis is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (CC BY-NC-ND) 4.0 License.SUMMARY\nBiological agents are widely used in the treatment of autoimmune rheumatic disorders. We report on serious adverse events during treatment with anti-tumor necrosis factor antibody in two of our patients with juvenile idiopathic arthritis. One patient was treated with a biological agent due to juvenile idiopathic arthritis complicated by uveitis, developing miliary tuberculosis during treatment. After treatment with antituberculotics, she recovered completely. Her underlying disease is currently in remission. Another patient was treated for juvenile spondyloarthritis and developed an inflammatory process of the central nervous system with serious neurological deficits. He was treated with high-dose corticosteroids, followed by slowly tapering doses of corticosteroids. His neurological deficits improved, but are still present. Similar cases have been described previously, but there are no recommendations how to treat arthritis afterwards in such patients. We would like to emphasize the need of developing guidelines for further treatment of arthritis after the occurrence of serious adverse effects during treatment with biological agents.\n\nKey words: \nRheumatologyArthritis, juvenileTumor necrosis factor-alpha – adverse effectsNeurologic manifestationsTuberculosis, miliary\n==== Body\nIntroduction\nBiological agents have an important role in the treatment of various autoimmune diseases. Their introduction has been a major breakthrough in the treatment of most seriously ill patients who did not respond well to conventional therapy in the field of rheumatology, as well as in some other fields of medicine, having become a cornerstone of their treatment and giving them a new opportunity for a normal life. However, the use of biological agents is associated with a risk of developing adverse effects due to the treatment, some of which may have serious consequences on patient health and can even be potentially fatal (1-7). Two cases of serious adverse effects during the treatment of juvenile idiopathic arthritis (JIA) with anti-tumor necrosis factor (TNF) receptor agent adalimumab in our patients have brought to our attention the fact that there are no recommendations and guidelines for further treatment of patient underlying disease after such an adverse event has occurred.\n\nCase Reports\nClinical charts of two patients with serious adverse effects during the treatment with anti-TNF agent were retrospectively reviewed. Reports in the literature describing similar side effects and treatment of patient underlying disease afterwards were analyzed and compared with our experiences.\n\nIn our practice, two patients developed serious adverse effects during the treatment of JIA with an anti-TNF receptor agent (adalimumab). The first case was development of miliary tuberculosis in a girl with JIA treated with adalimumab. Our patient was a 7-year-old girl with the polyarticular type of JIA, who had been ill since the age of two. She was treated with a nonsteroidal anti-inflammatory drug (NSAID), methotrexate, and occasionally with intra-articular injections of corticosteroids. By the age of four, she developed bilateral uveitis as a complication of JIA. Initially, she was treated with systemic corticosteroids and methotrexate in combination with topical ophthalmologic therapy (corticosteroids, NSAID and mydriatic eyedrops). Since there was no improvement, therapy with an anti-TNF receptor agent (etanercept) was started. Prior to the introduction of anti-TNF therapy, tuberculin skin test and interferon gamma release assay (IGRA, QuantiFERON test) were performed and they were negative.\n\nThe articular component of her disease responded well to biological therapy, but due to the progression of bilateral chronic uveitis, one anti-TNF agent was substituted by another (adalimumab) after one year of treatment. Tuberculin skin test and IGRA were performed and they were negative again, and chest radiography was normal. The switch of therapy was effective and remission of uveitis was induced. Twenty months after the beginning of treatment with adalimumab, she presented with prolonged subfebrile temperatures, loss of appetite, cough and running nose. She was admitted to the hospital, where she became febrile with temperatures over 39 °C and progression of cough, as well as elevated laboratory parameters showing acute inflammation (erythrocyte sedimentation rate (ESR) 43 mm/h, C-reactive protein (CRP) 60.3 mg/L). Thoracic multislice computed tomography (MSCT) scan showed plenty of small nodules diffusely spread over both lungs, in a way specific for miliary tuberculosis (Figs. 1 and 2). Sputum was negative for Mycobacterium (M.) tuberculosis, while the results of IGRA (QuantiFERON test) and M. tuberculosis polymerase chain reaction (PCR) were positive.\n\nFig. 1 Multislice computerized tomography (MSCT) of lungs showing widely spread nodules in lungs of a 7-year-old girl with tuberculosis acquired during treatment with TNF-alpha inhibitor (adalimumab).\n\nFig. 2 Radiography of the thorax of the same patient.\n\nSubsequently, we found out that due to deterioration in their social status, her family moved and started living with relatives, one of whom was treated for tuberculosis. She was treated for miliary tuberculosis with combined multidrug antituberculotic therapy for 9 months, while treatment with methotrexate and adalimumab was stopped. She is well now, without clinical or laboratory signs of active tuberculosis.\n\nFour months after discontinuation of anti-TNF therapy and methotrexate, she had a flare of uveitis and 3 months later a flare of JIA. Treatment with a systemic corticosteroid (0.5 mg/kg) and methotrexate (10 mg/m2) was started. She is currently treated with small doses of corticosteroids (0.2 mg/kg) and methotrexate, and her arthritis, as well as uveitis currently are in remission.\n\nAnother patient with serious adverse effects during the treatment with an anti-TNF agent was a boy with juvenile spondyloarthritis who developed an inflammatory process of the central nervous system (CNS) while he was treated with adalimumab. He had been treated due to JIA since he was four years old. Eventually, he developed sacroiliitis and spondyloarthritis, as well as enthesitis. During the time, he was treated with various NSAIDs, intra-articular and systemic corticosteroids, methotrexate, sulfasalazine and leflunomide. Finally, at the age of 13, because of further progression of the disease, treatment with anti-TNF agent adalimumab was started. Several months later, he was admitted to the hospital because of myositis. Within the next six months he was hospitalized two more times due to chest pain, when he had a rib fracture diagnosed, and due to epididymitis several weeks later. Every time during hospital treatment, anti-TNF therapy was temporarily discontinued, but his rheumatologist at another centre continued treatment afterwards. At the age of 14, 17 months after initiation of anti-TNF treatment, he reported severe headache, vertigo, loss of sense and muscle weakness in his right arm. At that time, he was treated due to juvenile spondyloarthritis with naproxen, sulfasalazine and adalimumab. Adalimumab therapy was promptly and permanently discontinued. He slowly recovered within a week, but not completely, with residual minor muscle weakness and tremor. We suspected the demyelinating process of the CNS, but magnetic resonance imaging (MRI) scans of the brain and cervical spine were normal.\n\nOne month later, sudden and severe deterioration occurred with muscle weakness and loss of feeling in his left arm, strong tremor and spontaneous myoclonus of larger groups of muscles of both left arm and leg, progressing in a few days to the right side of the body and exacerbating in intensity. He had accentuated reflexes on the left side of his body up to clonus. Broad spectrum neurological diagnostic workup was done, which showed pleocytosis in cerebrospinal fluid (CSF), with more IgG oligoclonal bands positive, without blood-CSF barrier dysfunction, implicating intrathecal synthesis and an active inflammatory process of the CNS. Treatment with high doses of corticosteroids was initiated, followed by slowly tapering the dose of corticosteroids, while sulfasalazine as a potentially neurotoxic agent was discontinued from therapy. Muscle strength gradually recovered and myoclonia diminished, but still with residual neurological sequels. Repeat MRI scan of the brain and whole spinal cord showed just unidentified bright object (UBO) lesions without signs of demyelination, and repeat CSF analysis within several months showed calming of the inflammatory process of the CNS. All serological tests for potential infectious causes were negative, as well as anti-ganglioside antibodies specific for peripheral neuropathies. No infectious or malignant causes of disease were found. ESR, CRP, complete blood count (CBC), urine and biochemical tests were all normal.\n\nNow he has minor motor asymmetry with mild muscle weakness of the left side of his body, and spondyloarthritis is in a low level of activity. He is currently being treated with naproxen and sulfasalazine that have been reintroduced in treatment.\n\nDiscussion\nThe use of biological agents, including anti-TNF receptor antibodies, is recognized as a risk factor for serious adverse effects, primarily infections (1, 5, 7). Among the potential causes of infection, one of the most important is M. tuberculosis, causing de novo tuberculosis infection or reactivation of latent tuberculosis (1, 8, 9). There are numerous case reports of tuberculosis infection during anti-TNF therapy in the literature, some of them showing life-threatening conditions (10, 11). Therefore, it is important to keep this possibility in mind and to screen patients for tuberculosis prior to and during anti-TNF treatment. Guidelines for screening are somewhat different among various authors and include clinical history, physical examination, chest radiography, tuberculin skin test and IGRA (12, 13).\n\nIn our first patient, screening was done prior to the introduction of anti-TNF treatment and then again before the switch of therapy, and it was negative on both occasions. The problem occurred during treatment when she and her family, due to deterioration in their social status, moved to live with their relatives, one of whom was treated for tuberculosis: Additional obstacle in our way was the fact that they kept it secret. Fortunately, the diagnosis was established in time to prevent serious complications, and she is now cured of tuberculosis.\n\nAmong various adverse effects of anti-TNF treatment, neurological adverse events are amongst those that occur more often. The most often events are CNS demyelination, optic neuritis, peripheral neuropathy and facial palsy, whereas transverse myelitis, progressive multifocal leukoencephalopathy, cerebrovascular disease, encephalopathy and CNS infections are not as often as those mentioned previously (1, 4, 14, 15).\n\nIn our patient, we immediately suspected a demyelinating process but repeat MRI scans of the CNS did not show demyelinating lesions. We found signs of active inflammatory process of the CNS, most likely of autoimmune origin, since all of the possible infectious causes were excluded. Our patient responded well to corticosteroid therapy, but there are still residual minor neurological deficits present.\n\nThere are numerous other possible adverse effects of biological therapy that a clinician should be aware of, such as infusion reactions, immune system disorders, hematologic adverse events, lung disease, cardiovascular effects of biologicals, sarcoidosis, as well as the possible relationship between biological agents and malignant disease (1).\n\nHowever, once such an adverse event occurs and after it is taken care for, there still remains a fact that we have a patient with rheumatic disease that was severe enough to require biological therapy due to the lack of disease control with conventional treatment, leaving us in a difficult situation of having to decide on further therapy of the underlying disease. Individual experiences reported in the literature are scarce, and to the best of our knowledge, there are no recommendations or guidelines for further treatment of such patients (15).\n\nConsidering our patients, in the girl with JIA and chronic uveitis, who was treated for miliary tuberculosis, in case of another flare of disease, we are planning to start treatment with the interleukin-6 inhibitor tocilizumab, whereas in the boy with juvenile spondyloarthritis and inflammatory process of the CNS, we do not intend to reintroduce biological therapy for the following two reasons: first, the etiology of inflammatory process is not completely resolved, even though we believe that it is an autoimmune process initiated by anti-TNF therapy, and second, neither the boy or his family are willing to start biological treatment again.\n\nDuring the treatment with biological agents, adverse events may occur, but there are no recommendations how to treat patients afterwards. We would like to emphasize the need of creating and developing guidelines for further treatment of such patients at the level of international expert societies, and on the principles of evidence-based medicine as far as it is possible.\n==== Refs\nReferences\n1 Nanau RM Neuman MG \nSafety of anti-tumor necrosis factor therapies in arthritis patients.\n\nJ Pharm Pharm Sci . 2014 ;17 (3 ):324 –61\n. 10.18433/J3WP4F 25224347 \n2 Burmester GR Mease P Dijkmans BA Gordon K Lovell D Panaccione R \nAdalimumab safety and mortality rates from global clinical trials of six immune-mediated inflammatory diseases.\n\nAnn Rheum Dis . 2009 ;68 (12 ):1863 –9\n. 10.1136/ard.2008.102103 19147611 \n3 Bongartz T Sutton AJ Sweeting MJ Buchan I Matteson EL Montori V \nAnti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials.\n\nJAMA . 10.1001/jama.295.19.2275 16705109 \n4 Nozaki K Silver RM Stickler DE Abou-Fayssal NG Giglio P Kamen DL \nNeurological deficits during treatment with tumor necrosis factor-alpha antagonists.\n\nAm J Med Sci . 10.1097/MAJ.0b013e31822b7bb8 21876428 \n5 Biotech J. Inc. [Internet] REMICADE® (infliximab). Highlights of Prescribing Information; c2013- [updated 2015 Oct; cited 2016 Dec 17]. Available from: http://www.remicade.com/shared/product/remicade/prescribing-information.pdf.\n6 AbbVie, Inc. [Internet] HUMIRA® (adalimumab). Highlights of Prescribing Information; c2014- [updated 2016 Oct; cited 2016 Dec 17] Available from: http://www.rxabbvie.com/pdf/humira.pdf.\n7 Amgen, Inc. [Internet](2013) ENBREL® (etanercept). Highlights of Prescribing information; c2013- [updated 2016 Nov; cited 2016 Dec 17] Available from: http://pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/enbrel/enbrel_pi.ashx\n8 Winthrop KL Baxter R Liu L Varley CD Curtis JR Baddley JW \nMycobacterial diseases and antitumour necrosis factor therapy in USA.\n\nAnn Rheum Dis . 2013 ;72 (1 ):37 –42\n. 10.1136/annrheumdis-2011-200690 22523429 \n9 Dixon WG Hyrich KL Watson KD Lunt M Galloway J Ustianowski A \nDrug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register (BSRBR).\n\nAnn Rheum Dis . 2010 ;69 (3 ):522 –8\n. 10.1136/ard.2009.118935 19854715 \n10 Hess S Hospach T Nossal R Dannecker G Magdorf K Uhlemann F \nLife-threatening disseminated tuberculosis as a complication of TNF-α blockade in an adolescent.\n\nEur J Pediatr . 2011 ;170 (10 ):1337 –42\n. 10.1007/s00431-011-1501-y 21625932 \n11 Malipeddi AS Rajendran R Kallarackal G \nDisseminated tuberculosis after anti-TNFalpha treatment.\n\nLancet . 2007 ;369 (9556 ):162 . 10.1016/S0140-6736(07)60078-6 17223480 \n12 Hatemi G Melikoglu M Ozbakir F Tascilar K Yazici H \nQuantiferon-TB Gold in tube assay for the screening of tuberculosis before and during treatment with tumor necrosis factor alpha antagonists.\n\nArthritis Res Ther . 2012 ;14 (3 ):R147 . 10.1186/ar3882 22709461 \n13 Solovic I Sester M Gomez-Reino JJ Rieder HL Ehlers S Milburn HJ \nThe risk of tuberculosis related to tumour necrosis factor antagonist therapies: a TBNET consensus statement.\n\nEur Respir J . 2010 ;36 (5 ):1185 –206\n. 10.1183/09031936.00028510 20530046 \n14 Deepak P Stobaugh DJ Sherid M Sifuentes H Ehrenpreis ED \nNeurological events with tumour necrosis factor alpha inhibitors reported to the Food and Drug Administration Adverse Event Reporting System.\n\nAliment Pharmacol Ther . 2013 ;38 (4 ):388 –96\n. 10.1111/apt.12385 23802849 \n15 Seror R Richez C Sordet C Rist S Gossec L Direz G \nPattern of demyelination occurring during anti-TNF-α therapy: a French national survey.\n\nRheumatology (Oxford) . 2013 ;52 (5 ):868 –74\n. 10.1093/rheumatology/kes375 23287362\n\n",
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"keywords": "Arthritis, juvenile; Neurologic manifestations; Rheumatology; Tuberculosis, miliary; Tumor necrosis factor-alpha – adverse effects",
"medline_ta": "Acta Clin Croat",
"mesh_terms": "D000068879:Adalimumab; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008297:Male; D010523:Peripheral Nervous System Diseases; D012189:Retrospective Studies; D000079424:Tumor Necrosis Factor Inhibitors; D014409:Tumor Necrosis Factor-alpha",
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"title": "HOW TO TREAT PATIENTS AFTER SERIOUS ADVERSE EFFECTS CAUSED BY TNF INHIBITORS?",
"title_normalized": "how to treat patients after serious adverse effects caused by tnf inhibitors"
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"abstract": "Gemcitabine is an antimetabolite drug used in the treatment of various solid tumours, including lung, pancreatic or gynaecological cancers. Innovative combinational strategies (e.g. gemcitabine+capecitabine or gemcitabine+oxaliplatin) make gemcitabine an extensively prescribed drug now. Gemcitabine is characterized by a narrow therapeutic index, and its liver elimination depends upon a key enzymatic step, driven by cytidine deaminase (CDA). CDA is prone to gene polymorphism, including the 208A>G mutation, which can result in marked enzymatic deficiency with subsequent impact on drug exposure levels and related toxicities. We have developed a simple and inexpensive method to determine phenotypically CDA status in cancer patients, as an attempt to detect those at risk upon gemcitabine intake. Conjointly to genotypic investigations, this method was used to phenotype, in a retrospective setting, a female patient displaying extremely severe, and eventually lethal, toxicities after administration of a standard gemcitabine/carboplatin protocol. Phenotypic investigation showed a marked CDA deficiency (-75%) in this patient when compared with a reference, nontoxic population. Genetic studies undertaken next to screen mutations, possibly at the origin of this deficiency, showed heterozygosity for the 79A>C single-point mutation, whereas surprisingly the canonical CDA 208A>G polymorphism was not found. Taken together, this case report demonstrates, for the first time, that CDA downregulation can lead to toxic-death in patients exposed to gemcitabine. Besides, we showed here that our cost-effective and simple phenotypic approach should enable, in the future, the detection of deficient patients at risk upon gemcitabine administration.",
"affiliations": "EA3286, Pharmacokinetics Laboratory, Mediterranee University, Marseilles, France.",
"authors": "Mercier|Cédric|C|;Raynal|Caroline|C|;Dahan|Laetitia|L|;Ortiz|Adrien|A|;Evrard|Alexandre|A|;Dupuis|Charlotte|C|;Blesius|Aurore|A|;Duluc|Muriel|M|;Franceschini|Fleur|F|;Giacometti|Sarah|S|;Salas|Sébastien|S|;Milano|Gérard|G|;Favre|Roger|R|;Seitz|Jean-François|JF|;Ciccolini|Joseph|J|",
"chemical_list": "D003841:Deoxycytidine; C056507:gemcitabine; D003564:Cytidine Deaminase",
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"mesh_terms": "D000368:Aged; D003564:Cytidine Deaminase; D003841:Deoxycytidine; D015536:Down-Regulation; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012016:Reference Values",
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"title": "Toxic death case in a patient undergoing gemcitabine-based chemotherapy in relation with cytidine deaminase downregulation.",
"title_normalized": "toxic death case in a patient undergoing gemcitabine based chemotherapy in relation with cytidine deaminase downregulation"
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"abstract": "Intravesical instillation of Bacillus Calmette-Guerin is one of the standard treatment options for superficial bladder cancer. While Bacillus Calmette-Guerin therapy is usually well tolerated with most patients experiencing only cystitis, in rare cases, it can lead to disseminated granulomatous disease. We present a case of a 72-year-old man with disseminated granulomatous disease from intravesical BCG instillation whose treatment was complicated by antimycobacterial drug toxicity.",
"affiliations": "Triborough GI Gastroenterology, NY Scientific Research Center, 1517 Voorhies Avenue, Brooklyn, NY 11235, USA.;Mount Sinai Beth Israel, 3201 Kings Highway, Brooklyn, NY 11234, USA.;ID Care, 105 Raider Blvd. Suite 101, Hillsborough, NJ 08844, USA.;Digestive Disease Center, 11 State Road, Suite 200, Princeton, NJ 08540, USA.;University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, University Medical Center at Princeton, 253 Witherspoon Street, Lambert House, Princeton, NJ 08540, USA.",
"authors": "Ghafouri|Sayed Ab Reshad|SAR|0000-0003-1029-2468;Brun|Alexander|A|;Bhalla|Rohit|R|;Margulies|Craig|C|;Skole|Kevin|K|",
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"doi": "10.1155/2018/8280527",
"fulltext": "\n==== Front\nCase Rep Oncol MedCase Rep Oncol MedCRIONMCase Reports in Oncological Medicine2090-67062090-6714Hindawi 10.1155/2018/8280527Case ReportDisseminated Granulomatous Disease from Intravesical Instillation of Bacillus Calmette-Guerin http://orcid.org/0000-0003-1029-2468Ghafouri Sayed Ab. Reshad sreghafouri@gmail.com\n1\nBrun Alexander \n2\nBhalla Rohit \n3\nMargulies Craig \n4\nSkole Kevin \n5\n\n1Triborough GI Gastroenterology, NY Scientific Research Center, 1517 Voorhies Avenue, Brooklyn, NY 11235, USA\n2Mount Sinai Beth Israel, 3201 Kings Highway, Brooklyn, NY 11234, USA\n3ID Care, 105 Raider Blvd. Suite 101, Hillsborough, NJ 08844, USA\n4Digestive Disease Center, 11 State Road, Suite 200, Princeton, NJ 08540, USA\n5University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, University Medical Center at Princeton, 253 Witherspoon Street, Lambert House, Princeton, NJ 08540, USAAcademic Editor: Jose I. Mayordomo\n\n2018 29 8 2018 2018 828052729 6 2018 3 8 2018 Copyright © 2018 Sayed Ab. Reshad Ghafouri et al.2018This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Intravesical instillation of Bacillus Calmette-Guerin is one of the standard treatment options for superficial bladder cancer. While Bacillus Calmette-Guerin therapy is usually well tolerated with most patients experiencing only cystitis, in rare cases, it can lead to disseminated granulomatous disease. We present a case of a 72-year-old man with disseminated granulomatous disease from intravesical BCG instillation whose treatment was complicated by antimycobacterial drug toxicity.\n==== Body\n1. Introduction\nBacillus Calmette-Guerin (BCG) is a viable strain of the virulent Mycobacterium bovis. It was developed at the end of the 19th century and has been used extensively as a vaccine against tuberculosis since the 1920s [1]. In 1976, Morales et al. first reported that instillation of BCG could be used as an alternative to chemotherapy in the treatment of in situ transitional cell carcinoma of the bladder [2]. Since then, BCG has become a commonly used treatment with proven efficacy.\n\nThe induction of local inflammation makes hematuria, cystitis, and transient fevers a common and almost an inherent part of the BCG treatment [3, 4]. Systemic complications from BCG therapy, such as pneumonitis, granulomatous hepatitis, and sepsis, are rare and usually occur after traumatic and difficult bladder catheterizations [5, 6]. We present a case of disseminated granulomatous disease secondary to BCG treatment, complicated by antimycobacterial drug toxicity.\n\n2. Case\nA 72-year-old male was admitted with anorexia, shaking chills, diaphoresis, hematuria, productive cough, and fever up to 103°F.\n\nTen months prior to his presentation, the patient had been diagnosed with high-grade papillary noninvasive urothelial carcinoma of the bladder with no invasion of the lamina propria or muscularis propria (American Joint Committee on Cancer stage TaN0M0). After the tumor was resected, he began intravesical BCG therapy. He had his final BCG instillation approximately 17 days prior to his admission. On the day of admission, he had significant gross hematuria, shaking chills, a productive cough, profuse diaphoresis, malaise, and fever up to 103°F.\n\nThe patient's past medical history included type 2 diabetes mellitus, hypertension, and coronary artery disease. Medications on admission were losartan, INH insulin, metformin, metoprolol, and rosuvastatin. The patient was originally from India and had lived in the United States for the past thirty years. He had a 15-pack year smoking history prior to quitting 25 years ago. His family history was significant for prostate cancer in his brother.\n\nUpon admission, the patient appeared fatigued and acutely ill. His temperature was 103°F, respiratory rate 24, blood pressure 160/80, pulse 84, and pulse oximetry 97% on 2 L nasal canula. His exam was notable for bilateral crackles at the lung bases; his abdomen was benign, and there was no costovertebral angle tenderness.\n\nLaboratory results included a white blood cell count of 3.6 × 109/L, hemoglobin of 14.4 g/dL and platelet count of 98 × 109/L. Liver function tests showed an alkaline phosphatase of 251 U/L, alanine transaminase of 71 U/L, and aspartate transaminase of 92 U/L. Urinalysis had moderate blood, 3–10 RBC/hpf, 0–5 WBC/hpf, negative leukocyte esterase, and negative nitrites. PA and lateral chest X-ray showed increased interstitial markings bilaterally, especially at the bases. Right upper quadrant ultrasound showed mild fatty infiltration of the liver.\n\nThe patient was placed on ceftriaxone for presumed community-acquired pneumonia but failed to improve. Lack of improvement on antibiotics coupled with the multiple systemic abnormalities (including (1) chest X-ray findings suggesting pneumonitis, (2) a rise in transaminases pointing towards hepatitis, and (3) thrombocytopenia indicating bone marrow involvement) lead to the possible diagnoses of disseminated mycobacteria. However, it was not clear whether this was truly disseminated mycobacteria or a hypersensitivity reaction from BCG. Therefore, the patient was initially started on methylPREDNISolone, INH, rifampin, and ethambutol.\n\nThe patient began to improve clinically, but after six days of therapy, his transaminases were markedly more elevated with worsening thrombocytopenia. At this point, concurrent medication toxicity was suspected. His antimycobacterial medications were held, and both a liver biopsy and a bone marrow biopsy were obtained in the following two days. His transaminases returned began to decrease shortly after antimycobacterial medications were held. Rifampin and ethambutol were restarted 24 hours later.\n\nThe liver biopsy showed chronic lobular and portal inflammation consisting predominantly of lymphocytes and histiocytes, focal interface hepatitis, and small noncaseating granulomas (see Figure 1). The bone marrow biopsy showed scattered noncaseating granulomas. Acid-fast stain for mycobacteria was negative on both biopsies. All blood cultures, urine cultures, and sputum cultures were ultimately negative.\n\nThe patient was discharged on rifampin, ethambutol, and prednisone eight days after the biopsy results came back. In the following week, he developed a recurrent rise in his transaminases, leading to cessation of antimycobacterial therapy due to possible rifampin hepatotoxicity. He remained stable with normal liver enzymes after completing six weeks of steroid treatment.\n\nBased on the aforementioned findings, the diagnosis of systemic granulomatous disease from BCG therapy was established, with hypersensitivity being the most likely etiology.\n\n3. Discussion\nWhile treatment of superficially invasive transitional cell carcinoma of the urinary bladder with BCG is considered effective and safe, local side effects are common (up to 90%), and systemic complaints can occur in up to 3% of patients [6, 7]. Risk factors for serious complications include traumatic catheter insertion, repeat instillation of BCG in patients with persistent local side effects (e.g., cystitis), and comorbidities [3, 8].\n\nIt is recommended not to give BCG therapy within the first 14 days of bladder surgery, and the BCG should not be given after a traumatic catheterization as it provokes disseminating BCG infection [9]. Systemic administration of antimycobacterial drugs was shown to be effective as the BCG strains are sensitive for most tuberculostatic medications. Two doses of 200 mg ofloxacin given shortly after BCG instillation have been demonstrated to reduce moderate to severe side effects [10]. Low dose BCG was tried in several studies in an attempt to decrease the frequency and severity of side effects and were found to be significantly less compared to full dose BCG treatment [11].\n\nOur patient, a diabetic, was having more widespread inflammatory response after his last BCG instillation. At issue is whether this response, i.e., systemic granulomatous disease, is a result of sepsis, a hypersensitivity reaction, or both.\n\nAll cultures in our patient were negative. It is notable, however, that with early disseminated granulomatous disease (defined as occurring within 8–12 weeks after the first BCG treatment) direct cultures, acid-fast smears and even DNA hybridization of granulomatous tissue infrequently demonstrate clear mycobacterium; blood cultures and bone marrow evaluations are also rarely positive [12]. The low yield is presumed to be due to an immunocompetent host forming well-developed granulomas without detectable organisms [12, 13]. In a study that combined results of 20 patients with early presentation, culture results were positive in 30% [12]. Lack of identifiable organisms in the majority of cases supports the theory that early disseminated granulomatous disease is more often a hypersensitivity reaction, and therefore, treatment with corticosteroids is advocated [13, 14]. In contrast, among patients with late presentation, cultures yield a positive result in 67%. The likely mechanism may be due to the reactivation of controlled early dissemination of Mycobacterium bovis now leading to active infection [12]. There have been no reported trials to assess optimal therapy for disseminated granulomatous disease. The absence of data, coupled with the fact that Mycobacterium bovis has been isolated from the tissue in both early [15] and late presentations [16], leads to the conclusion that corticosteroids should be combined with an antimycobacterial drug regimen until biopsy results are complete.\n\nOur patient was started on both an antimycobacterial regimen and systemic anti-inflammatory treatment. Soon after treatment was started, however, his transaminases increased sharply. They returned to their previous levels when antimycobacterial therapy was stopped.\n\nMild elevation of transaminases (<3x upper limit of normal) occurs in up to 20% of patients taking INH [17, 18]. Less than 1% develop severe hepatitis [17, 19]. The etiology of INH hepatotoxicity is unclear. Several studies suggest it is a direct result of toxic metabolites, while others support the theory that toxicity results from slow acetylation of the drug leading to the use of alternative, more toxin-inducing pathways [20, 21]. INH toxicity is difficult to diagnose by biopsy since the pathologic process ranges from mild patchy hepatitis to bridging and multilobular necrosis to severe hepatic necrosis [22, 23]. The biopsy results in our patient, including a lymphocyte predominance, seem to support the combination of acute drug toxicity and granulomatous hepatitis as the cause of the acute increase in our patient's liver enzymes. An eosinophil predominance would be expected in a pure hypersensitivity reaction [24].\n\nINH-induced hepatitis generally occurs 4 to 8 weeks after the start of therapy, but a more rapid onset has been well-documented [22, 25]. Age appears to be the most important risk factor of INH-induced hepatitis. Hepatic damage is rare in those less than 20 years of age, occurs in 1.2% of patients who are 35 to 49, and the incidence rises even further to 2.3% in people over 50 [26, 27]. Our patient was well over 50 years old. In addition, he was initially treated with a combination of INH and rifampin, which has been shown to lead to more rapid development of hepatitis in comparison to INH alone [28]. Rifampin increases hydrazine by induction of isoniazid hydrolase, which may explain the severe hepatotoxicity [29].\n\nThe recurrence of elevated transaminases one week post discharge is attributed to rifampin hepatotoxicity. Studies looking at patients taking prophylactic rifampin monotherapy report hepatotoxicity in about 1–2% [30, 31]. The pathophysiology of rifampin-induced hepatotoxicity is unknown and usually unpredictable. Hepatitis from hypersensitivity to rifampin has been reported but only in isolated case reports [32].\n\nGuidelines of the American Thoracic Society for management of antimycobacterial drug hepatotoxicity recommend continuation of medication when hepatotoxicity is mild [33]. However, all drugs should be discontinued if ALT rises to five times the normal, since continuation after signs of severe hepatic dysfunction develop tends to increase the severity of liver damage [33, 34]. Once ALT normalizes (ALT < 2 times upper limit of normal), rifampin (with or without ethambutol) should be restarted. If symptoms recur or ALT increases, rifampin is to be ceased.\n\nOur patient presented with elevated transaminases and ultimately had biopsy-proven disseminated granulomatous disease. He significantly improved with steroids after cessation of antimycobacterium therapy which is consistent with a hypersensitivity reaction to intravesical BCG therapy.\n\n4. Conclusion\nWe present a case of disseminated granulomatous disease secondary to intravesical BCG therapy for superficial bladder cancer. His treatment was complicated by presumed INH and rifampin hepatotoxicity. BCG therapy is considered an excellent alternative to chemotherapy in the treatment of superficial bladder tumors. Side effects are common, however, and systemic complications can occur. The exact mechanism of disseminated granulomatous disease is unclear, and treatment includes both antimicrobial and anti-inflammatory therapy.\n\nConflicts of Interest\nThe authors do not have any conflict of interest or any financial conflict to declare.\n\nFigure 1 Pathology slide of the liver showing noncaseating granulomas.\n==== Refs\n1 Luca S. Mihaescu T. History of BCG vaccine Maedica 2013 8 1 53 58 24023600 \n2 Morales A. Eidinger D. Bruce A. W. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors The Journal of Urology 1976 116 2 180 182 10.1016/S0022-5347(17)58737-6 820877 \n3 Pérez-Jacoiste Asín M. A. Fernández-Ruiz M. López-Medrano F. Bacillus Calmette-Guérin (BCG) infection following intravesical BCG administration as adjunctive therapy for bladder cancer: incidence, risk factors, and outcome in a single-institution series and review of the literature Medicine 2014 93 17 236 254 10.1097/MD.0000000000000119 2-s2.0-84922481923 25398060 \n4 Naudžiūnas A. Juškaitė R. Žiaugrytė I. Unikauskas A. Varanauskienė E. Mašanauskienė E. Tuberculosis complications after BCG treatment for urinary bladder cancer Medicina 2012 48 11 p. 82 10.3390/medicina48110082 \n5 Lamm D. L. van der Meijden A. P. M. Morales A. Incidence and treatment of complications of Bacillus Calmette-Guerin intravesical therapy in superficial bladder cancer The Journal of Urology 1992 147 3 596 600 10.1016/S0022-5347(17)37316-0 1538436 \n6 Brausi M. Oddens J. Sylvester R. Side effects of Bacillus Calmette-Guérin (BCG) in the treatment of intermediate- and high-risk Ta, T1 papillary carcinoma of the bladder: results of the EORTC genito-urinary cancers group randomised phase 3 study comparing one-third dose with full dose and 1 year with 3 years of maintenance BCG European Urology 2014 65 1 69 76 10.1016/j.eururo.2013.07.021 2-s2.0-84888827200 23910233 \n7 Valentini C. G. Bozzoli V. Larici A. R. Systemic granulomatous reaction secondary to treatment of bladder cancer with Bacillus Calmette-Guerin Mediterranean Journal of Hematology and Infectious Diseases 2012 4 1, article e2012040 10.4084/MJHID.2012.040 2-s2.0-84876002655 22811789 \n8 Yossepowitch O. Eggener S. E. Bochner B. H. Donat S. M. Herr H. W. Dalbagni G. Safety and efficacy of intravesical Bacillus Calmette-Guerin instillations in steroid treated and immunocompromised patients The Journal of Urology 2006 176 2 482 485 10.1016/j.juro.2006.03.066 2-s2.0-33745274756 16813873 \n9 Debois H. Loupi E. Saliou P. Surveillance of the safety of intravesical BCG therapy in France: quantitative analysis of serious adverse events notified over a period of five years Progrès en Urologie 2002 12 4 604 608 12463118 \n10 Colombel M. Saint F. Chopin D. Malavaud B. Nicolas L. Rischmann P. The effect of ofloxacin on Bacillus Calmette-Guerin induced toxicity in patients with superficial bladder cancer: results of a randomized, prospective, double-blind, placebo controlled, multicenter study The Journal of Urology 2006 176 3 935 939 10.1016/j.juro.2006.04.104 2-s2.0-33746521368 16890660 \n11 Martínez-Piñeiro J. A. Martínez-Piñeiro L. Solsona E. Has a 3-fold decreased dose of Bacillus Calmette-Guerin the same efficacy against recurrences and progression of T1G3 and Tis bladder tumors than the standard dose? Results of a prospective randomized trial The Journal of Urology 2005 174 4 1242 1247 10.1097/01.ju.0000173919.28835.aa 2-s2.0-24944548274 16145378 \n12 Gonzalez O. Y. Musher D. M. Brar I. Spectrum of bacille Calmette-Guérin (BCG) infection after intravesical BCG immunotherapy Clinical Infectious Diseases 2003 36 2 140 148 10.1086/344908 2-s2.0-0037439510 12522745 \n13 Colmenero J. D. Sanjuan-Jimenez R. Ramos B. Morata P. Miliary pulmonary tuberculosis following intravesical BCG therapy: case report and literature review Diagnostic Microbiology and Infectious Disease 2012 74 1 70 72 10.1016/j.diagmicrobio.2012.05.026 2-s2.0-84865299443 22749242 \n14 Molina J. M. Rabian C. D’Agay M. F. Modai J. Hypersensitivity systemic reaction following intravesical Bacillus Calmette-Guerin: successful treatment with steroids The Journal of Urology 1992 147 3 695 697 10.1016/S0022-5347(17)37354-8 1538462 \n15 Huang T. C. Management of complications of Bacillus Calmette-Guérin immunotherapy in the treatment of bladder cancer The Annals of Pharmacotherapy 2000 34 4 529 532 10.1345/aph.19145 2-s2.0-0034029227 10772442 \n16 Mavrogenis A. F. Sakellariou V. I. Tsiodras S. Papagelopoulos P. J. Late Mycobacterium bovis spondylitis after intravesical BCG therapy Joint Bone Spine 2009 76 3 296 300 10.1016/j.jbspin.2008.10.011 2-s2.0-67349254958 19303342 \n17 Centers for Disease Control and Prevention (CDC) Severe isoniazid-associated liver injuries among persons being treated for latent tuberculosis infection - United States, 2004-2008 Morbidity and Mortality Weekly Report 2010 59 8 224 229 20203555 \n18 Boelsterli U. A. Lee K. K. Mechanisms of isoniazid-induced idiosyncratic liver injury: emerging role of mitochondrial stress Journal of Gastroenterology and Hepatology 2014 29 4 678 687 10.1111/jgh.12516 2-s2.0-84896364866 24783247 \n19 Wang P. Pradhan K. Zhong X.-B. Ma X. Isoniazid metabolism and hepatotoxicity Acta Pharmaceutica Sinica B 2016 6 5 384 392 10.1016/j.apsb.2016.07.014 2-s2.0-84995378093 27709007 \n20 Chowdhury A. Santra A. Bhattacharjee K. Ghatak S. Saha D. R. Dhali G. K. Mitochondrial oxidative stress and permeability transition in isoniazid and rifampicin induced liver injury in mice Journal of Hepatology 2006 45 1 117 126 10.1016/j.jhep.2006.01.027 2-s2.0-33744935289 16545483 \n21 Metushi I. G. Nakagawa T. Uetrecht J. Direct oxidation and covalent binding of isoniazid to rodent liver and human hepatic microsomes: humans are more like mice than rats Chemical Research in Toxicology 2012 25 11 2567 2576 10.1021/tx300341r 2-s2.0-84869479030 23016703 \n22 Chalasani N. P. Hayashi P. H. Bonkovsky H. L. ACG clinical guideline: the diagnosis and management of idiosyncratic drug-induced liver injury The American Journal of Gastroenterology 2014 109 7 950 966 10.1038/ajg.2014.131 2-s2.0-84903897064 24935270 \n23 Kleiner D. E. Chalasani N. P. Lee W. M. Hepatic histological findings in suspected drug-induced liver injury: systematic evaluation and clinical associations Hepatology 2014 59 2 661 670 10.1002/hep.26709 2-s2.0-84893699696 24037963 \n24 Suzuki A. Brunt E. M. Kleiner D. E. The use of liver biopsy evaluation in discrimination of idiopathic autoimmune hepatitis versus drug-induced liver injury Hepatology 2011 54 3 931 939 10.1002/hep.24481 2-s2.0-80052023773 21674554 \n25 https://livertox.nih.gov/Isoniazid.htm \n26 Denholm J. McBryde E. Eisen D. Chen C. Penington J. Street A. Adverse effects of isoniazid preventative therapy for latent tuberculosis infection: a prospective cohort study Drug, Healthcare and Patient Safety 2014 6 145 149 10.2147/DHPS.S68837 2-s2.0-84937424892 \n27 Fountain F. F. Tolley E. Chrisman C. R. Self T. H. Isoniazid hepatotoxicity associated with treatment of latent tuberculosis infection: a 7-year evaluation from a public health tuberculosis clinic Chest 2005 128 1 116 123 10.1378/chest.128.1.116 2-s2.0-22244492630 16002924 \n28 Saukkonen J. J. Cohn D. L. Jasmer R. M. An official ATS statement: hepatotoxicity of antituberculosis therapy American Journal of Respiratory and Critical Care Medicine 2006 174 8 935 952 10.1164/rccm.200510-1666ST 2-s2.0-33749856322 17021358 \n29 De Rosa H. J. Baldan H. M. Brunetti I. L. Ximenes V. F. Machado R. G. P. The effect of pyrazinamide and rifampicin on isoniazid metabolism in rats Biopharmaceutics & Drug Disposition 2007 28 6 291 296 10.1002/bdd.557 2-s2.0-34548806539 17571294 \n30 Bouazzi O. E. Hammi S. Bourkadi J. E. First line anti-tuberculosis induced hepatotoxicity: incidence and risk factors The Pan African Medical Journal 2016 25 p. 167 10.11604/pamj.2016.25.167.10060 2-s2.0-85012101525 28292129 \n31 Tostmann A. Boeree M. J. Aarnoutse R. E. de Lange W. C. M. van der Ven A. J. A. M. Dekhuijzen R. Antituberculosis drug-induced hepatotoxicity: concise up-to-date review Journal of Gastroenterology and Hepatology 2008 23 2 192 202 10.1111/j.1440-1746.2007.05207.x 2-s2.0-39149145797 17995946 \n32 https://livertox.nih.gov/Rifampin.htm \n33 Nahid P. Dorman S. E. Alipanah N. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: treatment of drug-susceptible tuberculosis Clinical Infectious Diseases 2016 63 7 e147 e195 10.1093/cid/ciw376 2-s2.0-84990938502 27516382 \n34 https://pharmacobook.files.wordpress.com/2016/12/goodman-and-gilman_s-the-pharmacological-basis-of-therapeutics-12e-mcgraw-hill-education-_-medical-2011.pdf\n\n",
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"title": "Disseminated Granulomatous Disease from Intravesical Instillation of Bacillus Calmette-Guerin.",
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"abstract": "BRAF and MEK inhibitor combination therapy is the standard treatment for patients with BRAF V600E mutant metastatic melanoma. Neutrophilic panniculitis is a known rare complication of BRAF inhibitor therapy and can act as a potential mimic of melanoma metastases on 18F-FDG PET/CT. In this case series, we present three cases of BRAF inhibitor-induced panniculitis in patients being treated for BRAF-mutant metastatic melanoma and emphasize the use of ultrasound to differentiate between panniculitis lesions, which are typically ill-defined echogenic masses and subcutaneous soft tissue melanoma metastases, which present as hypoechoic vascular masses.",
"affiliations": "Department of Radiology, Mayo Clinic, 200 1st street SW, Rochester, MN, 55905, USA.;Department of Radiology, Mayo Clinic, 200 1st street SW, Rochester, MN, 55905, USA.;Department of Radiology, Mayo Clinic, 200 1st street SW, Rochester, MN, 55905, USA.;Department of Radiology, Mayo Clinic, 200 1st street SW, Rochester, MN, 55905, USA.;Department of Radiology, Mayo Clinic, 200 1st street SW, Rochester, MN, 55905, USA. Glazebrook.Katrina@mayo.edu.",
"authors": "Bartlett|David J|DJ|;Erie|Andrew J|AJ|;Baffour|Francis I|FI|;Broski|Stephen M|SM|;Glazebrook|Katrina N|KN|",
"chemical_list": "D019788:Fluorodeoxyglucose F18; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf",
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"keywords": "BRAF; Diagnostic ultrasound; Melanoma; PET/CT; Panniculitis",
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"mesh_terms": "D019788:Fluorodeoxyglucose F18; D006801:Humans; D008545:Melanoma; D009154:Mutation; D015434:Panniculitis; D000072078:Positron Emission Tomography Computed Tomography; D048493:Proto-Oncogene Proteins B-raf; D012878:Skin Neoplasms",
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"title": "BRAF inhibitor-induced panniculitis in patients treated for stage IV metastatic melanoma: a case series.",
"title_normalized": "braf inhibitor induced panniculitis in patients treated for stage iv metastatic melanoma a case series"
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"abstract": "Hypercalcemic crisis is a severe but rare complication of primary hyperparathyroidism (PHPT), and data on denosumab treatment of patients with this disease is still very limited. The aim of this paper is to investigate the hypocalcemic effect of denosumab in PHPT patients with severe hypercalcemia when surgery should be delayed or is impossible for some reasons. We performed a retrospective study of 10 patients. The analysis included the use of biochemical markers of calcium-phosphorus metabolism, which were followed after the administration of 60 mg of denosumab. The trend to calcium reduction was already determined on the 3rd day after denosumab administration. In most cases the decrease in serum calcium level to the range of 2.8 mmol/L on average or lower was observed on the 7th day (P = 0.002). In addition to a significant increase in calcium levels we confirmed a significant increase in the estimated glomerular filtration rate on 7th day (P = 0.012). After that, seven patients underwent successful parathyroidectomy and achieved eucalcemia or hypocalcemia, one patient developed the recurrence of parathyroid cancer after initial surgery, while two patients with severe cardiovascular pathology refused surgery. Our study shows that denosumab is a useful tool in PHPT-associated hypercalcemia before surgery or if surgery is contraindicated.",
"affiliations": "Endocrinology Research Center, Russian Federation, Moscow, Russia.;Endocrinology Research Center, Russian Federation, Moscow, Russia.;Endocrinology Research Center, Russian Federation, Moscow, Russia.;Endocrinology Research Center, Russian Federation, Moscow, Russia.;Endocrinology Research Center, Russian Federation, Moscow, Russia.;Faculty of Fundamental Medicine, ederal State Budget Educational Institution of Higher Education M.V. Lomonosov Moscow State University, Moscow, Russia.;Endocrinology Research Center, Russian Federation, Moscow, Russia.;Endocrinology Research Center, Russian Federation, Moscow, Russia.",
"authors": "Eremkina|Anna|A|;Krupinova|Julia|J|;Dobreva|Ekaterina|E|;Gorbacheva|Anna|A|;Bibik|Ekaterina|E|;Samsonova|Margarita|M|;Ajnetdinova|Alina|A|;Mokrysheva|Natalya|N|",
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"fulltext": "\n==== Front\nEndocr Connect\nEndocr Connect\nEC\nEndocrine Connections\n2049-3614 Bioscientifica Ltd Bristol \n\n33112830\n10.1530/EC-20-0380\nEC-20-0380\nResearch\nDenosumab for management of severe hypercalcemia in primary hyperparathyroidism\nA Eremkina et al.Denosumab and severe hypercalcemia in PHPTEremkina Anna 1 Krupinova Julia 1 Dobreva Ekaterina 1 Gorbacheva Anna 1 Bibik Ekaterina 1 Samsonova Margarita 2 Ajnetdinova Alina 1 Mokrysheva Natalya 1 1 Endocrinology Research Center, Russian Federation, Moscow, Russia\n2 Faculty of Fundamental Medicine, ederal State Budget Educational Institution of Higher Education M.V. Lomonosov Moscow State University, Moscow, Russia\nCorrespondence should be addressed to A Eremkina: eremkina.anna@endocrincentr.ru\n10 2020 \n01 10 2020 \n9 10 1019 1027\n25 9 2020 01 10 2020 © 2020 The authors2020The authors This work is licensed under a Creative Commons Attribution 4.0 International License.Hypercalcemic crisis is a severe but rare complication of primary hyperparathyroidism (PHPT), and data on denosumab treatment of patients with this disease is still very limited. The aim of this paper is to investigate the hypocalcemic effect of denosumab in PHPT patients with severe hypercalcemia when surgery should be delayed or is impossible for some reasons. We performed a retrospective study of 10 patients. The analysis included the use of biochemical markers of calcium-phosphorus metabolism, which were followed after the administration of 60 mg of denosumab. The trend to calcium reduction was already determined on the 3rd day after denosumab administration. In most cases the decrease in serum calcium level to the range of 2.8 mmol/L on average or lower was observed on the 7th day (P = 0.002). In addition to a significant increase in calcium levels we confirmed a significant increase in the estimated glomerular filtration rate on 7th day (P = 0.012). After that, seven patients underwent successful parathyroidectomy and achieved eucalcemia or hypocalcemia, one patient developed the recurrence of parathyroid cancer after initial surgery, while two patients with severe cardiovascular pathology refused surgery. Our study shows that denosumab is a useful tool in PHPT-associated hypercalcemia before surgery or if surgery is contraindicated.\n\nKey Words\ndenosumabprimary hyperparathyroidismhypercalcemiaparathyroid cancer\n==== Body\nIntroduction\nPrimary hyperparathyroidism (PHPT) and malignancy are the two most common causes of hypercalcemia (1). Hypercalcemic crisis (HC) is an uncommon, but severe complication of PHPT more specifically for parathyroid cancer (2). The risks of HC are significantly increased in patients with total albumin-corrected calcium >3.5 mmol/L or ionized calcium >2.5 mmol/L. Hypercalcemia may be associated with a spectrum of clinical manifestations, ranging from minor symptoms in the case of mild chronic hypercalcemia to dramatic symptoms as confusion and lethargy in HC, possibly leading to coma and death. The rate of increase of serum calcium often determines the symptoms and the required therapeutic interventions (3, 4).\n\nParathyroidectomy is the only cure for severe hypercalcemia, or HC caused by PHPT. Removing the parathyroid tumor significantly lowers the levels of parathyroid hormone (PTH) in blood, and thereby decreases serum calcium (5). However, immediate treatment for severe hypercalcemia or an HC should begin with adequate hydration with isotonic saline. Therapy with hypocalcemic drugs is also an option, which allows the patient to prepare for surgery. Bisphosphonates are widely used and approved for the treatment of hypercalcemia, but they have some limitations such as significant nephrotoxicity, like pamidronate-induced glomerulosclerosis and acute tubular necrosis. Although cinacalcet has been successfully applied in PHPT, it has been discontinued prematurely due to its side effects. Moreover, its hypocalcemic effect of cinacalcet is usually not immediate since step-by-step dose titration is most often required which may take several weeks in some cases, and the dose escalation is hugely limited by nausea side effect (6, 7).\n\nThe data on the efficacy and safety of denosumab led to its approval for postmenopausal osteoporosis, skeletal complications and hypercalcemia of malignancies. In case of postmenopausal osteoporosis denosumab reduces the risk of vertebral, non-vertebral and hip fractures and increases bone mineral density (8). At the same time, administering denosumab to patients with advanced cancers and bone metastases significantly decreases the incidence of skeletal-related events and hypercalcemia. It is, occasionally, the only way to lower calcium levels and achieve stable results. Unlike other anti-hypercalcemic drugs, denosumab can be used in the case of renal dysfunction (9).\n\nThe aim of this paper is to investigate the hypocalcemic effect of denosumab in PHPT patients with severe hypercalcemia then surgery should be delayed or is impossible for some reasons. Data on denosumab use in patients with PHPT is limited. The RANKL/RANK signaling pathway has a key role in the PHPT pathogenesis because of direct bone resorptive effects of increased RANKL in this disease. Denosumab binds RANKL with high affinity and specificity, preventing interaction with RANK on the osteoclast membrane. By blocking RANKL, denosumab inhibits osteoclast differentiation, activation and survival. This prevents bone resorption and thereby decreases blood calcium levels (10).\n\nMaterials and methods\nWe performed a retrospective study of all patients who received subcutaneously 60 mg of denosumab (Prolia®) for severe or symptomatic hypercalcemia due to PHPT to analyze the effects of denosumab on calcium levels. Ten patients were identified from the inpatient medical record system. Data were collected from January 2016 to June 2020 at the Department of Parathyroid Pathology.\n\nThe analysis included the biochemical markers of calcium-phosphorus metabolism: albumin-adjusted serum calcium concentrations (Ca, reference range (RR) 2.15–2.55 mmol/L), phosphate (P, RR 0.74–1.52 mmol/L), total alkaline phosphatase (AP, RR 40–150 U/I), intact parathyroid hormone (iPTH, RR 15–65 pg/mL), creatinine (RR 63–110 for men and 50–93 for women, mcmol/L), glomerular filtration rate calculation using the CKD-EPI creatinine equation (eGFR, mL/min/1.73 m2), and 24-h urinary calcium excretion for patients with eGFR >60 mL/min/1.73 m2 (RR 2.5–8 mmol/day). All parameters are shown as a median (minimum, maximum). The albumin-corrected serum calcium was calculated according to the following formula: serum total calcium (mg/dL) − 0.8 × (serum albumin (g/dL) − 4.0). In most cases biochemical parameters were measured at the baseline (Ca, P, AP, creatinine, eGFR, iPTH, 24-h urinary calcium), on the 3rd (Ca) and 7th day after denosumab administration (Сa, creatinine and eGFR). For laboratory tests the biochemical analyzer ARCHITECH c8000 (Abbott) and the electrochemiluminescence analyzer Cobas 6000 (Roche) were used. In four patients, calcium levels were available only on 9th day after injection. Further tests were conducted after surgery (if it was performed) or several months after the denosumab injection (if the surgical treatment was delayed for some reason). Severe hypercalcemia was defined as total albumin-corrected calcium levels >14 mg/dL (3.5 mmol/L). Symptomatic hypercalcemia was defined as an occurrence of hypercalcemic-related symptoms regardless of the achievement of calcium levels >14 mg/dL (3.5 mmol/L). Hypercalcemic-related symptoms included cognitive impairment and irritability, dizziness, nausea and vomiting, severe dehydration, cardiovascular disturbances. The diagnosis of osteoporosis was established based on the results of the radiography (Axiom R200, Siemens) and dual X-ray absorptiometry (Lunar iDXA, GE Healthcare). Bone mineral density (BMD) was measured at the lumbar spine (LS), femoral neck (FN), total hip (TH) and radius 33% (R33%). The X-ray or CT scans with lytic or multilobular cystic changes in bones confirmed the presence of osteitis fibrosa cystica. Baseline patient characteristics also included the low energy fractures, kidney stones and prior therapy of PHPT.\n\nThe study was approved by the Ethics Committee of the Endocrinology Research Centre (Moscow, Russia; protocol #1 of 17/01/2018). Informed consent has been obtained from each patient after full explanation of the purpose and nature of all procedures used.\n\nStatistical analysis was performed with the use of Statistica v. 13.3 (TIBCO Software Inc., Palo Alto, CA, USA). Comparison of two dependent groups for quantitative data was carried out using the Wilcoxon criterion, comparison of three dependent groups for quantitative data was carried out using the Friedman criterion. The initial critical level of significance in testing statistical hypotheses was assumed to be 0.05. At multiple comparisons of the parameters, it was recalculated with Bonferroni correction (P = 0.017).\n\nResults\nClinical characteristics\nThe median age of the patients was 53.5 years (min 25, max 79), two of them were males and eight females. Seven patients presented with multiple erosions of the stomach or duodenum, as well as moderate and severe anemias, which required correction before surgery and postponed urgent surgical treatment for PHPT. The patients received an injection of denosumab due to the development of life-threatening symptoms to stabilize their condition. In the examined group, one female patient had an atypical adenoma, two patients had morphologically confirmed parathyroid cancer, and five patients had typical adenoma of parathyroid gland. In the two other cases, the morphological diagnosis remains unknown due to refusal of surgery.\n\nIn the studied group the baseline median Ca concentration was 3.8 mmol/L (3.4;5.0), the iPTH – 933 pg/mL (345; 2146). The other baseline parameters were as follows: P 0.79 mmol/L (0.31; 1.18), AP 174.5 U/L (69; 514), creatinine 116.8 mcmol/L (34; 296.8), eGFR 45 mL/min/1.73 m2 (19;159), 24-h urinary calcium was available in only two patients and amounted to 7.9 and 10.9 mmol/day, respectively. Table 1 summarizes the main laboratory and instrumental results.\nTable 1 Demographic, biochemical, clinical and histopathological profile in hypercalcemic patients.\n\nCase\tSex\tAgea\tCa at baseline\tCa on 3rd dayb\tCa on 7th dayb\tCa on 9th dayb\teGFR baseline\teGFR on 7th dayb\tPTH baselina\tPTH a.i.\tAP\tPHPT complications\tHypercalcemic-related symptoms\tMorphological diagnosis\t\n1\tF\t79\t3.5\t2.85\t2.48\t\t36\t56\t513\t\t69\tOsteoporosis (L1–L4 −2.9 s.d., radius 33% −3.4 s.d. in T-score), kidney stones impaired renal function\tCognitive impairment, headaches, nausea and vomiting, dehydration, hypotension\tAdenoma\t\n2\tM\t75\t4.42\t3.78\t2.58\t\t28\t48\t773\t667\t155\tImpaired renal function\tCognitive impairment, dehydration\tAdenoma\t\n3\tF\t44\t3.34\t2.46\t2.42\t\t44\t61\t1052\t\t514\tOsteoporosis (radius 33% −3.2 s.d. in Z-score), kidney stones impaired renal function\tCognitive impairment, headaches, dizziness, nausea and vomiting, dehydration\tAdenoma\t\n4\tF\t30\t3.94\t2.94\t3\t\t124\t132\t1423\t1480\t502\tOsteoporosis (L1–L4 −4.9 s\n.d., radius 33% −4.6 s.d. in Z-score), low energy fractures (both femurs), osteitis fibrosa cystica, kidney stones\tDehydration, irritability, dizziness\tAdenoma\t\n5\tF\t25\t3.43\t3.23\t2.75\t2.39\t139\t144\t567\t665\t495\tOsteoporosis (L1–L4 -6.1 s.d., femur neck −4.9 s.d., total hip −5.8 s.d., radius 33% −7.6 s.d. in Z-score), low energy fractures (vertebral Th7-Th10, L4, radius and ulna)\tNausea, irritability, dehydration\tAdenoma\t\n6\tF\t65\t3.6\t3.19\t3\t\t46\t58\t1871\t5000\t461\tOsteoporosis (L1–L4 −4.3 s\n.d., total hip −2.8 s.d. in T-score), low energy fractures (humerus, radius, ribs), osteitis fibrosa cystica, kidney stones, impaired renal function\tDehydration, arrhythmia\tAtypical adenoma\t\n7\tF\t40\t3.99\t3.58\t2.75\t2.44\t39\t63\t1112\t1318\t2.66\tOsteoporosis (femur neck −3.3 s.d., Total hip −3.9 s.d., radius 33% −4.4 s.d. in Z-score), low energy fractures (femur), osteitis fibrosa cystica, kidney stones, impaired renal function\tNausea, irritability, headaches, dehydration\tAdenoma\t\n8\tM\t61\t4.11\t3.5\t2.82\t2.47\t19\t21\t2146\t1297\t194\tOsteoporosis (radius 33% −4.5 s.d., femur neck −3.9 s.d. in T-score), low energy fractures (radius), kidney stones, impaired renal function\tCognitive impairment, headaches, nausea, irritability, dehydration\tParathyroid cancer\t\n9\tF\t46\t3.4\t\t2.73\t\t85\t\t345\t\t82\tOsteoporosis (radius 33% −2.4 s.d. in Z-score)\tDehydration, dizziness\tParathyroid cancer (at the admission – recurrence with an unidentified metastases)\t\n10\tF\t68\t5\t\t\t2.73\t57\t−72 on 9th day\t814\t414\t145\tOsteoporosis (vertebral deformations, low energy fractures (radius)), kidney stones. impaired renal function\tNausea, irritability, dehydration\tAdenoma\t\n\naAge at the admission, bAfter denosumab injection.\n\nCa, albumin-adjusted serum calcium, RR 2.15–2.55 mmol/; iPTH, intact parathyroid hormone, RR 15–65 pg/mL; AP, total alkaline phosphatase, RR 40–150 U/L; eGFR, glomerular filtration rate using the CKD-EPI creatinine equation (eGFR, mL/min/1.73 m2); a.i., after injection before surgery.\n\n\n\nAs expected, most patients showed signs of bone disease. A significant BMD decrease in various parts of the skeleton occurred in nine individuals. Six patients had a history of low energy fractures and three of them had the radiographic features of osteitis fibrosa cystica and brown tumors. One young female patient had multiple vertebral fractures, while in two cases there were the initial signs of vertebral compression with a maximal body height loss of 15%. Two patients had pathological fractures of the femur followed by mobility limitation. Other fractures affected clavicula, radius, ulna and ribs (Table 1). Seven patients had kidney stones. Most stones were less than 10 mm in diameter. An eGFR less than 60 mL/min/1.73 m2 was observed in 70% (7/10) of patients, three of whom had stage 4 CKD (eGFR 15–29 mL/min/1.73 m2). The most frequent hypercalcemic-associated symptoms were dehydration (100%), nausea (60%), vomiting (20%) and irritability (50%). Neurologic symptoms (mild cognitive impairment and headaches as well as dizziness) occurred in 40 and 30%, respectively. One woman presented with arrhythmia (P. No 6) (Table 1).\n\nTreatment\nAll patients received a 60 mg single dose of denosumab. They were also treated with isotonic saline (1000–1500 mL/24 h) and cinacalcet in various doses. In half of all cases, a 30 mg dose of cinacalcet was given while three patients received 60 mg. Five patients received cinacalcet (30–120 mg) prior to the hospital admission, three patients with Ca in the 3.4–3.6 mmol/L range – as initial hypocalcemic therapy combined with isotonic saline right after admission. However, no significant decrease in Ca levels due to cinacalcet therapy was observed. In two patients, denosumab was administered concurrently with cinacalcet and saline hydration because of the severity of hypercalcemia (Ca baseline 3.94 and 4.42, respectively) and related symptoms. One female patient (No 3) initially received treatment with 90 mg of cinacalcet; the lack of effect required the addition of denosumab. Normocalcemia was achieved on 3rd day after injection and cinacalcet was canceled. In another patient (No 8) with parathyroid cancer and impaired renal function (eGFR 13 mL/min/1.73 m2) denosumab 60 mg was combined with cinacalcet 120 mg. We registered complete Ca normalization on the 10th day, then cinacalcet was gradually discontinued.\n\nReduction of hypercalcemia and hypercalcemic-related symptoms\nThe trend to calcium reduction was already determined on the 3rd day after denosumab administration (Ca baseline vs 3rd day, P = 0.012). In most cases (8/10) the decrease in serum calcium level to the range of 2.8 mmol/L on average or lower was observed on the 7th day (range 3–9 days). Ca levels decreased progressively (comparing Ca before denosumab administration and on the 3rd and 7th day after injection, P = 0.002 (Fig. 1)). Normocalcemia was achieved in four patients: one on the 3rd day and the others on the 9th day. After stabilization of Сa levels, eight patients underwent a gradual withdrawal of cinacalcet. We did not notice the reverse effect in calcium concentrations after cinacalcet cancellation before surgery. In two patients, calcium levels were stabilized at nearly 3 mmol/L. As a result, cinacalcet was prolonged until surgical treatment.\nFigure 1 Follow-up changes of serum calcium level before and after denosumab injection (Friedman criterion, P = 0.002).\n\n\n\nSerum calcium reduction was accompanied by the improvement of patient’s clinical state. The earliest change was an decrease of dehydration that occurred in the first three days in most cases. By the 7th and 9th day, the elimination or reduction of neurological and gastroenterological symptoms, such as headaches, weakness, nausea, vomiting, were noticed in the majority of patients. The two patients (Nos 2 and 10) who previously had the highest calcium levels had little changes in dyspeptic disorders during that period.\n\nChanges in PTH\nData on dynamics of PTH levels after denosumab injection (before surgery) were available in seven patients. No significant changes were observed in four of them, a decrease was recorded in two patients, and only one patient with generalized osteitis fibrosa cystica showed an increase in PTH from 1871 to 5000 pg/mL on the 10th day after denosumab administration (Table 1), and stabilization of blood calcium level at 3 mmol/L. On the 13th day this patient was radically operated with the development of hypocalcemia from ‘hungry bone syndrome’.\n\nIncrease in eGFR\nA significant increase in eGFR was recorded on the 7th day after denosumab injection (eGFR baseline vs 7th day, P = 0.012). The dynamic of eGFR before and after injection is shown in the Fig. 2.\nFigure 2 Follow-up changes of eGFR before and after denosumab injection (Wilcoxon criterion, P = 0.012).\n\n\n\nSurgical treatment and follow-up\nSeven patients underwent successful parathyroidectomy and achieved eucalcemia (n = 1) or hypocalcemia (n = 6, 1.97 mmol/L (1.7; 2.12)), which was successfully treated with per os active vitamin D and calcium supplements, not requiring calcium infusions. Pathology reports have not noted any bleeding or necrosis of parathyroid grands.\n\nTwo elderly patients with severe concomitant cardiovascular pathology categorically refused surgery. Biochemical monitoring in a month showed an increase in calcium level up to 3.2 mmol/L in one patient (No 1), which required the resumption of cinacalcet 60 mg (the patient continues to refuse surgery). During the next 2 months, Сa stabilized at 2.8–2.85 mmol/L. In second case (P No 2) the lab tests showed stable mild hypercalcemia 2.55–2.68 mmol/L with a follow-up period of 3 months. Interestingly, that low-normal Ca level was observed on the fourth month of therapy, 5 months after denosumab injection we detected an increase in the Ca level to and 2.32 mmol/L. One patient (No 9) developed the recurrence of parathyroid cancer. Because of unidentified metastases re-operation has been delayed. Denosumab was prescribed to control hypercalcemia. Pending results, the calcium level remains stable 1 month after the injection at 2.7–2.75 mmol/L.\n\nDiscussion\nManagement of hypercalcemia should be aimed at both lowering the serum calcium and the elimination pathogenic factor, if possible. Effective therapy reduces serum calcium by inhibiting bone resorption, enhancing renal excretion or decreasing intestinal absorption of calcium. The optimal choice depends on the cause and severity of hypercalcemia. Mild and moderate forms of hypercalcemia are often well tolerated (11), while severe hypercalcemia is a life-threatening condition (3, 4). One of the most common causes of hypercalcemia is PHPT.\n\nA retrospective review of 177 patients (12) who underwent surgical treatment of PHPT at a single institution, revealed 37 patients (21%) with severe hypercalcemia ≥3.5 mmol/L. The most frequent of presented symptoms were bone pain and fractures (81%), proximal muscles weakness (81%), and fatigue (83%). Mental status changes, kidney stones and nephrocalcinosis occurred less often – in 29, 24 and 19% of patients, respectively. Acute pancreatitis was found in 13%. This is totally consistent with our data as skeletal complications were identified most frequently, but as we noticed, the neurological disorders were more prevalent (60%).\n\nGenerally, the urgent management of hypercalcemia is based on intravenous rehydration with isotonic saline, which are usually combined with administration of loop diuretics, calcitonin, bisphosphonates or calcimimetics (6, 11). Dialysis is also an option for patients with severe hypercalcemia and renal insufficiency or heart failure, whom hydration cannot be safely administered (13).\n\nThe bisphosphonates show good evidence for protecting bone mineral density but no evidence for fracture risk reduction in PHPT and no consistent evidence for reduction of hypercalcaemia in PHPT or HC (4, 12, 14). However, therapy with bisphosphonates has some limitations and side effects including fever, which may exacerbate dehydration, bone pain during and post infusion, osteonecrosis of the jaw, uveitis, orbital inflammation, and possesses a risk of significant nephrotoxicity. Bisphosphonates may lead to decrease in eGFR and to permanent requirement in hemodialysis (4).\n\nA calcium-lowering effect can be produced by cinacalcet, a calcimimetic that interacts with the calcium sensing receptor (СaSR) on parathyroid cells leading to the downregulation of PTH with an attendant decline in serum calcium levels (4). In our study all patients received cinacalcet in various doses for hypercalcemia management. Nevertheless, in eight patients cinacalcet was initially given before the denosumab injection and no significant calcium decrease was observed (median Ca 3.55 mmol/L). This can be probably explained by a delayed hypocalcemic effect of the drug, inability to properly escalate the dose due to drug intolerance, or lack of CaSR sensitivity at the tumor level. The efficacy of cinacalcet in the management of parathyroid cancer-related hypercalcemia was initially assessed in an open-label single-arm study of 29 patients (dose titration from 60 to 360 mg daily). Over the 16-week study period, 62% of patients responded to therapy – serum calcium was reduced by at least 0.25 mmol/L; the greatest response was seen in patients with the highest baseline calcium levels. A decrease in PTH levels was not clinically significant (7). So, the clinically significant effect of cinacalcet can be achieved only at high doses, which are very hard to attain.\n\nMore recently, the novel inhibitor of osteoclast function denosumab has been shown to have a useful role as a hypocalcemic agent. Denosumab could be a treatment of first choice for PTH-related hypercalcemia, especially in severe renal impairment or when bisphosphonates are ineffective. Evidence suggests that denosumab could be effective in increasing BMD and lowering increased by PTH bone turnover in patients with PHPT (10, 15). According to DENOCINA study of PHPT patients (key inclusion criteria were a T-score between −1.0 and −3.5 at the lumbar spine, femoral neck, or total hip) (10), plasma calcium decreased significantly in the denosumab group during the first month, but afterwards it returned to baseline concentrations (all patients had baseline mild hypercalcemia). Normocalcemia was achieved only in combined group denosumab+cinaclcet (in 64% of patients).\n\nThe data on denosumab use in patients with severe resistant hypercalcemia secondary to PHPT is limited. There is description of individual clinical cases, more often of hypercalcemia related to parathyroid carcinoma. Hsu et al. described a 74-year-old woman with metastatic parathyroid carcinoma, managed with multiple medications including bisphosphonates, calcitonin or cinacalcet and even palliative radiotherapy with substandard effect (16). Only the use of 60 mg of denosumab allowed to normalize of calcium levels and the result of this achievement continued for several months (16). Von Schwartzenberg et al. reported a calcium-lowering effect of denosumab for uncontrollable hypercalcemia due to parathyrotoxicosis which was achieved after 60 mg subcutaneous injection in 1 day. Calcium levels remained stable between 2.6 and 2.7 mmol/L for 4 months, after another 60 mg of denosumab was injected. The long-term follow-up for more than 2 years showed that repeated low-dose denosumab injections (a summary six doses) were effective in maintaining stable calcium levels despite rising PTH and ineffective surgeries (17). Similar to this observation, calcium levels dropped rapidly within 2 days after denosumab injections and remained stable for about a month in a patient with renal cell carcinoma, lung metastases and bisphosphonate-refractory hypercalcemia (18). Remya Rajan et al. reported a case of PHPT with severe hypercalcemia (3.7 mmol/L) against the background of renal dysfunction (chronic kidney disease and with medullary nephrocalcinosis with eGFR of 21.35 mL/min/1.73 m2), in whom denosumab (60 mg subcutaneously) was used to lower the calcium levels prior to surgery. Serum calcium decreased on the 3rd day. After curative parathyroid surgery, calcium remained normal and there was no evidence of ‘hungry bone’ syndrome (19).\n\nThe question of the onset and completion of denosumab with regard to hypocalcemic effect in PHPT remains open. The median time to response (time taken to lower calcium <2.87 mmol/L) for denosumab in the management of malignant hypercalcemia has been described as 9 days (range 7–10) (9). The international study of Hu et al. showed the calcium-lowering effect of denosumab in 33 patients with malignant hypercalcemia in 10 days. The median response duration to denosumab (time from initial response to last day serum calcium ≤2.9 mmol/L) was 104 days (20). These results are in line with our findings as the significant decrease in serum calcium level to the range of 2.8 mmol/L or lower on average was observed on the 7th day (P = 0.002), however, in one patient, calcium normalization was observed as early as on the 3rd day after injection. Serum calcium level stabilized at 3 mmol/L in two patients. The absence of the desired effect in these cases can presumably be explained by the levels of PTH and AP (1871 and 1423 pg/mL; 461 and 502 U/L, respectively) and the presence of generalized osteitis fibrosa cystica, confirming extremely high bone resorption.\n\nThe effect of denosumab on PTH levels in our study was controversial. The main limitation is that lab tests were performed on different days after the drug administration. In most patients, PTH levels remained stable before surgery or even slightly decreased. Given the good hypocalcemic effect of the drug, it is difficult to explain these changes. In the DENOCINA trial plasma PTH increased rapidly after denosumab administration and then slowly, but significantly declined. Several previous studies on denosumab in postmenopausal osteoporosis have also shown the temporary increases in plasma PTH after the injection.\n\nDenosumab can lead to hypocalcemia, especially in patients severe renal impairment (eGFR <30 mL/min/1.73 m2). It is also associated with osteonecrosis of the jaw similar to parenteral bisphosphonates but this side effect is extremely rare and is usually associated with profound and long inhibition of bone resorption, and is not seen from a single injection. Besides, it does not have nephrotoxic effect and dose adjustment is not required depending on renal function. The improvement in the filtration function in our study may be explained both through active rehydration and a significant reduction in calcium levels. Severe hypercalcemia may lead to acute kidney injury by direct renal vasoconstriction and by decreases in extracellular fluid volume (21).\n\nMost of our patients underwent successful parathyroidectomy within several weeks of their injection; postoperative hypocalcemia was corrected with active vitamin D and calcium supplements per os. It is not possible to estimate how much denosumab influenced the course of postoperative hypocalcemia. However, the main reasons for its development include transient hypoparathyroidism and ‘hungry bone’ syndrome in patients with severe skeletal impairment.\n\nLonger follow-up assessment of the denosumab effect was possible in three cases. With a follow-up period of maximum 5 months, in two patients calcium levels remained stable (lower than 2.8 mmol/L), while one patient had a relapse of severe hypercalcemia, which required the resumption of cinacalcet. In recently reported cases of parathyroid-cancer related to hypercalcemia and also related to parathyroid carcinoma, dosing intervals of denosumab to achieve target calcium levels were as short as 1 month (2, 22, 23). However, there is evidence that hypercalcemia can be controlled by less frequent injection, up to 3–4 months without adverse events (17, 24).\n\nLimitations\nThe large heterogeneity of the study population with different types of PTH-related hypercalcemia (carcinoma and adenoma of parathyroid glands), different treatment schedules for the isotonic saline infusion and cinacalcet does not allow to fully estimate the impact of denosumab on serum calcium.\n\nConclusion\nThe effect of denosumab on RANKL signaling, inhibition of PTH-driven bone resorption and associated reduction of serum calcium levels makes it a useful tool to control severe hypercalcemia in patients with PHPT before surgery or if surgery is contraindicated for some reasons. Benefits include no restrictions for denosumab use in patients with concomitant chronic kidney disease.\n\nDeclaration of interest\nThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.\n\nFunding\nThis research was conducted using funds of the state assignment # AAAA-A18-118051590060-2.\n==== Refs\nReferences\n1 Zagzag J Hu MI Fisher SB Perrier ND Hypercalcemia and cancer: differential diagnosis and treatment\n. CA: A Cancer Journal for Clinicians \n2018 \n68 \n377 –3\n86\n. (10.3322/caac.21489 )30240520 \n2 Vellanki P Lange K Elaraj D Kopp PA El Muayed M Denosumab for management of parathyroid carcinoma-mediated hypercalcemia\n. Journal of Clinical Endocrinology and Metabolism \n2014 \n99 \n387 –3\n90\n. (10.1210/jc.2013-3031 )24178790 \n3 Ahmad S Kuraganti G Steenkamp D Hypercalcemic crisis: a clinical review\n. American Journal of Medicine \n2015 \n128 \n239 –2\n45\n. (10.1016/j.amjmed.2014.09.030 )25447624 \n4 Turner JJO Hypercalcaemia – presentation and management\n. Clinical Medicine \n2017 \n17 \n270 –273\n. (10.7861/clinmedicine.17-3-270 )28572230 \n5 Cannon J Lew JI Solórzano CC Parathyroidectomy for hypercalcemic crisis: 40 years’ experience and long-term outcomes\n. Surgery \n2010 \n148 \n807 –81\n2\n; discussion 812\n. (10.1016/j.surg.2010.07.041 )20800863 \n6 Sternlicht H Glezerman IG Hypercalcemia of malignancy and new treatment options\n. Therapeutics and Clinical Risk Management \n2015 \n11 \n1779 –17\n88\n. (10.2147/TCRM.S83681 )26675713 \n7 Silverberg SJ Rubin MR Faiman C Peacock M Shoback DM Smallridge RC Schwanauer LE Olson KA Klassen P Bilezikian JP Cinacalcet hydrochloride reduces the serum calcium concentration in inoperable parathyroid carcinoma\n. Journal of Clinical Endocrinology and Metabolism \n2007 \n92 \n3803 –380\n8\n. (10.1210/jc.2007-0585 )17666472 \n8 Cummings SR Martin JS McClung MR Siris ES Eastell R Reid IR Delmas P Zoog HB Austin M Wang A et al\nDenosumab for prevention of fractures in postmenopausal women with osteoporosis\n. New England Journal of Medicine \n2009 \n361 \n756 –7\n65\n. (10.1056/NEJMoa0809493 )19671655 \n9 Thosani S Hu MI Denosumab: a new agent in the management of hypercalcemia of malignancy\n. Future Oncology \n2015 \n11 \n2865 –28\n71\n. (10.2217/fon.15.232 )26403973 \n10 Leere JS Karmisholt J Robaczyk M Lykkeboe S Handberg A Steinkohl E Brøndum Frøkjær J Vestergaard P Denosumab and Cinacalcet for primary hyperparathyroidism (DENOCINA): a randomised, double-blind, placebo-controlled, phase 3 trial\n. Lancet: Diabetes and Endocrinology \n2020 \n8 \n407 –4\n17\n. (10.1016/S2213-8587(2030063-2 )32333877 \n11 Walsh J Gittoes N Selby P Society for Endocrinology Clinical Committee. SOCIETY FOR ENDOCRINOLOGY ENDOCRINE EMERGENCY GUIDANCE: Emergency management of acute hypercalcaemia in adult patients\n. Endocrine Connections \n2016 \n5 \nG9 –G\n11\n. (10.1530/EC-16-0055 )27935816 \n12 Singh DN Gupta SK Kumari N Krishnani N Chand G Mishra A Agarwal G Verma AK Mishra SK Agarwal A Primary hyperparathyroidism presenting as hypercalcemic crisis: twenty-year experience\n. Indian Journal of Endocrinology and Metabolism \n2015 \n19 \n100 –10\n5\n. (10.4103/2230-8210.131763 )25593835 \n13 Loh HH Mohd Noor N The use of hemodialysis in refractory hypercalcemia secondary to parathyroid carcinoma\n. Case Reports in Critical Care \n2014 \n2014 \n140906 (10.1155/2014/140906 )24829837 \n14 Phitayakorn R McHenry CR Hyperparathyroid crisis: use of bisphosphonates as a bridge to parathyroidectomy\n. Journal of the American College of Surgeons \n2008 \n206 \n1106 –1\n11\n5\n. (10.1016/j.jamcollsurg.2007.11.010 )18501807 \n15 Eller-Vainicher C Palmieri S Cairoli E Goggi G Scillitani A Arosio M Falchetti A Chiodini I Protective effect of denosumab on bone in older women with primary hyperparathyroidism\n. Journal of the American Geriatrics Society \n2018 \n66 \n518 –5\n24\n. (10.1111/jgs.15250 )29364518 \n16 Hsu P Liu C-Y Chen M-H Refractory hypercalcemia due to hyperparathyroidism in a patient with metastatic parathyroid carcinoma\n. Journal of Cancer Research and Practice \n2018 \n5 \n84 –8\n7\n. (10.1016/j.jcrpr.2018.01.002 )\n17 Jumpertz von Schwartzenberg R Elbelt U Ventz M Mai K Kienitz T Maurer L Rose T Rückert JC Strasburger CJ Spranger J Palliative treatment of uncontrollable hypercalcemia due to parathyrotoxicosis: denosumab as rescue therapy\n. Endocrinology, Diabetes and Metabolism Case Reports \n2015 \n2015 \n150082 (10.1530/EDM-15-0082 )\n18 Boikos SA Hammers HJ Denosumab for the treatment of bisphosphonate-refractory hypercalcemia\n. Journal of Clinical Oncology \n2012 \n30 e299. (10.1200/JCO.2012.41.7923 )\n19 Rajan R Cherian KE Kapoor N Paul TV Denosumab as a bridge to surgery in a patient with severe hypercalcemia due to primary hyperparathyroidism in the setting of renal dysfunction\n. Indian Journal of Endocrinology and Metabolism \n2019 \n23 \n269 –2\n70\n. (10.4103/ijem.IJEM_678_18 )31161118 \n20 Hu MI Glezerman IG Leboulleux S Insogna K Gucalp R Misiorowski W Yu B Zorsky P Tosi D Bessudo A et al\nDenosumab for treatment of hypercalcemia of malignancy\n. Journal of Clinical Endocrinology and Metabolism \n2014 \n99 \n3144 –31\n52\n. (10.1210/jc.2014-1001 )24915117 \n21 Moysés-Neto M Guimarães FM Ayoub FH Vieira-Neto OM Costa JAC Dantas M Acute renal failure and hypercalcemia\n. Renal Failure \n2006 \n28 \n153 –15\n9\n. (10.1080/08860220500531005 )16538974 \n22 Bowyer SE White AM Ransom DT Davidson JA Resistant hypercalcaemia in metastatic parathyroid carcinoma\n. Medical Journal of Australia \n2013 \n198 \n559 –5\n61\n. (10.5694/mja12.11243 )23725272 \n23 Karuppiah D Thanabalasingham G Shine B Wang LM Sadler GP Karavitaki N Grossman AB Refractory hypercalcaemia secondary to parathyroid carcinoma: response to high-dose denosumab\n. European Journal of Endocrinology \n2014 \n171 \nK1 –K\n5\n. (10.1530/EJE-14-0166 )24743399 \n24 Itoshima S Yuno A Kato T Kamada H Ikota A Usui T Shimatsu A Koizumi S Denosumab for the treatment of refractory hypercalcemia in metastatic parathyroid carcinoma\n. AACE Clinical Case Reports \n2015 \n1 \ne141 –e14\n4\n. (10.4158/EP14449.CR )\n\n",
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"title": "Denosumab for management of severe hypercalcemia in primary hyperparathyroidism.",
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"abstract": "Pure red cell aplasia (PRCA) can potentially occur after allogeneic hematopoietic stem cell transplantation (allo-HSCT) if recipient and donor ABO blood groups are mismatched, with the recipient having isoagglutinins against the donor blood group. Patient plasma cells that survive transplant conditioning produce anti-ABO isoagglutinins targeting donor erythroid precursors in the bone marrow and thus causing red cell aplasia. Therapeutic options include steroids, discontinuation of immunosuppression, plasmapheresis, donor lymphocyte infusion, rituximab, and bortezomib, all with limited benefit. Daratumumab utilized in the treatment of multiple myeloma is an anti-CD38 monoclonal antibody targeting plasma cells, which makes it a potentially efficient therapy for PRCA. The current case report presents a patient with post-allo-HSCT PRCA cured with daratumumab applied after failure of other therapies. Our findings demonstrate safety and high efficiency of daratumumab, suggesting its applicability as early treatment of post-allo-HSCT PRCA.",
"affiliations": "Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel.;Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel.;Department of Pathology, Rambam Health Care Campus, Haifa, Israel.;Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel.",
"authors": "Henig|Israel|I|;Yehudai-Ofir|Dana|D|;Zohar|Yaniv|Y|;Zuckerman|Tsila|T|",
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"issue": "144(6)",
"journal": "Acta haematologica",
"keywords": "Allogeneic hematopoietic stem cell transplantation; Daratumumab; Pure red cell aplasia",
"medline_ta": "Acta Haematol",
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"pubdate": "2021",
"publication_types": "D002363:Case Reports",
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"title": "Pure Red Cell Aplasia following ABO-Mismatched Allogeneic Hematopoietic Stem Cell Transplantation: Resolution with Daratumumab Treatment.",
"title_normalized": "pure red cell aplasia following abo mismatched allogeneic hematopoietic stem cell transplantation resolution with daratumumab treatment"
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"abstract": "We are reporting an unusual case of dural arteriovenous fistula (AVF) of the superior sagittal sinus (SSS) after tamoxifen treatment for breast cancer. A 30-year-old female arrived at the emergency room with a sudden headache and left sided weakness and sensory loss. In her past medical history, she was diagnosed with breast cancer 1 year prior, and subsequently underwent a breast conserving mastectomy with whole breast radiation and adjuvant chemotherapy with tamoxifen. At the time of admission, computed tomography showed a small acute intracerebral hemorrhage at the right parietal cortex, and magnetic resonance imaging showed that a dural AVF at the SSS with a prominent and tortuous venous enhancement along the centrum semiovale was present. Cerebral angiography showed that the dural AVF at the mid-portion of the SSS with meningeal arterial feeding vessels entering the wall of the SSS, then draining through the dilated cortical veins. Our patient had no signs of active malignancy or any abnormalities in her coagulation profile, so it can be concluded that the tamoxifen was the likely cause of the SSS thrombosis and dural AVF. The dural AVF was treated by an endovascular coil embolization for the arterialized segment of the SSS. The patient dramatically recovered favorably from left side motor and sensory deficit. The best clinical approach is to screen potential patients of tamoxifen hormonal therapy and educate them on the sign and symptoms of life threatening thromboembolic events while taking tamoxifen.",
"affiliations": "Department of Neurosurgery, College of Medicine, Ewha Womans University, Mokdong Hospital, Seoul, Korea.",
"authors": "Hwang|Sung-Kyun|SK|",
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"doi": "10.3340/jkns.2015.57.3.204",
"fulltext": "\n==== Front\nJ Korean Neurosurg SocJ Korean Neurosurg SocJKNSJournal of Korean Neurosurgical Society2005-37111598-7876The Korean Neurosurgical Society 10.3340/jkns.2015.57.3.204Case ReportA Case of Dural Arteriovenous Fistula of Superior Sagittal Sinus after Tamoxifen Treatment for Breast Cancer Hwang Sung-Kyun M.D.Department of Neurosurgery, College of Medicine, Ewha Womans University, Mokdong Hospital, Seoul, Korea.\nAddress for reprints: Sung-Kyun Hwang, M.D. Department of Neurosurgery, College of Medicine, Ewha Womans University, Mokdong Hospital, 1071 Anyangcheon-ro, Yangcheon-gu, Seoul 158-710, Korea. Tel: +82-2-2650-2872, Fax: +82-2-2650-2652, nshsg@ewha.ac.kr3 2015 20 3 2015 57 3 204 207 29 4 2014 21 6 2014 21 6 2014 Copyright © 2015 The Korean Neurosurgical Society2015This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.We are reporting an unusual case of dural arteriovenous fistula (AVF) of the superior sagittal sinus (SSS) after tamoxifen treatment for breast cancer. A 30-year-old female arrived at the emergency room with a sudden headache and left sided weakness and sensory loss. In her past medical history, she was diagnosed with breast cancer 1 year prior, and subsequently underwent a breast conserving mastectomy with whole breast radiation and adjuvant chemotherapy with tamoxifen. At the time of admission, computed tomography showed a small acute intracerebral hemorrhage at the right parietal cortex, and magnetic resonance imaging showed that a dural AVF at the SSS with a prominent and tortuous venous enhancement along the centrum semiovale was present. Cerebral angiography showed that the dural AVF at the mid-portion of the SSS with meningeal arterial feeding vessels entering the wall of the SSS, then draining through the dilated cortical veins. Our patient had no signs of active malignancy or any abnormalities in her coagulation profile, so it can be concluded that the tamoxifen was the likely cause of the SSS thrombosis and dural AVF. The dural AVF was treated by an endovascular coil embolization for the arterialized segment of the SSS. The patient dramatically recovered favorably from left side motor and sensory deficit. The best clinical approach is to screen potential patients of tamoxifen hormonal therapy and educate them on the sign and symptoms of life threatening thromboembolic events while taking tamoxifen.\n\nDural fistulaSuperior sagittal sinusTamoxifenBreast cancer\n==== Body\nINTRODUCTION\nTamoxifen, a selective estrogen receptor modulator with antagonistic effects in the breast, is an effective treatment for breast cancer. However, with these benefits comes the risk of a variety of side effects, including cerebral venous thrombosis. Although studies imply an association between chemotherapy with tamoxifen and cerebral venous thrombosis, their lack of control patients in their observations prevent definite conclusions. The possibility that chemotherapy with tamoxifen contributed to thrombotic complications has been suggested for patients with breast cancer1,3,7,11,12,14,18,19,20,22).\n\nA dural arteriovenous fistula (AVF) is characterized by abnormal arteriovenous shunting confined to the pachymeninges region. The precise cause of a dural AVF remains unclear, however, a host-related factor such as a cerebral sinus thrombosis is likely associated with the development of a dural AVF4,5,8,9,15,17). We are presenting the unusual case of a patient with breast cancer receiving tamoxifen treatment who developed a superior sagittal sinus (SSS) thrombosis and a dural AVF.\n\nCASE REPORT\nA 30-year-old female arrived at the emergency room with a sudden headache and left sided weakness and sensory loss. In her past medical history, she had been diagnosed with infiltrating ductal breast cancer 1 year before. She subsequently underwent a breast conserving mastectomy and was treated by a sentinel lymph node biopsy with radiation on the entire breast and adjuvant chemotherapy with tamoxifen daily (20 mg) for 11 months. At the time of admission, neurologic examination revealed signs of a mild left sided hemiparesis (grade 4) and mild sensory loss. Non-contrast computed tomography (CT) showed a small acute intracerebral hemorrhage at the right parietal cortex (Fig. 1A). Magnetic resonance imaging (MRI) demonstrated dural AVF at the mid-portion of the SSS with an occluded posterior segment of the SSS in addition to a prominent and tortuous venous enhancement along the centrum semiovale (Fig. 1B, C). Cerebral angiography showed that the dural AVF at the mid-portion of the SSS with a meningeal arterial feeding vessels entering the wall of the SSS, then draining through dilated cortical veins. The dilated cortical veins with venous hypertension are related to acute right intracerebral hemorrhage at the right parietal cortex (Fig. 2). Routine hematology and biochemistry of the laboratory findings were normal. Anticoagulation tests, antithrombin III, protein S, and C levels were also found to be normal. Our patient had no signs of active malignancy nor any abnormalities in her coagulation profile so it can be concluded that tamoxifen was the likely cause of the SSS thrombosis. The dural AVF at the arterialized segment of the SSS was treated by an endovascular coil embolization (Fig. 3). Post-embolization angiography showed disappearance of the dural AVF in the SSS (Fig. 4A, B). Postoperative CT revealed resolved subarachnoid hemorrhage without additional lesions. Postoperative MRI showed interval improvement of the dilated cortical veins (Fig. 4C). The patient dramatically recovered to a normal state with a left side motor and sensory deficit.\n\nDISCUSSION\nTamoxifen, a selective anti-estrogen property of hormonal therapy, is one of the widely used drug, specifically in br-east cancer patients. In addition, this drug has been shown to prevent breast cancer in high-risk patients when developing it for the first time or for contralateral recurrence. However, anti-estrogen therapy with tamoxifen has been known to increases the risk of venous sinus thrombosis1,3,7,11,12,13,14,18,19,20). Our patient had previously been diagnosed with breast cancer and was currently taking adjuvant tamoxifen therapy. She had no signs of active malignancy or any abnormalities in her coagulation profile, so it can be concluded that tamoxifen was the possible cause of the SSS thrombosis. She had two known contributing factors for her cerebral sinus thrombosis; cancer and anti-estrogen treatment. Cancer patients are particularly vulnerable to systemic venous thrombosis during the course of their illness. This is due to hypercoagulability caused by malignancy as well as disease and treatment-related complications11,18,19,21). The mechanisms by which tamoxifen increases the risk of venous sinus thrombosis are still unknown. The mechanism of action with regard to changes in coagulation parameters which could potentially explain venous thrombogenic activity of tamoxifen was not completely understood. They suggested that tamoxifen may contribute to a hypercoagulable state among patients with breast cancer. Alterations of hemostasis that may contribute to this hypercoagulable state include decreased levels of protein C and S, decreased levels of antithrombin III, and fibrinolytics (fibrinogen, plasminogen, tissue plasminogen activator). We believe that the increased thromboembolic complications observed among patients who received tamoxifen therapy for breast cancer is probably multi-factorial, but may be contributed to these perturbations of proteins C and S, and antithrombin III1,3,11,18,19,20,22).\n\nThe SSS was the most frequently affected sinus in reports of cancer patients with cerebral sinus thrombosis. The SSS may be more susceptible to thrombosis due to its length and location. Lower pressures and slower blood flow can lead to increased stasis of blood and subsequent thrombosis. The slower blood flow may lead to tissue hypoxia and a decrease in the clearance of clotting factors. In addition, it is contiguous throughout its length with the skull, a frequent site of bone metastasis, which can compress or invade the SSS. Venous sinus thrombosis is also more common in young women than in other groups, and development during puerperium is still common in developing countries. Oral contraceptives may play a role in the pathogenesis of venous sinus thrombosis in young women. Premenopausal patients who received chemotherapy and tamoxifen developed significantly more venous sinus thrombosis than patients who received chemotherapy without tamoxifen, and also suffered no arterial thrombotic complications. A postmenopausal woman taking estrogen-progesterone therapy was reported to have developed a venous sinus thrombosis21,22).\n\nA dural AVF is characterized by abnormal arteriovenous shunting confined to the region of the pachymeninges. In the analysis of dural AVFs by Awad et al.2), these lesions of SSS accounted for 7.4% of all dural AVFs. The precise cause of a dural AVF remains unclear, however, host-related factor such as a cerebral sinus thrombosis is likely associated with the development of a dural AVF. Hormonal or hemostatic mechanisms may play a role. The lesions may thrombose or regress spontaneously, and alternatively, it may acquire additional arterial sources that converge into the same region of involved dura. Reversal of blood flow into leptomeningeal channels may produce venous dilation, varicosities, and venous aneurysms. The symptom from these lesions, similar to other dural AVFs, depends on the pattern of venous drainage. If the venous drainage is shared by cortical veins, there is a high incidence of hemorrhage or neurological deficits like our patient5,6,8,9,10,15,16,17). Our patient revealed a vascular blood supply from the external carotid artery to the fistula through branches of the middle meningeal, and superficial temporal artery. This is similar to dural AVFs in other locations, especially when all anterograde drainage through the venous sinus has thrombosed, leaving retrograde cortical venous routes, which induce the intracerebral hemorrhage (Fig. 2).\n\nThe association between venous sinus thrombosis and a dural AVF has been recognized. This link is also thought to be related to the altered hemodynamics induced by a dural AVF. Hypercoagulable states are associated with numerous conditions. Factors involved in hypercoagulability include protein C, protein S, antithrombin III, and fibrinolytics (fibrinogen, plasminogen, tissue plasminogen activator). A disequilibrium or altered functionality of these factors can result in hypercoagulable states, contributing to venous sinus thrombosis and a dural AVF.\n\nCONCLUSION\nThe best clinical approach is to screen potential patients of tamoxifen hormone therapy and educate them on the signs and symptoms of life threatening thromboembolic events while taking tamoxifen. The search for the disease entity by which tamoxifen increases the risk of venous sinus thrombosis is still unknown. Future studies of women with breast cancer using tamoxifen should be designed to determine stroke etiologies, the role of additional chemotherapy, existing stroke risk factors, family history and the potential mechanisms of venous sinus thrombosis.\n\nFig. 1 A : Computed tomography axial image demonstrate a small intracerebral hemorrhage in the right parietal cortex. B and C : Magnetic resonance imaging demonstrate thrombosis at the posterior segment of superior sagittal sinus and dural arteriovenous fistula with a prominent and tortuous venous enhancement along the centrum semiovale.\nFig. 2 External carotid artery angiography demonstrate dural arteriovenous fistula at the mid-portion of a superior sagittal sinus. The meningeal arterial feeders enter the wall of the superior sagittal sinus, and, then drain through the dilated cortical veins (corkscrew vessels). The dilated cortical veins with venous hypertension, may be related to acute right intracerebral hemorrhage at the right parietal cortex.\nFig. 3 The dural arteriovenous fistula was treated by an endovascular coil embolization for a superior sagittal sinus through navigation of the meningeal artery.\nFig. 4 A and B : Post-embolization angiography shows the disappearance of the dural arteriovenous fistula at the mid-portion of the superior sagittal sinus. C : Postoperative MRI shows an interval improvement of the dilated cortical veins.\n==== Refs\n1 Akdal G Dönmez B Cakmakçi H Yener GG A case with cerebral thrombosis receiving tamoxifen treatment Eur J Neurol 2001 8 723 724 11784361 \n2 Awad IA Little JR Akarawi WP Ahl J Intracranial dural arteriovenous malformations : factors predisposing to an aggressive neurological course J Neurosurg 1990 72 839 850 2140125 \n3 Bushnell C The cerebrovascular risks associated with tamoxifen use Expert Opin Drug Saf 2005 4 501 507 15934856 \n4 Cognard C Casasco A Toevi M Houdart E Chiras J Merland JJ Dural arteriovenous fistulas as a cause of intracranial hypertension due to impairment of cranial venous outflow J Neurol Neurosurg Psychiatry 1998 65 308 316 9728941 \n5 Cognard C Gobin YP Pierot L Bailly AL Houdart E Casasco A Cerebral dural arteriovenous fistulas : clinical and angiographic correlation with a revised classification of venous drainage Radiology 1995 194 671 680 7862961 \n6 Cognard C Januel AC Silva NA Jr Tall P Endovascular treatment of intracranial dural arteriovenous fistulas with cortical venous drainage : new management using Onyx AJNR Am J Neuroradiol 2008 29 235 241 17989374 \n7 D'Angelo-Donovan D Guarino MJ Sagittal sinus thrombosis while on tamoxifen requiring craniectomy Del Med J 2012 84 31 32 22720357 \n8 Davies MA Saleh J Ter Brugge K Willinsky R Wallace MC The natural history and management of intracranial dural arteriovenous fistulae Part 1 : benign lesions Interv Neuroradiol 1997 3 295 302 20678360 \n9 Davies MA Ter Brugge K Willinsky R Wallace MC The natural history and management of intracranial dural arteriovenous fistulae Part 2 : aggressive lesions Interv Neuroradiol 1997 3 303 311 20678361 \n10 Davies MA TerBrugge K Willinsky R Coyne T Saleh J Wallace MC The validity of classification for the clinical presentation of intracranial dural arteriovenous fistulas J Neurosurg 1996 85 830 837 8893721 \n11 Duvelleroy Hommet C De Toffol B Corcia P Autret A Cerebral venous thrombosis and estrogen-progesterone therapy Eur Neurol 1998 39 245 247 9635480 \n12 Fatehi F Saadatnia M Zare M Cerebral venous sinus thrombosis following tamoxifen prescription Neurosciences (Riyadh) 2008 13 320 21063352 \n13 Finelli PF Thrombosis of the cerebral veins and sinuses N Engl J Med 2005 353 314 315 16038058 \n14 Finelli PF Schauer PK Cerebral sinus thrombosis with tamoxifen Neurology 2001 56 1113 1114 11320192 \n15 Halbach VV Higashida RT Hieshima GB Rosenblum M Cahan L Treatment of dural arteriovenous malformations involving the superior sagittal sinus AJNR Am J Neuroradiol 1988 9 337 343 3128082 \n16 King WA Martin NA Intracerebral hemorrhage due to dural arteriovenous malformations and fistulae Neurosurg Clin N Am 1992 3 577 590 1633481 \n17 Liu JK Choudhry OJ Barnwell SL Delashaw JB Jr Dogan A Single stage transcranial exposure of large dural venous sinuses for surgically-assisted direct transvenous embolization of high-grade dural arteriovenous fistulas : technical note Acta Neurochir 2012 154 Wien 1855 1859 22865057 \n18 Masjuan J Pardo J Callejo JM Andrés MT Alvarez-Cermeño JC Tamoxifen : a new risk factor for cerebral sinus thrombosis Neurology 2004 62 334 335 14745086 \n19 Meier CR Jick H Tamoxifen and risk of idiopathic venous thromboembolism Br J Clin Pharmacol 1998 45 608 612 9663819 \n20 Meyer MA Cerebral sinus thrombosis with tamoxifen Neurology 2001 57 2150 11739856 \n21 Raizer JJ DeAngelis LM Cerebral sinus thrombosis diagnosed by MRI and MR venography in cancer patients Neurology 2000 54 1222 1226 10746588 \n22 Saphner T Tormey DC Gray R Venous and arterial thrombosis in patients who received adjuvant therapy for breast cancer J Clin Oncol 1991 9 286 294 1988575\n\n",
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"issue": "57(3)",
"journal": "Journal of Korean Neurosurgical Society",
"keywords": "Breast cancer; Dural fistula; Superior sagittal sinus; Tamoxifen",
"medline_ta": "J Korean Neurosurg Soc",
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"pages": "204-7",
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"pubdate": "2015-03",
"publication_types": "D002363:Case Reports",
"references": "14745086;15934856;22865057;17989374;11320192;1633481;1988575;10746588;22720357;11784361;8893721;9663819;7862961;20678360;20678361;9635480;11739856;16038058;9728941;21063352;3128082;2140125",
"title": "A case of dural arteriovenous fistula of superior sagittal sinus after tamoxifen treatment for breast cancer.",
"title_normalized": "a case of dural arteriovenous fistula of superior sagittal sinus after tamoxifen treatment for breast cancer"
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"abstract": "BACKGROUND\nAngiosarcoma is a rare soft tissue malignancy of endothelial cells, generally associated with a poor prognosis. Due to its rarity, randomized trials are difficult to conduct and a consensus on the treatment of angiosarcoma has not been reached. The role, efficacy, and timing of chemotherapy in AS treatment remain uncertain, and as stated, no large-scale trials have been able to establish definitive recommendations.\n\n\nMETHODS\nHere we describe the successful use of chemotherapy followed by radiation for a case of lower extremity angiosarcoma, and a case of breast angiosarcoma treated with neoadjuvant chemotherapy followed by surgical resection. Systemic therapy consisted of weekly doxorubicin, paclitaxel, and cisplatin. This regimen resulted in a full clinical remission in the first patient and a pathologic complete response in the second.\n\n\nCONCLUSIONS\nThese cases suggest that the use of the doxorubicin, cisplatin and paclitaxel combination could be an effective alternative to radical surgical excision in extremity sarcomas, and an effective adjuvant treatment to mastectomy in cutaneous radiation-associated angiosarcoma of the breast due to their independent efficacy against angiosarcoma. A randomized trial utilizing neoadjuvant combined doxorubicin, paclitaxel and cisplatin followed by either surgery or radiation, with endpoints assessing pathologic and overall response as well as progression free survival is warranted based on these cases.\n\n\nCONCLUSIONS\nThe role of neoadjuvant chemotherapy in the treatment of angiosarcoma should be reconsidered considering its ability to provide important prognostic information and improve the likelihood of curative surgery.",
"affiliations": "Penn State Hershey College of Medicine and Milton S. Hershey Medical Center, Hershey, PA, United States. Electronic address: jlewcun@pennstatehealth.psu.edu.;Penn State Hershey College of Medicine and Milton S. Hershey Medical Center, Hershey, PA, United States.;Penn State Hershey College of Medicine and Milton S. Hershey Medical Center, Hershey, PA, United States.;Penn State Hershey College of Medicine and Milton S. Hershey Medical Center, Hershey, PA, United States.;Penn State Hershey College of Medicine and Milton S. Hershey Medical Center, Hershey, PA, United States.;Penn State Hershey College of Medicine and Milton S. Hershey Medical Center, Hershey, PA, United States.;Penn State Hershey College of Medicine and Milton S. Hershey Medical Center, Hershey, PA, United States. Electronic address: ddodge@pennstatehealth.psu.edu.",
"authors": "Lewcun|Joseph A|JA|;Pameijer|Colette|C|;Kass|Rena|R|;Cream|Leah|L|;Hershock|Diane|D|;Brooks|Ashton J|AJ|;Dodge|Daleela G|DG|",
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"doi": "10.1016/j.ijscr.2020.02.036",
"fulltext": "\n==== Front\nInt J Surg Case Rep\nInt J Surg Case Rep\nInternational Journal of Surgery Case Reports\n2210-2612 Elsevier \n\nS2210-2612(20)30110-3\n10.1016/j.ijscr.2020.02.036\nArticle\nDoxorubicin, paclitaxel, and cisplatin based chemotherapy for the treatment of angiosarcoma: Two case reports\nLewcun Joseph A. jlewcun@pennstatehealth.psu.edu⁎ Pameijer Colette Kass Rena Cream Leah Hershock Diane Brooks Ashton J. Dodge Daleela G. ddodge@pennstatehealth.psu.edu⁎ Penn State Hershey College of Medicine and Milton S. Hershey Medical Center, Hershey, PA, United States\n⁎ Corresponding authors. jlewcun@pennstatehealth.psu.eduddodge@pennstatehealth.psu.edu\n21 2 2020 \n2020 \n21 2 2020 \n68 83 87\n6 12 2019 10 2 2020 16 2 2020 © 2020 The Authors2020This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Highlights\n• The role and efficacy of chemotherapy in angiosarcoma treatment remains uncertain.\n\n• Doxorubicin, paclitaxel, and cisplatin may be an effective alternative to surgery.\n\n• Chemotherapy may limit the need for debilitating, radical excision in extremity.\n\n• Neoadjuvant chemotherapy may increase chances of curative surgery in the breast.\n\n\n\nIntroduction\nAngiosarcoma is a rare soft tissue malignancy of endothelial cells, generally associated with a poor prognosis. Due to its rarity, randomized trials are difficult to conduct and a consensus on the treatment of angiosarcoma has not been reached. The role, efficacy, and timing of chemotherapy in AS treatment remain uncertain, and as stated, no large-scale trials have been able to establish definitive recommendations.\n\nCase descriptions\nHere we describe the successful use of chemotherapy followed by radiation for a case of lower extremity angiosarcoma, and a case of breast angiosarcoma treated with neoadjuvant chemotherapy followed by surgical resection. Systemic therapy consisted of weekly doxorubicin, paclitaxel, and cisplatin. This regimen resulted in a full clinical remission in the first patient and a pathologic complete response in the second.\n\nDiscussion\nThese cases suggest that the use of the doxorubicin, cisplatin and paclitaxel combination could be an effective alternative to radical surgical excision in extremity sarcomas, and an effective adjuvant treatment to mastectomy in cutaneous radiation-associated angiosarcoma of the breast due to their independent efficacy against angiosarcoma. A randomized trial utilizing neoadjuvant combined doxorubicin, paclitaxel and cisplatin followed by either surgery or radiation, with endpoints assessing pathologic and overall response as well as progression free survival is warranted based on these cases.\n\nConclusion\nThe role of neoadjuvant chemotherapy in the treatment of angiosarcoma should be reconsidered considering its ability to provide important prognostic information and improve the likelihood of curative surgery.\n\nKeywords\nAngiosarcomaRadiation-induced angiosarcomaBreast cancerSarcomaNeoadjuvant chemotherapyCase report\n==== Body\n1 Introduction\nAngiosarcoma (AS), a malignant proliferation of vascular or lymphatic endothelial cells, develops in approximately 1 per million patients and comprises only 2 % of all soft tissue sarcomas [1–3]. It can occur in any soft-tissue structure, with approximately 15 % developing in the extremity and 20 % developing in the breast [2]. AS can be further subcategorized into those which arise de novo, such as primary breast or soft tissue AS, and those which arise due to secondary factors. Secondary angiosarcoma has a long-known association with both prior radiation therapy (RT) and chronic lymphedema, also referred to as Stewart-Treves syndrome. The incidence of radiation-associated AS of the breast has been estimated as less than one percent amongst patients receiving RT as part of breast conserving treatment [18]. Chronic lymphedema has been shown to be an even more rarely associated risk factor for the development of AS [21].\n\nThe overall survival observed across all types of AS is approximately 40 % [25]. Despite the increasingly favorable prognosis observed in other cancers of the breast over recent decades, the 5-year overall survival in AS is still estimated to be 40–50 % [4,5]. As AS is a rare tumor, randomized clinical trials are commonly not feasible and a consensus on treatment guidelines for AS has not been established. Surgical intervention remains the mainstay of management; local wide excision or amputation is often required for AS of the extremity, while mastectomy is often indicated in AS of the breast. For those with AS of the breast, 68 % of patients receive mastectomy or partial mastectomy alone. An estimated 17 % of breast AS patients receive adjuvant radiation therapy and only 6 % receive chemotherapy [5]. The role, efficacy, and timing of chemotherapy in AS treatment remain uncertain, and as stated, no large-scale trials have been able to establish definitive recommendations. Here we present two cases which were successfully treated with a weekly doxorubicin, paclitaxel, and cisplatin-based regimen. The success of the regimen in a case of lower extremity AS led to its subsequent successful use as neoadjuvant therapy in AS of the breast. These cases are reported in accordance with SCARE criteria [26].\n\n2 Case report 1\nA 59-year-old woman with type 2 diabetes mellitus and long-standing lower extremity edema was referred to our institution for treatment of a T2aN0M1 AS of the left lower extremity. Biopsy at an outside institution demonstrated neoplastic cells with strong diffuse expression of CD31 and pleomorphic spindle cell proliferation within the deep dermis. There was extensive cutaneous involvement with large purple bullae which extended from the medial malleolus to the anterior medial aspect of the knee. MRI imaging showed skin thickening with edema with focal areas of infiltrative abnormal signal and nodular enhancement isolated to the subcutaneous fat.\n\nDue to the extent of the malignancy, definitive surgical intervention for curative intent would have required amputation, which would have impeded quality of life and was declined by the patient. Radiotherapy was not practical due to the extent of disease, the large radiation field, and underlying vascular insufficiency. Systemic chemotherapy, which consisted of weekly doxorubicin 20 mg/m2 given as a continuous infusion for 18 h on day 1; cisplatin 30 mg/m2 on day 2 and paclitaxel 100 mg/m2 IV over 3 h on day 2 was selected as the initial treatment. This was given weekly for 3 weeks, every 28 days for 3 cycles. The patient experienced mild side effects which included generalized fatigue and nausea, as well as an episode of acute kidney injury after cycle 1. Carboplatin was substituted for cisplatin during cycle two because of renal insufficiency. However, cisplatin was again given during cycle 3. Six months after diagnosis, repeat MRI showed marked improvement after chemotherapy with decreased skin thickening and edema, and resolution of the deep enhancing nodules. After a disease-free interval of seven months, two new nodules appeared on the medial and lateral aspects of her left foot. Biopsy confirmed localized AS recurrence. The lesions were treated with radiation therapy totaling 30 fractions and 90 Grays. Six, 21-day cycles of single agent paclitaxel 80 mg/m2 on days 1, 8 and 15 were added for systemic anti-angiogenic therapy after the completion of radiation therapy. The patient developed peripheral neuropathy as a result of the paclitaxel regimen but otherwise tolerated the treatment well. Screening MRI has been conducted every three months which revealed no concerning findings. There was no evidence of subsequent clinical or radiographic recurrence three years after her diagnosis (Fig. 1).Fig. 1 (a) AS of the left lower extremity at first presentation. (b) AS of the left lower extremity after chemotherapy. (c) MRI of left lower extremity angiosarcoma at first presentation. (d) MRI after chemotherapy.\n\nFig. 1\n\n3 Case report 2\nA 64-year-old Caucasian female with type 2 diabetes mellitus presented to her breast surgeon with new areas of patchy erythema and ecchymosis on the inferior, medial quadrant of her left breast which had been present for several days. Her medical history was significant for bilateral breast cancer six years prior: a grade II, HER2-positive, ER/PR negative breast cancer in the left breast and a grade III ER/PR positive ductal carcinoma in situ in the right breast. Treatment had included bilateral partial mastectomies performed through reduction mammoplasties, adjuvant chemotherapy, and sequential whole breast radiation therapy. A breast cancer surveillance visit only one month revealed no significant findings on either mammography or clinical breast exam. On physical exam, the erythematous changes were irregularly margined, associated with both a thickening of the overlying skin and two dark purple, well circumscribed bullae-like areas within the confines of a tattoo. Ultrasound of the area revealed no collection or underlying mass. A punch biopsy was performed, and immunohistochemistry demonstrated positive staining for CD31, CD34, factor VIII, and vimentin, supporting the diagnosis of breast angiosarcoma. During the next week, additional lesions appeared involving the medial right breast. An MRI of the breasts showed avidly enhancing skin thickening and nodularity bilaterally, measuring 8 mm in thickness in the medial left breast and 4 mm in the medial, lower quadrant of the right breast.\n\nDue to the bilateral presentation of the angiosarcoma, disease extent within medial locations, and the rapidity of its growth, removal of involved skin by surgical resection would require bilateral mastectomies including en bloc resection of a wide area of skin over the sternum. Primary closure of the defect would not be possible, and the magnitude of the procedure would place the patient at significant risk of post-operative complications and poor healing, delaying any adjuvant treatment. After consultations and presentation at multidisciplinary tumor board, neoadjuvant chemotherapy with the same agents chosen for case report 1 was elected. Two cycles of neoadjuvant chemotherapy consisted of IV doxorubicin 20 mg/m2 given over 18 h weekly for three weeks on days 1, 8, and 15, IV paclitaxel 100 mg/m2 and IV cisplatin 30 mg/m2 infused weekly for three weeks on days 2, 9 and 16. Her chemotherapeutic course was complicated by neutropenia requiring one dose of doxorubicin to be withheld, as well as myalgias, nausea and anemia.\n\nAll skin changes of the left and right breasts resolved, and a post-treatment MRI demonstrated only minimal residual enhancement. The patient then underwent bilateral, in -continuity mastectomies and resection of the suprasternal tissue with VAC closure of the central defect. Histopathology revealed no residual cancer – a pathologic complete response. The initial plan was for delayed flap closure, however, the area contracted down to a small defect. Satisfactory closure was achieved with a split-thickness skin graft. The patient remains recurrence free two years from the date of diagnosis (Fig. 2).Fig. 2 (a) AS of the left, medial breast, prior to chemotherapy. (b) Post bilateral, in-continuity mastectomies with resection of the suprasternal tissue. (c) MRI of bilateral breast AS at first presentation. (d) MRI after neoadjuvant chemotherapy.\n\nFig. 2\n\n4 Discussion\nAngiosarcoma is an aggressive, heterogeneous disease for which there is a lack of consensus on treatment, making prognosis difficult to predict. AS has historically been viewed as a primarily surgical disease, and resection with negative margins remains the standard of treatment [6]. Adjuvant radiotherapy has been shown to moderately improve the recurrence free interval [7]. Only small, retrospective studies have evaluated the benefit of adjuvant chemotherapy, with any conclusions limited by small sample size. Meta-analysis of these studies has demonstrated no decrease in AS recurrence with chemotherapy, though a few studies have reported a benefit after surgical resection with negative margins [8]. Current National Comprehensive Cancer Network (NCCN) guidelines recommend consideration of preoperative chemotherapy only for advanced (stage IIIA-B) disease, which is based on low-level evidence [22]. These two cases demonstrate dramatic, successful treatment with a novel chemotherapy regimen, which was used as definitive treatment in case 1 and as neoadjuvant treatment in case 2.\n\nThe first line chemotherapeutic treatments for angiosarcoma have been standard sarcoma anthracycline-based regimens, combined with alkylating agents such as ifosfamide in the metastatic setting. Angiosarcoma sensitivity to anthracyclines, such as doxorubicin, has been shown to be similar to that of other soft tissue sarcomas, with 25 % of AS patients showing a complete or partial response [9]. However, unlike other soft tissue sarcomas, AS has also been shown to be highly sensitive to taxanes. Paclitaxel has been shown to be particularly effective in the treatment of advanced angiosarcoma [10,11]. The role of platinum-based alkylating agents such as cisplatin has not been established. It has been used off-label, in conjunction with doxorubicin for both sarcomas of the bone and soft tissue and was shown to be more effective than single agent doxorubicin in these tumors [12]. A doxorubicin, paclitaxel and cisplatin regimen has been previously reported to produce a long-term remission of metastatic angiosarcoma [13]. Doxorubicin has a relatively small therapeutic index, with potentially severe side effects including cardiotoxicity and myelosuppression [14]. Paclitaxel has been shown to produce cardiac disturbances such as transient asymptomatic bradycardia, as well as neutropenia, neuropathy and paresthesia [15]. However, the cardiac toxicity of doxorubicin and paclitaxel used as combination therapy has been shown to be similar to that of doxorubicin as single agent therapy [16]. Likewise, the extent of myelosuppression observed with doxorubicin and cisplatin combination therapy is nearly equivalent to that of doxorubicin alone [12]. Due to the expression of vascular endothelial growth factor (VEGFR) in AS, the VEGFR/VEGF pathway has also been proposed as a potential therapeutic target. However, clinical trials have shown limited survival benefit of VEGFR/VEGF targeted therapies when compared to current first line chemotherapeutic agents [23,24].\n\nOnly a small subset of studies has analyzed the effectiveness of neoadjuvant chemotherapy in the AS population. One study of 15 cases of periorbital angiosarcoma suggested a promising survival benefit [17]. However, the quality and quantity of overall evidence is lacking, and no large-scale trials have been conducted. Both cases illustrated here were in patients with unresectable disease at diagnosis, which necessitated the use of chemotherapy as initial therapy. For the patient in case 1, the extent of disease would have necessitated the loss of the limb and too large a field for radiation due to the risk of significant toxicities. The extent of disease in case 2 was also too widespread for surgical intervention alone. The regimen of weekly doxorubicin, paclitaxel, and cisplatin produced a clinical complete response in both patients. AS is a rapidly growing malignancy and positive margins on resection are common. Thus, a systemic treatment that increases the probability of margin negative resection warrants further study. In a recent single institution review (Brigham and Women’s Hospital, Dan-Farber Cancer Institute) of 33 patients with cutaneous radiation-associated angiosarcoma of the breast, resection of all irradiated skin trended toward better local recurrence-free survival (LRFS) and recurrence-free survival (RFS) [19]. A dramatic reduction in size makes resection far more attainable and further ensures negative margins, which has been proven to be one of the few factors that improves outcome [20]. Neoadjuvant chemotherapy provides important prognostic information and can improve the likelihood of curative surgery. Our first case suggests that the use of the doxorubicin, cisplatin and paclitaxel combination could be an effective alternative to radical surgical excision in extremity sarcomas and an effective adjuvant treatment to mastectomy in cutaneous radiation-associated angiosarcoma of the breast due to their independent efficacy against AS.\n\nUnfortunately, due to the rarity of AS and the diversity of tumor sites, a randomized trial utilizing doxorubicin, paclitaxel and cisplatin to assess overall response and progression free survival is not feasible. Therefore, an alternative means must be considered to generate additional evidence regarding the role of chemotherapy in AS and specifically this regimen’s efficacy. In recent years, cancer databases such as the National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) program have greatly facilitated the analysis of treatment efficacy and patient outcomes. While these databases provide some data on AS treatment, they fail to report what chemotherapeutic agents were utilized or in what combination. In a number of other rare malignancies, such as adrenal cortical carcinoma and pleuropulmonary blastoma, disease-specific databases have been successfully implemented and have provided extensive insight into tumor characteristics and molecular targets [27,28]. We advocate for the implementation of a similar, disease-specific, national registry of all patients diagnosed with AS. This would allow for a thorough evaluation of treatment methods and create a better understanding of the tumor’s response to specific treatment regimens, including the chemotherapy regimen utilized in our cases.\n\nSources of funding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nEthical approval\nThis study was exempt from ethical approval at our institution.\n\nConsent\nWritten consent was obtained from the patient for publication of these case reports and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request. Identifying details have been omitted wherever possible.\n\nAuthor contribution\nJoseph A. Lewcun: methodology, investigation, visualization, data curation, writing – original draft, writing – review & editing\n\nColette Pameijer: conceptualization, supervision, writing – review & editing\n\nRena Kass: conceptualization, investigation, writing – review & editing\n\nLeah Cream: investigation, validation, writing – review & editing\n\nDiane Hershock: investigation, validation, writing – review & editing\n\nAshton J. Brooks: conceptualization, investigation, writing – review & editing\n\nDaleela G. Dodge: guarantor, conceptualization, supervision, project administration, writing – review & editing\n\nRegistration of research studies\nThese case reports do not meet the Research Registry’s criteria of “first used in man” as all of these described chemotherapeutic agents have been utilized previously in other settings and for other purposes.\n\nGuarantor\nDaleela G. Dodge.\n\nProvenance and peer review\nEditorially reviewed, not externally peer-reviewed.\n\nDeclaration of Competing Interest\nThe authors have no conflicting financial or personal interests to disclose.\n==== Refs\nReferences\n1 Ferrari A. Sultan I. Huang T.T. Soft tissue sarcoma across the age spectrum: a population-based study from the Surveillance Epidemiology and End Results database Pediatr. Blood Cancer 57 6 2011 943 949 21793180 \n2 Young R.J. Brown N.J. Reed M.W. Hughes D. Path F.R.C. Woll P.J. Angiosarcoma Lancet Oncol. 11 2010 983 991 20537949 \n3 Enzinger F.M. Weiss S.W. Soft Tissue Tumors 1995 Mosby St. Louis 641 677 \n4 Yin M. Wang W. Drabick J.J. Harold H.A. Prognosis and treatment of non-metastatic primary and secondary breast angiosarcoma: a comparative study BMC Cancer 17 2017 295 298 28449661 \n5 Depla A.L. Scharloo-Karels C.H. de Jong M.A.A. Treatment and prognostic factors of radiation-associated angiosarcoma (RAAS) after primary breast cancer: a systematic review Eur. J. Cancer 50 2014 1779 1788 24731859 \n6 Bjerkehagen B. Smeland S. Walberg L. Radiation-induced sarcoma: 25-year experience from the Norwegian Radium Hospital Acta Oncol. 47 2008 1475 1482 18607853 \n7 Depla A.L. Scharloo-Karels C.H. de Jong M.A.A. Treatment and prognostic factors of radiation-associated angiosarcoma (RAAS) after primary breast cancer: a systematic review Eur. J. Cancer 50 2014 1779 1788 24731859 \n8 Sheth G.R. Cranmer L.D. Smith B.D. Radiation-induced sarcoma of the breast: a systematic review Oncologists 17 2012 405 418 \n9 Young R.J. Natukunda A. Litière S. Woll P.J. Wardelmann E. van der Graaf W.T.A. First-line anthracycline-based chemotherapy for angiosarcoma and other soft tissue sarcoma subtypes: pooled analysis of eleven European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group trials Eur. J. Cancer 50 2014 3178 3186 25459395 \n10 Skubitz K.M. Haddad P.A. Paclitaxel and pegylated‐liposomal doxorubicin are both active in angiosarcoma Cancer 104 2005 361 366 15948172 \n11 Penel N. Bui B.N. Bay J. Phase II trial of weekly paclitaxel for unresectable angiosarcoma: the ANGIOTAX study J. Clin. Oncol. 26 2008 5269 5274 18809609 \n12 Edmonson J.H. Ryan L.M. Blum R.H. Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas J. Clin. Oncol. 11 1993 1269 1275 8315424 \n13 Mathew P. Vakar-Lopez F. Troncoso P. Protracted remission of metastatic epithelioid angiosarcoma with weekly infusion of doxorubicin, paclitaxel, and cisplatin Lancet Oncol. 7 2006 92 93 16389189 \n14 Fukuda A. Tahara K. Hane Y. Comparison of the adverse event profiles of conventional and liposomal formulations of doxorubicin using the FDA adverse event reporting system PLoS One 12 2017 e0185654 \n15 Wood A.J. Rowinsky E.K. Donehower R.C. Drug therapy: paclitaxel (Taxol) N. Engl. J. Med. 332 1995 1004 7885406 \n16 Sledge G.W. Neuberg D. Bernardo P. Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an Intergroup Trial (E1193) J. Clin. Oncol. 21 2003 588 592 12586793 \n17 DeMartelaere S.L. Roberts D. Burgess M.A. Neoadjuvant chemotherapy–specific and overall treatment outcomes in patients with cutaneous angiosarcoma of the face with periorbital involvement Head Neck 30 2008 639 646 18213722 \n18 Fodor J. Orosz Z. Szabó É Angiosarcoma after conservation treatment for breast carcinoma: our experience and a review of the literature J. Am. Acad. Dermatol. 54 2006 499 504 16488303 \n19 Morgan E.A. Kozono D.E. Wang Q. Cutaneous radiation-associated angiosarcoma of the breast: poor prognosis in a rare secondary malignancy Ann. Surg. Oncol. 19 2012 3801 3808 22890593 \n20 Li G.Z. Fairweather M. Wang J. Orgill D.P. Bertagnolli M.M. Raut C.P. Cutaneous radiation-associated breast angiosarcoma: radicality of surgery impacts survival Ann. Surg. 265 2017 814 820 28267696 \n21 Stewart F.W. Treves N. Lymphangiosarcoma in postmastectomy lymphedema. A report of six cases in elephantiasis chirurgica Cancer 1 1948 64 81 18867440 \n22 von Mehren M. Randall R.L. Benjamin R.S. Soft tissue sarcoma, version 2.2018, NCCN clinical practice guidelines in oncology J. Natl. Comprehensive Cancer Netw. JNCCN 16 2018 536 \n23 Ray-Coquard I.L. Domont J. Tresch-Bruneel E. Paclitaxel given once per week with or without bevacizumab in patients with advanced angiosarcoma: a randomized phase II trial J. Clin. Oncol. 33 2015 2797 2802 26215950 \n24 Maki R.G. D’Adamo D.R. Keohan M.L. Phase II study of sorafenib in patients with metastatic or recurrent sarcomas J. Clin. Oncol. 27 2009 3133 3140 19451436 \n25 Buehler D. Rice S.R. Moody J.S. Angiosarcoma outcomes and prognostic factors: a 25-year single institution experience Am. J. Clin. Oncol. 37 5 2014 473 479 23428947 \n26 Agha R.A. Borrelli M.R. Farwana R. Koshy K. Fowler A. Orgill D.P. For the SCARE Group The SCARE 2018 statement: updating consensus surgical CAse REport (SCARE) guidelines Int. J. Surg. 60 2018 132 136 30342279 \n27 Ribeiro R.C. Sandrini F. Figueiredo B. An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma Proc. Natl. Acad. Sci. U. S. A. 98 16 2001 9330 9335 11481490 \n28 Messinger Y.H. Stewart D.R. Priest J.R. Pleuropulmonary blastoma: a report on 350 central pathology-confirmed pleuropulmonary blastoma cases by the International Pleuropulmonary Blastoma Registry Cancer 121 2 2015 276 285 25209242\n\n",
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"journal": "International journal of surgery case reports",
"keywords": "Angiosarcoma; Breast cancer; Case report; Neoadjuvant chemotherapy; Radiation-induced angiosarcoma; Sarcoma",
"medline_ta": "Int J Surg Case Rep",
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"title": "Doxorubicin, paclitaxel, and cisplatin based chemotherapy for the treatment of angiosarcoma: Two case reports.",
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"abstract": "Acquired immunodeficiency in thymoma (Good's syndrome) without hypogammaglobulinemia is a rare condition. Here we describe the case of a 29-year-old Japanese woman with thymoma-associated T cell immunodeficiency after radiation therapy. She was admitted to the hospital with refractory pneumonia, which resulted from as T cell immunodeficiency, as revealed through low peripheral lymphocytes and oral candidiasis triggered through radiotherapy and required long-term antimicrobial therapy. Although radiotherapy is commonly administered for thymoma, our findings suggest that physicians should consider carrying out lymphocyte counts during thymoma treatment.",
"affiliations": "Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.;Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.;Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.;Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.;Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.;Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.;Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.;Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.;Department of Radiology, Keio University School of Medicine, Tokyo, Japan.;Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.;Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.;Division of Neurology Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.;Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.;Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.",
"authors": "Nakagawara|Kensuke|K|;Chubachi|Shotaro|S|;Azekawa|Shuhei|S|;Otake|Shiro|S|;Saito|Ayaka|A|;Okada|Masahiko|M|;Lee|Ko|K|;Masaki|Katsunori|K|;Koike|Naoyoshi|N|;Kamata|Hirofumi|H|;Kawada|Ichiro|I|;Suzuki|Shigeaki|S|;Ishii|Makoto|M|;Fukunaga|Koichi|K|",
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"fulltext": "\n==== Front\nRespir Med Case Rep\nRespir Med Case Rep\nRespiratory Medicine Case Reports\n2213-0071\nElsevier\n\nS2213-0071(21)00070-8\n10.1016/j.rmcr.2021.101408\n101408\nCase Report\nThymoma-associated T-cell immunodeficiency after radiotherapy: A case report\nNakagawara Kensuke a\nChubachi Shotaro bachibachi472000@live.jp\na∗\nAzekawa Shuhei a\nOtake Shiro a\nSaito Ayaka a\nOkada Masahiko a\nLee Ko a\nMasaki Katsunori a\nKoike Naoyoshi b\nKamata Hirofumi a\nKawada Ichiro a\nSuzuki Shigeaki c\nIshii Makoto a\nFukunaga Koichi a\na Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan\nb Department of Radiology, Keio University School of Medicine, Tokyo, Japan\nc Division of Neurology Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan\n∗ Corresponding author. Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, 160-8582, Japan. bachibachi472000@live.jp\n02 4 2021\n2021\n02 4 2021\n33 10140822 2 2021\n14 3 2021\n24 3 2021\n© 2021 The Authors\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nAcquired immunodeficiency in thymoma (Good's syndrome) without hypogammaglobulinemia is a rare condition. Here we describe the case of a 29-year-old Japanese woman with thymoma-associated T cell immunodeficiency after radiation therapy. She was admitted to the hospital with refractory pneumonia, which resulted from as T cell immunodeficiency, as revealed through low peripheral lymphocytes and oral candidiasis triggered through radiotherapy and required long-term antimicrobial therapy. Although radiotherapy is commonly administered for thymoma, our findings suggest that physicians should consider carrying out lymphocyte counts during thymoma treatment.\n\nKeywords\n\nThymoma\nT-cell immunodeficiency\nMyasthenia gravis\nRadiotherapy\nOral candidiasis\nPneumoniae\n==== Body\n1 Introduction\n\nThymoma, originating from epithelial cells, is a rare thymus tumor and is typically treated through surgical resection, and metastatic tumors and lesions may be treated through chemotherapy or radiation therapy. The tumor is often associated with various autoimmune diseases including myasthenia gravis, pure red cell aplasia, and acquired immunodeficiency, which are affected by tumor progression and treatment. Good's syndrome is a typical thymoma-associated humoral and cellular immunodeficiency with hypogammaglobulinemia and confers opportunistic infections. In this case report, we report a case of intractable pneumonia with T-cell immunodeficiency resulting from radiotherapy for thymoma.\n\n2 Case presentation\n\nA 29-year-old woman presented with fever and productive cough at our hospital. She had undergone thymectomy for thymoma 9 years ago and had comorbid myasthenia gravis, pure red cell aplasia, and autoimmune hepatitis. She was prescribed immunosuppressants including cyclosporine (200 mg/d) and prednisolone (5 mg/d). Radiotherapy was initiated for a recurrent thymoma lesion 2 weeks before her admission delivered to a total dose of 54 Gy in 27 fractions (Fig. 1). Her bone marrow was an area spared from radiation therapy.Fig. 1 Dose distribution map of the radiation against the relapsed thymoma.\n\nShe received Volumetric Modulated Arc Therapy for a recurrent thymoma lesion with left pleural dissemination, avoiding her bone marrow; isodose line of radiation treatment. The green line represents 50 Gy, the light blue line represents 30 Gy, and the white line represents 10 Gy. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)\n\nFig. 1\n\nPneumococcal pneumonia episode in the previous months were remarkable in her medical history. Her chest examination revealed bilateral coarse crackles and rhonchi. Laboratory examination revealed leukocytosis with a left shift and elevated C-reactive protein. Hypogammaglobulinemia, fungal antigens, and Mycobacterium tuberculosis infection were unremarkable on the interferon-gamma release assay and anti-HIV antibodies. Chest computed tomography (CT) revealed infiltrations and a granular shadow in the bilateral lobes (Fig. 2A). She was diagnosed with broncho-pneumonia and hospitalized.Fig. 2A Chest computed tomographic images upon hospitalization.\n\nChest computed tomography revealed centrilobular granular and infiltrative shadows and thickening of the bronchial wall in bilateral lung fields.\n\nFig. 2A\n\nAfter admission, a 14-d course of piperacillin-tazobactam was initiated for broncho-pneumonia, and her symptoms and laboratory findings improved. However, after switching from piperacillin-tazobactam to an oral antimicrobial (levofloxacin), pneumonia reexercabted (Fig. 2B).Fig. 2B Chest computed tomographic images upon pneumonia exacerbation.\n\nThe centrilobular granular and infiltrative shadows were re-exacerbated and extensive infiltrative shadows were observed around the bronchi in the right upper lobe.\n\nFig. 2B\n\nTherefore, piperacillin-tazobactam treatment was resumed and pneumonia was under control again; however, drug fever and granulocytopenia caused by piperacillin-tazobactam was observed and hence cefepime was administered as an alternative. However, severe drug eruptions were observed 4 d after switching to cefepime, and drug eruption exacerbated even after a switch to meropenem. Therefore, antimicrobial treatment was discontinued. Antimicrobial therapy with cefepime, piperacillin-tazobactam, and meropenem were administered for 21 d. Drug eruption improved with no treatment after discontinuation of antimicrobial therapy. Immunodeficiency was suspected as the cause of recurrent lower respiratory tract infections because peripheral CD4-positive cells were reduced to 284 μ/L, and lymphocytopenia (<1,000/μL) occurred after radiation therapy for recurrent thymoma. Hypogammaglobulinemia was not observed; nonetheless, immunoglobulin was administered at 5,000 mg once daily for three consecutive days for severe infection. Furthermore, cyclosporine was gradually tapered to 100 mg/d after admission to control pneumonia. After discontinuation of antimicrobial therapy, fever recurred and the oxygen demand increased, and CT revealed new consolidation in her lower lobe of the left lung (Fig. 2C).Fig. 2C Chest computed tomographic images on the third onset of pneumonia.\n\nConsolidation of the right upper lobe improved, and a novel extensive infiltrative shadow was observed from the upper region to the basilar region of the left lower lobe.\n\nFig. 2C\n\nFor the third treatment cycle for pneumonia, a combination of vancomycin and doripenem, plus immunoglobulin, was initiated, because methicillin‐resistant Staphylococcus aureus (MRSA) and Pseudomonas fluorescens were detected in sputum cultures after hospitalization. Despite intensive treatment, no improvement in the oxygen demand and fever was observed. Since the patient had pneumonia refractory to broad-spectrum antimicrobial agents, pneumonia caused by agents other than bacterial was suspected as the cause of the respiratory failure and pneumonia findings on chest CT. Simultaneously, candidiasis was noted in the oral cavity (Fig. 3), and the decline in CD4-positive cells suggested T-cell immunodeficiency.Fig. 3 Candidiasis in the oral cavity and oropharynx with comorbid lymphocytopenia.\n\nFig. 3\n\nFurthermore, based on elevated serum β-D glucan levels and a positive PCR test for Pneumocystis jirovecii in sputum samples, P. jirovecii pneumonia was diagnosed as a cause of respiratory failure. Along with antimicrobial treatment, sulfamethoxazole (3,600 mg/d) and trimethoprim (720 mg/d) were initiated, and prednisolone was administered at 80 mg/d. Respiratory failure improved rapidly, and the infiltrative shadow on chest X-ray was obliterated. Prednisolone was tapered to a maintenance dose over 2 weeks, and anti-biotherapy and sulfamethoxazole/trimethoprim were administered for 3 weeks each and completed. During hospitalization, the peripheral lymphocyte count was elevated to almost 2,000/μL, and she was discharged on hospitalization day 99 without pneumonia recurrence after treatment for P. jirovecii pneumonia. Her clinical course after admission is described in Fig. 4. During her hospitalization, her gammaglobulin levels remained within the normal range, while her peripheral lymphocyte counts tended to slowly increase.Fig. 4 Clinical course of the patient, assessed in accordance with gammaglobulin levels, fever type, and peripheral lymphocyte counts.\n\nFig. 4\n\n3 Discussion\n\nHere we report the case of a woman with recurrent lower respiratory tract inflammation after radiation therapy for recurrent thymoma. She experienced three recurring episodes of pneumonia a few months immediately after radiotherapy. In each case, chest CT revealed infiltrative and centrilobular granular shadows at different sites, suggesting the involvement of systemic immunodeficiency in the background. Comorbid oral candidiasis and reduction of peripheral blood lymphocytes and CD4-positive cells further evidenced her condition. T-cell immunodeficiency associated with lymphocyte depletion was speculated to be the cause of the refractory pneumonia. Furthermore, the recurrence of lower respiratory infections was under control owing to elevated absolute lymphocyte counts during the clinical course (Fig. 4).\n\nImmunosuppressive medications such as prednisone and cyclosporine were suspected as the cause of T-cell immunodeficiency, whereas the patient had been taking these drugs for almost one year before she was hospitalized, and pneumonia, which had developed 2 months before radiation therapy, had been in remission upon 3 weeks of antimicrobial treatment despite taking an immunosuppressants (prednisone 5mg/d and cyclosporine 200 mg/d). Her peripheral blood lymphocytes were markedly reduced before and after radiation therapy (Fig. 5). Additionally, in this case, the intractable pneumonia developed after the radiotherapy. Therefore, the radiotherapy-induced T-cell immunodeficiency may have played a more important role in the development of the refractory pneumonia than the immunosuppressive medications.Fig. 5 Absolute lymphocyte count over a 7-month period.\n\nFig. 5\n\nGood's syndrome with hypogammaglobulinemia, low or absent B-cells in peripheral blood, and various defects in cell-mediated immunity, is an immunodeficiency reportedly associated with thymoma [1,2]. The treatment for Good's syndrome initially involves resection of the thymic tumor, followed by immunoglobulin replacement [3]. However, in this case, T-cell immunodeficiency was suggested to result from lymphocytes, including CD4-positive cells without hypogammaglobulinemia and the development of oral candidiasis and Pneumocystis pneumonia.\n\nA few cases of T-cell immunodeficiency after radiotherapy for thymoma have been previously reported [4,5]. Each case was similar to the present case, in that the lymphocyte count, including that of CD4-positive cells, was reduced, and systemic infections developed after radiotherapy. This case is different from previously reported cases in that we could identify a markedly reduced number of lymphocytes after irradiation. While it took years for the lymphocyte count to increase in these previously reported cases, it improved within a few months in the present case, suggesting that the period required for lymphocyte recovery after radiotherapy differs in each case.\n\nRadiation therapy is a common treatment method for thymoma and generally does not cause immunodeficiency [6,7] because the bone marrow is generally not targeted during radiation therapy to prevent inducing a loss of hematopoietic capacity. We focused on pre-radiation an increase in lymphocytes in this case. Therefore, the monoclonal thymoma-derived lymphocytes and polyclonal mature lymphocytes might have increased. Peripheral lymphocytosis is a characteristic finding in cases of thymoma-associated T-cell immunodeficiency [8]. Thymectomy for lymphocyte-rich and hematopoietic thymoma reportedly induces a marked reduction in the peripheral T-cell population. In patients presenting minimal thymopoiesis, minor effects on T-cell concentration have been observed [9]. In this case, cell-mediated immunity, further corroborated through thymoma-derived lymphocytosis before radiotherapy, might have been disrupted through lymphocyte depletion due to radiotherapy, resulting in the manifestation of background cellular immunodeficiency. The findings form the present case study suggest that clinicians should consider carrying out peripheral lymphocyte counts before and after radiation therapy for thymoma and consider the possibility of the development of T-cell immunodeficiency.\n\n4 Conclusion\n\nWe reported a case of refractory pneumonia associated with T-cell immunodeficiency after radiation therapy for thymoma. Clinicians need to be aware of the cell-mediated immunity of patients after radiotherapy for thymoma.\n\nFunding\n\nThis report did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nAuthor's contribution\n\nAll of the authors ensure to task force for preparing the manuscript and approved the final version of the manuscript. All authors contributed to the clinical care for the patient in specialized settings.\n\nConsent for publication\n\nWritten consent was obtained from the patient for publication of this case report and for use of accompanying images.\n\nSubmission declaration and verification\n\nThe present study was not published or is not currently submitted to any other journal.\n\nDeclaration of competing interest\n\nNone of the authors has any conflicts of interest or any financial ties to disclose.\n\nAcknowledgments\n\nWe would like to thank Editage (www.editage.jp) for English language editing.\n==== Refs\nReferences\n\n1 Masci A.M. Palmieri G. Vitiello L. Clonal expansion of CD8+ BV8 T lymphocytes in bone marrow characterizes thymoma-associated B lymphopenia Blood 101 8 2003 3106 3108 12515721\n2 Di Renzo M. Pasqui A. Bruni F. Thymoma and immunodeficiency N. Z.Med. J. 117 1188 2004 U750\n3 Kelleher P. Misbah S.A. What is Good's syndrome? Immunological abnormalities in patients with thymoma J. Clin. Pathol. 56 1 2003 12 16 12499426\n4 Wickemeyer J.L. Sekhsaria S. Prolonged severe immunodeficiency following thymectomy and radiation: a case report J. Med. Case Rep. 8 2014 457 25528459\n5 Kawamura T. Naito T. Kobayashi H. Acquired immunodeficiency associated with thymoma: a case report BMC Canc. 19 1 2019 762\n6 Berman A.T. Litzky L. Livolsi V. Adjuvant radiotherapy for completely resected stage 2 thymoma Cancer 117 15 2011 3502 3508 21287527\n7 Hetnał M. Małecki K. Wolanin M. Korzeniowski S. Walasek T. Thymoma: results of treatment and role of radiotherapy Rep. Practical Oncol. Radiother. 15 1 2010 15 20\n8 Christopoulos P. Fisch P. Acquired T-cell immunodeficiency in thymoma Crit. Rev. Immunol. 36 4 2016 315 327 28322136\n9 Sempowski G. Thomasch J. Gooding M. Effect of thymectomy on human peripheral blood T cell pools in myasthenia gravis J. Immunol. 166 4 2001 2808 2817 11160348\n\n",
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"keywords": "Myasthenia gravis; Oral candidiasis; Pneumoniae; Radiotherapy; T-cell immunodeficiency; Thymoma",
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"title": "Thymoma-associated T-cell immunodeficiency after radiotherapy: A case report.",
"title_normalized": "thymoma associated t cell immunodeficiency after radiotherapy a case report"
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"abstract": "To investigate the efficacy and toxicity profile of sequential intensity modulated radiation therapy (IMRT) followed by gemcitabine, dexamethasone, and cisplatin (GDP) on previously untreated high-risk, early stage upper aerodigestive tract natural killer/T-cell lymphoma (UADT-NKTCL).\n\n\n\nA phase 2 study was designed, and 40 high-risk patients with stage I(E)/II(E) UADT-NKTCL were enrolled between June 2010 and June 2014. High-risk patients were defined as those with at least 1 predefined risk factor: age >60 years, elevated serum lactate dehydrogenase, regional lymph node involvement, B symptoms, and primary tumor invasion. Patients received extended involved-site IMRT and GDP chemotherapy. The primary endpoint was the 2-year progression-free survival rate. Secondary endpoints were the 2-year overall survival rate, overall response rate, and toxicity.\n\n\n\nMedian follow-up time was 60.1 months. The overall response rate and complete remission rate were 97.5% and 95.0%, respectively. The 2- and 5-year progression-free survival rates were 84.7% and 79.4%, and the corresponding overall survival rates were 89.9% and 82.1%, respectively. The most frequent radiation-induced toxicities were mild mucositis and skin reaction. Grade 3/4 neutropenia (12 of 40 patients), thrombocytopenia (7 of 40), and anemia (2 of 40) were observed during chemotherapy.\n\n\n\nFirst-line IMRT followed by GDP represents an effective and well-tolerated protocol for high-risk, early stage UADT-NKTCL.",
"affiliations": "Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.;Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiation Oncology, Peking University Cancer Hospital & Institute, Beijing, China.;Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.;Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.;Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.;Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.;Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.;Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.;Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.;Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.;Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.;Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.;Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.;State Key Laboratory of Molecular Oncology and Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: yexiong12@163.com.;Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: dongmei030224@163.com.",
"authors": "Qi|Fei|F|;Wang|Wei-Hu|WH|;He|Xiao-Hui|XH|;Chen|Bo|B|;Gui|Lin|L|;Fang|Hui|H|;Liu|Peng|P|;Wang|Shu-Lian|SL|;Yang|Jian-Liang|JL|;Song|Yong-Wen|YW|;Yang|Sheng|S|;Qi|Shu-Nan|SN|;Zhou|Sheng-Yu|SY|;Li|Ye-Xiong|YX|;Dong|Mei|M|",
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"medline_ta": "Int J Radiat Oncol Biol Phys",
"mesh_terms": "D000328:Adult; D002945:Cisplatin; D003131:Combined Modality Therapy; D003841:Deoxycytidine; D003907:Dexamethasone; D005260:Female; D006801:Humans; D054391:Lymphoma, Extranodal NK-T-Cell; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D050397:Radiotherapy, Intensity-Modulated; D012008:Recurrence; D012306:Risk; D012449:Safety; D016896:Treatment Outcome",
"nlm_unique_id": "7603616",
"other_id": null,
"pages": "61-70",
"pmc": null,
"pmid": "30102205",
"pubdate": "2018-09-01",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Phase 2 Study of First-line Intensity Modulated Radiation Therapy Followed by Gemcitabine, Dexamethasone, and Cisplatin for High-Risk, Early Stage Extranodal Nasal-Type NK/T-Cell Lymphoma: The GREEN Study.",
"title_normalized": "phase 2 study of first line intensity modulated radiation therapy followed by gemcitabine dexamethasone and cisplatin for high risk early stage extranodal nasal type nk t cell lymphoma the green study"
} | [
{
"companynumb": "CN-HQ SPECIALTY-CN-2019INT000185",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "Gastrointestinal stromal tumors (GISTs) are the most common primary mesenchymal gastrointestinal neoplasms. However, GISTs occurring in kidney transplant recipients, including their treatment and outcome, are rarely described in literature. We hereby report two kidney transplant recipients with GISTs. Our first patient was diagnosed with high-risk epithelioid gastric GIST 2 years after kidney transplant. He received everolimus after resection and remained disease-free for 2 years before liver metastasis was confirmed. Imatinib therapy was planned but he died of fulminant pneumonia shortly. Our second patient was diagnosed with spindle cell GISTs in the mesentery 1 year after kidney transplant. Only partial response was obtained with imatinib as new lesions continued to develop. Withdrawal of cyclosporine and introduction of sirolimus resulted in complete shrinkage of existing tumors and no new lesions. He remained disease-free for more than 10 years. Combination therapy consisting of imatinib and inhibitors of mammalian target of rapamycin (mTORi) seems to be safe and effective in kidney transplant recipients. However, therapeutic drug monitoring of mTORi is essential to avoid nephrotoxicity. Further trials addressing the optimal dosage of imatinib and mTORi in kidney transplant recipients are recommended.",
"affiliations": "Department of Medicine, Queen Elizabeth Hospital, Hong Kong SAR.;Department of Medicine, Pamela Youde Nethersole Eastern Hospital, Hong Kong SAR.;Department of Medicine, Pamela Youde Nethersole Eastern Hospital, Hong Kong SAR.;Department of Medicine, the University of Hong Kong, Hong Kong SAR.;Department of Medicine, the University of Hong Kong, Hong Kong SAR.;Department of Medicine, Queen Elizabeth Hospital, Hong Kong SAR.",
"authors": "Cheung|Chi Yuen|CY|;Lo|Stanley Hok King|SH|;Chan|Ching Kit|CK|;Li|Fu Keung|FK|;Cheng|Ignatius Kum Po|IK|;Chau|Ka Foon|KF|",
"chemical_list": "D000068877:Imatinib Mesylate; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus",
"country": "Australia",
"delete": false,
"doi": "10.1111/ajco.12506",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1743-7555",
"issue": "13(1)",
"journal": "Asia-Pacific journal of clinical oncology",
"keywords": "gastrointestinal tumor; kidney transplant",
"medline_ta": "Asia Pac J Clin Oncol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D000068338:Everolimus; D046152:Gastrointestinal Stromal Tumors; D006801:Humans; D000068877:Imatinib Mesylate; D016030:Kidney Transplantation; D008297:Male; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases",
"nlm_unique_id": "101241430",
"other_id": null,
"pages": "104-106",
"pmc": null,
"pmid": "27461055",
"pubdate": "2017-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Gastrointestinal stromal tumors in kidney transplant recipients: Report of two cases and literature review.",
"title_normalized": "gastrointestinal stromal tumors in kidney transplant recipients report of two cases and literature review"
} | [
{
"companynumb": "PHHY2017HK023918",
"fulfillexpeditecriteria": "1",
"occurcountry": "HK",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Methadone use as a second-line agent for severe cancer-related pain is increasing in the field of hospice and palliative care. It has a number of qualities that make its use favorable, including lack of known active metabolites and presumed relative safety from adverse effects such as opioid-induced neurotoxicity (OIN). This article describes a case of a patient undergoing treatment of severe cancer-related pain who developed OIN in the setting of oral methadone use. As the use of methadone increases, more research into its pharmacologic and pharmacokinetic properties will be necessary.",
"affiliations": "1 Department of Palliative Medicine, Mayo Clinic Health System , Mankato, Minnesota.;2 Department of Palliative Medicine, Minneapolis VA Health Care System , Minneapolis, Minnesota.;3 Department of Palliative Medicine, University of Minnesota Medical Center , Minneapolis, Minnesota.",
"authors": "Hoff|Ann M|AM|;Hartwig|Kristopher N|KN|;Rosielle|Drew A|DA|",
"chemical_list": "D000701:Analgesics, Opioid; D008691:Methadone",
"country": "United States",
"delete": false,
"doi": "10.1089/jpm.2016.0502",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1557-7740",
"issue": "20(9)",
"journal": "Journal of palliative medicine",
"keywords": "cancer pain; methadone; myoclonus; neurotoxicity; palliative care",
"medline_ta": "J Palliat Med",
"mesh_terms": "D000701:Analgesics, Opioid; D006801:Humans; D008297:Male; D008691:Methadone; D008875:Middle Aged; D009369:Neoplasms; D020258:Neurotoxicity Syndromes; D010146:Pain; D010166:Palliative Care",
"nlm_unique_id": "9808462",
"other_id": null,
"pages": "1042-1044",
"pmc": null,
"pmid": "28488910",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Methadone-Induced Neurotoxicity in Advanced Cancer: A Case Report.",
"title_normalized": "methadone induced neurotoxicity in advanced cancer a case report"
} | [
{
"companynumb": "US-VISTAPHARM, INC.-VER201712-001630",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MORPHINE"
},
"drugadditional": nul... |
{
"abstract": "BACKGROUND\nPulmonary Langerhans cell histiocytosis (PLCH) is a rare disorder characterised by granulomatous proliferation of CD1a-positive histiocytes forming granulomas within lung parenchyma, in strong association with tobacco smoking, and which may result in chronic respiratory failure. Smoking cessation is considered to be critical in management, but has variable effects on outcome. No drug therapy has been validated. Cladribine (chlorodeoxyadenosine, 2-CDA) down-regulates histiocyte proliferation and has been successful in curbing multi-system Langerhans cell histiocytosis and isolated PLCH.\n\n\nMETHODS\nWe retrospectively studied 5 patients (aged 37-55 years, 3 females) with PLCH who received 3 to 4 courses of cladribine therapy as a single agent (0.1 mg/kg per day for 5 consecutive days at monthly intervals). One patient was treated twice because of relapse at 1 year. Progressive pulmonary disease with obstructive ventilatory pattern despite smoking cessation and/or corticosteroid therapy were indications for treatment. Patients were administered oral trimethoprim/sulfamethoxazole and valaciclovir to prevent opportunistic infections. They gave written consent to receive off-label cladribine in the absence of validated treatment.\n\n\nRESULTS\nFunctional class dyspnea improved with cladribine therapy in 4 out of 5 cases, and forced expiratory volume in 1 second (FEV1) increased in all cases by a mean of 387 ml (100-920 ml), contrasting with a steady decline prior to treatment. Chest high-resolution computed tomography (HRCT) features improved with cladribine therapy in 4 patients. Hemodynamic improvement was observed in 1 patient with pre-capillary pulmonary hypertension. The results suggested a greater treatment effect in subjects with nodular lung lesions and/or thick-walled cysts on chest HRCT, with diffuse hypermetabolism of lung lesions on positron emission tomography (PET)-scan, and with progressive disease despite smoking cessation. Infectious pneumonia developed in 1 patient, with later grade 4 neutrocytopenia but without infection.\n\n\nCONCLUSIONS\nData interpretation was limited by the retrospective, uncontrolled study design and small sample size.\n\n\nCONCLUSIONS\nCladribine as a single agent may be effective therapy in patients with progressive PLCH.",
"affiliations": "National Reference Centre for Rare Pulmonary Diseases, Department of Respiratory Medicine, Louis Pradel Hospital; Claude Bernard Lyon 1 University, Lyon, UMR 754, France. vincent.grobost@gmail.com.;National Reference Centre for Rare Pulmonary Diseases, Department of Respiratory Medicine, Louis Pradel Hospital; Claude Bernard Lyon 1 University, Lyon, UMR 754, France. chahera.khouatra@chu-lyon.fr.;National Reference Centre for Rare Pulmonary Diseases, Department of Respiratory Medicine, Louis Pradel Hospital; Claude Bernard Lyon 1 University, Lyon, UMR 754, France. romain.lazor@chuv.ch.;National Reference Centre for Rare Pulmonary Diseases, Department of Respiratory Medicine, Louis Pradel Hospital; Claude Bernard Lyon 1 University, Lyon, UMR 754, France. jean-francois.cordier@chu-lyon.fr.;National Reference Centre for Rare Pulmonary Diseases, Department of Respiratory Medicine, Louis Pradel Hospital; Claude Bernard Lyon 1 University, Lyon, UMR 754, France. vincent.cottin@chu-lyon.fr.",
"authors": "Grobost|Vincent|V|;Khouatra|Chahera|C|;Lazor|Romain|R|;Cordier|Jean-François|JF|;Cottin|Vincent|V|",
"chemical_list": "D000970:Antineoplastic Agents; D017338:Cladribine",
"country": "England",
"delete": false,
"doi": "10.1186/s13023-014-0191-8",
"fulltext": "\n==== Front\nOrphanet J Rare DisOrphanet J Rare DisOrphanet Journal of Rare Diseases1750-1172BioMed Central London 2543349219110.1186/s13023-014-0191-8ResearchEffectiveness of cladribine therapy in patients with pulmonary Langerhans cell histiocytosis Grobost Vincent vincent.grobost@gmail.com Khouatra Chahera chahera.khouatra@chu-lyon.fr Lazor Romain romain.lazor@chuv.ch Cordier Jean-François jean-francois.cordier@chu-lyon.fr Cottin Vincent vincent.cottin@chu-lyon.fr National Reference Centre for Rare Pulmonary Diseases, Department of Respiratory Medicine, Louis Pradel Hospital; Claude Bernard Lyon 1 University, Lyon, UMR 754 France Department of Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland Hospices Civils de Lyon, Hôpital Louis Pradel, Centre national de référence des maladies pulmonaires rares, Centre de compétences de l’hypertension pulmonaire, Service de pneumologie, Université de Lyon, Université Claude Bernard Lyon 1, INRA, Lyon, UMR754 France 30 11 2014 30 11 2014 2014 9 1912 9 2014 11 11 2014 © Grobost et al.; licensee BioMed Central Ltd. 2014This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nPulmonary Langerhans cell histiocytosis (PLCH) is a rare disorder characterised by granulomatous proliferation of CD1a-positive histiocytes forming granulomas within lung parenchyma, in strong association with tobacco smoking, and which may result in chronic respiratory failure. Smoking cessation is considered to be critical in management, but has variable effects on outcome. No drug therapy has been validated. Cladribine (chlorodeoxyadenosine, 2-CDA) down-regulates histiocyte proliferation and has been successful in curbing multi-system Langerhans cell histiocytosis and isolated PLCH.\n\nMethods and patients\nWe retrospectively studied 5 patients (aged 37–55 years, 3 females) with PLCH who received 3 to 4 courses of cladribine therapy as a single agent (0.1 mg/kg per day for 5 consecutive days at monthly intervals). One patient was treated twice because of relapse at 1 year. Progressive pulmonary disease with obstructive ventilatory pattern despite smoking cessation and/or corticosteroid therapy were indications for treatment. Patients were administered oral trimethoprim/sulfamethoxazole and valaciclovir to prevent opportunistic infections. They gave written consent to receive off-label cladribine in the absence of validated treatment.\n\nResults\nFunctional class dyspnea improved with cladribine therapy in 4 out of 5 cases, and forced expiratory volume in 1 second (FEV1) increased in all cases by a mean of 387 ml (100–920 ml), contrasting with a steady decline prior to treatment. Chest high-resolution computed tomography (HRCT) features improved with cladribine therapy in 4 patients. Hemodynamic improvement was observed in 1 patient with pre-capillary pulmonary hypertension. The results suggested a greater treatment effect in subjects with nodular lung lesions and/or thick-walled cysts on chest HRCT, with diffuse hypermetabolism of lung lesions on positron emission tomography (PET)-scan, and with progressive disease despite smoking cessation. Infectious pneumonia developed in 1 patient, with later grade 4 neutrocytopenia but without infection.\n\nDiscussion\nData interpretation was limited by the retrospective, uncontrolled study design and small sample size.\n\nConclusion\nCladribine as a single agent may be effective therapy in patients with progressive PLCH.\n\nKeywords\nHistiocytosisLangerhans cell granulomatosisCladribineChlorodeoxyadenosinePulmonary hypertensionissue-copyright-statement© The Author(s) 2014\n==== Body\nBackground\nLangerhans cell histiocytosis (LCH) is a rare disease of unknown origin characterised by the proliferation of CD1a- and S-100-positive histiocytes, forming granulomas involving the reticuloendothelial system, lymph nodes, axial bones, skin, lungs, central nervous system, and particularly the pituitary gland with diabetes insipidus. In contrast to multi-system LCH, LCH limited to the lungs or pulmonary LCH (PLCH) is strongly associated with tobacco smoking, with more than 90% of patients who are current or former smokers versus less than 50% in multi-system LCH [1,2]. Langerhans cell proliferation in the lungs culminates in bronchiolocentric granulomas, which may cavitate into inflammatory, thick-walled cysts. Lung lesions predominate in the upper lobes with relative sparing of the bases. With disease progression, PLCH may evolve into cicatricial, fibrotic, thin-walled cysts, with irreversible lung destruction, chronic respiratory insufficiency and frequent, severe pulmonary hypertension (PH). Mutually-exclusive mutations of BRAF (V600E) [3], MAP2K1 [4], and ARAF [5] have been identified in more than half of cases, likely contributing to clonal proliferation of Langerhans cells or precursor cells [6]. However, the potential role of corresponding inhibitors in PLCH is not known.\n\nSmoking cessation, considered critical in PLCH management, may be followed by disease remission [7,8], although the relationship between smoking cessation and disease improvement remains unclear. PLCH recurrence, despite smoking cessation, has been reported [9]. Corticosteroids have often been given as first-line therapy in progressive PLCH, especially with prominent nodules on imaging, but without controlled proof of efficacy [10].\n\nCladribine or chlorodeoxyadenosine (2-CDA), a purine nucleoside analog that is directly toxic to monocytes [11], has been used successfully in multi-system LCH [12-15]. It has been reported to induce remission or improve lung disease in several adults with PLCH [16-19], and is currently being evaluated in prospective clinical trials (www.clinicaltrials.gov, NCT01473797). However, placebo-controlled trials are difficult to conduct in patients with progressive disease and severe dyspnoea. Here, we report on our single-centre experience with 5 adult patients who received cladribine therapy for progressive, symptomatic PLCH with lung function impairment.\n\nMethods\nStudy population\nThis retrospective study was conducted in a tertiary centre with expertise in rare lung diseases. The diagnosis of PLCH was based on the following criteria: appropriate clinical presentation with a typical, high-resolution computed tomography (HRCT) pattern of nodules and/or cysts, relatively sparing the lung bases; or compatible clinical and imaging, and PLCH on video-assisted thoracoscopic lung biopsy. Genetic analysis of BRAF V600E mutation was performed in cases with available biopsy samples. The first course of treatment in patient 2 has been reported previously [16].\n\nCladribine therapy\nAll patients received oral and written information regarding off-label cladribine given as “rescue therapy”, and their written consent was obtained in all cases prior to treatment initiation. Although treatment was not conducted in the setting of a clinical trial, and because it was prescribed off-label, particular care was taken to follow a pre-defined treatment dose and design, and to capture all potential adverse events and drug reactions. Patients were advised not to smoke at visits. Cladribine was prescribed as a single agent in all cases, especially without concomitant corticosteroid therapy or vinblastine. Treatment consisted of 3 (or 4) courses, each with 0.1 mg/kg per day of subcutaneous cladribine for 5 consecutive days at monthly intervals. It was administered intravenously in 1 case (patient 2). Oral trimethoprim/sulfamethoxazole (cotrimoxazole, 400/80 mg per day) and valaciclovir (500 mg twice a day) were systematically prescribed until 6 months after the end of cladribine therapy to prevent opportunistic infections.\n\nInvestigations\nIn all patients, the following data were obtained to evaluate individual responses to therapy and benefit:tolerance as part of off-label treatment, before and 1 to 3 months after the last course of cladribine: smoking habits, World Health Organization (WHO) dyspnoea functional class, fever, weight loss, adverse events, prior and concomitant drug therapy, serum C-reactive protein (CRP) level, arterial blood gases, pulmonary function tests, including spirometry, plethysmography and low-dose HRCT. Transthoracic echocardiography was performed systematically before treatment initiation to screen for PH. Right heart catheterisation was undertaken in cases of suspected pre-capillary PH on echocardiography, e.g., with estimated systolic pulmonary artery pressure of 35 mmHg or greater. Selected cases were submitted to exploratory positron emission tomography (PET).\n\nInstitutional Review Board approval is not required for retrospective observational studies in France.\n\nResults\nFindings common to all 5 patients\nFive patients were treated, including 1 who received therapy twice because of PLCH relapse occurring 12 months after the last cladribine dose. The diagnosis was obtained by lung biopsy in 3 cases, and by clinical and imaging criteria in the 2 other patients in whom lung biopsy was declined due to PH (patient 1) or severe lung function impairment (patient 5). BRAF V600E mutation was present in patients 2 and 4, absent in patient 3, and no biopsy was performed in patients 1 and 5. On imaging, a typical pattern of nodules and thick-walled cysts was seen in patients 1, 2 and 3. Patient 4 presented multiple nodules without cystic changes. A pattern with predominant thin-walled cysts was apparent in patient 5.\n\nPatient 2 was a never-smoker, whereas all the 4 others had quit smoking. Patients 1 and 4 stopped smoking 3 months before cladribine initiation, but their lung function continued to deteriorate despite smoking cessation (Figure 1). Patient 5 had quit smoking 3 years prior to treatment. Patient 3 stopped smoking between the second and third courses of cladribine. Two patients (1 and 2) had received prednisolone without success before cladribine therapy, whereas the others were treatment-naive.Figure 1 \nEvolution of forced expiratory volume in 1 second (FEV1) before and after cladribine therapy in 5 patients. M-12: 12 months before cladribine; M-6: 6 months before cladribine; Day 1 (cladribine): initiation of cladribine therapy; M + 6: 6 months after cladribine treatment.\n\n\n\nDyspnoea, evaluated by functional class, improved after treatment in 4 cases, and forced expiratory volume in 1 second (FEV1) increased in all cases (Figure 1). Forced vital capacity (FVC) recuperated with therapy by a mean of 414 ml (0–1,000 ml), and FEV1 by a mean of 387 ml (100–920 ml). Further pulmonary function tests and arterial blood gases are reported in Table 1. Chest HRCT features improved with cladribine therapy in 4 cases, with regression in the number and size of nodules, and decreased cyst wall thickness in all cases. Representative examples of HRCT changes are shown in Figure 2. Patients were followed for 6–48 months (median: 22 months) after cladribine therapy ended.Table 1 \nPatient characteristics before and after cladribine treatment\n\n\n\t\nWHO functional class\n\t\n6-MWD (m)\n\t\nFVC (l)\n\t\nΔFVC (ml)\n\t\nFEV1 (l)\n\t\nΔFEV1 (ml)\n\t\nFEV1/FVC (%)\n\t\nDLco (%)\n\t\nPaO2 (mmHg)\n\t\n\nCladribine\n\t\nPre\n\t\nPost\n\t\nPre\n\t\nPost\n\t\nPre\n\t\nPost\n\t\t\nPre\n\t\nPost\n\t\t\nPre\n\t\nPost\n\t\nPre\n\t\nPost\n\t\nPre\n\t\nPost\n\t\n\nPatient 1 \nM, 45 y\n\tIV\tIII\t60\t220\t2.67 (56%)\t2.93 (62%)\t+260\t1.00 (28%)\t1.15 (32%)\t+150\t38\t37\t15\t16\t60 (3 l)\t65 (2 l)\t\n\nPatient 2 \nF, 37 y\n\tII\t0\tNA\tNA\t2.54 (66%)\t3.54 (95%)\t+1,000\t1.98 (61%)\t2.90 (90%)\t+920\t95\t82\t58\tNA\tNA\tNA\t\n\nPatient 2 \nF, 37 y relapse\n\tII\t0\tNA\tNA\t3.33 (87%)\t4.0 (110%)\t+670\t2.43 (75%)\t3.10 (95%)\t+670\t72\t79\t52\t70\tNA\tNA\t\n\nPatient 3 \nF, 55 y\n\tII-III\tI\tNA\tNA\t2.88 (112%)\t3.30 (126%)\t+420\t1.96 (89%)\t2.30 (104%)\t+340\t69\t71\t67\t62\t82.5\tNA\t\n\nPatient 4 \nM, 50 y\n\tII\tII\t495\tNA\t4.30 (98%)\t4.43 (101%)\t+130\t1.40 (41%)\t1.61 (47%)\t+210\t32\t36\t66\t68\t79.5\t91.5\t\n\nPatient 5 \nF, 40 y\n\tII-III\tII-III\t267\t282\t2.6 (78%)\t2.6 (79%)\t+0\t0.8 (29%)\t0.9 (31%)\t+100\t29\t18\t30\t28\t82.5\t84\t\nNA: not available; 6-MWD: 6-minute walk distance; DLco: diffusing capacity of carbon monoxide, FEV1: forced expiratory volume in 1 second; FVC: forced vital capacity; Δ: variation of FVC and FEV1 before and after cladribine treatment; PaO2: pulmonary arterial tension in blood gases, WHO: World Health Organization.\n\nResults were obtained within hours or days before the first course of cladribine therapy (“Pre”), then 1 month (up to 3 months) after the last cladribine dose (“Post”). Volumes are indicated after inhalation of short-acting bronchodilators.\n\nFigure 2 \nRepresentative HRCT features before (A, C, E, G, I, K) and after cladribine therapy (B, D, F, H, J, L) in 3 patients. A, B: patient 1; C, D: patient 2; E, F: patient 2 (relapse); G, H: patient 3.\n\n\n\nIndividual observations\nPatient 1: A 55-year-old man, current smoker, with a history of 50 pack-years, presented in November 2010 with dyspnoea functional class III. Pulmonary function tests indicated an obstructive ventilatory pattern with 16% diffusion capacity of carbon monoxide (DLco). At echocardiography, estimated systolic pulmonary arterial pressure was 86 mmHg. Right heart catheterisation disclosed pre-capillary PH, with mean pulmonary arterial pressure (mPAP) of 45 mmHg, pulmonary artery wedge pressure (PAWP) of 13 mmHg, cardiac index of 3 l/min/m2, and pulmonary vascular resistance (PVR) of 428 dyn.s−1.cm−5. Serum levels of NT-pro-brain natriuretic peptide and CRP were 417 pg/ml and 4 mg/l, respectively. No significant hypermetabolism was seen on PET-scan. PaO2 was 66 mmHg under 3 l/min nasal oxygen, and long-term nasal supplemental oxygen was initiated. The patient was advised to quit smoking, and bosentan was started (62.5 mg, then 125 mg twice a day). Four months later, despite decreased smoking, from 20 to 5 cigarettes per day, dyspnoea (functional class IV) and lung function worsened. Right heart catheterisation demonstrated hemodynamic improvement (mPAP: 45 mmHg, PAWP: 11 mmHg, PVR: 337 dyn.s−1.cm−5, cardiac index: 4 l/min/m2). The patient definitively stopped smoking. In April 2011, prednisolone (1 mg/kg per day) was initiated, with gradual tapering to 0.5 mg/kg per day over 3 months. In July 2011, lung function continued to deteriorate, with further decrease in FEV1 of 200 ml. Severe functional class IV dyspnoea persisted. Chest HRCT revealed a typically-diffuse nodular pattern with thin-walled cysts. Prednisolone was discontinued, and cladribine was initiated. After 4 courses of subcutaneous cladribine therapy with no significant adverse reactions, dyspnoea, lung function, PaO2 (Table 1), and HRCT findings (Figure 2) improved. Hemodynamic values rallied further (mPAP: 40 mmHg, PAWP: 11 mmHg, PVR: 240 dyn.s−1.cm−5, cardiac index: 4.87 l/min/m2). Unfortunately, the patient resumed smoking 6 months after cladribine therapy. PLCH relapsed, with increased dyspnoea and deterioration of lung function.\n\nPatient 2: A 37-year-old woman, non-smoker, was seen in 2006 for dry cough, dyspnoea functional class II, fever, night sweats, and weight loss. She had a medical history of operated benign prolactinoma, with no sign of pituitary LCH at histology. HRCT was typical for diffuse nodular PLCH, which was confirmed by surgical lung biopsy. Pulmonary function tests showed a restrictive pattern with reduced DLco. CRP level was 45 mg/l. PET-scan disclosed diffuse hypermetabolism of lung parenchyma. The patient received prednisolone (0.5 mg/kg per day from October to March 2007), with no change in clinical, functional, or imaging manifestations. She then received 4 courses of intravenous cladribine (from March to July 2008), which was well tolerated. All symptoms had resolved 4 months after treatment ended. CRP level was 1 mg/l. Lung function and HRCT findings improved. No hypermetabolism was found on PET-scan. In July 2009, PLCH relapsed with dry cough, dyspnoea functional class II, CRP level of 25 mg/l, and lung function deterioration (Table 1). Furthermore, a subcutaneous mass of the vertex had developed which, on MRI, corresponded to a cranial bone tumour without cerebral involvement. PET-scan showed diffuse lung hypermetabolism, with focal hypermetabolism of the cranial bone mass (SUV max was 3.9). The tumour was removed surgically. Histology disclosed a LCH bone lesion not invading the meninges, with positive CD1a and S-100 staining. The patient received 3 additional courses of intravenous cladribine with good tolerance. She was asymptomatic at the end of treatment. PET-scan showed no hypermetabolism. HRCT findings improved significantly. CRP level was 4 mg/l. Disease remission persisted to the last visit 4 years after the end of treatment.\n\nPatient 3: A 55-year-old woman, smoker (40 pack-years), presented with dyspnoea functional class II-III and chronic cough. CRP level was elevated at 83 mg/l. Chest HRCT showed a typical PLCH pattern, with numerous small nodules and thick-walled cysts. Pulmonary function tests indicated isolated reduction of DLco (72% of predicted), with normal spirometry – FVC: 2.47 l (95%); FEV1: 1.96 l (89%); FEV1:FVC: 75%; total lung capacity (TLC): 4.6 l (102%). Echocardiography was normal. PET-scan demonstrated diffuse lung hypermetabolism without extra-pulmonary involvement (SUV max: 5.5). Despite smoking cessation, FEV1 declined by 280 ml over 6 months of follow-up. Right lung surgical biopsy confirmed the PLCH. The patient then received 2 courses of subcutaneous cladribine, in March and April 2013. In May 2013, however, she presented right pneumothorax needing chest tube drainage, with recurrence in June 2013 requiring thoracic surgery with pleurodesis. A third course of cladribine therapy was administered in July 2013. In October 2013, she had dyspnoea functional class I, without cough. CRP level was 3 mg/l. HRCT findings showed significantly decreased nodules, with complete resolution of several thick-walled cysts (Figure 2). PET-scan after treatment found no significant hypermetabolism. Pulmonary function tests disclosed improvement of FEV1 (+300 ml) and FVC (+420 ml), with unchanged DLco.\n\nPatient 4: A 50-year-old current smoker (40 pack-years) was admitted in June 2011 for spontaneous left pneumothorax, night sweats, and weight loss (−7 kg). His past medical history included chronic obstructive pulmonary disease (GOLD class III) with emphysema, treated with inhaled tiotropium, budesonide and formeterol. Chest HRCT revealed diffuse micronodules without cysts, and “atypical emphysema”. PET-scan showed no pulmonary hypermetabolism. Lung surgical biopsy demonstrated PLCH, with involvement of the bronchioles, and emphysematous changes. Echocardiography was normal. Although pneumothorax had resolved, dyspnoea functional class II persisted, and pulmonary function tests indicated an obstructive pattern. Despite complete smoking cessation in March 2013, lung function continued to deteriorate, with FEV1 decreasing by 200 ml and FVC by 100 ml over 6 months, and dyspnoea functional class II. CRP level was 22 mg/l. Chest HRCT was unchanged. Cladribine therapy was initiated. Seven days after the first course, the patient presented infectious pneumonia, without neutropenia, and was successfully treated with intravenous ceftriaxone, but required transfer to the intensive care unit for 48 hours. The second course was complicated by severe neutropenia (grade 4) on day 12, without fever or infection. A 25% dose reduction of cladribine was decided for the third course, which was well tolerated. Cladribine therapy was followed by general improvement, with unchanged dyspnoea functional class II. FVC and FEV1 values increased by 130 ml and 200 ml, respectively. CRP level was 7 mg/l. HRCT findings improved significantly. PET-scan showed no hypermetabolism.\n\nPatient 5: A 40-year-old woman, ex-smoker (20 pack-years up to 3 years earlier), presented dyspnoea functional class II-III in association with diabetes insipidus. MRI showed isolated pituitary stalk enlargement. Hormonal analyses indicated isolated central diabetes insipidus, which was treated with desmopressin. Chest HRCT revealed thin-walled cysts and emphysematous-like lesions, without nodules or thick-walled cysts. PET-scan showed no significant hypermetabolism. Echocardiography was normal. Lung functional tests disclosed a severely-obstructive pattern: FVC: 2.6 l (80% of predicted), FEV1: 0.8 l (29%), FEV1:FVC: 29%, TLC: 6.7 l (134%), DLco: 30%. Αlpha-1 antitrypsin level, CRP and protein electrophoresis were normal. A diagnosis of PLCH was made. Treatment was attributed to long-term lung function decline despite smoking cessation and high-dose inhaled bronchodilators, with a mean decrease of 300 ml/year and 233 ml/year in FEV1 and FVC, respectively, over a 3-year period. The patient received 4 courses of subcutaneous cladribine therapy, with good tolerance. No improvement was observed in dyspnoea, arterial blood gases, and HRCT findings, but FEV1 recovered by 100 ml (Table 1, Figure 1), and the FVC decline was stopped. The patient was considered stable at the last visit, 2 years after the last cladribine dose, and evaluation for lung transplantation was postponed.\n\nDiscussion\nWe report on 5 patients successfully treated with cladribine for progressive PLCH with obstructive ventilator pattern. Cladribine treatment arrested the decline in FEV1 and was followed by either stabilization (patient 5) or improvement (patients 1 to 4) of airflow limitation. Although additional evidence is needed through placebo-controlled randomised trials, these observations suggest that cladribine, as a single agent, may be considered as rescue therapy in subjects with severe disease worsening despite smoking cessation and, in some cases, despite oral corticosteroids. All patients were younger than 55 years, and at least 2 of them (patients 1 and 5), in whom lung transplantation would have been considered over the mid-term, were stabilised after cladribine therapy, and transplantation was not deemed necessary.\n\nThe outcome of treatment may be more evident in individuals with moderately severe obstructive lung disease due to PLCH and not confounded by tobacco smoking, but disease stabilisation and some clinical benefits were also observed in patients 4 and possibly 5 with severe chronic obstructive ventilatory pattern related to both PLCH and history of tobacco-smoking. BRAF V600E mutation in 2 patients (2 and 4) did not seem to affect the response to cladribine. Three of 5 patients (3, 4, and 5) were treatment-naive, whereas cladribine was given after unsuccessful first-line prednisolone therapy in the first 2 cases who had rapidly progressive PLCH despite smoking cessation. Encouraging results in the first treated patients led us to consider potential cladribine therapy earlier in disease management of more recent cases. Given the currently low level of evidence, we think that treatment decisions should probably be based on the degree of lung impairment and on the rapidity of disease worsening. Interestingly, cladribine was successful in 1 patient with relapsing pulmonary disease (patient 2).\n\nChest HRCT showed improvement in most cases, with significantly decreased nodules and thick-walled cysts. No significant change was observed in HRCT findings in patient 5 with thin-walled cysts and emphysematous alterations consistent with relatively-stable lung function in this patient, likely corresponding to non-inflammatory disease. The observation is consistent with a pathological-radiological correlation study, suggesting that nodules on imaging generally correspond to an active granulomatous process at pathology, whereas cavitary lesions on imaging usually reflect still active inflammatory cavitary granulomas or cicatricial fibrous cysts [20]. Cladribine therapy may, therefore, be particularly effective in PLCH subjects with a predominant pattern of diffuse nodules and/or thick-walled cysts on HRCT.\n\nHypermetabolism on PET-scan has been reported in PLCH patients, with more frequent and higher metabolism early in the course of the disease and in those with nodular lung lesions as well as thick-walled cysts on chest imaging [21]. In the present series, patients 2 and 3, who had positive PET findings and predominantly diffuse nodules as well as thick-walled cysts at HRCT, were also those with the greatest improvement in lung function after cladribine therapy. Whether PET may be undertaken to identify patients with active nodular lung lesions and predict better responses to cladribine therapy remains to be investigated prospectively.\n\nCladribine further improved haemodynamics in 1 patient with severe PH associated with PLCH, consistent with reports showing involvement of pulmonary arteries and veins in granulomas and remodeled pulmonary arteries within Langerhans cell granulomas [22,23], as also seen in sarcoidosis.\n\nCladribine is a chemotherapeutic agent with potential toxicity, including infections related to immunosuppression, cytopenia, vomiting, diarrhoea, increased liver enzymes, rash, purpura and, less frequently, neurotoxicity. Treatment of our patients was remarkably uneventful, with the notable exception of 1 patient (#4) who had infectious pneumonia with bronchospasm successfully controlled by antibiotic therapy. Later, the patient had grade 4 neutrocytopenia without infection, which did not relapse after dose adjustment. Patients systematically received preventive therapy with oral trimethoprim/sulfamethoxazole and valaciclovir, and were monitored for cytopenia. The subcutaneous route was preferred to intravenous injection in most cases for convenience and good tolerance.\n\nLimitations of this study include small sample size related to low PLCH prevalence with, furthermore, a small proportion of patients incurring rapidly progressive disease refractory to smoking cessation and/or corticosteroids. Although placebo-controlled randomised trials would ideally be desirable for this condition, patient inclusion has recently proven to be challenging (www.clinicaltrials.gov, NCT01473797), as those at risk of progression to chronic respiratory insufficiency and their doctors are understandably reluctant to participate. Despite the retrospective design, patients in our study were monitored very closely, ensuring exhaustive capture of adverse events and outcome variables. Tolerance and safety were generally acceptable, with a favourable benefit:risk ratio, but long-term follow-up is warranted regarding potential secondary malignancies that could be facilitated by cladribine. Tobacco-smoking was a potentially-confusing factor in patient 3, who quit the habit between the second and third courses of cladribine. Patients received 3 to 4 courses of cladribine, but the optimal number of courses, and the potential utility of maintenance therapy, need to be explored further.\n\nConclusion\nIn conclusion, cladribine, as a single agent, may be effective therapy in PLCH patients. It may be considered, especially in subjects with progressive disease despite smoking cessation, with nodular lung lesions and/or thick-walled cysts on chest HRCT, and with diffuse hypermetabolism of lung lesions on PET-scan.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nVG: study conception and design, data acquisition, analysis and interpretation, manuscript drafting and final approval. CK: data acquisition, manuscript revision for important intellectual content and final approval. RL and J-F C: manuscript revision for important intellectual content and final approval. VC: study conception and design, data analysis and interpretation, manuscript redrafting and revision for important intellectual content and final approval. All authors read and approved the final manuscript.\n==== Refs\nReferences\n1. Hance AJ Basset F Saumon G Danel C Valeyre D Battesti JP Chretien J Georges R Smoking and interstitial lung disease. The effect of cigarette smoking on the incidence of pulmonary histiocytosis X and sarcoidosis Ann N Y Acad Sci 1986 465 643 656 10.1111/j.1749-6632.1986.tb18541.x 3488004 \n2. Watanabe R Tatsumi K Hashimoto S Tamakoshi A Kuriyama T Clinico-epidemiological features of pulmonary histiocytosis X Intern Med 2001 40 998 1003 10.2169/internalmedicine.40.998 11688843 \n3. Badalian-Very G Vergilio JA Degar BA MacConaill LE Brandner B Calicchio ML Kuo FC Ligon AH Stevenson KE Kehoe SM Garraway LA Hahn WC Meyerson M Fleming MD Rollins BJ Recurrent BRAF mutations in Langerhans cell histiocytosis Blood 2010 116 1919 1923 10.1182/blood-2010-04-279083 20519626 \n4. Brown NA Furtado LV Betz BL Kiel MJ Weigelin HC Lim MS Elenitoba-Johnson KS High prevalence of somatic MAP2K1 mutations in BRAF V600E negative Langerhans cell histiocytosis Blood 2014 124 10 1655 1658 10.1182/blood-2014-05-577361 24982505 \n5. Nelson DS Quispel W Badalian-Very G Van Halteren AG van den Bos C Bovee JV Tian SY Van Hummelen P Ducar M MacConaill LE Egeler RM Rollins BJ Somatic activating ARAF mutations in Langerhans cell histiocytosis Blood 2014 123 3152 3155 10.1182/blood-2013-06-511139 24652991 \n6. Berres ML Lim KP Peters T Price J Takizawa H Salmon H Idoyaga J Ruzo A Lupo PJ Hicks MJ Shih A Simko SJ Abhyankar H Chakraborty R Leboeuf M Beltrao M Lira SA Heym KM Bigley V Collin M Manz MG McClain K Merad M Allen CE BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups J Exp Med 2014 211 669 683 10.1084/jem.20130977 24638167 \n7. Von Essen S West W Sitorius M Rennard SI Complete resolution of roentgenographic changes in a patient with pulmonary histiocytosis X Chest 1990 98 765 767 10.1378/chest.98.3.765 2394160 \n8. Mogulkoc N Veral A Bishop PW Bayindir U Pickering CA Egan JJ Pulmonary Langerhans’ cell histiocytosis: radiologic resolution following smoking cessation Chest 1999 115 1452 1455 10.1378/chest.115.5.1452 10334170 \n9. Tazi A Montcelly L Bergeron A Valeyre D Battesti JP Hance AJ Relapsing nodular lesions in the course of adult pulmonary Langerhans cell histiocytosis Am J Respir Crit Care Med 1998 157 2007 2010 10.1164/ajrccm.157.6.9709026 9620939 \n10. Suri HS Yi ES Nowakowski GS Vassallo R Pulmonary langerhans cell histiocytosis Orphanet J Rare Dis 2012 7 16 10.1186/1750-1172-7-16 22429393 \n11. Carrera CJ Terai C Lotz M Curd JG Piro LD Beutler E Carson DA Potent toxicity of 2-chlorodeoxyadenosine toward human monocytes in vitro and in vivo. A novel approach to immunosuppressive therapy J Clin Invest 1990 86 1480 1488 10.1172/JCI114865 1700795 \n12. Saven A Figueroa ML Piro LD Rosenblatt JD 2-Chlorodeoxyadenosine to treat refractory histiocytosis X N Engl J Med 1993 329 734 735 10.1056/NEJM199309023291013 8102196 \n13. Stine KC Saylors RL Williams LL Becton DL 2-Chlorodeoxyadenosine (2-CDA) for the treatment of refractory or recurrent Langerhans cell histiocytosis (LCH) in pediatric patients Med Pediatr Oncol 1997 29 288 292 10.1002/(SICI)1096-911X(199710)29:4<288::AID-MPO9>3.0.CO;2-I 9251735 \n14. Saven A Burian C Cladribine activity in adult langerhans-cell histiocytosis Blood 1999 93 4125 4130 10361109 \n15. Pardanani A Phyliky RL Li CY Tefferi A 2-Chlorodeoxyadenosine therapy for disseminated Langerhans cell histiocytosis Mayo Clin Proc 2003 78 301 306 10.4065/78.3.301 12630583 \n16. Lazor R Etienne-Mastroianni B Khouatra C Tazi A Cottin V Cordier JF Progressive diffuse pulmonary Langerhans cell histiocytosis improved by cladribine chemotherapy Thorax 2009 64 274 275 10.1136/thx.2008.108944 19252036 \n17. Aerni MR Aubry MC Myers JL Vassallo R Complete remission of nodular pulmonary Langerhans cell histiocytosis lesions induced by 2-chlorodeoxyadenosine in a non-smoker Respir Med 2008 102 316 319 10.1016/j.rmed.2007.09.002 17935961 \n18. Goh NS McDonald CE MacGregor DP Pretto JJ Brodie GN Successful treatment of Langerhans cell histiocytosis with 2-chlorodeoxyadenosine Respirology 2003 8 91 94 10.1046/j.1440-1843.2003.00427.x 12856748 \n19. Lorillon G Bergeron A Detourmignies L Jouneau S Wallaert B Frija J Tazi A Cladribine is effective against cystic pulmonary Langerhans cell histiocytosis Am J Respir Crit Care Med 2012 186 930 932 10.1164/ajrccm.186.9.930 23118088 \n20. Soler P Bergeron A Kambouchner M Groussard O Brauner M Grenier P Crestani B Mal H Tazi A Battesti JP Loiseau P Valeyre D Is high-resolution computed tomography a reliable tool to predict the histopathological activity of pulmonary Langerhans cell histiocytosis? Am J Respir Crit Care Med 2000 162 264 270 10.1164/ajrccm.162.1.9906010 10903252 \n21. Krajicek BJ Ryu JH Hartman TE Lowe VJ Vassallo R Abnormal fluorodeoxyglucose PET in pulmonary Langerhans cell histiocytosis Chest 2009 135 1542 1549 10.1378/chest.08-1899 19447918 \n22. Harari S Brenot F Barberis M Simmoneau G Advanced pulmonary histiocytosis X is associated with severe pulmonary hypertension Chest 1997 112 1142 1144 9106608 \n23. Fartoukh M Humbert M Capron F Maitre S Parent F Le Gall C Sitbon O Herve P Duroux P Simonneau G Severe pulmonary hypertension in histiocytosis X Am J Respir Crit Care Med 2000 161 216 223 10.1164/ajrccm.161.1.9807024 10619823\n\n",
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"issn_linking": "1750-1172",
"issue": "9()",
"journal": "Orphanet journal of rare diseases",
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"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D017338:Cladribine; D005260:Female; D006646:Histiocytosis, Langerhans-Cell; D006801:Humans; D008171:Lung Diseases; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012907:Smoking; D016896:Treatment Outcome",
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"pmid": "25433492",
"pubdate": "2014-11-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24982505;24652991;10903252;11688843;12630583;12856748;3488004;2394160;1700795;8102196;9106608;9251735;9620939;10334170;10361109;17935961;19252036;19447918;20519626;22429393;23118088;24638167;10619823",
"title": "Effectiveness of cladribine therapy in patients with pulmonary Langerhans cell histiocytosis.",
"title_normalized": "effectiveness of cladribine therapy in patients with pulmonary langerhans cell histiocytosis"
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"abstract": "Introduction Computer tomography colonoscopy (CTC) is an increasingly prevalent procedure for the investigation of colorectal symptoms, or as a component of colorectal cancer screening. It is considered a low risk procedure, however colonic perforation is a recognized significant complication. Case Report We report the case of an 81-year-old female patient who underwent CTC after failed optical colonoscopy as part of routine colorectal cancer screening. Perforation of the rectum with surrounding pararectal air was confirmed on CTC. The patient had minimal symptoms and was treated successful non-operatively with bowel rest and antibiotics. Conclusion Perforation sustained during CTC is an uncommon complication. The incidence of perforation during CTC is still lower than that during optical colonoscopy. In the absence of significant abdominal signs and symptoms, this rare complication may be successfully managed non-operatively.",
"affiliations": "Department of Surgery, Rockhampton Hospital, Rockhampton, Australia.;Department of Surgery, Caboolture Hospital, Caboolture, Australia.",
"authors": "Zukiwskyj|Marianna|M|;Arafat|Yasser|Y|",
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"doi": "10.12688/f1000research.8242.1",
"fulltext": "\n==== Front\nF1000ResF1000ResF1000ResearchF1000Research2046-1402F1000Research London, UK 2701969610.12688/f1000research.8242.1Case ReportArticlesColon & RectumCase Report: Rectal perforation during CT colonography [version 1; referees: 2 approved]\n\nZukiwskyj Marianna a1Arafat Yasser 2\n1 Department of Surgery, Rockhampton Hospital, Rockhampton, Australia\n2 Department of Surgery, Caboolture Hospital, Caboolture, Australiaa marianna.zukiwskyj@uqconnect.edu.auAll authors contributed to the content of this manuscript. MZ and YA prepared the first draft of the manuscript. All authors were involved in the revision of the draft manuscript and have agreed to the final content.\n\n\nCompeting interests: No competing interests were disclosed.\n\n8 3 2016 2016 5 2994 3 2016 Copyright: © 2016 Zukiwskyj M and Arafat Y2016This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Introduction\n\nComputer tomography colonoscopy (CTC) is an increasingly prevalent procedure for the investigation of colorectal symptoms, or as a component of colorectal cancer screening. It is considered a low risk procedure, however colonic perforation is a recognized significant complication.\n\nCase Report\n\nWe report the case of an 81-year-old female patient who underwent CTC after failed optical colonoscopy as part of routine colorectal cancer screening. Perforation of the rectum with surrounding pararectal air was confirmed on CTC. The patient had minimal symptoms and was treated successful non-operatively with bowel rest and antibiotics.\n\nConclusion\n\nPerforation sustained during CTC is an uncommon complication. The incidence of perforation during CTC is still lower than that during optical colonoscopy. In the absence of significant abdominal signs and symptoms, this rare complication may be successfully managed non-operatively.\n\nRectal perforationCT ColonographyCTCThe author(s) declared that no grants were involved in supporting this work.\n==== Body\nIntroduction\nThe incidence of colorectal cancer worldwide has been reported as 9%\n1. It is the third most commonly diagnosed cancer worldwide\n1, and, excluding cutaneous cancers, is the mostly commonly diagnosed cancer in Australia\n2. National screening programmes are an important tool for the early detection of, and effective reduction in mortality from colorectal cancer\n2,\n3. Since its inception in 1994, computer tomography colonoscopy (CTC) has been increasingly utilized for both colorectal cancer screening and investigation of colorectal symptoms\n4. Indications for CTC include colorectal cancer screening, incomplete or failed optical colonoscopy, symptomatic or asymptomatic individuals who may have significant medical comorbidities considered high risk for optical colonoscopy. Advantages of CTC include minimal invasiveness, better patient tolerance, unlikely need for sedation, low incident of adverse events, and the occasional discovery of extra colonic pathology\n5,\n6. Colonic perforation is a significant albeit rare complication of CTC\n7.\n\nCase report\nAn 81-year-old Caucasian female underwent a CTC for colorectal cancer screening. She tested positive to a faecal occult blood stool test, and had experienced longstanding, infrequent, minimal and painless bright red rectal bleeding for a period of over twenty years. She gave no history of loss of weight, change in bowel habits, or family history of colorectal cancer. Past medical history was significant for atrial fibrillation requiring anticoagulation, diverticular disease and a hysterectomy 20 years prior with subsequent radiotherapy to the pelvis as histology had confirmed uterine cancer. In the last twenty years, four screening colonoscopies had been carried out, the last five years prior, and whilst clear of polyps, was significant for an asymptomatic narrowed segment of distal sigmoid which had to be traversed with a paediatric colonoscope. The patient underwent a CTC as, she had, earlier in the year, undergone a failed optical colonoscopy. CTC was carried out with manual air insufflation via a rectal soft tip Foley catheter until the patient felt slight discomfort, at which point a scout AP film was taken to ensure adequate bowel distension. It proceeded without complications. The official report noted a localized contained perforation demonstrated around the rectum (\nFigure 1,\nFigure 2). There was extensive diverticular disease demonstrated throughout the sigmoid colon, which was markedly narrowed throughout in keeping with stricture formation, which would be consistent with previous diverticulitis or radiation treatment (\nFigure 3). Further assessment of that region was difficult. The remainder of the large bowel had achieved excellent distension.\n\nFigure 1. CT colonography depicting contained rectal perforation.\nThe Foley catheter tip is seen in rectum as well as localized peri-rectal air.\n\nFigure 2. CT colonography coronal view depicting rectal perforation.\nThe Foley catheter is seen within the rectum as well as peri-rectal air.\n\nFigure 3. CT colonography depicting extensive diverticular disease and narrowing of the distal sigmoid.\nThe patient was admitted to the ward and commenced on prophylactic antibiotics (Tazocin 4.5g tds), and bowel rest. She complained of mild discomfort in the lower abdominal region, and had a soft abdomen with no evidence of peritonism. During the first two days of admission, she passed a small amount of blood clot per rectum. She was discharged on day five of admission, with no abdominal signs, having undergone an MRI which confirmed no peri-rectal collection and identified no obvious perforation. A further optical colonoscopy was attempted two months later, which failed to enter the sigmoid colon, citing severe diverticular disease as the reason. The patient currently remains asymptomatic.\n\nDiscussion\nCTC is widely considered as a minimally invasive technique with a low rate of adverse events. However, various complications arising from CTC have been reported in the literature. The most significant of these is colonic perforation. Since the inception of CTC, various publications have reported rates of perforation ranging from 0.009 to 0.1%\n4,\n6,\n7. This is in comparison to the rate of perforation at optical colonoscopy, which has been reported as ranging from 0.032% to 0.196%\n4, however is commonly quoted as 0.05% to 0.1%. The first meta-analysis on the rate of colonic perforated at CTC was conducted in 2014 by Bellini\net al., in which an overall perforation rate of 0.04% was reported\n7. The majority of the perforations occurred in the sigmoid colon at 41%, with rectal perforations accounting for 22.2%\n7. When the perforation rate was adjusted for symptomatic or asymptomatic individuals (those for whom CTC was purely a screening procedure), the perforation rate of symptomatic patients was 0.08%, compared with asymptomatic patients at 0.02%, and the odds ratio was reported as 19.2\n7. Various factors have been considered as increasing the likelihood of perforation. The use of rigid rectal catheters, CTC shortly after optical colonoscopy with biopsies, bowel containing inguinal herniae, a history of diverticular disease, CTC with manual insufflation of gas, and obstructing lesions have all been described as contributing to perforations in the literature\n4,\n7–\n9. However, given the rarity of perforations, the degree of contribution of each of the factors may vary amongst the current reviews.\n\nOnce a CTC perforation is confirmed, management may include operative and non-operative measures. The majority of reported CTC perforations have been managed non-operatively. Patients clinically suitable for non-operative management receive IV fluids, antibiotics and bowel rest. Bellini\net al. reports that 68% of perforated patients were successful managed non-operatively\n7.\n\nIn this case, our patient, whilst asymptomatic of colorectal symptoms, did have several risk factors for perforation. There was a history of diverticular disease and of a narrowing in the region of the sigmoid, which did not require intervention at the time of her previous colonoscopy five years prior. Manual rather than automatic insufflation was employed. A soft tipped catheter was employed, and whilst this does lessen the risk of traumatic injury, it does not negate it, as the integrity of the rectal mucosa as well as technique of insertion are factors. As the diverticular disease and stricture extended to the distal sigmoid, it could be inferred that, in this case, the site more likely at risk of perforation would be rectal, rather than sigmoid. The most recent optical colonoscopy had been six months prior and so was unlikely to be a factor.\n\nConclusion\nColonoscopy is considered the gold standard for intraluminal evaluation of the colon in a variety of settings. CT colonography is an accepted alternative to optical colonoscopy in the event of failed endoscopic evaluation, as a screening procedure and in high risk candidates. The incidence of perforation at CTC is low. Bellini\net al. reported fewer than 40 cases in their meta-analysis. As the majority of CTC perforations are managed non-operatively, the rate of CTC related surgical intervention was 0.008%\n7. Whilst the rate of perforation is accepted as lower than that of optical colonoscopy, the more significant advantage seems to be the much higher incidence of successful non-operative management of these patients\n7,\n10.\n\nConsent\nWritten informed consent for publication of their clinical details and clinical images was obtained from the patient.\n\n10.5256/f1000research.8864.r12800Referee response for version 1 Singh Baljit 1Referee\n1 Department of Colorectal Surgery, University Hospitals of Leicester NHS Trust, Leicester, UK\nCompeting interests: No competing interests were disclosed.\n\n21 3 2016 Version 1recommendationapproveA well written and interesting report. This highlights whilst this is a common procedure there is a small associated risk. However the authors suggest that in most cases this can be managed conservatively.\n\nI have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.\n\n10.5256/f1000research.8864.r12798Referee response for version 1 Winter Trevor 1Referee\n1 Kaiser Permanente, Bakersfield, CA, USA\nCompeting interests: No competing interests were disclosed.\n\n21 3 2016 Version 1recommendationapproveComputer tomography colography (CTC) has been used since 1994 for colorectal screening and investigation of colorectal symptoms mainly in patients who have had incomplete optical colonoscopy, or who have significant medial comorbidities considered at high risk for optical colonoscopy. CTC is generally considered a minimally invasive procedure. \n\nThis paper is a useful addition to the literature, highlighting the low complication rate of CTC, with a perforation rate of 0.009% to 0.1%, compared to the complication rate of optical colonoscopy of 0.032% to 0.19%. The paper also highlights the factors associated with perforation as use of rigid rectal catheters, manual insufflation of gas CTC shortly after optical colonoscopy with biopsies, inguinal herniae, diverticular disease, and obstructing lesion. The authors comment that the majority of reported CTC perforations have been managed conservatively with IV fluids, antibiotics and bowel rest.\n\nAlthough colonoscopy is still considered the gold standard, CTC is a valuable alternative in patients with incomplete optical colonoscopy or are considered to be of high risk for optical colonoscopy due to medical comorbidities.\n\nI have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.\n==== Refs\n1 \nHaggar FA Boushey RP :\nColorectal cancer epidemiology: incidence, mortality, survival, and risk factors. \nClin Colon Rectal Surg. \n2009 ;22 (4 ):191 –7 .\n10.1055/s-0029-1242458 \n\n21037809 \n2 \nNational Health and Medical Research Council :\nClinical practice guidelines for the prevention, early detection and management of colorectal cancer: a guide for general practitioners. \nCancer Council Australia. \n2008 \nReference Source\n\n3 \nLevin B Lieberman DA McFarland B :\nScreening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. \nGastroenterology. \n2008 ;134 (5 ):1570 –1595 .\n10.1053/j.gastro.2008.02.002 \n18384785 \n4 \nIafrate F Iussich G Correale L :\nAdverse events of computed tomography colonography: an Italian National Survey. \nDig Liver Dis. \n2013 ;45 (8 ):645 –50 .\n10.1016/j.dld.2013.02.020 \n23643567 \n5 \nFlak B Forster BB Pezim ME :\nCT colonography: A new technique for colorectal cancer screening. \nBCMJ. \n2008 ;50 (4 ):206 –11 .\nReference Source\n\n6 \nYee J Weinstein S Morgan T :\nAdvances in CT Colonography for Colorectal Cancer Screening and Diagnosis. \nJ Cancer. \n2013 ;4 (3 ):200 –9 .\n10.7150/jca.5858 \n\n23459511 \n7 \nBellini D Rengo M De Cecco CN :\nPerforation rate in CT colonography: a systematic review of the literature and meta-analysis. \nEur Radiol. \n2014 ;24 (7 ):1487 –96 .\n10.1007/s00330-014-3190-1 \n24816935 \n8 \nBaccaro LM Markelov A Wilhelm J :\nPneumoperitoneum after virtual colonoscopy: causes, risk factors, and management. \nAm Surg. \n2014 ;80 (6 ):549 –54 .\n24887791 \n9 \nAtalla MA Rozen WM Niewiadomski OD :\nRisk factors for colonic perforation after screening computed tomographic colonography: a multicentre analysis and review of the literature. \nJ Med Screen. \n2010 ;17 (2 ):99 –102 .\n10.1258/jms.2010.010042 \n20660440 \n10 \nHamdani U Naeem R Haider F :\nRisk factors for colonoscopic perforation: a population-based study of 80118 cases. \nWorld J Gastroenterol. \n2013 ;19 (23 ):3596 –601 .\n10.3748/wjg.v19.i23.3596 \n\n23801860\n\n",
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"issue": "5()",
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"keywords": "CT Colonography; CTC; Rectal perforation",
"medline_ta": "F1000Res",
"mesh_terms": null,
"nlm_unique_id": "101594320",
"other_id": null,
"pages": "299",
"pmc": null,
"pmid": "27019696",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": "23643567;21037809;24887791;23459511;23801860;18384785;20660440;24816935",
"title": "Case Report: Rectal perforation during CT colonography.",
"title_normalized": "case report rectal perforation during ct colonography"
} | [
{
"companynumb": "AU-ALSI-201800553",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OXYGEN"
},
"drugadditional": null,
"drugad... |
{
"abstract": "Ascending aortic pseudoaneurysm is a rare complication after HT. Surgery is the most conventional management, but in some patients, it is risky. We report the case of a ten-year-old child who underwent HT and developed an ascending aortic pseudoaneurysm in the aortic anastomosis. He was successfully treated with two covered stents through endovascular management. Endovascular therapy is an alternative management in high-risk patients. To our knowledge, this is the first report about endovascular therapy of an AAP after HT in a pediatric patient.",
"affiliations": "Instituto Nacional Cardiovascular \"Carlos Alberto Peschiera Carrillo\", Lima, Peru.;Instituto Nacional Cardiovascular \"Carlos Alberto Peschiera Carrillo\", Lima, Peru.;Medical School, Universidad Nacional Mayor de San Marcos, Lima, Peru.;Medical School, Universidad Nacional Mayor de San Marcos, Lima, Peru.",
"authors": "Skrabonja-Crespo|Antonio|A|https://orcid.org/0000-0002-5435-2146;Chavarri-Velarde|Fernando|F|https://orcid.org/0000-0003-2524-0003;Pinto-Salinas|Miguel|M|https://orcid.org/0000-0001-5789-3960;Tauma-Arrué|Astrid|A|https://orcid.org/0000-0003-2915-2158",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.13958",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "25(3)",
"journal": "Pediatric transplantation",
"keywords": "aneurysm; aorta; heart transplantation; pediatrics; stents",
"medline_ta": "Pediatr Transplant",
"mesh_terms": null,
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "e13958",
"pmc": null,
"pmid": "33333620",
"pubdate": "2021-05",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Percutaneous endovascular management of ascending aortic pseudoaneurysm after heart transplantation in a pediatric patient.",
"title_normalized": "percutaneous endovascular management of ascending aortic pseudoaneurysm after heart transplantation in a pediatric patient"
} | [
{
"companynumb": "PE-TEVA-2021-PE-1924505",
"fulfillexpeditecriteria": "1",
"occurcountry": "PE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "3"... |
{
"abstract": "We report a case of invasive strongyloidiasis in a patient from the French Antilles who had been living in France for many years, with no history of immunosuppression, and who was hospitalised in the intensive care unit for septic shock with multimicrobial hypoxaemia pneumonia and exudative enteropathy. Initiation of systemic corticosteroid therapy for septic shock seems to have precipitated onset of the parasitic infection, with recurrence of hypoxaemic pneumonia complicated by hypoxic cardiac arrest. The diagnosis was confirmed after roundworm larvae were found on bronchoalveolar lavage. Treatment with ivermectin was initiated, but the patient died in a context of postanoxic encephalopathy.",
"affiliations": "Intensive Care Unit, University Hospital of Besançon, Besançon, France.;Parasitology Unit, University Hospital of Besançon, Besançon, France.;Intensive Care Unit, University Hospital of Besançon, Besançon, France EA3920 and SFR FED 4234.;Intensive Care Unit, University Hospital of Besançon, Besançon, France EA3920 and SFR FED 4234.",
"authors": "Montini|Florent|F|;Grenouillet|Frederic|F|;Capellier|Gilles|G|;Piton|Gaël|G|",
"chemical_list": "D000305:Adrenal Cortex Hormones",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D017809:Fatal Outcome; D006323:Heart Arrest; D006801:Humans; D007411:Intestinal Diseases, Parasitic; D008297:Male; D008875:Middle Aged; D018410:Pneumonia, Bacterial; D012008:Recurrence; D012772:Shock, Septic; D013322:Strongyloidiasis",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "25819827",
"pubdate": "2015-03-27",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15337730;23108609;22187279;20545724;24269075;19317285;21246247;20733481;20172622;22855744;17940124",
"title": "Strongyloidiasis: an unusual cause of septic shock with pneumonia and enteropathy in western countries.",
"title_normalized": "strongyloidiasis an unusual cause of septic shock with pneumonia and enteropathy in western countries"
} | [
{
"companynumb": "FR-PFIZER INC-2015131137",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROCORTISONE"
},
"drugadditional": null,
... |
{
"abstract": "Philadelphia chromosome positive de novoacute myeloid leukemia (AML)is a rare disease with reported incidence of less than 1% of newly diagnosed cases of AML. Outcome of the disease is poor, owing to its resistance to conventional chemotherapy and variable response to imatinib besylate. We report a case of 24-year man who reported to our unit in November 2014 and was treated with conventional induction and consolidation chemotherapy with imatinib besylate. He achieved complete remission after induction chemotherapy and remained in remission. His cytogenetics also reverted to normal after consolidation chemotherapy. He relapsed after 3 months of maintenance imatinib besylate.",
"affiliations": "Department of Oncology, Allama Iqbal Medical College and Jinnah Hospital, Lahore.;Department of Oncology, Allama Iqbal Medical College and Jinnah Hospital, Lahore.;Department of Oncology, Allama Iqbal Medical College and Jinnah Hospital, Lahore.;Department of Oncology, Allama Iqbal Medical College and Jinnah Hospital, Lahore.",
"authors": "Quraishi|Arif Moin|AM|;Akram|Muhammad|M|;Saeed|Sarah|S|;Tahir|Muhammad|M|",
"chemical_list": "D000068877:Imatinib Mesylate; D003630:Daunorubicin",
"country": "Pakistan",
"delete": false,
"doi": "213",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1022-386X",
"issue": "26(11)",
"journal": "Journal of the College of Physicians and Surgeons--Pakistan : JCPSP",
"keywords": null,
"medline_ta": "J Coll Physicians Surg Pak",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D003630:Daunorubicin; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D010677:Philadelphia Chromosome; D035583:Rare Diseases; D012008:Recurrence; D012074:Remission Induction; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9606447",
"other_id": null,
"pages": "100-102",
"pmc": null,
"pmid": "28666495",
"pubdate": "2016-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Philadelphia Chromosome Positive de novo Acute Myeloid Leukemia.",
"title_normalized": "philadelphia chromosome positive de novo acute myeloid leukemia"
} | [
{
"companynumb": "PK-FRESENIUS KABI-FK201708521",
"fulfillexpeditecriteria": "1",
"occurcountry": "PK",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DAUNORUBICIN"
},
"drugadditional": null,... |
{
"abstract": "Chemotherapy dosing in neonates represents a major clinical challenge because of a lack of clinical pharmacology information in this patient population. In this study, we investigate the use of cisplatin dose adaptation based on therapeutic drug monitoring in a 2-week-old neonate with localized hepatoblastoma.\n\n\n\nCisplatin concentrations were determined in plasma and ultrafiltrate samples collected on each of six cycles of a monotherapy regimen, beginning with a dose of 1.6 mg/kg at 16 days of age. Pharmacokinetic data were analyzed to generate clearance (CL) and area under the curve (AUC0-∞) for each administration. Toxicity and clinical response were monitored.\n\n\n\nThe first cisplatin dose (1.6 mg/kg) resulted in an AUC0-∞ of 535 µg/mL · min, was well tolerated and associated with a good response. This AUC was, therefore, considered as an appropriate target for this patient. Increases in cisplatin CL were observed across consecutive treatment cycles, and, therefore, dose was gradually increased to finally reach 2.5 mg/kg on the sixth cycle. Treatment was well tolerated over the six courses and resulted in a good response, with the patient remaining in remission at 15 months. Cisplatin CL was significantly correlated to age (p = 0.013) and weight (p = 0.013).\n\n\n\nOur study provides useful data on the pharmacokinetics of cisplatin monotherapy in neonates treated within the first few weeks of life. These data provide a reference point to support clinicians in determining appropriate dosing regimens for neonates and support the implementation of therapeutic drug monitoring in such challenging patients.",
"affiliations": "Institut Claudius Regaud, IUCT-Oncopole, 1 Avenue Irène Joliot Curie, 31059, Toulouse Cedex 9, France. thomas.fabienne@iuct-oncopole.fr.;Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.;CHU Limoges, Pharmacologie, Toxicologie et Pharmacovigilance, Limoges, France.;Institut Claudius Regaud, IUCT-Oncopole, 1 Avenue Irène Joliot Curie, 31059, Toulouse Cedex 9, France.;CHU Limoges, Pharmacologie, Toxicologie et Pharmacovigilance, Limoges, France.;Department of Oncology for Children and Adolescents, Gustave Roussy Cancer Campus, Villejuif, France.;Institut Claudius Regaud, IUCT-Oncopole, 1 Avenue Irène Joliot Curie, 31059, Toulouse Cedex 9, France.;Unité d'Onco-Hématologie Pédiatrique, Hôpital Mère-Enfant, CHU Limoges, Limoges, France.",
"authors": "Thomas|Fabienne|F|0000-0001-9886-412X;Veal|Gareth J|GJ|0000-0002-1897-8678;El Balkhi|Souleiman|S|0000-0002-9743-5603;Lafont|Thierry|T|;Picard|Nicolas|N|0000-0001-8460-903X;Brugières|Laurence|L|0000-0002-7798-6651;Chatelut|Etienne|E|0000-0002-7740-9096;Piguet|Christophe|C|",
"chemical_list": "D000970:Antineoplastic Agents; D002945:Cisplatin",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00280-018-3625-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0344-5704",
"issue": "82(2)",
"journal": "Cancer chemotherapy and pharmacology",
"keywords": "Cisplatin; Hepatoblastoma; Neonate; Pharmacokinetics; SIOPEL",
"medline_ta": "Cancer Chemother Pharmacol",
"mesh_terms": "D000970:Antineoplastic Agents; D002945:Cisplatin; D016903:Drug Monitoring; D005260:Female; D018197:Hepatoblastoma; D006801:Humans; D007231:Infant, Newborn; D008113:Liver Neoplasms",
"nlm_unique_id": "7806519",
"other_id": null,
"pages": "361-365",
"pmc": null,
"pmid": "29922990",
"pubdate": "2018-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Therapeutic drug monitoring and dose adaptation of cisplatin in a newborn with hepatoblastoma: a case report.",
"title_normalized": "therapeutic drug monitoring and dose adaptation of cisplatin in a newborn with hepatoblastoma a case report"
} | [
{
"companynumb": "FR-MYLANLABS-2018M1061378",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "The diagnosis of pseudodementia may be difficult in a patient with a history of major depressive disorder. Clinical case history. A 70-year-old man with a history of major depressive disorder, in remission for 3 years, presented with confusion, agitation and cognitive disorder. The differential diagnosis included depression with pseudodementia, drug-induced dementia or Alzheimer disease. Mild cognitive improvement was noted after discontinuation of simvastatin. After 9 months of treatment for depression, the patient had remission that was sustained for >1 year, with mild residual difficulty remembering words of songs. The differential diagnosis of dementia includes major depressive disorder and adverse events from simvastatin.",
"affiliations": "Department of Psychiatry, Cooper Medical School of Rowan University, University of Medicine and Dentistry State of New Jersey/School of Osteopathic Medicine, Camden, New Jersey, USA. tobe@comcast.net",
"authors": "Tobe|Edward|E|",
"chemical_list": "D000928:Antidepressive Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2012()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D000544:Alzheimer Disease; D000928:Antidepressive Agents; D003704:Dementia; D003865:Depressive Disorder, Major; D003937:Diagnosis, Differential; D005162:Factitious Disorders; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008297:Male; D019821:Simvastatin",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "23242083",
"pubdate": "2012-12-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10366636;3889224;20430909;21562301;1353322;22305977",
"title": "Pseudodementia caused by severe depression.",
"title_normalized": "pseudodementia caused by severe depression"
} | [
{
"companynumb": "US-RANBAXY-2013US-65460",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SIMVASTATIN"
},
"drugadditional": null,
... |
{
"abstract": "Hodgkin lymphoma became to be a curative disease. The standard treatment has been established for Hodgkin lymphoma, but its optimization still is explored. Risk stratification is critical in terms of optimization. The favorable patients would be treated with less toxic regimens. PET results are now used to evaluate the treatment response, and recently interim PET has been shown as a good predictor of prognosis. Interim PET is now incorporated into the treatment strategy of Hodgkin lymphoma in clinical trials. Molecular targeting drugs have been developed. Brentuximab vedotin, a kind of antibody drug conjugate, showed favorable clinical results for relapsed Hodgkin lymphoma.",
"affiliations": null,
"authors": "Tokunaga|Takashi|T|;Nagai|Hirokazu|H|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0047-1852",
"issue": "72(3)",
"journal": "Nihon rinsho. Japanese journal of clinical medicine",
"keywords": null,
"medline_ta": "Nihon Rinsho",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D059248:Chemoradiotherapy; D006689:Hodgkin Disease; D006801:Humans",
"nlm_unique_id": "0420546",
"other_id": null,
"pages": "538-41",
"pmc": null,
"pmid": "24724416",
"pubdate": "2014-03",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Treatment of Hodgkin lymphoma.",
"title_normalized": "treatment of hodgkin lymphoma"
} | [
{
"companynumb": "CL-JNJFOC-20190902152",
"fulfillexpeditecriteria": "1",
"occurcountry": "CL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": n... |
{
"abstract": "Cytomegalovirus encephalitis is a challenging life-threatening complication following hematopoietic stem cell transplantation for which medical treatment is usually ineffective or toxic. However, in recent years, adoptive T-cell therapy has been reported to provide a significant chance of cure for patients with viral infections. Herein, two cases of pediatric patients successfully treated with third-party donor-derived virus-specific T cells for CMV meningoencephalitis are reported.",
"affiliations": "Department of Pediatric Hematology and Oncology, Hospital Universitario Vall d'Hebron, Barcelona, Spain.;Histocompatibility and Immunogenetics Laboratory, Banc de Sang I Teixits, Cell Therapy Unit, Banc de Sang i Teixits, Barcelona, Spain.;IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.;Banc de Sang i Teixits, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain.;Banc de Sang i Teixits, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain.;Banc de Sang i Teixits, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain.;Department of Pediatric Hematology and Oncology, Hospital Universitario Vall d'Hebron, Barcelona, Spain.",
"authors": "Alonso|Laura|L|0000-0002-7835-1594;Rudilla|Francesc|F|;Gimeno|Ramón|R|;Codinach|Margarita|M|;Blanco|Margarita|M|;Querol|Sergio|S|;Diaz de Heredia|Cristina|C|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.13584",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "23(8)",
"journal": "Pediatric transplantation",
"keywords": "CMV; encephalitis; hematopoietic stem cell transplant; virus-specific T cells",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D002648:Child; D003586:Cytomegalovirus Infections; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016219:Immunotherapy, Adoptive; D007223:Infant; D008297:Male; D008590:Meningoencephalitis; D011183:Postoperative Complications; D012074:Remission Induction",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "e13584",
"pmc": null,
"pmid": "31556188",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment of post-transplant CMV meningoencephalitis with third-party CMV virus-specific T cells: Lessons learned.",
"title_normalized": "successful treatment of post transplant cmv meningoencephalitis with third party cmv virus specific t cells lessons learned"
} | [
{
"companynumb": "PHHY2019ES226172",
"fulfillexpeditecriteria": "2",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FOSCARNET"
},
"drugadditional": null,
"druga... |
{
"abstract": "Treatment adaptation after hepatitis B virus (HBV) treatment failure relies on genotypic resistance testing. However, the results of such tests are not always consistent with treatment response. These discrepancies may be due to differences in resistance levels between isolates with the same genotypic resistance testing profiles. We explored this hypothesis by investigating six cases of entecavir treatment failure with an integrative strategy combining genotypic and phenotypic resistance testing, medical record review and therapeutic drug monitoring. Among isolates with genotypic reduced susceptibility to entecavir, one displayed a higher level of resistance to entecavir (mean fold change in entecavir IC50 of 1 508 ± 531 vs. 318 ± 53, p = 0.008). This isolate harbored a substitution (rt250L) at a position reported to be associated with resistance (rt250V). Reversion to wild-type amino acid at this position partially restored susceptibility to entecavir, confirming that the rt250L mutation was responsible for the high level of resistance to entecavir. This is the first description of entecavir treatment failure associated with selection of the rt250L mutation without other entecavir resistance mutations. One isolate with genotypic resistance to entecavir, harboring the rt173L mutation, displayed a lower level of resistance than the other, harboring the rt202G mutation (mean fold change of 323 ± 124 vs. 6 036 ± 2 100, p = 0.20). These results suggest that isolates harboring the rt250L mutations should be considered resistant to entecavir, whereas isolates harboring the rt173L mutations should be considered to display reduced susceptibility to entecavir. An integrative approach to antiviral drug resistance in HBV would provide a more accurate assessment of entecavir treatment failures and help to improve the accuracy of genotypic testing algorithms.",
"affiliations": "INSERM U1259, Université de Tours et CHRU de Tours, France; Service de Bactériologie-Virologie-Hygiène, CHRU de Tours, France. Electronic address: Julien.marlet@univ-tours.fr.;INSERM U1259, Université de Tours et CHRU de Tours, France; Service de Bactériologie-Virologie-Hygiène, CHRU de Tours, France.;INSERM U1259, Université de Tours et CHRU de Tours, France.;INSERM U1259, Université de Tours et CHRU de Tours, France.;INSERM U1259, Université de Tours et CHRU de Tours, France.;INSERM U1259, Université de Tours et CHRU de Tours, France.;Laboratoire de Biochimie, CHR d'Orléans, France.;Service d'Hépato-gastroentérologie, CHRU de Tours, France.;Service d'Hépato-gastroentérologie, CHRU de Tours, France.;Service d'Hépato-gastroentérologie, CHR d'Orléans, France.;Service de Médecine Interne et Maladies Infectieuses, CHRU de Tours, France.;Laboratoire de Biologie Médicale, CH de Bourges, France.;INSERM U1259, Université de Tours et CHRU de Tours, France; Service de Bactériologie-Virologie-Hygiène, CHRU de Tours, France.;INSERM U1259, Université de Tours et CHRU de Tours, France; Service de Bactériologie-Virologie-Hygiène, CHRU de Tours, France.",
"authors": "Marlet|Julien|J|;Lier|Clément|C|;Roch|Emmanuelle|E|;Maugey|Morgan|M|;Moreau|Alain|A|;Combe|Benjamin|B|;Lefeuvre|Sandrine|S|;d'Alteroche|Louis|L|;Barbereau|Didier|D|;Causse|Xavier|X|;Bastides|Frédéric|F|;Bachelier|Marie-Nadege|MN|;Brand|Denys|D|;Gaudy-Graffin|Catherine|C|",
"chemical_list": "D000998:Antiviral Agents; D004279:DNA, Viral; C413685:entecavir; D006147:Guanine",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.antiviral.2020.104869",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0166-3542",
"issue": "181()",
"journal": "Antiviral research",
"keywords": "Antiviral; Entecavir; HBV; Phenotypic; Polymerase; Resistance",
"medline_ta": "Antiviral Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D000998:Antiviral Agents; D004279:DNA, Viral; D016903:Drug Monitoring; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D006147:Guanine; D006515:Hepatitis B virus; D019694:Hepatitis B, Chronic; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D012189:Retrospective Studies; D017211:Treatment Failure",
"nlm_unique_id": "8109699",
"other_id": null,
"pages": "104869",
"pmc": null,
"pmid": "32735901",
"pubdate": "2020-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Revisiting HBV resistance to entecavir with a phenotypic approach.",
"title_normalized": "revisiting hbv resistance to entecavir with a phenotypic approach"
} | [
{
"companynumb": "FR-GLAXOSMITHKLINE-FR2020GSK157651",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
"drugadditional": nul... |
{
"abstract": "Many changes associated with bariatric surgery have the potential to affect warfarin dosing; yet current literature includes little data describing this phenomenon. Investigating this relationship may allow for determination of post-bariatric surgery warfarin dosing using stable pre-operative dosing levels. A retrospective chart review was completed for 10 patients stabilized on chronic warfarin therapy who underwent bariatric surgery. Data collection consisted of the following: warfarin requirement in mg/week, time in target range (TTR), creatinine, liver function, diarrhoea, medication changes, diet, and signs of bleeding and/or thrombosis. Three study patients underwent laparoscopic adjustable gastric banding procedures and seven patients underwent Roux-en-Y gastric bypass. The average (standard deviation) weekly warfarin dose required in the immediate post-operative interval was 64% (25%) of baseline dosing, corresponding to a TTR of 48%. At 6 months, patients required 85% (19%) of baseline weekly dosing, with TTR of 53.4%. At 1 year, dosing was 90% (16%) of baseline with TTR of 63.5%. Patients underwent medication changes as well as transient bouts of diarrhoea. Two patients suffered unspecified haemorrhages of the gastrointestinal tract (international normalized ratio [INR] = 2.3 and 9.8). This patient set demonstrated an initial drop in warfarin requirement, followed by escalating dosing trends that became more predictable as patients were farther out from procedure.",
"affiliations": "Department of Pharmacy, Methodist Hospital, St. Louis Park, MN, USA.",
"authors": "Schullo-Feulner|A M|AM|;Stoecker|Z|Z|;Brown|G A|GA|;Schneider|J|J|;Jones|T A|TA|;Burnett|B|B|",
"chemical_list": "D000925:Anticoagulants; D014859:Warfarin",
"country": "England",
"delete": false,
"doi": "10.1111/cob.12046",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1758-8103",
"issue": "4(2)",
"journal": "Clinical obesity",
"keywords": "Bariatric; INR; surgery; warfarin",
"medline_ta": "Clin Obes",
"mesh_terms": "D000328:Adult; D000925:Anticoagulants; D050110:Bariatric Surgery; D001777:Blood Coagulation; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D014859:Warfarin",
"nlm_unique_id": "101560587",
"other_id": null,
"pages": "108-15",
"pmc": null,
"pmid": "25826733",
"pubdate": "2014-04",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Warfarin dosing after bariatric surgery: a retrospective study of 10 patients previously stable on chronic warfarin therapy.",
"title_normalized": "warfarin dosing after bariatric surgery a retrospective study of 10 patients previously stable on chronic warfarin therapy"
} | [
{
"companynumb": "PHHY2015US116700",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": null,
"drugad... |
{
"abstract": "Portal hypertension is a predictor of liver-related clinical events and mortality in patients with hepatitis C and cirrhosis. The effect of interferon-free hepatitis C treatment on portal pressure is unknown. Fifty patients with Child-Pugh-Turcotte (CPT) A and B cirrhosis and portal hypertension (hepatic venous pressure gradient [HVPG] >6 mm Hg) were randomized to receive 48 weeks of open-label sofosbuvir plus ribavirin at Day 1 or after a 24-week observation period. The primary endpoint was sustained virologic response 12 weeks after therapy (SVR12) in patients who received ≥1 dose of treatment. Secondary endpoints included changes in HVPG, laboratory parameters, and MELD and CPT scores. A subset of patients was followed 48 weeks posttreatment to determine late changes in HVPG. SVR12 occurred in 72% of patients (33/46). In the 37 patients with paired HVPG measurements at baseline and the end of treatment, mean HVPG decreased by -1.0 (SD 3.97) mm Hg. Nine patients (24%) had ≥20% decreases in HVPG during treatment. Among 39 patients with pretreatment HVPG ≥12 mm Hg, 27 (69%) achieved SVR12. Four of the 33 (12%) patients with baseline HVPG ≥12 mm Hg had HVPG <12 mm Hg at the end of treatment. Of nine patients with pretreatment HVPG ≥12 mm Hg who achieved SVR12 and completed 48 weeks of follow-up, eight (89%) had a ≥20% reduction in HVPG, and three reduced their pressure to <12 mm Hg. Patients with chronic HCV and compensated or decompensated cirrhosis who achieve SVR can have clinically meaningful reductions in HVPG at long-term follow-up. (EudraCT 2012-002457-29).",
"affiliations": "Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.;University of Colorado Denver, Aurora, Colorado, USA.;Hospital U. Puerta de Hierro, CIBEREHD, Universidad Autonoma, Madrid, Spain.;Royal Prince Alfred Hospital, Centenary Research Institute, University of Sydney, Sydney, NSW, Australia.;Liver Unit, Hospital Clinic, IDIBAPS, CIBEREHD, Barcelona, Spain.;Gilead Sciences, Inc., Foster City, California, USA.;Gilead Sciences, Inc., Foster City, California, USA.;Gilead Sciences, Inc., Foster City, California, USA.;Gilead Sciences, Inc., Foster City, California, USA.;Intermountain Medical Center, Murray, Utah, USA.;University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.;Hôpital Beaujon, Department of Hepatology, AP-HP, INSERM UMR1149 and University Paris-Diderot, Clichy, France.;University of Auckland, Auckland, New Zealand.;Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.;Liver Unit, Hospital Clinic, IDIBAPS, CIBEREHD, Barcelona, Spain.",
"authors": "Afdhal|N|N|;Everson|G T|GT|;Calleja|J L|JL|;McCaughan|G W|GW|;Bosch|J|J|;Brainard|D M|DM|;McHutchison|J G|JG|;De-Oertel|S|S|;An|D|D|;Charlton|M|M|;Reddy|K R|KR|0000-0002-4898-7778;Asselah|T|T|;Gane|E|E|;Curry|M P|MP|;Forns|X|X|",
"chemical_list": "D000998:Antiviral Agents; D012367:RNA, Viral",
"country": "England",
"delete": false,
"doi": "10.1111/jvh.12706",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1352-0504",
"issue": "24(10)",
"journal": "Journal of viral hepatitis",
"keywords": "advanced liver disease; cirrhosis; decompensated cirrhosis; direct-acting antivirals; hepatic venous pressure gradient; portal hypertension",
"medline_ta": "J Viral Hepat",
"mesh_terms": "D000328:Adult; D000368:Aged; D000998:Antiviral Agents; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus; D006503:Hepatic Veins; D006526:Hepatitis C; D006801:Humans; D006975:Hypertension, Portal; D008103:Liver Cirrhosis; D008297:Male; D008875:Middle Aged; D017082:Portal Pressure; D012367:RNA, Viral; D000072230:Sustained Virologic Response; D013997:Time Factors; D019562:Viral Load",
"nlm_unique_id": "9435672",
"other_id": null,
"pages": "823-831",
"pmc": null,
"pmid": "28295923",
"pubdate": "2017-10",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Effect of viral suppression on hepatic venous pressure gradient in hepatitis C with cirrhosis and portal hypertension.",
"title_normalized": "effect of viral suppression on hepatic venous pressure gradient in hepatitis c with cirrhosis and portal hypertension"
} | [
{
"companynumb": "US-KADMON PHARMACEUTICALS, LLC-KAD201710-001106",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SOFOSBUVIR"
},
"drugadd... |
{
"abstract": "Nonsteroidal anti-inflammatory drugs (NSAIDs) are a major cause of hypersensitivity reactions. Several distinct clinical syndromes are described regarding NSAID hypersensitivity. Such a reaction is generally caused by a non-immunological mechanism. In susceptible patients, COX-1 inhibition leads to an imbalance in lipid mediators such as leukotrienes and prostaglandins. It is essential to distinguish multiple nonspecific NSAID hypersensitivity from single NSAID hypersensitivity, since the management of these respective syndromes is essentially different. This review provides an overview on all the aspects of NSAID hypersensitivity reactions, from pathophysiology to clinical symptoms, leading practical recommendations.",
"affiliations": "Department of Internal Medicine, section Allergy and Clinical Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands.",
"authors": "Hermans|M A W|MAW|;Otten|R|R|;Karim|A F|AF|;van Maaren|M S|MS|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-2977",
"issue": "76(2)",
"journal": "The Netherlands journal of medicine",
"keywords": null,
"medline_ta": "Neth J Med",
"mesh_terms": "D000707:Anaphylaxis; D000799:Angioedema; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D003888:Desensitization, Immunologic; D003875:Drug Eruptions; D004342:Drug Hypersensitivity; D057915:Drug Substitution; D006801:Humans; D012140:Respiratory Tract Diseases; D014581:Urticaria",
"nlm_unique_id": "0356133",
"other_id": null,
"pages": "52-59",
"pmc": null,
"pmid": "29515006",
"pubdate": "2018-03",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Nonsteroidal anti-inflammatory drug hypersensitivity: not always an allergy!",
"title_normalized": "nonsteroidal anti inflammatory drug hypersensitivity not always an allergy"
} | [
{
"companynumb": "NL-MYLANLABS-2018M1050864",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nAnthracyclines (ANTs) are a class of active antineoplastic agents with topoisomerase-interacting activity that are considered the most active agents for the treatment of breast cancer. We investigated the efficacy of carvedilol in the inhibition of ANT-induced cardiotoxicity.\n\n\nMETHODS\nIn this randomized, single-blind, placebo-controlled study, 91 women with recently diagnosed breast cancer undergoing ANT therapy were randomly assigned to groups treated with either carvedilol (n = 46) or placebo (n = 45). Echocardiography was performed before and at 6 months after randomization, and absolute changes in the mean left ventricular ejection fraction, left ventricular end diastolic volume, and left ventricular end systolic volume were determined. Furthermore, the percentage change in the left atrial (LA) diameter and other variables of left ventricular (LV) diastolic function, such as transmitral Doppler parameters, including early (E wave) and late (A wave) diastolic velocities, E/A ratio and E wave deceleration time, pulmonary venous Doppler signals, including forward systolic (S wave) and diastolic (D wave) velocities into LA, late diastolic atrial reversal velocity, and early diastolic tissue Doppler mitral annular velocity (e') were measured. In addition, tissue Doppler mitral annular systolic (s') velocity, as a marker of early stage of LV systolic dysfunction, E/e' ratio, as a determinant of LV filling pressure, and troponin I level, as a marker of myocardial necrosis were measured.\n\n\nRESULTS\nAt the end of follow-up period, left ventricular ejection fraction did not change in the carvedilol group. However, this parameter was significantly reduced in the control group (P < 0.001). Echocardiography showed that both left ventricular end systolic volume and LA diameter were significantly increased compared with the baseline measures in the control group. In pulse Doppler studies, pulmonary venous peak atrial reversal flow velocity was significantly increased in the control group. Moreover, a significant decrease in the mitral annuli early diastolic (e') and peak systolic (s') velocities and a significant increase in the E (the peak early diastolic velocity)/e' ratio in the control group were also observed. However, none of these variables were adversely changed at the end of follow-up in the carvedilol group. Furthermore, the TnI level was significantly higher in the control group than in the carvedilol group (P = 0.036) at 30 days after the initiation of chemotherapy.\n\n\nCONCLUSIONS\nProphylactic use of carvedilol may inhibit the development of anthracycline-induced cardiotoxicity, even at low doses.",
"affiliations": "*Department of Cardiology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; †Department of Hematology, Gastrointestinal Cancer Research Center, Mazandaran University of Medical Sciences, Sari, Iran; ‡Student Research Committee, Cardiovascular Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; §Cardiovascular Research Center, Mazandaran University of Medical Sciences, Sari, Iran; and ¶Department of Biostatics, Faculty of Health, Mazandaran University of Medical Sciences, Sari, Iran.",
"authors": "Nabati|Maryam|M|;Janbabai|Ghasem|G|;Baghyari|Saideh|S|;Esmaili|Khadige|K|;Yazdani|Jamshid|J|",
"chemical_list": "D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D015415:Biomarkers; D002227:Carbazoles; D002317:Cardiovascular Agents; D011412:Propanolamines; D019210:Troponin I; D000077261:Carvedilol",
"country": "United States",
"delete": false,
"doi": "10.1097/FJC.0000000000000470",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0160-2446",
"issue": "69(5)",
"journal": "Journal of cardiovascular pharmacology",
"keywords": null,
"medline_ta": "J Cardiovasc Pharmacol",
"mesh_terms": "D000328:Adult; D000368:Aged; D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D016279:Atrial Function, Left; D015415:Biomarkers; D001943:Breast Neoplasms; D002227:Carbazoles; D066126:Cardiotoxicity; D002317:Cardiovascular Agents; D000077261:Carvedilol; D018619:Echocardiography, Doppler, Pulsed; D005260:Female; D006331:Heart Diseases; D006801:Humans; D007492:Iran; D008875:Middle Aged; D011412:Propanolamines; D018570:Risk Assessment; D012307:Risk Factors; D016037:Single-Blind Method; D013318:Stroke Volume; D013997:Time Factors; D016896:Treatment Outcome; D019210:Troponin I; D016277:Ventricular Function, Left; D055815:Young Adult",
"nlm_unique_id": "7902492",
"other_id": null,
"pages": "279-285",
"pmc": null,
"pmid": "28141699",
"pubdate": "2017-05",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Cardioprotective Effects of Carvedilol in Inhibiting Doxorubicin-induced Cardiotoxicity.",
"title_normalized": "cardioprotective effects of carvedilol in inhibiting doxorubicin induced cardiotoxicity"
} | [
{
"companynumb": "IR-JNJFOC-20170516720",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": n... |
{
"abstract": "We report the case of a 68-year-old man who was placed on heparin as bridge therapy and subsequently developed an iliacus haematoma with associated femoral nerve palsy. His team involved the orthopaedic surgery team in delayed fashion after his symptom onset. Due to his active medical conditions, he did not undergo surgical decompression of his haematoma until late into his hospital course. Unfortunately, this patient did not regain meaningful function from his femoral nerve deficit. We believe this case highlights the high index of suspicion necessary for making this diagnosis as well as the repercussions of an untimely decompression for this acute, compressive neuropathy. Although we are surgeons and this is a surgical case, we hope to publish this case in a medical journal to raise awareness that surgical decompression does have a role in this diagnosis and should ultimately be pursued early in its course for optimal patient benefit.",
"affiliations": "Harvard Combined Orthopaedic Residency Program, Boston, Massachusetts, USA acrawford7@partners.org.;Harvard Combined Orthopaedic Residency Program, Boston, Massachusetts, USA.;Harvard Combined Orthopaedic Residency Program, Boston, Massachusetts, USA.;Orthopaedic Surgery, Brigham and Women's Hospital, Boston, Massachusetts, USA.",
"authors": "Crawford|Alexander M|AM|;Guild|Theodore T|TT|;Striano|Brendan M|BM|;Von Keudell|Arvind G|AG|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-239024",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(1)",
"journal": "BMJ case reports",
"keywords": "haematology (incl blood transfusion); neurological injury; orthopaedics; surgery",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D020428:Femoral Neuropathy; D006406:Hematoma; D006801:Humans; D007085:Ilium; D008297:Male",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33462039",
"pubdate": "2021-01-18",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Spontaneous iliacus haematoma with femoral nerve palsy: an appeal to involve surgical teams early.",
"title_normalized": "spontaneous iliacus haematoma with femoral nerve palsy an appeal to involve surgical teams early"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-21-01006",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
... |
{
"abstract": "Over the past two decades, tumor necrosis factor-α (TNF-α) inhibitors became one of the most important drugs in the treatment of patients with psoriatic arthritis. Unfortunately, some of the patients exhibit unwanted side effects of the treatment. We describe a patient with psoriasis, psoriatic arthritis and uveitis who was treated with adalimumab and after 4 months of the treatment developed clinical and neuroradiological signs of demyelinating disease of the central nervous system. She experienced no signs and symptoms of neurological disease prior to adalimumab administration. After a detailed neurological work-up she was diagnosed with relapsing-remitting type of multiple sclerosis and treated with oral and pulse glucocorticoids and later with dimethyl fumarate. Adalimumab was discontinued. The question remains was the demyelination induced by the TNF-α blockade or was it unmasked by the introduction of the cytokine blocking agent. In patients suffering from inflammatory arthritis, treating disease to target as well as a close follow-up and knowledge of potential side effects of treatment remains crucial in good clinical practice.",
"affiliations": "Division of Clinical Immunology and Rheumatology, Department of Internal Medicine, School of Medicine, University Hospital Center Zagreb, University of Zagreb, Zagreb, Croatia. mbaresic@kbc-zagreb.hr.;Division of Physical Medicine, Rehabilitation and Rheumatology, National Memorial Hospital Vukovar, Vukovar, Croatia.;Department of Neurology, School of Medicine, University Hospital Center Zagreb, University of Zagreb, Zagreb, Croatia.;Division of Clinical Immunology and Rheumatology, Department of Internal Medicine, School of Medicine, University Hospital Center Zagreb, University of Zagreb, Zagreb, Croatia.",
"authors": "Barešić|Marko|M|http://orcid.org/0000-0001-6281-5705;Reihl Crnogaj|Mirna|M|http://orcid.org/0000-0003-3074-1646;Zadro|Ivana|I|;Anić|Branimir|B|http://orcid.org/0000-0003-4940-0577",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00296-021-04995-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0172-8172",
"issue": "41(12)",
"journal": "Rheumatology international",
"keywords": "Adalimumab; Demyelinating disease; Multiple sclerosis; Psoriasis; Psoriatic arthritis; Tumor necrosis factor-α",
"medline_ta": "Rheumatol Int",
"mesh_terms": null,
"nlm_unique_id": "8206885",
"other_id": null,
"pages": "2233-2239",
"pmc": null,
"pmid": "34557936",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "4581554;26476218;20843542;28337644;21263460;26763428;28298374;24938855;29694270;19933767;19183179;18156204;22801493;11762947;23149905;24202614;8960740;19854301;26693636;16527311;33647875;31921355;21876428;28258191;25738172;26767188;29410647;22992073;22992072;25800129;4003395;27928949;23361084;27142710;31667904;30151838",
"title": "Demyelinating disease (multiple sclerosis) in a patient with psoriatic arthritis treated with adalimumab: a case-based review.",
"title_normalized": "demyelinating disease multiple sclerosis in a patient with psoriatic arthritis treated with adalimumab a case based review"
} | [
{
"companynumb": "HR-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-326508",
"fulfillexpeditecriteria": "1",
"occurcountry": "HR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drug... |
{
"abstract": "Chronic graft-versus-host disease (cGVHD) is the major complication following allogeneic stem cell transplantation (allo-SCT). Nephrotic syndrome (NS) and other types of glomerulonephritis have been proposed to be the very rare forms of renal cGVHD. From 1991 to 2011, 253 patients underwent allo-SCT at our center. We report here 4 cases (1.6%) presenting with varieties of glomerular manifestations associated with cGVHD. The first case was typical NS. The renal pathology showed membranous nephropathy (MN). The second case was also MN, but this patient also had the pathology of focal segmental glomerulosclrosis (FSGS) and acute tubular necrosis (ATN). The third case showed lupus nephritis-like glomerular lesions with a high anti-nuclear antibody (ANA) titer. The fourth case presented with rapidly progressive glomerulonephritis (RPGN)-like symptoms. The kidney histology in this case was not available. The patient responded well to immunosuppressive therapy, but NS later recurred. Therefore, overt glomerular diseases after allo-SCT in Thai patients are not very rare. Monitoring urinalysis during withdrawal of immunosuppressive drugs and also during follow-up of patients with cGVHD may be considered.",
"affiliations": "Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand. Electronic address: ch_chantiya@hotmail.com.;Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.;Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.;Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.",
"authors": "Chanswangphuwana|C|C|;Townamchai|N|N|;Intragumtornchai|T|T|;Bunworasate|U|U|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "46(10)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D002908:Chronic Disease; D005260:Female; D015433:Glomerulonephritis, Membranous; D006086:Graft vs Host Disease; D006801:Humans; D007678:Kidney Glomerulus; D008297:Male; D008875:Middle Aged; D036102:Peripheral Blood Stem Cell Transplantation",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "3616-9",
"pmc": null,
"pmid": "25498099",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Glomerular diseases associated with chronic graft-versus-host disease after allogeneic peripheral blood stem cell transplantation: case reports.",
"title_normalized": "glomerular diseases associated with chronic graft versus host disease after allogeneic peripheral blood stem cell transplantation case reports"
} | [
{
"companynumb": "PHHY2014TH167447",
"fulfillexpeditecriteria": "1",
"occurcountry": "TH",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,
"dr... |
{
"abstract": "We documented dramatic responses to infliximab in 4 tuberculous meningitis cases with severe paradoxical reactions after effective antibacterial treatment, despite high-dose steroids. In every instance, infliximab was used as a last resort after all other options were exhausted, resulting in delayed initiation that may have adversely affected patient outcomes.",
"affiliations": "The Marie Bashir Institute for Infectious Diseases and Biosecurity (MBI), University of Sydney, Sydney, Australia.;Department of Infectious Diseases and Microbiology, Concord Repatriation General Hospital, Sydney, Australia.;Department of Microbiology and Infectious Diseases, Royal North Shore Hospital, Sydney, Australia.;Department of Infectious Diseases and Microbiology, Flinders Medical Centre and Flinders University, Adelaide, Australia.;The Marie Bashir Institute for Infectious Diseases and Biosecurity (MBI), University of Sydney, Sydney, Australia.;The Marie Bashir Institute for Infectious Diseases and Biosecurity (MBI), University of Sydney, Sydney, Australia.;Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, Australia.;Department of Microbiology and Infectious Diseases, Royal North Shore Hospital, Sydney, Australia.;Department of Clinical Immunology/Allergy, Concord Repatriation General Hospital, Sydney, Australia.;Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, Australia.",
"authors": "Marais|Ben J|BJ|0000-0003-3404-2690;Cheong|Elaine|E|;Fernando|Shelanah|S|;Daniel|Santhosh|S|;Watts|Matthew R|MR|;Berglund|Lucinda J|LJ|;Barry|Simone E|SE|;Kotsiou|George|G|;Headley|Alex P|AP|;Stapledon|Richard A|RA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1093/ofid/ofaa604",
"fulltext": "\n==== Front\nOpen Forum Infect Dis\nOpen Forum Infect Dis\nofid\nOpen Forum Infectious Diseases\n2328-8957 Oxford University Press US \n\n10.1093/ofid/ofaa604\nofaa604\nBrief Report\nAcademicSubjects/MED00290\nEditor's Choice\nUse of Infliximab to Treat Paradoxical Tuberculous Meningitis Reactions\nhttp://orcid.org/0000-0003-3404-2690Marais Ben J 1 Cheong Elaine 2 Fernando Shelanah 3 Daniel Santhosh 4 Watts Matthew R 156 Berglund Lucinda J 16 Barry Simone E 7 Kotsiou George 3 Headley Alex P 8 Stapledon Richard A 7 1 \nThe Marie Bashir Institute for Infectious Diseases and Biosecurity (MBI), University of Sydney, Sydney, Australia\n2 \nDepartment of Infectious Diseases and Microbiology, Concord Repatriation General Hospital, Sydney, Australia\n3 \nDepartment of Microbiology and Infectious Diseases, Royal North Shore Hospital, Sydney, Australia\n4 \nDepartment of Infectious Diseases and Microbiology, Flinders Medical Centre and Flinders University, Adelaide, Australia\n5 \nCentre for Infectious Diseases and Microbiology Infectious Diseases and Microbiology (CIDM), Westmead Hospital, Sydney, Australia\n6 \nICPMR Westmead Hospital, NSW Health Pathology, Sydney, Australia\n7 \nDepartment of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, Australia\n8 \nDepartment of Clinical Immunology/Allergy, Concord Repatriation General Hospital, Sydney, Australia\nCorrespondence: B. J. Marais, MD, PhD, The Marie Bashir Institute for Infectious Diseases and Biosecurity (MBI), Locked Bag 4001, Westmead, New South Wales, 2145, Sydney, Australia (ben.marais@health.nsw.gov.au).\n1 2021 \n28 12 2020 \n28 12 2020 \n8 1 ofaa60426 8 2020 03 12 2020 09 12 2020 29 1 2021 © The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.2020This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nWe documented dramatic responses to infliximab in 4 tuberculous meningitis cases with severe paradoxical reactions after effective antibacterial treatment, despite high-dose steroids. In every instance, infliximab was used as a last resort after all other options were exhausted, resulting in delayed initiation that may have adversely affected patient outcomes.\n\nWe documented dramatic responses to infliximab in four tuberculous meningitis cases with paradoxical reactions unresponsive to high dose steroids. Infliximab was only used as a last resort after all other options were exhausted, but there is scope for earlier consideration.\n\ninfliximabparadoxical reactionstuberculous meningitis\n==== Body\nTuberculous meningitis frequently results in permanent neurological sequelae [1, 2]. The characteristic inflammatory exudate at the base of the brain may block cerebrospinal fluid (CSF) flow with resultant hydrocephalus or cause cerebral ischemia and stroke secondary to vasculitis [1, 2]. Mass effects associated with localized inflammation may also compromise critical structures, such as the optic chiasm [3]. These effects may occur with natural disease progression or as a paradoxical reaction, generally defined as clinical worsening after initial improvement on appropriate antibacterial treatment.\n\nTumor necrosis factor (TNFα) is critical for effective host defense against mycobacteria, and monoclonal antibodies that inhibit TNFα, such as infliximab, greatly increase tuberculosis vulnerability [4]. On the other hand, deterioration of tuberculosis patients after infliximab cessation suggests that TNFα may also contribute to disease pathology [5]. The use of infliximab to control paradoxical reactions in a patient with tuberculous meningitis was first demonstrated in 2008 [6]. Subsequent case reports support the initial observations [7–10], but awareness of infliximab benefit in select cases is low and completely overshadowed by the perception of risk. Most clinicians remain highly reluctant to consider infliximab use in any tuberculosis patient.\n\nWe present a series of tuberculous meningitis cases with likely paradoxical reactions in whom infliximab was used with good effect. The Table 1 provides an overview of the case presentation, treatment, clinical progress, and outcome, with a focus on the administration and clinical effect of infliximab.\n\nCase 1\nA 36-year-old male bus driver who migrated to Australia from India 15 months prior was diagnosed with miliary tuberculosis and cerebral tuberculomas. Sputum, bronchoalveolar lavage (BAL), cerebrospinal fluid (CSF), and blood were all culture negative at the time. He was discharged home on isoniazid, rifampicin, pyrazinamide, ethambutol, and oral prednisolone. Interim brain magnetic resonance imaging (MRI) showed improvement of tuberculomas before readmission 6 weeks later with new-onset ataxia and drowsiness. Findings on the repeat MRI included hydrocephalus and cerebritis, with the patient experiencing rapid progression to coma requiring intubation and ventilation.\n\nA brain biopsy was performed, and an external ventricular drain was inserted. The brain biopsy tested Xpert MTB/Rif positive, with rifampicin resistance detected. Empiric MDR treatment was commenced with moxifloxacin, amikacin, prothionamide, and linezolid added, awaiting culture results. Phenotypic drug susceptibility testing (DST) identified resistance to all first-line drugs with additional low-level resistance to moxifloxacin; line probe assays identified katG, rpoB, and gyrA mutations. First-line treatment, except pyrazinamide, was stopped, and the patient was continued on high-dose moxifloxacin with the addition of bedaquiline and clofazimine. On this regimen, the patient slowly improved and became more responsive, before deteriorating a second time with new midbrain tuberculomas, multiple infarcts, and increasing leptomeningeal enhancement on MRI.\n\nIn the absence of a clinical response to high-dose intravenous (IV) dexamethasone, a “trial dose” of infliximab was given. Fever and C-reactive protein (CRP) settled promptly, and the patient’s sensorium improved within days, allowing him to be weaned off the ventilator. Symptoms recrudesced 3 weeks later, with new parenchymal foci and increased enhancement around existing tuberculomas seen on MRI. A second dose of infliximab induced another prompt response, and the patient continued to make a slow recovery, receiving a total of 3 monthly doses. Linezolid (after 6 months) and amikacin (after 12 months) were ceased due to bone marrow suppression and sensorineural hearing loss, respectively. In total, the patient completed 24 months of treatment and was discharged to a disability home, where he lives independently with minimal caregiver help.\n\nCase 2\nA 32-year-old woman (on TB treatment) presented with a 7-day history of bilateral thigh pain and paraesthesia, gait disturbance, and urinary retention. Spinal MRI revealed compressive lesions at T5 and T11/12, occurring 4 months after commencing treatment for culture-confirmed miliary tuberculosis; CSF was not assessed at the time. Tuberculosis treatment consisted of isoniazid, rifampicin, pyrazinamide, ethambutol (isoniazid discontinued after documented high-level resistance), and moxifloxacin, with excellent treatment adherence and no vomiting or clinical indication of malabsorption, such as diarrhea. High-dose IV dexamethasone was initiated, and an urgent T4-6 and T11-12 laminectomy was performed, which was complicated by dense pachymeningeal adhesions. With new-onset fecal incontinence, further debulking of the T11/12 lesion was performed, but distressing symptoms persisted.\n\nHistopathology from both lesions showed necrotizing granulomas that were negative for acid fast bacilli and mycobacterial growth. In the absence of live bacilli or any documented steroid response, infliximab was started, with rapid clinical improvement. Full bowel and bladder control, as well as mobility, was regained within 2 weeks. In the absence of raised inflammatory markers, serial positron emission tomography (PET) scans were used to track treatment response with significant reduction in glucose uptake at 2 months and no ongoing activity detected at 4 months, when infliximab treatment was stopped.\n\nCase 3\nA 53-year-old woman visiting from Indonesia presented with paraplegia, fecal incontinence, and urinary retention, as well as headache and a third cranial nerve palsy. Extensive intracranial and intraspinal leptomeningeal and pachymeningeal enhancement was demonstrated on MRI. Her CSF grew a fully susceptible strain of Mycobacterium tuberculosis. Therapy with isoniazid, rifampicin, pyrazinamide, and moxifloxacin together with high-dose steroids led to initial improvement with resolution of headaches and the third nerve palsy, but after 7 weeks of treatment and while still on high-dose steroids, the patient experienced worsening headaches and new-onset vomiting. Repeat MRI demonstrated increased leptomeningeal inflammation with multiple new intracranial and intraspinal tuberculomas (Figures 1 and 2).\n\nFigure 1. T1-weighted postgadolinium MRI brain images demonstrating evolution of brain tuberculomas in Case 3; pre– and post–infliximab use. MRI of the brain at (A) time of presentation, (B) week 7 post–commencement of TB therapy with formation of multiple tuberculomas (pre-infliximab), and (C) week 21 post–commencement of TB therapy and after 3 doses of infliximab, demonstrating complete resolution of brain tuberculomas. Abbreviations: MRI, magnetic resonance imaging; TB, tuberculosis.\n\nFigure 2. T1-weighted postgadolinium MRI brain images demonstrating evolution of spinal tuberculomas in Case 3; pre– and post–infliximab use. MRI of the spine at (A) time of presentation, (B) week 7 post–commencement of TB therapy with formation of spinal cord tuberculoma (pre-infliximab), and (C) week 21 post–commencement of TB therapy and after 3 doses of infliximab, demonstrating incomplete resolution of spinal cord tuberculoma. Abbreviations: MRI, magnetic resonance imaging; TB, tuberculosis.\n\nTreatment with infliximab resulted in rapid clinical improvement. Fever and headaches briefly recurred before the second monthly dose, with a total of 3 monthly doses administered. High-dose oral steroids were continued for 4 months before slow tapering. Thalidomide and lenalidomide were trialed for longer-term inflammatory suppression, but both resulted in an extensive generalized rash and were discontinued. A progress MRI demonstrated significant improvement in leptomeningeal enhancement and ring-enhancing tuberculomas after 6 months of therapy. The patient returned to Indonesia 8 months after treatment initiation, having regained muscle strength, but sphincter function remained compromised.\n\nCase 4\nA 26-year-old male student from India was admitted with cough, weight loss, and lethargy. There were multiple lung cavities on chest computed tomography (CT), but he had no neurological signs and a noncontrast CT scan of the brain detected no intracranial pathology. He commenced treatment on standard first-line therapy without corticosteroids. Within days of treatment initiation, he developed headache, vomiting, and disorientation, with bilateral lower limb weakness and urinary retention. An MRI of the brain and spine demonstrated communicating hydrocephalus with extensive leptomeningeal enhancement involving the spine, as well as multilevel spondylodiscitis with paravertebral abscesses. A lumbar drain was inserted, and high-dose IV dexamethasone was commenced. The rifampicin dose was increased to 900 mg/d, and levofloxacin 750 mg/d was added. M. tuberculosis grown from sputum was subsequently shown to be fully drug susceptible.\n\nSix weeks later, while still on IV dexamethasone, the patient developed new fever, worsening leg weakness, and diplopia. MRI of the brain and spine demonstrated increased basal meningeal enhancement, a new left occipital tuberculoma, and evidence of compressive myelopathy with progression of the spondylodiscitis. Fever and neurological symptoms improved rapidly after a dose of infliximab. Following symptom recrudescence, repeat infliximab doses were given 3, 7, and 17 weeks later, each time followed by prompt improvement. Repeat MRI at 6 months demonstrated resolution of the meningitis, hydrocephalus, tuberculomas, and spondylodiscitis with improvement of the paravertebral abscesses, now regarded as too small for drainage. The antibacterial treatment was rationalized to rifampicin and isoniazid with a plan to treat for 12 months in total.\n\nDISCUSSION\nAll 4 cases experienced clinical deterioration despite adequate antibacterial treatment and high-dose corticosteroids. In every instance, infliximab therapy was followed by rapid clinical improvement; no adverse effects were reported. The pronounced and consistent temporal association in clinical improvement, as well as MRI and/or PET changes, suggests a strong therapeutic effect. Our findings support the observation that TNFα is a key driver of inflammation in TB meningitis [11], consistent with the therapeutic effect observed in previous reports [6–10], including those using other TNFα inhibitors, such as adalimumab [12] and thalidomide [3]. Monoclonal antibodies do not usually cross the blood–brain barrier but may do so in the presence of meningeal inflammation and barrier disruption. In rats with hepatic encephalopathy, infliximab significantly reduced neuroinflammation, as demonstrated on immunohistochemistry [13]. In all reported cases, infliximab was only considered after other treatment options were exhausted, but earlier commencement may have prevented some of the invasive procedures and permanent sequelae. It should be emphasized that anti-TNFα treatment should only be contemplated in the presence of effective antibacterial therapy with adequate CSF penetration [14].\n\nThe optimal timing and duration of anti-TNFα treatment, as well as the value of corticosteroid co-administration, remains unclear. Symptomatic improvement, inflammatory markers (if raised to begin with), and MRI or PET changes may guide treatment duration; 3–4 doses of infliximab led to significant and durable clinical improvement in all patients. Although optimal dosing and timing of delivery remain uncertain, a rational approach may be to give 5 mg/kg at 0, 2, and 6 weeks (similar to induction dosing recommended for patients with active psoriatic arthritis), with consideration of additional doses at 10–14 weeks guided by the treatment response. This is based on 3 monthly doses provided in the first description of infliximab use in TB meningitis [6] and the fact that our patients experienced “breakthrough symptoms” before the second monthly dose. Therapeutic drug monitoring would be useful to inform dosing schedules [15] but is rarely available and was not performed in our patients. The added value of high-dose corticosteroids is uncertain and requires further evaluation; in reported cases, deterioration occurred under “steroid cover.”\n\nRandomized controlled trials to assess the benefit of infliximab use in tuberculous meningitis, in conjunction with effective antibacterial treatment, would be highly informative and might be considered in the following situations: (1) in immune-competent (HIV-uninfected) patients with paradoxical reactions, (2) in TB/HIV-coinfected patients who experience immune reconstitution inflammatory syndrome (IRIS) affecting the central nervous system, and (3) as part of routine care to prevent severe and irreversible sequelae. Multicenter recruitment using standardized methods is preferred [16], although the numbers required to detect a pronounced therapeutic effect, which is the key clinical need, would be relatively small.\n\nTable 1. Tuberculous Meningitis Cases With Paradoxical Reactions Treated With Infliximab\n\nCase\tDiagnosis at Presentation\tSite of Paradoxical Reaction \tTB Treatment Regimen\tOther Treatment Before and After Infliximab\tInfliximab Dose\tOutcome \t\nCase 1: \n\nFlinders Hospital, Adelaide, \n\n36 y, male \n\nHIV uninfected, \n\nIndiaa\tMiliary TB with TBM\tMultiple brain tuberculomas and obstructed CSF flow with raised ICP \tEmpiric HRZE, \n\nthenc \n\nhigh-dose mfx, amk, lzdd, pto, Z, bdq, cfz\tBefore: High-dose steroidsb for 3 mo \n\nAfter: High-dose steroids for 4 mo; tapered over 2 mo\t10 mg/kg \n\nmonthly x3 \n\tRapid fever resolution with CRP decline; improved sensorium allowing weaning off the ventilator within days; \n\nlong term—mild cognitive deficit, require assistance with activities of daily living\t\nCase 2: \n\nConcord Hospital, Sydney, \n\n32 y, female \n\nHIV uninfected, \n\nChinaa\tMiliary TB with TBM\tMultiple spinal tuberculomas with edema and local mass effect\tEmpiric HRZE, \n\nthene \n\nRZE + mfx\tBefore: High-dose steroids for 2 mo; decompressive spinal surgery \n\nAfter: High-dose steroids for 2 mo; tapered over 1 mo\t5 mg/kg \n\n0, 2, 6, and 14 wk\tRapid restoration of bladder function (2 wk) and mobility (3–4 wk); \n\nlong term—full neurological recovery\t\nCase 3: \n\nRoyal North Shore Hospital, Sydney, \n\n55 y, female \n\nHIV uninfected, \n\nIndonesiaa\tTBM and necrotic lymph-adenitis \tMultiple brain and spinal cord tuberculomas with cauda equina syndrome\tHRZ + mfx \tBefore: High-dose steroids for 2 mo \n\nAfter: High-dose steroids for 4 mo; tapered over 2 mo; failed trial of thalidomide \t5 mg/kg \n\nmonthly x3 \n\tRapid resolution of fever and meningism; improvement in lower limb power; \n\nlong term—incomplete recovery with compromised sphincter function at discharge; regained mobility with ongoing improvement in lower limb power \t\nCase 4: \n\nWestmead Hospital, Sydney, \n\n26 y, male \n\nHIV uninfected, \n\nIndiaa \n\tPTB with CNS and bone involvement\tMultiple brain and spinal tuberculomas with raised ICP, compressive spinal myelopathy, and cold abscesses\tEmpiric HRZE, \n\nthen \n\nHR (900 mg) Z + lfx \n\tBefore: High-dose steroids for 6 wk with unsuccessful weaning \n\nAfter: High-dose steroids for 2 mo; tapered over 1 mo\t10 mg/kg \n\n(0, 3 wk) \n\n5 mg/kg \n\n(7, 17 wk)\tRapid resolution of fever and neurological improvement (reduced pressure effects); \n\nlong term—regained sphincter function and mobility with ongoing improvement on rehabilitation\t\nAbbreviations: amk, amikacin; bdq, edaquiline; cfz, clofazimine; CNS, central nervous system; E, ethambutol; H, isoniazid; ICP, intracranial pressure; lfx, levofloxacin; lzd, linezolid; mfx, moxifloxacin; PTB, pulmonary TB; pto, prothionamide; R, rifampicin; TB, tuberculosis; TBM, TB meningitis; Z, pyrazinamide. \n\n\naCountry of origin.\n\n\nbHigh-dose steroids included intravenous dexamethasone (4–8 mg 3–4x/d) and/or oral prednisone (1–2 mg/kg/d - maximum 60 mg/d).\n\n\ncAfter identification of pan-resistance to all first-line drugs, including high-level isoniazid and low-level moxifloxacin resistance.\n\n\ndLinezolid (6 months) and amikacin (12 months) stopped after demonstrated toxicity.\n\n\neIsoniazid replaced by moxifloxacin given high-level isoniazid monoresistance.\n\nAcknowledgments\n\nFinancial support. None.\n\n\nPotential conflicts of interest. None of the authors have financial relationships relevant to this article. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.\n\n\nPatient consent. Patients were treated at 4 different hospitals with different case report requirements. All institutional requirements and local ethical standards were met. Written patient consent was provided in all instances, except 1 patient who left Australia. No patient identifiers were disclosed, and all patients/families indicated agreement that relevant clinical information could be shared for academic purposes in order for other patients to benefit from the knowledge gained.\n==== Refs\nReferences\n1. \nMarais S , Thwaites G , Schoeman JF , et al. Tuberculous meningitis: a uniform case definition for use in clinical research\n. Lancet Infect Dis 2010 ; 10 :803 –12\n.20822958 \n2. \nWilkinson RJ , Rohlwink U , Misra UK , et al ; Tuberculous Meningitis International Research Consortium \nTuberculous meningitis\n. Nat Rev Neurol 2017 ; 13 :581 –98\n.28884751 \n3. \nSchoeman JF , Andronikou S , Stefan DC , et al. Tuberculous meningitis-related optic neuritis: recovery of vision with thalidomide in 4 consecutive cases\n. J Child Neurol 2010 ; 25 :822 –8\n.20519667 \n4. \nKeane J , Gershon S , Wise RP , et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent\n. N Engl J Med 2001 ; 345 :1098 –104\n.11596589 \n5. \nVidal CG , Fernandez SR , Lacasa JM , et.al Paradoxical response to antituberculous therapy in infliximab-treated patients with disseminated tuberculosis\n. Clin Infect Dis 2005 ; 40 :756 –9\n.15714425 \n6. \nBlackmore TK , Manning L , Taylor WJ , Wallis RS \nTherapeutic use of infliximab in tuberculosis to control severe paradoxical reaction of the brain and lymph nodes\n. Clin Infect Dis 2008 ; 47 :e83 –5\n.18840076 \n7. \nJorge JH , Graciela C , Pablo AP , Luis SH \nA life-threatening central nervous system-tuberculosis inflammatory reaction nonresponsive to corticosteroids and successfully controlled by infliximab in a young patient with a variant of juvenile idiopathic arthritis\n. J Clin Rheumatol 2012 ; 18 :189 –91\n.22647865 \n8. \nMolton JS , Huggan PJ , Archuleta S \nInfliximab therapy in two cases of severe neurotuberculosis paradoxical reaction\n. Med J Aust 2015 ; 202 :156 –7\n.25669480 \n9. \nHsu DC , Faldetta KF , Pei L , et al. A paradoxical treatment for a paradoxical condition: infliximab use in three cases of mycobacterial IRIS\n. Clin Infect Dis 2016 ; 62 :258 –61\n.26394669 \n10. \nAbo YN , Curtis N , Butters C , et al. Successful treatment of a severe vision-threatening paradoxical tuberculous reaction with infliximab: first pediatric use\n. Pediatr Infect Dis J 2020 ; 39 :e42 –5\n.31939874 \n11. \nDonald PR , Schoeman JF , Beyers N , et al. Concentrations of interferon gamma, tumor necrosis factor alpha, and interleukin-1 beta in the cerebrospinal fluid of children treated for tuberculous meningitis\n. Clin Infect Dis 1995 ; 21 :924 –9\n.8645841 \n12. \nWallis RS , van Vuuren C , Potgieter S \nAdalimumab treatment of life-threatening tuberculosis\n. Clin Infect Dis 2009 ; 48 :1429 –32\n.19364287 \n13. \nDadsetan S , Balzano T , Forteza J , et al. Infliximab reduces peripheral inflammation, neuroinflammation, and extracellular GABA in the cerebellum and improves learning and motor coordination in rats with hepatic encephalopathy\n. J Neuroinflammation 2016 ; 13 :245 .27623772 \n14. \nHuynh J , Thwaites G Marais BJ , Schaaf HS \nTuberculosis treatment in children: The changing landscape\n. Paediatr Respir Rev 2020 ; 36 :33 –43\n.32241748 \n15. \nSyversen SW , Goll GL , Jørgensen KK , et al. Therapeutic drug monitoring of infliximab compared to standard clinical treatment with infliximab: study protocol for a randomised, controlled, open, parallel-group, phase IV study (the NOR-DRUM study)\n. Trials 2020 ; 21 :13 .31907007 \n16. \nMarais BJ , Heemskerk AD , Marais SS , et al ; Tuberculous Meningitis International Research Consortium \nStandardized methods for enhanced quality and comparability of tuberculous meningitis studies\n. Clin Infect Dis 2017 ; 64 :501 –9\n.28172588\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2328-8957",
"issue": "8(1)",
"journal": "Open forum infectious diseases",
"keywords": "infliximab; paradoxical reactions; tuberculous meningitis",
"medline_ta": "Open Forum Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "101637045",
"other_id": null,
"pages": "ofaa604",
"pmc": null,
"pmid": "33542942",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article",
"references": "31939874;19364287;20519667;25669480;22647865;26394669;31907007;11596589;18840076;15714425;32241748;28884751;27623772;28172588;8645841;20822958",
"title": "Use of Infliximab to Treat Paradoxical Tuberculous Meningitis Reactions.",
"title_normalized": "use of infliximab to treat paradoxical tuberculous meningitis reactions"
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"abstract": "BACKGROUND\nThe efficacy and safety of proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors were confirmed by several clinical trials, but its effectiveness in routine clinical practice in China has not been evaluated. This study aims to describe the real world effectiveness of PCSK-9 inhibitors combined with statins compared with statins-based therapy among patients with very high risk of atherosclerotic cardiovascular disease (ASCVD).\n\n\nMETHODS\nThis is a multi-center observational study, enrolled patients from 32 hospitals who underwent percutaneous coronary intervention (PCI) from January to June in 2019. There are 453 patients treated with PCSK-9 inhibitors combined with statins in PCSK-9 inhibitor group and 2,610 patients treated with statins-based lipid lowering therapies in statins-based group. The lipid control rate and incidence of major adverse cardiovascular events (MACE) over six months were compared between two groups. A propensity score-matched (PSM) analysis was used to balance two groups on confounding factors. Survival analysis using Kaplan-Meier methods was applied for MACE.\n\n\nRESULTS\nIn a total of 3,063 patients, 89.91% of patients had received moderate or high-intensity statins-based therapy before PCI, but only 9.47% of patients had low-density lipoprotein cholesterol (LDL-C) levels below 1.4 mmol/L at baseline. In the PSM selected patients, LDL-C level was reduced by 42.57% in PCSK-9 inhibitor group and 30.81% (P < 0.001) in statins-based group after six months. The proportion of LDL-C ≤ 1.0 mmol/L increased from 5.29% to 29.26% in PCSK-9 inhibitor group and 0.23% to 6.11% in statins-based group, and the proportion of LDL-C ≤ 1.4 mmol/L increased from 10.36% to 47.69% in PCSK-9 inhibitor group and 2.99% to 18.43% in statins-based group ( P < 0.001 for both). There was no significant difference between PCSK-9 inhibitor and statins-based treatment in reducing the risk of MACE (hazard ratio = 2.52, 95% CI: 0.49-12.97, P = 0.250).\n\n\nCONCLUSIONS\nIn the real world, PCSK-9 inhibitors combined with statins could significantly reduce LDL-C levels among patients with very high risk of ASCVD in China. The long-term clinical benefits for patients received PCSK-9 inhibitor to reduce the risk of MACE is still unclear and requires further study.",
"affiliations": "Department of Cardiology, Chinese PLA General Hospital, Beijing, China.;Department of Cardiology, Chinese PLA General Hospital, Beijing, China.;Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing Key Laboratory of Precision Medicine of Coronary Atherosclerotic Disease, Clinical Center for Coronary Heart Disease, Capital Medical University, Beijing, China.;Department of Cardiology, Tianjin Chest Hospital, Tianjin, China.;Department of Cardiology, the First Hospital of Jilin University, Changchun, China.;Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.;Department of Cardiology, Hebei People's Hospital, Shijiazhuang, China.;Department of Cardiology, Kailuan General Hospital, Hebei Union University, Tangshan, China.;Department of Cardiology, Beijing Luhe Hospital, Capital Medical University, Beijing, China.;Department of Cardiology, Shanxi Cardiovascular Hospital, Taiyuan, China.;Department of Cardiology, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, China.;Department of Cardiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.;Department of Cardiology, Tangshan Worker's Hospital, Tangshan, China.;Department of Cardiology, China-Japan Friendship Hospital Affiliated Jilin University, Changchun, China.;Department of Cardiology, Handan Central Hospital, Hebei, China.;Heart Center, Beijing Key Laboratory of Hypertension, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.;Department of Cardiology, Handan Central Hospital, Hebei, China.;Department of Cardiology, the First Affiliated Hospital of Dalian Medical University, Liaoning, China.;Department of Cardiology, the Second Affiliated Hospital of Harbin Medical University, Harbin, China.;Department of Cardiology, the Second Affiliated Hospital of Shenyang Medical College, Shenyang, China.;Department of Cardiology, the Second Hospital of Shanxi Medical University, Taiyuan, China.;Department of Neurology, Xuanwu Hospital Capital Medical University, Beijing, China.;Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China.;Department of Cardiology, the Third Hospital of Shijiazhuang City, Shijiazhuang, China.;Department of Cardiology, the First Hospital of Shijiazhuang City, Shijiazhuang, China.;Department of Cardiology, Taigang General Hospital, Shanxi Medical University, Taiyuan, China.;Department of Cardiology, the Sixth Medical Center of Chinese PLA General Hospital, Beijing, China.;Department of Cardiology, Shengjing Hospital of China Medical University, Shengyang, China.;Department of Cardiology, Daqing Oilfield General Hospital, Heilongjiang, China.;Department of Cardiology, the Second Hospital of Baoding, Hebei, China.;Department of Cardiology and Macrovascular Disease, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China.;Department of Cardiology, Jilin Central Hospital, Changchun, China.;Heart Center, the First Hospital of Hebei Medical University, Shijiazhuang, China.;Department of Cardiology, Chinese PLA General Hospital, Beijing, China.",
"authors": "Liu|Yu-Qi|YQ|;Li|Dan-Dan|DD|;Chai|Meng|M|;Cong|Hong-Liang|HL|;Cong|Xiao-Qiang|XQ|;Dai|Jun|J|;DU|Rong-Pin|RP|;Gao|Ming|M|;Guo|Jin-Cheng|JC|;Guo|Yan-Qing|YQ|;Hong|Xiao-Jian|XJ|;Huang|Rong-Chong|RC|;Jia|Feng-Shun|FS|;Li|Jia-Yu|JY|;Li|Qing|Q|;Liu|Jia-Mei|JM|;Liu|Xin-Ping|XP|;Liu|Yu-Guo|YG|;Nie|Hong-Gang|HG|;Shao|Bing|B|;Shen|Xiao-Yu|XY|;Song|Hai-Qing|HQ|;Song|Yi-Jun|YJ|;Wang|Li-Jun|LJ|;Wang|Shuo|S|;Wu|Dong-Mei|DM|;Xia|Jing|J|;Yang|Zhi-Yong|ZY|;Yu|Hong-Ying|HY|;Zhang|Hui|H|;Zhang|Tie-Mei|TM|;Zhao|Ji-Yi|JY|;Zhao|Liang-Chen|LC|;Zheng|Ming-Qi|MQ|;Chen|Yun-Dai|YD|",
"chemical_list": null,
"country": "China",
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"doi": "10.11909/j.issn.1671-5411.2021.04.005",
"fulltext": "\n==== Front\nJ Geriatr Cardiol\nJ Geriatr Cardiol\nJGC\nJournal of Geriatric Cardiology : JGC\n1671-5411\nScience Press Beijing, China\n\njgc-18-4-261\n10.11909/j.issn.1671-5411.2021.04.005\nResearch Article\nReal world effectiveness of PCSK-9 inhibitors combined with statins versus statins-based therapy among patients with very high risk of atherosclerotic cardiovascular disease in China (RWE-PCSK study)\nLIU Yu-Qi 1\nLI Dan-Dan 1\nCHAI Meng 2\nCONG Hong-Liang 3\nCONG Xiao-Qiang 4\nDAI Jun 5\nDU Rong-Pin 6\nGAO Ming 7\nGUO Jin-Cheng 8\nGUO Yan-Qing 9\nHONG Xiao-Jian 10\nHUANG Rong-Chong 11\nJIA Feng-Shun 12\nLI Jia-Yu 13\nLI Qing 14\nLIU Jia-Mei 15\nLIU Xin-Ping 14\nLIU Yu-Guo 16\nNIE Hong-Gang 17\nSHAO Bing 18\nSHEN Xiao-Yu 19\nSONG Hai-Qing 20\nSONG Yi-Jun 21\nWANG Li-Jun 22\nWANG Shuo 23\nWU Dong-Mei 24\nXIA Jing 25\nYANG Zhi-Yong 26\nYU Hong-Ying 27\nZHANG Hui 28\nZHANG Tie-Mei 29\nZHAO Ji-Yi 30\nZHAO Liang-Chen 31\nZHENG Ming-Qi 32\nCHEN Yun-Dai 1*cyundai@vip.163.com\n\n1 Department of Cardiology, Chinese PLA General Hospital, Beijing, China\n2 Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing Key Laboratory of Precision Medicine of Coronary Atherosclerotic Disease, Clinical Center for Coronary Heart Disease, Capital Medical University, Beijing, China\n3 Department of Cardiology, Tianjin Chest Hospital, Tianjin, China\n4 Department of Cardiology, the First Hospital of Jilin University, Changchun, China\n5 Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China\n6 Department of Cardiology, Hebei People’s Hospital, Shijiazhuang, China\n7 Department of Cardiology, Kailuan General Hospital, Hebei Union University, Tangshan, China\n8 Department of Cardiology, Beijing Luhe Hospital, Capital Medical University, Beijing, China\n9 Department of Cardiology, Shanxi Cardiovascular Hospital, Taiyuan, China\n10 Department of Cardiology, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, China\n11 Department of Cardiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China\n12 Department of Cardiology, Tangshan Worker’s Hospital, Tangshan, China\n13 Department of Cardiology, China-Japan Friendship Hospital Affiliated Jilin University, Changchun, China\n14 Department of Cardiology, Handan Central Hospital, Hebei, China\n15 Heart Center, Beijing Key Laboratory of Hypertension, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China\n16 Department of Cardiology, the First Affiliated Hospital of Dalian Medical University, Liaoning, China\n17 Department of Cardiology, the Second Affiliated Hospital of Harbin Medical University, Harbin, China\n18 Department of Cardiology, the Second Affiliated Hospital of Shenyang Medical College, Shenyang, China\n19 Department of Cardiology, the Second Hospital of Shanxi Medical University, Taiyuan, China\n20 Department of Neurology, Xuanwu Hospital Capital Medical University, Beijing, China\n21 Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China\n22 Department of Cardiology, the Third Hospital of Shijiazhuang City, Shijiazhuang, China\n23 Department of Cardiology, the First Hospital of Shijiazhuang City, Shijiazhuang, China\n24 Department of Cardiology, Taigang General Hospital, Shanxi Medical University, Taiyuan, China\n25 Department of Cardiology, the Sixth Medical Center of Chinese PLA General Hospital, Beijing, China\n26 Department of Cardiology, Shengjing Hospital of China Medical University, Shengyang, China\n27 Department of Cardiology, Daqing Oilfield General Hospital, Heilongjiang, China\n28 Department of Cardiology, the Second Hospital of Baoding, Hebei, China\n29 Department of Cardiology and Macrovascular Disease, Beijing Tiantan Hospital, Capital Medical University, Beijing, China\n30 Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China\n31 Department of Cardiology, Jilin Central Hospital, Changchun, China\n32 Heart Center, the First Hospital of Hebei Medical University, Shijiazhuang, China\ncyundai@vip.163.com\n28 4 2021\n18 4 261270\nCopyright and License information: Journal of Geriatric Cardiology 2021\n2021\nhttps://creativecommons.org/licenses/by-nc-sa/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/\nBACKGROUND\n\nThe efficacy and safety of proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors were confirmed by several clinical trials, but its effectiveness in routine clinical practice in China has not been evaluated. This study aims to describe the real world effectiveness of PCSK-9 inhibitors combined with statins compared with statins-based therapy among patients with very high risk of atherosclerotic cardiovascular disease (ASCVD).\n\nMETHODS\n\nThis is a multi-center observational study, enrolled patients from 32 hospitals who underwent percutaneous coronary intervention (PCI) from January to June in 2019. There are 453 patients treated with PCSK-9 inhibitors combined with statins in PCSK-9 inhibitor group and 2,610 patients treated with statins-based lipid lowering therapies in statins-based group. The lipid control rate and incidence of major adverse cardiovascular events (MACE) over six months were compared between two groups. A propensity score-matched (PSM) analysis was used to balance two groups on confounding factors. Survival analysis using Kaplan-Meier methods was applied for MACE.\n\nRESULTS\n\nIn a total of 3,063 patients, 89.91% of patients had received moderate or high-intensity statins-based therapy before PCI, but only 9.47% of patients had low-density lipoprotein cholesterol (LDL-C) levels below 1.4 mmol/L at baseline. In the PSM selected patients, LDL-C level was reduced by 42.57% in PCSK-9 inhibitor group and 30.81% (P < 0.001) in statins-based group after six months. The proportion of LDL-C ≤ 1.0 mmol/L increased from 5.29% to 29.26% in PCSK-9 inhibitor group and 0.23% to 6.11% in statins-based group, and the proportion of LDL-C ≤ 1.4 mmol/L increased from 10.36% to 47.69% in PCSK-9 inhibitor group and 2.99% to 18.43% in statins-based group ( P < 0.001 for both). There was no significant difference between PCSK-9 inhibitor and statins-based treatment in reducing the risk of MACE (hazard ratio = 2.52, 95% CI: 0.49−12.97, P = 0.250).\n\nCONCLUSIONS\n\nIn the real world, PCSK-9 inhibitors combined with statins could significantly reduce LDL-C levels among patients with very high risk of ASCVD in China. The long-term clinical benefits for patients received PCSK-9 inhibitor to reduce the risk of MACE is still unclear and requires further study.\n==== Body\nAtherosclerotic cardiovascular disease (ASCVD) has been demonstrated to be the leading cause of death and disease burden in China and worldwide, and lipid lowering drugs are proven to be the cornerstone of treatment and beneficial to the cardiovascular disease (CVD) outcomes.[1–3] Numerous studies over the past decades have demonstrated a causal relationship between low-density lipoprotein cholesterol (LDL-C) and progression/manifestation of CVD. Elevation of LDL-C is an important risk factor associated with development of CVD events in acute coronary syndrome patients.[4,5]\n\nTo date, all guidelines recommended LDL-C control as the main intervention target for lipid management.[6–8] The Chinese guidelines for the prevention and treatment of dyslipidemia in adults (revised in 2016) recommended the management of dyslipidemia of ASCVD patients should be targeted at LDL-C < 1.8 mmoL/L, and/or LDL-C is reduced by at least 50%. [6] The AHA/ACC guidelines and China’s expert consensus in 2018 recommended that LDL-C should be controlled below 1.4 mmol/L or even lower for patients with very high risk of ASCVD (more than two severe ASCVD events or one severe ASCVD event combined with more than two high risk factors).[7] The 2019 ESC/EAS dyslipidemia guidelines have recommended a LDL-C target of 1.4 mmol/L as goal for patients with very high risk of ASCVD.[8] However, the proportion of patients with very high risk of ASCVD achieved the target value of LDL-C is low in China.[9] Based on the community study in China, the LDL-C achieved rate among ASCVD patients was only 6.8%, and only 14.5% of them were treated by anti-hyperlipidemia drugs.[9]\n\nAlthough guidelines recommended high-intensity statins as first-line therapy for patients with established CVD, Chinese patients have limited benefit from high intensive statin treatment.[10] The DYSIS-China study showed that high-intensity statins only resulted in an additional 6% reduction in LDL-C.[10] Ezetimibe is recommended as second-line therapy for patients who are either intolerant to statins or do not achieve their LDL-C goals despite receiving maximally tolerated statin therapy. Proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors, as a new class of cholesterol lowering drugs, have been approved for treating hyperlipidemia in China in 2019. The phase II clinical trial showed that PCSK-9 inhibitor monotherapy could further reduce LDL-C by 37.3% to 52.5%, and reduce by 45% to 60% combined with statins.[11] ODYSSEY outcomes and FOURIER studies have also shown that PCSK-9 inhibitors can further reduce LDL-C levels, major adverse cardiovascular events (MACE), and improve clinical outcomes.[12,13] Although these large randomized controlled trials (RCTs) have confirmed the clinical efficacy and safety of PCSK-9 inhibitors combined with statins, using PCSK-9 inhibitors in routine clinical practice of Chinese setting in very high risk of ASCVD patients has not been evaluated. In this study, we aim to compare the real world effectiveness of PCSK-9 inhibitors combined with statins or statins-based therapies among patients with very high risk of ASCVD.\n\nMETHODS\n\nStudy Design and Population\n\nThis study was based on a real world, multi-center patient cohort. Patients with very high risk of ASCVD who underwent percutaneous coronary intervention (PCI) in 32 hospitals were recruited from January to June in 2019 in China and were followed up for six months. A total of 453 patients treated with PCSK-9 inhibitors combined with statins and 2,610 patients treated with statins-based lipid lowering therapy were included in current study.\n\nPatients who met the following criteria are eligible for the study: (1) age ≥ 18 years with very high risk of ASCVD;[14] (2) underwent PCI during the study recruitment period; and (3) treated with statins-based lipid lowering drugs or PCSK-9 inhibitor. Patients who met any of the following criteria will not be eligible for this study: (1) malignant tumor or disease of the blood system; (2) severe hepatic and renal insufficiency; (3) severe allergic reactions history; (4) aspartate aminotransferase or alanine amino transferase more than three times the upper limit of normal (ULN); and (5) creatinine greater than three times the ULN.\n\nIn this study, patients’ LDL-C, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) at baseline and over six months after discharged from hospitals was compared. LDL-C control rate was analyzed and compared between patients with PCSK-9 inhibitors combined with statins and patients with statins-based agents. The impact of PCSK-9 inhibitors combined with statins or statins-based therapies on incidence of MACE was also compared. An independent Ethics Committee had approved the protocol (No.S2018-083). Written informed consents for both participation and publication were obtained from all participants.\n\nMeasures of Treatment Outcomes\n\nThe targeted lipid control rates were considered as LDL-C levels goals under 1.0 mmol/L or 1.4 mmol/L. The MACE included cardiac death, myocardial infarction (MI), target vessel revascularization (TVR), target lesion revascularization and stroke. The re-angina and re-hospitalization were also considered separately. Cardiac death was defined as any death due to cardiac cause, unwitnessed death and death of unknown cause. Spontaneous MI was defined as the presence of clinical or electrocardiographic changes consistent with myocardial ischemia and circulating cardiac biomarker concentrations above the ULN, in accordance with the universal definition.[15] TVR was defined as the requirement for a repeated PCI or surgical bypass of any segment of a target vessel.\n\nPropensity Score\n\nPropensity score-matched (PSM) method was applied to balance the confounding factors between PCSK-9 inhibitor group and statins-based group. The selected variables to be potential confounders associated with clinical outcomes were age, gender, body mass index (BMI), hypertension, diabetes mellitus, stroke, smoker, chronic kidney disease, LDL-C, HDL-C, TC and TG. The PCSK-9 inhibitor group and statins-based therapies groups were paired at 1:1 using nearest matching with a caliper size of 0.05. We adjusted for imbalanced variables including medical history, inpatient diagnosis following mixed-effect Cox model.\n\nStatistical Analysis\n\nContinuous variables were presented as mean ± SD or median (interquartile range). Categorical variables were presented as frequency and percentage. The difference of continuous variables between the subgroups was tested by Student’s t-test. The difference of categorical variables between the subgroups was tested by Pearson’s chi-squared test and Fisher’s exact probability test. Survival analysis using Kaplan-Meier methods associated with log-rank tests was applied for MACE. To explore prognostic factors associated with incidence of MACE, Cox proportional hazards regression model was used. All statistical tests were two-sided and statistical significance was set at P-value < 0.05, which were performed using Stata software version 14.0 (Stata Corp, College Station, TX, USA).\n\nRESULTS\n\nBaseline Demographic and Clinical Characteristics of Patients with Very High Risk of ASCVD\n\nA total of 453 patients treated with PCSK-9 inhibitors combined with statins and 2,610 patients treated with statins were recruited in the cohort. Among all patients, 89.91% of patients had received moderate or high-intensity statin therapy before PCI (Figure 1A), but only 9.47% of them had LDL-C levels below 1.4 mmol/L at baseline (Figure 1B). In the PSCK-9 inhibitor group, compared before and after treatment, the proportion of LDL-C < 1.0 mmol/L increased from 5.29% to 29.26%, the proportion of LDL-C < 1.4 mmol/L increased from 10.36% to 47.69% ( Figure 1C).\n\nFigure 1 The overall patient treated with statins and goal LDL-C level in the real world.\n\n(A): Different intensities of statin treatment; (B): LDL-C control before PCI; and (C): LDL-C control of the PCSK-9 inhibitor group and statins-based group over six months after PCI. LDL-C: low-density lipoprotein cholesterol; PCI: percutaneous coronary intervention.\n\nPSM selected a subgroup of 868 patients (434 patients treated with PCSK-9 and 434 patients treated with statins-based therapy) were used for comparative effectiveness analysis in current study. The follow-up rate of 868 patients was 100% at six months. The patient flow chart was showed in Figure 2.\n\nFigure 2 The flow chart of patients.\n\nLDL-C: low-density lipoprotein cholesterol; PCI: percutaneous coronary intervention; PCSK-9: proprotein convertase subtilisin/kexin type 9.\n\nThe baseline characteristics of matched patients were summarized in Table 1. There was no statistically significant difference in age, gender, BMI, comorbidities, smoker and medical treatment after matched, but incidence of past history of MI, PCI, coronary artery bypass grafting, ST-elevation myocardial infarction and ischemic cardiomyopathy in PSCK-9 inhibitor group was higher (all with P < 0.001). The unselected patients for PSM analysis treated with statins-based therapy were demonstrated in Table 2.\n\nTable 1 Demographic and diseases characteristics of patients in PCSK-9 inhibitor and statins-based treatment groups after matched.\n\nVariables\tStatins-based group (n = 434)\tPCSK-9 inhibitor group (n = 434)\tP-value\t\nData are presented as n (%). *Presented as median (interquartile range). PCSK-9: proprotein convertase subtilisin/kexin type 9.\t\nAge, yrs\t60 (54–66)*\t60 (52–68)*\t0.350\t\nMale gender\t287 (66.1%)\t294 (67.7%)\t0.614\t\nBody mass index\t24.68 (23.28−27.09)*\t24.77 (23.36−26.50)*\t0.059\t\nHypertension\t288 (66.4%)\t293 (67.5%)\t0.718\t\nDiabetes mellitus\t98 (22.6%)\t117 (27.0%)\t0.135\t\nStroke\t60 (13.8%)\t58 (13.4%)\t0.843\t\nChronic kidney disease\t3 (0.7%)\t7 (1.6%)\t0.341\t\nSmoker\t206 (47.5%)\t207 (47.7%)\t0.945\t\nMedical history\t\t\t\t\n Myocardial infarction\t24 (5.5%)\t121 (27.9%)\t< 0.001\t\n Percutaneous coronary intervention\t28 (6.5%)\t88 (20.3%)\t< 0.001\t\n Coronary artery bypass graft\t3 (0.7%)\t43 (9.9%)\t< 0.001\t\nInpatient diagnose\t\t\t\t\n Stable angina\t44 (10.1%)\t23 (5.3%)\t0.008\t\n Unstable angina\t273 (62.9%)\t263 (60.6%)\t0.485\t\n Non-ST-elevation myocardial infarction\t73 (16.8%)\t61 (14.1%)\t0.260\t\n ST-elevation myocardial infarction\t44 (10.1%)\t79 (18.2%)\t< 0.001\t\n Ischemic cardiomyopathy\t0\t8 (1.8%)\t−\t\nMedication\t\t\t\t\n Other lipid lowering therapy\t10 (2.3%)\t−\t−\t\n Aspirin\t390 (89.9%)\t392 (90.3%)\t0.820\t\n β-blocker\t170 (39.2%)\t186 (42.9%)\t0.270\t\n Calcium channel blockers\t149 (34.3%)\t155 (35.7%)\t0.669\t\n Renin angiotensin-aldosterone\t71 (16.4%)\t63 (14.5%)\t0.452\t\n\nTable 2 Demographic and diseases characteristics of patients in PCSK-9 inhibitor and statins groups before matched.\n\nVariables\tStatins group\n(n = 2,610)\tPCSK-9 inhibitor\ngroup (n = 453)\tP-value\tMatched\n(n = 434)\tUnmatched\n(n = 2,176)\tP-value\t\nData are presented as n (%). *Presented as median (interquartile range). PCSK-9: proprotein convertase subtilisin/kexin type 9.\t\nAge, yrs\t59 (52−65)*\t60 (51−68)*\t0.510\t60 (54−66)*\t59 (51−65)*\t0.002\t\nMale gender\t620 (23.8%)\t311 (68.7%)\t< 0.001\t287 (66.1%)\t332 (15.3%)\t< 0.001\t\nBody mass index\t25.71 (23.72−27.78)*\t24.78 (23.29−26.53)*\t< 0.001\t24.58 (23.70−26.34)*\t25.95 (23.95−28.08)*\t< 0.001\t\nHypertension\t1,521 (58.3%)\t302 (66.7%)\t0.001\t288 (66.4%)\t1,233 (56.7%)\t< 0.001\t\nDiabetes mellitus\t730 (28.0%)\t125 (27.6%)\t0.869\t98 (22.6%)\t632 (29.0%)\t< 0.001\t\nStroke\t172 (6.6%)\t61 (13.5%)\t< 0.001\t60 (13.8%)\t112 (5.1%)\t< 0.001\t\nChronic kidney disease\t19 (0.7%)\t7 (1.5%)\t0.80\t3 (0.7%)\t16 (0.7%)\t1.000\t\nSmoker\t1,315 (50.4%)\t216 (47.7%)\t0.289\t106 (24.4%)\t1,209 (55.6%)\t< 0.001\t\nMedical history\t\t\t\t\t\t\t\n Myocardial infarction\t225 (8.6%)\t123 (27.2%)\t< 0.001\t24 (5.5%)\t201 (9.2%)\t0.012\t\n Percutaneous coronary intervention\t316 (12.1%)\t90 (19.9%)\t< 0.001\t28 (6.5%)\t288 (13.2%)\t< 0.001\t\n Coronary artery bypass graft\t26 (1.0%)\t44 (9.7%)\t< 0.001\t3 (0.7%)\t23 (1.1%)\t0.605\t\nInpatient diagnose\t\t\t\t\t\t\t\n Stable angina\t231 (8.9%)\t25 (5.5%)\t0.018\t44 (10.1%)\t187 (8.6%)\t0.301\t\n Unstable angina\t1,589 (60.9%)\t274 (60.5%)\t0.844\t273 (62.9%)\t1,316 (60.4%)\t0.422\t\n Non-ST-elevation myocardial infarction\t494 (18.9%)\t66 (14.6%)\t0.026\t73 (16.8%)\t421 (18.9%)\t0.220\t\n ST-elevation myocardial infarction\t292 (11.2%)\t80 (17.7%)\t< 0.001\t44 (10.1%)\t248 (11.4%)\t0.432\t\n Ischemic cardiomyopathy\t4 (0.2%)\t8 (1.8%)\t< 0.001\t0\t4 (0.2%)\t−\t\nLaboratory test\t\t\t\t\t\t\t\n Low-density lipoprotein cholesterol, mmol/L\t2.31 (1.78−2.97)*\t3.04 (2.16−4.00)*\t< 0.001\t2.89 (2.19−3.58)*\t2.22 (1.74−2.82)*\t< 0.001\t\n High-density lipoprotein cholesterol, mmol/L\t0.97 (0.82−1.14)*\t1.08 (0.92−1.28)*\t< 0.001\t1.08 (0.90−1.24)*\t0.95 (0.81−1.12)*\t< 0.001\t\n Total cholesterol, mmol/L\t3.90 (3.30−4.70)*\t4.97 (3.95−6.04)*\t< 0.001\t4.81 (3.98−5.63)*\t3.77 (3.22−4.52)*\t< 0.001\t\n Triglycerides, mmol/L\t1.45 (1.04−2.01)*\t1.97 (1.24−3.09)*\t< 0.001\t1.70 (1.15−2.71)*\t1.42 (1.02−1.92)*\t< 0.001\t\n\nDuring the follow-up period, 46 patients used Evolocumab 420 mg per month treatment plan, and 388 patients used 140 mg per two weeks. The time on treatment was 4.4 ± 1.2 weeks, and number of injections of Evolocumab was 3.3 ± 1.2 for patients received 140 mg per two weeks plan.\n\nComparison of Lipid Profile between Two Treatment Groups\n\nThe LDL-C level was significantly reduced by 42.57% in PCSK-9 inhibitor group and 30.81% (P < 0.001) in statins-based group after six months follow-up. The TC level decreased by 25.15% and 21.02% ( P < 0.001) in PCSK-9 inhibitor group and statins-based group, respectively ( Figure 3). The proportion of LDL-C ≤ 1.0 mmol/L increased from 5.29% at baseline to 29.26% in the PCSK-9 inhibitor group and 0.23% to 6.11% in statins-based group over six months follow-up (P < 0.001, Figure 1C), and the proportion of LDL-C ≤ 1.4 mmol/L increased from 10.36% to 47.69% and 2.99% to 18.43% (P < 0.001).\n\nFigure 3 Comparison of lipid profile before and after imitation of PCSK-9 inhibitor and statins treatment groups.\n\n(A): Comparison of LDL-C between PCSK-9 inhibitor group and statins-based group; (B): comparison of HDL-C between PCSK-9 inhibitor group and statins-based group; (C): comparison of TC between PCSK-9 inhibitor group and statins-based group; and (D): comparison of TG between PCSK-9 inhibitor group and statins-based group. HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; TC: total cholesterol; TG: triglycerides.\n\nComparison of Cardiovascular Events between Two Treatment Groups\n\nThere was no significant difference between PCSK-9 inhibitors combined with statins and statins-based treatment in reducing the risk of MACE [hazard ratio (HR) = 2.52, 95% CI: 0.49−12.97,P = 0.250] (Figure 4). The results showed lower risk of re-hospitalization (adjusted HR = 0.09, 95% CI: 0.03−0.31,P < 0.001; Figure 5), but there were no differences in MACE, TVR, MI and re-angina between two groups.\n\nFigure 4 Kaplan-Meier curves of major adverse cardiovascular events.\n\nPCSK-9: proprotein convertase subtilisin/kexin type 9.\n\nFigure 5 Hazard ratios of using PCSK-9 inhibitor for MACE and other events.\n\nHR: hazard ratio; MACE: major adverse cardiovascular events; PCSK-9: proprotein convertase subtilisin/kexin type 9.\n\nDISCUSSION\n\nThe management of LDL-C plays a significant role in the prevention of ASCVD. However, our study showed that less than 10% of patients reached the recommended LDL-C ≤ 1.4 mmol/L goal when patients were with very high risk at baseline in China. After being discharged from hospitals over six months, patients who received PCSK-9 inhibitor therapy had a significant LDL-C reduction, about 50% of patients reached ≤ 1.4 mmol/L goal compared to those with statins-based therapy. There was no significant difference in reducing the risk of MACE between PCSK-9 inhibitor group and statins-based group.\n\nThe guidelines of dyslipidemia managements recommended that patients with acute coronary syndrome should start with medium-intensity statins, and adjust the appropriated dosage according to the efficacy and tolerance of individuals. If the cholesterol level fails to meet the goal, other lipid-regulating drugs, including Ezetimibe and PCSK-9 inhibitors, should be considered.[6–8] Compared to Zhang, et al.[9] study that only 14.5% of patients with dyslipidemia in China receive lipid lowering treatment, our study showed that more than 80% of patients received moderate or high-intensity statins-based therapy before PCI, which may be partially explained by higher awareness of hyperlipidemia management in ASCVD patients. Our study demonstrated a highly efficient lowering of LDL-C with PCSK-9 inhibitors treatment among the patients with very high risk of ASCVD, which was consistent with previous RCTs studies. The meta-analysis study showed that PCSK-9 inhibitors significantly reduced LDL-C by 54% to 74% versus placebo and 26% to 46% versus Ezetimibe.[16]\n\nThe most common anti-hyperlipidemia medicine was statins monotherapy before and discharged from hospitals. Ezetimibe can offer additional LDL-C reduction and be recommended to add to maximally tolerated statin therapy when the LDL-C level remains ≥ 1.8 mmol/L in patients with very high risk of ASCVD. However, only 15 patients at baseline and 63 patients during the follow-up in our study received combination therapy (statins + Ezetimibe) in China. Combination therapy (statins + Ezetimibe) was more effective for achieving LDL-C goals as safety as the equivalent statin monotherapy, which has been supported by many clinical trials.[14,15] Few patients treated by statins combined with Ezetimibe in our observational study could be one of the reasons of low achievement rate of LDL-C level at baseline. A total of 453 patients were prescribed PCSK-9 inhibitors after PCI with about one-month continuous time on treatment. The low usage of PCSK-9 inhibitors in China was consistent with other studies published in the USA, UK, and other countries.[17–19] Many factors may contribute to the low rates of prescribing for PCSK-9 inhibitors. The high cost of treatment in China could be the main reason limited the use of PCSK-9 inhibitors. With acceptable PCSK-9 inhibitor price or be reimbursed, it could benefit more patients especially those with very high risk of ASCVD in Chinese real world clinical practice.\n\nThis study is a real world, multi-center study based on the national-level patients’ cohort covered more than 30 hospitals in China. Therefore, our results could be generalized to the whole Chinese patients with very high risk of ASCVD. The study results derived from analysis by a propensity score matching, applied to minimize confounding and indication bias. However, it is capable to correct only known confounders and some predictive factors were unbalanced after matching, which could be considered as limitations of real world study design. We demonstrated a superior real world effectiveness of PCSK-9 inhibitor despite short-term usage and six months follow-up. Whether the short-term effectiveness could accurately reflect long-term outcomes for patients who received PCSK-9 inhibitor is unknown and requires further study.\n\nLIMITATIONS\n\nThis study is an observational study on patients underwent PCI from the real world, which has several limitations. Firstly, as this is an observational study, despite the establishment of full adjusted Cox model and propensity score weighting to remove the potential confounding factors, some potential factors may exist, which we have not considered. Secondly, in the real world, due to the economic limitation, PSCK-9 inhibitor was used only for one month. Therefore, the effect of long-term treatment with PSCK-9 inhibitor on patients underwent PCI on lipid lowering efficacy and clinical outcomes could not be obtained. Last but not least, the follow-up time of this study was six months, and the effect of PSCK-9 inhibitor on long-term prognosis required further data analysis in the next follow-up later.\n\nCONCLUSIONS\n\nIn conclusion, treatment with PCSK-9 inhibitors combined with statins could significantly reduce LDL-C levels among patients with very high risk of ASCVD in China real world clinical practice.\n\nACKNOWLEDGMENTS\n\nThis study was supported by the China Cardiovascular Health Alliance-Advanced Fund (2019-CCA-ACCESS-054), and the Beijing Lisheng Cardiovascular Health Foundation Pilot Fund Key Projects. All authors had no conflicts of interest to disclose.\n==== Refs\nReferences\n\n1 Baigent C, Keech A, Kearney PM, et al Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins Lancet 2005 366 1267 1278 10.1016/S0140-6736(05)67394-1 16214597\n2 Hess CN, Clare RM, Neely ML, et al Differential occurrence, profile, and impact of first recurrent cardiovascular events after an acute coronary syndrome Am Heart J 2017 187 194 203 10.1016/j.ahj.2017.01.016 28454804\n3 Li JJ, Zheng X, Li J Statins may be beneficial for patients with slow coronary flow syndrome due to its anti-inflammatory property Med Hypotheses 2007 69 333 337 10.1016/j.mehy.2006.09.070 17215087\n4 Cholesterol Treatment Trialists' (CTT) Collaboration, Baigent C, Blackwell L, et al Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170, 000 participants in 26 randomised trials Lancet 2010 376 1670 1681 10.1016/S0140-6736(10)61350-5 21067804\n5 Ference BA, Ginsberg HN, Graham I, et al Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel Eur Heart J 2017 38 2459 2472 10.1093/eurheartj/ehx144 28444290\n6 Zhu JR, Gao RL, Zhao SP, et al [Guidelines for prevention and treatment of dyslipidemia in Chinese adults (revised in 2016)] Chinese Circulation Journal 2016 31 937 953 10.3969/j.issn.1000-3614.2016.10.001\n7 Benjamin EJ, Virani SS, Callaway CW, et al Heart disease and stroke statistics-2018 update: a report from the American Heart Association Circulation 2018 137 e67 e492 10.1161/CIR.0000000000000558 29386200\n8 Mach F, Baigent C, Catapano AL, et al 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk Eur Heart J 2020 41 111 188 10.1093/eurheartj/ehz455 31504418\n9 Zhang M, Deng Q, Wang L, et al Prevalence of dyslipidemia and achievement of low-density lipoprotein cholesterol targets in Chinese adults: a nationally representative survey of 163, 641 adults Int J Cardiol 2018 260 196 203 10.1016/j.ijcard.2017.12.069 29622441\n10 Li Y, Zhao SP, Ye P, et al [Status of cholesterol goal attainment for the primary and secondary prevention of atherosclerotic cardiovascular disease in dyslipidemia patients receiving lipid-lowering therapy: DYSIS-China subgroup analysis] Zhonghua Xin Xue Guan Bing Za Zhi 2016 44 665 670 10.3760/cma.j.issn.0253-3758.2016.08.006 27545124\n11 Koren MJ, Scott R, Kim JB, et al Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study Lancet 2012 380 1995 2006 10.1016/S0140-6736(12)61771-1 23141812\n12 Schwartz GG, Steg PG, Szarek M, et al Alirocumab and cardiovascular outcomes after acute coronary syndrome N Engl J Med 2018 379 2097 2107 10.1056/NEJMoa1801174 30403574\n13 Sabatine MS, Giugliano RP, Keech AC, et al Evolocumab and clinical outcomes in patients with cardiovascular disease N Engl J Med 2017 376 1713 1722 10.1056/NEJMoa1615664 28304224\n14 Savarese G, De Ferrari GM, Rosano GM, et al Safety and efficacy of ezetimibe: a meta-analysis Int J Cardiol 2015 201 247 252 10.1016/j.ijcard.2015.08.103 26301648\n15 Cannon CP, Blazing MA, Giugliano RP, et al Ezetimibe added to statin therapy after acute coronary syndromes N Engl J Med 2015 372 2387 2397 10.1056/NEJMoa1410489 26039521\n16 Toth PP, Worthy G, Gandra SR, et al Systematic review and network meta-analysis on the efficacy of evolocumab and other therapies for the management of lipid levels in hyperlipidemia J Am Heart Assoc 2017 6 e005367 10.1161/JAHA.116.005367 28971955\n17 Chamberlain AM, Gong Y, Shaw KM, et al PCSK-9 inhibitor use in the real world: data from the National Patient-Centered Research Network J Am Heart Assoc 2019 8 e011246 10.1161/JAHA.118.011246 31020929\n18 Elamin AFM, Grafton-Clarke C, Wen Chen K, et al Potential use of PCSK-9 inhibitors as a secondary preventative measure for cardiovascular disease following acute coronary syndrome: a UK real-world study Postgrad Med J 2019 95 61 66 10.1136/postgradmedj-2018-136171 30709868\n19 Tai MH, Shepherd J, Bailey H, et al Real world treatment patterns of PCSK-9 inhibitors among patients with dyslipidemia in Germany, Spain, and the United Kingdom Curr Med Res Opin 2019 35 829 835 10.1080/03007995.2018.1532885 30289004\n\n",
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"journal": "Journal of geriatric cardiology : JGC",
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"title": "Real world effectiveness of PCSK-9 inhibitors combined with statins versus statins-based therapy among patients with very high risk of atherosclerotic cardiovascular disease in China (RWE-PCSK study).",
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"abstract": "Pulmonary hypertension (PH) is a known complication of pulmonary sarcoidosis and is associated with higher morbidity and mortality. Currently, there are no approved PH-targeted therapies for sarcoidosis-associated pulmonary hypertension (SAPH). Macitentan is frequently used as treatment for pulmonary arterial hypertension, but no results are known in the SAPH population.\nWe investigated the safety and effect of macitentan as treatment for SAPH.\nWe retrospectively reviewed our patient database for all SAPH patients receiving macitentan as treatment, with a minimum follow-up of twelve months for monitoring safety. Safety outcomes included reported side-effects, hospitalisations and mortality. Furthermore, six-minutes walking distance, New York Heart Association functional class and NT-proBNP levels were collected.\nSix cases (three men) with a median age of 64 years (range 52-74 years) were identified. During macitentan treatment, one patient experienced side effects and aborted therapy after five days of treatment and died 16 months later. Three patients were hospitalised during treatment for congestive heart failure. Four patients showed improvement of their functional class and three patients in exercise capacity after 12 months of therapy.\nMacitentan was well tolerated in five out of six cases with severe pulmonary sarcoidosis and PH. Functional capacity improved in four cases. Prospective controlled trials are warranted before therapeutic recommendations can be made. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (1): 74-78).",
"affiliations": "St. Antonius Hospital Nieuwegein, the Netherlands, department of cardiology.;St. Antonius Hospital Nieuwegein, the Netherlands, department of cardiology.;St. Antonius Hospital Nieuwegein, the Netherlands, department of cardiology.;St. Antonius Hospital Nieuwegein, the Netherlands, department of pulmonology.;St. Antonius Hospital Nieuwegein, the Netherlands, department of pulmonology.;St. Antonius Hospital Nieuwegein, the Netherlands, department of pulmonology.;St. Antonius Hospital Nieuwegein, the Netherlands, department of cardiology.",
"authors": "Mathijssen|H|H|;Huitema|M P|MP|;Bakker|A L M|ALM|;Mager|J J|JJ|;Snijder|R J|RJ|;Grutters|J C|JC|;Post|M C|MC|",
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"fulltext": "\n==== Front\nSarcoidosis Vasc Diffuse Lung Dis\nSarcoidosis Vasc Diffuse Lung Dis\nSarcoidosis, Vasculitis, and Diffuse Lung Diseases\n1124-0490 2532-179X Mattioli 1885 Italy \n\nSVDLD-37-74\n10.36141/svdld.v37i1.9292\nCase Series\nSafety of macitentan in sarcoidosis-associated pulmonary hypertension: a case-series\nMathijssen H. 12 Huitema M.P. 1 Bakker A.L.M. 1 Mager J.J. 2 Snijder R.J. 2 Grutters J.C. 23 Post M.C. 14 1 St. Antonius Hospital Nieuwegein, the Netherlands, department of cardiology\n2 St. Antonius Hospital Nieuwegein, the Netherlands, department of pulmonology\n3 University Medical Centre Utrecht, the Netherlands, department of pulmonology\n4 University Medical Centre Utrecht, the Netherlands, department of cardiology\nCorrespondence: H. Mathijssen, MD St. Antonius Hospital Koekoekslaan 1, 3435CM, Nieuwegein, The Netherlands E-mail: h.mathijssen@antoniusziekenhuis.nl\n2020 \n15 3 2020 \n37 1 74 78\n03 2 2020 05 3 2020 Copyright: © 2020 SARCOIDOSIS VASCULITIS AND DIFFUSE LUNG DISEASES2020This work is licensed under a Creative Commons Attribution 4.0 International LicenseBackground:\nPulmonary hypertension (PH) is a known complication of pulmonary sarcoidosis and is associated with higher morbidity and mortality. Currently, there are no approved PH-targeted therapies for sarcoidosis-associated pulmonary hypertension (SAPH). Macitentan is frequently used as treatment for pulmonary arterial hypertension, but no results are known in the SAPH population.\n\nObjective:\nWe investigated the safety and effect of macitentan as treatment for SAPH.\n\nMethods:\nWe retrospectively reviewed our patient database for all SAPH patients receiving macitentan as treatment, with a minimum follow-up of twelve months for monitoring safety. Safety outcomes included reported side-effects, hospitalisations and mortality. Furthermore, six-minutes walking distance, New York Heart Association functional class and NT-proBNP levels were collected.\n\nResults:\nSix cases (three men) with a median age of 64 years (range 52-74 years) were identified. During macitentan treatment, one patient experienced side effects and aborted therapy after five days of treatment and died 16 months later. Three patients were hospitalised during treatment for congestive heart failure. Four patients showed improvement of their functional class and three patients in exercise capacity after 12 months of therapy.\n\nConclusion:\nMacitentan was well tolerated in five out of six cases with severe pulmonary sarcoidosis and PH. Functional capacity improved in four cases. Prospective controlled trials are warranted before therapeutic recommendations can be made. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (1): 74-78)\n\nsarcoidosismacitentanpulmonary hypertensionendothelin receptor antagonist\n==== Body\nIntroduction\nPulmonary hypertension (PH) is a known complication of pulmonary sarcoidosis. Prevalence numbers range from 3% in early stage pulmonary sarcoidosis, up to 70% in patients awaiting lung transplantation.(1,2) Sarcoidosis-associated pulmonary hypertension (SAPH) is associated with increased morbidity and mortality.(3,4) The underlying pathophysiological mechanism of SAPH remains unclear. Hypothesised mechanisms include destruction of the pulmonary vascular bed by pulmonary fibrosis, granulomatous vasculopathy, extrinsic compression from thoracic lymphadenopathy, mediastinal fibrosis and cardiac involvement. (4–6) Currently, there are no approved PH-targeted treatments for SAPH. Although endothelin receptor antagonists are well used in pulmonary arterial hypertension, studies have shown mixed results in SAPH.(7,8) To our best knowledge, the safety and effect of the endothelin receptor antagnost macitentan in SAPH patients has not been evaluated. We report the results of a single centre case-series.\n\nMethods\nThe St. Antonius hospital is a tertiary referral centre for sarcoidosis and PH. We retrospectively reviewed our patient database between 2014-2018 to include all patients aged ≥18 years, diagnosed with both sarcoidosis and PH, received macitentan as treatment (mono- or dual therapy), and at least 12 months of follow-up for monitoring safety outcomes. The diagnosis of sarcoidosis was based on current clinical diagnostic guidelines.(9) PH was confirmed by right heart catheterization (RHC) and defined as a resting mean pulmonary artery pressure (mPAP) of ≥25mmHg. The decision to start treatment was made by a multidisciplinary team. Safety outcomes included side effects leading to (temporarily) aborting therapy, hospitalisation for heart failure or dyspnoea, and death.\n\nBaseline was defined as start of PH-targeted treatment. At baseline, N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, forced vital capacity (FVC), New York Heart Association (NYHA) functional class were measured and a six-minute walking distance (6-MWD) was obtained. Macitentan was administered at a dose of 10mg/day. If applicable, sildenafil was dosed 20mg three times daily. All outcome parameters were obtained by chart review. Written informed consent was obtained in all cases. The study was approved by the local institutional review board.\n\nResults\nFigure 1 shows the flowchart of case selection. In total, 27 patients with SAPH were identified between 2014-2018. Of these patients, 8 were treated with macitentan. Of these, 6 patients had a follow-up of at least twelve months, while the other two patients were recently started on macitentan. The baseline characteristics and outcome parameters of all cases are shown in table 1. Six patients (three men) with a median age of 64 years (range 52-74 years) were identified. All cases were Caucasian patients with biopsy confirmed sarcoidosis. RHC showed a median mPAP of 49 (27 – 66) mmHg and the pulmonary vascular resistance (PVR) was > 3 Wood Units (WU) in all cases.\n\nFig. 1. Table 1. Case characteristics\n\n\tCase 1\tCase 2\tCase 3\tCase 4\tCase 5\tCase 6\t\nDemographics\t\nAge (years)\t60\t74\t64\t52\t69\t65\t\nMale / female\tFemale\tMale\tMale\tFemale\tFemale\tMale\t\nTime since sarcoidosis diagnosis (years)\t8,3\t4,3\t20\t0,2\t22,5\t12,2\t\nPulmonary function\t\nFEV1 (% predicted)\t75.9\t90.0\t49.0\t54.9\t36.9\t25.6\t\nFVC (% predicted)\t104.1\t88.0\t69.0\t62.5\t50.4\t75.0\t\nDLCO SB (% predicted)\t76.4\t25.0\t-\t40.3\t13.9\t57.1\t\nFibrosis on HRCT\tYes\tYes\tNo\tNo\tYes\tYes\t\nHeamodynamics\t\t\t\t\t\t\t\nsPAP / dPAP (mmHg)\t110/40\t60/32\t43/19\t96/49\t85/35\t76/30\t\nmPAP (mmHg)\t63\t37\t27\t66\t55\t43\t\nPAWP (mmHg)\t6\t11\t10\t18\t5\t12\t\nPVR (Wood Units)\t10.3\t10.4\t3.2\t11.3\t13.9\t7.2\t\nCardiac output (L/min)\t5.6\t2.5\t5.3\t4.3\t3.6\t4.6\t\nSarcoidosis treatment\t\nSupplemental oxygen use\tNo\tYes\tYes\tYes\tYes\tNo\t\nImmunosuppressive treatment\tNo\tYes\tYes\tYes\tNo\tYes\t\nEscalation of immunosuppressive treatment during follow-up\tYes\tNo\tNo\tNo\tYes\tNo\t\nPH treatment\t\nInitial PH-targeted therapy\tMacitentan\tMacitentan\tDual\tMacitentan\tDual\tSildenafil\t\nTime before start dual treatment (months)\t3\t1\t-\t10\t-\t15\t\nFollow-up duration (months)\t42\t12\t12\t42\t36\t18\t\nOutcome parameters\t\nNYHA functional class at baseline\tIII\tIII\tIII\tIII\tIV\tIII\t\nNYHA functional class at 12 months\tII\tIII\tII\tII\tIII\tIII\t\nNYHA functional class at 24 months\tII\tIII\tII\tII\tIII\tIV\t\n6-MWD at baseline (meters)\t327\t365\t445\t364\t145\t341\t\n6-MWD at 12 months (meters)\t439\t-\t457\t367\t340\t244\t\n6-MWD at 24 months (meters)\t456\t-\t-\t422\t243\t-\t\nNT-proBNP at baseline (pg/mL)\t136\t959\t52\t3382\t5875\t346\t\nNT-proBNP at 12 months (pg/mL)\t110\t1516\t45\t3512\t343\t688\t\nNT-proBNP at 24 months (pg/mL)\t38\t-\t-\t1543\t210\t-\t\nFEV1: forced expiratory volume in 1 second; FVC: forced vital capacity; DLCO SB: diffusing capacity of the lung for carbon monoxide single breath; HRCT: high resolution chest tomography; sPAP: systolic pulmonary artery pressure; dPAP: diastolic pulmonary artery pressure; mPAP: mean pulmonary artery pressure; PAWP: pulmonary arterial wedge pressure; PVR: pulmonary vascular resistance; PH: pulmonary hypertension; NYHA: New York Heart Association; 6-MWD: six minute walking distance\n\nCase 1 was 60-year old female with suspected fibrosing pulmonary sarcoidosis and severe PH. Macitentan was started after PH diagnosis. After two months, sarcoidosis was proven on biopsy and immunosuppressive therapy with methotrexate 15mg/week was initiated due to active disease on FDG-PET (fluodeoxyglucose-positron emission tomography) with compression of the pulmonary artery. At three months, echocardiography showed improved right ventricular function and sildenafil was added. At 7 months, immunosuppressive therapy was switched to azathioprine 100mg/day due to side effects (depressive thoughts). At one year, there was an improvement of mPAP (47mmHg), PVR (5.0WU), 6-MWD, and NYHA functional class. NT-proBNP levels and the FVC remained stable. During her 3.5 years follow-up, macitentan was well tolerated with no reported side effects.\n\nCase 2 was a 74-year old male with fibrosing pulmonary sarcoidosis. RHC showed severe PH and macitentan was started. After four weeks, he was admitted for pneumonia and congestive heart failure. After recovery, sildenafil was added. At 12 months, no side effects were reported. NT-proBNP levels had increased, while NYHA functional class and FVC remained stable. A 6-MWD was not performed during follow-up due to persisting disabilities after a cerebrovascular event.\n\nCase 3 was 64-year old male with pulmonary sarcoidosis. After PH diagnosis, macitentan and sildenafil were started with good effect on NYHA functional class at 12 months while other outcome parameters remained stable or showed mild improvement. Macitentan was well tolerated.\n\nCase 4 was a 52-year old female, with recently diagnosed pulmonary sarcoidosis and severe PH. Macitentan treatment was started with initial good effect on functional capacity. At 10 months, she was hospitalized due to congestive heart failure. After recovery, RHC was repeated which showed a mPAP of 58mmHg and PVR 12.5WU. Sildenafil was added and after 24 months all outcome parameters improved, while FVC remained stable. During 3.5 years follow-up, macitentan was well tolerated and the patient remained clinically stable.\n\nCase 5 was 69-year old female patient with fibrosing pulmonary sarcoidosis and severely reduced exercise capacity. Dual treatment with macitentan and sildenafil was started. The FDG-PET showed enhanced inflammatory activity, and high-dosage prednisone was started at 6 weeks. At 12 months, there was an improvement in 6-MWD (340 vs 145m), NT-proBNP and NYHA functional class. FVC also improved during treatment (74.0% vs 50.4%). Echocardiography showed improvement in right ventricular function after 12 months. No side effects were reported during follow-up.\n\nCase 6 was a 65-year old male patient with fibrosing pulmonary sarcoidosis. After PH diagnosis, initial treatment with sildenafil was started. After 12 months of treatment, RHC showed a mPAP of 47mmHg with no subjective improvement. FDG-PET revealed no signs of inflammatory activity and macitentan was initiated. Macitentan was not well tolerated and aborted after five days due to severe muscle aches and fatigue. Several days later, this patient was hospitalised for increasing dyspnoea and sildenafil was aborted due to no clinical improvement. The patient was discharged home with oxygen therapy and diuretics and died sixteen months later due to right ventricular failure.\n\nDiscussion\nTo the best of our knowledge, this is the first case series describing the safety and effect of macitentan, either as monotherapy or as dual treatment with sildenafil, as treatment for SAPH in predominantly patients with fibrosing pulmonary sarcoidosis. We found that macitentan was well tolerated in five patients, but one patient aborted macitentan therapy due to side effects and died sixteen months later.\n\nJudson et al. investigated the role of the endothelin receptor antagonist ambrisentan as treatment for SAPH. They found that 11 out of 21 patients aborted ambrisentan therapy, mostly due to increasing dyspnoea.(7) In our case series, no patients aborted therapy due to dyspnoea. However three patients were hospitalised for dyspnoea due to congestive heart failure, but recovered with diuretic treatment. A known side-effect of a pulmonary vasodilator in parenchymal lung disease is the possible worsening of ventilation/perfusion mismatch, which could lead to increasing dyspnoea.(10,11) Unfortunately, we were not able to evaluate the effect of macitentan on gas exchange before and during treatment due to missing data for arterial blood gas analyses. The found rate of adverse events are in line with the MUSIC trial. This study showed that 12 months of macitentan therapy was well tolerated in patients with idiopathic pulmonary fibrosis, with 12.6% of patients aborting therapy due to adverse events.(12)\n\nFurthermore, four patients showed improvement of their functional class and three patients in exercise capacity after 12 months of therapy. A possible confounder for this improvement is the escalating immunosuppressive treatment for increased sarcoidosis activity. It is known In pulmonary sarcoidosis that immunosuppressive treatment can improve FVC.(13) This could explain the functional improvement in case 5 as this was the only case with an improved FVC during follow-up compared to baseline. In all other cases the FVC remained stable.\n\nIn conclusion, this is the first case-series describing the safety and effect of macitentan therapy in SAPH. Macitentan was well tolerated in five out of six cases with severe pulmonary sarcoidosis and PH. Functional capacity improved in four out of six cases. However, results of this case series need to be interpreted with caution. Prospective controlled trials are warranted before therapeutic recommendations can be made.\n\nAbbreviation list:\n6-MWD:six-minute walking distance\n\nFDG-PET:fluodeoxyglucose-positron emission tomography\n\nFVC:forced vital capacity\n\nmPAP:mean pulmonary artery pressure\n\nNT-proBNP:N-terminal pro-brain natriuretic peptide\n\nNYHA:New York Heart Association\n\nPH:pulmonary hypertension\n\nPVR:pulmonary vascular resistance\n\nSAPH:sarcoidosis-associated pulmonary hypertension\n\nRHC:right heart catheterization\n\nWU:Wood Units\n==== Refs\nReferences\n1 Huitema MP Bakker ALM Mager JJ Rensing BJWM Smits F Snijder RJ Prevalence of pulmonary hypertension in pulmonary sarcoidosis; the first large European prospective study Eur Respir J [Internet] 2019 Jul 18 1900897. Available from: http://erj.ersjournals.com/lookup/doi/10.1183/13993003.00897-2019 \n2 Shorr AF Helman DL Davies DB Nathan SD Pulmonary hypertension in advanced sarcoidosis: Epidemiology and clinical characteristics Eur Respir J 2005 May 25 5 783 8 15863633 \n3 Baughman RP Engel PJ Taylor L Lower EE Survival in sarcoidosis-associated pulmonary hypertension: The importance of hemodynamic evaluation Chest 2010 Nov 1 138 5 1078 1085 20348196 \n4 Sulica R Teirstein AS Kakarla S Nemani N Behnegar A Padilla ML Distinctive clinical, radiographic, and functional characteristics of patients with sarcoidosis-related pulmonary hypertension Chest 2005 128 3 1483 1489 16162747 \n5 Takemura T Matsui Y Saiki S Mikami R Pulmonary vascular involvement in sarcoidosis: A report of 40 autopsy cases Hum Pathol 1992 23 11 1216 1223 1427751 \n6 Nunes H Humbert M Capron F Brauner M Sitbon O Battesti JP Pulmonary hypertension associated with sarcoidosis: Mechanisms, haemodynamics and prognosis Thorax 2006 Jan 61 1 68 74 16227329 \n7 Judson MA Highland KB Kwon S Donohue JF Aris R Craft N Ambrisentan for sarcoidosis associated pulmonary hypertension Sarcoidosis Vasc Diffus Lung Dis 2011 28 2 139 145 \n8 Baughman RP Culver DA Cordova FC Padilla M Gibson KF Lower EE Bosentan for sarcoidosis-associated pulmonary hypertension: A double-blind placebo controlled randomized trial Chest 2014 145 4 810 817 24177203 \n9 Costabel U Hunninghake GW ATS/ERS/WASOG statement on sarcoidosis. Sarcoidosis Statement Committee. American Thoracic Society. European Respiratory Society. World Association for Sarcoidosis and Other Granulomatous Disorders Eur Respir J 1999 14 4 735 737 10573213 \n10 Corte TJ Keir GJ Dimopoulos K Howard L Corris PA Parfitt L Bosentan in pulmonary hypertension associated with fibrotic idiopathic interstitial pneumonia Am J Respir Crit Care Med 2014 190 208 217 24937643 \n11 Raghu G Treatment of Idiopathic Pulmonary Fibrosis With Ambrisentan Ann Intern Med 2013 158 641 649 23648946 \n12 Raghu G Million-Rousseau R Morganti A Perchenet L Behr J Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial Eur Respir J 2013 Dec 42 6 1622 1632 23682110 \n13 Nunes H Jeny F Bouvry D Uzunhan Y Valeyre D Indications for treatment of sarcoidosis Curr Opin Pulm Med 2019 25 5 505 518 31365385\n\n",
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"issue": "37(1)",
"journal": "Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG",
"keywords": "endothelin receptor antagonist; macitentan; pulmonary hypertension; sarcoidosis",
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"mesh_terms": "D000368:Aged; D000959:Antihypertensive Agents; D062186:Arterial Pressure; D016208:Databases, Factual; D065128:Endothelin Receptor Antagonists; D017079:Exercise Tolerance; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary; D008297:Male; D008875:Middle Aged; D011651:Pulmonary Artery; D011743:Pyrimidines; D020127:Recovery of Function; D012189:Retrospective Studies; D017565:Sarcoidosis, Pulmonary; D013449:Sulfonamides; D013997:Time Factors; D016896:Treatment Outcome",
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"title": "Safety of macitentan in sarcoidosis-associated pulmonary hypertension: a case-series.",
"title_normalized": "safety of macitentan in sarcoidosis associated pulmonary hypertension a case series"
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"abstract": "ESR1 mutation is frequently encountered in hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC), especially after aromatase inhibitor (AI) therapy, as a mechanism of resistance to endocrine therapy. Circulating tumor DNA-based detection of ESR1 mutation in plasma has been demonstrated as a prognostic and predictive factor for poor outcomes in subsequent AI therapy. In this case report, for the first time, we describe the detection of ESR1 mutation (p.Tyr537Ser) only in the cerebrospinal fluid (CSF) and not in the plasma of a patient with isolated leptomeningeal progression who was treated with AI for HR-positive, HER2-negative MBC (bone metastasis only). Circulating tumor DNA levels also appeared to be correlated with clinical evolution. We suggest that in the presence of isolated leptomeningeal metastasis and when tamoxifen or AI has been prescribed for HR-positive MBC, CSF should be screened for ESR1 mutations to potentially adjust systemic treatment.",
"affiliations": "Department of Medical Oncology, Institut Curie, PSL Research University, Saint Cloud, France.;Department of Genetics, Institut Curie, PSL Research University, Paris, France.;Department of Medical Oncology, Institut Curie, PSL Research University, Paris & Saint Cloud, France.;Department of Medical Oncology, Institut Curie, PSL Research University, Saint Cloud, France.;Department of Medical Oncology, Institut Curie, PSL Research University, Saint Cloud, France.",
"authors": "Carausu|Marcela|M|https://orcid.org/0000-0002-2414-2500;Melaabi|Samia|S|https://orcid.org/0000-0002-6508-2663;Pierga|Jean-Yves|JY|https://orcid.org/0000-0002-2863-9995;Bidard|François-Clément|FC|https://orcid.org/0000-0001-5932-8949;Cabel|Luc|L|https://orcid.org/0000-0001-5515-9180",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.4048/jbc.2020.23.e4",
"fulltext": "\n==== Front\nJ Breast Cancer\nJ Breast Cancer\nJBC\nJournal of Breast Cancer\n1738-6756 2092-9900 Korean Breast Cancer Society \n\n10.4048/jbc.2020.23.e4\nCase Report\n\nESR1 Mutation Detection and Dynamics in Meningeal Carcinomatosis in Breast Cancer\nhttps://orcid.org/0000-0002-2414-2500Carausu Marcela 1 https://orcid.org/0000-0002-6508-2663Melaabi Samia 2 https://orcid.org/0000-0002-2863-9995Pierga Jean-Yves 34 https://orcid.org/0000-0001-5932-8949Bidard François-Clément 15 https://orcid.org/0000-0001-5515-9180Cabel Luc 15 1 Department of Medical Oncology, Institut Curie, PSL Research University, Saint Cloud, France.\n2 Department of Genetics, Institut Curie, PSL Research University, Paris, France.\n3 Department of Medical Oncology, Institut Curie, PSL Research University, Paris & Saint Cloud, France.\n4 Paris Descartes University, Paris, France.\n5 Saint Quentin en Yvelines University, Paris Saclay University, Saint Cloud, Paris, France.\nCorrespondence to Luc Cabel. Department of Medical Oncology, Institut Curie, 35 Rue Dailly, 92210 Saint Cloud, France. luc.cabel@curie.fr\n4 2020 \n19 12 2019 \n23 2 218 223\n30 9 2019 03 12 2019 © 2020 Korean Breast Cancer Society2020Korean Breast Cancer SocietyThis 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.ESR1 mutation is frequently encountered in hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC), especially after aromatase inhibitor (AI) therapy, as a mechanism of resistance to endocrine therapy. Circulating tumor DNA-based detection of ESR1 mutation in plasma has been demonstrated as a prognostic and predictive factor for poor outcomes in subsequent AI therapy. In this case report, for the first time, we describe the detection of ESR1 mutation (p.Tyr537Ser) only in the cerebrospinal fluid (CSF) and not in the plasma of a patient with isolated leptomeningeal progression who was treated with AI for HR-positive, HER2-negative MBC (bone metastasis only). Circulating tumor DNA levels also appeared to be correlated with clinical evolution. We suggest that in the presence of isolated leptomeningeal metastasis and when tamoxifen or AI has been prescribed for HR-positive MBC, CSF should be screened for ESR1 mutations to potentially adjust systemic treatment.\n\nBreast neoplasmsCerebrospinal fluidEstrogen receptor alphaLiquid biopsyMeningeal carcinomatosis\n==== Body\nINTRODUCTION\nLeptomeningeal metastasis (LM) is the third most common metastatic complication of the central nervous system (CNS), which is defined by the seeding of the leptomeninges by malignant cells. The diagnosis is based on the cerebrospinal fluid (CSF) cytology with the detection of tumor cells or neuroimaging associated with suggestive clinical findings [1].\n\nLM is reported in up to 5% of patients with solid tumors, most commonly breast cancer (approximately 5%), lung cancer, and melanoma, and its incidence has increased in recent years [12]. Despite considerable progress in the treatment of breast cancer (BC) and multimodal therapy, the prognosis of LM remains dismal with a median overall survival (OS) of about 4 months [123].\n\nThe treatment for LM comprises active systemic therapy, intrathecal therapy, and radiotherapy or surgery when necessary. Due to lack of informative clinical trials, current recommendations are mostly based on expert opinion and consensus but with a low level of evidence, leaving a number of questions unresolved, such as the most reliable criteria for diagnosis and response to treatment, as well as the best indicators of time and type of treatment required for LM [2].\n\nCirculating tumor DNA (ctDNA) is a fraction of cell-free DNA released by the tumor cells, which can be measured in bodily fluids, such as plasma, sputum, urine, or CSF, and correlates with the tumor burden; thus, it is emerging as a new, noninvasive method to monitor and characterize malignant diseases. Numerous ctDNA applications have been demonstrated and several others are still under investigation. It is an important method of diagnosis, genomic characterization, and identification of mechanisms of resistance for precision treatment, monitoring of response to therapy, and relapse prediction [4]. The application of this type of liquid biopsy is also being increasingly studied in BC, and the prognostic value of detection and monitoring of the variant allele frequency (VAF) of ESR1 mutations (the gene encoding the main estrogen receptor) in plasma ctDNA has been demonstrated in hormone receptor (HR)-positive metastatic breast cancer (MBC) [5].\n\nHowever, it has been shown that plasma ctDNA is not always a reliable marker of the genomic and quantitative analysis of primary or metastatic CNS tumors, as compared to the CSF ctDNA, which is a more sensitive biomarker for CNS lesions [6].\n\nHere, we report the detection of an ESR1 mutation only in the CSF ctDNA and not in the plasma ctDNA of a patient with isolated LM progression from MBC treated with the aromatase inhibitor (AI) anastrozole. VAF dynamics in CSF were correlated with clinical evolution.\n\nCASE REPORT\nA 37-year-old woman was diagnosed with locally advanced T2N1 (pN2a), grade SBR II (3+2+2), estrogen receptor (ER)-positive, progesterone receptor (PR)-positive, human epidermal growth factor receptor 2 (HER2)-negative invasive lobular carcinoma of the left breast, with 41% Ki-67 staining positivity. She was treated surgically and underwent tumorectomy and left axillary lymphadenectomy, completed by left mastectomy, followed by adjuvant chemotherapy with six cycles of doxorubicin/ cyclophosphamide, radiotherapy, and endocrine therapy. She received tamoxifen for 5 years and treatment was continued with letrozole during postmenopause for 3 years. Nine years after the end of the endocrine therapy, she presented with the first metastatic recurrence (bone); she was treated with metastatic first-line anastrozole endocrine and denosumab antiresorptive therapies. Due to the young age at diagnosis, the patient was referred to genetic counseling, which did not reveal any relevant family history; however, she was further recommended to undergo genetic analysis of BRCA1, BRCA2, and PALB2, which also did not demonstrate any deleterious constitutional mutations. Eighteen months later, she presented with facial dysesthesia, followed by confusion. The imaging assessment (based on computed tomography) was negative for CNS progression and showed stable extracranial disease, but a lumbar puncture confirmed the diagnosis of leptomeningeal metastasis (presence of malignant cells compatible with a breast origin and CSF protein levels increased to 13.6 g/L). Intrathecal chemotherapy with methotrexate (D1–D5, D1=D15) was initiated and systemic therapy with AI was continued with initial clinical and laboratory improvement (CSF protein: 0.96 g/L). The patient received 3 months of intrathecal methotrexate injections prior to the onset of clinical symptoms of neurological deterioration, increasing levels of CSF proteins, and diffuse leptomeningeal disease and hydrocephalus by magnetic resonance imaging (MRI), suggestive of leptomeningeal metastasis resistant to intrathecal methotrexate chemotherapy. Intrathecal and systemic anticancer treatments were stopped and the patient was referred to palliative care.\n\nPaired plasma and CSF samples were obtained at the initiation of intrathecal chemotherapy during the collection of routine samples for diagnosis owing to the isolated CNS progression. These samples were subsequently analyzed by digital droplet polymerase chain reaction (ddPCR), which revealed the presence of an ESR1 mutation in exon 8 of the CSF ctDNA, with a concentration of 521 copies/ml and VAF of 28.6%. The mutation was detected based on a method previously described by Jeannot et al. [7] (Figure 1). These findings were confirmed by Sanger sequencing, which identified the c.1610A>C, p. (Tyr537Ser) mutation in exon 8. No ESR1 mutations were detected in exon 5 or 8 by ddPCR (limit of detection: 0.1%) in the plasma. Interestingly, analysis of CSF ctDNA in a sample collected after one month of intrathecal chemotherapy, concomitant with the initial clinical improvement and decreased levels of CSF protein, showed a reduction in the previously detected ESR1 mutation concentration to 80 copies/mL with a VAF of 4.6%.\n\nFigure 1 ESR1 mutation detection in ctDNA. Graphical representation of ctDNA analysis in paired samples of plasma (A) and CSF, first sample, (B) second sample one month later, (C) by ddPCR. (D) Detection of ESR1 mutation only in CSF and identification of c.1610A>C, p.Tyr537Ser mutation in exon 8 by Sanger sequencing.\nctDNA = circulating tumor DNA; CSF = cerebrospinal fluid; ddPCR = digital droplet polymerase chain reaction; MUT Ex 8 = mutation in exon 8; WT Ex 8 = exon 8 wild-type; WT Ex 5 = exon 5 wild-type; VAF = variant allele frequency.\n\nAll procedures followed were in accordance with the ethical standards of the Helsinki Declaration of 1975 (in its most recently amended version). A patient consent could not be obtained because of the decease of the patient. All relating data have been anonymized and we present no identifiable material.\n\nDISCUSSION\nDue to anatomical considerations and diverged evolution that is frequently observed in CNS metastatic lesions [8], CSF is likely to be a more reliable source of ctDNA than plasma for liquid biopsy of CNS malignant lesions.\n\nSeveral studies assessing the applicability of CSF ctDNA in CNS tumors have shown the detection of tumor mutations in CSF even in the presence of negative cytology [69]. These studies have also demonstrated the detection of actionable genomic alterations with a better concordance with CNS lesions (than in plasma), a correlation with CNS tumor burden, and detection of resistance mutations [69]. Importantly, it has been demonstrated that the blood-brain barrier may prevent ctDNA from entering the circulation [6]; therefore, the blood samples are likely to be uninformative for genomic characterization of CNS tumors.\n\nMoreover, the discovery of target genetic alterations in CSF could have a major clinical impact [1011]; for example, prescription of osimertinib for leptomeningeal metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR)-T790M mutation detected only in CSF and not in blood, may confer a long-term benefit [10].\n\nA few studies have even highlighted the utility of CSF ctDNA levels to monitor response to treatment of LM in NSCLC or melanoma, and these studies have reported modifications in VAF of genomic alterations according to response to treatment or relapse of disease [9]. Furthermore, in a patient with HER2-positive MBC with divergent intra- and extracranial responses to treatment, paired CSF and plasma ctDNA analysis mirrored the distinct courses of CNS and systemic disease [12].\n\nIn the present case, CSF ctDNA dynamics were correlated with the initial response to one month of intrathecal chemotherapy, with a significant decrease in ESR1 mutation VAF (from 28.6% to 4.6%), concomitant with clinical and laboratory (decreased CSF protein levels) improvement. Regrettably, our ctDNA analysis was performed retrospectively and no sample was available after clinical deterioration. Although we used a sensitive method of detection (ddPCR), no ESR1 mutation was detected in the plasma ctDNA, which could be explained by isolated CNS progression that was not associated with significant release of ctDNA into the blood, and acquisition of the ESR1 mutation only in CNS.\n\nDespite concerns regarding the intracranial diffusion of systemic therapies, current guidelines recommend that adapted systemic therapies may be considered for most patients with MBC and LM [2]. Systemic anastrozole therapy was maintained in our patient because of stable extracranial disease. Tamoxifen (selective estrogen receptor modulator; SERM) and letrozole (AI) have been shown to have a good distribution in the CNS [13]. Improved survival has also been reported with the continuation of endocrine therapy, including AI, tamoxifen or fulvestrant (selective estrogen receptor downregulator; SERD) for MBC in the presence of CNS metastases [13].\n\nESR1 mutations have been frequently found to be associated with HR-positive MBC, particularly after exposure to AI, suggesting that their occurrence may be a mechanism underlying secondary resistance to hormone deprivation therapy. These mutations have been shown to be prognostic factors for poor survival and predictive factors for poor outcomes in case of subsequent AI therapy [5].\n\nAlthough some ESR1 mutations maintain a certain degree of sensitivity to endocrine therapy agents other than AI, such as SERM or SERD, the Y537S mutation that was identified in the present case, appears to have the highest level of resistance to tamoxifen and fulvestrant [14].\n\nCombination therapies with CDK4/6 inhibitors or PI3K-Akt-mTOR axis inhibitors appear to increase the efficacy of endocrine therapy in the presence of ESR1 mutations [5], and the preclinical data suggest that palbociclib and abemaciclib (CDK4/6 inhibitors) could both achieve effective drug-free levels in the CNS, with better CNS diffusion of abemaciclib [15]. To the best of our knowledge, this is the first study to report the detection of an ESR1 mutation in the CSF of a patient with isolated leptomeningeal progression, especially when this mutation was not detected in the plasma. We suggest that in the presence of isolated leptomeningeal metastasis and when tamoxifen or AI has been prescribed for HR-positive MBC, the presence of ESR1 mutations should be assessed in CSF to possibly adjust systemic therapy.\n\nConflict of Interest: François-Clément Bidard declares having submitted patents related to circulating tumor DNA detection. The other authors declare that they have no competing interests.\n\nAuthor Contributions:\nConceptualization: Cabel L.\n\nData curation: Melaabi S.\n\nWriting - original draft: Carausu M.\n\nWriting - review & editing: Melaabi S, Pierga JY, Bidard FC, Cabel L.\n==== Refs\n1 Remon J Le Rhun E Besse B Leptomeningeal carcinomatosis in non-small cell lung cancer patients: a continuing challenge in the personalized treatment era Cancer Treat Rev 2017 53 128 137 28110254 \n2 Le Rhun E Weller M Brandsma D Van den Bent M de Azambuja E Henriksson R EANO-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with leptomeningeal metastasis from solid tumours Ann Oncol 2017 28 iv84 99 28881917 \n3 Gauthier H Guilhaume MN Bidard FC Pierga JY Girre V Cottu PH Survival of breast cancer patients with meningeal carcinomatosis Ann Oncol 2010 21 2183 2187 20430906 \n4 Siravegna G Mussolin B Venesio T Marsoni S Seoane J Dive C How liquid biopsies can change clinical practice in oncology Ann Oncol 2019 30 1580 1590 31373349 \n5 Carausu M Bidard FC Callens C Melaabi S Jeannot E Pierga JY \nESR1 mutations: a new biomarker in breast cancer Expert Rev Mol Diagn 2019 19 599 611 31188645 \n6 De Mattos-Arruda L Mayor R Ng CK Weigelt B Martínez-Ricarte F Torrejon D Cerebrospinal fluid-derived circulating tumour DNA better represents the genomic alterations of brain tumours than plasma Nat Commun 2015 6 8839 26554728 \n7 Jeannot E Darrigues L Michel M Stern MH Pierga JY Rampanou A A single droplet digital PCR for ESR1 activating mutations detection in plasma bioRxiv 2019 507608 \n8 Brastianos PK Carter SL Santagata S Cahill DP Taylor-Weiner A Jones RT Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets Cancer Discov 2015 5 1164 1177 26410082 \n9 Boire A Brandsma D Brastianos PK Le Rhun E Ahluwalia M Junck L Liquid biopsy in central nervous system metastases: a RANO review and proposals for clinical applications Neuro Oncol 2019 21 571 584 30668804 \n10 Gortais H Daniel C Bidard FC Jeannot E Callens C Cabel L T790M EGFR mutation detection in cerebrospinal fluid and response to osimertinib in a lung cancer patient with meningeal carcinomatosis J Thorac Oncol 2017 12 e138 e139 28838712 \n11 Li N Liu Y Duan J Yang B Bai H Sun R Prognostic significance of molecular characteristics of cerebrospinal fluid for non-small cell lung cancer patients with leptomeningeal metastasis Thorac Cancer 2019 10 1673 1682 31368671 \n12 Siravegna G Geuna E Mussolin B Crisafulli G Bartolini A Galizia D Genotyping tumour DNA in cerebrospinal fluid and plasma of a HER2-positive breast cancer patient with brain metastases ESMO Open 2017 2 e000253 29067216 \n13 Bergen ES Berghoff AS Medjedovic M Rudas M Fitzal F Bago-Horvath Z Continued endocrine therapy is associated with improved survival in patients with breast cancer brain metastases Clin Cancer Res 2019 25 2737 2744 30647078 \n14 Toy W Weir H Razavi P Lawson M Goeppert AU Mazzola AM Activating ESR1 mutations differentially impact the efficacy of ER antagonists Cancer Discov 2017 7 277 287 27986707 \n15 Raub TJ Wishart GN Kulanthaivel P Staton BA Ajamie RT Sawada GA Brain exposure of two selective dual CDK4 and CDK6 inhibitors and the antitumor activity of CDK4 and CDK6 inhibition in combination with temozolomide in an intracranial glioblastoma xenograft Drug Metab Dispos 2015 43 1360 1371 26149830\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1738-6756",
"issue": "23(2)",
"journal": "Journal of breast cancer",
"keywords": "Breast neoplasms; Cerebrospinal fluid; Estrogen receptor alpha; Liquid biopsy; Meningeal carcinomatosis",
"medline_ta": "J Breast Cancer",
"mesh_terms": null,
"nlm_unique_id": "101314183",
"other_id": null,
"pages": "218-223",
"pmc": null,
"pmid": "32395380",
"pubdate": "2020-04",
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"title": "ESR1 Mutation Detection and Dynamics in Meningeal Carcinomatosis in Breast Cancer.",
"title_normalized": "esr1 mutation detection and dynamics in meningeal carcinomatosis in breast cancer"
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"abstract": "OBJECTIVE\nWe aimed to assess the potential of near-infrared (NIR) imaging during minimally invasive oesophagectomy in patients with distal oesophageal cancer for detection of nodal metastases inside and outside the standard en bloc surgical field.\n\n\nMETHODS\nWe enrolled 6 patients diagnosed with distal oesophageal cancer for intraoperative lymphatic mapping with NIR imaging. Indocyanine green dye was injected endoscopically in 8 corners of the primary tumour at the start of the operation. The minimally invasive oesophagectomy with en bloc lymphadenectomy was performed using 3D optics. A separate endoscopic fluorescence imaging system was used to systematically detect the NIR signal of 23 lymphatic stations. The NIR-positive stations outside the en bloc resection area were also removed for histological analysis.\n\n\nRESULTS\nLymphatic mapping was successful in all patients. The NIR-positive areas were most commonly detected in the lower mediastinum (100% of patients), cardia (83%), region of the left gastric artery (67%), celiac axis (50%) and pericardial-diaphragmatic groove (50%). We detected NIR-positive areas outside the traditional en bloc field above the azygous arch in 50% of the patients. A total of 182 lymph nodes were resected from 6 patients. In 3 patients, a total of 19 lymph node metastases were detected, 4 of which were outside the en bloc field.\n\n\nCONCLUSIONS\nNIR imaging can be useful for detecting lymphatic stations that most likely present with metastatic disease and to guide the tailored extension of the traditional lymphadenectomy.",
"affiliations": "Department of Surgery, Central Finland Central Hospital, Jyväskylä, Finland.;Department of Surgery, Central Finland Central Hospital, Jyväskylä, Finland.;Department of Surgery, Central Finland Central Hospital, Jyväskylä, Finland.",
"authors": "Helminen|Olli|O|;Mrena|Johanna|J|;Sihvo|Eero|E|",
"chemical_list": "D004396:Coloring Agents; D007208:Indocyanine Green",
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"doi": "10.1093/ejcts/ezx141",
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"issue": "52(5)",
"journal": "European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery",
"keywords": "Lymph node metastases; Lymphatic mapping; Minimally invasive surgery; NIR imaging; Oesophageal cancer; Oesophagectomy",
"medline_ta": "Eur J Cardiothorac Surg",
"mesh_terms": "D000368:Aged; D004396:Coloring Agents; D004938:Esophageal Neoplasms; D016629:Esophagectomy; D005260:Female; D006801:Humans; D007208:Indocyanine Green; D008197:Lymph Node Excision; D008198:Lymph Nodes; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D019060:Minimally Invasive Surgical Procedures; D019265:Spectroscopy, Near-Infrared",
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"references": null,
"title": "Near-infrared image-guided lymphatic mapping in minimally invasive oesophagectomy of distal oesophageal cancer.",
"title_normalized": "near infrared image guided lymphatic mapping in minimally invasive oesophagectomy of distal oesophageal cancer"
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"abstract": "Ketamine is an N -methyl-D-aspartate receptor antagonist that has been used as an adjunct analgesic and sedative in critically ill children. Previous reports noted that ketamine has been used for a variable duration of 12 to 408 hours for this indication. We report on the use of ketamine infusions for >720 hours as a second-line sedative in addition to an opioid and dexmedetomidine infusion in a 2-month old and 17-month old. The purpose of this case report and review of the literature is to highlight the prolonged ketamine exposure of these two patients and to provide awareness to clinicians on the potential of withdrawal with extended ketamine administration. These children were started on initials doses of 5 and 15 µg/kg/min and titrated to peak doses of 20 and 25 µg/kg/min, respectively. They were continued for a total of 987 and 792 hours, respectively. No adverse events were noted during the ketamine infusions. One patient developed possible withdrawal symptoms 17 hours after ketamine discontinuation despite tapering of the infusion. These symptoms resolved with administration of as needed intravenous opioids and benzodiazepines, and the agitation normalized within 24 hours after ketamine discontinuation. Clinicians should consider tapering ketamine infusions in children receiving >72 hours of a continuous infusion by 5 µg/kg/min every 8 to 12 hours. Patients should be monitored for potential withdrawal symptoms including anxiety, allodynia, hyperalgesia, sweating, and drowsiness.",
"affiliations": "University of Oklahoma College of Pharmacy, Oklahoma City, Oklahoma, United States.;University of Oklahoma College of Pharmacy, Oklahoma City, Oklahoma, United States.;University of Oklahoma College of Pharmacy, Oklahoma City, Oklahoma, United States.;University of Oklahoma College of Pharmacy, Oklahoma City, Oklahoma, United States.;University of Oklahoma College of Pharmacy, Oklahoma City, Oklahoma, United States.",
"authors": "Moore|Eszter|E|;Mayes|Rebecca|R|;Harkin|Maura|M|;Miller|Jamie L|JL|;Johnson|Peter N|PN|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1055/s-0040-1713144",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2146-4626",
"issue": "10(3)",
"journal": "Journal of pediatric intensive care",
"keywords": "children; ketamine; withdrawal",
"medline_ta": "J Pediatr Intensive Care",
"mesh_terms": null,
"nlm_unique_id": "101592756",
"other_id": null,
"pages": "221-227",
"pmc": null,
"pmid": "34395041",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports",
"references": "23575437;26783355;8905436;22093817;30697129;24765619;11902308;31626685;29030928;2379394;16645479;8858657;3698618;20838196;28299720;10659115",
"title": "Extended Duration Ketamine Infusions in Critically Ill Children: A Case Report and Review of the Literature.",
"title_normalized": "extended duration ketamine infusions in critically ill children a case report and review of the literature"
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"abstract": "BACKGROUND\nPreclinical studies have highlighted the activity of lenalidomide in mantle cell lymphoma and its anti-proliferative synergy with dexamethasone.\n\n\nMETHODS\nIn this prospective, multicenter, phase II study, patients with relapsed/refractory mantle cell lymphoma who were not eligible for, or had relapsed after, intensive treatments received lenalidomide 25 mg/day (days 1-21 of each 28-day cycle) and dexamethasone (40 mg/day on days 1, 8, 15, and 22) for up to 12 months.\n\n\nRESULTS\nThe primary end-points, overall and complete response rates, were achieved by 17 of 33 (52%; 95% confidence interval [CI], 35-68%) and 8 of 33 patients (24%; 95% CI, 13-41%), respectively, by the end of treatment. Fifteen patients (45%) discontinued treatment prematurely, 13 due to lack of response. The median progression-free and overall survival were 12 months (95% CI, 5-19 months) and 20 months (95% CI, 12 months to not estimable), respectively. Treatment resulted in a significant increase in microvessel density (P=0.033) and non-significant increases in macrophage and natural killer cell counts, while serum levels of neoangiogenic factors did not change significantly. Grade 3/4 adverse events were neutropenia (53%), leukopenia (25%), thrombocytopenia (22%), infections (12%), and febrile neutropenia (12%).\n\n\nCONCLUSIONS\nThese results confirm a favorable safety and activity profile of lenalidomide in relapsed/refractory mantle cell lymphoma. The contribution of dexamethasone in achieving these results is unclear because of its possible detrimental effect on the immune activation generated by lenalidomide and a higher risk of developing infectious complications. (clinicaltrials.gov identifier: NCT00786851).",
"affiliations": "Clinica Ematologica, Centro Trapianti e Terapie Cellulari Carlo Melzi, Azienda Ospedaliero Universitaria S. M. Misericordia, p.le S. Maria Misericordia 15, 33100 Udine, Italy. zaja.francesco@aoud.sanita.fvg.it",
"authors": "Zaja|Francesco|F|;De Luca|Stefano|S|;Vitolo|Umberto|U|;Orsucci|Lorella|L|;Levis|Alessandro|A|;Salvi|Flavia|F|;Rusconi|Chiara|C|;Ravelli|Erika|E|;Tucci|Alessandra|A|;Bottelli|Chiara|C|;Balzarotti|Monica|M|;Brusamolino|Ercole|E|;Bonfichi|Maurizio|M|;Pileri|Stefano A|SA|;Sabattini|Elena|E|;Volpetti|Stefano|S|;Monagheddu|Chiara|C|;Vacca|Angelo|A|;Ria|Roberto|R|;Fanin|Renato|R|",
"chemical_list": "D015415:Biomarkers; D013792:Thalidomide; D003907:Dexamethasone; D000077269:Lenalidomide",
"country": "Italy",
"delete": false,
"doi": "10.3324/haematol.2011.051813",
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"issue": "97(3)",
"journal": "Haematologica",
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"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D015415:Biomarkers; D003907:Dexamethasone; D005260:Female; D006801:Humans; D000077269:Lenalidomide; D020522:Lymphoma, Mantle-Cell; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic; D012008:Recurrence; D016879:Salvage Therapy; D013792:Thalidomide; D016896:Treatment Outcome; D059016:Tumor Microenvironment",
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"pubdate": "2012-03",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": "16569772;19805688;21047686;19738071;17242396;18628480;21228334;14512311;19075279;18032762;18032763;19245430;18410453;9704731;18606983",
"title": "Salvage treatment with lenalidomide and dexamethasone in relapsed/refractory mantle cell lymphoma: clinical results and effects on microenvironment and neo-angiogenic biomarkers.",
"title_normalized": "salvage treatment with lenalidomide and dexamethasone in relapsed refractory mantle cell lymphoma clinical results and effects on microenvironment and neo angiogenic biomarkers"
} | [
{
"companynumb": "IT-MYLANLABS-2017M1010806",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LENALIDOMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Octreotide is a somatostatin analogue used for treating congenital chylothorax and congenital hyperinsulinism in infants. By increasing splanchnic arteriolar resistance and decreasing gastrointestinal blood flow, octreotide indirectly reduces lymphatic flow in chylous effusions.Splanchnic ischaemia following octreotide predisposes infants to necrotising enterocolitis (NEC). Although NEC occurrence in infants treated with octreotide for hyperinsulinaemic hypoglycaemia has been reported widely, its incidence in infants with chylothroax is low. We describe a case of congenital chylothorax in a preterm infant who had poor response to thoracentesis. Although octreotide initiation lead to resolution of chylothorax, he developed NEC. Cessation of octreotide and medical management resulted in rapid resolution of NEC. Since octreotide is generally used as the first-line treatment for chylous effusion, the risk of NEC should be considered, especially when the dosage is increased. Infants on octreotide should be closely observed for early signs and symptoms of NEC to avert surgical emergency.",
"affiliations": "Department of Neonatology, KK Women's and Children's Hospital, Singapore profschandran2019@gmail.com.;Department of Neonatology, KK Women's and Children's Hospital, Singapore.;Department of Neonatology, KK Women's and Children's Hospital, Singapore.;Department of Neonatology, KK Women's and Children's Hospital, Singapore.",
"authors": "Chandran|Suresh|S|http://orcid.org/0000-0001-5961-7441;Agarwal|Arpan|A|;Llanora|Genevieve Villablanca|GV|;Chua|Mei Chien|MC|",
"chemical_list": "D005765:Gastrointestinal Agents; D015282:Octreotide",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-232062",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(2)",
"journal": "BMJ case reports",
"keywords": "congenital disorders; gastrointestinal system; safety; unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D002916:Chylothorax; D020345:Enterocolitis, Necrotizing; D005765:Gastrointestinal Agents; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D015282:Octreotide; D000069258:Thoracentesis",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32051156",
"pubdate": "2020-02-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Necrotising enterocolitis in a newborn infant treated with octreotide for chylous effusion: is octreotide safe?",
"title_normalized": "necrotising enterocolitis in a newborn infant treated with octreotide for chylous effusion is octreotide safe"
} | [
{
"companynumb": "NVSC2020SG074997",
"fulfillexpeditecriteria": "1",
"occurcountry": "SG",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OCTREOTIDE"
},
"drugadditional": "1",
"druga... |
{
"abstract": "BACKGROUND\nUse of immune checkpoint inhibitors has expanded to a variety of malignancies including hepatocellular carcinoma, where nivolumab and pembrolizumab have shown durable responses in approximately a sixth of patients.\n\n\nMETHODS\nWe report herein a patient with metastatic hepatocellular carcinoma who achieved a durable response to the second-line agent nivolumab administered intravenous 240 mg every two weeks. After 18 months of therapy, nivolumab schedule was changed to intravenous 480 mg every four weeks, per patient's request and for convenience of administration. Four days after this change, the patient developed severe terminal ileitis.Management and outcome: This condition was managed in hospital with intravenous steroids. The patient improved clinically and was discharged on an oral steroid taper. A month later, nivolumab was reinstated at 200 mg intravenous infusions every two weeks, without any re-occurrence of terminal ileitis to date as of six months after the probable drug reaction.\n\n\nCONCLUSIONS\nTo our knowledge, this is the first report of terminal ileitis with nivolumab administered every four weeks. As postmarketing evaluation of nivolumab continues, similar side effects may be observed. Prompt diagnosis and steroid therapy in these cases are imperative to ensure a favorable outcome. Resuming immunotherapy once the adverse event has resolved appears to be a safe option.",
"affiliations": "Eisenhower Lucy Curci Cancer Center, Rancho Mirage, USA.;Eisenhower Lucy Curci Cancer Center, Rancho Mirage, USA.;Eisenhower Lucy Curci Cancer Center, Rancho Mirage, USA.;Eisenhower Lucy Curci Cancer Center, Rancho Mirage, USA.;Eisenhower Lucy Curci Cancer Center, Rancho Mirage, USA.;Department of Hematology-Oncology, Medical College of Wisconsin, Milwaukee, USA.",
"authors": "Dasanu|Constantin A|CA|https://orcid.org/0000-0003-0425-8394;Plaxe|Steven C|SC|;Gupta|Varun|V|;Popescu|Iliana M|IM|;Grover|Mayumi|M|;Alvarez-Argote|Juliana|J|",
"chemical_list": "D000077594:Nivolumab",
"country": "England",
"delete": false,
"doi": "10.1177/1078155220903367",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "26(6)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Drug reaction; immune checkpoint inhibitors; nivolumab; terminal ileitis",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D006528:Carcinoma, Hepatocellular; D003424:Crohn Disease; D006801:Humans; D007167:Immunotherapy; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D000077594:Nivolumab",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "1516-1519",
"pmc": null,
"pmid": "32028838",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe terminal ileitis induced by single-agent nivolumab administered every four weeks.",
"title_normalized": "severe terminal ileitis induced by single agent nivolumab administered every four weeks"
} | [
{
"companynumb": "US-BAYER-2020-239250",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugadditional": null,
"... |
{
"abstract": "We report the first application of ultra-deep sequencing (UDS) to varicella-zoster virus (VZV) genotypic antiviral testing in a case of acyclovir-resistant VZV infection initially detected by Sanger sequencing within a deeply immunocompromised heart transplant recipient. As added-value compared to Sanger analysis, UDS revealed complex dynamics of viral population under antiviral pressure. Varicella-zoster virus (VZV) is a ubiquitous human herpesvirus affecting populations worldwide. VZV is commonly acquired in youth whose primary infection usually manifests as benign varicella (chickenpox). After the initial infection, the virus establishes lifelong latency in sensory ganglia leading to a risk of subsequent reactivation. Reactivation usually results in the development of localized herpes zoster (HZ) lesions, a painful skin rash commonly known as shingles (Cohen, 2013). The incidence and severity of HZ increase with impaired specific cell-mediated immunity mainly as a result of increasing age, malignancy, immunodeficiency, organ transplantation, or immunosuppressive drug therapy (Cohen, 2013; Koo et al., 2014; Pavlopoulou et al., 2015). In particular, HZ remains a significant cause of morbidity among solid organ transplant (SOT) recipients, especially in patients undergoing heart transplantation (HT) compared with liver, kidney, or lung transplant recipients (Carby et al., 2007; Koo et al., 2014; Pavlopoulou et al., 2015). These particular individuals are at increased risk of primary infection, reactivation followed by dissemination with visceral involvement and associated with bacterial superinfection, and chronic recurrences (Cohen, 2013). VZV infections may also engender debilitating neuralgia among highly immunocompromised patients (Sampathkumar et al., 2009). HT is also associated with the risk of reactivation of other latent viruses belonging to the Herpesviridae family as herpes simplex virus (HSV). Currently licensed drugs to prevent or to cure HSV- or VZV-associated diseases target the viral DNA polymerase (Pol). Acyclovir (ACV) and its prodrug valacyclovir (VACV) are considered as the first-line therapy, whereas foscarnet (FOS) or cidofovir (CDV) constitute alternative options. After primophosphorylation by the viral thymidine kinase (TK), ACV targets the viral DNA polymerase and inhibits the viral genome replication by a chain termination mechanism. According to this mechanism of action, viral mutations conferring resistance to ACV have been mapped both in TK and Pol encoding genes. Viral mutations conferring resistance to FOS and CDV are only detected in Pol gene. VZV ACV-resistance is mostly mediated by TK alterations, consisting in either translational frameshifts, sometimes associated with premature stop codon, or amino acid substitutions. In the remaining cases, amino acid substitutions are detected within Pol (De et al., 2015; Piret and Boivin, 2014). Classically, Sanger sequencing has been recognized as the gold standard for the detection of drug resistance mutations (DRMs) within VZV TK and Pol genes (Perrier et al., 2016; Piret and Boivin, 2014). However, this approach cannot detect minor variants present at a frequency below 20%. Ultra-deep sequencing (UDS) has an enhanced sensitivity compared to Sanger method and allows quantitative evaluation of the viral mutants (Chin et al., 2013). We report here a case of VZV resistant infection in an HT recipient. Our retrospective study aimed at showing the utility of UDS for DRM detection as a complement of Sanger method.",
"affiliations": "INSERM U955 Eq18, IMRB, UPEC and AP-HP, Hôpital Universitaire Henri Mondor, Service de Virologie, Créteil, France.;Persistent Viral Infections Team, U1135, CR7, CIMI-UPMC and AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Virologie, Paris, France.;Hôpital Universitaire Henri Mondor, Service de Médecine et maladies infectieuses, Créteil, France.;INSERM U955 Eq18, IMRB, UPEC and AP-HP, Hôpital Universitaire Henri Mondor, Service de Virologie, Créteil, France.;Persistent Viral Infections Team, U1135, CR7, CIMI-UPMC and AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Virologie, Paris, France. Electronic address: sonia.burrel@aphp.fr.",
"authors": "Mercier-Darty|Mélanie|M|;Boutolleau|David|D|;Lepeule|Raphaël|R|;Rodriguez|Christophe|C|;Burrel|Sonia|S|",
"chemical_list": "D000998:Antiviral Agents; D013937:Thymidine Kinase; D004259:DNA-Directed DNA Polymerase",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.antiviral.2018.01.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0166-3542",
"issue": "151()",
"journal": "Antiviral research",
"keywords": "Antiviral resistance; Minor variants; Thymidine kinase; Ultra-deep sequencing; Varicella-zoster virus",
"medline_ta": "Antiviral Res",
"mesh_terms": "D000998:Antiviral Agents; D004259:DNA-Directed DNA Polymerase; D024882:Drug Resistance, Viral; D005838:Genotype; D016027:Heart Transplantation; D006562:Herpes Zoster; D014645:Herpesvirus 3, Human; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012189:Retrospective Studies; D013937:Thymidine Kinase; D016896:Treatment Outcome",
"nlm_unique_id": "8109699",
"other_id": null,
"pages": "20-23",
"pmc": null,
"pmid": "29337163",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports; D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Utility of ultra-deep sequencing for detection of varicella-zoster virus antiviral resistance mutations.",
"title_normalized": "utility of ultra deep sequencing for detection of varicella zoster virus antiviral resistance mutations"
} | [
{
"companynumb": "FR-GLAXOSMITHKLINE-FR2018034530",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ACYCLOVIR"
},
"drugadditional": "1",
... |
{
"abstract": "A 56-year-old epileptic patient underwent right hemicolectomy and cholecystectomy surgery under general endotracheal anesthesia. Anesthesia was maintained with sevoflurane, and sufentanil, rocuronium, and dexmedetomidine infusions. After the operation and confirmation of neuromuscular recovery, the patient woke from anesthesia within 15 min and successfully extubated. After the vital signs of patient were stable, the patient was transported to post anesthesia care unit (PACU). 6 h after the surgery, he fell into a stuporous state for lasting 14 h and EEG showed no epileptiform discharges. Stupor did re-occur in 2 days after operation. 36 hours after operation, all signs of the stuporous state resolved spontaneously. Apparent dexmedetomidine-induced stuporous state has not been reported in the human literature.",
"affiliations": "Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430030, Hubei, China.;Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430030, Hubei, China.;Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430030, Hubei, China.;Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430030, Hubei, China.;Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430030, Hubei, China.;Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430030, Hubei, China.;Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430030, Hubei, China.",
"authors": "Han|Dong-Ji|DJ|;He|Zhi-Gang|ZG|;Zhou|Zhi-Qiang|ZQ|;Feng|Li|L|;Liu|Cheng|C|;Xiang|Yan|Y|;Xiang|Hong-Bing|HB|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2165-591X",
"issue": "6(3)",
"journal": "American journal of neurodegenerative disease",
"keywords": "Dexmedetomidine; abdominal surgery; epilepsy; stupor",
"medline_ta": "Am J Neurodegener Dis",
"mesh_terms": null,
"nlm_unique_id": "101585753",
"other_id": null,
"pages": "26-31",
"pmc": null,
"pmid": "28804692",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "17869990;25654251;24038459;23642396;26823964;26074874;23953694;26629122;13814384;27626491;22528223;26379976;24876058;24967698;9728818;23657710;9275232;24140517;20650383;23993842;4664014;19573504;25962186;26101104;28224417;15725323;22245294;21056228;23340545;25524844;19818916;26312990;25442843;19818900;26596579;26312989;10391445;25819799;11046225;22003216;24100252",
"title": "One case with dexmedetomidine-induced stuporous state in epileptic patient undergoing abdominal surgery.",
"title_normalized": "one case with dexmedetomidine induced stuporous state in epileptic patient undergoing abdominal surgery"
} | [
{
"companynumb": "CN-MYLANLABS-2017M1062827",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DEXMEDETOMIDINE"
},
"drugadditional": null,
... |
{
"abstract": "We retrospectively analyzed nationwide records of 163 Fanconi anemia (FA) patients [aplastic anemia (AA), n = 118; myelodysplastic syndrome (MDS), n = 30; acute leukemia, n = 15] who underwent first allogeneic hematopoietic stem cell transplantation (HSCT) between 1987 and 2015 in Japan. An alternative donor was used in 119 (73%) patients, and 160 (98%) patients received a non-T-cell-depleted graft. With an 8.7-year median follow-up, 5-year overall survival (OS) was 81%. The 5-year OS was significantly higher in AA patients than in MDS and acute leukemia patients (89%, 71%, and 44%, respectively). In the MDS/leukemia group, factors associated with poor outcome in univariate analysis were older age at HSCT (≥ 18 years), conditioning regimen without anti-thymocyte or lymphocyte globulin, and grade II-IV acute graft-versus-host disease. After 1 year, of 137 survivors, 15 developed subsequent malignancies, of whom 12 were diagnosed with head and neck (HN)/esophageal cancer. An irradiation regimen and older age were associated with the risk of HN/esophageal cancer. Five of seven deaths were attributed to subsequent malignancies more than 5 years after HSCT. On the basis of the risk factors for HSCT in MDS/leukemia patients and subsequent malignancies, a more effective HSCT approach is required.",
"affiliations": "Department of Innovative Medical Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan. miharu@is.icc.u-tokai.ac.jp.;Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.;Department of Pediatrics and Data Center, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.;Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.;Department of Hematology and Oncology, Hyogo Prefectural Kobe Children's Hospital, Kobe, Japan.;Department of Pediatrics, Kyoto City Hospital, Kyoto, Japan.;Department of Hematology and Oncology, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan.;Department of Pediatrics, Tokai University School of Medicine, Isehara, Japan.;Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Japan.;Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.;Department of Pediatric Oncology, Fukushima Medical University Hospital, Fukushima, Japan.;Division of Pediatric Hematology and Oncology, Ibaraki Children's Hospital, Mito, Japan.;Division of Cell Therapy/Hematology, Jichi Medical University Hospital, Shimotsuke, Japan.;Division of Hematology/Oncology, Kanagawa Children's Medical Center, Yokohama, Japan.;Department of Pediatrics, Kyoto University Hospital, Kyoto, Japan.;Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.;Department of Pediatrics, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.;Central Japan Cord Blood Bank, Seto, Japan.;Department of Cancer Immunotherapy, Osaka University Graduate School of Medicine, Osaka, Japan.;Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan.;Department of Innovative Medical Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.",
"authors": "Yabe|Miharu|M|http://orcid.org/0000-0003-0697-5506;Morio|Tomohiro|T|;Tabuchi|Ken|K|;Tomizawa|Daisuke|D|;Hasegawa|Daiichiro|D|;Ishida|Hiroyuki|H|;Yoshida|Nao|N|;Koike|Takashi|T|;Takahashi|Yoshiyuki|Y|;Koh|Katsuyoshi|K|;Okamoto|Yasuhiro|Y|;Sano|Hideki|H|;Kato|Keisuke|K|;Kanda|Yoshinobu|Y|;Goto|Hiroaki|H|;Takita|Junko|J|;Miyamura|Takako|T|;Noguchi|Maiko|M|;Kato|Koji|K|;Hashii|Yoshiko|Y|;Astuta|Yoshiko|Y|;Yabe|Hiromasa|H|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-020-02991-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "113(1)",
"journal": "International journal of hematology",
"keywords": "Acute leukemia; Fanconi anemia; Hematopoietic stem cell transplantation; Myelodysplastic syndrome; Subsequent malignancies after hematopoietic stem cell transplantation",
"medline_ta": "Int J Hematol",
"mesh_terms": "D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D002648:Child; D002675:Child, Preschool; D004938:Esophageal Neoplasms; D005199:Fanconi Anemia; D005260:Female; D005500:Follow-Up Studies; D006258:Head and Neck Neoplasms; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D007564:Japan; D007938:Leukemia; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D012189:Retrospective Studies; D015996:Survival Rate; D013997:Time Factors; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "134-144",
"pmc": null,
"pmid": "32949371",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Long-term outcome in patients with Fanconi anemia who received hematopoietic stem cell transplantation: a retrospective nationwide analysis.",
"title_normalized": "long term outcome in patients with fanconi anemia who received hematopoietic stem cell transplantation a retrospective nationwide analysis"
} | [
{
"companynumb": "JP-OTSUKA-2021_013916",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BUSULFAN"
},
"drugadditional": null,
"d... |
{
"abstract": "Everolimus, a mammalian target of rapamycin inhibitor, is an emerging drug, which is being increasingly applied in oncology and solid organ transplantation. Oral ulcers are a frequent side effect associated with this immunosupressor. We report the case of a renal transplant recipient who developed disfiguring oral and perianal ulcers secondary to everolimus's toxicity. This is probably the first report of perianal involvement. Dermatologists need to be aware of the potential mucocutaneous adverse effects related to these new drugs that are becoming evermore common in our clinical practice.",
"affiliations": "Universidade Federal de São Paulo, São Paulo, BR.;Universidade Federal de São Paulo, São Paulo, BR.;Universidade Federal de São Paulo, São Paulo, BR.;Universidade Federal de São Paulo, São Paulo, BR.;Universidade Federal de São Paulo, São Paulo, BR.;Universidade Federal de São Paulo, São Paulo, BR.",
"authors": "Pasin|Victor Pavan|VP|;Pereira|Amanda Regio|AR|;Carvalho|Kalline Andrade de|KA|;Paiva|João Marcos Góes de|JM|;Enokihara|Milvia Maria Simões e Silva|MM|;Porro|Adriana Maria|AM|",
"chemical_list": "D007166:Immunosuppressive Agents; D000068338:Everolimus; D058570:TOR Serine-Threonine Kinases",
"country": "Spain",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\nAn Bras DermatolAn Bras DermatolAnais Brasileiros de Dermatologia0365-05961806-4841Sociedade Brasileira de Dermatologia 10.1590/abd1806-4841.20153672Case ReportNew drugs, new challenges for dermatologists: mucocutaneous ulcers\nsecondary to everolimus* Pasin Victor Pavan 1Pereira Amanda Regio 1de Carvalho Kalline Andrade 1de Paiva João Marcos Góes 1Enokihara Milvia Maria Simões e Silva 1Porro Adriana Maria 11 Universidade Federal de São Paulo (UNIFESP) - São Paulo,\nBrazil.MAILING ADDRESS: Amanda Regio Pereira, Rua Borges Lagoa, 508, Vila\nClementino, 04038-001 - São Paulo - SP, Brazil. E-mail:\namandaregiopereira@gmail.comConflict of Interest: None.\n\nMay-Jun 2015 May-Jun 2015 90 3 Suppl 1 165 167 04 5 2014 21 5 2014 © 2015 by Anais Brasileiros de DermatologiaThis is an Open Access article distributed under the terms of the Creative\nCommons Attribution Non-Commercial License which permits unrestricted\nnon-commercial use, distribution, and reproduction in any medium, provided the\noriginal work is properly cited.Everolimus, a mammalian target of rapamycin inhibitor, is an emerging drug, which is\nbeing increasingly applied in oncology and solid organ transplantation. Oral ulcers\nare a frequent side effect associated with this immunosupressor. We report the case\nof a renal transplant recipient who developed disfiguring oral and perianal ulcers\nsecondary to everolimus's toxicity. This is probably the first report of perianal\ninvolvement. Dermatologists need to be aware of the potential mucocutaneous adverse\neffects related to these new drugs that are becoming evermore common in our clinical\npractice.\n\nDrug eruptionsImmunosuppressive agentsUlcer\n==== Body\nINTRODUCTION\nMammalian target of rapamycin (mTOR) inhibitors, such as sirolimus and everolimus, are\nemerging drugs, which are being increasingly applied in oncology and to help prevention\nof rejection in solid organ transplant recipients.1 Oral ulcers have been reported as one of the most common\nside effects of everolimus, affecting up to 70% of the patients treated with this drug,\nleading to discontinuation of the therapy in many cases.2,3 We report a case\nof oral and perianal ulcers secondary to everolimus in a renal transplant recipient,\nhighlighting the severity of the lesions and the perianal involvement, which has not yet\nbeen described in indexed medical journals.\n\nCASE REPORT\nA 38-year-old, female patient with end-stage renal disease of unknown etiology,\nsubmitted to renal transplantation 3 months earlier, was hospitalized due to oral and\nperianal ulcers she had suffered from over the preceding 14 days, which were resistant\nto empirical therapy with oral acyclovir for 10 days (400mg every 8 hours). She had been\nunder immunosuppression with mycophenolate sodium (720mg daily), prednisone (30mg daily)\nand everolimus (0.5 mg daily). The latter had been introduced 2 months earlier. The\npatient was also diagnosed HIV positive 3 years before and presented with undetectable\nviral load and a CD4 count of 308 cells/µL upon admission, attributable to effective\nantiretroviral therapy (ART) with zidovudine, lamivudine, atazanavir and ritonavir.\nDermatology consultation was requested by the nephrology team. On examination, two oral\nulcers were found on the superior lip and tongue. Both were deep and painful, and the\nlabial lesion was partially necrotic and quite disfiguring (Figure 1). A deep, 2 cm-diameter ulcer in the perianal region was\nalso observed (Figure 2). Histopathology of both\nsites revealed chronic, non-specific ulcers, with scarce inflammatory lymphocytic\ninfiltrate (Figure 3). Signs of viral infection\nwere absent on histology. Immunohistochemical detection of herpes simplex virus 1 and 2\nand cytomegalovirus (CMV) resulted negative in these tissue samples. Antigenemia assay\nand blood polymerase chain reaction for CMV were also negative. Everolimus blood level\nwas 11.7 ng/ml, which is above the target (3-8 ng/ml), also favoring the possibility of\ndrug-related toxicity, a diagnosis of exclusion in this case. The ulcers started to heal\nafter everolimus discontinuation. Complete reepithelization, though, was observed only\nafter 40 days. A residual deformity with aesthetic and functional impairment remained in\nthe superior lip, affecting movements such as suction (Figure 4).\n\nFIGURE 1 Deep and painful oral ulcers, partially necrotic and quite disfi guring\n\nFIGURE 2 Deep, perianal ulcer, involving the skin and semi-mucous surface\n\nFIGURE 3 Histopathological aspects: chronic non-specific ulcer, with scarce infl ammatory\nlymphocytic infiltrate. Hematoxylin and eosin stain, 100x and 400x\n\nFIGURE 4 Complete reepithelization 40 days after everolimus discontinuation. Residual\ndeformity in the superior lip, with aesthetic and functional impairment\n\nDISCUSSION\nmTOR inhibitor-associated stomatitis is a newly recognized and frequent drug-related\ncomplication. It is a significant toxicity that leads to dose modifications, treatment\ndelay and interruption of antineoplastic and immunosuppressive regimens.2,4,5 Lesions are usually described as painful,\nlong-lasting oval ulcerations that resemble aphthous or herpetic stomatitis.3,4,6 Although its mechanisms remain unknown,\nit seems that the frequency, duration and severity of this side effect are associated\nwith high doses and blood levels of everolimus.2,3,6,7 Empiric treatments, such\nas sodium bicarbonate-based mouthwash and oral fluconazole, appear to be useless and\nmanaging the condition remains challenging.3\n\nSome aspects in the case reported are unusual, namely the severity of ulcers that led to\ntissue loss and drug discontinuation, and the perianal involvement, a location that has\nnot yet been mentioned in the indexed literature, according to extensive research in the\nmajor online databases.\n\nEverolimus metabolism occurs predominantly by means of the hepatic cytochrome P450\nsystem, resulting in multiple, possible pharmacological interactions.8\n\nBlood levels above target that were detected in this patient could be attributed to drug\ninteraction, probably with the protease inhibitors, atazanavir and ritonavir, which are\npotent inhibitors of the cytochrome P450 enzymes.9,10\n\nIn conclusion, we stress the need for dermatologists to become familiar with these new\ndrugs and related mucocutaneous adverse effects, which are becoming increasingly\nfrequent in our practice. A multidisciplinary approach is essential for the appropriate\nmanagement of cases like the one reported.\n\nFinancial Support: None.\n\nHow to cite this article: Pasin VP, Pereira AR, Carvalho KA, Paiva JMG,\nEnokihara MMSS, Porro AM. New drugs, new challenges to dermatologists: mucocutaneous\nulcers secondary to everolimus. An Bras Dermatol. 2015;90 (3 Suppl 1):S165-7.\n\n* Work performed at the Universidade Federal de São Paulo (UNIFESP) - São Paulo,\nBrazil.\n==== Refs\nReferences\n1 Peterson ME Management of adverse events in patients with hormone\nreceptor-positive breast cancer treated with everolimus: observations from a phase\nIII clinical trial Support Care Cancer 2013 21 2341 2349 23686401 \n2 Martins F de Oliveira MA Wang Q Sonis S Gallottini M George S A review of oral toxicity associated with mTOR inhibitor therapy in\ncancer patients Oral Oncol 2013 49 293 298 23312237 \n3 Ferté C Paci A Zizi M Gonzales DB Goubar A Gomez-Roca C Natural history, management and pharmacokinetics of Everolimus\ninduced-oral ulcers: Insights into compliance issues Eur J Cancer 2011 47 2249 2255 21489779 \n4 Boers-Doets CB Epstein JB Raber-Durlacher JE Ouwerkerk J Logan RM Brakenhoff JA Oral Adverse Events Associated with Tyrosine Kinase and Mammalian\nTarget of Rapamycin Inhibitors in Renal Cell Carcinoma: A Structured Literature\nReview Oncologist 2012 17 135 144 22207567 \n5 Lee WJ Lee JL Chang SE Lee MW Kang YK Choi JH Cutaneous adverse effects in patients treated with the multitargeted\nkinase inhibitors sorafenib and sunitinib Br J Dermatol 2009 161 1045 1051 19558553 \n6 Soefje SA Karnad A Brenner AJ Common toxicities of mammalian target of rapamycin\ninhibitors Target Oncol 2011 6 125 129 21499766 \n7 Campistol JM de Fijter JW Flechner SM Langone A Morelon E Stockfleth E mTOR inhibitor-associated dermatologic and mucosal\nproblems Clin Transplant 2010 24 149 156 \n8 Gurk-Turner C Manitpisitkul W Cooper M A Comprehensive Review of Everolimus Clinical Reports: A New Mammalian\nTarget of Rapamycin Inhibitor Transplantation 2012 94 659 668 22986894 \n9 Busti AJ Hall RG Margolis DM Atazanavir for the treatment of human immunodeficiency virus\ninfection Pharmacotherapy 2004 24 1732 1747 Josephson F. Drug-drug interactions in the treatment of HIV infection: focus\non pharmacokinetic enhancement through CYP3A inhibition. J Intern Med.\n2010;268:530-9. 15585441\n\n",
"fulltext_license": "CC BY-NC",
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"issue": "90(3 Suppl 1)",
"journal": "Anais brasileiros de dermatologia",
"keywords": null,
"medline_ta": "An Bras Dermatol",
"mesh_terms": "D000328:Adult; D001004:Anus Diseases; D000068338:Everolimus; D005260:Female; D006801:Humans; D007121:Immunocompetence; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D009055:Mouth; D012883:Skin Ulcer; D013280:Stomatitis; D058570:TOR Serine-Threonine Kinases",
"nlm_unique_id": "0067662",
"other_id": null,
"pages": "165-7",
"pmc": null,
"pmid": "26312705",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21499766;21489779;22207567;22986894;23312237;23686401;15585441;19558553;20236129",
"title": "New drugs, new challenges for dermatologists: mucocutaneous ulcers secondary to everolimus.",
"title_normalized": "new drugs new challenges for dermatologists mucocutaneous ulcers secondary to everolimus"
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"abstract": "Tumor programmed death-ligand 1 (PD-L1) expression in diffuse large B-cell lymphoma (DLBCL) is associated with inferior outcomes. The first-line immunologically-replete setting may be an opportune time for PD-1 inhibition. We evaluated pembrolizumab in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in untreated patients with DLBCL. Eligible patients were age 18 or older, had adequate organ function, and had DLBCL requiring full-course therapy. Patients received pembrolizumab 200 mg/cycle with R-CHOP, primarily to assess toxicity. Response assessment utilized standard criteria, and PD-L1 staining was performed at a validated central laboratory. Among 30 patients, toxicity was comparable to standard R-CHOP but with two grade ≥3 immune related adverse events (rash, pneumonitis). The overall and complete response rate was 90% and 77%. With 25·5 months of median follow-up, 2-year progression-free survival (PFS) is 83%. PD-L1 expression was associated with non-GCB subtype, and improved PFS and survival. Pembrolizumab can safely be added to R-CHOP, and is associated with a high CR rate and 2-year PFS. Improved PFS with PR-CHOP in PD-L1 expressing tumors contradicts historical data in R-CHOP treated patients, supporting evaluation of PD-L1 as a biomarker to identify DLBCL patients who may benefit from this first-line strategy.",
"affiliations": "Division of Medical Oncology, Department of Internal Medicine, University of Washington, Seattle, WA, USA.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.;Division of Medical Oncology, Department of Internal Medicine, University of Washington, Seattle, WA, USA.;Division of Medical Oncology, Department of Internal Medicine, University of Washington, Seattle, WA, USA.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.;Division of Medical Oncology, Department of Internal Medicine, University of Washington, Seattle, WA, USA.;Division of Medical Oncology, Department of Internal Medicine, University of Washington, Seattle, WA, USA.;Division of Medical Oncology, Department of Internal Medicine, University of Washington, Seattle, WA, USA.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.;Division of Hematopathology, Department of Laboratory Medicine, University of Washington, Seattle, WA, USA.;Division of Medical Oncology, Department of Internal Medicine, University of Washington, Seattle, WA, USA.",
"authors": "Smith|Stephen D|SD|0000-0001-5354-7593;Till|Brian G|BG|;Shadman|Mazyar S|MS|;Lynch|Ryan C|RC|;Cowan|Andrew J|AJ|;Wu|Qian V|QV|;Voutsinas|Jenna|J|;Rasmussen|Heather A|HA|;Blue|Katherine|K|;Ujjani|Chaitra S|CS|0000-0003-1977-1510;Shustov|Andrei|A|;Cassaday|Ryan D|RD|;Fromm|Jonathan R|JR|;Gopal|Ajay K|AK|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; D009363:Neoplasm Proteins; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; C582435:pembrolizumab; D011241:Prednisone",
"country": "England",
"delete": false,
"doi": "10.1111/bjh.16494",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1048",
"issue": "189(6)",
"journal": "British journal of haematology",
"keywords": "PD-1 inhibition; chemoimmunotherapy; diffuse large B-cell lymphoma; immunotherapy; pembrolizumab",
"medline_ta": "Br J Haematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins; D011241:Prednisone; D000069283:Rituximab; D014750:Vincristine",
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "1119-1126",
"pmc": null,
"pmid": "32030732",
"pubdate": "2020-06",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Pembrolizumab with R-CHOP in previously untreated diffuse large B-cell lymphoma: potential for biomarker driven therapy.",
"title_normalized": "pembrolizumab with r chop in previously untreated diffuse large b cell lymphoma potential for biomarker driven therapy"
} | [
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"companynumb": "US-ROCHE-2286365",
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"abstract": "We report the case of a 42-year-old woman who was diagnosed with breast cancer that recurred 3 years later, with supraclavicular lymphadenopathy and dermal involvement. The main drug used in the therapy was trastuzumab; however, the association of this drug with docetaxel was not able to decrease or cease the effect of the inflammatory BCA component with erythema and thickening of the skin as well as the supraclavicular lymphadenopathy previously diagnosed. Thus, a combined therapy was required. The patient was started on 6 cycles (1 per month) of trastuzumab subcutaneous 600 mg, pertuzumab intravenous 840 mg (as an attack dose, later on 420 mg), and xeloda oral 1000 mg. As a result, the patient showed a significant improvement in erythema and thickening of the skin in the neck and the right part of her trunk, besides decrease in supraclavicular lymphadenopathy. After 6 cycles, her skin was almost restored. Intravenous trastuzumab can be an effective single agent; however, its association with other chemotherapies-such as pertuzumab-can present a synergic effect, which can increase the survival expectations of metastatic HER2+ patients. Additionally, as reported in the literature, the use of xeloda plays a key role in restoring the skin health of patients with breast cancer presenting with skin metastasis. Our findings suggest that trastuzumab, pertuzumab, and xeloda combined therapy, following the schedule and posology handled in this study, can be a good treatment for recurrent HER2+ breast cancer with signs of supraclavicular lymphadenopathy and severe inflammatory BCA component with erythema and thickening of the skin.",
"affiliations": "Hospital Clínico Chillan Herminda Martín, Chillán, Ñuble, Chile.;Universidad Católica del Maule, Talca, Maule, Chile.;Hospital Clínico Chillan Herminda Martín, Chillán, Ñuble, Chile.",
"authors": "Saure Sarría|Victor Manuel|VM|;Arencibia|Ariel D|AD|;D'Afonseca|Vívian|V|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000069287:Capecitabine; D018719:Receptor, ErbB-2; C485206:pertuzumab; D000068878:Trastuzumab",
"country": "United States",
"delete": false,
"doi": "10.1177/2324709620942606",
"fulltext": "\n==== Front\nJ Investig Med High Impact Case Rep\nJ Investig Med High Impact Case Rep\nHIC\nsphic\nJournal of Investigative Medicine High Impact Case Reports\n2324-7096 SAGE Publications Sage CA: Los Angeles, CA \n\n10.1177/2324709620942606\n10.1177_2324709620942606\nCase Report\nXeloda Oral, Trastuzumab, and Pertuzumab Combined Drug Therapy Reduced\nCervical Lymphadenopathy and Dermal Involvement in Patient With Recurrent Breast Cancer:\nCase Report\nSaure Sarría Victor Manuel 1 Arencibia Ariel D. PhD2 D’Afonseca Vívian PhD1 1 Hospital Clínico Chillan Herminda Martín,\nChillán, Ñuble, Chile\n2 Universidad Católica del Maule, Talca, Maule,\nChile\nVictor Manuel Saure Sarría, Hospital Clínico Chillan\nHerminda Martín, Ramirez # 10, Chillán, Ñuble 3780000, Chile. Email:\ndrssvictor@gmail.com\n28 7 2020 \nJan-Dec 2020 \n8 232470962094260614 4 2020 16 6 2020 22 6 2020 © 2020 American Federation for Medical Research2020American Federation for Medical\nResearchThis article is distributed under the terms of the Creative Commons\nAttribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits\nnon-commercial use, reproduction and distribution of the work without further permission\nprovided the original work is attributed as specified on the SAGE and Open Access page\n(https://us.sagepub.com/en-us/nam/open-access-at-sage).We report the case of a 42-year-old woman who was diagnosed with breast cancer that\nrecurred 3 years later, with supraclavicular lymphadenopathy and dermal involvement. The\nmain drug used in the therapy was trastuzumab; however, the association of this drug with\ndocetaxel was not able to decrease or cease the effect of the inflammatory BCA component\nwith erythema and thickening of the skin as well as the supraclavicular lymphadenopathy\npreviously diagnosed. Thus, a combined therapy was required. The patient was started on 6\ncycles (1 per month) of trastuzumab subcutaneous 600 mg, pertuzumab intravenous 840 mg (as\nan attack dose, later on 420 mg), and xeloda oral 1000 mg. As a result, the patient showed\na significant improvement in erythema and thickening of the skin in the neck and the right\npart of her trunk, besides decrease in supraclavicular lymphadenopathy. After 6 cycles,\nher skin was almost restored. Intravenous trastuzumab can be an effective single agent;\nhowever, its association with other chemotherapies—such as pertuzumab—can present a\nsynergic effect, which can increase the survival expectations of metastatic HER2+\npatients. Additionally, as reported in the literature, the use of xeloda plays a key role\nin restoring the skin health of patients with breast cancer presenting with skin\nmetastasis. Our findings suggest that trastuzumab, pertuzumab, and xeloda combined\ntherapy, following the schedule and posology handled in this study, can be a good\ntreatment for recurrent HER2+ breast cancer with signs of supraclavicular lymphadenopathy\nand severe inflammatory BCA component with erythema and thickening of the skin.\n\nbreast cancersupraclavicular lymphadenopathyHER2-positivecombined chemotherapyinflammatory BCA componentcover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nBreast cancer is the most common cancer among women, with 2.1 million cases reported each\nyear. In Chile, breast cancer is also the main health concern for women, since nearly 4000\ncases are diagnosed each year, reaching 12.8% of the causes of death in the female\npopulation.1,2\n\nThe greatest concern of patients with breast cancer is the possibility of metastasis: it\ncan be found in any organ including in the skin and neck. Although rare, supraclavicular\nmetastasis—which happens when distant metastases of breast carcinomas reach the neck—also\noccurs in breast cancer patients and not only in head and neck malignances.3,4 Additionally, it is known that breast cancer\ncan evolve to the inflammatory form (known as inflammatory breast cancer), affecting the\nderma. This type of breast cancer is uncommon, but aggressive, invasive, and generally leads\nto metastasis earlier.5 Generally, when breast cancer spreads to other organs there are less chances of\nhealing. Moreover, the standard and systematic therapy can be difficult in some cases; for\nexample, when the patient has lymph node involvement, a combined therapy is required.6\n\nMany chemotherapies are being used on patients with recurrent breast cancer, HER2-positive,\nwith metastatic signs, erythema, thickening of the skin, and supraclavicular\nlymphadenopathy. Trastuzumab, a recombinant human monoclonal IgG1 antibody that targets the\nepidermal growth factor 2 (HER2) protein, is used for the treatment of breast cancer HER2-positive.7 As a single agent, it is a potent adjuvant against breast cancer; however, a synergic\neffect can be observed when this chemotherapy is associated with other drugs.8 A combined therapy of trastuzumab and pertuzumab plus docetaxel is a first-line\ntreatment in the metastatic setting.7,9\n\nIt is known, however, that docetaxel is a cytotoxic agent that often presents several acute\nand long-term secondary effects. Generally, several acute secondary effects such as fever,\ndyspnea, hypoxia, urticaria, and cardiorespiratory arrest can occur within minutes or hours\nafter drug administration.10 A good substitute to docetaxel used to treat breast cancer metastasis with cutaneous\ninvolvement is xeloda, generally associated with other anticancer agents. Sideras and colleagues11 reported the case of an 82-year-old female with breast cancer and cutaneous\nmetastasis presenting several nodules over the breast and chest wall. Xeloda was\nadministered in 700 mg/m2 doses, which were well tolerated; and after only 2\ncycles, the patient presented significant improvement in her inflammatory breast condition.\nAdditionally, the authors related no progression of the disease after 10 cycles of treatment.11\n\nIn this sense, we came across the study of a case of recurrent advanced stage breast\ncancer, in which cervical skin ulcer and inflammatory BCA component with erythema and\nthickening of the skin were detected after a 42-year-old woman consulted an oncologist for\nright supraclavicular lymphadenopathy appearance during breast cancer follow-up care. A\ncombined therapy using xeloda oral, trastuzumab, and pertuzumab was chosen for her\ntreatment, which resulted in a significant response with decreasing of supraclavicular skin\nulcer as well as decreasing of the inflammatory process in the breast skin.\n\nClinical Case\nA 42-year-old woman without other relevant medical history was diagnosed with breast cancer\nin 2013, when she was 36 years old. For the diagnosis of this breast cancer case,\nmacroscopic and microscopic evaluation in biopsies of right mammary gland and axillary tail\nwere performed. A core biopsy of mammary gland tissue measuring around 6.5 × 4.5 × 2.3 cm\nand with 41 g of weight was evaluated. At the macroscopic level, a fibrous area measuring 1\n× 1 × 1 cm in upper portion of this biopsy was identified. The remaining evaluated fragment\nof breast tissue presented adipose appearance. The core biopsy of the axillary tail, which\nwas represented by an irregular fragment of fibro-fatty tissue measuring 8 × 6 × 3.5 cm,\nshowed lymph node affection. Nine lymph nodes were dissected and 2 of them presented\nmetastatic appearance. Concerning the microscopy analysis, the core biopsy of mammary gland\ntissue presented a chronic inflammatory process with lobular involution (atrophy) as well as\nfatty involution and fibrosis. Additionally, the presence of a fibrous area with evident\nprocess of tumorigenesis was identified. Finally, a mild mammary duct ectasia and regular\nlymphocytic infiltration was identified. In the axillary tail, the 2 affected lymph nodes\nshowed an intranodal and perinodal metastatic tumor (1.1 cm of diameter). Other 7 evaluated\nlymph nodes presented chronic lymphadenitis with dystrophic calcifications in 2 of them.\nAccording to these findings, the tumor was characterized as T1N2M0.\n\nThirty months after the diagnosis, she presented a right supraclavicular nodule, which\nresulted, through core biopsy, in a poorly differentiated carcinoma, negative for hormonal\nreceptors HER2-positive, with a Ki-67 index around 30%. Furthermore, she presented severe\ninflammatory BCA component with erythema and thickening of the skin over the right breast\nand superior portion of trunk.\n\nThe patient’s therapy regarding medicine dosage and treatment schedule is shown in Table 1.\n\nTable 1. Patient’s Chemotherapy Schedule.\n\nAntitumor agent\tDosage\tClinical event\t\n6FAC\t6-Fluororacil 900 mg\nAdriamycin 90 mg\nCytoxan 900 mg\tT1N2M0\t\nRadiotherapy\t2 grays/25 dose\tPost-surgery (partial mastectomy and axillary dissection)\t\nTrastuzumab\t600 mg subcutaneous\tChemotherapy post radiotherapy and surgery\t\nDocetaxel\nTrastuzumab\tDocetaxel 112 mg\nTrastuzumab 600 mg\tBreast cancer recurrence with right supraclavicular nodule. After 2 cycles were\nsuspended due strong reaction in the patient.\t\nTraztuzumab\nMetastatic modality\tTrastuzumab 600 mg\tRight supraclavicular lymphadenopathy remained, impossibility to use\nradiotherapy\t\nTrastuzumab\nPertuzumab\nXeloda\tTrastuzumab subcutaneous 600 mg (28 cycles)\nXeloda oral 1000 mg (6\ncycles)\nPertuzumab endovenous 840 mg (attack dose) and 420 mg (6\ncycles)\tTreatment of severe breast dermal involvement and visible right supraclavicular\nlymphadenopathy\t\nResults\nDuring the phase of diagnosis, the patient received neoadjuvant chemotherapy involving\nfluorouracil, adriamycin, and cytoxan (6FAC) for a period of 6 months until she was\nsubmitted to partial mastectomy and axillary dissection. After this procedure, a new phase\nof treatment started including adjuvant radiotherapy (2 grays daily, 25 doses) for almost 2\nmonths, as well as trastuzumab therapy (see Table 1). She was followed-up for the next 9 months,\na period during which she remained asymptomatic.\n\nHowever, 30 months after the diagnosis and the start of the treatment, she presented a\nright supraclavicular nodule and dermal involvement. Due to these conditions, a treatment\nwith docetaxel and trastuzumab was started and administrated for 2 months, but it had to be\nsuspended after the first 2 cycles of docetaxel due to a strong allergic reaction of the\npatient. During docetaxel administration, the patient presented neutropenia grade 1 and an\nacute allergic reaction consisting of bronchospasm, headache, and dyspnea. However, the\ntherapy with trastuzumab continued and the trastuzumab chemotherapy in metastatic modality\nwas used to substitute docetaxel, due to the appearance of right supraclavicular nodule (see\nTable 1 for medicine\ndoses).\n\nDespite this treatment, the progression of right supraclavicular lymphadenopathy remained.\nThe radiotherapy team evaluated the case and decided to reject the radiation treatment due\nto the extensive injuries in the neck area. Even while receiving the therapy, the patient\npresented severe inflammatory BCA component with erythema and thickening of the skin\n(covering up to one third of the neck) and right clavicular and scapula associated with\ncervical lymphadenopathy ranging from stage I to IV. Due the advanced status of\nlymphadenopathy and evident inflammatory process in her derma, a treatment with paclitaxel\nwas offered, but it was rejected by the patient due to the previous allergic reaction to\ndocetaxel treatment.\n\nTo understand the development and severity of the evident lymphadenopathy cervical and\ndermal involvement in the patient and evaluate the lesions in her skin, a new computed\ntomography scan was requested. This first analysis evaluated skin, muscle, and right lymph\nnode involvement and showed that there was no presence of the disease in those areas, even\nthough the neck and cervical injuries were evident. Considering the unsatisfactory results\nof the previous treatments, it was decided to start a new therapy combining xeloda oral,\ntrastuzumab, and pertuzumab. During the initial 6 cycles of treatment, the patient showed a\nclear clinical improvement, with an evident decrease in the progress of cutaneous\nmetastasis.\n\nThe process of recovery of the skin and cervical area during the treatment is shown in\nFigure 1. All the mentioned\ntreatments were not able to cease or decrease the dermal involvement until the patient\nstarted the combined therapy. Figure\n1A-C shows the patient’s supraclavicular and neck region before the treatment.\nFigure 1D-F shows the patient’s\nevolution after 6 cycles of trastuzumab, pertuzumab, and xeloda.\n\nFigure 1. Patient’s treatment history. (A) Evident cervical skin ulcer; (B) and (C) dermal\ninvolvement in the neck and right breast, photos before chemotherapy and herceptin plus\npertuzumab treatment. (D) Improvement of skin ulcer; (E) and (F) dermal involvement\nimprovement, photos after 6 cycles of xeloda oral, trastuzumab, and pertuzumab drugs\ntreatment. The white arrows show the affected areas in study.\n\nDiscussion\nPatients with HER2-positive breast cancer generally present with poor prognosis and high\nrecurrence rates. Also, it is known that drugs such as trastuzumab and pertuzumab—human\nmonoclonal antibodies that act against the HER2 protein—are extensively used in the\ntreatment of breast carcinomas expressing this protein.8,12 The clinical features of breast cancer\npresented in this case study, which are the profile HER2-positive, hormonal receptor\nnegative, and metastatic cancer, have led to the use of trastuzumab as the main chemotherapy\ntreatment. Even though intravenous trastuzumab can be an effective single agent, one\ndisadvantage in the use of trastuzumab is the primary or acquired resistance observed in\nseveral patients, which can compromise its therapeutic effectiveness.8 Rates of resistance to trastuzumab observed in patients with breast cancer can range\nfrom 66% to 88%.13-17\n\nResistance to trastuzumab could be expected in this patient since the treatment with\ntrastuzumab metastatic modality, as a single agent, did not present any response concerning\nthe control of her breast dermal involvement and cervical skin ulcer. Given such conditions,\nthe combined therapy is recommended. Due to trastuzumab and pertuzumab blockage of the same\nprotein through different ways, in this study these drugs were combined to treat the patient\nwith breast cancer HER2-positive. Such combination can provide a more effective blockage of\nthe HER2 signaling pathways, resulting in a better antitumor strategy, which can potentiate\nthe antitumor activity18 as well as inhibit the survival of breast cancer cells.19,20 For the treatment of patients with breast\ncancer recurrence and dermal involvement, a combined therapy is also required. Generally,\npatients who received pertuzumab, trastuzumab, and docetaxel showed significant response to\nthe treatment and a higher increase in the progression-free survival and overall survival\nthan the group that only received trastuzumab, docetaxel, and placebo.9 However, many patients presented adverse events as classical hypersensitivity or\nacute side effects during docetaxel administration.9 The patient studied presented acute side effects as neutropenia grade 1 and acute\nallergic reaction consisting of bronchospasm, headache, and dyspnea. For this, another\nantitumor agent to treat her erythema and thickening of the skin was necessary. At this\npoint, the treatment applied showed no improvement in the dermal involvement of breast skin\nand decreasing of the supraclavicular lymphadenopathy.\n\nThus, xeloda was added to the treatment schedule since neither the therapy with trastuzumab\nand docetaxel in the indicated doses (Table 1) nor the trastuzumab metastatic modality were able to decrease or cease\nthe dermal involvement of the patient’s neck and the supraclavicular lymphadenopathy. In\nthis sense, it is important to mention that Tsuyuki and colleagues21 investigated 30 patients with advanced metastatic breast cancer and reported that\nxeloda is an effective drug to treat soft tissue lesions, such as primary tumor and\nmetastasis of skin and lymph nodes. In addition, they stated that the effective response of\nxeloda was significantly higher in soft tissues than in other types of metastasis (lung,\nliver, and bone). As a result, they suggested that the use of this drug as the upfront line\nfor soft tissue metastatic cases can contribute to the overall survival.21 Breast cancer with dermal involvement can be treated with xeloda. Two women aged 61\nand 82 years presented significant improvement in their erythema of the skin after 2 cycles\nof xeloda and did not show progression for more than 10 months.11\n\nThe patient studied here presented the same pattern that the one described in literature\nduring her treatment with the combined therapy using trastuzumab, pertuzumab, and xeloda.\nShe soon presented a substantial improvement in her lesions in the neck and skin as well as\na decrease in the lymphadenopathy; after 6 cycles of combined therapy, her skin was almost\nrestored (see Figure 1 D-F).\nAdditionally, a computed tomography scan performed after the treatment only showed signs of\nregional subcutaneous cell tissue edema. Normal blood count and normal cardiac analysis were\nalso obtained.\n\nThe effects of trastuzumab and pertuzumab use on dermal involvement of the patient were not\nvisible. However, it can be expected that this combined therapy helped avoid the appearance\nof new tumors in other areas and to maintain the patient without evident cancer progression.\nAdditionally, it is possible that the patient had acquired resistance to the use of\ntrastuzumab as a single agent, but when the treatment schedule was changed to a combination\nof trastuzumab and pertuzumab, the observed synergic activity potentiated the antitumor\naction of these medicines. Finally, in this study, xeloda plays a key role in the treatment\nof severe inflammatory BCA component with erythema, thickening of the skin, and\nsupraclavicular lymphadenopathy by restoring the skin health,20 turning this combined treatment into an effective strategy to treat patients who\npresent with recurrent breast cancer and show signs of cutaneous metastasis and\nsupraclavicular lymphadenopathy.\n\nConclusions\nA 42-year-old woman diagnosed with HER2-positive breast cancer presented recurrence in her\ntumor as well as supraclavicular lymphadenopathy and severe inflammatory BCA component with\nerythema and thickening of the skin. Since the lesions reached a higher level, the treatment\nwith neoadjuvant radiotherapy was not viable. In addition, the patient did not respond\nsatisfactorily to the treatment that consisted in the use of trastuzumab with dectaxel or\ntrastuzumab metastatic modality, complicating her therapy. Given these issues, it was\ndecided to start a combined therapy with trastuzumab, pertuzumab, and xeloda, which proved\nto be an effective combination showing improvements after 3 cycles, restoring the skin\nhealth and decreasing almost completely the lymphadenopathy detected after 6 cycles.\n\nEven though the effects of the medicines in this patient are still not perfectly clear, our\nresults suggest that the combined therapy with trastuzumab, pertuzumab, and xeloda,\nfollowing the schedule and posology described here, can be a good treatment for recurrent\nHER2-positive breast cancer with supraclavicular lymphadenopathy and severe dermal\ninvolvement. This conclusion was reached not only because the synergic action between\ntrastuzumab and pertuzumab increased the antitumor activity in both drugs but also because\nthe action of xeloda in soft tissue with metastasis restored the skin heath.\n\nThe authors would like to thank Hospital Clínico Chillan Herminda Martín for supporting\nthis work.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research,\nauthorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or\npublication of this article.\n\nEthics Approval: Our institution does not require ethical approval for reporting individual cases.\n\nInformed Consent: The patient provided written consent for publishing this work.\n==== Refs\nReferences\n1 \nWorld Health Organization . Breast cancer\n.\nAccessed March 13, 2020 \nhttps://www.who.int/cancer/prevention/diagnosis-screening/breast-cancer/en/\n2 \nWorld Health Organization . Cancer country profiles:\nChile\n. Accessed March 13, 2020 \nwww.who.int/cancer/country-profiles/chl_en.pdf?ua=1\n3 \nYang N Zhang Y Shi L , et al\nCase report: breast cancer metastasis\nto the contralateral neck 22 years remote from initial diagnosis: a case\nreport\n. Int J Clin Exp Med .\n2016 ;9 :18659 -18663\n.\n4 \nSesterhenn AM Albert US Barth P Werner JA. \nThe status of neck node metastases in breast cancer—loco-regional or\ndistant?\n\nBreast .\n2006 ;15 :181 -186\n. doi:10.1016/j.breast.2005.05.006 16061381 \n5 \nHa KY Glass SB Laurie L. \nInflammatory breast carcinoma\n. Proc (Bayl Univ Med\nCent) .\n2013 ;26 :149 -151\n. doi:10.1080/08998280.2013.11928940 23543972 \n6 \nAdachi K Sakurai K Kubota H , et al\nAdvanced-stage breast cancer\ndiscovered by cervical lymphadenopathy in an elderly patient—report of a case [in\nJapanese]\n. Gan To Kagaku Ryoho .\n2019 ;46 :312 -314\n.30914544 \n7 \nPrice L Brunt AM. \nTrastuzumab infusion reactions in breast cancer. Should we routinely\nobserve after the first dose?\n\nEur J Hosp Pharm .\n2018 ;250 :331 -333\n.\ndoi:10.1136/ejhpharm-2016-001155 \n8 \nMcKeage K Perry CM. \nTrastuzumab: a review of its use in the treatment of metastatic breast\ncancer overexpressing HER2\n. Drugs .\n2002 ;62 :209 -243\n. doi:10.2165/00003495-200262010-00008 11790161 \n9 \nSwain SM Baselga J Kim SB , et al; CLEOPATRA Study Group .\nPertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast\ncancer\n. N Engl J Med .\n2015 ;372 :724 -734\n.\ndoi:10.1056/NEJMoa1413513 25693012 \n10 \nHo MY Mackey JR. \nPresentation and management of docetaxel-related adverse effects in\npatients with breast cancer\n. Cancer Manag Res .\n2014 ;6 :253 -259\n. doi:10.2147/CMAR.S40601 24904223 \n11 \nSideras K Kahasky KM Kaur JS. \nResponse of cutaneous metastases from breast cancer to\ncapecitabine\n. Clin Med Oncol .\n2008 ;2 :415 -418\n. doi:10.4137/cmo.s521 21892308 \n12 \nSlamon D Eiermann W Robert N , et al; Breast Cancer International Research\nGroup . Adjuvant trastuzumab in HER2-positive breast\ncancer\n. N Engl J Med .\n2011 ;365 :1273 -1283\n.\ndoi:10.1056/NEJMoa0910383 21991949 \n13 \nKyi C Shah MA. \nA case report of trastuzumab dose in gastric cancer\n.\nJ Gastrointest Oncol .\n2013 ;4 :E19 -E22\n. doi:10.3978/j.issn.2078-6891.2013.015 24294514 \n14 \nPrice-Schiavi SA Jepson S Li P , et al\nRat Muc4 (sialomucin complex) reduces\nbinding of anti-ErbB2 antibodies to tumor cell surfaces, a potential mechanism for\nherceptin resistance\n. Int J Cancer .\n2002 ;99 :783 -791\n. doi:10.1002/ijc.10410 12115478 \n15 \nScaltriti M Rojo F Ocaña A , et al\nExpression of p95HER2, a truncated\nform of the HER2 receptor, and response to anti-HER2 therapies in breast\ncancer\n. J Natl Cancer Inst .\n2007 ;99 :628 -638\n. doi:10.1093/jnci/djk134 17440164 \n16 \nGarnock-Jones KP Keating GM Scott LJ. \nTrastuzumab: a review of its use as adjuvant treatment in human epidermal\ngrowth factor receptor 2 (HER2)-positive early breast cancer\n.\nDrugs .\n2010 ;70 :215 -239\n. doi:10.2165/11203700-000000000-00000 20108993 \n17 \nLu CH Wyszomierski SL Tseng LM , et al\nPreclinical testing of clinically\napplicable strategies for overcoming trastuzumab resistance caused by PTEN\ndeficiency\n. Clin Cancer Res .\n2007 ;13 :5883 -5888\n.\ndoi:10.1158/1078-0432.CCR-06-2837 17908983 \n18 \nWerner S Friess T Burtscher H Bossenmaier B Endl J Hasmann M. \nStrongly enhanced antitumor activity of trastuzumab and pertuzumab\ncombination treatment on HER2-positive human xenograft tumor\n.\nCancer Res .\n2009 ;69 :9330 -9336\n.\ndoi:10.1158/0008-5472.CAN-08-4597 19934333 \n19 \nBaselga J Sandra MS. \nCLEOPATRA: a phase III evaluation of pertuzumab and trastuzumab for\nHER2-positive metastatic breast cancer\n. Clin Breast\nCancer .\n2010 ;10 :489 -491\n. doi:10.3816/CBC.2010.n.065 21147694 \n20 \nNahta R Hung MC Esteva FJ. \nThe HER-2-Targeting antibodies trastuzumab and pertuzumab synergistically\ninhibit the survival of breast cancer cells\n. Cancer\nRes .\n2004 ;64 :2343 -2346\n.\ndoi:10.1158/0008-5472.can-03-3856 15059883 \n21 \nTsuyuki S Kawaguchisakita N Tsubota Y Ukikusa M Kohno Y \nMore effective positioning of capecitabine for advanced\nand metastatic breast cancer [in Japanese.]\n. Gan To Kagaku\nRyoho .\n2010 ;37 :649 -653\n.20414020\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2324-7096",
"issue": "8()",
"journal": "Journal of investigative medicine high impact case reports",
"keywords": "HER2-positive; breast cancer; combined chemotherapy; inflammatory BCA component; supraclavicular lymphadenopathy",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": "D061605:Administration, Intravenous; D000284:Administration, Oral; D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D000069287:Capecitabine; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D000072281:Lymphadenopathy; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D018719:Receptor, ErbB-2; D000068878:Trastuzumab; D016896:Treatment Outcome",
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"other_id": null,
"pages": "2324709620942606",
"pmc": null,
"pmid": "32720808",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17908983;23543972;17440164;12115478;24904223;21147694;19934333;15059883;21991949;20414020;21892308;16061381;20108993;31157052;30914544;11790161;24294514;25693012",
"title": "Xeloda Oral, Trastuzumab, and Pertuzumab Combined Drug Therapy Reduced Cervical Lymphadenopathy and Dermal Involvement in Patient With Recurrent Breast Cancer: Case Report.",
"title_normalized": "xeloda oral trastuzumab and pertuzumab combined drug therapy reduced cervical lymphadenopathy and dermal involvement in patient with recurrent breast cancer case report"
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"abstract": "Segmental arterial mediolysis (SAM) is a rare self-limiting non-atherosclerotic, non-inflammatory vasculopathy. SAM typically affects the visceral arteries of the abdomen to include the celiac, mesenteric, and renal arteries. SAM has a favorable prognosis in most cases with an asymptomatic course but can have mortality rates as high as 50% due to acute aneurysmal rupture. Very few cases of adverse long-term sequelae involving SAM have been described, and this report of chronic kidney disease represents a sentinel case illustrating that chronic disease can and does occur as a result of SAM and should be investigated for at follow-up.\nIn this case report, we describe a case of a 45-year-old male with erectile dysfunction but without any readily identifiable risk factors for chronic kidney disease (CKD) or vasculopathy, who presented with bilateral renal infarction and parenchymal infarcts due to SAM and who subsequently developed CKD at follow-up. We conduct a mini-literature review that discusses the pathogenesis of SAM in the context of vasospastic diseases, as well as compares the outcomes of observation-only, versus medical-management, versus endovascular-interventions in patients with SAM.\nThis is the first case to our knowledge of CKD occurring as an outcome of SAM without any preceding significant comorbidity, highlighting that whereas SAM is of itself rare and typically resolves, chronic disease can linger and should be evaluated for on follow-up. Further, we argue that radiological evidence of precursor vasospastic disease may exist in several locations apart from the index lesion and thus warrants wider whole-body radiographic exploration for lesions as an opportunity to prevent chronic sequelae as illustrated in this case report from occurring. Finally, a review of published case-series suggests that disease progression is less likely to occur after endovascular-intervention compared to observation-only or medical management and the risk of intervention vs conservative management should therefore be discussed with the patient.",
"affiliations": "Department of Medicine, Tripler Army Medical Center, Honolulu, HI, 96859, USA.;Department of Nephrology, Walter Reed National Military Medical Center, Bethesda, MD, 20889, USA.;Department of Radiology, Tripler Army Medical Center, Honolulu, HI, 96859, USA.;Department of Radiology, Tripler Army Medical Center, Honolulu, HI, 96859, USA.",
"authors": "O'Shea|John-Paul|JP|0000-0001-6899-5559;Gordon|Sarah|S|;Horak|Richard|R|;Meadows|J Matthew|JM|",
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"doi": "10.2147/IJNRD.S287829",
"fulltext": "\n==== Front\nInt J Nephrol Renovasc Dis\nInt J Nephrol Renovasc Dis\nijnrd\nijnrd\nInternational Journal of Nephrology and Renovascular Disease\n1178-7058\nDove\n\n287829\n10.2147/IJNRD.S287829\nCase Report\nSegmental Arterial Mediolysis (SAM) Leading to Chronic Renal Insufficiency\nO’Shea et al\nO’Shea et al\nhttp://orcid.org/0000-0001-6899-5559\nO’Shea John-Paul 1\nGordon Sarah 2\nHorak Richard 3\nMeadows J Matthew 3\n1 Department of Medicine, Tripler Army Medical Center, Honolulu, HI, 96859, USA\n2 Department of Nephrology, Walter Reed National Military Medical Center, Bethesda, MD, 20889, USA\n3 Department of Radiology, Tripler Army Medical Center, Honolulu, HI, 96859, USA\nCorrespondence: John-Paul O’Shea Department of Medicine, Tripler Army Medical Center, 99-571 Pohue St, Aiea, Honolulu, HI, 96701, USATel +1 504 986 8573 Email john-paul.oshea.civ@mail.mil\n22 4 2021\n2021\n14 117123\n24 10 2020\n19 12 2020\n© 2021 O’Shea et al.\n2021\nO’Shea et al.\nhttps://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).\nBackground\n\nSegmental arterial mediolysis (SAM) is a rare self-limiting non-atherosclerotic, non-inflammatory vasculopathy. SAM typically affects the visceral arteries of the abdomen to include the celiac, mesenteric, and renal arteries. SAM has a favorable prognosis in most cases with an asymptomatic course but can have mortality rates as high as 50% due to acute aneurysmal rupture. Very few cases of adverse long-term sequelae involving SAM have been described, and this report of chronic kidney disease represents a sentinel case illustrating that chronic disease can and does occur as a result of SAM and should be investigated for at follow-up.\n\nCase Presentation\n\nIn this case report, we describe a case of a 45-year-old male with erectile dysfunction but without any readily identifiable risk factors for chronic kidney disease (CKD) or vasculopathy, who presented with bilateral renal infarction and parenchymal infarcts due to SAM and who subsequently developed CKD at follow-up. We conduct a mini-literature review that discusses the pathogenesis of SAM in the context of vasospastic diseases, as well as compares the outcomes of observation-only, versus medical-management, versus endovascular-interventions in patients with SAM.\n\nConclusion\n\nThis is the first case to our knowledge of CKD occurring as an outcome of SAM without any preceding significant comorbidity, highlighting that whereas SAM is of itself rare and typically resolves, chronic disease can linger and should be evaluated for on follow-up. Further, we argue that radiological evidence of precursor vasospastic disease may exist in several locations apart from the index lesion and thus warrants wider whole-body radiographic exploration for lesions as an opportunity to prevent chronic sequelae as illustrated in this case report from occurring. Finally, a review of published case-series suggests that disease progression is less likely to occur after endovascular-intervention compared to observation-only or medical management and the risk of intervention vs conservative management should therefore be discussed with the patient.\n\nKeywords\n\nvasospastic\nvasculopathy\nerectile dysfunction\n==== Body\nBackground\n\nSegmental Arterial Mediolysis (SAM) is a rare (~1/100,000) self-limiting non-atherosclerotic, non-inflammatory vasculopathy that typically affects the medium and large visceral arteries of the abdomen to include the celiac, mesenteric and renal arteries, and typically has a favorable prognosis when patients overcome the acute vascular insult.1,4 The pathophysiology of SAM includes both an acute phase and a reparative phase. During the acute phase, symptoms include severe abdominal and/or flank pain or headaches due to dissection and aneurysmal rupture or infarction of the vascular beds.2 Acute intra-abdominal or retroperitoneal hemorrhage share the main cause of increased mortality (20–50%) observed in the acute phase.1,3 The most common long-term outcome of SAM reported in the literature is hypertension, but otherwise there are no other reports of significant chronic sequelae of this condition.\n\nHere we report a case of a 45-year-old male patient with no past medical history and normal baseline renal function who developed stage 3 Chronic Kidney Disease (CKD) after sustaining bilateral renal artery dissections secondary to SAM. This is the first reported case of CKD following SAM without prior comorbidities.\n\nCase Presentation\n\nA 45-year-old Caucasian male presented to the Emergency Department following 3 days of progressively worsening right lower quadrant abdominal pain and headaches. His past medical history was remarkable for long-standing back pain and erectile dysfunction. The patient was a social drinker and occasionally smoked. Initial clinical workup was unremarkable with normal blood pressure and renal function (BP 124/86; serum creatinine was 1.0 mg/dL with an eGFR of 90 mL/min/1.73 m2). A CT scan of the abdomen and pelvis was performed with intravenous contrast was performed per local protocol, revealing a right lower pole renal infarct. There was also perivascular inflammation involving the celiac artery. Initially a thrombotic/hypercoagulable state was hypothesized as the etiology. An ECG, transthoracic echocardiography bubble studies, d-dimer and coagulation studies were performed with no abnormal findings. Serologic studies evaluating for systemic vasculitis including ESR, CRP, ANCA and ANA were also negative. The patient was admitted for 3 days and was discharged on apixaban 5 mg once daily with stable creatinine and eGFR.\n\nThe patient represented to the ED 16 days later with recurrent right flank pain, blood pressure 151/88 mmHg, temperature 36.7°C, serum creatinine of 1.3 mg/dL, eGFR 65.7 mL/min/1.73 m2, ESR 32 mm/h, CRP 12.32 mg/dL. Urinalysis was bland with no granular or epithelial casts. A CT angiogram of the aorta was performed to evaluate for aortic dissection, which revealed progression of the previously seen right renal infarct, now extending into the mid pole. There was also an acute dissection of the anterior and posterior divisions of the right renal artery, with several smaller branch occlusions in the mid and lower pole. In addition, there was new perivascular inflammation involving the main right renal artery and persistent inflammation involving the celiac artery, but no dissection or end organ damage. Interventional radiology was consulted for management of the renal artery thrombus to prevent worsening of the infarct. The patient was taken for a renal artery angiogram which confirmed the presence of a dissection and multiple segmental and smaller branch occlusion in the mid to lower right kidney. A decision was made to initiate catheter-directed thrombolysis, and the patient was monitored in the ICU overnight per protocol. Within 48 hours after the initiation of catheter directed thrombolysis, suffered fever and urinalysis was leukocyte esterase and nitrite positive and had 2+ blood and 2+ protein and was subsequently managed with Cefepime for urinary tract infection although urine culture ultimately showed no growth. The following day, the patient returned to IR for a repeat angiogram which revealed no significant reduction in arterial thrombus burden and a persistent dissection. Due to the patient having normal blood pressure, and significant pain improvement, thrombolytic therapy was discontinued and the patient was initiated on dual antiplatelet therapy with aspirin (81 mg daily) and clopidogrel (75 mg daily). At the point of discharge, the sCr was 1.0 mg/dL, eGFR 89.0 mL/min/1.73 m2.\n\nTwelve days later, the patient was readmitted, at that time complaining of gross hematuria and passing tissue on urination with elevated creatinine (1.63 mg/dL) and eGFR (50.1 mL/min/1.73 m2). A CT angiogram of the renal arteries was performed, showing a new left lower pole renal infarct and a left renal artery segmental branch dissection (Figure 1). There was a similar appearance to the perivascular inflammation involving the celiac and right renal artery branches with no increase in right renal infarct size. Genetic testing panels including COL3A1 for collagen disorders yielded nothing.Figure 1 CT angiogram images, demonstrating bilateral renal artery lobar branch dissections (white arrows) on the right (A and B) and left (C), as well as associated parenchymal infarcts (white arrowheads). Digital subtraction angiogram of the right renal artery (D) demonstrating lobar and segmental branch dissections (white arrows), segmental branch occlusion (black arrow) and infarcted parenchyma (white arrowheads). Excreted contrast is also noted in the renal pelvis (P).\n\nAt that time other contributors to the acute kidney injury and gross hematuria, including variously: hypovolemia; post-renal obstructive causes; glomerular and tubulointerstitial nephropathies (eg, contrast-induced nephropathy, acute interstitial nephropathy, acute tubular necrosis; were considered but appeared unlikely given lack of obstruction found on imaging (renal ultrasound and CT) as well as profuse red blood cells and protein on urinalysis but otherwise bland urine microscopy). There was no albuminuria. Throughout his presentation, the patient maintained adequate urine output ~120–200 mL/hour (body mass 95.7 kg). At this stage and in light of the radiographic abnormalities including inflammatory changes involving the celiac and renal arteries with associated bilateral renal artery dissections and the absence of vasculitic-, collagen defect-, or thrombophilia-markers, the provisional diagnosis was a non-atherosclerotic non-inflammatory vasculopathy.\n\nAs there was no indication for surgical or additional endovascular management, the multidisciplinary team decided to manage the patient medically with atorvastatin (80 mg daily), Aspirin (81 mg daily), clopidogrel (75 mg daily), metoprolol (25 mg daily), amlodipine (5 mg daily) with blood pressure goals of <130/80 and counseling to adhere to a low sodium diet, home blood pressure monitoring and avoidance non-steroidal anti-inflammatories.\n\nWithin 2 weeks of this latter presentation, hematuria had been resolved, there was no proteinuria or albuminuria on urinalysis; however, serum creatinine remained elevated and eGFR depressed. At 15-month follow-up, his kidney function had stabilized with elevated creatinine (1.3–1.5 mg/dL) and eGR (58–63 mL/min/1.73 m2) levels meeting the KDIGO criterion for CKD stage G2/3. A Renal CTA at this time demonstrated chronic bilateral infarcts and persistent, but improved perivascular inflammatory changes of the celiac and renal arteries without recurrent or new dissection (Figure 2).Figure 2 Renal CT angiogram 15 months after the initial insult. Demonstrates chronic infarcts and atrophy of the lower renal poles (arrowheads) of the right (A) and left (B) kidneys.\n\nDiscussion and Conclusions\n\nNon-atherosclerotic non-inflammatory vasculopathies are uncommon with an overall combined incidence of <0.03%.1,5 Segmental Arterial Mediolysis itself contributes 1/20th of this incidence (0.001%). This incidence is distributed equally across all age groups, although there is a slight male preponderance. Hypertension is the most common preceding comorbidity reported, especially in cases of renal involvement.2,4,6–8 The pathogenesis leading to presentations of SAM is currently unknown, yet speculation ranges from embryological mesodermal defects9 to focal neuro-hormonal derangements resulting in vasospastic disease.1 Takagi et al speculated on embryological defects leading to the disease, based on the shared mesodermal origins of affected vessels and malignancies they observed in one patient.9\n\nThe vasospastic origin of SAM is speculatively based on theories of deranged trafficking of endothelins and catecholamines in smooth muscle wall-layers. Endothelins and catecholamines (epinephrine and norepinephrine) are potent vasopressors and endothelin-1 is a known potentiator of these and other vasoconstricting mediators.10,11 Based on a histological study of tissue samples from 10 patients stained for Endothelin-1, Slavin et al have argued that endothelin dysregulation may be a cause of potentiation of other vasoconstrictors especially at the smooth muscle nerve terminals.12 This leads to a segmental constriction of the cells in the medial layer of arteries and results in the established histopathological sequence of the disease: micro-ischemia; vacuolization and micro-bleeds progressing to gaps and wall weakening; and consequently aneurysms, rupture and hemorrhage, dissection and thrombosis, or infarction.1,2 The vasospastic theory of SAM resonates with the erectile dysfunction (ED) seen in the subject of this case report as well as other co-morbid vasospastic diseases seen in the subjects of other case reports.12 Although ED is multi-factorial in origin, various studies implicate endothelin mediated vasoconstriction of the corpus cavernosum as a cause of the condition.10,11\n\nOne or more vessels may be involved in the pathological process of SAM, with multiple vessels typically affected (46–85%).1,13 The vessels most commonly affected in SAM include the celiac artery and branches (80%), renal and cerebral vessels.2 The clinical presentation of SAM depends on which vascular beds have been dissected, thrombosed or infarcted, but chief complaints of abdominal, flank pain or headache predominate (with or without associated hematochezia, hematuria or stroke-like symptoms, respectively) and associated hypertension.2 Dramatic life-threatening hemorrhage into the abdomen, retroperitoneum, or brain can also be encountered.\n\nOther causes of widespread vascular disease should be considered, including: systemic vasculitis; mycotic aneurysms; collagen vascular diseases; degenerative vasculopathies (eg, cystic medial necrosis and cystic adventitial artery disease); hereditary aneurysmal syndromes (eg, Lowey-Dietz syndrome); and non-atherosclerotic/non-inflammatory vasculopathies (FMD and SAM).2 Workup for these differentials is clearly broad; however, Kalva et al describe a non-validated but convenient set of institutional diagnostic criteria used at Massachusetts General Hospital: Absence of atherosclerosis; absence of inflammatory markers (anti-nuclear antibodies, anti-neutrophil cytoplasmic antibodies, normal complement); absence of a clinical history suggesting another cause; absence of genetic markers for collagen vascular disorders; and segmental wall thickening, arterial dilatation, aneurysms, dissections, the “string-of-beads” appearance and absence of inflammation on imaging.6 In the reparative phase of the disease, fibrin and granulation tissue is deposited. This segmental thickening of arterial walls results in a string-of-beads sign (seen in about 30% of cases).14,15\n\nAfter initial abdominal CT to rule out life-threatening causes of abdominal or flank pain, dedicated CT angiogram should be considered as the imaging modality of choice both for diagnosis and follow-up.2,16,17 Although histopathology is the gold-standard for diagnosis of SAM, it is usually unfeasible or not required given the efficacy of CTA.16\n\nControversy exists over the extent of disease in SAM. Slavin et al observed that generally only 2 or more arterial segments from the same or adjoining vascular beds may be affected.1 However, cases of multiple distributions are not uncommon.1,12 We agree with the supposition of other authors that subclinical SAM is likely to be manifested systemically by typical preceding comorbidities. We argue that this not only includes the commonly reported comorbidity of hypertension but also vasospastic diseases such as those previously reported as well as the erectile dysfunction seen in our case.12 Recognition of the potential for a wider extent of the disease than is symptomatically apparent arguably justifies whole-body radiographic exploration for lesions.3,18\n\nApart from a multi-disciplinary approach which should involve internal medicine, interventional radiology and vascular surgery, management of SAM depends on the presentation: stable vs unstable. In unstable presentations, patients should be resuscitated appropriately and may require emergent surgery for hemorrhage control. Some patients may also be candidates for endovascular therapy depending on the clinical situation but must be reasonably stable1,6,13 The conservative management of SAM in patients who are hemodynamically stable is controversial. Based on the high mortality rates of SAM generally and the high attribution of death to medical management in the case series they studied (82%), some authors argue for the interventional approach (embolization) even for incidentally identified SAM lesions.8,13,19,20 In a non-systematic review of the literature on non-death outcomes of stable SAM cases at long-term follow-up (3 months to 102 months), we found that out of 37 cases conservatively (medically) managed, there was evidence of progression of this disease (death, recurrence, extension or new occurrence of aneurysms, dissection or infarction) in 14 patients (~38%). This was contrasted with progression in 9 out of 115 cases (8%), that were invasively managed surgically or with endovascular interventions (stenting, coiling, angioplasty) (see Supplementary Materials). Among those cases managed with observation only, 17 out of 19 patients died (89%). Although this is very poor quality evidence, it nevertheless lends support to invasive management for SAM in patients who are stable and are candidates.\n\nThe mainstay of medical management in stable patients is pain management, heart rate and blood pressure control to <130/80 mmHg and dual anti-platelet therapy (DAPT).6,21,22 Due to anti-inflammatory properties, statins may also impart benefit. Additionally, patients should be counselled to cease smoking.23 Although many care teams pursue anti-coagulation with heparin initially and during workup, this is usually ceased on diagnosis of SAM, given reports of recurrence as well as increased aneurysmal rupture with this therapy.3,6,18,23 Likewise, glucocorticoids should be avoided based on the case series of Lie and others who report the death of all SAM patients managed with glucocorticoids for presumptive vasculitis.3,24\n\nThe patient in this case report suffered a decline in renal function to CKD stage G2/3 within 9 months of initially presenting. This decline corresponded with CTA surveillance demonstrating stable bilateral renal infarcts and continued chronic vascular inflammation. The outcomes of long-term surveillance for SAM patients are under-reported with little information available regarding relevant sequelae beyond either the cessation of symptoms or radiographical evidence of disease stabilization.8,16 Although some patients have been followed for up to 9 years, most cases of reported SAM are followed-up for less than one year (see Supplementary Materials). As mentioned above, the majority of cases, including those with renal involvement, report resolution or at least no progression of the disease and it is widely reported to have a favorable prognosis.4,6,8,16 Nonetheless, clinical hypertension appears to be a not uncommon outcome and may indicate ongoing SAM related disease processes. This supports the argument made by other authors that SAM may represent a disease sitting on a continuum where FMD sits at the terminus.12,13 Similar to SAM, FMD is another non-atherosclerotic non-inflammatory vasculopathy. Whereas SAM presents with aneurysmal rupture, dissection and hemorrhage, FMD is known to present predominantly in middle-aged females with radiographical and clinical manifestations of arterial stenosis. Therefore, it is arguable that similar to hypertension, the CKD suffered by the patient in this report may be due to microvascular stenoses/occlusion that is not readily detectable on high-resolution CTA. Similar types of disease progression may be responsible for the consequent hypertension seen in other reports of SAM. To our knowledge, only 3 other cases of CKD associated with SAM have been reported. Unlike our patient, these three cases all involved patients with pre-existing co-morbidities. In two cases, CKD was present prior to the onset of the first event recognizably due to SAM.4,25 No information regarding the cause of CKD in those cases was reported. In the third case, the patient suffered from systemic sclerosis (SSc) and the decline in renal function was attributed to scleroderma renal crisis resulting from the combination of SSc and SAM.26\n\nThis is the first case report to our knowledge which describes CKD as a sequela of SAM without prior comorbidity. Although SAM is widely regarded as a disease with favorable prognosis, adverse sequelae such as chronic hypertension have been reported. It is the authors opinion that the instances of CKD and hypertension reported may be due to similar microvascular pathophysiology that is actually a characteristic of SAM progression. Further investigation on the long-term sequelae of SAM is required to gain a greater understanding of the relationship between SAM, FMD and associated co-morbidities.\n\nAcknowledgments\n\nThe views expressed are solely those of the authors and do not reflect the official policy or position of the US Army, the Department of Defense, or the US Government.\n\nAbbreviations\n\nCKD, chronic kidney disease; SAM, segmental arterial mediolysis; SSc, systemic sclerosis.\n\nData Sharing Statement\n\nThe datasets and Supplementary Materials referred to in this case report are available from the corresponding author on reasonable request.\n\nConsent for Publication\n\nWritten informed consent was obtained from the patient for publication of this Case report and any accompanying images.\n\nAuthor Contributions\n\nAll authors made substantial contributions to 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\n\nThe authors declare that they have no conflicts of interest.\n==== Refs\nReferences\n\n1. Slavin RE. Segmental arterial mediolysis: course, sequelae, prognosis, and pathologic-radiologic correlation. Cardiovasc Pathol. 2009;18 :352–360. doi:10.1016/j.carpath.2008.09.001 19026575\n2. Pillai AK, Iqbal SI, Liu RW, Rachamreddy N, Kalva SP. Segmental arterial mediolysis. Cardiovasc Intervent Radiol. 2014;37 :604–612. doi:10.1007/s00270-014-0859-4 24554198\n3. Cohen DL, Soulen MC. A patient with acute kidney pain and high blood pressure. Clin J Am Soc Nephrol. 2015;10 :696–702. doi:10.2215/CJN.10171014 25583291\n4. Inada K, Maeda M, Ikeda T. Segmental arterial mediolysis: unrecognized cases culled from cases of ruptured aneurysm of abdominal visceral arteries reported in the Japanese literature. Pathol Res Pract. 2007;203 :771–778. doi:10.1016/j.prp.2007.07.010 17920781\n5. Ko M, Kamimura K, Ogawa K, et al. Diagnosis and management of fibromuscular dysplasia and segmental arterial mediolysis in gastroenterology field: a mini-review. World J Gastroenterol. 2018;24 :3637–3649. doi:10.3748/wjg.v24.i32.3637 30166859\n6. Kalva SP, Somarouthu B, Jaff MR, Wicky S. Segmental arterial mediolysis: clinical and imaging features at presentation and during follow-up. J Vasc Intervent Radiol. 2011;22 :1380–1387. doi:10.1016/j.jvir.2011.07.001\n7. Heritz DM, Butany J, Johnston KW, Sniderman KW. Intraabdominal hemorrhage as a result of segmental mediolytic arteritis of an omental artery: case report. J Vasc Surg. 1990;12 :561–565. doi:10.1016/0741-5214(90)90011-X 2231968\n8. Kim HS, Min SI, Han A, Choi C, Min SK, Ha J. Longitudinal evaluation of segmental arterial mediolysis in splanchnic arteries: case series and systematic review. PLoS One. 2016;11 :e0161182. doi:10.1371/journal.pone.0161182 27513466\n9. Takagi C, Ashizawa N, Eishi K, et al. Segmental mediolytic arteriopathy involving celiac to splenic and left renal arteries. Intern Med. 2003;42 :818–823. doi:10.2169/internalmedicine.42.818 14518668\n10. Maas R, Schwedhelm E, Albsmeier J, Boger RH. The pathophysiology of erectile dysfunction related to endothelial dysfunction and mediators of vascular function. Vasc Med. 2002;7 :213–225. doi:10.1191/1358863x02vm429ra 12553745\n11. Ritchie R, Sullivan M. Endothelins & erectile dysfunction. Pharmacol Res. 2011;63 :496–501. doi:10.1016/j.phrs.2010.12.006 21185376\n12. Slavin RE, Inada K. Segmental arterial mediolysis with accompanying venous angiopathy: a clinical pathologic review, report of 3 new cases, and comments on the role of endothelin-1 in its pathogenesis. Int J Surg Pathol. 2007;15 :121–134. doi:10.1177/1066896906297684 17478765\n13. Tameo MN, Dougherty MJ, Calligaro KD. Spontaneous dissection with rupture of the superior mesenteric artery from segmental arterial mediolysis. J Vasc Surg. 2011;53 :1107–1112. doi:10.1016/j.jvs.2010.11.034 21276678\n14. Davran R, Cinar C, Parildar M, Oran I. Radiological findings and endovascular management of three cases with segmental arterial mediolysis. Cardiovasc Intervent Radiol. 2010;33 :601–606. doi:10.1007/s00270-009-9651-2 19629590\n15. Ro A, Kageyama N, Takatsu A, Fukunaga T. Segmental arterial mediolysis of varying phases affecting both the intra-abdominal and intracranial vertebral arteries: an autopsy case report. Cardiovasc Pathol. 2010;19 :248–251. doi:10.1016/j.carpath.2009.02.002 19375356\n16. Michael M, Widmer U, Wildermuth S, Barghorn A, Duewell S, Pfammatter T. Segmental arterial mediolysis: CTA findings at presentation and follow-up. AJR Am J Roentgenol. 2006;187 :1463–1469. doi:10.2214/AJR.05.0281 17114538\n17. Baker-LePain JC, Stone DH, Mattis AN, Nakamura MC, Fye KH. Clinical diagnosis of segmental arterial mediolysis: differentiation from vasculitis and other mimics. Arthritis Care Res. 2010;62 :1655–1660. doi:10.1002/acr.20294\n18. Oki T, Adachi H, Tahara H, Kino S. [Spontaneous renal artery dissection with renal infarction: a case report]. Hinyokika Kiyo. 2011;57 :611–614.22166823\n19. Chao CP. Segmental arterial mediolysis. Semin Intervent Radiol. 2009;26 :224–232. doi:10.1055/s-0029-1225666 21326567\n20. Soulen MC, Cohen DL, Itkin M, Townsend RR, Roberts DA. Segmental arterial mediolysis: angioplasty of bilateral renal artery stenoses with 2-year imaging follow-up. J Vasc Interv Radiol. 2004;15 :763–767. doi:10.1097/01.RVI.0000133543.32123.DC 15231892\n21. Britto MM, Lukies M, Milne C, Joseph T, Lee JC. Case of Segmental Arterial Mediolysis. BMJ Case Rep. 2018;2018 . doi:10.1136/bcr-2017-223731\n22. Salifu MO, Gordon DH, Friedman EA, Delano BG. Bilateral renal infarction in a black man with medial fibromuscular dysplasia. Am J Kidney Dis. 2000;36 :184–189. doi:10.1053/ajkd.2000.8292 10873889\n23. Onteddu NK, Hindi Z, Rajashekar G, Kalva SP. Segmental arterial mediolysis presenting as spontaneous bilateral renal artery dissection. Radiol Case Rep. 2018;13 :495–498. doi:10.1016/j.radcr.2017.11.017 29904497\n24. Lie JT. Systemic, cerebral, and pulmonary segmental mediolytc arteriopathy: villainous masqueraders of vasculitis. Cardiovasc Pathol. 1996;5 :305–314. doi:10.1016/S1054-8807(96)00071-3 25851787\n25. Inada K, Ikeda T, Hayashi T. A Study on 20 cases of segmental arterial mediolysis (SAM) with multiple aneurysms, with a special reference to incidence, treatment and prognosis. Nihon Rinsho Geka Gakkai Zasshi. 2008;69 :3101–3106. doi:10.3919/jjsa.69.3101\n26. Kaneko S, Watanabe E, Abe M, et al. Scleroderma renal crisis with coexisting segmental arterial mediolysis presenting as intraperitoneal bleeding: a case report. J Med Case Rep. 2019;13 :74. doi:10.1186/s13256-019-1993-z 30890184\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1178-7058",
"issue": "14()",
"journal": "International journal of nephrology and renovascular disease",
"keywords": "erectile dysfunction; vasculopathy; vasospastic",
"medline_ta": "Int J Nephrol Renovasc Dis",
"mesh_terms": null,
"nlm_unique_id": "101550217",
"other_id": null,
"pages": "117-123",
"pmc": null,
"pmid": "33911893",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
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"title": "Segmental Arterial Mediolysis (SAM) Leading to Chronic Renal Insufficiency.",
"title_normalized": "segmental arterial mediolysis sam leading to chronic renal insufficiency"
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"companynumb": "US-BAYER-2021A255303",
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"abstract": "Normal physiologic changes in pregnancy include mild hyponatremia. In some cases of preeclampsia, more significant hyponatremia has been associated with syndrome of inappropriate antidiuretic hormone secretion and hypervolemic hyponatremia. A 45-year-old gravida 2, para 0010 with a dichorionic twin gestation was diagnosed with preeclampsia at 30 weeks 6 days and noted to have concomitant hyponatremia of 125 mEq/L at our institution. Her hyponatremia was initially managed with furosemide and water restriction. She was delivered at 33 weeks 5 days due to worsening preeclampsia and continued significant hyponatremia despite treatment. Her hyponatremia resolved within 48 h after delivery. Our objectives were to discuss trends, treatment, and outcomes of cases with hyponatremia in preeclampsia. We performed a systematic review of the literature using Ovid Medline (1963-2017), Scopus (1962-2017), and PubMed (1963-2017, including Cochrane database). Relevant articles describing any case report of hyponatremia in preeclampsia were identified from the above databases without any time, language, or study limitations. Studies were deemed eligible for inclusion if they described a case of hyponatremia in the setting of preeclampsia. 18 manuscripts detailing 55 cases were identified. Pertinent demographic data and laboratory values were extracted. Maternal management strategy, diagnosis, delivery, and neonatal outcome data were also collected. Mean, range, standard deviation, and percentage calculations were used as applicable. Advanced maternal age (46 %), nulliparity (79 %), and multifetal gestation (34 %) were noted in patients with preeclampsia and low sodium. Hyponatremia was detected on average at 34 weeks gestation. 64 % were diagnosed with preeclampsia with severe features. When reported, diagnoses related to hyponatremia were syndrome of inappropriate antidiuretic hormone secretion (41 %) or hypervolemic hyponatremia (59 %). Indications for delivery included severe hyponatremia unresponsive to conservative measures in addition to other known obstetric or preeclamptic indications. Hyponatremia resolved within 48 h on average in cases where postpartum resolution was reported. It may be prudent to screen women with preeclampsia for electrolyte disturbances as part of their evaluation, especially in the setting of severe features. Initially, hyponatremia may be treated with medical management. In addition to established obstetric or preeclamptic indications, delivery may be considered if severe hyponatremia no longer responds to conservative measures.",
"affiliations": "Atlantic Health System Morristown Medical Center, 100 Madison Avenue, Morristown, New Jersey, 07960, United States.;Thomas Jefferson University Hospital. 833 Chestnut, Philadelphia, Pennsylvania, 19107, United States.;Thomas Jefferson University Hospital. 833 Chestnut, Philadelphia, Pennsylvania, 19107, United States.;New York Presbyterian Hospital/Weill Cornell Medical College, 525 E 68th Street, New York, New York, 10065, United States.;Thomas Jefferson University Hospital. 833 Chestnut, Philadelphia, Pennsylvania, 19107, United States. Electronic address: vincenzo.berghella@jefferson.edu.",
"authors": "Powel|Jennifer E|JE|;Rosenthal|Emily|E|;Roman|Amanda|A|;Chasen|Stephen T|ST|;Berghella|Vincenzo|V|",
"chemical_list": "D012964:Sodium",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.ejogrb.2020.03.052",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-2115",
"issue": "249()",
"journal": "European journal of obstetrics, gynecology, and reproductive biology",
"keywords": "Antepartum screening; Electrolytes; Gestational hypertension; Hyponatremia; Maternal physiology; Severe features",
"medline_ta": "Eur J Obstet Gynecol Reprod Biol",
"mesh_terms": "D001810:Blood Volume; D005260:Female; D006801:Humans; D007010:Hyponatremia; D007177:Inappropriate ADH Syndrome; D008875:Middle Aged; D011225:Pre-Eclampsia; D011247:Pregnancy; D011248:Pregnancy Complications; D059285:Pregnancy, Twin; D012964:Sodium",
"nlm_unique_id": "0375672",
"other_id": null,
"pages": "14-20",
"pmc": null,
"pmid": "32344245",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D000078182:Systematic Review",
"references": null,
"title": "Preeclampsia and low sodium (PALS): A case and systematic review.",
"title_normalized": "preeclampsia and low sodium pals a case and systematic review"
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"companynumb": "NVSC2020US199794",
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"occurcountry": "US",
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"activesubstancename": "FUROSEMIDE"
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"abstract": "Untreated infective endocarditis (IE) often produces infective emboli in major cerebral arteries. We describe a case of middle cerebral artery occlusion due to IE, which caused severe vasospasm and reocclusion after mechanical thrombectomy (MT). We present the pathologic findings of the occluded middle cerebral artery and investigate the precautions to be taken while performing MT due to IE. A 72-year-old man with atrial fibrillation treated with dabigatran presented with right hemiparesis and aphasia. A diffusion-weighted image showed a high-intensity area in the left temporoparietal junction, and magnetic resonance angiography revealed a left M2 occlusion. Because of an elevated activated partial thromboplastin time, the thrombolytic therapy was contraindicated; instead, MT was performed. Just after the withdrawal of a stent retriever, the left M2 segment showed severe vasospasm. The next day, the left M2 segment reoccluded. Transthoracic echocardiogram and blood culture findings revealed IE. On the ninth day, the patient died. According to the autopsy report, the cause of death was pulmonary embolism. Pathologic analysis of the occluded M2 segment revealed fibrin thrombi containing vast amounts of neutrophils and invasion of neutrophils into the internal elastic lamina. Severe vasospasm was thought to have occurred because the vascular injury caused by the stent retriever in the vessel had a marked inflammation background. Our findings suggest that devices that are less invasive to the vascular wall are required for performing MT due to IE. The Penumbra aspiration system is thought to be a suitable device.",
"affiliations": "Department of Neurosurgery, Kimitsu Chuo Hospital, Kisarazu City, Chiba, Japan.;Department of Neurosurgery, Kimitsu Chuo Hospital, Kisarazu City, Chiba, Japan. Electronic address: tajima5615@yahoo.co.jp.;Department of Pathology, Kimitsu Chuo Hospital, Kisarazu City, Chiba, Japan.;Department of Neurosurgery, Kimitsu Chuo Hospital, Kisarazu City, Chiba, Japan.;Department of Cardiology, Kimitsu Chuo Hospital, Kisarazu City, Chiba, Japan.;Department of Neurosurgery, Kimitsu Chuo Hospital, Kisarazu City, Chiba, Japan.;Department of Neurosurgery, Kimitsu Chuo Hospital, Kisarazu City, Chiba, Japan.;Department of Neurosurgery, Kimitsu Chuo Hospital, Kisarazu City, Chiba, Japan.;Department of Neurosurgery, Kimitsu Chuo Hospital, Kisarazu City, Chiba, Japan.",
"authors": "Nishino|Wataru|W|;Tajima|Yosuke|Y|;Inoue|Toru|T|;Hayasaka|Michihiro|M|;Katsu|Bi|B|;Ebihara|Koichi|K|;Kawauchi|Daisuke|D|;Kubota|Masaaki|M|;Suda|Sumio|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jstrokecerebrovasdis.2017.06.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1052-3057",
"issue": "26(9)",
"journal": "Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association",
"keywords": "Infective endocarditis; mechanical thrombectomy; middle cerebral artery; severe vasospasm",
"medline_ta": "J Stroke Cerebrovasc Dis",
"mesh_terms": "D000368:Aged; D001344:Autopsy; D002533:Cerebral Angiography; D038524:Diffusion Magnetic Resonance Imaging; D004697:Endocarditis, Bacterial; D017809:Fatal Outcome; D006801:Humans; D020244:Infarction, Middle Cerebral Artery; D018810:Magnetic Resonance Angiography; D008297:Male; D012008:Recurrence; D012720:Severity of Illness Index; D017131:Thrombectomy; D016896:Treatment Outcome; D020301:Vasospasm, Intracranial",
"nlm_unique_id": "9111633",
"other_id": null,
"pages": "e186-e188",
"pmc": null,
"pmid": "28669652",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe Vasospasm of the Middle Cerebral Artery after Mechanical Thrombectomy Due to Infective Endocarditis: An Autopsy Case.",
"title_normalized": "severe vasospasm of the middle cerebral artery after mechanical thrombectomy due to infective endocarditis an autopsy case"
} | [
{
"companynumb": "JP-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2017-BI-037787",
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"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "BACKGROUND\nMetoprolol and amiodarone are common antiarrhythmic drugs used in clinics throughout the world. The taste and smell alterations induced by antiarrhythmic drugs remain uncommon throughout the world, with less than 10 reported cases.\nIn this case report, we describe a case of a 73-year-old female, diagnosed with arrhythmias, was treated for metoprolol. At the third week of metoprolol treatment, the patient noticed a qualitative change in her ability to smell, also called dysosmia. After the metoprolol was tapered, her ability to smell was recovered. However, her arrhythmia was getting worse and the patient was given amiodarone. After using amiodarone for about 2 weeks, the patient felt hypogeusia, or loss of taste sensation.\nThe patient was diagnosed as dysosmia and taste disturbance induced by the antiarrhythmic drugs.\n\n\nMETHODS\nAfter noticed the side effects of the antiarrhythmic drugs, we asked the patient to abandon the drugs and have a radiofrequency ablation.\n\n\nRESULTS\nHer ability of smell and taste were recovered after withdrawing the antiarrhythmic drugs. Also, in the follow-up appointment, she reported no complaints of smell or taste anymore.\n\n\nCONCLUSIONS\nThese rare sensory disorders induced by anti-arrhythmic drugs were less documented in past literature. Our case report describes a patient with an arrhythmia who suffered reversible dysosmia and hypogeusia after taking metoprolol and amiodarone, respectively. We conclude that smell and taste disorders should be made aware to patients during the anti-arrhythmic treatment, helping to promote the safety of patients and drug compliance.",
"affiliations": "Department of Cardiology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College Department of Otorhinolaryngology Head and Neck Surgery, Fourth Clinical Medical College, Zhejiang Chinese Medical University Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P. R. China Department of Preventive Medicine, Loma Linda University Medical Center Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA.",
"authors": "Che|Xiaoru|X|;Li|Yuandong|Y|;Fang|Yuanjian|Y|;Reis|Cesar|C|;Wang|Huan|H|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D008790:Metoprolol; D000638:Amiodarone",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000011112",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 30024498MD-D-18-0122410.1097/MD.0000000000011112111123400Research ArticleClinical Case ReportAntiarrhythmic drug-induced smell and taste disturbances A case report and literature reviewChe Xiaoru MDaLi Yuandong MDbFang Yuanjian MDcReis Cesar MDdeWang Huan MDa∗NA. a Department of Cardiology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical Collegeb Department of Otorhinolaryngology Head and Neck Surgery, Fourth Clinical Medical College, Zhejiang Chinese Medical Universityc Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P. R. Chinad Department of Preventive Medicine, Loma Linda University Medical Centere Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA.∗ Correspondence: Huan Wang, Department of Cardiology, Zhejiang Provincial People's Hospital, No. 158 Shangtang Rd, 310014 Hangzhou, Zhejiang, P. R. China (e-mail: huanwang_pumc@163.com).7 2018 20 7 2018 97 29 e1111225 2 2018 23 5 2018 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc/4.0Abstract\nRationale:\nMetoprolol and amiodarone are common antiarrhythmic drugs used in clinics throughout the world. The taste and smell alterations induced by antiarrhythmic drugs remain uncommon throughout the world, with less than 10 reported cases.\n\nPatient concerns:\nIn this case report, we describe a case of a 73-year-old female, diagnosed with arrhythmias, was treated for metoprolol. At the third week of metoprolol treatment, the patient noticed a qualitative change in her ability to smell, also called dysosmia. After the metoprolol was tapered, her ability to smell was recovered. However, her arrhythmia was getting worse and the patient was given amiodarone. After using amiodarone for about 2 weeks, the patient felt hypogeusia, or loss of taste sensation.\n\nDiagnoses:\nThe patient was diagnosed as dysosmia and taste disturbance induced by the antiarrhythmic drugs.\n\nInterventions:\nAfter noticed the side effects of the antiarrhythmic drugs, we asked the patient to abandon the drugs and have a radiofrequency ablation.\n\nOutcomes:\nHer ability of smell and taste were recovered after withdrawing the antiarrhythmic drugs. Also, in the follow-up appointment, she reported no complaints of smell or taste anymore.\n\nLessons:\nThese rare sensory disorders induced by anti-arrhythmic drugs were less documented in past literature. Our case report describes a patient with an arrhythmia who suffered reversible dysosmia and hypogeusia after taking metoprolol and amiodarone, respectively. We conclude that smell and taste disorders should be made aware to patients during the anti-arrhythmic treatment, helping to promote the safety of patients and drug compliance.\n\nKeywords\namiodaroneantiarrhythmic drugsmetoprololside effectssmelltasteOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nAntiarrhythmic drugs, including metoprolol and amiodarone, are widely used in cardiac disease. Metoprolol is a common beta1-selective adrenoceptor blocking drug used mainly used for management of hypertension, coronary heart disease, heart failure, and various arrhythmias.[1] Similar to other beta-adrenergic blockers, the most common side effects of metoprolol include fatigue, weakness, headache, cold peripheries, and gastrointestinal reaction.[1] Metoprolol has the unique ability to enter the central nervous system (CNS) and affect its function.[2] Amiodarone is another effective antiarrhythmic drug used primarily for supraventricular and ventricular arrhythmias. The adverse events of amiodarone are relatively higher than other antiarrhythmic drugs.[3] Long-term use increases the risk for side effects, including hyperthyroidism, elevated aminotransferase, pulmonary toxicity, and gastrointestinal reaction.[4]\n\nCranial nerve function damage has rarely been reported in the past literature. To our knowledge, it was first introduced by Vital Durand[5] that a recurrent anosmia was induced by metoprolol. Following this report, these rare but serious adverse effects have gained increased attention. The taste and smell alterations induced by antiarrhythmic drugs remain uncommon throughout the world, with less than 10 reported cases. Herein, we first report a case of reversible dysosmia and hypogeusia following the use of antiarrhythmic drugs metoprolol and amiodarone, respectively.\n\n2 Case report\nA 73-year-old female was admitted to our clinic with chest distress and palpitations. The physical examination revealed no positive findings. Electrocardiograph (EEG) and dynamic EEG (DCG) showed arrhythmias, including paroxysmal atrial fibrillation, paroxysmal supraventricular tachycardia, atrial premature beats, and ventricular premature beats. A cardiac B-mode ultrasound showed mild aortic valvular regurgitation and left ventricular diastolic dysfunction. Coronary artery CT found stenosis of the left anterior descending artery (50%). Laboratory findings, including blood chemistry and myocardial enzymes, were normal. The patient was prescribed 100 mg aspirin once a day for 2 months by another center. We decided to continue this existing treatment and add metoprolol 47.5 mg/day for her symptoms. Before our treatment, no examination for sense of smell or taste was performed, and the patient did not report any abnormalities in her ability to smell or taste.\n\nAfter 2 weeks of metoprolol therapy, the patient reported decreased chest distress and palpitations. She reduced her metoprolol dose to 23.75 mg/day without reporting to the clinic her dose alteration. At the third week of metoprolol treatment, the patient noticed a smell disorder, reporting that she could not perceive the same smells as her relatives. And this disorder continued to worsen until complete anosmia. However, she continued this dosage and did not report to the clinic her new symptoms. During this period of time, the patient denied having exposure to chemicals, using other drugs, or experiencing a traumatic nose injury. Approximately 3 months after starting metoprolol, the patient returned to our clinic with the compliant of an olfactory disorder. No abnormalities were found during the endoscopic nasal examination, with normal color. No gland or turbinate hypertrophy was found. No obstruction or excess secretion was noted in the nasal passages, and the olfactory epithelium showed no signs of congestion or inflammation. It was determined that the olfactory dysfunction was an adverse effect of metoprolol. Considering her better initial symptoms and repeated DCG result, the metoprolol was tapered. The patient recovered from the olfactory dysfunction 3 weeks later, as determined by her ability to once again perceive the smell of soap. By the second month after discharging metoprolol, the patient's ability to recognize smells was returning back to baseline (Fig. 1). Also, in the follow-up appointment, she reported no complaints of smell or taste anymore.\n\nFigure 1 Dosage of metoprolol and amiodarone and time-course of dysosmia and dysgeusia in the antiarrhythmic treatment.\n\nNevertheless, the patient complained that her palpitations were getting worse following discontinuation of metoprolol. Dynamic electrocardiogram presented premature atrial beats and increasing paroxysmal atrial fibrillation. Therefore, the patient was given amiodarone 400 mg/day for 1 week to treat her arrhythmias, and then was tapered to 200 mg/day. However, after using amiodarone for approximately 2 weeks, the patient was not able to distinguish the tastes of bitter and spicy. Considering the potential side effects of amiodarone, we asked her to abandon the drug and have a radiofrequency ablation. Thus, the patient regained her ability to differentiate tastes 2 weeks following amiodarone discontinuation (Fig. 1).\n\nThe authors obtained written consent from the patient to describe her illness and publish this case report. Ethics committee approval is not included, as it is commonly accepted that case reports do not require such approval. In our work, we did not use patient data that would allow identifying her. The patient agreed to the diagnostic tests and treatments used to manage her medical conditions.\n\n3 Discussion\nMetoprolol and amiodarone have been wildly reported owing to their protective effects of the cardiovascular system. They can efficiently improve the morbidity and mortality of patients suffering from cardiovascular diseases, including hypertension, coronary heart disease, heart failure, and various arrhythmias.[6] In addition to common side effects of pulmonary or cardiac of beta blockers, metoprolol was more likely to cause CNS side effects through its higher concentrations in the brain.[1] Dysosmia, or smell disorder, is a rare side effect of metoprolol. Meanwhile, adverse events caused by amiodarone including lung toxicity and thyroid dysfunction were mainly related to the dosage and duration.[7] Although dysosmia has been reported as an adverse side effect of amiodarone, hypogeusia or taste disorder of amiodarone was rarely mentioned in the past.[3]\n\nSince first introduced by Vital Durand in 1985,[5] dysosmia and hypogeusia were subsequently reported as side effects of other cardiovascular drugs, including conversion enzyme [angiotensin-converting enzyme (ACE)] inhibitors,[8] calcium antagonist,[9] diuretics, and other antiarrhythmic drugs[10–23] (Table 1). In this case, the patient complained of an olfactory disorder after 3 weeks of using metoprolol, with ongoing use causing further deterioration. After discontinuing metoprolol, the patient regained her ability to smell. In addition, a taste disorder occurred after amiodarone treatment, and was subsequently reversed following discontinuation of the offending agent. Generally, these reversible sensory dysfunctions induced by metoprolol and amiodarone are rare, and the associated clinical research is lacking. Although past literature has summarized the drug-induced taste and smell disorders and the potential mechanisms, the actual frequency, clinical characteristics, and dosage correlation of drugs, especially antiarrhythmic drugs, remains vague.[11] The potential mechanism of cardiovascular drug-induced dysosmia or hypogeusia may involve complex mechanisms. Abnormalities of binding to olfactory receptors, inactivation of post-receptor signal transduction pathway, and dysfunction of the corresponding nerves induced by Na+ or Ca2+ channel inhibition, may be the potential causes of the smell disorder.[24] Other studies suggested that damage to receptor cells could be caused by interference of second messengers or intermediates of Na–K–ATPase, or inhibition of protein synthesis could also function in the pathogenesis of dysosmia.[12] Similarly, the taste disorder was also proposed to have resulted from the same mechanisms that caused dysosmia.[24] However, the receptors for the 5 basic tastes (sweet, sour, bitter, salty, and umami) may be regulated by different systems. The sour and salty tastes receptors are activated by H+ and Na+ channel, respectively, and the bitter, sweet, and umami tastes receptors are regulated by G-protein coupled receptor molecules with second messenger systems.[25] Hence, the exact mechanism and the dosage needed to cause clinical symptoms need to be elucidated in future studies.\n\nTable 1 The main literature of cardiovascular drugs caused smell and/or taste disorder.\n\nGenerally, smell and taste disturbance are not considered life-threatening side effects. They are often ignored by patients, families, and even medical staff. However, such disturbances can severely impair physical or mental health and eventually affect a patient's quality of life. Dysosmia and anosmia decrease the ability to detect natural gas, spoiled food, and smoke. It is noteworthy that a significant number of deaths caused by accidental gas poisonings were due to the inability to smell. Hypogeusia may reduce a patient's appetite and food intake, which leads to weight loss and even depression. Moreover, hypogeusia may lead to decrease compliance with drug regimens. Owing to lack of objective diagnostic standards and effective treatments, smell and taste disturbances caused by drugs might not be observed in a timely manner. This can result in irreversible nerve dysfunction and worse impact on the patient's quality of life.\n\nIn conclusion, the incidence of dysosmia or hypogeusia induced by cardiovascular drugs is rare. Here, we report on a patient who suffered from adverse events involving smell and taste following treatment with metoprolol and amiodarone. Considering the detrimental effects of dysosmia and dysgeusia with the long-term use of cardiovascular drugs, clinicians should not only be aware of the common side effects of the drug but also known rare side effects including smell and taste disorders. Besides, earlier detection would prevent irreversible damage to the patient and provide better drug compliance during their antiarrhythmic treatment.\n\nAuthor contributions\nConceptualization: Cesar Reis.\n\nData curation: Yuandong Li, Yuanjian Fang.\n\nInvestigation: Huan Wang.\n\nProject administration: Huan Wang.\n\nWriting – original draft: Xiaoru Che.\n\nWriting – review & editing: Yuandong Li, Yuanjian Fang.\n\nAbbreviations: CNS = central nervous system, DCG = dynamic electrocardiogram, EEG = electrocardiograph.\n\nThe authors report no conflict of interest.\n==== Refs\nReferences\n[1] Suzuki M \n[Beta-blocking agents] . Nihon Rinsho Jpn J Clin Med \n1995 ;53 :978–82 .\n[2] Bodin NO Borg KO Johnansson R \nTissue distribution of metoprolol-(3-h) in the mouse and the rat . Acta Pharmacol Toxicol (Copenh) \n1975 ;36 suppl 5 :116–24 .1079684 \n[3] Maruyama T Yasuda S Odashiro K \nAnosmia induced by amiodarone . Am J Med \n2007 ;120 :e9.\n[4] Van Cott TE Yehle KS DeCrane SK \nAmiodarone-induced pulmonary toxicity: case study with syndrome analysis . Heart Lung \n2013 ;42 :262–6 .23835168 \n[5] Vital Durand M \n[Recurrent anosmia under beta-blockers] . Presse Med \n1985 ;14 :2064.\n[6] Vedin A \nTen years of clinical experience with metoprolol . J Cardiovasc Pharmacol \n1987 ;10 suppl 2 :S80–5 .2481176 \n[7] Morady F Sauve MJ Malone P \nLong-term efficacy and toxicity of high-dose amiodarone therapy for ventricular tachycardia or ventricular fibrillation . Am J Cardiol \n1983 ;52 :975–9 .6637851 \n[8] Heeringa M van Puijenbroek EP \nReversible dysgeusia attributed to losartan . Ann Intern Med \n1998 ;129 :72.\n[9] Levenson JL Kennedy K \nDysosmia, dysgeusia, and nifedipine . Ann Intern Med \n1985 ;102 :135–6 .\n[10] Briggs ER \nTaste disturbances related to medication use . Consult Pharm \n2009 ;24 :538–43 .19689182 \n[11] Tuccori M Lapi F Testi A \nDrug-induced taste and smell alterations: a case/non-case evaluation of an Italian database of spontaneous adverse drug reaction reporting . Drug Saf \n2011 ;34 :849–59 .21879779 \n[12] Ishimaru T Yokogawa H \nOlfactory and gustatory disturbances caused by digitalism: a case report . Auris Nasus Larynx \n2006 ;33 :465–9 .16730151 \n[13] Vlasses PH Ferguson RK \nTemporary ageusia related to captopril . Lancet \n1979 ;2 :526.\n[14] Berman JL \nDysosmia, dysgeusia, and diltiazem . Ann Intern Med \n1985 ;102 :717.\n[15] Warner MD Peabody CA Berger PA \nOlfactory deficits and Down's syndrome . Biol Psychiatry \n1988 ;23 :836–9 .2966642 \n[16] Schlienger RG Saxer M Haefeli WE \nReversible ageusia associated with losartan . Lancet \n1996 ;347 :471–2 .8618505 \n[17] Ohkoshi N Shoji S \nReversible ageusia induced by losartan: a case report . Eur J Neurol \n2002 ;9 :315.\n[18] Castells X Rodoreda I Pedros C \nDrug points: dysgeusia and burning mouth syndrome by eprosartan . BMJ \n2002 ;325 :1277.12458247 \n[19] Kharoubi S \n[Drug induced anosmia with nifedipine] . Presse Med \n2003 ;32 :1269–72 .14506449 \n[20] Chen C Chevrot D Contamin C \n[Stomatitis and ageusia induced by candesartan] . Nephrologie \n2004 ;25 :97–9 .15185557 \n[21] Sadasivam B Jhaj R \nDysgeusia with amlodipine: a case report . Br J Clin Pharmacol \n2007 ;63 :253.17274793 \n[22] Finn BC Pellegrini D Bruetman JE \n[Reversible dysgeusia attributed to losartan] . Medicina \n2008 ;68 :347–8 .18786897 \n[23] Lulic I Kovic I \n[Can lacidipine cause smell disorders? A case report] . Lijec Vjesn \n2011 ;133 :98–100 .21612105 \n[24] Henkin RI \nDrug-induced taste and smell disorders. Incidence, mechanisms and management related primarily to treatment of sensory receptor dysfunction . Drug Saf \n1994 ;11 :318–77 .7873092 \n[25] Gilbertson TA Margolskee RF Doty RL \nMolecular physiology of gustatory transduction . Handbook of Olfaction and Gustation \n2003 ;703–730 .\n\n",
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"abstract": "In allogeneic stem cell mobilization, peripheral blood stem cell mobilization with filgrastim can be considered standard of care. Poor mobilizers may be at risk for inadequate stem cell collection during apheresis. He we present a successful case of salvage plerixafor use with filgrastim in a haploidentical identical transplant patient.",
"affiliations": "Department of Pharmacy, Yale-New Haven Hospital New Haven, Connecticut.;The University of Arizona Tucson, Arizona.;Division of Hematology, Oncology, Blood & Marrow Transplantation, Department of Medicine, University of Arizona Tucson, Arizona.;Division of Hematology, Oncology, Blood & Marrow Transplantation, Department of Medicine, University of Arizona Tucson, Arizona.;Department of Pharmacy, The University of Arizona Cancer Center Tucson, Arizona.",
"authors": "Nadeau|Michelle|M|;George|Laeth|L|;Yeager|Andrew M|AM|;Anwer|Faiz|F|;McBride|Ali|A|",
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"fulltext": "\n==== Front\nClin Case RepClin Case Repccr3Clinical Case Reports2050-09042050-0904John Wiley & Sons, Ltd Chichester, UK 10.1002/ccr3.327Case ReportsPlerixafor as a salvage mobilization strategy for haploidentical peripheral blood allogeneic stem cell transplantation Nadeau Michelle 1George Laeth 2Yeager Andrew M 3Anwer Faiz 3McBride Ali 41 Department of Pharmacy, Yale-New Haven HospitalNew Haven, Connecticut2 The University of ArizonaTucson, Arizona3 Division of Hematology, Oncology, Blood & Marrow Transplantation, Department of Medicine, University of ArizonaTucson, Arizona4 Department of Pharmacy, The University of Arizona Cancer CenterTucson, ArizonaCorrespondence Ali McBride, Department of Pharmacy, The University of Arizona Cancer Center, 3838 North Campbell Blvd, Tucson, AZ 85719. Tel: +1 520 694 0398; Fax: 520 694 4480; E-mail: ali.mcbride@uahealth.comFunding Information No sources of funding were declared for this study.\n\n9 2015 15 7 2015 3 9 728 730 09 9 2014 15 3 2015 30 4 2015 © 2015 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.2015This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Key Clinical Message\nIn allogeneic stem cell mobilization, peripheral blood stem cell mobilization with filgrastim can be considered standard of care. Poor mobilizers may be at risk for inadequate stem cell collection during apheresis. He we present a successful case of salvage plerixafor use with filgrastim in a haploidentical identical transplant patient.\n\nCLLmobilizationplerixaforstem cell transplant\n==== Body\nIntroduction\nCurrently, granulocyte colony-stimulating factor (G-CSF) is the standard agent used for mobilization of Peripheral Blood Stem Cells (PBSCs) for Stem Cell Transplant (SCT), in both the autologous and allogeneic setting 2. G-CSF is a growth factor that stimulates proliferation of progenitor cells. It is also thought to inhibit the activity of neutrophil elastase, which is involved in the production of stromal-cell-derived factor 1 (SDF-1), a chemokine that anchors stem cells to the bone marrow. G-CSF induces the activation of proteases within the bone marrow to degrade adhesive interactions, stimulating release of stem cells into circulation 3. The recommended dose of G-CSF is 10 μg/kg daily as a subcutaneous injection and continued until target CD34+ counts are achieved 2.\n\nOther options for mobilization include Plerixafor, a reversible bicyclam chemokine receptor 4 (CXCR4) inhibitor. Plerixafor competes with SDF-1 for binding to CXCR4, thus releasing anchored stem cells into the periphery 3. Plerixafor is FDA approved for use in combination with G-CSF for mobilization in autologous SCT for patients with non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM) 4. Higher stem cell yields are achieved when plerixafor is used with G-CSF, compared to single agent G-CSF or single-agent plerixafor. The use of plerixafor upfront however, is often reserved for patients at high risk for poor mobilization, given the cost implications for use of plerixafor for all patient subsets 2,5. In autologous stem cell collection trials, when plerixafor is added to G-CSF on day 4 of mobilization, the combination therapy yields higher cell counts per leukapheresis session compared to G-CSF alone, with fewer apheresis sessions to reach target CD34+ counts and early and stable engraftment 6. The optimal role of plerixafor in disease states beyond NHL and MM and for healthy donors for allogeneic SCT continues to be investigated. Initial clinical trials demonstrated high stem cell yields with use of plerifaxor for mobilization as a single-agent and as combination therapy with G-CSF in healthy volunteers 7. The use of plerixafor has also been evaluated for use in mobilization of HLA-matched sibling donors for allogeneic SCT. Nine donors received plerixafor and leukapheresis with a 1-week washout, at which point they received a second mobilization with single-agent G-CSF. Eight patients achieved target CD34+ cells defined as 2.0 × 106 CD34+ cells/kg following treatment with plerixafor, which was comparable to the CD34+ cell counts achieved in the G-CSF mobilized allografts. Subsequently, seven patients were successfully transplanted with the plerixafor mobilized stem cells with rates of graft-versus-host disease comparable to the G-CSF mobilized allografts 8. Current literature also cites reports using Plerixafor as a salvage mobilization strategy for allogeneic SCT in healthy donors failing to mobilize with single-agent G-CSF 9.\n\nThe failure rate for mobilization with single-agent G-CSF ranges between 5% and 30%. The addition of plerixafor to G-CSF-based regimens improves mobilization rates to 60% for autologous SCT 3. Further studies are needed to determine the efficacy of plerixafor as a salvage mobilization strategy for allogeneic SCT.\n\nClinical History\nWe report a case of a 57-year-old female who was selected as a sibling haplodonor for PBSCs for allogeneic SCT. Her brother was initially diagnosed with early stage chronic lymphocytic leukemia (CLL) when he was noted to have lympholeukocytosis during routine precytoscopy blood work. His initial Rai stage was unknown, with a high-risk presentation of unmutated IgVH. Following his initial diagnosis, he was managed with watchful waiting. On disease progression, he received six cycles of fludarabine, cyclophosphamide, and rituximab (FCR). One year after completing his last cycle of FCR, he was noted to have evidence of recurrent CLL and subsequently received six cycles of bendamustine and rituximab. The patient achieved a partial remission with this combination. Given this response, and the high-risk features of his CLL, the patient was scheduled for allogeneic SCT. Prior to transplant, busulfan, melphalan, and alemtuzumab were as used as a reduced-intensity preparative regimen.\n\nThe donor search for an allogeneic transplant was unsuccessful in identifying an HLA-matched unrelated donor. However, one of his two healthy sisters qualified as a haploidentical donor with 7/12 HLA match and a 3/6 match at HLA-A, -B, and -DRB1.\n\nFollowing pretransplant evaluation, mobilization of the donor was initiated with G-CSF 10 μg/kg daily, 5 days before leukapheresis. The first leukapheresis session yielded 2.66 × 106/kg cells CD34+ stem cells, and continued G-CSF administration yielded 1.25 × 106/kg CD34+ stem cells on day 2. Given insufficient mobilization, plerixafor was added to the regimen in an attempt to increase stem cell yield. The donor received one dose of plerixafor 240 μg/kg the evening prior to the third planned leukapheresis session. Addition of plerixafor led to a significant increased yield 8.63 × 106 CD34+ stem cells.\n\nThe patient received three consecutive days of haploidentical PBSC infusions for a total CD34+ cell dose of 12.54 × 106/kg (Fig.1). Posttransplant GVHD prophylaxis consisted of cyclosporine and mycophenolate mofetil. His posttransplant course was notable for chemotherapy-associated nausea, mucositis, and neutropenic fever, treated with empiric antibiotics. Day +28 bone marrow studies showed no evidence of CLL and peripheral blood chimerisms on day +30 showed 100% donor DNA. He was discharged on day +31 and thereafter, followed as an outpatient in the clinic. Peripheral blood chimerisms on day +66 continued to show 100% donor DNA. Both the 6-month and 1-year posttransplant evaluation continued to show no progression of disease, no evidence of disease in the bone marrow, and 100% donor DNA chimerisms in the bone marrow.\n\nFigure 1 Schematic of patient's current mobilization for haploidentical transplant. (A) Administration schedule of filgrastim and plerixafor during mobilization versus CD34+ counts. (B) Outcomes with sequential CD34+ count and leukocyte count during mobilization with growth factor mobilization and plerixafor. Patient was administered plerixafor on day 6 with successful apheresis on day 7 for collection.\n\nDiscussion\nOur report contributes to the increasing, yet limited, support for using plerixafor in combination with G-CSF for satisfactory mobilization of donor stem cells for allogeneic SCTs. We show here a marked increase in mobilization after plerixafor usage, followed by successful patient recovery up to 1 year posttransplant. This increased efficacy, coupled with findings that suggest stem cells mobilized by plerixafor may be more protective against GVHD 10, suggest the utility of conducting larger clinical trials investigating the use of plerixafor in conjunction with G-CSF for stem cell mobilization in the allogeneic transplant setting, while also observing any effects on relapse rate and GVHD incidence.\n\nConflict of Interest\nNone declared.\n==== Refs\nReferences\nBensinger WI Allogeneic transplantation: peripheral blood versus bone marrow Curr. Opin. Oncol 2012 24 191 196 22185938 \nDuong HK Savani BN Copelan E Peripheral blood progenitor cell mobilization for autologous and allogeneic hematopoietic cell transplantation: guidelines from the American Society for Blood and Marrow Transplantation Biol. Blood Marrow Transplant 2014 20 1262 1273 24816581 \nTanhehco YC Vogl DT Stadtmauer EA The evolving role of plerixafor in hematopietic progenitor cell mobilization Transfusion 2013 53 2314 2326 23362980 \nDevine SM Flomenberg N Vesole DH Rapid mobilization of CD34+ cells following administration of the CXCR4 antagonist AMD3100 to patients with multiple myeloma and non-Hodgkin's lymphoma J. Clin. Oncol 2004 22 1095 1102 15020611 \nGiralt S Costa L Schriber J Optimizing autologous stem cell mobilization strategies to improve patient outcomes: consensus guidelines and recommendations Biol. Blood Marrow Transplant 2014 20 295 308 24141007 \nFlomenberg N Devine S DiPersio JF AMD3100 plus G-CSF for autologous hematopoietic progenitor cell mobilization is superior to G-CSF alone Blood 2005 106 1867 1874 15890685 \nLemery SJ Hesieh MM Smith A A pilot study evaluating the safety and CD34+ cell mobilizing activity of escalating doses of plerixafor in healthy volunteers Br. J. Haematol 2011 153 66 75 21352197 \nDevine SM Andritsos L Todt L A pilot study evaluating the safety and efficacy of AMD3100 for the mobilization and transplantation of HLA-matched sibling donor hematopoietic stem cells in patients with advanced hematological malignancies Blood 2005 106 299 \nNeumann T Kruger WH Busemann C Successful mobilization of PBSCs in a healthy volunteer donor by addition of plerixafor after failure of mobilization with G-CSF alone Bone Marrow Transplant 2011 46 762 763 20676150 \nKean LS Sen S Onabajo O Significant mobilization of both conventional and regulatory T cells with AMD3100 Blood 2011 118 6580 6590 21989987\n\n",
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"title": "Plerixafor as a salvage mobilization strategy for haploidentical peripheral blood allogeneic stem cell transplantation.",
"title_normalized": "plerixafor as a salvage mobilization strategy for haploidentical peripheral blood allogeneic stem cell transplantation"
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"abstract": "A 73-year-old woman diagnosed with symptomatic multiple myeloma (MM; IgG-κ type, D&S: IIIA, ISS: 2) was administered bortezomib plus dexamethasone (BD) therapy. Post BD therapy, although autologous hematopoietic stem cell transplantation and thalidomide, lenalidomide, and melphalan/prednisolone/thalidomide (MPT) therapies were also performed, the patient remained unresponsive. However, the disease relapsed, and she eventually developed pantalgia. Therefore, the patient was admitted to our hospital and was administered pomalidomide and dexamethasone (Pd) therapy. The serum amylase (AMY) and urine AMY levels were 6,329 and 6,098 IU/l, respectively, which were salivary gland-type amylase (S-AMY). Notably, the markedly high levels immediately decreased after the first course of the Pd therapy; additionally, the pantalgia also disappeared. The S-AMY level in the supernatant from cultured bone marrow mononuclear cells was higher than that observed in a normal control. In addition, AMY was high when MM previously relapsed, suggesting the presence of AMY-producing MM. Although AMY-producing MM was first reported by Hata et al. in 1988, few cases have been reported in the new-drug era. In conclusion, AMY-producing MM frequently, including in our case (as the patient was refractory to treatment), is difficult to treat. However, our patient positively responded to the novel next-generation drugs such as pomalidomide and carfilzomib.",
"affiliations": "Department of Internal Medicine, Kohsei Chuo General Hospital.;Department of Internal Medicine, Kohsei Chuo General Hospital.;Department of Internal Medicine, Kohsei Chuo General Hospital.;Department of Internal Medicine, Kohsei Chuo General Hospital.;Department of Hematology, Juntendo University School of Medicine.;Department of Hematology, Juntendo University School of Medicine.;Department of Hematology, Juntendo University School of Medicine.",
"authors": "Aota|Yasuo|Y|;Gotoh|Akihiko|A|;Okuda|Yuko|Y|;Honda|Tadahiro|T|;Watanabe|Naoki|N|;Ando|Jun|J|;Komatsu|Norio|N|",
"chemical_list": "D009842:Oligopeptides; D013792:Thalidomide; D000069286:Bortezomib; C524865:carfilzomib; D003907:Dexamethasone; C467566:pomalidomide; D000681:Amylases",
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.59.865",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "59(7)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": "Carfilzomib; Multiple myeloma; Pomalidomide; Salivary-type amylase",
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000368:Aged; D000681:Amylases; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069286:Bortezomib; D003907:Dexamethasone; D005260:Female; D006801:Humans; D009101:Multiple Myeloma; D009842:Oligopeptides; D013792:Thalidomide",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "865-871",
"pmc": null,
"pmid": "30078795",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Recurrent amylase-producing multiple myeloma responding to pomalidomide and carfilzomib-containing therapies.",
"title_normalized": "recurrent amylase producing multiple myeloma responding to pomalidomide and carfilzomib containing therapies"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2019RR-219550",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MELPHALAN"
},
"druga... |
{
"abstract": "No published information exists to support the safe use of ticagrelor in patients with a clopidogrel allergy. This study involved an institutional review board-approved retrospective review of patients with a documented clopidogrel allergy who subsequently received ticagrelor between July 2011 and February 2014. We report the cases of two patients with a history of hypersensitivity to clopidogrel in whom ticagrelor was used successfully without documented incident. In addition, principles suggesting a lack of cross-sensitivity between ticagrelor and clopidogrel are reviewed. These cases combined with theoretical evidence support the use of ticagrelor in patients with hypersensitivity to clopidogrel.",
"affiliations": "Department of Pharmacy, Massachusetts General Hospital, Boston, Massachusetts.",
"authors": "Manchette|Anastasia M|AM|;Drucker|Adrienne G|AG|;Januzzi|James L|JL|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D000077486:Ticagrelor; D000241:Adenosine; D013988:Ticlopidine",
"country": "United States",
"delete": false,
"doi": "10.1002/phar.1446",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-0008",
"issue": "34(8)",
"journal": "Pharmacotherapy",
"keywords": "acute coronary syndrome; allergy; antiplatelet; clopidogrel; cross-reactivity; hypersensitivity",
"medline_ta": "Pharmacotherapy",
"mesh_terms": "D054058:Acute Coronary Syndrome; D000241:Adenosine; D000328:Adult; D000368:Aged; D000077144:Clopidogrel; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D008297:Male; D010975:Platelet Aggregation Inhibitors; D012189:Retrospective Studies; D000077486:Ticagrelor; D013988:Ticlopidine",
"nlm_unique_id": "8111305",
"other_id": null,
"pages": "e152-6",
"pmc": null,
"pmid": "24898185",
"pubdate": "2014-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute coronary syndrome antiplatelet alternatives in clopidogrel allergy.",
"title_normalized": "acute coronary syndrome antiplatelet alternatives in clopidogrel allergy"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/15/0054827",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
"drugadditiona... |
{
"abstract": "The number of older people with polypharmacy (more than six drugs taken simultaneously) is increasing. The greatest proportion consists of guideline drugs, analgesics and psychopharmaceuticals because in many cases of geriatric multimorbidity several underlying main diseases are present which must be treated according to the guidelines. Polypharmacy is a complex and difficult situation for all treating physicians because substantial side effects and intoxication can be induced but it can also be very difficult to recognize which drug was at fault and how a reduction can be safely made. This article describes the exemplary case of a 77-year-old patient with drug-induced delirium and demonstrates the procedure followed. The question of rapid assistance by the utilization of medication data bases is described and the importance of clinical pharmacists is demonstrated. In the future working with medication data bases will possibly become increasingly more important for physicians and hopefully simpler. The case presented here also shows that the effective and justified reduction of drugs can show a very good effect and is possible.",
"affiliations": "Hopital Meyriez, Chemin du Village 24, 3280, Meyriez, Schweiz. weinrebe@wep-medical.de.;SLK-Kliniken Heilbronn GmbH, Heilbronn, Deutschland.;Ergotherapie W 2, Heilbronn, Deutschland.;SLK-Kliniken Heilbronn GmbH, Heilbronn, Deutschland.;SLK-Kliniken Heilbronn GmbH, Heilbronn, Deutschland.;Hopital Meyriez, Chemin du Village 24, 3280, Meyriez, Schweiz.;Hopital Meyriez, Chemin du Village 24, 3280, Meyriez, Schweiz.",
"authors": "Weinrebe|W|W|http://orcid.org/0000-0001-7425-8117;Preda|R|R|;Bischoff|S|S|;Nussbickel|D|D|;Humm|M|M|;Jeckelmann|K|K|;Goetz|S|S|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00391-017-1285-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0948-6704",
"issue": "51(6)",
"journal": "Zeitschrift fur Gerontologie und Geriatrie",
"keywords": "Adverse drug reaction reporting systems; Delirium; Drug combinations; Drug-related side effects and adverse reactions; Multimorbidity",
"medline_ta": "Z Gerontol Geriatr",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D003376:Counseling; D003661:Decision Support Techniques; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D010595:Pharmacists; D019338:Polypharmacy",
"nlm_unique_id": "9506215",
"other_id": null,
"pages": "691-697",
"pmc": null,
"pmid": "28721543",
"pubdate": "2018-08",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "28280891;25879993;19591522;3944402;18179993;1991946;11677279;28290774;2240918;21707557;26384726;24733193;24292516;7183759",
"title": "Decision aids in complex polypharmacy : Medication data bases and counselling by clinical pharmacists.",
"title_normalized": "decision aids in complex polypharmacy medication data bases and counselling by clinical pharmacists"
} | [
{
"companynumb": "CH-SUN PHARMACEUTICAL INDUSTRIES LTD-2019RR-223997",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GABAPENTIN"
},
"drug... |
{
"abstract": "BACKGROUND\nHuman Cytomegalovirus (HCMV) still represents a crucial concern in solid organ transplant recipients (SOTRs) and the use of antiviral therapy are limited by side effects and the selection of viral mutations conferring antiviral drug resistance.\n\n\nMETHODS\nHere we reported the case of an HCMV seronegative patient with common variable immunodeficiency (CVID), multiple hepatic adenomatosis, hepatopulmonary syndrome and portal hypertension who received a liver transplant from an HCMV seropositive donor. The patient was treated with Valganciclovir (vGCV) and then IV Ganciclovir (GCV) at 5 week post-transplant for uncontrolled HCMV DNAemia. However, since mutation A594V in UL97 gene conferring resistance to ganciclovir was reported, GCV therapy was interrupted. Due to the high toxicity of Foscarnet (FOS) and Cidofovir (CDV), Letermovir (LMV) monotherapy at the dosage of 480 mg per day was administered, with a gradual viral load reduction. However, a relapse of HCMV DNAemia revealed the presence of mutation C325Y in HCMV UL56 gene conferring resistance to LMV.\n\n\nCONCLUSIONS\nIn conclusion, even if LMV is an effective and favorable safety molecule it might have a lower genetic barrier to resistance. A warning on the use of LMV monotherapy as rescue treatments for HCMV GCV-resistant infections in transplant recipients is warranted.",
"affiliations": "Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.;Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.;Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.;Unit of Infectious Diseases, ASST Papa Giovanni XXIII, 24129, Bergamo, Italy.;Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.;Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.;Pediatrics Clinic, Department of Clinical and Experimental Sciences, University of Brescia, ASST Spedali Civili of Brescia, Brescia, Italy.;Pediatrics Clinic, Department of Clinical and Experimental Sciences, University of Brescia, ASST Spedali Civili of Brescia, Brescia, Italy.;Pediatrics Clinic, Department of Clinical and Experimental Sciences, University of Brescia, ASST Spedali Civili of Brescia, Brescia, Italy.;Pediatrics Clinic, Department of Clinical and Experimental Sciences, University of Brescia, ASST Spedali Civili of Brescia, Brescia, Italy.;Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. fausto.baldanti@unipv.it.",
"authors": "Paolucci|Stefania|S|;Campanini|Giulia|G|;Cassaniti|Irene|I|;Tebaldi|Alessandra|A|;Novazzi|Federica|F|;Fratini|Alice|A|;Meini|Antonella|A|;Girelli|Federica|F|;Palumbo|Laura|L|;Plebani|Alessandro|A|;Baldanti|Fausto|F|",
"chemical_list": "D000085:Acetates; D000998:Antiviral Agents; D011799:Quinazolines; C000588473:letermovir; D015774:Ganciclovir",
"country": "England",
"delete": false,
"doi": "10.1186/s12879-021-06694-4",
"fulltext": "\n==== Front\nBMC Infect Dis\nBMC Infect Dis\nBMC Infectious Diseases\n1471-2334\nBioMed Central London\n\n6694\n10.1186/s12879-021-06694-4\nCase Report\nEmergence of Letermovir-resistant HCMV UL56 mutant during rescue treatment in a liver transplant recipient with ganciclovir-resistant infection HCMV: a case report\nPaolucci Stefania s.paolucci@smatteo.pv.it\n\n1\nCampanini Giulia g.campanini@smatteo.pv.it\n\n1\nCassaniti Irene i.cassaniti@smatteo.pv.it\n\n1\nTebaldi Alessandra a.tebaldi@asst-pg23.it\n\n2\nNovazzi Federica novazzifederica@gmail.com\n\n1\nFratini Alice alice.fratini01@universitadipavia.it\n\n1\nMeini Antonella antonella.meini@yahoo.it\n\n3\nGirelli Federica federicagirelli@hotmail.it\n\n3\nPalumbo Laura palumbolauretta@gmail.com\n\n3\nPlebani Alessandro alessandro.plebani@unibs.it\n\n3\nBaldanti Fausto fausto.baldanti@unipv.it\nf.baldanti@smatteo.pv.it\n\n14\n1 grid.419425.f 0000 0004 1760 3027 Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy\n2 grid.460094.f 0000 0004 1757 8431 Unit of Infectious Diseases, ASST Papa Giovanni XXIII, 24129 Bergamo, Italy\n3 grid.7637.5 0000000417571846 Pediatrics Clinic, Department of Clinical and Experimental Sciences, University of Brescia, ASST Spedali Civili of Brescia, Brescia, Italy\n4 grid.8982.b 0000 0004 1762 5736 Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy\n23 9 2021\n23 9 2021\n2021\n21 9943 12 2020\n14 9 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nHuman Cytomegalovirus (HCMV) still represents a crucial concern in solid organ transplant recipients (SOTRs) and the use of antiviral therapy are limited by side effects and the selection of viral mutations conferring antiviral drug resistance.\n\nCase presentation\n\nHere we reported the case of an HCMV seronegative patient with common variable immunodeficiency (CVID), multiple hepatic adenomatosis, hepatopulmonary syndrome and portal hypertension who received a liver transplant from an HCMV seropositive donor. The patient was treated with Valganciclovir (vGCV) and then IV Ganciclovir (GCV) at 5 week post-transplant for uncontrolled HCMV DNAemia. However, since mutation A594V in UL97 gene conferring resistance to ganciclovir was reported, GCV therapy was interrupted. Due to the high toxicity of Foscarnet (FOS) and Cidofovir (CDV), Letermovir (LMV) monotherapy at the dosage of 480 mg per day was administered, with a gradual viral load reduction. However, a relapse of HCMV DNAemia revealed the presence of mutation C325Y in HCMV UL56 gene conferring resistance to LMV.\n\nConclusions\n\nIn conclusion, even if LMV is an effective and favorable safety molecule it might have a lower genetic barrier to resistance. A warning on the use of LMV monotherapy as rescue treatments for HCMV GCV-resistant infections in transplant recipients is warranted.\n\nKeywords\n\nCase report\nHCMV\nLetermovir\nhttp://dx.doi.org/10.13039/100007365 Fondazione IRCCS Policlinico San Matteo 80207 Baldanti Fausto issue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\nAntiviral drugs for treatment of systemic human cytomegalovirus (HCMV) infection in immunocompromised patients include viral DNA synthesis inhibitors Ganciclovir (GCV)/Valganciclovir (vGCV), Foscarnet (FOS) and Cidofovir (CDV). However, these drugs are limited by significant side effects and the selection of viral mutations conferring antiviral drug resistance [1]. While GCV-resistant HCMV infections represent a crucial issue in transplant setting, being associated with higher risk of recurrent HCMV disease and high mortality rate [2, 3], FOS and CDV are used as rescue drugs for the treatment of GCV-resistant HCMV infections, because of their renal toxicity. Recently, new drugs with innovative mechanisms of action have been introduced in clinical practice, including Letermovir (LMV) which block the HCMV viral terminase complex and thus inhibits the cleavage/packaging of viral genomes [4, 5]. To date, due to very favorable safety profile, LMV has been approved for prophylaxis in hematopoietic stem cell transplant recipients (HSCTRs) [6]. On the other hand, some studies suggest that LMV might have a lower genetic barrier to resistance [7, 8]. Here, we report the rapid emergence of a LMV-resistant HCMV mutant in a liver transplant recipient undergoing LMV rescue treatment because of GCV-resistant HCMV infection, severe myelosuppression and kidney function impairment. This report is a warning on the use of LMV in monotherapy.\n\nCase presentation\n\nA 23-year-old woman with common variable immunodeficiency (CVID) was affected by multiple hepatic adenomatosis complicated by hepatopulmonary syndrome and portal hypertension. Renal dysfunction, fungal skin infections, sinusitis, otomastoiditis, and hypothyroidism were also documented. Immunoglobulins substitution therapy and replacement therapy for hypothyroidism were also administered. In October 24 2018, she received an orthotropic liver transplant. At the transplantation baseline, the patient was HCMV seronegative while her donor was HCMV-seropositive. Immunosuppressive therapy included steroids (5 mg/day) and tacrolimus (0.5 mg/day) (Fig. 1). HCMV DNAemia of 111,000 UI/mL was reported 5 weeks post-transplant. VGCV treatment (900 mg twice daily) was introduced. After 11 weeks of vGCV treatment viral load continued to increase up to 713,567 UI/mL, thus intravenous (IV) GCV treatment at 250 mg twice daily was introduced two weeks later, IV GCV dosage was reduced at 200 mg twice daily to minimize myelotoxicity. However, HCMV DNAemia after 13 weeks of treatment was still positive (2076 IU/mL). Colonoscopy and endoscopy performed in order to exclude HCMV-related enteritis did not show relevant finding. At that time, therapy was interrupted due to the worsening of neutropenia.\n\nFig. 1 HCMV DNAemia levels in IU/mL detected in whole blood (red line) are shown. Moreover, timeline of medication, including immunosuppressive regimens (tacrolimus and steroid) as well as antiviral therapies (vGCV, GCV, FOS, CDV, LMV and anti-HCMV IgG) is given in the graph. Occurrence of drug resistance (GCV and LMV) are also shown\n\nAt week 14, the patient was hospitalized for digestive hemorrhage and anemia. Then, she was transferred at Stroke Unit for limb hyposthenia due to concomitant cerebral ischemic event.\n\nAt week 16, HCMV DNAemia increased up to 3,000,000 UI/mL and mutation A594V in UL97 gene conferring resistance to GCV and vGCV was documented [9]. UL54 gene analysis excluded FOS resistance [10], thus FOS treatment (90 mg/kg three times daily) was initiated. Unfortunately, due to the onset of severe dyselectrolyemia, FOS was discontinued after 10 days of treatment and a rapid increased of HCMV DNAemia (35,000,000 IU/mL) was observed. GCV was initiated at the dosage of 230 mg twice daily but it was suspended after two weeks due to the very limited effect on HCMV DNAemia and worsening of anemia and thrombocytopenia.\n\nAt week 20, since the patient was highly immunosuppressed, tacrolimus was reduced and steroid was suspended. However, steroid had to be reintroduced after one week due to the onset of neurological complications. At that time, HCMV specific T-cell response determined by ELISpot assay [11] was undetectable, since the patient showed 91 CD4 T cells/µl, and 71 CD8 T cells/µl.\n\nAt week 21 the patient was hospitalized due to a respiratory distress, caused by HCMV lung infection and a methicillin-resistant Staphylococcus aureus (MRSA) septicemia.\n\nGCV therapy was reintroduced in combination with HCMV-specific immunoglobulin therapy (400 mg/kg once a week for two weeks and after 14 and 21 days reduced at 200 mg/kg). In addition, linezolid and daptomicin were administered for MRSA positive blood culture. A594V in UL97 gene was re-confirmed in blood sample. At week 30, HCMV viral load increased to 16,314,793 IU/mL.\n\nAt week 32 post-transplant, oral LMV treatment was started in monotherapy at a dose of 480 mg daily because of persisting neutropenia and a previous renal toxicity during FOS treatment. HCMV-specific T-cell response was still undetectable at that time when in presence of 76 CD4 and 67 CD8 absolute T cells counts/µl.\n\nAt LMV baseline, HCMV DNAemia was 2,800,980 IU/mL. After two weeks of therapy, HCMV DNAemia decreased to 461,160 IU/mL. Five weeks after starting LMV HCMV DNAemia was 42,336 IU/mL. Unfortunately, after 7 and 8 weeks of treatment HCMV DNA increased to 244,566 IU/mL and 703,080 IU/mL, respectively (Fig. 1). Thus, HCMV UL51, UL56 and UL89 genes encoding the terminase complex verify the potential emergence of LMV-resistance-associated mutation [12]. Mutation C325Y in HCMV UL56 terminase gene conferring high-level resistance to LMV [8, 13] was reported. Retrospectively, it was revealed that the mutation was already present as mixture with the wild type after 5 weeks LMV treatment. The patient was treated with CDV at the dosage of 5 mg/kg once a week. After 1-week CDV treatment, HCMV DNA increased up to 2,563,208 IU/mL. Emergence of CDV resistance was excluded by UL54 gene sequence analysis. The patient died after two weeks due to complications caused by HCMV infection.\n\nDiscussion and conclusions\n\nHCMV infection and the associated tissue diseases are still important causes of morbidity and mortality in immunocompromised-transplanted patients, especially in subjects at high risk such as HCMV-seronegative recipients who receive an organ from an HCMV-seropositive donor (D+/R−), due to the lack of prior HCMV immune response [14]. Limited treatment options are available when side effects like nephrotoxicity, electrolyte disturbances, and myelotoxicity or drug resistance occur. Recent studies indicated that LMV might be an important addition to the current strategies in HCMV disease as salvage therapies in SOTRs [15, 16]. LMV appears to be a good alternative to other antiviral especially in view of the favorable safety [17]. However, mutations conferring resistance to LMV have been reported both in HSCT and in SOT recipients [17–20] as soon as after 6 weeks of treatment [18]. Similarly, Hofmann and colleagues reported C351Y mutation in two patients treated with LMV after emergence of GCV-resistance. In both cases, a mismatch D/R was reported [21].\n\nIn the case here described, an even faster breakthrough of resistant HCMV during third-line treatment with LMV is reported. In this patient, congenital immunodeficiency associated with iatrogenic immunosuppression, primary HCMV infection likely concurred to the emergence of the GCV-resistance viral strain. Furthermore, LMV could only be administered in monotherapy due to significant myelo- and renal toxicity. It might be suggested that administration of LMV in higher dosage could be more effective, however in a recent study selection of LMV resistance was reported in two patients treated with 720 mg and 960 mg respectively [22]. Therefore, the use of LMV alone might be not sufficient to impair high level of HCMV replication [17, 18, 21]. Moreover, according to international consensus guidelines, monitoring of cell-mediated response should be included in management of solid organ transplant recipients [14].\n\nIn conclusion, a warning on the use of LMV monotherapy as rescue treatment for HCMV GCV-resistant infections in transplant recipients is warranted; thus combination therapy, if the patient’s condition permits, may provide better results in case of high viral load.\n\nAbbreviations\n\nGCV Ganciclovir\n\nvGCV Valganciclovir\n\nFOS Foscarnet\n\nLMV Letermovir\n\nHCMV Human cytomegalovirus\n\nCVID Common variable immunodeficiency\n\nAcknowledgements\n\nWe thank Daniela Sartori for careful preparation of the manuscript.\n\nAuthor’s contributions\n\nSP: data analysis and interpretation, drafted the article; GC: concept and design of the work; IC: samples collection and data analysis; FN, AF: samples collection and experimental design; AM, FG, LP, AP and AT: clinical data collection and patient enrollment; FB: critical revision of the article and final approval of the version. All authors contributed toward data analysis, drafting and revising the paper, gave final approval of the version to be published and agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.\n\nFunding\n\nThis work was supported by the Fondazione IRCCS Policlinico San Matteo, Ricerca Corrente (grant 80207) and Ministero della Salute, Ricerca Finalizzata (RF-2019-12370797). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n\nAvailability of data and materials\n\nAll data generated or analysed during this study are included in this published article.\n\nDeclarations\n\nEthics approval and consent to participate\n\nThis study was performed according to guidelines of the Institutional Review Board of the Fondazione IRCCS Policlinico San Matteo on the use of biologic specimens for scientific purpose in keeping with Italian law (art.13 D. Lgs. 196/2003).\n\nConsent for publication\n\nPatient next-of-kin gave written consent for relative’s clinical details to be published in this study.\n\nCompeting interests\n\nThe authors report no conflicts of interest in this work.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nStefania Paolucci and Giulia Campanini contributed equally to this work\n==== Refs\nReferences\n\n1. Lurain NS Chou S Antiviral drug resistance of human cytomegalovirus Clin Microbiol Rev 2010 23 4 689 712 10.1128/CMR.00009-10 20930070\n2. Avery RK Arav-Boger R Marr KA Kraus E Shoham S Lees L Trollinger B Shah P Ambinder R Neofytos D Ostrander D Forman M Valsamakis A Outcomes in transplant recipients treated with foscarnet for ganciclovir-resistant or refractory cytomegalovirus infection Transplantation. 2016 100 10 e74 80 10.1097/TP.0000000000001418 27495775\n3. Minces LR Nguyen MH Mitsani D Shields RK Kwak EJ Silveira FP Abdel-Massih R Pilewski JM Crespo MM Bermudez C Bhama JK Toyoda Y Clancy CJ Ganciclovir-resistant cytomegalovirus infections among lung transplant recipients are associated with poor outcomes despite treatment with foscarnet-containing regimens Antimicrob Agents Chemother. 2014 58 1 128 35 10.1128/AAC.00561-13 24145525\n4. Goldner T Hewlett G Ettischer N Ruebsamen-Schaeff H Zimmermann H Lischka P The novel anticytomegalovirus compound AIC246 (Letermovir) inhibits human cytomegalovirus replication through a specific antiviral mechanism that involves the viral terminase J Virol. 2011 85 20 10884 93 10.1128/JVI.05265-11 21752907\n5. Frange P Leruez-Ville M Maribavir, brincidofovir and letermovir: Efficacy and safety of new antiviral drugs for treating cytomegalovirus infections Med Mal Infect. 2018 48 8 495 502 10.1016/j.medmal.2018.03.006 29650261\n6. Marty FM Ljungman P Chemaly RF Maertens J Dadwal SS Duarte RF Haider S Ullmann AJ Katayama Y Brown J Mullane KM Boeckh M Blumberg EA Einsele H Snydman DR Kanda Y DiNubile MJ Teal VL Wan H Murata Y Kartsonis NA Leavitt RY Badshah C Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation N Engl J Med. 2017 377 25 2433 44 10.1056/NEJMoa1706640 29211658\n7. Razonable RR Role of letermovir for prevention of cytomegalovirus infection after allogeneic haematopoietic stem cell transplantation Curr Opin Infect Dis 2018 31 4 286 91 10.1097/QCO.0000000000000459 29746444\n8. Chou S Rapid in vitro evolution of human cytomegalovirus UL56 mutations that confer letermovir resistance Antimicrob Agents Chemother 2015 9 10 6588 93 10.1128/AAC.01623-15\n9. Lurain NS Weinberg A Crumpacker CS Chou S Sequencing of cytomegalovirus UL97 gene for genotypic antiviral resistance testing. Adult AIDS Clinical Trials Group-CMV Laboratories Antimicrob Agents Chemother. 2001 45 10 2775 80 10.1128/AAC.45.10.2775-2780.2001 11557468\n10. Baldanti F Lilleri D Campanini G Comolli G Ridolfo AL Rusconi S Gerna G Human cytomegalovirus double resistance in a donor-positive/recipient-negative lung transplant patient with an impaired CD4-mediated specific immune response J Antimicrob Chemother. 2004 53 3 536 9 10.1093/jac/dkh065 14739146\n11. Calarota SA Chiesa A Scaramuzzi L Adzasehoun KMG Comolli G Mangione F Esposito P Baldanti F Normalizing ELISPOT responses to T-cell counts: a novel approach for quantification of HCMV-specific CD4(+) and CD8(+) T-cell responses in kidney transplant recipients J Clin Virol 2014 61 1 65 73 10.1016/j.jcv.2014.05.017 24961915\n12. Pilorgé L Burrel S Aït-Arkoub Z Agut H Boutolleau D Human cytomegalovirus (CMV) susceptibility to currently approved antiviral drugs does not impact on CMV terminase complex polymorphism Antiviral Res. 2014 111 8 12 10.1016/j.antiviral.2014.08.014 25194992\n13. Goldner T Hempel C Ruebsamen-Schaeff H Zimmermann H Lischka P Geno- and phenotypic characterization of human cytomegalovirus mutants selected in vitro after letermovir (AIC246) exposure Antimicrob Agents Chemother. 2014 58 1 610 3 10.1128/AAC.01794-13 24189264\n14. Kotton CN Kumar D Caliendo AM Huprikar S Chou S Danziger-Isakov L Humar A The Transplantation Society International CMV Consensus Group The third international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation Transplantation 2018 102 6 900 31 10.1097/TP.0000000000002191 29596116\n15. Lischka P Zimmermann H Antiviral strategies to combat cytomegalovirus infections in transplant recipients Curr Opin Pharmacol. 2008 8 5 541 8 10.1016/j.coph.2008.07.002 18662804\n16. Chemaly RF Ullmann AJ Stoelben S Richard MP Bornhäuser M Groth C Einsele H Silverman M Mullane KM Brown J Nowak H Kölling K Stobernack HP Lischka P Zimmermann H Rübsamen-Schaeff H Champlin RE Ehninger G AIC246 Study Team Letermovir for cytomegalovirus prophylaxis in hematopoietic-cell transplantation N Engl J Med. 2014 370 19 1781 9 10.1056/NEJMoa1309533 24806159\n17. Frietsch JJ Michel D Stamminger T Hunstig F Birndt S Schnetzke U Scholl S Hochhaus A Hilgendorf I In vivo emergence of UL56 C325Y cytomegalovirus resistance to letermovir in a patient with acute myeloid leukemia after hematopoietic cell transplantation Mediterr J Hematol Infect Dis. 2019 11 1 e2019001 10.4084/MJHID.2019.001 30671207\n18. Jung S Michel M Stamminger T Michel D Fast breakthrough of resistant cytomegalovirus during secondary letermovir prophylaxis in a hematopoietic stem cell transplant recipient BMC Infect Dis. 2019 19 1 388 10.1186/s12879-019-4016-1 31068147\n19. Knoll BM Seiter K Phillips A Soave R Breakthrough cytomegalovirus pneumonia in hematopoietic stem cell transplant recipient on letermovir prophylaxis Bone Marrow Transplant. 2019 54 6 911 2 10.1038/s41409-018-0389-9 30401966\n20. Cherrier L Nasar A Goodlet KJ Nailor MD Tokman S Chou S Emergence of letermovir resistance in a lung transplant recipient with ganciclovir-resistant cytomegalovirus infection Am J Transplant. 2018 18 12 3060 4 10.1111/ajt.15135 30286286\n21. Hofmann E Sidler D Dahdal S Bittel P Suter-Riniker F Manuel O Walti LN Hirzel C Emergence of letermovir resistance in solid organ transplant recipients with ganciclovir resistant cytomegalovirus infection: a case series and review of the literature Transpl Infect Dis 2021 23 3 e13515 10.1111/tid.13515 33210830\n22. Turner N Strand A Grewal DS Cox G Arif S Baker AW Maziarz EK Saullo JH Wolfe CR Use of Letermovir as salvage therapy for drug-resistant cytomegalovirus retinitis Antimicrob Agents Chemother 2019 63 3 e02337 18 10.1128/AAC.02337-18 30642941\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2334",
"issue": "21(1)",
"journal": "BMC infectious diseases",
"keywords": "Case report; HCMV; Letermovir",
"medline_ta": "BMC Infect Dis",
"mesh_terms": "D000085:Acetates; D000998:Antiviral Agents; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D024882:Drug Resistance, Viral; D015774:Ganciclovir; D006801:Humans; D016031:Liver Transplantation; D009154:Mutation; D009364:Neoplasm Recurrence, Local; D011799:Quinazolines",
"nlm_unique_id": "100968551",
"other_id": null,
"pages": "994",
"pmc": null,
"pmid": "34556034",
"pubdate": "2021-09-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "30642941;24961915;21752907;29650261;29746444;14739146;24806159;24145525;18662804;30401966;27495775;30671207;20930070;11557468;31068147;33210830;30286286;26259791;29596116;25194992;29211658;24189264",
"title": "Emergence of Letermovir-resistant HCMV UL56 mutant during rescue treatment in a liver transplant recipient with ganciclovir-resistant infection HCMV: a case report.",
"title_normalized": "emergence of letermovir resistant hcmv ul56 mutant during rescue treatment in a liver transplant recipient with ganciclovir resistant infection hcmv a case report"
} | [
{
"companynumb": "IT-PBT-000099",
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"occurcountry": "IT",
"patient": {
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VALGANCICLOVIR"
},
"drugadditional": null,
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{
"abstract": "Delirium is common in daily practice. Drug-induced delirium constitutes approximately one-third of all cases of delirium. In cases characterized by the limited efficacy of a single antidepressant, a combination of two antidepressants is required, which may induce a complex drug-drug interaction. We reviewed a case of duloxetine- and bupropion-related delirium in an elderly male patient in our clinical practice. The patient was diagnosed with major depressive disorder and was treated with duloxetine. However, he developed delirium 10 days after bupropion was added to his treatment regimen. Three days after the cessation of bupropion, his delirious condition gradually improved. Duloxetine and bupropion are both cytochrome P450 2D6 inhibitors that may result in a higher level of hydroxybupropion. An increased level of hydroxybupropion may cause the elevation of dopamine and a risk of subsequent delirium. We should be aware of the risk of delirium induced by drug-drug interactions.",
"affiliations": "Department of Psychiatry, Changhua Christian Hospital, Changhua, Taiwan.;Department of Psychiatry, Taichung Veterans General Hospital, Taichung, Taiwan.;Department of Psychiatry, Changhua Christian Hospital, Changhua, Taiwan.;Department of Psychiatry, Changhua Christian Hospital, Changhua, Taiwan.",
"authors": "Ma|Szu-Pin|SP|;Tsai|Chia-Jui|CJ|;Chang|Cheng-Chen|CC|;Hsu|Wen-Yu|WY|",
"chemical_list": "D018687:Antidepressive Agents, Second-Generation; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D016642:Bupropion; D000068736:Duloxetine Hydrochloride",
"country": "England",
"delete": false,
"doi": "10.1111/psyg.12202",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1346-3500",
"issue": "17(2)",
"journal": "Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society",
"keywords": "CYP2D6; bupropion; concomitant; delirium; duloxetine",
"medline_ta": "Psychogeriatrics",
"mesh_terms": "D000369:Aged, 80 and over; D018687:Antidepressive Agents, Second-Generation; D016642:Bupropion; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003693:Delirium; D003865:Depressive Disorder, Major; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D000068736:Duloxetine Hydrochloride; D006801:Humans; D008297:Male; D016896:Treatment Outcome",
"nlm_unique_id": "101230058",
"other_id": null,
"pages": "130-132",
"pmc": null,
"pmid": "27046219",
"pubdate": "2017-03",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Delirium associated with concomitant use of duloxetine and bupropion in an elderly patient.",
"title_normalized": "delirium associated with concomitant use of duloxetine and bupropion in an elderly patient"
} | [
{
"companynumb": "TW-AJANTA PHARMA USA INC.-2020359",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DULOXETINE"
},
"drugadditional": "3",... |
{
"abstract": "Intoxications with sulpiride, an antipsychotic, are rare, and only limited literature is available. We describe a successful treatment of a sulpiride intoxication. A 67-year-old female, with a history of intentional suicide attempt, was admitted to the emergency department (ED) because of a suspected out-of-hospital cardiac arrest. At presentation, she was haemodynamically unstable, with a Glasgow Coma Scale of 3 and slight prolongation of QTc time. History taken from her husband raised suspicion of a suicide attempt with medication. Consultation of the on-call pharmacist and performance of a toxicology screening accelerated the diagnosis of a sulpiride intoxication. The patient was intubated because of respiratory insufficiency, admitted to the Intensive Care Unit (ICU) and treated with activated charcoal, laxatives and sodium bicarbonate. The following day, she was extubated with stable haemodynamics and a normalized ECG. Treatment of sulpiride intoxications is mainly symptomatic and consists of supportive care. An important note is the avoidance of antiarrhythmic drugs, except for lidocaine, epinephrine and dopamine, as they might worsen arrhythmia and hypotension.",
"affiliations": "Department of clinical pharmacy, Haaglanden Medical Centre, The Hague, The Netherlands.;Department of intensive care medicine, Haaglanden Medical Centre, The Hague, The Netherlands.;Laboratory, Apotheek Haagse Ziekenhuizen, The Hague, The Netherlands.;Department of intensive care medicine, Haaglanden Medical Centre, The Hague, The Netherlands.;Department of clinical pharmacy, Haaglanden Medical Centre, The Hague, The Netherlands.",
"authors": "Zonneveld|Svenja|S|https://orcid.org/0000-0001-7847-823X;Gawi|Adina|A|;Wilms|Erik B|EB|;van Vliet|Peter|P|;Westerman|Elsbeth M|EM|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/bcpt.13526",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1742-7835",
"issue": "128(4)",
"journal": "Basic & clinical pharmacology & toxicology",
"keywords": "case report; intoxication; sulpiride; toxicology; toxicology screening",
"medline_ta": "Basic Clin Pharmacol Toxicol",
"mesh_terms": null,
"nlm_unique_id": "101208422",
"other_id": null,
"pages": "628-631",
"pmc": null,
"pmid": "33128344",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Sulpiride intoxication: Case report of a rare intoxication.",
"title_normalized": "sulpiride intoxication case report of a rare intoxication"
} | [
{
"companynumb": "NL-TEVA-2020-NL-1863037",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREGABALIN"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nAlthough hypersensitivity reactions are well characterized for certain medications, vancomycin-associated drug-induced hypersensitivity syndrome (DIHS), or drug reaction with eosinophilia and systemic symptoms (DRESS), has yet to be defined.\n\n\nOBJECTIVE\nTo better define the clinical phenotype of vancomycin-associated DIHS.\n\n\nMETHODS\nA retrospective case series was conducted over an 8-year period at a single, academic institution. A total of 29 cases of DIHS/DRESS were identified, of which 4 were attributed to vancomycin. A literature review was performed; it identified 28 additional cases of vancomycin-induced DIHS. Vancomycin-associated acute interstitial nephritis was also reviewed to detect additional, previously uncharacterized cases of systemic hypersensitivity. The review yielded 11 additional cases.\n\n\nRESULTS\nIn this literature review and retrospective series, the incidence of renal dysfunction among vancomycin-induced cases (75% and 68% of cases in the series and literature, respectively) was notably higher than the overall reported incidence in DIHS (10%-40%). The degree of renal impairment was also significantly increased in the retrospective series (a median 4.98-fold change in baseline creatinine level vs a 2.25-fold increase in non-vancomycin-associated cases [P = .011]).\n\n\nCONCLUSIONS\nThe principal limitation of this study is the small sample size. Other notable limitations include the retrospective nature of the study and absence of confirmatory renal biopsies.\n\n\nCONCLUSIONS\nAlthough the current understanding of DIHS/DRESS is imperfect, our findings suggest that vancomycin-induced cases present with a unique phenotype characterized by a higher burden of renal involvement.",
"affiliations": "Department of Dermatology, University of Utah, Salt Lake City, Utah.;Department of Dermatology, University of California, San Francisco, California. Electronic address: foxli@derm.ucsf.edu.",
"authors": "Madigan|Lauren M|LM|;Fox|Lindy P|LP|",
"chemical_list": "D014640:Vancomycin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jaad.2019.02.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0190-9622",
"issue": "81(1)",
"journal": "Journal of the American Academy of Dermatology",
"keywords": "DIHS; DRESS; drug reaction with eosinophilia and systemic symptoms; drug-induced hypersensitivity syndrome; renal dysfunction; vancomycin",
"medline_ta": "J Am Acad Dermatol",
"mesh_terms": "D000046:Academic Medical Centers; D000328:Adult; D000367:Age Factors; D000368:Aged; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D063926:Drug Hypersensitivity Syndrome; D004802:Eosinophilia; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D011379:Prognosis; D012189:Retrospective Studies; D018570:Risk Assessment; D012737:Sex Factors; D014481:United States; D014640:Vancomycin; D055815:Young Adult",
"nlm_unique_id": "7907132",
"other_id": null,
"pages": "123-128",
"pmc": null,
"pmid": "30738120",
"pubdate": "2019-07",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Vancomycin-associated drug-induced hypersensitivity syndrome.",
"title_normalized": "vancomycin associated drug induced hypersensitivity syndrome"
} | [
{
"companynumb": "US-ZYDUS-039268",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugadditional": "3",
"drugadm... |
{
"abstract": "BACKGROUND\nHypercalcemia is one of the most common metabolic abnormalities encountered in any form of malignancy. Hypocalcemia, however, is a rare manifestation, especially in cancers with bone involvement. Here we present a case of hypocalcemia in a patient with multiple myeloma that was refractory to treatment.\n\n\nMETHODS\nA 73-year-old African American woman recently diagnosed with multiple myeloma, presented with a 2-day history of fever, vomiting and hypocalcemia. Ten days prior to admission she received zoledronic acid, Velcade® (bortezomib), Revlimid® (lenalidomide) and dexamethasone. Treatment was started with intravenous antibiotics and calcium gluconate boluses. After 24 hours of treatment her calcium level became undetectable (<5mg/dL). Continuous intravenous calcium gluconate infusions in addition to boluses were started. She remained persistently hypocalcemic and eventually developed tonic-clonic seizures. Vitamin D levels were found to be low and intravenous paricalcitol was initiated, which improved her calcium level.\n\n\nCONCLUSIONS\nUnderlying vitamin D deficiency can precipitate severe hypocalcemia in patients with multiple myeloma receiving bisphosphonates. This warrants baseline screening for vitamin D deficiency in these patients.",
"affiliations": "UAB Health Center Montgomery, 2055 East South Boulevard, Suite 202, Montgomery, AL 36116, USA. adrianaldave@uabmc.edu.",
"authors": "Noriega Aldave|Adrian P|AP|;Jaiswal|Shikha|S|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid",
"country": "England",
"delete": false,
"doi": "10.1186/1752-1947-8-353",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central 1752-1947-8-3532534229410.1186/1752-1947-8-353Case ReportSevere resistant hypocalcemia in multiple myeloma after zoledronic acid administration: a case report Noriega Aldave Adrian P 1adrianaldave@uabmc.eduJaiswal Shikha 2shikha16@gmail.com1 UAB Health Center Montgomery, 2055 East South Boulevard, Suite 202, Montgomery, AL 36116, USA2 East South Boulevard, Suite 202, Montgomery, AL 36116, USA2014 23 10 2014 8 353 353 7 3 2014 26 8 2014 Copyright © 2014 Noriega Aldave and Jaiswal; licensee BioMed Central Ltd.2014Noriega Aldave and Jaiswal; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Introduction\nHypercalcemia is one of the most common metabolic abnormalities encountered in any form of malignancy. Hypocalcemia, however, is a rare manifestation, especially in cancers with bone involvement. Here we present a case of hypocalcemia in a patient with multiple myeloma that was refractory to treatment.\n\nCase presentation\nA 73-year-old African American woman recently diagnosed with multiple myeloma, presented with a 2-day history of fever, vomiting and hypocalcemia. Ten days prior to admission she received zoledronic acid, Velcade® (bortezomib), Revlimid® (lenalidomide) and dexamethasone. Treatment was started with intravenous antibiotics and calcium gluconate boluses. After 24 hours of treatment her calcium level became undetectable (<5mg/dL). Continuous intravenous calcium gluconate infusions in addition to boluses were started. She remained persistently hypocalcemic and eventually developed tonic–clonic seizures. Vitamin D levels were found to be low and intravenous paricalcitol was initiated, which improved her calcium level.\n\nConclusions\nUnderlying vitamin D deficiency can precipitate severe hypocalcemia in patients with multiple myeloma receiving bisphosphonates. This warrants baseline screening for vitamin D deficiency in these patients.\n\nHypocalcemiaMultiple myelomaVitamin D deficiencyZoledronic acid\n==== Body\nIntroduction\nMultiple myeloma (MM) is a malignant proliferation of plasma cells, characterized by the presence of monoclonal immunoglobulin in serum and urine. Zoledronic acid (ZA) is a standard part of the treatment, as patients with MM usually have hypercalcemia secondary to bone destruction. However, some cases of hypocalcemia have been reported when bisphosphonates were used in patients with vitamin D deficiency [1-3]. Our case differs in the fact that our patient with MM developed severe hypocalcemia just after receiving her first dose of ZA.\n\nCase presentation\nA 73-year-old African American woman with diabetes mellitus, hypertension, and recently diagnosed immunoglobulin G MM, presented with 2 days’ history of fever, nausea, vomiting and dizziness. She was found to be obtunded in our Emergency department and was intubated for airway protection. She was febrile (39.33°C, 102.8°F), but hemodynamically stable. She demonstrated mild respiratory distress, had rales and wheezes on auscultation, and edema in both lower extremities. Initial laboratory results (Table 1) revealed pancytopenia, elevated creatinine and corrected calcium of 7.3mg/dL, other electrolytes were within normal limits. A chest radiograph revealed cardiomegaly and pulmonary edema. Ten days prior to admission she received one dose of ZA, three doses of bortezomib, and seven doses of daily lenalidomide in addition to weekly dexamethasone. A clinical diagnosis of neutropenic fever, acute renal failure and severe hypocalcemia was made. Treatment was started with intravenous vancomycin and cefepime. She was also given calcium gluconate boluses for her hypocalcemia.\n\nTable 1 Comparison of laboratory parameters at first chemotherapy dose, admission and hospital stay\n\nCHEMISTRY\tBiochemistry 1 day before chemotherapy\t1 day after zoledronic acid and Velcade\n® \n(bortezomib) administration\t3 days after admission\t1 day after paricalcitol initiated\t\nCorrected calcium (mg/dL)\t10.3\t7.3\t<5 (undetectable)\t8.4\t\nIonized calcium (mmol/L)\t–\t–\t0.66\t1.13\t\nCreatinine (mg/dL)\t0.99\t1.69\t8\t4.8\t\nGlomerular filtration rate (mL/minute/1.73m2)\t>60\t36\t6\t–\t\nVitamin D (ng/mL)\t–\t–\t13\t–\t\nLaboratory results not done.\n\nEven after 24 hours of treatment, her mental status did not improve. She remained febrile, her kidney functions worsened, and her calcium level became undetectable (<5mg/dL) and ionized calcium was 0.66mmol/L (see Table 1). She was started on continuous intravenous calcium gluconate infusion in addition to boluses, which still did not increase her calcium levels. We then tested for vitamin D levels which were found to be low (13ng/mL). The value of vitamin D was measured on the day in which renal function was most impaired (creatinine 8mg/dL). Intravenous paricalcitol was initiated, which did improve her calcium level, but, it did not revert to normal. Despite aggressive calcium replacement she remained persistently hypocalcemic and eventually developed tonic–clonic seizures. An electrocardiogram revealed a QT interval of 500ms using Bazett’s formula. Her neuroimaging, however, was normal except for several small calvarium lytic lesions (Figure 1). Her family eventually made the decision to focus on comfort measures only, following which, she had a cardiac arrest and died on hospital day 17.\n\nFigure 1 Computed tomography of brain (bone window). Computed tomography brain scan showing multiple lytic lesions in the calvarium (arrow).\n\nDiscussion\nZA is a long-acting bisphosphonate used for supportive therapy in MM and bone metastasis. It has a safety profile similar to that of pamidronate, but because of ease of administration, it is preferred over the latter. In the long run, both pamidronate and ZA have been shown to reduce skeletal related events, and decrease need for irradiation [4].\n\nBisphosphonates are generally well tolerated, although they are occasionally associated with adverse events namely hypocalcemia, nephrotoxicity, pancytopenia and osteonecrosis [5-7].\n\nRenal dysfunction is an undesired side effect that can occur after intravenous infusion of bisphosphonate [5]. In this case, her kidney functions were normal before starting chemotherapy, but a week after initiating ZA, she developed acute renal failure. This may also have been exacerbated by the MM nephropathy, but arguably her kidney functions had remained stable from the time of the diagnosis until she got her first dose of ZA.\n\nAll bisphosphonates can cause hypocalcemia, regardless of their method of administration, although this is infrequently found to be a clinically symptomatic problem [7,8]. Of note, symptomatic hypocalcemia after ZA is rarely reported.\n\nHypovitaminosis D and concurrent dexamethasone and ZA administration have been identified as independent risk factors for severe hypocalcemia when metastatic tumors are treated with ZA [9]. Corticosteroids decrease blood calcium levels by suppression of intestinal calcium absorption, depression of vitamin D activity and reabsorption of calcium in renal tubules.\n\nThere are some case reports about patients with MM with unrecognized vitamin D deficiency, who developed hypocalcemia following ZA that improved only after vitamin D replacement [1]; as can also be appreciated in this case.\n\nConclusions\nSome studies have reported up to 150% increase in mortality, among critical care unit patients, with ionized calcium levels below 0.8mmol/L [10]. Our patient had ionized calcium of 0.66mmol/L. Unfortunately, the level of vitamin D is not part of routine screening in patients receiving bisphosphonates for cancers. This case therefore serves to remind us that careful clinical and biochemical evaluation is required before administration of bisphosphonates in cancers to avoid undesired side effects; and vitamin D levels should be a part of screening before administering more potent and longer acting bisphosphonates, such as ZA.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAbbreviations\nMM: Multiple myeloma; ZA: Zoledronic acid.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\nAPNA wrote the introduction, case description, table and corrected discussion of the manuscript, SJ wrote discussion and conclusions. Both authors read and approved the final manuscript.\n\nAcknowledgment\nJewell H Halanych MD, MSc, participated in the correction of the manuscript.\n==== Refs\nSingh D Khaira NS Sekhon JS Symptomatic hypocalcaemia after treatment with zoledronic acid in a patient with multiple myeloma Ann Oncol 2004 15 12 1848 15550594 \nMaalouf NM Heller HJ Odvina CV Kim PJ Sakhaee K Bisphosphonate-induced hypocalcemia: report of 3 cases and review of literature Endocr Pract 2006 12 1 48 53 10.4158/EP.12.1.48 16524863 \nBroadbent A Glare P Crawford B Bisphosphonate-induced hypocalcemia associated with vitamin D deficiency in a patient with advanced cancer Am J Hosp Palliat Care 2005 22 5 382 384 10.1177/104990910502200512 16225361 \nRodan GA Fleisch HA Bisphosphonates: mechanisms of action J Clin Invest 1996 97 2692 2696 10.1172/JCI118722 8675678 \nHenley D Kaye J Walsh J Cull G Symptomatic hypocalcaemia and renal impairment associated with bisphosphonate treatment in patients with multiple myeloma Intern Med J 2005 35 726 728 10.1111/j.1445-5994.2005.00949.x 16313549 \nDiel IJ Bergner R Grötz KA Adverse effects of bisphosphonates: current issues J Support Oncol 2007 5 10 475 482 18240669 \nKmetec A Hajdinjak T Evaluation of safety and analgesic consumption in patients with advanced cancer treated with zoledronic acid Radiol Oncol 2013 47 3 289 295 24133394 \nHanamura M Iwamoto T Soga N Sugimura Y Okuda M Risk factors contributing to the development of hypocalcemia after zoledronic acid administration in patients with bone metastases of solid tumor Biol Pharm Bull 2010 33 4 721 724 10.1248/bpb.33.721 20410614 \nPeter R Mishra V Fraser WD Severe hypocalcaemia after being given intravenous bisphosphonate BMJ 2004 328 335 336 10.1136/bmj.328.7435.335 14764499 \nEgi M Kim I Nichol A Stachowski E French CJ Hart GK Hegarty C Bailey M Bellomo R Ionized calcium concentration and outcome in critical illness Crit Care Med 2011 39 314 321 10.1097/CCM.0b013e3181ffe23e 21099425\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "8()",
"journal": "Journal of medical case reports",
"keywords": null,
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000368:Aged; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D005260:Female; D006801:Humans; D006996:Hypocalcemia; D007093:Imidazoles; D009101:Multiple Myeloma; D014057:Tomography, X-Ray Computed; D014808:Vitamin D Deficiency; D000077211:Zoledronic Acid",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "353",
"pmc": null,
"pmid": "25342294",
"pubdate": "2014-10-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16524863;16225361;18240669;21099425;8675678;15550594;20410614;14764499;16313549;24133394",
"title": "Severe resistant hypocalcemia in multiple myeloma after zoledronic acid administration: a case report.",
"title_normalized": "severe resistant hypocalcemia in multiple myeloma after zoledronic acid administration a case report"
} | [
{
"companynumb": "US-ROXANE LABORATORIES, INC.-2015-RO-00852RO",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LENALIDOMIDE"
},
"drugadd... |
{
"abstract": "Ergotism is an ischaemic complication due to vasoconstriction throughout the body due to ingestion of ergotamine. A 34-year-old Hispanic man with HIV infection treated with saquinavir, ritonavir and abacavir/lamivudine presented to the emergency department complaining of left foot pain 1 week prior to admission. The affected extremity was cold with absence of pedal and tibial pulses. Arterial Doppler revealed absent arterial flow from the popliteal artery later confirmed by arteriography. Medication reconciliation revealed a recent prescription for migraine headache containing ergotamine. Drug was discontinued and the patient was started on cilostazol, enoxaparin and nitroglycerin patches on the affected limb. Complete resolution of symptoms and arteriography findings occurred 2 days after therapy began.",
"affiliations": "Internal Medicine, Texas Tech University Health Science Center at the Permian Basin, Odessa, Texas, USA.;Internal Medicine, Texas Tech University Health Science Center at the Permian Basin, Odessa, Texas, USA.;Department of Surgery, Division of Plastic and Reconstructive Surgery, Northwestern Memorial Hospital, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.;Critical Care Medicine, Centro Policlinico Valencia, Venezuela, Carabobo, Bolivarian Republic of Venezuela.",
"authors": "Iardino|Alfredo|A|http://orcid.org/0000-0002-9645-9072;Garner|Orlando|O|;Lorusso|Gabriella|G|;Lotta|Franco|F|",
"chemical_list": "D019380:Anti-HIV Agents; D000925:Anticoagulants; D065692:Cytochrome P-450 CYP3A Inhibitors; D015224:Dideoxynucleosides; D004338:Drug Combinations; D017984:Enoxaparin; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C492871:abacavir, lamivudine drug combination; D019259:Lamivudine; D005996:Nitroglycerin; D019258:Saquinavir; D000077407:Cilostazol; D019438:Ritonavir; D004878:Ergotamine",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-225130",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "drug interactions; drugs and medicines; infections; infectious diseases; interventional cardiology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D000925:Anticoagulants; D000077407:Cilostazol; D065692:Cytochrome P-450 CYP3A Inhibitors; D015224:Dideoxynucleosides; D004338:Drug Combinations; D004347:Drug Interactions; D017984:Enoxaparin; D004878:Ergotamine; D004881:Ergotism; D015658:HIV Infections; D006261:Headache; D006801:Humans; D007511:Ischemia; D019259:Lamivudine; D035002:Lower Extremity; D008297:Male; D005996:Nitroglycerin; D019438:Ritonavir; D019258:Saquinavir; D013777:Tetrazoles; D016909:Tibial Arteries; D018615:Ultrasonography, Doppler, Color; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29866692",
"pubdate": "2018-06-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23992606;25486450;15849674;10611116;26602197;28031641;11728055;11475806;28661928;27598502",
"title": "Headache in an HIV-Positive Patient: Dangerous Interaction.",
"title_normalized": "headache in an hiv positive patient dangerous interaction"
} | [
{
"companynumb": "US-HETERO CORPORATE-HET2018US00553",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ABACAVIR\\LAMIVUDINE"
},
"drugadditi... |
{
"abstract": "Posttransplant lymphoproliferative disorders define an important form of lymphoproliferative disease causally linked with a state of iatrogenic immune dysregulation inherent to the posttransplant setting. Most posttransplant lymphoproliferative disorders are in the context of Epstein-Barr virus-associated B-cell lymphoproliferative disease, most notably diffuse large-cell B-cell lymphoma. A less common variant falls under the rubric of posttransplant T-cell lymphoproliferative disease, which is largely unrelated to Epstein-Barr virus infection. Anaplastic large-cell lymphoma (ALCL) is the most recognized form of posttransplant T-cell lymphoproliferative disease. Although the 6p25.3 translocation is seen in a variety of B-cell lymphoproliferative disorders, this particular translocation in the spectrum of T-cell lymphoproliferative disease is a fairly specific finding pointing toward a diagnosis of primary cutaneous ALCL and a rare subset of lymphomatoid papulosis. This translocation in the peripheral T-cell lymphoma setting serves as a favorable prognostic predictor. We report a case of an 81-year-old heart transplant recipient who developed an expansile neck mass 17 years after his heart transplant. A diagnosis of cutaneous ALCL was subsequently made with cytogenetic analysis yielding the 6p25.3 translocation. The characteristic biphasic morphology of a small-cell epidermotropic neoplastic cell populace in concert with a dermal based large-cell infiltrate characteristic for those cases of ALCL harboring this translocation was seen. After excision of the nodule, his azathioprine was withheld. He is currently alive and well without evidence of disease.",
"affiliations": "*Department of Pathology and Laboratory Medicine, NewYork Presbyterian Hospital-Weill Cornell Medical Center, New York, NY; and †Dermatocor, Bostwick Laboratories, Uniondale, NY.",
"authors": "Olson|Luke C|LC|;Cheng|Esther|E|;Mathew|Susan|S|;Torres-Quinones|Marta|M|;Magro|Cynthia|C|",
"chemical_list": "D014408:Biomarkers, Tumor",
"country": "United States",
"delete": false,
"doi": "10.1097/DAD.0000000000000505",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0193-1091",
"issue": "38(6)",
"journal": "The American Journal of dermatopathology",
"keywords": null,
"medline_ta": "Am J Dermatopathol",
"mesh_terms": "D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D002896:Chromosomes, Human, Pair 6; D016027:Heart Transplantation; D006801:Humans; D016867:Immunocompromised Host; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D054446:Lymphoma, Primary Cutaneous Anaplastic Large Cell; D008297:Male; D012878:Skin Neoplasms; D014178:Translocation, Genetic",
"nlm_unique_id": "7911005",
"other_id": null,
"pages": "461-5",
"pmc": null,
"pmid": "26863058",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Primary Cutaneous Anaplastic Large-Cell Lymphoma With 6p25.3 Rearrangement in a Cardiac Transplant Recipient: A Case Report and Review of the Literature.",
"title_normalized": "primary cutaneous anaplastic large cell lymphoma with 6p25 3 rearrangement in a cardiac transplant recipient a case report and review of the literature"
} | [
{
"companynumb": "US-APOTEX-2018AP005091",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": null,
... |
{
"abstract": "Patients with inflammatory bowel disease who do not respond to steroid therapy often require treatment with immunomodulators in an attempt to achieve a response and maintain remission. However, a major concern and controversy is whether these treatments are putting the patients at a significantly increased risk of developing lymphomas. This case reports a patient with severe ulcerative colitis who had been previously treated with azathioprine and infliximab, and subsequently developed diffuse large B-cell colonic lymphoma.",
"affiliations": "Department of Gastroenterology, Ulster Hospital, Belfast, UK.",
"authors": "Allen|Patrick B|PB|;Laing|Georgina|G|;Connolly|Aoife|A|;O'Neill|Ciaran|C|",
"chemical_list": "D000911:Antibodies, Monoclonal; D005765:Gastrointestinal Agents; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2013()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D000911:Antibodies, Monoclonal; D003110:Colonic Neoplasms; D003937:Diagnosis, Differential; D020031:Epstein-Barr Virus Infections; D005765:Gastrointestinal Agents; D004854:Herpesvirus 4, Human; D006801:Humans; D015212:Inflammatory Bowel Diseases; D000069285:Infliximab; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D012812:Sigmoidoscopy; D014057:Tomography, X-Ray Computed; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "24081592",
"pubdate": "2013-09-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15475752;21830262;22115386;11781282;16508929;15138212;15979323;22766526;22031357;16854631;20104215;16009685;17600819;20412066;19837455;21122513;17213349;16540619;21122582;19749141",
"title": "EBV-associated colonic B-cell lymphoma following treatment with infliximab for IBD: a new problem?",
"title_normalized": "ebv associated colonic b cell lymphoma following treatment with infliximab for ibd a new problem"
} | [
{
"companynumb": "GB-MYLANLABS-2015M1007918",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": null,
... |
{
"abstract": "To assess the feasibility of transferring to the University of Tsukuba Hospital for proton beam therapy (PBT) during intensive chemotherapy in children with Ewing sarcoma family of tumors (ESFT) who had been diagnosed and started their first-line treatment at prefectural or regional centers for pediatric oncology.\nThe treatment of ESFT relies on a multidisciplinary approach using intensive neoadjuvant and adjuvant chemotherapies with surgery and radiotherapy. Multi-agent chemotherapy comprising vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide (VDC-IE) is widely used for ESFT, and the interval between each course is very important for maintaining the intensity and effect of chemotherapy.\nClinical information of patients who received PBT and VDC-IE between April 2009 and May 2016 was collected retrospectively. The intervals between each course of VDC-IE and adverse events were assessed.\nFifteen patients were evaluated. No delays in the intervals of chemotherapy due to transfer were observed. There were no adverse events caused during/just after transfer and no increases in adverse events. The estimated 4-year overall and event-free survival rates were 94.6% and 84.8%, respectively.\nAlthough the results of efficacy are preliminary, survival rates were comparable with past studies. More experience and follow-up are required to further assess the efficacy of PBT for patients with ESFT.\nMultidisciplinary therapy for children with ESFT involving transfer to our hospital for PBT during VDC-IE was feasible without treatment delay or an increase in adverse events.",
"affiliations": "Department of Radiation Oncology, University of Tsukuba Hospital, 2-1-1, Amakubo, Tsukuba, Ibaraki 305-8576, Japan.;Department of Child Health, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-8575, Japan.;Department of Child Health, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-8575, Japan.;Department of Child Health, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-8575, Japan.;Department of Pediatrics, University of Tsukuba Hospital, 2-1-1, Amakubo, Tsukuba, Ibaraki 305-8576, Japan.;Department of Pediatrics, University of Tsukuba Hospital, 2-1-1, Amakubo, Tsukuba, Ibaraki 305-8576, Japan.;Department of Child Health, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-8575, Japan.;Department of Child Health, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-8575, Japan.;Department of Pediatrics, University of Tsukuba Hospital, 2-1-1, Amakubo, Tsukuba, Ibaraki 305-8576, Japan.;Department of Pediatrics, University of Tsukuba Hospital, 2-1-1, Amakubo, Tsukuba, Ibaraki 305-8576, Japan.;Department of Pediatric Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-8575, Japan.;Department of Pediatric Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-8575, Japan.;Department of Diagnostic Pathology, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-8575, Japan.;Department of Radiology, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-8575, Japan.;Department of Radiation Oncology, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-8575, Japan.;Department of Child Health, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-8575, Japan.;Department of Radiation Oncology, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-8575, Japan.",
"authors": "Nakao|Tomohei|T|;Fukushima|Hiroko|H|;Fukushima|Takashi|T|;Suzuki|Ryoko|R|;Hosaka|Sho|S|;Yamaki|Yuni|Y|;Kobayashi|Chie|C|;Iwabuchi|Atsushi|A|;Imagawa|Kazuo|K|;Sakai|Aiko|A|;Shinkai|Toko|T|;Masumoto|Kouji|K|;Sakashita|Shingo|S|;Masumoto|Tomohiko|T|;Mizumoto|Masashi|M|;Sumazaki|Ryo|R|;Sakurai|Hideyuki|H|",
"chemical_list": null,
"country": "Poland",
"delete": false,
"doi": "10.1016/j.rpor.2018.08.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1507-1367",
"issue": "23(5)",
"journal": "Reports of practical oncology and radiotherapy : journal of Greatpoland Cancer Center in Poznan and Polish Society of Radiation Oncology",
"keywords": "DFS, disease-free survival; EFS, event-free survival; ESFT, Ewing sarcoma family of tumors; Ewing sarcoma family of tumors (ESFT); Multi-institutional; Multidisciplinary therapy; OS, overall survival; PBT, proton beam therapy; Pediatric; Proton beam therapy (PBT); UTH, University of Tsukuba Hospital; VDC-IE, vincristine, doxorubicin, cyclophosphamide, ifosfamide and etoposide",
"medline_ta": "Rep Pract Oncol Radiother",
"mesh_terms": null,
"nlm_unique_id": "100885761",
"other_id": null,
"pages": "442-450",
"pmc": null,
"pmid": "30197580",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "12377335;16985182;9788419;25754294;26573272;12594313;8874344;18353632;23317143;20656964;17035650;22386373;23758770;23091096;28503890;23778197;19349548;21856094;27165972;22517408;24122173;25949226;25128084;22564996",
"title": "Interinstitutional patient transfers between rapid chemotherapy cycles were feasible to utilize proton beam therapy for pediatric Ewing sarcoma family of tumors.",
"title_normalized": "interinstitutional patient transfers between rapid chemotherapy cycles were feasible to utilize proton beam therapy for pediatric ewing sarcoma family of tumors"
} | [
{
"companynumb": "JP-TEVA-2018-JP-963232",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MESNA"
},
"drugadditional": null,
"dr... |
{
"abstract": "Background: The ASPIRE (NCT01080391) phase 3 trial showed the efficacy of carfilzomib, lenalidomide and dexamethasone (KRd) triplet for relapse and refractory multiple myeloma (RRMM). However, little is known about safety and efficacy of KRd outside a clinical trial context. Methods: Herein we report real life results of KRd given to 130 RRMM patients from 12 Sicilian Centers. Results: Median age was 62 years; patients had received a median of two previous lines of treatment (range 1-10) and 52% were refractory to previous treatment. Median number of KRd cycles was 12 (2-29), with a mean duration of treatment of 12 months; 21 patients had received at least 18 cycles. Overall response rate was 61%, including 18% complete response. Median PFS was 22.9 months, median OS was not reached. Creatinine clearance >30 mL/min, quality of the best achieved response and standard Fluorescence In Situ Hybridization (FISH) risk were independent predictors of favorable outcome. Patients who received the full-dosage of carfilzomib in the first two cycles had a better outcome. Conclusions: KRd was effective and well tolerated and in a considerable proportion of patients, therapy continued beyond the 18th cycle. The finding of a better outcome in patients with the higher cumulative dose of carfilzomib in the first two cycle encourages to maintain the maximum tolerated dose.",
"affiliations": "Division of Hematology, Azienda Policlinico-OVE, University of Catania, 95125 Catania, Italy. ettaconticello@gmail.com.;Division of Hematology, Azienda Policlinico-OVE, University of Catania, 95125 Catania, Italy. sandrina.romano@gmail.com.;Division of Hematology, Azienda Policlinico-OVE, University of Catania, 95125 Catania, Italy. vdelfabro@yahoo.it.;Division of Hematology, Azienda Policlinico-OVE, University of Catania, 95125 Catania, Italy. enricaantoniamartino@libero.it.;Division of Hematology, Azienda Policlinico-OVE, University of Catania, 95125 Catania, Italy. valeriacalaf@gmail.com.;Division of Hematology, Azienda Policlinico-OVE, University of Catania, 95125 Catania, Italy. sapienzagius@gmail.com.;Division of Hematology, Azienda Policlinico-OVE, University of Catania, 95125 Catania, Italy. valerio_leotta@yahoo.it.;Division of Hematology, Azienda Policlinico-OVE, University of Catania, 95125 Catania, Italy. marinaparisi@hotmail.it.;Division of Hematology, Azienda Policlinico-OVE, University of Catania, 95125 Catania, Italy. urosmarkovic09041989@gmail.com.;Division of Hematology, Azienda Policlinico-OVE, University of Catania, 95125 Catania, Italy. brunga93@gmail.com.;Division of Hematology, Azienda Policlinico-OVE, University of Catania, 95125 Catania, Italy. leotta3@yahoo.it.;U.O.C. Ematologia, ASP8, 96100 Siracusa, Italy. cotemi@hotmail.it.;Division of Hematology, Dipartimento di Patologia Umana dell'Adulto e dell'Età Evolutiva, Policlinico G. Martino, University of Messina, 98122 Messina, Italy. vinnao@unime.it.;U.O.C. Ematologia, Azienda Ospedaliera Papardo, 98158 Messina, Italy. donamanni@gmail.com.;U.O.C. Ematologia, Azienda Ospedaliera Papardo, 98158 Messina, Italy. santoneri67@gmail.com.;U.O.C. OncoEmatologia e TMO, Dipartimento Oncologico, La Maddalena, 90146 Palermo, Italy. mamusso53@gmail.com.;U.O.C. OncoEmatologia e TMO, Dipartimento Oncologico, La Maddalena, 90146 Palermo, Italy. r.scalone69@gmail.com.;U.O.C. Ematologia A. O. Ospedali Riuniti Villa Sofia-Cervello, 90146 Palermo, Italy. clotildecangialosi@gmail.com.;U.O.C. Ematologia A. O. Ospedali Riuniti Villa Sofia-Cervello, 90146 Palermo, Italy. clotildecangialosi@hotmail.com.;U.O.C. Ematologia, ARNAS-Civico-Di Cristina-Benfratelli, 90147 Palermo, Italy. cardinaleg@libero.it.;U.O.C. Ematologia, ARNAS-Civico-Di Cristina-Benfratelli, 90147 Palermo, Italy. anxur.merenda@arnascivico.it.;Division of Hematology, Sant'Elia Hospital, 93100 Caltanissetta, Italy. maugericinzia@hotmail.com.;U.O.C. Ematologia, ARNAS Garibaldi, 95122 Catania, Italy. giusy83@virgilio.it.;SIMT Hematology, ASP7, 97100 Ragusa, Italy. massimo.poidomani@asp.rg.it.;U.O.C. Ematologia, Ospedale San Vincenzo, 98039 Taormina (ME), Italy. longo_giuseppe@hotmail.com.;U.O.C. Ematologia, Policlinico P. Giaccone, 90127 Palermo, Italy. melania.carlisi@unipa.it.;Department of Biomedical and Biotechnological Science, University of Catania, 95125 Catania, Italy. d.tibullo@unict.it.;Division of Hematology, Azienda Policlinico-OVE, University of Catania, 95125 Catania, Italy. diraimon@unict.it.",
"authors": "Conticello|Concetta|C|;Romano|Alessandra|A|0000-0002-6333-4433;Del Fabro|Vittorio|V|;Martino|Enrica Antonia|EA|;Calafiore|Valeria|V|;Sapienza|Giuseppe|G|;Leotta|Valerio|V|;Parisi|Marina Silvia|MS|;Markovic|Uros|U|;Garibaldi|Bruno|B|;Leotta|Salvatore|S|;Cotzia|Emilia|E|;Innao|Vanessa|V|;Mannina|Donato|D|0000-0001-8665-1258;Neri|Santo|S|;Musso|Maurizio|M|;Scalone|Renato|R|;Cangialosi|Clotilde|C|;Acquaviva|Francesco|F|;Cardinale|Giovanni|G|0000-0002-5072-2728;Merenda|Anxur|A|;Maugeri|Cinzia|C|;Uccello|Giuseppina|G|;Poidomani|Massimo|M|;Longo|Giuseppe|G|;Carlisi|Melania|M|;Tibullo|Daniele|D|;Di Raimondo|Francesco|F|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/jcm8060877",
"fulltext": "\n==== Front\nJ Clin MedJ Clin MedjcmJournal of Clinical Medicine2077-0383MDPI 10.3390/jcm8060877jcm-08-00877ArticleFeasibility, Tolerability and Efficacy of Carfilzomib in Combination with Lenalidomide and Dexamethasone in Relapsed Refractory Myeloma Patients: A Retrospective Real-Life Survey of the Sicilian Myeloma Network Conticello Concetta 1*https://orcid.org/0000-0002-6333-4433Romano Alessandra 1Del Fabro Vittorio 1Martino Enrica Antonia 1Calafiore Valeria 1Sapienza Giuseppe 1Leotta Valerio 1Parisi Marina Silvia 1Markovic Uros 1Garibaldi Bruno 1Leotta Salvatore 1Cotzia Emilia 2Innao Vanessa 3https://orcid.org/0000-0001-8665-1258Mannina Donato 4Neri Santo 4Musso Maurizio 5Scalone Renato 5Cangialosi Clotilde 6Acquaviva Francesco 6https://orcid.org/0000-0002-5072-2728Cardinale Giovanni 7Merenda Anxur 7Maugeri Cinzia 8Uccello Giuseppina 9Poidomani Massimo 10Longo Giuseppe 11Carlisi Melania 12Tibullo Daniele 13*Di Raimondo Francesco 1*1 Division of Hematology, Azienda Policlinico-OVE, University of Catania, 95125 Catania, Italy; sandrina.romano@gmail.com (A.R.); vdelfabro@yahoo.it (V.D.F.); enricaantoniamartino@libero.it (E.A.M.); valeriacalaf@gmail.com (V.C.); sapienzagius@gmail.com (G.S.); valerio_leotta@yahoo.it (V.L.); marinaparisi@hotmail.it (M.S.P.); urosmarkovic09041989@gmail.com (U.M.); brunga93@gmail.com (B.G.); leotta3@yahoo.it (S.L.)2 U.O.C. Ematologia, ASP8, 96100 Siracusa, Italy; cotemi@hotmail.it3 Division of Hematology, Dipartimento di Patologia Umana dell’Adulto e dell’Età Evolutiva, Policlinico G. Martino, University of Messina, 98122 Messina, Italy; vinnao@unime.it4 U.O.C. Ematologia, Azienda Ospedaliera Papardo, 98158 Messina, Italy; donamanni@gmail.com (D.M.); santoneri67@gmail.com (S.N.)5 U.O.C. OncoEmatologia e TMO, Dipartimento Oncologico, La Maddalena, 90146 Palermo, Italy; mamusso53@gmail.com (M.M.); r.scalone69@gmail.com (R.S.)6 U.O.C. Ematologia A. O. Ospedali Riuniti Villa Sofia-Cervello, 90146 Palermo, Italy; clotildecangialosi@gmail.com (C.C.); clotildecangialosi@hotmail.com (F.A.)7 U.O.C. Ematologia, ARNAS-Civico-Di Cristina-Benfratelli, 90147 Palermo, Italy; cardinaleg@libero.it (G.C.); anxur.merenda@arnascivico.it (A.M.)8 Division of Hematology, Sant’Elia Hospital, 93100 Caltanissetta, Italy; maugericinzia@hotmail.com9 U.O.C. Ematologia, ARNAS Garibaldi, 95122 Catania, Italy; giusy83@virgilio.it10 SIMT Hematology, ASP7, 97100 Ragusa, Italy; massimo.poidomani@asp.rg.it11 U.O.C. Ematologia, Ospedale San Vincenzo, 98039 Taormina (ME), Italy; longo_giuseppe@hotmail.com12 U.O.C. Ematologia, Policlinico P. Giaccone, 90127 Palermo, Italy; melania.carlisi@unipa.it13 Department of Biomedical and Biotechnological Science, University of Catania, 95125 Catania, Italy* Correspondence: ettaconticello@gmail.com (C.C.); d.tibullo@unict.it (D.T.); diraimon@unict.it (F.D.R.)19 6 2019 6 2019 8 6 87717 5 2019 12 6 2019 © 2019 by the authors.2019Licensee 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/).Background: The ASPIRE (NCT01080391) phase 3 trial showed the efficacy of carfilzomib, lenalidomide and dexamethasone (KRd) triplet for relapse and refractory multiple myeloma (RRMM). However, little is known about safety and efficacy of KRd outside a clinical trial context. Methods: Herein we report real life results of KRd given to 130 RRMM patients from 12 Sicilian Centers. Results: Median age was 62 years; patients had received a median of two previous lines of treatment (range 1–10) and 52% were refractory to previous treatment. Median number of KRd cycles was 12 (2–29), with a mean duration of treatment of 12 months; 21 patients had received at least 18 cycles. Overall response rate was 61%, including 18% complete response. Median PFS was 22.9 months, median OS was not reached. Creatinine clearance >30 mL/min, quality of the best achieved response and standard Fluorescence In Situ Hybridization (FISH) risk were independent predictors of favorable outcome. Patients who received the full-dosage of carfilzomib in the first two cycles had a better outcome. Conclusions: KRd was effective and well tolerated and in a considerable proportion of patients, therapy continued beyond the 18th cycle. The finding of a better outcome in patients with the higher cumulative dose of carfilzomib in the first two cycle encourages to maintain the maximum tolerated dose.\n\nKRd regimenmultiple myelomasalvage therapy\n==== Body\n1. Introduction\nMultiple myeloma (MM) is an incurable hematological cancer due to uncontrolled expansion of neoplastic plasma cells in the bone marrow. Despite the novel insights regarding the biology of the disease and the introduction of very effective second and third-generation novel agents, including lenalidomide, pomalidomide, carfilzomib and ixazomib, the prognosis is still variable based on the high rate of relapsed and refractory patients (RRMM). As a clinical consequence, several lines of treatments are usually required to ensure long-term control of the disease. Moreover, a progressive drug cross-resistance is likely to occur and at each relapse, disease becomes more refractory and the duration of response is progressively shorter [1]. Thus, nowadays one of the major clinical challenge is the choice of the most appropriate salvage therapy for relapsing or refractory patients.\n\nRecent randomized trials have shown the feasibility and efficacy of combination of second and third generation novel agents, at least in the industrialized countries, including the combination of carfilzomib and dexamethasone (ENDEAVOR) [2], panobinostat, bortezomib and dexamethasone (PANORAMA) [3] or daratumumab, bortezomib and dexamethasone (CASTOR) [4]. In other trials the backbone of lenalidomide and dexamethasone has been improved adding carfilzomib (ASPIRE) [5], ixazomib (TOURMALINE) [6], elotuzumab (ELOQUENT-2) [7], or daratumumab (POLLUX) [8]. All these trials have documented an advantage in term of response rate and progression free survival (PFS) in favor of the experimental arm. For example, in the ASPIRE trial, the experimental carfilzomib, lenalidomide and dexamethasone (KRd) cohort had longer median progression free survival (PFS, 26.3 versus 17.6 months) and higher overall response rate than the lenalidomide and dexamethasone (Rd) control cohort, as recently updated. Indeed, median overall survival (OS) was 48.3 months for KRd versus 40.4 months for Rd (hazard ratio, 0.79; p = 0.0045) [5,9].\n\nEven if these very encouraging results open new perspectives to ensure deep and durable responses in RRMM, it is still largely unknown how personalize therapy, taking advantage from each line of treatment, and which one could be the most appropriate sequence of treatment for each single patient. Worse yet, several trials have not distinguished relapsed from refractory MM, did not include frail patients (due to e.g., high PS ECOG (Eastern Cooperative Oncology Group Performace Status), impaired kidney function, reduced bone marrow reservoir), and did not distinguish double or single refractory to bortezomib or lenalidomide, making difficult to draw general indications for the clinical practice in real life [10]. Moreover, several drugs are used in different dosages and schedules and we are not still able to define which is the best drug dosage.\n\nSince November 2016 treatment with KRd has been available in Sicily for RRMM. Therefore, in order to evaluate the possibility to translate clinical trial results into efficacy in clinical practice, we retrospectively analyzed a series of Sicilian RRMM patients treated with KRd regimen with the aim to evaluate efficacy and tolerability out of clinical trials. We also investigate the impact on response of previous treatment and of cumulative dose of carfilzomib to provide further insights on the use of this therapy in RRMM patients, whose treatment is currently one of the most important unmet needs [1,10,11,12].\n\n2. Methods\n2.1. Patient Selection\nIn this real-life retrospective survey, 130 patients were enrolled at 12 Sicilian Centers on behalf of the Sicilian Myeloma Network from November 2016 to December 2018. The study was approved by the independent ethics committee of the coordinating center (n.34/2019/PO) and was conducted in accordance with International Conference on Harmonization guidelines on Good Clinical Practice and the principles of the Declaration of Helsinki. All patients provided written informed consent.\n\nPrimary endpoint was the rate of best responses to KRd. Secondary endpoints were time to progression or relapse, progression-free survival, overall survival, and safety.\n\n2.2. Procedures and Drug Administration\nAll patients received intravenous carfilzomib at the dose of 20 mg/m2 (30 min) on days 1 and 2, then of 27 mg/m2 on days 8, 9, 15 16 of the first cycle and days 1, 2, 8, 9, 15 and 16 of the subsequent cycles, dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16 and lenalidomide 25 mg daily orally on days 1–21 of each 28-day cycle. According to the ASPIRE schedule, treatment with the combination was planned for 18 months followed by treatment with lenalidomide and dexamethasone until progression.\n\nIn cases of specific predefined hematological and non-hematological toxic events, carfilzomib and lenalidomide dosages were reduced, according to the manufacturers’ recommendations and medical choice. Treatment was discontinued in cases of disease progression, unacceptable adverse events, or consent withdrawal, while in some centers it was decided to maintain in responding patients the KRd combination beyond the planned 18 cycles, until progression.\n\n2.3. Concomitant Medications\nOne hundred patients received treatment with bisphosphonates every 4 weeks during KRd treatment. An antibiotic and antiviral prophylaxis was carried out with trimethoprim and sulfamethoxazole (800 mg twice a day, twice a week) and acyclovir 200, 400 or 800 mg daily according to the policy of each center. Supportive therapy with erythropoietin (EPO) and granulocyte colony-stimulating factor (G-CSF) was administered accordingly to ASH/ASCO guidelines and policy of each single center [13,14].\n\n2.4. Safety and Efficacy Assessment\nEach patient’s medical history was recorded on day 1 of each cycle. Physical examinations were conducted, and blood was collected for hematology, renal and liver function tests at each cycle on day 1 and whenever it was considered necessary. Adverse events [15] were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTC) criteria (CTCAE) https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf.\n\nEfficacy assessment was recorded on day 1 of cycle 2 and every cycle thereafter. Response and progression were reported according to International Myeloma Working Group consensus criteria [16], including complete remission (CR, 100% reduction in M protein according to electrophoresis, with immunofixation negative), very good partial remission (VGPR, ≥90% reduction in serum M protein, and less than 100 mg urine M protein per day), partial remission (PR, ≥50% reduction in serum M protein, and less than 100 mg urine M protein per day), stable disease (SD), progression disease (PD); not valuable (NV). Minimal response was defined according to European Society for Blood and Marrow Transplantation criteria [17].\n\n2.5. Statistical Analysis\nDescriptive statistics were generated for analysis of results and two-sides p-values under 0.05 were considered significant. Qualitative results were summarized in counts and percentages. Overall response rate (ORR) was defined as PR or better (CR + VGPR + PR). OS and PFS were analyzed with Kaplan–Meier tests. Standard errors were calculated by the method of Greenwood, the 95% confidence intervals were computed as 1.96 times the standard error in each direction.\n\nPFS was calculated from the time of inclusion until the date of progression, relapse, death or the date the patient was last known to be in remission. OS was calculated from the time of inclusion until the date of death for any cause or the date the patient was last known to be alive. All calculations were performed using Graph Pad Prism version 5.00 for Windows, Graph Pad Software, San Diego California, CA, USA, www.graphpad.com and MedCalc version 12.30.0.0 (Producer: MedCalc Software bvba, Ostend (Belgium), www.medcalc.org).\n\n3. Results\n3.1. Patients’ Characteristics and Treatment\nOne hundred and thirty patients were included in the study and evaluated according to an intention-to-treat analysis. Demographic and disease characteristics are shown in Table 1. The series included patients with an ECOG performance status equal to 3 (15%) or 2 (15%), or 0–1 (70%), with a measurable disease defined by International Myeloma Working Group (IMWG) guidelines [16] and have completed at least two cycle of KRd. Data on cytogenetic abnormalities, detected by fluorescence in-situ hybridization on highly purified bone marrow plasma cells, distinguished as high-risk (including t(4;14), t(14;16) and del(17p)) and standard-risk (all the remaining patients), were available in 64 (49%) of patients.\n\nPrevious treatments (including number of previous lines of therapy, previous regimen with bortezomib, lenalidomide or pomalidomide, autologous or allogenic transplantation) are shown in Table 2. Half of patients were refractory to previous treatments (52%). Median number of the previous lines of treatment was two (range 1–10).\n\nOf the 130 patients included in the study, at time of analysis, 31 had not yet completed the planned 18 cycles of treatment (18 of them had received at least 12 cycles). Among the 21 patients who completed the 18 cycles, 18 were maintained on treatment (two patients had received 19 cycles, six patients 20 cycles and 10 patients 25 cycles). Seventy-eight patients (60%) discontinued the treatment for the following reasons: progression of disease (63), consent withdraw (four), intensification with high dose chemotherapy and autologous transplantation (four), toxicity (five), secondary malignancy (one), lost to follow up (one).\n\nAfter a median follow up of 23.9 (range 1–34) months from the start of study treatment, the median number of administered cycles was 12 (2–29) with a mean duration of treatment of 12 months. Fifty-one patients (39%) required drug reduction. Twelve patients shifted to a weekly schedule of carfilzomib and dexamethasone (on days 1–8–15 instead of 1–2, 8–9, 15–16) after two cycles for poor bone marrow reserve and thus completed the planned treatment without any further dose reduction.\n\n3.2. Safety\nThe regimen was well tolerated with grade 3–4 hematological and non-hematological adverse events affecting 46 (35%) and 48 (36%) patients respectively. Grade 3–4 hematological AEs occurred in 35%, anemia in 12%, neutropenia in 15%, thrombocytopenia in 15%. The most common non-hematological AEs were pneumonia (8%) and cardiovascular (CV, 8%, 11 patients: eight cases of hypertension, two cases of heart failure and one case of atrial flutter) (Table 3). In patients who developed serious AE, KRd dose reduction (51, 39%) and discontinuation (two, 0.1%) were applied.\n\nPlatelet transfusions support was required in five patients (0.3%). EPO support was used in 48 (37%) patients, and red blood cells transfusion in 12 patients (9%). Secondary prophylaxis with G-CSF administration (filgrastim 30 MU for two days every two weeks) was required to support 20 patients (15%). Thanks to the concomitant antibiotic and antiviral prophylaxis, none of the patients had Herpes zoster reactivation or Pneumocystis jurovecii related-pneumonia. Nausea and vomiting were mild (grade 1–2), affecting 10% of patients.\n\nIn 22 (17%) patients with reduced renal function at baseline, not requiring dialysis, carfilzomib was given at full dosage and lenalidomide 5 mg/day on days 1–21; in 8/22 non-dialyzed patients renal impairment improved progressively during KRd up to normalization of estimated glomerular filtration rate.\n\n3.3. Efficacy\nOverall response rate was 61% (79 patients); 24 patients (18%) achieved a complete response (CR), 25 patients (19%) achieved a very good partial response (VGPR), 30 (23%) achieved PR, 18 (13%) a minimal response (MR) and nine (7%) had a stable disease. Therefore, a clinical benefit was observed in 101 patients (77%). Progression occurred in 24 patients (22%), including 14 (11%) who did not achieve any response and 10 patients that achieve a minimal response within a median of six cycles (range 3–16) and then progressed. Data on efficacy are shown in Table 4. The median number of cycles to obtain the maximal response was six (range 2–9), in 7/79 it was obtained within the first two cycles.\n\nThe quality of achieved response improved cycle by cycle. Among the 21/130 (16%) patients that had received at least 18 cycles, ORR improved to 85% (including 40% CR, 20% VGPR, 25% PR). Among these 18 patients who received more than 18 cycles, three patients exhibited improvement in the quality of achieved response (two PR from MR and one CR from PR) while the others maintained the achieved response (including six patients who maintained CR) (Table 4).\n\nThe median progression free survival (PFS) was 22.9 months (Figure 1A), while the median overall survival (OS) was not reached (Figure 1B). The 2-years-PFS was longer in those patients who achieved VGPR or better than in those who did not (66.9 versus 33.3%, p = 0.0002, HR 3.19, 95% C.I. 1.53–6.64, Figure 2A). In the group of 64 patients with available FISH, the 19 patients with high-risk abnormalities had shorter median PFS than standard-risk (8.4 months versus unreached, p < 0.0001, HR 3.69, 95% C.I. 1.53–8.88, Figure 2B). Similarly, 2-years-OS was longer in those patients who achieved VGPR or better than in those who did not (78.0 versus 51.2% p = 0.0008, HR 4.50, 95% C.I. 1.79–11.33, Figure 2D) and in standard risk FISH (unreached versus 11.6 months, p = 0.0001, HR 4.59, 95% C.I. 1.64–12.88, Figure 2E).\n\nMedian cumulative carfilzomib received dose was 4000 mg/m2. Since all patients had received at least two KRd cycles, we evaluated the prognostic significance of carfilzomib cumulative dose limited to the first two cycles and we found that patients who received a cumulative dose of at least 310 mg/m2 (equivalent to full-dose) in the first two cycles, had longer median PFS (27.0 vs. 14.5 months, HR 1.99, 95% C.I. 1.21–3.31, p = 0.006, Figure 2C). However, median OS was not reached in both groups (Figure 2D), and there was not a statistically significant difference.\n\n3.4. Predictors of Outcome of KRd in the Real-Life Setting\nIn the attempt to identify patients that could obtain the most advantage by KRd treatment, univariate analysis of PFS and OS showed that previous exposure to more than two lines of treatment, including previous exposure to lenalidomide, was associated to shorter median PFS and OS (Table 5, Figure 3). However, it should be noted that patients previously treated with lenalidomide, although with a lower ISS stage, had a higher number of prior treatments (Supplementary Table S1). Despite the small number of patients who received pomalidomide before KRd (N = 16), we found that also prior exposure to pomalidomide was a negative predictor of PFS, but not OS, probably for the enrichment of other bad prognostic factors (Table 5, Supplementary Table S2).\n\nBoth PFS and OS were affected by kidney function, as shown in univariate and multivariate analysis (Table 5, Figure 4). Indeed, median PFS and OS were longer in patients with clearance creatinine >30 mL/min (respectively, 27.0 vs. 8.4 months, p = 0.0003, HR 2.72, 95% C.I. 1.24–5.98 and unreached median vs. 10.3 months, p < 0.0001, HR 3.59, 95% C.I. 1.47–8.78).\n\nPrevious exposure to thalidomide, autologous Bone Marrow Transplantation (BMT), sex, age, type of relapse (biochemical versus aggressive), did not affect neither PFS nor OS of patients treated with KRd. However, supportive treatment to prevent skeletal events with zoledronic acid was weakly associated to longer median OS than who did not receive (unreached vs. 18.2 months, p = 0.018, HR 0.49, C.I. 95% 0.24–1.00).\n\nThus, univariate analysis disclosed that the predictors of longer PFS were the number of prior lines received (<2, p = 0.0001), lack of previous exposure to lenalidomide (p = 0.0001) and pomalidomide (p = 0.02), a cumulative dose of carfilzomib of 310 mg/mq within the first two cycles (p = 0.006), creatinine clearance >30 mL/min (p = 0.0003) and high-quality response (at least VGPR, p = 0.0002, Table 5). In multivariate analysis the number of prior lines received (p = 0.04, HR 1.78, 95% C.I. 1.00–3.16), creatinine clearance >30 mL/min (p = 0.0002, HR 3.34, 95% C.I. 1.77–6.29) and a high-quality response (p = 0.002, HR 3.19, 95% C.I. 1.53–6.64) maintained independent significance as predictors of longer PFS.\n\nThe same factors could predict better OS in univariate analysis (Table 5). Multivariate analysis disclosed that concomitant exposure to zoledronic acid (p = 0.03, HR 0.49, 95% C.I. 0.26–0.94), creatinine clearance >30 mL/min (p = 0.0003, HR 3.89, 95% C.I. 1.87–8.07) and a high-quality response (p = 0.0015, HR 4.5, 95% C.I. 1.79–11.33) were independent predictors of OS in patients who received KRd.\n\nDespite the small sample size, in the sub-group of 64 patients with available FISH, high-risk FISH was associated to shorter both PFS and OS, in both univariate and multivariate analysis (respectively, HR: 4.28, C.I. 95% 2.09–8.79, p = 0.0001 and HR: 4.18, C.I. 95% 1.92–9.11, p = 0.0003, Figure 2, Table 5).\n\nIn the 21 patients who received at least 18 cycles, univariate and multivariate analysis confirmed clearance creatinine >30 mL/min as a positive predictor of PFS and OS (Supplementary Table S3).\n\n4. Discussion\nIn this real-life survey, we evaluated the feasibility and effectiveness of KRd in RRMM patients of 12 Sicilian Centers, belonging to the Sicilian Myeloma Network, outside of controlled clinical trials.\n\nWe confirmed that KRd is safe and feasible, the most common hematological side effect being asymptomatic thrombocytopenia and, among the non-hematological side effects, gastrointestinal, pneumonia and, to a lesser extent, cardiac ones were observed. There are several warnings about increased cardiotoxicity in MM patients treated with proteasome inhibitors but there is an unquestionable clinical benefit of carfilzomib in combination with lenalidomide and dexamethasone on PFS and OS in RRMM patients [9]. Reduction and management of cardiovascular risks has therefore become a priority in the management of these patients [18].\n\nWe found a correlation between cumulative carfilzomib dose in the first two cycles and PFS and OS, a parameter that closely reflects the dose-dependent effect of carfilzomib, although it should be underlined that patients who did not receive full dose of carfilzomib had often significant comorbidities, likely contributing to poorer outcome. This observation is consistent with previous reports about improved clinical outcomes associated to increased first-in-class-proteasome inhibitor bortezomib exposure [19]. Our findings further support the hypothesis that higher doses of carfilzomib are associated to improved outcome. The last interim analysis of the randomized, open-label phase III A.R.R.O.W. (NCT02412878) trial, that compared RRMM patients treated with carfilzomib once a week (70 mg/m2) or twice a week (27 mg/m2), showed that weekly carfilzomib at 70 mg/m2 significantly prolonged PFS, while in the control arm PFS and ORR were inferior to the phase III ASPIRE trial [20]. In a meta-analysis of 14 trials, combination regimens and higher carfilzomib dose offered better response with no significant extra toxicity [21]. Our data therefore confirm that in order to ensure the largest and deepest clinical benefit, carfilzomib should be administered without reduction and adverse events should be prevented and faced with a proactive management. To this purpose, supportive care with antibiotic prophylaxis associated to growth factors have a pivotal role. Indeed, in our series only 21 patients interrupted treatment due to infections or hematological toxicities.\n\nOur experience also indicates that it is possible to continue KRd treatment beyond the 18 cycles that were planned in the ASPIRE trial. Actually, among the 21 patients who completed the 18th cycle, 18 were maintained in treatment and three achieved a better response, without adding further toxicity. These results identify a specific population with good sensitivity to KRd therapy beyond 18 cycles; further studies are needed to confirm whether this prolonged exposure to KRd is recommended.\n\nORR was lower than what previously reported in the ASPIRE trial (61 versus 87%), with a comparable proportion of patients in CR [5]. In addition, the median PFS in our real-life experience was 22.9 months, weakly shorter than the 26 months reported in the ASPIRE trial. It should be underlined that in comparison with the study population of the ASPIRE trial [5], our patients had inferior performance status (15% of patients in our series had PS ECOG higher than three, 15% equal or higher than two while 90% of patients enrolled in ASPIRE had 0–1), received higher cumulative number of previous treatment, (range 1–10 versus 1–3), had an higher percentage of lenalidomide (40 vs. 20%) or even pomalidomide (12 vs. 0) exposure, had myeloma-related-renal injury (17% vs. 0), including some patients on dialysis, and three patients had already received an allogenic stem cell transplantation (Table 6).\n\nFurther sub-analysis of the ASPIRE showed that PFS was shorter in those patients who received KRd after previous exposure to lenalidomide [22]. Indeed, in the ASPIRE trial the superiority of KRd over Rd was only 5 months in patients previously treated with lenalidomide and further reduced to two months in lenalidomide refractory patients. Our findings confirm that also in real-life previous exposure to lenalidomide could reduce the KRd efficacy.\n\nThe difficulty in treating lenalidomide-refractory patients with carfilzomib is an important finding. In this regard, our data weaken the hypothesis that a patient resistant to lenalidomide can be easily rescued by adding a different class of drugs and should have a good response when combined carfilzomib and dexamethasone. This issue is currently under investigation by several groups. For example, in the ENDEAVOR trial, that compared the association of high-dose carfilzomib and dexamethasone (Kd) versus bortezomib and dexamethasone (Vd) in RRMM patients, lenalidomide refractory patients had dismal outcome, with a median PFS of only 8.6 months in Kd arm, not very different from the median PFS of 6.6 months in the Vd arm [23]. Kd elicited better outcome (PFS 18.7 months) in those patients who received one prior line of treatment containing bortezomib than lenalidomide (PFS 15.6 months) [23]. These observations are topical since several studies have indicated a clinical benefit of a maintenance therapy with lenalidomide in both transplant eligible [24,25] and non-transplant eligible patients [26], either for a fixed duration (18 months) or given continuously as shown by the FIRST trial [27]. Therefore, in the future an increasing number of MM patients will relapse during a treatment with lenalidomide and should be considered as lenalidomide refractory [1,16,22,28].\n\nFinally, in the ASPIRE trial, KRd was able to overcome the main factors involved in the bad outcome of RRMM, but results were less encouraging in the presence of high-risk FISH abnormalities. Despite the small number of patients with an evaluable FISH in our series, we found that high-risk RRMM patients still have a dismal outcome and should be addressed to clinical trials.\n\n5. Conclusions\nOur findings suggest that the ideal candidate for treatment with KRd should be a patient who relapses after a thalidomide- or bortezomib-based regimen, independently from prior autologous stem cells transplantation, as previously shown by ASPIRE [22] trial. Therefore, in the real life, where many patients receive KRd after being treated with lenalidomide, we shouldn’t expect the same brilliant results of the ASPIRE [5]. However, thanks to its low toxic profile, carfilzomib could be combined with drugs with different mechanisms of action other than lenalidomide. Our previous experience with a combination of bortezomib, doxorubicin, cyclophosphamide, and dexamethasone; or bortezomib, melphalan and dexamethasone [29,30] supports the idea that even patients that have been heavily pre-treated with the novel agents can retain a sensitivity to alkylating agents. Unfortunately, there are limited data on carfilzomib as part of other combinations, especially with alkylating agents, like melphalan. In newly-diagnosed elderly MM patients’ KMP did not improve PFS compared with VMP, suggesting that melphalan may not be an ideal drug to combine with carfilzomib in this setting [31]. Preliminary results of the MyelomaUKfive (MUKfive) trial are expected in the next year to evaluate carfilzomib in combination with cyclophosphamide and dexamethasone in RRMM.\n\nAcknowledgments\nAuthors are thankful to all patients, families and nurses who accepted to participate. We are also thankful to Marco Ragusa for his contribution in the study coordination.\n\nSupplementary Materials\nThe following are available online at https://www.mdpi.com/2077-0383/8/6/877/s1; Table S1: Comparison of patients’ characteristics treated or not with lenalidomide before treatment with KRd in real life, Table S2: Comparison of patients’ characteristics treated or not with pomalidomide before treatment with KRd in real life, Table S3: Univariate and multivariate analysis of PFS and OS in 21 patients who received at least 18 cycles of treatment.\n\nClick here for additional data file.\n\n Author Contributions\nProject administration: C.C.; Methodology, A.R.; Resources, D.T.; Data curation: V.D.F., E.A.M., V.C., G.S., V.L., M.S.P., U.M., B.G., S.L., E.C., V.I., D.M., S.N., M.M., R.S., C.C., F.A., G.C., A.M., C.M., G.U., M.P., G.L. and M.C.; Supervision, F.D.R.\n\nConflicts of Interest\nC.C., F.D.R., A.R., U.M. and V.L. received honoraria from Amgen. C.C., F.D.R. and A.R. received honoraria from Celgene. All the other authors declare no conflict of interest.\n\nFigure 1 Progression free survival (A) and overall survival (B) in 130 relapse and refractory multiple myeloma (RRMM) candidates to KRd as salvage regimen in a real-life approach.\n\nFigure 2 Progression free survival and overall survival in 130 RRMM candidates to KRd as salvage regimen in a real-life approach. Progression free survival in 130 RRMM candidates to KRd as salvage regimen in a real-life approach based on response achieved (A), FISH risk (data available for only 64 patients) (B), and cumulative dose of carfilzomib received (C). Overall survival in 130 RRMM candidates to KRd as salvage regimen in a real-life approach based on response achieved (D), FISH risk (data available for only 64 patients) (E), and cumulative dose of carfilzomib received (F).\n\nFigure 3 Progression free survival (A) and overall survival (B) based on previous exposure to lenalidomide in 130 RRMM candidates to KRd as salvage regimen in a real-life approach.\n\nFigure 4 Progression free survival (A) and overall survival (B) based on creatinine clearance in 130 RRMM candidates to KRd as salvage regimen in a real-life approach.\n\njcm-08-00877-t001_Table 1Table 1 Patient characteristics of 130 relapse and refractory multiple myeloma (RRMM) candidates to carfilzomib, lenalidomide and dexamethasone (KRd) as salvage regimen in a real-life approach.\n\nCharacteristics\t130 pts\t\n\nMedian age (range)\n\t62 (33–86)\t\n\nMales/Females, n (%)\n\t73/57 (56/44)\t\n\nSerum isotype\n\t\n\t\n IgG, n (%)\t77 (60)\t\n IgA, n (%)\t25 (19)\t\n IgM, n (%)\t1 (0.5)\t\n Micromolecular, n (%)\t25 (19)\t\n Non-secretory, n (%)\t2 (1)\t\n\nISS\n\t\n\t\n I, n (%)\t46 (35)\t\n II, n (%)\t43 (33)\t\n III, n (%)\t41 (32)\t\n\nDurie and Salmon staging\n\t\n\t\n IA, n (%)\t33 (25)\t\n IIA, n (%)\t15 (12)\t\n IIB, n (%)\t4 (3)\t\n IIIA, n (%)\t56 (43)\t\n IIIB, n (%)\t10 (8)\t\n Unknown, n (%)\t12 (9)\t\n\nFISH analysis available\n\t\n64 (49)\n\t\n Standard Risk, n (%)\t45 (70)\t\n High risk, n (%)\t19 (30)\t\n\n>3 bone lesions, n (%)\n\t70 (54)\t\n\nClearance creatinine <30 mL/min, n (%)\n\n\nDialyzed patients, n (%)\n\t22 (17)\n5 (4)\t\n\nExtramedullary disease, n (%)\n\t4 (3)\t\njcm-08-00877-t002_Table 2Table 2 Prior regimens used of 130 relapse and refractory multiple myeloma (RRMM) candidates to KRd as salvage regimen in a real-life approach.\n\nPrevious Regimens\t\n\t\n\nMedian (range)\n\t2 (1–10)\t\n 1–3 regimens\t114 (88)\t\n ≥4 regimens\t16 (12)\t\n\nPrevious exposure to novel agents, pts n (%)\n\t\n\t\n Bortezomib\t126 (96)\t\n Lenalidomide\t53 (40)\t\n Thalidomide\t78 (60)\t\n Pomalidomide\t16 (12)\t\n\nASCT (Autologous Stem Cell Transplant)\n\t\n\t\n Single\t40 (30)\t\n Double\t40 (30)\t\n No\t50 (38)\t\n\nAlloSCT (Allogenic Stem Cell Transplant)\n\t3 (2)\t\njcm-08-00877-t003_Table 3Table 3 Hematological and non-hematological toxicities in real-life KRd.\n\n\n\tEvents\t\nHematological Toxicity\tAll Grades\t3–4 Grade\t\n Anemia, n (%)\t46 (35)\t15 (12)\t\n Neutropenia, n (%)\t32 (25)\t19 (15)\t\n Piastrinopenia, n (%)\t39 (30)\t19 (15)\t\n\nNon Hematological Toxicity\n\t\nAll Grades\n\t\n3–4 Grade\n\t\n Gastrointestinal, n (%)\t40 (31)\t4 (3)\t\n Pneumonia, n (%) \t37 (28)\t11 (8)\t\n Cardiovascular, n (%)\t25 (19)\t11 (8)\t\n Neurologic, n (%) \t20 (15)\t6 (5)\t\n Fatigue, n (%)\t15 (12)\t2 (2)\t\n Vascular, n (%) \t9 (7)\t6 (5)\t\n Diabetes, n (%)\t2 (1)\t1 (1)\t\n Cutaneous, n (%) \t8 (6)\t1 (1)\t\n Pulmonary, n (%)\t4 (3)\t3 (2)\t\n Ophthalmological, n (%)\t3 (2)\t0 (0)\t\n ORL, n (%)\t9 (7)\t2 (2)\t\n Musculoskeletal, n (%)\t7 (5)\t0 (0)\t\n Hepatic, n (%)\t4 (3)\t2 (2)\t\n Renal, n (%)\t2 (1)\t1 (1)\t\njcm-08-00877-t004_Table 4Table 4 Response to KRd in 130 relapse and refractory multiple myeloma (RRMM) treated with KRd as salvage regimen in a real-life approach. according to International Myeloma Working Group (IMWG) criteria.\n\n\n\tBest Response in Patients Who Received Less Than 18 Cycles\tBest Response in Patients Who Received at Least 18 Cycles\tBest Response of All Patients\t\n\n\tn = 109 (100%)\tn = 21 (100%)\tn = 130 (100%)\t\n\nORR\n\t61 (55)\t18 (85)\t79 (60)\t\n CR\t15 (14)\t9 (40)\t24 (18)\t\n VGPR\t21 (19)\t4 (20)\t25 (19)\t\n PR\t25 (22)\t5 (25)\t30 (23)\t\n\nMR\n\t\n16 (15)\n\t\n2 (10)\n\t\n18 (14)\n\t\n\nSD\n\t\n8 (7)\n\t\n1 (5)\n\t\n9 (7)\n\t\n\nPD\n\t24 (22)\t\n0 (0)\n\t\n24 (19)\n\t\njcm-08-00877-t005_Table 5Table 5 Univariate and multivariate analysis of PFS and OS.\n\n\n\t\n\t\n\tUnivariate Analysis\tMultivariate Analysis\tUnivariate Analysis\tMultivariate Analysis\t\n\n\t\n\t\nn\n\tPFS @ 24 Months\tp-Value\tHR\n(95% CI)\tp-Value\tOS @ 24 Months\tp-Value\tHR\n(95% CI)\tp-Value\t\n\nAge\n\t≤65\t68\t50.5\t0.66\t\n\t\n\t66.4\t0.12\t\n\t\n\t\n\n\t>65\t62\t42.6\t55.4\t\n\nGender\n\tmale\t73\t55.1\t0.20\t\n\t\n\t55.6\t0.98\t\n\t\n\t\n\n\tfemale\t57\t38.1\t62.8\t\n\nISS\n\tI–II\t95\t50.4\t0.14\t\n\t\n\t60.8\t0.37\t\n\t\n\t\n\n\tIII\t35\t43.5\t57.8\t\n\nPrior lines\n\t1–2\t95\t56.7\t\n0.0001\n\t1.78\n(1.00–3.16)\t\n0.04\n\t70.0\t\n0.0002\n\t1.81\n(0.93–3.52)\t0.08\t\n\n\tmore than 2\t35\t22.4\t33.5\t\n\nPrevious lenalidomide\n\tno\t77\t58.0\t\n0.0001\n\t0.79\n(0.43–1.46)\t0.46\t72.2\t\n0.0001\n\t1.84\n(0.96–3.54)\t0.07\t\n\n\tyes\t53\t33.3\t41.4\t\n\nPrevious pomalidomide\n\tno\t114\t51.2\t\n0.02\n\t1.34\n(0.60–3.02)\t0.46\t62.4\t0.17\t\n\t\n\t\n\n\tyes\t16\t24.2\t42.2\t\n\nPrevious BMT\n\tno\t50\t33.4\t0.29\t\n\t\n\t55.7\t0.58\t\n\t\n\t\n\n\tyes\t80\t53.2\t61.8\t\n\nZoledronic acid exposure\n\tno\t31\t41.4\t0.11\t\n\t\n\t47.6\t\n0.018\n\t0.49\n(0.26–0.94) \t\n0.03\n\t\n\n\tyes\t99\t52.6\t63.4\t\n\nRelapse\n\tbiochemical\t31\t59.1\t0.54\t\n\t\n\t62.0\t0.37\t\n\t\n\t\n\n\tclinical\t99\t47.6\t52.6\t\n\nClCr\n\t<30 mL/min\t22\t19.9\t\n0.0003\n\t3.34\n(1.77–6.29)\t\n0.0002\n\t18.2\t\n<0.0001\n\t3.89\n(1.87–8.07)\t\n0.0003\n\t\n\n\t>30mL/min\t108\t53.5\t67.7\t\n\nK Cumulative dose (2 cycles)\n\t<310mg/mq\t64\t36.4\t\n0.006\n\t1.40\n(0.81–2.46)\t0.23\t54.2\t\n0.08\n\t\n\t\n\t\n\n\t>310mg/mq\t66\t59.1\t65.5\t\n\nBest response\n\t<VGPR\t90\t33.3\t\n0.0002\n\t3.19\n(1.53–6.64)\t\n0.002\n\t51.2\t\n0.0008\n\t4.50\n(1.79–11.33)\t\n0.0015\n\t\n\n\tCR + VGPR\t40\t66.9\t\n\t\n\t78.0\t\n\t\n\nFISH risk *\n\tStandard \t45\t50.2\t\n<0.0001\n\t4.28 *\n(2.09–8.79)\t\n0.0001\n\t23.0\t\n0.0001\n\t4.18 *\n(1.92–9.11)\t\n0.0003\n\t\n\n\tHigh\t19\t9.0\t\n\t\n\t71.3\t\n\t\n* available data for 64 patients only.\n\njcm-08-00877-t006_Table 6Table 6 Comparison of patients’ characteristics at baseline and response to KRd in real life and in the ASPIRE clinical trial.\n\n\n\tReal Life Study\tAspire Trial\t\nPerformance Status\nECOG > 3\t15%\t0\t\nPrevious Lines median (range)\t2\n(1–10)\t2\n(1–3)\t\nCreatinine ≤ 30 mL/min\t17%\t0\t\nPatients on Dialysis\t4%\t0\t\nPrior Lenalidomide exposure\t40%\t20%\t\nHigh risk patients \t21%\t12%\t\nPrior pomalidomide exposure\t12%\t0%\t\nPrior ASCT\t60%\t56%\n==== Refs\nReferences\n1. 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Lenalidomide after stem-cell transplantation for multiple myeloma N. Engl. J. Med. 2012 366 770 1781 10.1056/NEJMoa1114083 22356343 \n26. Dimopoulos M.A. Delforge M. Hájek R. Kropff M. Petrucci M.T. Lewis P. Nixon A. Zhang J. Mei J. Palumbo A. Lenalidomide, melphalan, and prednisone, followed by lenalidomide maintenance, improves health-related quality of life in newly diagnosed multiple myeloma patients aged 65 years or older: Results of a randomized phase III trial Haematologica 2013 98 84 788 10.3324/haematol.2012.074534 \n27. Benboubker L. Dimopoulos M.A. Dispenzieri A. Catalano J. Belch A.R. Cavo M. Pinto A. Weisel K. Ludwig H. Bahlis N. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma N. Engl. J. Med. 2014 371 906 917 10.1056/NEJMoa1402551 25184863 \n28. Dimopoulos M. Kyle R. Fermand J.P. Rajkumar S.V. San Miguel J. Chanan-Khan A. Ludwig H. Joshua D. Mehta J. Gertz M. Consensus recommendations for standard investigative workup: Report of the International Myeloma Workshop Consensus Panel 3 Blood 2011 117 701 4705 10.1182/blood-2010-10-299529 \n29. Romano A. Chiarenza A. Consoli U. Conticello C. Forte S. Uccello G. Vetro C. Cavalli M. Coppolino F. Palumbo G.A. Intravenous injection of bortezomib, melphalan and dexamethasone in refractory and relapsed multiple myeloma Ann. Oncol. 2013 24 1038 1044 10.1093/annonc/mds531 23136226 \n30. Romano A. Chiarenza A. Conticello C. Cavalli M. Vetro C. Di Raimondo C. Cunsolo R. Palumbo G.A. Di Raimondo F. Salvage therapy with pegylated liposomal doxorubicin, bortezomib, cyclophosphamide, and dexamethasone in relapsed/refractory myeloma patients Eur. J. Haematol. 2014 93 207 213 10.1111/ejh.12325 24673398 \n31. Facon T. Lee J.H. Moreau P. Niesvizky R. Dimopoulos M.A. Hajek R. Osman M. Aggarwal S. Klippel Z. San Miguel J. Phase 3 Study (CLARION) of Carfilzomib, Melphalan, Prednisone (KMP) v Bortezomib, Melphalan, Prednisone (VMP) in Newly Diagnosed Multiple Myeloma (NDMM) Clin. Lymphoma Myeloma Leuk. 2017 17 e26 e27 10.1016/j.clml.2017.03.045\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2077-0383",
"issue": "8(6)",
"journal": "Journal of clinical medicine",
"keywords": "KRd regimen; multiple myeloma; salvage therapy",
"medline_ta": "J Clin Med",
"mesh_terms": null,
"nlm_unique_id": "101606588",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31248142",
"pubdate": "2019-06-19",
"publication_types": "D016428:Journal Article",
"references": "18971951;20975064;21095116;21292778;21799510;22571201;23136226;23242595;24673398;24967371;25184863;25242045;25482145;25557740;26035255;26671818;27119237;27411022;27491641;27511158;27557302;27705267;28211054;28430175;28742454;29341834;29805768;29866475;29907552;30049825",
"title": "Feasibility, Tolerability and Efficacy of Carfilzomib in Combination with Lenalidomide and Dexamethasone in Relapsed Refractory Myeloma Patients: A Retrospective Real-Life Survey of the Sicilian Myeloma Network.",
"title_normalized": "feasibility tolerability and efficacy of carfilzomib in combination with lenalidomide and dexamethasone in relapsed refractory myeloma patients a retrospective real life survey of the sicilian myeloma network"
} | [
{
"companynumb": "IT-AMGEN-ITASP2019114492",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARFILZOMIB"
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"drugadditional": "3",
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{
"abstract": "Mitragynine is a novel psychoactive substance (NPS) that has emerged as a designer opioid being distributed on the street. Mitragynine, also known as kratom, has dose-dependent pharmacological effects and possesses both stimulant-like and sedative effects due to dual-binding of α-adrenergic and μ-opioid receptors. This herbal remedy readily available online has caused adverse effects including tachycardia, agitation, tremors, hallucination and death; however, this is the first reported suspected driving under the influence case involving mitragynine. Additional testing outside of the normal routine protocol for suspected impaired driving cases was performed based on the admission of kratom use from the suspect to the drug recognition expert (DRE) officer. Based on the evaluation, the DRE officer concluded that the driver was under the influence of a central nervous system stimulant and cannabis. An alkaline drug screen identified mitragynine in a 37-year-old female driver who was suspected of driving under the influence after nearly striking an oncoming vehicle. A blood amphetamine concentration was quantified at 0.052 mg/L and mitragynine and citalopram were reported qualitatively. The goal of this case study is to provide demographic history, adverse effects and a DRE evaluation in a driver known to have abused mitragynine.",
"affiliations": "Virginia Department of Forensic Science, 6600 Northside High School Rd, Roanoke, VA, USA.",
"authors": "Wright|Trista H|TH|",
"chemical_list": "D000662:Amphetamines; D011619:Psychotropic Drugs; D046948:Secologanin Tryptamine Alkaloids; D015283:Citalopram; C001801:mitragynine",
"country": "England",
"delete": false,
"doi": "10.1093/jat/bky028",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0146-4760",
"issue": "42(7)",
"journal": "Journal of analytical toxicology",
"keywords": null,
"medline_ta": "J Anal Toxicol",
"mesh_terms": "D000063:Accidents, Traffic; D000328:Adult; D000662:Amphetamines; D015283:Citalopram; D000066448:Driving Under the Influence; D005260:Female; D053593:Forensic Toxicology; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D011619:Psychotropic Drugs; D046948:Secologanin Tryptamine Alkaloids; D015813:Substance Abuse Detection; D019966:Substance-Related Disorders",
"nlm_unique_id": "7705085",
"other_id": null,
"pages": "e65-e68",
"pmc": null,
"pmid": "29718282",
"pubdate": "2018-09-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Suspected Driving Under the Influence Case Involving Mitragynine.",
"title_normalized": "suspected driving under the influence case involving mitragynine"
} | [
{
"companynumb": "US-MYLANLABS-2019M1002863",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HERBALS\\MITRAGYNINE"
},
"drugadditional": "3... |
{
"abstract": "A 39-year-old man with bipolar disorder was hospitalised for depression. He was started on quetiapine (titrated up to 300 mg), lactulose (a laxative) and tropatepine (an anticholinergic). Valpromide (a mood stabiliser) and prazepam were later added and rapidly withdrawn. Seven days after quetiapine initiation, the patient reported abdominal pain and constipation; 2 days later, CT revealed an important distention of the colon including the caecum and a pre-perforation. A subtotal colectomy was performed and histology confirmed necrotising ischaemic colitis. The patient survived. This is the first case reported so far of ischaemic colitis related to quetiapine, in the absence of other antipsychotics simultaneously prescribed. Tropatepine likely acted as a cofactor to determine colitis. Clinicians need to be aware of the potential danger of the co-prescription of quetiapine with tropatepine (and possibly other anticholinergics).",
"affiliations": "GHPG, Villejuif, France.;GHPG, Villejuif, France.;GHPG, Villejuif, France.;GHPG, Villejuif, France.",
"authors": "de Beaurepaire|Renaud|R|;Trinh|Isabelle|I|;Guirao|Sophie|S|;Taieb|Muriel|M|",
"chemical_list": "D014150:Antipsychotic Agents; D000069348:Quetiapine Fumarate",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D001714:Bipolar Disorder; D003082:Colectomy; D017091:Colitis, Ischemic; D006801:Humans; D008297:Male; D000069348:Quetiapine Fumarate; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "25721830",
"pubdate": "2015-02-26",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19572384;17311601;23345490;18495400;17519649;19687183;10340682;22011585;24926641;1356039;20857527",
"title": "Colitis possibly induced by quetiapine.",
"title_normalized": "colitis possibly induced by quetiapine"
} | [
{
"companynumb": "FR-ALEMBIC PHARMACEUTICALS LIMITED-2015SCAL000263",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "QUETIAPINE FUMARATE"
},
... |
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